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Xu, Wei, Yongping Song, Zengjun Li, Shenmiao Yang, Lihong Liu, Yu Hu, Wei Zhang, et al. "Safety, Tolerability and Efficacy of Orelabrutinib, Once a Day, to Treat Chinese Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia/Small Cell Leukemia." Blood 134, Supplement_1 (November 13, 2019): 4319. http://dx.doi.org/10.1182/blood-2019-123331.
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Bruton's Tyrosine Kinase (BTK) plays a critical role in B-cell receptor (BCR) signaling, which mediates B-cell proliferation, migration, and adhesion. As a therapeutic target, its clinical significance has been well established in multiple subtypes of non-Hodgkin's lymphoma (NHL). Orelabrutinib (ICP-022) is a novel, potent irreversible BTK inhibitor with much improved target selectivity in comparison to Ibrutinib and Acalabrunitib, which leads to improved safety profiles. With a proprietary formulation, Orelabrutinib achieves high bioavailability comparing to other BTK inhibitors. Results of Phase I study (another presentation on Orelabrutinib) demonstrated favorable pharmacokinetic and pharmacodynamic properties for Orelabrutinib. Sustained BTK occupancy at 24 hr was achieved with daily dosing regimen. In this presentation, we will report results from clinical study of Orelabrutinib in Chinese patients with r/r CLL/SLL. This is an open-label, multicenter, Phase II study with objectives to evaluate its safety, tolerability and efficacy following oral daily administration. The primary endpoint was objective response rate (ORR). The duration of response (DOR), progression-free survival (PFS) and safety were chosen as secondary endpoints. Response was assessed per 2008 IWCLL criteria with modification for PR with lymphocytosis (PR-L) (Cheson, Hallek 2012). This study is composed of two stages. The stage I was to assess the safety and tolerability of Orelabrutinib at 150 mg, QD in pts with r/r CLL/SLL, while the stage II was to evaluate its therapeutic benefits (N=80, 150 mg, QD). Total of 80 patients with r/r CLL (n=70)/SLL (n=10) were enrolled. As of 31 May 2019, 40 pts had completed six cycles of treatment (28 days/cycle). The Median follow-up was 6.3 months (range, 0.4-13.7 months). Safety: The most frequent (≥15%) any grade adverse events (AEs) of any cause were well characterized hematological toxicities: thrombocytopenia, neutropenia, and anemia; and respiratory system infections as well as purpura. No case of atrial fibrillation or secondary malignancy was reported. The most frequently (≥10%) reported ≥ Grade 3 AEs of any cause were neutropenia, thrombocytopenia, lung infection. Twenty-five pts experienced at least one serious AE. Of those, 13 were considered related to Orelabrutinib treatment, including platelet count decrease (3 pts), pneumonitis, pyrexia (2 pts each) and herpes zoster etc. (1 pt each). Efficacy: Of the 80 enrolled pts, seventy-eight pts were evaluable for response (by 31 of May 2019), the ORR was 88.5% (69/78). Among them, one patient was reported as CR, 39 pts were PR and 29 pts were PR-L. Stable disease was seen in 6/78 (7.7%). Total disease control rate is 96.2%. The median DOR was not reached, 6 months DOR rate was 89.8%. Subgroup analysis (age, disease stage, previous treatment, 17p deletion, 11q deletion, IGHV mutation) did not reveal significant differences. Conclusion: Orelabrutinib is safe and well tolerated. No significant adverse events like atrial fibrillation/flutter or secondary malignancies were reported. Orelabrutinib is efficacious to treat pts with r/r CLL/SLL. The improved safety, resulting from high target selectivity, and daily dosing regimen enable Orelabrutinib to be a valuable therapeutic choice both as monotherapy and likely in combination with other agents to treat B-cell malignancies. Disclosures Xu: Beijing InnoCare Pharma Tech Co., Ltd: Employment. Zhao:Beijing InnoCare Pharma Tech Co., Ltd: Employment. Zhang:Beijing InnoCare Pharma Tech Co., Ltd: Employment. Zhu:Beijing InnoCare Pharma Tech Co., Ltd: Employment.
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Song, Yuqin, Yongping Song, Lihong Liu, Mingzhi Zhang, Zhiming Li, Chunyan Ji, Wei Xu, et al. "Safety and Efficacy of Orelabrutinib Monotherapy in Chinese Patients with Relapsed or Refractory Mantle Cell Lymphoma: A Multicenter, Open-Label, Phase II Study." Blood 134, Supplement_1 (November 13, 2019): 755. http://dx.doi.org/10.1182/blood-2019-126305.
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Mantle cell lymphoma (MCL), a subtype of aggressive B-cell non-Hodgkin lymphoma (NHL), remains challenging with unsatisfied outcomes from standard therapy. The clinical significance of Bruton's Tyrosine Kinase (BTK) inhibitors has been validated in multiple subtypes of NHL. Ibrutinib, the first BTK inhibitor, has been approved by FDA for the treatment of refractory and relapse (r/r) MCL. In spite of encouraging efficacy, clinically often referred adverse events such as diarrhea, bleeding and atrial fibrillation, respectively following ibrutinib treatment. It has been hypothesized that poor target selectivity (inhibitive effect on EGFR, TEC, BMX and others) may partially explain the occurrence of these adverse events. As such, there are focused efforts to develop new BTK inhibitor with high target selectivity aiming to improve the safety. Orelabrutinib (ICP-022) is a novel, potent irreversible BTK inhibitor with high selectivity for BTK vs other kinases including TEC- and EGFR-family members. Results from Phase I study demonstrated excellent safety/tolerability profiles as well as favorable pharmacokinetic and pharmacodynamic properties. Sustained BTK occupancy at 24 hr was achieved with once daily dosing regimen. In this presentation, we describe the clinical results of orelabrutinib in Chinese patients with r/r MCL. This is an open-label, multicenter, two stages, phase II study. The primary endpoint was objective response rate (ORR) and the duration of response (DOR) and safety were chosen as secondary endpoints. The stage I was designed for regimen selection (RP2D, N=20 for 100 mg, bid and 150 mg, qd each, respectively), while the stage II for efficacy at RP2D (N=86 150 mg, qd). Response was assessed per Lugano criteria (2014). Total of 106 pts with r/r MCL were enrolled. As of 31 May 2019, sixty-two pts had completed six cycles of treatment (28 days/cycle). The median duration of treatment was 197.5 days. Safety: A total of 106 pts were enrolled and treated at 22 centers in China. The most frequent (>15%) adverse events (AEs) of any cause were mostly hematological toxicities including thrombocytopenia and neutropenia; and respiratory system infections as well as rash. The frequently reported (>10%) grade 3 or higher AEs of any cause were thrombocytopenia (12.3%). No grade 2 or higher hemorrhage was reported. No treatment related grade 3 GI or cardio toxicity was observed. Of the 106 patients, twenty-five experienced serious AEs and 13 of them were treatment-related (primarily occurred as hematologic toxicities and / or infections). Efficacy: Forty patients, divided into two cohorts (n=20 each), were enrolled in stage I. The regimen, 150 mg, qd, was selected as RP2D based on a better ORR and the convenience of once daily dosing. All patients who were enrolled in the stage I continued their treatment. At the time of reporting (the 31 May 2019), 97 patients had response assessments. The response rate was assessed by traditional CT image technology. The ORR was 82.5% (80/97) for combining both regimens with the complete response rate (CR) 24.7% (24/97), partial responses 57.7% (56/97). Stable disease was seen in 9.3% (9/97). The total disease control rate is 91.8%. Six (6.2%) patients progressed by the first response assessment. The median duration of response rate (DOR) has not been reached. Conclusion: Orelabrutinib is safe and well tolerated with no reported treatment related grade 3 or higher GI toxicity, atrial fibrillation/flutter and severe bleeding in this study. Orelabrutinib is efficacious to treat patients with r/r MCL. The improved safety, resulting from high target selectivity, and the convenience of daily dosing regimen provides orelabrutinib as the potential of preferred therapeutic choice for B cell malignancy. Disclosures Lu: Beijing InnoCare Pharma Tech. Co., Ltd.: Employment. Zhang:Beijing InnoCare Pharma Tech Co., Ltd: Employment. Zhao:Beijing InnoCare Pharma Tech Co., Ltd: Employment. Xu:Beijing InnoCare Pharma Tech Co., Ltd: Employment.
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Xu, Wei, Yongping Song, Tingyu Wang, Shenmiao Yang, Lihong Liu, Yu Hu, Wei Zhang, et al. "Updated Results from the Phase II Study of Orelabrutinib Monotherapy in Chinese Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia/Small Cell Leukemia." Blood 136, Supplement 1 (November 5, 2020): 26–27. http://dx.doi.org/10.1182/blood-2020-134531.
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Orelabrutinib (ICP-022) is a novel and highly selective irreversible BTK inhibitor. We previously reported that orelabrutinib had high bioavailability with ~100% BTK occupancy at 24 hours at 150 mg daily dosing regimen and demonstrated excellent safety and efficacy profiles at median follow-up of 8.7 months in a Phase I/II trial of refractory/relapsed (r/r) CLL/SLL (Chronic Lymphocytic Leukemia/Small Cell Leukemia). Here we present an updated analysis of efficacy and safety results from the clinical study of Orelabrutinib in Chinese patients with r/r CLL/SLL following extended treatment. This is an open-label, multicenter, phase II study with objectives to evaluate its safety and efficacy following an oral daily administration. The primary endpoint was objective response rate (ORR). The duration of response (DOR), progression-free survival (PFS) and safety were chosen as secondary endpoints. Response was assessed per 2008 IWCLL criteria with modification for partial remission (PR) with lymphocytosis (PR-L) (Hallek 2012) or the Lugano Classification (Cheson, 2014) for CLL and SLL, respectively. Results: A total of 80 patients with r/r CLL (n=70)/SLL (n=10) were enrolled. Eligible patients had relapsed after or were refractory to ≥1 prior treatment with median age of 60.0 (range, 36.0-78.0 years). There are 70% of patients for Rai stage 3-4 disease, 22.5% for 17p13.1 deletion [del(17p)] and/or TP53 mutation, 41.3% for unmutated immunoglobulin heavy chain variable region (IGHV) and 23.8% for 11q22.3 deletion [del(11q)]. The median follow-up time was 14.3 months (range, 0.2-21.6 months), and the last patient completed a minimum of 12 cycles of orelabrutinib treatment. Efficacy: The efficacy results presented here were evaluated by IRC (Independent review committee). Following a minimum of 12 cycles treatment, the ORR (PR-L or above) was 91.3% (95% confidence interval [CI]: 82.80 ~ 96.41%) with 10.0% of patients having complete response (CR), 63.8% PR and 17.5% PR-L. Median time for achieving first response was 1.87 months (range, 1.84 - 1.94 months). The median DOR and PFS were not reached. The estimated 12-month DOR was 77.1% (95% CI: 62.50-86.60%), PFS 81.1% (95% CI: 70.53 - 88.13%) and OS 86.3% (95% CI: 76.55 - 92.14%). Patients with Del(17p) and/or TP53 mutation achieved 100% ORR. The ORR is 94.7% for Del(11q)) and 93.9% for unmutated IGHV. Comparing to the first analysis results of which the median follow-up was 8.7 months, the CR rate had increased from 3.8% to 10.0%, and 8 patients with PR-L had converted to a deeper response. So, orelabrutinib showed a significant higher CR rate comparing to other BTK inhibitors at a similar treatment period and we anticipate a further increase of CR rate with longer duration of treatment. Safety: Most adverse events (AEs) were mild to moderate, similar to the first reported safety profiles at median follow-up of 8.7 months. Extended follow-up analysis did not reveal new safety nor toxicity concerns. The most frequent adverse events (AEs) of any cause/any grade were well characterized as hematological toxicities: thrombocytopenia, neutropenia, and anemia; upper respiratory tract infection, pneumonia and hypokalemia. No case of atrial fibrillation nor secondary malignancy was reported, no patient was observed for ≥3 hypertension and only one patient had ≥3 grade diarrhea. Major hemorrhage was reported in 2 patients, one with intracranial hemorrhage (65-year-old male patient with more than 10 years hypertension) and the other with vitreous hemorrhage which were resulted from posterior vitreous detachment that was assessed as unlikely related to the treatment of orelabrutinib. Once again, it has been further confirmed that orelabrutinib has excellent safety profiles following extended treatment. Conclusion: This updated and extended study further confirms that orelabrutinib is efficacious in treating r/r CLL patients with a higher CR rate, durable response and improved safety profiles. As a highly selective BTK inhibitor with favorable pharmacokinetic and pharmacodynamic properties, orelabrutinib provides a favorable therapeutic choice for patients with r/r CLL/SLL and a potential best candidate for combination therapy. Disclosures Zhu: Beijing InnoCare Pharma Tech Co., Ltd: Current Employment. Zhao:Beijing InnoCare Pharma Tech Co., Ltd: Current Employment. Zhang:Beijing InnoCare Pharma Tech Co., Ltd: Current Employment. Xu:Beijing InnoCare Pharma Tech Co., Ltd: Current Employment.
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Song, Yuqin, Wei Xu, Yongping Song, Lihong Liu, Song Lin, Zhiming Li, Ting Liu, et al. "Pooled Analysis of Safety Data from Clinical Trials of Orelabrutinib Monotherapy in Hematologic Malignancies." Blood 136, Supplement 1 (November 5, 2020): 43. http://dx.doi.org/10.1182/blood-2020-140172.
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Background: Bruton tyrosine kinase (BTK) is one of the key kinases implicated in the pathogenesis of multiple B cell malignancies. Orelabrutinib is a novel, highly selective and potent irreversible BTK inhibitor with minimal activities against other kinases (ITK, EGFR, ERBB2, etc.). As thus orelabrutinib may avoid off-target related adverse events and shall have improved safety profiles comparing to other BTK inhibitors. Here we present the safety profile of orelabrutinib analyzed based on data from 5 ongoing clinical studies in B cell malignancies (Table 1). Methods: Safety data of 266 patients (pts) from 5 ongoing orelabrutinib monotherapy studies were pooled and analyzed. All pts have been treated with at least one dose of oral orelabrutinib at ≥150 mg daily. The analysis includes the frequency and severity of adverse events (AEs), AEs of special interest, and AEs leading to treatment discontinuation or dose modifications. Results: Safety data were pooled from 266 pts with median age of 60 years (range 35.0-79.0, 69.2% males). The median duration of exposure was 11.0 months (range 0.2-22.0). The most common (occurring in ≥15% of pts) AEs were neutropenia (28.6%), thrombocytopenia (25.9%), Upper respiratory tract infection (24.4%), leukopenia (18.0%), anemia (16.2%) and rash (15.8%). Treatment related serious AEs (SAEs) were reported in 14.7% pts. The most common treatment related SAEs included thrombocytopenia (3.0%), lung infection (3.0%), pneumonitis (1.9%), anemia (1.1%) and lymphadentis (0.8%), The safety profiles were comparable in pts with various subtypes of B cell malignancies. It's noted that orelabrutinib has much less frequency of BTK off-target related adverse events, such as atrial fibrillation, diarrhea, major hemorrhage etc. Among all 266 pts, only one patient was reported with one episode of transient grade 1 atrial fibrillation, and no grade ≥3 atrial fibrillation was observed. Diarrhea of any grade was 7.1% and only one case (0.4%) was reported as grade 3. The major hemorrhage, defined as serious or ≥ G3 bleeding of any site, or central nervous system bleeding of any grade, was rarely observed; as only one case of cerebral hemorrhage, in 65-year-old male patient with more than 10 years hypertension was reported; the other three cases were subcutaneous hemorrhage, vitreous hemorrhage and vitreous hemorrhage/retinal hemorrhage. The later 2 cases of vitreous hemorrhage and/or retinal hemorrhage were resulted from posterior vitreous detachment and macular degeneration and both events were assessed as unlikely related to the treatment. Among 266 pts, the second primary malignancies were reported in only one pt with r/r MCL during orelabrutinib treatment. Grade ≥3 infection occurred in 41 pts (15.4%); most common infections were upper respiratory tract infection and lung infection. Most of the AEs were occurred during the early treatment, the frequency of the new event occurrence was significantly decreased during the later cycles. Dose reductions due to AEs occurred in 15 pts (5.6%), and treatment discontinuation due to AEs in 5.3% of pts with 2.3% related to orelabrutinib. Conclusions: Orelabrutinib shows excellent safety profiles and tolerability across various B-cell malignancies in long-term treatment. These data suggested orelabrutinib as a favorable treatment choice including the combinational therapy for B-cell malignancies. . Disclosures Zhu: Beijing InnoCare Pharma Tech Co., Ltd: Current Employment. Zhao:Beijing InnoCare Pharma Tech Co., Ltd: Current Employment. Xu:Beijing InnoCare Pharma Tech Co., Ltd: Current Employment.
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Song, Yuqin, Yongping Song, Lihong Liu, Mingzhi Zhang, Zhiming Li, Chunyan Ji, Wei Xu, et al. "Long-Term Safety and Efficacy of Orelabrutinib Monotherapy in Chinese Patients with Relapsed or Refractory Mantle Cell Lymphoma: A Multicenter, Open-Label, Phase II Study." Blood 136, Supplement 1 (November 5, 2020): 1. http://dx.doi.org/10.1182/blood-2020-141781.
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Background: In spite of years of effort, Mantle Cell Lymphoma (MCL) remains a clinical challenge. The clinical significance of Bruton's Tyrosine Kinase (BTK) inhibitor has been validated with the approvals by FDA for the treatment of multiple subtypes of NHL including refractory and relapse (r/r) MCL. However, some serious adverse events (AEs) due to poor target selectivity (inhibition of EGFR, TEC, BMX and others), such as diarrhea, sever bleeding and atrial fibrillation, remain as challenges in clinic. Orelabrutinib is a novel, potent irreversible BTK inhibitor with high selectivity for BTK. Results of early clinical study showed that it has excellent safety/tolerability profiles and favorable pharmacokinetic/pharmacodynamic properties. Sustained ~100% BTK occupancy at 24 hours was achieved with once daily dosing regimen of 50 mg and above. In this presentation, we will report an updated analysis of orelabrutinib in Chinese patients with r/r MCL with minimum of 12 cycles of treatment. Aims: To evaluate the sustained efficacy and long-term safety of orelabrutinib in Chinese patients with r/r MCL. Methods: This is an open-label, multicenter, two stages, phase II study. The primary endpoint was objective response rate (ORR) assessed per Lugano criteria (2014). Safety and other efficacy (DOR, PFS, OS) evaluations were chosen as secondary endpoints. Results: A Total 106 patients, were enrolled in this study with median follow up time of 15.0 months. 79.2% of the patients were male and median age of 62.0 years old. Most patients were at advanced stage (73.6% were at stage IV and 20.8% were at stage III). According to per protocol analysis, 87 (87.9%) patients achieved ORR and 93.9% patients achieved disease control. The median duration of response (DOR) was not reached, the DOR rate at 12 months was 73.7%, as expected the median PFS and OS were not reached, the PFS and OS rates at 12-month were 70.8% and 88.7% respectively. Comparing to the results of previous analysis, the CR rate, by conventional CT method, increased to 27.4% and it was expected a higher rate of in depth response may occur with prolonged treatment. Further analysis showed orelabrutinib was efficacious in all subgroups (age, gender, status, stage, prior therapy, etc.). Orelabrutinib demonstrated excellent safety profile in r/r MCL patients. The frequently reported treatment related adverse events (TRAE) were primarily hematological toxicities including thrombocytopenia, neutropenia, leukopenia, and hypertension. The frequently reported grade 3 or higher AEs of any cause was thrombocytopenia . No treatment related ≥grade 3 GI and cardio toxicity, nor severe bleeding, were observed. Of the 106 patients, 32 experienced serious AEs; and 17 of them, mainly hematological toxicities and / or infections were treatment-related. Comparing to the safety data of median follow up of 10.5 months, there was only a mild increase of adverse events rate after extended treatments; the safety profiles were essentially the same. These results suggested that safety events primarily occurred during early treatment and it appeared less eventful with orelabrutinib continue treatment. Conclusion: Orelabrutinib showed continuous efficacious in treating patients with r/r MCL. In addition, orelabrutinib is safe and well tolerated with no treatment related grade 3 or higher diarrhea, atrial fibrillation/flutter or severe bleeding in this study. Results of prolong treatment expected to produce a higher rate of in depth response without altering its safety profiles support orelabrutinib being a better selection for BTKi therapy. The improved safety as a resulting of high target selectivity, and the convenience of daily dosing regimen provides orelabrutinib as preferred therapeutic choice for B cell malignancy. Disclosures Zhang: Beijing InnoCare Pharma Tech Co., Ltd: Current Employment. Zhao:Beijing InnoCare Pharma Tech Co., Ltd: Current Employment. Xu:Beijing InnoCare Pharma Tech Co., Ltd: Current Employment.
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Guo, Ye, Chunwang Yuan, Jieer Ying, Xu Zhu, Guodong Luan, Bin Zhang, Renbin Zhao, and Jin Li. "Phase I result of ICP-192 (gunagratinib), a highly selective irreversible FGFR inhibitor, in patients with advanced solid tumors harboring FGFR pathway alterations." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): 4092. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.4092.
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4092 Background: ICP-192 (gunagratinib), developed by InnoCare Pharma, is a novel pan-FGFR (fibroblast growth factor receptors) inhibitor that potently and selectively inhibits FGFR activities irreversibly by covalent binding. Preclinical data showed that gunagratinib overcomes the acquired resistance to the first-generation reversible FGFR inhibitors, e.g., infigratinib. ICP-CL-00301 is a phase I, first-in-human, clinical study which includes a dose escalation followed by dose expansion. The safety and tolerability as well as pharmacokinetics/pharmacodynamics (PK/PD) of gunagratinib were evaluated in patients with advanced solid tumors, and the preliminary anti-tumor activity was evaluated by RECIST1.1 in patients with FGF/FGFR gene aberrations. Methods: In the dose-escalation stage, patients with advanced solid tumors with or without FGF/FGFR alterations were treated with escalating doses (2, 4, 8, 10, 12, 14, 16 mg etc.) of gunagratinib once daily in 21-day cycles until disease progression or unacceptable toxicity. During the dose-expansion stage, patients with cholangiocarcinoma harboring FGFR2 gene fusion/translocation received the treatment of gunagratinib daily at 12 mg continuously. Results: As of February 2021, a total of 30 patients had received the treatment of gunagratinib. The median age of the treated patients was 55.0 (range: 28 to 75 years) with 56.7% male and ECOG performance status between 0-1. The maximum tolerated dose (MTD) had not been reached. The most common treatment-related adverse events (TRAEs) ( > 20%) included hyperphosphatemia, hypercalcemia, increased ALT or AST, diarrhea and hypertriglyceridemia. Hyperphosphatemia is a commonly reported AE from other trials targeting FGFR and here serves as a PD biomarker of FGFR inhibition. This PD biomarker was observed in 73.3% of the patients treated with gunagratinib at all dose levels and was consistently observed at doses of 8 mg QD and above. Hyperphosphatemia was well managed with oral phosphate binders when necessary. The plasma exposure increased proportionally to the oral dosage levels of gunagratinib. Among the 12 patients with FGF/FGFR gene aberrations who have completed at least one tumor assessment, the overall response rate (ORR) was 33.3%, including 1 patient (8.3%) of cholangiocarcinoma with complete response (CR) and 3 patients (25%) with partial response (PR). The disease control rate (DCR) was 91.7% (11 of 12 patients). Conclusions: Gunagratinib is safe and well-tolerated in patients with advanced solid tumors. Anti-tumor activity was demonstrated in patients with FGF/FGFR gene aberrations in multiple tumor types, including cholangiocarcinoma (NCT03758664). Better response is expected with the increase of treatment durations. Clinical trial information: NCT03758664.
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Grzesik, Benjamin, Tom Baumann, Thomas Walter, Frank Flederer, Felix Sittner, Erik Dilger, Simon Gläsner, et al. "InnoCube—A Wireless Satellite Platform to Demonstrate Innovative Technologies." Aerospace 8, no. 5 (May 4, 2021): 127. http://dx.doi.org/10.3390/aerospace8050127.
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A new innovative satellite mission, the Innovative CubeSat for Education (InnoCube), is addressed. The goal of the mission is to demonstrate “the wireless satellite”, which replaces the data harness by robust, high-speed, real-time, very short-range radio communications using the SKITH (SKIpTheHarness) technology. This will make InnoCube the first wireless satellite in history. Another technology demonstration is an experimental energy-storing satellite structure that was developed in the previous Wall#E project and might replace conventional battery technology in the future. As a further payload, the hardware for the concept of a software-based solution for receiving signals from Global Navigation Satellite Systems (GNSS) will be developed to enable precise position determination of the CubeSat. Aside from technical goals this work aims to be of use in the teaching of engineering skills and practical sustainable education of students, important technical and scientific publications, and the increase of university skills. This article gives an overview of the overall design of the InnoCube.
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Villamarín-Bello, Beatriz, Berta Uriel-Latorre, Florentino Fdez-Riverola, María Sande-Meijide, and Daniel Glez-Peña. "Gold Standard Evaluation of an Automatic HAIs Surveillance System." BioMed Research International 2019 (September 23, 2019): 1–10. http://dx.doi.org/10.1155/2019/1049575.
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Hospital-acquired Infections (HAIs) surveillance, defined as the systematic collection of data related to a certain health event, is considered an essential dimension for a prevention HAI program to be effective. In recent years, new automated HAI surveillance methods have emerged with the wide adoption of electronic health records (EHR). Here we present the validation results against the gold standard of HAIs diagnosis of the InNoCBR system deployed in the Ourense University Hospital Complex (Spain). Acting as a totally autonomous system, InNoCBR achieves a HAI sensitivity of 70.83% and a specificity of 97.76%, with a positive predictive value of 77.24%. The kappa index for infection type classification is 0.67. Sensitivity varies depending on infection type, where bloodstream infection attains the best value (93.33%), whereas the respiratory infection could be improved the most (53.33%). Working as a semi-automatic system, InNoCBR reaches a high level of sensitivity (81.73%), specificity (99.47%), and a meritorious positive predictive value (94.33%).
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Li, Yijing, Yang Liu, Joseph McIntosh, Alexa A. Jordan, Angela Leeming, Courtney L. Andersen, Justin Cidado, Vivian Changying Jiang, and Michael Wang. "AZD4320 Is a Novel and Potent BCL-2/XL Dual Inhibitor in Targeting Aggressive Mantle Cell Lymphoma." Blood 136, Supplement 1 (November 5, 2020): 44. http://dx.doi.org/10.1182/blood-2020-140775.
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Introduction: Mantle cell lymphoma (MCL) is a rare subtype of B-cell non-Hodgkin's lymphoma. It is an incurable disease with frequent relapse from chemotherapies, targeted therapies, and cell therapies. Dysregulated expression of BCL-2 family members resulting in enhanced cell survival frequently occurs in many cancer types and often contributes to the development of therapeutic resistance. The BCL-2 inhibitor venetoclax has been shown to be effective in treating refractory/relapsed MCL patients. However, resistance often occurs and one of the underlying mechanisms of this resistance is the increased expression of other anti-apoptotic BCL-2 family members, such as BCL-XL and MCL-1. In this study, we assessed the in vitro and in vivo efficacy of a novel and highly potent BCL-2/XL dual inhibitor AZD4320 in preclinical models. Methods: Cell viability assay was tested after 72-hour treatment with AZD4320 in a panel of ibrutinib/venetoclax-sensitive and -resistant MCL cell lines by CellTiter-Glo (Promega). The assay was also done after a 24-hour treatment in primary PDX cells. Cell apoptosis assay was performed to determine if AZD4320 induces cell apoptosis in MCL cell lines. Furthermore, the in vivo efficacy of AZD4320 was assessed in a CAR-T resistant MCL patient-derived xenograft (PDX) model. Results: AZD4320 significantly inhibited cell proliferation in all tested MCL cell lines, including both ibrutinib/venetoclax-sensitive and -resistant cell lines. It had an IC50 value at a low nanomolar range between 0.59 nM to 18 nM. Consistently, AZD4320 was effective in targeting primary PDX cells ex vivo. AZD4320 induced cell apoptosis in a dose-dependent manner. AZD0466, the nanomedicine formulation of AZD4320 (30mg/kg, weekly, IV), dramatically inhibited tumor growth and prolonged mouse survival in an ibrutinib-CAR-T dual-resistant PDX mouse model. All mice tolerated the treatment dose without any body weight loss. Conclusion: The novel BCL-2/XL dual inhibitor AZD4320 demonstrated excellent anti-MCL activity in both ibrutinib/venetoclax-sensitive and -resistant MCL cells in vitro. This was further validated in vivo in a ibrutinib-CAR-T dual-resistant PDX model. These findings provide evidence that dual targeting of BCL-2 and BCL-XL by AZD4320 is promising as it may overcome therapeutic resistance in relapsed/refractory MCL. Disclosures Andersen: AstraZeneca: Current Employment, Current equity holder in publicly-traded company. Cidado:AstraZeneca: Current Employment, Current equity holder in publicly-traded company. Wang:OMI: Honoraria, Other: Travel, accommodation, expenses; Nobel Insights: Consultancy; Loxo Oncology: Consultancy, Research Funding; Celgene: Consultancy, Other: Travel, accommodation, expenses, Research Funding; Kite Pharma: Consultancy, Other: Travel, accommodation, expenses, Research Funding; OncLive: Honoraria; Lu Daopei Medical Group: Honoraria; Acerta Pharma: Research Funding; VelosBio: Research Funding; BioInvent: Research Funding; Juno: Consultancy, Research Funding; Dava Oncology: Honoraria; Verastem: Research Funding; Molecular Templates: Research Funding; Oncternal: Consultancy, Research Funding; Pulse Biosciences: Consultancy; AstraZeneca: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Beijing Medical Award Foundation: Honoraria; Pharmacyclics: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; MoreHealth: Consultancy; Guidepoint Global: Consultancy; Targeted Oncology: Honoraria; Janssen: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; InnoCare: Consultancy.
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Forni, Pier Massimo. "Forme innocue nel [French left quote]Decameron[French right quote]." MLN 104, no. 1 (January 1989): 39. http://dx.doi.org/10.2307/2904990.
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Liu, Yang, Shuangtao Zhao, Changying Changying Jiang, Yixin Yao, Joseph McIntosh, Alexa A. Jordan, Yijing Li, et al. "Interrogation of Dysregulated Pathways Enables Precision Medicine in Mantle Cell Lymphoma." Blood 136, Supplement 1 (November 5, 2020): 33. http://dx.doi.org/10.1182/blood-2020-140794.
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Background: Mantle cell lymphoma (MCL) is an aggressive B-cell malignancy that is initially responsive but ultimately relapses after frontline therapy. Although the first-in-class Bruton's tyrosine kinase (BTK) inhibitor ibrutinib has achieved a 68% overall response rate in relapsed/refractory MCL patients, most experience disease progression after ibrutinib treatment. Furthermore, the diverse heterogeneity of molecular alterations in each patient makes improving patient outcome with a uniform regimen extremely challenging. Therefore, identification of effective drug therapies, especially personalized therapeutic strategies are urgently needed. In this study, clinical patient samples were submitted for molecular profiling analysis to identify the dysregulated pathways for each patient. Isolated tumor cells underwent an in vitro drug screen with a panel of clinic drug candidates. Final in vivo efficacy evaluation on the patient derived xenograft (PDX) mouse models could be utilized to predict and validate the clinical response. Methods: We collected fresh peripheral blood specimens, surgical biopsies, bone marrow aspirates and apheresis samples under established IRB-approved protocols. The extracted tumor RNA was subjected to a CLIA-validated nanoString nCounter analysis to interrogate the dysregulated signaling pathways, and whole-exome sequencing (WES) was conducted to reveal the somatic mutations and DNA copy number alterations. High throughput cell viability assays of 23 clinical drug agents targeting multiple pathways associated with MCL pathogenesis were tested per patient sample using the CellTiter-Glo luminescent assay (Promega). Meanwhile, subcutaneous, intravenous and subrenal injections of the purified patient tumor cells were performed on NSG-mice to create corresponding PDX mouse models and these models were used for in vivo validation of rational therapeutic treatment options for precision medicine. Results: We collected and submitted 21 clinical patient samples for molecular profiling analysis and screened them through the designed drug panel. We identified correlations between the WES and nanoString nCounter analysis to interrogate the dysregulated pathways for each patient. The PI3K/mTOR signaling, cell cycle regulation, and apoptosis pathways were among the three most markedly enriched pathways in the relapsed MCL samples based on the hallmark gene set analysis. For example, aberrant apoptosis pathway was identified as the predominant cancer hallmark in one of the patients, the Bcl-2 inhibitor venetoclax and MCL-1 inhibitor AZD5991 were chosen as rational therapeutic treatment options. Indeed, both venetoclax and AZD5991 dramatically induced cell death in both primary patient cells and isolated PDX tumor cells ex vivo. Furthermore, administration of venetoclax at 50mg/kg eradicated the tumor growth in the PDX mouse model established from this patient (p<0.001). In another patient, dysregulated cell cycle pathway (E2F targets and G2M checkpoint) was the predominant cancer hallmark and treatment with CDK4/6 inhibitor abemaciclib (75mg/kg) significantly decreased the tumor size in the PDX model derived from this patient (p<0.0001). Conclusions: Interrogation of dysregulated pathways could be achieved by molecular profiling analysis, and suggest rational treatment options. Follow-up in vitro & in vivo drug efficacy determination facilitates the identification of potential therapeutic options for precision medicine in MCL patient to ultimately improve patient survival outcome. Disclosures Wang: AstraZeneca: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Molecular Templates: Research Funding; Celgene: Consultancy, Other: Travel, accommodation, expenses, Research Funding; OncLive: Honoraria; Nobel Insights: Consultancy; InnoCare: Consultancy; Lu Daopei Medical Group: Honoraria; Beijing Medical Award Foundation: Honoraria; Guidepoint Global: Consultancy; Pulse Biosciences: Consultancy; Oncternal: Consultancy, Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; MoreHealth: Consultancy; VelosBio: Research Funding; BioInvent: Research Funding; Juno: Consultancy, Research Funding; Kite Pharma: Consultancy, Other: Travel, accommodation, expenses, Research Funding; Acerta Pharma: Research Funding; Verastem: Research Funding; Loxo Oncology: Consultancy, Research Funding; Targeted Oncology: Honoraria; Dava Oncology: Honoraria; OMI: Honoraria, Other: Travel, accommodation, expenses.
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Liu, Yang, Vivian Changying Jiang, Joseph McIntosh, Alexa A. Jordan, Yijing Li, and Michael Wang. "Overcoming CAR T Resistance with Non-Covalent BTK Inhibitor Loxo-305 in Mantle Cell Lymphoma." Blood 136, Supplement 1 (November 5, 2020): 10. http://dx.doi.org/10.1182/blood-2020-137645.
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Background: Mantle cell lymphoma (MCL) is a distinctive B-cell non-Hodgkin's lymphoma characterized by poor prognosis. Despite clinical success of the covalent Bruton's tyrosine kinase (BTK) inhibitor ibrutinib, a subset of patients need to discontinue ibrutinib therapy due to treatment related adverse events, which are primarily caused by off-target effects. Furthermore, primary or acquired resistance to ibrutinib continues to emerge and often leads to dismal clinical outcomes. Therefore, exploration of more target-specific BTK inhibitors is crucial to minimize the adverse events and provide clinical benefit. CAR T therapy has achieved unprecedented response in patients with relapsed or refractory MCL. However, the development of resistant phenotypes is a new emerging medical challenge in MCL patients with unknown mechanisms. Here, we characterize the therapeutic efficacy of LOXO-305, a next generation non-covalent small molecule inhibitor with high selectivity for BTK. Preclinical efficacy of LOXO-305 alone or in combination with venetoclax (ABT199), a selective Bcl-2 inhibitor, was evaluated in MCL using in vitro and in vivo CAR T-resistant PDX models. Methods : In vitro cell viability was measured after 72 hour treatment with LOXO-305 alone and in combination with ABT-199 in MCL cell lines using Cell Titer Glo luminescent cell viability assay (Promega). To determine whether LOXO-305 induces cell death through cell apoptosis, we used annexin V/PI staining followed by flow cytometry analysis. To evaulate in vivo drug efficacy we used patient-derived xenograft (PDX) models established from primary patient samples. Results: LOXO-305 treatment, as a single agent, resulted in effective MCL cell growth inhibition in a panel of MCL cell lines including ibrutinib and/or ABT-199-resistant cell lines (IC50=6.6-24.4μM), except for JeKo BTK KD cells with BTK knockdown (KD) via CRISPR/Cas9 technology (IC50>30 μM). To improve the efficacy, we decided to investigate the potential of LOXO-305 in combination with ABT199, since the combo of ibrutinib and ABT199 is clinically beneficial in MCL patients. Indeed, LOXO-305 significantly improved the inhibitory effect of ABT-199 in the ABT-199 resistant Mino-R and JeKo BTK KD cells, suggesting that this combination could be further explored in overcoming ABT-199 resistance in MCL. The compelling synergistic effect was further confirmed by annexin V/PI apoptosis assay. Next, we assessed the in vivo efficacy of LOXO-305 in an ibrutinib-CAR T dual-resistant PDX model. LOXO-305 effectively reduced tumor size after 40 days of treatment as a single agent. Moreover, LOXO-305 treatment showed significant anti-tumor effects in an ibrutinib-ABT199-CAR T triple-resistant PDX model that recapitulates the most aggressive human MCL variants invivo. In this model, LOXO-305 treatment effectively decreased the tumor load in mice spleen and liver (p<0.05) as well as in bone marrow and peripheral blood, compared to vehicle-treated mice (p<0.001). Conclusions: By using various in vitro and in vivo multiple resistant MCL models we determined that LOXO-305 holds great promise for an effective single agent or combined treatment of the most eggressive forms of MCL, and that a continued investigation of the rationale for a combined therapy with ABT-199 is imperative to understand its role in overcoming ibrutinib-ABT199-CAR T triple resistance. Disclosures Wang: OMI: Honoraria, Other: Travel, accommodation, expenses; MoreHealth: Consultancy; Celgene: Consultancy, Other: Travel, accommodation, expenses, Research Funding; AstraZeneca: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Beijing Medical Award Foundation: Honoraria; Lu Daopei Medical Group: Honoraria; Loxo Oncology: Consultancy, Research Funding; Pulse Biosciences: Consultancy; Kite Pharma: Consultancy, Other: Travel, accommodation, expenses, Research Funding; Juno: Consultancy, Research Funding; BioInvent: Research Funding; VelosBio: Research Funding; Acerta Pharma: Research Funding; InnoCare: Consultancy; Oncternal: Consultancy, Research Funding; Nobel Insights: Consultancy; Guidepoint Global: Consultancy; Dava Oncology: Honoraria; Verastem: Research Funding; Molecular Templates: Research Funding; OncLive: Honoraria; Targeted Oncology: Honoraria.
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Jordan, Alexa A., Joseph McIntosh, Yang Liu, Angela Leeming, William Lee, Ingrid Karlsson, Linda Mårtensson, et al. "Targeting Antibody Checkpoint Fcgriib Using Monoclonal Antibody BI-1206 to Overcome Therapeutic Resistance in Mantle Cell Lymphoma." Blood 136, Supplement 1 (November 5, 2020): 35. http://dx.doi.org/10.1182/blood-2020-140849.
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Mantle cell lymphoma (MCL) is a rare but aggressive B-cell non-Hodgkin's lymphoma that represents 6% of all lymphomas in the United States. Recent therapies including anti-CD20 antibody rituximab, BTK inhibitors, and BCL-2 inhibitors alone or in combination have shown great anti-MCL efficacy. However, primary and acquired resistance to one or multiple therapies commonly occurs, resulting in poor clinical outcome. Therefore, resistance to such therapies is currently an unmet clinical challenge in MCL patients. Therapeutic strategies to overcome this resistance holds promise to significantly improve survival of refractory/relapsed MCL patients. Recent studies showed Fc gamma receptors (FcγRs) play important roles in enhancing the efficacy of antibody-based immunotherapy. In particular, FcgRIIB (CD32B), an inhibitory member of the FcγR family, is implicated in the immune cell desensitization and tumor cell resistance through the internalization of therapeutic antibodies such as rituximab. Based on our flow cytometry analysis, we demonstrated that FcgRIIB is highly expressed on the cell surface of MCL cell lines (n=10) and primary MCL patient samples (n=22). This indicates that FcgRIIB may play an important role in MCL malignancy and identifies FcgRIIB is a potential therapeutic target for the treatment of MCL. To address this, we tested the in vivo efficacy of BI-1206, a fully humanized monoclonal antibody targeting FcgRIIB, alone, or in combination with clinically approved or investigational drugs including rituximab, ibrutinib and venetoclax. In the first in vivo cohort, BI-1206, as a single agent, dramatically inhibited the tumor growth of ibrutinib-venetoclax dual-resistant PDX tumor models, suggesting that targeting FcgRIIB by BI-1206 alone has high anti-MCL activity in vivo. Next, we assessed whether BI-1206 can boost anti-MCL activity of antibody-based therapy such as rituximab in combination with ibrutinib or venetoclax using additional mice cohorts of cell line-derived xenograft and patient-derived xenograft models. BI-1206 significantly enhanced the in vivo efficacy of ibrutinib plus rituximab, and venetoclax plus rituximab, on tumor growth inhibition, including the JeKo-1 derived xenograft models, previously proven to be partially resistant to ibrutinib and venetoclax in vivo. This tumor-sensitizaton effect was further confirmed in the ibrutinib and venetoclax dual-resistant PDX models of MCL where BI-1206 was combined with venetoclax and rituximab. More detailed mechanistic studies are currently ongoing to reveal the mechanism of action of BI-1206-based combinations or as single therapy with the possibility that BI-1206 itself may have a cytotoxic anti-tumor direct activity in MCL. In conclusion, BI-1206 as single agent showed potent efficacy in overcoming ibrutnib-venetoclax dual resistance. Moveover, BI-1206 enhanced the in vivo efficacy of ibrutinib plus rituximab and venetoclax plus rituximab and overcomes resistance to these treatments resulting in enhanced anti-tumor effects. Disclosures Karlsson: BioInvent International AB: Current Employment. Mårtensson:BioInvent International AB: Current Employment, Current equity holder in publicly-traded company. Kovacek:BioInvent International AB: Current Employment, Current equity holder in publicly-traded company. Teige:BioInvent International AB: Current Employment, Current equity holder in publicly-traded company. Frendéus:BioInvent International AB: Current Employment, Current equity holder in publicly-traded company. Wang:Pulse Biosciences: Consultancy; Loxo Oncology: Consultancy, Research Funding; Kite Pharma: Consultancy, Other: Travel, accommodation, expenses, Research Funding; BioInvent: Research Funding; Juno: Consultancy, Research Funding; Beijing Medical Award Foundation: Honoraria; OncLive: Honoraria; Verastem: Research Funding; Molecular Templates: Research Funding; Dava Oncology: Honoraria; Guidepoint Global: Consultancy; Nobel Insights: Consultancy; Oncternal: Consultancy, Research Funding; InnoCare: Consultancy; Acerta Pharma: Research Funding; VelosBio: Research Funding; MoreHealth: Consultancy; Targeted Oncology: Honoraria; OMI: Honoraria, Other: Travel, accommodation, expenses; Celgene: Consultancy, Other: Travel, accommodation, expenses, Research Funding; AstraZeneca: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Lu Daopei Medical Group: Honoraria.
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Fontana, Piero, Urs Boutellier, and Marco Toigo. "Non-invasive haemodynamic assessments using Innocor™ during standard graded exercise tests." European Journal of Applied Physiology 108, no. 3 (October 29, 2009): 573–80. http://dx.doi.org/10.1007/s00421-009-1252-x.
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Che, Yuxuan, Yang Liu, Lingzhi Li, Holly Hill, Joseph McIntosh, Alexa A. Jordan, Dayoung Jung, Yixin Yao, Vivian Changying Jiang, and Michael Wang. "Abemaciclib-Based Combinational Therapies to Overcome Therapeutic Resistance in Mantle Cell Lymphoma." Blood 136, Supplement 1 (November 5, 2020): 33–34. http://dx.doi.org/10.1182/blood-2020-140856.
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Introduction The past decades witnessed dramatic improvement of overall survival rate of mantle cell lymphoma (MCL) patients by constant efforts in developing novel therapeutic strategies that include ibrutinib and venetoclax. Nevertheless, resistance is still a major challenge in refractory/relapsed MCL patients. Chromosomal translocation t(11:14)(q13:q32) of the cyclin D1 (CCND1) gene is the hallmark of MCL, which leads to overexpression of cyclin D1. This overexpression promotes aberrant cell cycle progression by activating CDK4/6. Abemaciclib is a selective CDK4/6 inhibitor used as a clinical treatment of breast cancer and has been shown to be effective in preclinical human MCL xenograft models. It has also been used in a phase II clinical trial as a single agent among refractory/relapsed MCL patients with an objective response rate of 35.7%. In this preclinical study, we aim to evaluate the benefit of a combinational therapeutic strategy using abemaciclib with other molecular targeting agents among MCL patients with therapeutic resistance. Methods Cytotoxic efficacy of abemaciclib as a single agent and in combination with other drugs on different MCL cell lines and primary lymphoma cells from MCL patients with or without resistance was used as a key criterion for screening beneficial therapeutic strategies. Cell apoptosis and cell cycle arrest assays were conducted to further evaluate those effective combinations. Western blot was performed to investigate the mechanism of action of the combinations. Finally, the efficacy of abemaciclib alone or in combination were assessed in ibrutinib-resistant or venetoclax-resistant MCL PDX models in vivo. Results Our preliminary data showed that all MCL cell lines involved in this study were highly sensitive to abemaciclib treatment with IC50 values ranging from 50 nM to 1 µM. Further investigation of abemaciclib cytotoxicity on ibrutinib and/or venetoclax resistant MCL cell lines showed effective inhibition with a higher IC50 values ranging from 5 µM to 10 µM. More importantly, abemaciclib had potent efficacy on cells from primary MCL patients as well as from patients with acquired ibrutinib resistance. Our recent findings revealed that the addition of PI3K inhibitor TGR-1202 significantly enhanced cytotoxicity of abemaciclib in both sensitive and resistant MCL cell lines. Abemaciclib significantly inhibited phosphorylation of Rb1, the active form of the protein, in 4 different MCL cell lines. The active Rb1 maintains the cell in the G1 phase, preventing progression through the cell cycle and acting as a growth suppressor. The result suggests that CDK4/6 inhibition with abemaciclib disrupts CDK4/6 suppressive activity towards pRb-E2F and induce cell cycle arrest in the MCL cells. Interestingly, abemaciclib somehow interrupted phosphorylation of Chk1, which is continuously phosphorylated and hence activated in the MCL cell lines. Inhibiting activation of Chk1 by abemaciclib may induce cell death via unmonitored and accumulated DNA damage. The efficacy of abemaciclib in combination with Bcl-2 or BTK inhibitors in MCL cell lines and isolated cells from MCL patients are ongoing. These data suggest that abemaciclib in combination with other therapeutic drugs could be beneficial in targeting therapeutic resistant MCL cells. Conclusions Abemaciclib showed impressive therapeutic potency on both MCL cell lines and isolated primary cells from MCL patients, which is likely due to the predominant contribution of cyclin D1-CDK4/6 pathway to malignancy. Other agents, such as PI3K inhibitors, can sensitize abemaciclib in therapeutic resistant MCL cells. Thus, an abemaciclib based multi-drug combinational strategy may be a promising therapy for refractory/relapsed MCL patients in the near future. Disclosures Wang: Beijing Medical Award Foundation: Honoraria; Lu Daopei Medical Group: Honoraria; Kite Pharma: Consultancy, Other: Travel, accommodation, expenses, Research Funding; Pulse Biosciences: Consultancy; Loxo Oncology: Consultancy, Research Funding; Targeted Oncology: Honoraria; OMI: Honoraria, Other: Travel, accommodation, expenses; Nobel Insights: Consultancy; Guidepoint Global: Consultancy; Dava Oncology: Honoraria; Verastem: Research Funding; Molecular Templates: Research Funding; OncLive: Honoraria; Celgene: Consultancy, Other: Travel, accommodation, expenses, Research Funding; AstraZeneca: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Oncternal: Consultancy, Research Funding; Juno: Consultancy, Research Funding; BioInvent: Research Funding; VelosBio: Research Funding; Acerta Pharma: Research Funding; InnoCare: Consultancy; MoreHealth: Consultancy; Pharmacyclics: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding.
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Desai, Sanjal H., Betsy Laplant, William R. Macon, Rebecca L. King, Yucai Wang, David J. Inwards, Ivana Micallef, et al. "Lenalidomide/RCHOP (R2CHOP) Produces High Response Rates and Overall Survival in New, Untreated Diffuse Large B Cell Lymphoma Transformed from Follicular Lymphoma- Results from MC078E." Blood 136, Supplement 1 (November 5, 2020): 47–48. http://dx.doi.org/10.1182/blood-2020-141298.
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Introduction: Transformation of low grade follicular lymphoma (FL) to diffuse large B cell lymphoma (DLBCL) carries a poor prognosis. In retrospective studies, 5-year survival of transformed DLBCL treated with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) without autologous stem cell transplant is 40-60%, underscoring need to improve frontline treatment of transformed DLBCL beyond R-CHOP. The overall response rate (ORR) to lenalidomide used as a single agent for relapsed transformed non Hodgkin lymphoma was 45% with 21% complete response (CR) rate and a median duration of response of 12 months (Witzig et al, Ann Onc 2011). These data provided the rationale to include patients with transformed DLBCL (with historical and concurrent FL) in MC078E, a phase II clinical trial testing lenalidomide plus R-CHOP (R2CHOP) for patients with new and untreated de novo and transformed DLBCL (NCT00670358). Here we present analysis of the subset of transformed DLBCL patients. Methods: Adult patients with transformed DLBCL and either historical or concurrent FL, stage >=2, measurable disease by Positron Emission Tomography/computed tomography (PET/CT) and adequate organ function were included. Patients with Central Nervous System (CNS) involvement, significant comorbidities, active non-lymphomatous malignancy, life-threatening thromboembolism (TE) and contraindication to aspirin prophylaxis were excluded. Study participants received up to 6 cycles of rituximab (375 mg/m2), cyclophosphamide (750 mg/m2), doxorubicin (50 mg/m2), and vincristine (1.4 mg /m2) on day 1, prednisone (100 mg) on day 1-5, pegfilgrastim on day 2, and Lenalidomide 25 mg day 1-10 of 21 day cycle. Tumor lysis prophylaxis was per local practice; patients also received TE prophylaxis with aspirin. Primary outcome was event free survival (EFS) at 12 months, where an event was defined as death, progression or subsequent anti-lymphoma therapy. Secondary outcomes included ORR, CR, progression free survival (PFS), and overall survival (OS). Response was evaluated by PET/CT after cycle 2 and cycle 6 with revised response criteria (Cheson et al, 2007). Adverse events were recorded according to CTCAE version 3.0. The Kaplan-Meier method was used to estimate time to event endpoints. Results: Thirty-nine patients were accrued from August 5, 2013 to July 28, 2020 and 33 were eligible by central pathology review. Median age was 64 (range 24-80) years and 18 (54%) were >60 years old. Eighteen (54%) were male, and 32 (97%) had ECOG performance status <2. Twenty-three (70%) had historical FL and 10 (30%) had concurrent FL. Twenty-six (79%) had advanced stage (III-IV). Median number of extra nodal sites were 1 (0-4). Thirteen (39%) had high international prognostic index (IPI) (4-5). Thirty-two (97%) completed at least 2 cycles (30 completed all 6 cycles) and were evaluable for response. ORR was 97% (32/33), 29 (88%) had CR and 3 had PR. EFS at 12 months was 87.9% (95% CI: 71.8, 96.6). Two-year PFS and OS were 84.5% (95% CI: 72.8%-98%) and 96.9% (95% CI: 91-100%) (Figure 1). Twenty nine completed study protocol, 4 discontinued protocol early for disease progression (1), adverse event (AE) (1), refusal (1) and noncompliance (1). Thirty (91%) had hematologic AE of grade 3 or above, 27 (82%) had neutropenia, 16 (48%) had thrombocytopenia, and 7 (21%) had anemia. Sixteen (48%) had grade 3 or above non-hematologic AE. Eight (24%) had febrile neutropenia. There were 3 deaths on this study, 1 due to progressive DLBCL, 1 due to AML and 1 due to malignant melanoma. Conclusion: R2CHOP appears effective in transformed DLBCL with high response rates, event free, progression free and overall survival seen in current study. This study supports the inclusion of anthracycline naive patients with transformed DLBCL in future randomized studies of lenalidomide or other novel immunomodulatory (IMiD) analogues. Disclosures Wang: Novartis: Research Funding; Innocare: Research Funding; Incyte: Research Funding. Ansell:Bristol Myers Squibb: Research Funding; Takeda: Research Funding; AI Therapeutics: Research Funding; Regeneron: Research Funding; Trillium: Research Funding; Affimed: Research Funding; Seattle Genetics: Research Funding; ADC Therapeutics: Research Funding. Witzig:Spectrum: Consultancy; Immune Design: Research Funding; Karyopharm Therapeutics: Research Funding; Acerta: Research Funding; Incyte: Consultancy; AbbVie: Consultancy; MorphSys: Consultancy; Celgene: Consultancy, Research Funding. Nowakowski:Celgene/BMS: Consultancy, Research Funding; MorphoSys: Consultancy, Research Funding; Ryvu: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite: Consultancy; Kymera: Consultancy; Curis: Consultancy; Seattle Genetics: Consultancy; NanoString: Research Funding.
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Lian, Junwei, Yu Xue, Alexa A. Jordan, Joseph McIntosh, Yang Liu, Michael Wang, Jia Zhou, and Vivian Changying Jiang. "Targeting Transcription Checkpoint Using a Novel CDK9 Inhibitor in Mantle Cell Lymphoma." Blood 136, Supplement 1 (November 5, 2020): 28–29. http://dx.doi.org/10.1182/blood-2020-140865.
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Introduction Mantle cell lymphoma (MCL) is an aggressive B-cell lymphoma that accounts for 5-8% of all non-Hodgkin lymphomas. Despite the Bruton's tyrosine kinase inhibitor ibrutinib and the BH3 mimetic BCL2 inhibitor venetoclax (ABT-199) have proven to be effective therapeutic strategies for MCL, most patients often experience disease progression after treatment. Thus, developing a novel drug to overcome this aggressive relapsed/refractory malignancy is an urgent need. Cyclin-dependent kinase 9 (CDK9) is a serine/threonine kinase belonging to the CDK family which regulates multiple cellular processes, particularly in driving and maintaining cancer cell growth. Unlike classical CDKs, CDK9 is a critical component of the positive transcription elongation factor b (P-TEFb) complex that mediates transcription elongation and mRNA maturation via phosphorylating RNA polymerase II (RNAP2). Previous studies demonstrated that CDK9 inhibition downregulates transcription levels of MCL-1 and MYC, which are crucial in both survival and proliferation of acute myeloid leukemia and diffuse large B-cell lymphoma. We and others found that the MYC signaling pathway was enhanced in MCL, especially in ibrutinib-resistant MCL patients. MYC is a core transcription factor driving lymphomagenesis. It does not possess enzymatic activity and has long been considered to be undruggable. MCL-1 is a key anti-apoptotic protein and is overexpressed in several hematologic malignancies. It was also found to be overexpressed in ibrutinib or venetoclax-resistant MCL cells. Thus, CDK9 is considered as a potential target that may inhibit MYC and MCL-1 pathways. Although recently it was shown that MC180295, a novel selective inhibitor of CDK9, has nanomolar levels anti-cancer potency, whether its beneficial effects extend to relapsed/refractory MCL has not yet been assessed. Methods We use three paired MCL cells sensitive/resistant to ibrutinib or venetoclax to test the efficacy of CDK9 inhibitor MC180295. Cell viability was measured by using Cell Titer Glo (Promega). Cell apoptosis assay and western blot analyses were used to identify affected pathways after MC180295 treatment. Finally, we used patient-derived xenograft (PDX) mouse models to test the therapeutic potential of MC180295 in MCL. Results First, we examined the potential efficacy of a CDK9 inhibitor MC180295 in MCL cells. MC180295 treatment results in growth inhibition of ibrutinib-resistant or venetoclax-resistant MCL cells. By assessing the caspase 3 and PARP activity, we found that MC180295 treatment induces cell death via cell apoptosis in MCL cell lines. Meanwhile, we found that RNAP2 phosphorylation at Ser2, the active form of RNAP2, is downregulated in MC180295 treated MCL cell lines. Consistent to previous studies, MC180295 treatment significantly reduces the protein level of MYC and MCL-1. In addition, we identified several other important proteins, such as cyclin D1 and BCL-XL, were also downregulated upon MCL180295 treatment. MC180295 was able to overcome ibrutinib-venetoclax dual resistance in PDX mouse models without severe side effects. To improve the efficacy of MC180295 as a single agent, we performed in vitro combinational drug screen with a number of FDA-approved or investigational clinical agents and found that MC180295 had a synergistic effect with venetoclax. We are currently investigating the underlying mechanism of action. Conclusion Taken together, our findings showed that targeting CDK9 by its specific inhibitor MC180295 is effective in targeting MCL cells, especially those with ibrutinib or venetoclax resistance and therefore supports the concept that CDK9 is a new target to overcome ibrutinib/venetoclax resistance in MCL. Disclosures Wang: MoreHealth: Consultancy; Dava Oncology: Honoraria; Beijing Medical Award Foundation: Honoraria; OncLive: Honoraria; Molecular Templates: Research Funding; Verastem: Research Funding; Guidepoint Global: Consultancy; Nobel Insights: Consultancy; Oncternal: Consultancy, Research Funding; InnoCare: Consultancy; Loxo Oncology: Consultancy, Research Funding; Targeted Oncology: Honoraria; OMI: Honoraria, Other: Travel, accommodation, expenses; Celgene: Consultancy, Other: Travel, accommodation, expenses, Research Funding; AstraZeneca: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Lu Daopei Medical Group: Honoraria; Pulse Biosciences: Consultancy; Kite Pharma: Consultancy, Other: Travel, accommodation, expenses, Research Funding; Juno: Consultancy, Research Funding; BioInvent: Research Funding; VelosBio: Research Funding; Acerta Pharma: Research Funding.
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Jiang, Vivian Changying, Shaojun Zhang, Junwei Lian, Yuanxin Wang, Rongjia Zhang, Yang Liu, Joseph McIntosh, et al. "Single Cell Transcriptomic Evolution and Resistance Mechanisms of BTK and BCL-2 Inhibition in Mantle Cell Lymphoma." Blood 136, Supplement 1 (November 5, 2020): 33–34. http://dx.doi.org/10.1182/blood-2020-140882.
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Introduction: Mantle cell lymphoma (MCL) is a rare and aggressive subtype of B-cell non-Hodgkin's lymphoma with high risk of relapse after frontline therapies. Ibrutinib and venetoclax are two efficacious therapies for refractory/relapsed MCL patients. However, resistance to these therapies occurs frequently and is an urgent unmet clinical need. To understand the underlying mechanism of how intra- and inter-tumor heterogeneity (ITH) and its immune microenvironment contributes to therapeutic resistance, we performed a state-of-art single cell RNA sequencing on longitudinal samples from ibrutinib and venetoclax dual-resistant MCL patients with side-by-side comparison to ibrutinib-sensitive patients in our discovery cohort. To support our novel findings, patient samples from multiple validation cohorts were collected and analyzed via various approaches. Methods: Patient specimens from our discovery cohort that included ibrutinib-sensitive and ibrutinib-venetoclax dual-resistant MCL patients were collected longitudinally and subject to single cell RNA sequencing using 10x genomics. Integrative computational analysis was conducted to uncover the ITH and tumor immune microenvironment at single cell resolution and the underlying mechanism of therapeutic resistance and clonal evolution. To validate the novel findings, additional cohorts of patient samples were collected and subject to bulk RNA sequencing, whole exome sequencing, and multi-color flow cytometry analysis. An orthotopic PDX model was established from one of the ibrutinib-venetoclax dual-resistant MCL patients and was used to validate the novel findings as well as to test the potential therapies in vivo to overcome resistance. Results: To understand the underlying mechanism of heterogeneity and therapeutic relapse, we carried out sequential single cell RNA sequencing on 21 specimens (18,794 cells in total) collected from ibrutinib-sensitive and ibrutinib-venetoclax dual-resistant MCL patients along the course of ibrutinib and/or venetoclax treatments. Integrative computational analysis revealed a high degree of ITH with distinct profiles of cellular and molecular transcriptome. We revealed 15 top cancer hallmarks associated with disease progression and therapeutic resistance, albeit with remarkable clinical, pathological, and genetic-based inter-patient heterogeneity. We observed appearance and clearance of multiple subpopulations in patient blood samples, which likely interprets the clinical ibrutinib-induced lymphocytosis phenomenon at single-cell resolution and disease-progression-associated clonal evolution, which were further validated. Our analysis revealed reprogramming of the tumor microenvironment and tumor immune evasion. Moreover, we revealed multiple actionable targets to help overcome therapeutic resistance as tailored anti-MCL strategies. We found that the 17q gain strongly correlated with this dual resistance and thus targeting survivin located at 17q by YM155 significantly inhibited tumor growth and prolonged mouse survival in the ibrutinib-venetoclax dual-resistant PDX model. Conclusions: This study is the first to describe the mechanisms underlying dual resistance to ibrutinib and venetoclax at the single cell level. We not only identified various pathways underlying this resistance, but also characterized the evolutionary dynamics by using a longitudinal sampling strategy to uncover the underlying mechanisms. We found that the 17q gain highly correlates with ibrutinib-venetoclax dual resistance and showed that inhibition of survivin, located at 17q, overcame this dual resistance. These data provide evidence that 17q gain may be the driving force of disease progression and therapeutic resistance. Moreover, for the first time in MCL, we characterized changes in tumor immune microenvironment and identified a T-cell exhaustion signature correlated with the dual resistance. These changes to the tumor microenvironment strongly suggest the role of immune resistance in mediating dual resistance to ibrutinib and venetoclax in MCL. Disclosures Wang: Lu Daopei Medical Group: Honoraria; Beijing Medical Award Foundation: Honoraria; OncLive: Honoraria; Molecular Templates: Research Funding; Verastem: Research Funding; Dava Oncology: Honoraria; Guidepoint Global: Consultancy; Nobel Insights: Consultancy; Oncternal: Consultancy, Research Funding; InnoCare: Consultancy; Acerta Pharma: Research Funding; VelosBio: Research Funding; BioInvent: Research Funding; Juno: Consultancy, Research Funding; Kite Pharma: Consultancy, Other: Travel, accommodation, expenses, Research Funding; Pulse Biosciences: Consultancy; Loxo Oncology: Consultancy, Research Funding; Targeted Oncology: Honoraria; OMI: Honoraria, Other: Travel, accommodation, expenses; Celgene: Consultancy, Other: Travel, accommodation, expenses, Research Funding; AstraZeneca: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; MoreHealth: Consultancy; Pharmacyclics: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding.
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Sheth, Shreya S., Dawn M. Maxey, Alice E. Drain, and Jeffrey A. Feinstein. "Validation of the Innocor Device for Noninvasive Measurement of Oxygen Consumption in Children and Adults." Pediatric Cardiology 34, no. 4 (October 30, 2012): 847–52. http://dx.doi.org/10.1007/s00246-012-0555-6.
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Yao, Yixin, Yuxuan Che, Yang Liu, Lingzhi Li, Alexa A. Jordan, Preetesh Jain, and Michael Wang. "MCL Cells in Tumor Microenvironment Impair T-Cell Metabolic Fitness and Effector Function." Blood 136, Supplement 1 (November 5, 2020): 16. http://dx.doi.org/10.1182/blood-2020-139611.
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Background: Mantle cell lymphoma (MCL) is an aggressive, incurable B cell malignancy. Major advances have been achieved with the development of clinically effective targeted agents including BTK and BCL-2 inhibitors. However, patients often relapse after these treatments. The emerging immune therapies combining immune checkpoint blockade and adoptive T-cell transfer are becoming increasingly desirable, but patient responses are heterogeneous, with a significant rate of failure. Tumor microenvironment (TME) plays an important role by inducing immune checkpoint and immune suppressive signaling or creating a metabolic barrier to antitumor immunity, particularly effector T-cells. To evade immune defenses, tumor and stromal cells cooperate and tactically express inhibitory ligands, such as PD-L1, while upregulating immune checkpoint receptors on effector T-cells and CAR T cells, resulting in negative signaling that leads to T-cell exhaustion, one of the major challenges in CAR T-cell therapy. Limited nutrient accessibility and a hostile immunosuppressive TME posts a strong barrier to effective immune therapies, with T-cell immunity being mostly affected. Impaired metabolism may also inhibit the function of effector T-cells while promoting suppressive activity of regulatory T-cells. Results: Our recent transcriptomic analysis of primary MCL clinical specimens comprised of microenvironment cell populations, revealed that genes related to immune function were dysregulated, particularly the genes responsible for IFNG-mediated anti-tumor immunity. Proliferation in response to TCR stimulation is an important measurement for T-cell effector function and potency. Reduced proliferation upon T-cell activation denotes T-cell dysfunction. Indeed, T-cells isolated from MCL specimens especially CAR T non-response patients exhibit diminished cell division upon stimulation with anti-CD3/CD28 beads (25-75% less expansion). To recapitulate the interplay between T-cells and TME, MCL cells were co-cultured with the non-MCL fraction from the purification, and T-cells were then phenotypically profiled. Intriguingly, MCL-derived T-cells mostly displayed exhaustion phenotypes, indicated by decreased expression of T-cell activation markers (CD25, CD28, CD38, and CD71), but increased expression of exhaustion and senescence molecules (CTLA4, LAG3 and PD-1). Moreover, MCL-derived T cells failed to induce the expression of cytokine, such as INF-γ (<1-1.8 vs. 7.1 fold induction) and TNF-α (<1-1.3 vs. 10.2 fold induction), upon TCR stimulation, in contrast to T-cells derived from healthy donors, implicative of reduced cytotoxicity towards tumor cells. The results led us to further attest our hypothesis that MCL cells induce T-cell exhaustion by modulating the expression of inhibitory molecules or immune checkpoint molecules. Metabolic fitness is crucial for T-cell survival and effector function upon activation. A stable mitochondria membrane potential (ΔΨm) is required to maintain metabolic fitness of effector T-cells. The rate of glucose uptake is considered a prominent indicator of T-cell activation. However, MCL derived T-cells displayed remarkable decreased glucose uptake (fold MFI <1-1.21 vs. 1.95), mitochondria mass (p = 0.011) and ΔΨm (fold MFI <1-1.28 vs. 1.9), compared to those from healthy donors, indicating T-cell mitochondrial biogenesis and fitness are impaired in the MCL cell dominated TME. To assess the anti-tumor immunity of T-cells in MCL, we also examined the cytotoxicity of MCL-derived tumor specific cytotoxic T-lymphocytes (CTL) and observed compromised effector activity compared to that from healthy donors. Conclusion: We presented evidence that MCL cancer cells suppress immune cell function by upregulating immunosuppressive signaling and forging a metabolic barrier to effector T-cells and immunotherapy. Targeting the MCL TME while enhancing T-cell metabolic fitness would dramatically advance current immunotherapy. Despite the success of checkpoint blockade and adoptive cell transfer therapy, complimentary approaches to overcome the metabolic barrier of immunosuppressive TME holds promise to dramatically enhance the efficacy of immunotherapies. Further, identification of the precise pathways and targets that determine T-cell metabolic fitness would facilitate developing new approaches to bolster current immunotherapy. Disclosures Wang: AstraZeneca: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Acerta Pharma: Research Funding; Oncternal: Consultancy, Research Funding; Guidepoint Global: Consultancy; Celgene: Consultancy, Other: Travel, accommodation, expenses, Research Funding; Dava Oncology: Honoraria; Molecular Templates: Research Funding; Juno: Consultancy, Research Funding; Kite Pharma: Consultancy, Other: Travel, accommodation, expenses, Research Funding; Pulse Biosciences: Consultancy; Loxo Oncology: Consultancy, Research Funding; Lu Daopei Medical Group: Honoraria; InnoCare: Consultancy; OncLive: Honoraria; Verastem: Research Funding; VelosBio: Research Funding; OMI: Honoraria, Other: Travel, accommodation, expenses; Nobel Insights: Consultancy; Beijing Medical Award Foundation: Honoraria; Pharmacyclics: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; BioInvent: Research Funding; MoreHealth: Consultancy; Targeted Oncology: Honoraria.
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Yao, Yixin, Lingzhi Li, Yuxuan Che, Joseph McIntosh, Holly Hill, Yang Liu, and Michael Wang. "Targeting the Synthetic Lethality Interaction of MTAP and PRMT5 to Overcome Drug Resistance and Enhance Anti-Cancer Immunity in Mantle Cell Lymphoma." Blood 136, Supplement 1 (November 5, 2020): 15. http://dx.doi.org/10.1182/blood-2020-138553.
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Background: Complex genetic, epigenetic alterations and metabolic reprogramming are among the hallmarks of mantle cell lymphoma, an aggressive B-cell type of non-Hodgkin's lymphoma. CDKN2A and MTAP are frequently co-deleted in human cancers including MCL. Deletion of MTAP gene results in the accumulation of methylthioadenosine (MTA), a selective inhibitor of protein arginine methyltransferase 5 (PRMT5), signifying a dependence of MTAP deleted tumors on PRMT5. PRMT5 plays an important role in normal cellular processes via epigenetic and post-translational modification of RNA splicing, DNA repair and cell cycle regulators. These pathways may be activated in response to targeted therapies to maintain tumor growth and survive chemotherapy. Sustained PRMT5 expression and activity could be therapeutically targeted in MTAP-deficient MCL. Mutations in RNA splicing factors are common in lymphoma and increase the susceptibility to perturbations in splicing events. Deregulated PRMT5 might induce alternative splicing, leading to loss of expression of proteins or epitopes, and subsequent immune evasion and failure of tumor specific immune therapy. Multiple mechanisms may co-exist. Results: CDKN2A and MTAP were commonly co-deleted in ibrutinib-resistant MCL tumors (71%, p = 0.01). To corroborate with this finding, we found that PRMT5 was overexpressed in both primary ibrutinib-resistant MCL and cell lines, with its expression levels inversely correlated with the patient responses to ibrutinib treatment (p = 0.004). Metabolomics analysis revealed elevated S-Adenosyl-methionine (SAM) and S-Adenosyl-homocysteine (SAH) (t-test p <0.001 and p <0.05), PRMT5 cofactor and product, respectively, in ibrutinib-resistant MCL cell lines. PRMT5 plays an important role in the regulation of cell cycle progression. Consistently, treatment with PRMT5 inhibitors induced cell cycle arrest in MCL cell lines (20% and 47% reduction in S phase for JVM13 and JVM2 respectively). Interestingly, treatment with the catalytic inhibitors (GSK3226595 and EPZ015666) led to S-phase stasis in which MCL cells seem incapable of replication. Meanwhile, PRMT5 inhibition with these inhibitors prevented the growth of MCL cell lines as indicated by remarkable decreases in the cell viability (IC50 = 1-1.4 µM and 0.58-0.95µM, respectively). PRMT5 enzymatic activity is required for its function in promoting cell cycle progression and proliferation, as treatment with its inhibitors leads to dramatic reduction in the level of SDMA-containing proteins, especially that of H4R3me2s. More importantly, pharmacological blockade of PRMT5 with single agent GSK3226595 significantly inhibited tumor growth in ibrutinib-resistant MCL PDX models (n = 5, p <0.05), implicating PRMT5 as an actionable target in MCL. PRMT5-mediated alternative splicing may contribute to immune escape and immune suppression. Indeed, our preliminary results revealed that T cells from MCL specimen with high expression of PRMT5 displayed decreased glucose uptake (fold MFI <1-1.23 vs. 2.2), mitochondria mass (p <0.01) and ΔΨm (fold MFI <1-1.26 vs. 2.3), by flow cytometry. Strikingly, the same patient-derived cytotoxic T-lymphocytes (CTL) exhibit reduced cytotoxicity towards autologous lymphoma cells, compared to those derived from healthy donors (p <0.05), strongly implicating impaired T cell metabolic fitness plus immune escape and suppression diminished T cell effector function. Conclusion: We presented evidence that MCL with MTAP deletion confers synthetic lethal dependence on PRMT5, making it an attractive therapeutic target. As an important metabolic and epigenetic regulator, loss of PRMT5 leads to malfunction of the constitutive splicing machinery that induces alternative splicing events, genetic instability and cell cycle arrest. Sustained PRMT5 expression and activity confers tumor aggressiveness and therapeutic resistance in MTAP-deficient MCL. Pharmacological blockade of PRMT5 may dramatically enhance T-cell immunity, while suppressing MCL cell proliferation and tumor growth in vivo. Further successful mechanistic studies would facilitate the identification of novel therapeutics and strategies to overcome resistance to targeted therapies and significantly improve the efficacy of immunotherapy for much better clinical outcomes of MCL. Disclosures Wang: Oncternal: Consultancy, Research Funding; Lu Daopei Medical Group: Honoraria; Juno: Consultancy, Research Funding; Guidepoint Global: Consultancy; Dava Oncology: Honoraria; MoreHealth: Consultancy; Targeted Oncology: Honoraria; Beijing Medical Award Foundation: Honoraria; Verastem: Research Funding; OncLive: Honoraria; Acerta Pharma: Research Funding; VelosBio: Research Funding; Molecular Templates: Research Funding; Nobel Insights: Consultancy; AstraZeneca: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Pulse Biosciences: Consultancy; Loxo Oncology: Consultancy, Research Funding; Kite Pharma: Consultancy, Other: Travel, accommodation, expenses, Research Funding; BioInvent: Research Funding; Celgene: Consultancy, Other: Travel, accommodation, expenses, Research Funding; OMI: Honoraria, Other: Travel, accommodation, expenses; InnoCare: Consultancy.
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Jiang, Vivian Changying, Junwei Lian, Shengjian Huang, Shaojun Zhang, Yang Liu, Linghua Wang, and Michael Wang. "Oncogenic MALT1 Promotes Cell Survival and Mediates Ibrutinib Resistance and Ibrutinib-Venetoclax Resistance in Mantle Cell Lymphoma." Blood 136, Supplement 1 (November 5, 2020): 18. http://dx.doi.org/10.1182/blood-2020-140871.
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Both as monotherapies and in combination, the Bruton's tyrosine kinase inhibitor ibrutinib and the BH3 mimetic BCL2 inhibitor venetoclax have proven to be efficacious and are now widely used treatment options for mantle cell lymphoma (MCL) patients. However, mono- and dual- resistance frequently develops, necessitating investigation into the mechanisms mediating resistance to these therapies. To investigate the mechanism of ibrutinib resistance, we generated two ibrutinib-resistant cells due to marked BTK knockdown via CRISPR/CAS9 from JeKo-1, which is ibrutinib-sensitive and venetoclax-resistant. To understand the mechanism of venetoclax resistance, we generated three venetoclax-resistant cell lines with acquired resistance via chronic exposure to increasing doses of venetoclax from ibrutinib/venetoclax double sensitive Mino and Rec-1 cells, and ibrutinib-resistant but venetoclax-sensitive Granta519 cells. All these paired cell lines with various resistance to ibrutinib and venetoclax were subject to whole transcriptome sequencing of these paired MCL cell lines. We discovered that mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is significantly overexpressed in ibrutinib-resistant and ibrutinib-venetoclax dual-resistant MCL cells, especially in cells with BTK knockdown. This was further validated in primary MCL patient cells (n=24). Interestingly, MALT1 overexpression inversely correlates with CARD11 expression and enhances non-canonical NF-κB signaling, suggesting a switch from a highly-dependent BTK-CARD11 mechanism to an independent mechanism in both ibrutinib-resistant and ibrutinib-venetoclax dual-resistant MCL cells. Chromosomal translocations of MALT1 are the hallmarks of MALT lymphoma, which result in oncogenic fusion of MALT1 products. MALT1 is constitutively active in driving aggressive ABC-type DLBCL. This indicates MALT1 can be oncogenic when its activity is dysregulated. Therefore, we hypothesized that constitutive MALT1 activity may be responsible for the resistance to ibrutinib and venetoclax in MCL cells. To demonstrate this relationship, MALT1 ablation using genetic manipulation resulted in significant growth defects both in vitro and in vivo. Pharmaceutical approaches using MALT1 inhibitor MI-2 resulted in similar effects on cell survival and using cell viability assays. Whole transcriptome sequencing analysis revealed that MYC, NF-kB, ROS, cell cycle and mTOR signaling are the most significantly downregulated pathways upon MI-2 treatment. Intriguingly, MYC, NF-kB, PI3K-AKT-mTOR and mTOR signaling pathways were reported to be upregulated in ibrutinib-resistant MCL cells compared to sensitive MCL cells. To address this further, proteomics analysis by reverse phase protein array (RPPA) using more than 400 antibodies confirmed that MI-2 significantly downregulated AKT-mTOR signaling. NF-kB modulation, ROS production, AKT-mTOR, and metabolism changes were further confirmed through multiple biochemical approaches. In addition, MI-2 treatment resulted in a dramatic reduction of MALT1 expression, suggesting that MI-2 treatment affected both its scaffold and paracaspase activities. Furthermore, MI-2 treatment resulted in significant inhibition of in vivo tumor growth of ibrutinib-venetoclax dual-resistant MCL subcutaneous xenografts and tumor homing to the spleen and bone marrow in an ibrutinib-venetoclax dual-resistant MCL patient-derived xenograft (PDX) mouse model. In conclusion, we discovered that MALT1, an essential regulator of NF-κB signaling, is hyperactive in ibrutinib-resistant cells and ibrutinib-venetoclax dual-resistant MCL cells, which puts MALT1 forward as a potentially new therapeutic target in ibrutinib and venetoclax-resistant MCL tumors. Genetic depletion or pharmaceutical inhibition of MALT1 resulted in remarkable defects in cell survival and cell proliferation. The MALT1 inhibitor MI-2 proved its in vivo potency by its pro-apoptotic effect and its significant tumor growth inhibition. In conclusion, targeting a hyperactive MALT1 is a promising therapeutic strategy that could lead to clinical implementation of a new treatment strategy meant to overcome ibrutinib and ibrutinib-venetoclax dual resistance in MCL patients by reversing the NF-kB and ROS/mTOR- mediated resistance in these tumors. Disclosures Wang: Targeted Oncology: Honoraria; Loxo Oncology: Consultancy, Research Funding; Pulse Biosciences: Consultancy; Kite Pharma: Consultancy, Other: Travel, accommodation, expenses, Research Funding; Juno: Consultancy, Research Funding; BioInvent: Research Funding; VelosBio: Research Funding; Acerta Pharma: Research Funding; InnoCare: Consultancy; Oncternal: Consultancy, Research Funding; Nobel Insights: Consultancy; Guidepoint Global: Consultancy; Dava Oncology: Honoraria; Verastem: Research Funding; Molecular Templates: Research Funding; OncLive: Honoraria; Beijing Medical Award Foundation: Honoraria; Lu Daopei Medical Group: Honoraria; MoreHealth: Consultancy; Celgene: Consultancy, Other: Travel, accommodation, expenses, Research Funding; AstraZeneca: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; OMI: Honoraria, Other: Travel, accommodation, expenses.
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Jiang, Vivian Changying, Shaojun Zhang, Shuangtao Zhao, Yang Liu, Joseph McIntosh, Linghua Wang, and Michael Wang. "Xeno-MCL: Genomic, Transcriptomic and Pathologic Landscape Associated with Disease Progression, Clonal Evolution and Tissue Tropism in Patient-Derived Xenografts of Mantle Cell Lymphoma." Blood 136, Supplement 1 (November 5, 2020): 20. http://dx.doi.org/10.1182/blood-2020-140878.
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Mantle cell lymphoma (MCL) is an aggressive subtype of non-Hodgkin lymphoma with poor diagnosis. Frequent relapse to frontline therapies is one of the major medical challenges in MCL. This is likely due to the extremely complex inter- and intra-tumor heterogeneity (ITH) in MCL patients. MCL patients display diverse clinicopathological profiles and tissue dissemination patterns, which can involve both nodal and extra nodal sites, including splenomegaly, hepatomegaly, lymphadenopathy, and involvement of bone marrow (BM), gastrointestinal (GI) tract, peripheral blood (PB), and the central nervous system. To date, it has not been reported how tissue tropism of MCL cells contribute to ITH, disease progression, and clonal evolution. This cannot be easily addressed using primary patient samples without simultaneous or sequential sampling from diverse dissemination sites, which is largely not feasible, especially for those requiring invasive collection. To this end, we established patient-derived xenograft (PDX) models from primary patient samples and characterize them in this study. Due to the distinct microenvironment, orthotopic PDX models have been shown to be much better platforms for preclinical and mechanistic studies than heterotopic or subcutaneous PDX (PDX_sc) models. Therefore, we established multiple MCL PDX models via intravenous (PDX_iv) or intraosseous routes and characterized them for the first time on how they recapitulate the disease in MCL patients in comparison to subcutaneous models when available. These PDX_iv models were successfully passed onto serious generations (up to 10) through IV or SC via PDX cells from spleen of PDX_iv or PDX_sc tumor, respectively (Figure 1). To understand the recapitulation of ITH in PDX models and their contribution to disease progression and clonal evolution, we collected specimens from both disseminated PDX_iv and PDX_sc cells from serious generations and subject them to a multi-dimensional investigation, including pathological, transcriptomic, and genetic profiling (Figure 1). Consistent in MCL patients, we observed a high degree of histopathological heterogeneity across PDX models originating from different patients, including splenomegaly, hepatomegaly, lymphadenopathy, and involvement of BM, GI tract and/or PB in our PDX_iv models. These models displayed similar dissemination patterns across generations when checked at 2 months after intravenous cell implantation, while additional dissemination sites may be reached at late disease stages, such as the stomach, colon, kidney and uterus. To understand the disease progression and clonal evolution, we performed whole exome sequencing (WES) on 62 PDX samples collected across tissues and generations, primary patient samples used to establish the models (n=6), and their matched germline samples (n=6). Our data revealed a high degree of recapitulation of PDX_iv to patients and genetic inter-patient heterogeneity. Clonal evolution events were investigated for both PDX_iv and PDX_sc models. We demonstrated that PDX_iv models passed by PDX cells from the spleen are genetically more stable than PDX_sc models, in which more frequent chromosomal gain/loss and/or gene mutations occurred toward later generations. Mutations in certain genes such as SVEP1 and STAB1, which play important roles in lymphocyte homing, were found to associate with tissue tropism. To further address this, we performed single-cell RNA sequencing on 41 PDX samples collected across tissues and generations together with primary patient samples (n=8) and PBMC samples from healthy donors (n=2). Transcriptomic profiling showed that G1 PDX_iv models recapitulated primary patient samples very well, and along generations, further upregulation of cancer hallmarks was observed, indicating disease progression into more aggressive stages along generations and late disease stages. Again, PDX_sc models were more transcriptionally dysregulated across generations. Moreover, in vivo efficacy studies showed that PDX cells responded differently to drug treatments such as venetoclax and rituximab based on their homing sites. In conclusion, we addressed the tissue tropism, therapeutic response, clonal evolution in MCL PDX models at multi-dimensional platforms, for the first time, and comparing the mutagenesis and disease progression of orthotopic and heterotopic PDX models at an unprecedented resolution. Figure 1 Disclosures Wang: Lu Daopei Medical Group: Honoraria; Beijing Medical Award Foundation: Honoraria; OncLive: Honoraria; Molecular Templates: Research Funding; Verastem: Research Funding; Dava Oncology: Honoraria; Guidepoint Global: Consultancy; Nobel Insights: Consultancy; Oncternal: Consultancy, Research Funding; InnoCare: Consultancy; Acerta Pharma: Research Funding; VelosBio: Research Funding; BioInvent: Research Funding; Juno: Consultancy, Research Funding; Kite Pharma: Consultancy, Other: Travel, accommodation, expenses, Research Funding; Pulse Biosciences: Consultancy; Loxo Oncology: Consultancy, Research Funding; Targeted Oncology: Honoraria; OMI: Honoraria, Other: Travel, accommodation, expenses; Celgene: Consultancy, Other: Travel, accommodation, expenses, Research Funding; AstraZeneca: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; MoreHealth: Consultancy; Pharmacyclics: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding.
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Khurana, Arushi, Raphael Mwangi, Stephen M. Ansell, Thomas M. Habermann, James R. Cerhan, Christopher Strouse, Brian K. Link, et al. "Estimates and Timing of Therapy Initiation during the First Decade for Patients with Follicular Lymphoma Who Were Observed at Diagnosis." Blood 136, Supplement 1 (November 5, 2020): 7–8. http://dx.doi.org/10.1182/blood-2020-141011.
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Background: Observation or "wait and watch" (W/W) strategy remains a viable option in the rituximab era for asymptomatic, stage II-IV, low-tumor burden patients with FL grade 1-2, 3A. Studies to date both in pre and post rituximab era have not shown an overall survival benefit from immediate treatment in such low-risk patients.To improve our understanding and to better counsel FL patients on W/W strategy, we sought to estimate the incidence of treatment initiation at landmark time points in our prospectively observed cohort from the Molecular Epidemiology Resource (MER) of the University of Iowa/Mayo Clinic Lymphoma Specialized Program of Research Excellence (SPORE). We further evaluate the association between the presence of GELF criteria (MER treatment criteria) at diagnosis and initiation of treatment patterns, transformation rates and cause of death in FL patients managed by W/W. Methods: FL patients on W/W strategy were identified from MER of the University of Iowa/Mayo Clinic Lymphoma SPORE. From 2002-2015, consecutive patients with newly diagnosed FL were offered enrollment. Patients were managed per treating physician and followed prospectively. Baseline clinical and pathological data were abstracted using a standard protocol. Cumulative incidence estimates of treatment initiation for follicular lymphoma were calculated using transformation to large cell lymphoma (as the first event) and death due to any cause as competing risks. Transformation was defined based on biopsy-proven disease. Patients were retrospectively considered to meet treatment criteria at diagnosis if they had the presence of any GELF criteria components per available abstracted data in the MER database. Not all GELF criteria were prospectively assessed and captured for all patients, and thus the MER treatment criteria utilized here will be conservative for formal GELF assessment. Results: A total of 401 FL patients were identified in MER on W/W strategy. Baseline characteristics for W/W patients showed a favorable profile such as normal LDH (89%), low and intermediate FLIPI score in 48% and 35% respectively, no B symptoms (97%), low tumor burden (<4 nodal groups) in 72%, and GELF positive vs. negative in 36% and 64% respectively. At a median follow up of 8 years (IQR 5.9-12), 64% initiated treatment for FL only. Cumulative incidence estimates of treatment initiation at sequential time points were calculated from the initiation of observation (Table1&2). At diagnosis, the likelihood of treatment initiation was 15%, 26%, and 42% in the next 1, 2, and 5 years. The incidence of treatment initiation decreased over time as patients remained treatment-free after diagnosis (Figure 1A [blue curve]). Patients that met MER treatment criteria had increased rates of therapy initiation (33.2% vs. 21.9%) in the next two years and untreated transformation to large cell lymphoma [red curve] (8.7% vs. 4.5%) during the next 5 years (Figure 1B). Despite this, the rate of lymphoma related death at 10 years was similar between groups (met treatment criteria = 6.2% vs. 7.1%) (Figure 1C, [green curve]). Discussion: The longer duration of W/W strategy suggests a decreasing need for treatment over time. We provide time point estimates, which would be helpful for counseling patients. Of note, long-term continuous oncologic assessment and follow-up is necessary since approximately 66% of patients in this mature cohort initiated treatment by 8 years median follow up. MER treatment criteria at diagnosis identified patients with higher rates of transformation and therapy initiation in the first two years but did not identify those with worse lymphoma specific survival. Identification of biological differences in patients with early vs. late or no progression is a critical next step in understanding outcomes in W/W patients. Disclosures Ansell: Bristol Myers Squibb: Research Funding; Seattle Genetics: Research Funding; Takeda: Research Funding; AI Therapeutics: Research Funding; Regeneron: Research Funding; Affimed: Research Funding; ADC Therapeutics: Research Funding; Trillium: Research Funding. Cerhan:BMS/Celgene: Research Funding; NanoString: Research Funding. Wang:Incyte: Research Funding; Innocare: Research Funding; Novartis: Research Funding. Witzig:MorphSys: Consultancy; AbbVie: Consultancy; Incyte: Consultancy; Acerta: Research Funding; Karyopharm Therapeutics: Research Funding; Immune Design: Research Funding; Spectrum: Consultancy; Celgene: Consultancy, Research Funding. Maurer:Morphosys: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Nanostring: Research Funding; Kite: Membership on an entity's Board of Directors or advisory committees; Celgene / BMS: Research Funding. Nowakowski:NanoString: Research Funding; Kite: Consultancy; Seattle Genetics: Consultancy; Kymera: Consultancy; Celgene/BMS: Consultancy, Research Funding; MorphoSys: Consultancy, Research Funding; Curis: Consultancy; Ryvu: Consultancy, Membership on an entity's Board of Directors or advisory committees.
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Bayfield, K. J., C. Saunders, E. Alton, and J. C. Davies. "ePS04.3 Comparison of CF and non-CF LCI results using the Exhalyzer D and Innocor™ devices." Journal of Cystic Fibrosis 14 (June 2015): S48. http://dx.doi.org/10.1016/s1569-1993(15)30154-5.
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Audil, Hadiyah Y., Paul J. Hampel, Daniel L. Van Dyke, Sara J. Achenbach, Kari G. Rabe, Stephanie A. Smoley, Timothy G. Call, et al. "Impact of Deletion6q23 Identified By FISH in Patients with Chronic Lymphocytic Leukemia." Blood 136, Supplement 1 (November 5, 2020): 12–13. http://dx.doi.org/10.1182/blood-2020-139068.
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Background: Cytogenetic abnormalities detected by fluorescence in situ hybridization (FISH) are known to differentially impact prognosis in patients with chronic lymphocytic leukemia (CLL). Deletion6q23 (del6q23) has been reported in ~2-3% of CLL patients at diagnosis; however, its prognostic significance remains indeterminate. Methods: We identified previously untreated CLL patients from the Mayo Clinic CLL Database seen between 1/1995 - 2/2020 who had FISH performed. The clinical characteristics, concomitant cytogenetic abnormalities, time to first therapy (TTFT), and overall survival (OS) were compared between patients with del6q23 to those without this abnormality. TTFT was analyzed from FISH date until treatment or last known untreated date, accounting for competing risk of death. OS was analyzed using Kaplan-Meier methods from FISH date. In a matched (CLL-IPI risk score and sex) analysis, Cox regression analysis was used to determine the association between TTFT/OS and presence of del6q23. The Mayo Clinic IRB approved this study. Results: A total of 3101 CLL patients were identified; their median age at diagnosis was 64 years and 66% were male. Of these patients, 42 (1.3%) had evidence of del6q23 by FISH. Compared to patients without del6q23, patients with del6q23 carried a more adverse clinical and cytogenetic profile at the time of diagnosis including advanced Rai stage (22% Rai III/IV vs. 9% Rai III/IV; P = 0.002), unmutated IGHV genes (91% vs. 43%; P < 0.001), and high/very high risk CLL-IPI (50% vs. 27%; P < 0.001). Del6q23 was the sole abnormality in 13 patients (31%). Of the remaining patients, del6q23 was concomitantly present with del13q in 8 patients (19%), and with either del11q or del17p in 21 patients (50%). Of the 42 patients with del6q23, 29 received first line therapy: chemoimmunotherapy in 16 patients, BTK inhibitor in 7 patients, and an anti-CD20 monoclonal antibody alone in 6 patients. The median follow-up of the entire cohort was 7.3 years. The median TTFT in patients with del6q23 was 0.7 years while the 5-year OS was 76%. Patients with del6q23 demonstrated significantly shorter TTFT and reduced OS when compared to patients without del6q23 (Figures 1A and 1B). The shorter TTFT was also evident for patients with del6q23 compared to patients without del6q23 divided according to the Dohner risk category (Figure 2A), although there was no difference in OS between these groups of patients (Figure 2B). Because del6q23 patients were enriched for other unfavorable prognostic markers, we identified four control patients without del6q23, matched by CLL-IPI risk score and sex, to each treatment-naïve patient with del6q23. Patients with del6q23 showed a borderline statistically significant shorter TTFT (median 0.7 years versus 3.9 years; P = 0.07) and a nonsignificant association with OS (median 10.9 years versus 10.3 years; P = 0.28). Conclusion: Del6q23 by FISH in previously untreated CLL represents an uncommon abnormality. When compared to patients without del6q23, patients with del6q23 tend to have more adverse clinical and cytogenetic profiles at baseline, which likely confer a worse prognosis as reflected by shorter TTFT compared to patients without this abnormality. Figure Disclosures Ding: Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; DTRM: Research Funding; Beigene: Membership on an entity's Board of Directors or advisory committees; alexion: Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Membership on an entity's Board of Directors or advisory committees; Octapharma: Membership on an entity's Board of Directors or advisory committees; Abbvie: Research Funding; Astra Zeneca: Research Funding. Wang:Novartis: Research Funding; Innocare: Research Funding; Incyte: Research Funding. Braggio:DASA: Consultancy; Bayer: Other: Stock Owner; Acerta Pharma: Research Funding. Kay:Sunesis: Research Funding; Abbvie: Research Funding; Tolero Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Meyer Squib: Membership on an entity's Board of Directors or advisory committees, Research Funding; Juno Theraputics: Membership on an entity's Board of Directors or advisory committees; Dava Oncology: Membership on an entity's Board of Directors or advisory committees; Oncotracker: Membership on an entity's Board of Directors or advisory committees; Rigel: Membership on an entity's Board of Directors or advisory committees; Morpho-sys: Membership on an entity's Board of Directors or advisory committees; Cytomx: Membership on an entity's Board of Directors or advisory committees; Agios Pharma: Membership on an entity's Board of Directors or advisory committees; Acerta Pharma: Research Funding; MEI Pharma: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees. Kenderian:Juno: Research Funding; Gilead: Research Funding; Lentigen: Research Funding; MorphoSys: Research Funding; Sunesis: Research Funding; Kite: Research Funding; Novartis: Patents & Royalties, Research Funding; Torque: Consultancy; Humanigen: Consultancy, Patents & Royalties, Research Funding; Mettaforge: Patents & Royalties; Tolero: Research Funding; BMS: Research Funding. Parikh:Ascentage Pharma: Research Funding; Merck: Research Funding; AbbVie: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; TG Therapeutics: Research Funding; Pharmacyclics: Honoraria, Research Funding; GlaxoSmithKline: Honoraria; Janssen: Honoraria, Research Funding; MorphoSys: Research Funding; Genentech: Honoraria; Verastem Oncology: Honoraria.
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Jiang, Vivian Changying, Yang Liu, Joseph McIntosh, Alexa A. Jordan, Angela Leeming, Zhihong Chen, Katti A. Jessen, Brian J. Lannutti, and Michael Wang. "Targeting ROR1 Using the Antibody Drug Conjugate Vls-101 in Aggressive Mantle Cell Lymphoma." Blood 136, Supplement 1 (November 5, 2020): 33. http://dx.doi.org/10.1182/blood-2020-137660.
Full textAbstract:
ROR1 is a transmembrane receptor with tightly controlled expression during embryonic development. While it is expressed on multiple tumor types it is not expressed in normal adult tissues. ROR1-positive B cell non-Hodgkin's lymphomas (B-NHL) include mantle cell lymphoma (MCL), and diffuse large B cell lymphoma. Given its unique expression pattern, ROR1 represents a tumor-specific therapeutic target with little or no normal tissue toxicity. VLS-101, utilizes the UC-961 anti-ROR1 antibody which is conjugated to monomethyl auristatin E (MMAE) via a cleavable linker. VLS-101/ROR1 complex induce internalization facilitates the release of a cytotoxic agent resulting in killing of ROR1-expressing cancer cells. With the rise of novel targeted therapies, resistance has been a major challenge among MCL patients. MCL is one of the most therapeutically resistant and aggressive forms of NHL-B, making it a challenging cancer to treat. The advancement of ibrutinib, a Bruton's tyrosine kinase (BTK) inhibitor, has been a beneficial change; however, ibrutinib-resistant MCL remains an urgent unmet clinical need. Furthermore, MCLs are either intrinsically resistant to ibrutinib, as well as to venetoclax (Bcl-2 inhibitor) and CAR T-cell therapy, or they may acquire resistance after a short response to these therapies. While many studies have looked into overcoming each of these different types of resistance, no studies have been conducted to overcome a multiple-resistance phenotype simultaneously. Therefore, identifying effective therapies that target these resistance mechanisms is crucial. In this study, we assessed the efficacy of VLS-101 in preclinical models of MCL with intrinsic or aquired resistance to ibrutinib, venetoclax, and CD19 CAR T therapies. By using MCL cell lines, primary patient samples and our established MCL patient-derived xenografts, we explored the expression of ROR1 in MCL and investigated the effects of in vitro and in vivo effects ROR1 targeting using VLS-101. To assess total and cell surface ROR1 expression we used flow cytometry (FACS), western blot analysis, and reverse-transcriptase-polymerase chain reaction (RT-PCR). Cell viability and apoptosis assays were performed to evaluate the in vitro efficacy of VLS-101 in MCL cell lines and primary patient MCL samples. To assess the apoptosis and cell cycle arrest in cells treated with VLS-101, we used annexin V/propidium iodide-staining followed by flow cytometry analyses. In vivo efficacy was tested using various PDX models with various multiple resistances. All 5 cell lines and all 9 PDX models of MCL tested showed high ROR1 mRNA and protein expression levels, whereas 3 out of 4 primary human samples expressed cell surface ROR1. VLS-101 treatment showed anti-MCL activity at the concentrations of 0.3-9 μg/ml in most of cell models tested, which correlated with a significant G2/M cell cycle arrest. Furthermore, VLS-101 induced a time- and dose-dependent apoptosis, as shown by increases in annexin V/propidium iodide-staining. VLS-101 treatment of ibrutinib-venetoclax dual-resistant ROR1+ PDX model resulted in significant regressions of the tumor bearing spleens and livers when compared to vehicle controls (p=0.0001 and p=0.002 respectively). In the ibrutinib-CD19 CAR T dual-resistant ROR1+ model, vehicle-treated animals showed s.c. tumor masses with a mean volume of 1440 mm3, whereas tumor masses were barely palpable (mean = 160 mm3) or had completely regressed in animals treated with VLS-101 at 1.0 mg/kg or 2.0 mg/kg, respectively. VLS-101 showed no adverse effects as monitored by animal clinical observations and weekly body weight measurements. Collectively, these results indicate that ROR1 expression on MCL cells can be utilized for selective targeting. These preclinical data document that the MMAE-containing ADC, VLS-101, can cause cell cycle arrest and induce apoptosis in vitro and safely induce tumor regressions in highly resistant in vivo PDX models of MCL derived from patient tumors. Importantly, our study revealed that even the heavyly pretreated tumors in the clinical setting may express targetable levels of ROR1 and that targeting ROR1 using ADC is a promising approach for the treatment of MCL. Building on these types of results, a Phase 1 clinical trial on VLS-101 (NCT03833180) is ongoing in patients with lymphoid cancers. Disclosures Jessen: VelosBio: Current Employment, Current equity holder in private company; eFFECTOR: Current equity holder in private company. Lannutti:VelosBio: Current Employment, Current equity holder in private company; Gilead Sciences: Current equity holder in publicly-traded company. Wang:Dava Oncology: Honoraria; AstraZeneca: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; MoreHealth: Consultancy; BioInvent: Research Funding; VelosBio: Research Funding; Acerta Pharma: Research Funding; Lu Daopei Medical Group: Honoraria; Molecular Templates: Research Funding; Oncternal: Consultancy, Research Funding; OMI: Honoraria, Other: Travel, accommodation, expenses; Janssen: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Celgene: Consultancy, Other: Travel, accommodation, expenses, Research Funding; InnoCare: Consultancy; Pulse Biosciences: Consultancy; Juno: Consultancy, Research Funding; Beijing Medical Award Foundation: Honoraria; Nobel Insights: Consultancy; Verastem: Research Funding; Kite Pharma: Consultancy, Other: Travel, accommodation, expenses, Research Funding; OncLive: Honoraria; Guidepoint Global: Consultancy; Loxo Oncology: Consultancy, Research Funding; Targeted Oncology: Honoraria.
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Bayfield, K., M. McGovern, A. Simpson, M. Embley, S. Cunningham, J. Davies, E. Alton, and J. Innes. "P207 Reliability Of Measurements Using Innocor Breath By Breath Analyser During A Maximal Exercise Test In Cystic Fibrosis Patients." Thorax 69, Suppl 2 (November 10, 2014): A167—A168. http://dx.doi.org/10.1136/thoraxjnl-2014-206260.336.
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Foo, Lin, Jerome Cornette, Jasmine Tay, and Christoph Lees. "B2. Measurement of cardiac output in a healthy pregnancy cohort: comparison of vicorder and inert gas re-breathing technique (Innocor)." Journal of Maternal-Fetal & Neonatal Medicine 29, sup2 (August 12, 2016): 7. http://dx.doi.org/10.1080/14767058.2016.1234767.
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Jain, Preetesh, Rashmi Kanagal-Shamanna, Lucy Navsaria, Chi Young Ok, Holly Hill, Dayoung Jung, Graciela M. Nogueras González, et al. "Comprehensive Analysis of Factors Predictive for Time to Transformation and Risk of Transformation in Patients (pts) with Mantle Cell Lymphoma." Blood 136, Supplement 1 (November 5, 2020): 41–42. http://dx.doi.org/10.1182/blood-2020-136978.
Full textAbstract:
Introduction: Mantle cell lymphoma commonly presents as classic variant histology, however 10-30% patients (pts) can transform into an aggressive histology (blastoid and/or pleomorphic variants). We have previously reported that genomic profile and clinical outcomes of transformed MCL pts are distinct from classic variant pts who never transformed (CNT) and that transformed pts have poor clinical outcomes. In this study, we analyzed the factors at initial diagnosis which can predict the time to transformation and the risk for transformation in a cohort of 369 pts with MCL. Methods: We analyzed charts from 369 pts with MCL (293 were CNT and 76 were transformed MCL). Statistical analysis was performed from baseline pt characteristics collected from the time of initial diagnosis in CNT group and at the time of initial diagnosis of classic variant MCL who later transformed (t-MCL). Time to transformation (TTT) was calculated from initial diagnosis to the date of transformation in those who transformed and last follow up in those who never transformed. Univariate and multivariate (MVA) logistic regression modeled the risk of transformation. Classification and regression tree (CART) analysis was performed to identify optimal cut off in categorical variables predictive of TTT. Results: Among the 369 pts, the median age was 62 yrs (range 34-90). Ki-67% values were available in 133 pts (36% of total) and median Ki-67% was 25% (range 1-80). Three hundred eight pts (84%) had initial bone marrow involvement and 66 pts (18%) had leukemic phase at diagnosis. The median follow up was 133 months and the median overall survival (OS) was 95 months and 43% were alive at the time of this analysis. Discernible difference were noted in pts who belong to t-MCL group compared to pts in the CNT group, pts in t-MCL group exhibited - higher values of median Ki-67% (30% vs 20% in CNT; p=0.04), higher LDH levels, higher proportions of pts with high risk simplified MIPI risk score, leukemic phase at initial diagnosis, complex karyotype and lower hemoglobin. First line treatments received by both groups were similar. Eleven pts got anti-CD19 CART therapy at some point and 7 pts were t-MCL and 4 were CNT group. The median time to transformation in months for those who transformed was 39 (range 5-240 months) while in CNT it was 51 months (1-257 months). We further identified that incremental Ki-67% was significantly associated with TTT and OS (Figure-1A-B). Using CART analysis we identified Ki-67% ≥60 is significantly associated with shorter TTT (HR, 6.26; 95% CI 2.58-15.21; p <0.001-1C). Shorter TTT was associated with elevated LDH, high risk MIPI score, CNS involvement at baseline, higher WBC counts, leukemic phase MCL, complex cytogenetics and R-chemotherapy as first line treatment. Longer TTT was associated with higher hemoglobin, CR after initial treatment (Figure-1D) and increased number of lines of treatment before transformation. In MVA, CNS involvement at baseline, bone marrow involvement, first line R-chemotherapy, high LDH (>729 IU/L), higher platelet count > 180 and high absolute lymphocyte count > 5000 k/ul were predictive of shorter TTT. Logistic regression model showed factors associated with the risk of transformation. In univariate analysis, higher risk was significantly associated with Ki-67% as a continuous variable - OR 1.03 (95% CI 1.01-1.05; p=0.006), leukemic phase at diagnosis, high risk MIPI score and complex cytogenetics. First line treatment with ibrutinib compared to R-HCVAD, was associated with decreased risk of transformation. In MVA, ibrutinib/BTK inhibitor therapy (n=51) as first line therapy was associated with decreased risk of transformation while CNS involvement was associated with higher risk of transformation. Conclusions: Routinely available clinical variables can help determine the risk for transformation of MCL and time to transformation. Progressive increase in Ki-67 and high MIPI risk score is associated with shorter TTT and increases the risk for transformation. Earlier usage of BTK inhibitor therapy may reduce the risk of developing histologic transformation in MCL pts. Disclosures Lee: Seattle Genetics: Research Funding; Takeda: Research Funding; Aptitude Health: Speakers Bureau; Oncternal Therapeutics: Research Funding; Guidepoint Blogal: Consultancy; Celgene: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding. Vega:NCI: Research Funding. Flowers:Celgene: Consultancy, Research Funding; Karyopharm: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Acerta: Research Funding; Spectrum: Consultancy; Pharmacyclics/Janssen: Consultancy; Leukemia and Lymphoma Society: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Research Funding; OptumRx: Consultancy; TG Therapeutics: Research Funding; BeiGene: Consultancy; Denovo Biopharma: Consultancy; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Cancer Prevention and Research Institute of Texas: Research Funding; Burroughs Wellcome Fund: Research Funding; Eastern Cooperative Oncology Group: Research Funding; National Cancer Institute: Research Funding; V Foundation: Research Funding; Kite: Research Funding; Bayer: Consultancy. Wang:Kite Pharma: Consultancy, Other: Travel, accommodation, expenses, Research Funding; AstraZeneca: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Beijing Medical Award Foundation: Honoraria; Dava Oncology: Honoraria; Molecular Templates: Research Funding; Verastem: Research Funding; InnoCare: Consultancy; Nobel Insights: Consultancy; OncLive: Honoraria; Loxo Oncology: Consultancy, Research Funding; MoreHealth: Consultancy; Oncternal: Consultancy, Research Funding; Targeted Oncology: Honoraria; Acerta Pharma: Research Funding; Guidepoint Global: Consultancy; Pharmacyclics: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Pulse Biosciences: Consultancy; Lu Daopei Medical Group: Honoraria; Juno: Consultancy, Research Funding; VelosBio: Research Funding; BioInvent: Research Funding; OMI: Honoraria, Other: Travel, accommodation, expenses; Celgene: Consultancy, Other: Travel, accommodation, expenses, Research Funding.
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Christopoulos, Georgios, Zachi I. Attia, Peter A. Noseworthy, Timothy G. Call, Wei Ding, Jose F. Leis, Eli Muchtar, et al. "Use of Artificial Intelligence Electrocardiography to Predict Atrial Fibrillation (AF) in Patients with Chronic Lymphocytic Leukemia (CLL)." Blood 136, Supplement 1 (November 5, 2020): 50–51. http://dx.doi.org/10.1182/blood-2020-142645.
Full textAbstract:
Background: Clinical factors including previous history of AF, heart failure, hypertension, valvular heart disease, increased age and male gender increase the risk of AF in CLL patients (Shanafelt, Leukemia and Lymphoma 2017). Treatment with Bruton tyrosine kinase inhibitors (BTKi) such as ibrutinib has also been associated with an increased risk of AF in CLL. We evaluated the role of artificial intelligence electrocardiography (AI-ECG) in predicting ibrutinib-induced AF (and, for reference, AF unrelated to ibrutinib) in patients with CLL. Methods: We identified two cohorts of CLL patients using the Mayo Clinic CLL Database. Cohort 1 included patients evaluated within 12 months of CLL diagnosis who did not ever receive ibrutinib. Cohort 2 included patients who were treated with ibrutinib. The electrocardiographic signature of AF in sinus rhythm was detected by an AI-ECG algorithm previously developed using a convolutional neural network (Attia, Lancet 2019). The baseline AI-ECG AF score (positive defined as >0.10 on a scale of 0-1 which offers best balance between sensitivity and specificity per Attia et al.) was computed based on ECGs obtained within 10 years prior to CLL diagnosis (Cohort 1) or 10 years prior to initiation of ibrutinib therapy (Cohort 2). Patients with AF at baseline, missing data, or with ECGs previously used to train the AI algorithm were excluded. Reverse Kaplan Meier diagrams were plotted for both cohorts grouped by AI-ECG positivity. Cox proportional hazards were fitted to assess the predictive ability of AI-ECG in both cohorts. Results: After screening 2,739 patients and applying exclusion criteria (126 patients had baseline AF) a total of 1,149 patients with median 4 (interquartile range [IQR] 2-9) baseline ECGs were included in the analysis (Figure 1A). Cohort 1 included 951 patients with a median follow up of 3.0 (IQR 0.6-7.0) years and positive baseline AI-ECG in 546 (57%) patients. Cohort 2 included 198 patients with a median follow up of 1.6 (IQR 0.7-3.2) years and positive baseline AI-ECG in 91 (46%) patients. In Cohort 1, the median age was 67 years (IQR 58-72), 681 (72%) of patients were men, 68% had low/intermediate risk CLL-International Prognostic Index (IPI), and 32% had high/very high-risk CLL-IPI. In Cohort 2, the median age was 69 years (IQR 62-75), 139 (70%) of patients were men, 13% had low/intermediate risk CLL-IPI, and 87% had high/very high-risk CLL-IPI. AF occurred during follow up in 164 patients (17%) in Cohort 1 and 46 patients (23%) in Cohort 2. In both Cohorts 1 and 2, a positive baseline AI-ECG significantly increased the incidence of AF during follow up (log rank <0.001) (Figure 1B and C). Hazard ratios (for positive vs. negative AI-ECG) were 33.9 (95% confidence interval [CI] 15.0-76.6) for Cohort 1 and 14.8 (95% CI 5.3-41.3) for Cohort 2. Conclusion: The addition of AI to a standard 12-lead ECG obtained during normal sinus rhythm - an inexpensive and ubiquitous test - predicts the occurrence of future AF in patients with CLL. This holds true irrespective of BTKi -based therapy and has important implications for the management of CLL patients. Disclosures Ding: Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; DTRM: Research Funding; Astra Zeneca: Research Funding; Abbvie: Research Funding; Octapharma: Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Membership on an entity's Board of Directors or advisory committees; alexion: Membership on an entity's Board of Directors or advisory committees; Beigene: Membership on an entity's Board of Directors or advisory committees. Kenderian:BMS: Research Funding; Gilead: Research Funding; Novartis: Patents & Royalties, Research Funding; Mettaforge: Patents & Royalties; Juno: Research Funding; MorphoSys: Research Funding; Lentigen: Research Funding; Sunesis: Research Funding; Tolero: Research Funding; Kite: Research Funding; Humanigen: Consultancy, Patents & Royalties, Research Funding; Torque: Consultancy. Wang:Novartis: Research Funding; Innocare: Research Funding; Incyte: Research Funding. Kay:Juno Theraputics: Membership on an entity's Board of Directors or advisory committees; Oncotracker: Membership on an entity's Board of Directors or advisory committees; Dava Oncology: Membership on an entity's Board of Directors or advisory committees; Rigel: Membership on an entity's Board of Directors or advisory committees; Morpho-sys: Membership on an entity's Board of Directors or advisory committees; Cytomx: Membership on an entity's Board of Directors or advisory committees; Agios Pharma: Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees; Sunesis: Research Funding; Abbvie: Research Funding; MEI Pharma: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta Pharma: Research Funding; Bristol Meyer Squib: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tolero Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kapoor:Cellectar: Consultancy; Janssen: Research Funding; Sanofi: Consultancy, Research Funding; Amgen: Research Funding; Takeda: Honoraria, Research Funding; Celgene: Honoraria; GlaxoSmithKline: Research Funding. Parikh:MorphoSys: Research Funding; Janssen: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Merck: Research Funding; AbbVie: Honoraria, Research Funding; Ascentage Pharma: Research Funding; Genentech: Honoraria; Verastem Oncology: Honoraria; GlaxoSmithKline: Honoraria; TG Therapeutics: Research Funding; Pharmacyclics: Honoraria, Research Funding.
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Coleman, Morton, David Jacob Andorsky, Abdulraheem Yacoub, Jason M. Melear, Suzanne R. Fanning, Kathryn S. Kolibaba, Frederick Lansigan, et al. "Patients with Relapsed/Refractory Marginal Zone Lymphoma in the MAGNIFY Phase IIIb Interim Analysis of Induction R2 Followed By Maintenance." Blood 136, Supplement 1 (November 5, 2020): 24–25. http://dx.doi.org/10.1182/blood-2020-134363.
Full textAbstract:
Background: Relapse is expected when treating patients with follicular lymphoma (FL) and marginal zone lymphoma (MZL), with a shortened response associated with each relapse. Lenalidomide combined with rituximab (R2) has shown enhanced activity, with a recently reported median progression free-survival (PFS) of 39.4 months in patients with relapsed/refractory (R/R) indolent non-Hodgkin lymphoma, including those with FL and MZL (AUGMENT; J Clin Oncol. 2019;37:1188). Methods: MAGNIFY is a multicenter, phase IIIb trial in patients with R/R FL grades 1-3b, transformed FL (tFL), MZL, or mantle cell lymphoma (MCL; NCT01996865) in which optimal lenalidomide duration is being explored. Patients received 12 cycles of R2 (lenalidomide 20 mg/d, d1-21/28 + rituximab 375 mg/m2 weekly in cycle 1 and then on day 1 of cycles 3, 5, 7, 9, and 11) followed by 1:1 randomization in patients with stable disease, partial response, or complete response/complete response unconfirmed (CR/CRu) to R2 versus rituximab maintenance for 18 months. Data presented here focus on induction R2 in efficacy-evaluable MZL patients compared with the overall population of FL grades 1-3a+MZL (not including FL grade 3b, tFL, or MCL) receiving ≥ 1 treatment with baseline/post-baseline assessments. The primary end point is progression-free survival (PFS) by 1999 International Working Group criteria. Results: As of November 30, 2019, 393 patients with FL grades 1-3a and MZL enrolled; 76 (19%) had MZL. The median age of MZL patients was 68 years (range, 46-90), 68 (89%) had stage III/IV disease, and 72 (95%) had prior rituximab-containing therapy. Overall response rate was 68% with 39% CR/CRu, and median duration of response was 38.6 months (95% CI, 29.4-not reached [NR]). The median PFS was 41.2 months (95% CI, 38.4-NR). Efficacy results for MZL subtypes and the overall population (FL grades 1-3a + MZL) are shown in the table. Forty-two patients (55%) have completed 12 cycles of R2, and 41 (54%) have been randomized and entered maintenance. Twenty-eight patients (37%) prematurely discontinued both lenalidomide and rituximab, primarily due to adverse events (AEs; n = 11; 14%) and progressive disease (n = 6; 8%). The most common (≥ 20%) all-grade AEs were neutropenia (49%), diarrhea (37%), anemia (25%), thrombocytopenia (24%), and constipation (24%). Most common (≥ 10%) grade 3/4 AEs were neutropenia (41%; 1 patient [1%] had febrile neutropenia), thrombocytopenia (13%), and leukopenia (11%). Conclusions: R2 is active with a tolerable safety profile in patients with R/R MZL. The efficacy and safety profile of R2 in MZL patients were similar to results observed in the overall MAGNIFY population. Disclosures Coleman: Seattle Genetics: Research Funding; EMD Serono Research and Development Institute Inc.: Research Funding; Innocare: Research Funding; ARCUS Biosciences: Research Funding; AstraZeneca Pharmaceuticals, LP (Acerta Pharma BV Trials): Research Funding; AstraZeneca Pharmaceuticals, LP: Research Funding; BMS (Celgene Corporation): Research Funding; Eli Lilly and Company: Research Funding; Genetech (F. Hoffman-LaRoche Ltd): Research Funding; Hutchinson MediPharma, LTD: Research Funding; Ipsen Group: Research Funding; Karyopharma Therapeutics, Inc.: Research Funding; Klus Pharma, Inc.: Research Funding; MeiPharma, Inc.: Research Funding; Merck Sharp & Dohme Corp.: Research Funding; Novartis Pharmaceuticals: Research Funding; Incyte Corporation: Research Funding; Boston BIoMedical, Inc.: Research Funding; BeiGene: Research Funding; Acerta: Research Funding. Andorsky:CTI: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Research Funding. Yacoub:Roche: Other: Support of parent study and funding of editorial support; Dynavax: Current equity holder in publicly-traded company; Ardelyx: Current equity holder in publicly-traded company; Incyte: Speakers Bureau; Hylapharm: Current equity holder in private company; Cara Therapeutics: Current equity holder in publicly-traded company; Agios: Honoraria, Speakers Bureau; Novartis: Speakers Bureau. Melear:Janssen: Speakers Bureau; AstraZeneca: Speakers Bureau. Fanning:Takeda: Consultancy, Speakers Bureau; Bristol Myers Squibb: Consultancy, Speakers Bureau; TG Therapeautics: Consultancy; Abbvie: Consultancy; Prisma Health: Current Employment; Sanofi Aventis: Speakers Bureau. Kolibaba:Atara Biotech: Consultancy; Compass Oncology: Ended employment in the past 24 months; Verastem: Honoraria; Seattle Genetics: Research Funding; Pharmacyclics: Research Funding; Novartix: Research Funding; Janssen: Research Funding; Gilead: Research Funding; Genentech: Research Funding; Celgene: Research Funding; Acerta: Research Funding; AbbVie: Research Funding; Sumitomo Dainippon Pharma Oncology: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Lansigan:BMS: Consultancy; Seattle Genetics: Consultancy; BMS Steering Committee for MAGNIFY Program: Membership on an entity's Board of Directors or advisory committees; Spectrum Pharma: Consultancy, Research Funding. Reynolds:IHA Hematology/Oncology Consultants: Current Employment. Nowakowski:Kymera: Consultancy; Ryvu: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other; Curis: Consultancy; Kite: Consultancy; MorphoSys: Consultancy, Research Funding; Denovo: Consultancy; Seattle Genetics: Consultancy; Nanostrings: Research Funding; Celgene/BMS: Consultancy, Research Funding; Roche: Consultancy, Research Funding. Gharibo:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company; Bayer: Ended employment in the past 24 months. Ahn:BMS: Current Employment, Current equity holder in publicly-traded company. Li:BMS: Current Employment, Current equity holder in publicly-traded company. Rummel:Roche: Honoraria; Amgen GmbH: Honoraria; Celgene: Consultancy, Honoraria; Janssen: Honoraria; Novartis Pharma GmbH: Honoraria. Sharman:BeiGene: Research Funding; Bristol Meyers Squibb: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Acerta: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Celgene: Consultancy, Research Funding.
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Al Hadidi, Samer, Ranjit Nair, Raphael E. Steiner, Sairah Ahmed, Paolo Strati, Simrit Parmar, Swami P. Iyer, et al. "Association of Epstein-Barr Virus with Advanced Stage and Survival Outcomes in Classic Hodgkin's Lymphoma." Blood 136, Supplement 1 (November 5, 2020): 37–38. http://dx.doi.org/10.1182/blood-2020-136338.
Full textAbstract:
Introduction Classic Hodgkin's lymphoma (cHL) is a highly curable lymphoid malignancy. Epstein-Barr virus (EBV) is associated with cHL, with a variable rate of detection in Hodgkin and Reed-Sternberg (HRS) cells among different histologic types and geographic areas.Although most adults worldwide are EBV seropositive, only a minority of patients infected with EBV will develop cHL. EBV is thought to be one of the causative agents for the development of cHL with an important pathobiology role. The goal of this study was to compare the presentation and the outcomes of patients with EBV+ HRS cells at the time of initial diagnosis of cHL. Methods This single-center study included patients with a diagnosis of cHL who were first seen at The University of Texas MD Anderson Cancer Center between January 1,2016 and May 28, 2020 for either newly diagnosed cHL or relapsed/refractory (R/R) cHL. Pathology was confirmed and analyzed for positivity of EBV (EBV +ve) in all patients by immunohistochemical (IHC) staining for by Epstein-Barr virus-encoded small RNA (EBER) with available paraffin blocks. The primary aims were to assess overall survival (OS), progression-free survival (PFS) and frequency of advanced disease. Descriptive statistics for categorical and continues variables were analyzed. Kaplan-Meier method was used for time-to-event analysis, including PFS and OS. Median time to event in months with 95% confidence interval (CI) was calculated. The Log-rank test was used to evaluate the difference in time-to-event endpoints between patient groups. Statistical software SAS 9.4 (SAS, Cary, NC) and S-Plus 8.2 (TIBCO Software Inc., Palo Alto, CA) were used for statistical analyses. Results Between 2016 and 2020, 644 patients met the inclusion criteria. Three hundred and fifty six patients (55%) had enough/available tissue to undergo testing for EBV at the time of initial diagnosis. The median age at diagnosis was 36 years with 51.4% males. Eighty-eight patients had positive EBV (25%) at diagnosis. The median age of +ve EBV was 37 years (Range: 18-83 years) compared to 33 years (Range: 18-85 years) for patients with -ve EBV. Mixed cellularity histology was more frequent in patients with +ve EBV when compared to the whole group of patients (32% vs. 7%; p-value: 0.03). Human immunodeficiency virus (HIV) was positive in a minority of the patients (8 patients out of 498 patients with available results) (1.6%) however 50% of the patients with HIV had +ve EBV at the time of diagnosis. Baseline demographics are summarized in Table 1. EBV was associated with the initial stage (stage II 38% in EBV +ve vs. 53% in EBV -ve, stage III 25% in EBV +ve vs. 14% in EBV -ve, stage IV 24% in EBV +ve vs. 31% in EBV -ve; p-value 0.0001). Most of the patients were treated with doxorubicin, bleomycin, vinblastine and decarbazine (ABVD) based therapy (77%). Other therapies included brentuximab vedotin (BV) (13%) and checkpoint inhibitors (CPIs) (6%). Median follow up was 1.97 years (range: 0.047- 44.09 years). PFS rate difference at 5 years was not statistically significant (64% in EBV +ve vs. 52% in EBV -ve; p-value 0.14). OS rate at 5 years was significantly lower in patients with +ve EBV (89% vs. 98%, p-value: 0.0014). OS rates at 10 years were similar (89% in EBV +ve vs. 88% in EBV -ve). Conclusions EBV at the time of diagnosis was associated with lower prevalence of localized cHL and inferior survival rates at 5 years of follow up (9% lower OS rate at 5 years). Implementation of different frontline therapy treatment algorithms specific to EBV +ve patients may help in improving the survival outcomes. Further research is needed to understand the biological significance of +ve EBV in cHL to help in developing novel agents targeting EBV positive cHL population with the ultimate goal of improving outcome. Disclosures Parmar: Cellenkos Inc.: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding. Iyer:Rhizen: Research Funding; CRISPR: Research Funding; Seattle Genetics, Inc.: Research Funding; Merck: Research Funding; Legend Biotech: Consultancy; Daiichi Sankyo: Consultancy; Trillium: Research Funding; Curio Biosciences: Honoraria; Target Oncology: Honoraria; Afffimed: Research Funding; Spectrum: Research Funding. Nieto:Novartis: Other: Grant Support; Astra Zeneca: Other: Grant Support; Affimed: Consultancy, Other: Grant Support; Secura Bio: Other: Grant Support. Chuang:Sage-Evidence=Based Medicine & Practice: Consultancy. Wang:Beijing Medical Award Foundation: Honoraria; Loxo Oncology: Consultancy, Research Funding; Pulse Biosciences: Consultancy; Nobel Insights: Consultancy; Verastem: Research Funding; Dava Oncology: Honoraria; AstraZeneca: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Molecular Templates: Research Funding; Celgene: Consultancy, Other: Travel, accommodation, expenses, Research Funding; OMI: Honoraria, Other: Travel, accommodation, expenses; Targeted Oncology: Honoraria; Lu Daopei Medical Group: Honoraria; Pharmacyclics: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; MoreHealth: Consultancy; Kite Pharma: Consultancy, Other: Travel, accommodation, expenses, Research Funding; BioInvent: Research Funding; VelosBio: Research Funding; Acerta Pharma: Research Funding; InnoCare: Consultancy; Oncternal: Consultancy, Research Funding; Juno: Consultancy, Research Funding; OncLive: Honoraria; Guidepoint Global: Consultancy. Lee:Celgene: Research Funding; Takeda: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Aptitude Health: Speakers Bureau; Seattle Genetics: Research Funding; Oncternal Therapeutics: Research Funding; Guidepoint Blogal: Consultancy.
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Kuhn, Miriam, Andreas Hornung, Heidi Ulmer, Christian Schlensak, Michael Hofbeck, and Gesa Wiegand. "Comparative Noninvasive Measurement of Cardiac Output Based on the Inert Gas Rebreathing Method (Innocor®) and MRI in Patients with Univentricular Hearts." Pediatric Cardiology 39, no. 4 (February 3, 2018): 810–17. http://dx.doi.org/10.1007/s00246-018-1824-9.
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Lansigan, Frederick, David Jacob Andorsky, Morton Coleman, Abdulraheem Yacoub, Jason M. Melear, Suzanne R. Fanning, Kathryn S. Kolibaba, et al. "Subgroup Analyses of Elderly Patients Aged ≥ 70 Years in MAGNIFY: A Phase IIIb Interim Analysis of Induction R2 Followed By Maintenance in Relapsed/Refractory Indolent Non-Hodgkin Lymphoma." Blood 136, Supplement 1 (November 5, 2020): 30–31. http://dx.doi.org/10.1182/blood-2020-134193.
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Background: Lenalidomide combined with rituximab (R2) has shown complimentary clinical activity and is a tolerable regimen in both untreated and relapsed or refractory (R/R) patients with indolent non-Hodgkin lymphoma. Patients with advanced age at diagnosis are considered to be high risk, supporting post-hoc subgroup analyses by age, with a focus on patients aged ≥ 70 years from the MAGNIFY study. Methods: MAGNIFY is a multicenter, phase IIIb trial in patients with R/R follicular lymphoma (FL) grades 1-3b, transformed FL (tFL), marginal zone lymphoma (MZL), or mantle cell lymphoma (MCL; NCT01996865) exploring optimal lenalidomide duration. Lenalidomide 20 mg on days 1-21 of a 28-day cycle + rituximab 375 mg/m2/week cycle 1 and then every 8 weeks starting with cycle 3 (R2) are administered for 12 cycles followed by 1:1 randomization in patients with stable disease, partial response, or complete response/complete response unconfirmed (CR/CRu) to R2 vs rituximab maintenance for 18 months. Data presented here focus on induction R2 in efficacy-evaluable FL grade 1-3a and MZL patients (FL grade 3b, tFL, and MCL not included) receiving ≥ 1 treatment with baseline/postbaseline assessments. The primary end point is progression-free survival (PFS) by 1999 International Working Group criteria. Post-hoc analyses were performed by analyzing data from patients aged ≥ 70 years at time of study entry. Results: As of November 30, 2019, 393 patients have enrolled and 152 (39%) were aged ≥ 70 years. Baseline characteristics including histology, disease status, and prior treatments of patients ≥ 70 and the overall population are shown in the table. Median PFS in the ≥ 70 subgroup was 36.0 months (95% CI, 28.3-NR). Overall response rate and CR/CRu were 75% and 38%, with a median duration of response that was not reached (95% CI, 27.1-NR). Efficacy results for the overall population are shown in the table. In patients ≥ 70 the most common (≥ 20%) any-grade treatment emergent adverse events (TEAEs) were fatigue (44%), neutropenia (41%), diarrhea (34%), constipation (34%), and nausea (27%). Neutropenia (35%) was the only grade 3/4 TEAE occurring in > 10% of patients (febrile neutropenia occurred in 3 patients [2%]). TEAEs led to lenalidomide dose reduction in 69 patients (46%) and discontinuation in 40 patients (26%). Seventy-eight patients ≥ 70 (51%) completed all 12 cycles of induction treatment, and 72 (47%) have entered the maintenance phase. Sixty-one patients ≥ 70 (40%), compared to 35% of patients in overall population, prematurely discontinued both lenalidomide and rituximab, due to TEAEs (n = 26; 17%), progressive disease (n = 15; 10%), patient withdrawal (n = 12; 8%), death (n = 5; 3%), and other reasons (n = 3; 2%). Neutropenia was the only TEAE leading to discontinuation of lenalidomide in more than 2 patients (n = 10; 7%). Conclusions: Similar to findings in the overall population, R2 treatment in advanced-age patients with R/R FL and MZL resulted in encouraging efficacy, and with close attention to dose reduction there is a tolerable safety profile. Table Disclosures Lansigan: BMS Steering Committee for MAGNIFY Program: Membership on an entity's Board of Directors or advisory committees; Spectrum Pharma: Consultancy, Research Funding; BMS: Consultancy; Seattle Genetics: Consultancy. Andorsky:AstraZeneca: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; CTI: Research Funding. Coleman:Novartis Pharmaceuticals: Research Funding; Merck Sharp & Dohme Corp.: Research Funding; Boston BIoMedical, Inc.: Research Funding; BeiGene: Research Funding; Acerta: Research Funding; Innocare: Research Funding; ARCUS Biosciences: Research Funding; AstraZeneca Pharmaceuticals, LP (Acerta Pharma BV Trials): Research Funding; AstraZeneca Pharmaceuticals, LP: Research Funding; BMS (Celgene Corporation): Research Funding; Eli Lilly and Company: Research Funding; EMD Serono Research and Development Institute Inc.: Research Funding; Genetech (F. Hoffman-LaRoche Ltd): Research Funding; Hutchinson MediPharma, LTD: Research Funding; Incyte Corporation: Research Funding; Ipsen Group: Research Funding; Karyopharma Therapeutics, Inc.: Research Funding; Klus Pharma, Inc.: Research Funding; MeiPharma, Inc.: Research Funding; Seattle Genetics: Research Funding. Yacoub:Novartis: Honoraria, Speakers Bureau; Agios: Speakers Bureau; Incyte: Speakers Bureau; Hylapharm: Current equity holder in private company; Cara therapeutics: Current equity holder in publicly-traded company; Ardelyx: Current equity holder in publicly-traded company; Dynavax: Current equity holder in publicly-traded company. Melear:AstraZeneca: Speakers Bureau; Janssen: Speakers Bureau. Fanning:Prisma Health: Current Employment; Abbvie: Consultancy; TG Therapeautics: Consultancy; Bristol Myers Squibb: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Sanofi Aventis: Speakers Bureau. Kolibaba:Compass Oncology: Ended employment in the past 24 months; Atara Biotech: Consultancy; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sumitomo Dainippon Pharma Oncology: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company; AbbVie: Research Funding; Acerta: Research Funding; Celgene: Research Funding; Genentech: Research Funding; Gilead: Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Research Funding; Verastem: Honoraria; Janssen: Research Funding; Novartix: Research Funding. Reynolds:IHA Hematology/Oncology Consultants: Current Employment. Nowakowski:Ryvu: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other; Nanostrings: Research Funding; Seattle Genetics: Consultancy; Curis: Consultancy; MorphoSys: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Kymera: Consultancy; Denovo: Consultancy; Kite: Consultancy; Celgene/BMS: Consultancy, Research Funding. Gharibo:Bayer: Ended employment in the past 24 months; Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Ahn:BMS: Current Employment, Current equity holder in publicly-traded company. Li:BMS: Current Employment, Current equity holder in publicly-traded company. Rummel:Celgene: Consultancy, Honoraria; Janssen: Honoraria; Amgen GmbH: Honoraria; Roche: Honoraria; Novartis Pharma GmbH: Honoraria. Sharman:Bristol Meyers Squibb: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Acerta: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; BeiGene: Research Funding; Genentech: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding.
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Wang, Hanyin, Shulan Tian, Qing Zhao, Wendy Blumenschein, Jennifer H. Yearley, Charla R. Secreto, Sutapa Sinha, et al. "Distinct Gene Expression Signatures in Patients with Richter's Syndrome and Chronic Lymphocytic Leukemia with Prior Exposure to Ibrutinib." Blood 136, Supplement 1 (November 5, 2020): 30–31. http://dx.doi.org/10.1182/blood-2020-136172.
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Introduction: Richter's syndrome (RS) represents transformation of chronic lymphocytic leukemia (CLL) into a highly aggressive lymphoma with dismal prognosis. Transcriptomic alterations have been described in CLL but most studies focused on peripheral blood samples with minimal data on RS-involved tissue. Moreover, transcriptomic features of RS have not been well defined in the era of CLL novel therapies. In this study we investigated transcriptomic profiles of CLL/RS-involved nodal tissue using samples from a clinical trial cohort of refractory CLL and RS patients treated with Pembrolizumab (NCT02332980). Methods: Nodal samples from 9 RS and 4 CLL patients in MC1485 trial cohort were reviewed and classified as previously published (Ding et al, Blood 2017). All samples were collected prior to Pembrolizumab treatment. Targeted gene expression profiling of 789 immune-related genes were performed on FFPE nodal samples using Nanostring nCounter® Analysis System (NanoString Technologies, Seattle, WA). Differential expression analysis was performed using NanoStringDiff. Genes with 2 fold-change in expression with a false-discovery rate less than 5% were considered differentially expressed. Results: The details for the therapy history of this cohort were illustrated in Figure 1a. All patients exposed to prior ibrutinib before the tissue biopsy had developed clinical progression while receiving ibrutinib. Unsupervised hierarchical clustering using the 300 most variable genes in expression revealed two clusters: C1 and C2 (Figure 1b). C1 included 4 RS and 3 CLL treated with prior chemotherapy without prior ibrutinib, and 1 RS treated with prior ibrutinib. C2 included 1 CLL and 3 RS received prior ibrutinib, and 1 RS treated with chemotherapy. The segregation of gene expression profiles in samples was largely driven by recent exposure to ibrutinib. In C1 cluster (majority had no prior ibrutinb), RS and CLL samples were clearly separated into two subgroups (Figure 1b). In C2 cluster, CLL 8 treated with ibrutinib showed more similarity in gene expression to RS, than to other CLL samples treated with chemotherapy. In comparison of C2 to C1, we identified 71 differentially expressed genes, of which 34 genes were downregulated and 37 were upregulated in C2. Among the upregulated genes in C2 (majority had prior ibrutinib) are known immune modulating genes including LILRA6, FCGR3A, IL-10, CD163, CD14, IL-2RB (figure 1c). Downregulated genes in C2 are involved in B cell activation including CD40LG, CD22, CD79A, MS4A1 (CD20), and LTB, reflecting the expected biological effect of ibrutinib in reducing B cell activation. Among the 9 RS samples, we compared gene profiles between the two groups of RS with or without prior ibrutinib therapy. 38 downregulated genes and 10 upregulated genes were found in the 4 RS treated with ibrutinib in comparison with 5 RS treated with chemotherapy. The top upregulated genes in the ibrutinib-exposed group included PTHLH, S100A8, IGSF3, TERT, and PRKCB, while the downregulated genes in these samples included MS4A1, LTB and CD38 (figure 1d). In order to delineate the differences of RS vs CLL, we compared gene expression profiles between 5 RS samples and 3 CLL samples that were treated with only chemotherapy. RS samples showed significant upregulation of 129 genes and downregulation of 7 genes. Among the most significantly upregulated genes are multiple genes involved in monocyte and myeloid lineage regulation including TNFSF13, S100A9, FCN1, LGALS2, CD14, FCGR2A, SERPINA1, and LILRB3. Conclusion: Our study indicates that ibrutinib-resistant, RS-involved tissues are characterized by downregulation of genes in B cell activation, but with PRKCB and TERT upregulation. Furthermore, RS-involved nodal tissues display the increased expression of genes involved in myeloid/monocytic regulation in comparison with CLL-involved nodal tissues. These findings implicate that differential therapies for RS and CLL patients need to be adopted based on their prior therapy and gene expression signatures. Studies using large sample size will be needed to verify this hypothesis. Figure Disclosures Zhao: Merck: Current Employment. Blumenschein:Merck: Current Employment. Yearley:Merck: Current Employment. Wang:Novartis: Research Funding; Incyte: Research Funding; Innocare: Research Funding. Parikh:Verastem Oncology: Honoraria; GlaxoSmithKline: Honoraria; Pharmacyclics: Honoraria, Research Funding; MorphoSys: Research Funding; Ascentage Pharma: Research Funding; Genentech: Honoraria; AbbVie: Honoraria, Research Funding; Merck: Research Funding; TG Therapeutics: Research Funding; AstraZeneca: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Kenderian:Sunesis: Research Funding; MorphoSys: Research Funding; Humanigen: Consultancy, Patents & Royalties, Research Funding; Gilead: Research Funding; BMS: Research Funding; Tolero: Research Funding; Lentigen: Research Funding; Juno: Research Funding; Mettaforge: Patents & Royalties; Torque: Consultancy; Kite: Research Funding; Novartis: Patents & Royalties, Research Funding. Kay:Astra Zeneca: Membership on an entity's Board of Directors or advisory committees; Acerta Pharma: Research Funding; Juno Theraputics: Membership on an entity's Board of Directors or advisory committees; Dava Oncology: Membership on an entity's Board of Directors or advisory committees; Oncotracker: Membership on an entity's Board of Directors or advisory committees; Sunesis: Research Funding; MEI Pharma: Research Funding; Agios Pharma: Membership on an entity's Board of Directors or advisory committees; Bristol Meyer Squib: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tolero Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Rigel: Membership on an entity's Board of Directors or advisory committees; Morpho-sys: Membership on an entity's Board of Directors or advisory committees; Cytomx: Membership on an entity's Board of Directors or advisory committees. Braggio:DASA: Consultancy; Bayer: Other: Stock Owner; Acerta Pharma: Research Funding. Ding:DTRM: Research Funding; Astra Zeneca: Research Funding; Abbvie: Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Membership on an entity's Board of Directors or advisory committees; alexion: Membership on an entity's Board of Directors or advisory committees; Beigene: Membership on an entity's Board of Directors or advisory committees.
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Hamid, Noor Fazira, Eta Wahab, and Nor Hazana Abdullah. "Relationship between Technological Factors and Innovation-Adoption among Technology-Based SMEs in Malaysia." GATR Global Journal of Business Social Sciences Review 1, no. 2 (April 13, 2013): 72–82. http://dx.doi.org/10.35609/gjbssr.2013.1.2(8).
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Objective- The purpose of this paper is to identify the relationship between technological factors and innovation-adoption among technology-based SMEs in Malaysia. Methodology/Technique - The study uses questionnaires survey and regression analysis to test the hypothesis in a sample of 172 from two listings which are InnoCert company list and MTDC list of technology companies. Findings This analysis involved the factors that influence innovation adoption, which are the technological factors are categorized into relative advantage, compatibility, complexity, trial-ability, observability, ease of use, and perceived usefulness. The result shows that an innovation-adoption is significantly influenced by technological factors (relative advantage, complexity, ease of use, and perceived usefulness). Novelty - The current state of innovation-adoption among technology-based SMEs in Malaysia is not well understood and clear. Factors that influence innovation-adoption among these technology-based companies need to be explored further since they have distinct characteristics compared to general SMEs. The significant impact of innovation on nation economic growth has propelled many countries, including Malaysia to strengthen their innovation capabilities. Among these SMEs, majority of innovation activities in has been centered on technology-based SMEs. Type of Paper Empirical paper Keywords: , Innovation, Adoption, Innovation Adoption, Organizational Innovation.
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Muchtar, Eli, Amber Koehler, Michael J. Johnson, Kari G. Rabe, Wei Ding, Timothy G. Call, Jose F. Leis, et al. "Immunogenicity of a Recombinant Herpes Zoster Vaccine in Patients with Chronic Lymphocytic Leukemia." Blood 136, Supplement 1 (November 5, 2020): 49–50. http://dx.doi.org/10.1182/blood-2020-140338.
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Introduction: In 2017, a two-dose recombinant zoster vaccine (RZV) containing glycoprotein E (gE) and a novel adjuvant was approved to prevent herpes zoster and its complications in adults ≥50 years of age in the US. There are limited data on the immunogenicity and safety of RZV in patients with chronic lymphocytic leukemia (CLL). Methods: Between 8/15/2018 and 11/4/2019, RZV-naïve patients with CLL and monoclonal B-cell lymphocytosis (MBL) seen at Mayo Clinic, Rochester, MN were enrolled in this IRB-approved study. All participants received two doses of vaccine, at 0 and 2 months after enrollment. Cell-mediated immunity was measured by dual-color interferon γ (IFN- γ) and interleukin 2 (IL-2) FLUOROSpot in peripheral blood mononuclear cells (PBMC) after depletion of ≥50% leukemic B cells. Results were reported in spot forming cells (SFC)/106 PBMC in wells stimulated with gE overlapping peptides or varicella zoster virus (VZV) inactivated cell lysate. Response rate was defined as the proportion of participants who achieved a ≥2-fold increase in IFN- γ or IL-2 SFC/106 PBMC one month after the second dose of vaccine compared with pre-vaccination baseline levels. We also determined the geometric mean fold rise (GMFR) and geometric mean count (GMC) of SFC /106 PBMC at baseline and 90 days after the first dose of vaccine. Two cohorts were enrolled: Cohort 1 consisted of individuals with previously untreated MBL and CLL; and Cohort 2 consisted of CLL participants who were on Bruton tyrosine kinase inhibitor (BTKi) therapy. We compared the response data to historic age-and sex-matched healthy controls who received RZV. Chi-square or Fisher's exact tests measured differences in response rates and Kruskall-Wallis tested for differences in continuous variables. Among CLL participants, multivariable regression analysis was used to investigate the association between day 90 SFC and prior BTKi treatment, accounting for age at RZV, age at CLL diagnosis, sex, and day 0 SFC. Results: Sixty-one participants were enrolled. Paired samples were available for 41 participants (22 in Cohort 1 and 19 [18 ibrutinib and 1 acalabrutinib] in Cohort 2), and 68 age- and sex-matched healthy controls. Baseline characteristics of MBL/CLL participants are shown in Table 1. Compared to healthy controls, participants with MBL/CLL had a significantly lower IFN-γ VZV-specific response rate (41% vs. 63%, p=0.03) and IFN-γ gE-specific response (56% vs. 96%, p<0.001); although there were no differences in IL-2 response rates to VZV (51% vs 68%, p=0.09) or gE (95% vs. 100%, p=0.14, Table 2). There were differences in GMFR between participants with MBL/CLL and controls that reached statistical significance for IFN-γ and IL-2 gE-specific responses and borderline significance for IFN-γ VZV-specific responses (Table 2). VZV-specific response rates did not significantly differ between individuals with untreated MBL/CLL and those receiving BTKi (52% vs. 28%, p=0.12 for IFN- γ; (62% vs. 39%, p=0.15 for IL-2), nor did IL-2 gE-specific responses (96% vs. 95%, p=1.0). However, untreated MBL/CLL participants had significantly higher IFN- γ gE-specific response rate compared to BTKi-treated individuals (73% vs. 37%, p=0.02, Table 2). IFN- γ and IL-2 VZV- and gE-specific SFC GMC was significantly higher at Day 90 compared to Day 0 in all vaccinees, although the magnitude of response was significantly lower in MBL/CLL participants compared to healthy controls (Table 3). Among participants with MBL/CLL, age at diagnosis, age at receipt of RZV, and sex did not predict response to vaccination after accounting for prevaccination values. No serious adverse events were noted among MBL/CLL participants while on this study. Additional analyses including determination of humoral immunogenicity and long-term follow up to ascertain risk of herpes zoster infection are ongoing at this time. Conclusion: RZV was associated with lower cell mediated immunogenicity in MBL/CLL participants compared to healthy older adults. Among individuals with CLL, BTKi treatment was associated with decreased cell mediated immunogenicity of the vaccine. Given the inferior response rates, an additional dose of RZV may be considered to boost responses and should be studied in this patient population. Disclosures Johnson: GSK: Research Funding. Ding:Abbvie: Research Funding; Astra Zeneca: Research Funding; DTRM: Research Funding; alexion: Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Membership on an entity's Board of Directors or advisory committees; Octapharma: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; Beigene: Membership on an entity's Board of Directors or advisory committees. Kenderian:Humanigen: Consultancy, Patents & Royalties, Research Funding; Torque: Consultancy; Novartis: Patents & Royalties, Research Funding; Kite: Research Funding; Gilead: Research Funding; Juno: Research Funding; BMS: Research Funding; Tolero: Research Funding; Mettaforge: Patents & Royalties; Lentigen: Research Funding; MorphoSys: Research Funding; Sunesis: Research Funding. Wang:Novartis: Research Funding; Incyte: Research Funding; Innocare: Research Funding. Kay:Juno Theraputics: Membership on an entity's Board of Directors or advisory committees; Oncotracker: Membership on an entity's Board of Directors or advisory committees; Dava Oncology: Membership on an entity's Board of Directors or advisory committees; Rigel: Membership on an entity's Board of Directors or advisory committees; Morpho-sys: Membership on an entity's Board of Directors or advisory committees; Cytomx: Membership on an entity's Board of Directors or advisory committees; Agios Pharma: Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees; Sunesis: Research Funding; Abbvie: Research Funding; MEI Pharma: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta Pharma: Research Funding; Tolero Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Meyer Squib: Membership on an entity's Board of Directors or advisory committees, Research Funding. Levin:GSK: Research Funding. Kennedy:ICW Ventures: Research Funding. Weinberg:GSK: Research Funding. Parikh:GlaxoSmithKline: Honoraria; AstraZeneca: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; TG Therapeutics: Research Funding; Merck: Research Funding; AbbVie: Honoraria, Research Funding; MorphoSys: Research Funding; Verastem Oncology: Honoraria; Pharmacyclics: Honoraria, Research Funding; Genentech: Honoraria; Ascentage Pharma: Research Funding.
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Jain, Preetesh, Shaojun Zhang, Rashmi Kanagal-Shamanna, Lucy Navsaria, Chi Young Ok, Guilin Tang, C. Cameron Yin, et al. "Outcomes of Acalabrutinib Failures in Relapsed Mantle Cell Lymphoma." Blood 136, Supplement 1 (November 5, 2020): 9–10. http://dx.doi.org/10.1182/blood-2020-137440.
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Introduction: Acalabrutinib is an irreversible BTK inhibitor (BTKi) in the treatment of relapsed patients (pts) with mantle cell lymphoma (MCL). We and others have previously reported that ibrutinib resistant MCL have poor outcomes and BTK mutations are uncommon in ibrutinib resistant MCL. However, the outcomes, causes of discontinuation, management and mutational landscape in MCL pts who discontinued acalabrutinib are not described. Methods: We reviewed charts from all relapsed MCL pts treated with acalabrutinib (n=26) in the relapsed setting and identified 21 pts who discontinued acalabrutinib, described in this analysis. Outcomes and management of patients after discontinuing acalabrutinib are reported. Whole-exome sequencing (WES) with SureSelect Human All Exon V6 was performed in 9 pts who progressed on acalabrutinib (10 tumor specimens and 5 matched germline samples); among these pts, 4 tumors were collected before acalabrutinib and 6 were collected after progression on acalabrutinib. One patient had paired sample at both time points (baseline and progression). Results: Among the 21 pts who discontinued acalabrutinib, 15 (71%) discontinued due to disease progression (2 pts transformed from classic to pleomorphic MCL at progression) and 6 discontinued due to intolerance (one for fatigue and idiopathic encephalopathy, one due to unrelated severe aortic stenosis, 2 others due to therapy related myelodysplasia and 2 due to cardiac issues). Two pts with cardiac issues had pre-existing coronary artery disease and one of them developed new onset atrial fibrillation. Overall, the median number of prior treatments was 2 (range, 1-3); all had prior chemo-immunotherapy and none with ibrutinib. The median duration on treatment with acalabrutinib was 8.3 months (1 to 50 months) and the median number of cycles of acalabrutinib treatment was 8 (range, 1-53). Thirteen pts had complete remission (CR) as their best response on acalabrutinib, 5 were primary refractory and 3 achieved partial remission. At the time of starting acalabrutinib, 12 pts had classic and 9 pts had blastoid (n=6) or pleomorphic (n=3) features, the median Ki-67 expression was 50% (range, 10-100). Pts who progressed, received acalabrutinib for a median duration of 8.3 months (range, 1-50) while those with intolerance, received acalabrutinib for a median duration of 9.4 months (range, 4-31). Median follow up after discontinuation was 38 months and the median post acalabrutinib survival was 24 months (not reached for progression and 7.4 months for intolerance; p =0.02, Figure-1A-B). Patients who discontinued due to intolerance could not get subsequent treatment for MCL. Among the 15 pts who progressed on acalabrutinib, 14 pts received systemic therapies for MCL [eight received ibrutinib based therapies (4 non responders, 3 achieved CR and 1 were PR and all pts progressed subsequently), 5 got chemo-immunotherapy, bortezomib, lenalidomide and progressed and one pt did not receive any treatment and was lost to follow up and died. Among the 15 pts who progressed on acalabrutinib, 6 patients who received anti-CD19 CAR-T therapy had significantly longer survival compared to those who did not get CART therapy; p = 0.007, Figure-1C. For all pts, at the time of last follow up, 10 pts were alive and in remission under follow up while 11 were dead. Recurrently mutated genes in these tumors included ATM (6/10; 60%), TP53 (4/10; 40%), KMT2C (3/10), MYCN (2/10), NOTCH1 (2/10), NOTCH3 (2/10), and MEF2B (2/10) (1-D). We did not detect any mutation or copy number alterations in BTK, PLCG2, TRAF2/3 and MYD88 that have been reported previously to be associated with ibrutinib resistance. To investigate the mutation evolution on acalabrutinib treatment, mutation profiles, particularly the mutation variant allelic fractions (VAFs), were compared between the baseline and progression samples from one patient. Mutation of MYCN, MEF2B, ATM, and NOTCH1 were identified in both tumors at similar VAFs, whereas mutation of CARD11 (two mutations), NLRC5 and B2M were detected only at progression. Conclusions: Relapsed MCL pts who fail acalabrutinib have poor outcomes. Advent of CART therapy has significantly improved survival of these heavily refractory pts. In this small cohort, we did not observe BTK mutations associated with acalabrutinib resistance in MCL pts. Further studies are ongoing to determine acalabrutinib resistance mechanism in MCL. Disclosures Lee: Takeda: Research Funding; Aptitude Health: Speakers Bureau; Bristol-Myers Squibb: Consultancy, Research Funding; Seattle Genetics: Research Funding; Oncternal Therapeutics: Research Funding; Guidepoint Blogal: Consultancy; Celgene: Research Funding. Westin:Astra Zeneca: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Morphosys: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Amgen: Consultancy; Kite: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Curis: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; 47: Research Funding. Nastoupil:LAM Therapeutics: Research Funding; TG Therapeutics: Honoraria, Research Funding; Merck: Research Funding; Novartis: Honoraria, Research Funding; Gilead/KITE: Honoraria; Gamida Cell: Honoraria; Bayer: Honoraria; Genentech, Inc.: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Karus Therapeutics: Research Funding; Janssen: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding. Vega:NCI: Research Funding. Flowers:Denovo Biopharma: Consultancy; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Pharmacyclics/Janssen: Consultancy; Celgene: Consultancy, Research Funding; Leukemia and Lymphoma Society: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Research Funding; Bayer: Consultancy; Eastern Cooperative Oncology Group: Research Funding; AbbVie: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Kite: Research Funding; Spectrum: Consultancy; National Cancer Institute: Research Funding; V Foundation: Research Funding; Cancer Prevention and Research Institute of Texas: Research Funding; Burroughs Wellcome Fund: Research Funding; Karyopharm: Consultancy; OptumRx: Consultancy; Gilead: Consultancy, Research Funding; BeiGene: Consultancy; Acerta: Research Funding. Wang:AstraZeneca: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Nobel Insights: Consultancy; Celgene: Consultancy, Other: Travel, accommodation, expenses, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; VelosBio: Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; MoreHealth: Consultancy; Oncternal: Consultancy, Research Funding; Molecular Templates: Research Funding; Beijing Medical Award Foundation: Honoraria; OncLive: Honoraria; Dava Oncology: Honoraria; Verastem: Research Funding; Guidepoint Global: Consultancy; Lu Daopei Medical Group: Honoraria; InnoCare: Consultancy; Acerta Pharma: Research Funding; BioInvent: Research Funding; Juno: Consultancy, Research Funding; Kite Pharma: Consultancy, Other: Travel, accommodation, expenses, Research Funding; Pulse Biosciences: Consultancy; Loxo Oncology: Consultancy, Research Funding; Targeted Oncology: Honoraria; OMI: Honoraria, Other: Travel, accommodation, expenses.
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Hampel, Paul J., Timothy G. Call, Kari G. Rabe, Sara J. Achenbach, Eli Muchtar, Saad S. Kenderian, Yucai Wang, et al. "Clinical Characteristics and Outcomes of Newly Diagnosed Patients with Chronic Lymphocytic Leukemia Who Are 80 Years of Age or Older." Blood 136, Supplement 1 (November 5, 2020): 26–27. http://dx.doi.org/10.1182/blood-2020-137578.
Full textAbstract:
INTRODUCTION Nearly 20% of patients (pts) are ≥ 80 years (yrs) of age at the time of CLL diagnosis. Increased medical comorbidities, as well as declining functional status and organ function, often accompany advanced age. However, clinical trials often enroll a disproportionally low number of people from this age demographic due to stringent eligibility parameters, which provides limited evidence to guide decisions. Here, we report clinical characteristics and outcomes of pts ≥ 80 yrs of age at the time of CLL diagnosis. METHODS Between 1/1995 and 3/2020, we identified previously untreated CLL pts from the Mayo Clinic CLL Database who were ≥ 80 yrs of age at the time of CLL diagnosis, and seen within 3 yrs of diagnosis. Baseline characteristics, treatments administered, and time to first treatment (TFT) were analyzed for all pts. Overall survival (OS) was measured from diagnosis date in all pts and separately from treatment date for treated pts. Time to next treatment (TTNT) was measured in treated pts from first treatment date to date of second treatment or last known treatment. TFT and TTNT were analyzed accounting for competing risk of death. Standardized mortality ratio (SMR) compared observed survival to survival in a Minnesota population. Cox multivariable regression models were used to determine which factors were associated with OS (treatment as a time-dependent covariate) and TTNT (accounting for competing risk of death). RESULTS Among the 213 pts identified, the median age was 83 yrs (range 80-97); baseline characteristics are summarized in Table 1. The median number of medical comorbidities among all pts was 4 (range 0-8). At least 1 comorbidity was present in 97% of pts, most commonly hypertension (57%), genitourinary (n=48%), rheumatological (46%), and dyslipidemia (n=43%). Median follow-up was 3.8 yrs. A total of 56 pts received treatment and the median TFT was 6.7 yrs. Over this 25 year interval, the treatment approaches included monoclonal antibody alone (n=17), chemotherapy alone (n=17), or chemoimmunotherapy (n=14), novel agents (n=3), and multi-agent Richter's transformation regimens (n=5). Chlorambucil-based treatments (chlorambucil n=13, chlorambucil, prednisone n=3) were the most frequently used chemotherapy regimens. The most common chemoimmunotherapy regimens included rituximab, cyclophosphamide, prednisone (RCP) with (n=3) or without vincristine (n=6), and chlorambucil with an anti-CD20 monoclonal antibody (n=4; obinutuzumab n=2, rituximab n=2). Among 17 pts who received monoclonal antibody alone, treatments included rituximab alone (n=11), rituximab plus methylprednisolone (n=2), obinutuzumab (n=2), and rituximab with alemtuzumab (n=2). Frontline novel agent treatments included ibrutinib alone (n=1), acalabrutinib alone (n=1), and ibrutinib, obinutuzumab, venetoclax (n=1). Five pts with Richter's transformation (diagnosed concurrent with CLL n=4) received multi-agent chemotherapy. Among the 56 treated pts, 22 pts received second line therapy after a median TTNT of 2.8 yrs from start of first therapy. The most common second line treatments were chlorambucil-based (n=6) and rituximab-based (n=6) regimens. Age, sex, absolute lymphocyte count, del17p, and unmutated IGHV were not predictive of TTNT. The median OS among all 213 pts was 4.6 yrs. SMR was 1.2 (p=0.008) when excluding pts with Richter's transformation. In univariable analyses, receipt of therapy (HR 3.92, 95%CI 2.11-7.28; p<0.001), age (per 5 year increase; HR 1.84, 95%CI 1.43-2.38; p<0.001) and unmutated IGHV (HR 2.03, 95%CI 1.12-3.67; p=0.02) were predictors of shorter OS. The OS among pts who received treatment (Figure 1) was similar when compared across time periods of treatment start year grouped as 1995-2001 (n=10), 2002-2013 (n=32), and 2014-2020 (n=14). Treatment categories by time period are shown in Table 2. CONCLUSIONS In this study of 213 pts ≥ 80 yrs of age at time of CLL diagnosis, the median time to first therapy was ~7 yrs. Although survival outcomes did not differ by era across the 25-year span of this study, pts treated with novel agents were underrepresented and are a patient population which warrants additional evaluation. The finding that pts with CLL in this cohort had a 20% higher risk of death compared to an age- and sex-matched population emphasize the need for ongoing efforts to improve clinical outcomes for CLL pts in this demographic category. Disclosures Kenderian: Torque: Consultancy; Mettaforge: Patents & Royalties; Humanigen: Consultancy, Patents & Royalties, Research Funding; Novartis: Patents & Royalties, Research Funding; Kite: Research Funding; Gilead: Research Funding; Juno: Research Funding; BMS: Research Funding; Tolero: Research Funding; Sunesis: Research Funding; MorphoSys: Research Funding; Lentigen: Research Funding. Wang:Incyte: Research Funding; Innocare: Research Funding; Novartis: Research Funding. Shanafelt:Genentech, Pharmacyclics LLC, an AbbVie Company, AbbVie, GlaxoSmithKline, and Merck: Research Funding; Mayo Clinic: Patents & Royalties: and other intellectual property. Braggio:DASA: Consultancy; Bayer: Other: Stock Owner; Acerta Pharma: Research Funding. Kay:Morpho-sys: Membership on an entity's Board of Directors or advisory committees; Bristol Meyer Squib: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tolero Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncotracker: Membership on an entity's Board of Directors or advisory committees; Juno Theraputics: Membership on an entity's Board of Directors or advisory committees; Rigel: Membership on an entity's Board of Directors or advisory committees; Cytomx: Membership on an entity's Board of Directors or advisory committees; Sunesis: Research Funding; MEI Pharma: Research Funding; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees; Agios Pharma: Membership on an entity's Board of Directors or advisory committees; Abbvie: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta Pharma: Research Funding; Dava Oncology: Membership on an entity's Board of Directors or advisory committees. Ding:alexion: Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Membership on an entity's Board of Directors or advisory committees; Octapharma: Membership on an entity's Board of Directors or advisory committees; Abbvie: Research Funding; Astra Zeneca: Research Funding; Beigene: Membership on an entity's Board of Directors or advisory committees; DTRM: Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding. Parikh:Merck: Research Funding; AstraZeneca: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; MorphoSys: Research Funding; Pharmacyclics: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Ascentage Pharma: Research Funding; Genentech: Honoraria; Verastem Oncology: Honoraria; GlaxoSmithKline: Honoraria; TG Therapeutics: Research Funding.
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Sinha, Sutapa, Wei Ding, Tammy Price-Troska, Reona Sakemura, Shulan Tian, Charla R. Secreto, Xiaosheng Wu, et al. "Identification of a Novel Role for PD-1 Signaling in Promotion Tumor Proliferation in B-Cell Lymphoma." Blood 136, Supplement 1 (November 5, 2020): 10–12. http://dx.doi.org/10.1182/blood-2020-136550.
Full textAbstract:
Introduction: PD-1 inhibits the cytotoxic T-cell functions via the interaction with its ligands (PDL1 and PDL2). Recently, our group showed a selective response (~40%) with PD-1 blocking antibody pembrolizumab in patients with Richter transformation (RT), particularly after prior exposure to ibrutinib (Wei Ding et al, Blood, 2017). Additionally, PD-1 showed an increased expression in tumor B-cells of patients with RT (Rong He et al, AJSP, 2018). Here we investigated the functional implications of the PD-1 signaling axis in lymphoma B-cell pathobiology. Methods: 26 CLL-involved lymph node (LN) and 20 RT-involved LN samples were tested for PD-1 expression by immunohistochemistry (mouse clone NAT105, Abcam). Then, we checked PD-1 expression in 10 lymphoma cell lines and 1 CLL cell line (MEC-1) by both, flow cytometry and Western blot (WB) analysis. Over-expression of PD-1 using pLEX-lentiviral system (Thermo Scientific) was evaluated for in vitro cell cycle regulation and in vivo tumor growth. Overexpression of PD-1 was further examined on the regulation of cell signaling pathways using human phospho kinase array kit (R&D) and WB analysis. Gene expression signatures in CLL and RT patients were also identified by Illumina-based RNA sequencing using Formalin-Fixed Paraffin-embedded (FFPE)-nodal tissue obtained by clinical biopsy (Tempus Labs; Chicago, IL). Results: The expression of PD-1 was significantly increased in RT-LN compared to CLL-LN (mean ± SEM in RT vs. CLL, 30.6% ± 4.7% vs. 11.5% ± 2.8%, p < 0.001) [Fig 1A]. PD-1 expression was highest in patients with RT where the last prior CLL therapy was ibrutinib. To test the role of PD-1 in lymphoma B-cells, its expression was assessed in lymphoma and CLL cell lines. The expression of PD-1 was found to be variable, but at very low-levels in lymphoma lines OCI-LY7 and OCI-LY19 (data not shown). Constitutive lentiviral (pLEX-PD-1)-mediated overexpression of PD-1 in OCI-LY7 and OCI-LY19 cells led to increased cell growth (1.4 and 1.9 fold compared to original lines on day 4, respectively, Fig 1BI-II), which was further confirmed by cell cycle analysis which showed an increase in S phase by 20.4% and 24.53% in OCI-LY7 and OCI-LY19 cells (Fig 1B III), respectively. When the luciferase + PD-1 expressing OCI-LY7 cells were injected intravenously (1X106 cells) into NSG mice, increased tumor growth was observed at 22 days of follow up by bioluminescence imaging (p<0.01, Fig 1C). Using phospho-kinase array, an overall decrease of phosphorylation was detected on multiple sites of p53 (S392, S15, S46) and CHK2 (T68) (data not shown). This finding was further confirmed by WB analyses (Fig1DI). In addition, decreased of total p53 and increased phosphorylation on both SHP-1 and SHP-2 were found in PD-1 overexpressing OCI-LY19 and OCI-LY17 cell lines (Fig 1DI). Immunoprecipitation experiments with anti-PD1 antibody showed that PD-1 was in the same complex with SHP-1 and SHP-2 in OCI-LY7 cells but only with SHP-2 in OCI-LY19 cells (Fig 1DII). In parallel, mRNA sequencing was performed on 11 nodal tissues from either RT (n=8) or progressive CLL (n=3) after they developed clinical progression. The expression of PD-1 (PDCD1) was positively correlated with the expression of SHP-1 (PTPN6, r=0.56) and Cyclin E1 (CCNE1, r=0.62), implicating a direct role of PD-1 in regulating cellular proliferation and the induction in phosphatase expression in RT and CLL. Conclusion: Our data support the notion that PD-1 overexpression in lymphoma cells modifies cell proliferation in vitro and in vivo and regulates the function of phosphatase SHP and p53- pathways. These findings also indicate that aggressive lymphoma or CLL leukemic cells have the ability to hijack the PD-1 pathway and may result in downregulation of the p53 mediated DNA repair. This novel information provide for new strategies to further evaluate the interaction of checkpoint signals with DNA repair pathway, and possibly provide novel targets for Richter's transformation. Disclosures Ding: alexion: Membership on an entity's Board of Directors or advisory committees; Beigene: Membership on an entity's Board of Directors or advisory committees; Abbvie: Research Funding; Astra Zeneca: Research Funding; Octapharma: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; DTRM: Research Funding; MEI Pharma: Membership on an entity's Board of Directors or advisory committees. Sakemura:Humanigen: Patents & Royalties. Parikh:Janssen: Honoraria, Research Funding; Merck: Research Funding; Pharmacyclics: Honoraria, Research Funding; Ascentage Pharma: Research Funding; GlaxoSmithKline: Honoraria; MorphoSys: Research Funding; AstraZeneca: Honoraria, Research Funding; Verastem Oncology: Honoraria; Genentech: Honoraria; AbbVie: Honoraria, Research Funding; TG Therapeutics: Research Funding. Wang:Novartis: Research Funding; Incyte: Research Funding; Innocare: Research Funding. Liu:Eisal: Research Funding; Genentech: Research Funding; GRAIL: Research Funding; Menarini Silicon Biosystems: Research Funding; Merck: Research Funding; Seattle Genetics: Research Funding; Tesaro: Research Funding. Braggio:DASA: Consultancy; Bayer: Other: Stock Owner; Acerta Pharma: Research Funding. Ansell:Seattle Genetics: Research Funding; Takeda: Research Funding; AI Therapeutics: Research Funding; ADC Therapeutics: Research Funding; Trillium: Research Funding; Affimed: Research Funding; Regeneron: Research Funding; Bristol Myers Squibb: Research Funding. Kenderian:Sunesis: Research Funding; Tolero: Research Funding; Torque: Consultancy; BMS: Research Funding; Gilead: Research Funding; Kite: Research Funding; Humanigen: Consultancy, Patents & Royalties, Research Funding; Mettaforge: Patents & Royalties; Novartis: Patents & Royalties, Research Funding; MorphoSys: Research Funding; Lentigen: Research Funding; Juno: Research Funding. Kay:Acerta Pharma: Research Funding; Oncotracker: Membership on an entity's Board of Directors or advisory committees; Juno Theraputics: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Research Funding; MEI Pharma: Research Funding; Sunesis: Research Funding; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees; Agios Pharma: Membership on an entity's Board of Directors or advisory committees; Cytomx: Membership on an entity's Board of Directors or advisory committees; Morpho-sys: Membership on an entity's Board of Directors or advisory committees; Dava Oncology: Membership on an entity's Board of Directors or advisory committees; Tolero Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Meyer Squib: Membership on an entity's Board of Directors or advisory committees, Research Funding; Rigel: Membership on an entity's Board of Directors or advisory committees.
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Wang, Michael, Preetesh Jain, Yixin Yao, Yang Liu, Shuangtao Zhao, Holly Hill, Omar Moghrabi, et al. "Ibrutinib Plus Rituximab (IR) Followed By Short Course R-Hypercvad/MTX in Patients (age ≤ 65 years) with Previously Untreated Mantle Cell Lymphoma - Phase-II Window-1 Clinical Trial." Blood 136, Supplement 1 (November 5, 2020): 35–36. http://dx.doi.org/10.1182/blood-2020-137259.
Full textAbstract:
Background - We investigated the efficacy and safety of using a combination of ibrutinib plus rituximab (IR) followed by short course (4 cycles) of R-HCVAD/MTX-ara-C as consolidation in previously untreated young (age ≤ 65 years) patients (pts) with mantle cell lymphoma (MCL). Using a chemo-free induction may reduce the toxicities, complications and the risk of second cancers which were observed with intensive chemoimmunotherapy regimen in MCL pts. Methods - We enrolled 131 previously untreated pts in this single institution, single arm, phase II clinical trial - NCT02427620. Pts received IR induction (part-A), until they achieved complete remission (CR) for up to a maximum of 12 cycles, followed by a maximum of 4 cycles of R-HCVAD/R-MTX-ara-C (part-B) as consolidation. None of the pts received stem cell transplant or maintenance therapy. The primary objective was to assess overall response rate (ORR), [defined as either a partial response (PR) or a complete response (CR)] after part A. Adverse events were coded as per CTCAE version 4. Among evaluable samples, minimal residual disease (MRD) by flow cytometry at best response, clonal evolution and MRD using circulating tumor DNA (ctDNA), whole exome (WES) and bulk RNA sequencing from baseline tissue samples was performed. Results - Among the 131 pts, the median age was 56 yrs (range - 35-65). High Ki-67 (≥30%) in 58/117 (49.5%) pts, 10 pts (8%) had high risk simplified MIPI score, 15 pts (11%) had aggressive MCL (blastoid/pleomorphic) and 114 pts (87%) had initial bone marrow involvement. Seventeen pts (13%) had had complex karyotype and 83% had positive SOX-11 expression. Baseline PET scan was available in 101 pts and 97 pts had PET positive disease. Median number of cycles on IR in part A was 7 (1-12). At week 16 on part A, the ORR was 95% (15% CR and 80% PR) and 5% pts had stable disease. Overall best response (ORR) on part A of therapy was 100% (88% CR and 12% PR) and at the time of last follow up after completion of part A and part B, ORR was 100% (98% CR). Median time to CR was 5 months (range 1-16). Pts with CR within 6 months are "early" CR (n=66) and those with CR ≥ 6 months were "late" CR (n=49) while pts who never had CR were grouped as no CR (n=13). With a median follow up of 37 months, the median PFS and OS were not reached (3 year 82% and 95% respectively). Twenty two pts (17%) relapsed after treatment, including 6 who transformed to aggressive MCL. PFS among pts with high and low Ki-67% was 58 months vs not reached (P=0.03) while no difference was observed in OS. PFS was significantly shorter in pts with aggressive histology (p=0.003) but not the OS. Overall 6 pts died (2 with progression, 2 due to disease transformation, one on study due to multiple complications including splenic hematoma, cardio-pulmonary arrest and progression and the last one expired outside and came off study due to encephalitis). Forty two pts came off study for various reasons [16 disease progression (including 4 transformation), 20 pt choice, 3 intolerance, two second cancer and one lost to follow up]. Grade 3-4 toxicities on part A were 4% myelosuppression and 8% each with fatigue, myalgia and rashes and 4% mucositis. None had grade 3-4 atrial fibrillation or bleeding. WES in 76 pts revealed deletions of BANK1, CCND1, TP53, UBR5, ATM, RB1, CDKN2A and BCL2 in late CR (n=14) (≥ 6 months) and no CR (n=12) pt groups vs early CR (< 6 months; n=30). KMT2C, NCOR2 SMARCA4 and NSD2 mutations were significantly different in late CR vs early CR groups. Furthermore, 68 pts had bulk RNA sequencing and a differential gene expression pattern was identified separating early vs late vs no CR groups. Immune response pathways were overexpressed in early CR pts while oncogenic signaling pathways were clustered in late CR and no CR groups. Conclusions - Chemo-free induction with IR induced durable and deep responses in young MCL pts in the frontline setting. Short course R-HCVAD chemotherapy minimized toxicities and consolidated responses. This combined modality treatment approach may significantly improve young MCL pts outcomes across all risk groups. Pathway analysis demonstrated immune response pathways to be associated with early CR on IR. Detailed analyses on MRD using ct-DNA will be reported. Disclosures Wang: Targeted Oncology: Honoraria; Loxo Oncology: Consultancy, Research Funding; OMI: Honoraria, Other: Travel, accommodation, expenses; MoreHealth: Consultancy; Pulse Biosciences: Consultancy; Molecular Templates: Research Funding; OncLive: Honoraria; VelosBio: Research Funding; Juno: Consultancy, Research Funding; BioInvent: Research Funding; Kite Pharma: Consultancy, Other: Travel, accommodation, expenses, Research Funding; Acerta Pharma: Research Funding; InnoCare: Consultancy; Oncternal: Consultancy, Research Funding; Nobel Insights: Consultancy; Guidepoint Global: Consultancy; Lu Daopei Medical Group: Honoraria; Celgene: Consultancy, Other: Travel, accommodation, expenses, Research Funding; AstraZeneca: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Beijing Medical Award Foundation: Honoraria; Verastem: Research Funding; Dava Oncology: Honoraria. Lee:Celgene: Research Funding; Guidepoint Blogal: Consultancy; Oncternal Therapeutics: Research Funding; Seattle Genetics: Research Funding; Aptitude Health: Speakers Bureau; Bristol-Myers Squibb: Consultancy, Research Funding; Takeda: Research Funding. Westin:BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Curis: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Astra Zeneca: Consultancy, Research Funding; Morphosys: Consultancy, Research Funding; Amgen: Consultancy; 47: Research Funding; Kite: Consultancy, Research Funding. Nastoupil:TG Therapeutics: Honoraria, Research Funding; Merck: Research Funding; Celgene: Honoraria, Research Funding; Bayer: Honoraria; Genentech, Inc.: Honoraria, Research Funding; Gamida Cell: Honoraria; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Karus Therapeutics: Research Funding; LAM Therapeutics: Research Funding; Gilead/KITE: Honoraria. Vega:NCI: Research Funding. Flowers:Millennium/Takeda: Consultancy, Research Funding; Kite: Research Funding; Leukemia and Lymphoma Society: Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy; TG Therapeutics: Research Funding; OptumRx: Consultancy; Acerta: Research Funding; Spectrum: Consultancy; Pharmacyclics/Janssen: Consultancy; Karyopharm: Consultancy; Burroughs Wellcome Fund: Research Funding; Gilead: Consultancy, Research Funding; Eastern Cooperative Oncology Group: Research Funding; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Denovo Biopharma: Consultancy; BeiGene: Consultancy; AbbVie: Consultancy, Research Funding; National Cancer Institute: Research Funding; V Foundation: Research Funding; Cancer Prevention and Research Institute of Texas: Research Funding; Celgene: Consultancy, Research Funding.
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Tian, Shulan, Hanyin Wang, Timothy G. Call, Eric W. Klee, Minetta C. Liu, Erik Jessen, Sameer A. Parikh, et al. "Genomic Profiling Reveals Molecular Heterogeneity in Patients with Richter's Syndrome (RS) and Progressive Chronic Lymphocytic Leukemia (CLL)." Blood 136, Supplement 1 (November 5, 2020): 16–17. http://dx.doi.org/10.1182/blood-2020-138397.
Full textAbstract:
Introduction: Novel targeted therapies have revolutionized treatments for both upfront and relapsed CLL. However, effective therapies have not been established for progressive CLL after developing resistance to both BTK inhibitor and BCL-2 inhibitors. Similarly, Richter's transformation (RS) remains an area of unmet clinical need. Hypothesizing that progressive CLL and RS possess significant but differential molecular abnormalities, we aimed to dissect the initial genomic profiles in a clinical cohort of patients seen in our routine clinical practice using targeted DNA sequencing and transcriptome analysis. Methods: Twelve CLL patients who had lymph node biopsies for evaluation of clinical progression at Mayo Clinic were included in this study. RNA sequencing and targeted DNA sequencing on a focused oncology panel of 1,711 genes were performed on Illumina HiSeq through Tempus Labs, Inc. (Chicago, IL). Differentially expressed (DE) genes were identified using edgeR at the cutoff of FDR <=0.05 and fold-change >=2. Somatic mutations and copy number alternations (CNAs) were identified through Mutect2 and PatternCNV, respectively. CN loss was defined to have log2(ratio) <=-0.93 and CN gain to have log2(ratio) >= 0.585. Pathway analysis was done through the Enrichr package. Results: Among the 12 patients, 7 had confirmed RS (large cell lymphoma histology) and 5 had CLL based on pathological findings. The clinical and therapeutic history for each patient is illustrated in Fig 1A. FISH results from 11 of the patients showed chromosomal abnormalities including del(13q), del(11q), del(17p) and tri(12) (Fig 1A). Hierarchical clustering of expression profiles from the top 10,000 most variable genes in expression revealed two major clusters (Fig 1A). Cluster C1 contains five RS cases, of which case S207 did not receive ibrutinib, S256 was on high-dose steroid and anti-CD20 post-ibrutinib therapy for >1 year before biopsy, and case S025 was treated for < 6 months with ibrutinib. These three form a subgroup separate from the other two RS in C1 who had 8 and 42 months of continuous ibrutinib therapy pre-biopsy, respectively. C2 contains two RS and five CLL cases. Within C2, CLL and RS cases showed similar transcriptomic profiles. Over 90% of the DE genes showed an overall increase of expression in C1, particularly within the 3-sample subgroup (Fig 1B). These genes are enriched in pathways known to play key roles in CLL, including PI3K-AKT signaling, NOTCH signaling and RAS/MAPK signaling, while genes up-regulated in C2 are enriched in WNT signaling. The results suggest marked differences in gene expression profiles and indicate molecular heterogeneity among RS and CLL patients. In addition, targeted DNA sequencing data were analyzed to identify somatic mutations and CNAs. The analysis confirmed the FISH results of del(13q), del(11q), del(17p) or tri(12) in 8 of the cases (Fig 1A). The mutation profiles are similar between C1 and C2 for the recurrently mutated genes published in CLL. However, we identified recurrent CNAs that occurred preferentially in C1 (covering 9 genes) or C2 (48 genes) (Fig 1C). Manual inspections of the reads coverage revealed that 5 of the 9 genes are from chr1q21.1 to chr1q22 that showed clear CN gains largely in C1. Of the 48 genes, 6 are from chrXp11 that showed CN losses, and 27 are from chr17q12 to chr17q25 that showed CN gains. Therefore, the majority of the 57 genes are from large-scale CNAs. Notably, for the CNAs mostly occurring in C2, the affected genes are enriched in WNT signaling, Cell cycle/protein kinase activity and chromatin modifying enzymes. Collectively, the results support the variability of transcriptomic signatures and genetic lesions between RS and CLL. Conclusion: This study revealed a noticeable heterogeneity in gene expression and genetic variation between RS and CLL, albeit in a small cohort. The vast majority of the DE genes showed elevated expression in C1 containing only RS cases, and these genes are enriched in PI3K-AKT signaling, NOTCH signaling, and RAS/MAPK signaling. The pattern is more pronounced for a subgroup in C1 who were overall less exposed to ibrutinib. For somatic variation, there is a strong tendency of occurrence of recurrent CNAs towards C2 cohort, mainly involving gains of chr17q and deletions of chrXp11. Given these advances we are encouraged to further pursue the genetic abnormalities with defined roles in aggressive and transformed CLL. Disclosures Liu: Eisal: Research Funding; Genentech: Research Funding; GRAIL: Research Funding; Menarini Silicon Biosystems: Research Funding; Merck: Research Funding; Seattle Genetics: Research Funding; Tesaro: Research Funding. Parikh:Genentech: Honoraria; Ascentage Pharma: Research Funding; AbbVie: Honoraria, Research Funding; Verastem Oncology: Honoraria; Pharmacyclics: Honoraria, Research Funding; GlaxoSmithKline: Honoraria; Merck: Research Funding; MorphoSys: Research Funding; TG Therapeutics: Research Funding; AstraZeneca: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Wang:Incyte: Research Funding; Innocare: Research Funding; Novartis: Research Funding. Kenderian:Gilead: Research Funding; Humanigen: Consultancy, Patents & Royalties, Research Funding; MorphoSys: Research Funding; Lentigen: Research Funding; Novartis: Patents & Royalties, Research Funding; Torque: Consultancy; Mettaforge: Patents & Royalties; BMS: Research Funding; Tolero: Research Funding; Sunesis: Research Funding; Juno: Research Funding; Kite: Research Funding. Kay:Tolero Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Juno Theraputics: Membership on an entity's Board of Directors or advisory committees; Cytomx: Membership on an entity's Board of Directors or advisory committees; Morpho-sys: Membership on an entity's Board of Directors or advisory committees; Agios Pharma: Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees; Sunesis: Research Funding; MEI Pharma: Research Funding; Acerta Pharma: Research Funding; Rigel: Membership on an entity's Board of Directors or advisory committees; Oncotracker: Membership on an entity's Board of Directors or advisory committees; Abbvie: Research Funding; Bristol Meyer Squib: Membership on an entity's Board of Directors or advisory committees, Research Funding; Dava Oncology: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Braggio:DASA: Consultancy; Bayer: Other: Stock Owner; Acerta Pharma: Research Funding. Ding:Astra Zeneca: Research Funding; DTRM: Research Funding; Beigene: Membership on an entity's Board of Directors or advisory committees; alexion: Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Membership on an entity's Board of Directors or advisory committees; Abbvie: Research Funding.
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Hampel, Paul J., Sameer A. Parikh, Timothy G. Call, Mithun Vinod Shah, Nabila Bennani, Aref Al-Kali, Kari G. Rabe, et al. "Venetoclax Has Modest Efficacy in the Treatment of Patients with Relapsed T-Cell Prolymphocytic Leukemia." Blood 136, Supplement 1 (November 5, 2020): 39–40. http://dx.doi.org/10.1182/blood-2020-134586.
Full textAbstract:
INTRODUCTION T-cell prolymphocytic leukemia (T-PLL) is a rare, aggressive malignancy of mature T-cells. Although responses may been seen with initial alemtuzumab-based therapy, relapse is inevitable and relapsed/refractory disease carries a dismal prognosis. T-PLL has shown in vitro sensitivity to venetoclax, and short-lived clinical responses to venetoclax monotherapy (Smith, Blood Advances 2020; Boidol, Blood 2017) or when given in combination with pentostatin (Alfayez, Leukemia & Lymphoma 2020). Given the lack of standard treatment options, we reviewed the outcomes of patients (pts) with relapsed T-PLL on venetoclax-based therapy. METHODS Using an institutional clinical database of pts with T-PLL seen in the Division of Hematology at Mayo Clinic, Rochester, MN, all pts treated with venetoclax or venetoclax-based therapies in a relapsed/refractory setting were identified. Clinical, laboratory, and pathology data, as well as treatment dosing and toxicity were ascertained retrospectively from the medical records. Diagnostic criteria and response definitions were utilized as per the T-PLL International Study Group (Staber, Blood 2019). RESULTS Between 8/2017 and 5/2020, 9 pts with relapsed/refractory T-PLL treated with venetoclax were identified. The median age was 63 years (range 49-75), and one-third were male. Baseline characteristics are detailed in Table 1. Rearrangement of TCL1 family genes was present in all 8 pts evaluated with fluorescence in situ hybridization (FISH). Using conventional cytogenetics, a complex karyotype was present in 4/6 pts tested. The median prior lines of therapy was 3 (range 1-4), including alemtuzumab in 8 of 9 pts (intravenous 7/8); and two pts had undergone prior hematopoietic stem cell transplantation (1 allogeneic; 1 autologous) after achieving a complete remission. Additional individual pt details are included in Table 2. Prior to venetoclax therapy initiation, 2 pts had B-symptoms (2 night sweats; 1 fever) and 6 pts had an ECOG score ≥ 2. Lymphadenopathy and splenomegaly were present in 6 and 9 pts, respectively. Extranodal involvement included 3 pts with cutaneous involvement and 5 pts with effusions (4 ascites; 1 pleural). The target maximum dose of venetoclax (800 mg [n=4]; 400 mg [n=1]) was reached by 5 pts at a median of 12 days (range 7-40 days). The other 4 pts had disease progression after a median of 10 days (range 5-22 days) during the dose ramp-up, including 2 pts undergoing rapid dose escalation. Altogether, 6 of the 9 pts initiated venetoclax with a rapid dose escalation. Bendamustine was given with venetoclax in 5/9 pts; median number of cycles 1 (range 1-4) with variable starting dosing (range 60-100 mg/m2). The disease control rate was 56%; best response was partial remission (PR) in 4 (44%) pts and stable disease (SD) in 1 (11%) pt. The 1 pt with SD received venetoclax monotherapy; however, the overall response rate among pts who received the combination of venetoclax and bendamustine was 80% (4/5 pts). One pt with a partial remission met all criteria for complete remission but did not have a confirmatory bone marrow biopsy. Cutaneous disease improved in 2 of 3 pts (both with PR as best response), and effusions improved in 2 of 5 pts (1 PR and 1 SD as best response). Among those in PR, the median decrease in absolute lymphocyte count was 67x109/L and the median decrease in lactate dehydrogenase was 1,162 U/L (normal range 122-222 U/L). Median duration of treatment for all pts was 42 days (range 4-201 days). All pts ultimately died during follow-up with a median overall survival of 53 days (range 4-464 days); Figure 1. All pts experienced at least one adverse event and 8 of 9 pts had a grade ≥ 3 toxicity, most commonly edema (n=7) and neutropenia (n=6). Five pts required dose interruptions due to neutropenia (n=3), tumor lysis syndrome (n=1), and edema (n=1). Three pts had dose reductions, all from 800 mg dosing, due to hematologic toxicity (n=2) and nausea (n=1). No pts discontinued venetoclax as a result of adverse events. CONCLUSION Treatment of pts with relapsed/refractory T-PLL remains a significant unmet need. The 9 pts described herein represent the largest cohort of pts treated with venetoclax-based therapy in this setting to the current date. Despite initial reports of clinical efficacy, our results show that venetoclax (with or without bendamustine) has modest efficacy in the treatment of relapsed/refractory T-PLL after prior alemtuzumab exposure. Disclosures Parikh: TG Therapeutics: Research Funding; Verastem Oncology: Honoraria; GlaxoSmithKline: Honoraria; AbbVie: Honoraria, Research Funding; Genentech: Honoraria; Merck: Research Funding; MorphoSys: Research Funding; Pharmacyclics: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Ascentage Pharma: Research Funding; AstraZeneca: Honoraria, Research Funding. Shah:Dren Bio: Consultancy. Bennani:Verastem: Other: Advisory Board; Affimed: Research Funding; Purdue Pharma: Other: Advisory Board; Kite/Gilead: Research Funding. Wang:Incyte: Research Funding; Novartis: Research Funding; Innocare: Research Funding. Kenderian:MorphoSys: Research Funding; Lentigen: Research Funding; Gilead: Research Funding; Juno: Research Funding; BMS: Research Funding; Tolero: Research Funding; Sunesis: Research Funding; Kite: Research Funding; Novartis: Patents & Royalties, Research Funding; Torque: Consultancy; Humanigen: Consultancy, Patents & Royalties, Research Funding; Mettaforge: Patents & Royalties. Kay:MEI Pharma: Research Funding; Oncotracker: Membership on an entity's Board of Directors or advisory committees; Abbvie: Research Funding; Morpho-sys: Membership on an entity's Board of Directors or advisory committees; Acerta Pharma: Research Funding; Cytomx: Membership on an entity's Board of Directors or advisory committees; Juno Theraputics: Membership on an entity's Board of Directors or advisory committees; Dava Oncology: Membership on an entity's Board of Directors or advisory committees; Bristol Meyer Squib: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tolero Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Rigel: Membership on an entity's Board of Directors or advisory committees; Agios Pharma: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sunesis: Research Funding; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees. Ding:Octapharma: Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Research Funding; alexion: Membership on an entity's Board of Directors or advisory committees; Beigene: Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; DTRM: Research Funding; Abbvie: Research Funding. OffLabel Disclosure: Venetoclax: off-label use in treatment of relapsed/refractory T-cell prolymphocytic leukemia
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Ruan, Jia, Alison J. Moskowitz, Neha Mehta-Shah, Lubomir Sokol, Zhengming Chen, Riyaad Rahim, Wei Song, et al. "Multi-Center Phase II Study of Oral Azacitidine (CC-486) Plus CHOP As Initial Treatment for Peripheral T-Cell Lymphoma (PTCL)." Blood 136, Supplement 1 (November 5, 2020): 33–34. http://dx.doi.org/10.1182/blood-2020-136023.
Full textAbstract:
INTRODUCTION: Nodal PTCL with T-follicular helper phenotype (PTCL-TFH), which includes angioimmunoblastic T-cell lymphoma (AITL), is characterized by recurrent mutations affecting epigenetic regulators such as TET2, DNMT3A, IDH2 and RHOA. The association of aberrant DNA methylation with lymphomagenesis provides rationale for clinical application of hypomethylating agents. Azacitidine, an epigenetic modifier which inhibits DNA methyltransferase, has shown clinical activity as a single agent and in combination in R/R PTCL. We report the findings of the first study of oral azacitidine (CC-486) plus CHOP as initial treatment for PTCL (ClinicalTrials.gov - NCT03542266). METHODS: This phase 2 study prioritized enrollment of PTCL-TFH. Subjects received CHOP on day 1 of each cycle for 6 cycles. Priming with oral azacitidine (CC-486) at 300 mg daily was administered for 7 days prior to cycle 1 of CHOP, and for 14 days before CHOP cycles 2-6. Supportive care included mandatory G-CSF. The primary endpoint is CR per 2014 IWG criteria. Secondary endpoints include ORR, safety and survival. Correlative biomarker studies are planned to assess genomic mutations by next-generation-sequencing (NGS), in addition to methylation and transcription profiles. Using a Simon two-stage design comparing an CR of ≥60% with treatment to an unacceptable CR of ≤35% (alpha=10%, power=80%), 9 or more CR out of 17 enrolled patients were required to declare the treatment worthy of further study. RESULTS: From 6/2018 to 3/2020, 21 subjects with previously untreated PTCL were enrolled at 4 centers, and the study met its accrual. At study entry, 17 patients (81%) had PTCL-TFH (16 AITL and 1 TFH), 3 with PTCL-NOS, 1 with ATLL, including 5 (24%) with CD30+ disease. The median age was 66 years (range 22-77), and the M:F ratio was 1.6:1. Nineteen (90%) had stage III/IV disease, 10 (48%) had elevated LDH, 7 (33%) had bone marrow involvement, and 9 (43%) had IPI 3-5. Treatment was generally well tolerated with expected side effects. Grade 3-4 hematologic toxicities included neutropenia (71.4%), thrombocytopenia (9.5%) and anemia (14.3%), with febrile neutropenia uncommon (14.3%). Grade 3-4 non-hematologic toxicities included fatigue (14.3%), hyponatremia (14.3%), diarrhea (4.8%), vomiting (4.8%), rash (4.8%), and elevated ALT (4.8%). One incidence each of influenza A, COVID-19 pneumonia, C.diff and strongyloides hyperinfection were observed and treated. There was no study treatment-related mortality to date. As of July 2020 at a median follow-up of 7 months (range 4-25 months), one subject withdrew consent after cycle 1 (patient preference), and 20 subjects had at least one response assessment, including 15 completed treatment, 2 progressed during treatment, and 3 nearing completion of therapy. At interim assessment after cycle 3 (n=20), the ORR was 85% with CR at 55% (90%CI of 34.7%-74.1%). To date, the preliminary end-of-treatment (EOT, n=17) CR was 76.5% (90%CI of 53.9%-91.5%) for all evaluable patients and was 86.7% for 15 PTCL-TFH, exceeding primary endpoint threshold. CR did not correlate with CD30 expression. The estimated 1-yr PFS for all patients was 56.8% (95%CI of 26.3%-87.3%), with 1-yrs PFS for PTCL-TFH at 61.1% (95%CI of 29.5%-92.7%), and the estimated 1-yr OS for all patients was 74.4% (95%CI of 48.8%-100.0%), with 1-yr OS for PTCL-TFH at 88.9% (95%CI of 68.4%-100.0%). Mutational status by NGS was determined in 15 patients to date. The frequencies of the TET2, RHOA,DNMT3A, and IDH2 mutations were 73%, 40%, 13% and 13%, respectively. TET2 mutations were significantly associated with CR (p=0.014), favorable PFS (p-0.012) and OS (p=0.042). In contrast, DNMT3A mutations were associated with adverse OS (p=0.028). CONCLUSIONS: This study provides the first demonstration that addition of hypomethylating agent oral azacitidine (CC486) to CHOP as initial therapy is feasible, safe, and induces high CR rate in PTCL-TFH subtype, with expected side effects. Although preliminary, the EOT CR to date exceeds the threshold of meeting study primary endpoint. Final efficacy data as well as response according to subtype and mutational profiling will be updated at ASH. This active combination will be further evaluated in the upcoming ALLIANCE/Intergroup randomized study A051902, comparing oral azacitidine-CHO(E)P with duvelisib-CHO(E)P against CHO(E)P in CD30 negative PTCL. Disclosures Ruan: Seattle Genetics: Research Funding; AstraZeneca: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Juno: Consultancy; BMS: Consultancy, Research Funding; Pharmacyclics: Research Funding; Kite Pharma: Consultancy. Moskowitz:Seattle Genetics: Research Funding; Incyte: Research Funding; Merck: Consultancy; Seattle Genetics: Consultancy; Bristol-Myers Squibb: Research Funding; Merck: Research Funding; Imbrium Therapeutics, L.P.: Consultancy; Miragen Therapeutics: Consultancy. Mehta-Shah:Bristol Myers-Squibb: Research Funding; Genetech: Research Funding; Innate Pharmaceuticals: Research Funding; Kyowa Kirin: Consultancy; Verastem: Research Funding; Karyopharm Therapeutics: Consultancy; Celgene: Research Funding; C4 Therapeutics: Consultancy. Sokol:EUSA Pharma: Consultancy, Honoraria, Speakers Bureau; Kymera Therapeutics: Membership on an entity's Board of Directors or advisory committees; Kyowa/Kirin Inc.: Membership on an entity's Board of Directors or advisory committees. Horwitz:Portola: Consultancy, Research Funding; Aileron: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Beigene: Consultancy; Daiichi Sankyo: Research Funding; C4 Therapeutics: Consultancy; ADCT Therapeutics: Consultancy, Research Funding; Millenium/Takeda: Consultancy, Research Funding; Innate Pharma: Consultancy; Corvus: Consultancy; Trillium: Consultancy, Research Funding; Kyowa Hakka Kirin: Consultancy, Research Funding; GlaxoSmithKline: Consultancy; Mundipharma: Consultancy; Infinity/Verastem: Research Funding; Forty Seven: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Miragen: Consultancy; Myeloid Therapeutics: Consultancy; Verastem: Consultancy, Research Funding; Vividion Therapeutics: Consultancy; Affirmed: Consultancy; ASTEX: Consultancy; Janssen: Consultancy; Kura Oncology: Consultancy. Rutherford:LAM Therapeutics: Research Funding; Juno: Consultancy; AstraZeneca: Consultancy; Seattle Genetics: Consultancy; Genentech/Roche: Research Funding; Regeneron: Research Funding; Celgene: Consultancy; Heron: Consultancy; Karyopharm: Consultancy, Research Funding; Dova: Consultancy; Kite: Consultancy. Coleman:Novartis Pharmaceuticals: Research Funding; Innocare: Research Funding; Merck Sharp & Dohme Corp.: Research Funding; BeiGene: Research Funding; Acerta: Research Funding; Ipsen Group: Research Funding; BMS (Celgene Corporation): Research Funding; AstraZeneca Pharmaceuticals, LP: Research Funding; Karyopharma Therapeutics, Inc.: Research Funding; ARCUS Biosciences: Research Funding; AstraZeneca Pharmaceuticals, LP (Acerta Pharma BV Trials): Research Funding; Incyte Corporation: Research Funding; Eli Lilly and Company: Research Funding; EMD Serono Research and Development Institute Inc.: Research Funding; Genetech (F. Hoffman-LaRoche Ltd): Research Funding; Hutchinson MediPharma, LTD: Research Funding; Klus Pharma, Inc.: Research Funding; MeiPharma, Inc.: Research Funding; Seattle Genetics: Research Funding; Boston BIoMedical, Inc.: Research Funding. Melnick:Jubilant: Consultancy; Epizyme: Consultancy; Constellation: Consultancy; Janssen: Research Funding; Daiichi Sankyo: Research Funding. Cerchietti:BMS: Research Funding. Leonard:ADC Therapeutics: Consultancy; MEI Pharma: Consultancy; Bayer: Consultancy; Gilead/Kite: Consultancy; Karyopharm: Consultancy; GenMab: Consultancy; Regeneron: Consultancy; Sutro: Consultancy; AstraZeneca: Consultancy; Roche/Genentech: Consultancy; BMS/Celgene: Consultancy; Epizyme: Consultancy; Miltenyi: Consultancy. Martin:Regeneron: Consultancy; I-MAB: Consultancy; Sandoz: Consultancy; Janssen: Consultancy; Karyopharm: Consultancy, Research Funding; Teneobio: Consultancy; Bayer: Consultancy; Beigene: Consultancy; Cellectar: Consultancy; Incyte: Consultancy; Kite: Consultancy; Morphosys: Consultancy; Celgene: Consultancy. OffLabel Disclosure: Oral azacitidine (CC-486) as hypomethylating agent for the treatment of peripheral T-cell lymphoma
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Jain, Preetesh, Guilin Tang, C. Cameron Yin, Chi Young Ok, Lucy Navsaria, Maria Badillo, Wendy Chen, et al. "Complex Karyotype Is a Significant Predictor for Worst Outcomes in Patients with Mantle Cell Lymphoma (MCL) Treated with BTK Inhibitors - Comprehensive Analysis of 396 Patients." Blood 136, Supplement 1 (November 5, 2020): 32–33. http://dx.doi.org/10.1182/blood-2020-137473.
Full textAbstract:
Introduction: Complex karyotype (Cx) refers to ≥3 unrelated cytogenetic abnormalities in addition to t(11;14) in MCL patients (pts). In limited pts treated with chemotherapy, pts with Cx exhibited poor outcomes compared to non-Cx group. Prognostic impact of Cx in pts treated with BTKi is unclear. We present the largest and most comprehensive analysis on the prognostic impact of Cx in MCL pts. Methods: We analyzed charts from 396 MCL pts with karyotype data. (271 were non-Cx and 125 were Cx). Karyotype status at initial MCL diagnosis was denovo (DN) while previously treated pts were secondary (S). Among Cx, n=80 pts were DN-Cx and 45 were S-Cx while in non-Cx group, 224 were DN-non-Cx and S-non-Cx were 47 pts. TP53 mutation/FISH data was available (n=134; 46 positive, 88 negative). Pt characteristics were obtained from the time of karyotype testing (at initial diagnosis in DN and at the time of testing in S group). Overall survival (OS) was calculated from test date to the last follow up and progression free survival (PFS) after first line therapy from treatment date to date of progression/death. Univariate and multivariate logistic regression modeled the risk of event and treatment response. Results: Cx pts had significant differences compared to non-Cx, including median Ki-67 (40 vs 20%), sMIPI (median 6 vs 4), poor performance status (p.s.), CNS involvement (7 vs 2%), blastoid (22 vs 7%), pleomorphic (12 vs 3%), higher LDH, WBC, ALC and β2M levels and low Hb and platelet counts, prior BTKi (35 vs 15%), TP53 positive (75 vs 17%), shorter median follow up from the test date (18 vs 33 months). Overall, 70 (56%) in Cx and 70 (26%) in non-Cx had died. Univariate analysis for OS showed, advanced age, higher values of Ki-67, WBC, LDH, β2M, MIPI scores, number of chromosomal aberrations, B symptoms, splenomegaly, CNS involvement, poor p.s., prior BTKi, blastoid/pleomorphic histology, TP53 positive status, non-responder to first line therapy and Cx (median 35 months vs 101 months in non-Cx respectively; p<0.001) to be significantly associated with shorter OS (1-A). In addition, S-Cx pts had the worst OS (median 2 months compared to 20, 13 and 55 months in DN-Cx, S-non-Cx and DN-non-Cx respectively; p<0.001) (1-B). In MVA, Cx; HR 1.83 (95% CI 1.08-3.12; p=0.02) and higher age, MIPI score, number of prior therapies, blastoid, CNS involvement, S-Cx category and non-responder to first line therapies predicted for significantly shorter OS. Due to many missing values for Ki-67% and TP53, these variables could not be fitted in model. In addition to other factors, Cx was associated with shorter PFS in univariate (median 12 vs 48 months for non-Cx; p<0.001) but not in MVA. S-Cx pts had the worst PFS (median 7 months compared to 61, 32 and 138 months in DN-Cx, S-non-Cx and DN-non-Cx respectively; p<0.001). Factors predictive for shorter PFS in the MVA, were advanced age, higher MIPI score, lines of prior therapies. Prior BTKi therapy is associated with significantly shorter PFS (2 months vs 13 months without prior BTKi; p=0.02) but not OS. Overall, Cx predicted for higher risk of not achieving CR from all different treatments - OR 3.3 (95% CI 2.01-5.14; p< 0.001). Among the 107 pts with Cx and 221 with non-Cx with available treatment data, 31 in Cx (1-C) and 101 in non-Cx were treated with BTKi with/without chemo-immunotherapy. Median PFS in both Cx and non-Cx groups was significantly longer with BTKi based therapies compared to R-HCVAD, R-Chemo and other therapies (excluding CAR-T and 1 pt with venetoclax-BTKi). PFS in S-Cx category (n=36), the worst category for survival outcomes, was not influenced by BTKi but was improved with CAR-T therapy (1-D). BTKi therapy improved PFS and OS in Cx and DN-Cx categories compared to R-HCVAD, R-chemo, other therapies (with/without SCT) but did not impact on S-Cx category with the worst outcomes. Response rate to BTKi were (92% vs 74%; p=0.01) in pts with non-Cx and Cx respectively. Conclusions: Cx pts remain a high risk MCL cohort in the BTKi era. Within Cx pts, DN-Cx had better outcomes compared to S-Cx category with the worst outcomes. Outcomes and treatment responses in non-Cx were significantly superior compared to Cx pts. CAR-T therapy holds a great promise for improving outcomes in S-Cx karyotype MCL patients. Disclosures Westin: BMS: Consultancy, Research Funding; Kite: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Curis: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Astra Zeneca: Consultancy, Research Funding; Morphosys: Consultancy, Research Funding; 47: Research Funding; Novartis: Consultancy, Research Funding; Amgen: Consultancy. Nastoupil:Bayer: Honoraria; Gamida Cell: Honoraria; Gilead/KITE: Honoraria; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Karus Therapeutics: Research Funding; Genentech, Inc.: Honoraria, Research Funding; LAM Therapeutics: Research Funding; TG Therapeutics: Honoraria, Research Funding; Merck: Research Funding; Celgene: Honoraria, Research Funding. Vega:NCI: Research Funding. Flowers:Burroughs Wellcome Fund: Research Funding; Eastern Cooperative Oncology Group: Research Funding; National Cancer Institute: Research Funding; V Foundation: Research Funding; AbbVie: Consultancy, Research Funding; Bayer: Consultancy; BeiGene: Consultancy; Celgene: Consultancy, Research Funding; TG Therapeutics: Research Funding; Millennium/Takeda: Consultancy, Research Funding; Acerta: Research Funding; Spectrum: Consultancy; Pharmacyclics/Janssen: Consultancy; Karyopharm: Consultancy; OptumRx: Consultancy; Gilead: Consultancy, Research Funding; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Denovo Biopharma: Consultancy; Cancer Prevention and Research Institute of Texas: Research Funding; Kite: Research Funding; Leukemia and Lymphoma Society: Membership on an entity's Board of Directors or advisory committees. Wang:Acerta Pharma: Research Funding; Juno: Consultancy, Research Funding; AstraZeneca: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Oncternal: Consultancy, Research Funding; Lu Daopei Medical Group: Honoraria; Dava Oncology: Honoraria; Guidepoint Global: Consultancy; Celgene: Consultancy, Other: Travel, accommodation, expenses, Research Funding; BioInvent: Research Funding; InnoCare: Consultancy; OMI: Honoraria, Other: Travel, accommodation, expenses; Janssen: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; VelosBio: Research Funding; Verastem: Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; MoreHealth: Consultancy; Nobel Insights: Consultancy; Beijing Medical Award Foundation: Honoraria; OncLive: Honoraria; Targeted Oncology: Honoraria; Loxo Oncology: Consultancy, Research Funding; Kite Pharma: Consultancy, Other: Travel, accommodation, expenses, Research Funding; Pulse Biosciences: Consultancy; Molecular Templates: Research Funding.
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Srour, Samer A., Jie Xu, Taha Al-Juhaishi, Raphael Eric Steiner, Joe Ensor, Sairah Ahmed, Simrit Parmar, et al. "Retrospective Review of Prognostic and Predictors Markers in Newly Diagnosed Angioimmunoblastic T Cell Lymphoma at UT MD Anderson Cancer Center." Blood 136, Supplement 1 (November 5, 2020): 27–28. http://dx.doi.org/10.1182/blood-2020-143228.
Full textAbstract:
Background: Compared to other peripheral T cell lymphomas (PTCLs), patients with AITL have an aggressive clinical course and poor outcomes with conventional chemotherapies. Previous studies reported overall survival (OS) of <40% at 5 years. Furthermore, the prognostic factors of AITL are not well established, particularly because they are derived from the composite of all types of PTCL. In order to elucidate clinical characteristics and biomarkers with prognostic significance in patients with AITL, we conducted a single institution, retrospective study. Methods: We performed a retrospective chart review for newly diagnosed AITL at our institution between February 1998 to August 2019. Patients with available clinical data were included in the analysis. Endpoints were progression-free survival (PFS) and OS. Other endpoints were to identify prognostic factors associated with survival. Univariate (UVA) and multivariate (MVA) Cox proportional hazards models were fitted to the data to assess the significance of variables at diagnosis on OS. A landmark analysis was conducted using only patients who achieved a complete remission (CR). Results: A total of 109 patients with a median age of 66 (range, 28-83) years and female predominance (56%) were identified. Patient and disease characteristics are outlined in Table 1. With a median follow up of 42 (range, 1-232) months, the median PFS and OS for all study patients were 16 and 49 months, respectively, with respective 4-year PFS and OS estimates of 26% and 52%. Fifty-nine (54%) of patients died during the study period. All variables listed in Table 1 were assessed in UVA. Among those factors, age<65, achieving CR to frontline therapy, and receipt of upfront stem cell transplantation (SCT) were associated with improved PFS and OS. The respective 4-year PFS for age <65 vs ≥65 for achieving CR to frontline therapy were 39% and 13% (p=0.0165), vs no CR were 34% and 6% (p<0.0001); the PFS for receipt of upfront SCT vs no SCT vs SCT for relapsed AITL were 57%, 19%, and 0% (p<0.0001) (Figure 1A-C). The respective 4-year OS for age <65 vs ≥65 were of 68% and 38% (p=0.0011), for achieving CR to frontline therapy vs no CR were 61% and 37% (p<0.0001), and for receipt of upfront SCT vs no SCT were 85% and 41% (p=0.0137). A subgroup analysis was performed for 73 patients with available data on CD30 staining. We found a trend for improved OS for patients with positive CD30 (4-year OS 60% vs 30% for negative CD30; p=0.07 (Figure 1D). In MVA we included variables with p<0.15 significance in UVA and excluded Stage I-II disease and CD30 status given small number and missing values, respectively. In MVA, age ≥65 (HR 2.563, 95% CI: 1.419-4.628; p=0.0018), not achieving CR (HR 6.113, 95% CI: 3.048-12.258; p<0.0001), not receiving upfront SCT (HR 2.204, 95% CI: 1.125-4.317; p=0.0212) were associated with worse PFS. Similarly, age ≥65 (HR 2.339, 95% CI: 1.214-4.509; p=0.0111), not achieving CR (HR 2.533, 95% CI: 1.24-5.174; p=0.0107), and not receiving upfront SCT (HR 2.395, 95% CI: 1.009-5.688; p=0.0477) were associated with inferior OS in MVA. Conclusions: Age <65 years, achieving CR to induction treatment, and upfront autologous SCT are strong predictors for improved PFS and OS. Further, we identified the potential prognostic role for CD30 status, for better OS. Upfront consolidation with SCT improves survival, however as majority of patients with AITL may not be transplant-eligible, it is imperative that novel therapies that disrupt the distinct biology be explored. Additional studies exploring additional prognostic markers will be provided at the annual meeting. Disclosures Parmar: Cellenkos Inc.: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding. Nastoupil:Pfizer: Honoraria, Research Funding; Karus Therapeutics: Research Funding; Celgene: Honoraria, Research Funding; Genentech, Inc.: Honoraria, Research Funding; Bayer: Honoraria; LAM Therapeutics: Research Funding; Janssen: Honoraria, Research Funding; Gamida Cell: Honoraria; Merck: Research Funding; Novartis: Honoraria, Research Funding; TG Therapeutics: Honoraria, Research Funding; Gilead/KITE: Honoraria. Nieto:Affimed: Consultancy, Other: Grant Support; Novartis: Other: Grant Support; Astra Zeneca: Other: Grant Support; Secura Bio: Other: Grant Support. Hosing:NKARTA Inc.: Consultancy. Lee:Takeda: Research Funding; Oncternal Therapeutics: Research Funding; Seattle Genetics: Research Funding; Celgene: Research Funding; Guidepoint Blogal: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Aptitude Health: Speakers Bureau. Westin:Novartis: Consultancy, Research Funding; Kite: Consultancy, Research Funding; Amgen: Consultancy; Janssen: Consultancy, Research Funding; Morphosys: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Astra Zeneca: Consultancy, Research Funding; Curis: Consultancy, Research Funding; 47: Research Funding; Genentech: Consultancy, Research Funding. Champlin:Actinium: Consultancy; Takeda: Patents & Royalties; Johnson and Johnson: Consultancy; Genzyme: Speakers Bureau; Omeros: Consultancy; DKMS America: Membership on an entity's Board of Directors or advisory committees; Cytonus: Consultancy. Khouri:Bristol Myers Squibb: Research Funding; Pfizer: Research Funding. Wang:Pharmacyclics: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Nobel Insights: Consultancy; Dava Oncology: Honoraria; Pulse Biosciences: Consultancy; Kite Pharma: Consultancy, Other: Travel, accommodation, expenses, Research Funding; MoreHealth: Consultancy; Loxo Oncology: Consultancy, Research Funding; Targeted Oncology: Honoraria; Janssen: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Guidepoint Global: Consultancy; AstraZeneca: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Juno: Consultancy, Research Funding; BioInvent: Research Funding; VelosBio: Research Funding; Acerta Pharma: Research Funding; InnoCare: Consultancy; Oncternal: Consultancy, Research Funding; Verastem: Research Funding; Molecular Templates: Research Funding; OncLive: Honoraria; Beijing Medical Award Foundation: Honoraria; Lu Daopei Medical Group: Honoraria; OMI: Honoraria, Other: Travel, accommodation, expenses; Celgene: Consultancy, Other: Travel, accommodation, expenses, Research Funding. Vega:NCI: Research Funding. Neelapu:Celgene: Other: personal fees, Research Funding; Novartis: Other: personal fees; Pfizer: Other: personal fees; Bristol-Myers Squibb: Other: personal fees, Research Funding; Legend Biotech: Other; Precision Biosciences: Other: personal fees, Research Funding; Adicet Bio: Other; Calibr: Other; Cell Medica/Kuur: Other: personal fees; Cellectis: Research Funding; Karus Therapeutics: Research Funding; Acerta: Research Funding; Kite, a Gilead Company: Other: personal fees, Research Funding; Merck: Other: personal fees, Research Funding; N/A: Other; Unum Therapeutics: Other, Research Funding; Poseida: Research Funding; Takeda Pharmaceuticals: Patents & Royalties; Allogene Therapeutics: Other: personal fees, Research Funding; Incyte: Other: personal fees. Flowers:National Cancer Institute: Research Funding; Kite: Research Funding; Leukemia and Lymphoma Society: Membership on an entity's Board of Directors or advisory committees; Eastern Cooperative Oncology Group: Research Funding; Cancer Prevention and Research Institute of Texas: Research Funding; AbbVie: Consultancy, Research Funding; Bayer: Consultancy; Burroughs Wellcome Fund: Research Funding; TG Therapeutics: Research Funding; Millennium/Takeda: Consultancy, Research Funding; Acerta: Research Funding; Spectrum: Consultancy; Pharmacyclics/Janssen: Consultancy; Karyopharm: Consultancy; OptumRx: Consultancy; Gilead: Consultancy, Research Funding; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Denovo Biopharma: Consultancy; Celgene: Consultancy, Research Funding; BeiGene: Consultancy; V Foundation: Research Funding. Iyer:Spectrum: Research Funding; Merck: Research Funding; Target Oncology: Honoraria; Afffimed: Research Funding; Seattle Genetics, Inc.: Research Funding; Rhizen: Research Funding; CRISPR: Research Funding; Trillium: Research Funding; Daiichi Sankyo: Consultancy; Curio Biosciences: Honoraria; Legend Biotech: Consultancy.
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Wang, Yucai, Marcella Tschautscher, Sameer A. Parikh, Timothy G. Call, Neil E. Kay, Patrick B. Johnston, Luis F. Porrata, et al. "Central Nervous System (CNS) Involvement of Richter Transformation: A Single Center Experience." Blood 136, Supplement 1 (November 5, 2020): 3–4. http://dx.doi.org/10.1182/blood-2020-139769.
Full textAbstract:
Introduction: Richter transformation (RT) refers to transformation of chronic lymphocytic leukemia (CLL) to diffuse large B-cell lymphoma (DLBCL) or other aggressive lymphomas. The incidence, clinical characteristics, and outcomes of RT with CNS involvement remain undefined. Methods: Biopsy-confirmed RT diagnosed from 4/1993 to 4/2018 was identified from the Mayo Clinic CLL database. RT cases with CNS involvement were further reviewed, with clinical characteristics, treatment and follow-up data abstracted. Overall survival (OS) was defined as time from CNS involvement to death from any cause and analyzed using the Kaplan-Meier method. Results: Among 204 CLL patients with biopsy-proven RT, 15 patients had documented CNS involvement by imaging (parenchymal n=11, ocular n=1, parenchymal and ocular n=1, leptomeningeal n=1, cranial and spinal nerve roots n=1). Biopsy confirmation of CNS involvement was available in 11 patients. Of these 15 patients, 10 had CNS involvement at initial RT diagnosis, and 5 patients developed CNS involvement at RT progression, with a median time from RT diagnosis to CNS involvement of 14.9 months (range 2.8-41.1). Prior to RT, 11 patients (73.3%) received no treatment for CLL, 3 (53.4%) received chemoimmunotherapy (CIT) only (1-3 lines), and 1 patient (6.7%) received CIT (1 line) and ibrutinib. CLL FISH results were available in 9 patients, with del(17p) in 2, trisomy 12 in 2, del(13q) in 3, and normal results in 2. One patient had TP53 mutation (FISH result unavailable). IgHV mutation status was known in 3 patients and 1 was unmutated. The median time to RT was 4.4 years (range 0-11.4). The median age at RT diagnosis was 70 years (range 59-78), and 9 (60%) were male. The histology of RT was DLBCL in all 15 patients (diagnosed by CNS biopsy in 8 and other biopsies in 7), with GCB subtype in 6 and non-GCB subtype in 3. MYC rearrangement was detected in 4 of 6 patients tested, and 2 of those also had BCL-2 rearrangement (MYC/BCL-2 double hit). Of the 10 patients with CNS involvement at initial RT diagnosis, 4 had isolated CNS involvement (confirmed by brain biopsy [n=2] or vitreous biopsy [n=2]). All 4 patients were treated with high dose (HD) methotrexate (MTX) based regimen, and 3 patients achieved complete remission (CR) and underwent autologous stem cell transplant with continued CR, while 1 patient achieved partial remission and received whole brain radiotherapy (WBRT) at disease progression. Six patients had both systemic and CNS involvement (confirmed by brain biopsy [n=2] or CSF examination [n=2] in 4; the other 2 were diagnosed by imaging). All 6 patients received CNS directed therapy (HD MTX [n=5] or WBRT [n=1]) as well as systemic therapy (R-CHOP [n=5] or HyperCVAD [n=1]), with varied short duration of disease control (Figure 1A). Of the 5 patients who developed CNS involvement at RT progression (after 1-2 lines of therapy including first-line R-CHOP), 2 had isolated CNS involvement (1 was confirmed by CSF examination and the other was by imaging only). Both were treated with HD MTX based regimen, and 1 achieved a durable remission of 2 years but eventually had CNS relapse, while the other had no response and received WBRT with limited benefit. Three patients had both systemic and CNS involvement (2 were confirmed by CSF examination and the other was by imaging only), and all 3 patients were treated with HD MTX based regimen but all had CNS disease progression within 3 months (Figure 1A). The OS after CNS involvement for all 15 RT patients was 9.4 months (95% CI 2.3-19.1). Patients with CNS involvement at initial RT diagnosis had numerically longer OS compared to patients who developed CNS involvement at RT progression (median OS 13.0 vs 4.1 months, P = 0.137; Figure 1B). Patients with isolated CNS involvement had better OS compared to patients with both CNS and systemic involvement (median OS 32.0 vs 5.3 months, P = 0.009; Figure 1C). Three of the 4 patients who only had isolated CNS involvement at the time of RT diagnosis have ongoing long term remission and survival (Figure 1A). Conclusions: In this large series of RT, approximately 1 in 14 patients had CNS involvement. Patients with isolated CNS involvement appeared to have favorable long term outcome; however, RT patients with both systemic and CNS involvement had extremely poor survival. The incidence, molecular characteristics, and optimal management of RT with CNS involvement in the novel agent era warrant future multicenter studies. Disclosures Wang: Incyte: Research Funding; Innocare: Research Funding; Novartis: Research Funding. Parikh:GlaxoSmithKline: Honoraria; Pharmacyclics: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; MorphoSys: Research Funding; TG Therapeutics: Research Funding; Merck: Research Funding; AbbVie: Honoraria, Research Funding; Ascentage Pharma: Research Funding; Genentech: Honoraria; Verastem Oncology: Honoraria. Kay:Tolero Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Meyer Squib: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta Pharma: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Research Funding; MEI Pharma: Research Funding; Sunesis: Research Funding; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees; Agios Pharma: Membership on an entity's Board of Directors or advisory committees; Cytomx: Membership on an entity's Board of Directors or advisory committees; Morpho-sys: Membership on an entity's Board of Directors or advisory committees; Rigel: Membership on an entity's Board of Directors or advisory committees; Oncotracker: Membership on an entity's Board of Directors or advisory committees; Dava Oncology: Membership on an entity's Board of Directors or advisory committees; Juno Theraputics: Membership on an entity's Board of Directors or advisory committees. Witzig:AbbVie: Consultancy; MorphSys: Consultancy; Immune Design: Research Funding; Karyopharm Therapeutics: Research Funding; Incyte: Consultancy; Spectrum: Consultancy; Celgene: Consultancy, Research Funding; Acerta: Research Funding. Nowakowski:MorphoSys: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding; Kite: Consultancy; Denovo: Consultancy; Kymera: Consultancy; Ryvu: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other; Curis: Consultancy; Seattle Genetics: Consultancy; Nanostrings: Research Funding. Ansell:Trillium: Research Funding; AI Therapeutics: Research Funding; Affimed: Research Funding; Regeneron: Research Funding; Takeda: Research Funding; ADC Therapeutics: Research Funding; Seattle Genetics: Research Funding; Bristol Myers Squibb: Research Funding. Kenderian:MorphoSys: Research Funding; Sunesis: Research Funding; Tolero: Research Funding; BMS: Research Funding; Juno: Research Funding; Gilead: Research Funding; Kite: Research Funding; Novartis: Patents & Royalties, Research Funding; Torque: Consultancy; Humanigen: Consultancy, Patents & Royalties, Research Funding; Lentigen: Research Funding; Mettaforge: Patents & Royalties. Ding:DTRM: Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; Beigene: Membership on an entity's Board of Directors or advisory committees; alexion: Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Membership on an entity's Board of Directors or advisory committees; Octapharma: Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Research Funding; Abbvie: Research Funding.
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Bayfield, Katie J., Alex Horsley, Eric Alton, Samantha Irving, Andrew Bush, and Jane C. Davies. "Simultaneous sulfur hexafluoride and nitrogen multiple-breath washout (MBW) to examine inherent differences in MBW outcomes." ERJ Open Research 5, no. 4 (October 2019): 00234–2018. http://dx.doi.org/10.1183/23120541.00234-2018.
Full textAbstract:
Multiple-breath washout (MBW) can be performed with different gases (sulfur hexafluoride (SF6) and nitrogen (N2)) and different devices, all of which give discrepant results. This study aimed to confirm previously reported differences and explore factors influencing discrepant results; equipment factors or the physical properties of gases used.MethodsHealthy controls (HCs) and participants with cystic fibrosis (CF) completed MBW trials on two commercially available devices (Exhalyzer D (N2) and Innocor (SF6)). Simultaneous washout of both gases at the same time on the commercial equipment and simultaneous washouts using a respiratory mass spectrometer (RMS) were completed in subsets. Primary outcomes were lung clearance index (LCI), breath number and time required to washout.ResultsBreath number was higher with N2 washout than SF6 in both HCs and patients with CF, whether washouts were completed individually or simultaneously. The difference was greater in more advanced disease, largely caused by differences in the final part of the washout. Results from commercial devices were similar to those obtained with the RMS.ConclusionsN2 MBW results were higher than SF6 MBW, with some of the largest differences reported to date being observed. The biggest impact was at the end of the washout and this was even the case when gases were washed out simultaneously. N2 and SF6 MBW results are inherently different and should be considered as independent measurements.
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Klocke, Fritz, Daniel Heinen, Fabian Schongen, Kristian Arntz, Yuan Liu, Vladimir Bäcker, and Björn Feldhaus. "Wear Protection of Deep Drawing Tools by Systematic Optimization of Highly Stressed Surfaces." Advanced Materials Research 907 (April 2014): 439–53. http://dx.doi.org/10.4028/www.scientific.net/amr.907.439.
Full textAbstract:
The automotive sector is one of the largest energy consumers in Germany. Requests from politics and industry to significantly reduce emissions require new developments during utilization as well as during production phase. In line with the framework concept "InnoCaT", where more than 60 companies and research facilities from Germany take part, possibilities for producing companies are developed and analyzed to reduce the resource and energy consumption and by this reducing costs along the entire process chain of car body manufacturing. One approach to design car bodies lighter and more efficiently is to use aluminium and high strength steels. By this means weight and sheet thickness are reduced. However higher strengths of the steels and the adhesion affinity of aluminium significantly increase the requirements regarding the used tool steel. Thus grooves or galling appear more frequent at highly stressed surfaces. To assure high lifetimes and by this increase especially the resource efficiency concerning use of material and setting-up times within the press plant, a local optimization at the highly stressed surfaces is necessary. For this a FEM/BEM-tool for a time efficient and exact calculation of the occurring tool loads for complex die profiles is developed. Based on this development of load calculation a shape-optimization is performed at the corresponding areas. After the geometric optimization of the tool a local laser surface treatment for further wear protection is carried out using laser cladding or laser alloying/ -dispersing. By combining the technologies a highly wear resistant surface is achievable, which increases the tool's lifetime as well as the reproducibility within production.