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1
Rosa, Rossana, Jose F. Suarez, Marco A. Lorio, Michele I. Morris, Lilian M. Abbo, Jacques Simkins, Giselle Guerra, et al. "Impact of antiretroviral therapy on clinical outcomes in HIV+ kidney transplant recipients: Review of 58 cases." F1000Research 5 (December 21, 2016): 2893. http://dx.doi.org/10.12688/f1000research.10414.1.
Abstract:
Background: Antiretroviral therapy (ART) poses challenging drug-drug interactions with immunosuppressant agents in transplant recipients. We aimed to determine the impact of specific antiretroviral regimens in clinical outcomes of HIV+ kidney transplant recipients. Methods: A single-center, retrospective cohort study was conducted at a large academic center. Subjects included 58 HIV- to HIV+ adult, first-time kidney transplant patients. The main intervention was ART regimen used after transplantation. The main outcomes assessed at one- and three-years were: patient survival, death-censored graft survival, and biopsy-proven acute rejection; we also assessed serious infections within the first six months post-transplant. Results: Patient and graft survival at three years were both 90% for the entire cohort. Patients receiving protease inhibitor (PI)-containing regimens had lower patient survival at one and three years than patients receiving PI-sparing regimens: 85% vs. 100% (p=0.06) and 82% vs. 100% (p=0.03), respectively. Patients who received PI-containing regimens had twelve times higher odds of death at 3 years compared to patients who were not exposed to PIs (odds ratio, 12.05; 95% confidence interval, 1.31-1602; p=0.02). Three-year death-censored graft survival was lower in patients receiving PI vs. patients on PI-sparing regimens (82 vs 100%, p=0.03). Patients receiving integrase strand transfer inhibitors-containing regimens had higher 3-year graft survival. There were no differences in the incidence of acute rejection by ART regimen. Individuals receiving PIs had a higher incidence of serious infections compared to those on PI-sparing regimens (39 vs. 8%, p=0.01). Conclusions: PI-containing ART regimens are associated with adverse outcomes in HIV+ kidney transplant recipients.
2
Dutta, Noton K., Abdullah Alsultan, Thomas J. Gniadek, Deborah A. Belchis, Michael L. Pinn, Khisimuzi E. Mdluli, Eric L. Nuermberger, Charles A. Peloquin, and Petros C. Karakousis. "Potent Rifamycin-Sparing Regimen Cures Guinea Pig Tuberculosis as Rapidly as the Standard Regimen." Antimicrobial Agents and Chemotherapy 57, no. 8 (June 3, 2013): 3910–16. http://dx.doi.org/10.1128/aac.00761-13.
Abstract:
ABSTRACTStrategies involving new drug combinations, as well as new uses of existing drugs, are urgently needed to reduce the time required to cure patients with drug-sensitive or multidrug-resistant (MDR) tuberculosis (TB). We compared the sterilizing activity of the standard first-line antitubercular regimen, rifampin-isoniazid-pyrazinamide (RHZ), with that of the novel regimen PA-824–moxifloxacin–pyrazinamide (PaMZ), which is currently being studied in clinical trials (NCT01498419), in the guinea pig model of chronic TB infection, in which animals develop necrotic granulomas histologically resembling their human counterparts. Guinea pigs were aerosol infected with ∼2 log10bacilli of wild-typeMycobacterium tuberculosisH37Rv, and antibiotic treatment was initiated 6 weeks after infection. Separate groups of animals received RHZ, PaMZ, or single or two-drug components of the latter regimen administered at human-equivalent doses 5 days/week for a total of 8 weeks. Relapse rates were assessed 3 months after discontinuation of treatment to determine the sterilizing activity of each combination regimen. PaMZ given at human-equivalent doses was safe and well tolerated for the entire treatment period and rendered guinea pig lungs culture negative more rapidly than RHZ did. After 1 month of treatment, 80% and 50% of animals in the RHZ and PaMZ groups, respectively, had lung culture-positive relapse. Both combination regimens prevented microbiological relapse when administered for a total of 2 months. Our data support the use of PaMZ as a novel isoniazid- and rifamycin-sparing regimen suitable for treatment of both drug-sensitive TB and MDR-TB.
3
Ruzicka, Daniel J., Mayuko Kamakura, Naho Kuroishi, Nobuyuki Oshima, Miyuki Yamatani, Jingbo Yi, Bruce Crawford, Kunihisa Tsukada, and Shinichi Oka. "Characteristics of 2-drug regimen users living with HIV-1 in a real-world setting: A large-scale medical claim database analysis in Japan." PLOS ONE 17, no. 6 (June 14, 2022): e0269779. http://dx.doi.org/10.1371/journal.pone.0269779.
Abstract:
Background Regimen simplification to 2-drug antiretroviral therapy (2-ART) may address potential tolerability issues, increase adherence, and reduce toxicity and potential drug-drug-interactions among people living with HIV-1 (PLWH). However, real-world treatment patterns and characteristics of 2-ART users are unclear. Methods This retrospective observational cohort study employed a large-scale medical claim database of Japanese hospitals to extract data on 4,293 PLWH aged ≥18 years with diagnosis of HIV and treated with any ART regimens between April 2008 and April 2019. A 2-ART cohort was compared with a 3-drug antiretroviral therapy (3-ART) cohort in terms of population characteristics, comorbid conditions, and treatment patterns. Treatment switching rates were calculated for each cohort followed by sensitivity analysis to confirm the robustness of the findings. Results There were 94 individuals identified in the 2-ART cohort. Compared to the standard 3-ART cohort (n = 3,993), the 2-ART cohort was older (median age 53 [IQR 44–64] vs 42 years [IQR 35–50]), with a lower proportion of males (87.2% vs 93.8%), higher Charlson Comorbidity Index (CCI) (median score 6 [IQR 5–8] vs 5 [IQR 4–6]), more co-medications (median 6 [IQR 4–11] vs 3 [IQR 2–7]), and a higher percentage of AIDS-defining conditions (66.0% vs 42.8%). The most common 2-ART were protease inhibitor (PI) + integrase strand transfer inhibitor (INSTI) and non-nucleoside reverse transcriptase inhibitor (NNRTI) + INSTI (33.0% and 31.9%, respectively). Overall, most of the regimens were nucleoside reverse transcriptase inhibitor (NRTI)-sparing (71.3%), with a decreasing trend over time (76.2% to 70.2%). ART regimen switch occurred more often in the 2-ART cohort than in the 3-ART cohort (33.0% vs 21.2%). Conclusion The profiles of individuals on 2-ART in Japan were demonstrated to be complex. Most were treated with NRTI-sparing regimens which may reflect an effort to reduce treatment-related toxicities.
4
Maggiolo, Franco, Nicola Gianotti, Laura Comi, Elisa Di Filippo, Laura Fumagalli, Silvia Nozza, Laura Galli, Daniela Valenti, Marco Rizzi, and Antonella Castagna. "Rilpivirine plus cobicistat-boosted darunavir as alternative to standard three-drug therapy in HIV-infected, virologically suppressed subjects: Final results of the PROBE 2 trial." Antiviral Therapy 26, no. 3-5 (May 2021): 51–57. http://dx.doi.org/10.1177/13596535211042226.
Abstract:
Background Primary analysis at 24 weeks showed that switching to rilpivirine plus darunavir/cobicistat was non-inferior to continuing a standard three-drug antiretroviral regimen in virologically suppressed people with HIV. We present efficacy and safety data from the 48-week analysis. Methods PROBE 2 is a randomized, open-label trial. Adults who were on a three-drug therapy and had had <50 HIV-1 RNA copies/mL for at least 6 months were randomly assigned (1:1) to 25 mg rilpivirine plus 800/150 darunavir/cobicistat once daily (early switch group) or to continue their regimen for 24 weeks before switching (late switch group). In the 48-week analysis, the efficacy endpoint was the proportion of participants with <50 copies/mL of HIV-RNA (US Food and Drug Administration snapshot algorithm). The trial is registered with ClinicalTrials.gov , number NCT04064632. Findings 160 participants were recruited and randomized. At week 48, 70 (87.5%) in the early switch group and 76 (94.8%) in the late switch group maintained HIV-RNA <50 copies/mL. Virological failure (≥50 HIV-RNA copies/mL) was not seen in any patient of the early switch group and in 2 subjects in the late switch group none of which had treatment emergent resistance-associated mutation. Adverse events leading to treatment discontinuation occurred in 7 (8.7%) participants in the early switch group and in none in the late switch group. Interpretation The combination of rilpivirine plus darunavir/cobicistat sustained virological suppression, was associated with a low frequency of virological failure, and had a favorable safety profile, which support its use as a nucleoside reverse transcriptase inhibitor-sparing and integrase inhibitor-sparing alternative to three-drug regimens.
5
Sleeper, Rebecca B. "Antipsychotic Dose-Sparing Effect with Addition of Memantine." Annals of Pharmacotherapy 39, no. 9 (September 2005): 1573–76. http://dx.doi.org/10.1345/aph.1g207.
Abstract:
OBJECTIVE: To describe a case of an antipsychotic-sparing effect achieved after the addition of memantine to the regimen of a patient with severe Alzheimer's disease and aggressive behavioral disturbances. CASE SUMMARY: A 78-year-old white man with severe Alzheimer's disease was receiving risperidone 2 mg 3 times daily for persistent aggressive and dangerous behavioral disturbances. Memantine was initiated, and the dose was titrated to 10 mg twice daily. The patient's response included improvement in functional status and resolution of problematic behaviors, allowing repeated reduction of the risperidone dose and ultimate discontinuation. DISCUSSION: Antipsychotics are often employed to treat behavioral disturbances for patients with Alzheimer's disease; however, the adverse effect potential of these agents remains a significant concern. Adjunctive medications that maintain or improve behavioral symptoms yet allow an antipsychotic-sparing effect are attractive. Such experiences have previously been described with other drug classes, but clinical experience is evolving with memantine. For this patient, the effect of this agent on behavioral symptoms and risperidone requirements is one example of such an antipsychotic-sparing effect. CONCLUSIONS: Response to memantine therapy may include behavioral improvements allowing a dose-sparing effect of antipsychotic medication. Changes in psychoactive drug burden may be a valuable surrogate marker of memantine's effects on behavior.
6
Tiberi, Simon, Marie-Christine Payen, Giovanni Sotgiu, Lia D'Ambrosio, Valentina Alarcon Guizado, Jan Willem Alffenaar, Marcos Abdo Arbex, et al. "Effectiveness and safety of meropenem/clavulanate-containing regimens in the treatment of MDR- and XDR-TB." European Respiratory Journal 47, no. 4 (March 10, 2016): 1235–43. http://dx.doi.org/10.1183/13993003.02146-2015.
Abstract:
No large study has ever evaluated the efficacy, safety and tolerability of meropenem/clavulanate to treat multidrug- and extensively drug-resistant tuberculosis (MDR- and XDR-TB). The aim of this observational study was to evaluate the therapeutic contribution, effectiveness, safety and tolerability profile of meropenem/clavulanate added to a background regimen when treating MDR- and XDR-TB cases.Patients treated with a meropenem/clavulanate-containing regimen (n=96) showed a greater drug resistance profile than those exposed to a meropenem/clavulanate-sparing regimen (n=168): in the former group XDR-TB was more frequent (49% versus 6.0%, p<0.0001) and the median (interquartile range (IQR)) number of antibiotic resistances was higher (8 (6–9) versus 5 (4–6)). Patients were treated with a meropenem/clavulanate-containing regimen for a median (IQR) of 85 (49–156) days.No statistically significant differences were observed in the overall MDR-TB cohort and in the subgroups with and without the XDR-TB patients; in particular, sputum smear and culture conversion rates were similar in XDR-TB patients exposed to meropenem/clavulanate-containing regimens (88.0% versus 100.0%, p=1.00 and 88.0% versus 100.0%, p=1.00, respectively). Only six cases reported adverse events attributable to meropenem/clavulanate (four of them then restarting treatment).The nondifferent outcomes and bacteriological conversion rate observed in cases who were more severe than controls might imply that meropenem/clavulanate could be active in treating MDR- and XDR-TB cases.
7
Fischl, Margaret A., Ann C. Collier, A. Lisa Mukherjee, Judith E. Feinberg, Lisa M. Demeter, Pablo Tebas, Marina Giuliano, et al. "Randomized open-label trial of two simplified, class-sparing regimens following a first suppressive three or four-drug regimen." AIDS 21, no. 3 (January 2007): 325–33. http://dx.doi.org/10.1097/qad.0b013e328011ddfa.
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Karoney, Mercy Jelagat, Mathew Kirtptonui Koech, Evangeline Wawira Njiru, and Willis Dixon Owino Ong’or. "Proximal tubular renal dysfunction among HIV infected patients on Tenofovir versus Tenofovir sparing regimen in western Kenya." PLOS ONE 17, no. 9 (September 15, 2022): e0273183. http://dx.doi.org/10.1371/journal.pone.0273183.
Abstract:
Introduction Tenofovir Disoproxil Fumarate (TDF) is the most widely used Anti-Retroviral Therapy (ART) drug due to its potency, safety profile and World Health Organization (WHO) recommendation. TDF causes proximal tubular renal dysfunction (PTRD) leading to Fanconi syndrome, acute kidney injury and chronic kidney disease. Modest rates (2–4%) of TDF related toxicity based on estimated Glomerular Filtration Rate (GFR) have been described, while TDF-induced PTRD has been reported to be 22%. TDF toxicity is more likely among African patients, it is reversible and TDF may be renal dosed in patients with dysfunction. The objective of this study was to assess proximal tubular renal dysfunction, global renal function, and their determinants among patients on TDF versus TDF-sparing regimen. Methods This was a cross-sectional study among people living with HIV/AIDS (PLWHA) attending the Academic Model Providing Access to Healthcare (AMPATH) program. The primary outcome of interest in this study was PTRD while the secondary outcome of interest was estimated GFR. PTRD was defined as any two of beta-2 microglobulin in urine, metabolic acidosis, normoglycemic glucosuria and fractional excretion of phosphate. Student’s t-test, chi-square and their non-parametric equivalents were used to test for statistical significance. Univariate and multivariate logistic regression analysis was carried out. Results A total of 516 participants were included in the final analysis, 261 on TDF while 255 were on TDF-sparing regimens. The mean (SD) age of all participants was 41.5 (12.6) years with majority being female (60.3%). The proportion of PTRD was 10.0% versus 3.1% in the TDF compared to TDF-sparing group (P<0.001). Mean estimated GFR was 112.8 (21.5) vs 109.7 (21.9) ml/min/1.73mm3 (P = 0.20) for the TDF compared to TDF-sparing group. TDF users were more likely to have PTRD compared to non-TDF users, adjusted Odds Ratio (AOR) 3.0, 95% CI 1.12 to 7.75. Conclusion There was significant PTRD in the TDF compared to TDF-sparing group without significant difference in estimated GFR. The clinical significance of these findings may not be clear in the short term.
9
Stürmer, Martin, Schlomo Staszewski, and Hans Wilhelm Doerr. "Quadruple Nucleoside Therapy with Zidovudine, Lamivudine, Abacavir and Tenofovir in the Treatment of HIV." Antiviral Therapy 12, no. 5 (July 2007): 695–704. http://dx.doi.org/10.1177/135965350701200514.
Abstract:
Highly active antiretroviral therapy (HAART) has significantly reduced morbidity and mortality in HIV-infected patients. However, problems such as short-term or long-term toxicity and the development of drug resistance could necessitate a change in the therapy regimen. Whereas various HAART options with low pill burden and favourable long-term tolerability profiles are available for naive patients, treatment of experienced patients tends to be more complex and remains a challenge. Treatment with class sparing nucleoside-only regimens could be an option in this context, but the combination of zidovudine (AZT), lamivudine (3TC) and abacavir (ABC) has shown to be inferior in terms of virological efficacy compared with the standard regimen. More promising data were obtained when AZT, 3TC and ABC were intensified with tenofovir (TDF), resulting in a quadruple nucleoside therapy. This regimen has demonstrated comparable potency to a standard regimen with AZT, 3TC and efavirenz in treatment-naive patients. Additionally, it has shown to be an efficient treatment option especially in moderately pretreated patients. This is accredited to the potency of the single components and the antagonistic selection pressure of AZT and TDF. The presence of L210W, or at least two of the mutations 41L, 67N, 70R, 215F/Y or 219Q/E, at or before baseline seems to be a predictor of non-response, whereas the presence of M184V does not impede virological response and might even be advantageous. This review summarizes current data on the combined use of AZT, 3TC, ABC and TDF in regard to virological and immunological outcome as well as genotypic predictors of response.
10
Kovalskaya, Galina N., Dina Y. Zhukova, and Ekaterina N. Mikhalevich. "Interaction of Drugs Used for the Treatment of Cardiovascular Diseases." Acta Biomedica Scientifica 4, no. 1 (April 4, 2019): 36–42. http://dx.doi.org/10.29413/abs.2019-4.1.6.
Abstract:
Combined therapy in cardiology is currently the most recognized method of treatment, especially in patients with hypertension. Approximately in 50 % of patients with hypertension, monotherapy is effective. However to achieve the desired effect in the remaining half of patients, simultaneous administration of two and sometimes three drugs is required. Numerous drugs with a fixed combination of two (and even three) antihypertensive drugs, often used in clinical practice, greatly simplify the dosage regimen of drugs and improve patients’ adherence to treatment. Unfortunately, simultaneous prescription of several drugs increases sharply the probability of inter-drug interaction with the increase in the number of prescribed drugs. The result of drug-drug intereaction may be unpredictable. Therefore, the ability to predict the possible adverse reactions in patients with cardiovascular diseases and to prescribe rationally combined pharmacotherapy is a guarantee of highly efficient and safe treatment.Currently, rational combinations of antihypertensive drugs of different groups make hypertension therapy more comfortable and increases patients’ adherence to treatment. The authors present topical combinations of antihypertensive drugs in one drug: angiotensin converting enzyme inhibitor + diuretic, β-adrenoblocker + diuretic; diuretic + angiotensin receptor antagonist; calcium antagonist + angiotensin receptor antagonist; calcium antagonist + β-adrenoblocker, and others.The article presents an overview of both rational (calcium antagonist + diuretic, β-adrenoblocker + diuretic,) and irrational (angiotensin converting enzyme Inhibitor + potassium-sparing diuretic, angiotensin receptor blocker + potassium-sparing diuretic) combinations of antihypertensive drugs. Combinations of some hypotensive and antianginal drugs with drugs of other groups with a high risk of adverse reactions are presented.
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Dwyer, Dominic E., Cassy Workman, Gillian Hales, Janaki Amin, David Cooper, John Miller, and Sean Emery. "Enfuvirtide in HIV-1-Infected Individuals Changing Therapy to A Nucleoside Reverse Transcriptase Inhibitor Sparing Regimen: The Alliance Study." Antiviral Therapy 11, no. 4 (May 1, 2005): 409–19. http://dx.doi.org/10.1177/135965350601100406.
Abstract:
The role of the fusion inhibitor enfuvirtide in nucleoside reverse transcriptase inhibitor (NRTI)-sparing regimens was assessed in an open-label study of fifty-nine highly antiretroviral drug exposed HIV-1-infected individuals. There was a reduction in plasma HIV-1 RNA of 1.43 (95% confidence interval [CI]: -2.06, -1.22) log10 copies/ml plasma over 96 weeks, and 44% (95% CI: 31, 58) of individuals had a viral load less than 400 copies/ml. A viral load below detection at 96 weeks was predicted by a baseline genotypic sensitivity score greater than 1. There was an average increase of 67 cells/μl (95% CI: 15, 120) from baseline CD4+ T-cell count to week 96, and the percentage of patients with CD4+ T-cell counts above 100 and 200 cells/μl increased over the trial. Injection site reactions (ISRs) were less common in people with CD4+ T-cell counts >250 cells/μl at any time during follow-up, and were more severe in patients with lower baseline peripheral fat. Adherence over 48 weeks to enfuvirtide injections ranged from 96.3-99.5%. During the 96 week trial there were two discontinuations due to ISRs and two discontinuations following hypersensitivity reactions. Over the 96 weeks of study lean body mass increased by an average 2.7 kg (95% CI; 1.7, 3.6 kg). Mean peripheral fat increased by 0.2 kg (95% CI; -0.2, 0.6 kg). Baseline NRTI-associated toxicities resolved in 17% of participants during follow-up. Enfuvirtide is an important component of antiretroviral therapy in highly treatment-experienced individuals where NRTI sparing may be desirable.
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Rabin, Bradford C., Kristina Reid, Tian-Zhi Guo, Eva Gustafsson, Chousheng Zhang, and Mervyn Maze. "Sympatholytic and Minimum Anesthetic Concentration-sparing Responses are Preserved in Rats Rendered Tolerant to the Hypnotic and Analgesic Action of Dexmedetomidine, a Selective α2-adrenergic Agonist." Anesthesiology 85, no. 3 (September 1, 1996): 565–73. http://dx.doi.org/10.1097/00000542-199609000-00016.
Abstract:
Background The development of tolerance to the sympatholytic and anesthetic-reducing effects of alpha(2) agonists after prolonged administration of dexmedetomidine and how the number of available alpha(2) adrenoceptors affects these dexmedetomidine-induced responses was studied. Methods The sympatholytic action of acute and chronic (3 and 10 micrograms.kg-1.h-1 for 7 days) dexmedetomidine, was assessed by the decrease in norepinephrine turnover in the locus coeruleus and hippocampus. The anesthetic-reducing effect of chronic (7 days) dexmedetomidine (5 and 10 micrograms.kg-1.h-1) was studied by determining the minimum alveolar concentration (MAC) for halothane that prevented rats from responding to a supramaximal noxious stimulus of dexmedetomidine (10 or 30 micrograms.kg-1), doses in the steep part of the dose-response curve. The receptor reserve for the norepinephrine turnover and anesthetic-sparing responses to dexmedetomidine was delineated with 0.3-1.0 mg.kg-1 N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, an irreversible alkylating agent. Results After chronic administration of dexmedetomidine at both doses, acute dexmedetomidine significantly decreased norepinephrine turnover in the hippocampus and locus coeruleus. The baseline minimum anesthetic concentration (MAC) and the MAC-sparing effect to acutely administered dexmedetomidine were preserved after chronic dexmedetomidine treatment. In the N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline experiments, the dexmedetomidine-induced norepinephrine turnover effect required less than 20% and greater than 4% alpha(2) adrenoceptor availability in the locus coeruleus and the dexmedetomidine induced MAC-sparing effect required less than 40% and greater than 20% alpha(2) adrenoceptor availability in the locus coeruleus. Conclusion Tolerance does not develop for either the sympatholytic or MAC-sparing actions of dexmedetomidine, although it is present for the hypnotic response. The durable quality of the sympatholytic and MAC-sparing responses to dexmedetomidine after chronic treatment is explained by a comparatively larger receptor reserve than is needed for the hypnotic and analgesic responses, which are blunted by the same drug treatment regimen.
13
Lewis, David A. "New treatment options for Neisseria gonorrhoeae in the era of emerging antimicrobial resistance." Sexual Health 16, no. 5 (2019): 449. http://dx.doi.org/10.1071/sh19034.
Abstract:
Neisseria gonorrhoeae, the causative agent of gonorrhoea, has rapidly evolved from an exquisitely susceptible pathogen into a ‘superbug’ with the capacity to exhibit an extensively drug resistant (XDR) phenotype. The threat of untreatable gonorrhoea now looms on the horizon while the arsenal of effective antimicrobial agents diminishes with time. Ceftriaxone remains the mainstay of first-line therapy as a single agent or as the backbone of a dual therapy regimen. The implementation of new assays to facilitate ‘precision’ treatment, based on the prediction of N. gonorrhoeae susceptibility to old anti-gonococcal drugs, may enable sparing use of ceftriaxone in those countries that can afford this technology. A few existing drugs, such as ertapenem, can be repositioned to help manage multi-drug resistant and XDR gonorrhoea. Recent clinical trials involving solithromycin and delafloxacin have generated disappointing results in that both agents failed to show non-inferiority to conventional ceftriaxone-based regimens. At present, zoliflodacin and gepotidacin appear to be the most promising antimicrobial agents in clinical development. Both drugs performed well in eradicating urogenital gonorrhoea in recent Phase 2 trials; however, treatment failures were reported at the oropharyngeal site, which is an important site of infection in men who have sex with men and sex workers. Given this observation, it is unlikely that either of these new agents could be promoted for monotherapy of gonorrhoea. The pre-clinical pipeline remains relatively empty of agents likely to progress to clinical development for gonorrhoea treatment and increased investment into gonorrhoea-specific drug discovery is recommended.
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Autar, Reshma S., Mark A. Boyd, Ferdinand WMN Wit, Kiat Ruxrungtham, Jongkol Sankote, Joep MA Lange, David A. Cooper, Praphan Phanuphak, David M. Burger, and Peter Reiss. "Relationships between Drug Exposure, Changes in Metabolic Parameters and Body Fat in HIV-Infected Patients Switched to a Nucleoside Sparing Regimen." Antiviral Therapy 12, no. 8 (November 2007): 1265–72. http://dx.doi.org/10.1177/135965350701200813.
Abstract:
Background The pathogenesis of metabolic disturbances in treated HIV infection is incompletely understood. Methods Relationships between fasted metabolic parameters, body composition, and drug plasma concentrations were investigated in 59 patients who switched from failed nucleoside analogue treatment to ritonavir-boosted indinavir and efavirenz therapy. Metabolic parameters, peripheral fat, visceral adipose tissue (VAT) and drug plasma concentrations were measured prospectively. Results Ritonavir exposure was found to be negatively correlated with high-density lipoprotein cholesterol (HDL-c) changes, with a 2.4% decrease in HDL-c for each unit increase in ritonavir concentration ratio. Significant associations between indinavir or efavirenz concentrations and metabolic disturbances were not observed. Total cholesterol (TC) correlated positively with high body mass index (BMI) and negatively with baseline limb fat mass: each unit increase in BMI and each kilogram reduction in baseline limb fat corresponded with a TC increase of 2.4% and 4.1%, respectively. Baseline triglyceride levels were lower in those patients with relatively greater limb fat mass: each kilogram reduction of total limb fat mass was associated with a 15.7% increase in triglyceride concentration. Changes in VAT were positively correlated with TC: for every unit TC increase a 0.3% VAT increase was observed (over 48 weeks). Conclusions Reduced limb fat mass at the start of the study treatment, increases in VAT mass, and higher plasma concentrations of ritonavir on study treatment were each - to varying degrees - associated with various metabolic disturbances.
15
Brugière, Olivier, Alexandre Vallée, Quentin Raimbourg, Marie-Noelle Peraldi, Sylvie Colin de Verdière, Laurence Beaumont, Abdulmonem Hamid, et al. "Conversion to belatacept after lung transplantation: Report of 10 cases." PLOS ONE 18, no. 3 (March 15, 2023): e0281492. http://dx.doi.org/10.1371/journal.pone.0281492.
Abstract:
Background Calcineurin inhibitors (CNIs) remain the cornerstone of maintenance immunosuppression (IS) after lung transplantation (LTx), although CNI-related life-threatening toxic effects may occur. Belatacept, a novel immunosuppressant that blocks a T-cell co-stimulation pathway, is a non-nephrotoxic drug indicated as an alternative to CNIs in kidney Tx. In LTx, there are only a few reports of belatacept conversion as a CNI-free or CNI-sparing IS treatment. Methods We reviewed a series of 10 LTx recipients with conversion to a CNI-free belatacept IS regimen within the first year post-LTx (n = 7) or a belatacept/low-dose CNI combination after the first year (n = 3). Results Use of belatacept was triggered by severe renal failure in 9 patients and under-IS with previous other IS-related toxicities in 1 patient. Mean estimated glomerular filtration rate after starting belatacept significantly improved at 6 months after initiation and at the last-follow-up (p = 0.006, and p = 0.002 respectively). The incidence of recurrent and/or severe acute cellular rejection (ACR) episodes was high in patients with CNI-free belatacept-based IS (n = 4/7). Chronic graft allograft dysfunction developed in 2 of 9 recipients under belatacept IS. Belatacept was stopped in 6 patients because of recurrent/severe ACR (n = 3), recurrent opportunistic infections (n = 1), center modified policy (n = 1), or other cause (n = 1). Conclusion Early conversion to CNI-free belatacept-based IS improved renal function in this series but was counterbalanced by a high incidence of recurrent ACR, including life-threatening episodes. Other studies are needed to better determine the indications for its use after LTx, possibly with lower immunological risk IS regimens, such as CNI-sparing belatacept.
16
Sultan, Mamoona, Adeena Khan, Syed Shahid Habib, and Dheyab Abdulsalam. "Unique clinical spectrum with distinguishing diagnostic features in Vogt-Koyanagi-Harada syndrome." BMJ Case Reports 12, no. 12 (December 2019): e231397. http://dx.doi.org/10.1136/bcr-2019-231397.
Abstract:
A 36-year-old ulcerative colitis male patient on treatment for 7 years was referred to dermatology with resistant alopecia universalis and hypopigmented patches on limbs for 5 months. During this time he also reported to ophthalmology with acute bilateral decreased vision for 5 days. His examination revealed hyperaemic discs, multifocal retinal detachments and choroidal granulomas. Taking into account the revised diagnostic criteria, atypical course of disease in the form of early cutaneous presentation followed by ophthalmic manifestations was attributed to Vogt-Koyanagi-Harada syndrome (VKHS) which was supported by relevant investigations including ophthalmic imaging, MRI and nerve conduction studies. Subclinical nerve conduction abnormalities and white matter demyelination were also seen for the first time in a patient of VKHS. Appropriate treatment was required to prevent visual complications; therefore, systemic corticosteroids with steroid sparing immunosuppressive drug therapy showed significant improvement in vision on follow-up. Cutaneous manifestations were resilient to the entire regimen.
17
Delyagin, Wassili M., and Inna V. Lukjanova. "Heart failure in children and adolescents (high yield topics for primary care pediatrician)." Pediatrics. Consilium Medicum, no. 3 (September 15, 2021): 277–84. http://dx.doi.org/10.26442/26586630.2021.3.200998.
Abstract:
HF in children is a life-threatening polyethiological state with a tendency to progression. There are acute and chronic heart failure, the causes of which are largely determined by age. Depending on the causes and features of hemodynamics, HF can occur with a stored (and borderline) and with a reduced ejection fraction. In early and young childhood, HF is manifested primarily by a decrease in appetite, sweating, decreased physical activity and a slowdown in physical development. At an older age, shortness of breath, edema, and enlargement of the liver are highlighted. The determination of biochemical markers of myocardial insufficiency (natriuretic peptide, troponin) is important for assessing the degree of HF, although the standards for their concentration for different age groups require further refinement. An instrumental study noted a decrease in myocardial contractility. Initially, myocardial oxygen consumption is increasing, which indicates its irrational use and corresponds to increased peroxidation. Subsequently, myocardial oxygen consumption decreases even without signs of coronary pathology. Treatment should include mandatory sufficient calorie intake, sparing regimen, complex drug therapy.
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Hong, H., D. W. Dowdy, K. E. Dooley, H. W. Francis, C. Budhathoki, H.-R. Han, and J. E. Farley. "Risk of hearing loss among multidrug-resistant tuberculosis patients according to cumulative aminoglycoside dose." International Journal of Tuberculosis and Lung Disease 24, no. 1 (January 1, 2020): 65–72. http://dx.doi.org/10.5588/ijtld.19.0062.
Abstract:
SETTING: The ototoxic effects of aminoglycosides (AGs) lead to permanent hearing loss, which is one of the devastating consequences of multidrug-resistant tuberculosis (MDR-TB) treatment. As AG ototoxicity is dose-dependent, the impact of a surrogate measure of AG exposure on AG-induced hearing loss warrants close attention for settings with limited therapeutic drug monitoring.OBJECTIVE: To explore the prognostic impact of cumulative AG dose on AG ototoxicity in patients following initiation of AG-containing treatment for MDR-TB.DESIGN: This prospective cohort study was nested within an ongoing cluster-randomized trial of nurse case management intervention across 10 MDR-TB hospitals in South Africa.RESULTS: The adjusted hazard of AG regimen modification due to ototoxicity in the high-dose group (≥75 mg/kg/week) was 1.33 times higher than in the low-dose group (<75 mg/kg/week, 95%CI 1.09–1.64). The adjusted hazard of developing audiometric hearing loss was 1.34 times higher than in the low-dose group (95%CI 1.01–1.77). Pre-existing hearing loss (adjusted hazard ratio [aHR] 1.71, 95%CI 1.29–2.26) and age (aHR 1.16 per 10 years of age, 95%CI 1.01–1.33) were also associated with an increased risk of hearing loss.CONCLUSION: MDR-TB patients with high AG dose, advanced age and pre-existing hearing loss have a significantly higher risk of AG-induced hearing loss. Those at high risk may be candidates for more frequent monitoring or AG-sparing regimens.
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Kast, Richard E., Marc-Eric Halatsch, and Rafael Rosell. "OPALS: A New Osimertinib Adjunctive Treatment of Lung Adenocarcinoma or Glioblastoma Using Five Repurposed Drugs." Cells 10, no. 5 (May 10, 2021): 1148. http://dx.doi.org/10.3390/cells10051148.
Abstract:
Background: Pharmacological targeting aberrant activation of epidermal growth factor receptor tyrosine kinase signaling is an established approach to treating lung adenocarcinoma. Osimertinib is a tyrosine kinase approved and effective in treating lung adenocarcinomas that have one of several common activating mutations in epidermal growth factor receptor. The emergence of resistance to osimertinib after a year or two is the rule. We developed a five-drug adjuvant regimen designed to increase osimertinib’s growth inhibition and thereby delay the development of resistance. Areas of Uncertainty: Although the assembled preclinical data is strong, preclinical data and the following clinical trial results can be discrepant. The safety of OPALS drugs when used individually is excellent. We have no data from humans on their tolerability when used as an ensemble. That there is no data from the individual drugs to suspect problematic interaction does not exclude the possibility. Data Sources: All relevant PubMed.org articles on the OPALS drugs and corresponding pathophysiology of lung adenocarcinoma and glioblastoma were reviewed. Therapeutic Opinion: The five drugs of OPALS are in wide use in general medicine for non-oncology indications. OPALS uses the anti-protozoal drug pyrimethamine, the antihistamine cyproheptadine, the antibiotic azithromycin, the antihistamine loratadine, and the potassium sparing diuretic spironolactone. We show how these inexpensive and generically available drugs intersect with and inhibit lung adenocarcinoma growth drive. We also review data showing that both OPALS adjuvant drugs and osimertinib have data showing they may be active in suppressing glioblastoma growth.
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Totiger, Tulasigeri M., Anirban Ghoshal, Jenna Zabroski, Anya Sondhi, Saanvi Bucha, Jacob Jahn, Yangbo Feng, and Justin Taylor. "Targeted Therapy Development in Acute Myeloid Leukemia." Biomedicines 11, no. 2 (February 20, 2023): 641. http://dx.doi.org/10.3390/biomedicines11020641.
Abstract:
Therapeutic developments targeting acute myeloid leukemia (AML) have been in the pipeline for five decades and have recently resulted in the approval of multiple targeted therapies. However, there remains an unmet need for molecular treatments that can deliver long-term remissions and cure for this heterogeneous disease. Previously, a wide range of small molecule drugs were developed to target sub-types of AML, mainly in the relapsed and refractory setting; however, drug resistance has derailed the long-term efficacy of these as monotherapies. Recently, the small molecule venetoclax was introduced in combination with azacitidine, which has improved the response rates and the overall survival in older adults with AML compared to those of chemotherapy. However, this regimen is still limited by cytotoxicity and is not curative. Therefore, there is high demand for therapies that target specific abnormalities in AML while sparing normal cells and eliminating leukemia-initiating cells. Despite this, the urgent need to develop these therapies has been hampered by the complexities of this heterogeneous disease, spurring the development of innovative therapies that target different mechanisms of leukemogenesis. This review comprehensively addresses the development of novel targeted therapies and the translational perspective for acute myeloid leukemia, including the development of selective and non-selective drugs.
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Eisbruch, Avraham, John M. Robertson, Carolyn M. Johnston, Joseph Tworek, Kevin R. Reynolds, James A. Roberts, and Theodore S. Lawrence. "Bromodeoxyuridine Alternating With Radiation for Advanced Uterine Cervix Cancer: A Phase I and Drug Incorporation Study." Journal of Clinical Oncology 17, no. 1 (January 1999): 31. http://dx.doi.org/10.1200/jco.1999.17.1.31.
Abstract:
PURPOSE: Preclinical studies show a significant increase in the ratio of the radiosensitizer bromodeoxyuridine (BUdR) in tumors versus the intestinal mucosa during the drug elimination period, compared with the ratio during drug infusion. We constructed a phase I study in patients with locally advanced cervix cancer, using alternating cycles of BUdR and radiation therapy (RT). PATIENTS AND METHODS: Eighteen patients with stage IIB to IVA cervix cancer participated. A treatment cycle consisted of a 4-day BUdR infusion followed by a week of pelvic RT, 15 Gy twice daily in 1.5-Gy fractions. After three cycles, additional BUdR was infused, followed by brachytherapy. The fraction of thymidine replaced by BUdR and the fraction of cells incorporating BUdR were determined in rectal mucosa and tumor biopsies at the end of the first BUdR infusion (day 5), at the middle of the first RT week (day 10), and at the time of brachytherapy. RESULTS: Dose-limiting toxicity was observed in one of 16 patients receiving 1,000 mg/m2/d × 4 days and inboth patients receiving 1,333 mg/m2/d × 4 days each cycle. After a median follow-up of 39 months, 12 patients (66%) were free of pelvic disease and nine (50%) were alive and disease free. The ratio of tumor to rectum BUdR incorporation averaged 1.5 to 1.8 and did not differ significantly between day 5 and day 10. A trend toward reduced ratio was observed at brachytherapy. Drug-containing cells in rectal biopsies migrated from the crypts to the mucosal surface. CONCLUSION: In this schedule, 1,000 mg/m2/d is the maximum-tolerated dose of BUdR. BUdR incorporation levels in tumors were consistent with clinically significant radiosensitization. The migration of BUdR-containing rectal mucosa cells from the crypts to the surface at the time of RT suggests that this regimen may offer a relative sparing of the mucosa from radiosensitization.
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Kim, You Sun. "Treatment of inflammatory bowel diseases: focusing on 5-aminosalicylates and immunomodulators." Journal of the Korean Medical Association 64, no. 9 (September 10, 2021): 596–604. http://dx.doi.org/10.5124/jkma.2021.64.9.596.
Abstract:
Background: Recently, the incidence and prevalence rates of inflammatory bowel disease (IBD) have increased worldwide, including in Korea. Although there has been considerable progress in the management of IBD following the discovery of biologic agents, 5-aminosalicylate (5-ASA) and immunomodulators are still considered cornerstones in the management of mild to moderate IBD.Current Concepts: 5-ASA plays a key role in inducing remission in patients with mild to moderate ulcerative colitis. High doses of 5-ASA are more effective in inducing remission in patients with moderate ulcerative colitis, and combination therapy of oral 5-ASA and topical 5-ASA agents is recommended. Although the effect of 5-ASA in patients with Crohn disease is limited, high doses of 5-ASA can be effective for patients with mild disease, inflammatory behavior, and colonic involvement. Maintaining remission is essential for patients with IBD. Good doctor-patient relationships and encouraging drug adherence are recommended. Regarding drug adherence, a once-daily regimen is preferred for patients’ satisfaction. Thiopurines, the most important immunomodulators, show therapeutic benefits, such as steroid-sparing effects and remission maintenance in ulcerative colitis and Crohn disease after induction therapy. However, several side effects, including severe leukopenia, can induce the discontinuation of thiopurines. Close monitoring and management decisions should be individualized according to the risk of relapse and adverse events.Discussion and Conclusion: In conclusion, 5-ASA and immunomodulators are cornerstones in the management of IBD. As such, clinicians should have knowledge of these drugs and patients’ characteristics for proper prescription.
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Sher, Taimur, Kena C. Miller, Sikander Ailawadhi, Debbie Manfredi, Margaret Wood, Wei Tan, Gregory Wilding, et al. "Bortezomib in Combination with Pegylated Liposomal Doxorubicin and Thalidomide (VDT), An Effective Steroid Independent Regimen for Previously Untreated Multiple Myeloma Patients: Final Result of a Phase II Study." Blood 114, no. 22 (November 20, 2009): 618. http://dx.doi.org/10.1182/blood.v114.22.618.618.
Abstract:
Abstract Abstract 618 Introduction: Steroids have been an important component of multiple myeloma (MM) therapeutics. High doses steroids as used in MM are associated with significant toxicity and morbidity. Development of steroid independent or steroid-lite regimens remains an important area of investigation in MM. Orlowski et al combined Doxil (D) with bortezomib (V) and showed enhanced anti-myeloma activity. In a phase II study in relapsed refractory MM patients, we observed further improvement in clinical efficacy with addition of thalidomide (T) to VD combination (VDT regimen). Encouraged by high response rates of this steroid sparing novel combination we investigated VDT regimen in treatment naïve MM patients. Final results of this phase II trial are reported here. Methods: Patients with previously untreated MM were eligible for this phase II trial. VDT regimen (V 1.3mg/m2 on days 1, 4,15,18; D 20mg/m2 on days 1,15 and T 200 mg daily continuously) given on a 4-week cycle for a maximum of 8 cycles. Acyclovir (400 mg BID) and weight adjusted low-dose warfarin (1 or 2mg for absolute body weight <70kg or ≥70kg, respectively) was given for prophylaxis of herpes zoster and deep vein thrombosis (DVT), respectively. Response was assessed using the modified Blade criteria. Results: Forty patients (26 males, 14 females; median age 60.5, range 40-80 yrs) were enrolled on this study. Among these 58%(n=23) had stage III (Durie-Salmon) disease with a median b2 microglobulin of 3.7 (range 1.6-16.5 mg/L) and median LDH of 443 (range 152-129 IU/L). Thirty-nine patients are eligible for response evaluation (1 too early for assessment). Overall response rate (CR/nCR+PR) was 79.4% (n=31) with 38% (n=15) patients achieving CR/nCR. The median progression free (PFS) and overall survival (OS) has not been reached. At 1 year the PFS and OS is 81% and 97%, respectively (1 patient died from disease progression to leukemic phase). Toxicity: Neutropenia was the most significant hematological toxicity with grade 3 and 4 neutropenia observed in 22.5% and 2.5% of the patients, respectively. Only 1 (2.2%) patient had febrile neutropenia. Clinically significant neuropathy (grade ≥2) was seen in 20% while grade ≥2 palmer planter erythrodysesthesia was seen in 15% (n=6) of the patients. Other grade 3 non-hematological toxicities included pneumonia (20%), pleural effusion (10%), pulmonary embolism (2%), DVT (2%), congestive heart failure (5%) and interstitial pneumonitis (2%). Conclusion Although effective, steroid based treatment regimen can be associated with significant toxicity especially among patients with concurrent co morbid conditions such as hypertension and diabetes mellitus. Furthermore, recent investigations demonstrate that decreasing steroid doses may actually improve PFS and OS despite a comparatively low initial ORR. In this clinical trial we hypothesized that rational combination of novel myeloma agents may actually preclude the need to rely on high-dose steroids without significantly compromising ORR. Consistent with our expectations, the VDT regimen has ORR comparable to some of the steroid-inclusive triple drug combinations. The toxicity profile of this combination was acceptable and the regimen was well tolerated. Thus we note that VDT is an effective and well tolerated steroid-independent induction regimen for MM patients. Disclosures: Off Label Use: A Phase II study of a novel combination in newly diagnosed myeloma patients. Miller:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Czuczman:Centocor Ortho Biotech: Research Funding. Sood:Celgene: Stock. Chanan-Khan:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immunogen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.
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Law, Lisa Y., Ryan Stevenson, Gwendolyn Ho, Bijay Nair, Asakura Laura, and Antoine Sayegh. "Venetoclax-Based Regimen for Treatment of Patients with Acute Myeloid Leukemia in Community Based Practices." Blood 134, Supplement_1 (November 13, 2019): 5081. http://dx.doi.org/10.1182/blood-2019-121816.
Abstract:
Introduction: There are limited options for acute myeloid leukemia (AML) patients who are too frail to receive intensive induction chemotherapy or who have relapsed /refractory disease. Early phase II trials published in 2016 demonstrated promising outcomes in AML with the BCL-2 inhibitor venetoclax, which was FDA approved in November 2018. We conducted a retrospective review of AML patients who received venetoclax at Kaiser Permanente Northern California (KPNC) specifically examining patients' characteristics and outcomes. Methods: This is a retrospective review of all KPNC patients who had a diagnosis of AML and received at least 1 prescription of venetoclax from January 1, 2016 through March 31, 2019. Data was abstracted from our electronic medical record. Variables included age, complete blood count, AML type, lines of therapy, prior use of hypomethylating agent, cytogenetics, somatic mutation, duration of treatment and chemotherapy regimen. Because none of the patients were treated under clinical trial protocol, most did not have a scheduled bone marrow biopsy to formally document disease status. Hematologic response (HR), defined here as neutrophil ≥ 0.5 x 109/L, platelet ≥ 50 x 109/L and RBC transfusion independence was used to access treatment effectiveness. Results were analyzed via descriptive statistics. Results: A total of 68 patients received venetoclax-based chemotherapy for treatment of AML. The median age was 68 (range 12-87). Among those 68 patients, 35% had venetoclax-based treatment as first line therapy, 35% as second line, and the remaining as third or later line (Table 1). Among those who received venetoclax as first line treatment, 58% had a HR. Among those who received venetoclax as second line treatment, 29% had a HR and 43% of those went on to allogeneic bone marrow transportation (BMT). 20% of those that received venetoclax in the third line setting had a HR and all went on to BMT. Patients who received venetoclax in fourth line or above did not have any significant response. Only 2 out of the 16 patients who received prior hypomethylating agent responded to venetoclax combination therapy. Four patients did not even complete cycle 1. 12 out of 68 patients were prescribed venetoclax based on FDA approved guidelines in November 2018. Of those 75% demonstrated HR. Conclusion While most of our patients used off-label venetoclax in a non-clinical trial setting, we confirm that venetoclax-based regimen is an effective treatment for AML, similar to published data. Our cohort represents a more heterogeneous population, which is more generalizable to the community. There is a higher response rate among those who used it in the first- and second-line setting (58% and 29% respectively). Venetoclax also showed efficacy in the second- or third-line setting, bridging patients to allogeneic BMT. Patients with prior hypomethylating agent are less likely to benefit from this drug. Venetoclax in combination with a hypomethylating agent is an effective AML regimen. Its efficacy deserves further studies, perhaps as a front-line treatment, sparing patients from intensive toxic inpatient induction chemotherapy. Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: This retrospective study evaluates the use of venenoclax-based regimen for treatment of AML. Clinicians have been using it since 2016, but the drug was not formally FDA approved for AML until November 2018.
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Horvath, Lena, and Andreas Pircher. "ASCO 2020 non-small lung cancer (NSCLC) personal highlights." memo - Magazine of European Medical Oncology 14, no. 1 (January 13, 2021): 66–69. http://dx.doi.org/10.1007/s12254-020-00673-2.
Abstract:
SummaryIn this article we summarize our personal non-small cell lung cancer (NSCLC) highlights of the virtual ASCO 2020 meeting, covering developments in early and advanced-stage NSCLC. Until recently early stage NSCLC patients were treated independently of their genetic profile. Now the ADAURA study proved that postoperative osimertinib significantly prolongs disease-free survival compared to standard chemotherapy in EGFR-mutated NSCLC , underlining the high efficacy of targeted therapies in early stages. In advanced-stage disease, of course immunotherapy (IO) was at the center of attention. Final analysis of KEYNOTE-189 (pembrolizumab plus chemotherapy versus chemotherapy alone) and 3‑year update of CheckMate 227 (nivolumab plus ipilimumab versus standard chemotherapy) proved the long-term overall survival benefit of IO combinations in the first-line setting independent of PD-L1 status. The innovative CheckMate 9LA study demonstrated rapid disease control with limited-course chemotherapy plus IO doublet, while sparing chemotoxicity and may soon become a new clinical treatment choice. Moreover, the phase II CITYSCAPE trial presented significant response rates of the TIGIT-inhibitor tiragolumab plus atezolizumab in PD-L1 positive NSCLC. For HER2-mutated patients a highly effective drug conjugate trastuzumab deruxtecan was presented in a phase II study, extending targeted agents in genetically driven NSCLC. Altogether, ASCO 2020 could excite with inspiring new data for an optimized and more individualized NSCLC treatment regimen, contributing to a better outcome for both early and late-stage diseased patients and continuing to decrease lung cancer mortality.
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Finn, Jonathan D., Patricia Favaro, J. Fraser Wright, Federico Mingozzi, Katherine A. High, and Valder R. Arruda. "Rabbit Anti-Thymocyte Globulin (rATG) Administrated Concomitantly with Liver Delivery of AAV2-hFIX Can Promote Inhibitor Formation In Rhesus Macaques." Blood 116, no. 21 (November 19, 2010): 3765. http://dx.doi.org/10.1182/blood.v116.21.3765.3765.
Abstract:
Abstract Abstract 3765 Adeno-associated viral (AAV) vectors are one of the most extensively studied vector platforms for gene therapy applications. Our group is currently developing AAV vectors for the therapeutic treatment of hemophilia B (HB) in humans. The first clinical trial using an AAV2 vector to express human Factor IX (hFIX) (AAV2-hFIX16) from the liver of HB patients revealed a cytotoxic T lymphocyte (CTL) response directed against AAV capsid that occurred 4–6 weeks following treatment that was associated with a decline in transgene expression. Thus, immunosuppressive (IS) therapies may be required during AAV2 vector administration at high doses to prevent or to halt the immune mediated destruction of transduced hepatocytes. Previous work in murine and non-human primate (NHP) models has shown that sustained AAV-mediated expression of transgenes can induce tolerance, and that this is in part, dependent on CD4+ CD25+ FoxP3+ regulatory T cells (Tregs). Here we investigate the safety of a Treg sparing anti-T cell IS regimen in the context of liver mediated AAV2 gene transfer. Rabbit anti-thymocyte globulin (rATG) is an immune suppressive drug that is used in solid organ transplant and autoimmune disease. rATG has been shown to dramatically deplete the majority of T-cells, however some studies have shown that rATG spares Tregs and can induce tolerance in human T cells. rATG was administered to rhesus macaques (along with an 8-week course of Mycophenolate Mofetil (MMF) and sirolimus) either at the time of AAV vector administration (AAV2-hFIX16), or 5 weeks post-vector administration (rescue therapy). The administration of ATG at week 5 had no detrimental effect on hFIX expression and was not associated with inhibitor formation (n=3) indicating that rATG might be safe to use as an IS ‘rescue' agent, after the detection of an ongoing immune response against transduced cells. Interestingly we observed that early administration of rATG prevented tolerance induction and resulted in inhibitor formation in 2 of 3 animals upon withdrawal of IS. The inhibitor formation was associated with transient elevations in circulating levels of IL-2, IL-4, IL-10 and IFN-g. These results are comparable to previous findings in NHP using an anti-CD25 IS regimen (Daclizumab) at the time of vector administration (Blood 2007, 110(7):2334-41). We conclude that the timing of IS regimens is critical, and that IS regimens that alter the numbers, frequency, and/or function of T-cells at the time of vector administration can result in neutralizing antibodies (inhibitors) to the transgene product (hFIX). These data suggest that there might be multiple mechanisms responsible for maintaining tolerance in this model, and that Tregs alone might not be sufficient. This study highlights the critical need for safety studies in large animal models of potential immune suppressive regimens in the context of gene transfer before translating to the clinic. Disclosures: High: Genzyme, Inc: Consultancy, Patents & Royalties; Third Rock Ventures: Consultancy; Novo-Nordisk: Consultancy; Shire, Inc.: Consultancy.
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Dybkær, Karen, Hanne Due, Rasmus Froberg Brøndum, Ken H. Young, and Martin Bøgsted. "Addition of Drug-Response Specific Micro-RNAs to the International Prognostic Index Improves Prognostic Stratification of GCB-DLBCL Patients Treated with R-CHOP." Blood 134, Supplement_1 (November 13, 2019): 1623. http://dx.doi.org/10.1182/blood-2019-122351.
Abstract:
Background: Patients with Diffuse large B-cell lymphoma (DLBCL) in approximately 40% of cases suffer from primary refractory disease and treatment induced immuno-chemotherapy resistance demonstrating that standard provided treatment regimens are not sufficient to cure all patients. Early detection of resistance is of great importance and defining microRNA (miRNA) involvement in resistance could be useful to guide treatment selection and help monitor treatment administration while sparing patients for inefficient, but still toxic therapy. Concept and Aims: With information on drug-response specific miRNAs, we hypothesized that multi-miRNA panels can improve robustness of individual clinical markers and serve as a prognostic classifier predicting disease progression in DLBCL patients. Methods: Fifteen DLBCL cell lines were tested for sensitivity towards rituximab (R), cyclophosphamide (C), doxorubicin (H), and vincristine (O). Cell line specific seeding concentrations was used to ensure exponential growth and each cell line was subjected to 16 concentrations in serial 2-fold dilutions and number of metabolic active cells was evaluated after 48 hours of drug exposure using MTS assay. For each drug, we ranked the cell lines according to their sensitivity and categorized them as sensitive, intermediate responsive, or resistant. Differential miRNA expression analysis between sensitive and resistant cell lines identified 43 miRNAs to be associated with response to compounds of the R-CHOP regimen, by selecting probes with a log fold change larger than 2. Baseline miRNA expression data were obtained for each cell line in untreated condition, and differential miRNA expression analysis identified 43 miRNAs associated to response to R-CHOP. Using the Affymetrix HG-U133+2 platform, expression levels of the miRNA precursors were assessed in 701 diagnostic DLBCL biopsies, and miRNA-panel classifiers were build using multiple Cox regression or random survival forest. Results: Generated prognostic miRNA-panel classifiers were tested for predictive accuracies and were subsequently evaluated by Brier scores and time varying area under the ROC curves (tAUC). Progression-free survival (PFS) was chosen as the outcome, since it is a treatment evaluation parameter as closely as possible to the time of drug exposure and the tested miRNAs were all associated directly to drug specific response. Furthermore, overall survival (OS) was used for verification of findings. Comparison of analyses conducted for the respective cohorts (All DLBCL, ABC, and GCB patients) showed the lowest prediction errors for all models within the GCB subclass with a multivariate Cox miRNA-panel model including miR-146a, miR-155, miR-21, miR-34a, and miR-23a~miR-27a~miR-24-2 cluster performed the best and successfully stratified GCB-DLBCL patients into high- and low-risk of disease progression. In addition, combination of the miRNA-panel and international prognostic index (IPI) substantially increased prognostic performance in GCB classified patients, indicating a prognostic signal from the response-specific miRNAs independent of IPI. In conclusion: We found as proof of concept that adding gene expression data detecting drug-response specific miRNAs to the clinically established IPI improved the prognostic stratification of GCB-DLBCL patients treated with R-CHOP. Disclosures No relevant conflicts of interest to declare.
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Soon, Gaik H., Ping Shen, Eu-Leong Yong, Paul Pham, Charles Flexner, and Lawrence Lee. "Pharmacokinetics of Darunavir at 900 Milligrams and Ritonavir at 100 Milligrams Once Daily when Coadministered with Efavirenz at 600 Milligrams Once Daily in Healthy Volunteers." Antimicrobial Agents and Chemotherapy 54, no. 7 (April 12, 2010): 2775–80. http://dx.doi.org/10.1128/aac.01564-09.
Abstract:
ABSTRACT Ritonavir-boosted darunavir with efavirenz may be considered a nucleoside-sparing regimen for treatment-naïve HIV-infected patients. However, the pharmacokinetics of this combination administered once daily have not been studied. We conducted a three-period interaction study with healthy volunteers. The subjects were given darunavir at 900 mg with ritonavir at 100 mg once daily for 10 days. Efavirenz at 600 mg once daily was added for 14 days. Darunavir-ritonavir was then stopped and efavirenz alone was given for 14 days. At the end of each period, blood was taken predosing and for up to 24 h postdosing to measure the drug concentrations. We recruited seven males and five females ages 24 to 49 years and weighing 50 to 83 kg. The darunavir trough concentrations were reduced after efavirenz administration (geometric mean ratio [GMR], 0.43; 90% confidence interval [CI], 0.32 to 0.57]; P < 0.001). The mean darunavir trough concentrations were 1,180 ng/ml (standard deviation, 1,138 ng/ml) after efavirenz administration, but all darunavir trough concentrations were above the 50% effective concentration (EC50) of 55 ng/ml for the wild-type virus. For darunavir, the area under the concentration-time curve from 0 to 24 h (AUC0-24) (GMR, 0.86; 90% CI, 0.75 to 0.97; P = 0.05) and the half-life (GMR, 0.56; 90% CI, 0.49 to 0.65; P < 0.001) were also significantly reduced. The darunavir peak concentrations were not significantly changed (GMR, 0.92; 90% CI, 0.82 to 1.03; P = 0.23). The ritonavir trough concentrations (GMR, 0.46; 90% CI, 0.33 to 0.63; P = 0.001), AUC0-24 (GMR, 0.74; 90% CI, 0.64 to 0.86; P = 0.004), and half-life (GMR, 0.80; 90% CI, 0.75 to 0.86; P < 0.001) were also significantly reduced. The efavirenz half-life was significantly longer when it was coadministered with darunavir-ritonavir than when it was given alone (GMR, 1.66; 90% CI, 1.24 to 2.23; P = 0.01), but there were no differences in the efavirenz trough or peak concentration or AUC0-24 when it was coadministered with darunavir-ritonavir. Efavirenz reduced the trough concentrations of darunavir significantly, but the concentrations remained above the EC50 for the wild-type virus. This regimen should be evaluated with treatment-naïve patients with no preexisting resistance.
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Ng, Loke, Yeo, Chng, and Tan. "A Meta-Analysis of the Utility of Preoperative Intravenous Paracetamol for Post-Caesarean Analgesia." Medicina 55, no. 8 (July 31, 2019): 424. http://dx.doi.org/10.3390/medicina55080424.
Abstract:
Background and objectives: Worldwide, the number of caesarean sections performed has increased exponentially. Some studies have reported better pain control and lower postoperative requirements for opioids when intravenous (IV) paracetamol was administered preoperatively. This meta-analysis thus aimed to investigate the utility of preoperative IV paracetamol for post-caesarean analgesia. Materials and Methods: By using the keywords (paracetamol OR acetaminophen) AND [cesarea* OR caesarea* OR cesaria* OR caesaria*], a systematic literature search was conducted using PubMed, Medline, Embase, Google Scholar and ClinicalTrials.gov databases for papers published in English between January 1, 1960 and March 1, 2019. Grey literature was searched as well. Results: Seven clinical trials were reviewed, while five randomized, placebo-controlled, double-blind studies were included in the final meta-analysis. Applying per-protocol analysis and a random-effects model, there was a significant reduction in postoperative opioid consumption and pain score in the group that received preoperative IV paracetamol, compared to placebo, as the standardized mean difference (SMD) were −0.460 (95% CI −0.828 to −0.092, p = 0.014) and −0.719 (95% CI: −1.31 to −0.13, p = 0.018), respectively. However, there was significant heterogeneity amongst the different studies included in the meta-analysis (I2 = 70.66%), perhaps owing to their diverse protocols. Some studies administered IV paracetamol 15 min before induction while others gave it before surgical incision. Conclusion: This is the first review on the topic. Overall, preoperative IV paracetamol has convincingly demonstrated useful opioid-sparing effects and it also appears safe for use at the time of delivery. It should be considered as a component of an effective multimodal analgesic regimen. Future studies could be conducted on other patient groups, e.g., those with multiple comorbidities or chronic pain disorders, and further delineate the optimal timing to administer the drug preoperatively.
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Jeny, Florence, Hilario Nunes, and Dominique Valeyre. "Current Medical Therapy for Sarcoidosis." Seminars in Respiratory and Critical Care Medicine 38, no. 04 (July 27, 2017): 523–31. http://dx.doi.org/10.1055/s-0037-1604032.
Abstract:
AbstractMost cases of sarcoidosis are mild and self-limited, with a spontaneous cure. However, in some patients, this disease may also be life-threatening, particularly when severe manifestations induce vital organ dysfunction. Sarcoidosis may also severely impair the quality of life through diverse, persistent disabling symptoms. To date, there is no curative treatment for sarcoidosis, but only anti-inflammatory drugs limiting the pathologic impact of sarcoidosis in reducing enhanced immunity reactions, granulomatous formation, and their consequences. Current anti-inflammatory treatments for sarcoidosis include corticosteroids as the first-line treatment; disease-modifying antisarcoid drugs, mainly immunosuppressive and immunomodulatory drugs, as second-line treatment; and finally tumor necrosis factor (TNF) inhibitors, as third-line treatment. Corticosteroids are most effective; they give rapid results, sometimes with serious, incremental adverse effects. A second-line treatment, mainly low-dose methotrexate and azathioprine, is indicated in case of corticosteroid resistance, intolerance, or contraindication or more often as a corticosteroid-sparing agent when a prolonged treatment of more than 10 mg/d equivalent prednisone is expected. TNF inhibitors are considered in severe refractory sarcoidosis. Infliximab has been proven effective. Usually, treatment for sarcoidosis lasts up to 1 year or longer. The usual drug regimen is made of an induction and then a maintenance protocol before a step-by-step decrease and eventual withdrawal. Contraindications may exist. Each therapeutic decision must follow a rigorous diagnostic evaluation to determine the disease impact, its outcome (progression or not), and its response to treatment in the long run. Pharmacogenetics is still in its infancy, but could help develop a more personalized therapy. Non anti-inflammatory treatments, such as implantable cardiac devices, are also useful, particularly for some organs. In the end, persistent disabling symptoms are very frequent and call for an accurate diagnosis, which may be difficult to treat.
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S., Sivakumar, and Banupriya K. "Monitoring of adverse drug reactions caused by methotrexate at the dermatology department of a tertiary care centre." International Journal of Research in Dermatology 3, no. 3 (August 24, 2017): 389. http://dx.doi.org/10.18203/issn.2455-4529.intjresdermatol20173078.
Abstract:
<p class="abstract"><strong>Background:</strong> <span lang="EN-IN">Dermatologists are using antineoplastic agent methotrexate for more than six decades for various skin diseases. Methotrexate is a dihydrofolate reductase inhibitor and has cytotoxic<strong>,</strong> anti-inflammatory and steroid sparing effect. However, long term use of methotrexate raises a concern about its safety. Careful monitoring of patients on methotrexate therapy can either minimize or prevent the adverse effects.</span><span lang="EN-IN">The aim of the study was to evaluate the adverse drug reactions caused by methotrexate therapy in the treatment of dermotological diseases.</span></p><p class="abstract"><strong>Methods:</strong> <span lang="EN-IN">Observational clinical study done in 56 patients with skin diseases, who were on methotrexate therapy. LFT, RFT, blood counts done at baseline and every 2 weeks till the end of six months. Adverse reactions were monitored and assessed using WHO-UMC scale</span>.<strong></strong></p><p class="abstract"><strong>Results:</strong> <span lang="EN-IN">Among sixteen Psoriasis patients on methotrexate (max 15 mg/wk) therapy, 62.5% experienced adverse effects and the most common ADR being GI upset in 6 patients. Other common adverse effects observed were elevated liver enzymes, leucopenia, thrombocytopenia, candidiasis and elevated serum creatinine. None of the patients in our study had pulmonary toxicity, life threatening adverse effects requiring hospitalisation or secondary lymphoma. Adverse effects caused by methotrexate were dose dependent. So low dose weekly methotrexate regimen with folate supplementation in the form of folic acid or folinic acid can minimize the adverse effects. </span></p><p class="abstract"><strong>Conclusions:</strong> <span lang="EN-IN">Our study was successful in identifying the adverse effects caused by methotrexate when used for various skin diseases in the department of dermatology.</span></p>
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Lauretti, Gabriela R., Izabel C. P. R. Lima, Marlene P. Reis, Wiliam A. Prado, and Newton L. Pereira. "Oral Ketamine and Transdermal Nitroglycerin as Analgesic Adjuvants to Oral Morphine Therapy for Cancer Pain Management." Anesthesiology 90, no. 6 (June 1, 1999): 1528–33. http://dx.doi.org/10.1097/00000542-199906000-00005.
Abstract:
Background Guidelines for cancer pain management include nonsteroidal antiinflammatory drugs with opioids administered in a time-contingent manner. This study was designed to evaluate the role of oral ketamine or transdermal nitroglycerin polymer, a nitric oxide donor, as coadjuvants to oral morphine in cancer pain therapy. Methods After institutional approval and informed patient consent were obtained, 60 patients with cancer pain were randomized to one of four groups (n = 15) and studied prospectively to evaluate analgesia and any adverse effects. A visual analog scale that consisted of a 10-cm line with 0 representing "no pain at all" and 10 representing "the worst possible pain" was introduced. All patients were regularly taking oral amitriptyline 50 mg at bedtime. The morphine regimen was adjusted individually to a maximal oral dose of 80-90 mg/day to keep the visual analog scale score less than 4. When patients reported pain (visual analog scale of 4 or more), despite taking 80-90 mg oral morphine daily, the test drug was added as follows: the control group (CG) received an additional 20 mg oral morphine (10 mg at 12-h intervals); the nitroglycerin group (NG) received a 5-mg nitroglycerin patch daily; the ketamine group (KG) received 0.5 mg/kg oral ketamine at 12-h intervals; and the dipyrone group (DG) received 500 mg oral dipyrone at 6-h intervals. Patients were free to manipulate their daily morphine consumption when the test drug was introduced to keep their visual analog scale score less than 4. Results The groups were similar with respect to demographic data and visual analog scale pain scores before treatment. The visual analog scale scores after the test drug was introduced were similar among the groups. The daily consumption of oral morphine was as follows: on day 15: CG = DG = NG (P > 0.05), CG > KG (P = 0.036); on day 20: CG > NG = KG (P < 0.02) (CG > KG, P < 0.005; CG > NG, P < 0.02), DG > KG (P < 0.05); on day 30: CG = DG > KG = NG (P < 0.05). Patients in the CG and DG groups reported somnolence, but patients in the NG and KG groups did not. Conclusions Low-dose ketamine and transdermal nitroglycerin were effective coadjuvant analgesics. In conjunction with their opioid tolerance-sparing function, joint delivery of ketamine or nitric oxide donors with opiates may be of significant benefit in cancer pain management.
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Gandola, L., M. Nantron, A. Marchianò, A. Pession, P. Indolfi, A. Di Cataldo, P. Collini, G. Arcamone, F. Fossati Bellani, and F. Spreafico. "Outcome in stage IV Wilms tumor treated according to the Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) trials." Journal of Clinical Oncology 27, no. 15_suppl (May 20, 2009): 10031. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.10031.
Abstract:
10031 Background: Children with metastases at diagnosis for Wilms tumor (WT) still display a worse prognosis compared to localized disease. Methods: We analyzed survival results in patients with stage IV WT enrolled in the AIEOP CNR92 and TW2003 clinical trials (3/1992–3/2008). Treatment strategy across these trials evolved in terms of sparing whole lung radiotherapy (RT) in case of complete disappearance of lung metastases after primary chemotherapy and a doxorubicin cumulative dose reduction from 360 mg/m2 to 240 mg/m2 in TW2003. Results: Of 553 in-study patients aged less than 18 years, 68 (12%) were classified as stage IV (38 patients in CNR92, 30 in TW2003; median age 58 months). Children displaying millimetric nodules visible only on computed tomography scan were excluded. Initial treatment consisted of 6-week 3-drug (vincristine, dactinomycin, doxorubicin) phase in 60 cases, while 8 had up-front nephrectomy. Adjuvant therapy included 8-month 3-drug chemotherapy for non anaplastic “local” tumor stage I to III (flank RT for stage III), or an intensified regimen for anaplastic histology, adding etoposide, carboplatinum and ifosfamide (6 patients). Overall 19 tumor failure occurred (3 in anaplastic tumors): metastases progression 9, abdominal relapse 5 (combined to liver and mediastinum in 1 case each), lung 4, liver 1. After a median follow-up of 53 months 5-yr RFS and OS were 71% ±6 and 77% ±5 for the whole cohort of children, respectively. Overall, RFS was 86% in patients who achieved a complete metastases remission (in 2 cases by surgery) compared to 55% in patients who did not (Logrank p<.05). Noteworthy the omission of lung RT in TW2003 trial for complete responders evaluated at week 6 did not jeopardize survival (85% RFS, vs 58% for those children with persistence of metastases and lung RT). There was a trend toward a worse outcome for patients with at least liver metastases (n 13) compared to those with other site (4-yr RFS 49% vs 74%, p=.1). Conclusions: Failure to obtain metastases complete remission, and maybe site other than lung, should be considered for chemotherapy intensification for metastatic WT. The impact of metastatic tumor burden deserves further analysis. Withholding RT in rapidly complete responders patients did not compromise outcome. No significant financial relationships to disclose.
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Mironov, S. P., M. B. Cykunov, G. M. Burmakova, and S. V. Andreev. "Lumbosacral pain in athletes and ballet dancers: spondylolysis and spondylolisthesis. Conservative treatment." N.N. Priorov Journal of Traumatology and Orthopedics 27, no. 1 (April 1, 2020): 11–18. http://dx.doi.org/10.17816/vto202027111-18.
Abstract:
The aim of the study was to develop an algorithm for conservative treatment of lumbosacral pain syndrome (PCBS) caused by spondylolysis in athletes and ballet dancers.
Materials and methods. The study included 212 patients athletes and ballet dancers with PCBS caused by spondylolysis (171 people) and grade III spondylolisthesis (41 people) of the lumbar vertebrae. Clinical, neurological, and X-ray studies, ultrasonography, computed tomography, scintigraphy, functional testing, as well as markers of bone resorption (calcium in urine) and bone formation (alkaline phosphatase) were performed.
Results. All patients underwent conservative treatment: functional therapy, physiotherapy, ozone and drug therapy. Functional rehabilitation treatment included three stages: 1 relief of pain; 2 restoration of support ability and stability of the spine; 3 restoration of special motor skills. As a result of treatment, the functional parameters of the muscles stabilizing the spine improved (tone, contractile activity, bioelectric parameters), and the muscle imbalance was eliminated. After treatment, in radiographs, in most cases, a defect was observed in the arch of the vertebra, but it was much smaller in width and did not affect professional performance. Complete restoration of the bone structure in the area of the arc defect was observed only with acute pathology, complete cessation of sports load and a long (1 year or more) sparing regimen (9 people). Excellent and good results were obtained in 171 (80.7%) patients, satisfactory in 36 (16.9%) patients. Five (2.4%) patients with spondylolisthesis were not able to continue their professional activities, the result of conservative treatment was regarded as unsatisfactory. Three of them were subsequently underwent surgical treatment.
Conclusion. The development of an individual program of conservative rehabilitation treatment for athletes and ballet dancers with spondylolysis and grade I and II spondylolisthesis, adequate and timely use of rehabilitation features lead to eliminating muscle imbalance and strengthening muscle corset. This, in turn, will contribute to the relief of pain, restoration of professional performance, prevention of progression of the area of bone reconstruction of the vertebral arches and spondylolisthesis
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Pei, Xin-Yan, Michael W. Sanderson, Leena E. Youssefian, Jessica Felthousen, Lora B. Kramer, Yun Dai, and Steven Grant. "Bcl-2 Antagonism Potentiates MEK1/2/Chk1 Inhibitor Lethality in Multiple Myeloma Cells Overexpressing Bcl-2 through a Stat3-Dependent Mechanism." Blood 124, no. 21 (December 6, 2014): 4763. http://dx.doi.org/10.1182/blood.v124.21.4763.4763.
Abstract:
Abstract Introduction: Multiple myeloma (MM) is characterized by deregulation of members of the Bcl-2 family of apoptotic regulatory proteins. This has led to the development of BH3-mimetics such as ABT-737 which inhibits Bcl-2/xL but not Mcl-1. Previously, we reported that simultaneous inhibition of Chk1 and MEK1/2 dramatically induced apoptosis in cultured and primary MM cells, including cells resistant to conventional agents, while sparing their normal counterparts (Pei et al., Blood 2007, 2011). Recently, we reported that this strategy circumvented MM cell resistance conferred by overexpression of Mcl-1, an important survival factor in this disease (Pei et al., PLoS One 2014). However, Bcl-2 overexpression confers significant resistance to the Chk1/MEK1/2 inhibition strategy. This raised the possibility that BH3-mimetics targeting Bcl-2 might circumvent this resistance mechanism. The purpose of the present studies was to determine whether BH3-mimetics could overcome such resistance while preserving anti-myeloma selectivity. An additional goal was to employ a new mathematical model to characterize interactions combining three novel agents that coordinately inhibit multiple survival signaling pathways. Methods: Various parental and Bcl-2 or Bcl-xL-over-expressing MM cell lines, as well as primary CD138+ MM cells were employed. ABT-737, the MEK1/2 inhibitor PD184352 (PD), and the Chk1/Wee1 inhibitor (Chk1i) were obtained from Abbott, Millipore and Calbiochem, respectively. Cells were exposed to agents alone or in various combinations for 4 -72 h, after which effects on apoptosis and signaling pathways were determined. Results: Co-administration of ABT-737 potentiated PD/Chk1i-mediated lethality in multiple parental MM cell lines, in association with Mcl-1 down-regulation, Bim up-regulation, and increased DNA damage (ΥH2A.X). Consistent with earlier findings, ectopic expression of Bcl-2 or Bcl-xL protected MM cells from the PD/Chk1i regimen. However, co-administration of ABT-737 significantly restored sensitivity towards PD/Chk1i lethality. Mathematical modeling indicated 3-agent synergistic interactions, particularly in Bcl-2 overexpressing cells. PD/Chk1i exposure inhibited phosphorylation (T705 and S727) of Stat3, another important survival factor for MM cells, while cells expressing constitutively active Stat3 (CA-STAT3) exhibited resistance to this regimen. However, the latter event was reversed by co-exposure to ABT-737. Moreover, combining ABT-737 with PD/Chk1i resulted in release of Bim from anti-apoptotic proteins including Bcl-2, Bcl-xL, and Mcl-1, accompanied by Bak and Bax conformational change (activation). Knock-down of Bim by shRNA significantly protected cells from apoptosis induced by the 3-agent combination, indicating a functional role for Bim in anti-MM activity of this regimen. Furthermore, similar interactions, together with down-regulation of pStat3, were also observed in bortezomib-resistant MM cells, as well as in patient-derived CD138+ MM cells. In contrast, the regimen was minimally toxic to normal cord blood CD34+ cells or CD138- bone marrow cells. Finally, co-culture of parental or bortezomib-resistant MM cells with HS-5 stromal cells induced up-regulation of pStat3, while treatment with ABT-737 in combination with PD/Chk1i prevented Stat3 activation and robustly induced apoptosis despite the presence of stromal cells. Conclusion: ABT-737 co-administration synergistically potentiates the lethality of the PD/Chk1i regimen in MM cells, including bortezomib-resistant and primary MM cells, but not in normal hematopoietic progenitors. It also overcomes PD/Chk1i resistance conferred by overexpression of Bcl-2 or Bcl-xL, as well as by microenvironmental factors. Mechanisms responsible for these interactions are likely to be multi-factorial, including inactivation of Stat3, up-regulation of Bim, release of Bim from Bcl-2, Bcl-xL, and Mcl-1, and activation of Bak and Bax. Collectively, these findings demonstrate that combining BH3-mimetics with Chk1/MEK1/2 inhibition circumvents multiple forms of drug resistance in MM cells while exhibiting minimal toxicit toward normal hematopoietic cells. They also argue that a strategy targeting three coordinate survival signaling pathways may be highly effective in killing MM cells, particularly those resistant to current anti-MM therapies. Disclosures No relevant conflicts of interest to declare.
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Winkler, K., G. Beron, G. Delling, U. Heise, H. Kabisch, C. Purfürst, J. Berger, J. Ritter, H. Jürgens, and V. Gerein. "Neoadjuvant chemotherapy of osteosarcoma: results of a randomized cooperative trial (COSS-82) with salvage chemotherapy based on histological tumor response." Journal of Clinical Oncology 6, no. 2 (February 1988): 329–37. http://dx.doi.org/10.1200/jco.1988.6.2.329.
Abstract:
Following observation of the predictive value of the histologic extent of tumor cell destruction after preoperative chemotherapy for metastasis-free survival (MFS) in osteosarcoma, a randomized study was undertaken with the aim of (1) sparing some patients the unpleasant side effects of highly toxic drugs like doxorubicin (DOX) and cisplatin (CPDD) by administering these drugs postoperatively only after poor response with a milder preoperative regimen, and (2) improving the prognosis of patients responding poorly to the initial treatment by use of a salvage chemotherapy postoperatively. The available patients were divided into two groups. Those in the study arm received a preoperative chemotherapy consisting of high-dose methotrexate (HDMTX) and the triple drug combination of bleomycin, cyclophosphamide, and dactinomycin (BCD) and were switched to DOX/CPDD postoperatively in case of poor response. DOX/CPDD was used besides HDMTX for initial treatment in the control arm, and BCD alternatively with CPDD/ifosfamide (IFO) for postoperative salvage treatment. The response rate of the study arm was significantly inferior to the control arm (26% v 60%; P less than .001). The actuarial 4-year MFS rate of poor responders after salvage chemotherapy also was poorest in the study arm (41%); it was unchanged in the control arm (53%) as compared with that of poor responders from the COSS-80 study without salvage chemotherapy (52%). The actuarial 4-year MFS rate of good responders was 73% in the study arm, 79% in the control arm, and not significantly different from that of the COSS-80 study (84%), although postoperative chemotherapy of good responders had been markedly shortened as compared with the COSS-80 study. The actuarial 4-year MFS rate of the study arm as a whole was inferior to that of the control arm (49% v 68%; P less than .1) and also inferior to the COSS-80 study (68%; P less than .01), indicating a failure of the employed salvage strategy in general and especially of the effort to restrict the use of the very effective but highly toxic drugs DOX and CPDD to patients resistant to a less toxic initial treatment.
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van der Lee, Miranda M. C., Tanja van Achterberg, Kaylee Hersmus, Annet Brouwers-Vos, Monique van der Vleuten, Maurien Pruis, Wendy Kappers, et al. "Abstract 3129: BYON4413, an in vivo active CD123-targeting antibody-drug conjugate, combines effectively with azacitidine and venetoclax in acute myeloid leukemia cell lines." Cancer Research 84, no. 6_Supplement (March 22, 2024): 3129. http://dx.doi.org/10.1158/1538-7445.am2024-3129.
Abstract:
Abstract Background: CD123, the alpha chain of the interleukin-3 receptor (IL-3Rα), is overexpressed in multiple hematologic malignancies and found particularly highly expressed on the surface of acute myeloid leukemia (AML) cells. Furthermore, increased CD123 expression on leukemic stem cells relative to non-neoplastic hematopoietic stem cells makes CD123 an attractive tumor-associated target for an antibody-drug conjugate (ADC). BYON4413 is an ADC that consists of a novel humanized IgG1 anti-CD123 antibody site-specifically conjugated with Byondis' proprietary duocarmazine linker-drug technology, ByonZine® and ByonShieLD®. The efficacy of BYON4413 is studied as monotherapy and in combination with azacitidine and venetoclax (AZA/VEN), since the AZA/VEN regimen is the standard of care (SOC) for AML patients who are ineligible for intensive chemotherapy. Method: A panel of CD123+ and CD123- hematological cell lines and AML patient-derived bone marrow mononuclear cells (BMMCs)/peripheral blood mononuclear cells (PBMCs) were utilized in in vitro studies to determine the cytotoxic effects of BYON4413. The induction of apoptosis and cell killing by BYON4413 in a triple combination with AZA/VEN was studied in vitro using the CD123+ AML cell lines MOLM-13 and MV4-11. AML patient and cell line-derived xenograft models were used to investigate the in vivo efficacy of BYON4413. Results: In vitro studies with human AML cell lines show that BYON4413 is highly effective in eradicating CD123+ cells while having little impact on CD123- cells. These results were confirmed ex vivo with AML patient-derived BMMCs/PBMCs. BYON4413 effectively killed AML patient-derived blasts while largely sparing healthy hematopoietic cells. The triple combination of BYON4413 with AZA/VEN enhanced both apoptosis and cell killing of AML cell lines compared to the singular BYON4413 treatment. In vivo studies demonstrate that BYON4413 is remarkably efficient at reducing the tumor burden in AML patient- and cell line-derived xenograft models. Conclusions: Preclinical studies show that BYON4413 has potential to be an effective targeted therapy against CD123+ hematological malignancies such as AML. The enhanced efficacy of BYON4413 together with AZA/VEN suggests that a clinical benefit from the triple combination may be achievable and is worth further exploration. A first-in-human dose-escalation and expansion trial with BYON4413, designed to enroll R/R AML and high-risk MDS patients, is scheduled to start in Q2 2024. Citation Format: Miranda M.C. van der Lee, Tanja van Achterberg, Kaylee Hersmus, Annet Brouwers-Vos, Monique van der Vleuten, Maurien Pruis, Wendy Kappers, Gijs Verheijden, Gerwin Huls, Glenn van Wigcheren, Ruud Ubink, Aloys Sesink, Alyson MacInnes, Jan Jacob Schuringa, Wim Dokter. BYON4413, an in vivo active CD123-targeting antibody-drug conjugate, combines effectively with azacitidine and venetoclax in acute myeloid leukemia cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3129.
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Normant, Emmanuel, Marcelo Lima Ribeiro, Nuria Profitos-Peleja, Pedro Blecua, Diana Reyes-Garau, Juliana Carvalho Santos, Marc Armengol, Miranda Fernández-Serrano, Hari P. Miskin, and Gael Roue. "The Ublituximab-Umbralisib (U2) Drug Regimen Potentiates the Activity of the Novel CD47-CD19 Bispecific Antibody, TG-1801, through the Activation of the G Protein-Coupled Receptor EBI2/GPR183." Blood 138, Supplement 1 (November 5, 2021): 1196. http://dx.doi.org/10.1182/blood-2021-150570.
Abstract:
Abstract Introduction: TG-1801 is a novel, bispecific anti-CD47 and anti-CD19 fully human IgG1 antibody that targets CD47 selectively on CD19+ B-cells, sparing red blood cells or platelets and blocking the CD47-SIRPα macrophage checkpoint on mature B cells. TG-1801 is currently in clinical trial as a single agent or in combination with ublituximab, a glyco-engineered CD20 antibody, in B-cell non-Hodgkin lymphoma (B-NHL). The doublet therapy of ublituximab with the dual PI3Kδ/CK1e inhibitor umbralisib ("U2" regimen), provides a non-chemotherapy backbone regimen on which several novel multidrug combinations are being explored clinically. Here we explored in vitro and in vivo potential synergies between TG-1801 and ublituximab, umbralisib, and the U2 combination, in preclinical models of B-NHL. Methods: A panel of n=12 human B-cell lymphoma cell lines and primary samples were cultured in vitro in the presence of bone marrow-derived stromal cells (BMSCs), M2-polarized primary macrophages, and primary circulating PBMCs as a source of effector cells. Cell response to TG-1801 +/- U2 treatments was analyzed by proliferation assay, western blot, transcriptomic analysis (qPCR array and RNA sequencing followed by gene set enrichment analysis) and quantification of antibody-dependent cell death (ADCC) and antibody-dependent cell phagocytosis (ADCP). In vivo, drug efficacy was determined in a Raji xenograft model, by dosing tumor-bearing mice for 17 days with ublituximab (5mg/kg, qw) +/- umbralisib (150mg/kg, bid), the combination of both and/or TG-1801 (5mg/kg, qw). Results: Here we show on a panel of lymphoma cells lines that the number of receptors per cell and the ratio CD47/CD19 do not impact TG-1801-mediated ADCC or phagocytosis (ADCP). In addition, we show that TG-1801 potentiated ublituximab-mediated ADCC and ADCP and exhibited a similar additive effect when added to U2 combination. In vivo, ublituximab alone displayed a tumor growth inhibition (TGI) of 88%, with 3/8 mice harboring a barely palpable tumor, while the umbralisib alone treatment arm showed a TGI of 50%, with 2/8 mice lacking detectable tumors. TG-1801 exhibited a 76% TGI with 1/8 tumor free-mouse. Most importantly, the combination of TG-1801 with umbralisib alone, ublituximab alone, and U2 achieved TGI of 85%, 93% and 93% respectively, with more tumor-free mice 35 days after the last dose in these three groups. Interestingly, this superior anti-tumor effect of the different TG-1801 combinations was associated with a higher infiltration of mouse macrophages within the tumors as assessed by F4/80 IHC labeling. RNA-seq analysis of the Raji xenografts and of n=4 representative in vitro B-NHL co-cultures treated with TG-1801, U2 or the triple combination uncovered the upregulation of the G-protein coupled receptor EBI2/GRP183 as a common event associated with the synergistic antitumor effects of TG-1801 and U2 in vitro and in vivo. A critical role of EBI2 in the regulation of macrophage activity, B cell migration and in the promotion of a pro-inflammatory phenotype was demonstrated upon exposure of the co-cultures with the EBI2 small molecule inhibitor NIBR189, which impaired the U2/TG-1801-evoked ADCP, B-cell cytoskeleton remodeling and inflammatory cytokine production. Conclusion: The data presented here set the preclinical rationale and support a combination strategy of the novel CD47-CD19 bispecific antibody TG-1801 in B-NHL with other B-cell targeted mechanisms, including umbralisib and ublituximab. Disclosures Normant: TG Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Miskin: TG Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Roue: TG Therapeutics, Inc.: Research Funding.
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Liguori, Nicholas R., Ashley Fss Uruchurtu, Young Lee, Leiqing Zhang, Abbas Abbas, Varun Prabhu, Lanlan Zhou, Christopher J. Azzoli, and Wafik S. El-Deiry. "Abstract 4064: Synergistic activity of Lurbinectidin plus ONC201 in SCLC is associated with ATF4, CHOP and pChk1 induction." Cancer Research 82, no. 12_Supplement (June 15, 2022): 4064. http://dx.doi.org/10.1158/1538-7445.am2022-4064.
Abstract:
Abstract Small cell lung cancer (SCLC) accounts for 15% of lung cancer and is responsive to chemotherapy but most patients relapse with drug-resistant disease and have very poor 5-year survival of less than 7%. One of the most notable advances in the last decade has been the approval of lurbinectedin for platinum resistant SCLC. Lurbinectedin is a small molecule inhibitor, targeting RNA polymerase II, and binding the minor grooves of DNA to induce double-strand breaks. The dismal SCLC survival rate underscores the need for a novel combination to increase patient survival outcomes. ONC201 is a pro-apoptotic TRAIL-inducing compound that activates the integrated stress response and appears to have efficacy in neuroendocrine tumors including paragangliomas. In our preclinical experiments, we explored the combination of ONC201 and lurbinectedin as a potentially effective treatment regimen for SCLC. Lurbinectedin has been shown to have effective cancer cell killing ability in multiple SCLC cell lines (H1048, H1105, H1882, H1417) at sub-nanomolar concentrations, while sparing healthy lung epithelial tissue cells (cell line HSAEC). We hypothesized that combining ONC201 and lurbinectedin will yield synergistic outcomes due to combining drugs that act by different potentially complementary mechanisms. We treated SCLC cell lines with ONC201 and lurbinectedin at increasing concentrations of the drugs. CellTiter Glo was used to perform cell viability assays, and combination index analysis (Combenefit software) revealed the most synergy between the agents occurred at the concentrations of 0.156 uM ONC201 and 0.047 nM lurbinectedin. We are expanding this combination’s efficacy in other SCLC lines and tumor types. Western blotting further examined these synergies and showed that PARP cleavage and expression of ATF4 and TRAIL death receptor DR5 were increased at higher concentrations of these agents. We further noted that combinatorial treatment with these agents induced marked upregulation of Phosphorylated Chk1 and CHOP at the highest treatment concentrations versus lower concentrations and control. These effects indicate effectiveness of the combinatorial treatment in causing DNA damage and instability, inducing double-stranded DNA breaks, as well as initiating the intrinsic apoptosis pathway through the integrated stress response, selectively in the malignant cells. Ongoing directions include testing similar concentrations of both ONC201 and lurbinectedin in additional SCLC cell lines, SCLC patient-derived organoids, and in vivo, as well as exploring immune correlates of the drug treatments. Keywords: SCLC; lurbinectedin; chemotherapy; imipridones; genomics Citation Format: Nicholas R. Liguori, Ashley Fss Uruchurtu, Young Lee, Leiqing Zhang, Abbas Abbas, Varun Prabhu, Lanlan Zhou, Christopher J. Azzoli, Wafik S. El-Deiry. Synergistic activity of Lurbinectidin plus ONC201 in SCLC is associated with ATF4, CHOP and pChk1 induction [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4064.
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Lu, Norman, Patricia Soulard, Kay Li, Heather Sadlish, Chris Yates, Xiubin Gu, Ibrahim Kays, et al. "Abstract 3306: RGT-M001, a first-in-class small molecule mRNA degrader of the oncogenic transcription factor c-Myb, demonstrated remarkable single agent anti-tumor efficacy in cancer patient-derived xenograft model." Cancer Research 84, no. 6_Supplement (March 22, 2024): 3306. http://dx.doi.org/10.1158/1538-7445.am2024-3306.
Abstract:
Abstract Dysregulated transcription factors (TFs) represent a unique class of drug targets that drive aberrant gene expression programs involved in the major hallmarks of cancers. However, developing drug-like small molecules targeting TF proteins for clinical purposes has proven to be extremely challenging. Here, we present a novel and innovative approach to degrade the RNA transcript of the master oncogenic transcription factor C-MYB, thereby preventing its undesirable expression, using potent and orally available small molecules. C-MYB is a transcription factor that regulates differentiation and proliferation programs in normal cells, including hematopoietic, stem and epithelial cells. In numerous cancer types, such as adenoid cystic carcinoma (ACC), leukemia, colorectal cancer, and breast cancer, C-MYB is a well-established oncogenic transcription factor, overactivated via different mechanisms, including chromosomal translocations and gene amplification. Here, we leveraged our integrative RNA-targeting platform to identify and validate actionable cryptic exon target sites in the human C-MYB gene. We identified RGT-M001, a potent small molecule that can selectively induce the inclusion of the cryptic exon into the final C-MYB transcripts, resulting in a robust decrease of C-MYB canonical transcripts and C-MYB protein in cells. In a functional assay, we demonstrated that RGT-M001 has potent cell-killing activity against a large panel of cancer cell lines overexpressing C-MYB (EC50 ~ 20 - 300nM), while sparing normal cells. To confirm RGT-M001's on-target effect, we demonstrated a robust correlation between RGT-M001 cell-killing activity and the knockdown of C-MYB RNA and protein. We further investigated the anti-tumor activity of RGT-M001 in an ACC patient-derived xenograft (PDx) mouse model harboring C-MYB-NFBI fusion. Recurrent or metastatic ACC is a malignant neoplasm of predominantly salivary gland origin for which effective approved therapies are lacking; the best reported ORR being 15.6% for lenvatinib. As a single agent, RGT-M001 reduced in vivo C-MYB transcript levels by >80% at peak drug exposure and induced a remarkable tumor growth inhibition response (~70% TGI) in the ACCX11 PDx mouse model, surpassing the therapeutic benchmark Lenvatinib (40% TGI). Importantly, the RGT-M001 regimen was well tolerated. Finally, we showed that the combination of RGT-M001 with the Notch Inhibitor AL-101 resulted in complete inhibition of tumor growth. In conclusion, these data demonstrate that small molecules targeting RNA are a safe and effective approach to address previously undruggable protein targets. Down-regulation of C-MYB by our RNA-targeting small molecules is an attractive therapeutic strategy to treat ACC and other cancers driven by C-MYB dysregulations. Citation Format: Norman Lu, Patricia Soulard, Kay Li, Heather Sadlish, Chris Yates, Xiubin Gu, Ibrahim Kays, Jae Lee, Sam Hasson, Zhiping Weng, Simon Xi, Travis Wager. RGT-M001, a first-in-class small molecule mRNA degrader of the oncogenic transcription factor c-Myb, demonstrated remarkable single agent anti-tumor efficacy in cancer patient-derived xenograft model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3306.
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Deisher, Theresa, Margaret Taylor, Arya Ashok, Peter Jarzyna, Yumna Zahid, Stephanie Lee-Diaz, Colleen Rylatt, Kendra Poulin, and Vaishnavi Parthasarathy. "AVM0703, a New Treatment Option for Lymphoma Patients." Blood 134, Supplement_1 (November 13, 2019): 5308. http://dx.doi.org/10.1182/blood-2019-128812.
Abstract:
AVM0703 is a new treatment option for lymphoma patients that can eliminate or reduce the dose of standard chemotherapy in the overall treatment plan. Radiation and chemotherapy have dramatically improved survival for patients with cancer. However, the American Cancer Society has reported that chemotherapy and radiation increase the chances of secondary cancers. In fact, the report states that chemotherapy is known to be a higher risk factor than radiation in causing leukemia. The need to decrease chemotherapy administration in young adults and pediatric populations becomes even more essential considering the risk for secondary cancers. Therefore, there is an urgent need for new therapies that are as efficacious as chemotherapy and are without the harmful side effects. AVM0703 is a repurposed small molecule that has significantly extended survival in a mouse model with aggressive B cell lymphoma (A20 mouse model). In addition to being a standalone treatment, AVM0703 can also be administered as a preconditioning agent before CART cell infusion. Two FDA approved breakthrough therapies, Kymriah and Yescarta are not yet available for 33% of patients who are frail and elderly, as they are too weak to undergo the required chemotherapy preconditioning. AVM0703 can have the same preconditioning effect as chemotherapy without the toxic side effects of chemo while sparing red blood cells, stem cells and platelets. AVM0703 demonstrated a significant improvement of the effect of CART cells in a mouse model of melanoma (data not shown). Preconditioning with AVM0703 before CART administration will allow frail and elderly patients access to FDA approved cell therapy treatments. To demonstrate the efficacy of AVM0703 in a lymphoma model, A20 tumor cells were inoculated subcutaneously into the right flank in a cohort of BALB/c mice. When the tumors reached ~ 100mm3, the mice were randomized into two cohorts, control and AVM0703-treated. The control group were vehicle-treated while AVM0703-treated group were administered the active drug on day 7, 10, 17, 23, 24, 28 and 35. Tumor volumes and body weights were measured thrice weekly. Overall the treatment was very well tolerated with no treatment related deaths or toxicity observed. Dramatic body weight loss defined as greater than 20 % decrease from baseline is a frequent concern with chemo treatment, however, it was not observed in any AVM0703-treated mice. The median survival time for the control group was 16 days where as the AVM0703-treated group had a median survival time of 34 days. Therefore, this data suggests that AVM0703 treatment almost doubled the survival time of mice bearing A20 tumors (Figure 1), a fast growing B cell lymphoma model. Most interestingly, when the data was compared to the CHOP regimen, a combination of 4 therapies in the same A20 model, the efficacy results were better than 1 cycle CHOP without the extremely toxic effects observed with CHOP cycles (Figure 2). As mentioned previously AVM0703 is a repurposed molecule with decades of clinical information available on safety and toxicity, allowing a rapid clinical development program. AVM0703 is a novel high-volume formulation with a target dose that is 25 times what is used currently. It has a unique mechanism of action targeting only cancer cells, lymphocytes and monocytes while sparing platelets, RBCs and stem cells. Due to its unique profile, AVM0703 can replace chemotherapy and reduce the financial and physical toxicities associated with it. AVM0703 presents a new treatment option for lymphoma patients that is safe and effective. Disclosures No relevant conflicts of interest to declare.
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Hamilton, Erika Paige, Manish R. Patel, Jordi Rodon, David S. Hong, Alison M. Schram, Pasi A. Janne, Patricia LoRusso, et al. "Masterkey-01: Phase I/II, open-label multicenter study to assess safety, tolerability, pharmacokinetics, and antitumor activity of BDTX-189, an inhibitor of allosteric ErbB mutations, in patients with advanced solid malignancies." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): TPS3665. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.tps3665.
Abstract:
TPS3665 Background: A significant unmet need exists for drugs targeting allosteric ErbB mutations (non-canonical mutations outside the ATP binding site). Current EGFR and HER2 tyrosine kinase inhibitors or mAbs have limited antitumor activity against allosteric mutations, resulting in toxicity before adequate drug exposure (Connell and Doherty, 2017). BDTX-189 is a potent and selective orally available irreversible inhibitor targeting unique oncogenic driver mutations of ErbB kinases in EGFR and HER2, while sparing WT EGFR. Preclinical studies demonstrated antitumor activity across a range of allosteric ErbB mutants, including extracellular domain allosteric mutations of HER2 as well as EGFR and HER2 kinase domain exon 20 insertions (Buck, 2019). This first-in-human trial (NCT04209465) is aimed to determine the recommended phase 2 dose (RP2) and schedule (Phase 1, P1), and evaluate the efficacy (Phase 2, P2) of BDTX-189. P1 primary objective is to determine the RP2 dose and schedule of monotherapy BDTX-189. Secondary objectives include assessment of safety, tolerability, pharmacokinetics (PK), pharmacodynamic (PD) effects in tumor, and preliminary efficacy. The P2 primary objective is to assess antitumor activity of monotherapy BDTX-189. Methods: The study will enroll patients (pts) ≥18 yrs with histologically or cytologically confirmed locally advanced or metastatic solid tumors with no standard therapy available or for whom standard therapy is unsuitable or intolerable. P1 dose-escalation will use a BOIN design (Yuan, 2016) and will enroll ≤ 88 pts with allosteric HER2 or HER3 mutation; EGFR or HER2 exon 20 insertion mutation; HER2 amplified or overexpressing tumor; or EGFR exon 19 deletion or L858R mutation. BDTX-189 will be dosed orally (PO) initially QD in 3 wk cycles. Regimen optimization will use PK, PD and safety data and may explore a BID schedule. An expansion cohort of ≤12 pts will further evaluate safety and preliminary efficacy of BDTX-189 prior to P2. P2, utilizing a Simon 2-stage design, will enroll ≤100 pts with NSCLC with EGFR or HER2 exon 20 insertion mutations (cohort 1); breast cancer with an allosteric ErbB mutation (cohort 2); tumors (except breast) with S310F/Y mutation (cohort 3); and other allosteric ErbB mutations not defined in cohorts 1-3 (cohort 4). Assessments include safety, tolerability, DLTs, evaluation of MTD, PK, PD, and preliminary antitumor activity. Enrollment began 1/2020. Clinical trial information: NCT04209465 .
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diCapua Siegel, David Samuel, Thomas Martin, Michael Wang, Ravi Vij, Andrzej J. Jakubowiak, Sundar Jagannath, Sagar Lonial, et al. "Results of PX-171-003-A1, An Open-Label, Single-Arm, Phase 2 (Ph 2) Study of Carfilzomib (CFZ) In Patients (pts) with Relapsed and Refractory Multiple Myeloma (MM)." Blood 116, no. 21 (November 19, 2010): 985. http://dx.doi.org/10.1182/blood.v116.21.985.985.
Abstract:
Abstract Abstract 985 Introduction: CFZ is a novel and highly selective epoxyketone proteasome inhibitor currently in clinical development for the treatment of multiple myeloma (MM). Ph 1 and 2 studies with CFZ have demonstrated durable single-agent antitumor activity in pts with relapsed or refractory (R/R) MM. The present study, PX-171-003-A1, was an open-label, single-arm Ph 2b trial and enrolled patients with multiply relapsed MM whose disease was refractory (defined as <25% response on, or progression during or <60 days after completion of, therapy) to their last treatment regimen. Patients must have received ≥2 prior therapies including: 1) bortezomib (BTZ) and either thalidomide (THAL) or lenalidomide (LEN), and 2) an alkylating agent. Materials and Methods: Pts received CFZ at 20 mg/m2 on a QDx2 schedule (Days 1, 2, 8, 9, 15, and 16 every 28 days) in cycle (C) 1 and were dose escalated to 27 mg/m2 on the same schedule thereafter for up to 12 C. Pts completing 12 C were eligible to enter an extension study (PX-171-010). The primary endpoint was overall response rate (ORR) (≥ partial response [PR]). Secondary endpoints included: clinical benefit response (CBR) (ORR + Minimal response [MR]), duration of response for ≥PR (DOR), overall survival (OS), time to progression (TTP), progression free survival (PFS), and safety. Responses and progression were determined according to the International Myeloma Working Group (IMWG) criteria and were assessed and confirmed by an Independent Response Committee (IRC). Results: 266 pts were enrolled with a median duration of MM of 5.4 years including 83% whose disease had progressed on or within 60 d of last therapy and 17% whose disease had achieved <25 % response to the regimen immediately preceding study entry. Of the 266 pts enrolled pts, 257 were evaluable for response; 9 patients were considered not evaluable based on missing baseline or lacking at least one post-baseline M-protein. An ORR (≥PR) of 24% with a median DOR of 7.4 mo (range 6.2–10.3) was determined. Responses are detailed in the table. The CBR (ORR + MR) was 36%. Median DOR of pts with MRs was 6.3 months, indicating that long-term MRs were observed. An additional 32% (83 pts) achieved SD for at least 6 wks. To date, 79 pts (30%) completed ≥6 C and >11% of pts have completed all 12 C of protocol specified therapy and most have entered the extension protocol; 15 pts remain on study (all >10 C). OS and TTP data for the overall population will also be reported. The enrolled pts in this study were heavily pretreated having received a median of 5 prior lines of therapy (range 1–20, median of 13 anti-myeloma agents). 85% of pts had received at least 2 and 37% had received at least 3 drugs in the regimen just prior to entering the study. Prior anti-myeloma agents included 99.6% (265/266 pts) BTZ (median 2 prior regimens containing BTZ), 99.6% either THAL (74%) or LEN (94%), 98% corticosteroids, 91% alkylating agents, and 74% stem cell transplant; 65% of pts were refractory to BTZ at any point in time prior to study entry. The most common treatment-emergent adverse events ≥ Grade (G) 3 regardless of relationship to study drug were predominantly hematologic and included thrombocytopenia (22%), anemia (20%), lymphopenia (10%), pneumonia (8%), neutropenia (8%), fatigue (7%), hyponatremia (5%), and hypercalcemia (5%). Although 206 pts (77%) had G1/2 peripheral neuropathy (PN) at baseline, new onset PN was infrequent and G ≥3 PN occurred in <1%. Interestingly, in this subset of patients, efficacy response was nearly identical to that seen in the full study population with an ORR (≥PR) of 24%. Conclusions: Single-agent CFZ achieved durable responses in pts with R/R MM whose disease had relapsed after all available therapies including BTZ and immunomodulatory agents. The CBR and median DOR achieved with this steroid-sparing regimen establish that CFZ has the potential to offer substantial clinical benefit to patients with relapsed or refractory disease. CFZ was well-tolerated and side effects were clinically manageable with no new or unexpected toxicities observed. Importantly, exacerbation of pre-existing PN was uncommon. Cumulative side effects were not observed, allowing prolonged single-agent dosing for chronic disease control. Disclosures: Siegel: Millenium: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Martin:Celgene: Honoraria; Onyx: Consultancy. Wang:Celgene: Research Funding; Onyx: Research Funding; Millenium: Research Funding; Novartis: Research Funding. Vij:Onyx: Honoraria. Jakubowiak:Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria; Centocor Ortho Biotech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Exelixis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Jagannath:Millenium, OrthoBiotec, Celgene, Merck, Onyx: Honoraria; Imedex, Medicom World Wide, Optum Health Education, PER Group: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Lonial:Millennium: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Onyx: Consultancy, Research Funding. Kukreti:Celgene: Honoraria; Roche: Honoraria; Ortho Biotech: Honoraria. Alsina:Millenium: Consultancy, Research Funding; Celgene: Research Funding; Novartis: Consultancy. Zonder:Millenium: Consultancy, Honoraria, Research Funding; Cephalon: Research Funding; Celgene: Honoraria. Wong:Onyx Pharmaceuticals: Employment. Vallone:Onyx Pharmaceuticals: Employment. Chang:Onyx Pharmaceuticals: Employment. Kauffman:Onyx Pharmaceuticals: Employment. Stewart:Millennium: Consultancy; Celgene: Honoraria. Singhal:Celgene: Speakers Bureau; Takeda/Millenium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Onyx : Research Funding.
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Marcelin, A. G., B. Visseaux, M. Wirden, L. Morand-Joubert, C. Soulie, C. Charpentier, B. Masquelier, D. Descamps, and V. Calvez. "NRTI-sparing regimens yield higher rates of drug resistance than NRTI-based regimens for HIV-1 treatment." Journal of Global Antimicrobial Resistance 2, no. 2 (June 2014): 103–6. http://dx.doi.org/10.1016/j.jgar.2013.12.001.
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Dai, Yun, Shuang Chen, Xin-Yan Pei, Viswanathan Ramakrishnan, Michael Wang, Robert Orlowski, Paul Dent, and Steven Grant. "Targeting CDK9 Dramatically Potentiates ABT-737-Induced Apoptosis in Human Multiple Myeloma Cells through a Bim-Dependent Mechanism." Blood 114, no. 22 (November 20, 2009): 297. http://dx.doi.org/10.1182/blood.v114.22.297.297.
Abstract:
Abstract Abstract 297 Background: High expression of the anti-apoptotic Bcl-2 family protein Mcl-1 is a critical survival mechanism in human multiple myeloma (MM) cells, and a key barrier to apoptosis induced by the Bcl-2/-xL antagonist ABT-737. De novo expression of the short-lived protein Mcl-1 is controlled transcriptionally by CDK9, a catalytic subunit of the PTEF-b transcription elongation complex (CDK9/cyclin T) that phosphorylates the C-terminal domain (CTD) of RNA polymerase II (RNA pol II) to promote elongation of nascent transcripts. Thus, approaches targeting CDK9 may enhance ABT-737 efficacy in MM cells. Methods: To test this hypothesis, we employed the pan-CDK inhibitor roscovitine and a highly-selective CDK9 inhibitor (CDK9i) in drug-naïve and drug-resistant MM cell lines, as well primary plasma cells. Results: Co-administration of non- or sub-toxic concentrations of roscovitine or CDK9i interacted in a highly synergistic manner with ABT-737 (e.g., 150-300 nM) to induce apoptosis in U266, RPMI 8226, H929, OPM-2, and MM.1S MM cells, as well as IL-6-depedent ANBL-6 and KAS 6/1 cells. In each case, Combination Index values were significantly less than 1.0. These regimens were fully active in various drug-resistant MM cells, including U266/VR and OPM-2/VR bortezomib-resistant cells, RPMI 8226/RR lenalidomide-resistant cells, MM.1R dexamethasone-resistant cells, RPMI 8226/LR5 melphalan-resistant cells, and RPMI 8226/Dox40 doxorubicin-resistant cells. They also effectively killed MM cells in the presence of stromal cells or growth factors (i.e., IL-6, IGF-1, BAFF, and APRIL). Co-administration of roscovitine significantly enhanced ABT-737 lethality in primary CD138+ MM cells, while largely sparing CD138− bone marrow cells. Notably, the majority of MM cell lines exhibited high expression of cyclin T1 rather than cyclin T2a/b, in association with constitutively-activated CDK9, manifested by high levels of phosphorylation of CDK9 and RNA pol II CTD at Ser2 and 5. Exposure of MM cells to either roscovitine or CDK9i strikingly reduced RNA pol II CTD phosphorylation at both sites (particularly Ser5), but did not affect CDK9 and cyclin T1 levels. Whereas treatment with ABT-737 alone led to a modest but clear increase in Mcl-1 expression, roscovitine or CDK9i completely blocked this event and substantially down-regulated basal Mcl-1 expression. Notably, similar phenomena occurred in U266/VR cells, which displayed higher basal levels of Mcl-1, an important candidate resistance mechanism, compared to parental cells. Moreover, knock down of Mcl-1 by stable transfection with shRNA dramatically increased U266 sensitivity to ABT-737. Co-treatment of MM cells with ABT-737 and roscovitine or CDK9i did not affect expression of other anti-apoptotic Bcl-2 family members such as Bcl-2 and Bcl-xL, but induced a Bcl-2 cleavage fragment. Expression profiling of BH3-only proteins in MM cells co-exposed to roscovitine and ABT-737 revealed a modest or a marked increase in expression of Bim (both EL and L isoforms) and Noxa (particularly a ∼27 kDa species), respectively, accompanied by a clear decrease in Puma levels. No changes in expression of other BH-3-only proteins (e.g., Bid, Bad, Bik, BMF, Hrk) were observed. Interestingly, knock down of Bim by stable transfection with shRNA dramatically diminished roscovitine/ABT-737 lethality, whereas Noxa knock-down by shRNA only partially protected cells from this regimen. In contrast, both shRNA approaches substantially protected U266 cells from bortezomib lethality. Conclusions: Collectively, these findings provide a mechanistic framework for targeting transcription by CDK9 inhibitors to diminish ABT-737-mediated Mcl-1 upregulation and to downregulate basal Mcl-1 levels, resulting in highly synergistic killing of MM cells, including those resistant to either conventional or novel anti-MM agents. They also suggest that the BH3-only protein Bim may be required for apoptosis triggered by this strategy, while up-regulation of Noxa may amplify MM cell killing in this setting. Disclosures: No relevant conflicts of interest to declare.
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Howard, Caleigh, Shu Wiley, Wenzhao Dong, Andrea Mendiola, Veronica Partridge, Sara LeMar, Paul Amador, et al. "Abstract 335: c-KIT targeted ETBs for cancer therapy and HSC transplant conditioning." Cancer Research 82, no. 12_Supplement (June 15, 2022): 335. http://dx.doi.org/10.1158/1538-7445.am2022-335.
Abstract:
Abstract Engineered toxin bodies (ETBs) are next-generation immunotoxins that harbor an antibody-derived targeting domain and a cytotoxic payload derived from Shiga-like toxin-1 catalytic subunit A (SLTA). SLTA has been engineered to reduce innate immunogenicity and therefore increase the safety of ETBs whilst retaining potent cytotoxic properties. When targeted via a binding domain, SLTA is internalized and routes to the cytosol leading to irreversible ribosome inactivation and ultimately cell death. ETBs have been developed to treat a wide variety of cancers, including breast, lymphoma, multiple myeloma and PD-L1 positive solid tumors. This technology holds promise for non-oncology indications as well, particularly as a targeted and non-genotoxic conditioning regimen for hematopoietic stem cell (HSC) ablation to prepare patients for autologous stem cell transplant. c-KIT (CD117) is a well-known marker of hematopoietic stem and progenitor cells and is overexpressed in a high percentage of certain cancers including GIST, SCLC and AML. While tyrosine kinase inhibitors such as imatinib are effective therapies for c-KIT mutant GIST, resistance often occurs by the development of secondary mutations in the intracellular signaling domains. Thus, c-KIT represents a potential ETB target for both oncological and HSC transplant conditioning indications. Here we present data highlighting the in vitro potency and efficacy of CD117-targeting ETBs on cancer cell lines as well as on primary human CD34+ HSCs. CD117-targeted ETBs demonstrate exquisite specificity in vitro by killing only target positive CD34+ cells at picomolar potency while sparing the progenitors that lack CD117 expression. However, relatively low CD117 receptor levels on CD34+ HSCs prevent complete killing in vitro, limiting the observed efficacy. To overcome this challenge, an additional cytotoxic payload was conjugated to the ETB molecule to capitalize on ETBs’ unique internalization and routing properties to deliver a secondary mechanism of action. ETB-drug conjugates (ETB-DCs) exhibited improved cytotoxicity in vitro, especially in CD117-low target cells. Moving forward, we plan to explore both the ETB and the ETB-DC therapeutic index in vivo with a series of CD117+ tumor efficacy and HSC depletion models. Citation Format: Caleigh Howard, Shu Wiley, Wenzhao Dong, Andrea Mendiola, Veronica Partridge, Sara LeMar, Paul Amador, Amit K. Chaudhary, Joseph D. Dekker, Jay Zhao, Ross Durland, Aimee Iberg. c-KIT targeted ETBs for cancer therapy and HSC transplant conditioning [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 335.
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Puoti, Massimo, Alessandro Cozzi-Lepri, Fausto Ancarani, Raffaele Bruno, Silvia Ambu, Teresa Ferraro, Paolo Tundo, et al. "The Management of Hepatitis B Virus/HIV-1 Co-Infected Patients Starting Their First Haart Regimen. Treating Two Infections for the Price of One Drug?" Antiviral Therapy 9, no. 5 (July 2004): 811–17. http://dx.doi.org/10.1177/135965350400900506.
Abstract:
We examined the impact of a lamivudine-containing highly active antiretroviral therapy (HAART) regimen on 164 hepatitis B virus/HIV co-infected individuals starting their first HAART. Lamivudine-treated patients (accounting for 73% of the study population) showed a significantly lower level of alanine aminotransferase over follow-up [–81.1 mU/ml mean difference; 95% confidence intervals (95% CI): –30.3; –131.7, P=0.003] and a significantly reduced risk of liver-related morbidity/mortality [Relative hazard (RH)=0.07; 95% CI: 0.01–0.38, P=0.002] than those starting a lamivudine sparing-regimen.
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Treon, Steven P., Kirsten Meid, Joshua Gustine, Christopher J. Patterson, Jeffrey V. Matous, Irene M. Ghobrial, and Jorge J. Castillo. "Long-Term Outcome of a Prospective Study of Bortezomib, Dexamethasone and Rituximab (BDR) in Previously Untreated, Symptomatic Patients with Waldenstrom's Macroglobulinemia." Blood 126, no. 23 (December 3, 2015): 1833. http://dx.doi.org/10.1182/blood.v126.23.1833.1833.
Abstract:
Abstract Background: Proteasome-inhibitor (PI) based therapy is highly effective and widely utilized in the treatment of Waldenstrom's Macroglobulinemia (WM), though published data on the long-term impact of PI-based therapy, including treatment-related peripheral neuropathy and secondary malignancies remains limited. Methods: We performed a prospective, multicenter study of bortezomib, dexamethasone and rituximab (BDR) in symptomatic, previously untreated WM patients. Treatment consisted of bortezomib 1.3 mg/m2 administered intravenously along with dexamethasone 40 mg on days 1, 4, 8, and 11; and rituximab 375 mg/m2 on day 11 as part of a 21-day cycle for 4 consecutive cycles as induction therapy. Maintenance therapy followed 12 weeks after induction therapy, and consisted of one cycle of BDR therapy every 12 weeks for a total of 4 cycles. Dose reduction or drug omission was permitted for toxicity. Herpes zoster prophylaxis and H2-blocker were required. Results: Twenty-three patients received a median of seven cycles of treatment. The median baseline characteristics were as follows: age 66 years; bone marrow involvement 55%; serum IgM 4,830 mg/dL; serum IgA 45 mg/dL; serum IgG 418 mg/dL; hemoglobin 10.1 g/dL; and B2M 3.3 mg/L. Extramedullary disease was present in 4 (17%) patients. Following treatment, median serum IgM levels declined to 557 mg/dL (p<0.001), and median hemoglobin levels rose to 14.3 g/dL (p=0.001) at best response. At last assessment, the median serum IgA and IgG were 36 and 476 mg/dL (p=0.66 and 0.28, respectively versus baseline). Using updated consensus response criteria (Owen et al, BJH 2013), the overall and major response rates were 96% and 91%, respectively, and categorical responses were as follows: CR (N=4); VGPR (N=8); PR (N=9); MR (N=1). The median time to response was 1.4 months. With a median follow-up of 8.5 years, the median time to progression was 5.5 years, with an estimated 5-year progression free survival rate of 57% (95% CI 32-72%). Patients attaining a CR showed a longer progression-free survival interval (long rank p=0.03). The 5-year overall survival was 95% (95% CI 72-99%). Kaplan Meier curves for progression-free (PFS) and overall survival (OS) are shown in Figure 1. Four patients died during the follow-up period, with only one death related to WM (amyloid progression). Three patients had invasive malignancies that occurred at 29.5 (N=1; Breast CA); 44.7 (N=1; Prostate CA); and 83.8 (N=1; Vulvar CA) months following initiation of protocol therapy. No unexpected toxicities occurred. The most common grade >2 toxicities were as follows: peripheral neuropathy (N=16); neutropenia (N=13); infections without neutropenia (N=13); thrombocytopenia (N=10) and steroid related hyperglycemia (N=6). Discontinuance of bortezomib occurred in 14 (60%) patients for peripheral neuropathy; dexamethasone for steroid intolerance in 3 (13%) patients; and rituximab for antibody-related neutropenia in one patient (4%). For the 16 patients experiencing bortezomib related peripheral neuropathy, neuropathic complaints resolved (N=8); decreased to Grade 1 (N=5); remained unchanged (N=2); or were unevaluable (N=1) with prolonged follow-up. Conclusions: BDR is a highly effective regimen producing high overall and major response rates, as well as long progression-free and overall survival intervals in previously untreated, symptomatic patients with WM. No unexpected toxicities were encountered. Secondary malignancies did not appear associated with protocol therapy. Reversible neurotoxicity constituted the most common adverse event associated with BDR using a twice-weekly schedule of administration of bortezomib, and resulted in high rates of proteasome-inhibitor discontinuance. Efforts to identify more neuropathy sparing approaches, including alternative schedules and routes of bortezomib administration, as well as novel neuropathy sparing proteasome-inhibitors are warranted given these encouraging long-term efficacy findings in WM. Disclosures No relevant conflicts of interest to declare.
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Yoshizawa, Toshio, Tomoko Yasuhiro, Hideyuki Honda, and Kazuhito Kawabata. "ONO-4059—a Potent and Selective Reversible Bruton’s Tyrosine Kinase (Btk) Inhibitor: Single Agent, Twice Daily (BD) Dosing and Dosing with Food Results in Sustained, High Trough Levels of ONO-4059, Translating into 100% Tumour Remission in a TMD-8 Xenograft Model." Blood 124, no. 21 (December 6, 2014): 4502. http://dx.doi.org/10.1182/blood.v124.21.4502.4502.
Abstract:
Abstract Purpose: Bruton’s tyrosine kinase (Btk) is a key regulator of the BCR signaling pathway and abberant BCR signaling has been implicated in the survival of malignant B-cells. The activated B-cell-like (ABC) sub-type of Diffuse Large B-Cell Lymphoma (DLBCL) correlates with poor prognosis. There is still a high unmet, medical need for new therapies, preferably chemo-sparing, to help treat patients with ABC-DLBCL and CLL as well as other B-cell malignancies. ONO-4059 is a highly selective, orally bioavailable inhibitor of Btk kinase activity with a potency (IC50) of 2.2 nM. ONO-4059 reversibly blocks BCR signaling and B-cell proliferation and activation. Data from the ongoing Phase 1 study (ONO-4059POE001), where ONO-4059 is administered as monotherapy (QD) demonstrated a best overall response rate of 47% (7/15) in non-GCB DLBCL patients (Walter et al, ASCO 2014; Rule et al, EHA 2014). We hypothesized that the efficacy of ONO-4059 could be further enhanced by increasing the drug trough concentration. To address this, we examined different dosing regimens of ONO-4059 in an ABC-DLBCL xenograft model. Methods: TMD-8 tumour cells (ABC-DLBCL cell line) were implanted sub-cutaneously into female SCID mice. Randomization of mice occurred when mean tumour volume was 100-200 or 400-450 mm3. ONO-4059 was administered orally or mixed in food at doses up to 20 mg/kg/day and animals were dosed QD or BD. Tumour volumes were measured twice a week after initiation of treatment, and tumour volumes were determined using the formula volume (= width2 x length)/2. Animals were euthanized when the tumours reached a maximum volume of 3,000 mm3. Results: For the100-200 mm3 tumour groups, tumour growth inhibition at the final treatment day was 23% in QD, 72.9% in BD and 100% in dose mixed in food, groups respectively. For the 400-450 mm3 tumour groups, no growth inhibition was observed in the QD group and, growth inhibitions of 27.5% in BD and 100% in dose mixed in food were observed. Interestingly, the treatment with ONO-4059-containing diets resulted in tumour remission in 10/10 animals, in both 100-200 and 400-450 mm3 treatment groups, whereas no tumour free animals were observed in the other treatment groups. The PK concentration and phosphorylated Btk (pBtk) inhibition levels of those animals whose dose was mixed in with food were higher than that of other treatment groups. Conclusion: Our previous study demonstrated that 100% tumour remission can be achieved partially with an ONO-4059 and GA101 or rituximab combination (Yoshizawa et al, ASH 2013). However, to date, no orally bioavailable targeted-agent administered as monotherapy has demonstrated 100% tumour remission in an advanced ABC-DLBCL xenograft model. Although the clinical data for ONO-4059 given as monotherapy (QD) is very encouraging in both relapsed and refractory CLL/NHL patients, this data indicates that a more frequent dosing regimen such as BD may be a more effective treatment, especially for non-GCB DLBCL and warrants further investigation in the clinical setting, along with food effect studies. Disclosures Yoshizawa: Ono Pharmaceutical Co., Ltd.: Employment. Yasuhiro:Ono Pharmaceutical Co., Ltd.: Employment. Honda:Ono Pharmaceutical Co., Ltd.: Employment. Kawabata:Ono Pharmaceutical Co., Ltd.: Employment.
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Wang, C., H. Song, Z. Yu, and M. Quan. "AB1009 THE EFFICACY OF TOCILIZUMAB ON THE TREATMENT OF TAKAYASU ARTERITIS IN CHINESE CHILDREN." Annals of the Rheumatic Diseases 79, Suppl 1 (June 2020): 1798.2–1798. http://dx.doi.org/10.1136/annrheumdis-2020-eular.5778.
Abstract:
Background:Takayasu arteritis (TA) is the most prevalent large-vessel vasculitis in children. Patients with TA have a high mobidity and mortality.It remains a therapeutic challenge because corticosteroids monotherapy can rarely cure TAK and the relapse rate is high during GC tapering.Objectives:The aim of this study is to investigate the efficacy and safety of tocilizumab (TCZ)in Chinese children with Takayasu arteritis(TAK).Methods:We retrospectively studied 6 TAK children treated with TCZ in our hospital from July 2017 to October 2018. The demographic and clinical data, laboratory examination results and vascular imaging data were collected.Results:Six pediatric patients with critical or refractory TAK treated with TCZ were analyzed, including 3 males and 3 females.The diagnosis age was ranging in age from 2 to 13 years(median age:7 years).Three patients were initially treated with TCZ and Mycophenolate Mofetil(MMF) as the first-line regimen without corticosteroid or with a quite rapid GC taper duration,two of which had lifte-threatening coronary arteries involved and heart failure.The other three paitients were swcithed to TCZ from conventional disease modifying anti-rheumatic drugs (DMARDs) or other biologics due to being refractory to them and recurrent relapses.Four patients were given TCZ at 4 weeks regular intervals for 10 to 22 months,while two patients withdrew TCZ because of disease deterioration and unbearable abdominal or chest pain after the second dose.After 6 months follow-up,four patients experienced significant clinical and biological improvement with angiographically progression in one patient. A corticosteroid-sparing effect is obvious. Drug-related side effects occur in 1 patients manifesting as a mild elevated liver fuction. Neither neutropenia nor infection was observed.Conclusion:Our study shows a clinical, biological, and radiological response in patients with refractory TAK treated with TCZ.References :[1]Hellmich B, Agueda A, Monti S,et al.2018 Update of the EULAR recommendations for the management of large vessel vasculitis. Ann Rheum Dis 2019;0:1–12. doi:10.1136/annrheumdis-2019-215672.[2]BravoMancheño B, Perin F, Guez Vázquez Del ReyMDMR, García Sánchez A, Alcázar Romero PP. Successful tocilizumab treatment in a child with refractory Takayasu arteritis.Pediatrics 2012;130(6):e1720-724.[3]Goel R, Danda D, Kumar S, Joseph G. Rapid control of disease activity by tocilizumab in 10 «difficult-to-treat» cases of Takayasu arteritis. Int J Rheum Dis 2013;16(6):754–61.[4]Cañas CA, Cañas F, Izquierdo JH, Echeverri A-F, Mejía M, Bonilla-Abadía F, et al. Efficacy and safety of anti-interleukin 6 receptor monoclonal antibody (tocilizumab) in Colombian patients with Takayasu arteritis. J Clin Rheumatol Pract Rep Rheum Musculoskelet Dis 2014;20(3):125–9.[5]Batu ED, Sönmez HE, Hazirolan T, Özaltin F, Bilginer Y, Özen S. Tocilizumab treatment in childhood Takayasu arteritis: case series of four patients and systematic review of the literature. Semin Arthritis Rheum 2017 Feb;46(4):529–35.Disclosure of Interests:None declared