Journal articles on the topic 'Low-grade chronic syndromes'
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Ismael San, Mauro-Martín, Collado-Yurrita Luis, Sanz-Rojo Sara, López-Oliva Sara, Conty Raquel, Puga Ana M., and Garicano-Vilar Elena. "Short-Time Strategy for Fibromyalgia Treatment Based on Olive Nutraceutical and Inflammatory Gut-Brain Axis Control Diet (IGUBAC) Diet®." Current Topics in Nutraceutical Research 17, no. 1 (June 1, 2018): 23–32. http://dx.doi.org/10.37290/ctnr2641-452x.17:23-32.
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Fibromyalgia syndrome is defined as chronic widespread pain and tenderness. It is associated with fatigue, sleep disorder, functional somatic syndromes, mental and physical disorders, as well as disability and diminished quality of life. We aimed to analyse the effects of an olive tree-based supplement and a gluten-free, FODMAP and low histamine diet (IGUBAC-Diet®), with antioxidant and anti-inflammatory characteristics, in women with fibromyalgia. A randomized, controlled, clinical trial, with 31 women (55.87±11.86 years) diagnosed with fibromyalgia was conducted in 2016. Chronic Pain Grade Scale, Pain Catastrophizing Scale, Fatigue Severity and Impact Scale were used. Anthropometric parameters and symptoms progression were measured before and after two months of treatment with olive tree-based supplement and IGUBAC-Diet®. Other secondary outcome measures include blood biochemical analysis. Patients improved Chronic Pain Grade Scale scores after intervention and all groups experienced a reduction in the perception of pain catastrophizing. Positive changes were found all groups for Fatigue Severity Scale, but not for Fatigue Impact Scale scores. Significant variations (p < 0.05) were observed in symptoms frequency. The olive tree-based food supplement and the gluten-free, FODMAP and low histamine diet had beneficial effects on the intensity of fibromyalgia symptoms. This short-time strategy may be used to improve fibromyalgia patient’s well-being.
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Amin, Hesham M., Sherry A. Pierce, Hagop M. Kantarjian, Michael J. Keating, Emil J. Freireich, Charles A. Koller, Miloslav Beran, Maher Albitar, Susan M. O’Brien, and Elihu H. Estey. "Increased Bone Marrow Erythroid Precursors Is Associated with Shorter Survival in Low-Grade Myelodysplastic Syndromes." Blood 104, no. 11 (November 16, 2004): 2371. http://dx.doi.org/10.1182/blood.v104.11.2371.2371.
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Abstract According to the FAB and WHO classifications, the diagnosis of acute erythroid leukemia is based on the numbers of nucleated red blood cells and myeloid blasts in the bone marrow. The WHO classification recognizes two types of acute erythroid leukemia; M6A with 51–80% erythroid precursors and with 20% or more of the non-erythroid precursors being myeloid blasts; and M6B with more than 80% of the nucleated cells in the bone marrow consisting of erythroid precursors, regardless of the percentage of the myeloid blasts. Previous studies have shown that many cases of acute erythroid leukemia arise in patients with a history of myelodysplastic syndrome and in other cases acute erythroid leukemia is associated with significant dysplastic features. The significance of the number of erythroid precursors is not well known in the myelodysplastic syndromes. In the present study, we included 617 consecutive patients with low-grade myelodysplasia (482 patients with refractory anemia [RA] and 135 patients with refractory anemia with ringed sideroblasts [RARS]). Among this group, 82 patients with 50% or more of erythroid precursors had shorter survival compared with 535 patients with less than 50% erythroid precursors (P < .01; Figure 1). The shorter survival in those with 50% or more of erythroid precursors may reflect the tendency of these patients to have worse International Prognostic Scoring System (IPSS) scores. Thus, among the patients with less than 50% erythroid precursors and primary MDS, 35% were IPSS low, 52% IPSS intermediate 1, and 13% IPSS intermediate 2. For the patients with 50% or more of erythroid precursors, the corresponding proportions were 14%, 57%, and 29%, respectively (P < .001). As a result of the association between IPSS and the percentage of erythroid precursors, the percentage of erythroid precursors had no effect on survival within individual IPSS groups. Similarly, the percentage of erythroid precursors had no prognostic significance in patients with refractory anemia with excess blasts (RAEB) or chronic myelomonocytic leukemia (CMML). Our findings demonstrate that in low-grade dysplasia (RA and RARS) the number of erythroid precursors may represent an important prognostic marker. These findings implicate that the percentage of erythroid precursors should be considered in the classification of the low-grade myelodysplastic syndromes. A multivariate analysis will be performed to ascertain the relative effects of IPSS score and the percentage of erythroid precursors on prognosis in patients with low-grade myelodysplasia. Figure Figure
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Currò, Diego, Edoardo Vergani, Carmine Bruno, Simone Comi, Claudia D'Abate, and Antonio Mancini. "Plasmatic lipocalin‐2 levels in chronic low‐grade inflammation syndromes: Comparison between metabolic syndrome, total and partial adult growth hormone deficiency." BioFactors 46, no. 4 (March 20, 2020): 629–36. http://dx.doi.org/10.1002/biof.1628.
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Hassan, Ebrahim Bani, Steven Phu, Elyce Warburton, Nihara Humaith, and Tissa Wijeratne. "Frailty in Stroke—A Narrated Review." Life 11, no. 9 (August 28, 2021): 891. http://dx.doi.org/10.3390/life11090891.
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This narrative review provides a summary introduction to the relationship between stroke and physical and cognitive frailty syndromes and the neuro-inflammatory similarities (including inflammaging) between the two. The review argues the potential effects of Post COVID-19 Neurological Syndrome (PCNS, also known as Long COVID) with similar pathophysiology. Many patients who have suffered from acute stroke experience long-lasting symptoms affecting several organs including fatigue, brain fog, reduced physical activity, loss of energy, and loss of cognitive reserve, culminating in the loss of independence and poor quality of life. This is very similar to the emerging reports of PCNS from different parts of the world. Stroke, particularly in older adults with comorbidities appears to impact the health and welfare of patients by reducing central neuronal input and neuromuscular function, with muscular atrophy and neuropsychiatric complications. The cumulative effects can potentially lead to a range of physical and cognitive frailty syndromes, which, in many cases may be attributed to persistent, maladapted, low grade, chronic inflammation. Meanwhile, post-COVID-19 Neurological Syndrome (also known as Long COVID Syndrome) appears to share a similar trajectory, adding further urgency for investigations into the mechanisms underlying this constellation of symptoms.
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Chen, Li, Rui Chen, Hua Wang, and Fengxia Liang. "Mechanisms Linking Inflammation to Insulin Resistance." International Journal of Endocrinology 2015 (2015): 1–9. http://dx.doi.org/10.1155/2015/508409.
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Obesity is now widespread around the world. Obesity-associated chronic low-grade inflammation is responsible for the decrease of insulin sensitivity, which makes obesity a major risk factor for insulin resistance and related diseases such as type 2 diabetes mellitus and metabolic syndromes. The state of low-grade inflammation is caused by overnutrition which leads to lipid accumulation in adipocytes. Obesity might increase the expression of some inflammatory cytokines and activate several signaling pathways, both of which are involved in the pathogenesis of insulin resistance by interfering with insulin signaling and action. It has been suggested that specific factors and signaling pathways are often correlated with each other; therefore, both of the fluctuation of cytokines and the status of relevant signaling pathways should be considered during studies analyzing inflammation-related insulin resistance. In this paper, we discuss how these factors and signaling pathways contribute to insulin resistance and the therapeutic promise targeting inflammation in insulin resistance based on the latest experimental studies.
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Terkawi, M. Alaa, Taku Ebata, Shunichi Yokota, Daisuke Takahashi, Tsutomu Endo, Gen Matsumae, Tomohiro Shimizu, Ken Kadoya, and Norimasa Iwasaki. "Low-Grade Inflammation in the Pathogenesis of Osteoarthritis: Cellular and Molecular Mechanisms and Strategies for Future Therapeutic Intervention." Biomedicines 10, no. 5 (May 10, 2022): 1109. http://dx.doi.org/10.3390/biomedicines10051109.
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Osteoarthritis (OA) is a musculoskeletal disease characterized by cartilage degeneration and stiffness, with chronic pain in the affected joint. It has been proposed that OA progression is associated with the development of low-grade inflammation (LGI) in the joint. In support of this principle, LGI is now recognized as the major contributor to the pathogenesis of obesity, aging, and metabolic syndromes, which have been documented as among the most significant risk factors for developing OA. These discoveries have led to a new definition of the disease, and OA has recently been recognized as a low-grade inflammatory disease of the joint. Damage-associated molecular patterns (DAMPs)/alarmin molecules, the major cellular components that facilitate the interplay between cells in the cartilage and synovium, activate various molecular pathways involved in the initiation and maintenance of LGI in the joint, which, in turn, drives OA progression. A better understanding of the pathological mechanisms initiated by LGI in the joint represents a decisive step toward discovering therapeutic strategies for the treatment of OA. Recent findings and discoveries regarding the involvement of LGI mediated by DAMPs in OA pathogenesis are discussed. Modulating communication between cells in the joint to decrease inflammation represents an attractive approach for the treatment of OA.
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Sulima, D. L., S. S. Suleymanova, A. A. Yakovlev, V. N. Koryagin, and V. V. Rassokhin. "Virological failures of primary interferon-free therapy in patients with chronic HCV RNA viremia and successful repeated interferon-free therapy." HIV Infection and Immunosuppressive Disorders 14, no. 3 (November 10, 2022): 100–109. http://dx.doi.org/10.22328/2077-9828-2022-14-3-100-109.
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Objective. Description of clinical forms of chronic HCV infection in the observed patients, clarifications of options and causes of virological failures of primary interferon-free therapy (DAAT/1) and the results of repeated interferon-free treatment (DAAT/2).Materials and methods. 8 patients with chronic RNA HCV viremia (subtypes 1b+/–1a and 3а/3ab) were prospectively observed who suffered a virological failure of primary interferon-free therapy with original inhibitors in the form of relapse of RNA HCV viremia and aviremic low-level replication RNA HCV in PBMCs (peripheral mononuclears), but then achieved HCV eradication with a repeated course of interferon-free therapy.Results. Two variants of virological failures of primary interferon-free therapy were noted — relapse of RNA HCV viremia and aviremic low-level replication of RNA HCV in PBMCs. A number of unfavorable prognosis signs (individual clinical and laboratory syndromes and laboratory parameters) were revealed, which were observed in most patients who did not achieve HCV eradication using primary interferon-free therapy with antiviral drugs: HCV-associated syndromes of low-grade systemic inflammation (LGSI), benign lymphoproliferation and autoantibody production, a high level viral load of HCV RNA viral load in blood plasma, HBV-coinfection without HBsAg and cirrhosis of the liver in the outcome of chronic hepatitis C. The target result of repeated interferon-free therapy, confirmed by the sustainable virological response after 12 weeks after the end of the treatment (SVR12), was achieved in all «losers» of primary interferon-free therapy.Conclusion. The unfavorable prognostic signs identified in the majority of «losers» of primary interferon-free therapy in the form of individual clinical and laboratory syndromes and laboratory parameters may be associated with potential virological inefficiency of therapy. Based on logistic regression analysis, the value of each of the identified features for predicting different outcomes of primary interferon-free therapy in a large group of patients with HCV is shown. Pangenotypic combinations of GLE/PIB+SOF+/–RBV and VEL/SOF+RBV inhibitors have shown their high antiviral efficacy in the treatment of relapse of RNA HCV viremia and aviremic low-level replication of RNA HCV in peripheral mononuclears for all the patients for whom primary interferon-free therapy was unsuccessful.
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Garcia-Manero, Guillermo, Lewis B. Silverman, Ivana Gojo, Laura Michaelis, Simrit Parmar, Stuart L. Goldberg, Hagop M. Kantarjian, et al. "A Randomized Phase IIa Study of Vorinostat in Patients with Low or Intermediate-1 Risk Myelodysplastic Syndromes: Preliminary Results." Blood 112, no. 11 (November 16, 2008): 5084. http://dx.doi.org/10.1182/blood.v112.11.5084.5084.
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Abstract Effective treatment options for patients with lower-risk myelodysplastic syndromes (MDS) are limited. However, around one-third of patients experience transformation to acute myeloid leukemia, and absent transformation, complications of chronic cytopenias (including infection), and iron-overload syndromes can be fatal. Although 5-azacitidine, decitabine, and lenalidomide have improved treatment options for patients with MDS, these are not routinely used in patients with lower-risk disease. Histone deacetylase (HDAC) enzymes are overexpressed in several tumor types including MDS, and regulate transcriptional and post-transcriptional processes. Vorinostat (Zolinza®) has been shown to inhibit class I and II HDAC enzymes, and has been approved by the FDA for the treatment of cutaneous manifestations of T-cell lymphoma in patients with persistent or recurrent disease, on or following 2 prior systemic therapies. Vorinostat induces cell-cycle arrest, apoptosis, or differentiation in a variety of cultured transformed cell lines, and has demonstrated activity against leukemias in in vivo non-clinical models and in phase I and II clinical trials. Efficacy data in these early phase trials prompted an investigation of vorinostat monotherapy in lower-risk MDS. The potency and tolerability of vorinostat suggest it may be effective in the treatment of MDS. Here, we report preliminary results of a randomized phase II study evaluating once-daily and three-times-daily (tid) intermittent dosing schedules of vorinostat in patients with low and intermediate-1 risk MDS. Primary objectives included assessment of the efficacy, safety, and tolerability of vorinostat. Eligible patients were aged ≥18 years, had either previously untreated disease, or were ≥4 weeks from any prior treatment regimen (including growth factors). Patients’ performance status was ≤2 on the ECOG performance scale, they had adequate organ function, and were either red blood cell transfusion dependent or had a hemoglobin level of ≤11g/dL at the time of screening, or had platelets ≤100 × 109/L at the time of screening. Eligible patients were assigned to 1 of 2 oral dosing regimens: vorinostat 400 mg daily or vorinostat 200 mg tid. Treatment was administered over a 21-day cycle (14 days’ therapy and 7 days’ rest), with patients receiving up to 8 cycles, or until the patient experienced unacceptable toxicity, disease progression, or withdrew consent. In total, 18 patients (12 male, 6 female; mean age 67.4 years) have been randomized, including 5 with low-risk MDS and 13 with intermediate-1 risk MDS, as defined by the International Prognostic Scoring System. Of the patients enrolled, 12 (3 low-risk and 9 intermediate-1 risk MDS) were evaluable for response and have received between 2 and 6 cycles of treatment. Stable disease has been reported in all 12 patients, with a reported duration of between 22–146 days (low-risk MDS) and 1–136 days (intermediate-1 risk MDS). A total of 11/18 (61%) patients have discontinued, 2 due to adverse events (1 event of grade 4 neutropenia [unrelated to study medication] and 1 event of grade 3 neuropathy [drug related]), 1 due to deviation from protocol, 4 due to lack of efficacy, 3 due to physician decision, 1 due to progressive disease, and 1 because of withdrawal of consent. Most adverse events were gastrointestinal disorders: diarrhea in 10 patients (7 grade 1, 3 grade 2), nausea in 9 patients (6 grade 1, 3 grade 2), and vomiting in 6 patients (5 grade 1, 1 grade 2). Grade 4 neutropenia, anemia, and thrombocytopenia were observed in 2, 1, and 1 patients, respectively; however these were unrelated to study medication. Data from this study indicate that vorinostat administered in a 21-day cycle has acceptable safety and tolerability.
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de Latour, Regis Peffault, Vanderson Rocha, Marie Robin, Celso A. Rodrigues, Delphine Rea, Jerome Laghero, Richard Traineau, et al. "Double Cord Blood Transplantation in Bone Marrow Failure Syndromes." Blood 110, no. 11 (November 16, 2007): 2018. http://dx.doi.org/10.1182/blood.v110.11.2018.2018.
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Abstract The outcome of severe aplastic anemia, refractory to immunosuppressive therapy or observed in case of Fanconi anemia (FA), is usually poor in the absence of Hematopoietic Stem Cell Transplantation (HSCT). Umbilical cord blood is an alternative stem cell source for patients without matched related or unrelated donors. However, single cord blood unit is associated with high transplant related mortality due to the low cell dose infused in previous highly transfused patients. We have driven the hypothesis that double cord blood transplantation (dCBT) could circumvent the cell dose problem. For the purpose of this study, we have studied 13 patients with bone marrow failure syndromes given 2 partially matched dCBT from 2004 to 2007. The diagnoses were FA (n=9), SAA (n=4) and PNH (n=1). Among those patients, 5 (39%) received a dCBT as a rescue of previous rejected transplants (2 SAA and 3 FA). All patients received a fludarabine-based regimen, with TBI (2 Gy) for 4 patients. Cord blood units were a 4/6 or 5/6 HLA A, B and DR match with the patient except one which was 3/6. Graft versus host disease (GVHD) prophylaxis consisted in CSA+MMF. Steroids were given from day 7 to day 14 and stopped in case of no GVHD. Five male (39%) and 8 female (61%) with a median age of 16 years (range 7–31) were treated. The cell doses infused were a median of 5.0 × 107 NC/Kg (4–9) and 5.3 × 105 CD34+ cells/Kg (2–8). Graft rejection was seen in 5 patients (2 previously allotransplanted). Among those patients, one displayed a temporary mixed chimerism before rejection and another presented an autologous reconstitution. Among the remaining 8 patients, the median time to an absolute neutrophils count > 500 was 25 days (range 14–42) and the median time to a platelet count > 20,000 was 39 days. In these last patients, we observed a complete donor chimerism with one cord blood unit during 100 days after dCBT. Acute GVHD grade II–III was scored in 9 patients (69%) (7 grade II, 2 grade III). No patients presented acute GVHD grade IV. Four patients out of 8 developed Chronic GVHD (3 limited and 1 extensive). Four patients died (1 GVHD, 2 fungal infection, 1 thrombotic microangiopathy). With a median follow-up of 13 months (range 1 to 19 months), the overall survival was 55% (±15%) for all patients. The median survival of patients who were transplanted twice was 50% (±25%). In conclusion, dCBT seems to be an option to treat patients with bone marrow failure syndromes and without a suitable compatible HLA donor. Those results need to be established on a large number of patients to warrant the inclusion of dCBT in the treatment strategy of diseases with high risk of rejection.
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Beran, Miloslav, Srdan Verstovsek, Steven M. Kornblau, Elihu H. Estey, Francis Giles, Guillermo Garcia-Manero, and Hagop M. Kantarjian. "Prolonged Administration of Arsenic Trioxide (Trisenox®) for Patients with Myelodysplastic Syndromes (MDS) and Chronic Myelomonocytic Leukemia (CMML) at MD Anderson Cancer Center: A Phase II Study." Blood 104, no. 11 (November 16, 2004): 4731. http://dx.doi.org/10.1182/blood.v104.11.4731.4731.
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Abstract The value of prolonged administration of arsenic trioxide (ATO) was examined in patients (pts) with MDS and CMML. ATO (0.25 mg/kg) was given intravenously over 1 hour daily for five days followed by 0.25 mg/kg twice weekly for 11 weeks. Pts were assessed at 4 weeks, at the end of the first course, and then monthly. Pts with stable disease were eligible for further courses. The study included 14 RBC transfusion-dependent MDS pts (6 RA/RARS, 8 RAEB; 12 IPSS risk Low/Int1, 2 Int2/High), and 3 CMML pts. Median age was 67 years (range 46–84). Six pts had a history of previous treatment other than supportive care. 16 pts were evaluable for toxicity and response. One pt received 3 courses, 3 received 2 courses, and 13 received 1 course. Hematologic responses (IWG criteria) were observed in 4 pts (25%) and 9 (6 MDS,3 CMML) had stable disease: FAB Type of response Time to response Duration RA Minor erythroid 2 months 3 mo, RBC independence RAEB Major neutrophil and platelet 2 mo 3 mo RAEB BM blast decrease 18% to <5% 1 mo 14 mo, stable pancytopenia RAEB Hematologic/cytogenetic CR 1 mo 6 mo Hematologic/cytogenetic CR was achieved in one pt: a 76 year old male, RAEB-2, Int 2, complex chromosomal abnormalities, who had previously failed thalidomide for 6 months and thalidomide + cyclosporin A for 3 months. Of the 3 CMML pts, one had transient reduction of absolute monocyte counts during each of 2 courses; all 3 had stable disease. In 24 courses there were 6 febrile episodes in 4 patients, requiring admission, all in pts with pre-existing neutropenia; 1 Grade 3 and 1 Grade 4 thrombocytopenia, 1 Grade 3 neutropenia, all requiring dose modification; 1 episode of accelerated functional cardiac rhythm; and 1 anemia-precipitated congestive heart failure, which was unlikely related to the drug. There were 22 episodes of Grade 1 or 2 drug-related toxicities. Four responses of 3–7+ mo. duration were observed, including 1 CR, suggesting activity in an as yet undefined subgroup of MDS pts. No benefit of prolonged treatment was documented. ATO was safe in this outpatient setting for elderly patients. Observed low toxicity and documented activity support future trials of ATO in combination with other agents in treatment of MDS.
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Beran, Miloslav, Elihu Estey, Susan O'Brien, Jorge Cortes, Charles A. Koller, Francis J. Giles, Steven Kornblau, et al. "Topotecan and Cytarabine Is an Active Combination Regimen in Myelodysplastic Syndromes and Chronic Myelomonocytic Leukemia." Journal of Clinical Oncology 17, no. 9 (September 1999): 2819. http://dx.doi.org/10.1200/jco.1999.17.9.2819.
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PURPOSE: To evaluate the efficacy and safety of the combination of topotecan and cytarabine in patients with myelodysplastic syndromes (MDSs) and chronic myelomonocytic leukemia (CMML). PATIENTS AND METHODS: Fifty-nine patients with MDSs and 27 with CMML were enrolled. They were either previously untreated (66%) or had received only biologic agents (14%) or chemotherapy with or without biologic agents (20%). Treatment consisted of topotecan 1.25 mg/m2 by continuous intravenous infusion daily for 5 days and cytarabine 1.0 g/m2 by infusion over 2 hours daily for 5 days. Prophylaxis included antibacterial, antifungal, and antiviral agents. At a median follow-up of 7 months, all 86 patients were assessable for response and toxicity. RESULTS: Complete remission (CR) was observed in 48 patients (56%; 61% with MDSs, 44% with CMML; P = .15). Similar CR rates were observed for patients with good-risk and poor-risk MDS (70% and 56%, respectively). The treatment effectively induced CR in patients with a poor-prognosis karyotype involving chromosomes 5 and 7 (CR, 71%) and secondary MDSs (CR, 72%). Fifty-four patients received one induction course, 25 patients received two, and the rest received more than two. The median number of continuation courses was two. The median overall duration of CR was 34 weeks (50 weeks for MDSs and 33 weeks for CMML). The median survival was 60 weeks for MDS and 44 weeks for CMML patients. CR and survival durations were longer in patients with refractory anemia with excess blasts (RAEB). Grade 3 or 4 mucositis or diarrhea was observed in three patients each. Fever was observed in 63%, and infections in 49% of patients. Six patients (7%) died during induction therapy. CONCLUSION: Topotecan and cytarabine induced high CR rates in unselected patients with MDSs and CMML, particularly among patients with poor-prognosis cytogenetics and secondary MDSs. Topotecan-cytarabine is an active induction regimen in MDS and CMML patients, is well tolerated, and is associated with a low mortality rate.
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Montalbano, Giuseppe, Kamel Mhalhel, Marilena Briglia, Maria Levanti, Francesco Abbate, Maria Cristina Guerrera, Enrico D’Alessandro, Rosaria Laurà, and Antonino Germanà. "Zebrafish and Flavonoids: Adjuvants against Obesity." Molecules 26, no. 10 (May 19, 2021): 3014. http://dx.doi.org/10.3390/molecules26103014.
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Obesity is a pathological condition, defined as an excessive accumulation of fat, primarily caused by an energy imbalance. The storage of excess energy in the form of triglycerides within the adipocyte leads to lipotoxicity and promotes the phenotypic switch in the M1/M2 macrophage. These changes induce the development of a chronic state of low-grade inflammation, subsequently generating obesity-related complications, commonly known as metabolic syndromes. Over the past decade, obesity has been studied in many animal models. However, due to its competitive aspects and unique characteristics, the use of zebrafish has begun to gain traction in experimental obesity research. To counteract obesity and its related comorbidities, several natural substances have been studied. One of those natural substances reported to have substantial biological effects on obesity are flavonoids. This review summarizes the results of studies that examined the effects of flavonoids on obesity and related diseases and the emergence of zebrafish as a model of diet-induced obesity.
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Sajid, Mohammad, and Sapna Negi. "Gut Microbes: A Plausible Association Between Inflammaging and Metabolic Disorders." International Journal of Probiotics and Prebiotics 15, no. 1 (August 9, 2020): 34–44. http://dx.doi.org/10.37290/ijpp2641-7197.15:34-44.
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Aging is associated with deterioration of cellular homeostasis and increased risk for several age-related metabolic disorders like obesity, diabetes mellitus, and cardiovascular diseases. Chronic and low-grade inflammation is linked with metabolic syndromes especially during aging (inflammaging). This inflammaging may enhance the risk for late-onset diseases. Gut microbes show a significant role in the regulation and pathogenesis of various metabolic disorders. Gut mucosal lining is a mechanical obstruction between gut microbiota and the host. Deterioration of the gut mucosal barrier may expedite biological aging by enabling exposure of gut microbes to the mucosal immunity. Further, the compromised mucosal immunity may lead to inflammation and if immunogenic microbial peptide(s) present in the gut mimics host protein(s), they can induce mild autoimmunity. Therefore, the pathology of metabolic disorders may be related to molecular mimicry stimulated by exposure of gut microbial peptide(s) during aging. This article reviews gut microbes induced inflammaging which can be a potential probiotic target for the treatment of non-communicable diseases.
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Frasca, Daniela, Alain Diaz, Maria Romero, Denisse Garcia, and Bonnie B. Blomberg. "B Cell Immunosenescence." Annual Review of Cell and Developmental Biology 36, no. 1 (October 6, 2020): 551–74. http://dx.doi.org/10.1146/annurev-cellbio-011620-034148.
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Innate and adaptive immune responses decline with age, leading to greater susceptibility to infectious diseases and reduced responses to vaccines. Diseases are more severe in old than in young individuals and have a greater impact on health outcomes such as morbidity, disability, and mortality. Aging is characterized by increased low-grade chronic inflammation, so-called inflammaging, that represents a link between changes in immune cells and a number of diseases and syndromes typical of old age. In this review we summarize current knowledge on age-associated changes in immune cells with special emphasis on B cells, which are more inflammatory and less responsive to infections and vaccines in the elderly. We highlight recent findings on factors and pathways contributing to inflammaging and how these lead to dysfunctional immune responses. We summarize recent published studies showing that adipose tissue, which increases in size with aging, contributes to inflammaging and dysregulated B cell function.
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Maio, M., A. Pinto, A. Carbone, V. Zagonel, A. Gloghini, G. Marotta, D. Cirillo, A. Colombatti, F. Ferrara, and L. Del Vecchio. "Differential expression of CD54/intercellular adhesion molecule-1 in myeloid leukemias and in lymphoproliferative disorders." Blood 76, no. 4 (August 15, 1990): 783–90. http://dx.doi.org/10.1182/blood.v76.4.783.783.
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Abstract Indirect immunofluorescence staining with monoclonal antibody (MoAb) CL203.4 of malignant cells from 269 patients with hematologic malignancies showed a heterogeneous expression of CD54/intercellular adhesion molecule-1 (ICAM-1). This marker was expressed by malignant cells of 57 out of 118 patients with myeloid malignancies and 69 out of 135 with B-lymphoid malignancies. On the other hand, CD54 was not detected on malignant cells of 16 patients with T-lymphoid malignancies. In myeloid malignancies, CD54 is preferentially expressed by “stem cell-derived” malignancies, being detectable on blast cells from almost all patients affected by chronic myelogenous leukemia in blast phase or myelodysplastic syndromes and by only 34% of patients with de novo acute myeloid leukemia (AML). The expression of CD54 did not correlate with any specific myeloid FAB subtype, although three cases of highly undifferentiated AML (FAB MO) displayed maximal levels of the antigen. The expression of CD54 in AML was significantly associated with that of CD34 and HLA-DR antigens. In B-lymphoid malignancies, CD54 expression appears to correlate with the differentiation stage of malignant cells, since B-origin acute lymphoblastic leukemias and conventional B-chronic lymphocytic leukemias (B-CLL; ie, “dim SIg” CLL) expressed lower levels of CD54 than more mature lymphoproliferative disorders (“bright SIg” CLL, prolymphocytic leukemias, and lymphoplasmacytic tumors). “High-grade” B- cell non-Hodgkin‧s lymphomas (B-NHL) express in general a higher level of CD54 than “low-grade” ones. This finding in conjunction with the expression of CD54 in all 17 patients with “bright SIg” CLL investigated (characterized by marked organomegaly and poor prognosis) suggest that the differential expression of CD54 in lymphoproliferative disorders may also relate to their degree of malignancy.
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Maio, M., A. Pinto, A. Carbone, V. Zagonel, A. Gloghini, G. Marotta, D. Cirillo, A. Colombatti, F. Ferrara, and L. Del Vecchio. "Differential expression of CD54/intercellular adhesion molecule-1 in myeloid leukemias and in lymphoproliferative disorders." Blood 76, no. 4 (August 15, 1990): 783–90. http://dx.doi.org/10.1182/blood.v76.4.783.bloodjournal764783.
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Indirect immunofluorescence staining with monoclonal antibody (MoAb) CL203.4 of malignant cells from 269 patients with hematologic malignancies showed a heterogeneous expression of CD54/intercellular adhesion molecule-1 (ICAM-1). This marker was expressed by malignant cells of 57 out of 118 patients with myeloid malignancies and 69 out of 135 with B-lymphoid malignancies. On the other hand, CD54 was not detected on malignant cells of 16 patients with T-lymphoid malignancies. In myeloid malignancies, CD54 is preferentially expressed by “stem cell-derived” malignancies, being detectable on blast cells from almost all patients affected by chronic myelogenous leukemia in blast phase or myelodysplastic syndromes and by only 34% of patients with de novo acute myeloid leukemia (AML). The expression of CD54 did not correlate with any specific myeloid FAB subtype, although three cases of highly undifferentiated AML (FAB MO) displayed maximal levels of the antigen. The expression of CD54 in AML was significantly associated with that of CD34 and HLA-DR antigens. In B-lymphoid malignancies, CD54 expression appears to correlate with the differentiation stage of malignant cells, since B-origin acute lymphoblastic leukemias and conventional B-chronic lymphocytic leukemias (B-CLL; ie, “dim SIg” CLL) expressed lower levels of CD54 than more mature lymphoproliferative disorders (“bright SIg” CLL, prolymphocytic leukemias, and lymphoplasmacytic tumors). “High-grade” B- cell non-Hodgkin‧s lymphomas (B-NHL) express in general a higher level of CD54 than “low-grade” ones. This finding in conjunction with the expression of CD54 in all 17 patients with “bright SIg” CLL investigated (characterized by marked organomegaly and poor prognosis) suggest that the differential expression of CD54 in lymphoproliferative disorders may also relate to their degree of malignancy.
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Liu, Yu, Jian-Ping Shi, Wu Xiong, Yang Liu, Yu Yan, Chao-Qi Yin, Yu-Qi Jiao, Xi Zhang, and Jian-Da Zhou. "Production of an Animal Model of Semi-Yin and Semi-Yang Syndrome with Diabetic Ulcers and Study of Its Pathological and Metabolic Features." Evidence-Based Complementary and Alternative Medicine 2021 (June 26, 2021): 1–16. http://dx.doi.org/10.1155/2021/6345147.
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Background. To create an animal model for diabetic ulcers with semi-Yin and semi-Yang (SYSY) syndrome and to study the pathological and metabolic features of SYSY syndrome. Methods. Firstly, based on the clinical characteristics of the SYSY syndrome of diabetic ulcer, an animal model of diabetic ulcers with SYSY syndrome being full-thickness skin defects was created by injecting streptozotocin (STZ) intraperitoneally, infecting with Staphylococcus aureus, and gastrically administering senna. Secondly, the content and distribution patterns of collagen fibers, the expression of neutrophils and macrophage markers, angiogenesis, and the expression of IL-1β and IL-10 in the rats with Yang syndrome, Yin syndrome, and SYSY syndrome of diabetic ulcers at different time points were detected. Representative traditional Chinese medicine (TCM) ointment of Yang syndrome, Yin syndrome, and SYSY syndrome was used to treat this animal model. The above indexes in each treatment group were detected. Finally, metabonomics was used to detect and analyze the changes of differential metabolites related to macrophage metabolism in Yang, Yin, and SYSY syndromes at different time points. Results. An animal model of diabetic ulcers with SYSY syndrome was established. The pathological features of the SYSY syndrome group were chronic low-grade inflammatory reactions. On the third day, the SYSY syndrome group displayed lower expression of CD16, CD68, CD163, IL-1β, and metabolites related to M1-type macrophages compared with other groups. On the seventh day, the SYSY syndrome group showed lower expression of CD31, IL-10, myeloperoxidase, and metabolites related to M2-type macrophages. Treatment with Chong He Ointment, a representative TCM ointment for SYSY syndrome, reversed the expression levels of these indexes and promoted wound healing in the SYSY group. Conclusion. SYSY syndrome presents a persistent pathological state of low inflammation, which may be caused by an insufficient activation of the M1-type metabolic pathway in macrophages in the early acute inflammatory stage, resulting in the incomplete clearance of pathogens and debris and continuous stimulation of macrophages to initiate the M1-type metabolic pathway. CD163, CD31, IL-10, and citric acid can be used as potential specific markers for the recovery and progression of SYSY syndrome.
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Vyas, Paresh, Nicolas Goardon, Alexander Sternberg, Wai-Kit Chu, Charles F. Craddock, Richard Benson, and Sylvie Freeman. "Reduced CD38 Expression on CD34+ Cells as a Diagnostic Test in Myelodysplastic Syndromes." Blood 112, no. 11 (November 16, 2008): 2670. http://dx.doi.org/10.1182/blood.v112.11.2670.2670.
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Abstract Low risk clonal myelodysplastic syndromes (MDS) (blast count less <5%, without ring sideroblasts and a normal karyotype) can be difficult to differentiate morphologically from dysplastic non-clonal disorders. Both cause clinically significant cytopenias in the elderly and are increasing in prevalence in an ageing population. Flow cytometry has been used to try and distinguish MDS from non-clonal cytopenias. However, no one simple flow-based marker reliably differentiates MDS from non-clonal cytopenias. This has given rise to a number of scoring systems combining multiple measurements. They have variable sensitivity/specificity in MDS diagnosis and can be complex, which detracts from their routine use in clinical non-specialist flow cytometry laboratories. Perhaps the most common abnormality that we, and others, have documented in MDS is reduced B-cell CD34+ progenitors. In addition, high risk MDS is associated with increased immature hematopoietic precursors/progenitors. As immature haematopoietic precursors have low CD38 expression whereas CD34+ B-cell progenitors express high CD38 levels, we hypothesised that the relative mean fluorescence intensity (RMFI) of CD38 expression on CD34+ cells would be decreased in MDS and could provide a simple useful single flow cytometric measurement diagnostic of MDS. We initially compared CD34+ cells from low-grade MDS patients (n=10), normal controls (n=5) and pathological controls with non-clonal cytopenias (n=10) (Figure 1). High numbers of nucleated bone marrow cells (>0.5×106) were acquired from each sample to provide an accurate analysis CD38 RMFI in low frequency CD34+ subsets. CD38 RMFI in CD34+ cells where lower in MDS patients (mean=27.6; range: 5.6–51.6) than normal controls (mean=58; range: 33.3–78.8) and, importantly, there was a more striking reduction and no overlap in the range of values, when compared to the pathological controls (mean=194.5; range: 60.9–573). We then studied a second prospective cohort of bone marrow samples from 90 MDS patients and, as control samples, 31 cases of acute myeloid leukaemia, 11 of chronic myelomonocytic leukaemia and mixed MDS and myeloproliferative disorder and 70 of non-clonal cytopenias in a independent laboratory that routinely provides clinical diagnostic service. Remarkably, a reduced threshold value of CD38 conjugated with phycoerthyrin (PE) RMFI as defined by receiver-operator characteristic (ROC) curve diagnosed low-grade MDS with 95% sensitivity (95% confidence interval, 87–99%) and 92% specificity (95% confidence interval, 82–97%) (Figure 2–the dotted line is the threshold value derived from the ROC curve). This was due principally to both a decreased number of CD34+ B-cell progenitors and an increase in immature CD34+ immature precursors (Figure 2B). CD34+ cells from RAEB patients displayed an even greater reduction in CD38-PE RMFI linked to an increased frequency of CD34+CD38lo/− progenitors (Figure 1B). Similar results were seen in AML samples (Figure 2). In conclusion, reduced CD38-PE RMFI on CD34+ cells is a simple single flow cytometric test that may be of value in the routine clinical diagnosis of MDS, especially cases with a low blast count and normal karyotype. Figure 1: (A), CD38RFMI in CD34+ cells in the first group of samples studied. (B), The percentage of CD34+CD19+ and CD34+CD38lo cells in the samples studied in (A) Figure 1:. (A), CD38RFMI in CD34+ cells in the first group of samples studied. (B), The percentage of CD34+CD19+ and CD34+CD38lo cells in the samples studied in (A) Figure 2: (A), CD38RFMI in CD34+ cells in the second group of samples studied. Samples in red are from patients with autoimmune cytopenias. (B), The percentage of CD34+CD19 and CD34+CD38lo cells in the samples studied in (A).. Figure 2:. (A), CD38RFMI in CD34+ cells in the second group of samples studied. Samples in red are from patients with autoimmune cytopenias. (B), The percentage of CD34+CD19 and CD34+CD38lo cells in the samples studied in (A)..
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Freyrie, Alessandra, Gianluigi Reda, Daniele Vincenti, Mariarita Sciumé, Francesca Binda, Francesca Guidotti, and Agostino Cortelezzi. "5-Azacitidine Therapy in Patients with Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia and Acute Myeloid Leukemia: a Single Institution Experience." Blood 120, no. 21 (November 16, 2012): 4963. http://dx.doi.org/10.1182/blood.v120.21.4963.4963.
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Abstract Abstract 4963 Overall survival (OS) is significantly improved by 5-azacitidine in intermediate-2 (int-2) and high risk myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML) with 10–29% marrow blasts, and acute myeloid leukemia (AML) with 20–30% marrow blasts, compared with conventional treatments, and currently appears as the standard of care, at least in patients who are not candidates to allogeneic stem cell transplantation (alloSCT). We retrospectively evaluated the efficacy and tolerability of 5-azacitidine in 25 patients treated at our institution from 2009 to 2012, outside of clinical trial. Our series was composed by 17 cases of MDS with IPSS risk int-2 or high, 6 AML with marrow blasts between 20% and 30% and 2 CMML. Patients were treated with 5-azacitidine at a dosage of 75 mg/m2/d subcutaneously for 7 days every 28 days (schedule 5 day on, 2 day off and 2 day on). Median age of our cohort was 72 years (range 37–81 y), male to female ratio was 0. 6 and the median number of cycles received was 7 (range 1–26). According to the MDS-specific comorbidity index 9 pts (53%) were classified as low-risk, 7 pts (41%) as intermediate risk and 1 pt (6%) as high risk. Seventeen (68%) patients (13 MDS, 3 AML, 1 CMML) who had received at least 4 cycles of therapy were evaluable. Median age of these 17 patients was 71 years (range 37–81 y), male to female ratio was 0. 8 and median number of cycles administered was 8 (range 4–26). The overall response rate (ORR) was 59% (10/17 patients). According to International Working Group (IWG) 2006 criteria, five patients (29%) reached complete remission (CR) after a median of 5 cycles of therapy (range 4–6), two patients (12%) obtained hematologic improvement with bone marrow complete remission (marrow CR) after 6 and 11 cycles of therapy respectively, three patients (18%) showed hematologic improvement (HI) after 5 cycles (range 4–6), while stable disease (SD) and progressive disease (PD) were observed in 4 (23%) and in 3 patients (18%) respectively after 5 cycles (range 4–7). Median duration of response was 12 months (range 6–26 mo); median overall survival from the beginning of 5-azacitidine, for all patients treated, was 14. 4 months (range 7–33 mo). We did not observe any differences in response rate according to age, bone marrow fibrosis, cytogenetics and transfusion requirements. In the responder group (10 patients) we did not observe grade 3 or 4 non-hematologic toxicity after a median observation time of 10 months (range 5–33 mo). Among non-responding patients, four (57%) recurred to hospitalization due to infectious or hemorrhagic complications (median observation time 15 months, range 7–33). 5-azacitidine confirmed to be an active therapy for patients with int-2 and high risk MDS and AML with low marrow blast counts not candidate to high intensity treatment for age and or comorbidities, showing high response rate and good tolerability. The low rate of serious adverse events and need of hospitalization improved patient's quality of life and reduced the utilization of medical resources. Disclosures: No relevant conflicts of interest to declare.
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Karantanos, Theodoros, Hua-Ling Tsai, Lukasz P. Gondek, Mark Levis, Margaret M. Showel, Amy E. DeZern, Ivana Gojo, Ravi Varadhan, Richard J. Jones, and Tania Jain. "Allogeneic Blood or Marrow Transplantation (BMT) with Post-Transplantation Cyclophosphamide (PTCy) Based Graft Versus Host Disease (GVHD) Prophylaxis for Myelodysplastic Syndrome/ Myeloproliferative Neoplasm-Overlap Syndromes (MDS/MPN)." Blood 136, Supplement 1 (November 5, 2020): 40. http://dx.doi.org/10.1182/blood-2020-138671.
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INTRODUCTION: MDS/MPN are a group of clonal hematopoietic disorders with overlapping features of MDS and MPN, and include chronic myelomonocytic leukemia (CMML), atypical chronic myeloid leukemia (aCML), MDS/MPN-unclassifiable along with juvenile myelomonocytic leukemia and MDS/MPN with ring sideroblast and thrombocytosis. Therapeutic options for MDS/MPN remain limited and BMT remains the only modality with curative potential. However, the overall survival of these patients following BMT remains poor marked by a high incidence of non-relapse mortality (NRM) and relapse. Moreover, most of the published cohorts consisted of patients receiving matched related donor grafts, with limited data on the outcomes of patients receiving grafts from alternative donors. In the current study, we aim to describe outcomes of BMT for MDS/MPN using PTCy as the GVHD prophylaxis platform and primarily haploidentical related (haplo) donors. PATIENTS AND METHODS: We performed a retrospective analysis of patients with MDS/MPN who underwent BMT with PTCy at Johns Hopkins between 1/2011-1/2019. Kaplan-Meier analysis was used to evaluate overall survival (OS), relapse-free survival (RFS), and GVHD/relapse-free survival (GRFS). Cumulative incidence of relapse and non-relapse mortality (NRM) were estimated non-parametrically in presence of competing events where NRM was a competing event of relapse, and vice versa. Univariate analysis was used to evaluate the impact of donor type, HCT-CI, and karyotype on these clinical outcomes via Cox proportional hazard models for OS/RFS/GRFS, and Fine-Gray's sub-distribution (s) hazard models for relapse/NRM/GVHD. RESULTS: Thirty-four consecutive patients (11 women and 23 men) with a median age of 63 years (range 51-74) at the time of BMT were identified. Of these, 21 (61.8%) had haplo donors and 31 (91%) received non-myeloablative conditioning with fludarabine, cyclophosphamide and total body irradiation. Median follow up was 3.9 years (range: 24 days - 8.4 years) based on reverse Kaplan-Meier approach. Other patient, disease and BMT related details are shown in Table 1. Time to neutrophil and platelet recovery was 22 days (range 19 - 28 days) and 31 days (range 22 - 67 days), respectively. Two (6%) patients had primary graft failure, both had received a marrow graft. At 3-years, probability of OS was 46% (95% CI: 31% - 68%), 3 RFS was 30% (17% - 51%), GRFS was 26% (14%-48%), cumulative incidence of relapse was 59% (95% CI: 41% - 77%) and incidence of NRM was 12% (95% CI: 1% - 23%). The incidence of grade 2-4 acute GVHD at 1 year following HCT was 24% but no patients had grade 3-4 acute GVHD. The cumulative incidence of any chronic GVHD at 3 years was 20% with 3 (9%) patients requiring systemic therapy. Univariate analysis showed that HCT-CI score at the time of HSCT was associated with higher incidence of relapse (sHR 5.22, 95% CI 2.26-12.08) and inferior RFS (HR 3.09, 95% CI 1.16-8.2). Other patient-, disease- and HCT-related factors were not statistically significantly associated with these clinical outcomes. The outcomes of patients with haplo donors (n=21) were also estimated at 3 years and estimates of OS were 56% (95% CI 38% - 82%), RFS 42% (95% CI 26% - 70%), GRFS 37% (21% - 66%), cumulative incidence of relapse 43% (95% CI 21% - 66%), NRM 14% (95% CI 1% - 30%), chronic GVHD 21% (95% CI 2% - 40%). No patients developed grade 3-4 acute GVHD. While the sample size is limited, comparison of K-M estimates for RFS and relapse with haplo donor (n=21) and matched related/unrelated donor (n=12), is shown in Figure 1. CONCLUSIONS: We report, for the first time, clinical outcomes of BMT for MDS/MPN with the PTCy based GVHD platform, and outcomes appear comparable with those previously described in other retrospective studies using conventional approach. Although limited by sample size for a statistical analysis, the outcomes with haplo donor BMT appear promising. The relatively high incidence of relapse in these patients appears to be the major factor contributing adversely to outcomes, while NRM and GVHD incidence with our non-myeloablative conditioning PTCy platform are low. We are currently exploring strategies to decrease relapse rates to further improve BMT outcomes in these patients. Disclosures Levis: Amgen: Honoraria; FujiFilm: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria; Menarini: Honoraria; Astellas: Honoraria, Research Funding. DeZern:MEI: Consultancy; Astex: Research Funding; Abbvie: Consultancy; Celgene: Consultancy, Honoraria. Gojo:BMS: Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Amgen: Research Funding; Merck: Research Funding; Amphivena: Research Funding. Jain:Takeda: Consultancy, Honoraria; CareDx: Other: Advisory Board; Bristol Myer Squibb: Other: for advisory board participation.
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Pinyol, Magda, Francesc Cobo, Silvia Bea, Pedro Jares, Iracema Nayach, Pedro L. Fernandez, Emilio Montserrat, Antonio Cardesa, and Elias Campo. "p16INK4a Gene Inactivation by Deletions, Mutations, and Hypermethylation Is Associated With Transformed and Aggressive Variants of Non-Hodgkin's Lymphomas." Blood 91, no. 8 (April 15, 1998): 2977–84. http://dx.doi.org/10.1182/blood.v91.8.2977.2977_2977_2984.
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The molecular mechanisms underlying the pathogenesis of aggressive lymphomas and the histological transformation of indolent variants are not well known. To determine the role of p16INK4a gene alterations in the pathogenesis of non-Hodgkin's lymphomas (NHLs) and the histological progression of indolent variants, we have analyzed the expression, deletions, and mutations of this gene in a series of 112 NHLs. Hypermethylation of the gene was also examined in a subset of tumors with lack of protein expression but without mutations or deletions of the gene. p16INK4a gene alterations were detected in 3 out of 64 (5%) indolent lymphomas but in 16 out of 48 (33%) primary or transformed aggressive variants. In the low-grade tumors, p16INK4a alterations were detected in 1 (4%) chronic lymphocytic leukemia (hemizygous missense mutation), 1 (6%) follicular lymphoma (homozygous deletion), and 1 (5%) typical mantle cell lymphoma (homozygous deletion). The two later cases followed an aggressive clinical evolution. In the aggressive tumors, p16INK4a gene alterations were observed in 2 (29%) Richter's syndromes (2 homozygous deletions), 3 (33%) transformed follicular lymphomas (1 homozygous deletion and 2 nonsense mutations), 3 (43%) blastoid mantle cell lymphomas (2 homozygous and 1 hemizygous deletions), 5 (28%) de novo large-cell lymphomas (1 homozygous deletion and 4 hypermethylations), 2 lymphoblastic lymphomas (2 homozygous deletions), and 1 of 2 anaplastic large cell lymphomas (hypermethylation). Protein expression was lost in all tumors with p16INK4a alterations except in the typical chronic lymphocytic leukemia (CLL) with hemizygous point mutation. Sequential samples of the indolent and transformed phase of three cases showed the presence of p16INK4a deletions in the Richter's syndrome but not in the CLL component of two cases, whereas in a follicular lymphoma the deletion was present in both the follicular tumor and in the diffuse large-cell lymphoma. In conclusion, these findings indicate that p16INK4a gene alterations are a relatively infrequent phenomenon in NHLs. However, deletions, mutations, and hypermethylation of the gene with loss of protein expression are associated with aggressive tumors and they may also participate in the histological progression of indolent lymphomas.
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Ramadan, Hanadi, Vu H. Duong, Najla H. Al Ali, Eric Padron, Ling Zhang, Jeffrey E. Lancet, Alan F. List, and Rami S. Komrokji. "Eltrombopag Use in Chronic Myelomonocytic Leukemia (CMML) Patients: A Cautionary Tale." Blood 126, no. 23 (December 3, 2015): 2897. http://dx.doi.org/10.1182/blood.v126.23.2897.2897.
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Abstract Introduction Thrombocytopenia is a management challenge for Myelodysplastic syndromes (MDS) patients (pts). The outcome of MDS Pts after hypomethylating agents (HMA) failure is poor. Eltrombopag is an oral, small non-peptide thrombopoietin (TPO) receptor agonist. It has biologically distinct effects in part to its binding site on the TPO receptor that is distinct from that for native TPO and other synthetic agonists. We report our experience among CMML pts treated with eltrombopag in the context of a phase I MDS study. Methods This is a phase I study. Pts are allocated to dose cohorts of 50, 100, 150, 200 mg/day. Key eligibility criteria include confirmed diagnosis of MDS or acute myeloid leukemia (AML) with 20-30% myeloblasts. All pts had HMA failure. The mean platelet count within a month of enrollment must be ≤ 50 X 109/L. Key exclusions include splenic enlargement > 8 cm, bone marrow fibrosis > grade 3. We identified CMML pts and compared the responses and adverse events to MDS patients. Results Among 33 pts enrolled on the phase I study, 7 were CMML pts. Table-1 summarizes baseline characteristics. The median age of CMML pts was 76 years, all were white males. Five pts were CMML-2. Majority were classified as higher risk by IPSS, revised IPSS and MD Anderson model. Four pts were proliferative CMML. Among CMML pts, one received eltrombopag at 50 mg, 2 pts at100 mg, 2 pts at 150 mg, and 2 pts at 200 mg. Three pts completed 8 weeks to be evaluable for response and toxicity. Hematological improvement or better by IWG 2006 criteria (HI+) was observed in 6/26 (23%) MDS pts and 1/7 (14%) CMML pts (p 0.16). The responding CMML pt had bilineage response. Five non CMML pts had a platelet response. Two CMML pts became platelet transfusion independent compared to 4 non CMML pts. The rate of AML transformation was 39% and 29% respectively in MDS and CMML pts (p 0.14). The median OS was 7 months for CMML pts compared to 5 months for non-CMML (p 0.2). Five (71%) CMML pts developed leukocytosis on treatment compared to 3 MDS pts (12%). (p 0.001). (3 out of 5 pts had proliferative type CMML). Leukocytosis developed within first cycle in all pts. In 2 CMML pts, leukocytosis resolved after stopping treatment. Four CMML pts (57%) showed peripheral myeloblasts on treatment compared to 11 (42%) in the MDS group (p 0.2). One CMML pt (14%) developed grade 3 fibrosis from grade 0-1 at baseline compared to 3 MDS pts (12%). Data will be presented on ongoing Next generation sequencing for somatic mutations comparing CMML pts to MDS pts and those who developed leukocytosis/circulating myeloblasts to pts who did not. Conclusions Eltrombopag yielded lower responses in CMML pts after HMA failure compared to MDS pts but namely due to stopping treatment in majority of pts due to leukocytosis or circulating myeloblasts. At the time being, eltrombopag should only be offered to CMML pts in the context of clinical trials. Table 1. Baseline Characteristics CMML (n=7) MDS (n= 26) P value Age Mean 77.5 75 0.20 Gender Male 7 [100%] 18 [69%] 0.09 Race White 7 [100%] 24 [92%] 0.40 ECOG PS 0 1 1 [14%] 6 [86%] 6 [23%] 20 [77%] 0.70 MyeloblastsPlateletsHgbWBC Mean % Mean Mean Mean 9 30 10.5 14 13 22 9.5 3 0.08 0.20 0.20 0.03 Cytogenetic Risk Good Intermediate Poor 4 [57%] 2 [29%] 1 [14%] 15 [56%] 3 [11%] 8 [33%] 0.40 WHO classification RCMD RAEB-1 RAEB-2 RAEB-t (AML) CMML-1 CMMl-2 MDS/MPN-U Del 5q 0 0 0 0 2 [29%] 5 [71%] 0 0 6 [23%] 7 [27%] 11 [42%] 1 [4%] 0 0 0 1 [4%] IPSS Low Int-1 Int-2 High 1 [14%] 0 4 [57%] 2 [29%] 0 11 [42%] 9 [35%] 6 [23%] 0.05 R-IPSS Very low Low Intermediate High Very High 0 1 [14%] 0 5 [72%] 1 [14%] 0 2 [8%] 5 [19%] 9 [35%] 10 [38%] 0.20 Disclosures Padron: Novartis: Speakers Bureau; Incyte: Research Funding. Lancet:Celgene: Consultancy, Research Funding; Amgen: Consultancy; Kalo-Bios: Consultancy; Seattle Genetics: Consultancy; Pfizer: Consultancy; Boehringer-Ingelheim: Consultancy. List:Celgene Corporation: Honoraria, Research Funding. Komrokji:Pharmacyclics: Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria, Research Funding. Off Label Use: use of eltrombopag in MDS and CMML.
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Merli, Pietro, Daria Pagliara, Federica Galaverna, Giuseppina Li Pira, Marco Andreani, Giovanna Leone, Donato Amodio, et al. "TCRαβ/CD19 depleted HSCT from an HLA-haploidentical relative to treat children with different nonmalignant disorders." Blood Advances 6, no. 1 (January 11, 2022): 281–92. http://dx.doi.org/10.1182/bloodadvances.2021005628.
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Abstract Several nonmalignant disorders (NMDs), either inherited or acquired, can be cured by allogeneic hematopoietic stem cell transplantation (HSCT). Between January 2012 and April 2020, 70 consecutive children affected by primary immunodeficiencies, inherited/acquired bone marrow failure syndromes, red blood cell disorders, or metabolic diseases, lacking a fully matched donor or requiring urgent transplantation underwent TCRαβ/CD19-depleted haploidentical HSCT from an HLA-partially matched relative as part of a prospective study. The median age at transplant was 3.5 years (range 0.3-16.1); the median time from diagnosis to transplant was 10.5 months (2.7 for SCID patients). Primary engraftment was obtained in 51 patients, while 19 and 2 patients experienced either primary or secondary graft failure (GF), the overall incidence of this complication being 30.4%. Most GFs were observed in children with disease at risk for this complication (eg, aplastic anemia, thalassemia). All but 5 patients experiencing GF were successfully retransplanted. Six patients died of infectious complications (4 had active/recent infections at the time of HSCT), the cumulative incidence of transplant-related mortality (TRM) being 8.5%. Cumulative incidence of grade 1-2 acute GVHD was 14.4% (no patient developed grade 3-4 acute GVHD). Only one patient at risk developed mild chronic GVHD. With a median follow-up of 3.5 years, the 5-year probability of overall and disease-free survival was 91.4% and 86.8%, respectively. In conclusion, TCRαβ/CD19-depleted haploidentical HSCT from an HLA-partially matched relative is confirmed to be an effective treatment of children with NMDs. Prompt donor availability, low incidence of GVHD, and TRM make this strategy an attractive option in NMDs patients. The study is registered at ClinicalTrial.gov as NCT01810120.
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Burgstaller, Sonja, Richard Greil, Reinhard Stauder, Sigrid Machherndl-Spandl, Michael Pfeilstöcker, Thomas Kuehr, Alois Lang, et al. "A Phase I Study of Lenalidomide in Patients with Chronic Myelomonocytic Leukaemia (CMML) – AGMT_CMML 1." Blood 124, no. 21 (December 6, 2014): 3268. http://dx.doi.org/10.1182/blood.v124.21.3268.3268.
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Abstract Introduction Chronic myelomonocytic leukaemia (CMML) is a clonal disorder of a haematopoietic stem cell characterized by the presence of an absolute monocytosis in peripheral blood. CMML is a rare disease with an incidence of 0.5 to 3 per 100 000 per year with median survival of 12 to 20 months. Coexistence of myelodysplastic and myeloproliferative features led 2001 to a classification of CMML outside myelodysplastic syndromes (MDS) within a group of myelodysplastic/myeloproliferative neoplasms (MDS/MPN) by the WHO. In the former FAB classification CMML was part of MDS. For these reasons data regarding the treatment of CMML is largely derived from MDS trials. The studies published so far suggest activity of lenalidomide in a proportion of patients, but the number of CMML patients included was very low. Therefore we conducted a phase 1 dose-escalation trial with lenalidomide in patients with WHO defined CMML. Methods Patients with a diagnosis of CMML according to WHO diagnostic criteria with an age of at least 18 years were eligible for study entry. Pretreatment was permitted but had to be stopped 4 weeks prior to initiation of study treatment. Exclusion criteria were impairment of renal (creatinine clearance < 30 ml/min) or hepatic function (AST, ALT > 2.5 ULN) and/or any other serious medical condition. Patients with platelets < 50 G/L were not included. Primary objective was to determine the maximum tolerated dose (MTD) of lenalidomide. Secondary objectives were safety and tolerability. Treatment with lenalidomide was started at a dose of 5mg daily in a cohort of 3 patients. Study treatment was administered day 1 to 28 of a 28-day cycle. In the absence of a dose limiting toxicity (DLT) in all 3 patients respectively not more than 1 out of 6 patients the dose was increased stepwise by 5mg up to a defined maximum dose of 20 mg daily. DLT was defined as one of the following parameters after cycle 1: grade 3/4 non hematologic-toxicity, febrile neutropenia, grade 4 neutropenia ≥ 7 days or grade 4 thrombocytopenia. Results 20 (17 male, 3 female) patients with CMML were enrolled in this phase 1 trial. Eighteen patients were evaluable for MTD evaluation (2 patients stopped study treatment due to rash before end of cycle 1). Median age was 72 years (range 59 – 81), the majority of patients was older than 70 years (n=14) and 2 patients were older than 80 years. Three out of these 20 patients had prior treatment (≤ 2) whereas the rest received lenalidomide as first line therapy. Prior regimens consisted of hydroxyurea and cytarabine. Median time from diagnosis to study entry (cycle 1, day 1) was 45 days (range 7 – 2309). Six patients were treated in the 5 mg cohort with no DLT. In the 10 mg cohort 2 out of 6 patients experienced DLTs (thrombocytopenia grade 4 (n=1), non- hematologic toxicity grade 3/4 – renal impairment (n=1)). Two out of 6 patients in the 15mg cohort had DLTs (thrombocytopenia grade 4 (n=2), non-hematologic toxicity grade 3/4 – tremor, vertigo (n=1)). Therefore lenalidomide 5mg daily was eventually confirmed as MTD. Other treatment related adverse events were anaemia (n=2), fatigue (n=2), pyrexia (n=3) and erythema (n=2). The median number of treatment cycles achieved was 3 (range 1-25) and 4 patients are still on study treatment. Reasons for discontinuation of study treatment were adverse events in 11 patients and eventual disease progression in 5 patients. At the time of this analysis 15 patients were evaluable for response assessment according to modified IWG criteria. The best response achieved was partial remission in 2 patients and stable disease in 10 patients. Lack of response with primarily progressive disease was seen in 3 patients. Conclusion Lenalidomide can safely be administered in patients with CMML. MTD of lenalidomide was determined as 5mg daily. Thrombocytopenia was the main toxicity observed in this cohort of patients. Efficacy needs to be confirmed in further trials. Disclosures Burgstaller: Celgene: Honoraria. Greil:Bristol-Myers-Squibb: Consultancy, Honoraria; Cephalon: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Research Funding; Amgen: Honoraria, Research Funding; Eisai: Honoraria; Mundipharma: Honoraria, Research Funding; Merck: Honoraria; Janssen-Cilag: Honoraria; Genentech: Honoraria, Research Funding; Novartis: Honoraria; Astra-Zeneca: Honoraria; Boehringer-Ingelheim: Honoraria; Pfizer: Honoraria, Research Funding; Roche: Honoraria; Sanofi Aventis: Honoraria; GSK: Research Funding; Ratiopharm: Research Funding. Stauder:Celgene: Consultancy, Honoraria, Research Funding; Ratiopharm: Honoraria, Research Funding; Novartis: Research Funding. Pfeilstöcker:Celgene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Janssen-Cilag: Honoraria. Kuehr:Celgene: Honoraria. Petzer:Celgene: Honoraria, unrestricted grant Other. Valent:Celgene: Honoraria.
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Ruutu, Tapani, Liisa Volin, Dietrich W. Beelen, Rudolf Trenschel, Juergen Finke, Marc Schnitzler, Jerzy Holowiecki, et al. "Reduced Toxicity Conditioning with Treosulfan and Fludarabine in Allogeneic Hematopoietic Stem Cell Transplantation for Myelodysplastic Syndromes: Results of an International Prospective Phase II Trial." Blood 112, no. 11 (November 16, 2008): 3274. http://dx.doi.org/10.1182/blood.v112.11.3274.3274.
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Abstract Recent preclinical and clinical data have revealed treosulfan a promising alternative conditioning agent for allogeneic hematopoietic stem cell transplantation. After previous dose-finding studies in high-risk patients suffering from various hematological malignancies this prospective, multicenter phase II trial was carried out to assess the safety and efficacy of treosulfan-based conditioning in MDS patients. Eleven centers from four countries participated. Forty-five patients (24 females, 21 males) with a median age of 50 years (range 22 – 63 years) were included. In 33 % of the transplantations the donor was related (MRD), in 67 % unrelated (MUD). Forty-seven per cent of the patients had received some kind of treatment before the transplantation, including 13 % given AML-like induction therapy. The IPSS risk groups were: 7 % “low”, 44 % “Int-1”, 31 % “Int-2” and 18 % “high”. At the time of transplantation 44 % of the patients had 5 % or more blasts in the bone marrow. In total, 9 % of all patients were considered non-eligible to standard conditioning therapy because of comorbidity or age. Treosulfan (14 g/m2, 2 hour infusion) was administered on days -6 to -4 and fludarabine (30 mg/m2, 30 min infusion) on days -6 to -2. The graft was peripheral blood stem cells in 89 % and bone marrow in 11 % of the transplantations. GvHD prophylaxis consisted of ciclosporine-A and a short course of MTX as well as ATG-Fresenius® (10 mg/m2 i.v., days -4 to -2) in case of MUD. This analysis is based on a median follow-up of 15 months (range 3.3 – 35.8 months). The conditional cumulative incidence (CI) of neutrophil (> 0.5 x 109/l), leukocyte (>1 x 109/l) and platelet (> 20 x 109/l) engraftment reached 91 %, 93 % and 89 % on day +28 and 98%, 98 % and 91 % overall, respectively. The median time to engraftment was 18, 17 and 17 days, respectively (G-CSF treatment was not recommended in the protocol). The CI of complete donor chimerism increased from 73 % (day +28) to 93 % (day +100). The frequencies (exceeding 5 %) of adverse events CTC grade III/IV with at least possible relatedness to the study drug and occurring during 28 days post-transplantation were 13 % for CTC category “gastrointestinal” and 24 % for “infection”. Frequencies for grade III/IV hyperbilirubinemia, mucositis/stomatitis and seizures were low (13 %, 2 % and 0 %, respectively). There were two cases of mild VOD which resolved before day +20 after the transplantation. The CI of grade II - IV acute GvHD was 24 % and that of grade III-IV 16 %. The CI of chronic GvHD at 1 year was 45 % and that of extensive cGvHD 25 %. The CI of non-relapse mortality was 9 % at 100 days and 15 % at 1 year, and that of relapse/progression 14 % at 1 year. The Kaplan-Meier estimates of OS and DFS at 1 year were 80 % and 71 %. These interim phase II data confirm promising safety and efficacy of this alternative treosulfan-based conditioning therapy in MDS patients, as previously reported for AML and CML patients by others. Final survival data with 1-year follow-up for all living patients will be available in September 2008. These encouraging results give a base for future trials comparing treosulfan/fludarabine conditioning with conventional conditioning regimens.
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Kenderian, Saad Sirop, Mark R. Litzow, Aref Al-Kali, Dennis A. Gastineau, Shahrukh K. Hashmi, William J. Hogan, and Mrinal M. Patnaik. "A Novel Prognostic Model To Predict Relapse After Allogeneic Stem Cell Transplantation For Myelodysplastic Syndromes." Blood 122, no. 21 (November 15, 2013): 2098. http://dx.doi.org/10.1182/blood.v122.21.2098.2098.
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Abstract Background Allogeneic stem cell transplantation (allo-SCT) is a potentially curative option for patients with myelodysplastic syndromes (MDS). However, allo-SCT can be associated with significant morbidity and mortality along with a risk for post-transplant disease relapse. While many MDS prognostic models exist, a prognostic model specifically designed to predict post-transplant disease relapse is yet to be developed. Therefore, we carried out this single institution study. Methods After due IRB approval, the Mayo Clinic MDS database (1995-2012) was retrospectively reviewed. This database contains comprehensive information on MDS clinical and pathological characteristics, treatments and SCT. Primary outcomes analyzed included disease free survival (DFS), overall survival (OS) and relapse rates at five years post allo-SCT. In addition, we evaluated transplant related mortality (TRM), non-relapse mortality (NRM), and rates of acute and chronic graft versus host disease (GVHD). DFS and OS were calculated from the time of transplantation. The prognostic relevance of several disease and transplant specific characteristics were analyzed, including: age, gender, World Health Organization (WHO) categories, therapy related MDS, cytogenetics, International Prognostic Scoring System (IPSS) and IPSS-Revised (IPSS-R) at the time of MDS diagnosis, transfusion dependence, bone marrow and circulating blast count at transplant, serum ferritin levels, SCT Co-morbidity Index, donor source, HLA matching, CMV serostatus, and conditioning regimen. Multivariate analysis was performed using the Cox Proportional Hazard Model. Survival was estimated and compared using the Kaplan Meier and Log Rank tests, respectively. Results From 1995 through 2012, 96 consecutive patients with MDS underwent allo-SCT at the Mayo Clinic, Rochester. Of these, 62 were male (65%) with a median age of 54 (24-68 years). The median follow up was 31 (1-181) months. Twenty seven patients (28%) had therapy related MDS and 39 (40%) had MDS with a monosomal karyotype. IPSS-R risk stratification identified 55 (57%) patients with very high, 20 (21%) with high and 21 (22%) with intermediate/good risk disease. Fifty (52%) patients received a reduced intensity conditioning. The TRM was 8% and NRM at 5 years was 22%. Acute (grade 2 to 4) GVHD developed in 57 (59%) patients and chronic extensive GVHD was noted in 52 (54%) patients. Five-year relapse, DFS and OS rates were 24%, 42%, and 44%, respectively. In a univariate analysis, IPSS-R (high/very high, P=0.005), therapy related MDS (P=0.009), bone marrow blast count at transplant (≥10%, P=0.01), and the presence of a monosomal karyotype (P=0.05) were significantly associated with worse DFS. On a multivariable analysis, only high or very high risk IPSS-R category (HR 7.8, P=0.005) and therapy related MDS (HR 3.9, P=0.04) retained their negative prognostic impact. Based on this finding, we developed a prognostic model that assigned one point to each of these two factors (low risk-0, intermediate-1 and high risk-2). This model successfully stratified patients based on DFS, with a 5-year DFS of 67%, 40% and 23% for low, intermediate and high risk categories respectively, P=0.0012. This model was also successful in risk stratifying patients with regards to OS (table 1, figure 1). The presence of chronic GVHD was associated with a significantly improved DFS (62% vs 24%, P<0.0001) and OS (78% vs 19%, P<0.0001), however, as this is a post-transplant outcome, it was not included in the analysis/model. Conclusions Although the IPSS-R has not been validated in therapy related MDS or in patients who have received MDS directed therapy, the high/very high risk categories along with therapy related MDS, serve as independent predictors of OS and disease relapse after allo-SCT. Using these two variables, our prognostic model efficiently stratified patients with regards to DFS, relapse rates, and OS. Given the smaller sample size validation in a larger patient cohort will be needed. Disclosures: No relevant conflicts of interest to declare.
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Merli, Pietro, Daria Pagliara, Tommaso Mina, Valentina Bertaina, Giuseppina Li Pira, Stefania Lazzaro, Simone Biagini, et al. "Alphabeta T and B-Cell Depleted HLA-Haploidentical Hematopoietic Stem Cell Transplantation (TBdepl-haploHSCT) in Children with Myelodysplastic Syndromes." Blood 138, Supplement 1 (November 5, 2021): 170. http://dx.doi.org/10.1182/blood-2021-153913.
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Abstract Background: Pediatric myelodysplastic syndromes (MDSs) are a heterogeneous group of clonal disorders, accounting for less than 5% of childhood hematologic malignancies. Usual indications to HSCT are: MDSs with excess of blasts, MDSs secondary to previously administered chemoradiotherapy and RCC associated with monosomy 7, complex karyotype, severe neutropenia, or erythrocyte/platelet transfusion dependence [Locatelli & Strahm, Blood 2018]. We previously demonstrated that TBdepl-haploHSCT is a suitable option for children with acute leukemia, with outcomes comparable to those reported in studies using either an HLA-identical sibling or an unrelated volunteer as donor. Here we present the results of this approach in children with MDSs. Patients and methods: Between February 2013 and February 2021, 23 children with MDSs other than juvenile myelomonocytic leukemia received TBdepl-haploHSCT from an HLA-partially matched relative at Ospedale Pediatrico Bambino Gesù, Rome, Italy or at IRCCS Fondazione Policlinico San Matteo, Pavia, Italy as part of a prospective study (#NCT01810120). All patients were prepared to the allograft using a fully-myeloablative conditioning regimen including a combination of cytotoxic drugs and/or total body irradiation (TBI). Anti-T-lymphocyte globulin (ATLG) was used before transplantation (12 mg/kg total dose, from days -5 to day -3) to modulate bi-directional donor/recipient alloreactivity. Rituximab (200 mg/sqm) was administered on day -1 to prevent post-transplantation EBV-induced lymphoproliferative disorders (PTLD). No patient received any post-transplant pharmacological GvHD prophylaxis. Results: Characteristics of patients enrolled in the study are shown in Table 1 (which reports also donor and graft characteristics). Median follow-up of surviving patients is 4.2 years (range: 0.5 - 8.5 years). Seventeen children were affected by refractory cytopenia of childhood (RCC) (2 cases occurring in the context of inherited bone marrow failure syndromes: one had GATA2 deficiency and the other SAMD9L mutation), while 1 and 5 were affected by MDS with excess of blasts 1 (EB1) and EB2 (one had GATA2 deficiency), respectively. Median time to neutrophil and platelet recovery was 14 (range 10-19) and 11 (range 9-14) days, respectively, with four patients (3 with RCC and 1 with EB2) experiencing primary graft failure, the cumulative incidence of this complication being 17.3% (95% CI 0.3-31.5). All these 4 patients were rescued with a second TBdepl-haploHSCT from the same or the other parent. Cumulative incidence of grade II-III acute GvHD was 11.4% (95% CI 0-25.2). One patient developed skin and gut GvHD after the second TBdepl-haploHSCT, while for all other patients skin was the sole organ involved; no case of grade IV GvHD was observed. One patient developed moderate chronic GvHD [cumulative incidence 5.2% (95% CI 0-14.8)], which completely resolved with low-dose steroids and ruxolitinib. Notably, no patient died for transplant-related complications. Six patients experienced CMV, 2 HHV-6 and 1 adenoviral infection/reactivation; one patient developed lung aspergillosis, which resolved with specific treatment. One patient affected by EB2, not in remission at time of transplant, relapsed 27 months after HSCT, the 5-year cumulative incidence of relapse being 7.1% (95% CI, 0-19.7); she eventually died after failing a second HSCT. The 5-year probability of overall and event-free survival were 92.3% (95% CI 56.6 -98.9) and 76.3% (95% CI 51.3-89.6) (Figure 1A and B), respectively. Five-year disease-free-survival was 90% (95% CI 47.3-98.5). Because of the low number of events, no prognostic factor related to OS and EFS was found. In particular, the MDS variant did not influence the patient's outcome. The median CD3+ cell count on day +30, +90, +180 and +360 were 113, 171, 558 and 1307/mcl, respectively. Conclusions: These data indicate that TBdepl-haploHSCT is a safe and effective transplant option also in children with MDS. Indeed, the low risk of both non-relapse mortality and acute/chronic GvHD makes this approach particularly attractive in the pediatric setting. Moreover, this haplo strategy compares favorably with T-cell replete approaches [Suo et al., 2020]. Figure 1 Figure 1. Disclosures Merli: JAZZ: Consultancy; SOBI: Consultancy. Locatelli: Miltenyl: Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees; bluebird bio, Inc.: Consultancy; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees.
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Reda, Gianluigi, Marta Riva, Ramona Cassin, Bruno Fattizzo, Martina Pennisi, Diana Giannarelli, Alfredo Molteni, Alessandra Freyrie, Roberto Cairoli, and Agostino Cortelezzi. "Impact of Bone Marrow Fibrosis and Early Response on Outcome after Azacitidine Therapy in 94 Patients with Myelodisplastic Syndromes, Chronic Myelomonocytic Leukemia and Acute Myeloid Leukemia." Blood 128, no. 22 (December 2, 2016): 3187. http://dx.doi.org/10.1182/blood.v128.22.3187.3187.
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Abstract Azacitidine (AZA) is effective in high risk myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia type 2 (CMML-2) and low blast count acute myeloid leukemia (AML) patients not suitable for more intensive treatment. Factors that may influence response to AZA are still under investigation. Bone marrow fibrosis is a potentially negative prognostic marker on overall survival (OS), but its clinical significance in this setting of patients remains to be clarified. We evaluated clinical predictors of OS and overall response rate (ORR; complete/partial response CR/PR; stable/progressive disease SD/PD) to AZA in a real life cohort. We studied 94 consecutive patients, treated at two Institutions from June 2009 till February 2016 with AZA subcutaneously (5+2+2 schedule) every 28 days, outside clinical trials. We analyzed data from routine laboratory analysis, bone marrow histology, morphology and cytogenetics at diagnosis. OS was measured from the starting of AZA treatment. Table 1 shows the clinical characteristics pre- and post-AZA: most patients (68%) were AREB1 or AREB2, 13% RCUD/RCMD or MDS NOS according to WHO 2008 classification, 17% AML, 2% CMML. At the onset of AZA therapy the majority of MDS cases (68%) showed an intermediate-2 risk, according to the International Prognostic Scoring System (IPSS) and high/very high risk (78%) according to IPSS-revised. Secondary and de novo cases, as well as cytogenetics risk groups, were equally represented; 50% of patients were transfusion dependant and moderate to severe neutropenia or thrombocytopenia were present in roughly 50/70% of cases respectively. As expected, bone marrow biopsies pre-AZA showed hypercellularity in most patients (65%). Remarkably, 47,5% of cases showed bone marrow fibrosis of ≥1 grade before AZA initiation. These findings were mostly unchanged at post-AZA evaluation. On the whole, 93 patients receiving > 4 cycles of therapy were available for response evaluation according to International Working Group 2006 criteria. After a median of 6 cycles (4-44), ORR was 41.9% (CR 18.3%, PR 11.8%, SD with hematologic improvement HI 11.8%), SD was 21.5%, PD 10.7% and 25.8% failed to achieve a response. Thirteen percent of patients reached at least partial cytogenetic response and 50% a HI. ORR was not influenced by monocytosis, neutropenia or IPSS cytogenetic risk category. Interestingly, pre-AZA marrow blast percentage, cytogenetic risk, time from diagnosis to AZA and the interval from 1st to 6th cycle had no impact on response. As regards marrow characteristics, patients with MF-0 pre-AZA displayed significantly lower PD rate and higher ORR, SD and HI than those with any grade of fibrosis (21.4% vs 51.4% and 78.6% vs 48,6%, respectively p=0.006, Fig1). This observation was also confirmed at marrow evaluation after AZA (22% versus 48% for PD and 78% versus 52% for ORR/SD/HI, p=0.05, Fig1). Regarding cellularity pre- and post-AZA, higher ORR,SD and HI and lower PD were observed for patients with normo/hypo compared to those with hyper-cellularity (Fig1) although not significantly. Forty-one percent of cases presented a hematologic toxicity (33% neutropenia and 18% thrombocytopenia of any grade) occurring after a median of 2 (1-18) AZA cycles. Moreover 28.6% of patients had an infection during AZA treatment, not related to neutropenia degree. Of note, toxicities did not affect median time from the 1st to the 6th AZA cycle (170,115-240 days), nor ORR. Median OS from the beginning of therapy was 18.5 months (12.7-24.4, 95% CI). IPSS high category [HR 2.24 (1.19-4.20) p=0.01], poor cytogenetics [2.19 (1.27-3.78) p=0.005], and lower ORR [0.46 (0.26-0.80) p=0.006] significantly affected OS. Unexpectedly, a response obtained after less than 4 cycles negatively impact OS [HR 0.86 (0.80-0.92) p<0.0001]. Notably, cases with pre-AZA fibrosis ≥MF-1 showed lower OS [2.26 (1.28-3.99) p=0.005]. In conclusion we provide evidence of no relationship between neutropenia and infections and of no impact of toxicities on dose-density and ORR to AZA treatment. Moreover, high marrow fibrosis and hypercellularity may affect response to AZA therapy. Further studies are needed to disclose the clinical/biological significance of marrow fibrosis/cellularity in the era of hypomethylating agents. Disclosures Reda: Roche: Membership on an entity's Board of Directors or advisory committees; Gilead: Research Funding.
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Gayoso, Jorge, Pascual Balsalobre, Mi Kwon, Pilar Herrera, Arancha Bermúdez, Antonia Sampol, Santiago Jimenez, et al. "Myeloablative Conditioning Haploidentical Stem Cell Transplantation (MAC-HAPLO) with Post-Transplant Cyclophosphamide (PTCy) As GvHD Prophylaxis in High Risk Leukemias/Myelosdysplastic Syndromes (MDS): Geth Experience." Blood 128, no. 22 (December 2, 2016): 4690. http://dx.doi.org/10.1182/blood.v128.22.4690.4690.
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Abstract Introduction: Allogeneic transplantation is the only curative option for patients with high risk leukemias or MDS. Only one third of them have an HLA identical sibling donor and around 60-70% will find an unrelated donor, that´s why haploidentical stem cell transplantation (HAPLO-HSCT) offers a therapeutic option to most of these patients. Myeloablative conditioning (MAC) produce better disease control than reduced intensity conditioning regimens (RIC), but with higher toxicity, rendering long term similar results. Patients and methods: We retrospectively evaluated the results of our MAC-HAPLO regimens in patients diagnosed with high risk leukemias or MDS (Fludarabine 30 mg/m2 x5 days, Cyclophosphamide14,5 mg/kg x2 days, IV Busulfan 3,2 mg/kg x 3 days (BUX3), or Fludarabine 40 mg/m2 x4 days and IV Busulfan 3,2 mg/kg x 4 days (BUX4)) with GVHD prophylaxis based on PT-CY (50 mg/kg on days +3 and +4) and a calcineurin inhibitor plus mycophenolate from day +5, performed in GETH centers (Spanish Group for Hematopoietic Transplantation). Results: From Feb-2012, 65 MAC-HAPLO HSCT have been reported by 14 centers. Median age was 41 years (15-67), 66% were males and all were in advanced disease phase or presented high risk features (AML 47/ALL 8/MDS 5/ Others 5). Previous HSCT had been employed in 12% (autologous in 5, allogeneic in 3), and in 88% the HAPLO-HSCT was their first transplant. Disease status at HAPLO-HSCT was morphologic CR in 80%, but disease persisted in 52% (MRD+ by flow or molecular markers 32%, morphologic disease 20%). Their disease risk index (DRI) was high or very high in 65%, and the comorbidity index (HCT-CI) was higher than 2 in 18%. PBSC was the graft source in 56 (86%), non T-cell depleted in all cases. The haploidentical donor was the patient´s mother (21.5%), father (12%), siblings (43%) or offspring (23%). MAC regimen was BUX3 in 25 (38.5%) and BUX4 in 40 patients (61.5%). Median infused CD34+ cells were 5.31 x10e6/kg (2.75-11.42). There were no graft failures. Median neutrophils engraftment was reached at day +17 (12-29) and platelets >20K at day +26 (11-150). Complete chimerism was obtained at a median of 28 days (13-135) in 60 evaluated patients. Cumulative incidence (CI) of non-relapse mortality (NRM) was 12.5% at day +100 and 19% at 1 year. CI of grade II-IV acute GVHD was 28.5% at day +100, and grade III-IV was 6.5%. CI of chronic GVHD at 2 years was 28%, being extensive in 8% . No differences in acute or chronic GvHD CI were seen when comparing BUX3 against BUX4. After a median follow-up of 17 months (5-50), estimated 24-months event-free survival (EFS) and overall survival (OS) were 58,5% and 60% respectively. CI of relapse or progression was 21%. No significant differences in NRM, EFS, OS and relapse incidence were detected between BUX3 and BUX4. The impact of CR prior to MAC-HAPLO, the DRI or chronic GvHD in the disease control have not been apropiately demostrated probably due to the limited number of events in our series. Conclusions: IV Busulfan based MAC-HAPLO with PT-CY in the treatment of high risk leukemias and MDS offers good disease control with manageable toxicity, with either BUX3 or BUX4. These efective MAC regimens combined with peripheral blood HAPLO donors could control high risk hematologic diseases in the long term. Severe acute or chronic GvHD are low frecuency events, but relapses persist as the main problem in this patients population. Disclosures No relevant conflicts of interest to declare.
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Sternberg, Alex, Rebecca H. Boucher, Helen C. Coulthard, Manoj Raghavan, Dominic J. Culligan, Aimee Jackson, Catherine Cargo, et al. "A Phase 1b Study of Eltrombopag and Azacitidine in Patients with High Risk Myelodysplastic Syndromes and Related Disorders." Blood 136, Supplement 1 (November 5, 2020): 10. http://dx.doi.org/10.1182/blood-2020-134227.
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Background: Azacitidine (AZA) based therapy is a standard of care in IPSS INT-2/High MDS/low blast count AML and CMML-2. Thrombocytopenia is an adverse prognostic factor in MDS; increased severity correlates with haemorrhagic complications and shorter AML progression time, and early platelet recovery after AZA is linked to better outcomes. Accumulation of AZA doses is important to patient response, but initial treatment with AZA can aggravate thrombocytopenia and impact outcome. Eltrombopag (ELT) is a thrombopoietin receptor (TpoR) agonist approved for adult chronic immune thrombocytopenic purpura. ELT has shown efficacy in low risk MDS and reduces thrombocytopenic events in advanced MDS and AML. The ELASTIC trial (ISRCTN05858391) is a single-arm phase 1b dose-finding study examining the safety and tolerability of ELT/AZA in patients with MDS/AML with expansion cohort (n=10) at MTD. We investigated if ELT/AZA would lead to earlier platelet recovery and improve AZA efficacy. Although a Phase 3 study testing ELT/AZA (SUPPORT) was terminated due to futility during the ELASTIC trial, we reasoned that drug sequencing may affect outcome. As ELASTIC patients received an ELT pre-phase, ELASTIC was run to completion. Methods: Patients with IPSS INT-2 or High MDS/CMML-2/AML <30% blasts were treated in a 3+3 trial design in cohorts of ≥3 patients with 25, 50, 100, 200 or 300mg/day ELT. AZA (75mg/m2) was administered for 7 days of a 28 day cycle. All patients received ELT and AZA and were treated for maximum 6 cycles. ELT was administered from day -7 of cycle 1. ELT continued through cycles 1-2 and 4-6 with no ELT during cycle 3. Patients were evaluated after cycle 1 for dose-limiting toxicities (DLTs). The primary outcome was safety and tolerability (including establishing the MTD) of ELT in combination with AZA. Key secondary outcomes were the effect of ELT on platelet counts, platelet transfusions and marrow blast percentage. Full blood count was measured weekly over the first 13 weeks and monthly thereafter; bone marrow was taken on day 8 of ELT and at the end of cycles 3 and 6. Results: Thirty-one patients were recruited from November 2014 to August 2018. Thirty (median age 74, range: 62-86) were evaluable for analysis in the safety population (AML=5, IPSS INT-2 MDS=12, IPSS High MDS=12, CMML-2=1); 1 patient was ineligible post registration. 11/30 (37%) were IPSS good risk, 3/30 (10%) intermediate risk and 14/30 (47%) high risk (2 unknown). ELT was well tolerated up to 300mg (25mg=5, 50mg=3, 100mg=4, 200mg=4, 300mg=14) and was safely combined with AZA. There were no DLTs in the DLT evaluable patients (n=15). The MTD was established as 300mg (n=14). There were 3 SUSARs, 19 SAEs, 28 SARs and 87 episodes of grade 3/4 AEs. There were 16 episodes of grade 3/4 neutropenia and 11 episodes of grade 3/4 anaemia. Five patients discontinued treatment due to toxicity (25mg=2, 300mg=3), 6 due to death (pneumonia=2, disease-related=4, ischaemic heart disease=1) and 1 withdrew. Platelet responses were seen at ELT 50mg and higher. At the MTD, median platelet count at baseline was 37 (IQR: 25-52), rising to 77 (IQR 50-108.5) and 74 (IQR: 32-430) at cycle 2 and 3 respectively. The median platelet nadir was 20.5 (IQR: 11-25) and 42 (IQR 18.5-51.5) after cycle 1 and 2 dropping to 20 (IQR: 9-160) after cycle 3 when ELT was stopped. Mean platelet transfusions did not change with ELT dose. There was no increase in delays to AZA dosing across the ELT dose cohorts. There was no change in bleeding incidents when patients received ELT. Overall, there was no increase in bone marrow blast percentage from baseline. The cycle 3 marrow aspirate was reached by 27/30 (90%) and 11/30 (37%) reached the cycle 6 marrow aspirate. At the end of 3 cycles there were 21 non-responders and 10 responders (CR=3, marrow CR=4, PR=3, SD=9). At the end of 6 cycles there were 22 non-responders and 9 responders (CR=3, marrow CR=4, PR=2, SD=5). 6/14 (43%) treated at the MTD responded while 3/16 (19%) treated at below the MTD responded. Conclusions: The combination of ELT with AZA is safe and tolerable. Clinically meaningful responses in platelets were seen in patients receiving 50mg or more ELT. At the MTD, there was a noticeable drop in platelet nadir in cycle 3 when patients were not receiving ELT. No change in platelet transfusion was identified across cohorts. The results suggest that an ELT pre-phase may improve platelet responsiveness in patients treated with AZA and warrants further exploration. Disclosures Sternberg: Celgene/BMS: Honoraria, Research Funding; GSK/Novartis: Honoraria, Research Funding. Raghavan:Celgene UK: Speakers Bureau. Culligan:Celgene: Consultancy, Honoraria, Speakers Bureau; Jazz: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Speakers Bureau; Diiachi-Sankyo: Consultancy, Honoraria; Pfizer: Consultancy; Novartis: Consultancy, Honoraria. Cargo:Novartis: Honoraria. Vyas:Celgene: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Forty Seven: Research Funding; Pfizer: Speakers Bureau; Daiichi Sankyo: Speakers Bureau; Astellas: Speakers Bureau; AbbVie: Speakers Bureau. OffLabel Disclosure: Eltrombopag is a second generation thrombopoietin receptor (TpoR) agonist approved for adult chronic immune thrombocytopenic purpura.
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List, Alan F., Gordon W. Dewald, John M. Bennett, Aristoteles Giagounidis, Azra Raza, Eric J. Feldman, Bayard L. Powell, et al. "Long-Term Clinical Benefit of Lenalidomide (Revlimid) Treatment in Patients with Myelodysplastic Syndrome and Chromosome Deletion 5q." Blood 108, no. 11 (November 16, 2006): 251. http://dx.doi.org/10.1182/blood.v108.11.251.251.
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Abstract Background: Myelodysplastic syndromes (MDS) are hematological disorders characterized by chronic anemia, and are often refractory to cytokine therapy. Two phase 2 studies evaluating lenalidomide in MDS (MDS-001 and MDS-003), demonstrated a high frequency of erythroid response in patients with a chromosome 5q31 deletion (List AF et al., N Eng J Med2005; 352:549–557 and List AF et al., in press). Herein we report on the durability of response with long term follow-up approaching 4 years. Methods: All enrolled subjects were evaluated for frequency and duration of red blood cell transfusion independence (RBC-TI), change in hemoglobin (Hgb), pathologic and cytogenetic response, and safety. Results: Ten 5q31- patients achieved a cytogenetic and/or major erythroid response in MDS-001. Four of these patients have maintained a major response for at least 2 years (range 2.2 to 3.7 years). In MDS-003, 99 (67%) of 148 enrolled patients achieved RBC-TI. Of the 99 responders 83 were Low/Int-1, 3 were Int-2/High and 13 were not classified. Median increase in Hgb from baseline to maximum achieved during RBC-TI was 5.4 g/dL (range 1.1, 11.4). The estimated median duration of response was 115.9 weeks, and 52 (53%) of 99 responders remain on study with ongoing RBC-TI response as of 30 June 2006. Duration of response was at least 52 weeks for 63 (64%), 78 weeks for 52 (53%), and 104 weeks for 36 (36%) of 99 responding patients. Variables (or co-variates) associated with longer duration of TI in multivariate analysis included low baseline transfusion requirement (<4 units per 8 wks, p=0.002), 5q- syndrome (p=0.01) and low IPSS (p=0.02) classifications. Among 85 evaluable patients, major cytogenetic responses were achieved in 37 (44%) and minor responses in 24 (28%). Cytogenetic responses occurred in patients with complex karyotypes as well as those with an isolated 5q31 deletion. The frequencies of major and minor cytogenetic responses were similar among patients with and without 5q- syndrome. The most common drug-related adverse events (AE) were Grade 3/4 neutropenia and thrombocytopenia, reported in 87 (59%) and 74 (50%) of 148 patients, respectively although hematologic AEs led to study discontinuation in only 13 (9%) of patients. Pneumonia was the only serious adverse event that occurred in >10% of patients (15/148; 10%). Adverse events were manageable through supportive treatment and dose reduction. Conclusion: Lenalidomide is an effective treatment in MDS patients with an associated chromosome 5q31 deletion, with RBC-TI and major erythroid response maintained for median duration > 2 years.
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Rudnicka, Ewa, Katarzyna Suchta, Monika Grymowicz, Anna Calik-Ksepka, Katarzyna Smolarczyk, Anna M. Duszewska, Roman Smolarczyk, and Blazej Meczekalski. "Chronic Low Grade Inflammation in Pathogenesis of PCOS." International Journal of Molecular Sciences 22, no. 7 (April 6, 2021): 3789. http://dx.doi.org/10.3390/ijms22073789.
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Polycystic ovary syndrome (PCOS) is a one of the most common endocrine disorders, with a prevalence rate of 5–10% in reproductive aged women. It’s characterized by (1) chronic anovulation, (2) biochemical and/or clinical hyperandrogenism, and (3) polycystic ovarian morphology. PCOS has significant clinical implications and can lead to health problems related to the accumulation of adipose tissue, such as obesity, insulin resistance, metabolic syndrome, and type 2 diabetes. There is also evidence that PCOS patients are at higher risk of cardiovascular diseases, atherosclerosis, and high blood pressure. Several studies have reported the association between polycystic ovary syndrome (PCOS) and low-grade chronic inflammation. According to known data, inflammatory markers or their gene markers are higher in PCOS patients. Correlations have been found between increased levels of C-reactive protein (CRP), interleukin 18 (IL-18), tumor necrosis factor (TNF-α), interleukin 6 (IL-6), white blood cell count (WBC), monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1α (MIP-1α) in the PCOS women compared with age- and BMI-matched controls. Women with PCOS present also elevated levels of AGEs and increased RAGE (receptor for advanced glycation end products) expression. This chronic inflammatory state is aggravating by obesity and hyperinsulinemia. There are studies describing mutual impact of hyperinsulinemia and obesity, hyperandrogenism, and inflammatory state. Endothelial cell dysfunction may be also triggered by inflammatory cytokines. Many factors involved in oxidative stress, inflammation, and thrombosis were proposed as cardiovascular risk markers showing the endothelial cell damage in PCOS. Those markers include asymmetric dimethylarginine (ADMA), C-reactive protein (CRP), homocysteine, plasminogen activator inhibitor-I (PAI-I), PAI-I activity, vascular endothelial growth factor (VEGF) etc. It was also proposed that the uterine hyperinflammatory state in polycystic ovary syndrome may be responsible for significant pregnancy complications ranging from miscarriage to placental insufficiency. In this review, we discuss the most importance evidence concerning the role of the process of chronic inflammation in pathogenesis of PCOS.
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Hou, Wen Bin, Wei Jia Sun, Xiao Wen Zhang, Yuan Xi Li, You You Zheng, Yu Xin Sun, Jian Ping Liu, and Zhao Lan Liu. "Five-Flavor Sophora flavescens Enteric-Coated Capsules for Ulcerative Colitis: A Systematic Review and Meta-Analysis of Randomized Clinical Trials." Evidence-Based Complementary and Alternative Medicine 2022 (January 12, 2022): 1–12. http://dx.doi.org/10.1155/2022/9633048.
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Background. Ulcerative colitis (UC), a chronic inflammatory bowel disease, is characterized by abdominal pain, diarrhea, and mucopurulent bloody stool. In recent years, the incidence and prevalence of UC have been increasing consistently. Five-flavor Sophora falvescens enteric-coated capsule (FSEC), a licensed Chinese patent medicine, was specifically used to treat UC. This review was aimed to assess the effectiveness and safety of FSEC for the treatment of UC. Methods. Six electronic databases were searched from inception to March 2021. Randomized clinical trials (RCTs) comparing FSEC or FSEC plus conventional Western medicine with conventional Western medicine in participants with UC were included. Two authors screened all references, assessed the risk of bias, and extracted data independently. Binary data were presented as risk ratios (RRs) with 95% confidence intervals (CIs) and metric data as mean difference (MD) with 95% CI. The overall certainty of the evidence was assessed by GRADE. Results. We included 15 RCTs (1194 participants, 763 in the FSEC group and 431 in the control group). The treatment duration ranged from 42 to 64 days. Twelve trials compared FSEC with conventional Western medicine, and two trials compared FSEC plus conventional medicine with conventional medicine. Another trial compared FSEC plus mesalazine with compound glutamine enteric capsules plus mesalazine. FSEC showed a higher clinical effective rate (improved clinical symptoms, colonoscopy results, and stools) (RR 1.12, 95% CI 1.05 to 1.20; 729 participants; 8 trials; low-quality evidence) as well as the effective rate of traditional Chinese medicine (TCM) syndromes (RR 1.10, 95% CI 1.01 to 1.20; 452 participants; 5 trials; low-quality evidence) compared to mesalazine. There was no significant difference in the adverse events between FSEC and control groups. Conclusions. FSEC may show effectiveness in UC treatment compared to conventional medicine, and the use of FSEC may not increase the risk of adverse events. Due to the limited number of clinical trials and low methodological quality of the included trials, our findings must be interpreted with discretion.
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Komrokji, Rami S., Guillermo Garcia-Manero, Lionel Ades, Abderrahmane Laadem, Bond Vo, Thomas Prebet, Aspasia Stamatoullas, et al. "An Open-Label, Phase 2, Dose-Finding Study of Sotatercept (ACE-011) in Patients with Low or Intermediate-1 (Int-1)-Risk Myelodysplastic Syndromes (MDS) or Non-Proliferative Chronic Myelomonocytic Leukemia (CMML) and Anemia Requiring Transfusion." Blood 124, no. 21 (December 6, 2014): 3251. http://dx.doi.org/10.1182/blood.v124.21.3251.3251.
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Abstract Introduction: Anemia, a hallmark of MDS, is challenging to treat, particularly after failure of erythropoiesis-stimulating agents (ESAs). Sotatercept (ACE-011) is a novel and first-in-class activin type IIA receptor fusion protein that acts on late-stage erythropoiesis to increase mature erythrocyte release into the circulation (Carrancio et al. Br J Haematol 2014;165:870-82). Treatment with sotatercept stimulated erythropoiesis and significantly increased hemoglobin (Hb) levels in healthy volunteers (Sherman et al. J Clin Pharmacol 2013;53:1121-30), supporting its clinical development for the treatment of anemia in patients (pts) with lower-risk MDS. Methods: The primary objective of this phase 2, open-label, dose-finding study is to determine a safe, tolerable, and effective dose of sotatercept resulting in erythroid hematological improvement (HI-E; modified IWG 2006 criteria) in pts with anemia and IPSS-defined Low or Int-1-risk MDS or non-proliferative CMML (white blood cells < 13,000/µL). Secondary objectives include rate of RBC-transfusion independence (RBC-TI) ≥ 8 weeks. Eligible pts had anemia (≥ 2 RBC units transfusion requirement in the 12 weeks prior to enrollment for Hb ≤ 9.0 g/dL) with no response, loss of response, or low chance of response to ESAs (serum erythropoietin [EPO] > 500 mIU/mL). Pts received subcutaneous sotatercept at dose levels of 0.1, 0.3, 0.5, or 1.0 mg/kg once every 3 weeks. ClinicalTrials.gov identifier: NCT01736683. Results: As of May 22, 2014, a total of 54 MDS pts were enrolled: 7, 6, 21, and 20 in the sotatercept 0.1, 0.3, 0.5, and 1.0 mg/kg dose groups, respectively. Median age was 71 years (range 56–86) and median time from diagnosis was 4 years (range 0–31); most pts were male (70%). Pts received a median of 6 RBC units (range 0–18) in the 8 weeks prior to treatment start. Forty-five pts (83%) received ≥ 4 RBC units in the 8 weeks prior to treatment start (high transfusion burden; HTB), and 9 pts (17%) received < 4 units in the 8 weeks prior to treatment start (low transfusion burden; LTB). Nineteen pts (35%) had IPSS Low and 34 pts (63%) had IPSS Int-1-risk MDS; IPSS risk data were missing for 1 pt. Fifty-one pts (94%) had prior treatment with ESAs, 30 (56%) with hypomethylating agents, 26 (48%) with lenalidomide, and 26 (48%) with other MDS treatments; 15 pts (28%) had serum EPO > 500 mIU/mL. Of the 53 pts evaluable for efficacy, HI-E was observed in 21 pts (40%) overall: 0, 4 (67%), 8 (40%), and 9 pts (45%) in the sotatercept 0.1, 0.3, 0.5, and 1.0 mg/kg dose groups, respectively. Nineteen of 44 HTB pts responded with a ≥ 4 RBC units/8 weeks transfusion burden reduction; duration of transfusion response appeared to be dose-dependent. Five HTB pts achieved RBC-TI ≥ 8 weeks, with RBC-TI duration ranging from 59–345+ days. Eight of 9 LTB pts showed Hb increases, not influenced by transfusion, ranging from 1.3–3.8 g/dL. Of these, 2 pts had a Hb increase ≥ 1.5 g/dL sustained for ≥ 8 weeks. Pts with Hb > 11.0 g/dL were subject to dose delay per protocol, which may have impacted Hb increase sustainability. RBC-TI ≥ 8 weeks was achieved in 6 LTB pts. Increases in platelet and neutrophil levels were seen in pts with baseline thrombocytopenia and pts with baseline neutropenia, respectively. Sotatercept was generally well tolerated. Twenty pts (37%) reported ≥ 1 suspected treatment-related adverse event (AE); fatigue (11%), headache (9.3%), decreased appetite (7.4%), and nausea (7.4%) were the most common. Of 35 pts (65%) who discontinued treatment, 28 discontinued due to lack of therapeutic effect and 4 due to AEs. Of those AEs leading to discontinuation, 3 were suspected to be treatment-related: 1 pt with grade 2 hemolytic anemia, 1 pt with grade 3 hypertension, and 1 pt with grade 2 muscular weakness in the sotatercept 0.3, 0.5, and 1.0 mg/kg dose groups, respectively. Other reasons for discontinuation were withdrawal of consent (n = 2; 4%) and pt decision (n = 1; 2%). Conclusions: Sotatercept was well tolerated in lower-risk MDS pts at the dose levels tested, with promising evidence of clinical activity in this largely HTB cohort of ESA-refractory, anemic, lower-risk MDS pts. Further exploration of higher sotatercept dose levels and longer-term treatment is planned. PF and AFL contributed equally to this abstract as senior co-authors. Disclosures Komrokji: Celgene Corporation: Consultancy, Research Funding. Off Label Use: Sotatercept (ACE-011) is an investigational agent that is being assessed for efficacy and safety in myelodysplastic syndromes.. Garcia-Manero:Celgene Corporation: Research Funding. Ades:Novartis: Research Funding; Celgene Corporation: Research Funding. Laadem:Celgene Corporation: Employment, Equity Ownership. Vo:Celgene Corporation: Employment. Prebet:Celgene Corporation: Honoraria. Boyd:US Oncology: Research Funding. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen Corporation: Membership on an entity's Board of Directors or advisory committees; Boehringer-Ingelheim Corporation: Membership on an entity's Board of Directors or advisory committees. Beyne-Rauzy:Novartis: Research Funding; Celgene: Research Funding. Zou:Celgene: Employment. Attie:Acceleron Pharma: Employment. Sherman:Acceleron Pharma: Employment, Equity Ownership. Fenaux:Novartis: Research Funding; Janssen: Research Funding; Celgene: Research Funding. List:Celgene: Consultancy.
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Gerds, Aaron T., Matt E. Kalaycio, Kwang Woo Ahn, Zhen-Huan Hu, Edwin P. Alyea, Uday R. Popat, Ronald M. Sobecks, and Wael Saber. "Outcomes after Umbilical Cord Blood Transplantation for Myelodysplastic Syndromes: A Center for International Blood and Marrow Transplant Registry (CIBMTR®) Study." Blood 126, no. 23 (December 3, 2015): 2003. http://dx.doi.org/10.1182/blood.v126.23.2003.2003.
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Abstract Background: Although, widespread application of innovative sequencing technologies is rapidly unraveling the molecular underpinnings driving the pathogenesis of myelodysplastic syndromes (MDS), allogeneic hematopoietic cell transplantation (HCT) remains the only therapeutic modality that has demonstrated curative potential. However, a significant proportion of patients lack a human leukocyte antigen (HLA)-matched sibling or unrelated donor, and alternative donor sources are needed to extend HCT to patients that are otherwise suitable. There have been few published series solely dedicated to describing the outcomes of adult patients who have undergone umbilical cord blood transplantation (UCBT) for MDS. Methods: We identified 176 adult MDS patients who underwent UCBT, at 59 centers, between 2004 and 2013 from the CIBMTR database. The primary endpoints were the estimated incidences of graft-vs-host-disease (GVHD), relapse, transplant-related mortality (TRM), disease free survival (DFS), and overall survival (OS). Multivariate models were built to assess the ability of the revised International Prognostic Scoring System (IPSS-R) to predict post-HCT outcome. Results: Median age at the time of transplant was 56 (18-73) with 32%, 27%, 34% having a comorbidity score (HCT-CI) of 0, 1-2, or ≥ 3, respectively. The median time from diagnosis to transplant was 9 (< 1-147) months; 23% of patients did not receive pre-HCT chemotherapy; 72% has a marrow blast count ≤ 5%. IPSS-R scores are shown in Table 1. Myeloablative and reduced-intensity/non-myeloablative conditioning was used in 35% and 65%, respectively; 43% incorporating ATG/alemtuzumab. Double units were used in 80%; median total nucleated cell dose (TNC) of 4 × 107 /kg (< 1-29); considering the unit with the higher number of HLA incompatibilities with the recipient, 60% had ≥ 2 mismatches. The 100-day probability of grade 2-4 acute GVHD was 38%. The 3-year probabilities of chronic GVHD, relapse, TRM, DFS, and OS was 28%, 32%, 40%, 28%, and 31%, respectively. In multivariate analysis using marginal Cox model to adjust for center effect, increasing IPSS-R score at the time of HCT was associated with inferior post-HCT TRM, DFS, and OS (Table 2). IPSS-R was associated with neither GVHD nor relapse. HCT-CI was associated with TRM (P = .001), DFS (P = .02), and OS (P = .001), and conditioning intensity was associated with relapse (P < .001). A higher proportion of myeloablative HCTs were done for those with high-risk disease by IPSS-R, but the interaction between conditioning intensity and IPSS-R for relapse was not significant. Conclusions: Treatment decisions and clinical trial design can be informed by providing a descriptive analysis of UCBT for MDS that incorporates a large number of patients from multiple centers. In this analysis, TRM was significantly associated with HCT-CI scores. Interestingly, IPSS-R, a model that specifically quantifies disease risk, at the time of HCT did not predict for post-HCT relapse, but did for TRM. Table 1. Pre-HCT risk scores IPSS-R prior to transplant Very low 18 (10) Low 41 (23) Intermediate 33 (19) High 34 (19) Very high 22 (13) Missing 28 (16) Table 2. Multivariate analysis* TRM IPSS-R N RR 95% CI Lower Limit 95% CI Upper Limit P -value OverallP -value Very low/Low 64 1 .006 Intermediate 34 .68 .34 1.35 .30 High/Very high 54 1.76 1.12 2.75 .01 Missing 28 2.05 .93 4.52 .08 DFS IPSS-R N RR 95% CI Lower Limit 95% CI Upper Limit P -value OverallP -value Very low/Low 64 1 .02 Intermediate 34 .83 .50 1.37 .50 High/Very high 54 1.39 1.02 1.91 .04 Missing 28 1.63 .95 2.81 .08 OS IPSS-R N RR 95% CI Lower Limit 95% CI Upper Limit P -value OverallP -value Very low/Low 65 1 .008 Intermediate 35 .88 .51 1.50 .60 High/Very high 55 1.55 1.12 2.14 .01 Missing 28 1.72 .91 3.26 .09 * When adjusting for center effect and HCT-CI Disclosures No relevant conflicts of interest to declare.
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Roberts, Laura, Rachel B. Salit, Lauren Longo, Elisabetta Xue, Corinne Summers, Colleen Delaney, Ann Dahlberg, and Filippo Milano. "Cord Blood Transplantation Is an Effective Treatment Option in Patients with Myelodysplastic and Myeloproliferative Syndromes." Blood 134, Supplement_1 (November 13, 2019): 2048. http://dx.doi.org/10.1182/blood-2019-126216.
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Background: Few registry studies have investigated the use of cord blood transplantation (CBT) for treatment of patients with myelodysplastic syndrome (MDS) and myeloproliferative disorders (MPN). To date, the outcomes reported have been not encouraging with excess of graft failures [1] and poor disease-free survival (DFS) [2]. The major obstacle to the success of CBT in this high-risk population has been related to the high rate of non-relapse mortality (NRM) due to the delayed time to engraftment. In this single-center study we retrospectively investigated clinical outcomes in patients with MDS and MPN undergoing a CBT. Methods: We reviewed clinical outcomes in 65 consecutive patients with either MDS (n=42) or MPN (n=23) who received a CBT at our institution between 2006 and 2018. The conditioning regimens used consisted of Cyclophosphamide (CY), Fludarabine (FLU), and total body irradiation (TBI) 13.2 Gy (n=16); Treosulfan, FLU, and TBI 2 Gy (n=26); Busulfan, CY, and FLU (n=6); or CY, FLU, and TBI (2 to 4 Gy) (n=17). All patients received Cyclosporine and Mycophenolate Mofetil for graft-versus-host disease (GVHD) prophylaxis. Cord blood units were HLA-typed at the antigen level for HLA-A and B, and high resolution for HLA-DRB1. Disease risk was classified as low to intermediate (n=37) and high to very high (n=28). Cytogenetics risk at diagnosis was favorable, intermediate and unfavorable in 11 (17%), 33 (51%) and 21 (32%) patients, respectively. Among patients with MDS, the R-IPSS score was low in 6 (14%), intermediate in 18 (43%), high in 8 (19%), and very-high in 10 (24%). Engraftment, relapse, NRM, and acute GVHD were calculated using cumulative incidence estimates adjusting for the appropriate competing risks. DFS and overall survival (OS) were assessed using the Kaplan-Meier method. Results: Patient characteristics are shown in Table 1. Median follow-up was 4.2 years (range, 0.5-12). The median age and weight were 46 years (range, 1-71) and 71 kg (range, 10-116). Six (9%) patients had failed a prior HCT. 56 (86%) patients received 2 cord blood units to achieve the required cryopreserved cell dose. The median cell doses infused were 2.6 x 107 (range, 1.4-15) TNC/kg and 0.12 x 106 (range, 0.02-0.78) CD34+ cells/kg. Neutrophils (>500 for 3 days) and platelet (>20x109/L for 7 days transfusion free) engraftment occurred at a median time of 20 days (range, 6-89) and 35 days (range, 13-85), respectively. There were only 4 (6%) cases of primary graft failure, 2 of which were patients with MDS and 2 patients with MPN, and no cases of secondary graft failures. 76% of MDS patients and 52% of MPN patients achieved platelet engraftment by day 100. OS at 3 years was 60% (95% Confidence Interval, CI: 47-71) and specifically was 63% (95% CI: 47-76) for MDS patients and 55% (95% CI: 32-73) for MPN patients. Disease free survival at 3 years was 54% (95% CI: 41-66) with a cumulative incidence of relapse of 21% (95% CI: 11-32). The cumulative incidence of NRM at day 100 and at 3 years were 9% (95% CI: 4-17) and 25% (95% CI: 15-36), respectively. No differences in DFS, relapse incidence, and NRM were seen between MDS and MPN patients (Table 2). The cumulative incidence of acute GVHD grade II-IV and III-IV were 74% (95% CI: 61-82) and 21% (95% CI: 12-32), respectively. Seventeen (26%) patients developed late acute GVHD at a median time of 186 days (range, 101-379), and 10 (15%) had overlap syndrome. Twenty-three (35%) patients were diagnosed with classical chronic GVHD: 18 (27%) with mild, 3 (5%) with moderate, and only two (3%) with severe grade. Conclusions: The results presented herein demonstrate that in patients with MDS and MPN undergoing CBT sustained engraftment was achievable without excessive graft failures. The rates of OS and DFS at 3 years were extremely encouraging and similar to what was observed after matched related and unrelated donors' transplants. [3,4]. Overall, our data suggest that CBT should be considered as a valid option for this high-risk population in case of lack of conventional donors. Disclosures Delaney: Biolife Solutions: Membership on an entity's Board of Directors or advisory committees; Nohla Therapeutics: Employment, Equity Ownership. Milano:ExCellThera: Research Funding; Amgen: Research Funding.
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Al Madhoun, Ashraf, Shihab Kochumon, Fatema Al-Rashed, Sardar Sindhu, Reeby Thomas, Lavina Miranda, Fahd Al-Mulla, and Rasheed Ahmad. "Dectin-1 as a Potential Inflammatory Biomarker for Metabolic Inflammation in Adipose Tissue of Individuals with Obesity." Cells 11, no. 18 (September 15, 2022): 2879. http://dx.doi.org/10.3390/cells11182879.
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In obesity, macrophage activation and infiltration in adipose tissue (AT) underlie chronic low-grade inflammation-induced insulin resistance. Although dectin-1 is primarily a pathogen recognition receptor and innate immune response modulator, its role in metabolic syndromes remains to be clarified. This study aimed to investigate the dectin-1 gene expression in subcutaneous AT in the context of obesity and associated inflammatory markers. Subcutaneous AT biopsies were collected from 59 nondiabetic (lean/overweight/obese) individuals. AT gene expression levels of dectin-1 and inflammatory markers were determined via real-time reverse transcriptase-quantitative polymerase chain reaction. Dectin-1 protein expression was assessed using immunohistochemistry. Plasma lipid profiles were measured by ELISA. AT dectin-1 transcripts and proteins were significantly elevated in obese as compared to lean individuals. AT dectin-1 transcripts correlated positively with body mass index and fat percentage (r ≥ 0.340, p ≤ 0.017). AT dectin-1 RNA levels correlated positively with clinical parameters, including plasma C-reactive protein and CCL5/RANTES, but negatively with that of adiponectin. The expression of dectin-1 transcripts was associated with that of various proinflammatory cytokines, chemokines, and their cognate receptors (r ≥ 0.300, p ≤ 0.05), but not with anti-inflammatory markers. Dectin-1 and members of the TLR signaling cascade were found to be significantly associated, suggesting an interplay between the two pathways. Dectin-1 expression was correlated with monocyte/macrophage markers, including CD16, CD68, CD86, and CD163, suggesting its monocytes/macrophage association in an adipose inflammatory microenvironment. Dectin-1 expression was independently predicted by CCR5, CCL20, TLR2, and MyD88. In conclusion, dectin-1 may be regarded as an AT biomarker of metabolic inflammation in obesity.
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DeZern, Amy E., Marianna Zahurak, Javier Bolanos-Meade, and Richard J. Jones. "Shortened Immunosuppression Following Peripheral Blood (PB) Haploidentical (haplo) Transplantation with Post-Transplant Cyclophosphamide (PTCy) Is Associated with Tolerable Rates of Graft-Vs-Host Disease (GVHD)." Blood 134, Supplement_1 (November 13, 2019): 3320. http://dx.doi.org/10.1182/blood-2019-122762.
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With PTCy as GVHD prophylaxis, nonmyeloablative (NMA) HLA- haplo and HLA-matched blood or marrow (BMT) have comparable outcomes. Previous reports showed that discontinuation of immunosuppression (IST) as early as day 60 after infusion of bone marrow (BM) haplo allograft with PTCy is feasible. However, there are certain diseases in which PB may be favored over BM grafts to augment engraftment rates; however, given the higher rates of GVHD with PB, excessive GVHD becomes a concern with early discontinuation of IST. We present a completed, prospective single-center trial of stopping IST at days 90 and 60 after NMA haplo PB. (NCT02556931) From 12/2015-7/2018, 117 evaluable patients (pts) with hematologic malignancies associated with higher rates of graft failure with PTCy (MDS, MPN, overlap syndromes, 2o AML, AML with MRD, MM, and CLL) received NMA PB allografts on trial. Haplo donors were preferred, but in patients lacking suitable haplo relatives, unrelated donors were employed with 6 in each IST cohort. The primary objective was to evaluate the safety and feasibility of reduced‐duration IST (from Day 5 through Day 90 in cohort 1 and through Day 60 in cohort 2.) Transplant inclusion criteria were standard and the conditioning included Cy (14.5 mg/kg IV D -6 and -5), fludarabine (D -6 to -2), TBI (200 cGy D -1) and T-cell replete PB. GVHD prophylaxis consisted of high-dose PTCy (50 mg/kg IV D 3 and 4), mycophenolate mofetil (D 5-35) and IST (tacrolimus/sirolimus) from D 5 forward. Priot to transplantation, pts were assigned to stop IST early if eligible, as defined by having ≥ 5% donor T cells at ~D 56 onward, no relapse, and no grade 2-4 acute or significant chronic GVHD. If ineligible to discontinue IST early, it continued through D 180. Monitoring rules declared reduced IST feasible if ≥ 33% of pts stopped IST early as planned. Safety stopping rules for early IST cessation were based on ≥ 5% graft failure, ≥ 5% NRM, ≥ 50% relapse, and ≥ 10% combined grade 3-4 acute GVHD and severe chronic GVHD, measured from the IST stop date to ~D 180. Historical data from 55 haplo transplants for MDS, CLL, and MPNs at our center using the same regimen and PB grafts informed safety calculations. Of the 117 pts (median age 64 years, range 24-78), the most common diagnoses were MDS (33%), AML (with MRD or arising from antecedent disorder) (31%), MPNs (21%) myeloma (10%), and CLL (6%). By refined Disease Risk Index, 13% were low risk, 69% intermediate and 18% high. Shortened IST was feasible in 75 pts (64%) overall. Ineligibility for shortened IST was due most commonly to GVHD (17 pts), followed by early relapse (11 pts), NRM (7 pts), patient/ physician preference (4 pts) or graft failure (3 pts). Of the 57 patients in the D90 cohort (median follow up 35 mos), 33 (58%) stopped IST early as planned. Of the 60 patients in the D60 cohort (median follow up 20 mos), 42 (70%) stopped IST early as planned. The graft failure rate was 2.6%. NRM was very similar in the two arms, 12% at both 12 and 18 months in the D90 cohort and 10% and 13% at 12 and 18 months in the D60 cohort. Relapse in D90 cohort is 40% at 18 months compared to 33% at 18 months in the D60 cohort. Figure 1 shows cumulative incidence (CI) of acute grade 2-4 and grade 3-4 GVHD. Although the CI of grade 1-2 GVHD may be slightly higher in day 60 cohort, it is only 40% at D180. Severe chronic GVHD was 12% (D90) and 11% (D60) at 540 days. One year OS is 75% and 78% for the D90 and D60 cohorts, respectively. At 12 months PFS is 54% in the D90 group and 67% in the D60. At 12 months, the GRFS is 33% in the D90 group, and 38% in the D60 group. (Figure 2) These data suggest that reduced-duration IST in pts receiving NMA haplo PB with PTCy is feasible and carries an acceptable safety profile. Risks of acute GVHD, chronic GVHD, graft failure and NRM appear similar to historical outcomes with IST until D180 and between the two cohorts. When comparing the D90 and D60 arms, grade 3-4, severe chronic GVHD, GRFS, OS and PFS were similar. Although a larger, prospective trial would be needed to uncover potential small differences in outcomes based on IST duration, these data show that similar to our findings with BM, many PB pts (64% in this trial) can discontinue IST as early as D60 without undue toxicity. The favorable toxicity profile of the PTCy platform, coupled with the feasibility and safety of early IST cessation, provides an ideal setting to incorporate novel post-transplantation approaches for relapse reduction. Figure 1 Disclosures DeZern: Astex Pharmaceuticals, Inc.: Consultancy; Celgene: Consultancy. Bolanos-Meade:Incyte Corporation: Other: DSMB fees.
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Tuscano, Joseph M., Izidore S. Lossos, Glen Justice, Julie M. Vose, Kenichi Takeshita, Annette Ervin-Haynes, Dennis Pietronigro, Jerome B. Zeldis, and Thomas M. Habermann. "Lenalidomide Oral Monotherapy Produces a 53% Response Rate in Patients with Relapsed/Refractory Mantle-Cell Non-Hodgkin’s Lymphoma." Blood 110, no. 11 (November 16, 2007): 2563. http://dx.doi.org/10.1182/blood.v110.11.2563.2563.
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Abstract Background: Mantle cell lymphoma (MCL) is a distinct type of non-Hodgkin’s Lymphoma characterized by being incurable with a low response rate and short progression free survival when treated with conventional chemotherapy agents. Lenalidomide (Revlimid®), an immunomodulatory drug, is approved for the treatment of relapsed/refractory multiple myeloma and myelodysplastic syndromes associated with a del(q5) cytogenetic abnormality. Lenalidomide has also shown activity in chronic lymphocytic leukemia and cutaneous T-cell lymphoma. Aim: To determine the activity and safety of lenalidomide in relapsed/refractory MCL. Methods: Patients with relapsed/refractory MCL and measurable disease ≥ 2 cm after at least 1 prior treatment regimen were eligible. Patients received 25 mg lenalidomide orally once daily on Days 1–21 every 28 days and continued therapy for 52 weeks as tolerated or until disease progression. Response and progression were evaluated using the IWLRC methodology. Results: Fifteen patients with MCL were enrolled. Median age was 67 (45–84) and 7 were female. Median time from diagnosis to lenalidomide was 5.1 (0.7–12.7) years and median number of prior treatment regimens was 4 (2–6). Eight patients (53%) exhibited an objective response (1 complete response (CR), 1 complete response unconfirmed (CRu) and 6 partial responses (PR)), 2 had stable disease (SD) and 5 had progressive disease (PD). All eight responses were in eleven patients having a tumor burden < 50 cm2 and a time since last rituximab therapy of ≥ 230 days. No responses were achieved in four patients having a tumor burden ≥ 50 cm2 or a time since last rituximab therapy of < 230 days. Four of 5 patients (80%) with a prior stem cell transplant responded. Progression free survival [PFS] is 5.7 months and ongoing. Seven patients (47%) required at least one dose reduction with a median time to first dose reduction of 2.3 months (1.2–4.9). Grade 4 adverse events were neutropenia (13%), thrombocytopenia (13%), and thromboembolism (13%). Most common Grade 3 adverse events were neutropenia (33%) and leukopenia (20%). Conclusion: Lenalidomide oral monotherapy produced a 53% response rate in relapsed/refractory MCL with manageable side effects.
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Tamari, Roni, Proli Anthony, Juntig Zheng, Ann A. Jakubowski, Esperanza B. Papadopoulos, Doris M. Ponce, Sean Devlin, et al. "Impact of Busulphan Exposure on Transplant Outcomes for Patients with Advanced Myelodysplastic Syndromes Undergoing CD34 Selected Allogeneic Hematopoietic Cell Transplantation." Blood 126, no. 23 (December 3, 2015): 1911. http://dx.doi.org/10.1182/blood.v126.23.1911.1911.
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Abstract CD34 selected stem cell transplants (SCT) have shown similar survival rates as unmodified SCT, with lower incidence of acute and chronic graft-versus-host disease (GVHD). A common conditioning regimen for patients with advanced myelodysplastic syndrome (MDS) undergoing CD34 selected SCT is a combination of busulphan, melphalan, fludarabine, and anti- thymocyte globulin (ATG). The ideal area under the curve (AUC) and overall dose intensity of busulphan is unknown in these pts. We aimed to study the relationship between busulfan AUCs and transplant outcomes in this pt population. This retrospective analysis included 68 pts with advanced MDS (RAEB-I and higher) who underwent CD34 selected SCT between 2000-2012. Median age was 58.05 yrs (26-73). There were 36 women (52.9%). HCT CI was ³ 3 in 37 pts (54.4%). MDS subtype at diagnosis by WHO criteria was: RA/RCMD-19 (all progressed to RAEB/AML), RAEB-I 20 &RAEB II 29; and by IPSS-R criteria in 65 pts: very low risk-4, low risk-9, intermediate risk-14, high risk-20 & very high risk-18. All pts were conditioned with busulphan IV 0.8 mg/kg dose, melphalan 140 mg/m2, fludarabine 125 mg/m2 & ATG . Thirty-nine pts received 10 doses of busulphan and 29 pts 12 doses. The dose was increased to reduce the relapse rate. Pharmakokinetic studies were done after first busulphan's dose and based on results adjustments were made to achieve a target dose of 1025-1315µM x min. G-CSF mobilized donor peripheral blood stem cells underwent CD34+ selection and depletion of T cells using CliniMACS immunomagnetic selection columns (Milteny Biotec). Donors were HLA matched, 48 (18 related & 30 unrelated) or mismatched unrelated, 20. The median first-dose busulphan AUC was 1,206 (723-2,180). In 27 pts (39.7%) this was within target range of 1,025-1,315 with 16 pts (23.5%) below and 25 (36.7%) above. The median total busulphan exposure for all pts was 12,822 (9,513-15,754), with 1st quartile range of 9,513-12,181 and 4th quartile range of 13,664-15,754. The median total exposure in the 10 doses group (group 10) was 12,520 (9,513-15,754) and in the 12 doses group (group12) 13,420 (9,860-15493). The 2-years overall survival (OS) was 61.5% (CI 44.5-74.7) in group 10 and 55.2%(35.6-71) in group 12 and 2-years relapse free survival (RFS) was 56.4% (39.6-70.2) in group 10 and 51.7% (32.5-67.9) in group 12. The 2-years cumulative incidence of relapse was 15.4% (CI 3.9-26.9) in group 10 and 13.8% (CI 0.9-26.6) in group 12. The non-relapse (NRM) mortality at 2 years was 28.2% (13.8-42.6) in group 10 and 34.5% (16.7-52.2) in group 12. aGVHD grade II-IV was 12.8% (2.2-23.5) in group 10 vs 23.1% (6.5-39.7%) in group 12. None of these differences were statistically significant. Further analysis by quartiles showed no differences in OS, RFS, relapse and NRM between the 4 groups. However, grade II-IV acute GVHD was significantly higher in the 4th quartile exposure, 35.6% (8.9-62.3) vs 5.9% (0-17.5), 11.8% (0-27.6) and 17.6% (0-36.4) in the 1st, 2nd and 3rd quartiles (p=0.046) (table 1). In thishomogenous cohort of pts, total busulphan exposure was only found to be associated with grade II-IV aGVHD, with higher incidence seen in pts who had exposure >13,664. Donor mismatch status was not associated with higher aGVHD in this cohort and therefore can not explain the increased aGVHD seen with higher busulphan exposure. A trend for better transplant outcomes was seen with total exposure of 12,182- 13,663 (2nd and 3rd quartiles); though the differences were not statistically significant. In CD34 selected allo-HSCT for pts with advanced MDS, the intensity of the conditioning has an impact on transplant outcomes and therefore determining the range of busulphan that offers best survival with minimal GVHD has important clinical implications. Table 1. Transplant outcomes (cumulative incidence with 95% CI): Total exposure 6-months CI ofaGVHD II-IV 2-year CI of Relapse 2-year CI NRM 2-year CI OS 2-year CI RFS Q1: 9,513-12,181, n=17 5.9 (0-17.5) 35.3 (11.6-59) 23.5 (2.4-44.7) 52.9 (27.6-73) 41.1 (18.6-62.6) Q2: 12,181-12,822, n=17 11.8 (0-27.6) 11.8 (0-27.7) 23.5 (2.6-44.4) 70.6 (43.1-86.6) 64.7(37.7-82.3) Q3: 12,823-13,663, n=17 17.6 (0-36.4) 5.9 (0-17.5) 35.3 (11.7-58.9) 58.8 (32.5-77.8) 58.5 (32.5-77.8) Q4: 13,664-15,754 n=17 35.6 (8.9-62.3) 5.9 (0-17.4) 41.2 (16.8-65.6) 52.9 (27.6-73) 52.9 (27.6,-73.0) p value* overall: 0.185, Q4 vs others: 0.046 0.221 0.409 0.663 0.540 Figure 1. Figure 1. Disclosures Giralt: SANOFI: Consultancy, Honoraria, Research Funding; CELGENE: Consultancy, Honoraria, Research Funding; AMGEN: Consultancy, Research Funding; JAZZ: Consultancy, Honoraria, Research Funding, Speakers Bureau; TAKEDA: Consultancy, Honoraria, Research Funding.
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Chung, Stephen S., Jenna D. Goldberg, Esperanza B. Papadopoulos, Ann A. Jakubowski, Sean Devlin, Farid Boulad, Miguel Perales, et al. "Unrelated Donor T-Cell Depleted (TCD) Hematopoietic Stem Cell Transplantation (HSCT) for Patients with Advanced Myelodysplastic Syndromes (MDS): The MSKCC Experience." Blood 120, no. 21 (November 16, 2012): 1996. http://dx.doi.org/10.1182/blood.v120.21.1996.1996.
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Abstract Abstract 1996 The outcomes of unrelated HSCT have markedly improved with the advent of high resolution HLA-typing. However, graft-versus host disease (GvHD) remains a limiting factor, particularly in mismatched transplants. Several studies have demonstrated that TCD reduces the incidence of acute and chronic GvHD, potentially allowing for improved outcomes in the mismatched setting. We have observed excellent long term survival in our early experience performing matched related TCD HSCT in patients with advanced MDS, particularly in patients who achieve a complete remission (CR) or second refractory cytopenia phase (RCy2) prior to transplant. We report here our experience performing unrelated TCD HSCT in 85 consecutive patients with advanced MDS. From 1989–2011, 85 patients with advanced MDS (IPSS Intermediate risk [IR]-1 or higher) and AML transformed from MDS underwent TCD HSCT (18 bone marrow [BM], 67 mobilized peripheral blood [PB]) from unrelated donors following conditioning with a total body irradiation-based (25 patients) or a busulfan-based (60 patients) myeloablative regimen. 49 donors were fully matched and 36 were partially matched (9/10 HLA matched: 23; 8/10 HLA matched: 8; 7/10 HLA matched: 1; and 5/6 HLA matched: 4 [before high resolution typing]). The median age was 55 (range 4–73). Prior to conditioning, 80 patients received chemotherapy (28 with a hypomethylating agent, 65 with intensive chemotherapy, and nine with both) and five patients did not receive chemotherapy. Prior to transplant, 34 of the 80 patients who received chemotherapy were in CR, 30 were in RCy2, and 15 failed to achieve remission (10 with RAEB, 5 with AML). Of the five patients who did not receive chemotherapy, two had refractory anemia and three had RAEB. The BM grafts were depleted of T-cells using the soybean agglutinin method followed by sheep RBC rosetting, and the G-CSF mobilized PB stem cell grafts were depleted of T-cells using immunomagnetic CD34+ selection (Isolex initially and CliniMACS after 09/2011). Rejection prophylaxis with ATG was used in all patients. No post-transplant pharmacologic prophylaxis for GvHD was given. 82 of 85 patients engrafted (92%). Three died before engraftment (3.5%, all <28 d after transplant) and two developed late graft failure (2.4%). The day-100 cumulative incidence (CI) of grade II-IV aGVHD was 19% (95% confidence interval [95%CI] 11%-28%), and the 1-year CI of aGvHD, including the late onset form, was 28% (95%CI 18%-38%). When only including grade III-IV aGVHD, the day-100 CI was 9.4% (95%CI 4.3%-17%) and the 1-year CI was 16% (95%CI 9.4%-25%). The 2-year CI of cGVHD was only 3.5% (95%CI 0.9%-9.1%). The overall survival (OS) was 53% (95%CI 43%-63%) at two years and 44% (95%CI 35%-75%) at five years. The relapse free survival (RFS) was 46% (95%CI 36%-57%) at two years and 41% (95%CI 31%-52%) at five years. There was no significant difference in OS/RFS among patients transplanted with fully HLA-matched, 9/10 HLA-matched, or 7–8/10 HLA-matched grafts. There was a trend towards worse OS in patients who had a poor risk (HR) IPSS score at any time prior to transplant; the 2-year OS in this group was 43% (95%CI 32%-60%) versus 64% (95%CI 49%-82%) in the IR-1/IR-2 IPSS groups (p=0.08). Likewise, there was a trend towards worse OS in patients who failed to achieve CR or RCy2 prior to transplant (2-year OS 32% [95%CI 16%-64%]), as compared with patients who achieved CR or RCy2 (2-year OS 58% [95%CI 48%-71%], p=0.25). The overall 1-year CI of relapse was low at 13% (95%CI 7%-21%). The 1-year CI of relapse was significantly higher in patients with IPSS poor risk cytogenetics (27%, 95%CI 5.2%-55%) as compared with intermediate (18%, 95%CI 0.1%-65%) and good (8.4%, 95%CI 0.04%-45%) risk cytogenetics (p=0.03). The 1-year NRM was 36% (95%CI 23%-49%) in those with HR disease and only 18% (95%CI 7%-33%) in those with IR-1/IR-2 risk disease. 5-year OS was superior in transplants done from 2000–2011 (48%, 95%CI 36%-59%) compared with 1989–1999 (25%, 95%CI 6%-50%, p=0.01), reflecting the availability of high resolution HLA-typing and improvements in supportive care. These results indicate that patients with advanced MDS can achieve durable remissions and long term survival after unrelated TCD HSCT with low rates of acute and chronic GVHD even with mismatched donors. Selecting patients for HSCT before progression to IPSS HR disease and induction into CR or RCy2 prior to transplant may maximize the efficacy of this approach. Disclosures: No relevant conflicts of interest to declare.
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Åström, Jenny, Linda Holmström, Bianka Karshikoff, Anna Andreasson, and Mike K. Kemani. "Evaluating the construct validity and internal consistency of the Sickness Questionnaire in a Swedish sample of adults with longstanding pain." Scandinavian Journal of Pain 22, no. 1 (December 19, 2021): 88–96. http://dx.doi.org/10.1515/sjpain-2021-0070.
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Abstract Objectives Low-grade inflammation is a possible contributing factor in the development and persistence of chronic primary pain syndromes. Related to inflammatory activity is sickness behavior, a set of behavioral responses including increased pain sensitivity, fatigue, malaise, fever, loss of appetite, as well as depressive behavior and anhedonia. To capture these behavioral responses and their relation to longstanding pain, psychometrically sound self-report questionnaires are needed. The Sickness Questionnaire (SicknessQ) was developed to assess self-reported sickness behavior based on studies on acute immune activation while maintaining relevance for persistent conditions. The aim of the current study was to evaluate aspects of the validity and reliability of the SicknessQ in a Swedish sample of persons with longstanding pain. Methods Aspects of construct validity were evaluated by means of performing a confirmatory factor analysis (CFA) (testing structural validity) and by relevant hypothesis testing i.e., that ratings of sickness behavior in combination with other related factors (e.g., depression and anxiety) would be significantly related to ratings of avoidance. Reliability was evaluated by means of analyzing the internal consistency of items. Results Following the CFA, a non-significant Chi-Square test (χ2 [32, N=190] = 42.95, p=0.094) indicated perfect model fit. Also, the relative fit indices supported adequate model fit (CFI = 0.978; TLI = 0.969; RMSEA = 0.0430). Sickness behavior (p<0.0001), depression (p<0.05) and pain duration (p<0.05) significantly contributed to the regression model, explaining 45% of the total variance in avoidance. Internal consistency was adequate, as indicated by a Cronbach’s α value of 0.82 for the entire questionnaire. Conclusions Results indicate that the SicknessQ has adequate structural validity as well as adequate internal consistency, and is significantly associated with avoidance. The SicknessQ appears to have utility as a self-report questionnaire to assess symptoms of sickness behavior for adults with longstanding pain.
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Lim, ZiYi, Aloysius Ho, Michelle Kenyon, Stephen Devereux, Rafael Duarte, Antonio Pagliuca, and Ghulam Mufti. "Reduced Intensity Conditioned Volunteer Unrelated Donor Transplants Using Alemtuzumab Are Safe and Effective in Older Patients with Myelodysplastic Syndromes." Blood 106, no. 11 (November 16, 2005): 444. http://dx.doi.org/10.1182/blood.v106.11.444.444.
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Abstract Use of myeloablative conditioning HSCT regimens have been limited to a select group of patients with MDS. This is due in part to the high transplant related mortality, which is closely associated with increasing recipient age as well as the degree of HLA parity. We have conducted a prospectively designed, single-center study to assess the efficacy of an RIC regimen consisting of fludarabine, busulphan, and alemtuzumab (FBC) in 75 patients with MDS utilizing hematopoietic stem cells (HSC) from VUD. The RIC protocol consisted of 30 mg/m2 fludarabine iv from day −9 to −5; 4 mg/kg oral busulphan from day −3 to −2; and 20 mg alemtuzumab iv from day −8 to −4. Patients received cyclosporine A for GvHD prophylaxis. All patients possessed relative or absolute contraindications to conventional myeloablative HSCT. 30 patients received RIC on the basis of advanced age alone. 13 patients had been treated for IPA within 3 months of transplantation. Median age of patients was 52 years (range 24–68 years). The stem cell source was BM in 28 patients and PBSC in 47 patients; median CD34 cell doses were 2.25 x 106/kg (range:0.7–9.7) and 6.2 x 106/kg (range:0.7–17.8), respectively. 23 (31%) donor-recipients were mismatched on 1 or more HLA loci. 49 patients (65%) had an IPSS stage of ≥Int-2, and 55 (73%) had received induction chemotherapy prior to HSCT. 67 patients (89%) had stable disease or were in complete morphological remission at time of transplant. Mean time to engraftment was 13 days for neutrophil count >0.5 x 109/L, and 16 days for an unsupported platelet count >20 x 109/L. Three patients had primary graft failure. With a median follow-up of 315 days (range:36–2096), 38 patients (51%) were alive at the time the data were censored. The median follow-up for survivors was 752 days (range:74–2096). The Kaplan-Meier estimates of OS at years 1 and 2 were 55% and 47%, respectively. Similarly, at years 1 and 2, NRM was 10% and 30%, respectively, and DFS was 48% and 40%, respectively. Significantly, the OS and DFS curves plateau at day+902 and day+799, respectively, suggesting that longer term disease eradication can be achieved. The prognostic significance of IPSS, cytogenetic risk and disease status at transplantation was maintained in our cohort. 20 patients received DLI post transplantation. DLI was given for falling donor chimerism in 10 recipients, with re-establishment of full-donor chimerism in 9 patients. While DLI was effective against cytogenetic relapses (response rate 50%), it was less effective against established morphologic relapse (response rate 33%). Limited and extensive de novo chronic GVHD occurred in 14 patients (18%) and 12 patients (17%) respectively. Following DLI, the overall cumulative incidence of acute grade III-IV GvHD at 2 years was 25%. When chronic extensive GvHD was present in the study, it significantly correlated with a lower relapse rate (p<0.05). CMV reactivation occurred in 21 (28%) patients at a median time of 59 days (range:29–215 days) following transplantation, with 2 patients developing CMV disease. Two patients had IPA post-transplant; however, none of the 13 patients with recent IPA pre-transplant experienced progression of the infection. In our cohort of older patients with a high degree of HLA disparity and significant co-morbidities, RIC HSCT regimen utilizing FBC, can serve as a platform for durable engraftment, with a low incidence of GVHD, favorable TRM, and long-term DFS.
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Milani, Raffaella, Salvatore Palmieri, Manuela Zanni, Filiberto Pollio, Anna Dodero, Francesco Spina, Adele Testi, et al. "Long-Term Outcome of Therapy-Related Myelodysplastic Syndromes and Acute Myeloid Leukemias Arising in Patients Treated for Lymphoma or Solid Tumors." Blood 110, no. 11 (November 16, 2007): 2464. http://dx.doi.org/10.1182/blood.v110.11.2464.2464.
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Abstract Several studies have shown that therapy-related MDS (tMDS) and AML (tAML) have a poor outcome with very few long-term survivors. Curative treatment strategies are not yet standardized and the role of hematopoietic stem cell transplantation (SCT) is still not fully elucidated in standard care treatment. We performed a retrospective outcome research with the aim of looking at the survival curves of tMDS and tAML patients treated at 7 different Institutions. According to the presence of comorbidities or a matched donor, 71 patients (pts) received the best treatment option based on attending physician opinion: 24 pts (group A) with tAML (n=13, FAB M0, M1, M2, M4) and tMDS (n=7 RAEB-2. n=4 RAEB-1) received allogeneic transplantation, 28 pts (group B) with tAML (n=20, FAB M0, M1, M2, M4, M5) and tMDS (n=3 RAEB-2, n=4 RAEB-1, n=1 RA) received chemotherapy and 19 pts (group C) received supportive care only (n=1 tAML, n=18 low-risk MDS or RAEB-1 (n=5)). Median age was 55 years (range 23–67) in group A, 61 years (range 27–73) in group B and 55 years (range 22–70) in group C. Conventional karyotype analysis was available in 12 pts of group A (n=7 complex, n=1 normal, n=2 isolated del(7q) or monosomy 7, n=1 isolated del(5q), n=1 trisomy 21) and in 15 pts of group B (n=3 complex, n=8 normal, n=1 isolated del(Y), n=1 isolated del(11), n=1 isolated trisomy 11, n=1 isolated trisomy 8). In the group A, all pts, because of age and/or comorbidities, received a fludarabine-based reduced-intensity conditioning followed by allogeneic peripheral blood SCT. Disease status at transplant was categorized as low risk (n=9 CR1 or CR2), high risk (n=3 PR, n=6 PD, n=2 refractory) and 4 pts were treated up-front. The median time from diagnosis to allografting was 6 months (range: 1–80 months). Pts received allogeneic stem cells from HLA-matched siblings (n=16), or HLA-matched unrelated donors (n=6), or haploidentical related donors (n=2). All pts engrafted. Acute GVHD grade II–IV occurred in 6 pts (n=1 post-DLIs), chronic GVHD developed in 6 pts (n=1 post-DLIs). OS at 5 years was 5.5%, the 4-year EFS was 0%, TRM at 100 days and at 1 year were 28%. No statistical differences were observed in TRM, EFS, and OS according to disease status at transplant and diagnosis of tMDS or tAML. DFS for pts in CR at transplant was 23% at 1 year. In the group B, pts received chemotherapy and 11 of them an autologous stem cell transplantation. OS at 5 years was 16%, EFS at 5 years was 10%, DFS at 1 year was 31%. TRM at 5 years was 30%. In the group C, OS was 28% at 5 years. Our data show that, in daily clinical practice, the outcome of patients receiving chemotherapy followed by allogeneic SCT is not improved compared to the patients not having a suitable donor. At the present time, considering the very low chance of cure, in therapy-related disorders the main goal for clinicians should be prevention.
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Kelly, Chris C. J., Helen Lyall, John R. Petrie, Gwyn W. Gould, John M. C. Connell, and Naveed Sattar. "Low Grade Chronic Inflammation in Women with Polycystic Ovarian Syndrome." Journal of Clinical Endocrinology & Metabolism 86, no. 6 (June 2001): 2453–55. http://dx.doi.org/10.1210/jcem.86.6.7580.
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Gawronski, Krzysztof, Kazimierz Sulek, Malgorzata Sidor, and Maria Domagala. "Proliferative Activity of Megakaryocytes in Myelo- and Lymphoproliferative Diseases." Blood 106, no. 11 (November 16, 2005): 4954. http://dx.doi.org/10.1182/blood.v106.11.4954.4954.
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Abstract Aim of the study: Evaluation of significance of investigation of Ki67 and AgNOR staining as an indices of proliferative activity of megakaryocytes. Material and methods: Bone marrow smears from 151 patients suffering from hematological malignancies: polycythemia vera (PV) − 14 cases, myelofibrosis (MF) − 14, essential thrombocythemia (ET) − 15, chronic myeloid leukemia (CML) − 11, myelodysplastic syndromes (MDS) − 18; acute myeloid leukemia (AML) − 30, acute lymphoblastic leukemia (ALL) − 10, low grade non-Hodgkin’s lymphomas (NHL) with bone marrow infiltration − 20, multiple myeloma (MM) − 19. Cytological slides were stored in the room temperature more than 24 hours and then stained using immunocytochemical method for Ki67 and cytochemical method for AgNOR. Slides were analyzed using illuminating microscope with digital image analysis (software LUCIA). Mean particles area, mean nuclear area and maturity of nucleus in AgNOR staining as well as intensity of Ki67 expression were evaluated, according to arbitrary scale (strong, medium, light, no reaction). Results: Look at the table 1 and table 2. Conclusions:There is a good correlation between expression of Ki-67 and AgNOR’s in megakaryocytes as well as between nuclear maturity and indices of Ki-67 and AgNOR in myeloproliferative disorders. Differences in AgNOR’s and Ki 67 staining area between myeloproliferative diseases and another hematological malignancies are also significant. Table 1: Values of indices of the Ki67 and AgNOR in megakaryocytes Diseases Mean nucleus surface μm2 Mean AgNOR particle area in nucleus of megakaryocytes μm2 Mean Ki67 particle area in nucleus of megakaryocytes μm2 Intensity of Ki67 expression in megakaryocytes Grade of megakaryocytes maturity PV 667,29 0,68 0,19 Medium III and IV ET 812,32 0,82 0,29 Strong / Medium III and IV MF 767,92 0,55 0,26 Strong / Medium III / IV CML 734,30 0,57 0,15 Medium / Light III / IV MDS 645,67 0,06 0,03 Light III / IV AML 679,04 0,04 No reaction No reaction IV ALL 712,23 0,03 No reaction No reaction IV NHL 798,56 0,04 No reaction No reaction IV MM 629,49 0,04 No reaction No reaction IV Table 2: Intensity of Ki67 expression in megakaryocytes in hematological disorders Diseases Strong – % of cells Medium – % of cells Light – % of cells No reaction – % of cells PV 36 43 14 7 ET 56 33 11 0 MF 51 32 16 1 CML 16 43 34 7 MDS 9 12 68 11 AML 0 0 0 0 ALL 0 0 0 0 NHL 0 0 0 0 MM 0 0 0 0
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Selleslag, Dominik L. D., Friedel Nollet, Johan Billiet, Jan Van Droogenbroeck, Achiel Van Hoof, Koen Van Eygen, Melanny Hidajat, and Arnold Criel. "Efficacy of Donor Lymphocyte Infusions in Myelodysplastic Syndromes Relapsing after Allogeneic Stem Cell Transplantation: Importance of Karyotype." Blood 104, no. 11 (November 16, 2004): 1450. http://dx.doi.org/10.1182/blood.v104.11.1450.1450.
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Abstract Few studies have reported on the efficacy of donor lymphocyte infusions (DLI) for myelodysplastic syndromes (MDS) relapsing after T-cell depleted allogeneic stem cell transplantation. Since 1996 we have treated 11 patients with DLI as a single therapeutic modality (without chemotherapy) for a relapse of MDS after allogeneic stem cell transplantation. Median age of the patients was 56 years (range 23 to 73 years). Initial diagnosis was RAEB (4 patients), RAEBt (3 patients), secondary AML(3 patients) and MDS with fibrosis (1 patient). Conditioning was myeloablative in 10 patients ( TBI -Cyclophosphamide, Busulfan-Cyclophosphamide or Busulfan-Melphalan) and non-myeloablative in 1 patient (Busulfan-Fludarabine-ATG). Source of stem cells was peripheral blood in all patients. Donors were HLA-identical siblings in 10 patients and HLA-matched unrelated in 1 patient. Allografts were T-cell depleted with Campath 1H in the bag in 8 of 11 patients. GVHD prophylaxis was cyclosporin in all patients combined with methotrexate in the 3 patients receiving unmodified stem cells. Relapse of MDS occurred at a median of 123 days (54 to 373 days) after allograft. At the time of DLI the percentage of blast cells in the bone marrow ranged from 3 % to 50 % (median 6 %); donor chimerism ranged from 14 % to 91 % (median 72%). The total dose of CD3 lymphocytes ranged from 0.1 to 30 x 10 7 /kg (median 0.6 x 10 7/kg) and was administered in 1 to 4 infusions (median 1). Time interval between first and second DLI varied between 7 and 180 days.Three of the 11 patients achieved a durable complete remission with 100 % donor chimerism after DLI. These 3 patients are currently disease free at 20, 30 and 40 months from the first DLI. All durable responses were associated with limited chronic GVHD requiring temporary immunosuppressive therapy. Time interval between the first DLI and the achievement of complete donor chimerism varied between 6 weeks and 9 months. One of the 11 patients achieved a short state of complete chimerism for 4 weeks and died from relapse 146 days after DLI. Five of the 11 patients progressed after DLI and 4 of them died from disease progression at 29 to 112 days after first DLI. Two patients died at 26 and 97 days after the first DLI from acute GVHD grade IV after having received only 1 x 10 6 CD3 lymphocytes /kg from HLA-identical sibling donors. None of the 6 patients with a complex karyotype responded to DLI while 3 of 3 patients with a single chromosomal abnormality ( t(1,14), t(1,17), t(1,3)) had a durable response (p-value = 0.01). We conclude that DLI is a powerful therapy for about 30 % of MDS patients relapsing after T-cell depleted allogeneic stem cell transplantation. DLI may result in durable remissions particularly in patients with non-complex cytogenetic abnormalities. However, even low doses of donor T lymphocytes may cause mortality from severe GVHD.
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Dawravoo, Arlene, Reem Karmali, Amy Rizman, Stephanie A. Gregory, Melissa L. Larson, Parameswaran Venugopal, and Jamile M. Shammo. "Lenalidomide-Induced Cytopenias In Patients with MDS Are Negatively Impacted by Reduced Glomerular Filtration Rate." Blood 116, no. 21 (November 19, 2010): 4958. http://dx.doi.org/10.1182/blood.v116.21.4958.4958.
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Abstract Abstract 4958 Background: The myelodsyplastic syndromes (MDS) are a heterogeneous group of hematopoietic stem cell disorders caused by dysplastic cellular proliferation accompanied by chronic peripheral cytopenias. Up to 90% of patients are found to be anemic upon presentation. Treatment with lenalidomide, a renally excreted drug, has been shown to abolish the need for red blood cell (RBC) transfusions in approximately two-thirds of MDS patients who harbor the deletion 5q abnormality. To date, there is no data regarding the degree of myelosuppression in patients with chronic kidney disease (CKD) who are receiving lenalidomide for the treatment of their MDS. Notably, increased myelosuppression related to abnormal glomerular filtration rate (GFR in mL/min) has been reported in myeloma patients on lenalidomide but has yet to be studied in patients with MDS (Niesvizky et al., 2007). We sought to evaluate the extent of cytopenias relative to GFR in patients who received lenalidomide for treatment of their MDS in the setting of the MDS 002/003 trials. Method and Patients: This is a retrospective chart review of patients with RBC transfusion dependent MDS treated with lenalidomide for symptomatic anemia in the setting of the 002/003 MDS trials at our center. All patients had an IPSS of low or intermediate risk-1 and were started on lenalidomide at 10mg daily. Patients were excluded from participation in the studies if their serum creatinine was > 2.5mg/dL. Blood counts prior to therapy and with each dosage change (defined as reduction, held dose or discontinuation) were recorded. Patients were stratified according to GFR <60 and GFR ≥60, with cytopenias related to lenalidomide identified in each group. Results: 31 patients were identified. The median age was 70.5 years. 10 patients were male. 13 patients had normal karyotypes. 16 patients had del5q. 3 patients had other cytogenetic abnormalities. 17 patients were receiving ESAs prior to the study. 9 patients had a GFR of < 60 (including 2 with del5q), and 22 patients had a GFR ≥ 60 (including 13 with del5q). Of the 9 patients with a GFR < 60, 7 patients (78%) had their dose reduced/held for one or more grade 3/4 cytopenias: 5 with neutropenia, 2 with thrombocytopenia, and 1 with anemia. Of the 22 patients with a GFR ≥ 60, 17 (77%) required a dose change with 3 discontinuing lenalidomide. However, only 10 of these 22 patients (45%) required a dose change for one or more grade 3/4 cytopenias: 8 with neutropenia, 7 with thrombocytopenia, and 1 with anemia. Patients with a GFR <60 were maintained on lenalidomide for an average of 15 cycles (range 1 – 30). Patients with GFR ≥ 60 were maintained on lenalidomide for an average of 20 cycles (range 2 – 60 months). Conclusion: The results of this study suggest that patients with CKD have a higher incidence of grade 3/4 myelosuppression when treated with lenalidomide. This effect appears to be greater than expected in those with non-del5q karyotypes and concurrent CKD. These observations require further investigation in a prospective manner. In the interim, consideration for initiating lenalidomide at a lower dose in patients with MDS and decreased renal function may reduce the incidence of myelosuppression, thereby potentially allowing for fewer dose modifications and longer treatment times. Our conclusion is in line with the recently published lenalidomide dose modification recommendations in patients with renal impairment and should prompt clinicians planning to treat MDS patients with lenalidomide to calculate GFR to determine an appropriate starting dose. Disclosures: Gregory: Celgene: Research Funding. Venugopal: Celgene: Speakers Bureau. Shammo: Celgene: Honoraria, Research Funding, Speakers Bureau.
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Bruno, Benedetto, Frank Cirrone, Kelli Cole, Kelsey Stocker, Maher Abdul-Hay, J. Andres Suarez-Londono, Tsivia Hochman, Judith Goldberg, and A. Samer Samer Al-Homsi. "Post-Transplant High Dose Cyclophosphamide and Bortezomib As Graft-Versus-Host Disease Prophylaxis Following Allogeneic Hematopoietic Stem Cell Transplantation." Blood 138, Supplement 1 (November 5, 2021): 3892. http://dx.doi.org/10.1182/blood-2021-151809.
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Abstract Introduction. Prevention of graft-versus-host disease (GvHD) following allogeneic hematopoietic cell transplantation (AHCT) remains a major challenge. The combination of methotrexate (MTX) and a calcineurin inhibitor has been the standard regimen for prophylaxis in patients receiving matched sibling donor (MSD) or matched unrelated donor (MUD) transplants for the past few decades. However, over 50% of patients undergoing AHCT still develop acute or chronic GvHD or even both, causing high rates of morbidity and mortality. Moreover, calcineurin inhibitors also have untoward toxic side effects. High dose post-transplant cyclophosphamide (PTCy), initially introduced for GvHD prevention in the setting of haploidentical transplantation, has now been studied in MSD and MUD transplants. We adopted a novel approach to prevent GvHD using a short course of PTCy and bortezomib. We hypothesized that such combination is safe and effective and omits the need for calcineurin or m-TOR inhibitors. Study Design. We report the outcomes of a prospective cohort of patients who received PTCy and bortezomib for GvHD prevention following MSD or MUD transplants. Twenty-eight patients were treated in a phase I-II trial and their clinical outcomes were previously reported (al-Homsi AS et al, BBMT 2019). Most of the remaining patients were treated on an extension trial. GvHD prevention consisted of PTCy 50 mg/kg IV on day +3 and +4, and bortezomib 1.3mg/m 2 IV 6 hours after transplant and again 72 hours after. Patients receiving MUD transplants also received rabbit ATG (thymoglobulin®) 5mg/kg total IV fractionated on day -4 to -2. All patients received peripheral blood grafts and standard supportive care as per Institutional policy. G-CSF was administered routinely until neutrophil engraftment. Results. Fifty-eight patients are included in this analysis. Median age was 60 (range 22-78) years. Fifty-three percent of patients were male. Underlying malignancies consisted of myeloid and lymphoid malignancies in 79.3% and 20.6%, respectively. Acute myeloid leukemia (50%) and myelodysplastic syndromes (24.1%) were the most common diseases. At transplant, disease risk index was low, intermediate, high and very high in 19.0%, 48.3%, 31.0% and 1.7% of patients, respectively. Median Pretransplant Assessment of Mortality Score (PAM) was 16.7 (5.4-29.4). Grafts were from MSD in 24.1% or MUD in 75.9% of patients. Recipient (R)/Donor (D) CMV status at transplant was as follows: R+/D+: 43%; R+/D-: 21%; R-/D+: 14% and R-/D-: 22%. Conditioning regimens consisted of reduced intensity fludarabine and busulfan in all but 2 patients who were conditioned with myeloablative fludarabine and busulfan. Overall, the regimen was remarkably well tolerated. Median times to neutrophil and platelet engraftment were 16 (13-28) and 26 (15-57) days respectively. No patient experienced primary graft failure. CMV and EBV reactivation rates were 46.6% and 24%. Cumulative incidences of grade II-IV and grade III-IV acute GVHD were 35% (95% CI: 22%-47%) and 15% (95% CI: 7%-25%) at day +120, respectively. Cumulative incidence of chronic GvHD was 14% at 1 year . Overall, 34% of patients required immunosuppression with systemic steroids after day +4 either for grade III-IV acute or chronic GvHD. Disease relapse rate was 26%. One-year cumulative incidence of transplant-related mortality was 14% (95% CI: 6%-25%). Median overall survival was 30.7 (95% CI: 15.7-not yet reached) months. One-year overall survival was 72% (95% CI: 57%-82%). One-year composite GvHD (acute and chronic) free and relapse free survival (GRFS) was 41.6% (95% CI: 28.9%-54%). Conclusion. PTCy and bortezomib combination for GvHD prophylaxis following MSD and MUD transplants is well tolerated and effective. It offers an alternative regimen to calcineurin and m-TOR inhibitor-containing regimens and may be preferred in certain settings including patients with limited resources, poor medication compliance, and with impaired renal function. A comparison of this cohort to a matched control group of patients receiving methotrexate and cyclosporine for GvHD prevention is ongoing. Disclosures Abdul-Hay: Amgen: Membership on an entity's Board of Directors or advisory committees; Servier: Other: Advisory Board, Speakers Bureau; Jazz: Other: Advisory Board, Speakers Bureau; Abbvie: Consultancy; Takeda: Speakers Bureau. Al-Homsi: Celyad: Other: Advisory Board; Daichii Sanyko: Consultancy. OffLabel Disclosure: Cyclophosphamide and Bortezomib are used for GvHD prevention
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Locatelli, Franco, Adrienne Moreno-Madureira, Pierre Teira, Mary Eapen, Mei-Jie Zhang, Stella M. Davies, Alessandra Picardi, et al. "Encoraging Results after Alternative Donor Transplantation for Myelodysplastic Syndrome." Blood 112, no. 11 (November 16, 2008): 1964. http://dx.doi.org/10.1182/blood.v112.11.1964.1964.
Full textAbstract:
Abstract Hematopoietic stem cell transplantation (HSCT) remains the treatment of choice for children with myelodysplastic syndromes (MDS). Umbilical cord blood (UCB) represents an alternative source of hematopoietic stem cells for transplantation in children without a HLA-matched sibling. We examined risk factors influencing outcomes after UCB transplantation (UCBT) in 70 children (40 males and 30 females; median age 7 years, range 0.8–18) with MDS reported to the European Working Group of MDS in Childhood, the Center for International Blood and Marrow Transplant Research or the Eurocord-European Blood and Marrow Transplant Group. Excluded were patients who had received prior autologous/allogeneic HSCT and those with Down syndrome, Fanconi anemia, or MDS that evolved to AML prior to HSCT. Patients had refractory cytopenia (RC, n=31), refractory anemia with excess blasts (RAEB, n=30), and RAEB in transformation (RAEB-t, n=9). All patients received a single UCB unit and myeloablative preparatory regimen. Karyotype analysis (available for 68 of 70 patients) was normal in 22 patients, while the remaining 46 had cytogenetic abnormalities, the most frequent being monosomy 7 (n= 23). In all pairs but one, donor-recipient histocompatibility was determined by serology (low-resolution typing) for HLA-A and -B and allele-level typing for DRB1. UCB units were HLA matched (A, B, DRB1) in 4 cases, 1-locus, 2-loci and 3-loci mismatched in 34, 26 and 5 cases, respectively. The day-60 probability of neutrophil recovery was 76%; in multivariate analysis, transplantation of HLA matched or 1-locus mismatched UCB, irradiation-containing preparatory regimen, cell dose ≥ 6x107/kg (pre-cryopreservation) and monosomy 7 were associated with faster neutrophil recovery. The 100-day probability of grade II-IV acute graft-versus-host disease (GVHD) was 30% (95% CI, 20–41). The 3-year cumulative incidence of chronic GVHD was 23% (95%CI 14–33). Five of 16 patients with chronic GVHD had limited and 11 extensive chronic GVHD. Twenty-nine patients died from transplantation-related complications, the 3-year cumulative incidence of transplantation-related mortality (TRM) was 41% (95% CI 29–52). Three deaths were related to GVHD. In multivariate analysis, TRM was lower when transplants were performed after 2001 (HR 0.41, 95%CI 0.20–0.84, p=0.015). Thirteen patients had recurrent disease and 11 were dead at last follow up. No variable predicted disease recurrence. With a medium follow-up of 39 months (range 10 – 105), the 3-year probability of disease-free survival (DFS) for the entire cohort was 39%; it was 50% when transplantation was performed after 2001 compared to 27% in the earlier period (p=0.02). After 2001, patients received UCB containing higher cell doses and the interval from diagnosis to transplantation was shorter. The 3-year DFS was 61% for the 23 patients with monosomy 7 compared to 30% for patients with other karyotypes (p=0.042). In multivariate analysis, year of transplantation (prior to 2001) and cytogenetic abnormalities other than monosomy 7 were independent risk factors predicting treatment failure, HR 2.38, (95% CI: 1.14–5.0, p=0.02) and HR 2.04,(95% CI: 1.11–3.70, p=0.02), respectively. The 3-year DFS was not influenced by MDS variant. Given the relatively small sample size the influence of MDS variant on transplant-outcome requires validation in a larger series. These data indicate that UCBT is an acceptable alternative in children with MDS without a HLA-matched related or unrelated adult bone marrow donor. The results of UCBT have improved in recent years and monosomy 7 does not confer an unfavourable outcome.