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Myelodysplasia syndrome clinical trials

Edward Li, Ernesto Lobaina
BACKGROUND: The FDA's extrapolation framework allows for a biosimilar to obtain licensure for indications that were not explicitly studied in the context of a clinical trial by extending conclusions from studies in 1 population to make inferences in other populations. Within routine clinical care, drugs and biologics are routinely used for medically accepted off-label indications. The appropriateness of these products for off-label indications are typically curated by compendia and guidelines, which have established processes and criteria for reviewing and evaluating the evidence to make such determinations...
December 2017: Journal of Managed Care & Specialty Pharmacy
Valerie D Roobrouck, Esther Wolfs, Michel Delforge, Dorien Broekaert, Soumen Chakraborty, Kathleen Sels, Thomas Vanwelden, Bryan Holvoet, Larissa Lhoest, Satish Khurana, Shubham Pandey, Chloé Hoornaert, Peter Ponsaerts, Tom Struys, Nancy Boeckx, Peter Vandenberghe, Christophe M Deroose, Catherine M Verfaillie
BACKGROUND AIMS: Myelodysplastic syndromes (MDS) are a group of clonal stem cell disorders affecting the normal hematopoietic differentiation process and leading to abnormal maturation and differentiation of all blood cell lineages. Treatment options are limited, and there is an unmet medical need for effective therapies for patients with severe cytopenias. METHODS: We demonstrate that multipotent adult progenitor cells (MAPC) improve the function of hematopoietic progenitors derived from human MDS bone marrow (BM) by significantly increasing the frequency of primitive progenitors as well as the number of myeloid colonies...
June 2017: Cytotherapy
Ioannis Koutsavlis
Hemoglobin thresholds and triggers for blood transfusions have changed over the years moving from a higher to a lower level. This review article summarizes the current evidence of transfusion thresholds in the hospitalized as well as in the outpatient setting and particularly in myelodysplasia. Fatigue is the main reported symptom in this group of patients and current clinical trials are looking for a more liberal approach of red cell transfusion and the effect on quality of life as opposed to the restrictive strategy used in the critical care setting...
2016: Anemia
Theresa Hahn, Lara E Sucheston-Campbell, Leah Preus, Xiaochun Zhu, John A Hansen, Paul J Martin, Li Yan, Song Liu, Stephen Spellman, David Tritchler, Alyssa Clay, Kenan Onel, Marcelo Pasquini, Philip L McCarthy
Clinical trials commonly use adjudication committees to refine endpoints, but observational research or genome-wide association studies rarely do. Our goals were to establish definitions of cause-specific death after unrelated-donor allogeneic hematopoietic cell transplantation (URD-HCT), to estimate discordance between reported and adjudicated cause-specific death, and to identify factors contributing to inconsistency in cause-specific death determination. A consensus panel adjudicated cause-specific death in 1484 patients who died within 1 year after HCT, derived from 3532 acute leukemia or myelodysplasia patients after URD-HCT from 2000 to 2011 reported by 151 US transplant centers to the Center for International Blood and Marrow Transplant Research...
September 2015: Biology of Blood and Marrow Transplantation
Thomas Prebet, Zhuoxin Sun, Maria E Figueroa, Rhett Ketterling, Ari Melnick, Peter L Greenberg, James Herman, Mark Juckett, Mitchell R Smith, Lisa Malick, Elisabeth Paietta, Magdalena Czader, Mark Litzow, Janice Gabrilove, Harry P Erba, Steven D Gore, Martin S Tallman
PURPOSE: Although azacitidine (AZA) improves survival in patients with high-risk myelodysplastic syndrome, the overall response remains approximately 50%. Entinostat is a histone deacetylase inhibitor that has been combined with AZA with significant clinical activity in a previous phase I dose finding study. DESIGN: Open label phase II randomized trial comparing AZA 50 mg/m(2)/d given for 10 days ± entinostat 4 mg/m(2)/d day 3 and day 10. All subtypes of myelodysplasia, chronic myelomonocytic leukemia, and acute myeloid leukemia with myelodysplasia-related changes were eligible for the study...
April 20, 2014: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
Pierre Fenaux, John F Seymour, Valeria Santini, Lew Silverman, Steven Gore, Alan List, Guillermo Sanz, Ghulam J Mufti, Eli Estey, Arlene S Swern, C L Beach, Eva Hellstrom-Lindberg
For cancers lacking standard treatments, comparing new agents with existing treatments is problematic. Here we discuss the study design from the AZA-001 trial, which compared azacitidine with 3 frequently used conventional care regimens (CCR) for higher-risk myelodysplastic syndromes. Before randomization, physicians preselected the most appropriate of 3 CCR for each patient, after thorough examination. Patients were then randomized to azacitidine or CCR. Patients randomized to CCR received their preselected treatment, thus including patients otherwise excluded as poor candidates for a single comparator...
February 2014: Leukemia Research
Mario Cazzola, Matteo G Della Porta, Luca Malcovati
Myelodysplasia is a diagnostic feature of myelodysplastic syndromes (MDSs) but is also found in other myeloid neoplasms. Its molecular basis has been recently elucidated by means of massive parallel sequencing studies. About 90% of MDS patients carry ≥1 oncogenic mutations, and two thirds of them are found in individuals with a normal karyotype. Driver mutant genes include those of RNA splicing (SF3B1, SRSF2, U2AF1, and ZRSR2), DNA methylation (TET2, DNMT3A, and IDH1/2), chromatin modification (ASXL1 and EZH2), transcription regulation (RUNX1), DNA repair (TP53), signal transduction (CBL, NRAS, and KRAS), and cohesin complex (STAG2)...
December 12, 2013: Blood
Lise J Estcourt, Deborah Pinchon, Emily Symington, Anne M Kelly, Carolyn Doree, Susan Brunskill, Liz Glidewell, Simon Stanworth
BACKGROUND: Relatively minor bleeding (e.g., bruising and/or petechiae) may cause patient distress. This systematic review's objective was to assess whether bleeding affects health-related quality of life (HRQoL) or illness perceptions or representations (IPs) in patients with hematologic malignancies or myelodysplasia (MDS). STUDY DESIGN AND METHODS: We searched, in full, 12 electronic databases (including CENTRAL, MEDLINE, and EMBASE) up to January 7, 2013, for eligible randomized controlled trials (RCTs), prospective cohort studies, and cross-sectional studies...
April 2014: Transfusion
E H Estey
Randomized trials have clearly demonstrated that the hypomethylating agents azacitidine and decitabine are more effective than 'best supportive care'(BSC) in reducing transfusion frequency in 'low-risk' myelodysplasia (MDS) and in prolonging survival compared with BSC or low-dose ara-C in 'high-risk' MDS or acute myeloid leukemia (AML) with 21-30% blasts. They also appear equivalent to conventional induction chemotherapy in AML with >20% blasts and as conditioning regimens before allogeneic transplant (hematopoietic cell transplant, HCT) in MDS...
September 2013: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Karen Seiter
The myelodysplastic syndromes (MDS) are a group of clonal hematopoietic disorders characterized by bone marrow failure and a risk of progression to acute myelogenous leukemia (AML). A precise diagnosis is critical, because there is overlap between the clinical and laboratory findings of MDS and other malignant and nonmalignant hematologic disorders. Several prognostic scoring systems (IPSS, WPSS, LR-PSS, and IPSS-R) assess a patient's risk of progression to AML and overall survival. Many patients are elderly, so age and comorbidities are an important consideration...
June 2013: Current Treatment Options in Oncology
Sara Galimberti, Francesca Guerrini, Flavia Salvi, Iacopo Petrini, Daniela Gioia, Emanuela Messa, Giuseppe A Palumbo, Daniela Cilloni, Mario Petrini, Alessandro Levis
BACKGROUND: Arsenic Trioxide (ATO) is effective in about 20% of patients with myelodysplasia (MDS); its mechanisms of action have already been evaluated in vitro, but the in vivo activity is still not fully understood. Since ATO induces apoptosis in in vitro models, we compared the expression of 93 apoptotic genes in patients' bone marrow before and after ATO treatment. For this analysis, we selected 12 patients affected by MDS who received ATO in combination with Ascorbic Acid in the context of the Italian clinical trial NCT00803530, EudracT Number 2005-001321-28...
September 10, 2012: Journal of Hematology & Oncology
Joachim M Baehring, Peter W Marks
Treatment-related myelodysplastic syndrome (t-MDS) and treatment-related acute myelogenous leukemia (t-AML) represent rare secondary events in patients with primary tumors of the nervous system and predominantly affect those treated with alkylating agents or topoisomerase II inhibitors. Temozolomide has become the standard chemotherapeutic agent for malignant gliomas. The emergence of this alkylating agent with little acute toxicity or cumulative myelosuppression has led to off-label protracted chemotherapy for many patients with malignant and even low-grade infiltrative gliomas, raising concern for increased risk of t-MDS/t-AML in the few long-term survivors...
May 2012: Neuro-oncology
(no author information available yet)
Some myelodysplastic syndromes carry a poor prognosis. This is also the case for chronic myelomonocytic leukaemia (related to myelodysplastic syndromes), and acute myeloblastic leukaemia, a frequent complication of myelodysplasia. The only treatment capable of providing long-term remission (in about 1 in 2 patients on average) is haematopoietic stem cell transplantation, but this burdensome treatment can only be used in a minority of cases. Azacitidine (Vidaza, Celgene), an agent that blocks DNA synthesis, is the first drug to receive EU marketing authorisation in these settings...
February 2011: Prescrire International
George Dranitsaris, Haytham Khoury
INTRODUCTION: Invasive fungal infections (IFI) remain a clinical concern in hematological patients with prolonged neutropenia because they are a major cause of morbidity and mortality. In a recent randomized trial, prophylaxis with posaconazole was associated with fewer IFI and related deaths relative to a fluconazole or itraconazole (Flu/Itra) control group (p < 0.001). In the current study, a cost effectiveness analysis was conducted to estimate the economic value of posaconazole as an alternative to Flu/Itra when used to prevent IFI in this patient population...
November 2011: Supportive Care in Cancer: Official Journal of the Multinational Association of Supportive Care in Cancer
Bob Löwenberg, Gareth Morgan, Gert J Ossenkoppele, Alan K Burnett, Pierre Zachée, Ulrich Dührsen, Daan Dierickx, Carsten Müller-Tidow, Pieter Sonneveld, Utz Krug, Elisabeth Bone, Nicolas Flores, Alison F Richardson, Leon Hooftman, Chris Jenkins, Sonja Zweegman, Faith Davies
PURPOSE: To identify the maximum-tolerated dose (MTD) and to evaluate the antileukemic activity of tosedostat (formerly CHR-2797), an orally bioavailable aminopeptidase inhibitor. PATIENTS AND METHODS: In phase I, the MTD of once daily oral doses of tosedostat in hematologic malignancies was defined. In phase II, the therapeutic activity of the maximum-acceptable dose (MAD) of tosedostat was evaluated in elderly and/or relapsing patients with acute myeloid leukemia (AML) or myelodysplastic syndrome...
October 1, 2010: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
Vincent T Ho, Matthew Vanneman, Haesook Kim, Tetsuro Sasada, Yoon Joong Kang, Mildred Pasek, Corey Cutler, John Koreth, Edwin Alyea, Stefanie Sarantopoulos, Joseph H Antin, Jerome Ritz, Christine Canning, Jeffery Kutok, Martin C Mihm, Glenn Dranoff, Robert Soiffer
Through an immune-mediated graft-versus-leukemia effect, allogeneic hematopoietic stem cell transplantation (HSCT) affords durable clinical benefits for many patients with hematologic malignancies. Nonetheless, subjects with high-risk acute myeloid leukemia or advanced myelodysplasia often relapse, underscoring the need to intensify tumor immunity within this cohort. In preclinical models, allogeneic HSCT followed by vaccination with irradiated tumor cells engineered to secrete GM-CSF generates a potent antitumor effect without exacerbating the toxicities of graft-versus-host disease (GVHD)...
September 15, 2009: Proceedings of the National Academy of Sciences of the United States of America
Arthur Frankel, Jen-Sing Liu, David Rizzieri, Donna Hogge
DT(388)IL3 fusion protein containing the catalytic and translocation domains of diphtheria toxin fused to human interleukin 3 was administered in an inter-patient dose escalation trial by 15 min i.v. infusions every other day for up to 6 doses to patients with chemo-refractory acute myeloid leukemia (AML) and myelodysplasia (MDS). The maximal tolerated dose was >12.5 microg/kg/dose. Transient grade 3 transaminasemia and grade 2 fevers, chills, hypoalbuminemia, and hypotension occurred. Peak DT(388)IL3 levels correlated with dose and day of administration but not antibody titer...
March 2008: Leukemia & Lymphoma
Charikleia Kelaidi, Virginie Eclache, Pierre Fenaux
Defined by isolated del 5q and no excess of marrow blasts, the '5q- syndrome' is a specific type of myelodysplastic syndrome (MDS) with particular characteristics, including severe anaemia, frequent thrombocytosis, typical dysmegakaryopoiesis and favourable outcome. Its pathogenesis remains uncertain, particularly regarding the role of the inactivation of gene(s) situated in 5q. Until the advent of lenalidomide, repeated red blood cell (RBC) transfusions were generally the only treatment for 5q- syndrome, which was resistant to other therapeutic approaches...
February 2008: British Journal of Haematology
Elaine M Sloand, Katayoun Rezvani
Patients with myelodysplastic syndrome (MDS) have intrinsic, usually acquired genetic defects in their hematopoietic stem cells, but some others exhibit T-cell-mediated inhibition of hematopoiesis and good responses to immunosuppression. In these cases, MDS shares a similar pathophysiology with aplastic anemia (AA). Here, we review the evidence supporting a role of the immune system in the pathophysiology of MDS and the results of clinical trials of immunosuppressive agents.
January 2008: Seminars in Hematology
Charles A Schiffer
The myelodysplastic syndromes (MDS) are a heterogeneous group of hematopoietic disorders. The molecular pathogenesis of the disease is poorly understood and a large number of fundamental biologic questions remain. This heterogeneity presents challenges in selecting therapy for individual patients as well as for evaluating response to treatment. Only a small number of randomized clinical trials have been conducted, although three new drugs (azacitidine, lenalidomide, and decitabine) have been approved for use in the last few years...
March 2007: Best Practice & Research. Clinical Haematology
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