| 1. |
- Dickinson, Michael, et al.
(författare)
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Azacitidine with or without eltrombopag for first-line treatment of intermediate- or high-risk MDS with thrombocytopenia
- 2018
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Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 132:25, s. 2629-2638
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Tidskriftsartikel (refereegranskat)abstract
- Azacitidine treatment of myelodysplastic syndromes (MDSs) generally exacerbates thrombocytopenia during the first treatment cycles. A Study of Eltrombopag in Myelodysplastic Syndromes Receiving Azacitidine (SUPPORT), a phase 3, randomized, double-blind, placebo-controlled study, investigated the platelet supportive effects of eltrombopag given concomitantly with azacitidine. International Prognostic Scoring System intermediate-1, intermediate-2, or high-risk MDS patients with baseline platelets <75 3 10(9)/L were randomized 1: 1 to eltrombopag (start, 200 mg/d [East Asians, 100 mg/d], maximum, 300 mg/d [East Asians, 150 mg/d]) or placebo, plus azacitidine (75 mg/m2 subcutaneously once daily for 7 days every 28 days). The primary end point was the proportion of patients platelet transfusion-free during cycles 1 through 4 of azacitidine therapy. Based on planned interim analyses, an independent data monitoring committee recommended stopping the study prematurely because efficacy outcomes crossed the predefined futility threshold and for safety reasons. At termination, 28/179 (16%) eltrombopag and 55/177 (31%) placebo patients met the primary end point. Overall response (International Working Group criteria; complete, marrow, or partial response) occurred in 20% and 35% of eltrombopag and placebo patients, respectively, by investigator assessment. There was no difference in hematologic improvement in any cell lineage between the 2 arms. There was no improvement in overall or progression-free survival. Adverse events with >= 10% occurrence in the eltrombopag vs placebo arm were febrile neutropenia and diarrhea. Compared with azacitidine alone, eltrombopag plus azacitidine worsened platelet recovery, with lower response rates and a trend toward increased progression to acute myeloid leukemia. This trial was registered at www.clinicaltrials.govas# NCT02158936.
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| 2. |
- Giagounidis, Aristoteles, et al.
(författare)
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Outcomes in RBC transfusion-dependent patients with Low-/Intermediate-1-risk myelodysplastic syndromes with isolated deletion 5q treated with lenalidomide: a subset analysis from the MDS-004 study
- 2014
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Ingår i: European Journal of Haematology. - : Wiley. - 1600-0609 .- 0902-4441. ; 93:5, s. 429-438
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Tidskriftsartikel (refereegranskat)abstract
- ObjectiveA subset analysis of the randomised, phase 3, MDS-004 study to evaluate outcomes in patients with International Prognostic Scoring System (IPSS)-defined Low-/Intermediate (Int)-1-risk myelodysplastic syndromes (MDS) with isolated del(5q). MethodsPatients received lenalidomide 10mg/d (days 1-21; n=47) or 5mg/d (days 1-28; n=43) on 28-d cycles or placebo (n=45). From the placebo and lenalidomide 5mg groups, 84% and 58% of patients, respectively, crossed over to lenalidomide 5 or 10mg at 16wk, respectively. ResultsRates of red blood cell-transfusion independence (RBC-TI) 182d were higher in the lenalidomide 10mg (57.4%; P<0.0001) and 5mg (37.2%; P=0.0001) groups vs. placebo (2.2%). Cytogenetic response rates (major+minor responses) were 56.8% (P<0.0001), 23.1% (P=0.0299) and 0%, respectively. Two-year cumulative risk of acute myeloid leukaemia progression was 12.6%, 17.4% and 16.7% in the lenalidomide 10mg, 5mg, and placebo groups, respectively. In a 6-month landmark analysis, overall survival was longer in lenalidomide-treated patients with RBC-TI 182d vs. non-responders (P=0.0072). The most common grade 3-4 adverse event was myelosuppression. ConclusionsThese data support the clinical benefits and acceptable safety profile of lenalidomide in transfusion-dependent patients with IPSS-defined Low-/Int-1-risk MDS with isolated del(5q).
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| 3. |
- Marques Ramos, Pedro, et al.
(författare)
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Next-generation sequencing of baseline genetic mutations and outcomes of eltrombopag and azacitidine therapy in patients with myelodysplastic syndromes and thrombocytopenia : Data from the SUPPORT clinical trial
- 2023
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Ingår i: eJHaem. - : John Wiley & Sons. - 2688-6146. ; 4:3, s. 876-881
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Tidskriftsartikel (refereegranskat)abstract
- Eltrombopag has been previously shown to be effective in reversing azacitidine-mediated thrombocytopenia. This was further investigated in the SUPPORT trial, a phase III study assessing the efficacy/safety of eltrombopag plus azacitidine in patients with intermediate- to high-risk myelodysplastic syndromes and thrombocytopenia. The results did not support a clinical benefit for the addition of eltrombopag to azacitidine. We investigated if the somatic mutational profiles in the patient cohort were associated with treatment outcomes. Based on the available data, we observed no imbalance in the mutational profiles between treatment arms or a clear association between identified somatic mutations and clinical outcomes.
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| 4. |
- Winter, Susann, et al.
(författare)
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Integrating the "Immunome" in the Stratification of Myelodysplastic Syndromes and Future Clinical Trial Design
- 2020
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Ingår i: Journal of Clinical Oncology. - : American Society of Clinical Oncology (ASCO). - 0732-183X .- 1527-7755. ; 38:15, s. 1723-
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Forskningsöversikt (refereegranskat)abstract
- Myelodysplastic syndromes (MDS) are characterized by ineffective hematopoiesis and often include a dysregulation and dysfunction of the immune system. In the context of population aging, MDS incidence is set to increase substantially, with exponential increases in health care costs, given the limited and expensive treatment options for these patients. Treatment selection is mainly based on calculated risk categories according to a Revised International Prognostic Scoring System (IPSS-R). However, although IPSS-R is an excellent predictor of disease progression, it is an ineffective predictor of response to disease-modifying therapies. Redressing these unmet needs, the "immunome" is a key, multifaceted component in the initiation and overall response against malignant cells in MDS, and the current omission of immune status monitoring may in part explain the insufficiencies of current prognostic stratification methods. Nevertheless, integrating these and other recent molecular advances into clinical practice proves difficult. This review highlights the complexity of immune dysregulation in MDS pathophysiology and the fine balance between smoldering inflammation, adaptive immunity, and somatic mutations in promoting or suppressing malignant clones. We review the existing knowledge and discuss how state-of-the-art immune monitoring strategies could potentially permit novel patient substratification, thereby empowering practical predictions of response to treatment in MDS. We propose novel multicenter studies, which are needed to achieve this goal.
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