Decitabine improves progression-free survival in older high-risk MDS patients with multiple autosomal monosomies: results of a subgroup analysis of the randomized phase III study 06011 of the EORTC Leukemia Cooperative Group and German MDS Study Group

Lübbert, Michael; Suciu, Stefan; Hagemeijer, Anne; Rüter, Björn; Platzbecker, Uwe; Giagounidis, Aristoteles; Selleslag, Dominik; Labar, Boris; Germing, Ulrich; Salih, Helmut R.; Muus, Petra; Pflüger, Karl-Heinz; Schaefer, Hans-Eckart; Bogatyreva, Lioudmila; Aul, Carlo; Witte, Théo de; Ganser, Arnold; Becker, Heiko; Huls, Gerwin; Helm, L. van der; Vellenga, Edo; Baron, Frédéric; Marie, Jean‐Pierre; Wijermans, Pierre W.

doi:10.1007/s00277-015-2547-0

Cited by 78 publications

(47 citation statements)

References 31 publications

(44 reference statements)

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“…The question of whether MK represents an independent prognostic factor of survival has been a focus of attention with many studies devoted to the subject. MK has been reported as a poor prognostic indicator in the whole patient population [17–20], as well as in patients treated with HMAs [21,22]. However, Valcárcel et al reported that the prognostic value of MK is the result of its strong association with a number of chromosomal abnormalities [23]; our study supports this finding by showing that in the context of CK, MK loses its prognostic significance.…”

Section: Discussionsupporting

confidence: 85%

Prognostic Impact of IPSS-R and Chromosomal Translocations in 751 Korean Patients with Primary Myelodysplastic Syndrome

et al. 2016

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Chromosomal translocations are rare in myelodysplastic syndrome (MDS) and their impact on overall survival (OS) and response to hypomethylating agents (HMA) is unknown. The prognostic impact of the revised International Prognostic Scoring System (IPSS-R) and for chromosomal translocations was assessed in 751 patients from the Korea MDS Registry. IPSS-R effectively discriminated patients according to leukaemia evolution risk and OS. We identified 40 patients (5.3%) carrying translocations, 30 (75%) of whom also fulfilled complex karyotype criteria. Translocation presence was associated with a shorter OS (median, 12.0 versus 79.7 months, P < 0.01). Multivariate analysis demonstrated that translocations (hazard ratio [HR] 1.64 [1.06–2.63]; P = 0.03) as well as age, sex, IPSS-R, and CK were independent predictors of OS. In the IPSS-R high and very high risk subgroup (n = 260), translocations remained independently associated with OS (HR 1.68 [1.06–2.69], P = 0.03) whereas HMA treatment was not associated with improved survival (median OS, 20.9 versus 21.2 months, P = 0.43). However, translocation carriers exhibited enhanced survival following HMA treatment (median 2.1 versus 12.4 months, P = 0.03). Our data suggest that chromosomal translocation is an independent predictor of adverse outcome and has an additional prognostic value in discriminating patients with MDS having higher risk IPSS-R who could benefit from HMA treatment.

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Section: Discussionsupporting

confidence: 85%

Prognostic Impact of IPSS-R and Chromosomal Translocations in 751 Korean Patients with Primary Myelodysplastic Syndrome

et al. 2016

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“…23 Similarly, in patients with higher-risk MDS and monosomal karyotype treated with a hypomethylating agent, the CR rate was low (17%) and overall survival remained short (7 months). 34 The fact that lenalidomide does not act on stem cells but only on progenitors may provide a possible explanation for the early relapses observed despite the achievement of a CR. 35 The postremission strategy with low-intensity chemotherapy combined with lenalidomide that we used was possibly suboptimal in this situation, suggesting that a high or intermediate dose of AraC combined with lenalidomide should be tested.…”

Section: Discussionmentioning

confidence: 99%

Lenalidomide combined with intensive chemotherapy in acute myeloid leukemia and higher-risk myelodysplastic syndrome with 5q deletion. Results of a phase II study by the Groupe Francophone Des Myélodysplasies

et al. 2016

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Patients with acute myeloblastic leukemia or higher risk myelodysplastic syndromes with 5q deletion (generally within a complex karyotype) respond poorly to intensive chemotherapy and have very poor survival. In this population, we evaluated escalating doses of lenalidomide combined with intensive chemotherapy in a phase II study. Treatment consisted of daunorubicin (45 mg/m2/day, days 1–3 in cohort 1, escalated to 60 mg/m2/day, days 1–3 in cohorts 2 and 3) combined with cytosine arabinoside (200 mg/m2/day, days 1–7) and lenalidomide (10 mg/day, days 1–21 in cohorts 1 and 2, escalated to 25 mg/day, days 1–21 in cohort 3). Eighty-two patients with 5q deletion were enrolled, including 62 with acute myeloblastic leukemia, 62/79 (78%) of whom had a complex karyotype (median 7 cytogenetic abnormalities, all but 2 of them monosomal) and three had unknown karyotypes. Thirty-eight patients (46%) achieved complete remission and the overall response rate was 58.5%. Among the 62 patients with a complex karyotype, 27 achieved complete remission (44%) and 21 had cytogenetic responses. A lower response rate was observed in patients with acute myeloblastic leukemia but other pretreatment factors, including cytogenetic complexity and treatment cohort, did not significantly influence response. Fifteen patients underwent allogeneic stem cell transplantation, including 11 patients in first remission. The 1-year cumulative incidence of relapse was 64.6% and the median overall survival was 8.2 months. By comparison with conventional intensive chemotherapy, the treatment protocol we used appeared to produce higher hematologic and cytogenetic complete remission rates in patients with very poor cytogenetics, but response duration was short in this very poor risk population, highlighting the need for better post-induction strategies. Clinical trial registry number: NCT00885508

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“…Decitabine (FDA-approved in 2006 for MDS) is not my first choice in patients with intermediate-2 and high risk MDS mainly due to the lack of a phase 3, randomized-controlled trial showing a clear survival benefit. 27–29 The exact for reason for this is unknown but some have proposed that the current dosing strategies may favor cytotoxic effects over DNMT inhibitory effects, 30 the ideal dose/schedule has not been determined, 31,32 and the fact that decitabine has a different mechanism of action as it only incorporates into DNA, while azacitidine incorporates into both DNA and RNA. 33 Overall, decitabine is thought to have similar rates of progression-free survival and hematologic responses compared with azacitidine in retrospective studies but may be associated with slightly more neutropenic/infectious complications especially in an older patient population.…”

Section: Introductionmentioning

confidence: 99%

Myelodysplastic Syndromes

Dao

2017

Medical Clinics of North America

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Synopsis Myelodysplastic syndrome (MDS) is a heterogeneous, clonal stem cell disorder of the blood and marrow typically diagnosed based on the presence of persistent cytopenia(s), dysplastic cells, and genetic markers. Common issues that arise in the clinical management include difficulty confirming MDS diagnosis, lack of a standard approach with novel agents in MDS, and few prospective long-term, randomized-controlled MDS clinical studies to guide allogeneic blood and marrow transplant. With the recent genetic characterization of MDS, certain aspects of these issues will be better addressed by integrating genetic data into clinical study design and clinical practice.

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Decitabine improves progression-free survival in older high-risk MDS patients with multiple autosomal monosomies: results of a subgroup analysis of the randomized phase III study 06011 of the EORTC Leukemia Cooperative Group and German MDS Study Group

Cited by 78 publications

References 31 publications

Prognostic Impact of IPSS-R and Chromosomal Translocations in 751 Korean Patients with Primary Myelodysplastic Syndrome

Prognostic Impact of IPSS-R and Chromosomal Translocations in 751 Korean Patients with Primary Myelodysplastic Syndrome

Lenalidomide combined with intensive chemotherapy in acute myeloid leukemia and higher-risk myelodysplastic syndrome with 5q deletion. Results of a phase II study by the Groupe Francophone Des Myélodysplasies

Myelodysplastic Syndromes

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