Minimizing risk of hypomethylating agent failure in patients with higher-risk MDS and practical management recommendations

Prébet, Thomas; Fenaux, Pierre; Gattermann, Norbert; Nilsson, Lars; Pfeilstöcker, Michael; Vyas, Paresh; List, Alan F.

doi:10.1016/j.leukres.2014.09.008

Cited by 26 publications

(20 citation statements)

References 74 publications

(86 reference statements)

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“…However, this argument does not discount interrupted courses of therapy such as 5–2-2. Since the benefit of azacitidine has most definitively been demonstrated in RCT using the 7–0-0 schedule, it becomes important to collect efficacy data on the alternative dosing schedules in order to ensure they are at least as equally effective as 7–0-0 [ 7 ]. The objective of the current systematic review is to evaluate the efficacy and tolerability of the 5–0-0, 5–2-2, and 7–0-0 azacitidine dosing regimens in MDS patients.…”

Section: Introductionmentioning

confidence: 99%

Systematic review of azacitidine regimens in myelodysplastic syndrome and acute myeloid leukemia

Shapiro

Lazo‐Langner

2018

BMC Hematol

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Background5-Azacitidine administered as a 7-day dosing regimen (7–0-0) is approved in high risk IPSS myelodysplastic syndrome (MDS) patients. Alternative regimens such as a 5-day (5–0-0) or 7-day with a weekend break (5–2-2) are commonly used. No randomized controlled trial has been done directly comparing all three dosing regimens. The objective of this study was to compare the efficacies of the 5–0-0, 5–2-2, and 7–0-0 regimens in MDS and AML.MethodsA systematic review was conducted using MEDLINE, EMBASE and CENTRAL. Eligible studies were randomized controlled trials (RCTs), observational prospective and retrospective studies. The primary clinical outcomes were Objective Response Rate (ORR) defined as the sum of complete response (CR), partial response (PR), and hematological improvement (HI) as defined by the IWG 2006 criteria. A meta-analysis of simple proportions was conducted using a random effects model with weights defined according to Laird and Mosteller. Comparisons between groups were not attempted due to the heterogeneity of study designs.ResultsThe only RCT directly comparing alternative azacitidine regimens showed no difference in ORR between the 5–0-0 and 5–2-2 regimens. All other RCTs compared a dosing regimen to conventional care. The pooled proportion of ORR was 44.8% with 95% CI (42.8%, 45.5%) for 7–0-0, 41.2% with 95% CI (39.2%, 41.9%) for 5–0-0, and 45.8% with 95% CI (42.6%, 46.4%) for 5–2-2.ConclusionsIndirect comparison of alternative azacitidine dosing regimens in MDS and AML shows a benefit for the 7-day regimen in attaining ORR. Additional RCTs are required to definitively address this comparison.Electronic supplementary materialThe online version of this article (10.1186/s12878-017-0094-8) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

Systematic review of azacitidine regimens in myelodysplastic syndrome and acute myeloid leukemia

Shapiro

Lazo‐Langner

2018

BMC Hematol

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“…The classical response criteria (age, adverse cytogenetic, blast count) may only partially apply to HMA therapy. Several groups have also presented potential candidates as prognostic biomarkers, for example, data on HMA metabolism [18] or methylation profile [18, 95], but large scale validation of the prognostic value and accessibility of the techniques remain issues. The impact of mutational spectrum is also debated, with several groups showing that TET2, or DNMT3A mutated patients may have a higher probability of response [96].…”

Section: Expert Opinionmentioning

confidence: 99%

“…A large number of investigational agents are currently combined with HMA and investigated in clinical trials, but to date none has demonstrated improvements in outcome [16]. Following HMA failure, patients have poor prognosis and limited options [17], and there is no consensus on how to manage this patient population [18]. …”

Section: Introductionmentioning

confidence: 99%

Hypomethylating agents (HMA) treatment for myelodysplastic syndromes: alternatives in the frontline and relapse settings

Singh

Gore

et al. 2017

Expert Opinion on Pharmacotherapy

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Introduction Hypomethylating agents (HMA) have played a pivotal role for treating myelodysplastic syndromes (MDS) over the past decade, inducing sustained hematological responses and delaying progression to leukemia. However, a vast majority of patients will experience treatment failure within 2 years, with poor prognoses and limited options, and management of this growing patient population remains unclear. Areas Covered With the introduction of new agents in the MDS field, a better understanding of the biology of MDS, and updated information on standard of care options (including allogeneic transplantation), we re-evaluate the global treatment strategy in MDS via novel agents, focusing in particular on investigational approaches for patients who fail to respond to HMA when applicable. This review aims to address two questions: what are reasonable alternatives to HMA in MDS, and what strategies can be used for patients experiencing HMA failure. Expert Opinion/Commentary HMA therapy remains a mainstay of treatment, even if additional research is still warranted to maximize its benefits for the different groups of patients. The outcome of patients experiencing HMA failure remains grim, without standard of care, but several new approaches seem promising, as there is an increasing focus on studying treatments for patients refractory to HMA treatment.

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“…[13][14][15][16] Consequently, it is strongly recommended to enroll patients with HMA failure in clinical trials. 17 Allogeneic stem cell transplantation, although potentially curative, is limited to a selected population based on criteria such as age and availability of donors. The availability of transplantation is also dependent on disease control, with a majority of patients requiring cytoreductive treatments prior to transplantation.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of induction chemotherapies after hypomethylating agent failure in myelodysplastic syndromes and acute myeloid leukemia

et al. 2018

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Hypomethylating agent (HMA) failure in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) carries a poor prognosis with limited treatment options. Although intensive, remission induction chemotherapy is often used subsequently, in particular to bridge to allogeneic transplantation, it is not clear whether an advantage exists for any particular regimen. Based on an international collaboration, we retrospectively analyzed induction response rate and survival in 366 patients after HMA failure. Patients received 7+3, intermediate- to high-dose cytarabine (IDAC), or purine nucleoside analog-based regimens. For the MDS cohort (n = 307), the overall response rate (ORR) was 41%; median overall survival (OS) was 10.8 months, and 40% of responding patients bridged to allogeneic stem cell transplant (allo-SCT). For the AML cohort (n = 59), the ORR was 32%, OS 6 months, and 42% of responding patients bridged to allo-SCT. Prognostic factors for response in MDS included adverse cytogenetics (odds ratio [OR], 0.46, = .01), age ≥65 years (OR, 0.47; < .01), and use of IDAC (OR, 2.91, = .01). Shorter survival was associated with adverse cytogenetics (hazard ratio [HR], 1.43; = .06). In the AML cohort, OS was decreased by disease progression at time of HMA failure (HR, 2.66; = .02) and prolonged with use of an anthracycline-containing regimen (HR, 0.37; = .01). In conclusion, intensive chemotherapy after HMA failure may be a reasonable treatment option for selected patients as a bridge to allogeneic transplantation and should be considered a potential platform for future investigations.

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Minimizing risk of hypomethylating agent failure in patients with higher-risk MDS and practical management recommendations

Cited by 26 publications

References 74 publications

Systematic review of azacitidine regimens in myelodysplastic syndrome and acute myeloid leukemia

Systematic review of azacitidine regimens in myelodysplastic syndrome and acute myeloid leukemia

Hypomethylating agents (HMA) treatment for myelodysplastic syndromes: alternatives in the frontline and relapse settings

Evaluation of induction chemotherapies after hypomethylating agent failure in myelodysplastic syndromes and acute myeloid leukemia

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