Targeting epigenetic pathways in acute myeloid leukemia and myelodysplastic syndrome: a systematic review of hypomethylating agents trials.
BACKGROUND
Aberrant DNA methylation has been identified as a key molecular event regulating the pathogenesis of myelodysplastic syndromes (MDS); myeloid neoplasms with an inherent risk of transformation to acute myeloid leukemia (AML). Based on the above findings, DNA hypomethylating agents (HMA) have been widely used to treat AML and MDS, especially in elderly patients and in those who are not eligible for allogeneic stem cell transplantation (SCT). Our goal was to determine if there is any therapeutic advantage of HMA vs. conventional care regimens (CCR) and indirectly compare the efficacy of azacitidine and decitabine in this patient population.


METHODS
Eligible studies were limited to randomized controlled trials comparing HMA to CCR in adult patients with AML or MDS.


RESULTS
Overall survival (OS) rate was 33.2 vs. 21.4 % (RR 0.83, 95 % CI 0.71-0.98) and overall response rate (ORR) 23.7 vs. 13.4 % (RR 0.87, 95 % CI 0.81-0.93) for HMA and CCR, respectively. In subgroup analyses, only azacitidine treatment showed OS improvement (RR 0.75, 95 % CI 0.64-0.98) and not decitabine. Cytogenetic risk or bone marrow blast count did not have independent prognostic impact.


CONCLUSIONS
Collectively, these results demonstrate that HMA have superior outcomes compared to CCR and suggest that azacitidine in comparison to decitabine, may be more effective.
Department of Medicine, University of Arizona, 1501 N. Campbell Ave., Tucson, AZ 85721 USA ; Hematology and Oncology, H. Lee Moffitt Cancer Center, Tampa, FL 12902 USA.
Seongseok
S
Yun
Molecular Pharmacology and Experimental Therapeutics, Department of Medicine, Mayo Clinic, Rochester, MN 55905 USA.
Nicole D
ND
Vincelette
Center for Health Outcomes and PharmacoEconomic Research, University of Arizona, Tucson, AZ 85721 USA ; Arizona Cancer Center, University of Arizona, Tucson, AZ 85721 USA.
Ivo
I
Abraham
Pharmacology, Department of Medicine, Mayo Clinic, Rochester, MN 55905 USA.
Keith D
KD
Robertson
Schulze Center for Novel Therapeutics, Department of Medicine, Mayo Clinic, Rochester, MN 55905 USA.
Martin E
ME
Fernandez-Zapico
Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN 55905 USA.
Mrinal M
MM
Patnaik
D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology* / Q000627:therapeutic use; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D019175:DNA Methylation / Q000187:drug effects*; D000077209:Decitabine; D044127:Epigenesis, Genetic / Q000187:drug effects*; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D009190:Myelodysplastic Syndromes / Q000188:drug therapy* / Q000235:genetics; D011379:Prognosis; D016032:Randomized Controlled Trials as Topic; D015996:Survival Rate; D016896:Treatment Outcome
D000964:Antimetabolites, Antineoplastic; D000077209:Decitabine; D001374:Azacitidine
AML; DNA hypomethylating agents; Epigenetics; MDS