Maintenance therapy with low-dose azacitidine after allogeneic hematopoietic stem cell transplantation for recurrent acute myelogenous leukemia or myelodysplastic syndrome: a dose and schedule finding study.
BACKGROUND
Recurrence is a major cause of treatment failure after allogeneic transplantation for acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS), and treatment options are very limited. Azacitidine is a DNA methyltransferase inhibitor with activity in myeloid disease. The authors hypothesized that low-dose azacitidine administered after transplant would reduce recurrence rates, and conducted a study to determine a safe dose/schedule combination.


METHODS
Forty-five high-risk patients were treated. Median age was 60 years; median number of comorbidities was 3; 67% were not in remission. By using a Bayesian adaptive method to determine the best dose/schedule combination based on time to toxicity, the authors investigated combinations of 5 daily azacitidine doses, 8, 16, 24, 32, and 40 mg/m2, and 4 schedules: 1, 2, 3, or 4 cycles, each with 5 days of drug and 25 days of rest. Cycle 1 started on Day +40.


RESULTS
Reversible thrombocytopenia was the dose-limiting toxicity. The optimal combination was 32 mg/m2 given for 4 cycles. Median follow-up was 20.5 months. One-year event-free and overall survival were 58% and 77%, justifying further studies to estimate long-term clinical benefit. No dose significantly affected DNA global methylation.


CONCLUSIONS
Azacitidine at 32 mg/m2 given for 5 days is safe and can be administered after allogeneic transplant for at least 4 cycles to heavily pretreated AML/MDS patients. The trial also suggested that this treatment may prolong event-free and overall survival, and that more cycles may be associated with greater benefit.
de Lima
Marcos
M
Department of Stem Cell Transplantation and Cell Therapy, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA. mdelima@mdanderson.org
Giralt
Sergio
S
Thall
Peter F
PF
de Padua Silva
Leandro
L
Jones
Roy B
RB
Komanduri
Krishna
K
Braun
Thomas M
TM
Nguyen
Hoang Q
HQ
Champlin
Richard
R
Garcia-Manero
Guillermo
G
D000328:Adult; D000368:Aged; D001374:Azacitidine / Q000008:administration & dosage* / Q000009:adverse effects; D019175:DNA Methylation; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D005260:Female; D006086:Graft vs Host Disease / Q000453:epidemiology; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics / Q000601:surgery*; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000188:drug therapy* / Q000235:genetics / Q000601:surgery*; D012008:Recurrence; D014184:Transplantation, Homologous
D001374:Azacitidine