Addition of All-Trans Retinoic Acid (ATRA) to the Combination of Fludarabine, Cytarabine, Idarubicin, with or without GCSF in Older, Higher Risk Patients with AML and High-Risk MDS Does Not Improve the Outcome in Those with NPM1 Mutation.

Previous studies have been conflicting in their findings regarding whether NPM1 gene mutations may be a marker for response to all-trans retinoic acid (ATRA) given as an adjunct to intensive chemotherapy in patients with acute myeloid leukemia (AML) (Schlenk RF, Haematologica, 2009, 94, 54–60, Burnett AK, Blood, 2010, 115,948, and Schlenk RF, abstract #80, ASH 2011).

we examined the impact of the addition of ATRA among patients with diploid cytogenetics treated on a randomized phase II study of fludarabine + cytarabine + idarubicine +/− GCSF +/− ATRA with available data on their NPM1 mutation status. Between September 1995 and November 1997, 215 patients with newly diagnosed AML (n=153) or high-risk MDS (RAEB or RAEB-T; n=62) were enrolled in the study. They had to have one of the unfavorable features of age > 71 years, antecedent hematological disorder (AHD), therapy- related disease, or high bilirubin (>2.9 mg/ml) or creatinine (>1.5 mg/ml) to be eligible to participate in the study (Estey E, Blood, 1999, 93, 2478). Among them 70 patients had diploid cytogenetic and are the subjects of this analysis.

The median age of the 70 patients was 66.5 (range, 23–87), 60% had AHD, 15.7% had therapy-related disease, and 40% were older than 71. Bone marrow samples were available for all patients for examination by immunohistochemistry (IHC) for the presence of cytoplasmic NPM (correlating to NPM1 mutation). Twenty (29%) of patients had NPM1 mutation. Among them 7 (35%) did and 13 (65%) did not receive ATRA in combination with chemotherapy. Complete remission (CR) was achieved in 5 (71.4%) of patients treated with ATRA as compared to 9 (69.2%) without ATRA (p=NS). The median event-free survival was 82 weeks vs. 56 weeks for patients receiving ATRA or not [(p=0.5), ranges, (10–173 weeks) and (1–646 weeks), respectively]. The median overall survival was 41 weeks vs. 60 weeks for patients receiving ATRA or not [(p=0.74), ranges, (3–452 weeks) and (0–735 weeks), respectively].

There was no significant difference in CR rate, EFS, or OS in this higher risk population of patients with NPM1 mutated diploid AML or high-risk MDS receiving ATRA as an adjunct to chemotherapy.

Kantarjian:Genzyme: Research Funding. Ravandi:genzyme: Research Funding.