In:
Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 80-80
Abstract:
Abstract 80 Background: Mutations in the nucleophosmin-1 gene (NPM1) are the most common genetic abnormalities in acute myeloid leukemia (AML) and define a provisional AML entity in the current WHO classification. In a retrospective biomarker study within a randomized trial of older patients with AML, we demonstrated that patients with mutated NPM1 and absence of a FLT3 internal tandem duplication (ITD) benefit from all-trans retinoic acid (ATRA) as adjunct to conventional chemotherapy (Schlenk et al. Haematologica 2009;94:54–69). Aims: To evaluate the impact of ATRA in combination with conventional chemotherapy on outcome, and to assess the NPM1 mutational status as predictive marker for response to this therapy in younger adult patients with AML entered in the prospective randomized controlled treatment trial AMLSG 07-04 (ClinicalTrials.gov Identifier: NCT00151242). Methods: Patients (18 to 60 years of age) were accrued between August 2004 and August 2009. They were randomized up-front for open-label treatment with ATRA. Induction therapy consisted of two cycles of ICE (idarubicin 12mg/m2, day 1,3,5 [in induction II reduced to d 1, 3]; cytarabine 100mg/m2 continuous i.v., day 1 to 7; etoposide 100mg/m2, day 1–3). For consolidation therapy, patients with high-risk AML, defined either by high-risk cytogenetics or induction failure, were assigned to receive allogeneic hematopoietic stem cell transplantation (HSCT) from a matched related (MRD) or unrelated donor (MUD). Starting from November 2006, AML with FLT3-ITD was also categorized as high-risk. All other patients were assigned to 3 cycles of high-dose cytarabine (HiDAC; 18g/m2 per cycle). In all but patients with core-binding-factor AML an allogeneic HSCT was intended when a MRD was available. During induction cycles, ATRA was given in a dosage of 45mg/m2 from day 6 to 8, and 15mg/m2 from day 9 to 21; and during HiDAC cycles in a dosage of 15mg/m2 from day 6 to 28. The primary end points of the study were event-free survival (EFS) and rate of complete remission (CR) after induction therapy; secondary end points were, relapse-free (RFS) and overall survival (OS). For survival analyses, patients receiving an allogeneic HSCT in first CR were censored at the date of transplantation. Forty patients were treated either with or without ATRA despite being randomized in the opposite treatment arm; predictive marker analyses were performed on a per protocol basis excluding those patients. Results: A total of 1112 patients were randomized, 562 (per protocol 542) in the standard arm, and 550 (per protocol 530) in the investigational arm with ATRA. Median follow-up was 3.3 years. NPM1 mutational status was assessed in 1018 patients (92%) and a mutation was identified in 289 (28%) patients. Pretreatment patient characteristics at diagnosis were well balanced between the standard and the ATRA-arm of the study, except for higher white blood counts (WBC) in the standard arm (median, 16.1/nl vs. 8.9/nl, p=0.001). The CR-rate was significantly increased in NPM1-mutated AML by ATRA (OR, 2.20; p=0.05), independent of the FLT3-ITD status (OR, 0.66; p=0.33); there was no effect of ATRA in NPM1-wild-type AML (OR, 1.00; p=0.99). Multivariable analyses on EFS revealed a significant risk reduction in NPM1-mutated AML by ATRA (hazard ratio [HR], 0.65; p=0.02), whereas there was no effect of ATRA in NPM1-wild-type AML (HR, 0.99; p=0.95). Other significant factors in NPM1-mutated AML were IDH1R132 mutation (HR, 1.72; p=0.04), IDH2R140 mutation (HR,1.73; p=0.03), FLT3-ITD (HR, 1.55; p=0.04), log-transformed WBC (HR, 1.47; p=0.03), and in NPM1-wild-type AML IDH2R172 mutation (HR,1.82; p=0.03), FLT3-ITD (HR, 1.56; p=0.002), logarithm of WBC (HR, 1.20; p=0.02), male gender (HR, 1.34; p=0.003), cytogenetic risk (p 〈 0.001; HR (high-risk vs intermediate risk), 2.18; HR (low-risk vs intermediate risk) 0.31). ATRA had no influence on the cumulative incidence of relapse. OS of patients treated with ATRA (n=549) was significantly better (p=0.02) compared with that of patients not treated with ATRA (n=562). Rates and severity of toxicities were similar in both treatment arms. Conclusions: ATRA in addition to conventional chemotherapy significantly improved response to induction therapy and EFS in NPM1 mutated-AML, as well as OS in the whole cohort of younger adult patients with AML. NPM1 mutation was confirmed as a predictive factor for response to this combination therapy. Disclosures: Schlenk: Roche GmbH: Research Funding; Amgen GmbH: Research Funding; Pfizer GmbH: Research Funding. Krauter:Novartis: Consultancy, Honoraria. Kuendgen:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Fiedler:Pfizer: Research Funding.
Type of Medium:
Online Resource
ISSN:
0006-4971
,
1528-0020
DOI:
10.1182/blood.V118.21.80.80
Language:
English
Publisher:
American Society of Hematology
Publication Date:
2011
detail.hit.zdb_id:
1468538-3
detail.hit.zdb_id:
80069-7
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