In patients with advanced IDH1-mutated relapsed or refractory AML, ivosidenib at a dose of 500 mg daily was associated with a low frequency of grade 3 or higher treatment-related adverse events and with transfusion independence, durable remissions, and molecular remissions in some patients with complete remission. (Funded by Agios Pharmaceuticals; ClinicalTrials.gov number, NCT02074839 .).

Key Points The presence of a mutation in SRSF2, SF3B1, U2AF1, ZRSR2, ASXL1, EZH2, BCOR, or STAG2 is highly specific for secondary AML. Secondary-type mutations define an s-AML–like disease within t-AML and elderly de novo AML that underlies clinical heterogeneity.

Purpose This study assessed the prognostic impact of postinduction NPM1-mutated ( NPM1m) minimal residual disease (MRD) in young adult patients (age, 18 to 60 years) with acute myeloid leukemia, and addressed the question of whether NPM1m MRD may be used as a predictive factor of allogeneic stem cell transplantation (ASCT) benefit. Patients and Methods Among 229 patients with NPM1m who were treated in the Acute Leukemia French Association 0702 (ALFA-0702) trial, MRD evaluation was available in 152 patients in first remission. Patients with nonfavorable AML according to the European LeukemiaNet (ELN) classification were eligible for ASCT in first remission. Results After induction therapy, patients who did not achieve a 4-log reduction in NPM1m peripheral blood-MRD (PB-MRD) had a higher cumulative incidence of relapse (subhazard ratio [SHR], 5.83; P < .001) and a shorter overall survival (OS; hazard ratio [HR], 10.99; P < .001). In multivariable analysis, an abnormal karyotype, the presence of FLT3-internal tandem duplication (ITD), and a < 4-log reduction in PB-MRD were significantly associated with a higher relapse incidence and shorter OS. In the subset of patients with FLT3-ITD, only age, white blood cell count, and < 4-log reduction in PB-MRD, but not FLT3-ITD allelic ratio, remained of significant prognostic value. In these patients with nonfavorable AML according to European LeukemiaNet, disease-free survival and OS were significantly improved by ASCT in those with a < 4-log reduction in PB-MRD. This benefit was not observed in those with a > 4-log reduction in PB-MRD, with a significant interaction between ASCT effect and PB-MRD response ( P = .024 and .027 for disease-free survival and OS, respectively). Conclusion Our study supports the strong prognostic significance of early NPM1m PB-MRD, independent of the cytogenetic and molecular context. Moreover, NPM1m PB-MRD may be used as a predictive factor for ASCT indication.

and overall survival were 30%, 51%, and 65%, respectively. These 3 end points compared very favorably with results obtained in the pre-imatinib LALA-94 trial. This study confirms the value of the combined approach and encourages prospective trials to define the optimal chemotherapy that has to be combined with imatinib and to carefully reevaluate the place of allogeneic SCT in this new context. (Blood.

Key Points• In adult patients with core binding factor AML, intensified induction is not associated with a better outcome in the context of intensive postremission therapy.• Minimal residual disease, rather than KIT or FLT3 gene mutations, should be used to identify core binding factor AML patients at higher risk of relapse.Not all patients with core binding factor acute myeloid leukemia (CBF-AML) display a good outcome. Modern risk factors include KIT and/or FLT3 gene mutations and minimal residual disease (MRD) levels, but their respective values have never been prospectively assessed. A total of 198 CBF-AML patients were randomized between a reinforced and a standard induction course, followed by 3 high-dose cytarabine consolidation courses. MRD levels were monitored prospectively. Gene mutations were screened at diagnosis. Despite a more rapid MRD decrease after reinforced induction, induction arm did not influence relapse-free survival (RFS) (64% in both arms; P 5 .91). Higher WBC, KIT, and/or FLT3-ITD/TKD gene mutations, and a less than 3-log MRD reduction after first consolidation, were associated with a higher specific hazard of relapse, but MRD remained the sole prognostic factor in multivariate analysis. At 36 months, cumulative incidence of relapse and RFS were 22% vs 54% (P < .001) and 73% vs 44% (P < .001) in patients who achieved 3-log MRD reduction vs the others. These results suggest that MRD, rather than gene mutations, should be used for future treatment stratifications in CBF-AML patients. This trial was registered at EudraCT as #2006-005163-26 and at www. clinicaltrials.gov as #NCT 00428558. (Blood. 2013;121(12):2213-2223

All-trans retinoic acid (ATRA) plus anthracycline chemotherapy is the reference treatment of newly diagnosed acute promyelocytic leukemia (APL), whereas the role of cytosine arabinoside (AraC) remains disputed. We performed a joint analysis of patients younger than 65 years included in Programa para el Estudio de la Terapéutica en Hemopatía Maligna (PETHEMA) LPA 99 trial, where patients received no AraC in addition to ATRA, high cumulative dose idarubicin, and mitoxantrone, and APL 2000 trial, where patients received AraC in addition to ATRA and lower cumulative dose daunorubicin. In patients with white blood cell (WBC) count less than 10 ؋ 10 9 /L, complete remission (CR) rates were similar, but 3-year cumulative incidence of relapse (CIR) was significantly lower in LPA 99 trial: 4.2% versus 14.3% (P ‫؍‬ .03), although 3-year survival was similar in both trials. This suggested that AraC is not required in APL with WBC count less than 10 ؋ 10 9 /L, at least in trials with high-dose anthracycline and maintenance treatment. In patients with WBC of 10 ؋ 10 9 /L or more, however, the CR rate (95.1% vs 83.6% P ‫؍‬ .018) and 3-year survival (91.5% vs 80.8%, P ‫؍‬ .026) were significantly higher in APL 2000 trial, and there was a trend for lower 3-year CIR (9.9% vs 18.5%, P ‫؍‬ .12), suggesting a beneficial role for AraC in those patients. IntroductionAcute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia characterized by its morphology, t(15; 17) translocation leading to PML-RARa fusion gene, and by a life-threatening coagulopathy. 1-5 All-trans retinoic acid (ATRA) combined with anthracycline-based chemotherapy yield complete remission (CR) rate in approximately 90% of newly diagnosed APLs and 25% to 30% subsequently relapse. 6 Maintenance treatment (especially combining continuous 6-mercaptopurine [6MP] and methotrexate [MTX] to ATRA) appears to further reduce the relapse risk to 10% to 15%. 6-9 Pretreatment white blood cell (WBC) count is the main factor associated with relapse in APL and a predictive model for relapse risk (Sanz score) based on pretreatment WBC and platelet counts allowing for the distinction among low-risk patients (with WBC count Ͻ 10 ϫ 10 9 /L and platelet count Ͼ 40 ϫ 10 9 /L), intermediaterisk patients (with WBC count Ͻ 10 ϫ 10 9 /L and platelet count Ͻ 40 ϫ 10 9 /L), and high-risk patients (with WBC count Ն 10 ϫ 10 9 /L). 10 Another sizable subset of patients die in CR from complications of consolidation treatment, mainly from infection due to chemotherapy-induced myelosuppression. 7,[11][12][13] To decrease mortality in CR, the Programa para el Estudio de la Terapéutica en Hemopatía Maligna (PETHEMA) group reduced the intensity of consolidation chemotherapy by avoiding cytosine arabinoside (AraC) in the chemotherapy regimen. 8,9 They observed CR rates comparable with regimens using a combination of AraC with anthracycline, a lower rate of death in CR (2%) and a low cumulative incidence of relapse (10%). On the other hand, the French-Belgian-Swiss APL group, i...

Neither elacytarabine nor any of the seven alternative treatment regimens provided clinically meaningful benefit to these patients. OS in both study arms and for all treatments was extremely poor. Novel agents, novel clinical trial designs, and novel strategies of drug development are all desperately needed for this patient population.

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