PracticeUpdate: Haematology & Oncology

EUROPEAN HEMATOLOGY ASSOCIATION 2016 CONGRESS 18

IDH1 and 2 mutations are frequent after conventional salvage therapy for refractory or relapsed acute myeloid leukaemia

IDH1/2 mutations have been found to represent a frequent (in this study approximately 19%) molecular alteration in acute myeloid leukaemia, and a substantial proportion of patients with acute myeloid leukaemia and IDH1/2 mutations experience refractory disease or relapse. This finding of an assessment of the mutational status of IDH1 and 2 in participants of eight German-Austrian Acute Myeloid Leukemia Study Group trials was reported at EHA 2016. K onstanze Döhner, MD, of the University of Ulm, Germany, explained that somatic mutations affecting and 75 (23%) patients, respectively. Five cases with IDH2 mutations involved other codons. In IDH1/2-mutated acute myeloid leukaemia, the complete response rate after induction therapy was 62% (327/530) (IDH1, 64%; IDH2, 61%). versus 0.63 year in those not receiving an alloHSCT.

Dr Döhner concluded that IDH1/2 mutations were found to represent a frequent (in this study approximately 19%) molecular alteration in acute myeloid leukaemia. A substantial proportion of patients with acute myeloid leukaemia with IDH1/2 mutations experience refractory disease or relapse. Median survival with conventional salvage treatment in these patients was 0.81 year, with IDH2-mutated patients and those receiving alloHSCT surviving significantly longer. The results represent a benchmark for clinical trials evaluating IDH inhibitors in this clinical setting.

isocitrate dehydrogenase 1 (IDH1) or 2 (IDH2) genes are found in 15% to 20% of patients with acute myeloid leukaemia. In mainly IDH2 mutations, the incidence of these mutations increases with age. The mutated enzymes emerge as promising therapeutic targets given their abnormal function to produce the oncometabolite 2-hydroxyglutarate. First selective inhibitors of mutant IDH1 and IDH2 proteins are in early clinical development. It is unknown, however, how results from single-agent inhibitor therapy compare to those of conventional salvage therapy. Dr Döhner and colleagues set out to assess the outcome of patients with refractory or relapsed acute myeloid leukaemia with IDH1/2 mutations. A total of 2825 adults with acute myeloid leukaemia (median age: 55 years, range 18– 84 years) who entered eight prospective first- line Acute Myeloid Leukemia Study Group trials of intensive conventional induction and consolidation therapy were included. Refractory disease was defined as failure to achieve complete remission after two cycles of induction. Mutational status of IDH1 and IDH2 was assessed at initial diagnosis using a combination of denaturing- high-performance liquid chromatography followed by direct DNA sequencing. IDH1/2 mutations were identified in 530 (18.8%) of 2825 patients, IDH1 mutations in 7.5% (212/2822), and IDH2 mutations in 11.5% (326/2825). Eight patients had a mutation in both IDH1 and IDH2. All but one IDH1 mutation involved codon R132. Among the IDH2 mutated cases, IDH and IDH2 mutations were detected in 246 (75%)

A total of 138 patients, including those who received only one induction cycle, were refractory to the primary induction. Among patients who received two induction cycles, 82 had refractory disease (IDH1, n=31; IDH2, n=50; IDH1 + IDH2, n=1). Two hundred and eight IDH1/2-mutated patients relapsed (IDH1, n=112; IDH2, n=92; IDH1 + IDH2, n=4). Median overall survival in patients with refractory disease (measured from the date of refractory disease) and relapse (measured from the time of relapse) was 1.03 and 0.79 years, respectively; in IDH1-mutated acute myeloid leukaemia 0.53 and 0.63 years, respectively, and in IDH2-mutated acute myeloid leukaemia 1.22 and 1.09 years, respectively. Median overall survival in all IDH1/2-mutated patients with refractory/relapsed disease was 0.81 year. Patients with IDH2 mutations had survived longer (P = 0.003), which was mainly attributed to cases carrying IDH2 mutations. Of the 82 patients with refractory disease, 39 (48%) received allogeneic haematopoietic- stem cell transplantation (alloHSCT). Median survival with alloHSCT was 1.80 years versus 0.53 year in those who did not undergo alloHSCT. Of 208 relapsed patients, 153 received intensive chemotherapy or alloHSCT, and 89 (58%) of the 153 patients subsequently achieved complete response or complete response with incomplete haematologic recovery. Seventy-four relapsed patients received alloHSCT. Median survival after relapse of patients receiving alloHSCT was 1.50 years

© EHA 2016

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