ABSTRACT
Mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) genes occur in about 20% patients with acute myeloid leukemia (AML), leading to DNA hypermethylation and epigenetic deregulation. We assessed the prognostic significance of IDH1/2 mutations (IDH1/2+) in 398 AML patients with normal karyotype (NK-AML), treated with daunorubicine + cytarabine (DA), DA + cladribine (DAC), or DA + fludarabine. IDH2 mutation was an independent favorable prognostic factor for 4-year overall survival (OS) in total NK-AML population (p = 0.03, censoring at allotransplant). We next evaluated the effect of addition of cladribine to induction regimen on the patients' outcome according to IDH1/2 mutation status. In DAC group, 4-year OS was increased in IDH2+ patients, compared to IDH-wild type group (54% vs 33%; p = 0.0087, censoring at allotransplant), while no difference was observed for DA-treated subjects. In multivariate analysis, DAC independently improved the survival of IDH2+ patients (HR = 0.6 [0.37-0.93]; p = 0.024; censored at transplant), indicating that this group specifically benefits from cladribine-containing therapy. In AML cells with R140Q or R172K IDH2 mutations, cladribine restrained mutations-related DNA hypermethylation. Altogether, DAC regimen produces better outcomes in IDH2+ NK-AML patients than DA, and this likely results from the hypomethylating activity of cladribine. Our observations warrant further investigations of induction protocols combining cladribine with IDH1/2 inhibitors in IDH2-mutant.
Subject(s)
Antineoplastic Agents/therapeutic use , Antineoplastic Combined Chemotherapy Protocols , Isocitrate Dehydrogenase/genetics , Leukemia, Myeloid, Acute/genetics , Adolescent , Adult , Aged , Cladribine/therapeutic use , Cytarabine/therapeutic use , Daunorubicin/therapeutic use , Humans , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/mortality , Middle Aged , Pharmacogenomic Variants , Poland/epidemiology , Randomized Controlled Trials as Topic , Retrospective Studies , Young AdultSubject(s)
Hypereosinophilic Syndrome/drug therapy , Imatinib Mesylate/therapeutic use , Mutation , Oncogene Proteins, Fusion , Receptor, Platelet-Derived Growth Factor alpha , mRNA Cleavage and Polyadenylation Factors , Adult , Aged , Aged, 80 and over , Female , Humans , Hypereosinophilic Syndrome/genetics , Male , Middle Aged , Poland , Protein Kinase Inhibitors , Treatment Outcome , Young AdultSubject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Gene Duplication , Karyotype , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/genetics , fms-Like Tyrosine Kinase 3/genetics , Cladribine/administration & dosage , Cytarabine/administration & dosage , Daunorubicin/administration & dosage , Humans , Leukemia, Myeloid, Acute/mortality , Treatment OutcomeABSTRACT
This prospective study estimated outcomes in 509 elderly patients with acute myeloid leukemia (AML) with different treatment approaches depending on Eastern Cooperative Oncology Group (ECOG) performance status and Charlson Comorbidity Index (CCI). Patients were stratified into fit (ECOG 0-2 and CCI 0-2) or frail (ECOG>2 and/or CCI>2) groups. Fit patients with CCI 0 received intensive chemotherapy whilst reduced-intensive chemotherapy (R-IC) was given to those with CCI 1-2. Frail patients received best supportive therapy. Fit patients presented a longer overall survival (OS) than frail subjects, but 8-week mortality rates were similar. The complete response (CR) rate between fit CCI 0 and CCI 1-2 subgroups was significantly different. Both of the fit subgroups showed similar 8-week mortality rates and OS probabilities. Allocating fit patients with CCI 1-2 to R-IC enabled an increase in the group of elderly patients who could be treated with the intention of inducing remission.
