11 research outputs found

    Treatment of chronic-phase chronic myeloid leukemia in patients randomized to dasatinib or imatinib after suboptimal responses to three months of imatinib therapy: final 5-year results from DASCERN

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    Early molecular response (EMR) at 3 months is predictive of improved overall survival (OS) and progression-free survival (PFS) in patients with chronic myeloid leukemia in the chronic phase (CML-CP). Although about one-third of patients treated with first-line imatinib do not achieve EMR, long-term OS and PFS are still observed in most patients. DASCERN (NCT01593254) is a prospective, phase IIb, randomized trial evaluating a switch to dasatinib in patients who have not achieved EMR after 3 months of treatment with first-line imatinib. Early analysis demonstrated an improved major molecular response (MMR) rate at 12 months with dasatinib versus imatinib (29% vs. 13%, P=0.005). Here, we report results from the final 5-year follow-up. In total, 174 patients were randomized to dasatinib and 86 to remain on imatinib. Forty-six (53%) patients who remained on imatinib but subsequently experienced failure were allowed to cross over to dasatinib per protocol. At a minimum follow-up of 60 months, the cumulative MMR rate was significantly higher in patients randomized to dasatinib versus imatinib (77% vs. 44%,

    Dasatinib discontinuation in patients with chronic-phase chronic myeloid leukemia and stable deep molecular response: the DASFREE study

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    Treatment-free remission (TFR) in patients with chronic myeloid leukemia in chronic phase (CML-CP) is considered a feasible option, especially with the ability of second-generation tyrosine kinase inhibitors to induce higher rates of sustained deep molecular response (DMR). DASFREE is an open-label, single-arm, multicenter phase II trial assessing TFR after dasatinib discontinuation in patients with CML-CP (N = 84). At 2 years, TFR was 46% in all patients. Multivariate analyses revealed statistically significant associations between 2-year TFR and duration of prior dasatinib (≄median; p = .0051), line of therapy (first line; p = .0138), and age (>65 years; p = .0012). No disease transformation occurred, and the most common adverse events experienced off treatment were musculoskeletal (observed in 30 patients); however, dasatinib withdrawal events were reported in nine patients (11%) by the investigator. Overall, these findings support the feasibility of discontinuing dasatinib for patients with CML-CP in sustained DMR in the first line and beyond

    AML-432 Overall Survival (OS) by IDH2 Mutant Allele (R140 or R172) in Patients With Late-Stage, Mutant-IDH2 Relapsed/Refractory Acute Myeloid Leukemia (AML) Treated With Enasidenib or Conventional Care Regimens (CCR) in the Randomized, Open-Label, Phase 3 IDHENTIFY Trial

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    Context : IDH2 mutations (mIDH2) occur in ~8%-19% of patients with AML, typically as R140Q (~75%) or R172K (~25%) point mutations, which have distinct functional effects and prognostic relevance. In the phase 3 IDHENTIFY trial, enasidenib did not significantly improve OS vs CCR in older patients with mIDH2 relapsed/refractory AML, but a trend for improved OS with enasidenib was detected in patients with IDH2-R172. Objective : Investigate molecular profiles and OS in mIDH2 variant subgroups (R140/R172). Methods : IDHENTIFY (NCT02577406) enrolled patients aged ≄60 years who had received 2-3 prior AML-directed therapies. Patients were randomized 1:1 to enasidenib 100-mg/day or CCR (azacitidine, intermediate- or low-dose Ara-C, or supportive care). Co-occurring mutations were identified by targeted NGS of BMMC DNA. Total 2-hydroxyglutarate was determined by LC/MS. Results : Of 319 patients enrolled, 88 (28%; 43 enasidenib, 45 CCR) had mIDH2-R172 and 229 (72%; 115 enasidenib, 114 CCR) had mIDH2-R140. Median baseline 2-hydroxyglutarate level and IDH2 VAF were similar between arms and mIDH2 subgroups. Patients with mIDH2-R172 had fewer baseline mutations (median 4 [range 2-8]) than those with mIDH2-R140 (5 [1-11]) (P<0.0001). Common co-mutations were SRSF2 and RUNX1 in the R140 cohort (59% each) and DNMT3A in the R172 cohort (57%). Compared with R172, R140 was enriched with SRSF2, FLT3 (-ITD/-TKD), NPM1, RUNX1, and JAK2, whereas DNMT3A and TP53 were more common with R172. In Cox multivariate analysis including mIDH2 variant, DNMT3A status, and number of baseline mutations, mIDH2-R172 was significantly correlated with improved OS (P=0.04 vs R140) in the enasidenib arm, and number of baseline mutations was significantly (P<0.01) associated with OS in the CCR arm. Median OS in the R172 subgroup was 14.6 months with enasidenib vs 7.8 months with CCR (HR, 0.59 [95%CI 0.35-0.98]; P=0.039); 1-year survival rates were 62% and 30%. In the R140 subgroup, median OS was 5.7 months in both arms (0.93 [0.70-1.24]; P=0.61), and 1-year survival rates were 29% and 25% with enasidenib and CCR. Conclusions: Mutational burden and co-mutational profiles differed between patients with mIDH2-R140 and mIDH2-R172 relapsed/refractory AML. In the R172 subgroup, median OS and 1-year survival rate with enasidenib were approximately double those with CCR

    Enasidenib plus azacitidine versus azacitidine alone in patients with newly diagnosed, mutant-IDH2 acute myeloid leukaemia (AG221-AML-005): a single-arm, phase 1b and randomised, phase 2 trial

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    Background: Enasidenib is an oral inhibitor of mutant isocitrate dehydrogenase-2 (IDH2) proteins. We evaluated the safety and activity of enasidenib plus azacitidine versus azacitidine alone in patients with newly diagnosed, mutant-IDH2 acute myeloid leukaemia ineligible for intensive chemotherapy. Methods: This open-label, phase 1b/2 trial was done at 43 clinical sites in 12 countries (the USA, Germany, Canada, the UK, France, Spain, Australia, Italy, the Netherlands, Portugal, Switzerland, and South Korea). Eligible patients were aged 18 years or older and had newly diagnosed, mutant-IDH2 acute myeloid leukaemia, and an Eastern Cooperative Oncology Group performance status of 0–2. In the phase 1b dose-finding portion, patients received oral enasidenib 100 mg/day or 200 mg/day in continuous 28-day cycles, plus subcutaneous azacitidine 75 mg/m2 per day for 7 days of each cycle. In phase 2, patients were randomly assigned (2:1) via an interactive web response system to enasidenib plus azacitidine or azacitidine-only, stratified by acute myeloid leukaemia subtype (de novo or secondary). The primary endpoint in the phase 2 portion was the overall response rate in the intention-to-treat population at a prespecified interim analysis (Aug 20, 2019) when all patients had at least 1 year of follow-up. Safety was assessed in all patients who received at least one dose of study drug. The trial is registered with ClinicalTrials.gov, NCT02677922, and is ongoing. Findings: Between June 3, 2016, and Aug 2, 2018, 322 patients were screened and 107 patients with mutant-IDH2 acute myeloid leukaemia were enrolled. At data cutoff for the interim analysis, 24 patients (including two from the phase 1 portion) were still receiving their assigned treatment. Six patients were enrolled in the phase 1b dose-finding portion of the trial and received enasidenib 100 mg (n=3) or 200 mg (n=3) in combination with azacitidine. No dose-limiting toxicities occurred and the enasidenib 100 mg dose was selected for phase 2. In phase 2, 101 patients were randomly assigned to enasidenib plus azacitidine (n=68) or azacitidine only (n=33). Median age was 75 years (IQR 71–78). 50 (74%; 95% CI 61–84) patients in the enasidenib plus azacitidine combination group and 12 (36%; 20–55) patients in the azacitidine monotherapy group achieved an overall response (odds ratio 4·9 [95% CI 2·0–11·9]; p=0·0003). Common treatment-related grade 3 or 4 adverse events with enasidenib plus azacitidine were thrombocytopenia (25 [37%] of 68 vs six [19%] of 32 in the azacitidine-only group), neutropenia (25 [37%] vs eight [25%]), anaemia (13 [19%] vs seven [22%]), and febrile neutropenia (11 [16%] vs five [16%]). Serious treatment-related adverse events were reported in 29 (43%) patients in the combination group and 14 (44%) patients in the azacitidine-only group; serious treatment-related adverse events occurring in more than 5% of patients in either group were febrile neutropenia (nine [13%] in the combination group vs five [16%] in the azacitidine-only group), differentiation syndrome (seven [10%] vs none), and pneumonia (three [4%] vs two [6%]). No treatment-related deaths were reported. Interpretation: Combination enasidenib plus azacitidine was well tolerated and significantly improved overall response rates compared with azacitidine monotherapy, suggesting that this regimen can improve outcomes for patients with newly diagnosed, mutant-IDH2 acute myeloid leukaemia
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