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Early responses predict better outcomes in patients with newly diagnosed chronic myeloid leukemia: results with four tyrosine kinase inhibitor modalities.

ABSTRACT: Early responses to tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML)-chronic phase (CP) are associated with improved outcome. We analyzed the impact of such a response on outcomes among patients treated with 4 TKI modalities as frontline therapy in CML-CP. A total of 483 patients who received 400 or 800 mg imatinib, nilotinib, or dasatinib were analyzed. The median follow-up was 72 mo. Landmark analysis at 3 mo by molecular response showed that the cumulative proportions of 3-y event-free survival (EFS) for 3-mo BCR-ABL levels was 95% for those with ?1%, 98% for >1% to 10%, and 61% for those with >10% (P = .001). The corresponding values by cytogenetic responses were 97% if Ph+ = 0%, 89% if Ph+ = 1% to 35%, and 81% if Ph+ >35% (P = .001). Cytogenetic response at 3 mo significantly discriminated for 3-y overall survival (OS): 98%, 96%, and 92%, respectively (P = .01). In multivariate analysis, young patients, high Sokal index, and treatment with imatinib 400 significantly predicted for poor (>35%) cytogenetic response at 3 mo. Early responses are predictive for EFS and failure-free survival and to a lesser extent OS, regardless of the treatment modality, although therapies other than standard-dose imatinib result in higher rates of deep early responses.

SUBMITTER: Jain P

PROVIDER: S-EPMC3743466 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature

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Early responses predict better outcomes in patients with newly diagnosed chronic myeloid leukemia: results with four tyrosine kinase inhibitor modalities.

Jain Preetesh P Kantarjian Hagop H Nazha Aziz A O'Brien Susan S Jabbour Elias E Romo Carlos Guillermo CG Pierce Sherry S Cardenas-Turanzas Marylou M Verstovsek Srdan S Borthakur Gautam G Ravandi Farhad F Quintás-Cardama Alfonso A Cortes Jorge J

Blood 20130425 24

Early responses to tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML)-chronic phase (CP) are associated with improved outcome. We analyzed the impact of such a response on outcomes among patients treated with 4 TKI modalities as frontline therapy in CML-CP. A total of 483 patients who received 400 or 800 mg imatinib, nilotinib, or dasatinib were analyzed. The median follow-up was 72 mo. Landmark analysis at 3 mo by molecular response showed that the cumulative proportions of 3-y ...[more]

PMID: 23620574

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Project description:PurposeIvosidenib is an oral inhibitor of the mutant isocitrate dehydrogenase 1 (IDH1) enzyme, approved for treatment of IDH1-mutant (mIDH1) acute myeloid leukemia (AML). Preclinical work suggested that addition of azacitidine to ivosidenib enhances mIDH1 inhibition-related differentiation and apoptosis.Patients and methodsThis was an open-label, multicenter, phase Ib trial comprising dose-finding and expansion stages to evaluate safety and efficacy of combining oral ivosidenib 500 mg once daily continuously with subcutaneous azacitidine 75 mg/m2 on days 1-7 in 28-day cycles in patients with newly diagnosed mIDH1 AML ineligible for intensive induction chemotherapy (ClinicalTrials.gov identifier: NCT02677922).ResultsTwenty-three patients received ivosidenib plus azacitidine (median age, 76 years; range, 61-88 years). Treatment-related grade ≥ 3 adverse events occurring in > 10% of patients were neutropenia (22%), anemia (13%), thrombocytopenia (13%), and electrocardiogram QT prolongation (13%). Adverse events of special interest included all-grade IDH differentiation syndrome (17%), all-grade electrocardiogram QT prolongation (26%), and grade ≥ 3 leukocytosis (9%). Median treatment duration was 15.1 months (range, 0.3-32.2 months); 10 patients remained on treatment as of February 19, 2019. The overall response rate was 78.3% (18/23 patients; 95% CI, 56.3% to 92.5%), and the complete remission rate was 60.9% (14/23 patients; 95% CI, 38.5% to 80.3%). With median follow-up of 16 months, median duration of response in responders had not been reached. The 12-month survival estimate was 82.0% (95% CI, 58.8% to 92.8%). mIDH1 clearance in bone marrow mononuclear cells by BEAMing (beads, emulsion, amplification, magnetics) digital polymerase chain reaction was seen in 10/14 patients (71.4%) achieving complete remission.ConclusionIvosidenib plus azacitidine was well tolerated, with an expected safety profile consistent with monotherapy with each agent. Responses were deep and durable, with most complete responders achieving mIDH1 mutation clearance.

Dataset Information

Early responses predict better outcomes in patients with newly diagnosed chronic myeloid leukemia: results with four tyrosine kinase inhibitor modalities.

Publications

Early responses predict better outcomes in patients with newly diagnosed chronic myeloid leukemia: results with four tyrosine kinase inhibitor modalities.

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