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Clofarabine, idarubicin, and cytarabine (CIA) as frontline therapy for patients ?60 years with newly diagnosed acute myeloid leukemia.

ABSTRACT: Clofarabine is a second generation nucleoside analogue with activity in adults with acute myeloid leukemia (AML). A phase I trial of clofarabine, idarubicin, and cytarabine (CIA) in relapsed and refractory AML had shown an overall response rate (ORR) of 48%. To explore this combination further, we conducted a phase II study of (CIA) in patients with newly diagnosed AML ?60 years. Patients ?18-60 years with AML and adequate organ function were enrolled. Induction therapy consisted of clofarabine (C) 20 mg m?² IV daily (days 1-5), idarubicin (I) 10 mg m?² IV daily (days 1-3), and cytarabine (A) 1 g m?² IV daily (days 1-5). Patients in remission received up to six consolidation cycles (C 15 mg m?² × 3, I 8 mg m?² × 2, and A 0.75 g m?² × 3). Fifty-seven patients were evaluable. ORR was 79%. With a median follow up of 10.9 months, the median overall survival (OS) was not reached, the median event-free survival (EFS) was 13.5 months. Most toxicities were ?grade 2. Four week mortality was 2%. In subgroup analysis, patients ?40 years had better OS (P?=?0.04) and EFS (P?=?0.04) compared to patients >40 years. Compared to historical patients treated with idarubicin and cyarabine (IA), the OS and EFS were significantly longer for CIA treated patients. In multivariate analysis, CIA retained its favorable impact on OS compared to IA. Thus, CIA is an effective and safe therapy for patients ?60 years with newly diagnosed AML.

SUBMITTER: Nazha A

PROVIDER: S-EPMC4110914 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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Clofarabine, idarubicin, and cytarabine (CIA) as frontline therapy for patients ≤60 years with newly diagnosed acute myeloid leukemia.

Nazha Aziz A Kantarjian Hagop H Ravandi Farhad F Huang Xuelin X Choi Sangbum S Garcia-Manero Guillermo G Jabbour Elias E Borthakur Gautam G Kadia Tapan T Konopleva Marina M Cortes Jorge J Ferrajoli Alessandra A Kornblau Steve S Daver Naval N Pemmaraju Naveen N Andreeff Michael M Estrov Zeev Z Du Min M Brandt Mark M Faderl Stefan S

American journal of hematology 20130909 11

Clofarabine is a second generation nucleoside analogue with activity in adults with acute myeloid leukemia (AML). A phase I trial of clofarabine, idarubicin, and cytarabine (CIA) in relapsed and refractory AML had shown an overall response rate (ORR) of 48%. To explore this combination further, we conducted a phase II study of (CIA) in patients with newly diagnosed AML ≤60 years. Patients ≥18-60 years with AML and adequate organ function were enrolled. Induction therapy consisted of clofarabine ...[more]

PMID: 23877926

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Project description:BACKGROUND:Outcomes for younger patients with acute myeloid leukaemia have moderately improved over the past two decades owing to better supportive care and recent introduction of novel targeted agents. Blocking PD-1 and its ligand's pathways enhances antileukaemia responses by enabling T cells in murine models. We aimed to assess the addition of nivolumab to frontline therapy with idarubicin and cytarabine in patients with newly diagnosed acute myeloid leukaemia or high-risk myelodysplastic syndrome. METHODS:This single-arm, phase 2 part of the phase 1-2 study of nivolumab in combination with idarubicin and cytarabine was done at the University of Texas MD Anderson Cancer Center (Houston, TX, USA). Eligible patients were aged 18-60 years (or >60 years if suitable for intensive chemotherapy), and had newly diagnosed acute myeloid leukaemia or high-risk myelodysplastic syndrome, and an Eastern Cooperative Oncology Group performance status of 0-2. Induction included cytarabine 1·5 g/m2 by 24-h continuous infusion daily on days 1-4 (3 days in patients >60 years) and idarubicin 12 mg/m2 daily on days 1-3. Nivolumab 3 mg/kg was started on day 24 (range 22-26) and continued every 2 weeks for up to a year in responders. Responders received either up to five consolidation cycles of attenuated doses of idarubicin and cytarabine, or allogeneic stem cell transplantation if eligible. The primary endpoint was event-free survival. Efficacy and safety analyses were done in all patients who received at least one dose of study treatment. Secondary endpoints were relapse-free survival and overall survival. This ongoing trial is registered with ClinicalTrials.gov, number NCT02464657. FINDINGS:Between Aug 7, 2015, and June 2, 2018, 44 patients were enrolled of whom 22 (50%) had adverse genetic risk by European Leukaemia Network classification. All patients were evaluable for safety and efficacy. At a median follow-up of 17·25 months (IQR 0·50-30·40), median event-free survival was not reached (95% CI 7·93-NR). Median relapse-free survival of responders was 18·54 months (95% CI 8·20-23·22). The median overall survival was 18·54 months (95% CI 10·81-28·81). Six patients had seven grade 3-4 immune-related adverse events with two cases of rash, two of colitis, and one each of transaminitis, pancreatitis, and cholecystitis. 19 (43%) of 44 patients achieved a response and proceeded to allogeneic stem cell transplantation, with grade 3-4 graft-versus-host disease observed in five (26%). No treatment related deaths were attributed to nivolumab. INTERPRETATION:Addition of nivolumab to induction chemotherapy with idarubicin and cytarabine is feasible in patients with newly diagnosed acute myeloid leukaemia or high-risk myelodysplastic syndrome. Post-transplant severe graft-versus-host disease could be improved, and earlier initiation of checkpoint inhibitor therapy is warranted in future studies. FUNDING:The MD Anderson Cancer Center Support Grant CA016672, and the MD Anderson Cancer Center Leukaemia SPORE CA100632 from the National Cancer Institute, Bristol Myers Squibb.

Dataset Information

Clofarabine, idarubicin, and cytarabine (CIA) as frontline therapy for patients ?60 years with newly diagnosed acute myeloid leukemia.

Publications

Clofarabine, idarubicin, and cytarabine (CIA) as frontline therapy for patients ≤60 years with newly diagnosed acute myeloid leukemia.

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