Clofarabine and high-dose cytarabine arabinoside (clara) for primary refractory or relapsed acute myeloid leukaemia: a prospective follow-up study of 60 patients

Abstract

BACKGROUND: Relapsed or refractory acute myeloid leukaemia (AML) is associated with a poor prognosis with a remission rate ranging between 10 to 40 percent with conventional salvage regimens. Clofarabine was designed to incorporate the anti-leukaemic properties of fludarabine and cladribine, both of which are active against AML. AIMS: The aim of this study was to prospectively evaluate the efficacy and tolerability of the salvage regimen combining clofarabine and high-dose cytarabine in patients with primary refractory or relapsed AML in the real-world scenario. METHODS: Patients with primary refractory or relapsed AML were prospectively recruited between 1 June 2009 and 31 December 2013. All data was censored on 30 June 2014. Patients were treated with Clofarabine at 40mg/m2/day from day 1 to day 5) in combination with cytarabine arabinoside (AraC) at 2g/m2/day from day 1 to day 5 (CLARA). Clinicopathologic features, treatment response and survivals were determined. Prognostic factors for response and survivals were determined using logistic regression and cox regression. RESULTS: 60 patients with primary refractory or relapsed AML were recruited (primary refractory,N=18; first relapse,N=31, second relapse,N=10, third relapse,N=1). 29 men and 31 women with a median age of 48.5 (range: 18-66) were recruited. They received a median of 2 (range:1-5) prior induction/re-induction regimens for AML. 36 patients (40%) had normal karyotype at diagnosis while 24 patients (60%) had abnormal karyotype. 8 patients had fms-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) and 5 patients had mutated nucleophosmin 1 (NPM1). 8 patients achieved complete remission (CR) and 25 patients achieved a complete remission with incomplete haematopoietic recovery (CRi) making the CR/CRi rate of 55%. 17 patients progressed after initial remission. 15 patients (25%) underwent allogeneic haematopoietic stem cell transplantation (HSCT) after remission. Grade 3/4 haematological toxicity was seen in all 60 patients. Febrile neutropenia occurred in 24 patients (40%) and grade 3/4 hepatotoxicity was seen in 5 patients (8%). With a median follow-up of 6.5 months (range: 1-43), the median overall survival was 8 months (95% confidence interval:5.04-10.96). The overall survival at 12 and 24 months was 38.9% and 29.7% respectively. Patients who were successfully bridged to allogeneic HSCT had a significantly better overall survival (P<0.001). The overall survival at 36 months in patients who underwent HSCT was 62.2%. The median progression-free survival following CLARA was 6 months. SUMMARY: Clofarabine in combination with high-dose cytarabine was effective in inducing a response in a significant proportion of patients with heavily-pretreated primary refractory or relapsed AML. Successful bridge to subsequent curative allogeneic HSCT was the major determinant of overall survival.