Patients with relapsed and/or refractory acute myeloid leukemia (AML) have a very dismal outcome and treatments are largely unsatisfactory. Salvage therapy is often limited by drug resistance and organ toxicities in patients who have already been exposed to multiple lines of chemotherapy. Clofarabine is a second generation nucleoside analogue with multiple mechanisms of action including inhibition of ribonucleotide reductase, suppression of DNA polymerase, direct DNA incorporation and induction of apoptosis. In this study, we evaluated the clinical outcome of patients with relapsed and/or refractory AML who received combination treatment of clofarabine and cytarbine (acronym CLARA) at Queen Mary Hospital in Hong Kong.
The treatment with CLARA comprised clofarabine 40 mg/m2 and cytarabine 2 gm/m2 given intravenously for five days. For patients who relapsed after allogeneic hematopoietic stem cell transplantation (HSCT), CLARA was followed by the infusion of either BM or mobilized peripheral blood stem cells (PBSC) from the original donor and immunosuppression (cyclosporine A at 1.5 mg/kg twice daily) was given from day 8 after HSC infusion. All patients received standard anti-microbial prophylaxes and G-CSF support during neutropenia. Remission status was confirmed by bone marrow examination.
Since 2009, a total of 55 patients have been recruited of whom 19 received CLARA at relapse after allogeneic HSCT. The median age of the patients was 45 years (range 20–64) and cytogenetic categorizations were favorable (N=7); intermediate (N=29) and unfavorable (N=14) in 50 evaluable patients. There were a median of two regimens (range 1–4) and five courses (range 1–12) of chemotherapy before CLARA. All patients developed grade 4 hematologic toxicity and 20% (no. of patients: grade 1–2=8; grade 3= 3) and 60% (grade 1–2=23; grade 3–4=10) developed dermatologic and liver toxicities. Six patients including three who relapsed after HSCT (out of 19 patients=16%) and three non-transplant patients (out of 36 patients=8%) died of treatment related mortality after CLARA (overall 11%). Twenty-seven patients (49%) achieved complete remission (CR) or CR with insufficient hematologic recovery (CRi). Patients who received CLARA for relapse post-HSCT had a higher CR/CRi (12 out 19 patients=63%) than the non-transplant patients (15 out of 36 patients=42%). The respective median disease-free (DFS) and overall-survivals (OS) of the post-HSCT relapse and non-transplant patients were 9.6 and 5.0 months (DFS) and 11.5 and 8.0 months (OS). CLARA is an effective salvage regimen for both post-HSCT relapse and non-transplant patients with tolerable side-effects. The optimal consolidation and maintenance strategies after CLARA would have to be further defined.
Clofarabine was provided by a compassionate program from Sanofi-aventis Hong Kong Ltd.
Off Label Use: Clofarabine.
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Asterisk with author names denotes non-ASH members.