Clofarabine in newly diagnosed AML patients: HOVON-102 study

Clofarabine, a nucleoside analogue, has been shown to exhibit anti-leukemic activity in older patients with Acute Myeloid Leukemia (AML). However, clofarabine in combination with standard induction chemotherapy has not been extensively evaluated in young to middle aged patients with AML.

In an article published in Blood, Bob Löwenberg from the Erasmus University Medical Center, Rotterdam, and colleagues published data from their phase III HOVON-102 randomized study which aimed to access the safety and efficacy of the added effect of clofarabine in combination with standard induction chemotherapy in newly diagnosed young and middle aged patients (18–65 years) with AML or high-risk Myelodysplastic Syndrome (Refractory Anemia with Excess Blasts [RAEB] with International Prognostic Scoring Scale [IPSS] ≥ 1.5). The study was conducted by the Hemato-Oncology Cooperative Group (HOVON) and the Swiss Group for Clinical Cancer Research (SAKK).  

Patients (n = 795 [AML, n = 715, RAEB, n = 80], median age = 55 years) were randomly assigned to receive 2 successive cycles of standard induction chemotherapy (idarubicine-cytarabine [cycle I] and amsacrine-cytarabine [cycle II] either with (n = 393, clofarabine arm) or without clofarabine (n = 402, control arm). Median follow-up length, of patients (n = 381) that were alive, was 36 months.

The key results of the study were:

• Complete Remission (CR) and CR with Insufficient Hematological Recovery (CRi) in the control arm and clofarabine arm; 85% and 4% vs 84% and 5%
• After first induction cycle, CR/CRi in the control arm and clofarabine arm; 66% vs 75%
• 4-year EFS in the control arm and clofarabine arm; 35% ± 3 vs 38% ± 3, HR = 0.90, P = 0.24
• 4-year relapse rate in patients achieving CR/CRi in the control arm and clofarabine arm; 44% ± 3 vs 35% ± 3
• Death in CR/CRi patients in the control arm and clofarabine arm; 15% ± 2 vs 22% ± 3, P = 0.57
• 4-year EFS in patients in the European-Leukemia-Net (ELN) 2010 Intermediate-1 prognostic risk subset in the control arm (n = 121) and clofarabine arm (n = 123); 26% ± 4 vs 40% ± 5, P = 0.002
•  4-year EFS in patients with ELN intermediate-risk and genotype with wild-type NPM1/FLT3 without Internal Tandem Duplications (FLT3-ITD negative) in the control arm (n = 68) and clofarabine arm (n = 67); 18% ± 5 vs 40% ± 7, P < 0.001
• More grade 3–4 Adverse Effects (AEs) and infections were observed in patients in the clofarabine treatment arm compared to control arm

In summary, clofarabine in combination with standard chemotherapy can reduce the probability of relapse but does not improve survival. Conversely, clofarabine improved the survival of patients in the intermediate prognostic subgroup and in patients without NPM1 and FLT3 mutations.

Abstract

Clofarabine has demonstrated antileukemic activity in acute myeloid leukemia (AML) but has yet to be critically evaluated in younger adults in the frontline with standard chemotherapy. We compared two induction regimens in newly diagnosed patients aged 18-65 with AML/high risk MDS, i.e., idarubicine-cytarabine (cycle I) and amsacrine-cytarabine (cycle II) without or with clofarabine (10 mg/m² on days 1-5 of each of both cycles). Consolidation involved chemotherapy with or without hematopoietic stem cell transplantation. Event free survival (EFS, primary endpoint) and other clinical endpoints and toxicities were assessed. 402 and 393 evaluable patients were randomized to the control or clofarabine induction treatment arms. Complete remission rates (89%) did not differ but were attained faster with clofarabine (66% versus 75% after cycle I). Clofarabine added grade III-IV toxicities, and delayed hematological recovery. At a median follow up of 36 months, the study reveals no differences in overall survival and EFS between the control (EFS 35% ±3 (SE) at 4 years) and clofarabine treatments (38% ±3) but a markedly reduced relapse rate (44% ± 3 versus 35% ± 3) in favor of clofarabine and an increased death probability in remission (15% ±2 versus 22% ±3). In the subgroup analyses, clofarabine improved OS and EFS for European-Leukemia-Net ELN 2010 Intermediate-I prognostic risk AML (EFS 26 % ±4 versus 40% ±5 at 4 years, Cox-P=0.002) and for the intermediate risk genotype NPM1wild type/FLT3 without internal-tandem-duplications (EFS 18% ±5 versus 40% ±7, Cox- P<0.001). Clofarabine improves survival in subsets of intermediate-risk AML only.