Clofarabine added to intensive treatment in adult patients with newly diagnosed ALL: the HOVON-100 trial
Anita W. Rijneveld, Bronno van der Holt, Okke de Weerdt, Bart J. Biemond, Arjen A. van de Loosdrecht, Lotte E. van der Wagen, Mar Bellido, Michel van Gelder, Walter J. F. M. van der Velden, Dominik Selleslag, Daniëlle van Lammeren‐Venema, Constantijn J.M. Halkes, Rob Fijnheer, Violaine Havelange, Geerte L. Van Sluis, Marie-Cecile Legdeur, Dries Deeren, Alain Gadisseur, Harm Sinnige, Dimitri Breems, Aurélie Jaspers, Ollivier Legrand, Wim Terpstra, Rinske Boersma, Dominiek Mazure, A. Triffet, Lidwine W. Tick, Karolien Beel, Johan Maertens, H. Berna Beverloo, Marleen Bâkkus, Christa Homburg, Válerie de Haas, Vincent H. J. van der Velden, Jan J. Cornelissen, the Dutch-Belgian HOVON Cooperative group
Abstract
Clofarabine (CLO) is a nucleoside analog with efficacy in relapsed/refractory acute lymphoblastic leukemia (ALL). This randomized phase 3 study aimed to evaluate whether CLO added to induction and whether consolidation would improve outcome in adults with newly diagnosed ALL. Treatment of younger (18-40 years) patients consisted of a pediatric-inspired protocol, and for older patients (41-70 years), a semi-intensive protocol was used. Three hundred and forty patients were randomized. After a median follow-up of 70 months, 5-year event-free survival (EFS) was 50% and 53% for arm A and B (CLO arm). For patients ≤40 years, EFS was 58% vs 65% in arm A vs B, whereas in patients >40 years, EFS was 43% in both arms. Complete remission (CR) rate was 89% in both arms and similar in younger and older patients. Minimal residual disease (MRD) was assessed in 200 patients (60%). Fifty-four of 76 evaluable patients (71%) were MRD- after consolidation 1 in arm A vs 75/81 (93%) in arm B (P = .001). Seventy (42%) patients proceeded to allogeneic hematopoietic stem cell transplantation in both arms. Five-year overall survival (OS) was similar in both arms: 60% vs 61%. Among patients achieving CR, relapse rates were 28% and 24%, and nonrelapse mortality was 16% vs 17% after CR. CLO-treated patients experienced more serious adverse events, more infections, and more often went off protocol. This was most pronounced in older patients. We conclude that, despite a higher rate of MRD negativity, addition of CLO does not improve outcome in adults with ALL, which might be due to increased toxicity. This trial was registered at www.trialregister.nl as #NTR2004.