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Randomized Controlled Trial
. 2022 Feb 22;6(4):1115-1125.
doi: 10.1182/bloodadvances.2021005624.

Clofarabine added to intensive treatment in adult patients with newly diagnosed ALL: the HOVON-100 trial

Anita W Rijneveld  1 , Bronno van der Holt  2 , Okke de Weerdt  3 , Bart J Biemond  4 , Arjen A van de Loosdrecht  5 , Lotte E van der Wagen  6 , Mar Bellido  7 , Michel van Gelder  8 , Walter J F M van der Velden  9 , Dominik Selleslag  10 , Daniëlle van Lammeren-Venema  11 , Constantijn J M Halkes  12 , Rob Fijnheer  13 , Violaine Havelange  14 , Geerte L van Sluis  15 , Marie-Cecile Legdeur  16 , Dries Deeren  17 , Alain Gadisseur  18 , Harm A M Sinnige  19 , Dimitri A Breems  20 , Aurélie Jaspers  21 , Ollivier Legrand  22 , Wim E Terpstra  23 , Rinske S Boersma  24 , Dominiek Mazure  25 , Agnes Triffet  26 , Lidwine W Tick  27 , Karolien Beel  28 , Johan A Maertens  29 , H Berna Beverloo  30 , Marleen Bakkus  31 , Christa H E Homburg  32 , Valerie de Haas  33 , Vincent H J van der Velden  34 , Jan J Cornelissen  1 ; Dutch-Belgian HOVON Cooperative group
Affiliations
Randomized Controlled Trial

Clofarabine added to intensive treatment in adult patients with newly diagnosed ALL: the HOVON-100 trial

Anita W Rijneveld et al. Blood Adv. .

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.

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Figures

None
Graphical abstract
Figure 1.
Figure 1.
CONSORT diagram of study. Arm B included CLO in prephase. In this diagram, the 2 age groups (younger and older than 40 years of age) are combined (for CONSORT diagrams in subgroups, see supplemental Figures 1-3). Treatment protocols are detailed in supplemental Tables 1 and 2. In this figure, induction includes induction course and consolidation A and B for patients ≤40 years and remission induction 1 and consolidation 1 for patients >40 years of age. Consolidation 1 consists of intensification course 1A and 1B and remission induction course 2 for younger and older patients, respectively, and consolidation 2 contains interphase and intensification 2 for younger and consolidation 2 for older patients.
Figure 2.
Figure 2.
Cumulative incidence of going off protocol not due to completion, relapse, or death in CR patients in standard arm and CLO-arm. Cumulative incidence for going of off protocol not due to completion, relapse, or death is shown in patients ≤40 years of age (A) and patients >40 years of age (B) in control (blue) vs CLO group (red).
Figure 3.
Figure 3.
EFS and overall survival of patients treated according to standard arm vs additional CLO. EFS (A-C) and OS (D-F) of patients treated according to standard arm vs additional CLO are shown. Panels A and D show survival of all age groups together. Panels B and E are patients ≤40 years of age. Panels C and F are patients >40 years of age.
See this image and copyright information in PMC

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