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

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.

SUBMITTER: Rijneveld AW

PROVIDER: S-EPMC8864640 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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

Rijneveld Anita W AW van der Holt Bronno B de Weerdt Okke O Biemond Bart J BJ van de Loosdrecht Arjen A AA van der Wagen Lotte E LE Bellido Mar M van Gelder Michel M van der Velden Walter J F M WJFM Selleslag Dominik D van Lammeren-Venema Daniëlle D Halkes Constantijn J M CJM Fijnheer Rob R Havelange Violaine V van Sluis Geerte L GL Legdeur Marie-Cecile MC Deeren Dries D Gadisseur Alain A Sinnige Harm A M HAM Breems Dimitri A DA Jaspers Aurélie A Legrand Ollivier O Terpstra Wim E WE Boersma Rinske S RS Mazure Dominiek D Triffet Agnes A Tick Lidwine W LW Beel Karolien K Maertens Johan A JA Beverloo H Berna HB Bakkus Marleen M Homburg Christa H E CHE de Haas Valerie V van der Velden Vincent H J VHJ Cornelissen Jan J JJ

Blood advances 20220201 4

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 med ...[more]

PMID: 34883506

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Project description:Acute myeloid leukemia (AML) is an aggressive hematological malignancy with a globally poor outcome, especially in patients ineligible for intensive chemotherapy. Until recently, therapeutic options for these patients included low-dose cytarabine (LDAC) or the hypomethylating agents (HMA) azacitidine and decitabine, which have historically provided only short-lived and modest benefits. The oral B-cell lymphoma 2 inhibitor, venetoclax, Venetoclax, an oral B-cell lymphoma 2 (BCL2) inhibitor, is now approved by the USA Food and Drug Administration (FDA) in combination with LDAC or HMA in older AML patients ineligible for intensive chemotherapy. Is now approved by the US Food and Drug Administration for this indication. In the pivotal clinical trials evaluating venetoclax either in combination with LDAC or with HMA, the rates of complete remission (CR) plus CR with incomplete hematological recovery were 54% and 67%, respectively and the median overall survival (OS) was 10.4 months and 17.5 months, respectively, comparing favorably with outcomes in clinical trials evaluating single-agent LDAC or HMA. The most common adverse events with venetoclax combinations are gastrointestinal symptoms, which are primarily low grade and easily manageable, and myelosuppression, which may require delays between cycles, granulocyte colony-stimulating factor (G-CSF) administration, or decreased duration of venetoclax administration per cycle. A bone marrow assessment after the first cycle of treatment is critical to determine dosing and timing of subsequent cycles, as most patients will achieve their best response after one cycle. Appropriate prophylactic measures can reduce the risk of venetoclax-induced tumor lysis syndrome. In this review, we present clinical data from the pivotal trials evaluating venetoclax-based combinations in older patients ineligible for intensive chemotherapy, and provide practical recommendations for the prevention and management of adverse events associated with venetoclax.

Dataset Information

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

Publications

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

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