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; Arjan 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 van Sluis; Marie-Cecile J C Legdeur; Dries H Deeren; Alain Pa Gadisseur; Harm A M Sinnige; Dimitri Breems; Aurélie Jaspers; Ollivier Legrand; Wim E Terpstra; Rinske Boersma; Dominiek Mazure; Agnes Triffet; Lidwine Tick; Karolien Anne Beel; Johan A Maertens; H Berna Beverloo; Marleen H Bakkus; Christa Homburg; Valerie de Haas; Vincent H J van der Velden; Jan J Cornelissen

doi:10.1182/bloodadvances.2021005624

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, Arjan 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 van Sluis, Marie-Cecile J C Legdeur, Dries H Deeren, Alain Pa Gadisseur, Harm A M Sinnige, Dimitri BreemsAurélie Jaspers, Ollivier Legrand, Wim E Terpstra, Rinske Boersma, Dominiek Mazure, Agnes Triffet, Lidwine Tick, Karolien Anne Beel, Johan A Maertens, H Berna Beverloo, Marleen H Bakkus, Christa Homburg, Valerie de Haas, Vincent H J van der Velden, Jan J Cornelissen

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

Clofarabine (CLO) is a nucleoside analogue with efficacy in relapsed/refractory acute lymphoblastic leukemia (ALL). This randomized phase III study aimed to evaluate whether CLO added to induction and consolidation would improve outcome in adults with newly diagnosed ALL. Treatment for younger (18-40 years) patients consisted of a pediatric inspired protocol and for older patients (41-70 years) of a semi-intensive protocol was used. 340 patients were randomized. After a median follow up of 70 months, 5-year 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, while in patients >40 years EFS was 43% in both arms. 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 negative after consolidation 1 in arm A vs 75/81 (93%) in arm B (p=0.001). Seventy (42%) patients proceeded to allogeneic hematopoietic stem cell transplantation in both arms. Five years OS was similar in both arms, 60% vs 61%. Among patients achieving CR, relapse rates were 28% and 24%, and non-relapse 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. The trial is registered at www.trialregister.nl as NTR2004.

Original language	English
Pages (from-to)	1115–1125
Number of pages	11
Journal	Blood advances
Volume	6
Issue number	4
Early online date	9 Dec 2021
DOIs	https://doi.org/10.1182/bloodadvances.2021005624
Publication status	Published - 22 Feb 2022

Keywords

ACUTE LYMPHOBLASTIC-LEUKEMIA
MINIMAL RESIDUAL DISEASE
STEM-CELL TRANSPLANTATION
PEDIATRIC-PATIENTS
CLINICAL-SIGNIFICANCE
ONCOLOGY-GROUP
STANDARD-RISK
PHASE-II
CYCLOPHOSPHAMIDE
CHEMOTHERAPY

Access to Document

10.1182/bloodadvances.2021005624Licence: CC BY-NC-ND

Cite this

Rijneveld, A. W., van der Holt, B., de Weerdt, O., Biemond, B. J., Van de Loosdrecht, A. A., van der Wagen, L. E., Bellido, M., van Gelder, M., van der Velden, W. J. F. M., Selleslag, D., van Lammeren-Venema, D., Halkes, C. J. M., Fijnheer, R., Havelange, V., Sluis, G. V., Legdeur, M.-C. J. C., Deeren, D. H., Gadisseur, A. P., Sinnige, H. A. M., ... Cornelissen, J. J. (2022). Clofarabine added to intensive treatment in adult patients with newly diagnosed ALL: the HOVON-100 trial. Blood advances, 6(4), 1115–1125. https://doi.org/10.1182/bloodadvances.2021005624

@article{c703c131ee3d4caa8896de7ae6091b65,

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

abstract = "Clofarabine (CLO) is a nucleoside analogue with efficacy in relapsed/refractory acute lymphoblastic leukemia (ALL). This randomized phase III study aimed to evaluate whether CLO added to induction and consolidation would improve outcome in adults with newly diagnosed ALL. Treatment for younger (18-40 years) patients consisted of a pediatric inspired protocol and for older patients (41-70 years) of a semi-intensive protocol was used. 340 patients were randomized. After a median follow up of 70 months, 5-year 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, while in patients >40 years EFS was 43% in both arms. 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 negative after consolidation 1 in arm A vs 75/81 (93%) in arm B (p=0.001). Seventy (42%) patients proceeded to allogeneic hematopoietic stem cell transplantation in both arms. Five years OS was similar in both arms, 60% vs 61%. Among patients achieving CR, relapse rates were 28% and 24%, and non-relapse 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. The trial is registered at www.trialregister.nl as NTR2004.",

keywords = "ACUTE LYMPHOBLASTIC-LEUKEMIA, MINIMAL RESIDUAL DISEASE, STEM-CELL TRANSPLANTATION, PEDIATRIC-PATIENTS, CLINICAL-SIGNIFICANCE, ONCOLOGY-GROUP, STANDARD-RISK, PHASE-II, CYCLOPHOSPHAMIDE, CHEMOTHERAPY",

author = "Rijneveld, {Anita W} and {van der Holt}, Bronno and {de Weerdt}, Okke and Biemond, {Bart J} and {Van de Loosdrecht}, {Arjan A} and {van der Wagen}, {Lotte E} and Mar Bellido and {van Gelder}, Michel and {van der Velden}, {Walter J F M} and Dominik Selleslag and {van Lammeren-Venema}, Dani{\"e}lle and Halkes, {Constantijn J M} and Rob Fijnheer and Violaine Havelange and Sluis, {Geerte van} and Legdeur, {Marie-Cecile J C} and Deeren, {Dries H} and Gadisseur, {Alain Pa} and Sinnige, {Harm A M} and Dimitri Breems and Aur{\'e}lie Jaspers and Ollivier Legrand and Terpstra, {Wim E} and Rinske Boersma and Dominiek Mazure and Agnes Triffet and Lidwine Tick and Beel, {Karolien Anne} and Maertens, {Johan A} and Beverloo, {H Berna} and Bakkus, {Marleen H} and Christa Homburg and {de Haas}, Valerie and {van der Velden}, {Vincent H J} and Cornelissen, {Jan J}",

note = "Copyright {\textcopyright} 2021 American Society of Hematology.",

year = "2022",

month = feb,

day = "22",

doi = "10.1182/bloodadvances.2021005624",

language = "English",

volume = "6",

pages = "1115–1125",

journal = "Blood advances",

issn = "2473-9529",

publisher = "The American Society of Hematology",

number = "4",

}

Rijneveld, AW, van der Holt, B, de Weerdt, O, Biemond, BJ, Van de Loosdrecht, AA, van der Wagen, LE, Bellido, M, van Gelder, M, van der Velden, WJFM, Selleslag, D, van Lammeren-Venema, D, Halkes, CJM, Fijnheer, R, Havelange, V, Sluis, GV, Legdeur, M-CJC, Deeren, DH, Gadisseur, AP, Sinnige, HAM, Breems, D, Jaspers, A, Legrand, O, Terpstra, WE, Boersma, R, Mazure, D, Triffet, A, Tick, L, Beel, KA, Maertens, JA, Beverloo, HB, Bakkus, MH, Homburg, C, de Haas, V, van der Velden, VHJ & Cornelissen, JJ 2022, 'Clofarabine added to intensive treatment in adult patients with newly diagnosed ALL: the HOVON-100 trial', Blood advances, vol. 6, no. 4, pp. 1115–1125. https://doi.org/10.1182/bloodadvances.2021005624

TY - JOUR

T1 - Clofarabine added to intensive treatment in adult patients with newly diagnosed ALL

T2 - the HOVON-100 trial

AU - Rijneveld, Anita W

AU - van der Holt, Bronno

AU - de Weerdt, Okke

AU - Biemond, Bart J

AU - Van de Loosdrecht, Arjan A

AU - van der Wagen, Lotte E

AU - Bellido, Mar

AU - van Gelder, Michel

AU - van der Velden, Walter J F M

AU - Selleslag, Dominik

AU - van Lammeren-Venema, Daniëlle

AU - Halkes, Constantijn J M

AU - Fijnheer, Rob

AU - Havelange, Violaine

AU - Sluis, Geerte van

AU - Legdeur, Marie-Cecile J C

AU - Deeren, Dries H

AU - Gadisseur, Alain Pa

AU - Sinnige, Harm A M

AU - Breems, Dimitri

AU - Jaspers, Aurélie

AU - Legrand, Ollivier

AU - Terpstra, Wim E

AU - Boersma, Rinske

AU - Mazure, Dominiek

AU - Triffet, Agnes

AU - Tick, Lidwine

AU - Beel, Karolien Anne

AU - Maertens, Johan A

AU - Beverloo, H Berna

AU - Bakkus, Marleen H

AU - Homburg, Christa

AU - de Haas, Valerie

AU - van der Velden, Vincent H J

AU - Cornelissen, Jan J

PY - 2022/2/22

Y1 - 2022/2/22

N2 - Clofarabine (CLO) is a nucleoside analogue with efficacy in relapsed/refractory acute lymphoblastic leukemia (ALL). This randomized phase III study aimed to evaluate whether CLO added to induction and consolidation would improve outcome in adults with newly diagnosed ALL. Treatment for younger (18-40 years) patients consisted of a pediatric inspired protocol and for older patients (41-70 years) of a semi-intensive protocol was used. 340 patients were randomized. After a median follow up of 70 months, 5-year 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, while in patients >40 years EFS was 43% in both arms. 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 negative after consolidation 1 in arm A vs 75/81 (93%) in arm B (p=0.001). Seventy (42%) patients proceeded to allogeneic hematopoietic stem cell transplantation in both arms. Five years OS was similar in both arms, 60% vs 61%. Among patients achieving CR, relapse rates were 28% and 24%, and non-relapse 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. The trial is registered at www.trialregister.nl as NTR2004.

AB - Clofarabine (CLO) is a nucleoside analogue with efficacy in relapsed/refractory acute lymphoblastic leukemia (ALL). This randomized phase III study aimed to evaluate whether CLO added to induction and consolidation would improve outcome in adults with newly diagnosed ALL. Treatment for younger (18-40 years) patients consisted of a pediatric inspired protocol and for older patients (41-70 years) of a semi-intensive protocol was used. 340 patients were randomized. After a median follow up of 70 months, 5-year 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, while in patients >40 years EFS was 43% in both arms. 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 negative after consolidation 1 in arm A vs 75/81 (93%) in arm B (p=0.001). Seventy (42%) patients proceeded to allogeneic hematopoietic stem cell transplantation in both arms. Five years OS was similar in both arms, 60% vs 61%. Among patients achieving CR, relapse rates were 28% and 24%, and non-relapse 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. The trial is registered at www.trialregister.nl as NTR2004.

KW - ACUTE LYMPHOBLASTIC-LEUKEMIA

KW - MINIMAL RESIDUAL DISEASE

KW - STEM-CELL TRANSPLANTATION

KW - PEDIATRIC-PATIENTS

KW - CLINICAL-SIGNIFICANCE

KW - ONCOLOGY-GROUP

KW - STANDARD-RISK

KW - PHASE-II

KW - CYCLOPHOSPHAMIDE

KW - CHEMOTHERAPY

U2 - 10.1182/bloodadvances.2021005624

DO - 10.1182/bloodadvances.2021005624

M3 - Article

C2 - 34883506

SN - 2473-9529

VL - 6

SP - 1115

EP - 1125

JO - Blood advances

JF - Blood advances

IS - 4

ER -

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

Abstract

Keywords

Access to Document

Fingerprint

Cite this