TY - JOUR
T1 - Benefits and risks of clofarabine in adult acute lymphoblastic leukemia investigated in depth by multi-state modeling
AU - Hermans, Sjoerd J.F.
AU - van Norden, Yvette
AU - Versluis, Jurjen
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 - van der Velden, Vincent H.J.
AU - de Wreede, Liesbeth C.
AU - Postmus, Douwe
AU - Pignatti, Francesco
AU - Cornelissen, Jan J.
N1 - Publisher Copyright:
© 2024 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.
PY - 2024/5
Y1 - 2024/5
N2 - Background: We recently reported results of the prospective, open-label HOVON-100 trial in 334 adult patients with acute lymphoblastic leukemia (ALL) randomized to first-line treatment with or without clofarabine (CLO). No improvement of event-free survival (EFS) was observed, while a higher proportion of patients receiving CLO obtained minimal residual disease (MRD) negativity. Aim: In order to investigate the effects of CLO in more depth, two multi-state models were developed to identify why CLO did not show a long-term survival benefit despite more MRD-negativity. Methods: The first model evaluated the effect of CLO on going off-protocol (not due to refractory disease/relapse, completion or death) as a proxy of severe treatment-related toxicity, while the second model evaluated the effect of CLO on obtaining MRD negativity. The subsequent impact of these intermediate events on death or relapsed/refractory disease was assessed in both models. Results: Overall, patients receiving CLO went off-protocol more frequently than control patients (35/168 [21%] vs. 18/166 [11%], p = 0.019; HR 2.00 [1.13–3.52], p = 0.02), especially during maintenance (13/44 [30%] vs. 6/56 [11%]; HR 2.85 [95%CI 1.08–7.50], p = 0.035). Going off-protocol was, however, not associated with more relapse or death. Patients in the CLO arm showed a trend towards an increased rate of MRD-negativity compared with control patients (HR MRD-negativity: 1.35 [0.95–1.91], p = 0.10), which did not translate into a significant survival benefit. Conclusion: We conclude that the intermediate states, i.e., going off-protocol and MRD-negativity, were affected by adding CLO, but these transitions were not associated with subsequent survival estimates, suggesting relatively modest antileukemic activity in ALL.
AB - Background: We recently reported results of the prospective, open-label HOVON-100 trial in 334 adult patients with acute lymphoblastic leukemia (ALL) randomized to first-line treatment with or without clofarabine (CLO). No improvement of event-free survival (EFS) was observed, while a higher proportion of patients receiving CLO obtained minimal residual disease (MRD) negativity. Aim: In order to investigate the effects of CLO in more depth, two multi-state models were developed to identify why CLO did not show a long-term survival benefit despite more MRD-negativity. Methods: The first model evaluated the effect of CLO on going off-protocol (not due to refractory disease/relapse, completion or death) as a proxy of severe treatment-related toxicity, while the second model evaluated the effect of CLO on obtaining MRD negativity. The subsequent impact of these intermediate events on death or relapsed/refractory disease was assessed in both models. Results: Overall, patients receiving CLO went off-protocol more frequently than control patients (35/168 [21%] vs. 18/166 [11%], p = 0.019; HR 2.00 [1.13–3.52], p = 0.02), especially during maintenance (13/44 [30%] vs. 6/56 [11%]; HR 2.85 [95%CI 1.08–7.50], p = 0.035). Going off-protocol was, however, not associated with more relapse or death. Patients in the CLO arm showed a trend towards an increased rate of MRD-negativity compared with control patients (HR MRD-negativity: 1.35 [0.95–1.91], p = 0.10), which did not translate into a significant survival benefit. Conclusion: We conclude that the intermediate states, i.e., going off-protocol and MRD-negativity, were affected by adding CLO, but these transitions were not associated with subsequent survival estimates, suggesting relatively modest antileukemic activity in ALL.
UR - http://www.scopus.com/inward/record.url?scp=85191706174&partnerID=8YFLogxK
U2 - 10.1002/cam4.6756
DO - 10.1002/cam4.6756
M3 - Article
C2 - 38680089
AN - SCOPUS:85191706174
SN - 2045-7634
VL - 13
JO - Cancer Medicine
JF - Cancer Medicine
IS - 9
M1 - e6756
ER -
