Cancer Medicine (May 2024)

Benefits and risks of clofarabine in adult acute lymphoblastic leukemia investigated in depth by multi‐state modeling

  • Sjoerd J. F. Hermans,
  • Yvette vanNorden,
  • Jurjen Versluis,
  • Anita W. Rijneveld,
  • Bronno van derHolt,
  • Okke deWeerdt,
  • Bart J. Biemond,
  • Arjan A. van deLoosdrecht,
  • Lotte E. van derWagen,
  • Mar Bellido,
  • Michel vanGelder,
  • Walter J. F. M. van derVelden,
  • Dominik Selleslag,
  • Daniëlle vanLammeren‐Venema,
  • Vincent H. J. van derVelden,
  • Liesbeth C. deWreede,
  • Douwe Postmus,
  • Francesco Pignatti,
  • Jan J. Cornelissen

DOI
https://doi.org/10.1002/cam4.6756
Journal volume & issue
Vol. 13, no. 9
pp. n/a – n/a

Abstract

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Abstract 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.

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