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. We developed two multi‐state models to identify in more depth why clofarabine (CLO) did not show a long‐term survival benefit despite more MRD‐negativity, as recently reported in the HOVON‐100 trial. Patients receiving CLO went off‐protocol (indicated by the left figures) more frequently than control patients (HR 2.00 1.13–3.52, p = 0.02)—especially during maintenance (HR 2.85 95%CI 1.08–7.50, p = 0.035)—and showed a trend towards an increased rate of MRD‐negativity (indicated by the right figures) (HR 1.35 0.95–1.91, p = 0.10); however, neither transition significantly affected subsequent survival estimates. 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.