Improved survival in Philadelphia Chromosome–Positive acute lymphoblastic leukemia with pre-transplant second- and third-generation TKIs and post-transplant prophylactic maintenance: A study from the EBMT ALWP

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Abstract Background: The use of tyrosine kinase inhibitors (TKIs) has improved the prognosis of patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). The current standard of care for fit patients involves combining TKIs with chemotherapy. Allogeneic hematopoietic cell transplantation (allo-HCT) remains a key component in the management of Ph+ ALL, particularly in patients with delayed measurable residual disease (MRD) clearance. Multiple TKIs are used in frontline therapy, including imatinib and more potent second- and third-generation TKIs. Early molecular remission is more frequently achieved with newer generation TKIs, and predicts better long-term outcomes. However, the impact of different TKIs used before and after allo-HCT on long-term clinical outcomes in Ph+ ALL remains to be explored. This study aimed to evaluate clinical outcomes associated with various TKIs used in pre-allo-HCT and the use of post-transplant TKI maintenance in patients with Ph+ ALL transplanted in first complete remission (CR1). Methods: This was a retrospective, registry-based analysis conducted using data from the European Society for Blood and Marrow Transplantation, approved by the Acute Leukemia Working Party. Adult patients (≥18 years) diagnosed with Ph+ ALL, treated with TKI-based induction therapy, and who underwent allo-HCT in CR1 regardless of MRD between 2010 and 2022 were included. The use of a prophylactic TKI was evaluated as a time dependent covariate in an adjusted Cox model. Results: A total of 958 patients were analyzed (median age: 44 years [range 18–76]; 54% male). The median time from diagnosis to transplant was 5.5 months. At the time of allo-HCT, 61% were MRD-undetectable, assessed by PCR (75%) or flow cytometry (21%). Donor types included matched related (37%), haploidentical (21%), and matched unrelated (26%). Peripheral blood stem cells were used in 84% of cases, with 79% receiving myeloablative conditioning, and 51% receiving total body irradiation. TKI use prior to transplant included imatinib (N=612, 64%), dasatinib (N=210, 22%), nilotinib (N= 96, 10%), and ponatinib (N=40, 4%). Ponatinib was used more recently (median transplant year: 2020), compared to second-generation TKIs (2018) and imatinib (2016) (p<0.001). Patients receiving ponatinib were older (median age: 51 vs. 44 vs. 45 years for ponatinib, second-generation TKIs, and imatinib, respectively; p<0.001). MAC was more frequently administered to patients treated with second-generation TKIs (86%) compared to imatinib (74%) and ponatinib (75%) (p<0.001). Other baseline characteristics, including MRD status, were balanced across groups. The 3-year post-allo-HCT prophylactic TKI incidence was 31% including imatinib, dasatinib, nilotinib and ponatinib, in 51%, 28%, 16%, and 3% respectively. After a median follow-up of 5.2 years (95%CI: 4.9-5.7), 3-year overall survival (OS) was 73% (95% CI: 70–76), and the OS with imatinib was 70%, dasatinib 78%, nilotinib 81%, and ponatinib 84%. Three-year leukemia-free survival (LFS) was 62% (95% CI: 59–65): imatinib 57%, dasatinib 69%, nilotinib 75%, ponatinib 70%. The 3-year relapse incidence was 21%: imatinib 24%, dasatinib 14%, nilotinib 13%, ponatinib 22%. Graft-versus-host disease-free, relapse-free survival was 47%: imatinib 43%, dasatinib 53%, nilotinib 51%, ponatinib 65%. Multivariable analysis showed that use of pre-transplant TKIs other than imatinib was independently associated with improved LFS (hazard ratio [HR]: 0.75; 95% CI: 0.58–0.97; p=0.03). Increasing age negatively affected both LFS (HR: 1.06; p=0.008) and OS (HR: 1.12; p<0.001). Use of a prophylactic post-allo-HCT TKI was associated with significantly improved LFS (HR: 0.62; 95% CI: 0.47–0.81) and OS (HR: 0.50; 95% CI: 0.36–0.70), both p<0.001. There was no significant interaction effect on OS between MRD status at HCT and prophylactic TKI use. Donor type, TBI use, and pre-transplant MRD status were not significant predictors of survival outcomes. Conclusion: In this large, multicenter cohort of patients with Ph+ ALL undergoing allo-HCT in CR1, the use of second- and third-generation TKIs during induction was associated with superior survival outcomes compared to imatinib. Post-transplant TKI prophylaxis significantly improved LFS and OS, regardless of pre-transplant MRD status. These findings support the incorporation of newer TKIs and prophylactic strategies in the transplant setting to optimize long-term outcomes in Ph+ ALL.

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