Relapse with post-transplant tyrosine kinase inhibitor (TKI) maintenance therapy in phliladelphia chromosome positive acute lymphoblastic leukemia (Ph+ALL) after allogeneic hematopoietic stem cell transplantation: Incidence and risk factor analysis

Abstract

Abstract Introduction Post-transplant maintenance (PTM) therapy with tyrosine kinase inhibitors (TKIs) is increasingly utilized in contemporary clinical practice for Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) following allogeneic hematopoietic stem cell transplantation (HCT). Despite widespread use, the efficacy of TKI-based PTM remains uncertain, with relapse rates post-HCT around 20–30%. TKI may lower relapse risk but does not eliminate it. We previously reported that TKI-based PTM in Ph+ ALL was associated with improved relapse-free survival (RFS) following allogeneic HCT in 245 Ph+ ALL patients (ASH 2024). The current study further evaluated the incidence of relapse in 126 Ph+ ALL patients received TKI-based PTM, analysed the risk factor for relapse, and explored the potential for additional therapeutic interventions beyond TKI maintenance to further improve outcomes in this population. Patients and method We conducted a multicenter, retrospective analysis in 126 patients (51.4%) received PTM with TKIs, from 245 patients with Ph+ ALL who underwent their first allogeneic HCT in complete remission from 4 countries (Canada, Germany, Saudi Arabia and China). The primary endpoint was the cumulative incidence of relapse (CIR) following TKI-based PTM. Secondary endpoints included RFS, overall survival (OS), non-relapse mortality (NRM), and chronic graft-versus-host disease (cGvHD), after initiation of TKI-based PTM. The OS and RFS were calculated using Kaplan-Meier method and compared with log-rank test. CIR, NRM, and cGvHD were assessed accounting for competing events and analyzed using Fine-Gray model. Results Out of 126 pts received PTM, ABL1 kinase-domain mutation (KDM) was detected in 13 pts prior to HCT: T315I (n=7) and others (n=6). The median time to start PTM was 3 months (range: 0.5-115 months) after HCT. Dasatinib was most frequently used (n=56) followed by imatinib (n=32), ponatinib (n=31), or other TKIs (n=7). The median dose of TKI for maintenance was dasatinib 50 mg (range 50-140 mg), imatinib 400 mg (100-600 mg) and ponatinib 15 mg (15-45 mg), while PTM was maintained for a median duration of 23 months (range: 0-163 months). Out of 126 pts who received TKI-PTM, TKI-PTM was discontinued in 63 (50%) pts, of whom 22 pts completed the planned treatment of 2 years, while 29 pts discontinued due to either relapse (n=25), TKI-related toxicity (n=13) and death (n=3). With a median follow-up duration of 32 months, there was 7pts (8%) relapsed in the PTM group, among whom 6 pts relapsed during PTM therapy and 1 pts relapsed after PTM stopped due to toxicity. The incidence of relapse after PTM starts was 11.5%, 12.8%, 16.8% and 16.8% at 2, 3, 4 and 5 years, respectively, showing a plateau of relapse incidence after 4 years. Between the pts relapse during PTM and those not, the patient and disease characteristics did not show any difference in age (median 40 vs 38 years, p=0.78), sex (p=0.33), BCR-ABL qPCR level prior to HCT (p=0.19), remission status prior to HCT (CR1 vs CR2/beyond, p=1.0) or type of TKI (p=0.6). However, a significant difference was observed with respect to the presence of ABL kinase mutation (T315I vs. other mutations vs no ABL1 mutation, n=5 (18.5%), n=5 (18.5%) and n=17 (63%) vs n=2 (2%), n=1 (1%), 96 (97%), p≤0.001). A total of 34 (27%) deaths were observed out of 126 pts with 74.4% of OS rate, 67.9% of RFS rate, 12.8% of CIR, 14% of NRM and 10% of cGvHD incidence at 3 years. In the multivariate analysis, ABL1-KDM status was significantly associated with increased relapse risk (HR 2.755, [95% CI 1.520–4.993], p = 0.00084). Of interest, cGvHD development during PTM-TKI did not show to reduce the risk of relapse without statistical significance (HR 0.63 [0.08-4.75], p = 0.65). Also, there is no difference in the risk of relapse (p=0.799), OS (p=0.876), RFS (p=0.754), NRM (p=0.806) or cGvHD incidence (p=0.307) according to their policy for TKI-PTM duration (2 years vs 5 years). Conclusion The incidence of relapse during TKI-based PTM was plateaued up to 16.8% at 4 years. Increased risk of relapse was noted especially in patients with ABL1-KDM, notably T315I, highlighting the need for ABL1-KDM-guided therapies. Of note, reduced risk of relapse with cGvHD development was not observed, thus not supporting addition of prophylactic donor lymphocyte infusion in the group receiving TKI-PTM. Further studies with larger number of patients are needed to reach a clearer conclusion on this.