Exploring Factors Supporting TKI Discontinuation in Patients With Ph+ ALL
Recent studies reveal promising outcomes for discontinuing TKI therapy in select patients with Philadelphia chromosome-positive acute lymphoblastic leukemia, suggesting potential long-term remission.
White blood cells in leukemia, AI generative: © Катерина Євтехова - stock.adobe.com
Over the past 2 decades, Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ ALL) has undergone a deep therapeutic transformation. Once associated with a dismal prognosis and poor long-term survival, it is now considered a potentially curable disease.1,2 This shift has been primarily driven by the introduction of tyrosine kinase inhibitors (TKIs), which have redefined the standard of care. In addition, the combination of TKIs plus chemotherapy or chemotherapy-free regimen has significantly improved the prognosis while reducing toxicity. More recently, immunotherapeutic strategies, particularly the combination of TKIs with the bispecific T-cell engager blinatumomab (Blincyto), targeting CD3 and CD19 have further expanded treatment options, enabling deeper remissions and broader transplant-free strategies.3,4
Equally impactful has been the improved understanding of the molecular pathogenesis of Ph+ ALL. The identification of additional genetic lesions, such as IKZF1plus and ABL-class mutations, has refined risk stratification and driven therapeutic decisions. Moreover, increasingly sensitive molecular techniques for measurable residual disease detection applied at well-defined time points have enabled more precise response assessment.5,6
Considering these advances and in light of findings from recent clinical trials showing that long-term survival is possible for patients with Ph+ ALL without allogeneic hematopoietic stem cell transplant (allo-HSCT), the decision to proceed with transplant has, paradoxically, become increasingly complex. Another area of growing clinical interest is the potential discontinuation of TKI therapy in patients who do not undergo allo-HSCT.
To date, 3 retrospective series—Samra et al, Kugler et al, and Dragani et al—have explored the feasibility of treatment-free remission (TFR) in adult patients with Ph+ ALL who did not undergo allo-HSCT.7-9 Samra et al reported outcomes from a subgroup of 9 patients who discontinued TKI therapy due to adverse events.7 The median duration of TKI therapy and deep molecular response (DMR) was 70 and 47 months, respectively. Among them, 3 patients (33%) experienced a molecular relapse, occurring at a median of 6 months after discontinuation. All 3 patients resumed TKI treatment, and 2 subsequently regained DMR after a median of 13 months. After a median follow-up of 49 months, the median TFR was not reached and the estimated 4-year TFR rate was 65%. The median duration of prior DMR was 22 months in patients who experienced relapse compared with 58 months in those who maintained remission (P =.096).
Dragani et al reported on retrospective data for 18 patients who discontinued TKI because of adverse events.9 The median time of TKI exposure prior to discontinuation was 84.5 months. Twenty-eight percent (5 of 18) of patients experienced molecular relapse. The median follow-up was 10 years (range, 0.8-26). The median overall survival (OS) was not reached, and the 5-year OS was 79%. Notably, the median recurrence-free survival (RFS) was not reached whereas the 5-year RFS was 63%.
Finally, Kugler et al reported on retrospective data about 14 patients with Ph+ ALL who were in first complete remission and who stopped TKI after a median duration of 60 months.8 The median complete molecular remission (CMR) duration before TKI discontinuation was 46.1 months (range, 2.7-121.3).
After a median follow-up of 42.5 months after TKI discontinuation, 3 patients (21%) experienced relapse (2 had molecular, 1 had morphologic) whereas 11 patients (79%) maintained TFR. The median time to relapse was 6.4 months (range, 4-16), and 2 of 3 patients who experienced relapse regained CMR after resuming TKI therapy. The median TFR was not reached, and the TFR rate was 85% at 12 months and 75% at 36 months.
Taken together, findings from these retrospective studies with relatively median long-term follow-up consistently suggest that TKI discontinuation is a feasible and potentially safe strategy in select patients with Ph+ ALL who have not undergone allo-HSCT. Notably, in findings from the studies by Kugler et al and Dragani et al, the median TFR and RFS were not reached, underscoring the possibility of long-term disease control off therapy.
A consistent finding across studies is the low rate of patients experiencing molecular relapse after TKI discontinuation, which ranges from 21% to 33%. Importantly, most patients who experienced relapse responded promptly to reinitiation of the same TKI, often regaining molecular remission.
Across all 3 cohorts, molecular relapses occurred early—within 4 to 6 months of TKI cessation—highlighting the critical need for close molecular monitoring during this high-risk period. A further consistent observation is that patients with a longer duration of deep molecular remission prior to TKI discontinuation were less likely to experience relapse, suggesting they may represent the most suitable candidates for this approach.
Although these studies provide encouraging signals supporting the TKI discontinuation in a subset of patients with Ph+ ALL, several limitations should be acknowledged. Among these are the retrospective nature of the data, the small sample sizes, and the heterogeneity in frontline treatment regimens, ranging from intensive chemotherapy plus TKI to mild chemotherapy combinations to chemotherapy-free protocols incorporating TKIs and blinatumomab. Prospective studies, ideally conducted within the framework of well-designed clinical trials, are urgently needed to validate these preliminary observations, define optimal eligibility criteria, and establish standardized molecular monitoring protocols in the context of TKI discontinuation.
