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Frontline dasatinib was linked to frequent T315I mutations at relapse in Ph+ ALL, while ponatinib showed fewer resistance mutations and favorable outcomes.
Treatment with first- and second-generation TKIs was associated with a higher rate of relapse compared with third-generation inhibitors in patients with Philadelphia chromosome (Ph)–positive acute lymphoblastic leukemia (ALL), according to data from a retrospective cohort analysis that were presented at the 2025 ASH Annual Meeting & Exposition.1
“A notable number of patients treated with the second-generation TKI dasatinib as [their] first-line TKI developed resistance mutations, primarily [in] T315I,” lead study author Virginia Tan, MD, an internal medicine resident at Oregon Health and Science University in Portland, and coauthors wrote in the poster presentation. “Few patients in this study received first-line blinatumomab which is expected to reduce the rate of relapse, as this was not yet standard of care during the treatment period for the majority of these patients,” Tan added.
Adults with Ph-positive ALL have experienced improved outcomes with the advent of TKIs, but a proportion will still relapse due to the development of acquired resistance mutations. Findings from the phase 3 PhALLCON trial (NCT03589326) demonstrated that receipt of the third-generation TKI ponatinib (Iclusig) as part of frontline therapy resulted in a higher likelihood of achieving minimal residual disease (MRD)–negative complete responses vs the first-generation TKI imatinib (Gleevec) in patients with Ph-positive ALL.2 One possible rationale is ponatinib’s ability to prevent or overcome the T315I mutation, Tan explained.
To better elucidate these differences, investigators conducted a study evaluating the effect of second-generation vs third-generation TKIs on the development of resistance mutations in patients with Ph-positive ALL receiving frontline therapy.1
The analysis included patients with Ph-positive ALL who received initial antileukemia therapy at Oregon Health & Science University between 2010 and 2025.
The primary outcome was the incidence of relapse, which was characterized by the return of MRD requiring a change in TKI therapy, morphologic relapse of 5% or more blasts in the bone marrow, development of extramedullary disease, or central nervous system relapse. Secondary outcomes included the development and type of resistance mutation at relapse.
Baseline characteristics of the study cohort (n = 67) indicated that the age at diagnosis was 53 years (range, 20-88). The median white blood cell count was 16,000 (range, 500-712,000). Most patients were female (n= 40; 60%) and Caucasian (n = 57; 85%). BCR-ABL transcripts comprised p190 (n = 33; 49%), p210 (n = 22; 33%), and UK (n = 12; 18%).
Most patients had received dasatinib in the first line (n = 50; 75%), followed by imatinib (n = 9; 13%) and ponatinib (n = 8; 12%). The median overall survival was 39 months (range, 5-137) and 59 months (range, 5-154) in relapsed and non-relapsed patients, respectively.
Across the overall cohort (n = 67), frontline chemotherapy regimens were heterogeneous, with hyper-CVAD-containing regimens (n = 20; 30%) and steroid-based approaches (n = 25; 37%) most commonly used. Treatment patterns largely mirrored those of the overall population in patients who received dasatinib and imatinib (n = 59), whereas patients who received ponatinib (n = 8) more frequently had exposure to low intensity regimens on clinical trials (n = 4; 50%).
Notably, no relapse was common across the cohort, occurring in 54% (n = 36) of patients overall, 49% (n = 29) in the dasatinib/imatinib group, and 87.5% (n = 7) in the ponatinib group. Molecular analysis at relapse demonstrated a predominance of ABL1 kinase domain mutations, particularly T315I, which was observed in 42% (n = 13) of all patients and exclusively in those treated with dasatinib and imatinib. Other mutations, including F317L (n = 3; 12%), E255K (n = 2; 6%), G250E (n = 1; 3%), and L384M/L387M (n = 1; 3% each), were less frequent overall, while 22% (n = 7) of patients had unknown or unevaluable mutation status. Notably, most patients (n = 47; 72%) proceeded to allogeneic stem cell transplant. At last follow-up, 57% (n = 38) of the overall cohort remained alive, with survival rates highest in the ponatinib-treated subgroup at 100% (n = 8).
All patients in the cohort achieved a complete morphologic remission, 31 (46%) of whom experienced relapse. Tan noted that there were insignificant differences between the patients whose disease relapsed vs not, although 51% of the former group received only steroids as their backbone treatment vs 27.7% of sustained responders.
With respect to frontline therapy, most had received dasatinib (Sprycel; n = 27; 87%) compared with imatinib (n = 3; 10%) or ponatinib (n = 1; 3%). Additionally, 80.6% of patients were on or had only received their first-line TKI at the time of relapse. Of patients with relapsed disease, 21 (68%) developed an ABL mutation; the remaining patients had unknown mutation status since they relapsed with insufficient disease for sequencing (n = 6; 19%), no detectable mutation (n = 3; 10%), or unknown mutation status (n = 1; 3%).
The most prevalent mutation was T315I alone (n = 13) or co-mutated with F359V (n = 1). All these patients had received dasatinib as their frontline TKI.
Overall, 29 of the 50 patients who received dasatinib in the first line ultimately relapsed. Of the 9 patients who received imatinib in the first line 3 (33%) progressed and 2 developed mutations––one was in E255K and the other was unknown. Eight patients received ponatinib in the first line and 1 (12.5%) developed a F317L mutation.
“A larger multicenter study incorporating more patients treated with second- and third-generation TKIs and upfront immunotherapy is warranted to confirm these results,” Tan concluded.
Disclosures: No disclosures were listed for Tan.
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