The impact of first line tyrosine kinase inhibitors (TKI) on the development of resistance mutations in patients with Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL)

Abstract

Abstract Introduction: Since the introduction of ABL-specific tyrosine kinase inhibitors (TKI), the prognosis for adults with Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) has drastically improved; however, a subset of patients will still relapse after the development of resistance mutations. A recent study demonstrated a significantly higher measurable residual disease negative (MRD-) complete remission when patients with Ph+ ALL received a the 3rd generation TKIs ponatinib (Pon) as part of first line (1L) therapy as compared to the 1st generation TKI Imatinib (Imat), possibly due to ponatinib's ability to prevent or overcome the T315I mutation. This study investigated the impact of 1L TKI, including 2nd generation TKIs, on development of resistance mutations in pts with Ph+ ALL. Methods: We conducted a retrospective cohort analysis in pts with Ph+ ALL who underwent initial treatment for their leukemia at Oregon Health & Science University between the years of 2010-2025. Pts included were >18 yrs and received a TKI as part of their induction therapy. The primary outcome was the incidence of relapse, which was defined as return of MRD, increase in MRD prompting a change in TKI therapy, morphologic relapse of >5% blasts in the bone marrow, development of extramedullary disease (EMD) or central nervous system (CNS) relapse. Secondary outcomes included time to relapse, developed of a resistance mutation at relapse and type of mutation that developed. Results: We identified 67 pts with Ph+ ALL that received TKI therapy as part of their induction regimen. The median age was 42.5 years (range 20-88 yrs), 59.7% of pts were female (n=40) and the majority were white (85%), with 6% Hispanic, 4% African American and 4% Asian pts. The median WBC count at diagnosis was 16.0 (range: 0.7-353) x 109/L 33 (49.3%) patients had a p190 transcript, 22 (44.8%) a p210 and 12 (18%) unknown. The majority of patients received das (n=50, 74.6%), 9 (13.4 %) pts received imat and 8 (11.9%) pts received pon as 1L TKI. Backbone treatment regimens included steroids alone (n=26, 39%), hyperCVAD (n=19, 28%), low intensity chemotherapy on the PHALLCON clinical trial (n=9, 13%), steroids and vincristine (n=5, 7%), blinatumomab (n=3, 4%), EWALL (n=2, 3%) and one patient each received ECOG1910, Linker regimen and CALGB8811/9111. Within the cohort, all pts achieved a complete morphologic remission, of which 31 pts eventually relapsed (46%). The median time to relapse was 11 months (mo) (range 2mo – 6.6 years) and sites of relapse included marrow (n=20), isolated EMD (n=2), return of MRD positivity (n=4), isolated CNS (n=2) and multiple sites (n=3). There were minimal demographic differences between relapsed (rel) and pts with sustained remission (SR) however 51% of rel patients received only steroids as their backbone regimen vs 27.7% of pts with SR. 1L TKI in the relapsed patients was das (n=27, 87%), imat (n=3, 10% and pon (n=1, 3%), 25 of 31 relapsed patients (80.6%) were on or had only been treated with their 1L TKI at the time of relapse. Of the 31 rel pts, 22 pts (71% of rel patients) developed an ABL mutation, 5 pts had unknown mutation status (16%), and 2 pts had no mutation detected (3%). The most common mutation was the T315I (n=13,12 pts T315I alone, 1 pt T315I + F359V mutations); all of the pts who developed this mutation received das as their 1L TKI Other mutations that developed in pts treated with das as their 1L TKI included F359V (1), G250E (1), F317L (1), L384M (1), L387M(1), E255V (1) and F317L + E255K (1). In total, 29 of the 50 pts who received 1L das relapsed (58%). Of the 9 patients treated with 1L imatinib, 3 progressed (33%) 2 developed mutations, 2 in E255K and 1 unknown. Of the 8 pts who received pon as 1L TKI, 1(12.5%) developed a mutation (F317L). Discussion: This is the first study to look at the impact of frontline TKI on the development of resistance mutations in Ph+ ALL. A notable number of patients treated with the 2nd generation TKI dasatinib as 1L TKI developed resistance mutations, primarily T315I. Notably few patients in this study received 1L blinatumomab, which is expected to reduce the rate of relapse. A larger multicenter study incorporating more patients treated with 1st and 3rd generation TKIs and upfront immumotherapy is warranted to confirm these results.