Randomized comparison of ponatinib versus imatinib in combination with chemotherapy in patients 55 years of age and older with newly diagnosed ph+ ALL: Molecular response and initial outcome analysis of the EWALL PH03 Study Free

:ABL1 tyrosine kinase inhibitors (TKIs) plus reduced intensity chemotherapy are considered standard of care for older patients (pts) with newly diagnosed Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL), but disease progression is common with first- or second-generation TKI. A recent registration trial (Jabbour E et al, JAMA 2024;331:1814-23) in adult patients indicates that the 3^rd-generation TKI ponatinib (PON) induces a higher rate of molecular responses than imatinib (IM) when combined with chemotherapy. Moreover, the bispecific T-cell engager blinatumomab (BLIN) has emerged as a potent front-line modality in Ph+ALL. This randomized European Working Group on Adult ALL (EWALL) PH03 study (EudraCT: 2018-003350-25) was initially designed as a three-arm trial to compare PON with IM in combination with chemotherapy in older pts with Ph+ALL, a third exploratory chemotherapy-free study arm combined PON with BLIN.

Eligible pts were ≥55y with newly diagnosed Ph+ ALL, an ECOG performance status score ≤2, and no clinically significant or uncontrolled cardiovascular or central nervous system disease. Patients were initially randomized in a 1:1:1 ratio, to receive the EWALL reduced-intensity chemotherapy (Rousselot et al, Blood,2016;128:774-82) combined with either PON (30mg/d)(Arm 1) or IM (800mg/d during induction, 600mg/d thereafter)(Arm 2) or PON combined with 5 cycles BLIN (Arm 3). CNS-directed prophylaxis was given per EWALL backbone. Following withdrawal of support for BLIN, the trial was amended to a two-armed trial with 1:1 randomization between IM and PON. Primary end point of this trial was measurable residual disease (MRD)-response (≤0.01% BCR::ABL1 [MR4]) after consolidation cycle 2, centrally assessed by qRT-PCR. Key secondary end point was event-free survival (EFS).

72 pts (median age, 66.8y; 29 [40.3%] female) were randomized (PON:n=36; IM:n=36) into study arms 1 and 2 and are included in this interim analysis, 10 pts were randomized to the PON+BLIN arms and will be reported separately. The complete remission rate after induction was 94% and 91% with PON and IM, respectively. 3 pts died (PON:n=2; IM:n=1) before reaching the primary endpoint (pre-consolidation 3) and 3 pts withdrew from trial treatment. The primary endpoint analysis (n=66 pts) showed a molecular remission (BCR::ABL1^IS ≤0.01%; MR4) in 64.7% (22/34 evaluable pts.) treated with PON and 43.8% (14/32 pts.) treated with IM (p=0.11). Complete molecular remissions (BCR-ABL not detectable (<0,0032%) with a quantitative range ≥10^-4.5) were achieved by 12/34 pts. (35.3%) and 9/32 pts. (28.1%) in the PON and IM arms, respectively. Up to the primary endpoint, 3 pts died (PON: n=2; IM: n=1) and 13 withdrew from trial treatment (PON: n=4, 11.1%; IM: n=9, 25%). Main reasons for withdrawal from study treatment were transfer to allogeneic stem cell transplantation (PON:n=2; IM:n=1), relapse (PON:n=0; IM:n=1) and intolerance to trial medication (PON:n=0; IM:n=2).

Adverse event rates were comparable between the PON and IM groups, including grade (G) 3 or 4 treatment-emergent adverse events (TEAEs) and treatment-related adverse events (65.6% and 59.3%, respectively). The most common G3 or G4 hematologic TEAEs were decreased platelet count (PON, 72.2%; IM, 77.8%), WBC count (66.7% and 86.1%, respectively), and ANC (77.8% and 88.9%, respectively). The most common G3 or G4 non-hematologic TEAEs were increased alanine aminotransferase (PON, 27.8%; IM, 2.8%) and increased lipase (8.3% and 0%, respectively), hypertension (11.1% and 2.8% respectively) and hypokalemia (0% and 5.6%, respectively). Pancreatitis occurred in 8.3% of pts in the PON group and 0% of pts in the IM group (no serious events). There was no significant difference in the incidence of severe cardiovascular events (PON:n=2; IM:n=0). Peripheral arterial occlusive disease and venous thrombosis (both G3) occurred in 2/36 pts receiving PON. For all pts (n=72), median EFS and overall survival was 6.44 months (IQR:2.6-12.06; range: 0.66-15.47) and 16.07 months (IQR: 2.96-17.28; range: 0.66-30.36), respectively.

Conclusion: In older pts with Ph+ALL receiving upfront reduced-intensity chemotherapy (EWALL), PON induces a higher, albeit not significant, deep molecular response rate compared to IM, The safety profile of PON was consistent with known AEs and did not lead to a higher rate of withdrawals from study treatment than IM. The impact on survival will require longer follow-up.