Efficacy and Toxicity of Frontline Ponatinib Plus Blinatumomab for Adult Ph+ ALL Patients of All Ages. Intermediate Analysis of the Gimema ALL2820

Introduction. The outcome of adult patients with newly diagnosed Philadelphia positive acute lymphoblastic leukemia (Ph+ ALL) has markedly improved in recent years, first due to the introduction of tyrosine kinase inhibitors (TKI) and more recently with the combination with immunotherapy (blinatumomab). In the previous GIMEMA LAL2116 trial, we showed the effectiveness of a chemo-free approach based on dasatinib followed by blinatumomab (Foà et al, NEJM 2020), with long-term (median follow-up 53 months) overall survival (OS) and disease-free survival (DFS) of 80.7% and 75.8%, respectively (Foà et al, JCO 2023). Nine relapses were recorded. To improve the results obtained and reduce relapses, in the experimental arm of the current phase III trial ALL2820 trial, ponatinib was used in place of dasatinib. The trial is expected to complete enrolment in 2024. Here we report the updated results in terms of complete hematologic remission (CHR), measurable residual disease (MRD) and OS, as well as toxicity profile of the experimental arm.

Methods. Between September 2021 and July 2024, 200 newly diagnosed adult Ph+ ALL patients were enrolled. One hundred thirty three patients were randomized to the experimental arm that contemplated a steroid pre-phase followed by a 70-day induction with ponatinib at 45 mg or 30 mg according to age (less or more than 65 years) followed by at least 2 cycles (maximum 5) of blinatumomab. Median age was 57 years (20-87), 27% of patients being >65 years; 52% were female, the white blood count was 11x10⁹/l (1-244); the p190 protein was detected in 70% of cases and 30% carried the p210 or 190/p210 protein.

Results. By the end of the induction, 110 patients (95%) achieved a CHR; 4 (3%) died in induction (pneumonia in 2, ileus paralyticus in 1 and death of unknown causes in 1) and 2 (1.5%) went off-study due to cardiac toxicity, while being in CHR. The remaining 17 cases are still receiving induction. A MRD response (complete molecular response plus positive non quantifiable) was recorded in 45% of cases.

By the end of the second cycle of blinatumomab, 93 of the 95 evaluable patients (98%) were in CHR, 1 withdraw consent due to non-compliance and 1 experienced a hematologic relapse. MRD response raised to 73%.

Overall, 52 grade >3 adverse events due to ponatinib were recorded, the most frequent being hepatic (20), hematologic (12) and pancreatic (8); cardiac toxicities were relatively rare, with only 5 events; finally, 5 infectious episodes (2 sepsis) and 2 cutaneous events were also reported.

The combination of ponatinib with blinatumomab led to 18 grade >3 adverse events: 8 were hematologic (5 in a single case), 4 were infections, 2 cytokine release syndromes and 2 neurologic related events were documented, as well as 2 gastrointestinal events.

Forty percent of patients required a dose reduction and/or a transient interruption: the most frequent toxicities were represented by grade 3 transaminitis in 10 patients and grade 2 in 6; an increase in pancreatic enzymes was observed in 6 cases (4 grade 3 and 2 grade 2); a cardiac toxicity was recorded in 6 patients, leading to a permanent discontinuation only in 2 cases. Other adverse events requiring a dose reduction were cutaneous rush, pharyngeal abscess, COVID-19 infection, and hematologic toxicity, documented in 1 case each. There was not a significant enrichment of toxicity leading to dose reduction/transient interruption in elderly.

So far, only 3 relapses (3%) have been recorded: 1 was BCR::ABL1-negative, suggesting the presence at diagnosis of a non Ph+ subclone, and 1 was recorded in a case who discontinued treatment for cardiovascular toxicity. Transplant allocation was based on an IKZF1^plus profile at presentation and MRD persistence; so far, only 12% of patients have been allografted. At a median follow-up of 6.4 months (range 0.1-32.3), the estimated 18-month OS is 91.6%.

Conclusions. The intermediate analysis of the GIMEMA ALL2820 trial shows the feasibility and efficacy of a frontline chemo-free induction/consolidation approach with ponatinib and blinatumomab for Ph+ ALL adults of all ages. The combination was overall well tolerated, with very few treatment discontinuations, also in the elderly, suggesting that a ponatinib dose adjustment according to age may prevent severe toxicities. Lastly, with the biology-driven transplant allocation only 12% of patients have been transplanted so far.