First results of the Phase III GIMEMA ALL2820 trial comparing ponatinib plus blinatumomab to imatinib and chemotherapy for newly diagnosed adult ph+ acute lymphoblastic leukemia patients Free

Introduction. The outcome of adult Ph+ ALL has improved with the introduction of tyrosine kinase inhibitors (TKI) and, more recently, the addition of immunotherapy, i.e. blinatumomab, as shown by the GIMEMA LAL2116 trial (Foà et al, NEJM 2020 & JCO 2024). To improve the results and formally compare the efficacy and safety of a chemo-free approach to a strategy based on a TKI + chemotherapy, the GIMEMA phase III ALL2820 protocol (2:1 random) was designed for newly diagnosed adult Ph+ ALL (>18 years, no upper age limit). We report the first results of both treatment arms, in terms of complete hematologic remission (CHR), safety and toxicity, measurable residual disease (MRD, i.e. complete molecular response and positive non-quantifiable) after induction (day +70) and after 2 cycles of blinatumomab/therapy (day +133) by intention-to-treat, and event-free survival (EFS).

Methods. The experimental (exp) arm was based on a steroid pre-phase followed by a 70-day induction with ponatinib at 45 or 30 mg according to age (< or >65 years) and at least 2 cycles (maximum 5) of i.v. blinatumomab. The control (cont) arm was based on imatinib 800 or 600 mg daily, depending on age (< or >65 years) + chemotherapy (6 or 4 cycles for patients < or >65 years). Response to induction was evaluated at day +70 after ponatinib or after 3 chemotherapy courses in the exp and cont arm, respectively. MRD response was set at day +133 (after 2 blinatumomab cycles or 4/6 chemotherapy cycles). A crossover to the exp arm was foreseen in MRD+ patients (pts) after cycle 4/6, or earlier in case of refractoriness or mutation development.

Results. Between September 2021 and January 2025, 236 pts were enrolled, 158 in the exp and 78 in the cont arm. Features did not differ among the 2 arms (exp and cont arm): median age 57 (19-84) vs 55 (20-80) years (28% and 27% patients >65 years), male gender 50% vs 59%, median white blood count (WBC) 11x10⁹/l (0.3-244) vs 18x10⁹/l (1-231), p190 fusion protein 70% vs 63%, p210 and/or p190/p210 30% vs 37%, IKZF1 deletion 34% vs 49%, IKZF1^plus34% vs 26%, no IKZF1 deletion 32% vs 26%. At the end of induction, there was a significantly higher CHR rate in the exp arm: 94.4% vs 79.4% (p=0.001). Non-CHR attainment in the exp arm were due to 6 (3.8%) deaths (pneumonia 4, paralyticus ileus 1, unknown cause 1), 1 early toxicity and subsequent relapse (0.6%), and 2 (1.2%) pts off study for cardiac toxicity while in CHR. In the cont arm, 8 (10.2%) pts died (septic shock 4, renal failure 1, cognitive deterioration 1, heart attack 1, pulmonary hemorrhage 1), 3 (3.8%) went off trial for toxicity, 2 withdrew consent (2.6%) and 3 (3.8%) were refractory. MRD response after induction was superimposable: 46.8% and 43.6% in the exp and cont arm. At day +133, MRD responses were higher in the exp arm: 111 (70.2%) compared to 41 (52.7%) (p=0.009). The % of pts becoming MRD- after further blinatumomab cycles rose to 80.3%. As per protocol, 29 (37.2%) pts in the cont arm crossed to the exp arm, 4 (13.8%) at very early time-points (1 refractoriness, 3 mutations). The crossover led to 18 (62.1%) pts becoming MRD-. So far, 10 relapses (4.2%) have occurred (median time to relapse 5 months), 7 (4.4%) in the exp and 3 (3.8%) in the cont arm. In both arms, 1 BCR::ABL1- relapse was detected, suggesting the presence of a Ph- subclone at diagnosis. In relapsed pts, the median WBC count was 22.4 x10⁹/l (2.4-144) and 10.4 x10⁹/l (2.7-11.7) in the exp and cont arm; the IKZF1^plus signature was identified only in 4 cases of the exp arm.Three relapses of the exp arm occurred in pts who discontinued treatment. Three additional deaths in 1^st CHR were recorded, 2 after allogeneic transplant and 1 for clinical deterioration.

The 18-months EFS (median follow-up 19.6 months, range 0.1-44) showed a significant advantage for the exp arm: 89.9%, CI: 85.1-94.9% vs 76.8%, CI: 67.6-87.3% (p=0.011).

Conclusions. The first results of the phase III GIMEMA ALL2820 trial show for the first time in a head-to-head comparison a significant advantage of a chemo-free targeted/immunotherapeutic strategy over a TKI/chemotherapy approach, with higher CHR and MRD responses, increasing further after additional blinatumomab cycles, fewer deaths and improved EFS. Compared to the GIMEMA LAL2116 trial, an increase in MRD negativity and less relapses were observed. A chemo-free approach should be the new standard for adult Ph+ ALL.