LONG-TERM Results of the Frontline Dasatinib/Blinatumomabprotocol (D-ALBA, GIMEMA LAL2116) for Adult Ph+ Acutelymphoblastic Leukemia

Introduction. The prognosis of Ph+ acute lymphoblastic leukemia (ALL) has changed profoundly following the advent of tyrosine kinase inhibitors (TKIs). Since 2000, the GIMEMA frontline studies for adult Ph+ ALL patients have been based on a TKI plus steroids in induction without systemic chemotherapy. This has allowed complete hematologic remission (CHR) rates of 94-100%, irrespective of age, with virtually no deaths in induction^1-5. We then designed an induction/consolidation chemotherapy-free frontline trial with dasatinib followed by blinatumomab (GIMEMA LAL2116, D-ALBA). The preliminary results^6,7 showed a CHR rate of 98% with 60% of molecular responses at the primary endpoint of the study (after 2 blinatumomab cycles); the OS and DFS were 95% and 88% at 18 months. Here we present the final long-term results of the study.

Methods. Post-consolidation treatment was left to the treating physicians and all the information has been collected in the GIMEMA LAL2217 ancillary study. Sixty-three patients were enrolled (median age 54 years, range 24-82); 2 patients withdrew from the trial, 1 died in CHR and 1 relapsed after induction due to a major protocol violation^6,7.

Results. After the primary endpoint, molecular responses increased further following additional blinatumomab cycles, being 75, 77, 70, 85, 90 and 93% at 2, 4, 6, 8, 10 and 12 months from the last blinatumomab cycle. At a prolonged follow-up, a persistent molecular negativity was found with 78.3, 73.1, 85, 87.4, 94.2, 90.2, 86.6 and 86.7% of responders at 16, 20, 24, 28, 32, 36, 42 and 48 months in the evaluable population.

At a median follow-up of 53 months, DFS and OS are 75.8% and 80.7% (Figure 1). A significantly better DFS and OS was observed in the 17 patients in molecular response at the end of induction (EOI) (100%) vs cases who were not (42) (68.6%) (p=0.016 and 0.036, respectively). These patients have so far not relapsed. After 2 blinatumomab cycles, DFS and OS did not differ between molecular (33) and non-molecular (22) responders: 82.9% and 89.4% vs 75.7% and 84.2%, underlying the effect of blinatumomab. A worse DFS from the EOI was recorded for IKZF1^plus patients (11; 45.5%) compared to those without IKZF1 deletion (25; 82.3%) or with IKZF1 only deletions (13; 74%) (p=0.029). Similar results were observed also for OS. A similar trend was observed also when DFS was calculated from the primary endpoint of the study (62.5% vs 84.8% vs 74%). The 4 patients with a concomitant IKZF1^plus signature and T315I mutation had the worse outcome.

After induction/consolidation, 29 patients continued treatment only with a TKI; 27 (93.1%) had obtained a deep molecular response after dasatinib/blinatumomab. Overall, 28 patients (96.5%) who did not receive systemic chemotherapy/transplant are in persistent CHR at a median follow-up of 48 months. Of the 24 patients transplanted in 1^st CHR, 13 (54.2%) were non-molecular responders at the primary endpoint and only 2 became molecularly negative after further blinatumomab. Twenty patients (83.3%) are alive in CHR at a median follow-up of 49 months, 1 has relapsed 1 month after the transplant and 3 have died of complications. Three/6 patients transplanted in 2^nd CHR are alive at 30, 40 and 52 months. The transplant-related mortality was 12.5% for patients transplanted in 1^st CHR and 13.7% overall.

Nine relapses have occurred: 4 hematologic, 4 involving the CNS and 1 nodal. The median time to relapse was 4.4 months (1.9-25.8). A IKZF1^plus signature, evaluated at diagnosis, was present in 4/8 evaluable cases. ABL1 mutations, evaluated on BM samples at relapse or at a concomitant MRD increase in extra-hematologic recurrences, were found in 7 cases.

Treatment was well tolerated with no unexpected long-term toxicities.

Conclusions. The final analysis of the D-ALBA study shows that a chemotherapy-free induction/consolidation regimen based on a targeted strategy and immunotherapy is feasible and effective in inducing durable long-term hematologic and molecular responses in Ph+ ALL patients of all ages. Half of the patients remained only on a TKI and never underwent systemic chemotherapy or a transplant. These results pave the way for a new era in the treatment of adult Ph+ ALL patients.

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2. Foà et al, Blood 2011
3. Chiaretti et al, Haematologica 2016
4. Chiaretti et al, Haematologica 2021
5. Martinelli et al, Blood Advances 2022
6. Foà et al, N Engl J Med 2020
7. Foà & Chiaretti, N Engl J Med 2022