A phase I study of asciminib in combination with dasatinib, prednisone, and blinatumomab for Ph-positive acute leukemia in adults.

Abstract

6509 Background: Treatment of Ph+ acute lymphoblastic leukemia (ALL) requires potent BCR:ABL1 inhibition. Acquired resistance to the ATP-competitive ABL1 inhibitor dasatinib (DAS) justifies combination with the allosteric inhibitor asciminib (ASC) to deepen responses and prevent mutational resistance. Our phase 1 study (NCT03595917) confirmed the safety and preliminary efficacy of DAS 140 mg/day(d) and ASC 80 mg/d (Luskin Blood 2024). Blinatumomab (blin), a bispecific CD19-CD3 T-cell engager, is effective consolidation for Ph+ ALL. Here we report a 15-patient (pt) expansion cohort testing the safety of DAS, ASC and blin. Methods: Pts ≥18 years (yrs) with Ph+ ALL or chronic myeloid leukemia (CML) blast crisis, no prior DAS or ASC treatment or ABL1 T315I were eligible. Induction: DAS 140 mg/day (d), ASC 80 mg/d and prednisone 60 mg/m 2 /d (max 120) 1-24 (tapered d 25-32). Consolidation: DAS 140 mg/d, ASC 80 mg/d, and blin (28 mcg/d d1-28 of a 42-d cycle) for 5 cycles. DAS and ASC are administered indefinitely. Dose-limiting toxicity (DLT) was CTCAEv5 non-heme toxicity grade (gr) 3+ during the first DAS, ASC, and blin combination cycle. Results: The 15-pt (9 male, 6 female) cohort accrued 08/2023-09/2024 (data cut 11/15/24). Median age was 62 yrs (range 25 – 83; 87% [13] ≥60). All pts were newly diagnosed: median WBC 11.1x10 3 /μL (20% [3] ≥50), transcript type p190 (11, 73%) vs p210 (4, 27%), IKZF1 plus in 36% (5/14). Most (87%, 13/15) were trackable by clonoSEQ. Median time to blin was 33 days (range 28 – 77). There were no DLTs during the 6-pt safety run-in so 9 additional pts enrolled with all completing at least 1 cycle of ASC, DAS, plus blin. DAS dose reductions were common (n=7) for pleural effusion (n=3), transaminitis (n=1), and other (n=3). ASC dose reduction to 40 mg/d was required in 1 pt (asymptomatic gr3 lipase increase). One pt (age 81) discontinued protocol after 1 blin cycle due to general health decline. Five pts were transplanted per physician discretion after 2 (n=2), 3 (n=2), or 4 (n=1) blin cycles (suspected CML n=2; high-risk genetics n=2; persistent BCR::ABL1 n=1). All others (n=9) have completed 4 or 5 blin cycles, or blin is ongoing. Responses deepened after the first cycle of blin (Table). No pt has progressed (median follow-up 238 days, 95% CI 112-420). Conclusions: Dual ABL1 inhibition with ASC and DAS can be safely combined with blin in Ph+ acute leukemia. An additional 25-pt cohort is planned with blin in combination with DAS and ASC at optimized doses. Clinical trial information: NCT03595917 . Response kinetics. Induction (ASC, DAS, prednisone) Consolidation Cycle 1 (ASC, DAS, blin) Hematologic CR 100% (15/15) 100% (14/14) Cytogenetic CR 86% (12/14) 100% (14/14) Flow Negative (<10 -4 ) 79% (11/14) 100% (14/14) BCR::ABL1 Molecular Response (MR)MR1MR2MR3MR4 87% (13/15) 60% (9/15) 20% (3/15) 7% (1/15) 100% (14/14) 100% (14/14) 57% (8/14) 43% (6/14) clonoSEQ Response<10 -4 <10 -6 (0 transcripts) 67% (6/9) 11% (1/9) 67% (6/9) 11% (1/9)