Real world outcomes of asciminib in relapsed/refractory Philadelphia chromosome positive B-ALL and blast Phase CML Free

Asciminib is a first-in-class STAMP (Specifically Targeting the ABL Myristoyl Pocket) inhibitor with distinct activity against BCR-ABL1, including T315I and other resistant mutations. While its efficacy is well established in chronic-phase CML, the real-world data on its use in relapsed/refractory (r/r) B-ALL and blast-phase CML (CML-BP), particularly among patients who are ponatinib-refractory or those with complex resistance mutations remains underexplored.

Methods We performed a retrospective analysis of adult patients with either B-ALL or CML-BP who received asciminib at our institution between November 1, 2021, and March 30, 2025. Safety and tolerability were assessed using CTCAE v5.0. Treatment efficacy was evaluated using BCR-ABL1 transcript levels (International Scale, IS) by qPCR and MRD (Minimal Residual Disease) by clonoSEQ. A successful molecular response was defined as achievement of major molecular response (MMR), corresponding to BCR-ABL1 ≤0.1% (IS). In B-ALL patients, MRD negativity by clonoSEQ was considered a successful response. For patients bridged to chimeric antigen receptor (CAR) T-cell therapy, response was defined as achievement of deep molecular remission (MRD-negative marrow) on Day 30 post-CAR-T biopsy.

Results Twenty adult patients (median age 57.5 years [range 21–81]; 45% male) were identified: 11 with B-ALL and 9 with BP-CML. 7 patients had >5% marrow blasts at asciminib initiation. Median number of prior TKI was 2 (range 1-5). 90% patients received prior ponatinib; 77% were refractory. Asciminib was prescribed alone (n=9) or in combination (n=11). Among 15 patients evaluated for BCR-ABL1 mutations, resistance mutations were detected in 11, including T315I (n=6), E255K (n=2), E255V (n=1), F317L (n=2), L248V (n=1), A279P (n=1), and Y253H (n=1).

The initial asciminib dose ranged from 40 to 400 mg daily (median 80 mg). 7 patients underwent dose escalation (median final dose 160 mg daily). The median duration of treatment was 174 days. Among six patients with T315I mutations, initial doses were 80 mg (n=1), 160 mg (n=3), and 400 mg (n=2); four were escalated to 400 mg. Three patients received asciminib as maintenance therapy (80 mg daily).

Only one patient discontinued therapy due to grade 4 neutropenia at a daily dose of 80 mg. One additional patient experienced grade 4 thrombocytopenia and grade 3 neutropenia, which resolved after dose reduction. One patient developed grade >3 hyperbilirubinemia, which resolved after a temporary treatment hold. The most common serious adverse event was grade ≥3 neutropenia (n=6), four of whom were on concurrent therapies which may have been contributive. Grade ≥3 thrombocytopenia and anemia were observed in three and one patient, respectively. Adverse event frequency did not correlate with dosage. 3 patients developed emergent resistance mutations post-asciminib, including STAMP domain mutations A337T and I502M, as well as ATP-binding site mutations E255K and E255V; These patients had received initial 160 mg dosing, with escalation to 320 or 400 mg in two cases.

Overall, 9 out of 20 patients (45%) achieved a successful molecular response. Among patients previously treated with ponatinib (n=18), 7 (39%) achieved a successful molecular response—35% (5/14) among ponatinib-refractory and 50% (2/4) in ponatinib-intolerant patients. Among those with T315I (n=6) prior to the start of asciminb, 33% (2/6) showed successful responses. Among the three patients with E255K/V mutations, only one achieved a successful molecular response; notably, this patient received a higher starting dose of 160mg. Three patients with B-ALL received asciminib as a bridge to CAR-T. Two had morphologic relapse and one had MRD-only disease pre-CAR-T; 2/3 (66%) achieved MRD-negative status at D30 bone marrow biopsy.

Conclusion Asciminib was well tolerated in this heavily pretreated cohort, including those previously exposed to ponatinib. The observed response rate in ponatinib-refractory (35%) and ponatinib intolerant (50%) patients, suggests its potential therapeutic role in resistant disease. While higher dosing may be effective in overcoming specific mutations, it could also contribute to the emergence of additional resistance mutations. These findings underscore the need for prospective studies to optimize dosing strategies, sequencing, and resistance monitoring.