Abstract
Background: The introduction of tyrosine kinase inhibitors (TKIs) has markedly improved the outcome of Philadelphia positive acute lymphoblastic leukemias (Ph+ ALL). Nevertheless, about 20-50% (depending on whole treatment strategy received) of patients still experience relapse. Asciminib, a novel TKI targeting the ABL myristoyl pocket of the BCR-ABL1 protein, has shown promising activity in the context of Ph positive diseases.
Aims: Clinical data about the use of asciminib of in Ph+ ALL/lymphoid blast crisis of chronic myeloid leukemia (LBC-CML) after conventional TKI failure remain limited. We retrospectively evaluated the efficacy of asciminib in patients treated within the Italian compassionate use program.
Methods: Data from patients treated with asciminib as monotherapy or in combination for relapsed/refractory Ph+ ALL or LBC-CML were collected. Major molecular response (MMR) was defined as a level of BCR-ABL1/ABL1 < 0.01%.
Results: From September 2021 to April 2025, 19 patients (12 Ph+ ALL, 7 LBC-CML) received asciminib.
Median age was 55 years (range 20–77) and 12 were male.
Prior to asciminib, patients had received a median of 2 prior TKIs (range 1–3). Six patients had received Blinatumomab, 10 Inotuzumab, 8 had relapsed after allogeneic transplantation and 5 had undergone CAR-T therapy.
Asciminib was started in hematologic relapse in 11 patients, in 7 with MRD relapse/ recurrence, and in 1 MRD-negative patient (the latter due to inacceptable toxicities during previous therapies). Central nervous system involvement was observed in 2 patients.
At the time of the analysis, median follow-up from asciminib initiation, calculated using the reversed Kaplan-Meier method, was 10.2 months (95% CI: 3.4–NA) and median duration of asciminib-based therapy was 2.71 months (range, 0.8–25.3).
Mutations of ABL1 TK domain were analyzed in 15 out of 19 patients before treatment with asciminib. Mutations in ABL1 were detected in 10 patients (66.6%) including T315I in 6, T315L in 1 and compound mutation (T315I+ E255V; F317L+E255V; F317C+Y253H) in 3.
Asciminib was administered as monotherapy in 63% of cases. Seven patients (37%) received combination therapy: one with imatinib (400 mg daily), five with ponatinib (30 mg daily), and one sequentially after high-dose chemotherapy and radiotherapy.
Daily asciminib doses in combination therapy ranged from 40 mg once daily (1 patient) to 40 mg twice daily (6 patients). Among those on monotherapy, 11 patients received 200 mg twice daily, and one patient 40 mg once daily. Thirteen patients (68.4%) achieved complete hematologic remission, 3 achieved partial remission, 1 had a stable disease, and two were refractory, dying shortly after treatment initiation. No difference in the response rate was observed between Ph+ ALL and LBC-CML.
Among the responders, seven patients (7/13) achieved a major molecular response.
Asciminib was generally well tolerated, both as monotherapy and in combination. Only 1 patient required a dose reduction from 40 mg twice daily to 40 mg once daily due to musculoskeletal pain while on combination therapy with imatinib 400 mg daily. One patient experienced hypertension, grade 4 thrombocytopenia and neutropenia but was managed without reducing asciminib dosage. An additional patient developed grade 1 thrombocytopenia. No other significant treatment-related adverse events were reported.
Survival analysis showed that the median overall survival (OS) was not reached, while the estimated 1-year OS was 62.9%. Log-rank analysis demonstrated a statistically significant survival benefit for patients treated with asciminib in combination therapy (p = 0.02). Among the 5 deaths, 4 were due to disease progression, and 1 occurred in a patient with non-blastic aplasia and BCR-ABL < 0.1%. Eight patients received subsequent lines of therapy after asciminib: 4 were consolidated with allogeneic transplantation, one received low-dose chemotherapy, and 3 who progressed under asciminib respectively received inotuzumab, ponatinib, or olverembatinib and subsequent immunotherapy.
Conclusions This represents the first real-life Italian cohort of patients with R/R Ph+ ALL or LBC-CML treated with asciminib. Our experience suggests that asciminib, particularly in combination regimens, warrants further investigation in these heavily pretreated patients to confirm the observed OS benefit.
