Asciminib for relapsed or refractory Philadelphia chromosome–positive acute lymphoblastic leukemia Open Access

TO THE EDITOR:

The management of Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph⁺ ALL) and lymphoid blast crisis chronic myelogenous leukemia (LBC-CML) has improved dramatically with the incorporation of tyrosine kinase inhibitors (TKIs) into the frontline treatment, initially with imatinib and later with second-generation TKIs.^1,2 However, 20% to 30% of patients experience relapse, mostly driven by BCR::ABL1 variant–acquired resistance with tyrosine kinase domain (TKD) mutations, particularly the T315I mutation. Ponatinib, a third-generation TKI with activity against BCR::ABL1^T315I is now considered as the most effective TKI for the treatment of Ph⁺ ALL.^3,4 Asciminib (ASC) is a STAMP (specifically targeting the ABL myristoyl pocket) agent that binds to the myristoylation site of the ABL1 protein, thereby stabilizing the protein in an inactive conformation and inhibiting BCR::ABL1 deregulated kinase activity.⁵ Although ASC received US Department Food and Drug Administration approval for first-line therapy⁶ in CML,^6,7 limited data are available regarding the use of ASC in Ph⁺ ALL and LBC-CML after TKIs failure, including ponatinib.⁸ Here, we report a real-world study on the use of ASC in patients with relapsed/refractory (R/R) Ph⁺ ALL and LBC-CML.

This is a multicenter retrospective observational study (EWALL-OBS22, National Institutes of Health data registration number F20230710155501) conducted in accordance with the Declaration of Helsinki. The study was conducted in 19 centers in France after obtaining nonopposition from surviving patients. Eligible patients were aged 18 years or more and received ASC, either alone or in combination, for the treatment of R/R Ph⁺ ALL or LBC-CML following prior TKIs based therapy. Refractoriness was assessed after induction and first salvage. ASC was provided by a named compassionate access program until November 2019 (Novartis) and was subsequently prescribed off-label after the program’s closure. Response criteria were complete remission (CR) and complete remission with incomplete count recovery (CRi). Measurable residual disease (MRD) negativity was defined by BCR::ABL1/ABL1 ratio <0.01% in bone marrow. The start date of ASC was used to determine overall survival (OS) and event free survival (EFS) with events defined by treatment failure, relapse, or death from any cause. Survival curves were estimated using the Kaplan-Meier method and compared using the log-rank test. Hazard ratios with 95% confidence intervals (CIs) were estimated using the Cox regression model. Qualitative parameters were described using frequency and percentage, and continuous parameters using median with range (min-max). Categorical variables were compared using the χ² test or Fisher exact test when expected counts were low. Continuous variables were analyzed using the Student t test if normally distributed or the Mann-Whitney U test. Analyses were performed using Stata and RStudio (version 2024.09.0+375) software.

A total of 41 patients (Ph⁺ ALL, n = 33; LBC-CML, n = 8) were retrospectively registered from November 2019 to April 2024. Median age was 56 (range, 19-84) years. Comorbidities (mainly cardiovascular risk factors) were present in 14 patients (34%). Twenty-three patients received ASC in the context of early access program and 18 patients received ASC off-label.

At the time of ASC initiation, 5 patients were refractory to their previous line of treatment, 24 were in hematological relapse, 1 patient had a central nervous system (CNS) restricted relapse, and 7 were in molecular relapse. Four patients in complete remission received ASC due to intolerance to all available TKIs and were excluded from the efficacy analysis (supplemental Figure 1). Most patients (n = 32, 78%) received ASC as a third or subsequent line of therapy (median 3), and 93% (n = 38) were previously treated with ponatinib. Eighteen patients experienced relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT), including 4 patients after a second transplant. Two patients relapsed after CAR T-cell therapy (Table 1).

TKD mutation screening was performed before ASC initiation in 35 cases and was positive in 27 samples (77.1%). T315I mutation was evidenced in most cases (n = 18, 67%). Eight patients had compound mutations (involving T315I in 4 of the cases). The 5 remaining cases had the following mutations: E255V, E255K, F311L, F317L, and Y253H.

In accordance with the pattern of mutations, ASC was started at the dose of 200 mg twice daily in 34 of the patients (83%),⁹ whereas 7 patients received a lower dose. In 10 cases, ASC was associated with chemotherapy (low intensity n = 8, standard dose n = 2). Eleven patients received ASC in combination with B-cell–directed immunotherapies (n = 6, blinatumomab or inotuzumab ozogamicin), another TKI (n = 3, ponatinib or dasatinib), donor lymphocyte infusion (n = 1), and chimeric antigen receptor (CAR) T cells (n = 1). The 20 remaining patients (48%) received ASC as a monotherapy. After ASC treatment, 10 patients proceeded to allo-HSCT and/or CAR T-cell therapy (allo-HSCT, n = 3; CAR T cell, n = 5; CAR T-cell therapy followed by allo-HSCT, n = 2).

Overall, 30 of 36 (83%) evaluable patients achieved CR or CRi, including 15 of 17 (88%) on ASC monotherapy and 15 of 19 (79%) on ASC in combination. MRD negativity was reached in 13 of 23 (57%) of patients with evaluable bone marrow samples. When excluding patients with molecular relapse at the time of ASC initiation, 23 of 29 evaluable patients (79%) achieved CR or CRi and MRD negativity was reached in 9 of 16 (56.3%) of patients with evaluable bone marrow samples, with no difference observed between LBC-CML and Ph⁺ ALL. Median follow-up was 7.6 months. Median OS and median EFS were 9.8 months (95% CI, 7.0 to not reached) and 4.9 months (95% CI, 3.4-11.7), respectively (Figure 1). Median EFS was higher when ASC was used in combination compared to monotherapy (7.93 months vs 4.23 months respectively). Median remission duration was 4.87 months (95% CI, 3.43-11.70). Sixteen patients experienced relapses including 12 hematological relapses, 2 molecular relapses, and 2 isolated CNS relapses highlighting the challenge of addressing CNS disease with ASC-based combinations. We analyzed TKD resistance mutations after ASC therapy in 7 patients who relapsed that had previously achieved CR with ASC (supplemental Table 1) and identified a new Q252H mutation in 2 cases (including a composite T315I/Q252H at 6%). Our retrospective data showed that 11 of 41 (27%) patients experienced grade 3 or 4 adverse events, predominantly cytopenia. Notably, no patients discontinued ASC treatment due to intolerance.

Despite the limitations due to the retrospective nature of our study, we were able to register consecutive patients with R/R Ph⁺ ALL or LBC-CML treated with ASC during the data collection period in France. A high response rate was observed with ASC regimen and most responders achieved a complete molecular response. As a consequence of these results, 29% of the patients were bridged to a cellular therapy after ASC therapy, with 6 patients bridged to CAR T cells, including 2 patients who received allo-HSCT after CAR T- cell therapy and 4 patients bridged to allo-HSCT (supplemental Figure 2). Analysis of resistance to ASC in patients who relapsed, revealed the emergence of the Q252H P-loop mutation,¹⁰ identified to confer resistance to ASC in vitro,^11,12 warranting further investigation.

In conclusion, our analysis of this first real-life cohort of patients with R/R Ph⁺ ALL and BCP-CML treated with ASC, showed a high CR rate and promising OS and EFS paving the way for further investigations of ASC in acute Ph⁺ leukemias, with the focus on combination therapies based on ASC such as immunotherapies.

Acknowledgments: The authors thank Sandrine Roux and Laure Morisset from the Department of Clinical Research (DRCI), Centre Hospitalier de Versailles. The authors also thank Centre Hospitalier de Versailles for funding this study and for editorial assistance.

Asciminib was provided by Novartis via compassionate access program. This work publication is solely the responsibility of the authors and Novartis had no role in gathering, analyzing, or interpreting the data.

Contribution: S.R. provided administrative support; M.C., A.C.-H., M.B., E.R., Y.H., B.L., L.L., T.L., V.C., M.P.G.H., A.P., G.R.G., L.G., N.D., L.W., Q.C., S.C., V.C., C.C., M.C., A.M., J.L., S.R., F.N., N.B., E.C., R.K., and P.R. provided study materials or patients; M.C., P.R., and N.K. performed collection and assembly of data; R.K. and E.C. performed central review of molecular and cytogenetic data; M.C., P.R., and N.S. performed data analysis and interpretation; M.C., N.S., and P.R. wrote the manuscript; and all authors performed conception and design and provided final approval of the manuscript.

Conflict-of-interest disclosure: The authors declare no competing financial interests.

Correspondence: Philippe Rousselot, Division of Hematology, Centre Hospitalier de Versailles, 177 rue de Versailles, 78150 Le Chesnay, France; email: phrousselot@ght78sud.fr.