Excellent Early and Major Molecular Responses Observed with Asciminib Treatment for CP-CML: Results from the ALLG CML13 Ascend-CML Study

ATP-competitive BCR::ABL1 inhibitors are effective in many patients with CP-CML patients. However, a significant minority experience treatment failure with currently available drugs due to resistance or toxicity. Asciminib, a first-in-class myristoyl site BCR::ABL1 inhibitor, is now indicated in many jurisdictions for CP-CML after ≥2 prior lines of treatment. The Australasian Leukaemia and Lymphoma Group (ALLG) CML13 ASCEND-CML trial assessed its tolerability and efficacy in the frontline setting, where data are scarce.

ALLG CML13 is a prospective open-label phase II study that completed enrolment in Dec 2022 at 14 sites. Patients commenced asciminib 40mg twice a day (BID) at time of diagnosis, and were assessed according to optimal 2020 ELN targets (BCR::ABL1 ≤10%, ≤1% & ≤0.1% at 3, 6, 12 months respectively); and ≤0.01% at 18 months. Patients in Major Molecular Response (MMR; BCR::ABL1 ≤0.1%) at 12 months were switched to 80mg QD for ease of administration. Patients with treatment failure (BCR::ABL1 >10% at 3 or 6 months; BCR::ABL1 >1% at 12 or 18 months) continued asciminib, with additional imatinib or dasatinib or nilotinib, according to physician preference. Patients with a suboptimal response at 6, 12, or 18 months, but without treatment failure, continued asciminib but with the dose doubled to 80mg BID. This is a pre-specified analysis of the co-primary end points: i) final analysis of Early Molecular Response (EMR, BCR::ABL1 ≤10% at 3 months) and ii) interim analysis of MMR by 12 months.

By data cut-off in May 2023, 101 patients had median follow-up of 20 (0-29) months (including 1 patient who enrolled but never started therapy due to elevated lipase at baseline). Grade 3/4 adverse events (AEs) included neutropenia and thrombocytopenia, (reported in 6% and 5% of patients, respectively); increased lipase/amylase reported in 8% (clinical pancreatitis reported in 2%), anaemia (2%), infection (2%) and 1% each of increased AST/ALT, back, abdominal and chest pain from pulmonary embolism. The only treatment emergent vascular event was a stroke, reported in a male patient aged 73 with pre-existing diabetes and hypertension, after 20 months of asciminib. Fifteen patients discontinued asciminib: 6 due to AEs (2 with persistent cytopenia requiring an allograft, 3 with recurrent asymptomatic lipase elevation, 1 with pancreatitis); 3 lost to follow-up; and 6 due to resistant disease (1 confirmed loss of MMR at 9 months, without ABL1 mutation; 1 transformed to lymphoid blast crisis at 6 months with myristoyl site mutations A337T/V and P465S; 1 loss of MMR at 6 months with A337T mutation; 1 loss of MR2 with V506L; and 2 with failure to achieve EMR - below). No other transformation occurred.

During the first 3 months of treatment, 85% of patients had an assigned dose density of >90%; 9% of patients dose reduced to <66%. EMR was achieved by 94/101 patients (93.1%; 96% CI 86-97%): 1 patient never started treatment, 1 patient missed this assessment, 3 patients had withdrawn by this timepoint, and 2 had BCR::ABL1 of 24% and 210%, respectively. Neither of the EMR failure patients had myristoyl site mutations; both were subsequently intolerant of combination TKI/asciminib therapy because of cytopenia and headaches, respectively and are now on dasatinib monotherapy. Six patients dose escalated and remain on asciminib 80mg BID: 3 after failing to achieve MMR by 12 months, & 3 failing to achieve MR4 after 18 months; 2 have since achieved their targets.

By 3 months, 48/101 (48%) patients achieved MMR and 12 (11.9%) achieved MR4. Considering only patients with >12 months of follow up, the interim rate of MMR by 12 months is 62/75 patients (82.7%; 98% CI 70-92%). With “off-protocol for any reason” as the competing risk, the cumulative incidences of MMR & MR4.5 by 12 months were 81.1% & 32.3% respectively (Figure).

ASCEND is one of the first studies using frontline asciminib, with excellent achievement of EMR and MMR, and low transformation rate. Rates of MMR at 12 months are comparable to those reported with second generation TKIs, though achievement of deeper responses appears more rapid with asciminib. Treatment was well tolerated in general: majority of AEs were grade I/II events that did not result in treatment discontinuation, and only one vascular event was observed. Early achievement of MMR and MR4 may accelerate eligibility for, & increased success of, treatment-free remission attempts.