Asciminib plus dasatinib and prednisone for Philadelphia chromosome-positive acute leukemia

Abstract

Dasatinib is an effective treatment for Philadelphia chromosome-positive (Ph+) acute leukemia, but some patients develop resistance. Combination treatment with dasatinib and asciminib, an allosteric inhibitor of BCR::ABL1, may deepen responses and prevent the emergence of dasatinib-resistant clones. In this phase 1 study (NCT03595017), 24 adults with Ph+ acute lymphoblastic leukemia (ALL; n = 22; p190, n = 16; p210, n = 6) and chronic myeloid leukemia in lymphoid blast crisis (n = 2) were treated with escalating daily doses of asciminib in combination with dasatinib 140 mg daily plus prednisone 60 mg/m2 daily to determine the maximum tolerated dose. After a 28-day induction, dasatinib and asciminib were continued indefinitely or until hematopoietic stem cell transplant. The median age was 64.5 years (range, 33-85; 50% aged ≥65 years). The recommended phase 2 dose of asciminib was 80 mg daily in combination with dasatinib and prednisone. The dose limiting toxicity at 160 mg daily was asymptomatic grade 3 pancreatic enzyme elevation without symptomatic pancreatitis. There were no vaso-occlusive events. Among patients with de novo ALL, the complete hematologic remission rates at days 28 and 84 were 84% and 100%, respectively. At day 84, 100% of patients achieved complete cytogenetic remission, 89% achieved measurable residual disease negativity (<0.01%) by multicolor flow cytometry, and 74% and 26% achieved BCR::ABL1 reverse transcription quantitative polymerase chain reaction <0.1% and <0.01%, respectively. Dual BCR::ABL1 inhibition with dasatinib and asciminib is safe with encouraging activity in patients with de novo Ph+ ALL. This trial was registered at www.clinicaltrials.gov as #NCT02081378.

Graphical abstract

Figure 1.

Phase 1 study participants underwent protocol therapy with serial bone marrow response assessments. Patients initiated treatment with dasatinib 140 mg daily and prednisone 60 mg/m² daily (days 1-24; tapered days 25-32) plus asciminib per 3 + 3 dose escalation protocol (DL1-DL3, 40 mg, 80 mg, and 160 mg once daily, respectively). Response was assessed every 28 days via bone marrow aspiration and core biopsy for morphologic, cytogenetic, flow cytometric, and molecular responses. After three 28-day cycles, at the discretion of patients and their treating physicians, patients could continue study treatment for additional 28-day cycles until intolerance or progression or discontinue study and proceed to HSCT or alternative consolidation. IT, intrathecal; RT-qPCR, reverse transcription quantitative polymerase chain reaction.

Figure 2.

Molecular responses deepened over time with dasatinib and asciminib combination therapy. (A) Depth of molecular responses over the course of induction therapy per bone marrow BCR::ABL1 messenger RNA (mRNA) levels. Included are evaluable patients with ALL treated at any asciminib dose level (DL). Depth of MRD is depicted as -log(10) values. (B) Molecular response dynamics per patient according to BCR::ABL1 isoform and asciminib DL. Dashed lines show key levels of -log(10) MRD, specifically molecular response 3.0, molecular response 4.0, and molecular response 4.5. Also shown are the CLIA-validated LoQ and LoD for BCR::ABL1 mRNA according to clinical molecular diagnostic assays used for each isoform. LoQ, limit of quantification; LoD, limits of detection; ND, not detected.

Figure 3.

Many study participants experienced durable responses and 11 successfully received bridging to definitive consolidation including HSCT. This swimmer plot depicts duration on study treatment (in 28-day cycles) and clinical disposition of study patients evaluable for response (n = 24). Shown are all patients including de novo ALL and relapsed/refractory CML-LBC (the latter indicated by a dark blue swimmer lane border), BCR::ABL1 p190 or p210 isoform, and treated at any DL (1-3). The dashed line indicates day 84.

Figure 4.

Dasatinib and asciminib combination achieved favorable OS and EFS in study participants. (A) OS by Kaplan-Meier method. Shown are all study patients with de novo ALL treated at any DL (DL1-DL3). One-year OS rate was 100%. Two-year OS rate was 75% (95% CI, 51-99). (B) EFS by Kaplan-Meier method. Shown are all study patients with de novo ALL treated at any DL (DL1-DL3) with at least 1 disease evaluation. One-year EFS was 63% (95% CI, 21-100). Two-year EFS rate was 63% (95% CI, 21-100).