Venetoclax in combination with dasatinib, prednisone, rituximab and blinatumomab for the upfront treatment of adults with Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL), Results from a Phase 1B study Free

Introduction:

The second-generation ABL tyrosine kinase inhibitor (TKI) dasatinib (Das) has shown impressive response rates in patients with Ph+ ALL, particularly when used in combination with immunotherapy (Foa NEJM 2020). However, acquired ABL mutations can contribute to progression. Venetoclax (Ven) is an oral inhibitor of BCL-2, an anti-apoptotic protein. The combination of Das and Ven has shown synergistic activity in pre-clinical studies (Leonard Sci Transl Med 2016). We hypothesize that Das and Ven induction is safe and tolerable in adult patients (pts) with Ph+ ALL and can produce high rates of measurable residual disease negativity (MRD-).

Methods:

This is a Phase 1B clinical trial (NCT04872790) studying the combination of Ven with standard of care Das and prednisone in newly diagnosed or relapsed Ph+ ALL patients (pts) ≥18 yrs. Key exclusion criteria included blast phase chronic myeloid leukemia (CML) and pleural or pericardial effusions. The primary objective was to determine a maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) for Ven using the modified toxicity probability interval (mTPI) design. The study was planned for 20 patients with 15 MTD-evaluable for dose-finding followed by an expansion cohort at the RP2D. Primary endpoints were rates of dose-limiting toxicities (DLTs, defined as study drug-related and non-disease-related Grade (Gr) 4 neutropenia for ≥28 days, and Gr 3+ non-hematologic toxicities and other adverse events (AEs). Secondary endpoints included MRD- rate at end of induction(d+84), and progression-free and overall survival. Pts were MTD-evaluable if they had a DLT and/or took both Ven and Das on ≥50% of days during the DLT period.

In cohorts of 3, patients were assigned to varying Ven dose levels (DLs): DL-1 = 100mg daily Day (D) 1-28; DL1 = 200mg daily D1-28; DL2 = 400mg daily D1-21 of a 28D cycle; DL3 = 400mg daily D1-28. Ven started on D3 in C1 with a 1-day ramp-up for DL2 and DL3. All pts received Das 140mg daily (100mg if ≥60 yrs), prednisone 2mg/kg (max of 120mg daily on D1-21, tapered off by D28), intrathecal methotrexate x 12, and rituximab (for CD20+ ALL). Induction was 3 cycles. After 6 pts were enrolled, a protocol amendment introduced four cycles of blinatumomab (Blina) given for 4 weeks on, 2 weeks off. Ven and Das continued during Blina consolidation and afterwards until pts reached 12 months of total treatment, after which they continued Das monotherapy. Pts could come off study therapy for hematopoietic stem cell transplant (HSCT).

Results:

As of July 2025, 17 pts have enrolled and completed at least cycle 1 of induction. The median age was 51 yrs (range 22-74 yrs), 41% were female, 76% White, and 24% Hispanic. All pts had newly diagnosed Ph+ ALL, 41% had p210 vs. 59% with p190, and 29% had altered IKZF1. At diagnosis, median WBC count was 6.0 (range: 0.4-483) x 10⁹/L and 24% had CNS involvement.

Dose-finding has completed with 3 pts assigned to DL1, 6 to DL2, and 8 to DL3. Among 15 MTD-evaluable pts (two pts on DL2 were not evaluable due to insufficient cycle 1 drug exposure), no DLTs were observed. The MTD was identified as DL3.

Gr 3+ treatment-related AEs have been observed in 41% of pts; neutropenic fever (n=2), other hem toxicity (n of events =11), headache, (n=1) dyspnea (n=1), hypoxia (n=1), and TLS (n=1). Three pts (18%) had a treatment-related serious AE (TSAE), including 2 pleural effusions deemed related to Das, and 1 subdural hemorrhage deemed possibly related to Das but also procedure related.

The CR rate at D28 was 100% with an end-of-induction MRD- rate of 56% by BCR-ABL PCR and 50% by clonoSEQ D+84 MRD- rate 69% BCR-ABL and 76% clonoseq. All pts in DL1 and 5 of 6 pts in DL2 proceeded to HSCT in CR1. To date, no pts in DL3 are planned for HSCT. Median duration of therapy was 3 months (with five pts still on-treatment). At a median follow-up of 15 months, 1-year OS was 92%. There have been two deaths, both off treatment (one 4 secondary to HSCT complications and one secondary to pneumonia at 13 months after discontinuing treatment).

Conclusions:

The combination of dasatinib + venetoclax is safe and tolerable in adult patients with Ph+ ALL as indicated by no DLTs and three SAEs that are known effects of das. High rates of MRD negativity, including in pts with the IKZF1+ signature, suggest encouraging activity. The study continues to monitor for later toxicities and complete enrollment is anticipated before December 2025.