Initial Results of a Phase I/II Study of Venetoclax in Combination with Azacitidine in Treatment-Naive and Relapsed/Refractory High-Risk Myelodysplastic Syndrome (MDS) or Chronic Myelomonocytic Leukemia (CMML)

Introduction:

Venetoclax (VEN) is an oral BCL2 inhibitor, that has been shown to overcome apoptotic stress in cells from patients (pts) with high-risk myelodysplastic syndrome (MDS). Pre-clinical evidence indicates that VEN plus azacytidine (Aza) combination results in synergistic effects in myeloid malignancies. The objective of this trial is to evaluate the safety, tolerability, and overall response rate (ORR) of VEN in combination with Aza in pts with treatment-naive high-risk MDS or chronic myelomonocytic leukemia (CMML) and pts that were relapsed/refractory (R/R) to prior hypomethylating agent (HMA) therapy.

Methods:

This is a single-arm phase I/II clinical trial for pts with treatment-naive high-risk MDS or CMML, or pts with R/R MDS or CMML post-HMA failure (NCT04160052). Pts with prior BCL2 inhibitor therapy or low-risk disease (IPSS low or Int-1) are excluded. Aza is administered at 75mg/m2 IV or SC for 5 days on days 1-5 of each treatment cycle. VEN is studied at 100 mg, 200 mg, or 400 mg daily, on days 1-7 or 1-14 of each cycle. The primary endpoint is to determine the maximum tolerated dose and dose-limiting toxicity (DLT) of VEN in combination with Aza, as well as to evaluate ORR, defined as achieving complete remission (CR), marrow complete remission (mCR), partial response (PR), or hematologic improvement (HI) lasting ≥4 weeks. Response is assessed based on the modified International Working Group 2006 criteria (Cheson et al Blood 2006). Overall survival (OS) is calculated from the start date of treatment to the date of death, or last follow-up. Progression-free survival (PFS) is calculated from the start date of treatment to the date of disease progression, or last follow-up. Duration of response is calculated from the date of response to the date of disease progression, or last follow-up. Safety profile events were recorded according to the CTCAE v5.0.

Results:

To date 9 pts were enrolled. Four pts received VEN at 100mg dose, 3 pts at 200mg dose, and 2 pts at 400mg dose on days 1-7. There has been no protocol defined DLTs. The median age was 66 years (range, 59-83), 89% were male, 67% with MDS, 67% with normal karyotype. Five pts (56%) were treatment-naive, and 4 (44%) with R/R disease. Of the treatment-naive cohort (N=5), 4/5 (80%) pts had normal karyotype and none had TP53 mutations. ORR rate in this treatment-naive cohort was 100%, all pts achieving mCR, of which 1 (20%) had neutrophil response. Of the R/R cohort (N=4), cytogenetics were normal in 2/4 (50%) and complex in 2/4 (50%), and 2/4 (50%) had TP53 mutations. ORR in this R/R cohort was 3/4 (75%), all achieving mCR. One pt (25%) had stable disease (Table 1 and Figure 1). With a median follow-up duration of 3.6 months (95% CI: 1.4-8.4), 3 (33%) had disease progression and 1 (11%) died. Pts received median 2 courses of therapy (range, 1-4). One pt went to transplant. Median progression-free survival (PFS) for the entire cohort was 4.6 months (95% CI: 3.4-NA) and median OS has not been reached (Figure 2). Median duration of response is 4.1 months (95% CI: 2.4-NA). Possibly/probably related grade 3/4 adverse events included neutropenia in 4/9 (44%), thrombocytopenia in 3/9 (33%), and anemia in 1/9 (11%) pts. There were no grade 5 events (Table 2).

Conclusions:

The administration of VEN with Aza appears safe and well tolerated in treatment-naive and R/R pts with high-risk MDS and CMML. The study continues to accrue.