Investigating the Combination of Ivosidenib Plus Venetoclax and Azacitidine in IDH-Mutated Myeloid Malignancies

In a small study of patients with IDH1-mutated myeloid malignancies, treatment with ivosidenib plus venetoclax, with or without azacitidine, had an acceptable safety profile and led to high rates of complete responses in patients with acute myeloid leukemia (AML). Curtis Andrew Lachowiez, MD, from The University of Texas MD Anderson Cancer Center, shared interim results from this study at the 2021 American Society of Clinical Oncology Annual Meeting.

Research has shown that malignancies that harbor the IDH1-mutation demonstrate increased reliance on the anti-apoptotic protein BCL2, Dr. Lachowiez explained, suggesting an enhanced susceptibility to the BCL2 inhibitor venetoclax. In this phase Ib/II trial, investigators enrolled a total of 25 adults with IDH1-positive malignancies: four with myelodysplastic syndromes (MDS), 13 with newly diagnosed AML (including de novo and secondary), and eight with relapsed/refractory AML.

Most of the patients had adverse-risk disease (n=14), and median IDH1 variant allele frequency at enrollment was 22.7%.

Treatment consisted of 28-day cycles of ivosidenib 500 mg daily (starting on day 14), combined with venetoclax with or without azacitidine at one of three dose levels (DLs):

  • DL1: ivosidenib plus venetoclax 400 mg (n=6)
  • DL2: ivosidenib plus venetoclax 800 mg (n=6)
  • DL3: ivosidenib plus venetoclax 400 mg plus azacitidine 75 mg/m2 on days 1-7 (n=13)

After a median follow-up of 16.1 months, the overall response rate was 92%, including 67% in DL1 and 100% in DL2 and DL3.

The rate of composite complete response (CRc; including CR with incomplete or complete hematologic recovery) was 84% (TABLE). Rates of CRc were highest in the DL2 and DL3 groups, and in patients with newly diagnosed AML or MDS.

Patients received a median of four treatment cycles, and responses were ongoing at one year in 62% of patients (33% with DL1; 50% with DL2; and 82% with DL3).

The rate of one-year overall survival (OS) was 68% for the entire study population: 83% in DL3, 67% in DL2, and 50% in DL1. The authors added that rates of one-year OS were 71% among patients with newly diagnosed AML, 50% in relapsed/refractory AML, and 100% in MDS. Of patients whose disease responded to treatment, 60% achieved measurable residual disease (MRD) negativity, which correlated with improved OS (median OS = not reached vs. 8.5 months; p=0.038).

The most common grade 3/4 adverse events included febrile neutropenia (28%) and pneumonia (24%). The investigators added that two patients experienced tumor lysis syndrome and four experienced differentiation syndrome, but that all cases resolved with medical management.

“Ivosidenib plus venetoclax, with or without azacitidine, was associated with both an expected and tolerable safety profile and resulted in high composite complete response rates in both the doublet and triplet cohorts,” Dr. Lachowiez stated in his presentation, adding that “patients had durable responses across various disease groups.” The study is continuing to enroll patients and these initial results will need to be confirmed in larger studies.

Study authors report no relevant conflicts of interest.

Reference

Lachowiez CA, Borthakur G, Loghavi S, et al. A phase Ib/II study of ivosidenib with venetoclax +/- azacitidine in IDH1-mutated myeloid malignancies. Abstract #7012. Presented at the 2021 American Society of Clinical Oncology Annual Meeting, June 4-8, 2021.

TABLE. Outcomes According to Dose Levels

All

(N=25)

DL1

(n=6)

DL2

(n=6)

DL3

(n=13)

Overall response rate 23 4 6 13
Composite complete response 21 4 6 11
Partial response 1
Event-free survival NR (9.4 months – NR) 9.6 (2.8 – NE) 9.4 (7 – NE) NR
Overall survival NR 9.7 (4.5 – NE) NR (8.5 – NE) NR
NR = not reached; NE = not estimable