AZA + Glutaminase Inhibition with Telaglenastat (CB-839) for Advanced MDS: An Updated Interim Analysis

Background:

Malignant cells exploit cellular metabolism for their survival through various mechanisms. A significant dependency of malignant myeloid cells on glutamine metabolism has been demonstrated in vitro. Glutamine can be metabolized by glutaminase to form glutamate, a precursor for the citric acid cycle. CB-839 is an oral allosteric inhibitor of glutaminase that has been shown to reduce the level of glutamate in AML cells, with a consequent decrease in oxidative phosphorylation and survival. We report an updated interim analysis of a phase Ib/II clinical study evaluating the safety and efficacy of CB-839 in combination with azacitidine for the treatment of patients with MDS.

Methods:

This is a single arm phase Ib/II trial of CB-839 in combination with azacitidine (AZA) for patients with intermediate and high-risk MDS. Eligibility includes adult patients with high-risk MDS (IPSS Int-2 or high risk) or Int-1 risk MDS with high-risk mutations in TP53, ASXL1, EZH2, or RUNX1. Patients with prior hypomethylating agent (HMA) treatment were eligible. The primary outcome for the phase Ib portion was to identify the safety and recommended phase II dose of CB-839 in combination with AZA, confirmed as 600mg bid continuously with standard 7-day AZA dosing. The primary outcome for the phase II portion is clinical efficacy using IWG response criteria. Secondary endpoints include evaluation of pharmacokinetics (PK), drug exposure levels, and overall survival.

Results:

23 patients with MDS were enrolled between December 2017 and June 2020. Baseline characteristics are listed in Table 1. The median age was 71 (range, 49-83). 7 patients had prior HMA exposure (median 6 prior cycles, range 4-9), and 1 patient was previously treated with a non-HMA regimen. 8 patients (34.7%) had therapy-related MDS. 9 patients (39.1%) had complex cytogenetics. The most frequent mutations were ASXL1 (43.5%), TET2 (43.5%), TP53 (34.8%), and RUNX1 (30.4%).

The most common drug-related non-hematologic adverse events (AEs) of any grade were nausea (52.2%), constipation (39.1%), fatigue (26.1%), anorexia (17.4%), and generalized weakness (17.4%). The most common therapy-related grade >3 AEs were transaminitis (13%), thrombocytopenia (26%), and neutropenia (30.4%). Five patients (21.7%) required dose reduction(s) of CB-839, with reductions due to transaminitis (n=2), myelosuppression (n=2), weakness (n=2), nausea (n=1), and fatigue (n=1). 30 and 60 day mortality were 0% and 4.3%, respectively.

Best responses are detailed in Table 2. Objective response was defined as CR, morphologic CR (mCR), or hematologic improvement (HI), and was achieved in 15 out of 23 (65.2%) patients, including 5 CR and 10 mCR with or without HI. CR/mCR/HI rate was 62.5% (5/8) in previously-treated patients. Median number of cycles received was 4 (range, 1-17). 5 patients proceeded to allogeneic stem cell transplant. At median follow-up of 10.3 months (range, 1.0-28.5), 6 patients remain on study. Median OS (mOS) has not been reached; 1 year overall survival is 53.1% (Figure 1). Patients with TP53 mutations had CR/mCR rate of 62.5% (5/8) and mOS of 8 months. Patients with complex cytogenetics had CR/mCR rate of 66.7% (6/9) and mOS of 10.1 months.

Bone marrow samples from a subset of patients were analyzed by multiparameter flow cytometry to fractionate phenotypically defined malignant leukemic stem cells (LSCs) as well as blast populations. We isolated hematopoietic stem and progenitor cells (HSPC, Lin−CD34+CD38−) expressing at least one LSC marker (CD45RA, CD123, or IL1RAP). At the same time, we isolated HSPCs that were triple-negative for CD45RA, CD123, and IL1RAP to enrich for pre-malignant stem cells. Analysis of representative samples showed a reduction in LSCs after treatment. We also observed an increase in progenitor cells (Lin-CD34+CD38+), showing increased differentiation after CB-839 treatment. This pattern was seen in 5 responders examined. We did not observe a reduction in LSCs in patients that did not respond clinically.

Conclusions:

CB-839 in combination with AZA is a safe and effective regimen for patients with advanced MDS. Encouraging responses were seen in previously-treated and genomically high-risk patients. Of interest, CB-839 demonstrated in vivo activity against LSCs, with an increase in myeloid progenitor cells consistent with myeloid differentiation in responding patients. The trial continues to accrue. (NCT03047993)