Venetoclax Plus PegC May Overcome Resistance to Prior BCL-2 Inhibitors in R/R AML

The combination of venetoclax (Venclexta) plus pegcrisantaspase (PegC) induced complete remissions in heavily pretreated patients with relapsed/refractory acute myeloid leukemia (AML), including those with prior exposure to venetoclax, according to data from a phase 1 study (NCT04666649) published in Blood.1

In the efficacy-evaluable population (n = 18), the overall CR rate was 33%, with 2 patients achieving CR, 2 achieving CR with partial hematologic recovery (CRh), and 2 achieving CR with incomplete hematologic recovery (CRi). Half of responders had undetectable measurable residual disease (MRD). Additionally, 1 patient (6%) achieved a partial remission (PR) and remained on the trial for 6 months with no other therapy.

Among efficacy-evaluable patients who were previously treated with venetoclax-containing regimens (n = 12), 33% achieved CR/CRh/CRi, demonstrating the potential synergistic activity of PegC with venetoclax. In patients without prior venetoclax exposure (n = 6), the CR/CRh/CRi rate was also 33%. For patients treated at the maximum tolerated dose (MTD) in cohort 2 and the expansion cohort (n = 13), the CR/CRh/CRi rate was 31%.

“We observed a significant CR rate even in patients who were previously treated with venetoclax, suggesting that the addition of PegC overcomes resistance to prior exposure to BCL-2 inhibitor-based therapy,” corresponding author Ashkan Emadi, MD, PhD, and colleagues wrote in the paper. “...We [also] found that this combination can effectively deplete plasma glutamine.”

Emadi is chair of the Department of Medical Oncology, Alexander Bland Osborn Endowed Chair and Distinguished Professor of Medical Oncology at West Virginia University (WVU) School of Medicine; physician-in-chief of Medical Oncology, as well as the associate center director of Translational Research at WVU Cancer Institute, in Morgantown.

Patients with relapsed/refractory AML continue to experience poor outcomes despite recent advances in the AML treatment paradigm. One emerging strategy to address resistance against standard regimens, including the combination of venetoclax and DNA methyltransferase inhibitors, targets the elevated glutamine dependency of myeloblasts.

Preclinical AML models have demonstrated antileukemic activity with PegC in combination with venetoclax, indicating that the combination could overcome resistance to venetoclax in complex karyotype AML. Additionally, PegC-mediated glutamine depletion appeared to synergize with BCL-2 inhibition, inhibiting cap-dependent mRNA translation and accordingly addressing MCL-1 overexpression—a suggested mechanism of resistance to venetoclax.

These findings informed the development of a phase 1 clinical trial evaluating the safety, efficacy, pharmacology, and molecular mechanisms of VenPegC in patients with R/R AML. This dose escalation and expansion study enrolled adult patients with confirmed AML, as classified by the 2016 World Health Organization (WHO) criteria, whose disease was relapsed or refractory to prior treatments and who had no remaining standard therapeutic alternatives. Patients with IDH1/2 or FLT3 mutations were required to have undergone prior treatment with targeted therapies if available, and prior exposure to venetoclax was permitted. Other key inclusion criteria were an ECOG performance status of at least 2 and adequate organ function.

Patients with previous exposure to any asparaginase or pegylated products, a history of pancreatitis unrelated to cholelithiasis, a history of unprovoked venous thromboembolic events, hemorrhagic or thromboembolic stroke, major hemorrhagic events within 3 weeks prior to treatment initiation, uncontrolled infections, uncontrolled seizures, and pregnancy or lactation were not eligible for the study.

Patients were enrolled onto 1 of 3 dose-escalation cohorts. Cohorts 1 through 3 received 400 mg of oral venetoclax daily on days 1 to 28, adjusted for azole antifungals if required; cohort 4 received 600 mg. PegC was administered on days 1 and 15 of each 28-day cycle at escalating doses of 500 IU/m² (cohort 1; n = 5), 750 IU/m² (cohort 2; n = 8), and 1000 IU/m² (cohort 3, n = 4). The MTD was determined to be 750 IU/m² of PegC and 400 mg of venetoclax. The dose expansion phase involved 10 additional patients treated at the recommended phase 2 dose.

Investigators added that, “Overall, 13 patients were treated at the MTD, and importantly this regimen was given entirely in the outpatient setting.”

Treatment continued until unacceptable toxicity, withdrawal of consent, or death. Patients with disease progression could remain on treatment if no alternatives were available and clinical benefit was observed.

The study’s primary end points were the incidence of dose-limiting toxicity (DLT) and MTD. Key secondary end points were rates of CR; CRh or CRi blood count recovery; overall survival; rates of hematologic improvement; and adverse effects (AEs).

Between June 4, 2021, and August 3, 2023, 27 patients were enrolled onto the study, with a data cutoff date of September 2, 2023. Two patients who consented did not receive venetoclax or PegC; one transitioned to hospice care due to complications from prior therapies, and the other died from septic shock before receiving study treatment.

Among the treatment population, which comprised 25 patients who received venetoclax and at least 1 dose of PegC, 60% of patients had refractory AML, and 40% had relapsed AML. The median age was 63 years (range, 24-79), 44% of patients were male, and 44% were non-White. Most patients received 1 (36%) or 2 (36%) prior lines of therapy. The median number of prior chemotherapy regimens was 3 (range, 1-6), and 52% were refractory to their most recent treatment. Patients had previously received intensive chemotherapy (56%); DNA methyltransferase inhibitor-based regimens (44%), including venetoclax-containing therapies (68%); and allogeneic hematopoietic stem cell transplantation (12%). Severe pancytopenia was common at baseline, with a median absolute neutrophil count of 0.24 x 10⁹/L (range, 0.2-7.2) and a median platelet count of 20 x 10⁹/L (range, 6-180). Common mutations included TP53 and complex karyotype mutations (36%), KRAS/NRAS (28%), DNMT3A (24%), NMP1 (16%), RUNX1 (16%), FLT3-ITD (12%), IDH1/2 (12%), PTPN11 (12%), and FLT3-TKD (8%).

“Our study enrolled a wide age range of patients, with a median age of 63 years. One of the major strengths of this clinical trial is a very high proportion of underrepresented minority enrollment; 44% of the patients were non-Caucasian, reflecting the population profile of real-world patients with AML and addressing inclusivity in clinical trials, which is one of the most challenging issues in current clinical research,” investigators added.

Seven patients did not complete cycle 1 of treatment. Of these, 5 experienced fatal infections related to severe neutropenia from AML or prior therapies. One patient, aged 79 with significant comorbidities, cleared peripheral blasts shortly after the first PegC dose but died on day 10 of cycle 1 from an unknown cause. Another patient opted for hospice care shortly after enrollment for personal reasons unrelated to an AE. The efficacy-evaluable population comprised 18 patients who completed at least 1 cycle of VenPegC.

Additional Efficacy and Pharmacokinetic Data

A broader analysis performed on the treatment population, showed peripheral blood blast clearance after a single dose of PegC in 52% of patients. The CR/CRh/CRi rate was 24%, with a median event-free survival (EFS) of 30 days and a median overall survival (OS) of 47 days. The median OS was 100 days in responders vs 28 days in non-responders (log-rank P = .007). Subsequent off-study therapies provided minimal durable responses in patients with progressive disease following treatment with the study regimen.

A post-hoc subgroup analysis of the treatment population evaluated response rates according to AML mutational characteristics. Responses were observed in 40% of patients with KRAS/NRAS/PTPN11 mutations (n = 10), typically associated with BCL-1 inhibitor resistance. This included 3 CRs and 1 PR. All patients with a RUNX1 mutation (n = 4) achieved a CR after 1 cycle. Notably, 3 of these patients had prior exposure to venetoclax-containing regimens. One patient with AML who was primary refractory to induction therapy and a venetoclax-containing regimen, and who harbored a concurrent TP53 mutation, achieved a CR after 1 cycle.

“Intriguingly, we [also] found that patients with AML with RUNX1 mutations may be particularly sensitive to [the venetoclax plus PegC] combination. These findings suggest that patients with AML with RUNX1 mutations might be sensitive to treatment with [venetoclax plus PegC] due to a metabolic vulnerability to mRNA translation inhibition resulting from a baseline decrease in biosynthetic activity and decrease in RUNX1 translation,” investigators explained.

Pharmacokinetic analyses demonstrated that PegC effectively achieved therapeutic levels of serum asparaginase activity (NSAA) in most patients. Of the 24 evaluable patients, 71% achieved NSAA of at least 0.1 IU/mL 1 week after the first PegC dose. Four additional patients who did not reach this threshold after the first dose achieved it by day 21 of cycle 1, resulting in 88% achieving therapeutic NSAA. No patients exhibited silent inactivation of crisantaspase, defined as persistent NSAA less than 0.1 IU/mL after repeated doses.

Moreover, mean baseline plasma glutamine (435 µmol/L) decreased significantly after each PegC dose, with an average reduction of 170 µmol/L (range 53-284). Moreover, plasma glutamate levels increased by a mean of 210 µmol/L (range 130-326). However, a rebound in glutamine and glutamate levels was observed approximately two weeks post-dose, consistent with the amidohydrolase activity of PegC. Notably, PegC-induced plasma amino acid modulation did not significantly alter plasma venetoclax concentrations.

“We found that PegC effectively reduced plasma glutamine levels, with an expected rise in plasma glutamate levels in patients with therapeutic NSAA levels. While effective reduction in plasma glutamine was observed, a rebound increase in plasma glutamine within 2 weeks after PegC may correspond to an increase in glutamine synthesis mediated by skeletal muscle, which acts as the primary store of glutamine,” investigators noted.

Understanding the Safety Profile

In the dose-escalation phase, no DLTs were observed in cohort 1. In cohort 2, 1 patient experienced transient asymptomatic grade 3 hypertriglyceridemia, which resolved within 48 hours and prompted cohort expansion. No additional DLTs were observed in this group. In cohort 3, 2 patients developed grade 3 hyperbilirubinemia, both of whom received prior chemotherapy and venetoclax-containing regimens. 

Investigators noted that, “The 2 patients who had experienced [DLTs] were both heavily pretreated, with 4 and 6 prior lines of therapy [including venetoclax-containing regimens] and might have been at higher risk for additional toxicities.”

The most common any-grade treatment-related AEs included decreased antithrombin III levels (52%), elevated transaminases (36%-48%), fatigue (28%), and hypofibrinogenemia (24%). Hyperbilirubinemia occurred in 60% of patients, with grade 3 or higher elevations observed in 20% of patients. Commonly reported grade 3 or higher AEs included febrile neutropenia (56%), sepsis (24%), aspartate aminotransferase level increase (24%), bilirubin increase (20%), fibrinogen decrease (16%), fatigue (16%), hypertriglyceridemia (12%), anemia (12%),, dyspnea (12%), hypocalcemia (12%), hypotension (12%), and alanine aminotransferase increase (12%).

Other AEs of special interest related to pegylated asparaginases, such as venous thromboembolism, hemorrhage, pancreatitis, hypersensitivity reactions, and hepatic failure, were not observed at grade 3 or higher within the first 30 days of treatment. Notably, one patient in the dose expansion cohort developed a Guillain-Barré-like syndrome after four cycles, presenting as upper and lower extremity weakness without central nervous system involvement; this resolved with intravenous immunoglobulin. Additionally, a hypersensitivity reaction occurred in one patient in the expansion cohort.

Based on these phase 1 findings, a multicenter, non-randomized, open-label phase 2 clinical trial is planned to further investigate the therapeutic potential of PegC and venetoclax in relapsed/refractory AML. The protocol is currently under regulatory evaluation and approval.

“Given our observation that patients with RUNX1 mutations may be a subgroup where this approach is particularly effective, a prespecified efficacy analysis will be performed on patients with RUNX1 mutations,” investigators concluded.

Reference

Liu Y, Bollino DR, Bah OM, et al. A phase 1 study of the amino acid modulator pegcrisantaspase and venetoclax in relapsed or refractory acute myeloid leukemia. Blood. Published online October 22, 2024. doi:10.1182/blood.2024024837