Targeting metabolism in acute myeloid leukemia: the next therapeutic frontier?

In the Blood article titled “Phase 1 study of the amino acid modulator pegcrisantaspase and venetoclax in relapsed/refractory acute myeloid leukemia”, Liu et al. report the results of a phase I clinical trial (NCT04666649) evaluating the safety and preliminary efficacy of combining the B-cell lymphoma 2 (BCL-2) inhibitor venetoclax (VEN) with pegylated crisantaspase (PegC) in patients with relapsed or refractory acute myeloid leukemia (AML) (1).

Their rationale builds on extensive preclinical evidence demonstrating that metabolic modulation can sensitize AML cells to VEN. The serine/threonine kinase mammalian target of rapamycin (mTOR) forms two distinct complexes, mTORC1 and mTORC2, which regulate protein translation through phosphorylation of protein S6 kinase (P70S6K) and eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) (2). Primary AML samples frequently exhibit hyperactivation of mTORC1, and its inhibition has been shown to suppress protein synthesis and induce apoptosis (3). A key driver of mTORC1 activation is the intracellular availability of the amino acid leucine, which is transported into cells via the SLC7A5/3A2 transporter in exchange for glutamine (4). Thus, glutamine availability represents a critical upstream regulator of mTORC1 signaling, and therapeutic strategies targeting glutamine depletion have gained interest in AML. PegC is a long-acting asparaginase derived from Erwinia chrysanthemi with significant in vivo glutaminase activity capable of depleting plasma glutamine levels (5). In preclinical AML models, the combination of VEN and PegC demonstrated potent anti-leukemic activity and overcame VEN resistance by reducing expression of myeloid cell leukemia-1 (MCL-1), a key mediator of resistance to BCL-2 inhibition (6-8). These compelling data formed a solid basis for the current phase I evaluation of VEN plus PegC in relapsed/refractory AML, including in patients with prior VEN exposure. The trial employed a standard 3+3 dose-escalation design in which participants received oral VEN 400 mg daily and escalating doses of PegC (500, 750, or 1,000 IU/m²) administered intravenously on days 1 and 15 of 28-day cycles. This was an especially high-risk population: 60% had refractory AML, 40% had relapsed disease, and more than half (56%) had progressed after intensive chemotherapy. Among the 18 patients who completed at least one cycle and were evaluable for efficacy, 68% had previously received VEN. Regimen-limiting toxicities (RLT) included grade 3 hypertriglyceridemia (resolving within 48 hours) and grade 3 hyperbilirubinemia. The maximum tolerated dose (MTD) was PegC 750 IU/m² on days 1 and 15 in combination with VEN 400 mg daily. The overall complete remission (CR) rate was 33%, including responses among patients with prior VEN exposure: 2 CRs, 2 CR with partial hematologic recovery (CRh), and 2 CR with incomplete recovery (CRi). Three responders achieved measurable residual disease (MRD) negativity. A post-hoc analysis of mutational profiles (n=25) revealed encouraging activity in high-risk RAS-pathway mutations (KRAS, NRAS, PTPN11), which are typically associated with resistance to BCL-2 inhibition. Notably, all four patients with RUNX1-mutated AML achieved CR, highlighting a potential molecular subgroup with heightened sensitivity to this metabolic-BCL-2 targeting strategy.

The regimen appears to achieve robust asparaginase activity in approximately 90% of patients during the first cycle, corroborating prior pharmacokinetic and mechanistic observations (5,6). The authors describe the regimen as entirely outpatient. However, more than half of the patients experienced febrile neutropenia (56%), and 24% developed septicemia, raising concerns regarding the feasibility and safety of delivering this therapy in an outpatient setting. These concerns are further amplified by the frailty typical of this patient population, as well as the highly selected nature of the enrolled cohort. Although not powered to draw definitive efficacy conclusions, this trial provides a meaningful clinical signal that supports further evaluation in larger, randomized studies. Notably, this approach is based on a distinct therapeutic concept: exploiting metabolic vulnerabilities to overcome apoptotic resistance while maintaining a favorable toxicity profile and enabling molecularly informed patient selection.

Although a relatively rare cancer, AML is a complex cancer with a significant biologic heterogeneity and a global incidence of almost 150,000 new cases in 2021, a figure which likely represents a significant underestimation (9-12). AML is often devastating, especially among older patients and in low- and middle-income countries which have limited access to novel therapies and health care resources (13-16) including allogeneic hematopoietic stem cell transplantation. For several decades, the management of AML has largely relied on the combination of cytarabine, administered for seven days, and an anthracycline given for three days (the traditional “7+3”). Despite its clinical activity, 5-year survival rates have not exceeded 40%, with little progress over the past three decades (17). Induction therapy with “7+3” is typically followed by consolidation using the same agents or by potentially curative allogeneic hematopoietic stem cell transplantation. Consolidation strategies are guided by both patient- and disease-specific factors, including age, comorbidities, cytogenetics and molecular risk, and MRD status (18). Since 2017, advances in diagnostic strategies and the widespread use of next-generation sequencing (NGS) have substantially improved understanding of disease biology and molecular drivers, leading to the approval of several targeted therapies by the U.S. Food and Drug Administration (FDA).

Midostaurin, an FMS-like tyrosine kinase 3 (FLT3) inhibitor, was approved in April 2017 for patients with newly diagnosed FLT3-internal tandem duplication (ITD) or tyrosine kinase domain (TKD)-mutated AML (19). Gilteritinib, another FLT3 inhibitor, was approved in November 2018 for relapsed or refractory FLT3-ITD/TKD-mutated AML (20). More recently, quizartinib was approved in April 2023 in combination with standard cytarabine and anthracycline induction, followed by cytarabine consolidation, as well as for maintenance monotherapy after consolidation, for patients with newly diagnosed FLT3 ITD-mutated AML (21). Targeted therapies for isocitrate dehydrogenase (IDH)-mutated AML soon followed. Ivosidenib, an IDH1-inhibitor, received approval for patients aged ≥75 years with newly diagnosed IDH1-mutated AML (May 2019) and for relapsed/refractory IDH1-mutated AML (July 2018) (22). Olutasidenib, another IDH1-inhibitor, received approval in December of 2022 for adult patients with relapsed/refractory IDH1-mutated AML (23). Enasidenib, an IDH2 inhibitor, was approved in August 2017 for relapsed/refractory IDH2-mutated AML (24). Additional “precision” approaches included targeting CD33-positive AML with gemtuzumab ozogamycin (GO), which was approved in September 2017 for use in combination with daunorubicin and cytarabine in newly diagnosed CD33-positive AML, as well as monotherapy in relapsed/refractory disease (25).

Arguably the most transformative advance in AML occurred with the approval of VEN in combination with hypomethylating agents (HMAs) or low-dose cytarabine (LDAC) for older or medically unfit patients. VEN, a BCL2 inhibitor, demonstrated initial success in chronic lymphocytic leukemia, prompting preclinical and clinical evaluation in AML (26,27). Early studies of VEN monotherapy in relapsed/refractory AML, with dose escalation up to 1,200 mg daily, yielded limited activity, with composite complete remission (CR/CRi) of 19% (28). In contrast, frontline combination therapy with VEN plus LDAC or HMAs produced substantially higher response rates, with CR/CRi rates of 61% and 54%, respectively (29,30). These findings led to the randomized phase III VIALE-A and VIALE-C trials. VIALE-A randomized 431 patients with newly diagnosed AML who were ineligible for intensive chemotherapy (due to age ≥75 years or significant comorbidities) to azacitidine plus placebo or azacitidine plus VEN. The composite CR rate was 17.9% in the azacitidine-placebo arm compared with 36.7% in the azacitidine-VEN arm (P<0.001), and median overall survival (OS) improved from 9.6 to 14.7 months, respectively (P<0.001) (31). VIALE-C randomized 211 similarly ineligible patients to LDAC plus placebo or LDAC plus VEN. Median OS was 8.4 months in the LDAC-VEN arm versus 4.1 months in the LDAC-placebo arm (P=0.04), with a hazard ratio of 0.67 (95% confidence interval: 0.47–0.96, P=0.03) (30). These results supported FDA approval of VEN in combination with azacitidine, decitabine, or LDAC for patients with newly diagnosed AML who are ineligible for intensive chemotherapy due to advanced age or comorbidities (32). In September 2020, the oral formulation of azacitidine was approved for the continued treatment of patients with AML who achieved CR or CRi following intensive induction chemotherapy and are not candidates for transplantation (33).

More recently, menin has emerged as a critical therapeutic target in AML. Menin, encoded by the MEN1 gene, plays a key role in epigenetic regulation and forms oncogenic complexes with mutant NPM1 or KMT2A/MLL fusion proteins, driving leukemogenesis (34). Menin inhibitors such as revumenib and ziftomenib have been approved for relapsed/refractory AML. Revumenib received approval for relapsed/refractory acute leukemias harboring NPM1 mutations or KMT2A rearrangements (35,36), while ziftomenib was approved for relapsed/refractory NPM1-mutated AML in patients lacking satisfactory alternative treatment options (37).

Numerous additional targeted strategies are under investigation in AML. BTX-A51 is a first in-class inhibitor of casein kinase 1α (CK1α) and cyclin-dependent kinases (CDK) 7 and 9, that activates p53 signaling and induces leukemic cell apoptosis. In a phase I trial of patients with relapsed/refractory AML and MDS, 10% achieved CRi. Responders were enriched among patients with RUNX1 mutations, with all responders harboring RUNX1 mutations and a CR/CRi rate of 30% in this subgroup (38). Other approaches, more closely aligned with Liu and colleagues’ work, focused on targeting disease-sustaining metabolic dependencies in AML: dysregulated amino acid, lipid, and carbohydrate metabolism has emerged as a promising therapeutic vulnerability (39). For example, dietary tryptophan is metabolized through the kynurenine pathway, a process catalyzed in part by indoleamine-2,3-dioxygenase (IDO) or tryptophan-2,3-dioxygenase. Elevated serum kynurenine levels have been associated with inferior OS in AML (40), and IDO is constitutively expressed in AML blasts suggesting a potential mechanism for immune evasion (41). These observations have prompted clinical investigation of IDO inhibitors, including linrodostat, indoximod, and epacadostat (41,42).

Additional metabolic strategies have targeted lipid metabolism, based on preclinical observations that statins can induce apoptosis and promote differentiation in leukemic cells (43). A phase II study combining chemotherapy with high-dose pravastatin in relapsed/refractory AML reported response rates of 75%, including 56% CR rate, and a median OS of 12 months (P=0.0003) (44). Numerous independent studies have demonstrated upregulation of the glycolytic pathway in AML, with increased glycolytic activity correlating with in vitro resistance to chemotherapy (45,46). These observations have prompted evaluation of glycolytic metabolism as a potential therapeutic target. 2-deoxglucose (2-DG), a glucose analog that inhibits glycolysis and induces autophagy, has shown preclinical activity in AML (46). Treatment of primary human AML cells with 2-DG in vitro resulted in suppressed proliferation, increased apoptosis, and synergy with BCL-2 inhibition (47). Clinically, 2-DG has been evaluated in phase I studies in solid tumors, as monotherapy and in combination with chemotherapy, and has demonstrated acceptable tolerability, although definitive efficacy remains uncertain (39,48). These examples align with an emerging direction in AML therapeutics that focuses on targeting metabolic dependencies within an otherwise highly dynamic disease. Liu et al. (1) not only build on the novel strategy of glutamine depletion, but also provides mechanistic insight and a biologic rationale for combining PegC and VEN, demonstrating synergistic activity between the two agents. The observed activity in RUNX1-mutated disease further underscores the potential for molecularly informed patient selection and highlights an avenue warranting deeper investigation.

The “renaissance” in the diagnostic and therapeutic landscape of AML has largely been driven by advances in molecular profiling. However, despite the remarkable efficacy of targeted agents, often inducing deep remissions and prolonging survival, their impact remains limited to disease control rather than a cure. At present, a cure in AML is still achieved primarily through cytotoxic chemotherapy or allogeneic hematopoietic stem cell transplantation. This reality reflects the aggressive, heterogenous, and polyclonal nature of AML. Strategies that combine the scope of metabolic targeting with the precision of molecularly guided therapy, could offer a promising middle ground.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Chinese Clinical Oncology. The article has undergone external peer review.

Peer Review File: Available at https://cco.amegroups.com/article/view/10.21037/cco-2025-1-191/prf

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Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://cco.amegroups.com/article/view/10.21037/cco-2025-1-191/coif). The authors have no conflicts of interest to declare.

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