ENHANCE-ing outcomes in acute myeloid leukemia through immunotherapy: are we there yet?

For adult patents with newly diagnosed acute myeloid leukemia (AML), who are ineligible for intensive chemotherapy, the phase 3 VIALE-A trial established the current new standard of care(1). The combination of azacitidine and venetoclax showed a median overall survival (OS) of 14.7 months and an estimated 2-year OS rate of 37.5% compared to 9.6 months and an estimated 2-year OS rate of 16.9% in the azacitidine monotherapy control arm(1,2). In the ENHANCE-3 study—a phase 3, randomized, double-blind, placebo-controlled, multicenter study—investigators sought to improve upon this combination with the addition of immunotherapy(3).

Magrolimab is a monoclonal antibody targeting CD47, an antiphagocytic signal overexpressed on AML blasts and leukemia stem cells that functions as a "don't eat me" signal, enabling immune evasion and correlating with poor prognosis(4). Blocking CD47 with monoclonal antibodies enhances macrophage-mediated phagocytosis and has demonstrated robust antileukemic activity in preclinical models and xenografts (5).

Stemming from promising early phase clinical studies, magrolimab combined with azacitidine showed efficacy in both TP53-wild type and patients with TP53-mutant AML with a median OS of 19 months and 10 months, respectively(6). This led to two additional clinical trials: ENHANCE-2 and ENHANCE-3. ENHANCE-2 assessed survival outcomes in TP53-mutated AML patients treated with magrolimab and azacitidine, as compared to either venetoclax plus azacitidine (in unfit patients) or intensive 7+3 chemotherapy(7). In this study, magrolimab plus azacitidine failed to improve overall survival compared to control groups. Median OS was inferior in both the non-intensive [4.4 vs. 6.6 months, hazard ratio (HR): 1.13] and intensive (7.3 vs. 11.1 months, HR: 1.43) arms, with a hazard ratio consistently favoring the control groups. Secondary efficacy endpoints, including overall response rate, similarly showed worse trend with magrolimab and azacitidine, while comparable rates of grade ≥3 adverse events were observed between arms. Given the absence of a survival benefit and a trend towards worse outcomes compared to control, the study was terminated for futility. Investigators suggested that that shorter than anticipated magrolimab exposure (8 weeks) may have contributed to the negative outcome, as responses in the prior phase Ib study occurred after several months of therapy. However, higher rates of early progression, intolerance and early death limited treatment duration, suggesting that inadequate exposure was likely a consequence of insufficient disease control rather than sole explanation for trial failure.

Following the success of the VIALE-A trial, ENHANCE-3 sought to improve upon the disease responses observed with the doublet through addition of magrolimab to azacitidine and venetoclax. In this large, randomized phase 3 study, newly diagnosed AML patients considered ineligible for chemotherapy were assigned to azacitidine and venetoclax with either magrolimab or placebo. Despite much hope and hype, the triplet did not show overall survival benefit— regardless of risk stratification or TP53 status—and owing to futility, was stopped at prespecified interim analysis. The magrolimab arm demonstrated a median OS of 10.7 months with an (estimated 1-year OS of 48.3%) vs. 14.1 months in the control arm with an (estimated 1-year OS of 54.5%). For TP53 mutant AML or wild-type TP53 AML, previously reported one-year OS rates were 53% and 83%, respectively; however, it was substantially lower at 48% in the ENHANCE-3 study.

Meanwhile, the median OS in the control arm was similar to that of the VIALE-A trial (14.1 vs. 14.7 months). Despite those differences, the rates of complete remission (CR) were similar in both groups (41.3% vs. 46.0%).

Although prior trials (Table 1) showed similar treatment-emergent adverse events (TEAEs), infectious complications were higher in the magrolimab arm including grade 5 infections (11.1% vs. 6.5%). This included higher rates of sepsis (6.9% vs. 3.3%) and pneumonia (3.7% vs. 2.2%). As a result, this led to an increased incidence of fatal TEAEs and early deaths within 60 days. Reasons for this are unclear as there were comparable rates of infections (any grade), neutropenic fever, neutropenia, and drug interruptions owing to neutropenia between treatment arms. Infection prophylaxis was not mandated and raises the possibility of potentially lowering the incidence of serious infections.

In addition, the majority of patients with TP53-mutated AML and adverse European Leukemia Net (ELN) genetic risk in both arms may have also affected outcomes. The magrolimab arm had a higher proportion of patients with adverse genetic risk per ELN 2017 criteria vs. the control arm (44.4% vs. 35.4%). TP53-mutated AML was higher in both groups as compared to historical controls (magrolimab arm, 22.5%; control arm, 30.6%). Interestingly, the 4-gene signature stratification, identified from experience with venetoclax/azacitidine, did not reveal any OS benefit in the magrolimab arm(9).

Admittedly, the role of immunotherapy in AML continues to be complicated and has yet to find a place in the growing treatment armamentarium of this disease. The biggest hurdles are identifying targetable surface antigens and the complex interactions that occur within the tumor microenvironment including the innocent bystander effect on healthy cells. Monoclonal antibodies that are currently being investigated in clinical trials target surface CD33, CD123, or CD70 (e.g., cusatuzumab). A recent phase 1/2 study was published using cusatuzumab combined with azacitidine to patients with newly diagnosed AML not eligible for intensive chemotherapy. Of the 38 patients, 19 achieved an objective response and 14 a complete response with a median duration of response of 4.5 months and median OS of 11.5 months(10).

Randomized and early phase clinical trials evaluating the addition of immune check point inhibitors have also failed to demonstrate meaningful clinical improvement in response depth or survival. The BLAST AML-2 trial, a randomized phase II study of azacitidine and venetoclax with addition of pembrolizumab did not improve minimal residual disease (MRD)-negative complete remission (CR) or CR with incomplete count recovery rates compared to azacitidine and venetoclax alone and was associated to trend for worse outcomes (11). Interim analysis of the AARON trial, an open label phase 1/2 study, showed that azacitidine and venetoclax in combination with relatlimab (anti-LAG-3) and nivolumab (anti-PD-1) was safe in the frontline setting for patients not fit for intensive chemotherapy with adverse risk AML and showed promising efficacy (12). STIMULUS-AML1/AML 484 is a phase 2 trial combined sabatolimab (anti-TIM-3), with azacitidine and venetoclax, but results did not show significant survival advantage. A subset analysis suggests that TP53-mutated patients may benefit from the addition of sabatolimab to the azacitidine and venetoclax backbone as evidenced by higher CR rates and longer OS than in recently published reports, but these encouraging results warrant further investigation (13).

Within this context, ENHANCE-3 is the one of the largest prospective trials in adult patients with newly diagnosed AML who are ineligible for intensive treatment. While the highly anticipated results of ENHANCE-3 were not what was hoped, this study provided many important insights, sparked additional questions in AML management, and serves as a springboard for future drug development. On its own, macrophage activation may not be enough to promote a sustained adaptive immune response and known mechanisms such as immune evasion through CD47 upregulation, pro-inflammatory tumor microenvironment, and antigen sink from CD47 expression on erythrocytes need to be further explored(14). In addition to being one of the largest prospective trials in this patient population, it is also the first published and completedto evaluate a triplet combination. Notably, the toxicity of such a regimen highlights the importance of dose-finding when combined with a standard of care regimens in this patient population. Finally, despite the initial enthusiasm and promising results observed in earlier phase studies, this study highlights the importance of conducting larger, randomized controlled trials in order to truly change clinical practice.

Acknowledgments

None.

Footnote

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

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-26-0021/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-26-0021/coif). B.B. has received consulting fees from Servier, Bristol Myers Squibb, and AstraZeneca; honoraria from Novartis, Kite, Daiichi Sankyo, Syndax, Servier Pharma, and J&J; and holds scientific steering committee role for BMS. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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