Tailoring Frontline Combination Therapies for AML Patients Unfit for Intensive Chemotherapy
While the use of azacytidine and venetoclax (VEN-AZA) combination therapy has been especially beneficial for AML patients who are unfit for intensive chemotherapy with specific molecular profiles such as NPM1-positive or IDH-mutated AML,1 these regimens continue to show limited durability in response for many patients. As a result, research has increasingly focused on how regimens with increased complexity may improve outcomes, particularly through the addition of agents such as FLT-3 or IDH inhibitors to VEN-AZA, forming “triplet” therapies.2

Early-phase studies indicate that triplet therapies may offer higher response and improved MRD-negativity rates,2,3 though the challenge lies in balancing efficacy with increased toxicity. For example, the myelosuppressive effects of VEN-AZA alone can be significant,4,5 and adding a third agent often requires strict dose modifications and frequent monitoring to mitigate these effects.4,5 In practice, some institutions have adopted protocols in which venetoclax is dosed for only 14 days in triplet regimens to enhance tolerability.4 However, without randomized data to support these approaches, many clinicians rely on clinical trials to guide implementation.4

In the case of patients with FLT-3 mutations, recent studies indicate that the combination of VEN-AZA with FLT-3 inhibitors such as gilteritinib shows some promise but presents practical hurdles in terms of approval and administration.6 Some experts suggest a sequential approach, incorporating FLT-3 inhibitors in the second cycle once initial cytoreduction has been achieved.7,8 This strategy may reduce the risk of tumor lysis and other adverse events,8 potentially allowing for a more controlled introduction of triplet therapies in the frontline setting.7,8

For mutation-agnostic approaches, adding emerging therapies to VEN-AZA remains an area of active research. Combinations with agents that may not directly target specific mutations but could provide additive or synergistic effects are currently under investigation. Among these, menin inhibitors are being evaluated as a potential partner to VEN-AZA with reduced myelosuppression.9 Immunotherapy combinations are also of interest, with the potential advantage of reduced toxicity overlap, although myelosuppression remains a challenge with any AML treatment.10,11

Ultimately, while triplet regimens are a promising frontier in the treatment of unfit AML patients, careful patient selection and individualized dose adjustments are essential. The goal remains to maximize quality of life and therapeutic benefit, especially for those patients who are ineligible for intensive therapy, making clinical trials a critical platform for validating the role of these emerging combinations.

CD47 Inhibition as Non-intensive Therapy in AML
CD47 inhibition, targeting the “don’t-eat-me” signal on AML cells, represents a novel immunotherapeutic approach, particularly for TP53-mutant AML.12,13 While early studies showed promise,14 recent phase III trials have raised concerns due to anemia and inconsistent efficacy,15 leading to a reevaluation of CD47 inhibition strategies. Currently, agents with modified targeting mechanisms are under investigation to potentially mitigate toxicity and improve outcomes.13,16 The mixed results from CD47 trials underscore the complexity of developing effective AML therapies, and for now, clinical applications in AML remain in early trials as research continues.

Bispecific and T-cell Redirecting Therapies in AML
Bispecific antibodies and T-cell redirecting therapies, which have achieved success in B-cell malignancies, are promising yet complex options for AML.17 These therapies work by targeting specific myeloid antigens, aiming to direct the immune response selectively against leukemia cells.18 However, challenges unique to AML include antigen sink—where the targeted antigen appears on multiple cell types, including healthy ones—and a higher incidence of cytokine release syndrome (CRS),19,20 both of which can complicate treatment and limit the effectiveness of these agents.

In early trials, bispecific antibodies showed activity in AML patients with lower disease burden, but responses were typically short-lived, often due to CRS and other dose-limiting toxicities.21 To mitigate these effects, there is growing support for using these agents earlier in the treatment course, especially in MRD-positive or low-burden disease settings where the immune system may better sustain responses.22 Additionally, combining bispecifics with hypomethylating agents, such as azacytidine, may provide a more tolerable and effective approach by enhancing immune activity without impairing T-cell function.23

Bispecific antibodies are emerging as valuable therapeutic options in AML, particularly for patients ineligible for allogeneic stem cell transplant (allo-SCT) or as adjuncts to improve transplant outcomes.24 By positioning these therapies as pre-transplant consolidation or as treatment for patients with high-risk or MRD-positive disease, bispecifics could maximize the impact of transplant and potentially enhance survival rates.17 Emerging studies are now exploring novel target antigens specific to AML, which may offer a more tailored approach and improved tolerability for patients in the future.25

The Evolving Role of CAR T-cell Therapies in AML
CAR T-cell therapy, while transformative in B-cell malignancies, faces substantial challenges in AML due to the complexities of the disease and patient-specific factors. In AML, CAR T-cell studies have predominantly involved heavily pretreated patients with advanced disease, which often results in compromised T-cell function and reduced availability of functional T-cells necessary for effective CAR T-cell production.26 Unlike in other cancers, AML patients in these trials often have extensive treatment histories and compromised T-cell reserves, increasing the difficulty of achieving durable responses.27

To enhance the efficacy of CAR T-cell therapy in AML, ongoing research is exploring its earlier application in the treatment course, particularly in MRD-positive or MRD-negative consolidation settings.27 Administering CAR T-cell therapy when residual disease levels are low and immune function is better preserved may improve outcomes by mitigating the challenges associated with significant T-cell depletion.27 Furthermore, advances in CAR T-cell engineering, such as targeting multiple antigens, are being investigated to address the heterogeneity of AML.28

The choice between autologous and allogeneic CAR T-cell therapies is a significant consideration when planning treatment strategies in AML. While autologous CAR T-cells have been standard in other cancers, allogeneic CAR T-cells offer logistical advantages, such as streamlined manufacturing and genetic modifications to enhance persistence and reduce rejection.27 New trials involving multi-edit allogeneic CAR T-cell products targeting antigens such as CLL-1 are underway, aiming to create T-cells that perform more effectively against AML's heterogeneous blast population.27 Integrating CAR T-cell therapy with allo-SCT may extend remission duration and provide more durable outcomes for challenging AML cases.27

Since AML is a rare and complex disease, harmonizing trial designs and promoting collaboration among academic and community centers is crucial for identifying ideal candidates for CAR T-cell therapy. With ongoing research, CAR T-cell therapy may eventually provide a viable pre-transplant consolidation strategy, and with continued advancements, multi-targeting CAR T-cells hold promise for reshaping AML treatment.

Treating Patients with AML with Non-intensive Therapies in the Community Setting
The integration of non-intensive regimens, such as hypomethylating agents combined with venetoclax (HMA-VEN) and targeted agents such as ivosidenib (HMA-IVO), as well as triplet therapies, has expanded AML management into community oncology settings.29 However, administering these therapies necessitates meticulous dosing and monitoring, particularly with complex regimens such as triplet therapies. Experts advocate for early patient referral to specialized centers to assess clinical trial eligibility and oversee initial therapy phases, where rapid adjustments and close observation are crucial.

Managing AML in the community setting can presents challenges, particularly during the initiation of triplet therapies, which require meticulous coordination.30 In certain regions, academic centers offer resources such as advanced practice providers (APPs) to support community clinicians by facilitating prompt follow-ups and real-time treatment adjustments.31 This collaborative approach bridges the gap between community and academic centers, allowing patients to receive specialized care close to home.30

Education and training are also important for empowering community oncologists to manage non-intensive AML therapies confidently. Knowledge-sharing initiatives and support from academic centers can create “champions” within community practices who become familiar with newer regimens and can mentor others. By building these collaborative networks, community oncology practices can extend non-intensive AML care effectively, improving patient outcomes through continuity of care and timely access to specialized resources.

Conclusion
The treatment landscape for AML patients unfit for intensive chemotherapy continues to expand, offering new opportunities for improving outcomes. Selecting appropriate therapies requires a nuanced understanding of genetic markers and close collaboration with specialized centers. Key strategies include using the results of next-generation sequencing (NGS) to inform treatment planning with targeted therapies, such as FLT-3 or IDH inhibitors, and referring patients to centers for advanced clinical trials, especially for complex regimens and emerging therapies such as CAR T-cells and bispecifics. Engaging specialized centers early strengthens patient options and provides community oncologists with valuable resources for delivering individualized AML care.

View the entire accredited panel discussion between three international clinical experts in AML, and hear more of this animated discussion on the most exciting and innovative clinical trials available today for this challenging patient population.

Provided by MediCom Worldwide, Inc.
Supported by an educational grant from Pfizer, Inc.