Bridging the gap: AML induction in low-resource settings Open Access

In this issue of Blood Global Hematology, De la Garza-Salazar et al¹ demonstrate that in a resource-limited setting, a lower-intensity outpatient regimen of venetoclax and azacitidine with itraconazole can achieve similar remission and survival rates with significantly fewer complications compared to standard intensive chemotherapy in adults with newly diagnosed acute myeloid leukemia (AML).

Intensive chemotherapy (IC) remains the standard of care for AML induction in medically-fit adults,² yet this standard presumes reliable access to inpatient monitoring and costly augmented supportive care. In low- and middle-income countries (LMICs), where infection-related mortality is high and hospital resources are limited, providing this level of care may not be feasible, or offer the same benefit vs risk ratio.^3-5 The question of how to deliver effective AML therapy safely and affordably outside of high-resource systems has become one of the most pressing challenges in global hematology.

In this article, De la Garza-Salazar et al present a pragmatic response to that challenge. Their retrospective study compared outcomes among 100 adults with newly diagnosed AML treated at 2 centers in Monterrey, Mexico, a self-described resource-limited setting. Patients received either conventional IC induction with cytarabine and an anthracycline, or an outpatient regimen of azacitidine and low-dose venetoclax with itraconazole (VenAza). The investigators leveraged the pharmacologic interaction between venetoclax and itraconazole, a CYP3A4 inhibitor, to reduce the required dose of venetoclax, resulting in cost savings of ∼75%.

Despite an increased incidence of older and higher-risk cytogenetic features in the VenAza cohort, these patients experienced markedly fewer complications compared with those receiving IC. Febrile neutropenia, a frequent cause of early death in AML induction, occurred less frequently in the VenAza cohort (50% vs 91%), resulting in profoundly decreased 60-day mortality (4.5% vs 26.8%). Hospitalization rates were cut by half, with 50% of the VenAza patients completing induction entirely as outpatients. Response rates were numerically lower with VenAza (60% vs 77%), although this was not statistically different between treatment cohorts, and median relapse-free survival was improved with VenAza (10 vs 6 months). Importantly, there was no difference in median overall survival, and the rate of transition to allogeneic stem cell transplantation was similar in both cohorts (32% with VenAza vs 30% with IC).

These data add to the growing body of evidence challenging the long-standing dichotomy which divides AML therapy into those fit for intensive therapy and unfit for intensive therapy. In many high-resource health care systems, VenAza remains a regimen reserved for older adults who are considered unfit^6-8 and not appropriate for transplantation. The observation that this lower-intensity regimen achieved comparable efficacy with lower early mortality in adults across a range of ages and fitness suggest that treatment intensity is not the sole determinant of outcome, particularly when supportive-care resources are limited.

Further, this work holds broad relevance for the global hematology community, where a central challenge is to expand access to effective therapy without compromising safety. Even in well-resourced systems, many patients receive care in community hospitals where limitations in inpatient capacity, transfusion support, rapid infection/sepsis protocols, and access to urgent subspecialty consultation may be limited. The ability to deliver an effective AML regimen in an outpatient setting therefore has implications far beyond LMICs.

It is important to recognize that the retrospective design of this study introduces potential bias. The VenAza cohort was accrued more recently, thus follow-up time was therefore shorter, and general improvements in supportive care over time are acknowledged. Treatment following induction was furthermore not standardized: consolidation treatment (including access to transplant) varied according to response and available resources, as any therapy following induction required out-of-pocket payment. Additionally, the VenAza patients were generally older and more likely to have secondary or adverse-risk AML compared with the patients receiving IC. The fact that outcomes were nonetheless comparable, underscores the regimen’s promise, but prospective validation will be essential. The randomized PARADIGM trial⁹ will provide important clarity regarding whether a lower-intensity VenAza regimen can replace IC in select patients.

By adapting a modern AML therapy to fit local realities, both clinical and economic, De la Garza-Salazar et al demonstrate that safety, cost, and accessibility can coexist with efficacy in the treatment of AML. Their findings invite the hematology community to look beyond conventional treatment hierarchies and to pursue adaptable, pragmatic solutions that improve access to effective care.

Conflict-of-interest disclosure: The authors declare no competing financial interests.