Azacitidine and venetoclax for HR-MDS: election results pending

In this issue of Blood, Garcia et al¹ identify the recommended phase 2 dose and schedule of therapy with azacitidine and venetoclax for the treatment of higher risk myelodysplastic syndromes (MDS; HR-MDS) and report on the safety and efficacy of the combination, with a complete response (CR) and hematologic improvement (HI) rate that approaches 50%.

HR-MDS is a life-threatening diagnosis associated with a median survival that falls short of a single, 2-year term in office for a US congressman and far short of the 4-year German Bundestag or 5-year British House of Commons or Lok Sabha India Parliament terms. This risk group is defined by the International Prognostic Scoring System-Revised groups of very high, high, and, sometimes, intermediate (score >3.5, though in this trial it was defined as a score >3).² HR-MDS is a disease of older age, fraught with the risk of impending transformation to acute myeloid leukemia (AML), disease-related and competing causes of death, and consequently a dismal survival. Hematopoietic cell transplantation (HCT) is the only curative-intent therapy, yet it remains a pipe dream for most patients due to comorbidities, waning performance status, and misalignment with patient and physician goals of care.³ 

Despite the urgency for developing improvements in therapies, the standard for HR-MDS for the past 2 decades has steadfastly remained monotherapy with a hypomethylating agent (either azacitidine or decitabine). Contrast this to diagnoses such as multiple myeloma that now flaunt quadruple therapies as a standard, with improved overall survival as a welcome consequence.

The study by Garcia et al tries to make inroads to a combination therapy standard. After initially administering azacitidine and venetoclax similar to how the drugs are given to patients with AML, and realizing a 20% septic death rate, the investigators cut the venetoclax dosing schedule in half, to 14 days of a 28-day cycle, combined with 7-day azacitidine dosing. Among 107 patients enrolled on this schedule, the CR rate was 29.9% and combined CR and HI was 48.6% (the authors also report marrow CR, but this has been eliminated as an acceptable International Working Group response criterion).⁴ The median overall survival was good, at 26 months, and 39% of patients went on to receive HCT.

These response rates were higher than those found in AZA-001 (in which the CR rate was 17%), the only prospective MDS trial to ever have a significant survival advantage for a drug intervention: azacitidine, with a median survival of 24 months, compared with conventional care, with a median survival of 15 months.⁵ But does that make them better?

Unfortunately, the campaign trail to election of a combination standard in HR-MDS is littered with single-arm trial results even better than those found here and subsequent randomized trials that fell flat. For example, the CR rates in the phase 1b study of the anti-CD47 monoclonal antibody magrolimab plus azacitidine and the phase 2 study of the NEDD8-activating enzyme inhibitor pevonedistat plus azacitidine were 32.6% and 40%, respectively.^6,7 However, randomized phase 3 studies of magrolimab plus azacitidine and pevonedistat plus azacitidine reported CR rates of 21.3% (23.6% with azacitidine) and 24% (32% with azacitidine), respectively, with no event-free or overall survival advantage for either combination.⁸ 

Why is not more therapy always better for patients with HR-MDS? The answer lies in toxicities that either offset efficacy benefits or that delay administration of effective therapy. In the study by Garcia et al, even with a truncated, 14-day schedule, the venetoclax dose was reduced in more than half of the study patients and interrupted in ∼90% during the course of therapy, with 94% of patients experiencing grade 3 or 4 treatment-emergent adverse events. Recently, in older adults with AML who are biologically and chronologically similar to patients with HR-MDS, the venetoclax and azacitidine combination has met the needs of its electorate by attenuating venetoclax duration even further, to 7 days, to improve tolerability without apparent compromise in efficacy,⁹ particularly in octogenarians and nonagenarians.¹⁰ It remains to be seen whether the reported schedule of 14 days of venetoclax is optimal in HR-MDS.

It is true that neither of the above-mentioned add-on therapies (magrolimab or pevonedistat) that failed to be elected to the office of MDS combination standard had marked single-agent activity in MDS. The combination of venetoclax with azacitidine, however, is the standard of care in older adults with AML, a related myeloid malignancy. Thus, the MDS clinical and research community is cautiously optimistic about the tolerability and clinical activity of venetoclax with azacitidine in patients with treatment-naive HR-MDS, particularly those who are younger or who have HR-MDS that is achingly close to AML. We eagerly await the general election results from the randomized phase 3 VERONA trial (ClinicalTrials.gov identifier: NCT04401748), in which patients with HR-MDS are randomized to azacitidine and venetoclax or azacitidine monotherapy, anticipated in late 2025.

Conflict-of-interest disclosure: M.A.S. serves on advisory boards for Bristol Myers Squibb, Kurome, and Geron. S.V. declares no competing financial interests.