Key Ideas

Three recent studies provide important insights into the management of myelodysplastic syndromes and rare hematologic malignancies. The phase 3 VERONA trial found that adding venetoclax to azacitidine did not improve overall survival in higher-risk myelodysplastic syndromes (MDS), despite higher response rates. A 312-patient multicenter study highlights the poor outcomes of MECOM-rearranged AML and the important role of allogeneic hematopoietic cell transplantation in eligible patients. Recent advances in BPDCN are also expanding treatment options for this rare hematologic malignancy.

Rethinking Risk in High-Risk Blood Cancers

Myelodysplastic syndromes and acute leukemias encompass a broad spectrum of disease biology, and recent studies highlight how these biologic differences can influence treatment and outcomes. The first is a large phase 3 trial that did not meet its primary survival endpoint but provides important insights into the role of venetoclax-based therapy in higher-risk MDS. The second examines MECOM-rearranged AML, a rare and particularly adverse-risk subtype of acute myeloid leukemia. The third focuses on BPDCN, a rare hematologic malignancy for which the therapeutic landscape continues to evolve.

High-Risk MDS: Why Adding Venetoclax to Azacitidine Falls Short

Myelodysplastic syndromes and acute myeloid leukemia (AML) exist along a disease continuum but remain biologically distinct, and therapeutic advances in AML do not necessarily translate directly to MDS. Higher-risk MDS is associated with poor survival, and allogeneic hematopoietic cell transplantation remains the only potentially curative treatment for eligible patients.

Venetoclax plus azacitidine is a standard treatment for many older or medically unfit patients with newly diagnosed AML, raising the question of whether this combination could improve outcomes in higher-risk MDS. The phase 3 VERONA trial addressed this question by randomizing 509 treatment-naive patients with intermediate- or higher-risk MDS to venetoclax plus azacitidine or placebo plus azacitidine. The study did not demonstrate a significant improvement in overall survival: median OS was 22.18 months with venetoclax plus azacitidine versus 21.68 months with placebo plus azacitidine (HR, 0.91; P=.38), despite higher response rates with the venetoclax combination.

The results do not necessarily exclude a role for venetoclax in selected patients with higher-risk MDS. Subgroup analyses suggested trends toward higher response rates among patients with increased bone marrow blasts and certain molecular features, but these findings require further study and should not be interpreted as evidence of a survival benefit. More broadly, the VERONA results underscore that therapeutic strategies effective in AML cannot simply be extrapolated to higher-risk MDS. Improved molecular classification and risk stratification, including use of the IPSS-M, and development of novel therapeutic approaches remain important priorities.

MECOM-Rearranged AML: A Very High-Risk Leukemia Subtype

MECOM-rearranged AML is a rare and very high-risk subtype of AML, accounting for approximately 2%–4% of cases. Classic cytogenetic abnormalities include inv(3)(q21q26) and t(3;3)(q21;q26), as well as other less common rearrangements involving 3q26. Despite advances in AML therapy, outcomes remain poor, and data regarding the optimal frontline treatment strategy are limited.

Our multicenter study evaluated 312 patients with MECOM-rearranged AML across two research consortia and a large real-world community oncology database. Composite complete remission was achieved in 35% of patients overall and was higher with intensive chemotherapy than with HMA plus venetoclax or HMA alone (42%, 37%, and 12%, respectively; P<.001). Median overall survival was 14.8 months with intensive chemotherapy, 7.8 months with HMA plus venetoclax, and 6.2 months with HMA alone. Intensive chemotherapy was associated with higher odds of achieving composite complete remission and enabled more patients to proceed to allogeneic hematopoietic cell transplantation.

Allogeneic transplantation was the strongest independent predictor of improved overall survival (HR, 0.21; P<.001), with a median overall survival of 24 months among transplanted patients. These findings support early evaluation for transplant eligibility and efforts to achieve disease control that allows eligible patients to proceed to transplantation. Nevertheless, outcomes remain suboptimal even with intensive therapy and allo-HCT, highlighting the need for clinical trials and novel MECOM-directed therapeutic strategies. 

BPDCN: Evolving Treatment Options and the Role of Transplantation

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive hematologic malignancy with historically poor outcomes. In a retrospective study across the three Mayo Clinic sites, we evaluated 70 patients with BPDCN. The median age was 69 years, 81% were male, and skin and bone marrow involvement were present in 79% and 74% of patients, respectively. Central nervous system involvement was identified in 13%, and 25% had a concurrent or antecedent myeloid malignancy.

Frontline treatment was heterogeneous and included AML-type regimens, ALL-type regimens, and tagraxofusp. Among patients with available treatment data, complete remission rates were 92% with hyper-CVAD, 89% with HMA plus venetoclax, 74% with intensive AML therapy, and 60% with tagraxofusp. The proportion of patients proceeding to allo-HCT differed by frontline regimen, although these differences were no longer significant after adjustment for age.

Median overall survival for the entire cohort was 14.5 months. Nineteen patients underwent allo-HCT, with median overall survival of 51 months compared with 10 months among patients who did not undergo transplantation. A landmark analysis addressing immortal-time bias continued to demonstrate improved survival associated with HCT (P=.037). In a time-varying Cox model, however, the association between allo-HCT and improved survival did not reach statistical significance (HR, 0.42; 95% CI, 0.17–1.05; P=.06). Abnormal karyotype and age ≥50 years were independently associated with worse outcomes.

These findings underscore the importance of achieving remission and evaluating eligible patients early for allo-HCT, while also highlighting the need for improved therapeutic strategies and better risk stratification in BPDCN. 

For Patients

If you or a loved one has been diagnosed with myelodysplastic syndrome, acute myeloid leukemia, or blastic plasmacytoid dendritic cell neoplasm (BPDCN), recent studies provide important information that may help guide discussions about treatment.

For higher-risk MDS, adding venetoclax to azacitidine increased response rates in the phase 3 VERONA trial but did not improve overall survival. This does not mean that venetoclax has no role in MDS, but its use should be individualized based on disease characteristics, treatment goals, and eligibility for stem cell transplantation.

For patients with MECOM-rearranged AML, achieving remission is an important first step, but outcomes remain challenging. Our multicenter study showed that intensive chemotherapy was associated with higher remission rates and allowed more patients to proceed to allogeneic stem cell transplantation. For eligible patients, early evaluation for transplantation and consideration of clinical trials are particularly important.

For patients with BPDCN, several treatment approaches can achieve remission, and allogeneic stem cell transplantation remains an important consideration for eligible patients. In our Mayo Clinic study, patients who underwent transplantation had favorable survival, although outcomes varied according to age and disease characteristics. These findings support early discussion of treatment goals, transplant eligibility, and available clinical trials. 

Key Takeaways

  • The phase 3 VERONA trial found that adding venetoclax to azacitidine increased response rates but did not improve overall survival compared with azacitidine alone in higher-risk MDS. 

  • MECOM-rearranged AML remains a very high-risk AML subtype with frequent relapse and poor survival. Intensive chemotherapy was associated with higher remission rates and more frequent transition to allogeneic hematopoietic cell transplantation (allo-HCT).

  • In MECOM-rearranged AML, allo-HCT was the strongest independent predictor of improved overall survival, supporting early transplant evaluation for eligible patients. 

  • n BPDCN, achieving remission and successfully bridging eligible patients to allo-HCT are important treatment goals. Abnormal karyotype and age ≥50 years were independently associated with worse outcomes in the Mayo Clinic cohort.

  • Clinical trial enrollment should be considered for patients with these rare hematologic malignancies given the limitations of current treatment approaches.

References

  1. Garcia-Manero G, Platzbecker U, Fenaux P, et al. Primary analysis of the randomized, phase 3 VERONA study of venetoclax with azacitidine versus placebo with azacitidine in patients with treatment-naive, intermediate- and higher-risk myelodysplastic syndromes. Presented at the Society of Hematologic Oncology (SOHO) 2025 Annual Meeting; Abstract MDS-1497.

  2. Garcia-Manero G, Platzbecker U, Fenaux P, et al. Subgroup analyses from the randomized, phase 3 VERONA study of venetoclax with azacitidine versus placebo with azacitidine in patients with treatment-naive, intermediate- and higher-risk myelodysplastic syndromes. Presented at the American Society of Hematology (ASH) 2025 Annual Meeting; Abstract 235. 

  3. Arana Yi C, et al. Real-world outcomes in MECOM-rearranged AML: the largest multicenter cohort reported to date. Presented at the European Hematology Association (EHA) 2026 Congress; Abstract 6007.

  4. U.S. Food and Drug Administration. FDA approves pivekimab sunirine-pvzy for blastic plasmacytoid dendritic cell neoplasm, an ultra-rare hematologic malignancy. May 27, 2026. 

  5. Pemmaraju N, Lane AA, Sweet KL, et al. Tagraxofusp in blastic plasmacytoid dendritic-cell neoplasm. N Engl J Med. 2019;380(17):1628-1637. 

  6. Andres E, et al. Retrospective analysis of blastic plasmacytoid dendritic cell neoplasm across three Mayo Clinic sites. Presented at the American Society of Clinical Oncology (ASCO) Annual Meeting; Abstract e18508.