Improving Outcomes in High-Risk MDS and CMML: Which Needle(s) to Use Remain Lost in the Haystack

Myelodysplastic syndromes (MDS) comprise a spectrum of clonal myeloid stem cell disorders characterized by variable degrees of cytopenias and risk of transformation to acute myeloid leukemia (AML). Chronic myelomonocytic leukemia (CMML) is also a myeloid stem cell disorder with risk of leukemic transformation; it is both clinically (e.g., peripheral blood monocytosis often accompanied by leukocytosis and other myeloproliferative features such as hepatosplenomenaly) and biologically distinct from MDS.¹  Allogeneic hematopoietic stem cell transplantation remains the only curative treatment for these disorders, and nontransplant therapeutic options for higher-risk AML and CMML are limited. Frontline treatment of newly diagnosed, higher-risk MDS and CMML with a hypomethylating agent such as azacitidine improves peripheral cytopenias, transfusion requirements, and quality of life.^2-4  As azacitidine is the only drug shown to prolong survival in this setting,²  only approximately 30 to 40 percent of treated patients respond, and disease progression remains inevitable, studies combining azacitidine with other agents with potentially synergistic or additive effects have been tried. Early-stage studies combining azacitidine with lenalidomide⁵  or a histone deacetylase inhibitor (e.g., vorinostat)⁶  have shown promising results. To determine whether the benefits of these combination therapies hold in a large randomized study, Dr. Mikkael Sekeres and colleagues conducted a multicenter, randomized, three-arm phase II/III study of azacitidine combined with lenalidomide or with vorinostat versus azacitidine monotherapy in patients with higher-risk MDS or CMML.⁷ 

The study included 277 adult patients (median age, 70 years; range, 28-93 years) with higher-risk MDS, defined as intermediate-2 or high-risk IPSS score and/or bone marrow blasts of at least 5 percent (n=224), or CMML (n= 53) from 90 clinical centers. Patients were randomly assigned 1:1:1 to 75 mg/m² daily azacitidine on days 1 to 7 of a 28-day cycle (n = 92); azacitidine plus 10 mg/day lenalidomide on days 1 to 21 (n = 93); or azacitidine plus 300 mg vorinostat twice daily on days 3 to 9 (n = 92). The primary end point of the study was overall response rate per 2006 International Working Group MDS response criteria.⁸ 

After a median follow-up of 23 months, the overall response rate (ORR) was 38 percent for all azacitidine-based regimens. The ORR was similar for all patients regardless of treatment with single-agent azacitidine (38%), azacitidine plus lenalidomide (49%; p=0.14 vs. azacitidine monotherapy), or azacitidine plus vorinostat (27%; p=0.16 vs. azacitidine monotherapy). Moreover, the distribution of patients achieving complete response, partial response, hematopoietic improvement, and marrow complete response were similar across all treatment groups, apart from a higher rate of hematologic improvement defined by neutrophil count in patients receiving azacitidine plus lenalidomide compared to azacitidine monotherapy (19% vs. 5%; p=0.007). The median response duration (15 months for the entire cohort) also did not differ significantly between treatment arms. In subgroup analyses, no differences in ORR were seen for therapy-related MDS, IPSS subgroups, transfusion-dependent patients, or allogeneic transplantation rates across treatment arms. Notably, among patients with CMML, the ORR (38% for the entire cohort) was significantly higher for those receiving azacitidine plus lenalidomide than for those receiving azacitidine monotherapy (68% vs. 28%; p=0.02); the median duration of response did not differ across treatment arms. The study was not adequately powered to address overall survival (OS). Genetic testing for somatic mutations in MDS genes was available in 113 patients. OS was higher in patients with DNMT3A mutations compared with patients without (67% vs. 34%; p=0.025). Response duration was worse for those with mutations in TET2 (p=0.046) and TP53 (p=0.003). Response duration improved significantly with fewer mutations (HR = 6.86 for two more mutations vs. no mutations; p=0.01).

All groups demonstrated similar serious adverse events. Patients treated with the vorinostat combination exhibited more grade 3 or higher gastrointestinal toxicities than with azacitidine alone (15% vs. 4%; p=0.02). Patients treated with the lenalidomide combination experienced more grade 3 or higher rashes (16% vs. 3%; p=0.005). Notably, patients treated with any combination appeared more likely to undergo non–protocol-defined dose modifications than patients treated with monotherapy, which may have negatively impacted response and OS outcomes. Indeed, researchers observed an association between lenalidomide dose reduction and worse OS (HR = 1.30; p=0.05).