Hope for Myelodysplastic Syndromes and Chronic Myelomonocytic Leukemia

Combination therapy shows improved response in some

Combination therapies could help improve outcomes for patients with myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML), which belong to a spectrum of disorders associated with cytopenias, a high risk of transformation to acute myeloid leukemia (AML), and short survival times.

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“MDS are the most commonly diagnosed myeloid neoplasms in the United States, having an incidence rate of 4.6 in every 100,000 citizens,” says Mikkael Sekeres, MD, MS, Director of the Leukemia Program at Cleveland Clinic’s Taussig Cancer Institute. That means there are about 15,000 new diagnoses every year.

Patients with high-risk MDS have a median survival of nine months to two years with a 54 percent to 84 percent risk of transforming to AML during that period.

Testing combination therapies in hopes of improving patient response

These disorders are typically treated with azacitidine (AZA) or decitabine monotherapy. “Once one of these drugs fails a patient, further treatment options are limited and survival time is less than six months,” Dr. Sekeres says.

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Research conducted by Dr. Sekeres, the principal investigator of the North American Intergroup trial, and his team seeks to determine whether treating high-risk MDS and CMML with lenalidomide or vorinostat in combination with azacitidine will improve outcomes and response rates. This is the largest prospective trial conducted in the area of MDS therapeutics in North America, according to Dr. Sekeres. The results will be presented at the 2014 American Society of Hematology Annual Meeting.

Criteria for 282 patients enrolled in the study

Participant criteria and exclusions:

  • 18 years of age or older
  • Diagnosed MDS and one of these World Health Organization (WHO) classifications:
  • Chronic myelomonocytic leukemia-2
  • Refractory anemia with excess blasts -1 (RAEB-1)
  • Refractory anemia with excess blasts -2 (RAEB-2)
  • Investigators excluded patients with RAEB in transformation because the WHO defines these patients as having AML and, by design, the study was limited to patients with MDS.
  • Participants could have an IPSS score of intermediate-2 (1.5-2.0 points) or high (>2.5 points) regardless of percentage of myoblasts.
  • Participants had to have an Eastern Clinical Oncology Group status of less than two and could not be hematopoietic stem cell transplantation candidates.
  • At first, patients had to have a minimum platelet count of 50,000/L, but this was amended to 20,000/L.
  • Patients could not use erythropoiesis-stimulating agents during the study.

“Patients who met criteria were then randomized to receive azacitidine monotherapy or AZA in combination with either lenalidomide or vorinostat,” according to Dr. Sekeres.

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Combination therapy brings hope for MDS and CMML subgroups

Phase II, which included analysis of 276 patients (six ineligible patients were excluded), concluded that combination therapy may prove beneficial for certain MDS subgroups. “While overall response rates were similar among all three study arms, subgroups, such as patients with CMML, appeared to benefit from combination therapy. And those who remained on combination therapy appeared to have a DFS advantage compared to monotherapy,” says Dr. Sekeres.
Even with these promising observations for combination therapy in MDS subgroups, longer-term outcome data must be assessed before investigators can make further conclusions.