New Strategies Improve Outcomes for Lower-Risk MDS


Myelodysplastic syndrome is a challenging and complicated disease with median outcomes ranging from 5.3 years in patients with lower-risk disease to just 8.4 months in the very high-risk population.

Gail J. Roboz, MD

Myelodysplastic syndrome (MDS) is a challenging and complicated disease with median outcomes ranging from 5.3 years in patients with lower-risk disease to just 8.4 months in the very high-risk population.1,2 However, newly approved agents entering the armamentarium are providing better outcomes for patients with MDS, especially for those with lower-risk disease.

Gail J. Roboz, MD, professor of medicine and director of the Clinical and Translational Leukemia Program at the Weill Medical College of Cornell University and the NewYork-Presbyterian Hospital, detailed potential causes and risk factors for the disease at the 38th Annual CFS® virtual conference.

MDS, Roboz said, is a heterogeneous group of clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis, progressive pancytopenia, morphological abnormalities.1 MDS has propensity to transform to acute myeloid leukemia (AML), but the risk for AML is not as great as many patients fear. “Actually...the risk of progression to AML is only in about 25% to 35% of patients,” she said.

Risk factors include prior exposure to chemotherapy and/or radiation, advancing age, congenital diseases such as Fanconi anemia and congenital neutropenia, and environmental toxins including World Trade Center exposure. Roboz added that MDS affects older patients—median age at diagnosis is 77 years—who often have other concomitant illnesses and comorbidities that must be considered when developing a treatment plan.

The Revised International Prognostic Scoring System (IPSS-R) classifies patients from very low risk to very high risk based on criteria including bone marrow cytogenetics, marrow blast percentage, cytopenias, patient age, and lactate dehydrogenase level.2 Roboz said it is more accurate to classify patients in the very low–, low-, and intermediate-risk groups as “lower risk.” Overall survival in the lower-risk group is generally less than 3.5 years.1

“The point being that ‘low risk,’ usually to patients, means they don’t have to worry about it and they’ll live forever,” Roboz said. “And I would say that’s actually not true at all.”

There are several different prognostic systems available, each of which includes different factors. Roboz said it is becoming increasingly complicated to have a prognostic scoring system that includes every prognostic element, but there are ways to use machine learning and artificial intelligence to consider the various factors.

“Ultimately, you do have treatment goals that are separated into the lower-risk and higher-risk groups with the fundamental goal of treatment to improve marrow function, decrease transfusions, and decrease impact on quality of life in the lower-risk patients. In the higher-risk patients, we’re trying to reduce transformation to AML and also [implement] potentially curative therapy with allogeneic transplant,” she said.

New Agents Provide Treatment Options

The FDA has approved 2 new treatments for adults with MDS in 2020, luspatercept-aamt (Reblozyl) and the oral combination of decitabine and cedazuridine (Inqovi).

Luspatercept is indicated for the treatment of anemia failing an erythropoiesis stimulating agent (ESA) and requiring 2 or more red blood cell (RBC) units over 8 weeks in adult patients with very low– to intermediate-risk MDS with ring sideroblasts or with myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis. It is not indicated for use as a substitute for RBC transfusions in patients who require immediate correction of anemia.3

The erythroid maturation agent was approved based on data from the double-blind, placebo-controlled, phase 3 MEDALIST trial (NCT02631070). The findings showed that 38% of patients treated with luspatercept had RBC-transfusion independence for at least 8 weeks compared with 13% of those in the placebo group (P < .001), meeting the primary end point of the study.4

Data from MEDALIST also met the secondary end point of hematologic improvement-erythroid (HI-E) for at least 8 weeks as assessed by International Working Group 2006 criteria. In weeks 1 through 24, 53% of patients in the luspatercept group had HI-E responses compared with 12% of those in the placebo group. Furthermore, 59% percent of patients treated with luspatercept had an HI-E response in weeks 1 through 48 versus 17% of patients receiving placebo.

“Patients had clearly statistically significant benefit with luspatercept with independence from RBC transfusions across these time intervals. [These were] very significant changes from the placebo,” Roboz said. “Mean changes in hemoglobin level…were both clinically and statistically significant improvements with luspatercept.”

The decitabine and cedazuridine combination is indicated for patients with previously untreated and untreated de novo and secondary MDS with the following subtypes: refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, and chronic myelomonocytic leukemia (CMML). The regimen is also indicated for patients classified as intermediate-1, intermediate-2, and high-risk per the International Prognostic Scoring System (IPSS).5,6

Investigators assessed the novel regimen in 2 open-label, randomized, crossover trials. The first, ASTX727-01-B (NCT02103478), included a total of 80 patients with MDS, including those with intermediate-1, intermediate-2, or high-risk IPSS scores, or CMML.6 The second, ASTX727-02 (NCT03306264), included 133 patients with either MDS or CMML, including all French-American-British classification criteria and IPSS intermediate-1, intermediate-2, or high-risk prognostic scores.5

Findings from ASTX727-01-B showed that the combination resulted in a complete response (CR) rate of 18% (95% CI, 10%-28%) and a median duration of CR of 8.7 months. Of 41 patients who were dependent on RBC and/or platelet transfusions at baseline, 49% (n = 20) became independent during any consecutive 56-day post baseline period. Of the 39 patients who had been independent of both RBC and platelet transfusions at baseline, 64% (n = 25) remained independent during any consecutive 56-day post baseline period.6

In ASTX727-02, investigators observed a 99% geometric mean ratio of the 5-day cumulative decitabine area under the curve after 5 consecutive once-daily doses of the oral combination versus intravenous decitabine (90% CI, 93-106). Twenty-one percent of patients experienced a CR (95% CI, 15%-29%) with a median duration of CR of 7.5 months.

Of 57 patients who had been dependent on RBC and platelet transfusions at baseline, 53% (n = 30) achieved independence during the 56-day post baseline period. Among 76 patients who had been independent of both RBC and platelet transfusions at baseline, 62% remained independent during the 56-day post-baseline period.6

“[These are] now in the armamentarium for patients and there are fortunately [many investigational approaches] because we still need more options in MDS,” Roboz said.


  1. Roboz GJ. New and future strategies for lower-risk MDS. Presented at: 38th Annual CFS®; November 4-6, 2020.
  2. Revised International Prognostic Scoring System (IPSS-R) for myelodysplastic syndromes risk assessment calculator. MDS Foundation. Accessed November 4, 2020.
  3. US Food and Drug Administration (FDA) approves Reblozyl (luspatercept-aamt), the first and only erythroid maturation agent, to treat anemia in adults with lower-risk myelodysplastic syndromes (MDS). News release. Bristol Myers Squibb. April 3, 2020. Accessed November 4, 2020.
  4. Fenaux P, Platzbecker U, Mufti GJ, et al. Luspatercept in patients with lower-risk myelodysplastic syndromes. N Eng J Med. 2020;382(2):140-151. doi:10.1056/NEJMoa1908892
  5. Garcia-Manero G, Griffiths EA, Steensma DP, et al. Oral cedazuridine/decitabine for MDS and CMML: a phase 2 pharmacokinetic/pharmacodynamic randomized crossover study. Blood. 2020;136(6):674-683. doi:10.1182/blood.2019004143
  6. FDA approves oral combination of decitabine and cedazuridine for myelodysplastic syndromes. FDA. July 7, 2020. Accessed November 4, 2020.
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