Expanding Clones Seen in Minority of Patients With Aplastic Anemia Treated With Eltrombopag

Researchers suspect that mutations may be leukemogenic

By Jaroslaw Maciejewski, MD, PhD

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Maciejewski_insetThe introduction of the cMpl agonist eltrombopag for patients with aplastic anemia (AA) was met with great expectations as an alternative for older patients, those with significant comorbidities, or those refractory to immunosuppressive therapy (IST). It was also greeted as an alternative to anabolic steroids.

However, there was also a potential dark side in eltrombopag’s effects: theoretical focalization of clonal expansion of mutant clones, leading to secondary myelodysplastic syndrome (MDS). Complicating matters, it has been shown that some patients presenting with aplastic anemia have mutations characteristic of sMDS, constituting a risk for progression to MDS.

Study examines 13 IST-refractory patients treated with eltrombopag

A study of 208 patients treated at Cleveland Clinic for aplastic anemia revealed 13 (median age 68 years) treated with eltrombopag for IST-refractory disease. The median duration of treatment was 85 weeks, and the overall response rate was 46 percent (6/13), while 38 percent (5/13) showed stable disease. Of the two non-responders, one developed a paroxysmal nocturnal hemoglobinuria (PNH) clone and the other progressed to acute myeloid leukemia (AML).

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Authors of the study hypothesized that next-generation sequencing would cast light on the detection of clonal events, specifically, that clonal analysis before and after therapy would shed light on eltrombopag’s effects on clonal evolution. Results of the study were described in an abstract at the 57th American Society of Hematology Annual Meeting & Exposition in Orlando, Fla.

Analysis of tissue before therapy revealed the presence of a sole clonal mutational event in 3/13 cases, including CEBPA, EZH2 and BCOR prior to therapy. In two patients, existing clones increased, while in five other patients new clones emerged and expanded. Of note is that in some instances, hematologic responses were achieved despite the presence of subclonal mutations. In a concluding statement, the study’s authors note observing occasional expansion of clones with potentially pathogenic mutations during treatment with eltrombopag. A case-control study is underway at Cleveland Clinic on patients with refractory aplastic anemia without treatment with eltrombopag.

The authors suggest that, although ideally a prospective trial would be needed to establish the risk of clonal evolution to MDS in patients with aplastic anemia and determine the need of clonal monitoring.

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Dr. Maciejewski is head of the Department of Translational Hematology and Oncology Research at Cleveland Clinic Cancer Center. For more information, please contact Dr. Maciejewski at maciejj@ccf.org or 216.445.5962.