Study: Eltrombopag May Help Hasten Platelet Recovery in Acute Myeloid Leukemia

Interim analysis signals efficacy in older patients

Interim results from an ongoing trial suggest eltrombopag, a thrombopoietin receptor agonist, may help accelerate platelet recovery in older patients being treated for acute myeloid leukemia (AML).

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Results of the interim analysis have been accepted for presentation at the 2016 American Society of Hematology Annual Meeting in San Diego.

Consequences of delayed platelet recovery include increased risk of bleeding, increased need for platelet transfusion, alloimmunization to platelets and, importantly, delayed complete remission.

The phase II trial enrolled 13 patients between September 2014 and June 2016. Patients, all over 60 years of age, received eltrombopag during 7+3 induction chemotherapy (IC) for AML in this trial. The proportion of patients who reached a platelet count of ≥ 50,000/µL by day 24 of IC served as the primary endpoint.

Results thus far with eltrombopag have been reassuring, investigators say.

“Eltrombopag has never been tried before with 7+3 in up-front treatment of AML, and hence there were a lot of unknowns,” says lead investigator Sudipto Mukherjee, MD, MPH, of Cleveland Clinic Cancer Center. “In our prespecified interim analysis of 13 patients, all responded to eltrombopag and moreover, it was safe and effective.”

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Eltrombopag has several characteristics that provided a rationale to test it in AML. “Eltrombopag does not cause proliferation of leukemic blasts in in vivo experiments or xenotransplantation models,” Dr. Mukherjee says. “It is not immunogenic, it does not cause formation of platelet-neutralizing antibodies, and it stimulates production of platelets but does not cause activation of platelets.”

Emphasis on AML in older patients

“Delayed platelet recovery is a particularly severe problem in older people compared to younger patients with AML,” Dr. Mukherjee says. For that reason, the study’s eligibility criteria excluded anyone younger than 60 years of age, and the median age for the interim analysis was 64 years.

Enrolled patients had ECOG scores of 0 to 2, no active secondary malignancies, and no evidence of marrow fibrosis at the time of diagnosis. Acute promyelocytic leukemia, acute megakaryocytic leukemia, and AML out of myeloproliferative neoplasms were also excluded. By CALGB criteria, 82 percent had intermediate cytogenetics, 9 percent had adverse karyotype and in 9 percent cytogenetic analysis was unsuccessful. IC treatment consisted of an anthracycline for three days followed by seven days of infusional cytarabine.

Patients with a marrow blast count of <5 percent on day 14 started daily eltrombopag treatment the following day. Participants received a dose of 200 mg/day (100 mg/day for East Asian patients). The study design allowed for dose escalation in case of slow platelet recovery.

Primary endpoint met by most patients

All 13 patients responded to eltrombopag. “No patient had blood clots with platelet recovery, and no leukemic progression was seen in any of the patients,” Dr. Mukherjee notes. “There were no grade 3 or 4 toxicities, and in no instance was there any need for dose reduction or dose delays.”

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Eight patients achieved a platelet count ≥ 50,000/µL by day 24 of IC, and all but one patient had achieved complete response by 42 days after IC. There was a trend by which median platelet transfusion requirement decreased from one unit every 3.6 days during IC to one unit every 4.8 days during eltrombopag treatment. Similarly, the trend for median red blood cell transfusion requirement was a decrease from one unit every two days to one unit every 3.6 days.

Monitoring trends, outcomes as study continues

Although the results are preliminary, Dr. Mukherjee expresses optimism. “This is the first finding showing safety and efficacy of eltrombopag in up-front treatment of AML in older patients in conjunction with aggressive 7+3 remission chemotherapy,” he says.

The study design requires accrual of 31 patients, and 17 are enrolled at the time of this posting. “The trends we have seen so far in the interim analysis are what we will be monitoring closely as we accrue more patients,” Dr. Mukherjee says.

Investigators will also monitor hemoglobin and neutrophil count recovery, as well as long-term outcomes. They will continue to watch for any significant adverse effects, especially thrombotic events and disease progression, he says.

Despite the promising preliminary results, Dr. Mukherjee cautions, “This is an interim analysis, and we will have to wait for the study to be completed and final results to be presented before making the decision to move this to a randomized study.”