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Idasanutlin active in refractory polycythemia vera
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ATLANTA — Idasanutlin demonstrated clinical activity among patients with refractory polycythemia vera, according to study results presented at ASH Annual Meeting and Exposition.
The agent also appeared well tolerated.
Polycythemia vera and essential thrombocythemia are associated with considerable symptom burden. These chronic myeloproliferative neoplasms also are associated with a heightened risk for thrombosis and progression to myelofibrosis.
JAK2 inhibitors, hydroxyurea and interferon are commonly used to treat these conditions; however, hematopoietic stem cell-depleting therapies may offer an alternative option to improve outcomes.
MDM2, a negative regulator of P53, often is overexpressed in CD34-positive, p53 wild-type myeloproliferative neoplasm cells.
Idasanutlin (RG7388, Roche), an oral MDM2 antagonist, contributes to upregulation of p53 and downstream activators of apoptosis, according to study background.
Results of a preclinical study — published in 2014 in Blood — supported the clinical evaluation of idasanutlin in patients with polycythemia vera and essential thrombocythemia.
John O. Mascarenhas, MD, associate professor of medicine at Icahn School of Medicine at Mount Sinai, and colleagues conducted a single-institution phase 1 dose-escalation trial that included 12 patients with JAK2V617F-positive polycythemia vera (n = 11) or essential thrombocythemia (n = 1). Seven of the 12 patients were women; median patient age was 63.5 years (range, 32-83).
All patients were resistant to or intolerant of hydroxyurea and/or interferon therapy, and none had received prior therapy with JAK2 inhibitors.
Study participants received oral idasanutlin at one of two dose levels — 100 mg daily (n = 6) or 150 mg daily (n = 6) — for five consecutive days.
The first cycle consisted of 56 days to allow for the evaluation of dose-limiting toxicities. Subsequently, treatment was administered in 28-day cycles.
Researchers defined dose-limiting toxicities as any nonhematologic grade 3 or higher adverse event, grade 2 or higher thrombocytopenia, or grade 3 or higher anemia or neutropenia.
Patients received a median seven treatment cycles (range, 1-12) during a median 33 weeks (range, 8-107) of follow-up.
Three patients discontinued treatment (patient decision, n = 2; physician decision, n = 1).
No dose-limiting toxicities were identified at either dose level during the first treatment cycle, and no hematologic treatment-emergent adverse events occurred at any time during the study.
The only significant treatment-emergent adverse events observed were one case of grade 3 fatigue and one grade 3 headache, both of which occurred in the 100-mg cohort.
Other grade 1 or grade 2 treatment-emergent adverse events reported in at least two patients in each dose cohort included diarrhea (66.7% in 100-mg cohort vs. 50% in 150-mg cohort), nausea (66.7% vs. 33.3%), constipation (50% in each cohort), gastroesophageal reflux disease (50% in each cohort), fatigue (16.7% vs. 50%), headache (33.3% vs. 33.3%) and abdominal pain (33.3% vs. 0%.).
Seven of nine (78%) evaluable patients achieved a European LeukemiaNet response by the seventh cycle. Seven of 10 (70%) evaluable patients achieved a 50% or greater improvement in total symptom score from baseline.
No thrombotic or major hemorrhagic episodes occurred, and researchers reported no cases of progression to myelofibrosis.
Mascarenhas and colleagues assessed bone marrow pathologic response in two patients after five cycles. In one case, results showed histological improvement, with normalization of megakaryocyte number and overall marrow cellularity, as well as less pronounced megakaryocytic atypia. The other patient had resolution of bone marrow fibrosis.
Median JAK2V617F variant allele frequency declined from 45% at baseline (n = 12) to 12% after seven treatment cycles (n = 6) and 13% after nine treatment cycles (n = 6).
Patients who did not achieve partial response after six cycles were eligible to continue receiving idasanutlin in combination with pegylated interferon-alfa dosed at 45 µg weekly.
One patient eligible to receive combination therapy achieved phlebotomy freedom, as well as normalization of palpable spleen, leukocyte count and polycythemia vera-related symptoms by the eighth cycle. The patient also achieved a 20% reduction in JAK2V617F variant allele frequency.
Researchers reported a significant increase in percentage of mononuclear cells expressing MDM2 among study participants compared with normal controls (P = .01).
Eighty-five percent of study participants achieved approximately fivefold increases in serum levels of macrophage inhibitory cytokine-1 (MIC-1) — a downstream mediator of the p53 pathway — after 5 days of idasanutlin administration. Six of the 12 treated patients had persistent elevation in MIC-1 levels on day 15.
A multicenter phase 2 study is underway to evaluate idasanutlin at the 150-mg daily dose. – by Mark Leiser
Reference:
Mascarenhas J, et al. Abstract 254. Presented at: ASH Annual Meeting and Exposition; Dec. 9-12, 2017; Atlanta.
Disclosure: Mascarenhas reports research funding from CTI BioPharma, Incyte, Janssen, Merck, Novartis and Promedior; a data safety monitoring board role with Novartis; and a clinical trial steering committee role with Incyte.
Perspective
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Ruben A. Mesa, MD
There remain unmet needs for patients with polycythemia vera and essential thrombocythemia. We have nonspecific myelosuppression, such as hydroxyurea, which is not ideal on many levels. We have interferons that can have some activity, but they also can have toxicities and they are not an option for all patients. JAK inhibition can be helpful in terms of symptom relief for these patients, but it sometimes leaves us wanting in terms of control of counts and things of that nature. There is clearly a desire to try to more effectively help these patients avoid disease progression and achieve deeper response.
Data from this nutlin inhibitor suggests that trying to go after these diseases through the p53 pathway is both interesting and also highly efficacious in this early study.
We have spent the last several years thoroughly investigating JAK inhibitors, and with some real benefit. But getting good leads outside the JAK/STAT pathway have been limited, so this is an exciting abstract and the signal suggests and important need to continue to investigate both the pathway and this new class of nutlin inhibitors.
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