Original Study
Evidence for Clinical Differentiation and Differentiation Syndrome in Patients With Acute Myeloid Leukemia and IDH1 Mutations Treated With the Targeted Mutant IDH1 Inhibitor, AG-120

https://doi.org/10.1016/j.clml.2016.04.006Get rights and content

Abstract

Background

Cancer-associated isocitrate dehydrogenase (IDH) mutations block normal cellular differentiation via production of the oncometabolite, R-2-hydroxyglutarate. In patients with acute myeloid leukemia (AML) receiving targeted mutant IDH inhibitor therapy, neutrophil recovery within the setting of clinical differentiation syndrome (DS) has been anecdotally described.

Patients and Methods

We describe 3 patients who developed clinically apparent DS during monotherapy with the mutant IDH1 inhibitor, AG-120, for relapsed/refractory AML.

Results

AG–120-induced differentiation commenced within the first 60 days of treatment, notably in the same time frame as clinical response, strengthening the purported mechanism of targeted mutant IDH inhibitor therapy via successful myeloid maturation. Symptoms of DS were nonspecific and included culture-negative fever, edema, hypotension, malaise, and pleural and/or pericardial effusions, in addition to marked neutrophil-predominant leukocytosis.

Conclusion

DS can occur during treatment with targeted mutant IDH1 inhibitor therapy. Patients might present with nonspecific clinical manifestations often in the setting of leukocytosis related to exuberant neutrophil recovery. Prompt identification and initiation of treatment interventions, including hydroxyurea, corticosteroids, and/or consideration of temporary treatment discontinuation, are important to facilitate prompt resolution.

Introduction

Differentiation syndrome (DS) is a potentially fatal complication of effective leukemia treatment first described in patients with acute promyelocytic leukemia (APL) treated with all-trans-retinoic acid (ATRA).1 The reported incidence in APL ranges from 2% to 27%,2 likely because of the heterogeneity and range of clinical symptoms, as well as imprecise diagnostic criteria. In APL, signs and symptoms of DS have been described 2 to 47 days after treatment initiation, and include increasing white blood cell count (WBC) and absolute neutrophil count (ANC), culture-negative fever, weight gain, edema, dyspnea, interstitial infiltrates, pleural effusion, pericardial effusion, hypotension, and renal failure.1, 3, 4 The underlying pathophysiology remains poorly understood, but is thought to be related to release of inflammatory vasoactive cytokines and tissue infiltration by briskly maturing cells.2, 5 Myeloid differentiation and clinical DS have also been described in patients with acute myeloid leukemia (AML) receiving therapy with fms-related tyrosine kinase 3 inhibitors and hypomethylating agents, including neutrophilic skin infiltrates retaining the aberrant FLT3-internal tandem duplication mutation in some instances.6, 7

Isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) mutations are noted in approximately 20% of patients with AML.8 Cancer-associated IDH1/2 mutations block normal cellular differentiation and drive tumorigenesis by promoting abnormal reduction of α-ketoglutarate (α-KG) to the oncometabolite, R-2-hydroxyglutarate (2-HG).9, 10 2-HG accumulation inhibits multiple α-KG-dependent dioxygenases, including histone and DNA demethylases, which regulate the cellular epigenetic state.11 The first-in-human phase I clinical study of the novel, oral mutant IDH1 inhibitor, AG-120, is ongoing (ClinicalTrials.gov NCT02074839), and early results in 66 patients indicate that monotherapy is well tolerated, with an overall response rate of 36% according to International Working Group (IWG) criteria in a primarily relapsed/refractory AML population.12 Responses occur without a period of bone marrow aplasia, unlike standard cytoreductive therapy.

Section snippets

Patients and Methods

Neutrophil recovery in the setting of a clinical DS in patients receiving mutant IDH inhibitor therapy has been anecdotally described, but the clinical patterns of differentiation have not been previously reported. Herein, we describe 3 patients treated at our institution who developed clinically apparent differentiation and DS during AG-120 monotherapy for relapsed/refractory AML.

Case 1

A 53-year-old man was found to have incidental anemia during a routine physical examination. Results of complete blood count (CBC), bone marrow aspirate and biopsy, and cytogenetic and molecular studies at presentation are shown in Table 1. He received intensive cytarabine-based induction AML chemotherapy, which was associated with complications (Table 1) and end of cycle 1 staging bone marrow showed primary refractory disease with 77% myeloblasts.

Because of the presence of an IDH1-R132C

Discussion

The discovery of recurrent pathogenic IDH mutations and the advent of mutant IDH inhibitors has been one of the most significant translational advances in the management of AML in the past decade. AG-120 inhibits the mutant IDH1 enzyme and reduces aberrant serum 2-HG levels, which induces differentiation of leukemia cells.13

The pathophysiology of DS in AML remains incompletely understood. In APL, ATRA and arsenic trioxide are thought to induce release of cytokines from differentiating myeloid

Conclusion

Differentiation syndrome can occur during treatment with the mutant IDH1 inhibitor, AG-120. The timing of onset and the signs and symptoms can vary, and might present with dramatic clinical manifestations in addition to marked leukocytosis and exuberant neutrophil recovery. DS should be considered in all patients treated with AG-120 experiencing rapid neutrophil-predominant leukocytosis, culture-negative fever, constitutional symptoms, and pleural or pericardial effusions. Steroid therapy

Disclosure

Courtney D. DiNardo has received research support from, and has served on an advisory board for Agios Pharmaceuticals, Inc. Formatting assistance was provided by Helen Varley, PhD, CMPP, Excel Scientific Solutions, Horsham, UK, and supported by Agios.

Acknowledgments

This work was supported in part by the M.D. Anderson Cancer Center Support Grant CA016672 and by the generous philanthropic contributions to M.D. Anderson's MDS/AML Moon Shot Program. All patients were enrolled in the phase I clinical trial of AG-120 (NCT02074839) sponsored by Agios Pharmaceuticals, Inc, who performed a courtesy review of this report before submission.

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