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Risk Factors for Severe Neuropsychiatric Toxicity in Patients Receiving Interferon Alfa-2b and Low-Dose Cytarabine for Chronic Myelogenous Leukemia: Analysis of Cancer and Leukemia Group B 9013

From the Memorial Sloan-Kettering Cancer Center, Weill Medical College of Cornell University, and New York Presbyterian Hospital, New York, NY; Cancer and Leukemia Group B Statistical Office, Durham, NC; The University of Chicago, Chicago, IL; and Wayne State University School of Medicine, Detroit, MI.

Address reprint requests to M.L. Hensley, MD, MSc, Developmental Chemotherapy Service, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, Box 426, New York, NY 10021; email hensleym{at}mskcc.org

PURPOSE: Recombinant interferon alfa-2b (rIFN2b) is a standard therapy for chronic myelogenous leukemia (CML). Severe neuropsychiatric toxicity has been described in patients receiving rIFN2b, although the frequency of and the risk factors for developing this toxicity are not well described. The purpose of this study was to identify predictors for the development of severe neuropsychiatric toxicity in CML patients receiving rIFN2b-based therapy.

PATIENTS AND METHODS: From a prospective cohort of 91 Philadelphia chromosome–positive, previously untreated, chronic-phase CML patients treated on Cancer and Leukemia Group B (CALGB) 9013, a phase II trial of rIFN2b plus cytarabine, the following were recorded at baseline: age, sex, race, pretreatment history of neurologic or psychiatric diagnosis, spleen size, blood counts, and peripheral blast count. Best response to treatment, rIFN2b cumulative dose, dose duration, and dose-intensity were recorded during follow-up. Severe neuropsychiatric toxicity was defined as grade 3 or 4 events, according to CALGB expanded common toxicity criteria. Univariate and multivariate logistic regression analyses were used to identify variables that were associated with the development of severe neuropsychiatric toxicity.

RESULTS: Severe neuropsychiatric toxicity developed in 22 patients (24.0%; 95% confidence interval [CI], 15.2% to 32.8%). Toxicity resolved after withdrawal of treatment in all patients. Five of six patients developed recurrence of symptoms with rechallenge. Twelve (63%) of 19 patients with a pretreatment neurologic or psychiatric diagnosis developed severe neuropsychiatric toxicity, as compared with 10 (14%) of 72 patients without a pretreatment neurologic or psychiatric diagnosis (P = .001), resulting in a relative risk of 4.55 (95% CI, 2.33 to 8.88) for developing severe neuropsychiatric toxicity. No other variables were independently associated with the development of neuropsychiatric toxicity.

CONCLUSION: CML patients with a pretreatment history of a neurologic or psychiatric diagnosis are at significantly increased risk of developing severe neuropsychiatric toxicity during therapy with rIFN2b plus cytarabine. Monitoring for neuropsychiatric symptoms and avoiding rechallenge are recommended measures for such patients receiving rIFN2b-based therapy.

The research for CALGB 9013 was supported in part by grants from the National Cancer Institute (CA31946) to the Cancer and Leukemia Group B (R.L.S., chairman), and by grants from CALGB Statistical Office (grant no. CA33601), The University of Chicago (grant no. CA41287), Weill Medical College of Cornell University (grant no. CA07968), and the Cancer and Leukemia Group B, Chicago, IL.

The contents of this study are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute.

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