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.
OBJECTIVE
Recombinant interferon alfa-2b (rIFNalpha2b) is a standard therapy for chronic myelogenous leukemia (CML). Severe neuropsychiatric toxicity has been described in patients receiving rIFNalpha2b, 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 rIFNalpha2b-based therapy.


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 rIFNalpha2b 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, rIFNalpha2b 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.


CONCLUSIONS
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 rIFNalpha2b plus cytarabine. Monitoring for neuropsychiatric symptoms and avoiding rechallenge are recommended measures for such patients receiving rIFNalpha2b-based therapy.
Hensley
M L
ML
Memorial Sloan-Kettering Cancer Center, Weill Medical College of Cornell University, and New York Presbyterian Hospital, New York, NY 10021, USA. hensleym@mskcc.org
Peterson
B
B
Silver
R T
RT
Larson
R A
RA
Schiffer
C A
CA
Szatrowski
T P
TP
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects* / Q000627:therapeutic use; D017322:Clinical Trials, Phase II as Topic; D015331:Cohort Studies; D003561:Cytarabine / Q000008:administration & dosage / Q000009:adverse effects; D005260:Female; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage / Q000009:adverse effects*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy*; D016015:Logistic Models; D008297:Male; D001523:Mental Disorders / Q000139:chemically induced*; D008875:Middle Aged; D015999:Multivariate Analysis; D020258:Neurotoxicity Syndromes / Q000209:etiology*; D011994:Recombinant Proteins; D012044:Regression Analysis; D012307:Risk Factors
D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D003561:Cytarabine