© 1994 by Oxford University Press
Journal of the National Cancer Institute, Vol. 86, No. 19, 1450-1457,
October 5, 1994
© 1994 Oxford University Press
Risk of Leukemia Following Treatment for Non-Hodgkin's Lymphoma
Epidemiology and Biostatistics Program, Division of Cancer Etiology, National Cancer institute Bethesda, Md.
The University of Texas M. D. Anderson Cancer Center Houston
The Ontario Cancer Treatment and Research Foundation Toronto, Canada
The Netherlands Cancer Institute Amsterdam
University Hospital Uppsala, Sweden
The University of Iowa Iowa City
The Dr. Daniel den Hoed Cancer Center Rotterdam, The Netherlands
Mayo Clinic Rochester, Minn.
The University of Texas Health Sciences Center San Antonio, Tex.
Princess Margaret Hospital Toronto
Correspondence to: Lois B.Travis, M.D., National Cancer Institute, Executive Plaza North, Suite 408, Bathesda, MD 20892.
BACKGROUND:: There have been few evaluations of the risk of acute nonlymphocytic leukemia (ANLL) following therapy for non-Hodgkin's lymphoma (NHL). Further, the relationship between cumulative dose of cytotoxic drug, radiation dose to active bone marrow, and the risk of ANLL following NHL have not been well described. Purpose: Our purpose was to examine the risk of ANLL in relationship to all prior treatment for NHL. Methods: Within a cohort study of 11 386 2-year survivors of NHL, 35 case patients with secondary ANLL were identified and matched to 140 controls with NHL who did not develop ANLL. The primary eligibility criteria for the cohort included a diagnosis of NHL as a first primary cancer from January 1, 1965, through December 31, 1989; age 18 through 70 years at the time of initial diagnosis; and survival for 2 or more years without the development of a second invasive primary malignancy. Detailed information on chemotherapeutic drugs and radiotherapy was collected for all patients. Standard conditional logistic regression programs were used to estimate the relative risk (RR) of ANLL associated with specific therapies by comparing the exposure histories of case patients with individually matched controls. Results: Significant excesses of ANLL followed therapy with either prednimustine (RR= 13.4; 95% confidence interval [CI] = 1.1–156; P trend for dose <. 05) or regimens containing mechlorethamine and procarbazine (RR= 12.6; 95% CI = 2.0–79; F<. 05). Elevated risks of leukemia following therapy with chlorambucil were restricted to patients given cumulative doses of 1300 mg or more (RR= 6.5; 95% CI = 1.6–26; P<.05). Cyclophosphamide regimens were associated with a small, nonsignificant increased risk of ANLL (RR= 1.8; 95% CI = 0.7– 4.9), with most patients receiving relatively low cumulative doses (< 20 000 mg). Radiotherapy given at higher doses without alkylating agents was linked to a non significant threefold risk of ANLL compared with lower dose radiation or no radiotherapy. Conclusions: Our resultssuggest that prednimustine may be a human carcinogen, with a positive dose-response gradient evident for ANLL risk. The low, nonsignificant risk of leukemia associated with cyclophosphamide was reassuring because this drug is commonly used today. Despite the excesses of ANLL associated with specific therapies, secondary leukemia remains a rare occurrence following NHL. Of 10 000 NHL patients treated for 6 months with selected regimens including low cumulative doses of cyclophosphamide and followed for 10 years, an excess of four leukemias might be expected. [J Natl Cancer Inst 86: 1450– 1994]
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