Travis L B, Curtis R E, Stovall M, Holowaty E J, van Leeuwen F E, Glimelius B, Lynch C F, Hagenbeek A, Li C Y, Banks P M
Epidemiology and Biostatistics Program, National Cancer Institute, Bethesda, Md 20892.
J Natl Cancer Inst. 1994 Oct 5;86(19):1450-7. doi: 10.1093/jnci/86.19.1450.
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.
Our purpose was to examine the risk of ANLL in relationship to all prior treatment for NHL.
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.
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; P < .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 nonsignificant threefold risk of ANLL compared with lower dose radiation or no radiotherapy.
Our results suggest 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.
非霍奇金淋巴瘤（NHL）治疗后急性非淋巴细胞白血病（ANLL）风险的评估较少。此外，细胞毒性药物的累积剂量、对活跃骨髓的辐射剂量与NHL后ANLL风险之间的关系尚未得到充分描述。
我们的目的是研究ANLL与NHL既往所有治疗相关的风险。
在一项对11386名NHL 2年幸存者的队列研究中，确定了35例继发性ANLL病例患者，并与140例未发生ANLL的NHL对照患者进行匹配。该队列的主要纳入标准包括：1965年1月1日至1989年12月31日诊断为NHL作为首个原发性癌症；初次诊断时年龄在18至70岁之间；存活2年或更长时间且未发生第二种侵袭性原发性恶性肿瘤。收集了所有患者关于化疗药物和放疗的详细信息。通过比较病例患者与个体匹配对照的暴露史，使用标准条件逻辑回归程序来估计与特定疗法相关的ANLL相对风险（RR）。
使用泼尼松氮芥治疗后ANLL显著增加（RR = 13.4；95%置信区间[CI] = 1.1 - 156；剂量趋势P <.05），或者使用包含氮芥和丙卡巴肼的方案治疗后ANLL显著增加（RR = 12.6；95% CI = 2.0 - 79；P <.05）。使用苯丁酸氮芥治疗后白血病风险升高仅限于累积剂量达到或超过1300 mg的患者（RR = 6.5；95% CI = 1.6 - 26；P <.05）。环磷酰胺方案与ANLL风险小幅、无显著增加相关（RR = 1.8；95% CI = 0.7 - 4.9），大多数患者接受的累积剂量相对较低（< 20000 mg）。与低剂量放疗或不放疗相比，在不使用烷化剂的情况下给予较高剂量放疗与ANLL风险增加三倍但无显著意义相关。
我们的结果表明泼尼松氮芥可能是一种人类致癌物，ANLL风险存在明显的剂量反应梯度。与环磷酰胺相关的白血病低风险且无显著意义令人放心，因为该药物如今常用。尽管特定疗法与ANLL风险增加相关，但继发性白血病在NHL后仍然罕见。在10000例接受包括低累积剂量环磷酰胺的选定方案治疗6个月并随访10年的NHL患者中，预计白血病额外增加4例。
