非霍奇金淋巴瘤治疗相关急性髓性白血病风险增加

《血液》(Blood)杂志2月14日在线发表的一项研究显示，过去30年来，化疗相关急性髓性白血病的风险显著改变，在非霍奇金淋巴瘤患者中趋于增加，而在卵巢癌和骨髓瘤患者中趋于降低。此外，治疗相关急性髓性白血病(t-AML)的风险自2000年起在食管癌、前列腺癌和宫颈癌患者中趋于增加，并且自20世纪90年代起在骨和关节癌及子宫内膜癌患者中趋于增加(2013 Feb. 14 [doi: 10.1182/blood-2012-08-448068])。

这项研究由美国国立癌症研究所癌症流行病学和遗传学部门的Lindsay Morton博士及其同事进行，采用了9个监测、流行病学和最终结果(SEER)注册库中的癌症注册数据，涉及1975~2008年间426,068例因初次原发性恶性肿瘤接受化疗的成人患者。

在这些患者中，801例随后发生AML。该发生率是一般人群的预期发生率(170.5例)的4.7倍。在这段时间内，在以下癌症患者中观察到的t-AML风险尤其显著：骨/关节癌(风险是一般人群的19.25倍)、软组织癌(14.41倍)、 卵巢癌(8.68倍)、肺癌(6.82倍)、非霍奇金淋巴瘤(16.65倍)和骨髓瘤(10.43倍)。研究者表示，非霍奇金淋巴瘤患者初始治疗后t-AML风险的显著改变可归因于后续对持续性或复发性/难治性非霍奇金淋巴瘤的广泛治疗。

卵巢癌和骨髓瘤患者化疗后的t-AML风险随时间推移而显著降低。肺癌患者t-AML风险也降低，但降幅无统计学显著性。研究者表示，卵巢癌患者t-AML风险的降低与20世纪80年代初临床治疗实践从烷化剂马法兰转变至含铂化疗的趋势一致。骨髓瘤患者t-AML风险的降低可能缘于马法兰治疗剂量和/或治疗时间的减少。肺癌患者t-AML风险的降低可能反映了治疗领域的一些进展。

在1999~2008年期间，食管癌、肛门癌、宫颈癌和前列腺患者的t-AML风险显著增加，尽管这一结论是基于较小的样本量得出。在乳腺癌方面，t-AML风险在1975~1978年期间最高，在20世纪80年代显著降低，在20世纪90年代又出现非显著增加，反映出较高的t-AML风险主要集中在乳腺癌诊断后的最初几年。胃癌、结肠癌和直肠癌患者的t-AML风险未显著增加。

研究者表示，t-AML发生率的增加可能是由于过去10年内接受细胞毒性药物的患者数量较多。未来需进一步探讨临床上引入的新型靶向和免疫调节药物导致白血病的倾向性及(新)辅助治疗和维持治疗的广泛应用。探讨患者发生治疗相关白血病的遗传易感性也具有意义，如果证实某些遗传因素导致患者在治疗后易于发生二次恶性肿瘤，临床医生就能够更准确地权衡化疗的获益和相关白血病风险。

该研究获美国国立癌症研究所内部项目支持。参与这项研究的研究者来自美国国立癌症研究所、俄克拉何马城退伍军人事务医疗中心和芝加哥大学儿科。研究者声明无经济利益冲突。

相关评论：移植是否导致t-AML风险增加？

斯坦福大学血液病门诊主任Steven Coutré博士认为该研究结果值得关注，但上述论文未对t-AML风险增加的原因进行深入探讨。作者指出，卵巢癌患者t-AML风险的降低可能是缘于所用标准化疗的改变。而非霍奇金淋巴瘤患者t-AML风险增加是否是因为有相反的相似治疗改变呢？已知与t-AML相关的移植是否存在应用增加的情况？这些患者是否曾接受含烷化剂方案强化治疗？所有这些问题都值得进一步探讨。Coutré博士声明无经济利益冲突。

爱思唯尔版权所有  未经授权请勿转载

By: ELIZABETH MECHCATIE, Internal Medicine News Digital Network

The risks of chemotherapy-related acute myeloid leukemia have changed significantly over the last 30 years, increasing in people treated for non-Hodgkin’s lymphoma and decreasing in people treated for ovarian cancer and myeloma.

Further, treatment-associated acute myeloid leukemia (t-AML) has increased since 2000 in people treated for esophageal, prostate, and cervical cancers, and in those treated since the 1990s for bone and joint cancers and endometrial cancers, reported Lindsay Morton, Ph.D., and her associates online Feb. 14 in Blood (2013 Feb. 14 [doi: 10.1182/blood-2012-08-448068]).

The incidence of t-AML is likely to increase because more patients have been treated with cytotoxic agents over the last 10 years, wrote Dr. Morton, of the division of Cancer Epidemiology and Genetics at the National Cancer Institute, and her colleagues. More research is needed "to evaluate the leukemogenicity of new targeted and immunomodulatory agents introduced into the clinic, and increasing use of (neo) adjuvant and maintenance therapies," they said.

"It will be interesting to evaluate the role of a patient’s genetic susceptibility to treatment-related leukemia," Dr. Morton said in a press release. "If certain inherited traits predispose patients to a second malignancy as a result of treatment, clinicians could more accurately weigh the risk of leukemia against the established benefits of chemotherapy."

The researchers based their conclusions on cancer registry data from nine Surveillance, Epidemiology, and End Results (SEER) registries for more than 400,000 adults treated from 1975 to 2008 with chemotherapy for their first primary malignancy. Despite major changes in cancer treatments, no large published study has attempted to quantify the risks of AML after chemotherapy for different types of primary malignancies in adults since 1984, they pointed out.

No data on specific drugs and doses were available in the SEER registries, but "our results are consistent with changing treatment practices and differential leukemogenicity of specific treatments, with increasing t-AML risks after chemotherapy likely associated with increasing use of (neo) adjuvant therapy, multiple courses of therapy, duration/intensity of treatment, and newly introduced agents," the authors said.

Among the 426,068 patients treated between 1975 and 2008, 801 subsequently developed AML. That rate is 4.7 times higher than the 170.5 cases expected for the general population. The risks of t-AML during this time were "especially pronounced" among those treated for cancers of the bone/joints (19.25 times greater risk than the general population), soft tissue (14.41), ovary (8.68), lung (6.82), non-Hodgkin’s lymphoma (16.65), and myeloma (10.43).

The "striking changes" in the risk in t-AML after initial treatment for non-Hodgkin’s lymphoma "may be explained by more widespread use of subsequent therapy for persistent or relapsed/refractory non-Hodgkin’s lymphoma," they wrote.

The risk of t-AML after chemotherapy for ovarian cancer and myeloma dropped significantly over time. The risk associated with lung cancer treatment also declined, but the drop was not statistically significant. The drop in t-AML associated with treatment for ovarian cancer is "consistent" with the shift from the alkylating agent melphalan to platinum-based chemotherapy in the early 1980s, the authors said. The drop in t-AML in myeloma patients may be due to decreases in the dose and/or length of treatment with melphalan. A possible drop in t-AML associated with lung cancer may reflect "modest advances in treatment," they added.

The risk of t-AML was significantly increased among patients treated during 1999-2008 for cancers of the esophagus, anus, cervix, and prostate, although this conclusion was based on small numbers.

For breast cancer, the risks was greatest during 1975-1978 and significantly lower in the 1980s, with a nonsignificant increase in the 1990s, reflecting the higher t-AML risk that is "concentrated in the initial years" after a diagnosis of breast cancer.

The risks were not significantly higher for cancers of the stomach, colon, and rectum.

The study was supported by the Intramural Program of the National Cancer Institute. Dr. Morton’s coauthors were from the NCI, the Veterans Affairs Medical Center in Oklahoma City, and the department of pediatrics at the University of Chicago. The authors had no disclosures.

Commentary: Could transplants account for the increase?

Dr. Steven Coutré comments: While interesting, this report provides little insight into possible reasons for an observed increase in treatment-associated acute myeloid leukemia. As the authors point out, t-AML has declined in patients treated for ovarian cancer, likely due to a change in the standard chemotherapy used.  For non-Hodgkin’s lymphoma, one would like to know if there has been a similar change in treatment, in the opposite direction, that accounts for an increase in t-AML. Is there a greater use of transplant, which is known to be associated with t-AML? Have these patients been treated more intensively with alkylator-based regimens?

Dr. Coutré is associate professor, division of hematology, and director of the hematology clinic at Stanford (Calif.) University. He had no disclosures.

View on the News

Could transplants account for the increase?

While interesting, this report provides little insight into possible reasons for an observed increase in treatment-associated acute myeloid leukemia. As the authors point out, t-AML has declined in patients treated for ovarian cancer, likely due to a change in the standard chemotherapy used.  For non-Hodgkin’s lymphoma, one would like to know if there has been a similar change in treatment, in the opposite direction, that accounts for an increase in t-AML. Is there a greater use of transplant, which is known to be associated with t-AML? Have these patients been treated more intensively with alkylator-based regimens?

Dr. Steven Coutré is associate professor, division of hematology, and director of the hematology clinic at Stanford (Calif.) University. He had no disclosures.