弥漫大B细胞淋巴瘤：新版指南纳入MYC

佛罗里达州好莱坞——美国国家综合癌症网络(NCCN)最近更新了弥漫大B细胞淋巴瘤(DLBCL)指南，纳入致癌基因MYC作为肿瘤免疫组化检测组合的一个必不可少的组成部分。此外，新版指南还强调了荧光原位杂交在检测MYC易位方面的价值。

作为NCCN非霍奇金淋巴瘤指南专家组主席，纽约威尔康奈尔医学院的医学教授Andrew D. Zelenetz博士在今年的NCCN年会上表示，1.2014版指南中反映出的变化是基于近期的研究数据，研究表明DLBCL中MYC表达与接受CHOP(环磷酰胺、阿霉素、长春新碱、强的松)治疗的患者结局较差相关。

他说：“最近几年的新数据表明，MYC表达可能与结局特别差相关。事实上，我们发现起作用的不光是DLBCL中MYC表达，而是MYC和BCL2同时表达。”他指出：“最初是在MYC基因和BCL2基因都易位的肿瘤中发现的，这类患者的结局非常差。”

Zelenetz博士说，同时存在这两种基因易位的“双重打击(double-hit)”现象相对罕见，仅见于大约6%的患者，但最新数据表明在接受R-CHOP (利妥昔单抗、环磷酰胺、阿霉素、长春新碱、强的松)治疗的DLBCL患者中，免疫组化检测结果提示实际上超过40%的细胞都存在MYC蛋白表达，再加上超过70%的细胞都存在BCL2 蛋白表达(相当于“双重打击评分”为2分)，这类患者的结局比那些评分为0分或1分的患者要差得多。

在双重打击评分为2分的患者中，应答率显著降低，总生存期和无进展生存期也都显著缩短(J. Clin. Oncol. 2012;30:3460-7)。

Zelenetz博士说：“如今，这类患者不占少数。事实上，前来就诊的患者中大约30%都存在这种情况；重要的是，这与细胞来源之间并没有严格的相关性。”

他说，目前这一数据被广泛引用，作为MYC阳性肿瘤的治疗基础，实际上这也正是该数据所反映的内容。“但这一数据也经常被误解为反映了‘双重打击’淋巴瘤的治疗。其实在这些患者中，只有1例或2例真正存在‘双重打击’淋巴瘤，所以这其实反映的是MYC阳性淋巴瘤的治疗，我们已知这类患者的结局与不存在BCL2的MYC阳性淋巴瘤患者非常相似。”

他补充道，事实上，目前还没有针对双重打击患者的循证标准治疗，因此确实需要在这类患者中开展前瞻性临床试验。他指出：“在这方面，指南并没有建议相应的治疗，因为的确没有相关数据，开展相关的临床试验非常必要。”

DLBCL指南的其他一些变化包括：

• 取消了I、II期非大型(直径小于10 cm)疾病治疗方案中有关“存在不良危险因素”与“不存在不良危险因素”的划分。Zelenetz博士解释道，无论是否存在不良危险因素，治疗推荐意见都是一样的。不过，他指出，是否存在不良危险因素可能决定了结局上的差异，这也是上一版指南为何对此进行区分的原因。

• 有关早期患者影像学复查的变化。上一版指南建议“治疗完成后，CT扫描不超过每6个月一次，共2年，之后仅在有临床指征时开展CT扫描”，新版指南改为“仅在有临床指征时开展CT扫描”。

• 有关III、IV期疾病的推荐意见等级变化。对于有应答的疾病，后续治疗推荐意见“继续采用R-CHOP方案共6个周期”被定为1级推荐意见；针对“治疗结束后重新分期为完全应答”的患者，推荐意见“考虑采用放疗来治疗初始大型疾病”从2B级改为2A级推荐意见。

Zelenetz博士声明担任Cancer Genetics和Gilead公司的科学顾问，并且接受了Celgene、Cephalon以及其他公司提供的咨询费、酬金和/或研究经费或者其他类型的研究支持。

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HOLLYWOOD, FLA. – The National Comprehensive Cancer Network guidelines for diffuse large B-cell lymphoma have been updated to include the oncogene MYC as an essential component of the immunohistochemistry panel for tumors.

The updated guideline also highlights the value of fluorescence in situ hybridization for detecting MYC translocation.

The changes, which are reflected in version 1.2014 of the guidelines, are the result of recent data showing that MYC expression in diffuse large B-cell lymphoma (DLBCL) is associated with poor outcomes in patients receiving CHOP-based therapy (cyclophosphamide, doxorubicin, vincristine, prednisone), according to Dr. Andrew D. Zelenetz, chair of the National Comprehensive Cancer Network Non-Hodgkin’s Lymphomas Guidelines panel.

"Emerging data over the last number of years suggests that expression of MYC might be associated with a particularly poor outcome. In fact, what we have found is that it’s not the expression of MYC in DLBCL, but it appears to be the expression of MYC in conjunction with BCL2," he said, noting that "this was originally described in tumors with both translocation of the MYC gene and the BCL2 gene, and these patients had a very, very poor outcome," he said at the annual conference of the National Comprehensive Cancer Network.

This "double-hit" phenomenon with both translocations is relatively uncommon, affecting only about 6% of patients, but additional data has emerged showing that actual expression of the MYC protein in more than 40% of cells, coupled with expression of the BCL2 protein in more than 70% of cells on immunohistochemistry (which equates to a "double-hit score" of 2) confers a far worse outcome than a score of 0 or 1 in patients with DLBCL undergoing R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), he said.

Patients with a double-hit score of 2 had a significantly lower response rate and significantly shorter overall and progression-free survival (J. Clin. Oncol. 2012;30:3460-7).

"But this is no longer a minor population of patients. This actually represents about 30% of patients who walk in the door, and, importantly, it does not have a strict correlation with cell of origin," said Dr. Zelenetz, who is a professor of medicine at Weill Cornell Medical College, New York.

This data is widely cited as the basis for treatment of MYC-positive tumors, and that is, indeed, what the data shows, he said.

"But it is misinterpreted many times as showing the treatment for double-hit lymphoma. In fact, in this series, only one or two cases actually had a double-hit lymphoma, so this was really the treatment of MYC-positive lymphoma, which we know has very similar outcomes when compared to MYC-positive lymphoma in the absence of BCL2," he said.

In fact, there is no evidence-based standard of care for these patients, so double-hit patients really need to go on prospective clinical trials, he added, noting that "the guidelines are silent on the appropriate treatment here because there literally is no data, and here clinical trials are essential."

Among other changes to the DLBCL guidelines are:

• Removal of the separation between "adverse risk factors present" and "adverse risk factors not present" in reference to treatment of stage I, II, nonbulky (less than 10 cm) disease. The treatment recommendation is the same regardless, Dr. Zelenetz explained. He noted, however, that outcomes differ based on the presence or absence of adverse risk factors, which is why the distinction was made in the previous version of the guidelines.

• A change regarding follow-up imaging in early-stage patients. The guideline was changed from "CT scan no more often than every 6 months for 2 years after completion of treatment, then only as clinically indicated," to "repeat CT scan only as clinically indicated."

• Category changes for stage III, IV disease. For responding disease, the follow-up therapy recommendation to "continue R-CHOP to a total of 6 cycles" was clarified as a category 1 recommendation, and an "after end-of-treatment restaging with a complete response" recommendation to "consider RT [radiation therapy] to initially bulky disease" was changed from a category 2B to a category 2A recommendation.

Dr. Zelenetz is a scientific adviser for Cancer Genetics and Gilead, and has received consulting fees, honoraria, and/or grant or other research support from Celgene, Cephalon, and other companies.