马拉维若可预防血液肿瘤患者移植物抗宿主病

马拉维若——抗逆转录病毒的HIV鸡尾酒疗法中的一种成分——可能还具有预防异基因造血干细胞移植术后急性移植物抗宿主病(GVHD)的作用(N. Engl. J. Med. 2012;367:135-45)。

《新英格兰医学杂志》7月11日在线发表的一项单中心研究显示，对38例成年血液肿瘤患者在标准预防的基础上加用1个月疗程的马拉维若(Selzentry)，可降低异基因造血干细胞移植术后GVHD发病率。宾夕法尼亚大学Abramson癌症中心的Ran Reshef博士指出，与此同时，马拉维若并不妨碍造血干细胞植入，或增加肿瘤复发率，或增加感染并发症。

马拉维若是首个获准的趋化因子(C-C motif)5受体(CCR5)拮抗剂，可以阻断CCR5及其配体的信号传导，“而后者参与GVHD和实体器官排斥反应的发生机制”。阻断CCR5已被证明可防止小鼠模型发生GVHD，人类基因研究显示编码CCR5的基因的某些多态性具有对抗GVHD的保护作用。

研究者首先开展了Ⅰ期临床试验，以确定用于HIV感染患者的马拉维若剂量对于接受低强度预处理干细胞移植的患者也是安全的，并且能达到目标血药浓度。这一队列包括急性髓细胞白血病患者、非霍奇金淋巴瘤患者、骨髓增生异常综合征患者、骨髓增生性疾病患者、慢性淋巴细胞白血病患者、再生障碍性贫血患者、多发性骨髓瘤患者、霍奇金淋巴瘤患者，以及慢性髓细胞白血病患者。

所有受试者均接受标准GVHD预防，包括口服他克莫司和静脉注射甲氨蝶呤，以及标准抗菌药物预防(伏立康唑、阿昔洛韦和复方新诺明)。绝大多数受试者被认为GVHD风险高，原因包括年龄大(68%以上＞60岁）、供者-受者的人类白细胞抗原(HLA)不相容、癌症较严重，以及合并症负担大。“对于与这些受试者相似的患者，通常预期的急性GVHD发生率高于50%。”

此后，研究者开展了Ⅱ期临床试验，对其中35例患者进行了评估。口服马拉维若300 mg，每日2次，从移植前2天开始，持续至第30天。中位随访20个月(范围:14~35个月)。结果显示，造血干细胞植入迅速完成，马拉维若的毒性作用很小。“7例患者很快停药，原因是发现肝功能3级异常（2例）或3~4级黏膜炎（5例）。再次用药时未再发生肝功能异常。

主要终点——第100天时GVHD累计发生率——14.7%的患者发生Ⅱ~Ⅳ级急性疾病。值得注意的是，没有1例GVHD累及肝脏或肠道。与此相似，6个月时的GVHD仍然主要限于皮肤，仅有2.9%的病例累及肝脏，仅有8.8%累及肠道。此时中度疾病和重度疾病的发病率分别为23.6%和5.9%。与之相对，这两项指标在研究者所在医院通常分别为38.5%和21.9%。

在接受来自HLA匹配同胞的干细胞的11例患者亚组中，第100天时无1例患者发生急性GVHD，6个月时无1例患者发生中至重度GVHD。

由于这是一项单中心的Ⅰ/Ⅱ期试验，仅招募了38例患者，“因此马拉维若降低急性GVHD的价值还有待前瞻性随机试验的评估”。

这项研究获得了马拉维若的生产商辉瑞、白血病与淋巴瘤学会、国立卫生研究院、Abramson癌症中心、美国血液病学会和美国临床肿瘤学会的支持。Reshef博士的同事报告称与辉瑞、百时美-施贵宝、Celgene和Millennium有联系。

爱思唯尔  版权所有

By: MARY ANN MOON, Internal Medicine News Digital Network

Maraviroc, an ingredient in retroviral cocktails used to treat HIV, might also have a role in preventing acute graft-vs.-host disease after allogeneic hematopoietic stem-cell transplantation.

Adding a 1-month course of maraviroc (Selzentry), an inhibitor of T-cell chemotaxis, to standard prophylaxis appeared to reduce the incidence of acute graft-vs.-host disease (GVHD) after allogeneic transplants in a single-center study of 38 adults with hematologic cancers, which was published online July 11 in the New England Journal of Medicine.

At the same time, maraviroc did not disrupt hematopoietic engraftment, raise the incidence of cancer recurrence, or increase infectious complications, said Dr. Ran Reshef of the Abramson Cancer Center and the division of hematology and oncology at the University of Pennsylvania, Philadelphia, and his associates.

Maraviroc is the first drug available in the class of chemokine (C-C motif) receptor 5 (CCR5) antagonists. It prevents the signaling of CCR5 and its ligands, "which have been implicated in the pathogenesis of GVHD and solid-organ rejection." CCR5 is crucial to lymphocyte recruitment to tissues involved in GVHD. Blockade of CCR5 protects against GVHD in mouse models, and human genetic studies have shown that certain polymorphisms in the gene that encodes CCR5 are protective against GVHD.

Currently, maraviroc is used in combination antiretroviral therapy for a subtype of HIV that uses only the CCR5 coreceptor to enter cells. "We hypothesized that CCR5 blockade with maraviroc early after allogeneic hematopoietic stem-cell transplantation might inhibit lymphocyte trafficking and decrease the incidence of acute GVHD," Dr. Reshef and his colleagues said (N. Engl. J. Med. 2012;367:135-45).

They conducted a phase I clinical trial to confirm that the established dose for HIV patients was safe, and achieved target drug levels in patients who have undergone reduced-intensity conditioning and stem-cell transplantation. The cohort included patients with acute myeloid leukemia, non-Hodgkin’s lymphoma, myelodysplastic syndromes, myeloproliferative disorder, chronic lymphocytic leukemia, aplastic anemia, multiple myeloma, Hodgkin’s lymphoma, and chronic myeloid leukemia.

All the study subjects received standard GVHD prophylaxis including oral tacrolimus and IV methotrexate, as well as standard antimicrobial prophylaxis with voriconazole, acyclovir, and trimethoprim-sulfamethoxazole.

Most of the study subjects were considered high risk for GVHD because of their age (68% were older than 60 years), donor-recipient HLA incompatibility, cancer severity, and heavy burden of comorbidity. "The anticipated incidence of acute GVHD in similar patients is typically more than 50%," the investigators noted.

After the dose-confirming study, the researchers then performed a phase II clinical trial evaluating 35 of the same patients. Maraviroc (300 mg) was given orally twice daily from 2 days before transplantation until day 30. The study subjects were followed for a median of 20 months (range, 14-35 months).

Engraftment was rapid, and maraviroc produced few toxic effects. "Administration of the drug was briefly suspended in 7 patients because of grade 3 abnormalities on liver-function testing (in 2 patients) or grade 3 or 4 mucositis (in 5). Liver-function abnormalities did not recur when the drug was restarted," Dr. Reshef and his associates said.

The primary end point – the cumulative incidence of GVHD at day 100 – was 14.7% for grade II-IV acute disease. Remarkably, there were no cases of GVHD involving the liver or gut.

Similarly, at 6 months GVHD remained largely confined to the skin, and involved the liver in only 2.9% of cases and the gut in only 8.8%. At this point the incidence of moderate disease was 23.6% and severe disease only 5.9%. In comparison, these rates at their institution typically are 38.5% and 21.9%, the researchers said.

In the subset of 11 patients who received stem cells from an HLA-matched sibling, there were no cases of acute GVHD at day 100 and no moderate to severe GVHD at 6 months.

Thus, cases of skin GVHD developed at the expected rates, but the absence of liver or gut GVHD lead to a low incidence of severe disease.

"The outcomes of this study are especially favorable considering the study population, which included older patients and a high proportion of matched unrelated donors and HLA-mismatched donors." In addition, almost half the study subjects had major coexisting illnesses.

Cumulative rates of relapse and death were not higher than expected for patients with these disease characteristics who were given reduced-intensity regimens, the authors said.

Because this was a single-center, phase-I/phase-II trial involving only 38 patients, "the value of maraviroc in lowering the rate of acute GVHD will need to be assessed in a prospective, randomized trial," Dr. Reshef and his colleagues added.

This study was supported by Pfizer, maker of maraviroc; the Leukemia and Lymphoma Society; the National Institutes of Health; the Abramson Cancer Center; the American Society of Hematology; and the American Society of Clinical Oncology. Dr. Reshef’s associates reported ties to Pfizer, Bristol-Myers Squibb, Celgene, and Millennium.

Maraviroc Cuts Post-Transplant GVHD Rate in Hematologic Cancers