2个单位脐带血移植不能改善生存率

亚特兰大——美国血液病学会(ASH)年会上公布的一项Ⅲ期研究显示，与1个单位的足量脐带血(UCB)移植相比，2个单位UCB移植不能改善血液肿瘤儿童患者的生存率。

John E. Wagner博士

这项研究由明尼苏达大学医学中心成人和儿童血液和骨髓移植临床研究项目主任John E. Wagner博士及其同事进行。在2006年12月~2012月2月间，研究者从32个移植中心纳入224例年龄1~21岁的急性淋巴细胞白血病(ALL)、急性髓细胞性白血病、自然杀伤细胞白血病、慢性髓细胞性白血病或骨髓增生异常综合征患者。所有患者至少有2个UCB单位可用，每个单位至少与患者有4/6 HLA相合，并且2个单位之间有3/6 HLA相合。患者被随机分成两组，一组接受常规1个单位UCB移植(n=113)，另一组接受2个单位UCB移植(n=111)。1个单位UCB组和2个单位UCB组分别有2.7%和1%的患者交叉至对方组。两组中仅有1.8%的患者未接受移植。两组在年龄、性别、人种、体能状态和疾病状态方面的匹配性较好。所有患者中的ALL患者比例稍高于50%。

中位随访25个月后，92%的患者处于缓解状态，其中60%处于二次缓解。第42天时，2个单位UCB组和1个单位UCB组分别有86%和89%的患者的中性粒细胞计数恢复(P=0.08)。2个单位UCB组6个月时血小板恢复的患者比例显著低于1个单位UCB组(66% vs. 76%；P=0.04)。

1个单位UCB组和2个单位UCB组的100天Ⅱ~Ⅳ级急性移植物抗宿主病(GVHD)发生率相似(56% vs. 57%；P=0.88)，1年慢性GVHD发生率也相似(28% vs. 31%；P=0.60)。然而，2个单位UCB组中1个患者亚组的Ⅲ~Ⅳ级急性GVHD发生率显著高于1个单位UCB组(23% vs. 14%；P=0.04)。

2个单位和1个单位UCB移植后，移植相关复发的风险均非常低(14% vs. 12%；P=0.37)。2个单位和1个单位UCB组的1年无病生存率也相似，分别为64%和68%(P=0.22)。1个单位UCB移植组和2个单位UCB移植组的1年总生存率分别为71%和65%(P=0.13)。

Wagner博士表示，1个单位UCB组和2个单位UCB组的平均总有核细胞剂量分别为3.9 x 107个细胞/kg体重和7.2 x 107个细胞/kg体重，这样的细胞剂量不足以检出总生存率方面的差异。可能需要进一步增加剂量才能显出差异。不过，两组中观察到的总生存率和植活率均高于既往COBLT研究的结果，后者对儿童白血病患者使用中位细胞剂量5.1×107后发现，中性粒细胞恢复和血小板植活累计发生率分别为80%和50%，总生存率为67.4%(Blood 2008;112:4318-27)。

该研究获美国国立心肺血液研究所、国立癌症研究所和儿童肿瘤组支持。Wagner博士及其同事声明无相关经济利益冲突。

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By: PATRICE WENDLING, Internal Medicine News Digital Network

ATLANTA – Survival was not enhanced among children with blood cancers after transplantation with two units of umbilical cord blood versus an adequately dosed single-unit transplant.

Among 224 children in a phase III study, overall survival at 1 year was 71% with a single-unit umbilical cord blood (UCB) transplant and 65% with a double-unit UCB transplant (P = .13).
 
All other outcomes were similar, except for a lower incidence of platelet recovery and higher incidence of grade III-IV acute graft-versus-host disease after double UCB transplants, Dr. John E. Wagner reported on behalf of the Blood and Marrow Transplant Clinical Trials Network at the annual meeting of the American Society of Hematology.

And for patients who don’t have an adequate single cord unit based on cell dose, "a double cord blood unit was certainly as good as, or an acceptable alternative, to the single," he said. "So it allowed us to extend the transplant experience."

One of the major shortcomings of UCB transplantation is that units containing a minimum of 2.5 x 107 total nucleated cells/kg of patient body weight are frequently unavailable. The optimal number of transplanted umbilical stem cells remains unclear, but cell dose is an important factor influencing engraftment, or the ability of cells to take root, and survival.

Pilot studies suggested that infusion of two partially HLA-matched UCB units is safe, leading investigators to hypothesize that higher cell doses achieved with double UCB transplant would translate into improved survival, explained Dr. Wagner, scientific director of clinical research for the adult and pediatric blood and bone marrow transplant program at the University of Minnesota Medical Center in Minneapolis.

Between December 2006 and February 2012, investigators at 32 transplant centers enrolled 224 patients, aged 1-21 years, with acute lymphoblastic leukemia (ALL), acute myeloid leukemia, natural killer cell leukemia, chronic myeloid leukemia, or myelodysplastic syndrome. All had at least two available UCB units – each at least 4 of 6 HLA-matched to the patient and 3 of 6 matched between units.

Patients were randomized to receive a conventional single UCB (n = 113) or double UCB (n = 111) transplant. In all, 2.7% of the single UCB group and 1% of the double UCB group crossed over to the opposite arm. Only 1.8% of patients in both groups were not transplanted.

The groups were well matched for age, gender, race, performance status, and disease status. A little more than half of all patients had ALL.

After a median follow-up of 25 months, 92% of patients were in remission, with 60% of these in a second or subsequent remission.

Neutrophil counts had recovered at day 42 in 86% of the double UCB group and in 89% of the single UCB group (P = .08). Platelet recovery at 6 months was significantly lower after double UCB transplant (66% vs. 76%; P = .04), Dr. Wagner said.

Rates were nearly identical in the single and double UCB groups for grade II-IV acute graft-versus-host-disease at 100 days (56% vs. 57%; P = .88) and for chronic GVHD at 1 year (28% vs. 31%; P = .60), although a subpopulation in the double UCB group was significantly more likely to experience grade III-IV acute GVHD (23% vs. 14%; P = .04).

More importantly, there was a very low risk of transplant-related relapse after double or single UCB transplant (14% vs. 12%; P = .37), he observed.

Disease-free survival at 1 year was also similar in the double and single UCB groups at 64% vs. 68% (P = .22).

Dr. Wagner said the average total nucleated cell doses of 3.9 x 107 in the single UCB group and 7.2 x 107 in the double UCB group were not adequate for detecting differences in overall survival. "It probably will take a much greater dose escalation to be able to see that [difference]," he said.

Still, he noted that the overall survival and engraftment rates seen in both arms are superior to what was expected based on historical data sets, including the Cord Blood Transplantation Study (COBLT). It reported cumulative incidences for neutrophil recovery and platelet engraftment of 80% and 50%, and an overall survival of 67.4% in children with hematologic malignancies, despite a median cell dose of 5.1 x 107 (Blood 2008;112:4318-27).

One possible explanation, he suggested, is a new conditioning regimen that includes 1,320 cGy of total body irradiation and cyclophosphamide 120 mg/kg, but replaces the equine antithymocyte globulin used in the COBLT study with fludarabine (Fludara) 75 mg/m2. All patients also received cyclosporine and mycophenolate mofetil for GVHD prophylaxis.

"What this showed us is that it’s not just receiving a double perhaps that has some benefit for some patients, but also the conditioning regimen that we had changed simultaneously at the University of Minnesota," Dr. Wagner said.

He also highlighted similar findings from a very recent study he coauthored that reported comparable adjusted risks of neutrophil recovery, transplant-related mortality, and overall mortality after double UCB and adequately dosed single UCB transplants in 409 adults with acute leukemia (Blood 2012 Dec. 9 [Epub ahead of print]).

The study was supported by the National Heart, Lung, and Blood Institute; the National Cancer Institute; and the Children’s Oncology Group. Dr. Wagner and his coauthors reported no relevant conflicts of interest.