Townsley Danielle M, Scheinberg Phillip, Winkler Thomas, Desmond Ronan, Dumitriu Bogdan, Rios Olga, Weinstein Barbara, Valdez Janet, Lotter Jennifer, Feng Xingmin, Desierto Marie, Leuva Harshraj, Bevans Margaret, Wu Colin, Larochelle Andre, Calvo Katherine R, Dunbar Cynthia E, Young Neal S
From the Hematology Branch (D.M.T., T.W., R.D., B.D., O.R., B.W., J.V., J.L., X.F., M.D., H.L., A.L., C.E.D., N.S.Y.) and the Office of Biostatistics Research (C.W.), National Heart, Lung, and Blood Institute, and the Nursing Research and Translational Science Section, Department of Nursing (M.B.), and the Hematology Section, Department of Laboratory Medicine (K.R.C.), Clinical Center - all at the National Institutes of Health, Bethesda, MD; and the Division of Clinical Hematology, Antônio Ermírio de Moraes Cancer Center, Hospital A Beneficência Portuguesa de São Paulo, São Paulo (P.S.).
N Engl J Med. 2017 Apr 20;376(16):1540-1550. doi: 10.1056/NEJMoa1613878.
Acquired aplastic anemia results from immune-mediated destruction of bone marrow. Immunosuppressive therapies are effective, but reduced numbers of residual stem cells may limit their efficacy. In patients with aplastic anemia that was refractory to immunosuppression, eltrombopag, a synthetic thrombopoietin-receptor agonist, led to clinically significant increases in blood counts in almost half the patients. We combined standard immunosuppressive therapy with eltrombopag in previously untreated patients with severe aplastic anemia.
We enrolled 92 consecutive patients in a prospective phase 1-2 study of immunosuppressive therapy plus eltrombopag. The three consecutively enrolled cohorts differed with regard to the timing of initiation and the duration of the eltrombopag regimen (cohort 1 received eltrombopag from day 14 to 6 months, cohort 2 from day 14 to 3 months, and cohort 3 from day 1 to 6 months). The cohorts were analyzed separately. The primary outcome was complete hematologic response at 6 months. Secondary end points included overall response, survival, relapse, and clonal evolution to myeloid cancer.
The rate of complete response at 6 months was 33% in cohort 1, 26% in cohort 2, and 58% in cohort 3. The overall response rates at 6 months were 80%, 87%, and 94%, respectively. The complete and overall response rates in the combined cohorts were higher than in our historical cohort, in which the rate of complete response was 10% and the overall response rate was 66%. At a median follow-up of 2 years, the survival rate was 97%; one patient died during the study from a nonhematologic cause. Marked increases in bone marrow cellularity, CD34+ cell number, and frequency of early hematopoietic progenitors were noted. Rates of relapse and clonal evolution were similar to our historical experience. Severe rashes occurred in two patients, resulting in the early discontinuation of eltrombopag.
The addition of eltrombopag to immunosuppressive therapy was associated with markedly higher rates of hematologic response among patients with severe aplastic anemia than in a historical cohort. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number, NCT01623167 .).
获得性再生障碍性贫血是由免疫介导的骨髓破坏所致。免疫抑制疗法有效，但残留干细胞数量减少可能会限制其疗效。对于免疫抑制治疗无效的再生障碍性贫血患者，艾曲泊帕（一种合成的血小板生成素受体激动剂）使近半数患者的血细胞计数出现临床上的显著增加。我们将标准免疫抑制疗法与艾曲泊帕联合应用于既往未接受治疗的严重再生障碍性贫血患者。
我们将92例连续患者纳入一项免疫抑制治疗加用艾曲泊帕的前瞻性1-2期研究。连续入组的三个队列在艾曲泊帕治疗方案的起始时间和疗程方面有所不同（队列1从第14天至6个月接受艾曲泊帕治疗，队列2从第14天至3个月，队列3从第1天至6个月）。对各队列分别进行分析。主要结局为6个月时的完全血液学缓解。次要终点包括总体缓解、生存、复发以及向髓系癌的克隆演变。
队列1、队列2和队列3在6个月时的完全缓解率分别为33%、26%和58%。6个月时的总体缓解率分别为80%、87%和94%。联合队列的完全缓解率和总体缓解率高于我们的历史队列，历史队列中的完全缓解率为10%，总体缓解率为66%。在中位随访2年时，生存率为97%；1例患者在研究期间死于非血液学原因。骨髓细胞密度、CD34+细胞数量以及早期造血祖细胞频率均有显著增加。复发率和克隆演变率与我们的历史经验相似。2例患者出现严重皮疹，导致艾曲泊帕提前停用。
与历史队列相比，严重再生障碍性贫血患者在免疫抑制治疗中加用艾曲泊帕后的血液学缓解率显著更高。（由美国国立心肺血液研究所资助；ClinicalTrials.gov编号，NCT01623167。）
