A Randomized Phase II Crossover Study of Imatinib or Rituximab for Cutaneous Sclerosis after Hematopoietic Cell Transplantation.
A Randomized Phase II Crossover Study of Imatinib or Rituximab for Cutaneous Sclerosis after Hematopoietic Cell Transplantation.
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DOI：
10.1158/1078-0432.ccr-15-1443
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发表时间：
2016-01-15
期刊：
影响因子：
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通讯作者：
Flowers ME
中科院分区：
文献类型：
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作者：
Arai S;Pidala J;Pusic I;Chai X;Jaglowski S;Khera N;Palmer J;Chen GL;Jagasia MH;Mayer SA;Wood WA;Green M;Hyun TS;Inamoto Y;Storer BE;Miklos DB;Shulman HM;Martin PJ;Sarantopoulos S;Lee SJ;Flowers ME
皮肤硬化症(CS)发生在20%的慢性移植物抗宿主病(GVHD)患者中，并会影响患者的行动能力和生活质量。我们进行了一项前瞻性、多中心、随机、双臂II期交叉试验，伊马替尼(200 mg/d)或利妥昔单抗(375 mg/m2每周4次静脉注射，3个月后重复)用于治疗18个月内确诊的CS(NCT01309997)。主要终点是6个月后的显著临床反应(SCR)，定义为皮肤硬化或关节活动范围的定量改善。治疗成功定义为6个月时SCR无交叉、无复发或死亡。次要终点包括血液中B细胞类型的变化(BAFF水平和细胞亚群)，患者报告的结果，以及在每种治疗中有效和无效之间的组织病理学。随机服用伊马替尼的35名参与者中有9名(26%，95%可信区间13-43%)观察到SCR，而随机服用利妥昔单抗的37名参与者中有10名(27%，95%可信区间14-44%)观察到SCR。治疗成功的患者中，伊马替尼组6例(17%，95%可信区间7-34%)，利妥昔单抗组5例(14%，95%可信区间5-29%)。利妥昔单抗治疗成功的患者在登记时激活的B细胞(CD27+)百分比较高(p=0.01)，但在伊马替尼治疗的患者中并非如此。这些结果支持了对CS更有效治疗的需要，并表明激活的B细胞定义了CS患者的一个亚群，他们更有可能对利妥昔单抗有反应。
Cutaneous sclerosis (CS) occurs in 20% of patients with chronic graft-versus-host disease (GVHD) and can compromise mobility and quality of life. We conducted a prospective, multi-center, randomized, two-arm phase II crossover trial of imatinib (200 mg daily) or rituximab (375 mg/m2 intravenously weekly × 4 doses, repeatable after 3 months) for treatment of CS diagnosed within 18 months (NCT01309997). The primary endpoint was significant clinical response (SCR) at 6 months, defined as quantitative improvement in skin sclerosis or joint range of motion. Treatment success was defined as SCR at 6 months without crossover, recurrent malignancy or death. Secondary end points included changes of B cell profiles in blood (BAFF levels and cellular subsets), patient-reported outcomes, and histopathology between responders and non-responders with each therapy. SCR was observed in 9 of 35 (26%, 95% CI 13-43%) participants randomized to imatinib and 10 of 37 (27%, 95% CI 14-44%) randomized to rituximab. Six (17%, 95% CI 7-34%) patients in the imatinib arm and 5 (14%, 95% CI 5-29%) in the rituximab arm had treatment success. Higher percentages of activated B cells (CD27+) were seen at enrollment in rituximab-treated patients who had treatment success (p = 0.01), but not in imatinib-treated patients. These results support the need for more effective therapies for CS and suggest that activated B cells define a subgroup of patients with CS who are more likely to respond to rituximab.