Salvage Chemoimmunotherapy With Inotuzumab Ozogamicin Combined With Mini-Hyper-CVD for Patients With Relapsed or Refractory Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia A Phase 2 Clinical Trial
Salvage Chemoimmunotherapy With Inotuzumab Ozogamicin Combined With Mini-Hyper-CVD for Patients With Relapsed or Refractory Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia A Phase 2 Clinical Trial
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DOI：
10.1001/jamaoncol.2017.2380
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发表时间：
2018-02-01
期刊：
影响因子：
28.4
通讯作者：
Kantarjian, Hagop
中科院分区：
文献类型：
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作者：
Jabbour, Elias;Ravandi, Farhad;Kantarjian, Hagop
复发或难治性（R/R）急性淋巴细胞白血病（ALL）患者的预后较差。Inotuzumab ozogamicin是一种与卡奇霉素结合的CD 22单克隆抗体，在R/R ALL中具有单药活性。目的评价Inotuzumab ozogamicin联合低强度化疗在R/R ALL患者中的疗效和安全性。设计、设置和参与者干预化疗的强度低于hyper-CVAD（环磷酰胺，长春新碱，阿霉素[商品名，阿霉素;辉瑞公司]，和地塞米松），并被称为迷你高CVD（微型HCVD：环磷酰胺和地塞米松剂量减少50%，无蒽环类药物，甲氨蝶呤剂量减少75%，阿糖胞苷0.5 g/m2 × 4剂）。Inotuzumab在前4个疗程的第3天给药，第1周期剂量为1.8 ~ 1.3mg/m2，随后的周期剂量为1.3 ~ 1.0mg/m2。次要终点包括安全性、无复发生存期（RFS）、异基因干细胞移植（ASCT）率和微小残留病（MRD）阴性率。结果59例患者（30例女性和29例男性），中位年龄为35岁（范围，18-87岁）。总体而言，46例患者（78%）缓解，其中35例（59%）达到完全缓解。应答者的总体MRD阴性率为82%。26例患者（44%）接受了ASCT。3 - 4级毒性反应包括长期血小板减少（81%; n = 48）、感染（73%; n = 43）和高胆红素血症（14%; n = 8）。9例患者（15%）发生静脉闭塞性疾病（VOD）。中位随访时间为24个月，中位RFS和OS分别为8个月和11个月。1年RFS和OS率分别为40%和46%。在挽救治疗1、挽救治疗2和挽救治疗3或以上的患者中，1年OS率分别为57%、26%和39%（P= 0.03）。结论和相关性inotuzumab与低强度mini-HCVD化疗的组合在R/R ALL中显示出令人鼓舞的结果。VOD的风险应仔细考虑在以前的肝损伤患者和移植候选人。
IMPORTANCE The outcome of patients with relapsed or refractory (R/R) acute lymphoblastic leukemia (ALL) is poor. Inotuzumab ozogamicin, a CD22 monoclonal antibody bound to calicheamicin, has single-agent activity in R/R ALL.OBJECTIVE To evaluate the efficacy and safety of inotuzumab ozogamicin plus low-intensity chemotherapy in patients with R/R ALL.DESIGN, SETTING, AND PARTICIPANTS A single-arm, phase 2 study of adults with R/R B-cell ALL conducted at The University of Texas MD Anderson Cancer Center, Houston.INTERVENTIONS The chemotherapy used was lower intensity than hyper-CVAD (cyclophosphamide, vincristine, doxorubicin [ trade name, Adriamycin; Pfizer], and dexamethasone) and is referred to as mini-hyper-CVD (mini-HCVD: cyclophosphamide and dexamethasone at 50% dose reduction, no anthracycline, methotrexate at 75% dose reduction, and cytarabine at 0.5 g/m(2) x 4 doses). Inotuzumab was given on day 3 of the first 4 courses at 1.8 to 1.3mg/m(2) for cycle 1 followed by 1.3 to 1.0mg/m(2) for subsequent cycles.MAIN OUTCOMES AND MEASURES The primary end pointswere the overall response rate and overall survival (OS). Secondary end points included safety, relapse-free survival (RFS), the rate of allogeneic stem cell transplantation (ASCT), and the minimal residual disease (MRD) negativity rate. RESULTS Fifty-nine patients (30 women and 29 men) with a median age of 35 years (range, 18-87 years) were treated. Overall, 46 patients (78%) responded, 35 of them (59%) achieving complete response. The overall MRD negativity rate among responders was 82%. Twenty-six patients (44%) received ASCT. Grade 3 to 4 toxic effects included prolonged thrombocytopenia (81%; n = 48), infections (73%; n = 43), and hyperbilirubinemia (14%; n = 8). Veno-occlusive disease (VOD) occurred in 9 patients (15%). With a median follow-up of 24 months, the median RFS and OS were 8 and 11 months, respectively. The 1-year RFS and OS rates were 40% and 46%, respectively. The 1-year OS rates for patients treated in salvage 1, salvage 2, and salvage 3 or beyond were 57%, 26%, and 39%, respectively (P=.03).CONCLUSIONS AND RELEVANCE The combination of inotuzumab with low-intensity mini-HCVD chemotherapy shows encouraging results in R/R ALL. The risk of VOD should be considered carefully in patients with previous liver damage and among transplant candidates.