Solh Melhem M, Hinojosa Gabriel, Laporte Justin, Solomon Scott R, Morris Lawrence E, Zhang Xu, Holland H Kent, Bashey Asad
Blood and Marrow Transplant Program at Northside Hospital, Atlanta, GA, USA.
Center for Clinical and Translational Sciences, University of Texas Health Science Center at Houston, Houston, TX, USA.
Adv Hematol. 2021 Mar 23;2021:8868142. doi: 10.1155/2021/8868142. eCollection 2021.
T-replete haploidentical donor transplants using posttransplant cyclophosphamide (haplo) have greatly expanded donor availability and are increasingly utilized. Haplo were originally performed using truly nonmyeloablative conditioning and a bone marrow graft. We have also developed myeloablative conditioning and peripheral blood stem cell (PBSC) grafts for use with haplo. However, some patients may not tolerate myeloablative conditioning but may still benefit from a more dose-intensified preparative regimen to control malignancy and diminish graft rejection. To this end, we enrolled 25 patients on a prospective phase II trial utilizing a regimen of fludarabine 30 mg/m/day × 5 days and Melphalan 140 mg/m on day -1 (flu/Mel) followed by infusion of unmanipulated PBSC graft from a haploidentical donor. GVHD prophylaxis included cyclophosphamide 50 mg/kg/day on days 3 and 4, mycophenolate mofetil on day 35, and tacrolimus on day 180. Median age was 57 years (range from 35 to 68). Transplantation diagnosis included AML ( = 11), ALL ( = 4), MDS/MPD ( = 6), NHL/CLL ( = 3), and MM ( = 1). Using the refined Disease Risk Index (DRI), patients were low ( = 1), intermediate ( = 13), and high/very high ( = 11). 22 out of 25 patients engrafted with a median time to neutrophil and platelet engraftment of 18 days and 36 days, respectively. All engrafting patients achieved full peripheral blood T-lymphocyte and myeloid donor chimerism at day 30. The 180-day cumulative incidence for acute GVHD grades II-IV and III-IV was seen in 20% (95% CI 8%-37%) and 8% (95% CI 2%-22%), respectively. The 2-year cumulative incidence of chronic GVHD was 16% (95% CI 5%-33%) (moderate-severe 12% (95% CI 3%-27%)). After a median follow-up of 28.3 months, the estimated 2-year OS, DFS, NRM, and relapse were 56% (95%CI 33-74%), 44% (95%CI 23%-64%), 20% (95% CI 8%-37%), and 36% (95% CI 17%-55%), respectively. Among patients with high/very high risk DRI, 2-year OS was 53% compared to 69% for low/intermediate DRI. When compared with a contemporaneous cohort of patients at our center receiving haploidentical transplant with nonablative fludarabine, Cytoxan, and total body irradiation flu/Cy/TBI regimen, the outcomes were statistically similar to the 2-year OS at 56% vs. 63% =0.75 and DFS at 44% vs. 46% =0.65.
使用移植后环磷酰胺的全相合单倍体供者移植（单倍体移植）极大地扩大了供者来源，且应用越来越广泛。单倍体移植最初采用真正的非清髓性预处理和骨髓移植。我们也开发了用于单倍体移植的清髓性预处理和外周血干细胞（PBSC）移植。然而，一些患者可能无法耐受清髓性预处理，但仍可能受益于更强化剂量的预处理方案以控制恶性肿瘤并减少移植排斥。为此，我们纳入了25例患者进行一项前瞻性II期试验，采用氟达拉滨30mg/m²/天×5天和马法兰140mg/m²于第-1天的方案（氟达拉滨/马法兰），随后输注来自单倍体供者的未处理PBSC移植。移植物抗宿主病（GVHD）预防措施包括第3天和第4天给予环磷酰胺50mg/kg/天，第35天给予霉酚酸酯，第180天给予他克莫司。中位年龄为57岁（范围35至68岁）。移植诊断包括急性髓系白血病（AML，n = 11）、急性淋巴细胞白血病（ALL，n = 4）、骨髓增生异常综合征/骨髓增殖性疾病（MDS/MPD，n = 6）、非霍奇金淋巴瘤/慢性淋巴细胞白血病（NHL/CLL，n = 3）和多发性骨髓瘤（MM，n = 1）。使用改良的疾病风险指数（DRI），患者为低风险（n = 1）、中风险（n = 13）和高/极高风险（n = 11）。25例患者中有22例植入，中性粒细胞和血小板植入的中位时间分别为18天和36天。所有植入患者在第30天实现了外周血T淋巴细胞和髓系供者完全嵌合。急性GVHD II-IV级和III-IV级的180天累积发生率分别为20%（95%可信区间8%-37%）和8%（95%可信区间2%-22%）。慢性GVHD的2年累积发生率为16%（95%可信区间5%-33%）（中重度为12%（95%可信区间3%-27%））。中位随访28.3个月后，估计的2年总生存率（OS）、无病生存率（DFS）、非复发死亡率（NRM）和复发率分别为56%（95%可信区间33%-74%）、44%（95%可信区间23%-64%）、20%（95%可信区间8%-37%）和36%（95%可信区间17%-55%）。在高/极高风险DRI患者中，2年OS为53%，而低/中风险DRI患者为69%。与我们中心同期接受非清髓性氟达拉滨、环磷酰胺和全身照射（氟达拉滨/环磷酰胺/全身照射）方案的单倍体移植患者队列相比，结果在统计学上相似，2年OS为56%对63%（P = 0.75），DFS为44%对46%（P = 0.65）。
