Nonmyeloablative haploidentical peripheral blood stem cell transplantation in congenital anemias

非清髓性单倍相合外周血干细胞移植治疗先天性贫血

• 批准号: 10929172
• 负责人: Courtney Joseph
• 金额: $ 282.99万
• 依托单位: NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10929172
• 关键词: Acute; Acute Graft Versus Host Disease; Allogenic; Antibodies; Anticoagulation; Autoimmune; Autologous; Bone Marrow Purging; Bone Marrow Transplantation; Brain; CD3 Antigens; Cardiac; Cells; Chimerism; Cirrhosis; Congenital Anemia; Control Groups; Cyclophosphamide; Data; Development; Disease; Dose; End stage renal failure; Engraftment; Evans Syndrome; Event; Family member; Goals; Graft Rejection; Graft Survival; Granulocyte Colony-Stimulating Factor; Health; Heart; Heart Diseases; Heart failure; Hematologic Neoplasms; Hematopoiesis; Hematopoietic; Hemoglobin; Human Herpesvirus 4; Immunosuppression; Incidence; Inflammatory; Infusion procedures; Kidney; Kidney Diseases; Laboratories; Liver; Long-Term Effects; Low Dose Radiation; Lung; Lung diseases; Lymphoid; Lymphoproliferative Disorders; Manuscripts; Morbidity - disease rate; Morphology; Multiple Organ Failure; Mus; Myelogenous; Myeloproliferative disease; Neurocognitive; Organ; Patients; Peripheral Blood Stem Cell; Peripheral Stem Cell Transplantation; Phase; Phase I/II Trial; Phenotype; Proto-Oncogene Protein c-kit; Protocols documentation; Publishing; Pulmonary Hypertension; Radiation; Reaction; Recording of previous events; Refractory; Regimen; Reporting; Risk; Siblings; Sickle Cell Anemia; Sirolimus; Site; Stroke; T-Lymphocyte; Therapeutic; Toxic effect; Transplantation; Umbilical cord structure; Viral; Whole-Body Irradiation; alemtuzumab; beta Thalassemia; chronic graft versus host disease; chronic thromboembolic pulmonary hypertension; clinical remission; clinical risk; cohort; conditioning; curative treatments; experience; falls; follow-up; genetic risk assessment; genetic risk factor; graft vs host disease; high risk; immunoregulation; improved; mortality; neurotoxicity; novel; participant enrollment; personalized approach; post-transplant; primary endpoint; reconstitution; retransplantation; second transplant; sickling; success; transplant centers

Based on our murine data, we developed a phase 1 and 2 protocol employing alemtuzumab, 400cGy total body irradiation (TBI), and escalating doses of post-transplant cyclophosphamide (PT-Cy) ranging from 0mg/kg in cohort 1, 50mg/kg in cohort 2, and 100mg/kg in cohort 3. A total of 21 patients with sickle cell disease and 2 patients with beta-thalassemia were transplanted and had baseline complications, including cirrhosis, pulmonary hypertension, heart failure, and end-stage renal disease. The engraftment rate improved from 1/3 (33%) in the first cohort to 5/8 (63%) in the second cohort to 10/12 (83%) in the third cohort. The percentage of donor myeloid and CD3 chimerism also improved with subsequent cohorts. With median follow-up exceeding 8 years, the overall survival is 57.1%; 6 died after the return of their sickle cell disease, and 3 following repeat transplant for sickle cell disease. There was no mortality before 100 days post-transplant. At present, 0% in the first cohort, 12.5% in the second cohort, and 33% in the third cohort remain free of their disease. There was no Grade 2-4 acute or moderate to severe chronic graft-versus-host disease (GVHD). Therefore, we have shown that PT-Cy improves engraftment in patients with SCD who are at high risk for early mortality. 3 patients were re-transplanted with myeloablative conditioning and the same donor, and 2 are alive and free of sickle cell disease. As we reached the stopping rules for the study, we opened a new protocol that added additional immunosuppression in an attempt to improve the success rate while maintaining a low risk of GVHD. Since June 2017, 22 patients have been transplanted. 21 patients achieved high donor chimerism levels. One patient with a history of stroke and chronic thromboembolic pulmonary hypertension on anticoagulation died 60 days after her second transplant. Two patients developed refractory Evans syndrome followed by an unexpected severe hyperinflammatory reaction that led to multi-organ failure in both patients, fatal in both. One patient died from neurotoxicity related to Epstein-Barr Virus-associated post-transplant lymphoproliferative disorder (PTLD). Two patients developed acute GVHD, one Grade 2 and one Grade 4. One patient rejected his graft and required infusion of his backup autologous cells. Two patients with slowly falling donor myeloid chimerism levels experienced the return of their sickle cell disease at 2.5 years post-transplant. Five patients developed PTLD, 2 uncontrolled. Four patients developed autoimmune complications, 2 uncontrolled. Because of the high incidence of unexpected complications, the protocol has recently halted accrual. We have recently submitted a new haploidentical protocol for scientific review. The protocol will enroll patients with severe SCD, including those with compromised organ function. The protocol will include nongenotoxic conditioning with an anti-c-Kit antibody with the goal of maximizing donor chimerism levels long-term while minimizing toxicity. Our clonal hematopoiesis protocol in patients with sickle cell disease and deep phenotyping of major organs in patients with sickle cell disease are enrolling patients to help us identify clinical and genetic risk factors of heart, lung, and kidney disease and myeloid malignancy development after curative therapies for sickle cell disease. We have published one manuscript that described a high incidence of hematologic malignancies after unsuccessful curative therapies and mixed chimerism for sickle cell disease. We also recently reported that cardiac morphology improves in patients with sickle cell disease who underwent nonmyeloablative HLA-matched sibling transplant at one of three sites at 2 years post-transplant.

基于我们的鼠数据，我们开发了一项I期和II期方案，采用Alemtuzumab、400 cGy全身照射（TBI）和递增剂量的移植后环磷酰胺（PT-Cy），剂量范围为队列1中的0 mg/kg、队列2中的50 mg/kg和队列3中的100 mg/kg。 共有21例镰状细胞病患者和2例β地中海贫血患者接受了移植，并出现了基线并发症，包括肝硬化、肺动脉高压、心力衰竭和终末期肾病。 植入率从第一队列的1/3（33%）提高到第二队列的5/8（63%），再到第三队列的10/12（83%）。 供体髓系和CD 3嵌合体的百分比也随着后续队列而改善。 中位随访时间超过8年，总生存率为57.1%; 6例在镰状细胞病复发后死亡，3例在镰状细胞病重复移植后死亡。 移植后100天内无死亡。 目前，第一队列中的0%、第二队列中的12.5%和第三队列中的33%仍然没有患病。 无2-4级急性或中度至重度慢性移植物抗宿主病（GVHD）。 因此，我们已经证明PT-Cy可以改善早期死亡风险高的SCD患者的植入。 3例患者在清髓性预处理和同一供体下再次移植，2例存活且无镰状细胞病。 当我们达到研究的停止规则时，我们打开了一个新的方案，增加了额外的免疫抑制，试图提高成功率，同时保持GVHD的低风险。 自2017年6月以来，已有22名患者接受了移植。 21例患者达到高供体嵌合水平。 一名有中风和慢性血栓栓塞性肺动脉高压病史的患者在第二次移植后60天死亡。 2例患者发生难治性Evans综合征，随后发生意外的重度炎症反应，导致2例患者发生多器官衰竭，2例患者均死亡。 1例患者死于与EB病毒相关的移植后淋巴组织增生性疾病（PTLD）相关的神经毒性。2例患者发生急性GVHD，1例为2级，1例为4级。 一名患者排斥了他的移植物，需要输注他的备用自体细胞。 两名供者骨髓嵌合体水平缓慢下降的患者在移植后2.5年时经历了镰状细胞病的复发。5例患者发生PTLD，2例未控制。4例患者发生自身免疫性并发症，2例未控制。由于意外并发症的发生率很高，该方案最近停止了累积。我们最近提交了一份新的单倍性方案供科学审查。该方案将招募重度SCD患者，包括器官功能受损的患者。该方案将包括使用抗c-Kit抗体进行非遗传毒性处理，目的是长期最大化供体嵌合水平，同时最小化毒性。我们在镰状细胞病患者中的克隆造血方案和镰状细胞病患者主要器官的深度表型分析正在招募患者，以帮助我们确定镰状细胞病治愈性治疗后心脏、肺和肾脏疾病以及骨髓恶性肿瘤发展的临床和遗传风险因素。我们发表了一篇文章，描述了镰状细胞病治疗失败后血液恶性肿瘤的高发病率和混合嵌合体。我们最近也报道了镰状细胞病患者在移植后2年在三个部位之一接受非清髓性HLA匹配的同胞移植后，心脏形态得到改善。

项目成果

The case for HLA-identical sibling hematopoietic stem cell transplantation in children with symptomatic sickle cell anemia.

对有症状的镰状细胞性贫血儿童进行 HLA 相同同胞造血干细胞移植的病例。

• DOI: 10.1182/bloodadvances.2017007708
• 发表时间: 2017
• 期刊: Blood advances
• 影响因子: 7.5
• 作者: Fitzhugh,CourtneyD;Walters,MarkC
• 通讯作者: Walters,MarkC

Alternative Donor/Unrelated Donor Transplants for the β-Thalassemia and Sickle Cell Disease.

• DOI: 10.1007/978-1-4939-7299-9_5
• 发表时间: 2017
• 期刊: Advances in experimental medicine and biology
• 作者: Fitzhugh CD;Abraham A;Hsieh MM
• 通讯作者: Hsieh MM

A sensitive and rapid ultra high-performance liquid chromatography with tandem mass spectrometric assay for the simultaneous quantitation of cyclophosphamide and the 4-hydroxycyclophosphamide metabolite in human plasma.

• DOI: 10.1016/j.jchromb.2018.04.016
• 发表时间: 2018-06-01
• 期刊: Journal of chromatography. B, Analytical technologies in the biomedical and life sciences
• 作者: Hall OM;Peer CJ;Fitzhugh CD;Figg WD
• 通讯作者: Figg WD

Early Myeloid Derived Suppressor Cells (eMDSCs) Are Associated With High Donor Myeloid Chimerism Following Haploidentical HSCT for Sickle Cell Disease.

• DOI: 10.3389/fimmu.2021.757279
• 发表时间: 2021
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Bhat DK;Olkhanud PB;Gangaplara A;Seifuddin F;Pirooznia M;Biancotto A;Fantoni G;Pittman C;Francis B;Dagur PK;Saxena A;McCoy JP;Pfeiffer RM;Fitzhugh CD
• 通讯作者: Fitzhugh CD

Thrombospondin-1, Platelet Factor 4, and Galectin-1 Are Associated with Engraftment in Patients with Sickle Cell Disease who Underwent Haploidentical Hematopoietic Stem Cell Transplantation.

• DOI: 10.1016/j.jtct.2022.01.027
• 发表时间: 2022-05
• 期刊: TRANSPLANTATION AND CELLULAR THERAPY
• 影响因子: 3.2
• 作者: Shaikh, Ahmad;Olkhanud, Purevdorj B.;Gangaplara, Arunakumar;Kone, Abdoul;Patel, Sajni;Gucek, Marjan;Fitzhugh, Courtney D.
• 通讯作者: Fitzhugh, Courtney D.