Haploidentical Stem Cell Transplantation with Post-Transplant Cyclophosphamide in Fanconi Anemia: Improving Outcomes with Improved Supportive Care in India

IF 4.3 Q1 Medicine
Ramya Uppuluri , Venkateswaran Vellaichamy Swaminathan , Kesavan Melarcode Ramanan , Satishkumar Meena , Harika Varla , Balasubramaniam Ramakrishnan , Indira Jayakumar , Revathi Raj
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引用次数: 10

Abstract

Fanconi anemia is the most common inherited bone marrow failure syndrome, and hematopoietic stem cell transplantation (HSCT) is the only curative option. Post-transplant cyclophosphamide (PTCy) is challenging in this group of children, given their increased sensitivity to chemotherapy. We performed a retrospective analysis of the data on children diagnosed with Fanconi anemia who underwent a haploidentical HSCT with PTCy from January 2014 to December 2019. Nineteen children (male/female, 0.75:1) underwent 21 haplo-HSCTs with PTCy. Fludarabine, low-dose cyclophosphamide, and 200 centi-gray total body irradiation were included in the conditioning regimen with 25 mg/kg PTCy on days +3 and +4. Haplo-graft was from a sibling in 38% and father in 57% of transplants. The source of stem cells was peripheral blood stem cells in 81% and bone marrow in 19% of transplants, with a median CD34 dose of 5.0 × 106/kg. We documented engraftment in 84% and primary graft failure in 10% of transplants. N-acetylcysteine (NAC) was infused concomitantly during cyclophosphamide in 13 children. Grade 2 and 3 mucositis was lower among those who received NAC as compared to those who did not (30% and 15% versus 33% and 50%), while transaminitis was higher among those who did not receive the infusion. The incidence of acute graft-versus-host disease (GVHD) was 68%, and 81% of these were steroid responsive (grade I/II). We documented chronic GVHD in 25% children, predominantly involving the skin and mouth, which responded to low-dose steroids and ruxolitinib. Serum ferritin was monitored twice weekly as a surrogate marker for cytokine release syndrome due to nonavailability of IL-6 levels. A 1- or 2-log increase in the titers of ferritin associated with clinical features guided the early addition of steroids in the periengraftment period. The mean survival was found to be less among those with high serum ferritin (>10,000 ng/dL) in the periengraftment period as compared to those with ferritin <10,000 ng/dL (mean survival of 25 ± 10 months versus 50 ± 6 months, respectively). The overall survival in our cohort was 68.4%, with a mean survival time of 41.5 months (95% confidence interval, 29.3 to 53.8 months), with a statistically significant correlation between inferior outcome and having received over 15 transfusions before HSCT (P = .01). PTCy can be considered a viable option in children with Fanconi anemia, particularly in resource-limited settings given the high costs of HSCTs. Focused interventions in this subset of children help improve survival outcomes. Early identification of cytokine release syndrome and risk-adapted steroid therapy during engraftment helps prevent mortality. The concomitant use of NAC during cyclophosphamide infusion helps reduce oxygen free radical related tissue damage and regimen-related toxicity.

单倍体干细胞移植与移植后环磷酰胺治疗范可尼贫血:改善印度支持治疗的结果
范可尼贫血是最常见的遗传性骨髓衰竭综合征,造血干细胞移植(HSCT)是唯一的治疗选择。移植后环磷酰胺(PTCy)在这组儿童中具有挑战性,因为他们对化疗的敏感性增加。我们对2014年1月至2019年12月期间接受PTCy单倍同型HSCT治疗的诊断为范可尼贫血的儿童进行了回顾性分析。19名儿童(男/女,0.75:1)接受了21例含PTCy的单倍hsct。氟达拉滨、低剂量环磷酰胺和200厘灰全身照射在+3和+4天以25 mg/kg PTCy进行调节。单倍体移植来自兄弟姐妹的占38%,来自父亲的占57%。干细胞来源为外周血干细胞(81%)和骨髓(19%),中位CD34剂量为5.0 × 106/kg。我们记录了84%的移植成功,10%的移植失败。13例患儿在环磷酰胺治疗期间同时输注n -乙酰半胱氨酸(NAC)。2级和3级粘膜炎在接受NAC的患者中比未接受NAC的患者低(30%和15%对33%和50%),而在未接受NAC输注的患者中,转氨炎的发生率更高。急性移植物抗宿主病(GVHD)的发生率为68%,其中81%对类固醇有反应(I/II级)。我们记录了25%的儿童慢性GVHD,主要涉及皮肤和口腔,对低剂量类固醇和鲁索利替尼有反应。每周监测两次血清铁蛋白,作为细胞因子释放综合征的替代标志物,因为无法获得IL-6水平。与临床特征相关的铁蛋白滴度的1-或2-log的增加指导了在植入期早期添加类固醇。与铁蛋白含量为1万ng/dL的患者相比,高血清铁蛋白(1万ng/dL)患者在移植围期的平均生存时间较短(平均生存时间分别为25±10个月和50±6个月)。我们队列的总生存率为68.4%,平均生存时间为41.5个月(95%可信区间为29.3 ~ 53.8个月),不良预后与HSCT前输血超过15次有统计学意义(P = 0.01)。PTCy可以被认为是范可尼贫血儿童的可行选择,特别是在资源有限的环境中,鉴于hsct的高成本。对这部分儿童进行重点干预有助于改善生存结果。在植入过程中早期识别细胞因子释放综合征和适应风险的类固醇治疗有助于预防死亡。在环磷酰胺输注期间同时使用NAC有助于减少氧自由基相关的组织损伤和方案相关的毒性。
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来源期刊
CiteScore
6.60
自引率
0.00%
发文量
1061
审稿时长
3-6 weeks
期刊介绍: Biology of Blood and Marrow Transplantation publishes original research reports, reviews, editorials, commentaries, letters to the editor, and hypotheses and is the official publication of the American Society for Transplantation and Cellular Therapy. The journal focuses on current technology and knowledge in the interdisciplinary field of hematopoetic stem cell transplantation.
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