Stem cell transplantation after reduced‐intensity conditioning for sickle cell disease

Sickle cell disease (SCD) is still associated with substantial morbidity and reduced life expectancy. Disease‐related mortality rises to 14% in adolescents and young adults. Overall and disease‐free survival following haematopoietic stem cell transplantation (HSCT) is 90% and 95%, respectively. To reduce transplant‐associated late effects, the feasibility of a highly immunosuppressive reduced‐intensity conditioning (RIC) regimen was explored in children with SCD and a matched sibling donor. Eight patients (median age, 9 yr) and symptomatic SCD were included. The conditioning regimen consisted of fludarabine, melphalan and either thiotepa or total lymphoid irradiation plus antithymocyte globuline or alemtuzumab. The graft was bone marrow in seven and cord blood in one case. The conditioning regimen was well tolerated and no severe infectious complications occurred. All patients displayed mixed chimaerism on day +28. After a median follow‐up of 4 yr, 3/8 patients have mixed leucocyte chimaerism and 8/8 patients have 100% donor erythropoiesis. HSCT from matched sibling donors following a RIC regimen was well tolerated and resulted in cure in all patients studied. If confirmed in larger patient cohorts, these observations will have important implications for the indications of HSCT in children with SCD.     

Treosulfan‐based conditioning regimen for allogeneic haematopoietic stem cell transplantation in children with sickle cell disease

Although allogeneic haematopoietic stem cell transplantation (HSCT) still represents the only consolidated possibility of cure for sickle cell disease (SCD) patients, its use has been limited by the risk of morbidity and mortality associated with conventional myeloablative therapy. The introduction of treosulfan to replace busulfan in conditioning regimens has recently been explored by virtue of its lower toxicity profile. We report our experience with a treosulfan/thiotepa/fludarabine conditioning for human leucocyte antigen (HLA)‐matched sibling or unrelated donor‐HSCT in 15 children with SCD, and compare patient outcomes with those of a historical cohort (15 patients) given a busulfan‐based regimen. Engraftment was achieved in 28 out of 30 patients (93%), with one case of graft failure in either group. The conditioning regimen was well tolerated in both groups, with no cases of grade III‐IV regimen‐related toxicity. The 7‐year overall survival (OS) and disease‐free survival (DFS) for the whole cohort were 100% and 93%, respectively, with a 93% DFS in both busulfan and treosulfan groups. No SCD‐related adverse events occurred after engraftment in patients with complete or mixed donor chimerism. This retrospective analysis suggests that a treosulfan‐based conditioning regimen is able to ensure engraftment with excellent OS/DFS and low regimen‐related toxicity in patients with SCD.     

亚标准预处理方案造血干细胞移植治疗血液肿瘤性疾病

目的 :观察亚标准预处理方案造血干细胞移植治疗血液系统肿瘤疾病的疗效、副作用。方法 :采用环磷酰胺、全身放疗做基础预处理方案 ,同时给予免疫球蛋白、甲氨喋呤、泼尼松等治疗。对HLA半相合者加环孢素、骁悉、抗淋巴细胞球蛋白预防移植物抗宿主病。输入单个核细胞 2 .0～ 7.0× 10 9/kg。 结果 :移植后中性粒细胞最低下降为 0 ,血小板 3～ 7× 10 9/L ,血红蛋白 6 0～ 110 g/L ,持续 12～ 2 1d。 30例中 3例死亡 ,存活率 90 % ,2 4例 (80 % )无病生存 ,随访 5年以上 (最长者 12年 )无严重合并症。结论 :亚标准预处理方案造血干细胞移植是根据个体差异及药物不同敏感性等具体情况给予不同剂量预处理方案 ,经染色体嵌合体检测 ,DNA基因鉴定及发生GVHD情况看 ,其干细胞能有效植入 ,且副作用小 ,并发症轻 ,是一个值得进一步观察的方法     

Allogeneic hematopoietic stem cell transplantation following reduced-intensity conditioning regimen in children: a single-center experience

This single-center retrospective study reported the outcome of 19 children treated with a reduced-intensity conditioning (RIC) regimen prior to allogeneic stem cell transplantation (allo-SCT), for hematologic malignancies (n = 17), bone marrow failure (n = 1), and neuroblastoma (n = 1). Children were ineligible for standard myeloablative conditioning because of severe comorbidities (n = 9), a previous auto or allo-SCT (n = 7) or a prior history of extensive chemotherapy (n = 3). All patients underwent a fludarabine-based RIC regimen, and received grafts from matched-related donors (n = 5), match-unrelated donors (n = 6), or unrelated cord blood (UCB, n = 8). In this series, two patients treated with UCB failed to engraft and 63% achieved full donor chimerism at day 100 after allo-SCT. With a median follow-up of 537 d (range, 115-4136), treatment-related mortality was 16% and overall survival was 47%. The principal cause of death was disease relapse (n = 7). Acute graft versus host disease (GVHD) occurred in 53% of patients, while only 10% developed extensive chronic GVHD. Overall, results from this series suggest that RIC allo-SCT can be a valid alternative treatment option in unfit children with malignant hematological diseases. Prospective studies are needed to enlarge pediatric experience in this domain and better identify those children more suitable for a RIC allo-SCT approach.     

Hematopoietic stem cell transplantation for sickle cell disease: The changing landscape

Allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curative therapy for sickle cell disease (SCD); however, its use is limited by lack of suitable human leukocyte antigen (HLA)-matched donors and decreased application in older patients with significant morbidity. Myeloablative, HLA-identical sibling transplantation in children with SCD offers excellent long-term survival, with overall and event-free survival rates of 95% and 92%, respectively. However, the risk of graft-versus-host-disease, infections, infertility, and other long-term transplant complications, further limits its widespread use. Recent approaches using reduced intensity conditioning (RIC) are associated with lower toxicity, allowing extension of this modality to children and adults with significant morbidity; however, these approaches are also associated with increased risk of graft failure. The optimal RIC regimen that strikes the optimal balance between maximizing the rate of stable engraftment while minimizing transplant-related morbidity and mortality is unknown. Alternative donor transplants, most prominently, partial HLA-mismatched related transplants (haploidentical), are being investigated with promising initial results. This review will discuss long-term results of HLA-matched sibling HSCT for SCD, and recent updates on HLA-matched unrelated donor and unrelated umbilical cord blood HSCT for SCD.     

Brain parenchymal damage after haematopoietic stem cell transplantation for severe sickle cell disease

Prospective magnetic resonance imaging (MRI), magnetic resonance angiography (MRA), neuropsychological testing and neurological examinations were performed to determine the long-term effect of successful haematopoietic stem cell transplantation on the neurological status of nine children with sickle cell disease. A scoring system for severity of brain parenchymal and vascular lesions was developed and applied. Neurological examinations and neuropsychometric tests were stable, but MRI and MRA studies were not. Transient changes occurred early in two patients. Persistent changes occurred in five. Parenchymal lesions occurred in zero of two patients without prior lacunae or infarcts and in all seven with prior lacunae or infarcts (P = 0.0278).     

Conventional versus reduced-intensity conditioning regimen for allogeneic stem cell transplantation in patients with hematological malignancies

BACKGROUND: Allogeneic hematopoietic stem cell transplantation (HSCT) from human leukocyte antigen (HLA)-compatible sibling donors is a potential curative treatment for hematological and non-hematological malignancies. Nevertheless, high mortality rates may be associated with this therapy, especially in older patients, those with other comorbidities or who receive a second HSCT. PATIENTS AND METHODS: We analyzed the factors associated with transplant-related mortality (TRM) and overall survival in 157 consecutive adult patients (104 males and 53 females) who received a HSCT [29 bone marrow (BM) transplantation and 128 peripheral blood (PB) transplantation] from a HLA-identical sibling between January 1995 and March 2002 in our institution. One hundred patients received a standard conditioning prior to HSCT (STAND) and 57 patients received a reduced-intensity conditioning (RIC) HSCT. Fifty-eight patients were in an early phase at transplant and 99 in a non-early phase. Median age was 46 yr (16-66), and 90 patients (57%) were >45 yr of age. RESULTS: Patients in the RIC group were older than those in the STAND group, and had a higher proportion of non-early disease phases including a prior autologous HSCT in 39%. Median follow-up for survivors was 28 and 15 months in the STAND and RIC groups (P < 0,001), respectively. Cumulative incidence of TRM at 2 yr was 30% [95% confidence interval (CI) 22-41%] for the STAND group and 22% (95% CI 13-37%) for the RIC group [non-significant (NS)]. Factors associated with a higher TRM in multivariate analysis were: STAND vs. RIC conditioning regimen [relative risk (RR) 5.4; 95% CI 2.3-12.8; P < 0.001]; age > or =45 yr vs. <45 yr (RR 5; 95% CI 2.4-10.8, P < 0.001); second vs. first HSCT (RR 2.8, 95% CI 1.3-6.3, P = 0.01) and non-T-cell-depleted vs. T-cell-depleted graft (RR 2.7, 95% CI 1.3-5.8, P = 0.009). Overall survival (OS) at 2 yr was 52.5 +/- 10.4% for STAND group and 59 +/- 16.8% in RIC group. Factors associated with poorer OS in multivariate analysis were: STAND vs. RIC conditioning regimen (RR 3.4, 95% CI 1.7-6.9, P = 0.001); age > or =45 vs <45 yr (RR 2.5, 95% CI 1.4-4.5, P = 0.002) and diagnosis [other than chronic myeloid leukemia (CML) vs. CML] (RR 2.6, 95% CI 1.2-5.7 P = 0.02). CONCLUSIONS: Our results indicate that the introduction of RIC allogeneic HSCT for patients at high risk for TRM (advanced age, prior HSCT and non-T-cell depletion) leads to a reduction in the TRM and improvement in the OS.     

单倍体移植治疗白血病疗效观察

目的探讨单倍体移植治疗白血病的疗效。方法在单倍体移植时采用阿糖胞苷（Ara-c）、马利兰（Bu）、环磷酰胺（CTX）、甲基环己亚硝脲（Me-CCNU）联合作为预处理方案,用CTX、重组人粒细胞集落刺激因子（rhG-CSF）、环孢素A（CSA）、麦考酚酸酯（MMF）、抗胸腺细胞球蛋白（ATG）、白细胞介素11（IL-11）及甲氨蝶呤（MTX）联合预防急性移植物抗宿主病（aGVHD）,治疗7例白血病;结果 7例患者完全植入,白细胞〉1.0×109/L中位时间为16.9 d,Ⅲ~Ⅳ度aGVHD发生率为14.3%,中位随访时间25.6个月,无复发,至今仍存活。结论单倍体移植治疗白血病时,用Ara-c、Bu、CTX、Me-CCNU联合作为预处理方案,用CTX、rhG-CSF、CSA、MMF、ATG、IL-11及MTX联合预防aGVHD是安全、有效的。     

Hematopoietic stem cell transplantation for acute myeloid leukemia: A review

Increasing numbers of patients are receiving allogeneic hematopoietic cell transplantation (HCT) for acute myeloid leukemia (AML). Scientific and clinical advances in supportive care, donor selection, and conditioning regimens have resulted in lower transplant-related mortality, extension of care to a wider population of patients, and improvements in survival. Recent era has witnessed an explosive information about the molecular pathophysiology of AML. By early identification of patients at a high risk of relapse, it is expected that a majority of eligible patients will receive HCT in first complete remission. Novel conditioning regimens have been explored to improve transplant outcomes in AML. Currently, a stem cell source can be found for virtually all patients who have an indication to receive HCT. This area of investigation will likely continue to be of intense interest in terms of optimizing transplant outcomes.     

造血干细胞移植治疗炎症性肠病进展

炎症性肠病(IBD)是胃肠道慢性炎性肉芽肿性疾病,其发病与环境、遗传因素相关,传统治疗包括抗炎和抑制免疫等治疗.新近的研究提示造血干细胞移植(HSCT)治疗IBD有效,此文就HSCT治疗IBD的研究现状和存在的问题进行概述.     

Haematopoietic stem cell transplantation for severe sickle cell disease in childhood: a single centre experience of 50 patients

Despite improvements in medical management, sickle cell disease (SCD) remains associated with severe morbidity and decreased survival. Allogeneic haematopoietic stem cell transplantation (HSCT) remains the only curative approach. We report the outcome of 50 consecutive children with severe SCD that received HSCT in our unit between November 1988 and April 2013. The stem cell source was bone marrow (n = 39), cord blood (n = 3), bone marrow and cord blood (n = 7) and peripheral blood stem cells (n = 1). All patients had ≥1 severe manifestation: 37 presented with recurrent vaso‐occlusive crises/acute chest syndrome, 27 cerebral vasculopathy and 1 nephropathy. The conditioning regimen consisted of busulfan + cyclophosphamide (BuCy) before November 1991 and BuCy + rabbit antithymocyte globulin after that date. Since 1995, all patients have been treated with hydroxycarbamide (HC) prior to transplantation for a median duration of 2·7 years. Median age at transplantation and median follow‐up was 8·3 and 7·7 years, respectively. Acute graft‐versus‐host disease (GVHD) and chronic GVHD were observed in 11 and 10 patients, respectively. An excellent outcome was achieved, with 8‐year overall survival and event‐free survival (EFS) rates of 94·1% and 85·6%, respectively. Since HC introduction, no graft failure occurred and EFS reached 97·4%. Prior treatment with HC may have contributed to successful engraftment.     

Infectious complications in chronic graft-versus-host disease: a retrospective study of 145 recipients of allogeneic hematopoietic stem cell transplantation with reduced- and conventional-intensity conditioning regimens

Abstract: To assess infectious complications associated with chronic graft-versus-host disease (cGVHD) after allogeneic hematopoietic stem cell transplantation (HSCT) with reduced- and conventional-intensity conditioning regimens (RIC, n =91; CIC, n =54, respectively), we retrospectively analyzed data from 145 consecutive patients with cGVHD after allogeneic HSCT from a human leukocyte antigen-matched related or unrelated donor. In the present retrospective analysis, 57% (83/145) of patients with cGVHD developed infections, with a mortality rate of 27% (22/83). The incidences of bacteremia ( n =28), central venous catheter-related infections ( n =11), bacterial pneumonia ( n =4), invasive aspergillosis ( n =7), and adenoviral hemorrhagic cystitis ( n =8) were significantly higher in patients with prednisolone dose ≥1 mg/kg at the time of diagnosis of cGVHD. The present results suggest that infections associated with cGVHD, especially after high-dose prednisolone, are predictive of poor outcome regardless of whether the patient received RIC or CIC.     

Successful reduced intensity allogeneic stem cell transplantation for systemic AL amyloidosis

No established treatments for systemic AL amyloidosis have been determined, and only four reports have described allogeneic stem cell transplantation for this disease. We report the case of a patient with orthostatic hypotension, diarrhea, nephrotic syndrome, and cardiac amyloidosis due to systemic AL amyloidosis. Reduced intensity allogeneic stem cell transplantation (RIST) was performed using a conditioning regimen comprising fludarabine 125 mg/m2 and melphalan 90 mg/m2. Hematologically complete remission and symptomatic improvement were obtained without severe transplantation-related complications. RIST may thus offer a useful treatment strategy for systemic AL amyloidosis complicated by cardiac amyloidosis.     

氟达拉滨替代环磷酰胺的移植预处理方案治疗儿童白血病的临床研究

目的探讨预处理含氟达拉滨单倍型造血干细胞移植（Allo-HSCT）的方案在治疗儿童急性白血病的疗效和安全性。方法 34例白血病患儿进行Allo-HSCT治疗,所有患儿预处理用氟达拉滨取代静脉环磷酰胺,移植后观察方案相关毒副作用、移植物抗宿主病（GVHD）发生和无病生存,并与以往完成的18例单倍型移植预处理含环磷酰胺的结果比较。结果 34例患儿均取得完全供者植入,能较好耐受此预处理方案,无肝静脉阻塞病和出血性膀胱炎发生,出血性膀胱炎发生与对照组比较减少（P〈0.05）。Ⅲ度以上急性GVHD 4例,巨细胞病毒感染发生情况与对照组比较无统计学差异。随访3～40个月,21例患儿仍无病存活（57.5%）。结论儿童白血病单倍型移植接受预处理含氟达拉滨Allo-HSCT方案可降低相关毒副作用,预处理用氟达拉滨取代静脉环磷酰胺安全可行。     

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造血干细胞移植(HSCT)是目前惟一能治愈先天性溶血性贫血(如重型地中海贫血和鐮状细胞贫血)的治疗方法。HLA相合同胞供者移植治疗儿童患者的总生存(OS)率超过90%,无事件生存(EFS)率超过80%。无关供者移植使更多无HLA相合同胞供者的患者获得移植机会。     

Hematopoietic stem cell transplantation for paroxysmal nocturnal hemoglobinuria: long-term results of a retrospective study on behalf of the Gruppo Italiano Trapianto Midollo Osseo (GITMO)

Background

Paroxysmal nocturnal hemoglobinuria is an acquired clonal disorder of the hemopoietic stem cells for which the only curative treatment is allogeneic hematopoietic stem cell transplantation.

Design and Methods

The aim of this retrospective study was to assess the long-term clinical and hematologic results in 26 paroxysmal nocturnal hemoglobinuria patients who received hematopoietic stem cell transplantation in Italy between 1988 and 2006. The patients were aged 22 to 60 years (median 32 years). Twenty-three donors were HLA-identical (22 siblings and one unrelated) and 3 were HLA-mismatched (2 related and one unrelated).

Results

Fifteen patients received a myeloablative conditioning consisting of busulfan and cyclophosphamide (in all cases from identical donor) and 11 were given a reduced intensity conditioning (8 from identical donor and 3 from mismatched donor). The cumulative incidence of graft failure was 8% (4% primary and 4% secondary graft failure). Transplant-related mortality for all patients was 42% (26% and 63% for patients transplanted following myeloablative or reduced intensity conditioning, respectively). As of October 31, 2009, 15 patients (11 in the myeloablative conditioning group and 4 in the reduced intensity conditioning group) are alive with complete hematologic recovery and no evidence of paroxysmal nocturnal hemoglobinuria following a median follow-up of 131 months (range 30–240). The 10-year Kaplan-Meier probability of disease-free survival was 57% for all patients: 65% for 23 patients transplanted from identical donor and 73% for 15 patients transplanted with myeloablative conditioning. No thromboembolic event nor recurrence of the disease were reported following transplant.

Conclusions

The findings of this study confirm that most patients with paroxysmal nocturnal hemoglobinuria may be definitively cured with hematopoietic stem cell transplantation.