Hematopoietic stem cell transplantation for Diamond-Blackfan anemia: a report from the Aplastic Anemia Committee of the Japanese Society of Pediatric Hematology

Transfusion-dependent Diamond-Blackfan anemia (DBA) patients opt for allogeneic hematopoietic stem cell transplantation (HSCT) as curative therapy. Clinical outcomes of 19 transplanted Japanese patients were analyzed. Prior to HSCT, 10 patients (53%) suffered hemosiderosis with organ dysfunction, and all eight with short stature (42%) had adverse effects of prednisolone. Median age at the time of HSCT was 56 months. Transplantation sources were 13 bone marrow [six human leukocyte antigen (HLA)-matched siblings, and six HLA-matched and one HLA-mismatched unrelated donors], five cord blood (two HLA-matched siblings and three HLA-mismatched unrelated donors), and one peripheral blood from haploidentical mother. All 13 patients with bone marrow transplantation (BMT) and two with sibling cord blood transplantation (CBT) had successful engraftment. Of three patients who underwent unrelated CBT, one died after engraftment, and the other two had graft failure but succeeded in a second BMT from an HLA-disparate father and unrelated donor, respectively. One died shortly after haploidentical PBSCT. The five-yr failure-free survival rate after BMT was higher than CBT (100%: 40%, p=0.002). Platelet recovery was slower in seven unrelated BMT than in six sibling BMT (p=0.030). No other factors were associated with engraftment and survival. These results suggest that allogeneic BMT, but not unrelated CBT, is an effective HSCT for refractory DBA.     

Multiple extramedullary relapses without bone marrow involvement after second allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia

EMR without BM involvement after allogeneic HSCT is extremely rare, especially in children; only a few cases have been reported. A two-yr-old boy was diagnosed with AML (M4) and underwent allogeneic HSCT in first complete remission with BM from HLA-matched unrelated donor without GVHD. Four yr later, he had a BM relapse and after induction and consolidation chemotherapy, he received a second HSCT from an unrelated donor using peripheral blood stem cells. His second post-transplant course was complicated by extensive chronic GVHD involving the skin, oral cavity, and lungs, which was treated with tacrolimus and corticosteroid. Two yr later, he noticed a mild swelling in the right cheek area. The BM showed a complete remission marrow and a soft tissue biopsy was compatible with granulocytic sarcoma. PET-CT showed multifocal bone involvements. He received chemotherapy, and the chloromas decreased in size. We report a case of diffuse EMR of AML without BM involvement after a second allogeneic HSCT.     

Sirolimus‐associated pericardial effusion with cardiac tamponade and interstitial pneumonitis in a hematopoietic stem cell transplant recipient

Sirolimus, a mammalian target of rapamycin (mTOR) inhibitor, is a potent immunosuppressant that is increasingly used in prevention and treatment of graft‐vs‐host disease (GVHD) in allogeneic hematopoietic stem cell transplant (HSCT) patients. However, data regarding its adverse effects in HSCT patients remain limited. We describe an 18‐year‐old HSCT patient with a history of invasive fungal infection, who developed pericardial effusion with cardiac tamponade and interstitial pneumonitis while receiving sirolimus for GVHD prophylaxis. Our case illustrates potentially life‐threatening complications of sirolimus use in allogeneic HSCT patients.     

Successful hematopoietic stem cell transplantation from an HLA‐mismatched parent for engraftment failure after unrelated cord blood transplantation in patients with juvenile myelomonocytic leukemia: Report of two cases

JMML is an aggressive hematopoietic malignancy of early childhood, and allogeneic HSCT is the only curative treatment for this disease. Umbilical cord blood is one of donor sources for HSCT in JMML patients who do not have an HLA‐compatible relative, but engraftment failure remains a major problem. Here, we report two cases of JMML who were successfully rescued by HSCT from an HLA‐mismatched parent after development of primary engraftment failure following unrelated CBT. Both patients had severe splenomegaly and underwent unrelated CBT from an HLA‐mismatched donor. Immediately after diagnosis of engraftment failure, both patients underwent HSCT from their parent. For the second HSCT, we used RIC regimens consisting of FLU, CY, and a low dose of rabbit ATG with or without TBI and additionally administered ETP considering their persistent severe splenomegaly. Both patients achieved engraftment without severe treatment‐related adverse effects. After engraftment of second HSCT, their splenomegaly was rapidly regressed, and both patients showed no sign of relapse for over 4 years. These observations demonstrate that HSCT from an HLA‐mismatched parent could be a feasible salvage treatment for primary engraftment failure in JMML patients.     

Successful induction of therapeutic urinary concentration by intravenous ganciclovir and oral valganciclovir with remission of adenoviral hemorrhagic cystitis after cord blood transplantation

AdV11‐HC is one of the major complications after allogeneic HSCT in Japan. We previously reported that the intravenous infusion of ganciclovir was effective against AdV11‐HC in a post‐transplant patient. We here report a case of a 10‐year‐old boy who underwent cord blood transplantation for the treatment of relapsed lymphoblastic lymphoma. He developed AdV11‐HC with an elevated AdV load in his urine and blood on day 14 after HSCT. He was immediately treated with intravenous ganciclovir; he rapidly achieved a remission of AdV11‐HC with a decreased AdV load in his urine and blood. He remained in remission of AdV11‐HC, even after we switched ganciclovir to oral valganciclovir on day 63. A pharmacokinetics study of his urine revealed that therapeutic concentrations of ganciclovir could be achieved by both intravenous ganciclovir and oral valganciclovir. These findings suggested that both intravenous ganciclovir and oral valganciclovir could be promising alternatives for the treatment of AdV11‐HC in post‐transplant patients.     

Favorable outcomes after allogeneic hematopoietic stem cell transplantation in children with high-risk or advanced acute myeloid leukemia

The role of allogeneic hematopoietic stem cell transplantation (HSCT), including transplantation from an alternative donor (AD), has not been clearly defined for children with high-risk or advanced acute myeloid leukemia (AML). We retrospectively reviewed outcomes in 29 children (median age at HSCT, 6.7 y; range, 1.0-16.2 y) with high-risk or advanced AML who underwent allogeneic HSCT at the Asan Medical Center between 1998 and 2008. Donors included a matched sibling donor (MSD) for 7 patients (24%), an unrelated volunteer for 21 patients (72%), and a haploidentical mother for 1 patient (3%). The 3-year estimates of overall survival and event-free survival (EFS) were 77% [95% confidence interval (CI), 65%-99%] and 70% (95% CI, 57%-93%), respectively, whereas the cumulative incidences of relapse and transplant-related mortality were 33% (95% CI, 5%-58%) and 7% (95% CI, 0%-44%), respectively. The 3-year EFS rates did not differ between MSD and AD HSCT. Univariate analysis showed that age ≥ 10 years at diagnosis was the only factor associated with poorer EFS. Development of acute graft-versus-host disease predicted a significantly lower incidence of relapse. These findings may provide further evidence that allogeneic HSCT is a curative therapy for children with high-risk or advanced AML, and suggest the efficacy of AD transplantation.     

Correction of chronic granulomatous disease after second unrelated-donor umbilical cord blood transplantation

Allogeneic hematopoietic stem cell transplantation (HSCT) is curative for chronic granulomatous disease (CGD), but many patients lack a suitably matched related donor. We report successful outcomes after mismatched, unrelated-donor umbilical cord blood transplantation (uUCBT) in two boys with X-linked CGD. Both patients experienced autologous recovery after first transplants, required second transplants to achieve durable donor engraftment, and are alive 27 and 15 months post-transplant. Both had invasive fungal disease and received granulocyte transfusions. In conclusion, uUCBT is effective in children with CGD, but immunosuppression in the conditioning regimen may need to be increased to decrease the risk of graft rejection.     

Rapid full engraftment and successful immune reconstitution after allogeneic hematopoietic stem cell transplantation with reduced intensity conditioning in Omenn syndrome

Abstract:  OS is a variant of SCID characterized by generalized erythroderma, alopecia, eosinophilia, and elevated IgE levels. It is fatal unless treated with allogeneic HSCT, which is the only curative approach. However, treatment related complications and graft rejection are major obstacles to the success of treatment. In this report, we describe a patient with OS, complicated by prolonged cytomegalovirus infection, successfully treated by reduced intensity conditioning allogeneic HSCT from sibling donor.     

Human herpesvirus 7 in pediatric hematopoietic stem cell transplantation

BACKGROUND: Little is known about the significance of human herpesvirus 7 (HHV-7) in pediatric hematopoietic stem cell transplantation (HSCT). OBJECTIVE: To evaluate children post autologous and allogeneic HSCT, with a positive PCR or immunohistochemistry for HHV-7 either from blood, cerebrospinal fluid (CSF) or any other pathology specimen. Clinical data for these patients were collected examining symptoms and signs, engraftment, acute infectious complications, graft versus host disease (GVHD) where applicable, and survival. RESULTS: Between June 1999 and June 2003, 265 HSCT were performed in The Hospital for Sick Children, Toronto, allogeneic (n = 163) and autologous (n = 102). Nine children were positive for HHV-7 at a median of 21 days (range 16-27 days) post-HSCT. All had allogeneic transplantation. The most common underlying diagnosis was acute leukemia and 7 had matched unrelated donor (MUD) transplantation. Eight of the nine patients had grade II-IV acute GVHD and all of them had multiple infectious episodes with fungal, bacterial and other viral pathogens. Although not fully attributed to HHV-7, the clinical syndrome varied from fever, vomiting and diarrhea to septic shock. Four patients died due to GVHD and sepsis. CONCLUSION: HHV-7 was uncommon post-HSCT. It was associated with severe GVHD and sepsis secondary to severe immunosuppression.     

High human herpesvirus 6 viral load in pediatric allogeneic hematopoietic stem cell transplant patients is associated with detection in end organs and high mortality

Human Herpes Virus 6 (HHV‐6) reactivation occurs in approximately half of patients following allogeneic hematopoietic stem cell transplant (HSCT). While encephalitis and delayed engraftment are well‐documented complications of HHV‐6 following HSCT, the extent to which HHV‐6 viremia causes disease in children is controversial. We performed a retrospective review of HHV‐6 reactivation and possible manifestations in pediatric allogeneic HSCT patients at a single institution. Of 89 children and young adults who underwent allogeneic HSCT over a three‐and‐a‐half‐year period, 34 patients reactivated HHV‐6 early post‐transplant. Unrelated donor stem cell source and lack of antiviral prophylaxis were risk factors for the development of HHV‐6 viremia. Viremia correlated with the presence of acute graft‐versus‐host disease, but not chronic graft‐versus‐host disease. We identified two subgroups within the viremic patients—a high‐risk viremic and tissue‐positive group that reactivated HHV‐6 and had suspected end‐organ disease and a low‐risk viremic but asymptomatic group that reactivated HHV‐6 but did not exhibit symptoms or signs of end‐organ disease. Peak viral load was found to be strongly associated with mortality. Prospective studies in larger numbers of patients are needed to further investigate the role of HHV‐6 in causing symptomatic end‐organ disease as well as the association of viral load with mortality.     

HLA,GVHD, and parenteral nutrition are risk factors for hepatic complications in pediatric HSCT

Hepatic dysfunction is common after allogeneic hematopoietic stem cell transplantation (HSCT). The aim of this retrospective study was to determine the risk factors, frequency, and outcome of hepatic complications post‐HSCT in children. Two hundred and thirty‐seven cases of allogeneic HSCT in children were included. Data on biochemical liver function at start of HSCT, at +1, +3, +6, and +9 months, and at each subsequent yearly follow‐up were extracted. Patients were stratified into groups with hepatocellular (none and mild, and moderate to severe) and hepatobiliary (none and present) dysfunction. Statistical analysis included variables such as diagnosis, age, conditioning regimen, and HLA type. Results: One hundred and fifty‐six (66%) patients displayed hepatocellular dysfunction post‐HSCT. In most cases transient, but 32% had a persistent abnormality three yr post‐HSCT. Risk factors were chronic GVHD (OR 4.20, p = 0.003) and donor HLA‐A*01 (OR 2.97, p = 0.02). HLA‐DQB1*03 decreased the risk (OR 0.35, p = 0.02). Hepatobiliary dysfunction was less frequent (12%) but carried a poor prognosis. aGVHD grade II–IV (OR 2.7, p = 0.02) and long‐term TPN (OR 3.25, p = 0.01) increased the risk. Conclusion: GVHD is an important risk factor for liver dysfunction post‐HSCT. Specific HLA types may also contribute as a risk factor, while others seem to have a protective effect.     

造血干细胞移植后早期感染29例临床分析

目的了解儿童脐血及外周血造血干细胞移植早期感染发生的情况及其影响因素.方法采用回顾性的临床统计,分析了造血干细胞移植早期感染的29例病例的临床资料.结果 31例造血干细胞移植患儿移植后早期感染的发生率为94%(29例).首次发生移植早期感染的时间为0～+22 d(移植后为"+"),中位时间+6.2 d,高峰时间为+4～+7 d;感染持续时间为3～20 d,中位时间8.9 d.二次感染的8例感染发生的时间为+13～+27 d,中位时间+18.8 d.所有29例患儿首次感染均发生在中性粒细胞绝对计数>0.5×109/L之前,移植后的WBC数量的恢复情况与移植后早期感染的发生和持续时间密切相关.移植早期感染最常见为口腔炎、胃肠炎等消化道粘膜炎,其次为呼吸道感染;本组病例血培养以G革兰阴性杆菌阳性率最高.移植早期预防性使用泰能较对照[(+4.7±2.1) d]可推迟首次感染发生的时间[(+8.6±5.1 )d].结论移植后早期感染发生的高峰时间为+4～+7 d,感染持续时间为3～20 d,中位时间8.9 d;主要为消化道粘膜炎及呼吸道感染;血培养阳性细菌以革兰阴性杆菌为主.移植前预防性使用亚胺培南+西司他丁(商品名泰能)可以推迟移植后早期感染的发生时间,对移植早期感染的预防有一定的效果.     

Retrospective analysis of children with high‐risk acute myeloid leukemia who underwent allogeneic hematopoietic stem cell transplantation following complete remission with initial induction chemotherapy in the AML‐05 clinical trial

In the AML‐05 clinical trial conducted by the Japanese Pediatric Leukemia/Lymphoma Group from 2006 to 2010, children with high‐risk acute myeloid leukemia (HR AML) received allogeneic hematopoietic stem cell transplantation (allo‐HSCT) at first complete remission (CR1). The aim of this study was to investigate the impact of allo‐HSCT on the outcome of HR AML. Patients with either monosomy 7, 5q?, t(16;21), Ph1, FLT3‐ITD, or induction failure after the first course of chemotherapy were eligible for transplant. Of 53 children with HR AML, 51 received allo‐HSCT—45 in CR1, five in CR2, and one with non‐CR. t(8;21), t(9;11), and t(16;21) abnormalities were identified in eight, five, and four patients, respectively. The stem cell sources varied—bone marrow in 30 patients, peripheral blood in three, and cord blood in 18. The median follow‐up was 62 months. The overall survival (OS) rates at 3 years were 73% and 25% for patients who received transplant at CR1 and ≥CR2, respectively. Multivariable analysis showed that patients with chronic graft‐versus‐host disease (cGVHD) had better OS. This study supports that allo‐HSCT is a suitable treatment for HR AML in CR1. The favorable outcome associated with cGVHD indicates that a graft‐versus‐leukemia effect might be occurring.     

Allogeneic hematopoietic stem cell transplantation for infants with idiopathic myelofibrosis

IMF is a rare disease in children that can present during infancy and has a protracted course. The only known curative approach for this disease in adult patients is allogeneic HSCT. There are very few reports describing the long‐term outcome of young children following stem cell transplantation for IMF. We report on eight patients less than two yr of age with IMF that did not resolve with supportive care measures. All patients underwent myeloablative conditioning regimen with busulfan and cyclophosphamide ± ATG followed by HSCT from matched related (n = 6) or unrelated donor (n = 2). All patients achieved neutrophil and platelet engraftment. Four patients had grade II‐III acute GVHD, and chronic GVHD developed in five patients (three mild and two severe). At a median follow‐up of eight and a half yr (0.7–9), all patients are alive with complete resolution of their hematologic manifestations. At the last follow‐up, all patients had normal endocrine function except for one patient who developed hypothyroidism. To date, this is the largest cohort of young children with IMF treated successfully with HSCT, with the longest duration of follow‐up. In conclusion, our study showed that HSCT is a curative option for infants with IMF.     

脐带血异基因造血干细胞移植后噬血细胞性淋巴组织细胞增生症1例临床分析

目的探讨异基因造血干细胞移植后噬血细胞性淋巴组织细胞增生症(HLH)的临床特征、诊断及治疗。方法回顾性分析1例急性髓系白血病非血缘相关脐带血造血干细胞移植(AML-URD-UCBT)患儿术后并发HLH的临床特点并复习相关文献。结果患儿移植术后第6天(+6 d,下同)出现皮肤、肝脏、肠道急性移植物抗宿主病(aGVHD),先后给予糖皮质激素、环孢素A(CsA)、赛尼哌、霉酚酸酯(MMF)、他克莫司(FK506)等免疫抑制治疗后,aGVHD症状好转,但+26 d后出现活动性巨细胞病毒(CMV)感染合并HLH,给予静脉注射用丙种球蛋白、无环鸟苷、更昔洛韦抗CMV治疗,输红细胞、血小板、血浆、纤维蛋白原等支持治疗,参照HLH-2004方案予依托泊苷、糖皮质激素及CsA治疗后,+61 d检测血CMV早期/晚期基质蛋白(CMV-PP65)转阴,+55、+63 d骨髓象未见噬血细胞,呈HLH完全缓解骨髓象,临床症状及血常规等实验室指标好转;+83 d检测血CMV-PP65及CMV脱氧核糖核酸(CMV-DNA)转阳,+86 d因严重肺部感染、肺出血、消化道出血及多器官功能衰竭而死亡。结论异基因造血干细胞移植后aGVHD及抗aGVHD的免疫抑制治疗,是引起移植后CMV感染相关HLH的危险因素;HLH-2004方案未考虑到异基因造血干细胞移植后HLH的特殊性,需进一步研究有针对性的治疗方案,以提高疗效。     

VPS 45‐associated primary infantile myelofibrosis – Successful treatment with hematopoietic stem cell transplantation

PMF of infancy is a recently described autosomal recessive disorder presenting with severe bone marrow failure, accelerated neutrophil apoptosis, and significant platelet dysfunction, caused by a mutation in the VPS45 gene. In this study, we update our group of patients with PMF, highlighting different aspects of this disease, and evaluating the effectiveness of HSCT for the treatment of this disorder. Update of clinical data, hematological features, molecular studies, treatment and final outcome of four children diagnosed with VPS 45‐associated PMF of infancy. The patients described had clinical and hematological findings consistent with MF. Molecular studies showed that all patients were homozygous for the Thr224Asn mutation in the VPS 45 gene. HSCT was carried out in three patients and was successful in two. VPS 45‐associated MF is a novel primary immune deficiency that can be successfully corrected by HSCT if applied early in the course of disease using appropriate conditioning. The diagnosis of VPS 45‐associated PMF should be considered in all children presenting with SCN with subsequent development of pancytopenia. Long‐term follow‐up of these patients is necessary to identify extra‐hematological manifestations of VPS45 deficiency.     

Successful allogeneic stem cell transplant for leukocyte adhesion deficiency using an adjusted busulfan-containing regimen

LAD is a rare and fatal congenital disorder in which there is a defect of the leukocyte adhesion molecule (CD18) on neutrophils. Severe LAD results in frequent and potentially fatal infections. Although allogeneic HSCT is the only curative treatment for severe LAD, strategies for HSCT remain to be established since a high engraftment failure rate and severe persistent infection are still seen. We report a four-month-old boy with LAD who was successfully treated with allogeneic HSCT from an HLA-complete matched sibling following a conditioning regimen of pharmacokinetically adjusted individual busulfan doses.     

Hematopoietic stem cell transplantation from unrelated donors in children with DOCK8 deficiency

DIDS is a unique form of combined immune deficiency characterized by an unusual susceptibility to cutaneous viral infections, severe allergies with eosinophilia and elevated immunoglobulin E titers, autoimmunity, and cancer. HSCT is considered the standard of care for this deadly disease. We have retrospectively analyzed the outcome of allogeneic HSCT from unrelated donors in patients with DIDS. Data from four patients, with five transplants, are presented. All patients received transplants from unrelated donors' BM, except for one patient who received a cord blood transplant. The conditioning regimens were based on myeloablative protocols for BM derived transplants; a NM regimen was pursued for the patient who received a cord blood transplant, which resulted in graft rejection. Although recurrent pneumonia and skin infections resolved immediately after transplantation, all patients subsequently developed human herpesvirus infection, including cutaneous herpetic lesions, cytomegalovirus reactivation, and zona zoster, which could be attributed to the use of ATG. Despite the presence of serious morbidities prior to transplantation, all patients recovered successfully. DIDS can be successfully treated with allogeneic HSCT from unrelated donors following a myeloablative conditioning regimen, with a reasonable safety profile.     

The second mini-transplant for unstable mixed chimerism within the first 100 days after hematopoietic stem cell transplant in severe thalassemia

Allogeneic HSCT is the only curative treatment for severe thalassemia disease. MC occurs in one-third of these patients within the first two months after HSCT; this is a major risk factor of graft rejection, especially when RHCs are more than 25%. There is still no consensus for the management of MC, especially in the early phase of HSCT. The DLI has also been described in the treatment of MC following HSCT for hemoglobinopathies, but its success is still not guaranteed. The second HSCT has been an approach used in an attempt to cure patients who reject their graft. Concern about toxicity of conditioning regimen, the second HSCT is usually delayed for at least a year after the first HSCT. We would like to demonstrate the successful use of the second mini-allogeneic HSCT in hemoglobin E/β-thalassemia with evidence of unstable MC in the first 100 days after allogeneic HSCT to prevent further graft loss after allogeneic HSCT.     

Expanding options to improve outcomes following hematopoietic stem cell transplantation

Allogeneic hematopoietic stem cell transplantation (HSCT) offers a curative option for children with a number of potentially lethal malignant and non-malignant conditions. Decisions regarding the appropriateness of HSCT for a given patient involve careful consideration of the risks associated with HSCT and the likelihood of cure. This is particularly important as the procedure is being used with increasing frequency for diagnoses such as high-risk sickle cell anemia where the disease is associated with shortened lifespan but death generally occurs in adulthood. Recent advances in supportive care such as improved anti-microbial agents, the use of reduced intensity conditioning regimens and high-resolution HLA typing that allows for better donor selection have all contributed to improved outcomes. However, the risk of treatment-related mortality remains approximately 5-10%, in part due to complications such as veno-occlusive disease (VOD) for which there has been less progress.