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.     

Infliximab for steroid refractory or dependent gastrointestinal acute graft‐versus‐host disease in children after allogeneic hematopoietic stem cell transplantation

Yang J, Cheuk DKL, Ha SY, Chiang AKS, Lee TL, Ho MHK, Chan GCF. Infliximab for steroid refractory or dependent gastrointestinal acute graft‐versus‐host disease in children after allogeneic hematopoietic stem cell transplantation. Abstract: aGVHD of the GI tract is common after allogeneic HSCT. Corticosteroids are the mainstay of treatment. Recent data suggest infliximab might be beneficial for steroid refractory aGVHD. We reviewed our experience in 10 pediatric patients who developed severe steroid refractory aGVHD (stage 3, n = 6; stage 4, n = 4), after an allogeneic matched unrelated HSCT for various hematological diseases (leukemia, n = 7; thalassemia, n = 3). The median age was 9.5 yr (range, 0.8–18.5 yr). All patients received 10 mg/kg infliximab weekly for 3–4 doses. Eight patients had CR and two had partial response. None of the patients developed therapy‐related adverse effects. All patients developed infections subsequently, which may or may not be related to infliximab. Five patients developed chronic GVHD (cGVHD) (four severe, one mild). Six patients died at 66–1451 days post‐transplant, from infection (n = 3), aGVHD (n = 1), lung cGVHD (n = 1), or idiopathic pneumonia (n = 1). Four patients were alive at 238–924 days post‐transplant, all of whom had an increase in BMI by six months post‐transplant. In conclusion, infliximab is well tolerated and appears effective in children with steroid refractory or dependent GI aGVHD. Infection is common and mortality remains high.     

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.     

Toxic epidermal necrolysis in a child 6 months post‐hematopoietic stem cell transplantation

TEN is a rare and critical disease mostly caused by drugs. It is mediated by activated CD8+ T cells that cause keratinocyte apoptosis with the assistance of cytokines/chemokines. We herein report a pediatric case of TEN after allogeneic HSCT with precursor B‐cell acute lymphoblastic leukemia (pre‐B‐ALL) in second complete remission. Although we did not evaluate the T‐cell subpopulation in blood or skin lesion of the patient, an imbalanced immune reconstitution after HSCT might additively contribute to the development of TEN.     

Multiple viral infections post‐hematopoietic stem cell transplantation are linked to the appearance of chronic GVHD among pediatric recipients of allogeneic grafts

Olkinuora HA, Taskinen MH, Saarinen‐Pihkala UM, Vettenranta KK. Multiple viral infections post‐hematopoietic stem cell transplantation are linked to the appearance of chronic GVHD among pediatric recipients of allogeneic grafts.
Pediatr Transplantation 2010:14:242–248. © 2009 John Wiley & Sons A/S. Abstract: Delayed immune reconstitution and the ensuing opportunistic infections among children following hematopoietic stem cell transplantation (HSCT) are associated with increased treatment‐related morbidity and mortality (TRM). We retrospectively evaluated the impact of viral infections on the posttransplant recovery of pediatric recipients of stem cell grafts as a reflection of their posttransplant immunoreconstitution in a single institution setting. The case histories of 124 children (during 1/1999‐9/2006) were reviewed for infectious episodes, and correlated with their respective clinical parameters. Patients with a high risk for CMV received prophylaxis, but failures in the prophylaxis were common (40%). 110/124 (89%) of these allogeneic patients had at least one viral reactivation/clinical infection posttransplant. In this group of pediatric patients chronic GVHD (P<0,001) and secondary graft failure were significantly (P=0,001) associated with early (during the first 100 days post HSCT), multiple (≥ 2) viral infections. Our data indicate that viruses are common pathogens among pediatric recipients of allogeneic stem cell grafts. In this group of patients multiple viral infections early on seem to reflect an even more severe degree of immunological derangement in the recipient and identify a group of patients with an increased risk of chronic GVHD and secondary graft failure.     

Home care during neutropenia after allogeneic hematopoietic stem cell transplantation in children and adolescents is safe and may be more advantageous than isolation in hospital

After ASCT, children are isolated in hospital to prevent neutropenic infections. Patients living within two‐h drive from the hospital were given the option of treatment at home after ASCT. Daily visits by an experienced nurse and phone calls from a physician from the unit were included in the protocol. We compared 29 children and adolescents treated at home with 58 matched hospital controls. The children spent a median time of 13 days at home (range 2–24 days) and 6 (0–35) days in hospital. The cumulative incidence of acute GVHD grades II–IV was 21% in the home‐care children and 39% in the controls (p = 0.1). Chronic GVHD and probability of relapse were similar in the two groups. TRM at five yr was 11% in the home‐care patients and 18% in the controls. Overall survival at three yr was 77% and 62%, respectively (p = 0.33). None of the patients died at home. Median costs were 38 748 euros in the home‐care patients and 49 282 euros in those treated in the hospital (p = 0.2). We conclude that it is safe for children and adolescents to be treated at home during the pancytopenic phase after ASCT.     

Pediatric hematopoietic stem cell transplantation in China: Data and trends during 1998–2012

The success of treating a wide variety of pediatric diseases with HSCT, hematologic malignancies in particular, has resulted in an increased number of long‐term survivors. This study is the first large‐scale, multicentre report that describes the evolution of pediatric HSCTs in China during the period of 1998–2012. Of all 1052 patients, 266 cases were treated with autologous HSCs and 786 used allogeneic HSCs. The disease indications for HSCTs mainly included leukemias, lymphoma, solid tumors, and non‐malignant disorders. The total number of HSCTs, especially unrelated donor transplants, appeared to be increasing year by year. For patients with neuroblastoma, the therapeutic efficacy seemed to be poor, with a five‐yr OS and DFS rate of 34.5 ± 14.3% and 20.7 ± 9.6%, respectively. In contrast, the survival of patients with SAA was prominently improved, and their five‐yr OS and DFS rates were 82.8 ± 4% and 80.7 ± 4.1%, respectively. Patients who received cord blood transplants had a lower incidence of acute GVHD than that of PB and/or BM transplants from unrelated donors. This report offers us a valuable resource for evaluating the changes in HSCTs in China over the past 14 yr.     

Liver transplantation in a child with liver failure due to chronic graft-versus-host disease after allogeneic hematopoietic stem cell transplantation from the same unrelated living donor

Englert C, Ganschow R. Liver transplantation in a child with liver failure due to chronic graft‐versus‐host disease after allogeneic hematopoietic stem cell transplantation from the same unrelated living donor. Abstract: We report a case of a six‐yr‐old boy who developed chronic GVHD of the liver, intestines, and skin following allogeneic hematopoietic SCT. The boy received an allogeneic hematopoietic stem cell transplant at the age of two yr because of early recurrence of ALL. Chimerism analysis showed complete chimerism. In the following year, he developed GVHD despite adequate immunosuppressive therapy. Liver biopsy showed liver GVHD resulting in liver cirrhosis by the age of five yr. LTx was performed with a left liver lobe from the unrelated donor from whom the stem cells had been taken. Immunosuppressive therapy consisted of low‐dose steroids and low‐dose cyclosporine. The postoperative course was uneventful. Graft function was excellent, and we performed protocol biopsies at seven days and three wk as well as three, six, and nine months after transplantation; none of these showed any signs of rejection or GVHD. Immunosuppressive therapy was discontinued nine months after LTx. Three yr after transplantation, the boy is in good condition with normal graft function. To our knowledge, this is the first report on LTx following allogeneic hematopoietic SCT from the same unrelated living donor.     

Acute graft‐versus‐host disease in pediatric allogeneic hematopoietic stem cell transplantation. Single‐center experience during 10 yr

a‐GvHD may complicate allogeneic HSCT. In this retrospective single‐center study, we evaluated incidence and risk factors of a‐GvHD in 197 consecutive allogeneic pediatric HSCTs applying Glucksberg and NIH a‐GvHD classifications. Among 179 eligible transplants, the cumulative incidence of grade 0–I a‐GvHD was 48% and grade II–IV was 52%. None of the considered variables significantly influenced the incidence of grade II–IV a‐GvHD. Malignancy and myeloablation were associated with an increased risk of classic a‐GvHD (p < 0.01). Seventy‐two percentage of children are alive, with a significant difference in OS and TRM between grade 0 and I vs. grade II and IV a‐GvHD; this observation was reproduced in the non‐malignant setting, while only a disparity in TRM was evidenced in children with malignancy. In our experience, the incidence of a‐GvHD was similar, regardless of donor type. Myeloablation and malignant disease represented the only risk factors for classic a‐GvHD. Our results highlight the need for a better prevention of this complication in the non‐malignant setting.     

Haploidentical hematopoietic stem cell transplantation for paediatric high‐risk T‐cell acute lymphoblastic leukaemia

Paediatric HR T‐cell ALL demonstrates dismal prognosis with chemotherapy, and poor outcomes could be improved with allo‐SCT. HID‐SCT is an almost immediately available choice; however, few studies have focused on the outcomes of HID‐SCT for paediatric HR T‐ALL. Forty‐eight consecutive HR T‐ALL children who underwent HID‐SCT were included. Survival outcomes and factors predictive of outcomes were retrospectively analysed. Of the 48 patients, 35 were in CR1, 10 in CR2, and three in relapse. The cumulative incidence of grade 3/4 aGVHD was 10.4% and that of extensive cGVHD was 28.4%. The CIR at three yr was 30.8% and that of NRM at three yr was 14.7%. At a median follow‐up of 20.0 (range 2.5–124.2) months, the three‐yr LFS was 54.4%. Children who received transplants during CR1 had a better LFS (65.7% vs. 26.0%, p = 0.008) and a lower relapse rate (19.8% vs. 56.7%, p = 0.014) compared to those during non‐CR1. HID‐SCT is feasible for HR T‐ALL children, and survival outcomes are better when performed in CR1 compared to non‐CR1. Prospective clinical trials would be needed to confirm that.     

Favorable preliminary results using TLI/ATG‐based immunomodulatory conditioning for matched unrelated donor allogeneic hematopoietic stem cell transplantation in pediatric severe aplastic anemia

Pillai A, Hartford C, Wang C, Pei D, Yang J, Srinivasan A, Triplett B, Dallas M, Leung W. Favorable preliminary results using TLI/ATG‐based immunomodulatory conditioning for matched unrelated donor allogeneic hematopoietic stem cell transplantation in pediatric severe aplastic anemia.
Pediatr Transplantation 2011: 15: 628–634. © 2011 John Wiley & Sons A/S. Abstract: To assess whether a tolerance‐induction regimen could be applied for unrelated (MUD) HCT in SAA, we retrospectively reviewed our HCT experience using unmanipulated 10/10 HLA‐matched bone marrow grafts from MSD vs. MUD donors. Conditioning was CTX 200 mg/kg (CTX) + rabbit ATG 10 mg/kg (ATG) for MSD (n = 9) and TLI (800 cGy) + CTX/ATG for MUD HCT (n = 5). Immunoprophylaxis was CSA and short‐course MTX. Median patient age was 14.7 yr, median time to HCT 1.5 yr, and median follow‐up 3 yr. Outcome measures included EFS, time to engraftment, and cumulative incidence of GVHD (CIN of GVHD) for MSD and MUD cohorts. EFS and stable engraftment rate were 100%. CIN of acute GVHD was: MSD, Grade I–II: 1 (11%), Grade III–IV: 0%; MUD, Grade I–II: 1 (20%), Grade III–IV: 1 (20%). CIN of chronic GVHD was: MSD, limited: 1 (11%), extensive: 0%; MUD, limited: 0%, extensive: 0%. All immunosuppressive‐compliant patients successfully weaned immunosuppression. Although in limited patients, our results suggest that immunomodulatory TLI added to backbone CTX/ATG conditioning is a promising option for MUD HCT in SAA patients, which we will examine in a prospective clinical trial.     

Haploidentical hematopoietic cell transplantation for disseminated Ewing sarcoma

We describe the case of a 13‐year‐old girl with multifocal disseminated Ewing sarcoma family of tumor (ESFT) who received a 5/8 human leukocyte antigen‐matched haploidentical hematopoietic cell transplantation to generate a graft‐versus‐tumor effect. The patient had grade 2 acute graft‐versus‐host disease (GVHD) of the skin and chronic GVHD nausea and abdominal pain that required prednisolone for 17 months, but has been free from ESFT for 3 years 10 months after therapy. The present case suggests a beneficial effect of haploidentical hematopoietic cell transplantation in disseminated ESFT.     

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??Allogeneic-hematopoietic stem cell transplantation??HSCT?? is the most important or even the only radical cure for some primary immunodeficiency diseases. The long-term survival is 90% or even higher with HLA matched sibling donor transplantation. In total??the overall survival for the patients with severe combined immunodeficiency disease??Wiskott-Aldrich sydrome and chronic granulomatous disease is 70%??80% and 90%??respectively. Proper conditioning regimen promotes the success of transplantation??while severe graft versus host disease and reactivation of cytomegalovirus in patients negetively affect the overall survival and life quality after transplantation. This review summerized the rencent advances in allogeneic-HSCT for primary immunodeficiency patients with respect to alternative donor transplantation??conditiong regimen consideration??prevention and treatment of graft versus host disease and reactivation of cytomegalovirus.