The second therapeutic trial for children with hematological malignancies who relapsed after their first allogeneic SCT: Long-term outcomes

Nishikawa T, Inagaki J, Nagatoshi Y, Fukano R, Nakashima K, Ito N, Sawa D, Kawano Y, Okamura J. The second therapeutic trial for children with hematological malignancies who relapsed after their first allogeneic SCT: Long‐term outcomes. Abstract: The impact of a second all‐SCT on the long‐term outcomes of children who relapse after allo‐SCT has been unclear. We retrospectively analyzed the long‐term outcomes of different salvage treatments for such children. Sixty‐six children with hematological malignancies (40 ALL, 22 AML, three MDS, and one CML) who relapsed after a first allo‐SCT received either a second allo‐SCT (n = 16) or CTx and/or DLI (n = 50). The median follow‐up for all children was 9.1 yr. The five‐yr OS after relapse was significantly better in patients who underwent a second allo‐SCT (42.9%) than in patients treated with CTx and/or DLI (11.8%) (p < 0.05). However, this advantage diminished with increasing time. The eight‐yr OS for these groups of patients were 21.4% and 11.8%, respectively (p = n.s.). Among the 16 patients who received a second allo‐SCT, two died more than five yr after the second allo‐SCT. A second allo‐SCT can therefore lead to a prolonged OS in patients who relapse after allo‐SCT. However, a second allo‐SCT should be selected carefully. This is because the mortality rate is still high, even when there is an extensive duration of time following the second allo‐SCT.     

Stem cell transplantation in primary immunodeficiency disease patients

BACKGROUND: Primary immunodeficiency diseases (PID) are rare but have a high associated risk of death from overwhelming infection in early childhood. Stem cell transplantation (SCT) can be curative for PID, but standardized protocols for each disease have not yet been established. METHODS: Between May 1995 and May 2005, nine patients diagnosed with a PID received SCT at the Department of Pediatrics, Hokkaido University Hospital. The median age of the patients (eight boys and one girl) was 1.0 year (range: 6 months-4 years). Five patients had Wiskott-Aldrich syndrome (WAS), three had severe combined immunodeficiency (SCID), and one had X-linked hyper-IgM syndrome (X-HIGM). Four patients received bone marrow transplantation (BMT), and five received cord blood stem cell transplantation (CBSCT). All patients, including those with SCID, received a conditioning regimen: six (WAS and X-HIGM) received a myeloablative conditioning regimen, and three (SCID) received a reduced-intensity conditioning regimen. RESULTS: All the patients are alive and have stable, complete chimerism, based on a median follow-up period of 4 years. Moreover, all patients have good immune reconstitution, and none required immunoglobulin replacement therapy. Two patients had significant acute graft-versus-host disease (GVHD), and three patients had chronic GVHD. Four of the nine patients developed cytomegalovirus (CMV) infection after SCT. CONCLUSION: The transplantation procedures appear to have provided a permanent cure in nine PID patients. Early diagnosis and prompt performance of SCT with an optimal donor and conditioning regimen contributed to the favorable outcomes.     

Early post-transplant vaccination with pandemic influenza A/H1N1 vaccine in pediatric heart transplant recipients

Pandemic influenza A/H1N1 virus has the potential to cause severe disease in pediatric transplant patients. A pandemic vaccine against H1N1 is effective in immunocompetent children. We investigated the immunogenicity of this vaccine when given in the first six months after heart transplantation. Four patients younger than two yr received two doses of vaccine and one patient older than seven yr received one dose. Titers were obtained using the HAI at baseline and after final immunization. Five patients were enrolled, ages 0.5-7 yr. Median age at the time of transplant was five months (range 3 wk-7 yr). All patients received induction with anti-thymoglobulin and maintenance immunosuppression with tacrolimus, MMF, and prednisone. Patients were immunized with the adjuvanted H1N1 vaccine after heart transplant at median time of nine wk (range 5-23 wk) post-transplant. Three of five developed protective titers against H1N1. A proportion of pediatric patients may respond to influenza vaccine even when immunized in the early post-transplant period.     

Long-term follow-up in adult living donors for combined liver/bowel transplant in pediatric recipients: a single center experience

Pediatric candidates for combined liver/bowel transplant (LBTx) experience a very high mortality on the cadaver waiting list. Our transplant center has successfully used adult living donors to treat pediatric candidates for LBTx. We report the long-term follow-up of this unique cohort of organ donors. The charts of six adult donors for LBTx performed between 2004 and 2007 were reviewed. All the pertinent clinical data were carefully reviewed and integrated with phone interviews of all donors. A total of six children (average age 13.5 months) received living donor LBTx. Average follow-up for the donors was 42 months (range 29-51). The donors' median age was 25 yr (19-32); five women and one man. The average median hospital stay was nine days. There were no peri-operative complications. At present all donors remain in good health. Three of the five mothers became pregnant after donation. Five of the six children are currently alive and well whereas one died with functioning grafts six months post-transplant due to plasmoblastic lymphoma. Living donor LBTx is an effective therapy for combined hepatic and intestinal failure in children less than five yr. The donor operation can be performed with minimal morbidity.     

Successful renal transplantation in children with spina bifida: long term single center experience

We report long-term follow up data on cadaveric renal transplantation for end stage renal failure (ESRF) in spina bifida children. Between February 1989 and July 2001, 12 cadaveric renal transplants were performed in 10 children, eight females and two males. Mean age at transplantation was 13.4 yr (range 9-16). Of the patients, eight were wheelchair bound and two were independently mobile. Before transplantation surgical management of the urological tract included, enterocystoplasty and clean intermittent-self catheterization in five patients and ileal conduit urinary diversion in one. A total of eight patients were on renal replacement therapy before receiving the graft while two underwent preemptive transplantation. The 1- and 5-yr graft survival rates were 81 and 81%, respectively. Four grafts failed--two patients have successfully undergone subsequent transplantation. Causes of graft failure were chronic rejection in two, acute rejection and vascular thrombosis in one and vascular thrombosis in one patient, respectively. Two patients died after graft nephrectomy. At a median follow-up of 4.08 yr (range 1 day to 10.65 yr), eight of the 12 grafts are functioning with median serum creatinine of 123 mmol/L (range 65-169). These data demonstrate the feasibility of cadaveric renal transplantation in patients with spina bifida and ESRF. We currently recommend that patients with spina bifida should not be deprived of the benefits of renal transplantation.     

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.     

The use of partially HLA-mismatched donors for allogeneic transplantation in patients with mucopolysaccharidosis-I

Allogeneic bone marrow transplantation (BMT) from an HLA-matched sibling appears to improve survival and diminish some of the physiologic derangements seen in children with mucopolysaccharidosis (MPS)-I (Hurler Syndrome), an inherited metabolic storage disease resulting from the lack of alpha-L-iduronidase enzyme activity. Death is usually expected in the first decade of life. Unfortunately, most patients lack an HLA-matched sibling donor and alternative donors have been identified for transplant. This study reports on a five-year median follow-up (range: 985-2,355 days) in 11 Hurler Syndrome patients who underwent allogeneic BMT from partially mismatched related donors (PMRDs). The median age was 20 months (range: 11-44 months). The overall survival rate was 64% (95% CI 34-94%). The overall graft failure rate (36%) was higher than reported with matched sibling BMT. All patients with sustained engraftment experienced improvement in physical manifestations, such as corneal opacity, gum and tongue hypertrophy, hepatosplenomegaly and joint mobility. Skeletal abnormalities, such as dysostosis-multiplex, were stabilized but not reversed. Some patients have continued to show decline in neuropsychometric testing, while others appear to stabilize and one has demonstrated improvement. Until better methods for replacing enzyme activity are developed, BMT from a matched sibling of alternative donors can be considered a viable intervention for Hurler Syndrome patients to achieve partial improvement or stabilization from the deterioration caused by substrate storage, particularly in minimally affected patients early in life.     

Daclizumab therapy for children with corticosteroid-resistant acute graft-vs.-host disease

Abstract:  MAbs such as daclizumab have shown promising results in the treatment of corticosteroid-resistant aGVHD. Data describing the efficacy of MAbs in children are limited. We describe the efficacy of daclizumab in children with corticosteroid-resistant aGVHD. Seventeen children (0.4–16.2 yr) received daclizumab for aGVHD. Safety was evaluated in all 17. Response was evaluated in the 15 children who received a full course of daclizumab. A PR was defined as improvement of aGVHD symptoms in at least one organ without worsening in other organs. We observed an overall response rate (CR plus PR) of 40% (6/15). Four children had a CR and two had a PR. aGVHD involving the gut had the highest response rate (five of 10; 50%). Adverse effects attributed to daclizumab were limited to an episode of reactive arthritis. Mortality was high (47%; eight of 17) though five of the six responders to daclizumab survived. The mean length of follow-up in the surviving nine patients was 32 months (range seven to 48). We conclude that daclizumab is effective in the treatment of children with corticosteroid-resistant aGVHD, especially in patients with gut involvement.     

Combined liver and kidney transplantation and kidney after liver transplantation in children: Indication,postoperative outcome,and long‐term results

CLKT and sequential KALT are decided on a case‐by‐case basis in children for special indications such as ARPKD or PH1. We report on 21 children who underwent CLKT or KALT at our hospital between 1998 and 2013. Eleven children were diagnosed with PH1 and six with ARPKD. Other diagnosis were Joubert syndrome (n = 1), nephronophthisis (n = 1), CF (n = 1), and hepatocellular carcinoma (n = 1). Children (12 males, nine females) were aged 7.8 ± 6.2 yr (range, 10 months to 18 yr) at time of transplantation. Average wait time was 1.9 ± 0.9 yr (range, four months to 2.3 yr). Fifteen patients received dialysis prior to transplantation. In PH1 patients, four children received CLKT, five received KALT, and two infants have received only an LTx, whereas all six patients with ARPKD received CLKT. In patients with other indications, CLKT was performed in three cases and KALT in one girl. Cumulative 10‐yr survival of all 21 patients was 78.4%. At the time of transfer into adult care, 13 patients retained stable liver and kidney function. Regardless the underlying diagnosis, CLKT and KALT can be performed in children with good surgical outcomes and long‐term survival.     

Chemotherapy in the management of infantile fibrosarcoma

Infantile fibrosarcoma (IF) has traditionally been treated with surgery, which may have considerable morbidity. Chemotherapy has been suggested in order to reduce the need for extensive surgery. Nine children with histologically confirmed IF who received chemotherapy are described. Six children were treated with chemotherapy initially, two following conservative surgery, and one following recurrence after surgery. All received vincristine (V) and actinomycin D (A), and six received additional drugs including ifosfamide (I), cyclophosphamide (C), adriamycin (Ad), etoposide (E), and cis-platinum (CDDP). Objective responses were achieved in eight: three responded completely (CR), two responded partially (PR), which allowed conservative surgery, one had stable disease, one had an initial PR, but subsequently had tumour recurrence 1 month after cessation of treatment, necessitating further surgery and chemotherapy, and one had an initial PR but died following local and regional metastases. One child had no response to chemotherapy but is alive with stable residual disease. Thus, five of nine children achieved a CR—three with chemotherapy alone. With the inclusion of chemotherapy as part of their treatment, five children, for whom curative surgery may have resulted in amputation, remain alive with limbs intact. Chemotherapy including V and A should be given to infants with fibrosarcoma in whom curative surgery would be mutilating. © 1993 Wiley-Liss, Inc.     

Combined enzyme replacement and haematopoietic stem cell transplantation in Hurler syndrome

We report the long-term follow-up of successful treatment of mucopolysaccharidosis type I H (MPS IH, Hurler syndrome) with combined enzyme replacement therapy and haematopoietic progenitor stem cell transplant.     

High-dose chemotherapy and blood stem cell autografts for children with first relapsed acute lymphoblastic leukemia: A pilot study of the children's cancer and leukemia study group of Japan (CCLSG)

This study was performed to determine the value of high-dose chemotherapy and peripheral blood stem cell autografts (PBSCT) in the treatment of children with first relapsed acute lymphoblastic leukemia (ALL). Eighteen children underwent PBSCT during the second complete remission (CR) and had a minimum 10 month follow-up. The median age of the patients was 11 yr (range, 2–17 yr). Fifteen patients received the “MCVAC” regimen, one received high-dose MCNU + busulfan therapy, one received high-dose melphalan + VP-16, and one received melphalan + carboplatin + cytosine arabinoside + MCNU. None of these regimens included total body irradiation. Eight patients developed recurrence of the disease at 1 to 19 mo (median, 3 mo) after PBSCT. Patients in whom the first relapse occurred sooner, that is, within 16 mo of initial therapy, tended to have a better survival rate than those who developed relapse after 30 mo (six of seven survived versus four of 11; not significant). Although the preliminary data provided little conclusive information, it did suggest that incorporation of PBSCT in the salvage protocol of relapsed childhood ALL can be justified. © 1994 Wiley-Liss, Inc.     

Hematopoietic stem cell transplantation effects on spinal cord compression in Hurler

Hurler syndrome type 1 (MPS‐1) is an autosomal recessive lysosomal disorder due to the deficiency of the enzyme alpha‐L‐iduronidase which is necessary for the degradation of dermatan and heparan sulfate. It is characterized by deposit of glycosaminoglycans in tissues, progressive multisystem dysfunction, and early death. HSCT for children with MPS‐I is effective, resulting in increased life expectancy and improvement of clinical parameters. The spinal MRI performed on a female 10 yr old undergoing HSCT at the age of 18 months and receiving ERT revealed a considerable decrease in soft tissue around the tip of odontoid causing a significant reduction in spinal cord compression. In light of this result, we suppose that combined ERT and HSCT are successful in Hurler I disease.     

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.     

Related donor hematopoietic stem cell transplantation for Fanconi anemia without radiation: a single center experience in Turkey

Abstract:  Eight children with FA underwent allogeneic HSCT without using irradiation for the conditioning regimen. Patients received two different conditioning regimens: first two patients received BU 1.5 mg/kg/day for four days and CY 10 mg/kg/day for four days and the other regimen was: Flu 30 mg/m²/day for five days, CY 10 mg/kg/day for two days, and ATG-Fresenius 9–10 mg/kg/day for four days. GVHD prophylaxis consisted of CsA + MTX for the first two patients and only CsA for the others. All patients received HLA-identical stem cells from related donors. Primary engraftment was demonstrated in all patients. No patient developed acute GVHD and one patient had chronic GVHD. Only one patient who received BU based regimen died because of VOD. Overall, seven patients (87.5%) are alive with stable full donor chimerism at a median follow-up time of 2.5 yr (range: 1.7–8.9 yr). None of the patients developed secondary malignancy. Based on our data, we conclude that Flu-based, non-irradiation conditioning regimen was safe with low organ toxicity and stable engraftment in FA patients undergoing HSCT from matched related donors.     

High survival rates after liver transplantation for hepatoblastoma and hepatocellular carcinoma

Kosola S, Lauronen J, Sairanen H, Heikinheimo M, Jalanko H, Pakarinen M. High survival rates after liver transplantation for hepatoblastoma and hepatocellular carcinoma.
Pediatr Transplantation 2010: 14:646–650. © 2010 John Wiley & Sons A/S. Abstract: Unresectable malignant liver tumors may be treated by LTx. We evaluated the results of LTx for HB and HCC. All patients transplanted for HB or HCC between 1990 and 2007 were included. Effects of histologic tumor type, primary tumor resection, disease staging, and serum AFP levels at diagnosis and at transplantation on disease recurrence and survival were evaluated. Twelve patients with median age of five (range, 2–16) were transplanted and followed for a median of 11 (2–18) yr. Six patients had HB and six had HCC. At diagnosis, eight patients were staged as PRETEXT III and four patients as PRETEXT IV. Two patients had pulmonary metastases. All patients received neoadjuvant chemotherapy. Median time from diagnosis to LTx was seven (2–133) months. At LTx, none of the patients had radiological evidence of extrahepatic disease, and the median AFP level was 85 (6–15 180) μg/L. No routine chemotherapy after LTx was used.The overall one‐, five‐, and 10‐yr cumulative survival rates were 100%, 80%, and 67%, respectively. Survival was comparable between the two tumor types (4/6 for both). Two deaths occurred secondary to tumor recurrence, one of each tumor type. Both of these patients had an AFP response of <99%. Six of eight patients with primary LTx survived, when compared to two of four transplanted after primary resection. PRETEXT tumor staging had no effect on survival. LTx even without post‐transplantation chemotherapy is an effective treatment option for unresectable HB and HCC with comparable survival. Incomplete AFP response to chemotherapy and primary tumor resection were associated with decreased survival.     

Mucopolysaccharidosis type III (Sanfilippo disease) in Sweden: clinical presentation of 22 children diagnosed during a 30‐year period

Aim: The aim of this study was to present the natural clinical course in children and adolescents with MPS III diagnosed during a 30‐year period in Sweden. Methods: The patients were identified from metabolic laboratory records between 1975 and 2004. Patient data were assessed from interviews of parents and by clinical examination and records from the patients. Results: A total of 15 children, 68%, with MPS IIIA were diagnosed at a median age of 6.8 years (range 1.2–18.9 years). One boy had MPS IIIB and five children MPS IIIC, diagnosed at ages between 1.9 and 11.6 years. In one child the type was not determined. The median age of children with type IIIA who had deceased was 16.2 years (range 10.4–31.2 years). Ten individuals with MPS III are alive at ages between 5 and 29 years. In four families, two children were affected. Conclusion: In 22 Swedish children with Sanfilippo disease an early normal development followed by a delay in speech and an appearance of behaviour problems was found in most children during the early preschool period. Mental retardation was diagnosed in almost all individuals before starting school. Early diagnosis is important in this devastating, progressive disorder, not only for genetic counselling but also for participation in future treatments.     

Conversion from calcineurin inhibitor to sirolimus in pediatric chronic allograft nephropathy

CAN is a major cause for allograft loss in renal transplantation. Sirolimus was recently introduced as a potent non-nephrotoxic alternative to CNIs. In the present study, effects of a conversion protocol were investigated in pediatric CAN with declining GFR, defined by a Schwartz formula clearance below 60 mL/1.73 m2/min, steadily increasing SCr and allograft biopsy. In eight children with a median age of 12.8 yr, sirolimus was started at median 32 months after transplantation with a loading dose of 0.24 mg/kgBW, followed by 0.2 mg/kgBW/day, aimed at trough levels of 15-20 ng/mL. CNIs were reduced to 50% at start of sirolimus and discontinued at median seven days when target levels of sirolimus were reached. Following conversion, changes of GFR significantly stabilized (-2.9 vs. +0.4 mL/min/1.73 m2/month, p = 0.025). Individual GFR increased in five of eight patients (p = 0.026), only one child exhibited unaltered progression of graft failure. In the responders, mean SCr improved by 0.3 mg/dL (p = 0.043). Effects were not dependent on GFR at conversion, nor time post-transplantation. Blood pressure, hematological parameters and proteinuria remained stable during the observation period, serum lipids transiently increased. About half of the children suffered from infectious complications. No child had to be taken off sirolimus; there was no graft loss during the observation period. In conclusion, conversion from CNIs to sirolimus is an effective protocol with tolerable side effects to stabilize renal graft function for at least one yr in the majority of children with biopsy proven CAN.     

Mid-term follow-up after multiple system organ failure following cardiac surgery in children

Multiple system organ failure after cardiac surgery in children is a severe complication with unknown mid- and long-term sequelae. We therefore evaluated 11 children (aged 20-126 mo, median: 67 mo) having survived multiple system organ failure after cardiac operations for congenital cardiac defects in a cross-sectional follow-up study 12-76 mo (median: 32 mo) after surgery. Clinical and laboratory examinations included cardiac, pulmonary, renal, hepatic, neurological and psychological function tests. All patients had adequate cardiac function. Lung mechanics were abnormal in three children and glomerular renal function was abnormal in two patients. Slight elevation of gamma-glutamyl transpeptidase and coagulation factor deficiency was present in six and seven patients, respectively (five of whom had undergone the Fontan operation). Severe neurological sequelae such as diplegia (n = 1) and mental retardation (n = 1) were observed in two patients. In addition, five children presented delayed motor, graphomotor and/or speech development. Two children were found to have abnormal intelligence. We conclude that with the exception of neurological impairment, mid-term sequelae of multiple system organ failure after cardiac surgery in children are mild. However, longer follow-up using an appropriate control group is mandatory.     

Outcome in six children with mucopolysaccharidosis type IH, Hurler syndrome, after haematopoietic stem cell transplantation (HSCT)

AIM: To follow-up six children with severe mucopolysaccharidosis type IH, Hurler syndrome, who were treated before 24 months of age with haematopoietic stem cell transplantation. METHODS: In Sweden, during the last 10-year period, six consecutive children born with severe mucopolysaccharidoses type IH have been successfully transplanted using matched unrelated donors between the ages of 11 and 24 months (mean age 18 months). Three children received intravenous enzyme replacement therapy once a week, from diagnosis until engraftment of their bone marrow. RESULT: Two children developed chimerism and a progressive increase in recipient cells and later received a successful re-transplantation. One to two years after transplantation the children demonstrated some developmental delays in cognitive function. Latterly this was followed by normalization. Orthopaedic operations on the spine and hips and carpal tunnel syndrome were still required following transplantation. Cardiac valve involvement remained progressive in the children. CONCLUSION: The outcome of six children in this study confirms that early haematopoietic stem cell transplantation in mucopolysaccharidosis type I, Hurler syndrome, preserves an affected child's mental ability. Consequently, it is essential that clinical recognition and early diagnosis take place, providing an additional challenge to paediatricians treating this condition.