Haploidentical stem cell transplantation as a salvage therapy for cord blood engraftment failure in a patient with Fanconi anemia

A 7‐year‐old male with Fanconi Anemia who developed primary graft failure following one antigen‐mismatched unrelated cord blood transplantation and a nonradiation‐based conditioning, underwent a second hematopoietic stem cell transplantation (HSCT) from his 2‐loci mismatched haploidentical father, using a nonradiation‐based regimen, 79 days after the first HSCT. A sustained hematological engraftment was achieved at 9 days post‐second HSCT. At 15 months post‐second HSCT; the patient demonstrated normal blood counts, sustained donor chimerism, and no evidence of GVHD. Haploidentical HSCTs as primary or secondary sources of stem cells, with appropriate T‐cell depletion, may be a readily available option in the absence of HLA‐matched related or unrelated donors. Pediatr Blood Cancer. 2010;55:580–582. © 2010 Wiley‐Liss, Inc.     

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.     

儿童第二次非血缘供者造血干细胞移植2例

目的探索非血缘造血干细胞移植后复发病例进行第二次移植的可行性。方法患幼年型慢性粒单细胞性白血病(JMML)及重型β-地中海贫血的两例患儿接受非血缘供者造血干细胞移植后分别于移植后的10个月和1个月后原疾病复发,前者给予福达华加环磷酰胺预处理后输注原供者干细胞,降低预防移植物抗宿主病强度;后者给予含TBI预处理,移植另一非血缘供者外周血干细胞。结果两例患者第二次移植后均获得稳定植入,JMML患者并发急慢性移植物抗宿主病,完全缓解至+24月;地中海贫血患者已完全脱离输血状态至+23月。结论对于非血缘造血干细胞移植后复发的患儿,第二次非血缘供者造血干细胞移植是可行的。     

Non‐sibling hematopoietic stem cell transplantation using myeloablative conditioning regimen in children with Maroteaux‐Lamy syndrome: A brief report

Maroteaux‐Lamy syndrome is a rare inherited lysosomal storage disorder with a progressive course. HSCT is a curable option for treatment in these patients. The following report describes our experience in HSCT for three patients with Maroteaux‐Lamy syndrome using non‐sibling donors. All of the patients received the same myeloablative regimen consisting of intravenous busulfan, cyclophosphamide, and rabbit antithymocyte globulin. Patients underwent HSCT from haploidentical other‐related (n=1), full‐matched other‐related (n=1), and one‐locus‐mismatched unrelated donor. Stem cell sources included bone marrow (n=1), peripheral blood (n=1), and cord blood (n=1). Currently, two patients who received transplant from other‐related donors showed full engraftment and regression of the symptoms of the disease, while for the patient with unrelated cord blood donor, graft failure resulted in progression of the disease and death. The result of our study showed beneficial effects of HSCT even from heterozygote donor. Due to rarity of the disease, future multicenter studies are recommended to find the best treatment approaches based on the patients’ status.     

Unrelated cord blood transplantation for second hemopoietic stem cell transplantation

BACKGROUND: The Kanagawa Cord Blood Bank (KCBB) reports the treatment of 12 patients who received umbilical cord blood transplantation (CBT) from unrelated donors as their second hemopoietic stem cell transplantation (HSCT). METHODS: Provided by the KCBB, between February 1997 and September 2000, 12 patients had unrelated CBT as a second HSCT. Six patients were male and six female; nine patients were in malignant, and three were in non-malignant conditions. The median age of the patients was 7.9 years (range, 2.2-28.0), and the median bodyweight was 22.5 kg (12.0-55.0). The HLA-A and -B serological and DR genotypical disparities between the patients and CBT donors were as follows: one patient was a 0-mismatch, six were 1-mismatches, and five were 2-mismatches. RESULTS: The median time between first and second HSCT was 14.0 months (1.0-47.0). The overall survival rate was 25.0%, three years after CBT (Kaplan-Meier estimate). Mortality after CBT as a second HSCT accounted for nine cases, six from infection and three from treatment-related mortality other than infection. CONCLUSION: Cord blood transplantation offers the advantage of rapid availability, absence of donor risk, and possibly less HLA restriction. In these contexts, unrelated CBT should be considered as a source of HSCT for a second transplant.     

Allogeneic hemopoietic stem cell transplantation (HSCT) for Wiskott-Aldrich syndrome: a report of the Spanish Working Party for Blood and Marrow Transplantation in Children (GETMON)

Allogeneic stem cell transplantation is the only curative treatment for Wiskott-Aldrich syndrome. The authors retrospectively analyzed the outcome with this procedure in 13 patients with severe Wiskott-Aldrich syndrome transplanted in 5 Spanish centers from 1989 to 2006. A patient was transplanted twice from the same donor due to a late engraftment failure. Age at transplant ranged from 7 to 192 months (median 30 months). There were 10 matched donors (3 related and 7 unrelated), 2 mismatched unrelated, and 1 haploidentical. Conditioning regimen consisted of busulfan and cyclophosphamide (BuCy) in 11 cases and fludarabine and melfalan (1) or BuCy (1). ATG was added in transplants from non-genetically matched donors. GvHD prophylaxis consisted of cyclosporine and methotrexate in most patients plus T-cell depletion in the haploidentical HSCT. Nine of the 13 transplanted patients are alive with complete clinical, immunologic, and hematologic recovery 8-204 months (median 101 months) after HSCT. Eight surviving patients had been transplanted from matched donors (3 related and 5 unrelated) and 1 from a haploidentical donor. Four patients died, 2 transplanted from matched donors (1 from acute GvHD and organ failure, 1 from a lymphoproliferative disorder after a second transplant), and 2 transplanted from mismatched unrelated donors (1 from acute GvHD and organ failure, 1 from graft failure and infection). Allogeneic hemopoietic stem cell transplantation must be utilized in all patients with severe Wisckott-Aldrich syndrome, using the most suitable graft variant for each patient.     

Non‐total body irradiation myeloablative conditioning with intravenous busulfan and cyclophosphamide in hematopoietic stem cell transplantation for malignant infantile osteopetrosis

HSCT is the only curative treatment for MIOP. We prospectively investigated the outcome of HSCT using intravenous busulfan‐based conditioning regimen from 2008 to 2013. Nineteen patients (median age = 17 months) underwent transplantation from HLA‐matched related donors (n = 14), HLA‐haploidentical related donors (n = 2), partially matched cord blood donors (n = 2), and HLA‐matched unrelated donor (n = 1). Bone marrow (n = 9), peripheral blood (n = 8), and cord blood (n = 2) were used as stem cell sources. All but one patient demonstrated primary engraftment. Two patients experienced secondary graft failure. During the follow‐up period, three patients showed mixed chimerism (45%, 45%, and 70% of donor cells were engrafted in each one of these patients) but are disease free. Two‐yr OS and DFS were 84.2% and 73.7%, respectively. Improvement of visual acuity and partial reversal of mild conductive hearing loss occurred in two and four patients, respectively. The causes of death among three patients were infection, GvHD, and disease progression. In conclusion, due to major side effects of MIOP such as visual and hearing loss, early treatment using myeloablative conditioning without irradiation HSCT is suggested. The use of an HLA‐matched related donor seems to be highly successful in this regard. Also, according to results of our study, mixed chimerism may be sufficient to resolve symptoms of disease.     

PEDIATRIC ONCOLOGY AND THE INTERNET

Allogeneic stem cell transplantation is the only curative treatment for Wiskott-Aldrich syndrome. The authors retrospectively analyzed the outcome with this procedure in 13 patients with severe Wiskott-Aldrich syndrome transplanted in 5 Spanish centers from 1989 to 2006. A patient was transplanted twice from the same donor due to a late engraftment failure. Age at transplant ranged from 7 to 192 months (median 30 months). There were 10 matched donors (3 related and 7 unrelated), 2 mismatched unrelated, and 1 haploidentical. Conditioning regimen consisted of busulfan and cyclophosphamide (BuCy) in 11 cases and fludarabine and melfalan (1) or BuCy (1). ATG was added in transplants from non-genetically matched donors. GvHD prophylaxis consisted of cyclosporine and methotrexate in most patients plus T-cell depletion in the haploidentical HSCT. Nine of the 13 transplanted patients are alive with complete clinical, immunologic, and hematologic recovery 8–204 months (median 101 months) after HSCT. Eight surviving patients had been transplanted from matched donors (3 related and 5 unrelated) and 1 from a haploidentical donor. Four patients died, 2 transplanted from matched donors (1 from acute GvHD and organ failure, 1 from a lymphoproliferative disorder after a second transplant), and 2 transplanted from mismatched unrelated donors (1 from acute GvHD and organ failure, 1 from graft failure and infection). Allogeneic hemopoietic stem cell transplantation must be utilized in all patients with severe Wisckott-Aldrich syndrome, using the most suitable graft variant for each patient.     

Unrelated donor cord blood transplantation for childhood severe aplastic anemia after a modified conditioning

Treatment of severe aplastic anemia (SAA) patients who lack human leukocyte antigen (HLA)-matched donors and failed immunosuppressive therapy (IST) is challenging. Recently, umbilical cord blood transplantation (CBT) after non-myeloablative therapy has been reported in adult but not in childhood SAA. However, most cases resulted in mixed donor chimerism and incomplete hematological recovery. We reported an 11-yr-old girl with recurred SAA 5 yr after IST who underwent unrelated donor CBT after a modified regimen. This patient had renal and cardiac dysfunction, and lacked suitable bone marrow donors. The 3.9 x 10(7)/kg CB cells from an HLA one-locus mismatched unrelated donor were infused after conditioning with total body irradiation (5 Gy), melphalan (120 mg/m(2)), and fludarabin (120 mg/m(2)). Hematological recovery was favorable in complete chimerism. A major complication was only skin graft-versus-host disease (grade I). CB could be an alternate stem cell source for childhood SAA after modified preparative regimen.     

Bone marrow transplant for a girl with bone marrow failure and cerebral palsy

Bone marrow transplantation (BMT) has been used with increasing frequency to treat congenital bone marrow failure syndrome (CBMFs) successfully. Decision to perform BMT, however, is difficult in the case of comorbidity because of regimen‐related toxicities. We describe here a child with CBMFs, severe cerebral palsy (CP) at Gross Motor Function Classification System level V and mental retardation (MR) who was transfusion dependent despite various medications. She underwent BMT from an HLA‐1 locus‐mismatched unrelated donor. Although engraftment was successful, no neurological improvement was seen 5 years after BMT. While CBMFs patients who have CP and MR could undergo transplantation safely, they may not benefit neurologically from BMT.     

Durable engraftment and correction of hematological abnormalities in children with congenital amegakaryocytic thrombocytopenia following myeloablative umbilical cord blood transplantation

The use of HSCT is the only potentially curative treatment for CAMT, but access is limited by the availability of suitable donors. We report five consecutive patients with CAMT who received MAC and partially HLA‐mismatched, UCBT (unrelated, n = 4). Median times to neutrophil (>500/μL) and platelet (≥20 000 and ≥50 000/μL) engraftment were 19, 57, and 70 days, respectively. Acute GvHD, grade II, developed in one patient, who subsequently developed limited chronic GvHD. At median follow‐up of 14 yr, all patients are alive with sustained donor cell engraftment. To our knowledge, this is the largest single‐center series of UCBT for patients with this disease and suggests that UCBT is a successful curative option for patients with CAMT.     

Second allogeneic hematopoietic stem cell transplantation for juvenile myelomonocytic leukemia: case report and literature review

Juvenile myelomonocytic leukemia (JMML) is a rare clonal myeloproliferative disease in young childhood. Hematopoietic stem cell transplantation (HSCT) is the only way to cure the disease, but relapse after HSCT remains a major cause of treatment failure. A 5-year-old girl with JMML, who had experienced a relapse after the first transplant, did not respond to donor lymphocyte infusion and withdrawal of immune-suppressing agents. She was successfully treated using a second transplant. Detailed reports from the English literature since 1988 relating to a total of 13 JMML patients undergoing a second transplant were reviewed. Seven of the 13 JMML patients (54%) were alive and disease-free, with a median follow-up of 53 months after the second transplant. Within the first 6 months following the initial transplant, 10 JMML patients suffered either autologous recovery (n = 6) or early relapse (n = 4). Seven of the 10 (70%) were alive, with a median survival period of 53 months after the second transplant. Six JMML patients underwent retransplantation within 6 months of the first transplant, with three of these (50%) alive at follow-ups of 24, 57, and 90 months after the second procedure. The authors conclude that a second transplant within 6 months may be worth considering for JMML patients who experience autologous recovery or earlier relapse after the first transplant.     

Hematopoietic stem cell transplantation in patients with severe congenital neutropenia: An analysis of 18 Japanese cases

Oshima K, Hanada R, Kobayashi R, Kato K, Nagatoshi Y, Tabuchi K, Kato S; for the Hematopoietic Stem Cell Transplantation Committee of the Japanese Society of Pediatric Hematology. Hematopoietic stem cell transplantation in patients with severe congenital neutropenia: An analysis of 18 Japanese cases.
Pediatr Transplantation 2010: 14:657–663. © 2010 John Wiley & Sons A/S. Abstract: We studied the outcome of allogeneic HSCT in patients with SCN. Between 1989 and 2005, 18 patients with SCN in Japan received HSCT for reasons other than malignant transformation, i.e., because of the lack of or a partial response to treatment with r‐HuG‐CSF. The median age of the patients at the first HSCT was three and a half yr (range 0.2–16.7 yr). Nine patients received stem cells from an HLA‐identical sibling donor and nine from an alternative donor. Twelve and six patients received myeloablative and non‐myeloablative conditioning regimens, respectively. Engraftment occurred at the first HSCT in 12 patients, four patients received a second HSCT for graft failure, and two patients died. The cause of death was renal failure and graft failure at the first and second HSCT, respectively. The cumulative incidence of grade II–IV acute GVHD and TRM at the first transplantation was 11% and 5.6%, respectively. Of our patients, 16 are alive and in complete remission, with a median follow‐up of six and a half yr. Our results suggest that HSCT is beneficial for patients with SCN refractory to r‐HuG‐CSF treatment.     

Cord blood transplantation in children with relapsed or refractory severe aplastic anemia

Early results of cord blood transplantation (CBT) for severe aplastic anemia were poor with a high rate of engraftment failure. We carried out CBT in 5 children with relapsed or refractory severe aplastic anemia, using immunosuppressive preparative regimens. The median time from the diagnosis to the CBT was 16 months (15 to 47 mo), with all the children having failed at least 1 course of immunosuppressive therapy. The conditioning regimens consisted of fludarabine, cyclophosphamide, and antithymocyte globulin. One patient had an HLA-identical sibling donor, and 4 had unrelated donors selected from an NMDP-affiliated cord blood bank. Two patients received double-unit grafts to attain a target TNC dose of at least 3.0×10/kg. Donor/recipient HLA matching was 6 of 6 (n=2) and 5 of 6 (n=5). The median nucleated cell dose infused was 5.6 (range, 3.6 to 6.1) ×10 cells/kg. The median infused CD34 dose was 2.9 (range, 1.8 to 7.5) ×10 cells/kg. All the patients achieved neutrophil engraftment at a median of 13 days (range, 11 to 25 d). The median time to platelet engraftment was 48 days (range, 34 to 56 d). After CBT, acute GVHD developed in 4 cases, CMV reactivation in 1, pneumonia in 1, and sepsis in 1. Four patients successfully engrafted, but 1 failed to engraft and had delayed autologous recovery. However, all patients were now transfusion-independent at the time of reporting. This result suggests that CBT using optimal conditioning regimens can be a salvage treatment for patients without a suitable bone marrow donor and warrants further prospective studies.     

Secondary neuroendocrine tumor after allogeneic bone marrow transplantation

Here we report a case of aggressive neuroendocrine tumor (NET), which is an extremely rare secondary solid tumor that occurs after allogeneic hematopoietic cell transplantation (allo‐HSCT). A patient with chronic active Epstein–Barr virus infection received allo‐HSCT from an HLA‐DR two allele‐mismatched unrelated donor. Four years later, he developed NET with multiple metastases. He received thoraco‐abdominal irradiation as a conditioning regimen, and developed repeated episodes of intestinal graft‐versus‐host disease, for which he received long‐term immunosuppressive therapy. Although these factors may be potential contributing factors to the development of secondary NET, the exact pathogenesis remains unclear.     

Simultaneous control of third-degree graft-versus-host disease and prevention of recurrence of juvenile myelomonocytic leukemia (JMML) with 6-mercaptopurine following fulminant JMML relapse early after KIR-mismatched bone marrow transplantation

The authors describe a young boy with juvenile myelomonocytic leukemia (JMML) who relapsed 45 days after HLA and killer immunoglobulin-like receptor (KIR) mismatched unrelated donor bone marrow transplant (MMUD-BMT) and subsequently developed life-threatening graft-versus-host disease (GvHD). Treatment with 6-mercaptopurine (6-MP) appeared to control severe GvHD and possibly prevented recurrence of leukemic relapse.     

Successful allogeneic hemopoietic stem cell transplantation in a case of Wiskott–Aldrich syndrome and non‐Hodgkin lymphoma

WAS is a severe X‐linked recessive disorder characterized by microthrombocytopenia, eczema, and immunodeficiency. A six‐yr‐old boy with WAS diagnosed as B‐cell NHL (Stage III) localized in the liver who underwent successful HSCT from HLA‐one antigen mismatch sibling donor has been presented here. His conditioning regimen included ATG, busulfan, and fludarabine. He received 2.3 × 10⁶/kg CD 34(+) stem cells and 11 × 10⁸/kg nucleated cells at day 0. Neutrophil engraftment was achieved at day +14 and platelet engraftment at day +20. He has been in CR for more than two yr after transplantation. Thus, HSCT is an effective treatment for children with WAS even after development of lymphoma.     

Treatment of refractory CMV-infection following hematopoietic stem cell transplantation with the combination of foscarnet and leflunomide

BACKGROUND: Treatment of cytomegalovirus (CMV) disease after allogeneic hematopoietic stem cell transplantation (HSCT) is limited by toxicities of current antiviral drugs and the occurrence of drug resistant strains. Leflunomide, an immunosuppressive agent used for treatment of rheumatoid arthritis, also has activity against CMV by impairing viral assembly. Here we report the control of refractory CMV disease by the combined use of foscarnet and leflunomide. PATIENTS AND RESULTS: A 1S-year-old boy with juvenile myelo-monocytic leukemia (JMML) received an allogeneic HSCT with bone marrow stem cells from a mismatched, unrelated donor (MMUD, recipient and donor CMV-positive). CMV-reactivation two months post transplantation (Tx) could only be controlled by the use of cidofovir. Because of secondary graft failure, the boy received a second HSCT with peripheral blood stem cells (PBSC) of the same donor after overall 6 months. CMV-infection was noticed three weeks later, associated with a considerable rise of both CMV-copy number and pp65-antigen. Since reinduction with cidofovir was ineffective and ganciclovir not warranted due to the history of graft failure, the child then received a combination of foscarnet/leflunomide, leading to a rapid decline of his CMV-copy number and to an afebrile state. Hematological, hepatic or renal toxicities were not observed. CONCLUSION: This case report suggests that leflunomide may be of use in the management of transplant recipients with CMV-infection refractory or intolerant to conventional antiviral therapy.     

Unrelated hematopoietic stem cell transplantation for Cernunnos-XLF deficiency

Abstract:  Cernunnos-XLF deficiency is a rare CI characterized by a defective DNA DSB repair mechanism. Its clinical manifestations are growth retardation, dysmorphic features, malformations, and severe B- and T-cell lymphopenia. BM failure may complicate the clinical picture. To date, there have been no described patients with CSy undergoing allogeneic HSCT. We report a case of CSy treated successfully with unrelated allogeneic HSCT after a reduced-intensity conditioning regimen. Two yr after HSCT, the patient maintains full donor engraftment, normal hematopoiesis, and progressively improving immune competence, thus suggesting that HSCT may be the treatment of choice for CSy.     

Successful reduced‐intensity stem cell transplantation for GATA2 deficiency before progression of advanced MDS

A 13‐yr‐old boy bearing lymphedema and congenital deafness had distinct hematological abnormalities consisting of reduced monocytes, B cells, and dendritic cells in the peripheral blood as well as MDS with normal karyotype in the bone marrow. The patient was diagnosed with Emberger syndrome by sequencing of GATA2 DNA, and underwent RIST from an HLA‐matched unrelated donor. Prompt engraftment and immunological reconstitution were observed without any severe RRT. As most patients with GATA2 anomaly died due to the development of AML or active infections, RIST could be a promising treatment option before progression of advanced MDS.