Mitsuko Akaihata

Nonmyeloablative stem cell transplantation for nonmalignant diseases in children with severe organ dysfunction

Allogeneic stem cell transplantation (SCT) can cure several nonmalignant diseases in children. However, patients frequently have significant morbidity before transplantation and there is a high transplant-related mortality. Nonmyeloablative SCT might achieve the same goals but with less toxicity. Six pediatric patients with nonmalignant diseases underwent nonmyeloablative SCT from different stem cell sources. All patients were conditioned with fludarabine/melphalan with additional anti-thymocyte globulin for haploidentical grafts and prophylaxis for graft-versus-host disease (GVHD) consisting of tacrolimus and methotrexate with additional prednisolone for haploidentical grafts. Hematopoietic stem cells were neither T-cell depleted nor purged. All patients had severe organ dysfunction that precluded transplantation with conventional conditioning. Five of the six are alive and in complete disease resolution at a median of 19 months (range, 7–53 months) after SCT. One patient died of bacteremia before engraftment. Three patients achieved complete donor chimerism. Two patients remained stable mixed chimerism. Short-term toxicities were minimal. Acute and chronic GVHD were not seen. In summary, the fludarabine-based nonmyeloablative regimen followed by SCT provides a good approach for children with nonmalignant diseases. Even patients with severe organ dysfunctions had adequate engraftment with acceptable toxicities.

Successful unrelated cord blood transplantation for chronic granulomatous disease: a case report and review of the literature.

Abstract:  CGD is a rare inherited immunodeficiency disorder that is caused by disability of oxidative killing. We presented a two‐yr‐old boy with CGD who was suffering from multiple systemic abscesses. He received the first BMT from his HLA‐haploidentical mother after conditioning with Flu, melphalan, and ATG. Although the maximum of 42% donor chimerism was achieved, it disappeared 73 days after the BMT. Then, we performed 5/6‐matched unrelated cord blood re‐transplantation after conditioning with Flu, Bu, and TBI (2 Gy). Engraftment and complete donor chimerism were achieved on days 18 and 19, respectively. The patient is now free from infection and maintains complete donor chimerism without GVHD 36 months after the cord blood re‐transplantation. We postulate that the unrelated CBT has a potential to be an alternative strategy and might be beneficial for patients with CGD who do not have an HLA‐identical donor.

Feasibility of tacrolimus, methotrexate, and prednisolone as a graft-versus-host disease prophylaxis in non-T-cell-depleted haploidentical hematopoietic stem cell transplantation for children

Mochizuki K, Kikuta A, Ito M, Sano H, Akaihata M, Kobayashi S, Ohto H, Hosoya M. Feasibility of tacrolimus, methotrexate, and prednisolone as a graft‐versus‐host disease prophylaxis in non‐T‐cell‐depleted haploidentical hematopoietic stem cell transplantation for children. 
Clin Transplant 2011: 25: 892–897.

T‐cell‐replete haploidentical stem cell transplantation is highly efficacious for relapsed and refractory childhood acute leukaemia

Despite improvements in first‐line therapies, the outcomes of relapsed or refractory childhood acute leukaemia that has not achieved complete remission after relapse, has relapsed after stem cell transplantation (SCT), has primary induction failure and has relapsed with a very unfavourable cytogenetic risk profile, are dismal.

Loss of mismatched HLA in myeloid/NK cell precursor acute leukemia relapse after T cell-replete haploidentical hematopoietic stem cell transplantation.

Myeloid/natural killer cell precursor acute leukemia (MNKL) is an aggressive disease with a high relapse rate even after allogeneic hematopoietic stem cell transplantation (SCT). We report a patient with MNKL who had a donor lymphocyte infusion (DLI) for relapse after T cell‐replete human leukocyte antigen (HLA)‐haploidentical SCT, but relapsed again 20 months later with loss of mismatched HLA. This case suggests that a strong graft‐versus‐leukemia effect of haploidentical SCT can be expected in MNKL patients. In the haploidentical setting, DLI should be considered for patients with relapsed leukemia whose leukemic cells have not lost HLA cell surface expression. Pediatr Blood Cancer 2014; 61:1880–1882.

Comprehensive technical and patient-care optimization in the management of pediatric apheresis for peripheral blood stem cell harvesting

BACKGROUND Pediatric apheresis for peripheral blood stem cell transplantation should be carried out with due concern for low corporeal blood volume and vulnerability to hypocalcemia-related complications, hypovolemic shock, and hypervolemic cardiac overload. STUDY DESIGN AND METHODS We retrospectively investigated a total of 267 apheresis procedures from 1990 to 2013 on 93 children between 0 and 10 years old, including 89 patients and 4 healthy donors, with body weights of 6.3 to 44.0 kg. RESULTS The median CD34+ cell yield per apheresis procedure was 2.3 × 106 CD34+ cells/kg (0.2-77.9 × 106 CD34+ cells/kg). Adverse events occurred in 11.6% of procedures (n = 31), including mild perivascular pain (n = 12), emesis (n = 9), hypotension (n = 3), urticaria (n = 2), numbness (n = 2), chest pain (n = 1), facial flush (n = 1), and abdominal pain (n = 1). Among hypotensive events, shock in a 9.6 kg one-year-old boy required emergency treatment in 1996. Thereafter, we adopted continuous injection of calcium gluconate, ionized calcium monitoring, central venous catheter access and circuit priming with albumin in addition to concentrated red cells. Since then we have had fewer complications: 16.4% per apheresis during 1990-1997 versus 5.8% during 1998-2013. No healthy pediatric donors suffered from any late-onset complications related to apheresis or G-CSF administration. CONCLUSION By employing appropriate measures, peripheral blood stem cell apheresis for small children can have an improved safety profile, even for children weighing <10 kg.

Clinical analysis of combination therapy for febrile neutropenic patients in childhood cancer

The objective of this study was to evaluate the efficacy and safety of our combination therapy in febrile neutropenic children with cancer.

Pulmonary arterial hypertension associated with chronic active Epstein–Barr virus infection

Chronic active Epstein–Barr virus (EBV) infection (CAEBV), characterized by persistent infectious mononucleosis‐like symptoms, can lead to cardiovascular complications including coronary artery aneurysm or myocarditis. Here, we present the case of an 11‐year‐old boy with pulmonary arterial hypertension (PAH) and junctional ectopic tachycardia associated with CAEBV. The patient did not have any major symptoms attributed to CAEBV, such as fever, lymphadenopathy or splenomegaly when the PAH developed. Mild liver dysfunction was found at the first examination, and it persisted. Two years after the PAH symptoms appeared, CAEBV was evident, based on deteriorated liver function, hepatosplenomegaly, and coronary artery aneurysms. CAEBV should be considered as a cause of secondary PAH, particularly when liver dysfunction coexists.

Malignant peritoneal mesothelioma in a child: chemotherapy with gemcitabine and platinum was effective for the disease unresponsive to other treatments

Malignant peritoneal mesothelioma in children is a very rare disease and has a poor prognosis. Unlike malignant mesothelioma in adults, there is no clear causal association between this very rare malignancy in children and asbestos exposure. We report a case of peritoneal mesothelioma in an 11-year-old boy who presented with ascites. He was diagnosed with malignant mesothelioma on the basis of histopathological findings. His disease showed resistance to pemetrexed, but was treated successfully with platinum-based therapy with gemcitabine. He has achieved long-term survival in partial remission with stable disease.

A case with severe combined immunodeficiency diagnosed with disseminated BCG infection by detecting specific RD gene deletion

Because the Bacillus Calmette-Guérin (BCG) prevents infants from contracting miliary tuberculosis and tuberculosis meningitis, BCG vaccination is recommended for those under 6 months old in Japan. Complications such as favorable local inflammatory reactions including redness, induration, and abscess formation may occur, but severe adverse effects such as osteomyelitis, periostitis, and disseminated BCG infection are generally rare. We report an 11-month-old boy with severe combined immunodeficiency dying of serious disseminated BCG infection despite anti-tuberculosis therapy and blood stem cell transplantation. He was vaccinated with disseminated BCG infection at 4 months before severe combined immunodeficiency diagnosis was confirmed by specific RD gene deletion based on allele-specific polymerase chain reaction. Although BCG is considered safe, we should keep in mind that subjects with immunological deficiency may suffer severe BCG complications.