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Studies using Fanconi anaemia (FA) mutant mouse models suggested that the combination of a defective FA pathway and aldehyde dehydrogenase-2 (ALDH2) dysfunction could provoke bone marrow failure, leukaemia and developmental defects, and that both maternal and fetal aldehyde detoxification are crucial to protect the developing embryo from DNA damage. We studied the ALDH2 genotypes of 35 Japanese FA patients and their mothers. We found that a normal maternal ALDH2 allele was not essential for fetal development of ALDH2-deficient patients, and none of the post-natal clinical parameters were clearly affected by the maternal ALDH2 genotype in these patients.

Summary Reports of non-anaplastic peripheral T-cell lymphoma (PTCL) in paediatric patients, especially results of stem cell transplantation (SCT), are relatively rare. We herein report the results of SCT using the Transplant Registry Unified Management Program system of the Japanese Society of Stem Cell Transplantation in paediatric patients with non-anaplastic PTCL. We analysed 26 patients (13 females and 13 males) aged 18 years with nonanaplastic PTCL who underwent a total of 28 SCT. Median age at transplantation was 135 years (range: 0–18 years). PTCL not otherwise specified was diagnosed in 17 patients; extranodal Natural Killer (NK)/T cell lymphoma, nasal type in nine; and subcutaneous panniculitis-like T-cell lymphoma in two. Transplantation was with syngeneic donor in one, related donor in 10; unrelated donor in 10; and auto transplantation in 7. Fiveyear overall survival rate and event-free survival rate was 6296% and 5556%, respectively. Male gender, chronic graft-versus-host disease (GVHD), and reduced intensity conditioning were good prognostic factors in all patients. In 20 patients with refractory or relapsed disease, male gender and chronic GVHD were also good prognostic factors. This study is the first report concerning transplantation in children with non-anaplastic PTCL, although the number of patients was small. Larger studies are needed to confirm these findings.

A total of 57 patients with Wiskott-Aldrich syndrome (WAS) were studied after undergoing stem cell transplantation (SCT) in Japan between January 1985 and December 2004. Eleven patients received transplants from human leucocyte antigen (HLA)-matched related donors, 10 from HLA-mismatched related donors, 21 from unrelated bone marrow donors, and 15 from unrelated cord blood donors. Nine of the 57 patients rejected the initial graft. The overall 5-year survival rate was 73.7% and the 5-year failure-free survival rate was 65.7% (failure was defined as rejection or death). The overall 5-year survival rates for patients receiving bone marrow and cord blood from unrelated donors were both 80.0%. Based on univariate analysis, the factors associated with poor survival were: transplantation from an HLA-mismatched related donor, patient age of more than 5 years at the time of transplantation, and a conditioning regimen other than busulfan and cyclophosphamide (BU-CY) or busulfan, cyclophosphamide and antithymocyte globulin (BU-CY-ATG). In a multivariate analysis, a conditioning regimen other than BU-CY and BU-CY-ATG was the only independent factor associated with transplantation failure. Given the improved outcome for WAS patients following transplantation from an unrelated donor, we conclude that patients with WAS should receive SCT as soon as possible after diagnosis.

Fanconi anaemia (FA) is a genetically heterogeneous chromosome instability syndrome characterised by bone marrow failure and congenital anomalies. Although an increasing number of reports suggest that reversion mosaicism noted in peripheral blood lymphocytes (PBLs) is associated with mild haematopoietic failure in FA, myeloid cells are rarely directly examined. We here report a patient with prolonged mild pancytopenia in whom proliferation of revertant cells was detected in mature myeloid cells but not in PBLs. While this patient had inherited heterozygous mutations, 2546delC and 3720-3724del, in the major FA gene FANCA, Epstein-Barr virus-immortalised lymphoblastoid cells from the patient had 2546C > T instead of 2546delC, resulting in expression of a functional missense protein. As the identical reversion was detected in polymorphonuclear granulocytes and mononuclear phagocytes, sustained haematopoiesis in the patient can be attributed to a selective growth advantage of revertant myeloid cells. It is noteworthy that such a myeloid lineage-selective mosaicism is overlooked in routine examination of PBLs. Recognition of this status will expand the role of reversion mosaicism in the pathophysiology of FA.

Allogeneic haematopoietic stem cell transplantation (HSCT) is still considered to play an important role as a consolidation therapy for high-risk infants with acute lymphoblastic leukaemia (ALL). Here, we retrospectively analysed outcomes of HSCT in infants with ALL based on nationwide registry data of the Japan Society for Haematopoietic Cell Transplantation. A total of 132 allogeneic HSCT for infant ALL with KMT2A (MLL) gene rearrangements, which were performed in first complete remission (CR1), were analysed. The 5-year overall survival rate after transplantation was 67·4 ± 4·5%). Although recent HSCT (after 2004) had a trend toward better survival, no statistical correlation was observed between outcomes and each factor, including age at diagnosis, initial leucocyte count, cytogenetics, donor types or conditioning of HSCT. Myeloablative conditioning with total body irradiation did not provide a better survival (60·7 ± 9·2%) over that with busulfan (BU; 67·8 ± 5·7%). Two of the 28 patients treated with irradiation, but none of the 90 BU-treated patients, developed a secondary malignant neoplasm. In conclusion, allogeneic HSCT using BU was a valuable option for infant ALL with KMT2A rearrangements in CR1.

In childhood acute promyelocytic leukaemia (APL), the efficacy of therapy combining cytarabine with all-trans retinoic acid (ATRA) and anthracyclines remains unclear in terms of long-term prognosis. Between August 1997 and March 2004, 58 children with APL (median age: 11 years) were enrolled into an acute myeloid leukaemia (AML) study (AML99-M3) and followed up for a median time of 86 months. The regimen included ATRA and anthracyclines combined with cytarabine in both induction and consolidation. In induction, two patients died of haemorrhage and four patients developed retinoic acid syndrome. Of 58 patients, 56 (96·6%) achieved complete remission, two of whom relapsed in the bone marrow after 15 and 19 months respectively. Sepsis was a major complication, with an incidence of 5·6-10·9% in the consolidation blocks, from which all but one of patients recovered. Consequently, 7-year overall and event-free survival rates were 93·1% and 91·4% respectively, and cumulative incidence of relapse plateaued at 3·6% after 2 years. Follow-up survey of 54 patients revealed no patients with late cardiotoxicity or secondary malignancy, except one with asymptomatic prolongation of QTc interval. This study suggests that the combination of cytarabine with ATRA and anthracycline-based therapy may have useful implications in the perspective of long-term prognosis and late adverse effects for childhood APL.

The incidence of graft rejection was determined in 66 children with acquired aplastic anaemia (AA) following bone marrow transplantation (BMT) from a related donor. Eleven of 65 evaluable patients experienced either early or late rejection. Multivariate analysis identified previous immunosuppressive therapy with antithymocyte-globulin (ATG) and ciclosporin (CsA) as a risk factor for graft rejection (relative risk: 16.6, P = 0.001). Patients who received ATG and CsA had a significantly lower probability of failure-free survival than those who did not (69.7 +/- 6.2% vs. 87.9 +/- 8.0%, P = 0.044). These results suggest that BMT should be instituted immediately in children with severe AA who have human leucocyte antigen-identical siblings.

A pilot study was undertaken using a fludarabine-based conditioning regimen to improve haematopoietic cell transplantation (HCT) from alternative donors in 27 Fanconi anaemia (FA) patients. Patients were conditioned with 150-180 mg/m2 of fludarabine, 40 mg/kg of cyclophosphamide, 5-10 mg/kg of antithymocyte globulin, and 300-450 cGy of thoracoabdominal/total body irradiation. One patient who received unrelated cord blood transplantation failed to engraft, another patient died of sepsis. The 1-year overall survival was 96.3% (95% CI, 89-100). This conditioning regimen exerted an immunosuppressive effect that enabled durable engraftment in alternative donor HCT without severe toxicity.