B-Cell Precursor-Acute Lymphoblastic Leukemia With EBF1-PDGFRB Fusion Treated With Hematopoietic Stem Cell Transplantation and Imatinib: A Case Report and Literature Review.

A 9-year-old girl was diagnosed with B-cell precursor-acute lymphoblastic leukemia (BCP-ALL). Although she entered remission after induction therapy, she relapsed 15 months after maintenance therapy cessation. Since further investigation revealed EBF1-PDGFRB fusion, her condition was treated as BCR-ABL1-like acute lymphoblastic leukemia. She was started on a tyrosine kinase inhibitor, imatinib, and chemotherapy and underwent umbilical cord blood transplantation following reduced intensity conditioning. She has remained in complete remission for 36 months after cord blood transplantation. This case demonstrates the successful use of a tyrosine kinase inhibitor to treat BCP-ALL with a fusion transcript and highlights the need for a standardized treatment protocol.

Familial Mediterranean Fever After Cord Blood Transplantation for Familial Hemophagocytic Lymphohistiocytosis.

Familial Mediterranean fever (FMF) is a hereditary autoinflammatory disorder accompanied by periodic fever and sterile serositis. We report a 5-year-old boy with FMF, who underwent second unrelated cord blood transplantation (CBT) for recurrent familial hemophagocytic lymphohistiocytosis. Periodic attacks of fever and abdominal pain started 6 months after CBT. He was diagnosed with FMF according to the Tel-Hashomer criteria and treated successfully with colchicine. Genetic testing showed heterozygous p.E148Q mutation in the MEFV gene from both donor and recipient cells. Several CBT-related factors including use of an immunosuppressant can potentially be involved in the pathogenesis of FMF in our patient.

Long-term prognosis of human herpesvirus 6 reactivation following allogeneic hematopoietic stem cell transplantation.

BACKGROUND: Patients undergoing hematopoietic stem cell transplantation (HSCT) frequently have HHV-6 reactivation typically during the early phase following HSCT. The long-term clinical complications and prognosis, however, remain unclear. METHODS: Between September 2010 and October 2012, whole blood samples from 105 patients collected weekly from prior to 6 weeks after HSCT underwent multiplex polymerase chain reaction (PCR) to screen for viral DNA, followed by real-time PCR for quantitative estimation. In 48 patients, only HHV-6 was detected in at least one sample. In 30 patients, no viral DNA was detected. Long-term clinical records were reviewed in March 2016. All 48 HHV-6-positive patients, and 24 patients in whom no viral DNA detected, were followed up. RESULTS: Median maximum HHV-6 DNA load in the blood of the HHV-6 reactivation group (n = 48) was 11 800 copies/µg peripheral blood leukocyte DNA (range, 52-310 000 000). Hemophagocytic syndrome (HPS) was diagnosed in two subjects with HHV-6 reactivation. Acute graft-versus-host disease (GVHD) developed more frequently in patients with HHV-6 reactivation than in patients without viral reactivation (P = 0.002), but there was no difference in incidence of chronic GVHD. There was no difference in engraftment of neutrophils and platelets between groups. There was also no difference in overall survival between groups. Onset of HPS, however, was associated with lower overall survival (P = 0.009). CONCLUSIONS: Human herpesvirus 6 reactivation was associated with acute GVHD, but not with chronic GVHD, engraftment or overall survival. Onset of HPS, however, predicts lower overall survival.

HHV-6 encephalitis may complicate the early phase after allogeneic hematopoietic stem cell transplantation: Detection by qualitative multiplex PCR and subsequent quantitative real-time PCR.

Viral reactivation following hematopoietic stem cell transplantation (HSCT) can cause various complications especially viral encephalitis. In this prospective study, we investigated the correlation of post-HSCT viral reactivation in blood with CNS dysfunction. We employed a multiplex PCR that detects 13 kinds of viruses as a first-line screening test and real-time PCR for subsequent quantitative evaluation. Five hundred ninety-one whole blood samples were collected from 105 patients from before until 42 days after HSCT. Seven patients developed CNS dysfunction such as altered consciousness. In six of the seven, the multiplex PCR test detected HHV-6 DNA in at least one sample. In contrast, DNA from other viruses, such as CMV, EBV, HHV-7, adenovirus, and HBV was never detected in any of the seven patients throughout the study period. Quantitative measurement of whole blood HHV-6 DNA levels demonstrated four of the six HHV-6 DNA loads were elevated at successive time points during the CNS dysfunction. In addition, the virus DNA peaks were temporally associated with the development of CNS dysfunction. CSF was tested in two of the four patients and high HHV-6 DNA levels comparable to those in whole blood were confirmed in both. These four patients were, thus, suspected to have developed HHV-6 encephalitis, a rate of 3.8% in the study population. Our results suggest that early diagnosis of probable HHV-6 encephalitis can be improved by confirming high HHV-6 DNA load in blood.

Large-scale multiplex polymerase chain reaction assay for diagnosis of viral reactivations after allogeneic hematopoietic stem cell transplantation.

Viral reactivations following hematopoietic stem cell transplantation are thought to result from the breakdown of both cell-mediated and humoral immunity. As a result, many viruses could be reactivated individually or simultaneously. Using a multiplex polymerase chain reaction (PCR), we prospectively examined many kinds of viral DNAs at a time in 105 patients who underwent allogeneic hematopoietic stem cell transplantation. In total, 591 whole blood samples were collected weekly from pre- to 42 days post-transplantation and the following 13 viruses were tested; herpes simplex virus 1 (HSV-1), HSV-2, varicella-zoster virus (VZV), Epstein-Barr virus (EBV), cytomegalovirus (CMV), human herpes virus 6 (HHV-6), HHV-7, HHV-8, adenovirus, BK virus (BKV), JC virus (JCV), parvovirus B19, and hepatitis B virus (HBV). Several viral DNAs were detected in 12 patients before hematopoietic stem cell transplantation. The detection rate gradually increased after transplantation and peaked at 21 days. The most frequently detected virus was HHV-6 (n = 63; 60.0%), followed by EBV (n = 11; 10.5%), CMV (n = 11; 10.5%), and HHV-7 (n = 9; 8.6%). Adenovirus and HBV were each detected in one patient (1.0%). Detection of HHV-6 DNA was significantly more common among patients undergoing cord blood transplantation or with steroid treatment. EBV DNA tended to be more common in patients treated with anti-thymocyte globulin. Multiplex PCR was useful for detecting many viral reactivations after hematopoietic stem cell transplantation, simultaneously. Cord blood transplantation, steroid treatment, or anti-thymocyte globulin use was confirmed to be risk factors after transplantation.

Comparison of continuous and twice-daily infusions of cyclosporine A for graft-versus-host-disease prophylaxis in pediatric hematopoietic stem cell transplantation.

BACKGROUND: Cyclosporine A (CsA) is used widely for graft-versus-host disease (GVHD) prophylaxis in hematopoietic stem cell transplantation (HSCT); however, the optimal schedule of its administration has not been established. Although comparative studies of adult patients undergoing HSCT have demonstrated enhanced efficacy and safety of twice-daily infusion (TD) compared with continuous infusion (CIF) of CsA, to our knowledge, similar studies have not yet been performed in pediatric groups. PROCEDURE: A self-administered questionnaire was used to retrospectively compare the clinical outcome and incidence of CsA-associated adverse events of 70 pediatric acute myelogenous leukemia patients who were receiving CsA by TD (n = 36) or CIF (n = 34) as GVHD prophylaxis for their first allogeneic HSCT. RESULTS: The cumulative incidences of grade II-IV acute GVHD and chronic GVHD, as well as the overall survival and event-free survival rates, did not differ significantly between the TD and CIF groups; however, the incidence of severe hypertension was significantly higher in the CIF group than the TD group. CONCLUSIONS: The analysis presented here indicates that TD and CIF administration of CsA have similar prophylactic effect on pediatric GVHD and suggest that TD is associated with a lower rate of toxicity than CIF in pediatric patients undergoing HSCT. Pediatr Blood Cancer 2015;62:291-298. © 2014 Wiley Periodicals, Inc.

Extramedullary relapse in RARA rearrangement-negative acute promyelocytic leukemia successfully treated in combination with chemotherapy, local radiotherapy, and cord blood transplantation.

RARA rearrangement-negative acute promyelocytic leukemia (APL) is uncommon, and its extramedullary relapse is extremely rare. We report a 5-year-old girl with RARA rearrangement-negative APL, which recurred solely at the external auditory canal and mastoid air cells. She was successfully treated with chemotherapy, local radiotherapy, and unrelated cord blood transplantation. She has maintained complete remission for 24 months after transplantation. The clinical features and our therapeutic strategy in this patient will provide valuable information for extramedullary relapse of RARA rearrangement-negative APL.

Extramedullary Tumor of Cerebral Falx: An Unusual Presentation of Acute Megakaryocytic Leukemia.

In childhood acute myelogenous leukemia, extramedullary tumor is an occasional clinical symptom. However, extramedullary acute megakaryocytic leukemia is extremely rare. Here, we report an extremely rare case of acute megakaryocytic leukemia in a patient who presented with extramedullary tumor of cerebral falx as a first manifestation before the diagnosis of systemic bone marrow leukemia.

Risk factor analysis of non-Hodgkin lymphoma-associated haemophagocytic syndromes: a multicentre study.

Haemophagocytic syndrome is often associated with malignant lymphoma; however, few studies have examined lymphoma-associated haemophagocytic syndrome (LAHS). A total of 1239 patients with non-Hodgkin lymphoma were analysed at 12 institutions in Hokkaido prefecture between January 2007 and December 2011 to assess the incidence, prognosis and risk factors of LAHS. The cumulative incidence rate of LAHS was 2·8% (35/1239). Overall survival (OS) in patients with LAHS was significantly inferior to those without LAHS (3-year OS: 35·6 vs. 59·0% respectively, P < 0·0001). The cumulative incidence of LAHS was higher in patients with T/Natural Killer (NK)-cell lymphoma than in those with B-cell lymphoma (8·2 vs. 1·8% respectively, P < 0·0001). The characteristics of patients with and without early death (within the first 120 d after developing LAHS) were subsequently compared to evaluate the prognostic factor of LAHS. The results obtained showed that the rate of early death after developing LAHS was higher in patients with T/NK-cell lymphoma than in those with B-cell lymphoma (62·5 vs. 10·5%, P = 0·0033). In conclusion, the complication and mortality rates of LAHS were higher in patients with T/NK-cell lymphoma after they developed LAHS than in those with B-cell lymphoma.

Primary orbital neuroblastoma in a 1-month-old boy.

Neuroblastoma is a malignant tumor predominantly occurring in children and usually arising from the adrenal gland or sympathetic ganglia. We describe a neuroblastoma in a 1-month-old boy arising from his left orbital cavity. This tumor was refractory to chemotherapy or radiotherapy, requiring enucleation of the left eye for complete removal of the intraorbital tumor. Thereafter, he received high-dose chemotherapy followed by autologous peripheral blood stem cell transplantation, and has been in complete remission for 3 years. Unlike neuroblastomas arising from the adrenal gland or sympathetic ganglia, primary orbital neuroblastoma may be refractory even in early infancy.

Successful treatment of childhood hypocellular acute myeloid leukemia.

Hypocellular acute myeloid leukemia (AML) is extremely rare in childhood. We report on a 7-year-old girl with hypocellular AML who was treated successfully with granulocyte-colony stimulating factor (G-CSF) and combined chemotherapy. High-dose G-CSF induced complete remission and she subsequently received reduced intensity conditioning and unrelated cord blood transplantation; however, this resulted in early rejection. After a complete hematological recovery, she received 3 courses of combination chemotherapy oriented toward AML. She has remained in complete remission for over 1 year after the completion of the therapy. G-CSF effectively induced remission, and combination chemotherapy has been proven to be feasible for patients with childhood hypocellular AML.

Human cytomegalovirus UL97 D605E polymorphism has a high prevalence in immunocompetent Japanese infants and children.

There is no existing data on UL97 mutation in human cytomegalovirus (HCMV) isolates obtained from individuals who have never been exposed to ganciclovir (GCV). UL97 codons 439 to 645 from 61 CMV isolates from 61 immunocompetent Japanese infants and children were sequenced directly. No known GCV resistance mutations were found, meaning that the UL97 mutation had resulted from the use of GCV. On the other hand, a mutation at codon 605 (D to E) was frequently identified (56/61: 91.8%). This could be a genetic marker for HCMV in East Asian counties, because of its low prevalence in the strains of HCMV circulating in Western countries.

Platelet transfusion refractoriness attributable to HLA antibodies produced by donor-derived cells after allogeneic bone marrow transplantation from one HLA-antigen-mismatched mother.

PTR is a serious problem in patients being treated for hematologic disorders. Two patients with acute leukemia developed PTR after allogeneic BMT from one HLA-antigen-mismatched mother attributable to HLA antibodies, which could not be detected in their serum before BMT. HLA antibodies, whose specificity resembled that of each patient, were detected in each donor's serum. Each donor had probably been immunized during pregnancy by their partner's HLA antigens expressed by the fetus, consequently, transplanted donor-derived cells provoked HLA antibodies in each recipient early after BMT, and those HLA antibodies induced PTR. If the mothers are selected as donors for their children, they should be tested for the presence of HLA antibodies.

Successful treatment of refractory Langerhans cell histiocytosis with pulmonary aspergillosis by reduced-intensity conditioning cord blood transplantation.

The prognosis of multisystem LCH in children with risk organ involvement is extremely poor when they fail to respond to conventional chemotherapy. In such patients, allogeneic SCT may produce complete and sustained remission; however, high-dose myeloablative regimens are frequently associated with treatment-related morbidity and mortality. More recently, allogeneic SCT following an RIC regimen has been performed as an alternative salvage approach. We describe a nine-month-old boy with refractory multisystem LCH with pulmonary aspergillosis who was successfully treated with reduced-intensity cord blood transplantation.

An infant with self-healing cutaneous Langerhans cell histiocytosis followed by isolated thymic relapse.

Thymic involvement with Langerhans cell histiocytosis (LCH) typically occurs in children as part of multi-system (M-S) LCH. Patients who develop skin-only LCH during infancy may either follow a self-healing course with spontaneous regression or may progress to M-S involvement. We describe a male infant who developed isolated thymic LCH after spontaneous complete regression of isolated cutaneous lesions. His erythrocyte sedimentation rate and C-reactive protein increased temporarily during the skin-only stage of LCH, and increased again considerably during the thymic relapse. Even for patients with skin-only LCH, these laboratory data might indicate possible relapse or late progression of the disease.

Treatment of an infant with severe acute refractory immune thrombocytopenic purpura using combination therapy including rituximab.

Some infants with acute immune thrombocytopenic purpura (ITP) do not respond to first-line therapy, and currently there is no consensus on therapy for these refractory cases. We describe a 12-week-old infant with acute ITP who was unresponsive to intravenous immunoglobulin and corticosteroid, and developed gastrointestinal bleeding. Several combination therapies were unsuccessful. After four doses of rituximab followed by intravenous immunoglobulin and corticosteroid, his platelet counts gradually increased. Combined therapy which includes rituximab may be a promising treatment for severe acute refractory ITP.

Quantification of BK polyoma viruria in Japanese children and adults with hemorrhagic cystitis complicating stem cell transplantation.

Polyoma BK virus (BKV) is frequently found in the urine of stem cell transplantation (SCT) patients with hemorrhagic cystitis (HC), but also occurs in SCT patients without HC. How BK viruria relates to the development of HC in SCT patients, especially in children, has not yet been fully evaluated. In the present study, we analyzed the relationship of several factors including urinary BKV load to HC development in children and adults undergoing SCT. We employed a quantitative PCR assay and evaluated 37 patients (aged 9 months-62 years) of whom 12 developed HC and 25 did not. Older age was a risk factor for the development of HC; however, other factors such as sex, primary disease, type of SCT, conditioning regimen and aGVHD were not. Peak urinary BKV values in HC patients were not higher than those in non-HC patients. Severity of HC also did not correlate with urinary BKV loads. However, in some patients who secreted higher urinary BKV loads, the peak loads were closely related with the onset of HC. Higher BKV loads may be a risk factor for the development of HC in conjunction with other coexisting factors.

A case of primary familial congenital polycythemia with a novel EPOR mutation: possible spontaneous remission/alleviation by menstrual bleeding.

A 10-year-old girl with persistent erythrocytosis and ruddy complexion was diagnosed with primary familial congenital polycythemia (PFCP) involving a novel heterozygous mutation of c.1220C>A, p.Ser407X in exon 8 of the erythropoietin receptor gene (EPOR). This mutation causes truncation of EPOR, resulting in loss of the cytoplasmic region, which is necessary for negative regulation of erythropoietin signal transmission. Genetic analysis showed that the mutated EPOR was inherited from her mother. Her mother had polycythemia and had undergone venesection several times when she was young, but her polycythemic state appeared to have resolved. Venesection was not needed to maintain Hct levels within normal range. For the case reported here, venesection was also conducted to maintain the blood Hct level below 50%. We observed that after the patient experienced menarche, the volume and frequency of venesection needed to maintain Hct level < 50% were clearly reduced compared with those before menarche. These findings suggest that, in female patients with this type of EPOR mutation, menstruation might reduce blood volume in a manner similar to venesection. Spontaneous remission of erythrocytosis may thus occur after the start of menstrual bleeding.

Treatment of McLeod phenotype chronic granulomatous disease with reduced-intensity conditioning and unrelated-donor umbilical cord blood transplantation.

Patients with chronic granulomatous disease (CGD) complicated by antimycotics-refractory invasive aspergillosis have an extremely poor prognosis if they cannot undergo allogeneic hematopoietic stem cell transplantation from a suitable related donor while in good clinical condition. We successfully treated a 20-year-old man with very rare McLeod phenotype CGD with reduced-intensity conditioning and unrelated-donor umbilical cord blood transplantation. We postulate that reduced-intensity conditioning-allogeneic hematopoietic stem cell transplantation is a promising therapeutic strategy for patients with CGD even if only unrelated-donor umbilical cord blood is available.