Successful Bone Marrow Transplantation in a Patient with Acute Myeloid Leukemia Developed from Severe Congenital Neutropenia Using Modified Chemotherapy and Conditioning Regimen for Leukemia.

Severe congenital neutropenia (SCN) is characterized by chronic neutropenia with recurrent infections from early infancy and a predisposition to myelodysplastic syndrome/acute myeloid leukemia (AML). Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative treatment for patients with SCN who develop myelodysplastic syndrome/AML. We report an 8-year-old girl with SCN carrying an ELANE mutation that had been refractory to granulocyte colony-stimulating factor. The patient experienced recurrent infections and then developed AML. The counts of leukemic blasts that harbored both CSF3R and RUNX1 mutations spontaneously decreased with antimicrobial therapy, leading to partial remission. After AML recurrence, HSCT was successfully performed using modified chemotherapy and a conditioning regimen. Serial donor lymphocyte infusions against mixed chimerism induced complete donor chimerism over 4 years without any infections or AML relapse. This case suggests the importance of carefully managing neutropenia-related infections, leukemia progression, and HSCT in patients with SCN developing AML.

[Successful second allogeneic hematopoietic stem cell transplantation with azacitidine as bridging therapy for relapsed juvenile myelomonocytic leukemia].

Hematopoietic cell transplantation (HCT) is the only curative therapy for juvenile myelomonocytic leukemia (JMML). Meanwhile, an established conventional chemotherapy before HCT remains unavailable. Studies have shown that azacitidine (AZA), which is a DNA methyltransferase inhibitor, is clinically effective for JMML as a bridging therapy for HCT; a prospective clinical trial in Japan is ongoing. Herein, we present a case of a patient with JMML who was administered AZA as bridging therapy for both first and second HCT. A 3-year-old boy with neurofibromatosis type 1 was administered with intravenous AZA (75 mg/m2/day for 7 days, intervals of 28 days, and four cycles) and received myeloablative HCT (unrelated bone marrow). When relapse occurred on day 123, four additional AZA therapy cycles were administered, and the patient received a second nonmyeloablative HCT (cord blood). After seven AZA therapy cycles as post HCT consolidation, hematological remission was sustained for 16 months after the second HCT. No severe adverse events occurred. AZA is effective for JMML as a bridging therapy for HCT and has robust cytoreductive potential despite the risk of relapse.

High serum cystatin C levels in juvenile myelomonocytic leukemia patients without abnormal kidney function.

BACKGROUND: In pediatric cancer patients, the estimated glomerular filtration rate based on serum cystatin C (CysC) was reported to be suitable for estimating kidney function because of low serum creatinine (Cr) and high serum ß2-microglobulin. Recently, however, serum CysC levels have been reported to be elevated in some cancer patients other than those with juvenile myelomonocytic leukemia (JMML), regardless of normal kidney function. CASE REPORTS: We describe two pediatric cases of JMML with an elevated serum CysC level. Urinalysis tests showed no abnormalities and no evidence of nephritis or nephropathy, and there were no findings indicating abnormal kidney function, such as Cr clearance in one case or the estimated glomerular filtration rate based on serum Cr in both cases, except for the serum CysC levels. There were no other causes of a high serum CysC level, including hyperthyroidism and steroid administration. The patients were treated with a conventional dosage of drugs, and their serum CysC levels decreased to the normal range when they were in complete remission after treatment. CONCLUSION: An elevated serum CysC level may reflect tumor burden independent of kidney function in JMML patients. Therefore, creatinine or inulin clearance should be determined to more accurately estimate kidney function for administering an optimal dose of anticancer drugs. In addition, a high serum CysC level may be a potential biomarker of cancer progression.

Hematopoietic stem cell transplantation for infants with high-risk KMT2A gene-rearranged acute lymphoblastic leukemia.

The role of allogeneic hematopoietic stem cell transplantation (HSCT) for infants with acute lymphoblastic leukemia (ALL) and KMT2A gene rearrangement (KMT2A-r) is controversial in terms of both its efficacy and potential for acute and late toxicities. In Japanese Pediatric Leukemia/Lymphoma Study Group trial MLL-10, by introducing intensive chemotherapy, indication of HSCT was restricted to patients with high-risk (HR) features only (KMT2A-r and either age <180 days or presence of central nervous system leukemia). Of the 56 HR patients, 49 achieved complete remission. Forty-three patients received HSCT in first remission including 38 patients receiving protocol-specified HSCT with conditioning consisting of individualized targeted doses of busulfan, etoposide, and cyclophosphamide. Three-year event-free survival (EFS) of 56.8% (95% confidence interval [CI], 42.4% to 68.8%) and overall survival of 80.2% (95% CI, 67.1% to 88.5%) were accomplished. Univariable analysis showed that Interfant-HR criteria and flow cytometric minimal residual disease (MRD; ≥0.01%), both at the end of induction and at the end of consolidation (EOC), were significantly associated with poorer EFS. In the multivariable analysis, positive MRD at EOC was solely associated with poor EFS (P < .001). Rapid pretransplant MRD clearance and tailored HSCT strategy in the MLL-10 trial resulted in a favorable outcome for infants with HR KMT2A-r ALL. However, considering the high rate of potentially life-threatening toxicities and the risk of late effects, its indication should be further restricted or even eliminated in the future by introducing more effective therapeutic modalities with minimal toxicities. This trial was registered at the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR) as #UMIN000004801.

Single-Arm Non-Blinded Multicenter Clinical Trial on T-Cell-Replete Haploidentical Stem Cell Transplantation Using Low-Dose Antithymocyte Globulin for Relapsed and Refractory Pediatric Acute Leukemia.

Although approximately 70% of pediatric hematological malignancies are curable, approximately 30% remain fatal. No standard treatment is available in patients showing relapse and those with refractory disease. Although different methods are adopted in different hospitals, its efficacy is extremely limited. In recent years, haploidentical stem cell transplantation, involving high-dose cyclophosphamide administration post-transplanta tion, has been used, mainly in adults; however, its application is limited to removal of alloreactive T cells. Multicenter single-arm clinical trials of T-cell replete haploidentical stem cell transplantation (TCR-haplo-SCT) will be conducted in children with relapsed and refractory acute leukemia. After myeloablative conditioning using total body irradiation or busulfan, intensive graft versus host disease prophylaxis is administered, consisting of low-dose rabbit anti-human thymocyte globulin, tacrolimus, methotrexate, and prednisolone. An external control group is set up for the study. The treatment period is around 3 months, and the follow-up period is 2 years from transplantation completion.The aim of this study is to verify the efficacy and safety of TCR-haplo-SCT and present it as a new immune cell therapy for improving survival rate in children with relapsed and refractory acute leukemia.

Reduced-intensity conditioning is effective for hematopoietic stem cell transplantation in young pediatric patients with Diamond-Blackfan anemia.

Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative therapy for the hematologic manifestations of Diamond-Blackfan anemia (DBA). However, data regarding the optimal conditioning regimen for DBA patients are limited. We retrospectively compared the outcomes of DBA patients who underwent HSCT using either myeloablative conditioning (MAC) or reduced-intensity conditioning (RIC) regimens. The patients belonged to a cohort treated at our hospitals between 2000 and 2018. HSCT was performed in 27 of 165 patients (16.4%). The median age at the time of HSCT was 3.6 years. Stem cell sources included bone marrow for 25 patients (HLA-matched sibling donors, n = 5; HLA-mismatched related donors, n = 2; HLA-matched/mismatched unrelated donors, n = 18) or cord blood for 2 patients. MAC or RIC regimens were used in 12 and 15 patients, respectively. Engraftment was successful in all 27 patients who underwent HSCT. Three patients who underwent HSCT using MAC regimens developed sinusoidal obstruction syndrome. The 3-year overall survival (OS) and failure-free survival rates (FFS) post-transplantations were 95.2% and 88.4%, respectively, with no significant differences between MAC and RIC regimens. Our data suggest that HSCTs using RIC regimens are effective and obtain engraftment with excellent OS and FFS for young DBA patients.

Clinical features of children with polycythemia vera, essential thrombocythemia, and primary myelofibrosis in Japan: A retrospective nationwide survey.

Background: Philadelphia-negative (Ph-negative) myeloproliferative neoplasms (MPNs), including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), are exceptionally rare during childhood. Thus, clinical features of pediatric Ph-negative MPNs remain largely unknown. This study was therefore performed to address this. Methods: We performed a retrospective study to collect clinical information of children diagnosed with Ph-negative MPNs from 2000 to 2016 using questionnaires in qualified institutions in Japan. The results obtained from the questionnaire survey were then combined with those from the national registry data. Results: Among 50 children identified, five had PV, 44 had ET, and one had PMF. Median age at diagnosis was 14.0, 9.0, and 0 years, respectively. Male to female ratio was 4:1, 21:23, and 1:0, respectively. Detection rates of the JAK2 V617F variant were 0/5 in PV and 9/39 in ET. Frequencies of complications, such as thrombosis and subsequent leukemia, were lower than complication frequencies in adults. We identified two children who developed subsequent leukemia, which has not been reported previously, and one of them died. Conclusion: This is the first nationally representative survey of pediatric Ph-negative MPNs. Given its rarity, an international collaboration with comprehensive genetic analyses might be needed to fully elucidate the clinical and genetic features.

Retrospective analysis of children with high-risk acute myeloid leukemia who underwent allogeneic hematopoietic stem cell transplantation following complete remission with initial induction chemotherapy in the AML-05 clinical trial.

In the AML-05 clinical trial conducted by the Japanese Pediatric Leukemia/Lymphoma Group from 2006 to 2010, children with high-risk acute myeloid leukemia (HR AML) received allogeneic hematopoietic stem cell transplantation (allo-HSCT) at first complete remission (CR1). The aim of this study was to investigate the impact of allo-HSCT on the outcome of HR AML. Patients with either monosomy 7, 5q-, t(16;21), Ph1, FLT3-ITD, or induction failure after the first course of chemotherapy were eligible for transplant. Of 53 children with HR AML, 51 received allo-HSCT-45 in CR1, five in CR2, and one with non-CR. t(8;21), t(9;11), and t(16;21) abnormalities were identified in eight, five, and four patients, respectively. The stem cell sources varied-bone marrow in 30 patients, peripheral blood in three, and cord blood in 18. The median follow-up was 62 months. The overall survival (OS) rates at 3 years were 73% and 25% for patients who received transplant at CR1 and ≥CR2, respectively. Multivariable analysis showed that patients with chronic graft-versus-host disease (cGVHD) had better OS. This study supports that allo-HSCT is a suitable treatment for HR AML in CR1. The favorable outcome associated with cGVHD indicates that a graft-versus-leukemia effect might be occurring.

Extracellular signal-regulated kinase activation of self-healing Langerhans cell histiocytosis: A case report.

A 3-month-old boy developed small papules on his trunk. After the papules increased in number, the patient was diagnosed with Langerhans cell histiocytosis based on the pathological findings. He was referred to our department for further examination. Upon initial examination, the papules and nodules were scattered on his back, abdomen and lumbar region. Because he did not present with any organ involvement except the skin, he was diagnosed with single-system and skin-limited Langerhans cell histiocytosis. Skin rashes were treated with a topical steroid and started regressing 3 months after onset. All papules disappeared 6 months after onset. In this boy, the Langerhans cell histiocytosis tumor cells expressed phosphorylated extracellular signal-regulated kinases. In Langerhans cell histiocytosis, BRAF V600E and other genes are known to mutate to act as driver mutations in stem cells of the myeloid dendritic cell lineage. Consequently, extracellular signal-regulated kinases are continuously activated, which contributes to Langerhans cell histiocytosis carcinogenesis.

Possible involvement of IL-6-producing tissue-resident macrophages in early-onset pericardial effusion pathogenesis after hematopoietic stem cell transplantation.

PURPOSE: Pericardial effusion (PE) is a potentially life-threatening complication following hematopoietic stem cell transplantation (HCT). A higher incidence of early-onset PE, unrelated to graft-versus-host disease, before day 100 after HCT has been reported in pediatric patients, but the pathogenic mechanism is poorly understood. Aiming to determine the pathogenesis of early-onset PE in pediatric patients, we analyzed the cytokine concentration and cell population in the pericardial fluid of four pediatric patients with PE. METHODS: Between January 2009 and December 2015, four patients requiring pericardiocentesis for clinically significant PE were identified in 60 patients. We evaluated the interleukin-6 (IL-6), interferon-γ, IL-1ß, and tumor necrosis factor-α levels in PE. Two patients were available for analysis with intracellular cytokine flow cytometry and a chimerism assay. RESULTS: All patients showed the accumulation of pericardial macrophages and high concentrations of IL-6 in PE. Notably, the accumulated pericardial macrophages were CD163+ CD15+ CD14+ cells of host origin that produced IL-6. CONCLUSION: These IL-6-producing tissue-resident macrophages may be key players in the pathogenesis of early-onset PE.

Constitutional abnormalities of IDH1 combined with secondary mutations predispose a patient with Maffucci syndrome to acute lymphoblastic leukemia.

Maffucci syndrome is a nonhereditary disorder caused by somatic mosaic isocitrate dehydrogenase 1 or 2 (IDH1 or IDH2) mutations and is characterized by multiple enchondromas along with hemangiomas. Malignant transformation of enchondromas to chondrosarcomas and secondary neoplasms, such as brain tumors or acute myeloid leukemia, are serious complications. A 15-year-old female with Maffucci syndrome developed B-cell precursor acute lymphoblastic leukemia (BCP-ALL). A somatic mutation in IDH1 was detected in hemangioma and leukemic cells. KRAS mutation and deletion of IKZF1 were detected in leukemic cells. Patients with Maffucci syndrome may, therefore, be at risk of BCP-ALL associated with secondary genetic events that affect lymphocyte differentiation.

Comparison of second transplantation and donor lymphocyte infusion for donor mixed chimerism after allogeneic stem cell transplantation for nonmalignant diseases.

BACKGROUND: Donor mixed chimerism (MC) is an increasing problem after hematopoietic stem cell transplantation (HSCT) for nonmalignant diseases. PROCEDURE: In this study, a self-administered questionnaire was used to retrospectively compare efficacy and safety in 49 patients undergoing second HSCT (n = 13) or donor lymphocyte infusion (DLI; n = 36) as treatment for MC. RESULTS: The response rate to DLI of patients with secondary graft failure (GF) (25.0%) was significantly lower than that of patients without secondary GF (81.3%; P = 0.041). Among patients undergoing DLI, the rates of successful response were significantly higher in patients having at least 30% donor chimerism (94.1%) than in patients having less than 30% donor chimerism (61.1%; P = 0.041). Furthermore, the rates of successful response were significantly higher in patients receiving larger first or maximum doses of DLI. Sixteen (50.0%) of 32 patients without secondary GF attained complete chimerism after DLI. The cumulative incidence of grade II-IV acute graft-versus-host disease and cytopenia was 37.6 and 26.1%, respectively. CONCLUSIONS: DLI yields promising response rates in most patients with higher donor chimerism levels, whereas second HSCT is more likely to benefit patients with lower donor chimerism levels.

Sarcomatoid Carcinoma of the Bladder in a Child: Case Report of a Successful Treatment Including Gemcitabine and Cisplatin.

This report describes an unusual case of sarcomatoid carcinoma of the bladder in a 3-year-old girl. Although saving the patient's life is most essential, it is also essential to consider quality of life. The patient underwent neoadjuvant chemotherapy with gemcitabine and cisplatin for bladder preservation. The tumor considerably decreased in size. After 4 courses of chemotherapy, the patient underwent a partial cystectomy followed by postoperative irradiation with 2 courses of chemotherapy. Seventy months after the operation, she remains alive, showing complete remission with normal bladder function. Chemotherapy resulted in tumor shrinkage and allowed for bladder preservation.

Invasive Bacterial Infection in Patients with Interleukin-1 Receptor-associated Kinase 4 Deficiency: Case Report.

Interleukin-1 receptor-associated kinase 4 (IRAK4) deficiency (OMIM #607676) is a rare primary immunodeficiency of innate immune defect. We identified 10 patients from 6 families with IRAK4 deficiency in Japan, and analyzed the clinical characteristics of this disease. Nine patients had homozygous c.123_124insA mutation, and 1 patient had c.123_124insA and another nonsense mutation (547C>T). Umbilical cord separation occurred on the 14th day after birth or thereafter. Two patients had no severe infections owing to the prophylactic antibiotic treatment. Severe invasive bacterial infections occurred before the age of 3 in the other 8 patients. Among them, 7 patients had pneumococcal meningitis. Five patients died of invasive bacterial infection during infancy, although intravenous antibiotic treatment was started within 24 hours after onset in 4 patients among them. Analysis of cerebrospinal fluid of the patients who had fatal meningitis revealed very low glucose levels with only mild pleocytosis. The clinical courses of invasive bacterial infections were often rapidly progressive despite the early, appropriate antibiotic treatment in IRAK4 deficiency patients. The early diagnosis and appropriate prophylaxis of invasive bacterial infections are necessary for the patients.