工藤 寿子

INTRODUCTION: Although the prognosis of Langerhans cell histiocytosis (LCH) is excellent, the high recurrence rate and permanent consequences, such as central diabetes insipidus and LCH-associated neurodegenerative diseases, remain to be resolved. Based on previous reports that patients with high-risk multisystem LCH show elevated levels of inflammatory molecules, we hypothesised that dexamethasone would more effectively suppress LCH-associated inflammation, especially in the central nervous system (CNS). We further hypothesised that intrathecal chemotherapy would effectively reduce CNS complications. We administer zoledronate to patients with multifocal bone LCH based on an efficacy report from a small case series. METHODS AND ANALYSIS: This phase II study (labelled the LCH-19-MSMFB study) is designed to evaluate the significance of introducing dexamethasone and intrathecal chemotherapy for multisystem disease and zoledronate for multifocal bone disease in previously untreated, newly diagnosed children, adolescents (under 20 years) and adults under 40 years. The primary endpoint is the 3-year event-free survival rate by risk group of under 20 years and the 3-year event-free survival rate of 20 years and over. ETHICS AND DISSEMINATION: This study was approved by the Central Review Board of the National Hospital Organisation Nagoya Medical Centre (Nagoya, Japan) on 21 January 2022 and was registered in the Japan Registry of Clinical Trials (https://jrct.niph.go.jp/en-latest-detail/jRCTs041210027). Written informed consent will be obtained from all patients and/or their guardians. TRIAL REGISTRATION NUMBER: jRCTs041210027.

About 100 cases of Langerhans cell histiocytosis (LCH) occur annually in Japan. It predominantly occurs in infants, presenting as multisystem disease or multifocal bone involvement. However, LCH can also occur in adults aged 20 to 40. Single-system skin involvement is rare, with most cases presenting with multisystem disease, including bone lesions, which respond to chemotherapy. In adults, lung lesions that improve with smoking cessation are well-known, although multisystem disease is more common and requires aggressive therapeutic intervention similar to that in children. In some infant cases, progression of liver, spleen, and bone marrow lesions can be difficult to control and can become severe. However, targeted molecular therapies are now available as a lifesaving option. More than 30% of cases of multisystem LCH recur at least once, often leading to long-term complications. In particular, the emergence of central diabetes insipidus, anterior pituitary dysfunction, and central nervous system neurodegenerative disorders several years after the diagnosis of LCH is a unique feature not observed in other diseases. New therapeutic strategies are needed to counter these problems.

Chemotherapy with cytarabine, vincristine (VCR), and prednisolone has achieved low mortality rates in pediatric patients with Langerhans cell histiocytosis (LCH). However, relapse rates remain high, making event-free survival (EFS) rates unsatisfactory. A nationwide clinical trial, LCH-12, tested a modified protocol in which the early maintenance phase was intensified with increasing dosages of VCR. Patients newly diagnosed with multifocal bone (MFB) or multisystem (MS) LCH and aged < 20 years at diagnosis were enrolled between June 2012 and November 2017. Of the 150 eligible patients, 43 with MFB were treated for 30 weeks and 107 with MS LCH were treated for 54 weeks. One patient with MS LCH died of sepsis during the induction phase. The 3-year EFS rates among patients with MFB LCH, risk organ (RO)-negative MS LCH, and RO-positive MS LCH were 66.7% (95% confidential interval [CI], 56.5-77.0%), 66.1% (95% CI 52.9-76.4%), and 51.1% (95% CI 35.8-64.5%), respectively, similar to previously observed rates. EFS rates were significantly lower in patients with disease activity scores > 6 than in those with scores ≤ 6. The strategy that included more intense treatment with VCR was not effective. Other strategies are required to improve outcomes in patients with pediatric LCH.

Central nervous system (CNS) involvement in anaplastic large cell lymphoma (ALCL) at diagnosis is rare and leads to poor prognosis with the use of the standard ALCL99 protocol alone. CNS-directed intensive chemotherapy, such as an increased dose of intravenous MTX, increased dose of dexamethasone, intensified intrathecal therapy, and high-dose cytarabine, followed by cranial irradiation, has been shown to improve survival in this population. In this paper, the authors describe a 14-year-old male with an intracranial ALCL mass at onset who received CNS-directed chemotherapy followed by 23.4 Gy of whole-brain irradiation. After the first systemic relapse, the CNS-penetrating ALK inhibitor, alectinib, was applied; it has successfully maintained remission for 18 months without any adverse events. CNS-penetrating ALK inhibitor therapy might prevent CNS relapse in pediatric ALK-positive ALCL. Next-generation ALK inhibitors could be introduced as a promising treatment option, even for primary ALCL with CNS involvement, which could lead to the omission of cranial irradiation and avoid radiation-induced sequalae. Further evidence of CNS-penetrating ALK inhibitor combined therapy for primary ALK-positive ALCL is warranted to reduce radiation-induced sequalae in future treatments.

Eczema herpeticum (EH) is a disseminated cutaneous infection with herpes simplex virus (HSV) that develops in patients with atopic dermatitis. The kinetics and clinical significance of HSV viremia in EH are poorly understood. Herein, we report HSV DNAemia in a child with EH 12 months after the completion of chemotherapy for Hodgkin lymphoma.

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Langerhans cell histiocytosis (LCH) is characterized by immature dendritic cell proliferation, which is currently classified as an inflammatory myeloid neoplasm. Clinical features and outcomes vary from spontaneously regressing isolated bone disease to fatal liver, spleen, or hematopoietic system (risk organ) involvement-positive multisystem disease. LCH cells have the only mutation in the mitogen-activated protein kinase (MAPK) signaling pathway gene, represented by the BRAF V600E mutation, which is the driver mutation. The type of disease depends on the stage of hematopoietic cell differentiation at which the mutation occurs. LCH cells acquire anti-apoptosis and senescence-associated secretory phenotype by oncogene-induced senescence, with migration failure to lymph nodes. These cause LCH cell accumulation and various inflammatory cell recruitment in the lesion, resulting in severe inflammation. Tissue damage in LCH is due to this inflammation, not the LCH cell proliferation. Patients with a risk of organ involvement without the initial treatment response may be rescued by allogeneic hematopoietic stem cell transplantation after reducing the disease activity with MAPK inhibitors. Intravenous zoledronic acid and intrathecal cytarabine injections have been introduced into the ongoing clinical trial in Japan to reduce bone recurrence and prevent neurodegeneration as sequelae.

We previously reported that risk-stratified therapy and intensive postremission chemotherapy (PRC) contributed to the improved survival of childhood acute myeloid leukemia (AML) in the AML99 study, which led us to consider a reduction in the number of PRC courses with more restrictive indications for stem cell transplantation (SCT) in the successor AML-05 study. We here report the outcome of AML patients without core-binding factor mutation (non-CBF AML) in the AML-05 study. Two-hundred eighty-nine children (age < 18 years old) with non-CBF AML were eligible. Patients with unfavorable cytogenetics and/or poor bone marrow response to the first induction course were candidates for SCT in the AML-05 study. After two courses of induction, a further three courses of PRC were given in AML-05, while four courses were given in the AML99 study. The 3-year event-free survival (EFS) rate in the AML-05 study (46.7%, 95% CI: 40.6-52.6%) was comparable to that of non-CBF AML in the AML99 study (51.5%, 95% CI: 42.7-59.6%) (P = .16). However, the 3-year overall survival (OS) rate in the AML-05 study (62.9%, 95% CI: 56.3-68.8%) was slightly lower than that in the AML99 study (71.6%, 95% CI: 63.2-78.5%) (P = .060), mainly due to decreased remission induction rate and increased nonrelapsed mortality. In conclusion, reductions in the number of PRC courses from four to three, together with repetitive cycles of high-dose cytarabine, were acceptable for non-CBF childhood AML.

BACKGROUND: Aggressive systemic mastocytosis (ASM) is a rare malignant disease characterized by disordered mast cell accumulation in various organs. We here describe a female ASM patient with a previous history of ovarian dysgerminoma. METHODS: Molecular cytogenomic analyses were performed to elucidate an etiological link between the ASM and dysgerminoma of the patient. RESULTS: This patient was affected by ovarian dysgerminoma which was treated by chemotherapy and surgical resection. Having subsequently been in complete remission for 2 years, she developed symptoms of ASM. A somatic D816A mutation in the KIT gene was detected in her bone marrow, which facilitated the diagnosis of ASM. Unexpectedly, this KIT D816A variant was also detected in the prior ovarian dysgerminoma sample. Whole-exome sequencing allowed us to identify a somatic nonsense mutation of the TP53 gene in the bone marrow, but not in the dysgerminoma. Microarray analysis of the patient's bone marrow revealed a copy-number-neutral loss of heterozygosity at the TP53 locus, suggestive of the homozygous nonsense mutation in the TP53 gene. In addition, the loss of heterozygosity at the TP53 locus was also detected in the dysgerminoma. CONCLUSIONS: These results indicated that either the mast cells causing the ASM in this case had originated from the preceding ovarian dysgerminoma as a clonal evolution of a residual tumor cell, which acquired the TP53 mutation, or that both tumors developed from a common cancer stem cell carrying the KIT D816A variation.

Varicella-zoster virus (VZV) reactivation from the enteric nervous system can cause ileus (Ogilvie's syndrome) in adult patients. Since no pediatric cases have been described, we sought to retrospectively analyze VZV reactivation in pediatric hematology-oncology patients to determine whether VZV infection including subclinical VZV reactivation can induce gastrointestinal complications such as Ogilvie's syndrome. Thirty-five patients who received chemotherapy at our institution between September 2013 and June 2018 were included. Serum samples were collected weekly during hospitalization and every 3 months during outpatient maintenance chemotherapy. A real-time polymerase chain reaction assay was used to measure VZV DNA load in serum. The clinical features of patients with VZV infection were retrospectively analyzed. Of 1165 serum samples, 7 (0.6%) were positive for VZV DNA. VZV DNA was detected in 3 of 35 patients. In patient A, VZV DNA was detected during two episodes. The first episode involved varicella-like eruptions caused by the Oka VZV vaccine strain. The second episode involved herpes zoster (HZ) caused by the same strain. Patients B and C had a clinical course that was typical for HZ caused by wild-type VZV. No gastrointestinal symptoms were observed at the time of VZV infection in these three patients. VZV DNA was not detected in any other samples. No pediatric cases with Ogilvie's syndrome caused by VZV reactivation were demonstrated in this cohort. Additionally, no subclinical VZV reactivation was found in this cohort. Further study is needed to elucidate the precise incidence of pediatric Ogilvie's syndrome caused by VZV reactivation.

Fludarabine/cyclophosphamide-based conditioning regimens are standard in bone marrow transplantation (BMT) for acquired bone marrow failure in children, however, graft failure may occur. Using the data from a nationwide transplantation registry, we compared the outcomes of children aged <16 years with acquired aplastic anemia and refractory cytopenia of childhood who underwent allogeneic BMT with either fludarabine/melphalan (n = 71) or fludarabine/cyclophosphamide (n = 296) between 2000 and 2016. The fludarabine/melphalan regimen provided excellent outcomes, with 3-year overall survival and failure-free survival rates of 98% and 97%, respectively. The 83% 3-year failure-free survival in the fludarabine/cyclophosphamide group was significantly inferior (P = 0.002), whereas the overall survival did not differ between the two groups. Late graft failure was the most common cause of treatment failure in the fludarabine/cyclophosphamide group, which experienced a significantly higher incidence of late graft failure than the fludarabine/melphalan group (11% vs. 3%; P = 0.035). Multivariate analyses showed that the fludarabine/melphalan regimen was associated with a better failure-free survival (hazard ratio [HR] 0.12; P = 0.005) and lower risk of late graft failure (HR 0.16; P = 0.037). Fludarabine/melphalan-based conditioning regimen can be a promising option for children with acquired bone marrow failure receiving BMT.

BACKGROUND: The number of hematopoietic stem cell transplantation (HSCT) procedures performed for pediatric acute promyelocytic leukemia (APL) has decreased in the all-trans retinoic acid (ATRA) era. Although HSCT is still widely adopted as part of salvage therapy for relapsed patients, there is no general consensus about the optimal transplant type (autologous [auto-HSCT] or allogeneic HSCT [allo-HSCT]). PROCEDURES: We retrospectively reviewed the clinical data of 95 childhood APL patients who underwent their first HSCT between 1990 and 2014. Of the 95 patients, 40 (42%), 41 (43%), and 3 (3%) underwent HSCT procedures after achieving their first complete remission (CR1), CR2, and CR3, respectively, and 11 (12%) underwent HSCT while in a non-CR state. RESULTS: The non-CR group exhibited significantly worse five-year overall survival (5yOS) and disease-free survival (5yDFS) (5yOS: 46%; 5yDFS: 46%) than the CR1 (5yOS: 80%; 5yDFS: 78%) and CR2 + CR3 groups (5yOS: 81%; 5yDFS: 76%) (P = 0.013 and P < 0.01, respectively). Of the patients treated in CR2, no significant differences in 5yOS or the five-year cumulative incidence of relapse (5yRI) were detected between the auto-HSCT and allo-HSCT groups (5yOS: 85%, vs 78%, P = 0.648; 5yRI: 9%, vs 11%, P = 0.828). Among the patients who underwent allo-HSCT in CR2, those with matched sibling donors displayed a significantly higher 5yRI (33%) than those with other types of donors (0%, P = 0.015). CONCLUSIONS: Even after relapsing, childhood APL can be cured with HSCT if CR is achieved. These findings demonstrate that achieving CR followed by HSCT is the preferred strategy for treating children with relapsed or refractory APL.

BACKGROUND: Human herpesvirus-6B (HHV-6B) infection after allogenic hematopoietic stem cell transplantation (allo-HSCT) is known to be associated with post-transplant limbic encephalitis in adults. Meanwhile, the association between HHV-6B infection and central nervous system complications remains unclear in pediatric allo-HSCT patients. METHODS: In this study, HHV-6B infection was monitored for more than 50 days after HSCT using virus isolation and real-time PCR. Clinical information such as patient background and encephalitis status was collected retrospectively from medical records. Risk factors for HHV-6B infection were determined by the Cox proportional hazards model, and the clinical features of HHV-6B encephalitis in pediatric allo-HSCT patients were elucidated. RESULTS: Human herpesvirus-6B infection was observed in 74 (33.8%) of 219 patients at 3-47 days (median 18, interquartile range 13-20). Risk factors identified in multivariable analysis were hematological malignancy (hazards ratio [HR], 5.0; 95% confidence interval [CI], 2.3/12.5; P < .0001), solid tumor (HR, 4.8; CI, 1.5/16.3; P = .0104), unrelated donor (HR, 2.1; CI, 1.0/4.6; P = .0378), and sex-mismatched donor (HR 1.8; CI, 1.1/3.0; P = .0257). HHV-6B encephalitis occurred in only one of the 219 patients (0.46%); this patient demonstrated the typical clinical course of posterior reversible encephalopathy syndrome. CONCLUSION: Hematological malignancy, solid tumor, unrelated donor, and sex-mismatched donor were significant risk factors for HHV-6B infection after pediatric allo-HSCT. In pediatric allo-HSCT patients, the incidence of HHV-6B encephalitis was low and the clinical features differed from those in adult patients.

The efficacy of and indications for hematopoietic stem cell transplantation (HSCT) in pediatric Langerhans cell histiocytosis (LCH) remain undetermined. This retrospective study analyzed 30 children with refractory LCH who underwent HSCT in Japan between 1996 and 2014. Eleven patients received a myeloablative conditioning (MAC) regimen, while 19 patients received a reduced-intensity conditioning (RIC) regimen. Among the 26 patients with complete data, 23 patients had risk organ (RO) involvement during clinical course. Disease status at HSCT was no active disease (NAD) (4), active disease-regression (AD-r) (2), active disease-stable (AD-s) (4), and active disease-progressive (AD-p) (16). Seventeen of the 30 patients (57%) were alive with a median follow-up of 433 days (range 9-5307) after HSCT. Death occurred within 3 months after HSCT in eight of 13 patients. RIC and MAC patients were similar in both overall survival (OS) (56.8% vs. 63.6%, respectively, p = 0.789) and failure-free survival (56.8% vs. 54.6%, respectively, p = 0.938). Regarding disease status at HSCT, the six patients with NAD/AD-r experienced better outcomes than the 20 with AD-s/AD-p (5-year OS, 100% vs. 5

Sinusoidal obstruction syndrome (SOS) is a lethal complication after hematopoietic stem cell transplantation (HSCT). Defibrotide (DF) is the only drug internationally recommended for SOS treatment in Western countries. Recombinant human soluble thrombomodulin (rhTM), which is promising for the treatment of patients with disseminated intravascular coagulation, is also reported to be potentially effective for SOS. To clarify the safety and efficacy of DF and rhTM, we conducted a retrospective survey of these agents in Japan. Data from 65 patients who underwent allogeneic HSCT and received DF (n  =  24) or rhTM (n  =  41) for SOS treatment were collected. The complete response rates for SOS on day 100 were 50% and 54% in the DF and rhTM groups, respectively. The 100-day overall survival rates were 50% in the DF group, and 48% in the rhTM group. Several severe hemorrhagic adverse events were observed in one patient in the DF group and five patients in the rhTM group. The main causes of death were SOS-related death, and no patient died of direct adverse events of DF or rhTM. Our results suggest that rhTM, as well as DF, can be effective as a novel treatment option for SOS.