Future Perspective for ALK-Positive Anaplastic Large Cell Lymphoma with Initial Central Nervous System (CNS) Involvement: Could Next-Generation ALK Inhibitors Replace Brain Radiotherapy for the Prevention of Further CNS Relapse?

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.

Intensification of treatment with vinca alkaloid does not improve outcomes in pediatric patients with Langerhans cell histiocytosis: results from the JPLSG LCH-12 study.

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.

Systemic herpes simplex virus infection in a child with eczema herpeticum.

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.

[Elucidated pathogenesis and therapeutic prospects in Langerhans cell histiocytosis].

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.

An aggressive systemic mastocytosis preceded by ovarian dysgerminoma.

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.

Attempts to optimize postinduction treatment in childhood acute myeloid leukemia without core-binding factors: A report from the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG).

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.

Long-term outcomes of children with extracutaneous juvenile xanthogranulomas in Japan.

BACKGROUND: Juvenile xanthogranuloma (JXG) is the most common non-Langerhans cell histiocytosis in children. The mortality and morbidity of JXG with extracutaneous lesions remain unclear. METHODS: Data of patients aged < 18 years who were diagnosed with JXG between 2001 and 2010 were retrospectively collected through a nationwide survey. RESULTS: Twenty patients (11 male and nine female) had extracutaneous lesions. The median observation time was 10 years (range, 0-17). Six patients presented with symptoms at birth. The median age at diagnosis was 8.5 months (range, 0 month-13 years). Fifteen patients underwent treatment for JXG, including chemotherapy (n = 11), and five did not receive treatment. All patients except one survived; 17 were disease-free and two survived with disease. One newborn-onset patient with liver, spleen, and bone marrow involvement died of the disease. Permanent sequelae included central diabetes insipidus, growth hormone deficiency, and panhypopituitarism detected at diagnosis in three, one, and two patients, respectively. Four patients had visual impairment (optic nerve compression and intraocular invasion in two each), three had epilepsy, one had mental retardation, and one had a skin scar. Eight patients who had intracranial lesions were older at diagnosis, and had a higher frequency of disease-related comorbidities and permanent sequelae than those without intracranial involvement. CONCLUSIONS: Patients with extracutaneous JXG had good outcomes, although those with intracranial lesions had serious permanent sequelae. Effective and safe treatment regimens for patients with intracranial JXG need to be developed.

Conditioning regimen for allogeneic bone marrow transplantation in children with acquired bone marrow failure: fludarabine/melphalan vs. fludarabine/cyclophosphamide.

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.

Hematopoietic stem cell transplantation for pediatric acute promyelocytic leukemia in Japan.

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.

Frequency of subclinical herpes zoster in pediatric hematology-oncology patients receiving chemotherapy: A retrospective cohort analysis.

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.

Nationwide retrospective review of hematopoietic stem cell transplantation in children with refractory Langerhans cell histiocytosis.

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. 54.5%, respectively, p = 0.040). Disease state at the time of HSCT was the most important prognostic factor.

Human herpesvirus-6B infection in pediatric allogenic hematopoietic stem cell transplant patients: Risk factors and encephalitis.

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.

Hematopoietic stem cell transplantation for pediatric acute myeloid leukemia patients with KMT2A rearrangement; A nationwide retrospective analysis in Japan.

OBJECTIVE: Pediatric acute myeloid leukemia (AML) with KMT2A rearrangement is detected in 15-20% of all pediatric AML patients and is associated with adverse outcomes even after allogeneic hematopoietic stem cell transplantation (HSCT). To investigate outcomes and prognostic factors, we investigated 90 pediatric AML patients with KMT2A rearrangement after allogeneic HSCT. METHODS: We retrospectively analyzed Japanese registration data for patients who had received allogeneic HSCT between 1988 and 2011. Median age was 3 years (range, 0-15 years), and no gender difference was evident. Median observation period was 119 months. RESULTS: The 3-year overall survival (OS) rate of KMT2A-rearranged AML was 52.1% (95% confidence interval (CI), 42.4-64%, n = 90), and the 3-year disease-free survival (DFS) rate was 46.7% (95%CI, 36.8-58.2%). The 3-year DFS of KMT2A-rearranged AML was not significantly poorer than that of other AML (P = 0.09), and no significant difference was also seen in 3-year OS rate (P = 0.21). Multivariate analysis showed disease status (complete remission) at HSCT was associated with better outcomes. A significant difference in treatment-related mortality (TRM) was apparent between HSCT from a HLA full-matched related donor and that from a haploidentical donor (P = 0.001). DISCUSSION: HSCT is a curative option for pediatric AML with KMT2A rearrangement. Pretransplant status was the most significant prognostic indicator for relapse and survival. Enhancing supportive therapy to reduce TRM will further improve treatment outcomes of KMT2A-rearranged pediatric AML.

[Status of Langerhans cell histiocytosis in children and adults].

Whether Langerhans cell histiocytosis (LCH) is an inflammatory disorder or a neoplasm is an ongoing debate. On the basis of the identification of the BRAF V600E mutation in 2010, LCH should be defined as an inflammatory myeloid neoplasia. Mutually exclusive BRAF V600E (50-60%) and MAP2K1 (12-25%) mutation renders the ERK activation. BRAF V600E mutations were detected in approximately 50-60% of patients with Erdheim-Chester disease (ECD), and these patients are being treated with vemurafenib, a selective BRAF V600 kinase inhibitor, approved by the US Food and Drug Administration. The Japan Langerhans cell histiocytosis study group-02 protocol study showed five-year overall survival rate of 92% and event-free survival of 46% in risk-organ involvement of positive multi-system LCH. We aimed to improve the quality of life by reducing relapses and development of late complications. It is essential to achieve a close cooperation between hematologists catering to pediatric and adult patients with LCH. Furthermore, novel targeted therapies of MAPK inhibitors are required along with intensified chemotherapy to achieve better outcomes in patients with LCH in Japan.

Hematopoietic stem-cell transplantation in children with refractory acute myeloid leukemia.

Allogeneic hematopoietic stem cell transplantation (HSCT) can be used to treat children with refractory acute myeloid leukemia (AML). This retrospective analysis aimed to describe the outcomes and risk factors in such children. Data were collected through the nation-wide registry program in Japan. A total of 417 AML (median age: 13 years) patients 20 years or younger at HSCT, between January 2001 and December 2015, were included. A total of 314 patients died, and the median follow-up duration of the survivors was 1052 days. The most frequent cause of death was leukemia progression (58%). The 3-year overall survival (OS) rate was 23% (95% confidence interval [CI]: 19-28%). Chronic GVHD was associated with improved 3-year OS (47%, 95% CI, 36-57%, hazard ratio: 0.603, p = 0.001). Low performance status, presence of more than 25% of marrow blasts, presence of blasts in the blood at transplantation, FAB (other than M1 or M2), male donors, and number of transplantations ≥ 2 were adverse pre-HSCT variables. Patients with 0, 1-2, 3-4, 5, and 6-7 pre-HSCT variables had 3-year OS rates of 52%, 32%, 19%, 8, and 0%, respectively. Our findings may help experts decide if HSCT should be performed in such cases.

Impact of graft-versus-host disease on relapse and survival after allogeneic stem cell transplantation for pediatric leukemia.

Graft-versus-host disease (GVHD) occasionally leads to morbidity and mortality but is thought to reduce the risk of relapses in patients with a hematological malignancy. However, information on the effect of GVHD in pediatric leukemia is limited. Using a nationwide registry, we retrospectively analyzed 1526 children who underwent allogeneic stem cell transplantation for leukemia. Grades 0-I acute GVHD were associated with a higher relapse rate at three years after transplantation, at 25.4 and 24.3%, respectively, than grades II, III, or IV acute GVHD at 18.9%, 21.2%, and 2.6%, respectively. In contrast, the overall survival curve of the grades 0 and I GVHD groups (79.0% and 79.5%, respectively) approximated that of the grade II GVHD group (76.3%), and the probability of survival was worst in the severe GVHD groups (66.9% for grade III and 42.5% for grade IV). Chronic GVHD also reduced the relapse risk but conferred no survival advantage. Acute lymphoblastic leukemia was more sensitive to acute GVHD than acute myeloid leukemia (AML) while AML was more sensitive to chronic GVHD. Our study reproduced the preventive effects of GVHD against pediatric leukemia relapses but failed to demonstrate a significant survival advantage.

Comparison of conditioning regimens for autologous stem cell transplantation in children with acute myeloid leukemia: A nationwide retrospective study in Japan.

BACKGROUND: Indications for hematopoietic stem cell transplantation (HSCT) have decreased with the improvement in chemotherapy for pediatric acute myeloid leukemia (AML) in the last decade. We conducted reevaluation of autologous HSCT (AHSCT) to compare myeloablative conditioning (MAC) regimens for pediatric AML without the need for consideration of toxicities caused by allogeneic immune reactions. PROCEDURE: This retrospective study analyzed the clinical outcomes of 220 children with AML who underwent consecutive AHSCT between 1989 and 2002 in Japan by the national prospective registry. The transplantation outcomes of various conditioning regimens were compared. RESULTS: The median follow-up period of the survivors was 160 months. The clinical outcomes of busulfan + cyclophosphamide ± etoposide or busulfan + melphalan regimens were significantly superior compared with other busulfan-based and total body irradiation-based regimens (leukemia-free survival [LFS]: 68% vs 42% and 55%, P = 0.001; overall survival [OS]: 74% vs 49% and 61%, P < 0.001). Multivariate analysis showed that busulfan + cyclophosphamide ± etoposide and busulfan + melphalan regimens were independent favorable factors for LFS (hazard ratio: 0.46; P < 0.001) and OS (hazard ratio: 0.40; P < 0.001) compared with the other busulfan-based regimen, and both age 2 years or older and advanced stage at AHSCT were independent poor predictors for LFS and OS, simultaneously. CONCLUSION: Busulfan + cyclophosphamide ± etoposide and busulfan + melphalan regimens exhibited superior antileukemic effects compared with other BU-based myeloablative regimens.