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.

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.

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.

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.

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.

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.

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.

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.

[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.

Late-phase human herpesvirus 6B reactivation in hematopoietic stem cell transplant recipients.

BACKGROUND: We sought to determine whether late-phase human herpesvirus 6B (HHV-6B) infection in hematopoietic stem cell transplant (HSCT) recipients was associated with serious outcomes and mortality. METHODS: The occurrence and course of HHV-6B infection was monitored for at least 60 days after transplant using virus isolation and real-time polymerase chain reaction. Risk factors for late-phase HHV-6B infection were examined, and the propensity score was calculated with significant risk factors. The inverse probability-weighted multivariable logistic regression analysis was performed to estimate odds ratios (ORs) and the 95% confidence intervals (95% CI) for mortality. RESULTS: Late-phase HHV-6B infection was observed in 12/89 (13.5%) of the HSCT recipients. Older age (OR: 10.3, 95% CI: 2.1/72.9, P = .0027), hematologic malignancy (OR: 10.3, 95% CI: 1.8/97.1, P = .0063), unrelated donor transplantation (OR: 5.3, 95% CI: 1.1/36.0, P = .0345), and sex-mismatched donor transplantation (OR: 6.3, 95% CI: 1.4/39.5, P = .0149) were identified as risk factors for late-phase HHV-6B infection. Fifteen subjects died (17%). Inverse probability-weighted multivariable logistic model analysis revealed that late-phase HHV-6B infection was an independent risk factor for mortality (OR: 4.2, 95% CI: 1.7/11.0, P = .0012). Among 5 of the fatal cases of late-phase HHV-6B infection, viral infection might be associated with severe clinical manifestations. CONCLUSION: Late-phase HHV-6B infection in HSCT recipients was associated with worse outcomes. The full spectrum of clinical features of the infection has not been fully elucidated, and therefore, recipients with high-risk factors for late-phase HHV-6B infection should be carefully monitored.

Secondary cancer after a childhood cancer diagnosis: viewpoints considering primary cancer.

BACKGROUNDS: Multidisciplinary therapy has increased the risk of subsequent late effects, but detailed analyses on secondary cancers in childhood cancer survivors (CCSs) are limited in Asian countries. METHODS: This was a retrospective cohort study comprising 10,069 CCSs who were diagnosed between 1980 and 2009 across 15 Japanese hospitals. We conducted secondary analyses to estimate the incidence of secondary cancer according to each primary malignancy and to elucidate the association between primary and secondary cancers. We also explored the risk factors for the development of secondary cancer in each independent primary malignancy. RESULTS: The cumulative incidence of secondary cancer at 20 years varied among primary cancers: hematological malignancy, 3.1% (95% CI 2.2-4.3); retinoblastoma, 6.6% (95% CI 1.5-16.8); pediatric solid tumor, 2.5% (95% CI 1.3-4.2); brain tumors, 5.2% (95% CI 1.7-11.8) bone/soft tissue sarcoma, 5.2% (95% CI 2.3-10.1); and others, 3.3% (95% CI 1.6-6.0) (p = 0.015). The cumulative incidence of secondary cancers is highest in those with osteosarcoma (13.1%) followed by those with hepatoblastoma (8.4%) and retinoblastoma (6.6%). Close association between the primary and secondary cancer diagnoses was found. The risk factors for secondary cancer development depended on the primary cancer, but autologous/allogeneic stem cell transplantation was a relatively common risk factor. CONCLUSION: The cumulative incidence of secondary cancer varied among primary cancers. The primary cancer was closely associated with the secondary cancer but stem cell transplantation was a common risk factor for secondary cancers among CCSs.

Case report of severe myocarditis in an immunocompromised child with Respiratory Syncytial Virus infection.

BACKGROUND: Respiratory syncytial virus (RSV) infection is common and may be severe among patients with preexisting cardiac anomalies, but direct involvement of myocardial damage is not common in those patients. Additionally, myocardial involvement has been rarely described among immune compromised children. CASE PRESENTATION: A 4-year-old girl with acute lymphoblastic leukemia who received maintenance chemotherapy in an outpatient clinic developed systemic inflammatory response syndrome. RSV infection was confirmed by a positive rapid antigen test and serological assay. Subsequently, she was diagnosed with severe myocarditis caused by RSV infection, which was diagnosed by abnormal findings of cardiac echography and ECG and elevated biomarkers for myocardial damage. Then, she was treated in the intensive care unit for 13 days. High amounts of RSV type B RNA was detected in tracheal aspirates and serum sample. CONCLUSION: This case report emphasizes that RSV infection may be associated with myocarditis in immunocompromised children receiving maintenance chemotherapy.

Allogeneic Hematopoietic Stem Cell Transplantation for Adolescents and Young Adults with Acute Myeloid Leukemia.

Few reports have focused on adolescent and young adult (AYA) patients with acute myeloid leukemia (AML) treated with hematopoietic stem cell transplantation (HSCT). We performed a retrospective analysis based on data obtained from a Japanese nationwide registration database to compare HSCT outcomes in AYA patients with AML with those in children with AML. An analysis of the 2973 patients with de novo AML who received allogeneic HSCT from 1990 to 2013 showed inferior 5-year overall survival (OS) (54% versus 58%, P <.01) and increased treatment-related mortality (TRM) (16% versus 13%, P = .02) in AYA patients. Multivariate analysis for both OS and TRM showed a significant negative impact on AYAs. However, the negative impact of older age lost its significance in an additional analysis focusing on 1407 recent transplant recipients with high-resolution HLA typing (2000 to 2013). Finally, we analyzed the impact of transplantation center type on HSCT outcomes in 317 adolescent patients (15 to 18 years old) and found no difference in outcomes between patients treated at a pediatric or an adult hospital. Higher age was a strong predictive factor for inferior OS resulting from increased TRM, which can be eliminated with better donor selection using high-resolution HLA typing.

Inflammatory serum cytokines and chemokines increase associated with the disease extent in pediatric Langerhans cell histiocytosis.

OBJECTIVE: Langerhans cell histiocytosis (LCH) is characterized by immature dendritic cell proliferation, infiltration of LCH lesions by various inflammatory cells, and a lesional cytokine storm. It is classified into three groups on the basis of disease extent, namely, multisystem with risk-organ involvement (MS+), multisystem without risk-organ involvement (MS-), and single-system (SS) disease. We comprehensively analyzed whether serum levels of cytokines/chemokines reflect the disease extent. METHODS: Serum samples from 52 children with LCH (eight, 25, and 19 with MS+, MS-, and SS, respectively) and 34 control children were analyzed quantitatively for 48 humoral factors. DNA samples extracted from biopsied LCH lesions from 12 patients were tested for BRAF V600E status. RESULTS: The LCH patients had significantly higher serum levels of IL-1Ra, IL-3, IL-6, IL-8, IL-9, IL-10, IL12, IL-13, IL-15, IL-17, IL-18, TNF-α, G-CSF, M-CSF, MIF, HGF, VEGF, CCL2, CCL3, CCL7, CXCL1, and CXCL9 than the controls by univariate analysis. Of these IL-9, IL-15 and MIF were significant by multivariate analysis; but not differed between MS and SS diseases. MS disease associated with significantly higher IL-2R, IL-3, IL-8, IL-18, M-CSF, HGF, CCL2, CXCL1, and CXCL9 levels than SS disease by univariate analysis. Of these, CCL2 and M-CSF were significant by multivariate analysis. IL-18 levels were significantly higher in MS+ disease than MS- disease. The LCH patients with BRAF V600E mutation had higher serum levels of CCL7. CONCLUSION: Numerous inflammatory cytokines and chemokines play a role in LCH. Of those, more specific ones reflect the disease extent (MS vs. SS and MS+ vs. MS-) or the BRAF V600E mutation status. It is thought that the most responsible cytokines and chemokines involved in the poor outcome may become future candidate therapeutic targets in LCH.

Long-term outcomes of 95 children with moderate aplastic anemia treated with horse antithymocyte globulin and cyclosporine.

BACKGROUND: Currently, the standard management of moderate aplastic anemia (MAA) has not been well described, although the superiority of the combination of antithymocyte globulin (ATG) and cyclosporine (CyA) over CyA alone has been demonstrated in terms of hematological responses and failure-free survival (FFS). PROCEDURE: We adopted this therapeutic strategy and treated 95 children with MAA who were enrolled in two consecutive prospective studies between October 1992 and August 2009. RESULTS: For these patients, the 6-month response rate was 54.7% (complete response, 13.7%; partial response, 41.1%). There were no statistically significant differences in the overall response rates between the transfusion-dependent (48.8%, n = 41) and transfusion-independent groups (59.3%, n = 54; P = 0.4). Treatment failure was defined as the requirement of salvage treatment, and was observed in 52 patients. The 10-year FFS was 44.0% (95% confidence interval [CI], 32.9%-54.6%). Of the 22 patients who underwent a second immunosuppressive therapy (IST), 12 responded. Forty patients underwent hematopoietic stem cell transplantation as second- or third-line therapy and three died of complications. Consequently, the 10-year overall survival rate was 96.0% (95% CI, 88.0%-98.7%) with a median follow-up period of 103 months (range, 29-221 months). CONCLUSIONS: Although current guidelines recommend only observation for patients with transfusion-independent MAA, the results of our study justify early intervention with ATG and CyA in those patients. A prospective randomized trial is warranted to clarify the risks and benefits of early intervention with IST and observation alone until progression to severe AA in patients with MAA.

High event-free survival rate with minimum-dose-anthracycline treatment in childhood acute promyelocytic leukaemia: a nationwide prospective study by the Japanese Paediatric Leukaemia/Lymphoma Study Group.

We evaluated the efficacy of treatment using reduced cumulative doses of anthracyclines in children with acute promyelocytic leukaemia (APL) in the Japanese Paediatric Leukaemia/Lymphoma Study Group AML-P05 study. All patients received two and three subsequent courses of induction and consolidation chemotherapy respectively, consisting of all-trans retinoic acid (ATRA), cytarabine and anthracyclines, followed by maintenance therapy with ATRA. Notably, a single administration of anthracyclines was introduced in the second induction and all consolidation therapies to minimize total doses of anthracycline. The 3-year event-free (EFS) and overall survival rates for 43 eligible children were 83·6% [95% confidence interval (CI): 68·6-91·8%] and 90·7% (95% CI: 77·1-96·4%), respectively. Although two patients died of intracranial haemorrhage or infection during induction phases, no cardiac adverse events or treatment-related deaths were observed during subsequent phases. Patients not displaying M1 marrow after the first induction therapy, or those under 5 years of age at diagnosis, showed inferior outcomes (3-year EFS rate; 33·3% (95% CI: 19·3-67·6%) and 54·6% (95% CI: 22·9-78·0%), respectively). In conclusion, a single administration of anthracycline during each consolidation phase was sufficient for treating childhood APL. In younger children, however, conventional ATRA and chemotherapy may be insufficient so that alternative therapies should be considered.

Whole-exome sequencing reveals the spectrum of gene mutations and the clonal evolution patterns in paediatric acute myeloid leukaemia.

Acute myeloid leukaemia (AML) is a molecularly and clinically heterogeneous disease. Targeted sequencing efforts have identified several mutations with diagnostic and prognostic values in KIT, NPM1, CEBPA and FLT3 in both adult and paediatric AML. In addition, massively parallel sequencing enabled the discovery of recurrent mutations (i.e. IDH1/2 and DNMT3A) in adult AML. In this study, whole-exome sequencing (WES) of 22 paediatric AML patients revealed mutations in components of the cohesin complex (RAD21 and SMC3), BCORL1 and ASXL2 in addition to previously known gene mutations. We also revealed intratumoural heterogeneities in many patients, implicating multiple clonal evolution events in the development of AML. Furthermore, targeted deep sequencing in 182 paediatric AML patients identified three major categories of recurrently mutated genes: cohesion complex genes [STAG2, RAD21 and SMC3 in 17 patients (8·3%)], epigenetic regulators [ASXL1/ASXL2 in 17 patients (8·3%), BCOR/BCORL1 in 7 patients (3·4%)] and signalling molecules. We also performed WES in four patients with relapsed AML. Relapsed AML evolved from one of the subclones at the initial phase and was accompanied by many additional mutations, including common driver mutations that were absent or existed only with lower allele frequency in the diagnostic samples, indicating a multistep process causing leukaemia recurrence.

Role of Second Transplantation for Children With Acute Myeloid Leukemia Following Posttransplantation Relapse.

BACKGROUND: In children with acute myeloid leukemia (AML), hematopoietic stem cell transplantation (HSCT) in first remission is indicated for patients with a relatively high risk of relapse. Second HSCT is a curative option; however, few reports have been published about a second HSCT in children for AML with posttransplantation relapse. PROCEDURE: Using the database provided by the Japanese Society of Hematopoietic Cell Transplantation, we analyzed 46 children with AML who underwent a second allogeneic HSCT after achieving a second remission. RESULTS: The median duration from the first to second HSCT was 20 months, and the source of the second HSCT was related bone marrow (BM) in 22, related peripheral blood in 6, unrelated BM in 14, and unrelated cord blood in 4 patients. Twenty-five children eventually died of the following causes: progressive disease in 14 and transplant-related toxicities in 9. The 5-year overall survival rate was 41.7 ± 7.7%. An interval of less than 24 months between the first and second HSCT was a significant poor prognostic factor. CONCLUSIONS: Children with AML who experience a relapse after HSCT in first remission have a good chance of survival with a second HSCT if a second remission is achieved.