Trametinib for a child with refractory Rosai-Dorfman-Destombes disease harboring a novel somatic mutation in MAP2K1.

Rosai-Dorfman-Destombes disease (RDD) is a rare histiocytosis characterized by accumulation of S100 + , CD68 + , and CD1a- histiocytes, with emperipolesis. It occurs predominantly in black adolescents and young adults, but rarely in Japanese children. Recently, oncogenic mutations in mitogen-activated protein kinase (MAPK) pathway genes were reported in 30-50% of patients with RDD, and several studies have described treatment of adult patients with MAPK inhibitors. Here, we present the case of a Japanese boy with refractory RDD without signs of cardiofaciocutaneous (CFC) syndrome who harbored MAP2K1 p.Lys59del and responded to trametinib. The patient had lymph node, nasal cavity, kidney, upper respiratory tract, and intracranial involvement. RDD progressed after multi-agent chemotherapy, but responded to trametinib (0.025 mg/kg). Trametinib did not eliminate the mass lesions, but trametinib plus minimal prednisolone (0.1 mg/kg) resulted in a good outcome for more than 15 months, without significant adverse effects. MAP2K1 p.Lys59del has been described as a germline mutation in a patient with CFC syndrome, but not as a somatic mutation in patients with malignancies. Trametinib may be a promising drug for children with RDD that is refractory to multi-agent chemotherapy. Its long-term efficacy and safety alone and in combination with chemotherapy should be investigated.

Allogeneic Hematopoietic Cell Transplantation for Juvenile Myelomonocytic Leukemia with a Busulfan, Fludarabine, and Melphalan Regimen: JPLSG JMML-11.

Juvenile myelomonocytic leukemia (JMML), which is classified as a myelodysplastic/myeloproliferative neoplasm, is a rare hematologic malignancy of childhood. Most patients with JMML require allogeneic hematopoietic cell transplantation (HCT) as a curative therapy. A Japanese retrospective analysis demonstrated favorable outcomes for a busulfan (BU) + fludarabine (FLU) + melphalan (MEL) regimen, with an overall survival (OS) of 72% and an event-free survival (EFS) of 53%. To further validate the efficacy and safety of this regimen, the Japan Pediatric Leukemia/Lymphoma Study Group (JPLSG) conducted a nationwide prospective study, JMML-11. Between July 2011 and June 2017, 28 patients with newly diagnosed JMML were enrolled in JMML11. Low-dose chemotherapy for tumor control before HCT was recommended, and patients treated with AML-type chemotherapy and azacitidine were excluded. The conditioning regimen comprised i.v. BU, 16 doses administered every 6 h, with dose adjustment based on pharmacokinetic (PK) studies on days -11 to -8; FLU, 30 mg/m2/day or 1 mg/kg/day for patients <10 kg or age <1 year on days -7 to -4; and MEL, 90 mg/m2/day or 3 mg/kg/day for patients <10 kg or <1 year on days -3 to -2. The donor was selected by the physician in charge. A family donor was available for 7 patients (3 HLA-matched siblings, 3 HLA-1-antigen mismatched parents, and 1 haploidentical father). Overall, 21 patients received grafts from unrelated donors, including 8 HLA-matched donors and 13 HLA-mismatched donors. The graft source was related bone marrow (BM) for 7 patients, unrelated BM for 14 patients, and unrelated cord blood for 7 patients. Neutrophil engraftment was achieved in 21 of 28 patients (75%), with a median of 20.5 days (range, 11 to 39 days) after transplantation. The 3-year OS, 3-year EFS, 3-year relapse rate, and 3-year transplantation-related mortality were 63% (95% confidence interval [CI], 42% to 78%), 52% (95% CI, 32% to 69%), 18% (95% CI, 6% to 34%), and 21% (95% CI, 9% to 38%), respectively. WBC count before the conditioning regimen (≥7.0 × 109/L) was significantly associated with inferior EFS and OS. Body surface area ≥.5 m2, spleen size <4 cm before conditioning, and HLA-matched unrelated BM donors were significantly associated with better OS. Adverse effects related to the conditioning regimen included febrile neutropenia (86%), diarrhea (39%), hypoxemia (21%), and mucositis (18%). BU-associated toxicity, including sinusoidal obstruction syndrome (SOS) and thrombotic microangiopathy (TMA), occurred in 7 patients (25%; SOS, n = 6; TMA, n = 2). Retrospective analysis of PK data after the first BU dose in 23 patients, including 6 with SOS and 17 without SOS, did not show significant differences between groups. The JMML-11 study confirms the positive results of previous retrospective analyses. BU+FLU+MEL might become a standard conditioning regimen for patients with JMML.

A nationwide survey of late effects in survivors of juvenile myelomonocytic leukemia in Japan.

We conducted a cross-sectional study using a questionnaire to explore the late effects in survivors of allogenic hematopoietic stem cell transplantation (HSCT) for juvenile myelomonocytic leukemia (JMML). The attending pediatric hematologists/oncologists completed the questionnaires. Of the 30 survivors, approximately 83% showed more than one late effect. The identified late effects included endocrine, dental, skin, ophthalmologic, musculoskeletal, pulmonary, neurocognitive, and cardiovascular dysfunction. The prevalence of short stature, pulmonary, cardiovascular, and nephrological complications was significantly elevated among survivors who were 12 years or more lapsed after HSCT. Therefore, a multidisciplinary follow-up system for survivors of JMML is crucial.

A questionnaire study of support for adult survivors of childhood cancer.

BACKGROUND: Childhood cancer survivors (CCSs) entering adulthood experience different problems, including late therapy-related complications. Long-term follow up (LTFU) is important for early intervention and psychosocial support for CCSs with late complications but it is frequently discontinued. This study aimed (i) to identify clearly the factors responsible for LTFU discontinuation, and (ii) to define the support needs of CCSs. METHODS: From July, 2017 to March, 2019 we conducted a questionnaire survey of 121 CCSs aged ≥ 18 years at the time of the survey to investigate people who have experienced childhood cancer and identify their support needs. This was conducted in cooperation with patient associations throughout Japan. The LTFU levels were determined by CCSs themselves based on their treatment history. Long-term follow-up rates and LTFU discontinuation factors were assessed using the Kaplan-Meier method and the Cox proportional-hazards model. RESULTS: Late complications were the most common problem encountered by CCSs (80%). The most common support need was "explanation of late complications by a physician," reported by 86.9% of respondents. The rate of LTFU continuation decreased over time. The LTFU was discontinued both for physicians' reasons (35.6%) and patients' reasons (64.4%). Not knowing the extent or level of one's LTFU was reported to be an independent factor (P < 0.05) preventing LTFU continuation. As necessary support to continue LTFU, 67.9% of respondents stated the need for "explanation of LTFU by a doctor" and 60.7% stated "convenience of outpatient visit". CONCLUSIONS: Childhood cancer survivors require support, especially for late complications. It is necessary to continue LTFU, raising LTFU awareness among physicians and CCSs.

A retrospective analysis of azacitidine treatment for juvenile myelomonocytic leukemia.

Juvenile myelomonocytic leukemia (JMML) is a pediatric hematological malignancy with a poor prognosis. Although several case series have been published describing hematological and molecular responses to azacitidine (AZA) treatment in patients with JMML, the efficacy and safety profile of AZA is not well investigated, especially in Asian children and children undergoing hematopoietic stem cell transplantation (HSCT). We retrospectively analyzed 5 patients who received a total of 12 cycles (median 2 cycles) of AZA treatment in Japan. All five patients were boys and their ages at the time of treatment were 21, 23, 24, 26, and 46 months, respectively. All five patients tolerated AZA treatment, including four patients who received AZA after HSCT. Therapeutic toxicity with AZA was mostly limited to hematological toxicity. The only serious non-hematological adverse event was hyperbilirubinemia (grades III-IV) observed in a patient who received AZA after a second HSCT. Two out of five patients treated with AZA achieved a partial response (PR), while three patients treated for post-transplant relapse did not have an objective response. Future prospective studies should be conducted to develop combination therapies with AZA and other molecular targeted drugs for high-risk patients.

NUDT15 variants confer high incidence of second malignancies in children with acute lymphoblastic leukemia.

The effect of genetic variation on second malignant neoplasms (SMNs) remains unclear. First, we identified the pathogenic germline variants in cancer-predisposing genes among 15 children with SMNs after childhood leukemia/lymphoma using whole-exome sequencing. Because the prevalence was low, we focused on the association between SMNs and NUDT15 in primary acute lymphoblastic leukemia (ALL) cases. NUDT15 is one of the 6-mercaptopurine (6-MP) metabolic genes, and its variants are common in East Asian individuals. The prevalence of NUDT15 hypomorphic variants was higher in patients with SMNs (n = 14; 42.9%) than in the general population in the gnomAD database (19.7%; P = .042). In the validation study with a cohort of 438 unselected patients with ALL, the cumulative incidence of SMNs was significantly higher among those with (3.0%; 95% confidence interval [CI], 0.6% to 9.4%) than among those without NUDT15 variants (0.3%; 95% CI, 0.0% to 1.5%; P = .045). The 6-MP dose administered to patients with ALL with a NUDT15 variant was higher than that given to those without SMNs (P = .045). The 6-MP-related mutational signature was observed in SMN specimens after 6-MP exposure. In cells exposed to 6-MP, a higher level of 6-MP induced DNA damage in NUDT15-knockdown induced pluripotent stem cells. Our study indicates that NUDT15 variants may confer a risk of SMNs after treatment with 6-MP in patients with ALL.

The outcomes of relapsed acute myeloid leukemia in children: Results from the Japanese Pediatric Leukemia/Lymphoma Study Group AML-05R study.

BACKGROUND: The prognosis of children with acute myeloid leukemia (AML) has improved with the efficacy of hematopoietic cell transplantation (HCT) as a second-line therapy and improvements in supportive care following anthracycline- and cytarabine-based chemotherapy; however, the outcomes of children with relapsed AML still remain unsatisfactory. PROCEDURE: In order to identify prognostic factors and improve their prognosis, we analyzed 111 patients who relapsed after treatment with the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) AML-05 protocol and who were registered in the retrospective JPLSG AML-05R study. RESULTS: The 5-year overall survival rate was 36.1%. The major determinant of survival was duration from the diagnosis to relapse. The mean duration in the nonsurviving group (10.1 ± 4.1 months) was shorter than that in the surviving group (16.3 ± 8.3 months) (P < .01). Moreover, achieving a second complete remission (CR2) prior to HCT was associated with a good prognosis (P < .01). Etoposide, cytarabine, and mitoxantrone (ECM)- or fludarabine, cytarabine, and granulocyte colony-stimulating factor (FLAG)-based regimens were therefore recommended for reinduction therapy (P < .01). A genetic analysis also revealed the prognostic significance of FMS-like tyrosine kinase 3 (FLT3)-internal tandem duplication as a poor prognostic marker (P = .04) and core binding factor-AML, t(8;21), and inv(16) as good prognostic markers (P < .01). CONCLUSIONS: Achieving a CR2 prior to HCT is important in order to improve the prognosis of relapsed pediatric AML. Recent molecular targeted therapies, such as FLT3 inhibitors, may contribute to overcome their prognoses. Larger prospective investigations are necessary to establish individualized treatment strategies for patients with relapsed childhood AML.

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 Outcomes after Allogeneic Hematopoietic Stem Cell Transplantation in Children with Juvenile Myelomonocytic Leukemia: A Report from the Japan Society for Hematopoietic Cell Transplantation.

Hematopoietic stem cell transplantation (HSCT) is the only curative treatment for juvenile myelomonocytic leukemia (JMML), but few large studies of HSCT for JMML exist. Using data from the Japan Society for Hematopoietic Cell Transplantation registry, we analyzed the outcomes of 129 children with JMML who underwent HSCT between 2000 and 2011. The 5-year overall survival (OS) rate and cumulative incidence of relapse were 64% and 34%, respectively. A regimen of busulfan/fludarabine/melphalan was the most commonly used (59 patients) and provided the best outcomes; the 5-year OS rate reached 73%, and the cumulative incidences of relapse and transplantation-related mortality were 26% and 9%, respectively. In contrast, the use of the irradiation-based myeloablative regimen was the most significant risk factor for OS (hazard ratio [HR], 2.92; P = .004) in the multivariate model. In addition, chronic graft-versus-host disease (GVHD) was strongly associated with lower relapse (HR, 0.37; P = .029) and favorable survival (HR, 0.22; P = .006). The current study has shown that a significant proportion of children with JMML can be cured with HSCT, especially those receiving the busulfan/fludarabine/melphalan regimen. Based on the lower relapse and better survival observed in patients with chronic GVHD, additional treatment strategies that focus on enhancing graft-versus-leukemia effects may further improve survival.

The effect of graft-versus-host disease on outcomes after allogeneic stem cell transplantation for refractory lymphoblastic lymphoma in children and young adults.

BACKGROUND: Patients with relapsed or refractory lymphoblastic lymphoma (LBL) have a poor prognosis. The efficacy of allogeneic blood stem cell transplantation for treatment of this disease remains unclear in terms of transplantation-related toxicity. Acute and chronic graft-versus-host diseases (GVHD) are both harmful to patients after allogeneic transplantation, but may have some positive effects through a substitute graft-versus-lymphoma effect. METHODS: To investigate the effect of GVHD on the survival of patients with refractory LBL, we retrospectively studied the outcomes of 213 patients with LBL who underwent first allogeneic stem cell transplantation before the age of 18 years, between 1990 and 2015 in Japan. RESULTS: The five-year overall survival (OS) and event-free survival rates after stem cell transplantation were 50.3% (95% confidence interval [CI], 43.2-56.9) and 47.8% (95% CI, 40.8-54.4), respectively. In univariate landmark analyses, the probability of OS was significantly better in patients with aGVHD than in those without (P = 0.002, five-year OS 58.1% vs 39.0%). The probability of OS was also better in patients with cGVHD than in those without (P = 0.036, five-year OS 72.2% vs 54.7%). Multivariate analysis demonstrated that only aGVHD was associated with better OS (hazard ratio, 0.63; 95% CI, 0.42-0.94, P = 0.024). Progression and recurrence statuses at SCT were associated with poor prognosis. The patients with grade II aGVHD showed the best prognosis (five-year OS: 65.6%). CONCLUSION: Our results suggest that the occurrence of aGVHD may be associated with better outcomes in patients with relapsed/refractory LBL who undergo allogeneic transplantation.

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.

Perioperative safety and haematostatic efficacy of a new bypassing agent pd-FVIIa/FX (Byclot) in haemophilia patients with high-responding type inhibitors.

: The novel agent pd-FVIIa/FX is a 1 : 10 protein weight mixture of activated factor VII (FVIIa) and factor X (FX) derived from donated blood plasma. A phase III clinical trial of pd-FVIIa/FX revealed high efficacy for bleeding episodes in haemophilia patients with inhibitors. However, up to now, only one case of this new agent being used for surgery had been reported. The objective of this study is to evaluate the perioperative haemostatic efficacy and safety of pd-FVIIa/FX in haemophilia patients with inhibitors. We retrospectively reviewed 25 operation charts from 14 haemophilia patients with high-responding inhibitors using pd-FVIIa/FX during the perioperative period. Efficacy was evaluated by attending physicians and results divided into four groups (excellent, good, fair, and poor). The operation chart was provided by nine Japanese medical institutes with expertise in haemophilia management. Out of the total of 25 surgical procedures, 44% (11/25) were classified as major surgery and the remainders were minor surgeries. In all of the surgeries but one, rFVIIa and/or APCC were administered in combination or sequential method. In all cases except one, the haemostatic efficiency rate was judged as excellent or good by treating physicians for an overall efficacy rate of 96%. No thrombotic adverse effects were reported. This study's results suggest that both combination and sequential therapy of pd-FVIIa/FX and other bypassing agents are well tolerated and effective for the control of perioperative bleeding in haemophilia patients with high-responding inhibitors.

Nationwide survey of pediatric hypodiploid acute lymphoblastic leukemia in Japan.

BACKGROUND: Ploidy is a highly significant prognostic factor for pediatric acute lymphoblastic leukemia (ALL). Children with hypodiploid ALL have poor outcomes despite current intensive chemotherapy. Little has been investigated with regard to hypodiploid ALL in Japanese children. METHODS: We retrospectively collected clinical data on hypodiploid ALL cases from the registries of prospective multicenter trials conducted by the four independent clinical study groups in Japan between 1997 and 2012. RESULTS: A total of 117 ALL patients with hypodiploidy were analyzed in this study. There were 101, eight, and eight patients with 45, 44, and fewer than 44 chromosomes, respectively. The 5 year overall survival rates differed significantly: 86.0%, 87.5%, and 62.5% for patients with 45, 44, and fewer than 44 chromosomes, respectively (P = 0.037). Of the eight patients with 44 chromosomes, seven were alive, including five patients who maintained complete remission without undergoing hematopoietic stem cell transplantation (HSCT). Of the eight patients with fewer than 44 chromosomes, six were good responders to prednisolone and none had induction failure, but the relapse rate was high (5/8). No patients had central nervous system relapse. Four patients underwent HSCT after relapse, but only one survived. CONCLUSIONS: Outcomes of Japanese ALL patients with fewer than 44 chromosomes were poor, as previously reported in other countries. Although the sample size was small, patients with 44 chromosomes had better prognoses than those previously reported. Further studies including international collaboration are needed to improve outcomes for pediatric ALL patients with fewer than 44 chromosomes.

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.

Allogeneic hematopoietic stem cell transplantation for children and adolescents with high-risk cytogenetic AML: distinctly poor outcomes of FUS-ERG-positive cases.

Allocating patients with acute myeloid leukemia and high-risk cytogenetic abnormalities (HR-AML) for allogeneic hematopoietic stem cell transplantation (allo-HSCT) is part of the standard treatment protocol; however, whether allo-HSCT truly improves the outcomes in these patients is debatable. Data on 169 children and adolescents with HR-AML who received their first allo-HSCT in first or second remission between 2000 and 2015 were extracted from a nationwide, Japanese HSCT registry. The 3-year disease-free survival (DFS) and overall survival (OS) rates were 55.2% (95% CI, 46.8-62.9%) and 69.6% (61.4-76.3%), respectively, for all the HR-AML patients. In univariate analysis, the cytogenetic subgroup had a significant impact on both the DFS (P = 0.011) and OS (P < 0.001) rates. In particular, 14 patients with t(16;21) showed an extremely poor outcome. Additionally, older age at allo-HSCT (10-19 years old, P = 0.025), myeloablative conditioning with total-body irradiation (P = 0.019), and grade II-IV acute graft-versus-host disease (GVHD, P = 0.049) were associated with inferior OS. The donor type and occurrence of chronic GVHD did not affect the outcome. Multivariate analysis revealed t(16;21) to be associated with increased overall mortality (hazard ratio = 4.416, P < 0.001). Because the outcome of patients with certain HR-AML subgroups, such as t(16;21)-positive cases, is extremely poor even with allo-HSCT in remission, a novel therapy is urgently required.

[Congenital leukemia showing lineage switch following induction chemotherapy and attaining long-term remission after HLA-haploidentical stem cell transplantation].

Congenital leukemia is a rare subgroup of childhood leukemia. Lineage switches in leukemic cells are relatively rare events, which have been occasionally reported in congenital leukemia. To the best of our knowledge, the survival of congenital leukemia patients with lineage switch has not been previously documented. This lack of documentation may be attributable to extremely poor prognosis of these patients. We describe a case of a newborn female with initial diagnosis of MLL-AF4 positive B-precursor acute lymphoblastic leukemia, who developed lineage switch to acute monocytic leukemia following the induction therapy. Although morphological remission was temporary, she received an HLA-haploidentical bone marrow transplant from her father with non-remission status because of an early relapse at the age of 4 months. Despite many difficulties such as graft-versus-host disease, growth impairment, and psychomotor retardation, she remained in remission for 3 years and 7 months after the transplant. This successful outcome suggests that the graft-versus-leukemia effect was potentially accomplished in the patient. Taken together, early HLA-haploidentical stem cell transplant following remission is required for congenital leukemia patients with lineage switch, and it may be an effective alternative for refractory patients.

ZNF384-related fusion genes define a subgroup of childhood B-cell precursor acute lymphoblastic leukemia with a characteristic immunotype.

Fusion genes involving ZNF384 have recently been identified in B-cell precursor acute lymphoblastic leukemia, and 7 fusion partners have been reported. We further characterized this type of fusion gene by whole transcriptome sequencing and/or polymerase chain reaction. In addition to previously reported genes, we identified BMP2K as a novel fusion partner for ZNF384 Including the EP300-ZNF384 that we reported recently, the total frequency of ZNF384-related fusion genes was 4.1% in 291 B-cell precursor acute lymphoblastic leukemia patients enrolled in a single clinical trial, and TCF3-ZNF384 was the most recurrent, with a frequency of 2.4%. The characteristic immunophenotype of weak CD10 and aberrant CD13 and/or CD33 expression was revealed to be a common feature of the leukemic cells harboring ZNF384-related fusion genes. The signature gene expression profile in TCF3-ZNF384-positive patients was enriched in hematopoietic stem cell features and related to that of EP300-ZNF384-positive patients, but was significantly distinct from that of TCF3-PBX1-positive and ZNF384-fusion-negative patients. However, clinical features of TCF3-ZNF384-positive patients are markedly different from those of EP300-ZNF384-positive patients, exhibiting higher cell counts and a younger age at presentation. TCF3-ZNF384-positive patients revealed a significantly poorer steroid response and a higher frequency of relapse, and the additional activating mutations in RAS signaling pathway genes were detected by whole exome analysis in some of the cases. Our observations indicate that ZNF384-related fusion genes consist of a distinct subgroup of B-cell precursor acute lymphoblastic leukemia with a characteristic immunophenotype, while the clinical features depend on the functional properties of individual fusion partners.

Transplantation for juvenile myelomonocytic leukemia: a retrospective study of 30 children treated with a regimen of busulfan, fludarabine, and melphalan.

We report the outcomes of 30 patients with juvenile myelomonocytic leukemia (JMML) who received unmanipulated hematopoietic stem cell transplantation (HSCT) with oral or intravenous busulfan, fludarabine, and melphalan between 2001 and 2011. Mutations in PTPN11 were detected in 15 patients. Six patients received human leukocyte antigen (HLA)-matched HSCT from related donors, and 24 patients received HSCT from alternative donors, including 13 HLA-mismatched donors. Primary engraftment failed in five patients, all of whom had received allografts from HLA-mismatched donors. HLA-mismatched HSCT resulted in poorer event-free survival than HLA-matched HSCT (28.8 vs. 70.6 %). Three patients died of transplantation-related causes, and eight patients experienced hematological relapse (including five patients who died due to disease progression). Eight patients received a second HSCT, and four of these patients have survived. The 5-year estimated overall survival for all patients was 72.4: 88.9 % for the patients without a mutation in PTPN11 (n = 10) and 58.3 % for the patients with a mutation in PTPN11 (n = 15) (P = 0.092). The conditioning regimen reported in the present study achieved hematological and clinical remission in >50 % of patients with JMML who received HSCT from alternative donors, and may also be effective for JMML patients with PTPN11 mutation.