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.

Characteristics of RAS pathway mutations in juvenile myelomonocytic leukaemia: a single-institution study from Korea.

Juvenile myelomonocytic leukaemia (JMML), a rare clonal haematopoietic disorder of childhood, is characterised as a myelodysplastic/myeloproliferative neoplasm. Despite ground-breaking genetic discoveries, JMML remains difficult to diagnose given its diverse clinical features and disease course. A total of 24 patients with JMML were diagnosed and treated at a single institution, and their genetic profiles and association with clinical and laboratory characteristics were analysed. In all, 22 of the patients received allogeneic haematopoietic stem cell transplantation after myeloablative conditioning, mostly from a haploidentical family donor. RAS pathway mutations were identified in 88% of patients: PTPN11 [nine (38%)], NRAS [nine (38%)], KRAS [two (8%)], NF1 [five (21%)] and CBL [one (4%)]. Secondary mutations were found in 25% of patients: SETBP1, JAK3, ASXL1, GATA2, KIT, KDM6A, and BCOR. Six patients showed cytogenetic abnormalities, including three with monosomy 7. The estimated 5-year event-free survival (EFS) and overall survival (± standard error) of the entire cohort were 58·9 (10·9)% and 73·5 (10·8)% respectively. NRAS (+) patients had a higher 5-year EFS than NRAS (-) patients [72·9 (16·5)% vs. 52·5 (13·1)%, P = 0·127]. NRAS (+) patients had a better 5-year EFS than PTPN11 (+) patients [41·7 (17·3)%, P = 0·071]. Our study revealed the genetic characteristics of Korean JMML patients with RAS pathway and secondary mutations.

Vitamin D status in children with leukemia, its predictors, and association with outcome.

BACKGROUND: Children and adolescents with leukemia are potentially at high risk of vitamin D inadequacy, which may have clinical relevance for skeletal morbidity, infections, and cancer outcome. This study aimed to evaluate vitamin D status at the time of diagnosis to investigate its predictors and association with overall survival in children with leukemia. PROCEDURE: We included all 295 children and adolescents diagnosed with leukemia at our institution between 1990 and 2016 who had available serum sample from the time of diagnosis. We analyzed serum 25-hydroxyvitamin D and parathyroid hormone levels and correlated them with clinical data. RESULTS: The 25-hydroxyvitamin D level was deficient (< 25 nmol/L), insufficient (25-50 nmol/L), sufficient (50-75 nmol/L), and optimal (> 75 nmol/L) in 6.4%, 26.8%, 39.7%, and 27.1% of the children, respectively. Older age and a more recent time of sampling (calendar year) predicted lower 25-hydroxyvitamin D level. In preschool children (age ≤6 years), lower 25-hydroxyvitamin D level was also associated with acute myeloid leukemia, and a 25-hydroxyvitamin D level < 50 nmol/L was associated with inferior overall survival. In school-aged children (age > 6 years), the 25-hydroxyvitamin D level showed significant seasonal variation. CONCLUSION: It remains unclear whether vitamin D supplementation in pediatric leukemia patients will improve outcome.

Juvenile Myelomonocytic Leukemia in Turkey: A Retrospective Analysis of Sixty-five Patients.

OBJECTIVE: This study aimed to define the status of juvenile myelomonocytic leukemia (JMML) patients in Turkey in terms of time of diagnosis, clinical characteristics, mutational studies, clinical course, and treatment strategies. MATERIALS AND METHODS: Data including clinical and laboratory characteristics and treatment strategies of JMML patients were collected retrospectively from pediatric hematology-oncology centers in Turkey. RESULTS: Sixty-five children with JMML diagnosed between 2002 and 2016 in 18 institutions throughout Turkey were enrolled in the study. The median age at diagnosis was 17 months (min-max: 2-117 months). Splenomegaly was present in 92% of patients at the time of diagnosis. The median white blood cell, monocyte, and platelet counts were 32.9x109/L, 5.4x109/L, and 58.3x109/L, respectively. Monosomy 7 was present in 18% of patients. JMML mutational analysis was performed in 32 of 65 patients (49%) and PTPN11 was the most common mutation. Hematopoietic stem cell transplantation (HSCT) could only be performed in 28 patients (44%), the majority being after the year 2012. The most frequent reason for not performing HSCT was the inability to find a suitable donor. The median time from diagnosis to HSCT was 9 months (min-max: 2-63 months). The 5-year cumulative survival rate was 33% and median estimated survival time was 30±17.4 months (95% CI: 0-64.1) for all patients. Survival time was significantly better in the HSCT group (log-rank p=0.019). Older age at diagnosis (>2 years), platelet count of less than 40x109/L, and PTPN11 mutation were the factors significantly associated with shorter survival time. CONCLUSION: Although there has recently been improvement in terms of definitive diagnosis and HSCT in JMML patients, the overall results are not satisfactory and it is necessary to put more effort into this issue in Turkey.

Mutation in NRAS in familial Noonan syndrome--case report and review of the literature.

BACKGROUND: Noonan syndrome (NS), a heterogeneous developmental disorder associated with variable clinical expression including short stature, congenital heart defect, unusual pectus deformity and typical facial features, is caused by activating mutations in genes involved in the RAS-MAPK signaling pathway. CASE PRESENTATION: Here, we present a clinical and molecular characterization of a small family with Noonan syndrome. Comprehensive mutation analysis of NF1, PTPN11, SOS1, CBL, BRAF, RAF1, SHOC2, MAP2K2, MAP2K1, SPRED1, NRAS, HRAS and KRAS was performed using targeted next-generation sequencing. The result revealed a recurrent mutation in NRAS, c.179G > A (p.G60E), in the index patient. This mutation was inherited from the index patient's father, who also showed signs of NS. CONCLUSIONS: We describe clinical features in this family and review the literature for genotype-phenotype correlations for NS patients with mutations in NRAS. Neither of affected individuals in this family presented with juvenile myelomonocytic leukemia (JMML), which together with previously published results suggest that the risk for NS individuals with a germline NRAS mutation developing JMML is not different from the proportion seen in other NS cases. Interestingly, 50% of NS individuals with an NRAS mutation (including our family) present with lentigines and/or Café-au-lait spots. This demonstrates a predisposition to hyperpigmented lesions in NRAS-positive NS individuals. In addition, the affected father in our family presented with a hearing deficit since birth, which together with lentigines are two characteristics of NS with multiple lentigines (previously LEOPARD syndrome), supporting the difficulties in diagnosing individuals with RASopathies correctly. The clinical and genetic heterogeneity observed in RASopathies is a challenge for genetic testing. However, next-generation sequencing technology, which allows screening of a large number of genes simultaneously, will facilitate an early and accurate diagnosis of patients with RASopathies.

Analysis of risk factors influencing outcomes after cord blood transplantation in children with juvenile myelomonocytic leukemia: a EUROCORD, EBMT, EWOG-MDS, CIBMTR study.

We retrospectively analyzed 110 patients with juvenile myelomonocytic leukemia, given single-unit, unrelated donor umbilical cord blood transplantation. Median age at diagnosis and at transplantation was 1.4 years (age range, 0.1-6.4 years) and 2.2 years (age range, 0.5-7.4 years), respectively. Before transplantation, 88 patients received chemotherapy; splenectomy was performed in 24 patients. Monosomy of chromosome 7 was the most frequent cytogenetic abnormality, found in 24% of patients. All but 8 patients received myeloablative conditioning; cyclosporine plus steroids was the most common graft-versus-host disease prophylaxis. Sixteen percent of units were HLA-matched with the recipient, whereas 43% and 35% had either 1 or 2 to 3 HLA disparities, respectively. The median number of nucleated cells infused was 7.1 × 10(7)/kg (range, 1.7-27.6 × 10(7)/kg). With a median follow-up of 64 months (range, 14-174 months), the 5-year cumulative incidences of transplantation-related mortality and relapse were 22% and 33%, respectively. The 5-year disease-free survival rate was 44%. In multivariate analysis, factors predicting better disease-free survival were age younger than 1.4 years at diagnosis (hazard ratio [HR], 0.42; P = .005), 0 to 1 HLA disparities in the donor/recipient pair (HR, 0.4; P = .009), and karyotype other than monosomy 7 (HR, 0.5; P = .02). Umbilical cord blood transplantation may cure a relevant proportion of children with juvenile myelomonocytic leukemia. Because disease recurrence remains the major cause of treatment failure, strategies to reduce incidence of relapse are warranted.

Malignant diseases in Noonan syndrome and related disorders.

The overall risk of cancer in children with Noonan (NS), cardio-facial-cutaneous, Costello or LEOPARD syndrome is high, although no precise estimates are available. There are few data on cancer in adults with NS, but the reported numbers of malignancies in adults do not seem excessive. Juvenile myelomonocytic leukemia (JMML) is a rare aggressive leukemia in young children. A JMML-like myeloproliferative disorder has been described in about 30 neonates with NS and the PTPN11 mutation. The disorder often regresses spontaneously, but fatal complications may occur. A review of the literature indicates an increased risk of acute lymphoblastic leukemia and acute myeloid leukemia in NS. Young children with Costello syndrome have an extremely high risk of rhabdomyosarcoma, and also an increased risk of neuroblastoma and bladder carcinoma. Registry-based studies of patients with NS and related disorders diagnosed with molecular genetics and a high-quality long-term follow-up are necessary to further estimate the incidence of malignancy.

Juvenile myelomonocytic leukemia: a report from the 2nd International JMML Symposium.

Juvenile myelomonocytic leukemia (JMML) is an aggressive childhood myeloproliferative disorder characterized by the overproduction of myelomonocytic cells. JMML incidence approaches 1.2/million persons in the United States (Cancer Incidence and Survival Among Children and Adolescents: United States SEER Program 1975-1995). Although rare, JMML is innately informative as the molecular genetics of this disease implicates hyperactive Ras as an essential initiating event. Given that Ras is one of the most frequently mutated oncogenes in human cancer, findings from this disease are applicable to more genetically diverse and complex adult leukemias. The JMML Foundation (www.jmmlfoundation.org) was founded by parent advocates dedicated to finding a cure for this disease. They work to bring investigators together in a collaborative manner. This article summarizes key presentations from The Second International JMML Symposium, on 7-8 December 2007 in Atlanta, GA. A list of all participants is in Supplementary Table.

Mixed myeloproliferative and myelodysplastic disorders.

When the French-American-British (FAB) classification system was first devised in the 1970s for the myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML) was included in the FAB MDS classification schema. It always appeared out of place, however, at least when compared with the other FAB MDS categories, as CMML clearly has some features of a myeloproliferative disorder. Yet CMML also did not fit well with the traditional four myeloproliferative disorders. In the 1990s there was ongoing discussion about distinguishing a proliferative type of CMML versus a dysplastic type of CMML, based primarily on the total white blood cell count. In 2001 the World Health Organization reclassified most of the hematologic malignancies, creating a new category of mixed myelodysplastic/myeloproliferative diseases. Finally, CMML has an appropriate home, along with other disorders that seem to fit quite well in this "mixed" category.