Clinical features and prognosis of juvenile myelomonocytic leukemia: an analysis of 63 cases / 中国当代儿科杂志

OBJECTIVES@#To investigate the clinical features of juvenile myelomonocytic leukemia (JMML) and their association with prognosis.@*METHODS@#Clinical and prognosis data were collected from the children with JMML who were admitted from January 2008 to December 2016, and the influencing factors for prognosis were analyzed.@*RESULTS@#A total of 63 children with JMML were included, with a median age of onset of 25 months and a male/female ratio of 3.2∶1. JMML genetic testing was performed for 54 children, and PTPN11 mutation was the most common mutation and was observed in 23 children (43%), among whom 19 had PTPN11 mutation alone and 4 had compound PTPN11 mutation, followed by NRAS mutation observed in 14 children (26%), among whom 12 had NRAS mutation alone and 2 had compound NRAS mutation. The 5-year overall survival (OS) rate was only 22%±10% in these children with JMML. Of the 63 children, 13 (21%) underwent hematopoietic stem cell transplantation (HSCT). The HSCT group had a significantly higher 5-year OS rate than the non-HSCT group (46%±14% vs 29%±7%, P<0.05). There was no significant difference in the 5-year OS rate between the children without PTPN11 gene mutation and those with PTPN11 gene mutation (30%±14% vs 27%±10%, P>0.05). The Cox proportional-hazards regression model analysis showed that platelet count <40×109/L at diagnosis was an influencing factor for 5-year OS rate in children with JMML (P<0.05).@*CONCLUSIONS@#The PTPN11 gene was the most common mutant gene in JMML. Platelet count at diagnosis is associated with the prognosis in children with JMML. HSCT can improve the prognosis of children with JMML.

Understanding the Molecular Basis of Juvenile Myelomonocytic Leukemia and Its Application for Novel Drugs Development / 임상소아혈액종양

To date, hematopoietic stem cell transplantation (HSCT) is the only choice of therapy for most patients with juvenile myelomonocytic leukemia (JMML). Relapse remains a major problem. Approximately 90% of patients carry either somatic or germline mutations of genes participating in RAS signal transduction such as PTPN11, CBL, K-RAS, N-RAS, or NF1 in their leukemic cells, allowing an understanding of the molecular pathophysiology of JMLL and the development of novel drugs. As these genetic aberrations are mutually exclusive, the genetic change observed in JMML helps us to establish the diagnosis of JMML. Furthermore, the genetic abnormalities of JMML are an important prognostic factor, as the type of abnormality may determine disease progression. Recent studies have revealed a strong association between hypermethylation of some genes and already known poor prognostic factors such as older age, elevated fetal hemoglobin at diagnosis, and somatic mutation of PTPN11. These molecular characteristics may be the basis for a guideline to determine the treatment, especially when to proceed with HSCT. Recently, novel drugs have been used based on these molecular characteristics. 5-Azacitidine, an inhibitor of DNA methyltransferase and tipifarnib, a selective farnesyl transferase inhibitor, have been used to improve the outcome of JMML. In addition, drugs which inhibit the RAS signal transduction have been developed, which are less toxic and will improve outcome in the near future.

Juvenile myelomonocytic leukemia:a clinical and gene analysis of 21 cases / 中华实用儿科临床杂志

Objective To analyze the clinical characteristics of juvenile myelomonocytic leukemia(JMML) and the PCNA levels of the hyperoxia -exposure group (6 h)decreased,and the difference in PCNA protein expres-sion levels was significant of gene diagnose for JMML.Methods Clinical data were retrospectively analyzed in 21 pa-tients suffering from JMML based on new 2009 World Health Organization diagnostic criteria from January 201 3 to June 201 4 in Beijing Children′s Hospital,Capital Medical University.Results There were 85.7% (1 8 /21 cases)patients within 4 -year -old children,and the median age was 23 months (2 -86 months).Fever and abdominal symptoms were the prominent clinical symptoms,52.4% (1 1 /21 cases)with fever,38.1 % (8 /21 cases)with abdominal dis-tention,diarrhea and other abdominal symptoms,80.5% (1 9 /21 cases)had splenomegaly (mild 1 9.1 %,middle 33.3%,severe 38.1 %),and some patients had other tissue infiltration,such as rash,yellow tumor and lymphnode enlargement.Peripheral blood cell count showed that the white blood cells increased because of anemia or thrombocyto-penia,ranging from 1 0.40 ×1 09 /L to 82.1 4 ×1 09 /L(median,26.1 0 ×1 09 /L),and the monocyte counts ranged from 1 .46 ×1 09 /L to 21 .60 ×1 09 /L(median,3.79 ×1 09 /L),characteristics of JMML gene abnormality was detected in 1 7 cases:including 1 1 single gene mutation,and 6 cases with double gene mutations.PTPN11 was the highest frequency of occurrence,accounting for 52.9% (9 /1 7 cases),and NF1 mutation was 35.3% (6 /1 7 cases).All the patients were followed up by phone call,the median follow -up time was 371 days (57 -562 days),6 patients were lost to follow -up,7 patients died,2 patients were alive after hematopoietic stem cell transplantation,1 patient converted to acute non lymphocytic leukemia,and 5 patients were still alive after receiving symptomatic treatment.Among dead cases,PTNT11 gene mutation and NF1 gene mutation were detected in 6 patients;among living children after hematopoietic stem cell transplantation,RAS and PTNT11 mutations were detected in 2 patients;among living children after symptomatic treat-ment,RAS mutation was detected in 2 patients and PTPN11 +CBL mutation in 1 case.Conclusions The symptom and laboratory examination of JMML have no specificistics,with poor prognosis,gene diagnose has guiding significance for JMML diagnose and for selecting therapy.

A Case of Long-term Survival with Autologous Recovery after Double Cord Blood Transplantation for Juvenile Myelomonocytic Leukemia / 임상소아혈액종양

A 1.1 year old boy was admitted to the Seoul National University Children's Hospital because of incidental findings of hepatosplenomegaly, skin lesion and multiple intra- abdominal lymphadenopathies. Anemia and thrombocytopenia were found based on the initial complete blood count (CBC) measurements. Because of bicytopenia and hepatosplenomegaly, bone marrow examination was performed which revealed hypercellular marrow with increased monocytes and granulopoiesis. The hemoglobin F level was high for his age, and monocyte production was increased. The patient was diagnosed with juvenile myelomonocytic leukemia at the age of 1.2 years. Chemotherapy with cytarabine, etoposide, vincristine, and isotretinoin was initiated. After 6 cycles of chemotherapy, the CBC normalized. He underwent double cord blood transplantation (dCBT), but chimerism studies showed autologous recovery. However, he did not show relapse during the 5 years post-transplant during which he received isotretinoin. He is surviving disease-free 9 years after dCBT.

A Case of Long-term Survival with Autologous Recovery after Double Cord Blood Transplantation for Juvenile Myelomonocytic Leukemia / 임상소아혈액종양

A 1.1 year old boy was admitted to the Seoul National University Children's Hospital because of incidental findings of hepatosplenomegaly, skin lesion and multiple intra- abdominal lymphadenopathies. Anemia and thrombocytopenia were found based on the initial complete blood count (CBC) measurements. Because of bicytopenia and hepatosplenomegaly, bone marrow examination was performed which revealed hypercellular marrow with increased monocytes and granulopoiesis. The hemoglobin F level was high for his age, and monocyte production was increased. The patient was diagnosed with juvenile myelomonocytic leukemia at the age of 1.2 years. Chemotherapy with cytarabine, etoposide, vincristine, and isotretinoin was initiated. After 6 cycles of chemotherapy, the CBC normalized. He underwent double cord blood transplantation (dCBT), but chimerism studies showed autologous recovery. However, he did not show relapse during the 5 years post-transplant during which he received isotretinoin. He is surviving disease-free 9 years after dCBT.

Cytogenetic studies of Brazilian pediatric myelodysplastic syndrome cases: challenges and difficulties in a large and emerging country

Myelodysplastic syndromes (MDS) and juvenile myelomonocytic leukemia (JMML) are rare hematopoietic stem cell diseases affecting children. Cytogenetics plays an important role in the diagnosis of these diseases. We report here the experience of the Cytogenetic Subcommittee of the Brazilian Cooperative Group on Pediatric Myelodysplastic Syndromes (BCG-MDS-PED). We analyzed 168 cytogenetic studies performed in 23 different cytogenetic centers; 84 of these studies were performed in patients with confirmed MDS (primary MDS, secondary MDS, JMML, and acute myeloid leukemia/MDS+Down syndrome). Clonal abnormalities were found in 36.9% of the MDS cases and cytogenetic studies were important for the detection of constitutional diseases and for differential diagnosis with other myeloid neoplasms. These data show the importance of the Cooperative Group for continuing education in order to avoid a late or wrong diagnosis.

Cytarabine Monotherapy as Bridging Treatment for Hematopoietic Stem Cell Transplantation in Children with Juvenile Myelomonocytic Leukemia / 임상소아혈액종양

BACKGROUND: Mutations leading to hyperactivation of the RAS pathway play a critical role in the pathogenesis of juvenile myelomonocytic leukemia (JMML). Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative therapy, and the role of anti-leukemic treatment prior to HSCT is still controversial. In this study, we analyzed the response of cytarabine monotherapy as a bridging therapy for HSCT in children recently diagnosed with JMML.METHODS: We retrospectively reviewed the medical records of patients with JMML at Seoul St. Mary's Hospital from December 2009 to April 2012.RESULTS: A total 7 patients with JMML were diagnosed and treated with chemotherapy and HSCT. At presentation, all patients showed hepatosplenomegaly and the median leukocyte count was 41.9x109/L (range, 34.3-85.0), median monocyte count was 5.6x109/L (range, 2.7-26.3) and median fetal hemoglobin (HbF) was 13.5% (range, 2.8-42.7). Karyotypic abnormalities in bone marrow cells were noted in 2 cases. Three patients had mutation of NRAS and 2 patients had mutation of NF1. One of the patients with NF1 mutations had characteristic clinical features and familial history of neurofibromatosis. All patients were treated with non-intensive sequential cytarabine chemotherapy (70 mg/m2/day, I.V., 4-12 days) before HSCT and achieved complete hematologic response. All patients underwent unrelated (N=2) or familial mismatched (N=5) HSCT, and all patients successfully engrafted. All patients, except one who relapsed, are alive with leukemia free, although the duration of follow-up is short.CONCLUSION: In our cohort of NRAS prevalent patients, non-intensive cytarabine monotherapy was effective as pre-transplant bridging treatment for JMML.

Cytarabine Monotherapy as Bridging Treatment for Hematopoietic Stem Cell Transplantation in Children with Juvenile Myelomonocytic Leukemia / 임상소아혈액종양

BACKGROUND: Mutations leading to hyperactivation of the RAS pathway play a critical role in the pathogenesis of juvenile myelomonocytic leukemia (JMML). Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative therapy, and the role of anti-leukemic treatment prior to HSCT is still controversial. In this study, we analyzed the response of cytarabine monotherapy as a bridging therapy for HSCT in children recently diagnosed with JMML. METHODS: We retrospectively reviewed the medical records of patients with JMML at Seoul St. Mary's Hospital from December 2009 to April 2012. RESULTS: A total 7 patients with JMML were diagnosed and treated with chemotherapy and HSCT. At presentation, all patients showed hepatosplenomegaly and the median leukocyte count was 41.9x109/L (range, 34.3-85.0), median monocyte count was 5.6x109/L (range, 2.7-26.3) and median fetal hemoglobin (HbF) was 13.5% (range, 2.8-42.7). Karyotypic abnormalities in bone marrow cells were noted in 2 cases. Three patients had mutation of NRAS and 2 patients had mutation of NF1. One of the patients with NF1 mutations had characteristic clinical features and familial history of neurofibromatosis. All patients were treated with non-intensive sequential cytarabine chemotherapy (70 mg/m2/day, I.V., 4-12 days) before HSCT and achieved complete hematologic response. All patients underwent unrelated (N=2) or familial mismatched (N=5) HSCT, and all patients successfully engrafted. All patients, except one who relapsed, are alive with leukemia free, although the duration of follow-up is short. CONCLUSION: In our cohort of NRAS prevalent patients, non-intensive cytarabine monotherapy was effective as pre-transplant bridging treatment for JMML.

Leucemia mielomonocítica juvenil: relato de caso / Juvenile myelomonocytic leukaemia: case report

A leucemia mielomonocítica juvenil (LMMJ) é uma doença rara, que representa de 2 por centoa 3 por cento de todas as leucemias pediátricas. É uma doença clonal de células da linhagem mieloide, que apresenta características de mieloproliferação e de displasia. Os sinais e os sintomas são resultantes da infiltração de células monocíticas malignas em órgãos não hematopoéticos. Os sintomas mais comuns são febre, tosse, infecção, fraqueza, palidez, linfadenopatia, hepatoesplenomegalia, lesões cutâneas e manifestações hemorrágicas. Como a LMMJ exibe um curso clínico muito agressivo e responde pobremente à quimioterapia, o transplante de células-tronco hematopoéticas é a única modalidade terapêutica curativa. Neste estudo, relatamos o caso de um paciente do sexo masculino, com um ano e dez meses de idade, que compareceu na emergência do Hospital de Clínicas de Porto Alegre por apresentar febre, com diagnóstico prévio de mononucleose feito em outra Instituição. A apresentação clínica, em conjunto com os achados laboratoriais, permitiu o diagnóstico correto. O paciente foi tratado com quimioterapia e submetido a transplante de células-tronco hematopoéticas.

Juvenile myelomonocytic leukemia (JMML) is a rare hematopoietic malignancy, which accounts for 2 to 3 percent of all pediatric leukemia. JMML is a myeloproliferative disorder characterized by monoclonal overproduction of myeloid cells. The signs and symptoms are a result of the infiltration of monocytic cells into non-hematopoietic organs; the most common symptoms are fever, cough, infection, weakness, pallor, lymphadenopathy, hepatosplenomegaly, skin lesions and bleeding. JMML runs an aggressive clinical course and responds poorly to chemotherapy. Hematopoietic stem cell transplantation is the only curative treatment. We describe the case of a 22-month-old male child, who appeared in the emergency room of Hospital de Clínicas de Porto Alegre because of fever and with a previous diagnosis of mononucleosis made at another Institution. The clinical presentation together with laboratory findings allowed the correct diagnosis. The patient was treated with chemotherapy and underwent hematopoietic stem cell transplantation.

Allogeneic Hematopoietic Stem Cell Transplantation in Juvenile Myelomonocytic Leukemia / 소아과

PURPOSE: The purpose of this study was to evaluate the outcome of children with juvenile myelomonocytic leukemia(JMML) treated with allogeneic hematopoietic stem cell transplantation(allo- HSCT). METHODS: Eleven JMML patients aged 8-39 months underwent allo-HSCT. The sources of grafts were unrelated donors(n=7), HLA-matched siblings(n=3) and an HLA 1-antigen mismatched familial donor. All patients had received chemotherapy +/- 13-cis-retinoic acid(CRA) before transplant, and CRA was used, posttransplant, in six patients. RESULTS: Only three patients were in complete remission(CR) at the time of transplantation. Initial chimeric status revealed complete donor chimerism(CC) in five patients, mixed chimerism(MC) in five and autologous recovery(AR) in one. One patient with MC having persistent splenomegaly eventually turned to CC and CR after rapid tapering of cyclosporine, combined with daily use of CRA. An AR case relapsed shortly after transplant but was rescued with second, unrelated cord blood transplantation. Ultimately, six patients are alive, event-free, with a median follow-up of 15.5 months posttransplant. All three deaths occurred in patients who failed to achieve CC, leading to disease progression. CONCLUSION: We suggest that graft-versus-leukemia effect play an important role and CRA a possible role in posttransplant leukemic involution in JMML. In patients whose leukemic burden is still high with MC after transplant, early tapering of immunosuppressants and introduction of CRA might provide a chance of a cure for some patients.

A Case of Juvenile Myelomonocytic Leukemia in a Six Months Old Infant / 대한혈액학회지

Myelodysplastic syndrome (MDS) in childhood is a rare hematologic malignancy and its classification has been the subject of some controversy. Cases of pediatric MDS are subdivided into those with features of adult-type MDS and those with myeloproliferative features occasionally observed in infancy and early childhood. There appears to be an international consensus to rename the disease juvenile myelomonocytic leukemia (JMML), which includes all leukemias of childhood previously classed as chronic myelomonocytic leukemia (CMML), juvenile chronic myelogenous leukemia (JCML), and infantile monosomy 7 syndrome. We experienced a 6-month-old female infant with JMML who developed extensive extramedullary hematopoiesis. The patient developed abdominal distention, hepatosplenome-galy, anemia, thrombocytopenia, and leukocytosis with significant monocytosis and was found to have a high hemoglobin F level of 30%. Her bone marrow biopsy section and aspirate smears revealed normocellularity with no increment of blast cells and no dysplastic changes. Cytogenetic analysis revealed a normal 46, XX karyotype. Her liver, spleen, lymph nodes, and appendix were found to be heavily infiltrated by partially differentiated myelomonocytic cells. These findings supported the diagnosis of JMML with extensive extramedullary hematopoiesis.