Myelodysplastic and Myeloproliferative Disorders of Childhood: A Study of 167 Patients

Blood ◽  
1999 ◽  
Vol 93 (2) ◽  
pp. 459-466 ◽  
Author(s):  
Sandra Luna-Fineman ◽  
Kevin M. Shannon ◽  
Susan K. Atwater ◽  
Jeffrey Davis ◽  
Margaret Masterson ◽  
...  
Keyword(s):  
Clinical Features ◽  
Age At Onset ◽  
Myeloproliferative Disorders ◽  
Juvenile Myelomonocytic Leukemia ◽  
Genetic Associations ◽  
Adult Type ◽  
Hemoglobin F ◽  
Monosomy 7 ◽  
Prognostic Features ◽  
Myelomonocytic Leukemia

Abstract Myelodysplastic syndromes (MDS) and myeloproliferative syndromes (MPS) of childhood are a heterogeneous group of clonal disorders of hematopoiesis with overlapping clinical features and inconsistent nomenclature. Although a number of genetic conditions have been associated with MDS and MPS, the overall contribution of inherited predispositions is uncertain. We report a retrospective study examining clinical features, genetic associations, and outcomes in 167 children with MDS and MPS. Of these patients, 48 had an associated constitutional disorder. One hundred one patients had adult-type myelodysplastic syndrome (A-MDS), 60 had juvenile myelomonocytic leukemia (JMML), and 6 infants with Down syndrome had a transient myeloproliferative syndrome (TMS). JMML was characterized by young age at onset and prominent hepatosplenomegaly, whereas patients with A-MDS were older and had little or no organomegaly. The most common cytogenetic abnormalities were monosomy 7 or del(7q) (53 cases); this was common both in patients with JMML and those with A-MDS. Leukemic transformation was observed in 32% of patients, usually within 2 years of diagnosis. Survival was 25% at 16 years. Favorable prognostic features at diagnosis included age less than 2 years and a hemoglobin F level of less than 10%. Older patients tended to present with an adult-type MDS that is accommodated within the French-American-British system. In contrast, infants and young children typically developed unique disorders with overlapping features of MDS and MPS. Although the type and intensity of therapy varied markedly in this study, the overall outcome was poor except in patients with TMS.

Myelodysplastic and Myeloproliferative Disorders of Childhood: A Study of 167 Patients

Blood ◽  
1999 ◽  
Vol 93 (2) ◽  
pp. 459-466 ◽  
Author(s):  
Sandra Luna-Fineman ◽  
Kevin M. Shannon ◽  
Susan K. Atwater ◽  
Jeffrey Davis ◽  
Margaret Masterson ◽  
...  
Keyword(s):  
Clinical Features ◽  
Age At Onset ◽  
Myeloproliferative Disorders ◽  
Juvenile Myelomonocytic Leukemia ◽  
Genetic Associations ◽  
Adult Type ◽  
Hemoglobin F ◽  
Monosomy 7 ◽  
Prognostic Features ◽  
Myelomonocytic Leukemia

Myelodysplastic syndromes (MDS) and myeloproliferative syndromes (MPS) of childhood are a heterogeneous group of clonal disorders of hematopoiesis with overlapping clinical features and inconsistent nomenclature. Although a number of genetic conditions have been associated with MDS and MPS, the overall contribution of inherited predispositions is uncertain. We report a retrospective study examining clinical features, genetic associations, and outcomes in 167 children with MDS and MPS. Of these patients, 48 had an associated constitutional disorder. One hundred one patients had adult-type myelodysplastic syndrome (A-MDS), 60 had juvenile myelomonocytic leukemia (JMML), and 6 infants with Down syndrome had a transient myeloproliferative syndrome (TMS). JMML was characterized by young age at onset and prominent hepatosplenomegaly, whereas patients with A-MDS were older and had little or no organomegaly. The most common cytogenetic abnormalities were monosomy 7 or del(7q) (53 cases); this was common both in patients with JMML and those with A-MDS. Leukemic transformation was observed in 32% of patients, usually within 2 years of diagnosis. Survival was 25% at 16 years. Favorable prognostic features at diagnosis included age less than 2 years and a hemoglobin F level of less than 10%. Older patients tended to present with an adult-type MDS that is accommodated within the French-American-British system. In contrast, infants and young children typically developed unique disorders with overlapping features of MDS and MPS. Although the type and intensity of therapy varied markedly in this study, the overall outcome was poor except in patients with TMS.

C-Cbl but Not TET2 Mutations Are Present in Patients with Juvenile Myelomonocytic Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 420-420 ◽  
Author(s):  
Hideki Muramatsu ◽  
Hideki Makishima ◽  
Anna Malgorzata Jankowska ◽  
Heather Cazzolli ◽  
Christine O'Keefe ◽  
...  
Keyword(s):  
Copy Number ◽  
Significant Proportion ◽  
High Density ◽  
Juvenile Myelomonocytic Leukemia ◽  
Kras Mutations ◽  
Hemoglobin F ◽  
Hematopoietic Stem ◽  
Monosomy 7 ◽  
Gm Csf ◽  
Myelomonocytic Leukemia

Abstract Abstract 420 Juvenile myelomonocytic leukemia (JMML) is a distinct subtype of myelodysplastic syndrome/myeloproliferative disorder (MDS/MPD) which, in analogy to chronic myelomonocytic leukemia (CMML), is characterized by excessive proliferation of myelomonocytic cells, but unlike CMML it occurs in young children and shows characteristic hypersensitivity to granulocyte-macrophage colony-stimulating factor (GM-CSF). Chromosomal defect are present in 22% of patients in particular involving del7/7q. Mutations of genes involved in GM-CSF signal transduction, including RAS and PTPN11, can be identified in a majority of children with JMML, constitutional mutations of NF1 can be found in another 10% of patients with JMML, but in significant proportion of patients no molecular lesions were identified. To further clarify the molecular pathogenesis of JMML we have applied a high density SNP array-based karyptyping and screened for associated mutations including established defected in RAS, PTPN11 and NF1 but also c-Cbl and TET genes, recently identified in patients with CMML and MDS/MPD. We studied 49 children with JMML diagnosed between 1988 and 2008 in 28 institutions throughout Japan. The median age at diagnosis was 28 months (range, 1-75 months). Karyotypic abnormalities were detected in 11 patients, including 7 patients with monosomy 7. Two children had clinical evidence of NF1 mutations. Out of 49 patients, 32 received hematopoietic stem cell transplantation (HSCT). We performed mutational analysis of the genes known to be affected by mutations in JMML. PTPN11 mutations were found in 26/49 (53%) while NRAS and KRAS mutations were found in 2/49 (4%) and 1/49 (2%), respectively. None of the patients screened showed the presence of TET2 mutations, previously shown to be present in a significant proportion of patients with MDS/MPD, including CMML. High-density Affymetrix 250K single nucleotide polymorphism array (SNP-A) were applied as a karyotyping platform to identify LOH and submicroscopic copy number changes. Signal intensity was analyzed and SNP calls determined using Gene Chip Genotyping Analysis Software Version 4.0 (GTYPE). Copy number and areas of UPD were investigated using Hidden Markov Model and CNAG v3.0 software. Compared to the results of conventional metaphase cytogenetics (MC), SNP-A identified significantly more genetic abnormalities (25% vs 49%; p=.02). In 1 patient UPD17q was present ivolving NF1 locus. In 4 patients UPD11q involving c-cbl locus (11q23.1) was found. Sequencing of c-Cbl gene family revealed mutations of c-Cbl in 5/49 (10%), and no Cbl-b mutations. All but 1 mutations were homozygous and were located in the RFD (exon 8 and intron 8). C-Cbl mutations were mutually exclusive with PTPN11, NRAS, and KRAS mutations or had clinical diagnosis of NF1. Unlike in CMML, no UPD4q24 or homo- or heterozygous TET2 mutations were found. Histomorphologic analysis did not reveal any distinct c-Cbl mutation-associated features or differences in count between patients grouped based on the presence of specific mutations. Similarly, there were no differences in gender, or the presence of cytogenetic abnormalities and the probability of 2 year overall survival of c-Cbl mutant cases between patients grouped according to mutational status. All patients with c-Cbl mutations displayed GM-CSF hypersensitivity at initial presentation but did not differ in this feature from the remaining JMML patients. However, mutant c-Cbl cases showed earlier presentation (median age 12 months vs. 29 months, p = .037) and lower median hemoglobin F fraction (3.5 % vs. 25%, p=.02). In sum, c-Cbl mutations constitute a novel important pathogenic lesion in JMML. While their presence suggests functional similarity to CMML, absence of TET2 mutation in JMML and rarity of PTPN11 mutations in CMML constitute important distinctive features of both diseases. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Correlation of Clinical Features With the Mutational Status of GM-CSF Signaling Pathway-Related Genes in Juvenile Myelomonocytic Leukemia

2009 ◽  
Vol 65 (3) ◽  
pp. 334-340 ◽  
Author(s):  
Nao Yoshida ◽  
Hiroshi Yagasaki ◽  
Yinyan Xu ◽  
Kazuyuki Matsuda ◽  
Ayami Yoshimi ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Clinical Features ◽  
Juvenile Myelomonocytic Leukemia ◽  
Gm Csf ◽  
Mutational Status ◽  
Myelomonocytic Leukemia

Correlation of Clinical Features with the Mutational Status of GM-CSF Signaling Pathway-Related Genes in Children with Juvenile Myelomonocytic Leukemia

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1528-1528 ◽  
Author(s):  
Nao Yoshida ◽  
Hiroshi Yagasaki ◽  
Ayami Yoshimi ◽  
Yoshiyuki Takahashi ◽  
Yinyan Xu ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Clinical Outcome ◽  
Clinical Features ◽  
Juvenile Myelomonocytic Leukemia ◽  
Gm Csf ◽  
Ptpn11 Mutation ◽  
Mutational Status ◽  
Hbf Level ◽  
Mutation Age ◽  
Myelomonocytic Leukemia

Abstract Juvenile myelomonocytic leukemia (JMML) is a rare clonal myeloproliferative disorder that affects young children. It is characterized by specific hypersensitivity to granulocyte-macrophage colony-stimulating factor (GM-CSF) in vitro. Mutations in RAS, NF1, or PTPN11 positioned in the GM-CSF signal pathway, are thought to be involved in the pathogenesis of JMML. However, no information is available on the relationship between these mutations and clinical features of JMML. The impacts of these mutations on clinical outcome also remain unclear. We tested 49 Japanese children with JMML for N-RAS, K-RAS, and PTPN11 mutations and evaluated their clinical significance. We also assessed correlations between mutational status and clinical and laboratory findings, including age at diagnosis, fetal hemoglobin (HbF), platelet count, and cytogenetic abnormality, all which have been proposed as prognostic factors for JMML. Of the 49 JMML patients, cytogenetic abnormalities were detected in 13, including 8 with monosomy 7. For 2 patients, a clinical diagnosis of neurofibromatosis type 1 (NF1) was confirmed. PTPN11 and N-/K-RAS mutations were found in 22 (45%) and 8 (16%) patients, respectively. Neither PTPN11 nor RAS mutations nor NF1 were present in 17 (35%) patients, and no simultaneous aberrations in these genes were found. In patients with the PTPN11 mutation, age at diagnosis was older (35 vs 11 months; P=0.001, or 12 months; P<0.01) and HbF level was higher (31 vs 10%; P=0.03, or 16%; P<0.01) than for patients with the RAS mutation or without any aberration, suggesting that the clinical outcome for patients with the PTPN11 mutation might be poorer, because a higher HbF level and older age have been reported to be poor prognostic factors. In fact, overall survival (OS) at 5 years was lower for patients with the PTPN11 mutation than for those without (20±9% vs 58±9%; P=0.02). In addition to PTPN11 mutation, age older than 24 months (P<0.01) and abnormal karyotype (P=0.02) were also associated with poor prognosis for OS. Of the 49 patients, 33 received stem cell transplantation (SCT). OS probabilities for patients with and without a mutation in PTPN11 at 5 years after SCT were 25±10% and 64±12%, respectively (P=0.04). More importantly, mutation in PTPN11 was the only unfavorable factor for relapse after SCT (P<0.01). Seven patients died owing to relapse and 12 from complications. All patients who died after relapse had a PTPN11 mutation. In summary, our results suggest that PTPN11-mutated JMML might be a distinct subgroup with specific clinical characteristics and a poor outcome.

Mutations In GATA2 Are Rare In Juvenile Myelomonocytic Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1526-1526
Author(s):  
Elliot Stieglitz ◽  
Y. Lucy Liu ◽  
Peter D. Emanuel ◽  
Robert P. Castleberry ◽  
Todd Michael Cooper ◽  
...  
Keyword(s):  
Point Mutation ◽  
Trans Configuration ◽  
Juvenile Myelomonocytic Leukemia ◽  
Sequence Variants ◽  
Wild Type ◽  
Monosomy 7 ◽  
Atypical Features ◽  
The Impact ◽  
Myelomonocytic Leukemia ◽  
Chronic Neutropenia

Abstract Germline mutations in GATA2, a gene that encodes for transcription factors involved in hematopoiesis and vascular development, have recently been described in MonoMAC syndrome, Emberger syndrome and in select cases of mild chronic neutropenia. These disorders are unified by their predisposition to myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Patients with MonoMAC syndrome have also been noted to display monosomy 7 in their bone marrows in up to 50% of cases. Overexpression of GATA2 due to somatic mutations in cases of de novo pediatric AML, has also been shown to be a negative predictor of outcome. Juvenile myelomonocytic leukemia is a rare childhood malignancy with overlapping features of MDS and myeloproliferative neoplasm (MPN) that can transform to AML and is characterized by hyperactive RAS signaling. Mutations in NF1, NRAS, KRAS, PTPN11, and CBL are found in 85-90% of newly diagnosed patients, and monosomy 7 is the most common recurrent karyotypic abnormality seen in JMML. We therefore hypothesized that mutations in GATA2 may play a role in the development of JMML. Samples from 57 patients with JMML were screened for GATA2 mutations. Patient samples and clinical data were collected from the Children's Oncology Group (COG) trial AAML0122. DNA was extracted as per previous protocols from peripheral blood or bone marrow and whole genome amplified using Qiagen REPLI-g kit according to manufacturer specifications. We performed bidirectional Sanger sequencing (Beckman Coulter Genomics) of the entire coding region of GATA2 (NM_001145661.1) and aligned the sequences using CLC Workbench software (CLC Bio, Aarhus, Denmark). Only missense, splice site or nonsense mutations were evaluated using SIFT (Sorting Tolerant From Intolerant) to predict the impact on the structure and function of identified mutations on the protein. Patient J384 was found to have a nonsense point mutation at c.988C>T (R330X) in the N-terminal region of the zinc finger portion of the protein (Figure 1a). This hotspot mutation has been reported in several patients with mild chronic neutropenia who displayed a predisposition to developing MDS and AML. The patient was also found to have a missense point mutation at c.962T>G (L321R) predicted to be damaging by SIFT. Subcloning of the gene using a TA cloning kit with pCR 2.1 vector (Invitrogen), followed by direct sequencing of individual colony picks, revealed that the two sequence variants only occurred in a trans configuration. Out of 40 amplicons sequenced, 20 were found to have the c.988C>T transition, 16 were found to be have the c.962T>G variant, and four were found to be wild type. We therefore hypothesize that the c.988C>T was inherited as a germline event and that c.962T>G was somatically acquired in the majority of the remaining wild type alleles. No other point mutations or insertions/deletions were discovered in this cohort.Figure 1Identification of 2 distinct GATA2 mutations in patient J384.Figure 1. Identification of 2 distinct GATA2 mutations in patient J384. This patient was previously identified to have a KRAS G12D mutation (c.35G>A) as well as monosomy 7. This patient died prior to undergoing transplant within months of diagnosis. While the patient technically met criteria for the diagnosis of JMML, it should be noted there were several atypical features, including older age at diagnosis (4 years and 10 months), and absence of hypersensitivity in myeloid progenitor cells to the cytokine granulocyte–macrophage colony stimulating factor (GM-CSF) in colony assay. This raises the possibility that patient J384 actually had MonoMAC syndrome with MDS and not JMML. This represents the first description of a GATA2 mutation in a patient suspected of having JMML. To our knowledge, this is the first report of a biallelic mutation in GATA2, combining a germline mutation with somatic acquisition. In addition, MonoMAC syndrome has not been reported to be associated with KRAS mutations to date. GATA2 mutations should therefore be considered in patients with atypical features of MDS or JMML. Panel (a) Bidirectional sequencing of patient sample J384 revealed two distinct sequence variants in both the forward (shown here) and reverse strands. Panel (b) Sequencing of 40 individual colony picks revealed that each sequence variant occurred in a trans configuration (CP 9 and CP13 are shown here as examples). In addition, 10% of colony picks (i.e. CP 32) revealed a wild type sequence, indicating that at least one of the two variants was a somatic event. Disclosures: No relevant conflicts of interest to declare.

Aberrant DNA methylation characterizes juvenile myelomonocytic leukemia with poor outcome

Blood ◽  
2011 ◽  
Vol 117 (18) ◽  
pp. 4871-4880 ◽  
Author(s):  
Christiane Olk-Batz ◽  
Anna R. Poetsch ◽  
Peter Nöllke ◽  
Rainer Claus ◽  
Manuela Zucknick ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Cox Regression ◽  
Cpg Island ◽  
Cpg Islands ◽  
Prognostic Scores ◽  
Juvenile Myelomonocytic Leukemia ◽  
Hematopoietic Stem ◽  
Prognostic Features ◽  
Aberrant Dna Methylation ◽  
Myelomonocytic Leukemia

Abstract Aberrant DNA methylation contributes to the malignant phenotype in virtually all types of cancer, including myeloid leukemia. We hypothesized that CpG island hypermethylation also occurs in juvenile myelomonocytic leukemia (JMML) and investigated whether it is associated with clinical, hematologic, or prognostic features. Based on quantitative measurements of DNA methylation in 127 JMML cases using mass spectrometry (MassARRAY), we identified 4 gene CpG islands with frequent hypermethylation: BMP4 (36% of patients), CALCA (54%), CDKN2B (22%), and RARB (13%). Hypermethylation was significantly associated with poor prognosis: when the methylation data were transformed into prognostic scores using a LASSO Cox regression model, the 5-year overall survival was 0.41 for patients in the top tertile of scores versus 0.72 in the lowest score tertile (P = .002). Among patients given allogeneic hematopoietic stem cell transplantation, the 5-year cumulative incidence of relapse was 0.52 in the highest versus 0.10 in the lowest score tertile (P = .007). In multivariate models, DNA methylation retained prognostic value independently of other clinical risk factors. Longitudinal analyses indicated that some cases acquired a more extensively methylated phenotype at relapse. In conclusion, our data suggest that a high-methylation phenotype characterizes an aggressive biologic variant of JMML and is an important molecular predictor of outcome.

Prospective Study of 90 Children Requiring Treatment for Juvenile Myelomonocytic Leukemia or Myelodysplastic Syndrome: A Report From the Children’s Cancer Group

2002 ◽  
Vol 20 (2) ◽  
pp. 434-440 ◽  
Author(s):  
William G. Woods ◽  
Dorothy R. Barnard ◽  
Todd A. Alonzo ◽  
Jonathan D. Buckley ◽  
Nathan Kobrinsky ◽  
...  
Keyword(s):  
Myelodysplastic Syndrome ◽  
Prospective Study ◽  
De Novo ◽  
Refractory Anemia ◽  
Juvenile Myelomonocytic Leukemia ◽  
Allogeneic Bone ◽  
Monosomy 7 ◽  
Cancer Group ◽  
De Novo Aml ◽  
Myelomonocytic Leukemia

PURPOSE: We report the first large prospective study of children with myelodysplastic syndrome (MDS) and juvenile myelomonocytic leukemia (JMML) treated in a uniform fashion on Children’s Cancer Group protocol 2891. PATIENTS AND METHODS: Ninety children with JMML, various forms of MDS, or acute myeloid leukemia (AML) with antecedent MDS were treated with a five-drug induction regimen (standard or intensive timing). Patients achieving remission were allocated to allogeneic bone marrow transplantation (BMT) if a matched family donor was available. All other patients were randomized between autologous BMT and aggressive nonmyeloablative chemotherapy. Results were compared with patients with de novo AML. RESULTS: Patients with JMML and refractory anemia (RA) or RA-excess blasts (RAEB) exhibited high induction failure rates and overall remission of 58% and 48%, respectively. Remission rates for patients with RAEB in transformation (RAEB-T) (69%) or antecedent MDS (81%) were similar to de novo AML (77%). Actuarial survival rates at 6 years were as follows: JMML, 31% ± 26%; RA and RAEB, 29% ± 16%; RAEB-T, 30% ± 18%; antecedent MDS, 50% ± 25%; and de novo AML, 45% ± 3%. For patients achieving remission, long-term survivors were found in those receiving either allogeneic BMT or chemotherapy. The presence of monosomy 7 had no additional adverse effect on MDS and JMML. CONCLUSION: Childhood subtypes of MDS and JMML represent distinct entities with distinct clinical outcomes. Children with a history of MDS who present with AML do well with AML-type therapy. Patients with RA or RAEB respond poorly to AML induction therapy. The optimum treatment for JMML remains unknown.

Analysis of Risk Factors Influencing Outcomes After Unrelated Cord Blood Transplantation In Children with Juvenile Myelomonocytic Leukemia. An Eurocord, EBMT, EWOG-MDS, CIBMTR Study

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 533-533
Author(s):  
Alessandro Crotta ◽  
Vanderson Rocha ◽  
Mary Eapen ◽  
John E. Wagner ◽  
Margaret L. MacMillan ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Cord Blood ◽  
Cord Blood Transplantation ◽  
Juvenile Myelomonocytic Leukemia ◽  
Advisory Committees ◽  
Monosomy 7 ◽  
Factors Associated ◽  
Blood Transplantation ◽  
Unrelated Cord Blood ◽  
Myelomonocytic Leukemia

Abstract Abstract 533 Juvenile myelomonocytic leukemia (JMML) is a rare and lethal myeloproliferative disease of young childhood. Currently, allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative treatment option. DFS at 5 years after HLA identical and unrelated HSCT was 55% (n=48) and 49% (n=52) in a largest series of patients published so far and mainly transplanted with bone marrow cells. Unrelated Cord Blood Transplantation (UCBT) is considered an alternative option for patients who lack an HLA-matched donor. We retrospectively analyzed 110 children, given a first single unmanipulated UCBT, from 1995 to 2010, and reported to Eurocord-EBMT and CIBMTR. Median age was 1 year (range 0.08–6.4) at diagnosis and 2 years (0.5-7.5) at transplantation, respectively. Median time interval between diagnosis and UCBT was 6 months (1-58); before transplantation, 88 patients were treated with low- or high-dose chemotherapy and splenectomy was performed in 24 children. Among 100 patients with available cytogenetic data, monosomy of chromosome 7 was the most frequent abnormality (24%). All but 8 patients received a myeloablative conditioning, Busulfan-Cyclophosphamide-Melphalan (BuCyMel) was used in 48 patients, total body irradiation (TBI) and Cyclophosphamide in 19 patients and combination of Busulfan-Cyclophosphamide with other drugs in 21 patients. Cyclosporin+steroid was the most common graft-versus-host disease (GvHD) prophylaxis (80%) and ATG was added in 86% of patients. Nineteen percent of units were HLA-identical (antigen level for HLA-A and B, allelic for DRB1), while 43% and 38% had 1 or 2–3 mismatches, respectively. Median TNC infused was 7.1×10e7/kg (1.7-27.6). Median follow-up was 44 months (3-169). At 60 days, cumulative incidence (CI) of neutrophil (PMN) recovery was 80±4%, with a median time to PMN recovery of 25 days. Grades II-IV acute GvHD developed in 45 patients, 100 days-CI of grade II-IV aGvHD was 40±5%. Among 90 patients at risk, 17 developed chronic GvHD and 4 years-CI was 16±4%. At 4 years CI of relapse was 37±5% (n=38); age older than 1 year at diagnosis was the only independent factor associated with increased risk of relapse (HR 2.3, p=0.038). Of note, among 58 patients with available data for level of fetal hemoglobin (HbF), a higher level of HbF (>35%) seemed to be associated with increased relapse incidence (57% versus 31% for remainders; p=0.05). At 4 years, DFS was 43±5%, in multivariate analysis independent factors associated with better DFS were: age younger than 1 year at diagnosis (53% vs 30%, HR 2.4, p=0.001), graft with 0 or 1 HLA mismatched cord blood unit (48% vs 34%, HR=2.1, p=0.006) and cytogenetic without monosomy 7 (48% vs 26%; HR=1.95, p=0.027). At 4 years, CI of transplant related mortality (TRM) was 20±4%; in multivariate analysis, cytogenetic with monosomy 7 (HR=2.7, p=0.036) and transplantation performed before 2003 (HR=3.7, p=0.015) were factors associated with increased TRM. In fact, CI of TRM was 14% after 2003 compared to 30% before 2003. Estimated overall survival (OS) at 4 years was 51±5%, and in multivariate analysis factors associated with decreased OS were: age older than 1 year at diagnosis (42% vs 60%; HR=2.03, p=0.032), and cytogenetic with monosomy 7, (30% vs 57%; HR=2.6, p=0.004). Fifty-one patients died after transplant, 53% for relapse and 47% for transplant related causes. In conclusion, UCBT may cure approximately 50% of patients with JMML who lack a matched related donor. Presence of monosomy 7 is associated with decreased DFS and increased TRM, independent of other factors. Other patient- (age at diagnosis) and transplantation-related factors (HLA and year of transplantation) were also associated with outcomes. Disease recurrence remains the major cause of treatment failure, and strategies to reduce the risk of relapse are warranted. Disclosures: Wagner: CORD:USE: Membership on an entity's Board of Directors or advisory committees; VidaCord: Membership on an entity's Board of Directors or advisory committees.

Gene Expression–Based Classification As an Independent Predictor of Clinical Outcome in Juvenile Myelomonocytic Leukemia

2010 ◽  
Vol 28 (11) ◽  
pp. 1919-1927 ◽  
Author(s):  
Silvia Bresolin ◽  
Marco Zecca ◽  
Christian Flotho ◽  
Luca Trentin ◽  
Andrea Zangrando ◽  
...  
Keyword(s):  
Gene Expression ◽  
Clinical Outcome ◽  
Juvenile Myelomonocytic Leukemia ◽  
Microarray Gene Expression ◽  
Hemoglobin F ◽  
Hematopoietic Stem ◽  
Probability Of Survival ◽  
Prognostic Relevance ◽  
Therapeutic Decisions ◽  
Myelomonocytic Leukemia

Purpose Juvenile myelomonocytic leukemia (JMML) is a rare early childhood myelodysplastic/myeloproliferative disorder characterized by an aggressive clinical course. Age and hemoglobin F percentage at diagnosis have been reported to predict both survival and outcome after hematopoietic stem cell transplantation (HSCT). However, no genetic markers with prognostic relevance have been identified so far. We applied gene expression–based classification to JMML samples in order to identify prognostic categories related to clinical outcome. Patients and Methods Samples of 44 patients with JMML were available for microarray gene expression analysis. A diagnostic classification (DC) model developed for leukemia and myelodysplastic syndrome classification was used to classify the specimens and identify prognostically relevant categories. Statistical analysis was performed to determine the prognostic value of the classification and the genes identifying prognostic categories were further analyzed through R software. Results The samples could be divided into two major groups: 20 specimens were classified as acute myeloid leukemia (AML) –like and 20 samples as nonAML-like. Four patients could not be assigned to a unique class. The 10-year probability of survival after diagnosis of AML-like and nonAML-like patients was significantly different (7% v 74%; P = .0005). Similarly, the 10-year event-free survival after HSCT was 6% for AML-like and 63% for nonAML-like patients (P = .0010). Conclusion Gene expression–based classification identifies two groups of patients with JMML with distinct prognosis outperforming all known clinical parameters in terms of prognostic relevance. Gene expression–based classification could thus be prospectively used to guide clinical/therapeutic decisions.

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