scholarly journals DNMT3A mutations in De Novo Myelodysplastic Syndrome: Distinct Clinico-Biological Features and Prognostic Relevance

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3799-3799
Author(s):  
Ming-En Lin ◽  
Hsin-An Hou ◽  
Yuan-Yeh Kuo ◽  
Wen-Chien Chou ◽  
Ming Cheng Lee ◽  
...  
Keyword(s):  
Myelodysplastic Syndrome ◽  
Poor Prognosis ◽  
Who Classification ◽  
De Novo ◽  
Gene Mutations ◽  
Refractory Anemia ◽  
Single Mutation ◽  
Idh Mutation ◽  
Biological Features ◽  
Fab Classification

Abstract Abstract 3799 Background and Purpose Mutations of the DNMT3A gene, which encodes the enzyme DNA methyltransferase 3A, were identified in patients with myeloid malignancies and are associated with poor prognosis in primary AML patients. However, the clinical and prognostic implications of these mutations in myelodysplastic syndrome (MDS) remain to be determined. Methods and Materials A total of 328 de novo MDS patients diagnosed according to French-American-British (FAB) criteria at the National Taiwan University Hospital who had cryopreserved bone marrow cells for study were recruited into mutational analyses. Mutations in DNMT3A gene at exon 2–23 were analyzed by polymerase chain reaction and direct sequencing. The results were correlated with clinical features, cytogenetics, gene mutations and treatment outcomes. Results Among the 328 patients, 115 patients (35.0%) had refractory anemia (RA), 19 (5.8%) had RA with ring sideroblasts (RARS), 122 (37.2%) had RA with excess blasts (RAEB), 35 (10.7%) had RAEB in transformation (RAEBT), and 37 (11.3 %) had chronic myelomonocytic leukemia (CMMoL). DNMT3A mutations at 20 different positions were identified in 33 patients, including thirteen missense mutations, two nonsense mutations and five frame-shift mutations. Among these 33 patients, 31 had single mutation of DNMT3A, and the other 2 patients had double mutations. The most common mutation was R882H (n = 8), followed by R882C (n = 7), Y735C (n=2), and R720H (n=2). All other mutations were detected in only one patient each. Totally, DNMT3A mutations were identified in 33 (10.1%) of 328 patients diagnosed according to the FAB classification and in 25 (9.8%) of 256 diagnosed according to 2008 WHO classification. DNMT3A-mutated patients were older (median age, 74 years vs. 66 years, P=0.048) and had higher platelet counts at diagnosis than DNMT3A-wild patients (median, 123.5×103/μL vs. 73 ×103/μL, P=0.016). According to FAB classification, patients with RARS had the highest incidence (26.3%) of DNMT3A mutations, followed by RAEBT (14.3%), RAEB (11.5%), and CMMoL (8.1%), whereas those with RA had the lowest incidence (5.2%, P=0.035). Chromosome data were available in 308 patients (93.9%) at diagnosis and clonal chromosomal abnormalities were detected in 155 patients (50.3%). There was no difference in the distribution of 2008 WHO classification, karyotype and international prognostic scoring system (IPSS) between patients with and without DNMT3A mutations. To investigate the association of gene mutations in the pathogenesis of MDS, a mutational screening of 10 other genes was also performed. Among the 33 patients with DNMT3A mutations, 16 patients (48.5%) showed additional molecular abnormalities at diagnosis, including seven with concurrent IDH1/IDH2 mutations, seven ASXL1 mutations, five AML1/RUNX1 mutations, two MLL-PTD, two RAS mutations and one JAK2 mutation. Eight of these 16 patients (50%) had two other concurrent mutations, and the others had one additional mutation. It's clear that DNMT3A mutation was closely interacted with IDH mutation in MDS (IDH mutation occurring in 21.2% of DNMT3A-mutated patients vs. 3.4% in DNMT3A-wild ones, P=0.001). With a median follow-up of 57.6 months (range, 0.1–250.7 months), there was no significant difference in overall survival (OS) between patients with and without DNMT3A mutation by either FAB or 2008 WHO classifications (median, 22.5 months vs. 30.9 months, P=0.669 and 25.2 months vs. 34.9 months, P=0.538, respectively) as well as in the rate of acute transformation. However, among the subgroup of patients with RA by FAB classification or refractory cytopenia with unilineage dysplasia by 2008 WHO classification, DNMT3A-mutated patients had significantly shorter OS than DNMT3A-wild patients (median, 28.3 months vs. 39.8 months, P<0.001 and 23.8 months vs. 40.3 months, P=0.026, respectively). Further, DNMT3A mutation is an independent poor prognostic factor in these two subgroups. Conclusion Our findings provided evidence that DNMT3A mutations could be detected in a substantial portion of de novo MDS patients. DNMT3A mutations are associated with distinct clinical and biological features and poor prognosis in selected groups of patients. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Differential U2AF1 mutation sites, burden and co-mutation genes can predict prognosis in patients with myelodysplastic syndrome

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Haiqiong Wang ◽  
Yongbo Guo ◽  
Zhenkun Dong ◽  
Tao Li ◽  
Xinsheng Xie ◽  
...  
Keyword(s):  
Survival Rate ◽  
Myelodysplastic Syndrome ◽  
Gene Mutation ◽  
Poor Prognosis ◽  
Gene Mutations ◽  
Chromosome 8 ◽  
Common Mutation ◽  
Mutation Load ◽  
Mutation Site ◽  
Increased Risk

Abstract To investigate the U2AF1 gene mutation site, mutation load and co-mutations genes in patients with myelodysplastic syndrome (MDS) and their effects on prognosis. Gene mutation detection by next-generation sequence and related clinical data of 234 MDS patients were retrospectively collected and analyzed for the relationship between the clinical characteristics, treatment efficacy and prognosis of U2AF1 gene mutation. Among the 234 MDS patients, the U2AF1 gene mutation rate was 21.7% (51 cases), and the median variant allele frequency was 39.5%. Compared with the wild type, the U2AF1 mutant had a higher incidence of chromosome 8 aberration, and was positively correlated with the occurrence of ASXL1, RUNX1, SETBP1 gene mutation, negatively correlated with SF3B1, NPM1 genes mutation (p < 0.05). The most common mutation site of U2AF1 was S34F (32 cases), while U2AF1 Q157P site mutations had a higher incidence of chromosome 7 abnormalities (p = 0.003). The U2AF1 gene mutation more frequently coincided with signal pathway related gene mutations (p = 0.043) with a trend of shortened overall survival. Among patients with U2AF1 gene mutations, those with ASXL1 mutations were prone to develop into acute myeloid leukemia, those with RUNX1 mutations had an increased risk of relapse, and those with TET2 mutations had higher 1-year survival rate. Compared with the patient group of lower mutation load (VAF ≤ 40%), the group with higher mutation load of U2AF1 (VAF > 40%) had a significantly lower 1-year survival rate (46.1% and 80.5%, p = 0.027). The criteria of U2AF1 VAF > 40% is an independent indicator for poor prognosis of MDS patients. VAF > 40% of U2AF1 is an independent factor of short OS in MDS patients. MDS patients with a mutation in the Q157P site of U2AF1 and a higher U2AF1 mutation load suggests poor prognosis, and co-mutated genes in U2AF1 can affect disease progression and prognosis.

scholarly journals Incidence and Outcomes of Pediatric Myelodysplastic Syndrome in the US

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1285-1285
Author(s):  
Ana Xavier ◽  
Matthew A. Kutny ◽  
Luciano J Costa
Keyword(s):  
Overall Survival ◽  
Myelodysplastic Syndrome ◽  
Pediatric Patients ◽  
De Novo ◽  
The United States ◽  
Refractory Anemia ◽  
Histological Subtype ◽  
Risk Of Death

Background There is lack of epidemiological data on pediatric myelodysplastic syndrome (p-MDS) in the literature. MDS became reportable to the Surveillance, Epidemiology and End Results (SEER) Program in 2001, providing an opportunity to estimate the incidence and survival of pediatric patients with MDS in the United States. Methods We utilized data from the National Cancer Institute SEER-18 to determine the incidence and long term overall survival (OS) of pediatric patients (ages 0 to 20 years) diagnosed with de novo MDS or therapy-related MDS. Inclusion criteria was diagnosis of MDS (International Classification of Diseases-Oncology, Third Edition, ICD-O-4 codes 9980/3, 9991/3, 9992/3, 9982/3, 9985/3, 9983/3, 9986/3, 9986/3, 9989/3, 9985/3, 9975/3, and 9987/3) between 2001 and 2011. Follow up was updated through the end of 2011 (November 2013 submission). Overall survival was estimated using the method of Kaplan-Meier. A Cox proportional hazard model was used to compare the effects of age, race, gender, histological subtype, and etiology (de novovs. therapy-related) on survival. Results The incidence of p-MDS was 1.16 cases/1 million population*year. A greater incidence occurred in children younger than 1 year of age possibly reflecting congenital bone marrow failure syndromes (Figure 1). A total of 314 p-MDS cases were included in the analysis with median follow up of 31 months (range 0-131). Median age of patients was 9 years; 167 (53.3%) had MDS unclassifiable (NOS), 40 (12.7%) had therapy-related MDS (t-MDS), 44 (14%) had refractory anemia with excess blasts (RAEB), 32 (10.3%) had refractory anemia (RA), 17 (5.4%) had refractory cytopenia with multilineage dysplasia (RCMD), 6 (1.9%) had refractory anemia with ring sideroblasts (RARS), 5 (1.6%) had refractory anemia with excess blasts in transformation (RAEBT), and 3 (0.9%) had MDS associated with isolated del(5q). Male patients comprised 154 (49%) of cases. Racial groups included white (218, 69.4%), 52 (15.7%) black, 37 (11.8%) of other races, and 7 (2.3%) the race was unknown. The 5 year-OS for the entire cohort was 68% (95% C.I.=62.3-73.7). Patients with t-MDS had significantly worse 5 year-OS (41.2%; 95%C.I.=23.8-58.6) compared to those with de novo MDS (71.3%; 95%C.I.=65.3-77.2; P=0.004, Figure 2). In multivariate analysis of age, race, gender, histological subtype, and etiology (de novovs. therapy-related) utilizing Cox regression model, only t-MDS was associated with higher risk of death (HR=2.07, 95% C.I.=1.25-3.42, P=0.005). Conclusions Pediatric MDS is a rare disorder, with higher incidence among children younger than 1 year of age. Over two thirds of p-MDS patients will become long-term survivors, although significantly inferior outcome is seen in t-MDS. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

scholarly journals Gene mutation spectrum of patients with myelodysplastic syndrome and progression to acute myeloid leukemia

2021 ◽  
pp. IJH34
Author(s):  
Ming Liu ◽  
Fang Wang ◽  
Yang Zhang ◽  
Xue Chen ◽  
Panxiang Cao ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myelodysplastic Syndrome ◽  
Myeloid Leukemia ◽  
High Throughput Sequencing ◽  
Gene Mutations ◽  
Refractory Anemia ◽  
Sequencing Technology ◽  
Transcription Factor Genes ◽  
Spectrum Of Patients ◽  
Acute Myeloid

Aim: This study aimed to investigate the regularity of gene mutations in patients with myelodysplastic syndrome (MDS) and in those that progressed to acute myeloid leukemia (MDS/AML). Patients & methods: High-throughput sequencing technology was used to detect gene mutations in 99 newly diagnosed patients with MDS or MDS/AML. Results: Gene mutations were detected in 88 patients. The mutation incidence in the MDS/AML group was significantly higher than that in the MDS group. Statistically significant differences were observed between the MDS with refractory anemia (MDS-RA) and MDS-RA with excess blasts groups and between the MDS/AML and MDS-RA groups. Conclusion: Our data demonstrate that there is a cumulative accumulation of gene mutations, especially in transcription factor genes, during disease progression in MDS and MDS/AML.

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.

Chronic Myelomonocytic Leukemia With Preexisting Myelodysplastic Syndrome Or Myeloproliferative Neoplasm: Two Stages Of One Disease With Poor Prognosis

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1342-1342 ◽  
Author(s):  
Yin Xu ◽  
Aine Yung ◽  
Brian Kwok ◽  
Karen Macdonell ◽  
Bashar Dabbas ◽  
...  
Keyword(s):  
Myelodysplastic Syndrome ◽  
De Novo ◽  
Myeloproliferative Neoplasm ◽  
Chronic Myelomonocytic Leukemia ◽  
Chromosome Abnormalities ◽  
Refractory Anemia ◽  
Jak2 Mutation ◽  
Cytogenetic Abnormalities ◽  
Two Stages ◽  
Myelomonocytic Leukemia

Abstract Introduction Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic malignancy characterized by persistent monocytosis with features of a myelodysplastic syndrome (MDS) and/or myeloproliferative neoplasm (MPN). While most cases present as de novo disease, a subset of CMML has been described in the literature to evolve from a preexisting MDS (MDS-CMML). CMML with preexisting MPN (MPN-CMML) has not been characterized to our knowledge. It is uncertain whether CMML patients with preexisting MDS or MPN have one or more disease processes and if such patients behave differently from patients who present with de novo CMML. In an attempt to address these questions, we compared the clinicopathologic features between groups of MDS-CMML, MPN-CMML, and de novo CMML in the present study. Methods 126 cases with newly diagnosed CMML were retrieved from our database over a 3-year period. 22 cases had preexisting MDS (n=15) or MPN (n=7). Prior diagnoses of MDS included refractory anemia (n=5), refractory anemia with ring sideroblasts (n=2), MDS with isolated 5q deletion (n=1), refractory cytopenia with multilineage dysplasia (n=6), and refractory anemia with excess blasts-1 (n=1). Prior diagnoses of MPN included essential thrombocythemia (n=1), primary myelofibrosis (n=3), and MPN NOS (n=3). Cytogenetic studies were performed in all cases. Other parameters obtained included age, gender, hemoglobin, white blood cell count, monocytes, platelets, bone marrow blasts and histology, and JAK2/MPL mutations. 22 consecutive cases of de novo CMML were included for comparative analysis. Results CMML with preexisting MDS or MPN comprised 17% of CMML (22/126 patients). Among these 22 patients, 15 were male and 7 female with a median age of 79 (range 61-86) years. Median age of the patients at CMML stage was similar to that of patients with de novo CMML (77 years; range 65-89). The median time between disease presentation as MDS or MPN and CMML was 22 months. Patients presented with marked monocytosis at the CMML stage (mean: 23% and 4564/uL) as compared to the stage of MDS (mean: 13% and 794/uL; p<0.001) or MPN (mean: 6.4% and 1216/uL; p<0.001); and the monocyte count was similar to that present in de novo CMML (mean: 24% and 4313/uL). Marrow blasts were significantly increased at the CMML stage as compared to the stage of MDS (mean: 5.3 vs. 1.6; p=0.017), MPN (mean: 5.1 vs. 1.9; p=0.048), or de novo CMML (5.2 vs. 1.9; p=0.009). There was no significant difference in average hemoglobin, platelet count or marrow cellularity between cases at the two disease stages or among the MDS-CMML and MPN-CMML subgroups. However, the marrows of MPN-CMML showed significantly increased diffuse reticulin fibrosis (p=0.002) and marked megakaryocytic hyperplasia (p=0.002) as compared to MDS-CMML. CMML with preexisting MDS or MPN is more frequently associated with cytogenetic abnormalities than de novo CMML (50% vs. 23%), although this difference did not reach statistical significance (p=0.116). 8 (36%) cases had chromosome abnormalities at the MDS or MPN stages; 7 (87%) of the 8 cases demonstrated persistent chromosome abnormalities at the CMML stage. In addition, 4 (18%) patients acquired chromosome abnormalities at the CMML stage. JAK2 mutation was seen in 1 (7%) of 15 cases of MDS-CMML and 4 (57%) of 7 cases of MPN-CMML. Notably, 2 cases of JAK2 positive MPN became JAK2 negative at the CMML stage; one of the patients had been previously treated with a JAK2 inhibitor. No MPL mutation was found in any case. Conclusions CMML with preexisting MDS or MPN is not uncommon. The majority of cases exhibit persistent chromosomal abnormalities from the preexisting MDS or MPN, supporting the notion of one disease with two stages of presentation. The findings of a higher frequency of cytogenetic abnormalities and occasional cytogenetic evolution may suggest that chromosome alteration is one of the mechanisms involved in triggering disease progression to CMML. JAK2 V617F was more frequent in MPN-CMML, which correlated with myelofibrosis and megakaryocytic hyperplasia. However, loss of JAK2 mutation can occur at CMML stage. Loss/inhibition of JAK2 activity may contribute to a change in disease course. Our study revealed that CMML with preexisting MDS or MPN is characterized by more advanced disease with increased marrow blasts and therefore may be associated with a poorer prognosis. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Azacitidin Is Effective in the Therapy Related Myelodysplastic Syndrome.

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5554-5554
Author(s):  
Hirofumi Yamauchi ◽  
Masahiro Yokoyama ◽  
Yuko Mishima ◽  
Noriko Nishimura ◽  
Kyoko Ueda ◽  
...  
Keyword(s):  
Overall Survival ◽  
Myelodysplastic Syndrome ◽  
Research Funding ◽  
Poor Prognosis ◽  
De Novo ◽  
Genetic Alterations ◽  
Poor Risk ◽  
Significant Difference ◽  
One Year

Abstract Introduction: Myelodysplastic syndromes (MDS) are clonal hematopoietic neoplasms characterized by abnormal maturation of precursor cells which often translates into peripheral blood cytopenias and a high rate of transformation to acute myeloid leukemia (AML) due to accumulation of genetic alterations. The AZA-001 trial showed azacitidine (AZA) significantly prolonged median overall survival compared with conventional care regimens (24.5 vs 15.0 months; P=0.0001). AZA is standard first-line treatment for Intermediate-2 and High-risk myelodysplastic syndrome patients who are not immediate candidates for allogeneic stem cell transplantation, but this study included no cases of therapy related MDS (t-MDS). T-MDS is known to have poor prognosis, therefore it is very important to analyze the outcome of patients with t-MDS treated in the front-line with AZA. Methods: We studied newly diagnosed 29 MDS patients who were treated by AZA in our hospital from July, 2010 to April, 2016, retrospectively. AZA was given subcutaneously at 75 mg/㎡per day for 5 or 7 days every 28 days. Results: We analyzed 29 MDS patients. According to the WHO classification, there were 12 RA, 15 RCMD, 10 RAEB-1, 2 RAEB 2 and 1 MDS-U. The median age was 70 year (range 49-88), and men was 12 (41.3%). There were 12 de novoMDS cases (41.3%) and 17 t-MDS cases (58.6%). All of the t-MDS patients had previously received chemotherapy (17 patients, 100%) and 9 patients had also received radiotherapy (9 patients, 53%). Very poor risk group was 47.1% (9/17) in t-MDS group compared to 25.0% (3/12) in de novo MDS group (P=0.26). Median follow up time was 11.4 months (range 1.4-47.8). Twenty five patients (86.3%) were treated by AZA for 5 days. Four patients (13.7%) were treated by AZA for 7 days, but all 4 patients decreased the dosing period to 5 days due to unacceptable toxicity. AZA was given for a median of 4 cycles (range 1-33). In 29 MDS patients, 1-year overall survival (OS) was 60.5% (95% CI, 38.7-76.7%) and 1-year PFS was 40.1% (95% CI, 18.8-60.6%). After a median follow-up of 11.4 months, median OS was 18.7 months (95% CI, 9.4-21). One-year OS was 59.3% in t-MDS group compared to 63.6% in de novo MDS group (P=0.294). 1-year PFS was 38.4% in t-MDS group compared to 40.4% in de novo MDS group (P=0.626). One-year OS was 37.5% in very poor risk karyotype group (R-IPSS) compared to 74.6% in not very poor risk karyotype group (P=0.000748). 1-year PFS was 43.2% in very poor risk karyotype group compared to 39.0% in not very poor risk karyotype group (P=0.594). Focusing on t-MDS group, 1-year OS was 46.9% in very poor risk karyotype group (8/17 47%) compared to 74.1% in not very poor risk karyotype group (9/17 53%) (P=0.054). 1-year PFS was 48.0% in very poor risk karyotype group compared to 26.0% in not very poor risk karyotype group (P=0.339). Conclusions: In our study, 1-year OS in all MDS patients was 60.5%. It was slightly poor prognosis than 1-year OS in AZA-001 trial (about 70%). Our study include t-MDS cases (58.6%). Additionally, AZA was given for a median of 4 cycles in our study but 6 cycles in the AZA-001 trial. It showed severe patient's background of our study. These difference may cause the lower median OS and poorer prognosis. There trended to be more patients who had very poor risk karyotype in t-MDS group, but there was no significant difference between t-MDS and de novoMDS for the 1-year OS and PFS. Azacitidin is effective in the therapy related myelodysplastic syndrome. Disclosures Yokoyama: Chugai: Consultancy. Mishima:Chugai: Consultancy. Nishimura:Chugai: Consultancy. Terui:Yanssen: Honoraria. Hatake:Kyowa Kirin: Honoraria, Research Funding; Chugai: Research Funding; Otsuka: Consultancy; Meiji-Seika: Consultancy.

Clonal T Cell Expansion in High Risk Myelodysplastic Syndrome (MDS).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3435-3435
Author(s):  
Jeffrey S. Painter ◽  
Bai Fanqi ◽  
Alan Cantor ◽  
Alan F. List ◽  
P.K. Epling-Burnette
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
High Risk ◽  
Myelodysplastic Syndrome ◽  
Peripheral Blood ◽  
Cell Expansion ◽  
Who Classification ◽  
Refractory Anemia ◽  
Risk Patients ◽  
T Cell Expansion

Abstract Myelodysplastic Syndrome (MDS), a hematologic malignancy, is associated with cytogenetic and molecular abnormalities in maturing hematopoietic cells that occurs in 40–70% of cases. These abnormalities directly contribute to increased apoptosis and ineffective hematopoiesis of erythroid and myeloid progenitors while frequently sparing lymphoid subsets. In addition to these direct mechanisms of hematopoietic failure, failed hematopoiesis mediated indirectly by an autoimmune mechanism has been suggested to have importance in a subset of patients with the disease. Autoimmune-mediated bone marrow suppression is suggested by the positive outcome of several clinical trials using immunosuppressants. Depletion of autoreactive T cells with deleterious effects on bone marrow formation is considered the immunologic foundation for these therapeutic responses and bone marrow hypocellularity has been indicated as the best predictor of response. Antigen-driven expansion of immunodominant T cell clones can lead to overrepresentation of cells expressing individual T Cell Receptors (TCRs), which is known as TCR skewing. Treatment of hypocellular MDS patients with immunosuppressive therapies is associated with normalization of a skewed TCR- phenotype. The overall incidence of immunodominant T cell expansions has not been determined. The goal of our study was to assess the frequency of clonal T cell expansion in peripheral blood of MDS patients. Peripheral blood was analyzed from 52 patients for T cell CDR3-length skewing by genomic multi-plex PCR. All patients met the clinical criteria of MDS as defined by the WHO classification scheme. Patients with Refractory Anemia (RA) with and without Ringed Sideroblasts (RARS) represented 13% (n=7), Refractory Cytopenia with Multilineage Dysplasia (RCMD and RCMD-RS) represented 48% (n=25), and Refractory Anemia with Excess Blasts (RAEB1, RAEB2, and MDS that had progressed to AML) represented 38% (n=20). TCR-skewing occurred in 29 out of 52 patients with MDS (55%) compared to one out of 20 (5%) in age-matched normal controls. There was no difference in the frequency of clonal expansions based on the WHO classification. Based on the International Prognostic Scoring System (IPSS), we found that high risk patients (Int-2 and high) had a significantly higher incidence of clonal expansions than did patients with low risk disease (low and Int-1) (47% vs. 20%, respectively, p&lt;0.05). Indeed, patients with the highest incidence of having clonal T cell expansion were in the Int-2 risk category (86% by TCR-Vβ analysis, n=7). Of 47 patients with known bone marrow cellularity classification, we enrolled only eight (17%) that were classified as hypocellular, ten (21%) normal cellular, and 29 (62%) hypercellular. No patient with a hypocellular bone marrow in our analysis showed evidence of clonal T cell expansion (p&lt;0.05). These results suggest that clonal T cell expansion occurs prominately in high risk patients. We believe that cellular immunity in MDS could have both beneficial and deleterious effects. Antigen-specific cellular immune responses against pre-leukemic cells would be advantageous, while autoimmune destruction of normal bone marrow cells in the environment of an aggressive immune response would be deleterious. More information is needed about the role that clonal T cell expansion plays in high risk MDS.

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