scholarly journals Towards CD177 As a Predictive Biomarker for Hypomethylating Agent Response in Myelodysplastic Syndrome

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4665-4665
Author(s):  
James Ignatz-Hoover ◽  
Pingfu Fu ◽  
Shufen Cao ◽  
Benjamin Tomlinson ◽  
Howard Meyerson
Keyword(s):  
Bone Marrow ◽  
Flow Cytometry ◽  
High Risk ◽  
Risk Stratification ◽  
Myelodysplastic Syndrome ◽  
Treatment Response ◽  
Myelodysplastic Syndromes ◽  
Bone Marrow Biopsies ◽  
Wide Range ◽  
Very High

Abstract Background Myelodysplastic syndrome (MDS) represents a heterogenous spectrum of pre-leukemic conditions with a wide range of outcomes. Higher risk MDS as classified by the revised international prognostic scoring system (IPSS-R) score is associated with poor overall survival and up to 30% of patients progressing to acute myeloid leukemia. Hypomethylating agents (HMA) such as azacitadine can improve cytopenias and delay progression to leukemia in about 30% of patients, but these agents may take months to promote response and initially exacerbate cytopenias. Thus treatment related biomarkers that help predict eventual hematologic response are of interest. CD177 is expressed in neutrophils and plays a role in cellular adhesion. In healthy cells, it exhibits bimodal expression by flow cytometry that is stable over time within an individual. The percentage of CD177 positive neutrophils is often decreased in hematopoietic malignancies and myelodysplastic syndromes. Our group has demonstrated that CD177 has diagnostic utility in the identification of myelodysplastic syndromes. As transcription of CD177 is regulated by CpG methylation of its promotor, we hypothesized that treatment with HMAs may improve CD177 expression in clinical responders and potentially guide continuation of HMA therapy. Methods To interrogate the above, we performed a retrospective review of patients with a diagnosed with MDS or MDS/MPN overlap syndromes who received disease modifying therapy with HMA at our institution from 2015 to 2018. Inclusion criteria required documentation of serial bone marrow biopsies with aspirate flow cytometry analysis. CD177 positivity was determined by increase in mean florescence intensity compared to isotype controls. Data was analyzed with using cox multivariate and univariate analysis correlating to treatment response. Results Of the 237 patients, 27 patients met the above criteria. Their average age was 62 (21 to 77) at time of diagnosis with 20 men and 7 women. They exhibited a range of R-IPSS risk stratification with four very high risk, eight high risk, six intermediate risk, and four low risk. Five cases were MDS/MPN overlap. Patients received on average 10 months of HMA treatment with a wide range from 1 month to 42 months of treatment. Median baseline CD177 positivity was 16, 31, 28.5, and 72 percent respectively amongst R-IPSS groups. Of the 27 patients analyzed with repeat bone marrow biopsies, eight patients exhibited 20% or greater increase in CD177(+) neutrophils, ten exhibited a decrease in CD177(+) neutrophils of 20% or greater, and nine exhibited less than a 20% change in CD177(+) neutrophils. with similar distribution of R-IPSS risk stratification amongst groups. (CD177-decreased: 1 very high, 3 high, 1 intermediate, 2 low risk, CD177-stable 1 very high, 2 high, 2 intermediate, and 1 low, Improved-CD177 1 very high, 4 high, 2 intermediate and 1 low). Cox proportional hazard analysis suggests that patients exhibiting a decrease or stable CD177 were less likely to exhibit a treatment response with results trending to significance (OR= 0.13 p=0.099). Conclusion Our initial data suggests that change in CD177 may help predict HMA treatment response. More uniform prospective analysis is indicated to compared CD177 changes over initial treatment. Furthermore, CD177 in peripheral blood and bone marrow samples correlate excellently (R 2=0.95). Prospective studies are underway to correlate CD177 change and initial treatment response utilizing flow analysis of pre-treatment CBCs. Disclosures No relevant conflicts of interest to declare.

Flow Cytometric Detection of Human Telomerase Reverse Transcriptase Expression in CD34 Positive Precursor Fraction in Myelodysplastic Syndrome Bone Marrow.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4300-4300
Author(s):  
Hiroshi Handa ◽  
Takafumi Matsushima ◽  
Norifumi Tsukamoto ◽  
Masamitsu Karasawa ◽  
Hiroyuki Irisawa ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Flow Cytometry ◽  
High Risk ◽  
Myelodysplastic Syndrome ◽  
Disease Progression ◽  
Risk Group ◽  
Telomerase Activity ◽  
Low Risk ◽  
Htert Expression ◽  
Trap Assay

Abstract Telomerase activity has been found in most common cancers indicating that telomerase detection may be a useful marker in cancer diagnosis. For detection of telomerase activity and the expression of associated genes in cells, TRAP assay and RT-PCR are customarily used. Immunohistochemical detection of hTERT is useful to detect telomerase-positive cells in a background of non- cancerous cells. We developed a method for the detection of intra-nuclear hTERT protein, in a sub-population of hematopoietic cells, using concurrent staining cell surface antigen and multi color flow cytometry. Human leukemia and myeloma cell lines showed 100% positivity, whereas neutrophils of normal subjects showed 0% positivity, it is consistent with telomerase activity assessed by TRAP assay (r=0.71, p<0.0001) and previous observations. Then we applied this method to analyze hTERT expression in myelodysplastic syndrome (MDS). Forty MDS patients samples were obtained, 36 patients were diagnosed as low risk MDS (RA), 14 patients were diagnosed as high risk MDS (RAEB or RAEB-t) according to FAB classification. All samples were acquired after informed consent was obtained from the patients. Expression of hTERT protein was higher in CD34-positive blast-gated cells than CD34-negative blast-gated cells. The percentage of the CD34+ cells expressing hTERT ranged from 9.66% to 90.91% in low risk MDS patients, whereas from 50.46% to 97.68% in high risk MDS. The expression level was higher in the high risk group compared to that in the low risk group in MDS (p=0.0054, p=0.0084). This observation implied that telomerase up-regulation and hTERT expression were important for disease progression and could be a marker of more advanced disease. In subsets of MDS and AML bone marrow specimens obtained from these patients, we examined the hTERT expression in CD34+/CD38 high cells and CD34+/CD38 low cells containing stem cell fraction. Of interest, some of the patients showed higher expression of hTERT in CD34+/CD38 low cells than in CD34+/CD38 high cells. This observation is inconsistent with previous reports describing normal bone marrow hematopoietic cell findings. We speculated that this phenomenon could be a marker of MDS abnormality and that telomerase up-regulation may be initiated in the more primitive precursor fraction containing hematopoietic stem cells during the disease progression. Telomerase studies may be useful for definition of the risks associated with disease severity. Multi-parameter nature of flow cytometry and its ability to identify cellular sub-populations will facilitate a fuller understanding of the mechanisms of activation of telomerase.

Hesk Ratio: A Complementary Tool for the Diagnosis of Myelodysplastic Syndromes and a Novel Method for Flow Cytometry Analysis

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4946-4946
Author(s):  
Evgenia Verigou ◽  
Georgia Kolliopoulou ◽  
Nikoleta Smirni ◽  
Elisavet Hala ◽  
Polixeni Lampropoulou ◽  
...  
Keyword(s):  
Mathematical Model ◽  
Bone Marrow ◽  
Flow Cytometry ◽  
High Risk ◽  
Myelodysplastic Syndromes ◽  
Myeloid Cells ◽  
Antigen Expression ◽  
Low Risk ◽  
Empirical Parameter ◽  
Analytical Approaches

Abstract Abstract 4946 Establishing the diagnosis of Myelodysplastic Syndromes (MDS) is a challenging task for hematologists due to the heterogeneity of this clinical entity. Several attempts have been made to include findings from advanced technologies to the diagnostic criteria of MDS, but still in the majority of cases, morphology of peripheral blood and bone marrow remains the cornerstone for the diagnosis. Flow cytometry(FC) can identify abnormal antigen expression on myeloid cells. FC has been proposed as a complementary method in the diagnosis of low and intermediate risk MDS, particularly for patients not exhibiting characteristic karyotype abnormalities. On the other hand, recent literature suggests that these findings are not MDS-related, questioning the specificity of immunophenotyping for the diagnosis of MDS. The aim of the present study is to maximize the utility of FC data and simplify their interpretation for the diagnosis of MDS, by developing new analytical approaches of digital data, other than the conventional sequential biparametric analysis. The applied methodology was based on a mathematical model of scale analysis. Bone marrow(BM) samples from 50 subjects were analysed for the expression of CD45PC7, CD11bPC5, CD16FITC and CD13PE (antigens by Beckman Coulter, FC500 flow cytometer Beckman Coulter). 36 patients were diagnosed with MDS (23 low risk, 13 high risk) and 14 patients had other than an MDS diagnosis (ITP, chronic idiopathic neutropenia, systemic lupus erythematosus, LGL leukemia, age-related cytopenias, aplastic anemia, myelofibrosis etc). Additionally, 3 BM samples of patients with post-MDS acute myeloid leukemia(AML) were analysed. The data used for the development of the mathematical model were the following: two populations (neutro1, neutron2) were gated according to their CD45 and CD13/CD16 antigen expression (Figure 1i-1v).Seven subpopulations of Neutrophils were defined on CD11b/CD16 density plot N=g+h+i and O=k+j (Figure 1vi). In an attempt to identify correlations between data that cannot be routinely revealed by sequential biparametric analysis, we have developed the HeSK* ratio, which is given by: where x is the median of CD11b in gate O, y is the median of CD16 in gate O, z is the median of CD45 in gate neutro, pO is the percentage of gate O in the total CD11b/CD16 diagram gated in neutro, pN is the percentage of gate N in the total CD11b/CD16 gated in neutro and 1000 is an empirical parameter. The HeSK ratio combines fluorescence levels of CD16, CD11b and CD45 with the percentage of two distinct neutrophil populations (N and O), which differ in their maturation and differentiation stage. The ratio can quantify the abnormal differentiation profile of mature myeloid cells and thus distinguish MDS from non-MDS samples with statistical significance P<0. 0001 (Kruskal Wallis test) as indicated in graph 1. Descriptive statistics are shown in table 1. · HeSK ratio is based upon a novel FC analysis method that could change the conventional biparametric routine FC analysis and quantify patterns that are not evaluated properly. Mathematical modeling of antigen expression patterns optimizes the interpretation of single immunophenotype findings. · The present study proposes HeSK as a complementary diagnostic tool for MDS and a strong indicator for the classification of the patients according to their prognosis as well. *the name HeSK comes from the initials of the 4 main authors (H=Hala, e=Evgenia, S=Smirni, K=Kolliopoulou). Table 1 non MDS low risk MDS high risk MDS Number of values 14 23 13 Minimum 50,76 4,789 0,2850 25% Percentile 304,8 26,11 17,05 Median 2133 92,52 47,64 75% Percentile 10650 228,9 144,3 Maximum 55040 3043 671,7 Mean 10320 316,1 122,7 Std. Deviation 17860 647,9 185,1 Std. Error 4773 135,1 51,33 Figure 1 Figure 1. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Therapeutic Cancer Vaccination Targeting Shared Tumor Associated Antigens in Combination with Azacitidine for High Risk Myelodysplastic Syndrome - a Phase I Clinical Trial

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 23-24
Author(s):  
Staffan Holmberg-Thydén ◽  
Inge Høgh Dufva ◽  
Anne Ortved Gang ◽  
Marie Fredslund Breinholt ◽  
Lone Schejbel ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Combination Therapy ◽  
Myelodysplastic Syndrome ◽  
Treatment Response ◽  
Neutrophil Count ◽  
Intracellular Cytokine Staining ◽  
Peptide Vaccine ◽  
Hypomethylating Agents ◽  
Tumor Associated Antigens

Background: Standard care for patients with high risk myelodysplastic syndrome (MDS) is hypomethylating agents, such as azacitidine (AZA). AZA can induce expression of silenced genes, including methylated tumor associated antigens. Such tumor associated antigens may be recognized by T cells, and therefore exploited for immunotherapeutic targeting. To our knowledge, this is the first clinical study that combine hypomethylating agents with a multi-peptide therapeutic cancer vaccine in a hematological malignancy. Method: In this open label phase 1 trial (ClinicalTrials.gov NCT02750995), we combine AZA with a peptide vaccine targeting antigens encoded from NY-ESO-1, MAGE-A3, PRAME and WT-1, which have previously been demonstrated to be upregulated by AZA treatment. Four long synthetic peptides containing previously described class I and class II epitopes for a variety HLA types was emulsified in Incomplete Freund's Adjuvant for subcutaneous injection. Patients were included following verified treatment response to six courses of AZA monotherapy. Result: Five patients were included in the study and treated with the vaccine. The combination therapy showed only few adverse events during the study period, whereof none classified as serious. There was one instance of grade 4 toxicity; a case of neutrophil count decrease, requiring administration of prophylactic antibiotics, and two instances of grade 3 toxicity; platelet count decrease and neutrophil count decrease. No vaccine-specific immune response could be detected using intracellular cytokine staining or ELISpot assays, however changes in the phenotypic composition of immune cells and their expression of stimulatory and inhibitory markers were identified in individual patients. All patients progressed to AML with a mean time to progression from inclusion (TTP) of 4.9 months (range 2.8 to 7.6). Survival was 17 months (range 10.9 to 30.6) from MDS diagnosis. Sequencing of bone marrow showed clonal evolution of malignant cells, as well as appearance of novel mutations. Conclusion: The patients progressed to AML with an average time of only five months after initiating the combination therapy. This may be unrelated to the experimental treatment, but the trial was terminated early as there was no sign of clinical benefit or immunological response. Figure 1. (a) Trial design. All participants received six courses of AZA prior to inclusion and were evaluated with bone marrow biopsy for treatment response. Vaccination was given together with the next three courses of AZA. (b) Vaccine composition. Synthetic long peptides from NY-ESO-1, PRAME, MAGE-A3 and WT-1 were emulsified in adjuvant Montanide ISA 51. Figure 1 Disclosures No relevant conflicts of interest to declare.

Demethylation of a hypermethylated P15/INK4B gene in patients with myelodysplastic syndrome by 5-Aza-2′-deoxycytidine (decitabine) treatment

Blood ◽  
2002 ◽  
Vol 100 (8) ◽  
pp. 2957-2964 ◽  
Author(s):  
Michael Daskalakis ◽  
Tudung T. Nguyen ◽  
Carvell Nguyen ◽  
Per Guldberg ◽  
Gabriele Köhler ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Myelodysplastic Syndrome ◽  
Mononuclear Cells ◽  
Denaturing Gradient Gel Electrophoresis ◽  
Methylation Status ◽  
Bone Marrow Biopsies ◽  
Methylation Inhibitor ◽  
Gradient Gel Electrophoresis

p16 and p15, 2 inhibitors of cyclin-dependent kinases, are frequently hypermethylated in hematologic neoplasias. Decitabine, or 5-Aza-2′-deoxycytidine, reverts hypermethylation of these genes in vitro, and low-dose decitabine treatment improves cytopenias and blast excess in ∼50% of patients with high-risk myelodysplastic syndrome (MDS). We examined p15and p16 methylation status in bone marrow mononuclear cells from patients with high-risk MDS during treatment with decitabine, using a methylation-sensitive primer extension assay (Ms-SNuPE) to quantitate methylation, and denaturing gradient gel electrophoresis (DGGE) and bisulfite-DNA sequencing to distinguish individually methylated alleles. p15 expression was serially examined in bone marrow biopsies by immunohistochemistry. Hypermethylation in the 5′ p15 gene region was detected in 15 of 23 patients (65%), whereas the 5′ p16 region was unmethylated in all patients. Among 12 patients with hypermethylation sequentially analyzed after at least one course of decitabine treatment, a decrease in p15 methylation occurred in 9 and was associated with clinical response. DGGE and sequence analyses were indicative of hypomethylation induction at individual alleles. Immunohistochemical staining for p15 protein in bone marrow biopsies from 8 patients with p15 hypermethylation revealed low or absent expression in 4 patients, which was induced to normal levels during decitabine treatment. In conclusion, frequent, selectivep15 hypermethylation was reversed in responding MDS patients following treatment with a methylation inhibitor. The emergence of partially demethylated epigenotypes and re-establishment of normal p15 protein expression following the initial decitabine courses implicate pharmacologic demethylation as a possible mechanism resulting in hematologic response in MDS.

P-ERK1/2 Is a Predictive Factor of Response to ESA Treatment in Myelodysplastic Syndromes.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 294-294
Author(s):  
Emilie Frisan ◽  
Patrycja Pawlikowska ◽  
Cécile Pierre-Eugène ◽  
Valérie Bardet ◽  
Laure Gibault ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Flow Cytometry ◽  
Myelodysplastic Syndromes ◽  
Conflicts Of Interest ◽  
Marrow Cell ◽  
Wilcoxon Test ◽  
Response To Treatment ◽  
Erythroid Cell ◽  
Erythroid Progenitors ◽  
Bone Marrow Biopsies

Abstract Abstract 294 Endogenous serum erythropoietin (sEPO) less than 500UI/L and a transfusion requirement lower than 2 units per month are the best predictive factors for response to treatment by erythropoiesis-stimulating agents (ESA) in low/int-1 myelodysplastic syndromes (MDS). However, the highest response rate hardly reaches 60% suggesting that other factors may influence the response. To investigate the biological signature of response to ESA, we enrolled 100 low/int-1 MDS patients in a prospective study of erythropoiesis at diagnosis before they were treated with ESA. According to the IWG 2006 criteria, 43 patients were non-responders. These patients had significantly higher serum EPO level, higher number of transfusion per month, and lower number of bone marrow-deriving BFU-E and CFU-E than responders. Analysis of CD34+-deriving erythroid progenitors by in vitro liquid culture, demonstrated that all MDS patients (n=54) had an increased apoptosis and a delayed expression of erythroid marker, glycophorin A (GPA). A collapse of EPO-induced DNA synthesis was observed in non-responders, while EPO-dependent erythroid cell differentiation and survival to Fas-induced apoptosis was equivalent in the two groups. Thus, non-responders exhibited an early and isolated default in EPO-induced cell proliferation, suggesting a defect in EPO-R signaling. Immunofluorescence to p-ERK1/2 before and after EPO-R stimulation in immature erythroblasts was negative in 6/8 non-responders, and positive in all 11 responders. Immunohistochemistry to p-ERK1/2 on bone marrow biopsies in 5 non-responders was negative and positive in immature cells in 4 responders. By flow cytometry, p-ERK1/2 expression in the CD71+/GPA− bone marrow cell fraction corresponding to immature erythroblasts (n=30) was significantly lower in non-responders (n=16) than in responders (n=14; Wilcoxon-test: p<0.0001). Receiver operator curve (ROC) analysis of the flow cytometry test demonstrated a good predictive value for the response to ESA with a 0.96 area under the curve (AUC) [95%CI: 0.89 – 1.00]. ROC were also constructed for BFU-E number, serum EPO level, and number of transfusion per month and the AUC were computed. p-ERK1/2 was equivalent to BFU-E and superior to serum EPO level or number of transfusion in predicting the response to ESA. Although requiring validation in a larger cohort, these results suggest that p-ERK1/2 is a ready tool available for the prediction of response to ESA in MDS patients. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Identification of Predictive Factors for Overall Survival at Baseline and during Azacitidine Treatment in High-Risk Myelodysplastic Syndromes Treated in the Clinical Practice

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5518-5518
Author(s):  
Emilia Scalzulli ◽  
Matteo Molica ◽  
Alunni Fegatelli Danilo ◽  
Lorenzo Rizzo ◽  
Roberto Latagliata ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Overall Survival ◽  
Clinical Practice ◽  
High Risk ◽  
Myelodysplastic Syndromes ◽  
Prognostic Score ◽  
Advisory Board ◽  
Transfusion Dependency ◽  
Very High ◽  
Bone Marrow Blasts

Abstract Background. 5-Azacitidine (5-AZA) had changed the therapeutic approach to intermediate-2/high IPSS risk myelodysplastic syndromes (MDS) improving the outcome of patients, even in the absence of a complete response. However, real-life experiences have reported contradicting results compared to the AZA001 randomized study. Aim of our analysis was to identify the clinico-biological features at baseline and during treatment associated with the overall survival (OS) and progression-free survival (PFS) at two years in a consecutive cohort of patients treated with hypometylating agent in the clinical practice. Moreover, we propose a new prognostic score for the identification of OS after the first four cycles of therapy. Patients and Method. We retrospectively analyzed a series of 110 MDS patients treated at a single institution with 5-AZA between September 2003 and January 2017. Patients were diagnosed according to the WHO 2016 criteria. 5-AZA was administered at a dose of 75 mg/m2 according to the 5+2+2 schedule every 28 days. Results. A male predominance was observed (male/female: 66%/34%) with a median age of 70 years (range 38-85). The median dose of 5-AZA received was 135 mg/day (range 105-150) after a median time from diagnosis of 2.3 months (range 0.1-119). Median duration of therapy was 9.5 cycles (range 1-77) with a median time on treatment of 8.5 months (range 1-86.7). OS of the whole cohort was 66.1% (CI 95% 57.2-76.4) at 1 year and 38.3% (CI 95% 29.4-49.9) at 2 years. Seventy-seven patients (70%) performed four cycles of therapy. According to the IWG criteria, 42 patients (54.5%) achieved a complete remission (CR), 11 (14.2%) a partial remission (PR), 17 (22.4%) maintained a stable disease (SD), 2 (2.5%) and 5 (6.4%) presented a progression disease (PD) and a failure, respectively. The 2-year OS was 68% in patients who obtained a CR/PR, 20% in patients with SD and 16% in patients with PD/failure (p<0.001). No differences in terms of OS were observed for gender (p=0.622) and age at baseline (<65years, 65-75 and >75 years, p=0.075). The baseline bone marrow blasts percentage did not impact on OS and PFS (OS, p=0.867; PFS, p=0.611). According to the Revised International Prognostic Score (R-IPSS), 22 (20%), 46 (42.8%) and 42 (38.2%) patients were classified as intermediate, high and very high-risk patients, respectively. We identified that the very high-risk group had an inferior 2-year OS (17%) compared to intermediate-group patients (64%, p<0.001). Indeed, we did not find significant difference according to the IPSS stratification (intermediate 42% vs high-risk 22%, p=0.253). Transfusion-independency at baseline was identified as a favorable prognostic factor on 1-year (66.8%) and 2-year OS (43.4%) compared to patients with transfusion dependency (36.4% and 22.2% if they required 1 unit/month or more than 1 unit at baseline at 2 years, p<0.001). After four cycles received, the persistence of bone marrow blasts >10% identified patients with a worse outcome, with a 2-year OS of 9.4% compared to 60.3% for patients with 0-5% blasts and 44.7% for patients with 5-10% blasts (p=0.002). The occurrence of one infection during the first four cycles impacted on the 2-year OS (31.6% vs 58.3% in patients without, p=0.032). We applied a dynamic prognostic score according to age, cytogenetic risk, transfusion need, number of 5-AZA cycles performed and type of response after the fourth cycle (Table 1): the combination of these variables identified 3 categories of risk with a significantly different 2-year OS: low-risk (72.3%), intermediate (19.8%) and high-risk (8.9%) (p<0.001, Fig. 1). Conclusions. Our results in a large and consecutive MDS cohort treated outside of clinical trials defined prognostic factors, such as transfusion dependency, persistence of >10% blasts after four cycles and absence of infections, capable of identifying patients with a good outcome. A prognostic score is proposed that requires independent validations in similar cohorts of patients. Disclosures Rizzo: Sapienza University, Rome: Other: Resident in Hematology. Foà:NOVARTIS: Speakers Bureau; CELTRION: Other: ADVISORY BOARD; GILEAD: Speakers Bureau; JANSSEN: Other: ADVISORY BOARD, Speakers Bureau; ROCHE: Other: ADVISORY BOARD, Speakers Bureau; CELGENE: Other: ADVISORY BOARD, Speakers Bureau; AMGEN: Other: ADVISORY BOARD; ABBVIE: Other: ADVISORY BOARD, Speakers Bureau; INCYTE: Other: ADVISORY BOARD. Breccia:Pfizer: Honoraria; Novartis: Honoraria; BMS: Honoraria; Incyte: Honoraria.

Disease Characteristics and Prognosis of Myelodysplastic Syndrome Presenting with Isolated Thrombocytopenia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3477-3477 ◽  
Author(s):  
Julie B Waisbren ◽  
Shira N. Dinner ◽  
Irene Helenowski ◽  
Juehua Gao ◽  
Brandon McMahon ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Myelodysplastic Syndrome ◽  
Bone Marrow Biopsy ◽  
Major Bleeding ◽  
Low Risk ◽  
Hypomethylating Agents ◽  
Bleeding Events ◽  
Major Bleeding Events ◽  
Very High

Abstract Background Myelodysplastic syndrome (MDS) presenting with isolated thrombocytopenia (TCP) represents a rare subset of this heterogenous malignancy. Prior small studies have suggested an indolent course. However, because this presentation is uncommon, there are clinical challenges in diagnosis and management. The aim of this study is to better define the morphologic, cytogenetic, and prognostic features of MDS presenting with isolated TCP. Methods Using the Northwestern University Electronic Data Warehouse, MDS patients were selected between 2004 and 2014 using ICD-9 codes and billing data. The diagnosis of MDS was determined by a practicing hematologist/oncologist according to World Health Organization criteria and confirmed with bone marrow biopsy results. Inclusion criteria were patients with isolated thrombocytopenia as defined by (PLT) <100×109/L, absolute neutrophil count (ANC) > 1.5×109/L and hemoglobin (Hgb) > 10 g/dl. Those with rapidly progressive TCP, confounding bone marrow disorders or those with suspected secondary causes of cytopenia were excluded. Data obtained from patient charts included demographics, peripheral blood counts, bone marrow biopsy results, bleeding complications, treatment history, and disease progression. IPSS-R scores were calculated on all patients. Overall survival rate and acute myeloid leukemia (AML) free event rates were determined via the Kaplan Meier method and compared between risk groups using the log-rank test. A P-value < 0.05 was considered statistically significant. Results Baseline characteristics: Of 404 MDS patients, 50 (12%) presented with isolated TCP. Among these 50, the median age was 72 and 34 were men (68%). Fourteen patients had TCP for greater than 2 years before diagnosis. Idiopathic thrombocytopenic purpura (ITP) was the presumed diagnosis in 17 patients. Median cell counts at the time of diagnosis were hemoglobin 12.0 g/dl, WBC 4.4 x 109/L and PLT 64 x 109/L. The most common cytogenetic profile was normal (n=28), and del 20q was the most common mutation seen in isolation (n=4) or in combination (n=3). Seven patients had complex cytogenetic profiles. Twenty-four patients fell into IPSS-R low or very low risk categories, 18 patients were IPSS-R intermediate (Int) risk and 7 patients were IPSS-R high or very high risk. Treatment + outcomes: Ten patients developed AML, 3 with low risk disease, 4 with Int-risk disease, 4 with high or very high-risk disease and 1 with an unknown IPSS-R score. Twenty-three patients were treated with hypomethylating agents including 5-Azacitidine or Decitabine. Three patients received thrombopoietin (TPO) receptor agonists. It is unclear by retrospective chart analysis if treatment resulted in improved outcomes. Fourteen of the 50 MDS patients presenting with isolated TCP died. Causes of death included AML (n=6), sepsis (n=4), intracranial bleeding (n=1), and unknown (n=1). Nine of the 14 patients who died were treated with hypomethylating agents, TPO agonists or both. There were 2 cases of major bleeding events, each intracranial and each in patients with PLT counts over 50. Discussion In our tertiary care center, the prevalence of isolated TCP in MDS was 12%. Patients with isolated TCP and MDS had similar demographics compared to patients with MDS at large. There were 17 patients (34%) that were first diagnosed with ITP. Need for bone marrow biopsy in asymptomatic patients with isolated TCP and normal peripheral smears is not clearly defined, however may be indicated in patients with demographics more typical of MDS (older male). The patients in this study distributed across all IPSS-R categories and many had an aggressive course. This is in contrary to previous studies that have suggested that MDS with isolated TCP has a relatively favorable prognosis. Next generation sequencing may uncover additional mutations in these patients that would help with risk stratification and development of targeted therapies. For example RUNX1 mutation carriers have been shown to present with thrombocytopenia and an increased risk of MDS/AML, and GATA2 mutants present with rapid onset MDS and often have a poor prognosis. Despite varying degrees of thrombocytopenia, incidence of major bleeding events was low. Treatment remains uncertain in this unique MDS subgroup. More studies are needed to address treatment options, including safety and efficacy of TPO agonists for this patient population. Disclosures Stein: Incyte Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Investigation of a 22-gene genomic classifier (GC) for risk stratification and molecular subtyping in an Asian prostate cancer (PCa) cohort.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 249-249
Author(s):  
Wei Loong Sherman Yee ◽  
Wai Yee Woo ◽  
Adelene Sim ◽  
Kar Perng Low ◽  
Alice Meng ◽  
...  
Keyword(s):  
High Risk ◽  
Risk Stratification ◽  
Racial Differences ◽  
White Men ◽  
Risk Groups ◽  
Molecular Subtyping ◽  
Basal Subtype ◽  
Grid Database ◽  
Risk Patients ◽  
Very High

249 Background: A 22-gene GC has been proposed to refine risk stratification of localized PCa by conventional NCCN criteria, and this may potentially influence treatment recommendations. Nonetheless, majority of studies looking at the utility of GC were conducted in White and non-White men from Western cohorts. We therefore investigated the association of GC with NCCN risk groups (RG) in an Asian PCa cohort. Additionally, we examined for inter-racial differences in molecular subtyping between Asian and White/non-White PCa. Methods: GC (Decipher Biosciences Inc., CA) was performed on diagnostic biopsies of men who were treated with radiotherapy +/- hormonal therapy at a single institution (N = 75). ISUP Gleason’s grade (GG) and tumor cellularity were reviewed by an expert GU pathologist. RNA was extracted from 2 x 2.0-mm tumor cores using Qiagen AllPrep DNA/RNA FFPE Kit (Qiagen, Germany) and gene expression was performed on Affymetrix Human Exon 1.0 ST Array (ThermoFischer, CA). PAM50 molecular subtyping was derived using the DecipherGRID database. Results: We profiled 80 tumors from 75 patients, comprising of 18 (24.0%), 9 (12.0%), 21 (28.0%), and 19 (25.3%) NCCN low-/favorable intermediate-, unfavorable intermediate-, high- and very high-RG, respectively; of note, 8 (10.7%) patients had regional/metastatic disease at diagnosis. Using the GC, 27 (33.8%), 14 (17.5%) and 39 (48.8%) were classified as low- (<0.45), intermediate- (0.45-0.6) and high-RG, respectively (>0.6). When stratified using a three-tier clinico-genomic (CG) classification system (Spratt et al. 2017), 6 of 21 (28.6%) NCCN-defined high-risk and 4 of 19 (21.1%) very high-risk patients were downgraded to CG-defined intermediate-/low-risk, while 2 of 27 (7.4%) NCCN low-/intermediate-risk patients were in fact upgraded to CG high-risk. Next, we interrogated the PAM50 basal-luminal signature in our cohort. Interestingly, when matched to White (N = 5762) and non-White (N = 155) for NCCN RG, ISUP GG and age, we observed a high proportion of basal subtype (62.7%) in Asians, which contrasted the prevalence observed in White (16.7%) and non-White (15.9%) North American patients (Chi-sq P <0.001). Conclusions: Here, we demonstrated the utility of the 22-gene GC for refining the NCCN risk stratification in a largest Asian PCa dataset to-date. An unexpectedly high proportion of PAM50 basal-subtype was observed, suggesting race-specific differences of the tumor transcriptome.

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