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310 RISK OF BONE MARROW FAILURE CONDITIONS IN PATIENTS UNDERGOING INVASIVE CARDIAC PROCEDURES
S154
Poster Presentations – 13th International Symposium on Myelodyspastic Syndromes / Leukemia Research 39 S1 (2015) S1–S166
309 FREQUENCY AND PROGNOSTIC IMPACT OF SF3B1 AND DNMT3A MUTATIONS IN REFRACTORY ANEMIA WITH RING SIDEROBLASTS (RARS) I. Martín1, E. Such1, A. Vicente2, B. Navarro3, M. López-Pavía1, M. Gómez3, M. Ibáñez1, M. Tormo3, S. Oltra4, J. Cervera5, G. Sanz1 1 Hematology, University Hospital La Fe, Valencia, Spain; 2 Hematology, Hospital de la Ribera, Valencia, Spain; 3Hematology, Hospital Clínic Universitari, Valencia, Spain; 4Genetics Unit, University Hospital La Fe, Valencia, Spain; 5Genetics Unit and Hematology, University Hospital La Fe, Valencia, Spain Introduction: The incidence of mutations in the splicing gene SF3B1 in patients with RARS is 78% and confers a favorable prognostic value. Recently, it has been shown that SF3B1 and DNMT3A mutations overlap more often than expected by chance, indicating a possible biologic cooperation between these pathogenic lesions. DNMT3A mutations are believed to adversely affect the good prognosis of SF3B1+ patients but this issue has not been specifically addressed in RARS. Objectives: To assess the frequency, prognostic value, and mutational co-occurrence of SF3B1 and DNMT3A mutations in a large series of patients with RARS at diagnosis. Methods: SF3B1 and DNMT3A genes were studied in 131 RARS patients diagnosed according to FAB classification criteria [WHO: 84 (64%) RARS, 37 (28%) RCMD-RS, 10 (8%) RARS-T]. All samples were provided by the Biobank La Fe. SF3B1 molecular characterization (exons 13, 14 and 15) was performed by Sanger sequencing. R882-DNMT3A hotspot mutation (exon 23) was analyzed by high-resolution melting. Results: 23 out of 131 samples (17.6%) showed no changes in these genes (SF3B1-DNMT3A-), 108/131 (82.4%) had somatic mutations in SF3B1, and 6 of them (5.6%) showed a co-mutation (SF3B1+DNMT3A+). In the overall series, SF3B1+ patients presented with a higher platelet count (median 267 vs. 185 x 109/L, respectively; P = 0.001) and within the RARS subgroup by WHO criteria SF3B1+ patients had a longer OS than SF3B1patients (median: 102 vs. 35 months; P = 0.03). On the other hand, all DNMT3A+ patients had a normal karyotype, and 5 of them (83.3%) were low risk patients according to the IPSS. Despite this apparently favorable profile, SF3B1+DNMT3A+ patients showed a higher RBC transfusion-dependency at diagnosis (100% vs. 53.5%; P =0.025), a shorter OS (median: 30 vs. 102 months; P = 0.038), and a higher risk of progression to AML at 5 years (44% vs. 1%; P =0.001) than SF3B1+DNMT3A- patients. Conclusions: DNMT3A is mutated in 5.6% of SF3B1+ patients with RARS and its presence overshadows the excellent prognosis expected in this subgroup of patients.
310 RISK OF BONE MARROW FAILURE CONDITIONS IN PATIENTS UNDERGOING INVASIVE CARDIAC PROCEDURES M.C. Ornstein1, S. Mukherjee1, P. Elson2, C. Pierce3, A. Zarzour1, Y. Saunthararajah1, A. Maggiotto1, S. Hobson1, A.S. Advani1, A.T. Gerds1, H. Carraway1, M. Kalaycio1, J.P. Maciejewski1, S. Ellis3, E. Blackstone3, M.A. Sekeres1 1 Hematology and Medical Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland, USA; 2Quantitative Health Sciences, Cleveland Clinic, Cleveland, USA; 3Heart and Vascular Institute, Cleveland Clinic, Cleveland, USA Background: Coronary artery disease (CAD) rates are rising in the United States, resulting in more use of early coronary intervention strategies including coronary artery bypass grafting (CABG), bare metal stents (BMS), and drug eluting stents (DES) containing the
mitotoxic agents mammalian target of rapamycin or topoisomerase inhibitors. We hypothesize that these interventions can have mutagenic effects on the circulating stem cells at the time of cardiac injury, leading to bone marrow failure (BMF). Methods: We conducted a retrospective cohort study of 29,340 patients (pts) who underwent invasive cardiac procedures including CABG, BMS, and DES between 2002 and 2011, to assess excess risk of BMF. Disease- and treatment-related information was collected by cross-referencing CAD and myelodysplastic syndrome (MDS) registries. BMF conditions included MDS, MPN, MDS/MPN overlap, and idiopathic cytopenia of undetermined significance (ICUS). The primary endpoint was the interval from cardiac procedure to BMF development. Proportional hazards models were used for univariable and multivariable analyses. Results: Complete data were available on 25,636 pts: 14,178 (55%) CABG only, 4,754 (19%) BMS, and 6,704 (26%) DES. Overall, 70% of pts were male; 75% were overweight (BMI>25). Median age at the time of cardiac intervention was 67 years (range 18-97); 43% of pts were ≥70. With a median follow-up of 3.3 years (range, .1-12.4), the overall crude incidence rate of BMF was 42/100,000 (95%C.I. 30-55) person years of follow-up. Of the 43 BMFs reported (0.17%): 16 (37%) MDS; 9 (21%) MPNs; 4 (9%) MDS/MPN; 14 (33%) ICUS. Median time to BMF was 3.6 years (range, 0.5-10.4). Rates and time to BMF were similar in all intervention groups. In univariable analyses, advanced age (p=.002) and higher BMI (p=.01) were associated with increased risks of BMF. Only advanced age was significant in multivariable analyses (p=.02). When compared to Surveillance, Epidemiology and End Result (SEER) population, the incidence rate of BMF was higher than expected in our CAD cohort (Table 1). Conclusion: CAD pts undergoing invasive cardiac procedures have higher rates of BMF compared to population estimates. However, within the CAD cohort, no increase in risk was seen with use of DES compared to BMS or CABG. Our findings suggest that this population is especially vulnerable to the risk of developing BMF and a close surveillance of blood counts is warranted following intervention. Table 1. Incidence Rates of BMF/100,000 persons BMF Subtype
SEER-17
Cleveland Clinic CAD Cohort
MDS
4.8
16.5
MDS/MPN
0.4
2.5
MPN
2.6
10.4
311 MYELODYSPLASTIC SYNDROMES (MDS), THEN AND NOW: A COMPARISON OF TWO PATIENT COHORTS, 30 YEARS APART M. Mittelman1, S. Svorai-Litvak1, O. Ben-Tal2, H.S. Oster1, I. Krigner2, R.S. Siegel3 1 Internal Medicine, Tel Aviv Sourasky Medical Center and Sackler Faculty of Medicine Tel Aviv University, Tel-Aviv, Israel; 2Institute of Hematology, Tel Aviv Sourasky Medical Center and Sackler Faculty of Medicine Tel Aviv University, Tel-Aviv, Israel; 3Hematology Oncology, George Washington University Medical Center, Washington DC, USA Background: The recent progress in MDS raised the question: Do patients (pts) differ from pts 2-3 decades ago? Is the outcome better? We compared disease features and outcome between two pt cohorts, 30 years (yr) apart. Patients and Methods: Clinical, lab and prognostic data were collected from charts of two groups of pts: 1) DC: consecutive pts, George Washington (GW) University and the VA hospitals, Washington DC (1986-1987). 2) TA: transfusion-dependent MDS pts at Tel Aviv Sourasky Hospital (1999-2009). Data were transferred into NIH- approved (# 700004948) software.
Poster Presentations – 13th International Symposium on Myelodyspastic Syndromes / Leukemia Research 39 S1 (2015) S1–S166
309 FREQUENCY AND PROGNOSTIC IMPACT OF SF3B1 AND DNMT3A MUTATIONS IN REFRACTORY ANEMIA WITH RING SIDEROBLASTS (RARS) I. Martín1, E. Such1, A. Vicente2, B. Navarro3, M. López-Pavía1, M. Gómez3, M. Ibáñez1, M. Tormo3, S. Oltra4, J. Cervera5, G. Sanz1 1 Hematology, University Hospital La Fe, Valencia, Spain; 2 Hematology, Hospital de la Ribera, Valencia, Spain; 3Hematology, Hospital Clínic Universitari, Valencia, Spain; 4Genetics Unit, University Hospital La Fe, Valencia, Spain; 5Genetics Unit and Hematology, University Hospital La Fe, Valencia, Spain Introduction: The incidence of mutations in the splicing gene SF3B1 in patients with RARS is 78% and confers a favorable prognostic value. Recently, it has been shown that SF3B1 and DNMT3A mutations overlap more often than expected by chance, indicating a possible biologic cooperation between these pathogenic lesions. DNMT3A mutations are believed to adversely affect the good prognosis of SF3B1+ patients but this issue has not been specifically addressed in RARS. Objectives: To assess the frequency, prognostic value, and mutational co-occurrence of SF3B1 and DNMT3A mutations in a large series of patients with RARS at diagnosis. Methods: SF3B1 and DNMT3A genes were studied in 131 RARS patients diagnosed according to FAB classification criteria [WHO: 84 (64%) RARS, 37 (28%) RCMD-RS, 10 (8%) RARS-T]. All samples were provided by the Biobank La Fe. SF3B1 molecular characterization (exons 13, 14 and 15) was performed by Sanger sequencing. R882-DNMT3A hotspot mutation (exon 23) was analyzed by high-resolution melting. Results: 23 out of 131 samples (17.6%) showed no changes in these genes (SF3B1-DNMT3A-), 108/131 (82.4%) had somatic mutations in SF3B1, and 6 of them (5.6%) showed a co-mutation (SF3B1+DNMT3A+). In the overall series, SF3B1+ patients presented with a higher platelet count (median 267 vs. 185 x 109/L, respectively; P = 0.001) and within the RARS subgroup by WHO criteria SF3B1+ patients had a longer OS than SF3B1patients (median: 102 vs. 35 months; P = 0.03). On the other hand, all DNMT3A+ patients had a normal karyotype, and 5 of them (83.3%) were low risk patients according to the IPSS. Despite this apparently favorable profile, SF3B1+DNMT3A+ patients showed a higher RBC transfusion-dependency at diagnosis (100% vs. 53.5%; P =0.025), a shorter OS (median: 30 vs. 102 months; P = 0.038), and a higher risk of progression to AML at 5 years (44% vs. 1%; P =0.001) than SF3B1+DNMT3A- patients. Conclusions: DNMT3A is mutated in 5.6% of SF3B1+ patients with RARS and its presence overshadows the excellent prognosis expected in this subgroup of patients.
310 RISK OF BONE MARROW FAILURE CONDITIONS IN PATIENTS UNDERGOING INVASIVE CARDIAC PROCEDURES M.C. Ornstein1, S. Mukherjee1, P. Elson2, C. Pierce3, A. Zarzour1, Y. Saunthararajah1, A. Maggiotto1, S. Hobson1, A.S. Advani1, A.T. Gerds1, H. Carraway1, M. Kalaycio1, J.P. Maciejewski1, S. Ellis3, E. Blackstone3, M.A. Sekeres1 1 Hematology and Medical Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland, USA; 2Quantitative Health Sciences, Cleveland Clinic, Cleveland, USA; 3Heart and Vascular Institute, Cleveland Clinic, Cleveland, USA Background: Coronary artery disease (CAD) rates are rising in the United States, resulting in more use of early coronary intervention strategies including coronary artery bypass grafting (CABG), bare metal stents (BMS), and drug eluting stents (DES) containing the
mitotoxic agents mammalian target of rapamycin or topoisomerase inhibitors. We hypothesize that these interventions can have mutagenic effects on the circulating stem cells at the time of cardiac injury, leading to bone marrow failure (BMF). Methods: We conducted a retrospective cohort study of 29,340 patients (pts) who underwent invasive cardiac procedures including CABG, BMS, and DES between 2002 and 2011, to assess excess risk of BMF. Disease- and treatment-related information was collected by cross-referencing CAD and myelodysplastic syndrome (MDS) registries. BMF conditions included MDS, MPN, MDS/MPN overlap, and idiopathic cytopenia of undetermined significance (ICUS). The primary endpoint was the interval from cardiac procedure to BMF development. Proportional hazards models were used for univariable and multivariable analyses. Results: Complete data were available on 25,636 pts: 14,178 (55%) CABG only, 4,754 (19%) BMS, and 6,704 (26%) DES. Overall, 70% of pts were male; 75% were overweight (BMI>25). Median age at the time of cardiac intervention was 67 years (range 18-97); 43% of pts were ≥70. With a median follow-up of 3.3 years (range, .1-12.4), the overall crude incidence rate of BMF was 42/100,000 (95%C.I. 30-55) person years of follow-up. Of the 43 BMFs reported (0.17%): 16 (37%) MDS; 9 (21%) MPNs; 4 (9%) MDS/MPN; 14 (33%) ICUS. Median time to BMF was 3.6 years (range, 0.5-10.4). Rates and time to BMF were similar in all intervention groups. In univariable analyses, advanced age (p=.002) and higher BMI (p=.01) were associated with increased risks of BMF. Only advanced age was significant in multivariable analyses (p=.02). When compared to Surveillance, Epidemiology and End Result (SEER) population, the incidence rate of BMF was higher than expected in our CAD cohort (Table 1). Conclusion: CAD pts undergoing invasive cardiac procedures have higher rates of BMF compared to population estimates. However, within the CAD cohort, no increase in risk was seen with use of DES compared to BMS or CABG. Our findings suggest that this population is especially vulnerable to the risk of developing BMF and a close surveillance of blood counts is warranted following intervention. Table 1. Incidence Rates of BMF/100,000 persons BMF Subtype
SEER-17
Cleveland Clinic CAD Cohort
MDS
4.8
16.5
MDS/MPN
0.4
2.5
MPN
2.6
10.4
311 MYELODYSPLASTIC SYNDROMES (MDS), THEN AND NOW: A COMPARISON OF TWO PATIENT COHORTS, 30 YEARS APART M. Mittelman1, S. Svorai-Litvak1, O. Ben-Tal2, H.S. Oster1, I. Krigner2, R.S. Siegel3 1 Internal Medicine, Tel Aviv Sourasky Medical Center and Sackler Faculty of Medicine Tel Aviv University, Tel-Aviv, Israel; 2Institute of Hematology, Tel Aviv Sourasky Medical Center and Sackler Faculty of Medicine Tel Aviv University, Tel-Aviv, Israel; 3Hematology Oncology, George Washington University Medical Center, Washington DC, USA Background: The recent progress in MDS raised the question: Do patients (pts) differ from pts 2-3 decades ago? Is the outcome better? We compared disease features and outcome between two pt cohorts, 30 years (yr) apart. Patients and Methods: Clinical, lab and prognostic data were collected from charts of two groups of pts: 1) DC: consecutive pts, George Washington (GW) University and the VA hospitals, Washington DC (1986-1987). 2) TA: transfusion-dependent MDS pts at Tel Aviv Sourasky Hospital (1999-2009). Data were transferred into NIH- approved (# 700004948) software.