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Role of Antimicrobial Prophylaxis in Patients with Higher-Risk Myelodysplastic Syndrome or Acute Myeloid Leukemia Receiving Azacitidine Therapy
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Poster Presentations – 14th International Symposium on Myelodysplastic Syndromes / Leukemia Research 55 S1 (2017) S45–S167
mutations, and have since been found in other blood (chronic lymphocytic leukaemia) and solid ( pancreatic) cancers. SF3B1 mutations are thought to function as driver mutations in the MDS subtype, refractory anaemia with ring sideroblasts (RARS), with >80% of RARS patients having an SF3B1 mutation. Our previous studies identified a complex formed between BRCA1, BCLAF1 and SF3B1 following DNA damage, which functions to initiate the correct splicing of DNA damage response (DDR) genes. However, the impact of SF3B1 mutations on the repair of DNA damage and/or response to DNA damaging agents is unknown. The most common SF3B1 mutation is a nucleotide substitution resulting in a lysine to glutamate substitution at position 700 (K700E). The CRISPR/Cas gene editing system was used to create an isogenic model harbouring the K700E mutation within the K-562 myeloid cell line. Using this model, we have assessed the impact of the SF3B1-K700E mutation on the function of cellular DNA damage response (DDR) pathways. Our results indicate that cells expressing SF3B1K700E harbour a cellular DNA repair defect in comparison to their isogenic wildtype counterparts, which is evidenced by their inability to efficiently repair ionising radiation induced DNA damage. Similarly, the K-562K700E cells exhibited a significant sensitivity to the DNA damaging agent etoposide compared to the K-562WT cells. Moreover, preliminary data suggests errors in the splicing of certain DDR genes following normal transcription in the K562K700E cells following DNA damage, which may explain the sensitivity to DNA damaging agents and defective DNA repair observed in these cells. In summary, SF3B1 mutations confer a deficit in the DDR, shown by the greater sensitivity of the K-562K700E cells to DNA damaging agents. Therefore, the presence of a K700E mutation in SF3B1 in patients with RARS, and indeed patients with other cancers, could allow for better treatment stratification and targeted therapies such as PARP inhibitors.
to higher mortality (27% vs 9%, p = 0.08). Median overall survival was 16 (13–20) months, with no differences between patients with or without infections. In the multivariate analysis, a neutrophil count below 0.5 × 109/L (OR 12.5 [2.6–50]) and antimicrobial prophylaxis (OR 0,1 [0.02–04]) were independent factors for the development of infection. Conclusions: Infectious events have a significant impact in the early clinical course of azacitidine-treated patients by increasing hospital admissions and transfusion requirements. Antimicrobial prophylaxis may prevent infections, leading to a decreased need for supportive care in these patients with poor outcome.
279 ROLE OF ANTIMICROBIAL PROPHYLAXIS IN PATIENTS WITH HIGHER-RISK MYELODYSPLASTIC SYNDROME OR ACUTE MYELOID LEUKEMIA RECEIVING AZACITIDINE THERAPY F. Avila1, N. Lorenzana2, S. Alonso1, E. Colado1, T. Bernal3 1 Hematology, Hospital Universitario Central Asturias, Oviedo, Spain; 2 Departamento de Medicina, Universidad de Oviedo, Oviedo, Spain; 3 Hematology- Departamento de Medicina, Hospital Universitario Central Asturias- Universidad de Oviedo, Oviedo, Spain
280 IMPACT OF RED BLOOD CELL TRANSFUSIONS ON SURVIVAL IN LOWER-RISK MDS PATIENTS INCLUDED IN THE EUROPEAN LEUKEMIANET MDS (EUMDS) REGISTRY L. de Swart1, S. Crouch2, A. Smith2, P. Fenaux3, A. Symeonidis4, J. Cermak5, E. Hellström-Lindberg6, G. Sanz7, R. Stauder8, L. Malcovati9, U. Germing10, S. Langemeijer1, M. Skov Holm11, M. Mittelman12, K. Ma˛dry13, A. Almeida14, A. Savic15, R. Itzykson3, D. Bowen16, T. de Witte17 1 Hematology, Radboud University Medical Center, Nijmegen, The Netherlands; 2University of York, Epidemiology and Cancer Statistics Group, York, United Kingdom; 3Assistance Publique des Hôpitaux de Paris AP-HP and Université Paris 7, Hôpital Saint-Louis, Paris, France; 4 Medicine- Div. Hematology, University of Patras Medical School, Patras, Greece; 5Clinical Hematology, Institute of Hematology & Blood Transfusion, Praha, Czech Republic; 6Medicine- Division Hematology, Karolinska Institutet, Stockholm, Sweden; 7Hematology, Hospital Universitario y Politécnico La Fe, Valencia, Spain; 8Internal Medicine V Haematology and Oncology, [email protected], Innsbruck, Austria; 9University of Pavia, Hematology OncologyFondazione IRCCS Policlinico San Matteo, Pavia, Italy; 10Haematology Oncology and Clinical Immunology, Universitätsklinik Düsseldorf, Düsseldorf, Germany; 11Hematology, Aarhus University Hospital, Aarhus, Denmark; 12Tel Aviv Sourasky Ichilov Medical Center, Medicine A, Tel Aviv, Israel; 13Warszawa Medical University, Hematology Oncology and Internal Medicine, Warszawa, Poland; 14 Instituto Português de Oncologia de Lisboa, Serviço de Hematologia, Lisboa, Portugal; 15Clinical Center of Vojvodina- University of Novi Sad, Clinic of Hematology, Novi Sad, Serbia; 16Leeds Teaching Hospitals, St. James’s Institute of Oncology, Leeds, United Kingdom; 17 Tumorimmunology, Nijmegen Center for Molecular Life SciencesRadboud University Medical Center, Nijmegen, The Netherlands
Purpose: To analyze the impact of antimicrobial prophylaxis on morbidity and mortality after the onset of azacitidine treatment in patients with higher-risk myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) not considered for intensive treatment. Methods: Retrospective, single center study including all patients with MDS or AML receiving azacitidine treatment from 2007 to 2016. The primary outcome was incidence of infection during the first four treatment cycles. Secondary objectives were need for hospital admission, transfusional requirements, treatment-related mortality and overall survival. Risk factors for infection were calculated using a multivariate, logistic regression model, including a propensity score to adjust for baseline characteristics. Results: Seventy-six patients, corresponding to 283 azacitidine cycles were studied. There were infectious events in 43% percent of the patients, 60% of them were due to a gram-negative bacteria. Patients with infections had more severe hematological diseases according to international scores and more comorbidities. Development of infections led to more hospital admissions, increased red blood cells and platelet requirements and a trend
Background: Overall survival (OS) of lower-risk MDS patients treated with red blood cell transfusions (RBCT) is usually reduced, but whether the intensity of RBCT is important for prognosis is unknown. The EUMDS Registry is a non-interventional, observational study with data on 2,109 newly diagnosed lower-risk MDS patients from 17 European countries, collected at registration/ diagnosis and at 6 months intervals. Methods: Data on the number of RBCT units, received during each visit-interval, were analyzed using proportional hazards regression with time-varying covariates. The cumulative dose received at the end of each interval was divided by the time since the beginning of the first interval in which a transfusion was received, to give a dose density. In separate OS analyses, transfusion covariates were adjusted by relevant confounders, including age, gender, patient condition ( proxied by EQ-5D index), number of cytopenias at diagnosis, and the cumulative number of RBCT received before diagnosis. We analyzed a cohort of 1,711 patients with all relevant data available. Results: The distribution of the RBCT intensities in the inter-visit intervals of patients is shown in Figure 1A. OS in patients receiving
Poster Presentations – 14th International Symposium on Myelodysplastic Syndromes / Leukemia Research 55 S1 (2017) S45–S167
mutations, and have since been found in other blood (chronic lymphocytic leukaemia) and solid ( pancreatic) cancers. SF3B1 mutations are thought to function as driver mutations in the MDS subtype, refractory anaemia with ring sideroblasts (RARS), with >80% of RARS patients having an SF3B1 mutation. Our previous studies identified a complex formed between BRCA1, BCLAF1 and SF3B1 following DNA damage, which functions to initiate the correct splicing of DNA damage response (DDR) genes. However, the impact of SF3B1 mutations on the repair of DNA damage and/or response to DNA damaging agents is unknown. The most common SF3B1 mutation is a nucleotide substitution resulting in a lysine to glutamate substitution at position 700 (K700E). The CRISPR/Cas gene editing system was used to create an isogenic model harbouring the K700E mutation within the K-562 myeloid cell line. Using this model, we have assessed the impact of the SF3B1-K700E mutation on the function of cellular DNA damage response (DDR) pathways. Our results indicate that cells expressing SF3B1K700E harbour a cellular DNA repair defect in comparison to their isogenic wildtype counterparts, which is evidenced by their inability to efficiently repair ionising radiation induced DNA damage. Similarly, the K-562K700E cells exhibited a significant sensitivity to the DNA damaging agent etoposide compared to the K-562WT cells. Moreover, preliminary data suggests errors in the splicing of certain DDR genes following normal transcription in the K562K700E cells following DNA damage, which may explain the sensitivity to DNA damaging agents and defective DNA repair observed in these cells. In summary, SF3B1 mutations confer a deficit in the DDR, shown by the greater sensitivity of the K-562K700E cells to DNA damaging agents. Therefore, the presence of a K700E mutation in SF3B1 in patients with RARS, and indeed patients with other cancers, could allow for better treatment stratification and targeted therapies such as PARP inhibitors.
to higher mortality (27% vs 9%, p = 0.08). Median overall survival was 16 (13–20) months, with no differences between patients with or without infections. In the multivariate analysis, a neutrophil count below 0.5 × 109/L (OR 12.5 [2.6–50]) and antimicrobial prophylaxis (OR 0,1 [0.02–04]) were independent factors for the development of infection. Conclusions: Infectious events have a significant impact in the early clinical course of azacitidine-treated patients by increasing hospital admissions and transfusion requirements. Antimicrobial prophylaxis may prevent infections, leading to a decreased need for supportive care in these patients with poor outcome.
279 ROLE OF ANTIMICROBIAL PROPHYLAXIS IN PATIENTS WITH HIGHER-RISK MYELODYSPLASTIC SYNDROME OR ACUTE MYELOID LEUKEMIA RECEIVING AZACITIDINE THERAPY F. Avila1, N. Lorenzana2, S. Alonso1, E. Colado1, T. Bernal3 1 Hematology, Hospital Universitario Central Asturias, Oviedo, Spain; 2 Departamento de Medicina, Universidad de Oviedo, Oviedo, Spain; 3 Hematology- Departamento de Medicina, Hospital Universitario Central Asturias- Universidad de Oviedo, Oviedo, Spain
280 IMPACT OF RED BLOOD CELL TRANSFUSIONS ON SURVIVAL IN LOWER-RISK MDS PATIENTS INCLUDED IN THE EUROPEAN LEUKEMIANET MDS (EUMDS) REGISTRY L. de Swart1, S. Crouch2, A. Smith2, P. Fenaux3, A. Symeonidis4, J. Cermak5, E. Hellström-Lindberg6, G. Sanz7, R. Stauder8, L. Malcovati9, U. Germing10, S. Langemeijer1, M. Skov Holm11, M. Mittelman12, K. Ma˛dry13, A. Almeida14, A. Savic15, R. Itzykson3, D. Bowen16, T. de Witte17 1 Hematology, Radboud University Medical Center, Nijmegen, The Netherlands; 2University of York, Epidemiology and Cancer Statistics Group, York, United Kingdom; 3Assistance Publique des Hôpitaux de Paris AP-HP and Université Paris 7, Hôpital Saint-Louis, Paris, France; 4 Medicine- Div. Hematology, University of Patras Medical School, Patras, Greece; 5Clinical Hematology, Institute of Hematology & Blood Transfusion, Praha, Czech Republic; 6Medicine- Division Hematology, Karolinska Institutet, Stockholm, Sweden; 7Hematology, Hospital Universitario y Politécnico La Fe, Valencia, Spain; 8Internal Medicine V Haematology and Oncology, [email protected], Innsbruck, Austria; 9University of Pavia, Hematology OncologyFondazione IRCCS Policlinico San Matteo, Pavia, Italy; 10Haematology Oncology and Clinical Immunology, Universitätsklinik Düsseldorf, Düsseldorf, Germany; 11Hematology, Aarhus University Hospital, Aarhus, Denmark; 12Tel Aviv Sourasky Ichilov Medical Center, Medicine A, Tel Aviv, Israel; 13Warszawa Medical University, Hematology Oncology and Internal Medicine, Warszawa, Poland; 14 Instituto Português de Oncologia de Lisboa, Serviço de Hematologia, Lisboa, Portugal; 15Clinical Center of Vojvodina- University of Novi Sad, Clinic of Hematology, Novi Sad, Serbia; 16Leeds Teaching Hospitals, St. James’s Institute of Oncology, Leeds, United Kingdom; 17 Tumorimmunology, Nijmegen Center for Molecular Life SciencesRadboud University Medical Center, Nijmegen, The Netherlands
Purpose: To analyze the impact of antimicrobial prophylaxis on morbidity and mortality after the onset of azacitidine treatment in patients with higher-risk myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) not considered for intensive treatment. Methods: Retrospective, single center study including all patients with MDS or AML receiving azacitidine treatment from 2007 to 2016. The primary outcome was incidence of infection during the first four treatment cycles. Secondary objectives were need for hospital admission, transfusional requirements, treatment-related mortality and overall survival. Risk factors for infection were calculated using a multivariate, logistic regression model, including a propensity score to adjust for baseline characteristics. Results: Seventy-six patients, corresponding to 283 azacitidine cycles were studied. There were infectious events in 43% percent of the patients, 60% of them were due to a gram-negative bacteria. Patients with infections had more severe hematological diseases according to international scores and more comorbidities. Development of infections led to more hospital admissions, increased red blood cells and platelet requirements and a trend
Background: Overall survival (OS) of lower-risk MDS patients treated with red blood cell transfusions (RBCT) is usually reduced, but whether the intensity of RBCT is important for prognosis is unknown. The EUMDS Registry is a non-interventional, observational study with data on 2,109 newly diagnosed lower-risk MDS patients from 17 European countries, collected at registration/ diagnosis and at 6 months intervals. Methods: Data on the number of RBCT units, received during each visit-interval, were analyzed using proportional hazards regression with time-varying covariates. The cumulative dose received at the end of each interval was divided by the time since the beginning of the first interval in which a transfusion was received, to give a dose density. In separate OS analyses, transfusion covariates were adjusted by relevant confounders, including age, gender, patient condition ( proxied by EQ-5D index), number of cytopenias at diagnosis, and the cumulative number of RBCT received before diagnosis. We analyzed a cohort of 1,711 patients with all relevant data available. Results: The distribution of the RBCT intensities in the inter-visit intervals of patients is shown in Figure 1A. OS in patients receiving