489 results on '"Sean M Devlin"'
Search Results
252. Determinants of fatal bleeding during induction therapy for acute promyelocytic leukemia in the ATRA era
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Sean M. Devlin, Simon Mantha, Martin S. Tallman, Jae H. Park, Richard Stone, Marnie Collins, Harry J. Iland, Diana Zannino, Dan Douer, Frederick R. Appelbaum, Mark R. Litzow, Steven Coutre, Bayard L. Powell, Kristina Laumann, Peter H. Wiernik, Richard A. Larson, Megan Othus, Eytan M. Stein, Debra A. Goldman, Jacob M. Rowe, Harry P. Erba, Susan Geyer, and Ju Whei Lee
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Acute promyelocytic leukemia ,medicine.medical_specialty ,Daunorubicin ,Clinical Trials and Observations ,Immunology ,Antineoplastic Agents ,Hemorrhage ,Tretinoin ,Biochemistry ,Gastroenterology ,Cohort Studies ,03 medical and health sciences ,Leukocyte Count ,0302 clinical medicine ,Leukemia, Promyelocytic, Acute ,Prednisone ,Internal medicine ,medicine ,Idarubicin ,Humans ,Cumulative incidence ,neoplasms ,Clinical Trials as Topic ,business.industry ,Hazard ratio ,Induction chemotherapy ,Cell Biology ,Hematology ,Induction Chemotherapy ,medicine.disease ,Prognosis ,Surgery ,030220 oncology & carcinogenesis ,Multivariate Analysis ,Cytarabine ,business ,030215 immunology ,medicine.drug - Abstract
Acute promyelocytic leukemia (APL) is commonly complicated by a complex coagulopathy. Uncertainty remains as to which markers of bleeding risk are independent predictors. Drawing from 5 large clinical trials that included all-trans retinoic acid (ATRA) as part of induction, we assessed known determinants of bleeding at baseline and evaluated them as potential predictors of hemorrhagic death (HD) in the first 30 days of treatment. The studies included were ALLG APML3 (single arm of ATRA + idarubicin ± prednisone), ALLG APML4 (single arm of ATRA + idarubicin + arsenic trioxide + prednisone), CALGB C9710 (single arm of ATRA + cytarabine + daunorubicin), Eastern Cooperative Oncology Group-American College of Radiology Imaging Network (ECOG-ACRIN) E2491 (intergroup I0129, consisting of daunorubicin + cytarabine vs ATRA), and SWOG S0521 (single-arm induction of ATRA + cytarabine + daunorubicin). A total of 1009 patients were included in the original trials, of which 995 had sufficient data to be included in our multivariate analysis. In this final cohort, there were 37 HD cases during the first 30 days following induction, for an estimated cumulative incidence of 3.7% (95% confidence interval [CI], 2.6% to 5.0%). Using multivariate Cox proportional hazards regression, the hazard ratio of HD in the first 30 days was 2.17 (95% CI, 0.84-5.62) for an ECOG performance status of 3-4 vs 0-2 and 5.20 (95% CI, 2.70-10.02) for a white blood cell count of ≥20 000/μL vs
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- 2016
253. Upfront Use of Plerixafor and Granulocyte-Colony Stimulating Factor (GCSF) for Stem Cell Mobilization in Patients with Multiple Myeloma: Efficacy and Analysis of Risk Factors Associated with Poor Stem Cell Collection Efficiency
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Hani Hassoun, Heather Landau, Mabel Rodriguez, Sean M. Devlin, Neha Korde, Sergio Giralt, Lilian Reich, Nikoletta Lendvai, Sham Mailankody, David J. Chung, Adebayo Ogunniyi, Alexander M. Lesokhin, Ola Landgren, Nelly G. Adel, and Guenther Koehne
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Oncology ,Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Benzylamines ,Cyclams ,CXCR4 ,Article ,03 medical and health sciences ,0302 clinical medicine ,Heterocyclic Compounds ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Granulocyte Colony-Stimulating Factor ,medicine ,Humans ,Multiple myeloma ,Hematopoietic Stem Cell Mobilization ,Lenalidomide ,Aged ,Retrospective Studies ,Aged, 80 and over ,Mobilization ,business.industry ,Plerixafor ,Remission Induction ,Hematology ,Middle Aged ,medicine.disease ,Hematopoietic Stem Cells ,Granulocyte colony-stimulating factor ,Immunoglobulin Isotypes ,Treatment Outcome ,030220 oncology & carcinogenesis ,Immunology ,Female ,Stem cell ,business ,Multiple Myeloma ,Biomarkers ,030215 immunology ,medicine.drug - Abstract
Plerixafor (P), an agent that selectively and reversibly binds to the chemokine receptor CXCR4, has been approved in combination with G-CSF (P + G-CSF) for stem cell (SC) mobilization in patients with multiple myeloma (MM). The goal of this study was to determine the SC collection success rate of P + G-CSF using a clinically relevant outcome defined as the ability to collect at least 5 × 106 CD34+ cells/kg to allow safely two transplants, and identify risk factors impacting SC mobilization. One hundred and thirty-eight patients were mobilized with P + G-CSF upfront following induction. The SC collection success rate was 92.8%. We identified exposure to lenalidomide alone (p = .038), WBC count
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- 2016
254. Prevalence of Functional Impairment and Geriatric Vulnerability during Pre-Transplant Geriatric Assessment in an Academic Hematopoietic Cell Transplantation Center
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Miguel-Angel Perales, Armin Shahrokni, Beatriz Korc-Grodzicki, Sean M. Devlin, Gunjan L. Shah, Molly Maloy, Ann A. Jakubowski, Richard J. Lin, Sergio Giralt, and Parastoo B. Dahi
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Transplantation ,medicine.medical_specialty ,Functional impairment ,Hematopoietic cell ,business.industry ,Emergency medicine ,Vulnerability ,Medicine ,Geriatric assessment ,Center (algebra and category theory) ,Hematology ,business - Published
- 2018
255. Rituximab Use, Immune Reconstitution, and Vaccination after Ex-Vivo CD34-Selected Myeloablative Allogeneic Hematopoietic Cell Transplantation (HCT)
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Florent Malard, Molly Maloy, Katherine Smith, Sean M. Devlin, Taylor Borrill, Kenneth Seier, Meighan Palazzo, Christina Cho, Elaina V. Preston, Marcel R.M. van den Brink, Miguel-Angel Perales, Gunjan L. Shah, and Peter Maslak
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Transplantation ,Hematopoietic cell ,business.industry ,CD34 ,Hematology ,Vaccination ,Immune system ,Immunology ,Medicine ,Rituximab ,business ,Ex vivo ,medicine.drug - Published
- 2018
256. Efficacy of Donor Lymphocyte Infusion in CD34+ Selected Allogeneic Hematopoietic Stem Cell Transplant for Myeloid and Lymphoid Malignancies: A Single Center Experience
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Ann A. Jakubowski, Sergio Giralt, Molly Maloy, Miguel-Angel Perales, Sean M. Devlin, Esperanza B. Papadopoulos, Adam Bryant, and Hugo Castro-Malaspina
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Transplantation ,Myeloid ,medicine.anatomical_structure ,business.industry ,Immunology ,CD34 ,Medicine ,Hematology ,Allogeneic hematopoietic stem cell transplant ,business ,Single Center ,Donor lymphocyte infusion - Published
- 2018
257. Pharmacokinetics and Toxicities after Evomela® (Propylene Glycol Free Melphalan) with Hematopoietic Stem Cell Transplant (HCT) for Multiple Myeloma (MM), AL Amyloidosis (AL), Lymphoma, Acute Myeloid Leukemia (AML), and Myelodysplastic Syndrome (MDS)
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Heather Landau, Hugo Castro-Malaspina, Sean M. Devlin, Brian C. Shaffer, Roni Tamari, Boglarka Gyurkocza, Ryan Schofield, David J. Chung, Andrew Lin, Craig S. Sauter, Valkal Bhatt, Esperanza B. Papadopoulos, Dean Carlow, Guenther Koehne, Parastoo B. Dahi, Caitlin Sarubbi, Stephen Harnicar, Gunjan L. Shah, Matthew J. Matasar, Sergio Giralt, and Craig H. Moskowitz
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Melphalan ,Transplantation ,business.industry ,Hematopoietic stem cell ,Myeloid leukemia ,Hematology ,medicine.disease ,Lymphoma ,03 medical and health sciences ,0302 clinical medicine ,medicine.anatomical_structure ,Pharmacokinetics ,030220 oncology & carcinogenesis ,medicine ,Cancer research ,AL amyloidosis ,business ,Multiple myeloma ,030215 immunology ,medicine.drug - Published
- 2018
258. Analysis of Cytomegalovirus (CMV) Infections in the First 180 Days in Adult Sero-Positive Cord Blood Transplantation (CBT) Recipients Reveals High Infection Rates and Treatment Burden
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Susan E. Prockop, Sergio Giralt, Ioannis Politikos, Andromachi Scaradavou, Genovefa A. Papanicolaou, Gunjan L. Shah, Richard J. O'Reilly, Juliet N. Barker, Alexandra G. Jacob, Parastoo B. Dahi, Carmen Lau, Valkal Bhatt, Miguel-Angel Perales, Sean M. Devlin, Kristine Naputo, Aishat Afuye, Doris M. Ponce, and Molly Maloy
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Transplantation ,business.industry ,Immunology ,Treatment burden ,Cmv infections ,Congenital cytomegalovirus infection ,medicine ,Hematology ,medicine.disease ,business ,Cord blood transplantation - Published
- 2018
259. Feasibility and Toxicity of Pharmacokinetic (PK)-Directed Dosing of Evomela® (propylene glycol free melphalan, PGF-MEL) for Multiple Myeloma (MM) and AL Amyloidosis (AL) Patients Undergoing Autologous Hematopoietic Stem Cell Transplant (AHCT)
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Caitlin Sarubbi, Poguang Wang, David J. Chung, Dean Carlow, Heather Landau, Valkal Bhatt, Gunjan L. Shah, Sean M. Devlin, Ryan Schofield, Parastoo B. Dahi, Roger W. Giese, Elizabeth Hoover, Guenther Koehne, Andrew Lin, Roni Tamari, Stephen Harnicar, Sergio Giralt, and Elaina V. Preston
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Melphalan ,Transplantation ,business.industry ,Hematopoietic stem cell ,Hematology ,Pharmacology ,medicine.disease ,03 medical and health sciences ,0302 clinical medicine ,medicine.anatomical_structure ,Pharmacokinetics ,030220 oncology & carcinogenesis ,Toxicity ,medicine ,AL amyloidosis ,Dosing ,business ,Multiple myeloma ,030215 immunology ,medicine.drug - Published
- 2018
260. Characterizing Ionizing Radiation Exposure after T-Cell Depleted Allogeneic Hematopoietic Cell Transplantation
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Esperanza B. Papadopoulos, Richard J. O'Reilly, Omer Aras, Molly Maloy, Roni Tamari, Lawrence T. Dauer, Sean M. Devlin, Marcel R.M. van den Brink, Ann A. Jakubowski, Theodore S. Rappaport, Sergio Giralt, Christina Cho, Miguel-Angel Perales, and Hugo Castro-Malaspina
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Transplantation ,Hematopoietic cell ,010308 nuclear & particles physics ,business.industry ,T cell ,02 engineering and technology ,Hematology ,01 natural sciences ,Ionizing radiation ,medicine.anatomical_structure ,0103 physical sciences ,0202 electrical engineering, electronic engineering, information engineering ,Cancer research ,medicine ,020201 artificial intelligence & image processing ,business - Published
- 2018
261. Therapeutic Cyclosporine-a (CSA) Levels in the First 7 Days after Cord Blood Transplantation (CBT) Are Critical to Prevent Severe Acute Graft-Versus-Host Disease (aGVHD)
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Hugo Castro-Malaspina, Jonathan U. Peled, Ann A. Jakubowski, Craig S. Sauter, Andromachi Scaradavou, Miguel-Angel Perales, James W. Young, Ioannis Politikos, Marcel R.M. van den Brink, Parastoo B. Dahi, Molly Maloy, Sergio Giralt, Kristine Naputo, Aishat Afuye, Roni Tamari, Juliet N. Barker, Brian C. Shaffer, Sean M. Devlin, Alan M. Hanash, Boglarka Gyurkocza, Esperanza B. Papadopoulos, Valkal Bhatt, Gunjan L. Shah, Alexandra G. Jacob, Richard J. O'Reilly, and Doris M. Ponce
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Transplantation ,medicine.medical_specialty ,business.industry ,Internal medicine ,Acute graft versus host disease ,medicine ,Hematology ,business ,Gastroenterology ,Cord blood transplantation - Published
- 2018
262. Long-Term Follow-Up of Adult Double Unit Cord Blood (CB) Transplantation (dCBT) Recipients Reveals High Rates of Progression-Free Survival after a Novel Cy/ Flu/ Thio/ TBI 400 Intermediate Intensity Conditioning Regimen
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Andromachi Scaradavou, Ann A. Jakubowski, James W. Young, Scott T. Avecilla, Richard J. O'Reilly, Ioannis Politikos, Brian C. Shaffer, Molly Maloy, Esperanza B. Papadopoulos, Boglarka Gyurkocza, Christopher Mazis, Craig S. Sauter, Sergio Giralt, Gunjan L. Shah, Alexandra G. Jacob, Sean M. Devlin, Roni Tamari, Marcel R.M. van den Brink, Doris M. Ponce, Hugo Castro-Malaspina, Jonathan U. Peled, Juliet N. Barker, Parastoo B. Dahi, Kristine Naputo, Aishat Afuye, and Miguel-Angel Perales
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High rate ,Transplantation ,medicine.medical_specialty ,business.industry ,Long term follow up ,Urology ,Hematology ,Intensity (physics) ,Conditioning regimen ,Cord blood ,Medicine ,Progression-free survival ,business - Published
- 2018
263. Role of Consolidation Therapy Prior to CD34− Selected Allogeneic Stem Cell Transplantation for Adult Patients with Acute Myeloid Leukemia in First Remission
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Ellin Berman, Sean M. Devlin, Junting Zheng, Ann A. Jakubowski, Esperanza B. Papadopoulos, Molly Maloy, and Amer Assal
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Oncology ,Transplantation ,medicine.medical_specialty ,Adult patients ,business.industry ,First remission ,CD34 ,Myeloid leukemia ,Hematology ,Consolidation therapy ,Internal medicine ,Medicine ,Stem cell ,business - Published
- 2018
264. Association of Immune Marker Changes With Progression of Monoclonal Gammopathy of Undetermined Significance to Multiple Myeloma
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Sigurdur Y. Kristinsson, Ruth M. Pfeiffer, Kazunori Murata, Sydney X. Lu, Charlene McShane, Jonathan N. Hofmann, Sham Mailankody, Mark P. Purdue, Ahmet Dogan, Theresia Akhlaghi, Katie L. Thoren, Sean M. Devlin, Ola Landgren, Neha Korde, Lakshmi V. Ramanathan, Malin Hultcrantz, Even H Rustad, Ingemar Turesson, Magnus Björkholm, Dickran Kazandjian, and Loredana Santo
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Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Cancer ,Odds ratio ,medicine.disease ,Immunoglobulin light chain ,Isotype ,03 medical and health sciences ,0302 clinical medicine ,SDG 3 - Good Health and Well-being ,hemic and lymphatic diseases ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,030212 general & internal medicine ,Risk assessment ,business ,Multiple myeloma ,Monoclonal gammopathy of undetermined significance ,Original Investigation ,Cohort study - Abstract
IMPORTANCE: Multiple myeloma is consistently preceded by monoclonal gammopathy of undetermined significance (MGUS). Risk models that estimate the risk of progression from MGUS to multiple myeloma use data from a single time point, usually the initial workup. OBJECTIVE: To longitudinally investigate the alterations of serum immune markers with stable vs progressive MGUS. DESIGN, SETTING, AND PARTICIPANTS: This prospective cross-sectional cohort study included 77 469 adult participants aged 55 to 74 years in the screening arm of the National Cancer Institute Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial who had a diagnosis of progressing MGUS (n = 187) or stable MGUS (n = 498), including light-chain subtype, from November 1993, through December 2011. For each participant, all available serially stored prediagnostic serum samples (N = 3266) were obtained. Data analysis was performed from April 2018, to December 2018. MAIN OUTCOMES AND MEASURES: Serum protein and monoclonal immunoglobulin levels, serum free light chains, and serum light chains within each immunoglobulin class were measured. RESULTS: Of 685 individuals included in the study, 461 (67.3%) were men; the mean (SD) age was 69.1 (5.6) years. In cross-sectional modeling, risk factors associated with progressive MGUS were IgA isotype (adjusted odds ratio [OR], 1.80; 95% CI, 1.03-3.13; P = .04), 15 g/L or more monoclonal spike (adjusted OR, 23.5; 95% CI, 8.9-61.9; P 10) serum free light chains ratio (adjusted OR, 46.4; 95% CI, 18.4-117.0; P
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- 2019
265. 1018 - CD97 IS A CRITICAL REGULATOR OF ACUTE MYELOID LEUKEMIA STEM CELL FUNCTION
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Gaëlle H. Martin, Sean M. Devlin, Carolien M. Woolthuis, Sohini Chakraborty, Stephen Chung, Francine E. Garrett-Bakelman, Nainita Roy, Alexis Desrichard, Jörg Hamann, Wenhuo Hu, Iryna berezniuk, Timothy A. Chan, and Christopher Y. Park
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Cancer Research ,medicine.drug_class ,Myeloid leukemia ,Cell Biology ,Hematology ,Biology ,medicine.disease ,Monoclonal antibody ,Leukemia ,Haematopoiesis ,Antigen ,hemic and lymphatic diseases ,Monoclonal ,Genetics ,Cancer research ,medicine ,Cytotoxic T cell ,Stem cell ,Molecular Biology - Abstract
Despite advances in our understanding of the genetic origins of acute myeloid leukemia (AML), treatment options have remained essentially unchanged for 30 years, and clinical outcomes remain poor. AML is maintained by leukemia stem cells (LSCs), which are critical for disease maintenance as well as re-initiating disease after therapy. We previously identified novel markers and therapeutic targets in AML and MDS by comparing the transcriptomes of stem cells to normal purified HSCs, leading to the identification of CD99 as an antigen selectively expressed on LSCs. Moreover, novel monoclonal antibodies against CD99 exerted significant cytotoxic effects against AML and MDS stem cells. Recently, we identified CD97 as an antigen expressed in the vast majority of human AMLs. CD97 regulates migration of normal hematopoietic cells as well as the invasive properties of solid cancers, but little is known about its function in AML. Our studies have revealed several features of CD97 that make it particularly important with in AML including: 1) CD97 is one of the most commonly expressed human AML antigens; 2) CD97 promotes blast growth and survival, and limits differentiation; 3) CD97 regulates LSC function, as demonstrated in serial and limiting dilution transplant experiments, but is not required for HSC function; 4) Consistent with the critical role CD97 in AML, CD97 is an independent prognostic variable for overall survival (OS) in both univariate and multivariate analyses. Lastly, novel monoclonal and synthetic antibodies against CD97 appear to exhibit significant anti-leukemic effect, making CD97 a viable therapeutic target.
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- 2019
266. Abstract LB-304: Oncologic therapy for solid tumors alters the risk of clonal hematopoiesis
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Maria E. Arcila, Marc Ladanyi, Teng Gao, Kenneth Offit, Stuart Gardos, Michael Walsh, Michael F. Berger, Antonin Berthon, Lindsay M. Morton, Matahi Moarii, Laura Boucai, Nilanjan Chatterjee, Ryan Ptashkin, Mariko Yabe, Diana Mandelker, Ahmet Zehir, Minal Patel, Elli Papaemmanuil, Ross L. Levine, Jessica Schulman, Martin S. Tallman, David M. Hyman, Sean M. Devlin, Gunes Gundem, Daniel Kelly, Catherine C. Coombs, Aijazuddin Syed, Lior Z. Braunstein, Virginia M. Klimek, Luis A. Diaz, Dean F. Bajorin, Axel Martin, Kelly L. Bolton, John Philip, Dominik Glodzik, Choonsik Lee, Mark E. Robson, Elsa Bernard, Zsofia K. Stadler, Howard I. Scher, Montserrat Garcia-Closas, David B. Solit, and Akshar Patel
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Oncology ,Cancer Research ,medicine.medical_specialty ,Myeloid ,business.industry ,Clonal hematopoiesis ,Chatterjee ,Sequencing data ,Cancer ,medicine.disease ,Leukemia ,medicine.anatomical_structure ,Internal medicine ,Cohort ,medicine ,Mutation detection ,business - Abstract
Solid tumor patients often suffer from cytopenias and are at risk for therapy-related myeloid neoplasms (tMN). Somatic mutations in leukemia-associated genes can occur in normal healthy individuals, referred to as clonal hematopoiesis (CH). CH is associated with cytopenias, risk of leukemia and cardiovascular disease. We and others have shown that CH is frequent in cancer patients. Characterization of the relationship between exposure to specific oncologic regimens and CH and how these relate to cytopenias and tMN risk would inform treatment decisions and tMN prevention strategies. To determine the relationship between CH and oncologic therapy we interrogated CH in a cohort of 9045 solid tumor patients. Subjects were sequenced using a targeted panel of cancer-associated mutations used to screen tumor samples against a blood control sample. Mutation detection was performed on blood-derived sequencing data using the matched tumor as a comparator and accounted for background sequencing error rates. CH was identified in 23% of patients. In multivariate regression analyses adjusted by age, CH was more often found in current smokers (OR=1.20, 95%CI=1.07-1.35, p CH is frequent in solid tumor patients and can be reliably detected when a matched tumor normal targeted gene sequencing approach is performed. Beyond age, CH is strongly associated with race, smoking and importantly prior exposure to oncologic therapy with evidence of specific treatment effects. Screening of CH in cancer cohorts is critical to the development of future clinical guidelines and risk-adapted prevention strategies for tMN. Note: This abstract was not presented at the meeting. Citation Format: Kelly Bolton, Ryan Ptashkin, Lior Braunstein, Teng Gao, Sean M. Devlin, Daniel Kelly, Catherine Coombs, Minal Patel, Matahi Moarii, Elsa Bernard, Antonin Berthon, Laura Boucai, Dominik Glodzik, Axel Martin, Zsofia Stadler, Michael Walsh, Diana Mandelker, Akshar Patel, Jessica Schulman, Gunes Gundem, Aijazuddin Syed, Maria Arcila, David B. Solit, Mark E. Robson, Marc Ladanyi, Choonsik Lee, John Philip, Dean Bajorin, Montserrat Garcia-Closas, Stuart Gardos, David Hyman, Martin Tallman, Mariko Yabe, Kenneth Offit, Howard Scher, Virginia Klimek, Luis Diaz, Nilanjan Chatterjee, Michael F. Berger, Lindsay Morton, Ross Levine, Ahmet Zehir, Elli Papaemmanuil. Oncologic therapy for solid tumors alters the risk of clonal hematopoiesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-304.
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- 2019
267. PF546 THE SFGM-TC MDS SCORE AT DAY 180 IS ASSOCIATED WITH POST-TRANSPLANT OUTCOMES IN PATIENTS WITH MYELODYSPLASTIC SYNDROME WHO UNDERWENT CD34+ SELECTED ALLOGENEIC STEM CELL TRANSPLANT
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Sergio Giralt, Miguel-Angel Perales, Roni Tamari, Josel D. Ruiz, M. Sanchez Escamilla, Sean M. Devlin, H. Castro-Malaspina, Molly Maloy, Brian C. Shaffer, and A. Alarcon
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medicine.medical_specialty ,business.industry ,Internal medicine ,CD34 ,Medicine ,In patient ,Hematology ,Stem cell ,business ,Post transplant - Published
- 2019
268. Ixazomib and dexamethasone in high risk smoldering multiple myeloma: A clinical and correlative pilot study
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Neha Korde, Sean M. Devlin, Eric L. Smith, Hani Hassoun, Alexander M. Lesokhin, Oscar B Lahoud, Nikoletta Lendvai, Ola Landgren, Malin Hultcrantz, Sham Mailankody, Meghan Salcedo, and Elizabet Tavitian
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Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,medicine.disease ,Ixazomib ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Increased risk ,chemistry ,Median time ,030220 oncology & carcinogenesis ,Internal medicine ,Medicine ,business ,Dexamethasone ,Multiple myeloma ,030215 immunology ,medicine.drug - Abstract
8051 Background: Patients with high risk smoldering multiple myeloma (HR-SMM) have an increased risk of progression to multiple myeloma (MM)- median time < 2 years. The standard management of these patients currently is close clinical monitoring; however, randomized trials show longer progression-free and overall survival in in HR-SMM patients treated with the oral immunomodulatory drug lenalidomide. We report the use ixazomib, the first oral proteasome inhibitor, in combination with dexamethasone in the setting of HR-SMM. Because proteasome inhibitors can provide deep clinical responses in patients with MM, we set the pre-specified threshold for efficacy high (overall response rate of ≥75%). Methods: In this single arm pilot trial of ixazomib/dexamethasone, patients received 12 4-week cycles of ixazomib/dexamethasone followed by ixazomib maintenance for 24 cycles. The primary endpoint is best overall response after 12 cycles and second objectives include duration of response, safety, and progression free survival. Results: 14 patients with HR-SMM were enrolled between 06/2016 and 03/2018. The median age is 65 years and 10 (71%) of patients were male. 11 (79%) patients were high-risk by the PETHEMA criteria, 2 (14%) by the Mayo Clinic criteria and 1 (7%) by both. At data cut-off (02/07/2019), patients completed a median of 17 cycles and 10 (71%) are continuing treatment. 4 patients have stopped treatment (2 patients for raise in serum markers without progression to MM, and 1 each for toxicities, and co-morbidities unrelated to treatment). 9 (64%) achieved an objective response (8 PR, and 1 VGPR) and no patient has progressed to MM. Non-heme adverse events included 3 grade 1 GI events, 2 grade 3 lung infection, 1 grade 2 acute kidney injury, and 1 had grade 1 fatigue that was possibly related to treatment. Conclusions: Ixazomib/dexamethasone appears well tolerated with high overall response (9/14; 64%) in patients with HR-SMM. Although the trial does not meet our pre-specified threshold for efficacy (i.e. best overall response rate of 75%), with a median follow-up of 17 months, no patient progressed to MM and only 2 patients had serologic progression. These results support further evaluation of ixazomib/dexamethasone alone and in combination with other agents as treatment for patients with HR-SMM. Clinical trial information: NCT02697383.
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- 2019
269. Inferior survival after microbiota injury: A multicenter allo-HCT study
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Nelson J. Chao, Ying Taur, Jonathan U. Peled, Sergio Giralt, Eric G. Pamer, Joao B. Xavier, Ernst Holler, Miguel-Angel Perales, Luigi A Amoretti, Roberta J. Wright, Daigo Hashimoto, Takanori Teshima, Marcel R.M. van den Brink, Robert R. Jenq, Anthony D. Sung, Antonio L.C. Gomes, Emily Fontana, Daniela Weber, Sean M. Devlin, and Eric R. Littmann
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Transplantation ,03 medical and health sciences ,Cancer Research ,0302 clinical medicine ,Oncology ,Hematopoietic cell ,business.industry ,030220 oncology & carcinogenesis ,Immunology ,Medicine ,business ,Microbiota composition ,030215 immunology - Abstract
7015 Background: Relationships between microbiota composition and clinical outcomes following allogeneic hematopoietic cell transplantation (allo-HCT) have been described in single-center studies. Geographic variations in human microbial communities and differences in clinical practices across institutions raise the question of whether these associations are generalizable. We report the first multi-center study of the intestinal microbiota in allo-HCT. Methods: Intestinal communities in 8,768 fecal samples from 1,362 allo-HCT patients at 4 centers on 3 continents were profiled by 16S sequencing. Associations between microbiota composition and clinical outcomes were analyzed with proportional-hazards analysis in an observational study. Results: We observed reproducible patterns of microbiota injury characterized by loss of diversity and domination by single taxa. Low diversity in the neutrophil engraftment period was reproducibly associated with increased risk of death (multivariate HR 0.48 [0.30-0.77] p = 0.002 in the largest cohort). These reductions in OS were in part due to an increased risk of transplant-related mortality and graft-vs-host disease. Baseline pre-HCT samples already bore evidence of microbiome disruption; low diversity prior to transplantation was associated with poor survival. A bacterial-composition risk score that was trained in one cohort predicted mortality in the other three cohorts (multivariate HR 1.42 [1.04-1.93] p = 0.03), indicating that not only a diversity metric but also a signature of specific bacterial abundances is informative about post-HCT mortality risk across independent institutions. Conclusions: We demonstrate a relationship between microbiota and survival after allo-HCT that is independent of transplant center and geographic location. The diversity of clinical practices across institutions imposed significant heterogeneity in the study, yet we observed reproducible microbiota injury patterns and associations with outcomes. This concordance suggests that approaches to manipulate the intestinal microbiota in allo-HCT may be generalizable.
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- 2019
270. Baseline identification of clonal V(D)J sequences for DNA-based minimal residual disease detection in multiple myeloma
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Sean M. Devlin, Austin Jacobsen, Maria E. Arcila, Malin Hultcrantz, Jeffrey E. Miller, Caleb Ho, Akshar Patel, Theresia Akhlaghi, Denise Chen, Ola Landgren, Mikhail Roshal, Even H Rustad, Ying Huang, Elli Papaemmanuil, and Venkata Yellapantula
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Male ,0301 basic medicine ,Neoplasm, Residual ,Physiology ,Biochemistry ,Plasma Cell Disorders ,Hematologic Cancers and Related Disorders ,White Blood Cells ,Database and Informatics Methods ,Spectrum Analysis Techniques ,0302 clinical medicine ,Animal Cells ,Immune Physiology ,Medicine and Health Sciences ,Neoplasm ,Multiple myeloma ,Hemodilution ,Immune System Proteins ,Multidisciplinary ,V(D)J recombination ,Hematology ,Middle Aged ,Flow Cytometry ,3. Good health ,Myelomas ,medicine.anatomical_structure ,Oncology ,Spectrophotometry ,030220 oncology & carcinogenesis ,Medicine ,Female ,Cytophotometry ,Cellular Types ,Antibody ,Multiple Myeloma ,Immunoglobulin Heavy Chains ,Sequence Analysis ,Research Article ,Bioinformatics ,Sequence analysis ,Science ,Immune Cells ,Plasma Cells ,Immunology ,Bone Marrow Cells ,Biology ,Research and Analysis Methods ,Antibodies ,DNA sequencing ,Immunoglobulin kappa-Chains ,03 medical and health sciences ,medicine ,Humans ,Myelomas and Lymphoproliferative Diseases ,Aged ,Blood Cells ,Biology and Life Sciences ,Cancers and Neoplasms ,Proteins ,Cell Biology ,Sequence Analysis, DNA ,medicine.disease ,Minimal residual disease ,Molecular biology ,V(D)J Recombination ,030104 developmental biology ,biology.protein ,Bone marrow - Abstract
Tracking of clonal immunoglobulin V(D)J rearrangement sequences by next generation sequencing is highly sensitive for minimal residual disease in multiple myeloma. However, previous studies have found variable rates of V(D)J sequence identification at baseline, which could limit tracking. Here, we aimed to define the factors influencing the identification of clonal V(D)J sequences. Bone marrow mononuclear cells from 177 myeloma patients underwent V(D)J sequencing by the LymphoTrack assays (Invivoscribe). As a molecular control for tumor cell content, we sequenced the samples using our in-house myeloma panel myTYPE. V(D)J sequence clonality was identified in 81% of samples overall, as compared with 95% in samples where tumor-derived DNA was detectable by myTYPE. Clonality was detected more frequently in patients with lambda-restricted disease, mainly because of increased detection of kappa gene rearrangements. Finally, we describe how the tumor cell content of bone marrow aspirates decrease gradually in sequential pulls because of hemodilution: From the initial pull used for aspirate smear, to the final pull that is commonly used for research. In conclusion, baseline clonality detection rates of 95% or higher are feasible in multiple myeloma. Optimal performance depends on the use of good quality aspirates and/or subsequent tumor cell enrichment.
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- 2019
271. Impact of Pre-Transplant Measurable Residual Disease on Relapse Incidence and Progression-Free Survival in Older AML/MDS Patients Following Allogeneic Hematopoietic Cell Transplantation
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Miguel-Angel Perales, Roni Tamari, Hugo Castro-Malaspina, Esperanza B. Papadopoulos, Brian C. Shaffer, Sergio Giralt, Boglarka Gyurkocza, Sean M. Devlin, Eytan M. Stein, Molly Maloy, Aaron D Goldberg, Ann A. Jakubowski, Martin S. Tallman, Theresa A. Elko, and Richard J. Lin
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Transplantation ,medicine.medical_specialty ,business.industry ,Incidence (epidemiology) ,Context (language use) ,Hematology ,Regimen ,hemic and lymphatic diseases ,Internal medicine ,Cohort ,Medicine ,Cumulative incidence ,Progression-free survival ,business ,Cause of death - Abstract
Background Relapse continues to be the major cause of death in AML/MDS patients following allogeneic hematopoietic cell transplantation (HCT). Advanced age has emerged as a strong predictor of relapse due to both generally increased disease risk and reduced ability to deliver myeloablative conditioning due to comorbidities and functional impairment. The impact of measurable residual disease (MRD) prior to HCT has not been assessed in the context of older patients receiving CD34+ selected allografts. Methods We retrospectively examined 297 AML/MDS patients aged 60 years and older who underwent first allo-HCT at our institution from 2001 to 2016. We included only patients who received either a conventional or CD34+ selected graft. We collected MRD data using flow cytometry, cytogenetics (karyotype and/or FISH), and molecular mutation analysis from patients who had achieved a hematologic complete remission pre-HCT. Factors associated with the cumulative incidence of relapse (RI) and progression-free survival (PFS) were analyzed using cause-specific hazard models. Results The median age was 65.8 years (range 60-78.4), and 42% were women. One hundred and eighty-four patients had AML (62%). Fifty-nine percent of patients had HCT-CI >2; 51% had pre-HCT KPS >80; and 37% had high/very high disease risk index (DRI). Seventy-five percent of patients received a myeloablative regimen and 61% received a CD34+ selected graft. Sixteen percent of patients had a mismatched donor. With a median follow-up of 5.1 year for survivors, the 2- and 5-year overall survival was 50% (95% CI: 44-55) and 39% (95% CI: 33-45) respectively. The 2- and 5-year of PFS was 46% (95% CI: 40-51) and 37% (95% CI: 31-43) respectively. By June 30, 2018, 93 patients had relapsed, or their disease progressed, with 3-year cumulative RI of 31% (95% CI: 26-36). Two hundred and four patients had available MRD data and 71, 35%, were MRD positive pre-HCT. In multivariate analysis of RI (Table below), high/very high DRI score (HR 2.2, 95% CI: 1.3-3.8, p=0.004) and MRD positivity (HR 1.9, 95% CI: 1.1-3.2, p=0.027) were associated with an increased risk, with CD34+ selection approaching statistical significance for a reduced risk (HR 0.6, 95% CI: 0.3-1, p=0.064). In multivariate analysis of PFS, only high/very high DRI score (HR 1.8, 95% CI: 1.2-2.7, p=0.003) was associated with an increased risk. Conclusions In this study, we characterized relapse following allogeneic HCT in an older cohort of AML/MDS patients. While limited by the retrospective nature with likely underestimation of MRD status due to different assays and time periods, and by the lack of data on post-transplant maintenance, we confirmed the association of pre-HCT MRD with relapse risk. CD34+ selection has no impact on the risk of relapse.
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- 2019
272. Robustness of Approaches to ROC Curve Modeling under Misspecification of the Underlying Probability Model
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Sean M. Devlin, Scott S. Emerson, and Elizabeth Thomas
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Statistics and Probability ,Receiver operating characteristic ,Robustness (computer science) ,Parametric model ,Covariate ,Econometrics ,Statistics::Methodology ,Semiparametric regression ,Estimating equations ,Parametric statistics ,Semiparametric model ,Mathematics - Abstract
A variety of statistical regression models have been proposed for the comparison of ROC curves for different markers across covariate groups. Pepe developed parametric models for the ROC curve that induce a semiparametric model for the market distributions to relax the strong assumptions in fully parametric models. We investigate the analysis of the power ROC curve using these ROC-GLM models compared to the parametric exponential model and the estimating equations derived from the usual partial likelihood methods in time-to-event analyses. In exploring the robustness to violations of distributional assumptions, we find that the ROC-GLM provides an extra measure of robustness.
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- 2013
273. Safety and Efficacy of Combined Ruxolitinib and Thalidomide in Patients with Myelofibrosis: Initial Results of a Phase II Study
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Tawni Goodman, Prithviraj Bose, Kelly Marek, Sean M. Devlin, Srdan Verstovsek, Nicole Ard, Eytan M. Stein, Michael J. Mauro, Naveen Pemmaraju, Tapan M. Kadia, Kelsey Alvarez, and Raajit K. Rampal
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Ruxolitinib ,medicine.medical_specialty ,Thrombocytosis ,business.industry ,Anemia ,Immunology ,Phases of clinical research ,Cell Biology ,Hematology ,medicine.disease ,Pomalidomide ,Biochemistry ,Thalidomide ,03 medical and health sciences ,Regimen ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Internal medicine ,Clinical endpoint ,Medicine ,business ,030215 immunology ,medicine.drug - Abstract
Background: Among the most frequent and challenging hematologic manifestations of myelofibrosis (MF) are anemia and thrombocytopenia, the presence of which portends an adverse outcome. Few effective modalities to address these cytopenias exist, particularly thrombocytopenia. Further, although the FDA-approved JAK1/2 inhibitor Ruxolitinib (RUX) has demonstrated significant clinical efficacy in MF patients, RUX frequently results in anemia and thrombocytopenia. Thrombocytopenia in particular often results in dose attenuation of RUX. Thalidomide (THAL) is a first-in-class immunomodulatory agent. Studies of THAL in MF patients, alone and with prednisone, have demonstrated improvements in anemia and thrombocytopenia. We therefore sought to examine whether combination of RUX and THAL could result in improvement in both disease-related and therapy-related cytopenias, as well as improve overall disease response in patients with MF. Here we report initial analysis of this study (NCT03069326). Methods: We conducted a multicenter two stage phase II trial designed to assess the effect of RUX and THAL combination in subjects with primary, post-polycythemia vera, or post-essential thrombocythemia myelofibrosis. Patients taking RUX at the time of enrollment must have had less than PR per IWG-MRT/ELN 2013 criteria, or be refractory, to RUX single-agent therapy. Patients must have been taking RUX for a minimum of 3 months, and must have been on a stable dose of RUX for a minimum of 4 weeks immediately prior to enrollment. Treatment-naïve patients received single-agent RUX for 3 months (run-in phase) per label, and went on to combination therapy if they achieved less then a PR per IWG-MRT/ELN criteria. Each cycle of therapy was 28 days. Response assessment was evaluated according to the IWG-MRT/ELN 2013 criteria. Platelet response criteria in patients with baseline thrombocytopenia (less than lower limit of normal) included: Major response (≥75% increase in platelet count), Intermediate Response (≥50% increase) and Minor Response (≥25% increase). Adverse events were assessed using the NCI CTCAE v. 4.0. The primary endpoint was the proportion of treated subjects that achieved a response by IWG-MRT criteria and by platelet response criteria. Results: A total of 25 patients are planned to be accrued. At the time of this writing, a total of 18 patients have been accrued. The median age was 70.5 years (47-85). 8 patients had received prior therapies other than RUX, including imetelstat, momelotinib, danazol, pomalidomide, darbepoetin alpha and sotatercept. 7 patients enrolled to the run-in phase. 14 patients received red blood cell transfusions prior to study enrollment. Evaluation of platelet count in patients with baseline thrombocytopenia demonstrated a significant increase in platelet count at cycle 3 of therapy compared to baseline (Figure 1A and B; P Conclusions: The combination of THAL and RUX has demonstrated a promising efficacy signal in this initial analysis of an ongoing phase II study, and appears to be well tolerated. Platelet count increases were observed in all patients who entered study with baseline thrombocytopenia, a response which appears to be maintained in the majority of patients observed 6 months after starting combination therapy. As well, anemia responses were observed in 3 of 5 evaluable patients. Collectively, these data indicate a potential role for this regimen in patients with anemia and/or thrombocytopenia, who otherwise have limited treatment options. Updated data on duration of response and overall response of all accrued patients will be presented. Disclosures Rampal: Constellation: Research Funding; Celgene: Honoraria; Incyte: Honoraria, Research Funding; Jazz: Consultancy, Honoraria; Stemline: Research Funding. Verstovsek:Italfarmaco: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Stein:Celgene: Consultancy; Bayer: Consultancy; Agios: Consultancy; Daiichi Sankyo: Consultancy; Novartis: Consultancy; Pfizer: Consultancy. Kadia:Pfizer: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy; Amgen: Consultancy, Research Funding; Takeda: Consultancy; Takeda: Consultancy; Celgene: Research Funding; BMS: Research Funding; Novartis: Consultancy; Abbvie: Consultancy; Amgen: Consultancy, Research Funding; Celgene: Research Funding; BMS: Research Funding; Jazz: Consultancy, Research Funding; Abbvie: Consultancy; Jazz: Consultancy, Research Funding. Mauro:Bristol-Myers Squibb: Consultancy; Novartis: Consultancy, Research Funding; Pfizer: Consultancy; Takeda: Consultancy. Pemmaraju:SagerStrong Foundation: Research Funding; daiichi sankyo: Research Funding; novartis: Research Funding; abbvie: Research Funding; cellectis: Research Funding; samus: Research Funding; Affymetrix: Research Funding; stemline: Consultancy, Honoraria, Research Funding; celgene: Consultancy, Honoraria; plexxikon: Research Funding. Bose:Blueprint Medicines Corporation: Research Funding; Astellas Pharmaceuticals: Research Funding; Incyte Corporation: Honoraria, Research Funding; Constellation Pharmaceuticals: Research Funding; Celgene Corporation: Honoraria, Research Funding; Pfizer, Inc.: Research Funding; CTI BioPharma: Research Funding.
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- 2018
274. Impact of Pre-Transplant Rituximab on Efficacy of Revaccination of Lymphoma Patients after Autologous Hematopoietic Stem Cell Transplantation
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Kenneth Seier, Craig S. Sauter, Gunjan L. Shah, Craig H. Moskowitz, Sean M. Devlin, Matthew J. Matasar, Parastoo B. Dahi, Miguel-Angel Perales, Sergio Giralt, Elaina V. Preston, Meighan Palazzo, and Michael Scordo
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Oncology ,medicine.medical_specialty ,Carmustine ,Cyclophosphamide ,business.industry ,medicine.medical_treatment ,Immunology ,Cell Biology ,Hematology ,Hematopoietic stem cell transplantation ,ThioTEPA ,medicine.disease ,Biochemistry ,Lymphoma ,Transplantation ,immune system diseases ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Rituximab ,business ,Busulfan ,medicine.drug - Abstract
Background: Guidelines recommend reimmunization starting 12 months after autologous hematopoietic stem cell transplant (AHCT). However, lymphoma patients routinely receive rituximab, an anti-CD20 monoclonal antibody that depletes CD20+ B-cells and may impair response to vaccination. We have shown that rituximab use may prevent on time vaccination in patients who undergo an allogeneic stem cell transplant (BBMT 2018 S427-S428). We therefore aimed to evaluate the impact of rituximab on responses to revaccination after AHCT and included patients with B-cell Non-Hodgkin Lymphoma (B-NHL) and T-cell NHL (T-NHL) and Hodgkin Lymphoma (HL), with the latter two groups not routinely receiving rituximab. Methods: Lymphoma patients who underwent AHCT between 2012 - 2016 were identified from the institutional database and included if they had completed the primary series and had pre- and post-vaccination titers to evaluate for response. Patients were divided by histology (B-NHL vs T-NHL and HL), and chart reviewed confirmed if they had received pre- or post- AHCT rituximab. Vaccine responses were determined by comparison of pre- and post- vaccination titers. Patients were classified as responders, non-responders, immune by pre-vaccination titer, and not evaluable due to missing data (had not received vaccine or had missed pre- or post-vaccination titers) by previously described criteria (Palazzo BBMT 2017). Descriptive statistics were used to summarize results, and the Fishers exact test was used for comparisons. Results: Of the 161 patients who met our inclusion criteria, 104 (65%) received rituximab pre-AHCT with 20% of these receiving additional rituximab post-HCT. Of the 57 patients who did not receive pre-AHCT rituximab, 2% received post-AHCT rituximab. The median age of the whole group was 53 years (range, 19-73), with patients not receiving rituximab being younger (median age 43 years (range 19-71) vs 58 years (21-73), p Most patients received the completed series for each vaccine (84% Haemophilus influenzae, 99% pneumococcus, 96% polio, 66% tetanus, 76% diphtheria, 91% pertussis, 78% Hepatitis A, and 84% Hepatitis B), but vaccine responses varied by vaccine type with 48% responding to Haemophilus influenzae, 45% pneumococcus, 32% tetanus, 34% diphtheria, 52% pertussis, 31% Hepatitis A, and 37% Hepatitis B (Figure 1). Response to polio vaccine could not be calculated as 53% retained immunity and the rest of the patients were non-evaluable possibly due to a change in assay. No patients retained immunity to pneumococcus or diphtheria on the pre-vaccine titers. Univariate analyses were performed for pertussis, diphtheria, Hepatitis A, Hepatitis B and Pneumococcal vaccines evaluating the association with age, gender, disease type, and rituximab exposure. More females than males responded to B. pertussis (90% vs 78%, p=0.045). Hepatitis A and Hepatitis B response was associated with a younger age (50.7 years vs 59.6 years, p=0.037 and 54.2 years vs 62.4 years, p=0.007, respectively), and disease type was associated with pneumococcal response (62% HL vs 39% NHL, p=0.022). Patients who did not receive rituximab were more likely to respond to pneumococcus and Hepatitis B (63% vs 35%, p=0.001, and 82% vs 56%, p=0.026, respectively, Figure 2). Conclusions: Response to reimmunization with inactivated vaccines in lymphoma patients after AHCT is similar to previously reported populations, but prior rituximab exposure appears to impact response. Disclosures Matasar: Seattle Genetics: Honoraria. Moskowitz:Merck & Co: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Consultancy, Research Funding; Celgene: Consultancy. Sauter:Juno Therapeutics: Consultancy, Research Funding; Sanofi-Genzyme: Consultancy, Research Funding; Spectrum Pharmaceuticals: Consultancy; Novartis: Consultancy; Precision Biosciences: Consultancy; Kite: Consultancy. Shah:Amgen: Research Funding; Janssen: Research Funding. Perales:Abbvie: Other: Personal fees; Incyte: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees and Clinical trial support; Takeda: Other: Personal fees; Merck: Other: Personal fees; Novartis: Other: Personal fees.
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- 2018
275. Cancer-Associated Thrombosis: Anatomic Distribution of the Index Event Is Not a Reliable Predictor of Recurrence Risk
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Sean M. Devlin, Gerald A. Soff, Jodi V. Mones, Eva S Haegler-Laube, Jonathan Wills, Jeanette Batista, Yimei Miao, Gemma Bendheim, Cy Wilkins, Debra M. Sarasohn, and Simon Mantha
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Rivaroxaban ,medicine.medical_specialty ,Surrogate endpoint ,business.industry ,Deep vein ,Immunology ,Cell Biology ,Hematology ,equipment and supplies ,medicine.disease ,Lower risk ,Biochemistry ,Thrombosis ,Pulmonary embolism ,medicine.anatomical_structure ,Embolism ,Internal medicine ,medicine ,cardiovascular diseases ,Vein ,business ,medicine.drug - Abstract
Introduction: Cancer associated thrombosis (CAT) is a common complication of cancer, associated with significant morbidity and mortality. While incidence varies with cancer type, stage, chemotherapy, and other factors, estimates are that up to 20% of cancer patients will experience at least one venous thromboembolic (VTE) episode. VTE consist of deep vein thrombosis (DVT) and/or pulmonary embolism (PE), and there is a spectrum of vascular involvement. DVTs are classified as proximal (popliteal vein or above) and PE may be subsegmental, segmental, lobar, main, or saddle embolism. Our standard approach has been to treat all DVTs and all PEs in cancer patients, regardless of the size of the involved vessel. However, it is not clear if the risk of recurrent VTE in a patient with a "small" subsegmental PE, or a calf vein DVT, is comparable to that of an individual with a larger vascular involvement. In this study, we characterized the largest vessel involved in the initial VTE episode, and the relationship with recurrent VTE. Methods: All patients at MSKCC with CAT are monitored within an existing Quality Assessment initiative. From 1/1/2014 through 10/31/2016, 1072 patients with CAT were treated with rivaroxaban (Riva). (The overall outcomes of this cohort are the subject of a separate abstract.) In this study we compared the rate of recurrent VTE in patients with a distal (calf) DVT with proximal DVT, and PE. We designated the most proximal, or largest thrombosed vessel. As patients with a PE do not routinely undergo Doppler leg ultrasound, we are unable to differentiate PE with a DVT from those without. We also analyzed if the PE was unilateral or bilateral. We used competing risk endpoints for the purpose of this analysis, including recurrent VTE, major bleeding, clinically relevant non-major bleeding leading to discontinuation of Riva, and death. Results: In the Table, we present the data on the relationship of the initial VTE and the risk of recurrence. The majority of CAT events (55%) were PE. There were no significant differences in the rates of recurrent VTE between patients with a PE, a distal DVT or proximal DVT. Within patients with a PE as the index VTE event, there was no significant association between the risk of recurrent VTE and the size of the PE. A subsegmental PE as an index event was associated with a comparable rate of recurrent VTE when compared with segmental and more proximal vessel involvement. The only meaningful trend towards a higher rate of recurrent VTE was in patients whose index event was a bilateral PE, compared with unilateral, although this association did not reach statistical significance. Conclusions: The goal of this Quality Assessment initiative was to evaluate the risk of recurrent VTE in cancer patients to determine if distal DVT's or subsegmental PEs had a significantly lower rate of recurrence than other VTE episodes. Our analysis indicated that the risk of recurrent VTE is not related to the size of the index thrombosed vessel. Within PE, from large, proximal index events through to subsegmental PE, the risk of recurrent VTE is comparable. Similarly, there was only a trend towards lower risk of recurrent VTE in patients with an index distal DVT, versus proximal DVT. But this association was not statistically significant, with overlapping 95% confidence intervals. The one parameter that appeared to have the strongest prediction of recurrent VTE was patients with bilateral PE, versus unilateral. However, this too was only a trend, not statistically significant, and was not one of the parameters within our initial hypotheses. We were unable to identify any subgroup of index VTE, based on vessels involved, that had a significantly lower rate of recurrent VTE while on anticoagulation. Within cancer patients, a subsegmental PE or a distal, calf vein DVT are associated with a risk of recurrent VTE comparable to thrombosis of larger vessels. Table Table. Disclosures Soff: Janssen: Research Funding; Amgen: Research Funding. Mantha:Janssen: Research Funding; GLG: Consultancy; Heidell, Pittoni, Murphy & Bach, LLP: Consultancy.
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- 2018
276. Dysgeusia Is Associated with Higher Melphalan Pharmacokinetic Levels and Results in Poorer Caloric Intake and Worse Symptom Burden after Autologous Stem Cell Transplantation for Multiple Myeloma
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Natasia Rodriguez, Jonathan U. Peled, David J. Chung, Gunjan L. Shah, Marissa L. Buchan, Brooke Mastrogiacomo, Michael Scordo, Sergio Giralt, Elaina V. Preston, Andrew Lin, Dean Carlow, Andrea Knezevic, Molly Maloy, Ryan Schofield, Heather Landau, and Sean M. Devlin
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Melphalan ,medicine.medical_specialty ,Quinine ,Calorie ,business.industry ,Sodium ,Immunology ,chemistry.chemical_element ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Gastroenterology ,Dysgeusia ,Autologous stem-cell transplantation ,chemistry ,Pharmacokinetics ,Internal medicine ,Medicine ,medicine.symptom ,business ,Multiple myeloma ,medicine.drug - Abstract
Background: Taste disturbance, or dysgeusia, negatively affects quality of life and may lead to poorer nutritional status after high-dose melphalan and autologous stem cell transplantation (mel-AHCT) for patients with multiple myeloma (MM). Despite its frequency, dysgeusia has received limited prospective study. Here, we report the interim results of an on-going prospective clinical trial aimed at evaluating the feasibility of performing chemical gustometry, and quantifying the effects of dysgeusia on patient-reported symptom burden and nutritional status in MM patients undergoing mel-ASCT. We also sought to identify novel associations between mel serum and salivary pharmacokinetic (PK) levels and dysgeusia. Methods: For this study, chemical gustometry was considered feasible for use as an endpoint in a future clinical trial if > 60% of the patients could complete > 60% of the evaluations. Chemical gustometry was performed according to the Henkin method (Henkin et al., Am J Otolaryngol 2013) at baseline (pre-AHCT) and on days -1, +7, +14, and +30 to test the 5 basic flavors: sweet (sucrose), sour (citric acid), salty (sodium chloride), bitter (quinine), and umami (monosodium glutamate). These data were used to calculate a total gustometry score (maximum value of 30). At the above time-points as well as day +3 and +10, caloric intake (kcal) was calculated using the USDA 5-Step Multiple-Pass Approach with 24-hour recall, and patient-reported symptom burden was assessed using the MD Anderson Symptom Inventory-Myeloma Module (MDASI-MM). Serum PK levels were drawn at 6 times points after mel infusion to calculate an area under the curve (AUC). Spearman rank-sum correlation was calculated for serum mel AUC and its association with total gustometry scores, caloric intake, and MDASI scores over time using a scaled 30-day AUC. A peak salivary mel level was measured at 75 minutes after infusion, and correlated with total gustometry scores, caloric intake, and MDASI scores. Results: To date, 22 patients with MM undergoing mel-AHCT have been enrolled and have follow-up data through day +30. Eighteen patients (82%) completed > 60% of all assessments. Median age was 62 (41-75), and 11 (50%) were female. Nineteen (86%) patients received mel 200 mg/m2 and 3 (14%) received mel 140 mg/m2. Median serum mel AUC was 12.6 mg*h/L (range 5.8-17.5), and median salivary mel was 119 ng/ml (range 25-662). Higher serum mel AUC correlated with higher salivary mel levels [Spearman correlation 0.59, p=0.004] as shown in Figure 1. Higher serum mel AUC was associated with poorer caloric intake from pre-ASCT to day +30 [Spearman correlation -0.45, p=0.04] as shown in Figure 2. Higher serum melphalan AUC was also associated with higher total MDASI scores (worse symptom burden) from pre-ASCT to day +30 [Spearman correlation 0.57, p=0.005], but was not significantly associated with total gustometry scores. A higher peak salivary mel level was associated poorer caloric intake from pre-ASCT to day +30 [Spearman correlation -0.49, p=0.02]. Among all patients, MDASI scores appeared highest on day +10, and total gustometry scores and caloric intake appeared lowest on days +7 and +10, respectively. At days +7, +14, and +30, 9 of 16 patients (56%), 8 of 17 patients (47%), and 9 of 19 (47%) had a drop of at least 1 point in gustometry score compared to baseline, respectively. Overall, gustometry scores appeared to improve by day +30, but often did not return to baseline (Figure 3A-C). Conclusion: Chemical gustometry is feasible and comprehensively evaluates changes in taste function in MM patients after AHCT. The lowest gustometry scores were apparent on day +7 and often did not return to baseline by day +30, confirming the persistence of dysgeusia after AHCT. Moreover, higher serum and salivary mel levels are associated with poorer caloric intake and higher symptom burden scores within the first 30 days after AHCT. Preventing mel overexposure by targeted mel PK dosing may reduce dysgeusia, improve caloric intake, and limit symptom burden in MM patients after AHCT. Disclosures Shah: Janssen: Research Funding; Amgen: Research Funding. Peled:Seres Therapeutics: Research Funding.
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- 2018
277. Double-Unit Cord Blood (CB) Transplantation with Haplo-Identical CD34+ Cells (haplo-dCBT) May Speed Neutrophil Recovery Although Successful Bridging Is Contingent on Close Haplo-Winning CB Unit HLA-Match
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Doris M. Ponce, Roni Tamari, Katharine C. Hsu, Ann A. Jakubowski, Andromachi Scaradavou, Juliet N. Barker, Hugo Castro-Malaspina, Kristine Naputo, Aishat Afuye, Esperanza B. Papadopoulos, Valkal Bhatt, Brian C. Shaffer, Boglarka Gyurkocza, Sergio Giralt, Parastoo B. Dahi, Christina Cho, Ioannis Politikos, Sean M. Devlin, Miguel-Angel Perales, Marcel R.M. van den Brink, James W. Young, Gunjan L. Shah, Craig S. Sauter, Molly Maloy, Michael Scordo, Richard J. O'Reilly, Scott T. Avecilla, and Christopher Mazis
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0301 basic medicine ,Cd34 cells ,Immunology ,Cell Biology ,Hematology ,Human leukocyte antigen ,Hematologic Neoplasms ,Haplo identical ,Biology ,Neutrophil recovery ,medicine.disease ,Biochemistry ,Transplantation ,03 medical and health sciences ,030104 developmental biology ,Cord blood ,medicine ,Aplastic anemia - Abstract
Background : While dCBT is associated with high rates of sustained donor engraftment, delayed neutrophil recovery in adults is frequent and can contribute to extended hospitalization and early transplant-related mortality. Methods : We investigated engraftment after myeloablative dCBT supplemented with CD34+ selected haploidentical PBSC (haploCD34+) in patients (pts) with high risk hematologic malignancies or aplastic anemia in a phase II clinical trial. The aim was to abrogate neutropenia (ANC >/= 500 within 14 days) with a haplo myeloid bridge prior to CB engraftment. Pts did not receive ATG due to the increased mortality risk reported in adult CBT. Double unit CB grafts allowed comparison to dCBT controls without haploidentical graft supplementation. Results : 78 adult pts [median age 48.5 years (range 21-68), median weight 82 kgs (range 48-138), 44 (56%) CMV+, 3 with prior allografts] underwent haplo-dCBT between 9/2012-12/2017. Diagnoses included 54 (69%) acute leukemias, 10 (13%) MDS/ MPN (all ≤ 10% blasts at work-up), 10 (17%) NHL/ HD and 1 aplastic anemia. Conditioning was myeloablative (1 Cy 120/ Flu 75/ TBI 1375, 77 intermediate intensity Cy 50/ Flu 150/ Thio 5-10/ TBI 400) with CSA/ MMF. CB units had a median infused TNC of 2.3 (range 1-5.7) x 107/kg/unit & median infused viable CD34+ cell dose of 1.1 (range 0.1-3.1) x 105/kg/unit with a median 5/8 (range 2-7) unit-recipient HLA-allele match. Haplo CD34+ grafts [procured from children (46%), siblings (31%), parents (13%) or extended family (10%)] had a median infused CD34+ dose of 5.2 x 106/kg (range 1.1-16.8) and a median infused CD3+ dose of 1.6 x 103/kg (range 0.3-13.7). Sixty-one (78%) haplos were 4/8 and 17 (22%) were 5-7/8 HLA-matched to the pt. In 77 evaluable pts (1 pt died on day 14), 4 engraftment patterns were observed (Table 1). All but 2 pts had sustained CB engraftment with either an optimal haplo-bridge (Gp. 1, 34/77, 44%), a transient bridge with a second nadir preceding CB engraftment (Gp. 2, 20/77, 26%), or no bridge (Gp. 3, 21/77, 27%). The 2 remaining pts had CB/ haplo graft failure (Gp. 4, 2/77, 3%); both were successfully re-transplanted with single CB units. While there was no difference in the day 100 TRM in the 34 optimal bridge pts vs pts with transient or no bridge [9% (95%CI 2-21) vs 15% (95%CI 6-27), p = 0.388], optimal bridge pts had faster platelet recovery [19 (range 14-41) vs 44.5 days (range 14-67)] and earlier hospital discharge [28.5 (range 20-60) vs 36 days (range 28-98)]. Similar to dCBT alone, chimerism analysis revealed sustained engraftment in haplo-dCBT is mediated by a "winning" CB unit. This was heralded by winning unit-derived T-cells seen as early as day +28. Although universal, the speed of haplo rejection varied, and a high haplo chimerism percentage early post-transplant did not guarantee successful bridging. Analysis of factors potentially predicting an optimal bridge is shown in Table 2. The median winning CB unit-haplo 8-allele HLA-match was 3/8 (range 1-7/8). In univariate analysis, higher haplo CD34+ dose/kg, > 4/8 haplo-recipient HLA-match and ≥ 3/8 winning unit-haplo HLA-match were associated with a higher likelihood of bridging. Haplo CD34+ dose and winning unit-haplo HLA-match remained significant in multivariate analysis. Conclusions: While haplo-dCBT can be associated with enhanced neutrophil recovery, this platform does not guarantee a successful myeloid bridge due to early haplo rejection by the winning CB unit. This universal haplo rejection highlights the importance of the CB graft dose and quality with this ATG-free strategy as the CB will mediate sustained engraftment. Our findings have significance for strategies that combine unmanipulated CB with any third-party or ex vivo expanded T-cell depleted product given higher product CD34+ cell dose and better HLA-match to the unmanipulated CB unit could improve the likelihood of successful myeloid bridging. The data also support alternative approaches to improve myeloid recovery after CBT such as optimized unit selection and vivo expansion. Disclosures O'Reilly: Atara Biotherapeutics: Consultancy, Patents & Royalties, Research Funding. Perales:Takeda: Other: Personal fees; Novartis: Other: Personal fees; Incyte: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees and Clinical trial support; Merck: Other: Personal fees; Abbvie: Other: Personal fees. Sauter:Juno Therapeutics: Consultancy, Research Funding; Sanofi-Genzyme: Consultancy, Research Funding; Spectrum Pharmaceuticals: Consultancy; Novartis: Consultancy; Precision Biosciences: Consultancy; Kite: Consultancy. Shah:Janssen: Research Funding; Amgen: Research Funding.
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- 2018
278. MRD-Response Driven Phase I/II Study for Newly Diagnosed Multiple Myeloma Patients Using Higher Doses of Twice-Weekly Carfilzomib (45 and 56 mg/m2) in Combination with Lenalidomide and Dexamethasone
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Caleb Ho, Heather Landau, Allison Sams, Sean M. Devlin, Elizabet Tavitian, Maria E. Arcila, David J. Chung, Ola Landgren, Ahmet Dogan, Hani Hassoun, Eric L. Smith, Sham Mailankody, Donna Mastey, Oscar B Lahoud, Neha Korde, Mikhail Roshal, Sergio Giralt, Meghan Salcedo, Victoria Diab, Alexander M. Lesokhin, Michael Scordo, Nikoletta Lendvai, and Malin Hultcrantz
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medicine.medical_specialty ,business.industry ,Immunology ,Phases of clinical research ,Cell Biology ,Hematology ,Neutropenia ,medicine.disease ,Biochemistry ,Carfilzomib ,Minimal residual disease ,Clinical trial ,Transplantation ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,chemistry ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,Clinical endpoint ,business ,030215 immunology ,Lenalidomide ,medicine.drug - Abstract
Introduction Newly diagnosed multiple myeloma (NDMM) patients who achieve and maintain minimal residual disease (MRD) negativity demonstrate clinical benefit with prolonged progression-free survival and overall survival. Based on available data showing MRD negativity with standard dose KRD (36 mg/m2) approximating 40% (Korde JamaOnc 2015), we designed a MRD response-adapted treatment study for NDMM, where the number of treatment cycles is determined based on MRD status, instead of the traditional paradigm of fixed number of cycles followed by autologous hematopoietic cell transplantation (AHCT). We integrated a flow-based MRD driven platform in this phase I/II study evaluating higher doses of twice-weekly carfilzomib (Car) (45 and 56 mg/m2) in combination with lenalidomide (Len) and dexamethasone (Dex). Methods Eligible NDMM patients were given escalating doses of Car (45 and 56 mg/m2), Len, and Dex in a single arm, phase I standard 3+3 schema design, based on dose-limiting toxicities (DLTs) occurring in cycle 1. Treatment consisted of 28-day cycles with Car 20/45 mg/m2 or 20/56 mg/m2 - days 1, 2, 8, 9 15 and 16; Len 25 mg - days 1-21; and Dex 40 mg weekly cycles 1-4, 20 mg after cycle 4. AHCT eligible patients underwent stem cell collection after 6 cycles, and then continue with protocol therapy. Patients achieving MRD negative status (serum, urine, and bone marrow with 10-color flow) received 2 additional cycles from the time of conversion and then stop therapy. Patients with less than an MRD negative response after any cycle continued therapy until treatment completion (max 12 cycles), disease progression, or unacceptable toxicity. The primary endpoint of the phase II study was to determine the MRD negative rate at the MTD dose, using a Simon's optimal two-stage design. Herein, we have updated results on phase I and phase II portions of the study with a median follow-up of 20.7 months (1.4-31.1). For available data, we present MFC and NGS MRD platforms. Results Twenty-nine patients have enrolled onto study between October 2016 - June 2018, with 18 in phase 1 and stage I of phase II and 11 in stage II of phase II, thus completing target accrual. There were 16 males, 13 females, median age 61 (43-75) years. Baseline characteristics included 18(62%) ISS-I, 9(31%) ISS-II, and 2(7%) ISS-III, and 7(24%) patients high risk FISH (t(4,14), t(14,16), p53 deletion). There were no DLTs within the first cycle that met protocol criteria (0/3 patients in 20/45 mg/m2 cohort and 0/6 patients in 20/56 mg/m2). The MTD chosen was 20/56 mg/m2, and an additional 20 patients were enrolled. Three patients came off study (56 mg/m2 cohort): one due to MI (during C2); one due to intolerable rash (during C2); and one due to personal preference (during C2). Among all 29 patients, grade 3/4 non-hematologic toxicities included 6(21%) rash, 5(17%) electrolyte disturbances, 4(14%) infections, 3(10%) GI, 2(7%) cardiopulmonary, 2(7%) VTE, 2(7%) mood, 2(7%) cataract, and 1(3%) hyperglycemia, and grade 3/4 hematologic toxicities included 12(41%) lymphopenia, 2(7%) leukopenia, 1(3%) neutropenia, and 1(3%) thrombocytopenia. Ten patients had 13 SAEs. For the 15 patients completing protocol therapy, a median number of 11 (7-12) cycles were delivered, and best responses include 9(60%) sCR/CR MRD neg and 6(40%) obtaining VGPR. Among patients reaching sCR/CR MRD neg status, the median time to reach was 8 (5-9) cycles. Among the eleven patients currently remaining on study, 7 have received at least 1 cycle of therapy (response eligible) and best responses thus far, included 1(14%) sCR/CR MRD pending, 4(57%) VGPR, and 2(29%) PR with a median number of 4 (1-8) cycles delivered. Table comparison of MRD platforms shown in sCR/CR patients. Among patients that remain on study, median 20.7 months, no patients have progressed and all remain alive. One patient that came off study due to personal preference during cycle 2 achieved a PR, and has progressed since. Conclusion In this phase I/II clinical trial assessing higher doses of twice-weekly Car dosing in combination with Len and Dex, we established MTD 56 mg/m2 and demonstrated a MRD platform using multi-parametric flow cytometry can be successfully used to tailor individualized treatment plans. Higher doses of twice weekly Car (45 and 56 mg/m2) in combination with Len and Dex, resulted in rapid and deep responses with approximately 60% MRD negative rate, and a safety profile similar to KRD standard dose (Car 36 mg/m2). Table. Table. Disclosures Korde: Amgen: Research Funding. Mailankody:Janssen: Research Funding; Physician Education Resource: Honoraria; Takeda: Research Funding; Juno: Research Funding. Hassoun:Oncopeptides AB: Research Funding. Lesokhin:Janssen: Research Funding; Squibb: Consultancy, Honoraria; Genentech: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Serametrix, inc.: Patents & Royalties: Royalties; Takeda: Consultancy, Honoraria. Smith:Celgene: Consultancy, Patents & Royalties: CAR T cell therapies for MM, Research Funding. Arcila:Invivoscribe, Inc.: Consultancy, Honoraria. Ho:Invivoscribe, Inc.: Honoraria. Landgren:Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding; Karyopharm: Consultancy; Pfizer: Consultancy.
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- 2018
279. Molecular Predictors and Current Management of Minimal Residual Disease (MRD) Following Induction Chemotherapy for Acute Myeloid Leukemia (AML)
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Justin Taylor, Martin S. Tallman, Andrew Dunbar, Ross L. Levine, Elli Papaemmanuil, Maria E. Arcila, Kamal Menghrajani, Miguel-Angel Perales, Esperanza B. Papadopoulos, Sean M. Devlin, Sergio Giralt, Erin McGovern, Christopher Famulare, Bartlomiej Getta, Mikhail Roshal, Jacob L. Glass, Noushin Farnoud, Aaron D. Viny, Jessica Schulman, Brian C. Shaffer, Boglarka Gyurkocza, Aaron D Goldberg, Minal Patel, Sheng Cai, Yanming Zhang, and Zachary D. Epstein-Peterson
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Oncology ,medicine.medical_specialty ,Anthracycline ,business.industry ,Immunology ,Induction chemotherapy ,Cancer ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Minimal residual disease ,body regions ,Clinical trial ,Transplantation ,medicine.anatomical_structure ,hemic and lymphatic diseases ,Internal medicine ,Cytarabine ,medicine ,Bone marrow ,business ,medicine.drug - Abstract
Background: MRD is a powerful prognostic factor in AML. Emerging data indicate that allogeneic stem cell transplant (alloSCT) with MRD results in outcomes equivalently poor to alloSCT with morphologic AML (Araki et al., JCO 2016). Genomic predictors of MRD are unclear, and relative efficacy of therapies for MRD remains elusive. Objectives: Here we provide an integrated analysis of responses for 163 patients (pts) who underwent induction chemotherapy with baseline next-generation sequencing (NGS) followed by serial immunophenotypic monitoring for MRD. Methods:163 patients starting in April 2014 who underwent induction chemotherapy at Memorial Sloan Kettering Cancer Center were retrospectively studied. All received anthracycline + cytarabine, with or without investigational agents. Immunophenotypic MRD was identified in bone marrow aspirates (BMA) by multiparameter flow cytometry. Any level of residual disease was considered MRD+. Molecular analysis was obtained from pre-induction BMA by NGS using 28 or 49 gene panels. Cytogenetics/FISH were performed using standard techniques. Results: Patient characteristics are in Table 1. 7/163 (4.9%) died within 30 days of induction.153 pts had BM biopsy after induction prior to further therapy. 124/153 underwent flow after induction. 65/124 (52.4%) achieved CR/CRi after induction alone, 31/124 (25%) MRD+CR/CRi, and 34/124 (27.4%) MRD-CR/CRi. Pre-induction molecular analysis from 126 suggests that certain cytogenetic and molecular abnormalities correlate with achievement of MRD-CR. (Figure 1) Only 2/25 (8%) with RUNX1, 0/13 with SF3B1, and 0/11 with TP53 mutations achieved MRD-CR/CRi as best response after 1 cycle of induction. Only 3 additional RUNX1, 2 SF3B1, and 0/11 TP53 achieved MRD-CR/CRi as best response after a second cycle of therapy. In contrast, 7/8 with CBF AML (inv16 and no KIT mutation, n=4) or (t(8;21), n=3) achieved MRD-CR/CRi (n=5) or CR without flow (n=2) after 1 cycle of induction. 91/163 (55.8%) underwent alloSCT following induction or additional therapy. Post-alloSCT follow-up indicates potential value in converting MRD+ to MRD-. 84/91 were evaluable for MRD with flow cytometry prior to alloSCT. 41/84 (48.8%) were MRD-, 30/84 (35.7%) MRD+, and 13/84 (15.4%) persistent AML. 13/41 (31.7%) MRD-pre-alloSCT were MRD- post-induction. 28/41 (68.2%) MRD+ or persistent AML converted to MRD- prior to alloSCT following additional therapy. 23/29 MRD+CR/CRi pts after induction were intermediate/unfavorable and therefore transplant candidates. 19/23 MRD+CR/CRi intermediate/unfavorable underwent transplant (9 without post-induction therapy, 10 after consolidation), while 4 did not proceed to transplant due to relapse after induction (n=1), relapse after consolidation (n=2), and patient preference. There was no significant difference in post-transplant OS between early MRD-CR immediately following induction and later conversion to MRD-CR prior to alloSCT (Figure 1B). Post-transplant analysis reveals that most pts who enter transplant with persistent AML (n=13) or MRD+ (n=30) clear MRD (30/43, 69.7%) by the first post-transplant BM (median 32 days, Figure 1C). Despite initial post-transplant MRD clearance, pts who entered alloSCT with persistent AML or MRD+ had poorer post-transplant OS compared to pts who entered alloSCT with MRD- (p=0.02, Figure 1D). Conclusion: Our data show that AML pts with specific molecular mutations (RUNX1, SF3B1, and TP53) are unlikely to achieve MRD-CR/CRi after induction chemotherapy. We further show that additional therapy such as consolidation may be advantageous for some MRD+ pts to achieve MRD-CR prior to alloSCT, although others remain resistant to MRD clearance. Post-transplant OS is improved in pts who are MRD- at time of transplant, regardless of whether they required additional therapy beyond induction to achieve this state. Our results suggest that development of MRD-eradicating therapies after AML induction has the potential to improve post-transplant outcomes. Disclosures Goldberg: AROG: Research Funding; Pfizer: Research Funding; Celgene: Consultancy. Arcila:Invivoscribe, Inc.: Consultancy, Honoraria. Perales:Takeda: Other: Personal fees; Merck: Other: Personal fees; Abbvie: Other: Personal fees; Incyte: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees and Clinical trial support; Novartis: Other: Personal fees. Tallman:ADC Therapeutics: Research Funding; Daiichi-Sankyo: Other: Advisory board; Orsenix: Other: Advisory board; Cellerant: Research Funding; BioSight: Other: Advisory board; AROG: Research Funding; AbbVie: Research Funding.
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- 2018
280. Depth of Response and Outcomes in Patients with Multiple Myeloma Undergoing Autologous Stem Cell Transplantation
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Gunjan L. Shah, Sham Mailankody, Kenneth Seier, Malin Hultcrantz, Heather Landau, Neha Korde, Michael Scordo, Sean M. Devlin, David J. Chung, Nikoletta Lendvai, Sergio Giralt, Eric L. Smith, Ola Landgren, and Alexander M. Lesokhin
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education.field_of_study ,medicine.medical_specialty ,business.industry ,Immunology ,Population ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Minimal residual disease ,Transplantation ,03 medical and health sciences ,0302 clinical medicine ,Autologous stem-cell transplantation ,Maintenance therapy ,030220 oncology & carcinogenesis ,Internal medicine ,Medicine ,business ,education ,Multiple myeloma ,Progressive disease ,030215 immunology ,Lenalidomide ,medicine.drug - Abstract
Background: For multiple myeloma (MM) patients, depth of response after induction therapy and after autologous hematopoietic stem cell transplantation (AHCT) has been shown to be important for progression free (PFS) and overall survival (OS) in some studies. Furthermore, the impact of minimal residual disease (MRD) on outcomes and treatment decisions has been widely discussed. We aimed to evaluate outcomes by depth of response after induction and AHCT. Methods: MM patients who received their first AHCT within 1 year of starting induction were identified from the institutional registry. MRD was assessed by non-10 color flow cytometry. Response was defined by the International Myeloma Working Group criteria. Summary statistics were used to describe the population. Kaplan-Meier methodology estimated PFS and OS by response status pre-AHCT and at post-AHCT restaging. Results: Between 2012 - 2014, 182 MM patients met our inclusion criteria, with 83% alive at last follow-up. The median age at AHCT was 60 years (range 29-76) with 57% male. By the International Staging System (ISS), 50% were stage I, 26% stage II, and 24% stage III. High risk cytogenetics were detected in 24%. Isotype was IgG in 55%, IgA 21%, Kappa Free Light Chain (KFLC) 11%, and lambda FLC (LFCL) 9%. First induction therapy included bortezomib in 90% and lenalidomide in 79%. Median time to AHCT was 5.5 months (range 2.8-11.7). The median follow-up from AHCT was 3.7 years (range 0.22 - 4.6 years), with 84% of patients receiving lenalidomide maintenance, and 9% receiving an additional autologous or allogenic transplant at relapse. Response prior to the initial AHCT was a complete remission (CR) in 13.7% (MRD negative 6.6%, positive 4.4%, unknown 2.7%), very good partial remission (VGPR) 38%, partial remission (PR) 40%, stable disease (SD) 5%, and progressive disease (PD) 4%. At post-AHCT restaging, responses had improved to 42% CR (MRD negative 23%, positive 6%, unknown 13%), 35% VGPR, 19% PR, 2% SD, and 3% PD. Median PFS from AHCT for the entire cohort was 3.2 years (95% CI 2.4 - 4 years) with 1-year and 3-year PFS 85% and 52%, respectively. Median OS was not reached (NR) (95% CI 4.4 years - NR) with 1-year and 3-year OS 97% and 88%, respectively (Figure 1). PFS from AHCT was significantly longer in patients with an MRD negative CR prior to AHCT with median PFS not reached (95% CI 1.7 - NR) compared to MRD positive/unknown CR, VGPR, and ≤ PR [3.64 years (95% CI 1.09-3.64), 3.46 years (95% CI 2.4 - NR), and 2.44 years (1.68-3.56 years), respectively, p=0.048] (Figure 2A). From post-AHCT restaging, PFS was also significantly longer in patients with an MRD negative CR prior to AHCT with median PFS not reached compared to MRD positive/unknown CR, VGPR, and ≤ PR [3.49 years (95% CI 0.86-3.49), 3.56 years (95% CI 2.5 - NR), and 2.4 years (1.6-3.33 years), respectively, p=0.026] (Figure 2B). However, there was no difference in PFS based on the post-AHCT restaging with median PFS in MRD negative CR, MRD positive/unknown CR, VGPR, and ≤ PR of 3.49 years (95% CI 2-NR), not reached (95% CI 1.4-NR), 2.96 years (95% CI 1.7-NR), and 2.86 years (95% CI 1.7 - NR) (p=0.78, Figure 2C), respectively. OS from AHCT was not significantly different by pre-AHCT response, and the median was not reached in any group (p=0.33, Figure 3A). Finally, the median OS from post-AHCT restaging by pre-AHCT response or by post-AHCT response was also not reached in any group (p=0.32 and 0.31, respectively; Figure 3B & C). Conclusion: For MM patients, AHCT deepened responses and increased the CR rate. We were unable to show a significant difference in outcomes at post AHCT restaging, which may be due to the effect of maintenance therapy, the small numbers of MRD negative patients, or the sensitivity of the MRD assay available during this time period, though potentially show that MRD positive patients do as well as MRD negative patients after AHCT. We plan to add additional patients treated in the more recent years who were assessed by more sensitive methods. Disclosures Shah: Janssen: Research Funding; Amgen: Research Funding. Korde:Amgen: Research Funding. Lesokhin:Janssen: Research Funding; Genentech: Research Funding; Takeda: Consultancy, Honoraria; Serametrix, inc.: Patents & Royalties: Royalties; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Squibb: Consultancy, Honoraria. Mailankody:Janssen: Research Funding; Physician Education Resource: Honoraria; Takeda: Research Funding; Juno: Research Funding. Smith:Celgene: Consultancy, Patents & Royalties: CAR T cell therapies for MM, Research Funding. Landgren:Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy; Merck: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding.
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- 2018
281. Treatment Outcomes in Monoclonal Immunoglobulin Deposition Disease (MIDD): A Two Center Experience
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Sham Mailankody, Timothy Tiutan, Nikoletta Lendvai, Eric L. Smith, David J. Chung, Malin Hultcrantz, Ola Landgren, Alexander M. Lesokhin, Jessica Flynn, Sergio Giralt, Insara Jaffer-Sathick, Steven P. Salvatore, Neha Korde, Adriana C Rossi, Hani Hassoun, Matthew J. Pianko, Heather Landau, and Sean M. Devlin
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Oncology ,medicine.medical_specialty ,Free Immunoglobulin Light Chain ,biology ,Myeloma protein ,business.industry ,Immunology ,Plasmacytosis ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Immunoglobulin kappa-Chains ,Internal medicine ,medicine ,biology.protein ,Antibody ,business ,Nephrotic syndrome ,Multiple myeloma ,Monoclonal Immunoglobulin Deposition Disease - Abstract
Background: Monoclonal immunoglobulin deposition disease (MIDD) is a rare complication of plasma cell dyscrasias in which deposition of immunoglobulin light and/or heavy chains results in organ dysfunction, most commonly affecting the kidneys. MIDD can present with new onset hypertension, hematuria, renal insufficiency and proteinuria. The rarity of MIDD contributes to the uncertainty regarding optimal therapy (typically targeting the clonal plasma cells), and the relationship between hematologic response and renal outcome. We report here the experience at Memorial Sloan Kettering Cancer Center and New York Presbyterian Hospital/Weill Cornell Medical Center. Methods: An electronic query of pathology records was performed to identify patients with a biopsy-proven diagnosis of MIDD. Patients were eligible for inclusion in this analysis if they had received treatment and had been subsequently followed at either institution. A retrospective review of clinical records extracted patients' baseline characteristics and treatment history. Hematologic responses were assessed according to International Myeloma Working Group uniform response criteria (Kumar, S. et al 2016 Lancet Oncol 17(8): e328-346) and renal organ responses were evaluated based on changes in serum creatinine (SCr), and proteinuria, a modification of criteria previously reported (Kourelis, T. V., et al 2016, Am J Hematol 91(11): 1123-1128.; Nasr, S.H. et al. 2009, J Am Soc Nephrol 20(9): 2055-2064. The primary objective was to determine the rate of hematologic response after initial therapy. Secondary objectives included: (i) Estimation of renal response rate; (ii) Identification of risk factors associated with renal response using the Wilcoxon Rank Sum and Fisher's Exact Tests. Results: Among 54 patients identified who were diagnosed and started treatment between 1/1999 and 1/2016, 29 met criteria for inclusion. Baseline characteristics at diagnosis included: Median age of 50 (range, 32-79); 17 (59%) were male; 22 (75%) had hypertension. Renal parameters at diagnosis: median SCr of 2.4 mg/dl (range, 0.4-19), median CrCl 23 ml/min (range, 4-131), median proteinuria 2383.7mg/24h (range 4.7-13,000), nephrotic-range proteinuria syndrome in 13 (45%), hematuria in 4/25 pts (16%; 4 unknown), 7 were on hemodialysis (HD) prior to initiation of therapy, and 26 (90%) patients had monoclonal kappa light chain deposits. Hematologic parameters included median free light chain ratio of 67.9 (2.8-1179.0), detectable M-spike in 11 pts with a mean level of 0.6 g/dL and median bone marrow plasmacytosis of 20% (range, 0-90%). Induction treatment regimens included bortezomib in 18 (62%), lenalidomide in 6 (21%), cyclophosphamide in 8 (28%), and 21 (73%) underwent autologous stem cell transplant (ASCT) during the course of their treatment. Outcomes are shown in Table 1. Hematologic response among the 29 pts at completion of first line therapy included an overall response rate (ORR) of 93% with sCR (N=14, 48%); CR (N=5, 17%), VGPR (N=6, 20%), PR (N=2, 6.9%), Not available (N=2, 7%). Renal response (Table 1) among 29 patients included CR (N=9, 31%), PR (N=14, 48%) and End Stage Renal Disease (ESRD) (N=6, 21%). Among 7 patients on HD at baseline, 3 remained on HD despite treatment, while 4 stopped HD after treatment, 2 as a result of the treatment and 2 after renal transplant. 3 patients progressed to ESRD and required HD during treatment. Baseline beta-2 microglobulin (B2M), SCr, and eGFR at diagnosis were factors associated with renal response (p Conclusions: In this cohort, we observed a high rate of hematologic response (65.5% reaching CR) to upfront treatment regimens. A majority of patients received bortezomib-based regimens and ASCT. We observed a large proportion of patients whose renal impairment from MIDD improved significantly after receiving therapy directed at the underlying clonal neoplasm, with 75.8% reaching PR or better, nearly a third of patients achieving a renal CR, and 2/7 patients on HD at diagnosis discontinuing HD after treatment. Our experience presented here serves to inform the treatment approach of patients with MIDD. Given the scarcity of outcome data in MIDD, especially in the era of novel anti-myeloma therapy, prospective studies to optimize the management of these patients are needed. Disclosures Rossi: Celgene: Consultancy. Smith:Celgene: Consultancy, Patents & Royalties: CAR T cell therapies for MM, Research Funding. Korde:Amgen: Research Funding. Mailankody:Janssen: Research Funding; Juno: Research Funding; Physician Education Resource: Honoraria; Takeda: Research Funding. Lesokhin:Squibb: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Genentech: Research Funding; Janssen: Research Funding; Serametrix, inc.: Patents & Royalties: Royalties. Landgren:Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Consultancy; Merck: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy; Celgene: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Hassoun:Oncopeptides AB: Research Funding.
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- 2018
282. Evaluation of Cord Blood (CB) Unit TNC & CD34+ Cell Content & Donor-Recipient High-Resolution 8 HLA-Allele Match By Patient Ancestry: An Evaluation of 513 CB Units in a Racially & Ethnically Diverse Population of Adults with Hematologic Malignancies
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Christopher Mazis, Melissa Nhaissi, Andromachi Scaradavou, Ioannis Politikos, Gunjan L. Shah, Beth Suri, Sean M. Devlin, Nancy A. Kernan, Eric Davis, Candice Cooper, Marcel R.M. van den Brink, Deborah Wells, Sergio Giralt, Molly Maloy, and Juliet N. Barker
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education.field_of_study ,business.industry ,Cd34 cells ,Immunology ,Population ,High resolution ,Cell Biology ,Hematology ,Human leukocyte antigen ,Ethnically diverse ,Biochemistry ,Transplantation ,Cord blood ,Medicine ,Allele ,education ,business - Abstract
Introduction: Optimal CB unit selection guidelines recommend consideration of CD34+ cell dose & 8-allele donor-recipient HLA-match. How graft characteristics for these parameters vary by patient (pt) race/ ethnicity, however, is not known. Methods: We analyzed the infused graft & back-up unit cryopreserved total nucleated cell (TNC) x 107 & CD34+ x 105 cell content, the cell dose (incorporating pt weight), & 4-6/6 & 8-allele HLA-match by pt ancestry in CB transplant (CBT) recipients transplanted 1/2014-6/2018. Units were chosen based on banking practices (e.g. RBC depleted, standard cryo volumes), TNC & CD34+ dose & 4-6/6 & 8-allele HLA-match with dose usually taking priority over match given pt size at our center. The analysis included transplanted units (considered the best choice) & the next best high resolution typed back-up units (reserved but not shipped). Pt racial/ ethnic origins were prospectively obtained by detailed family history & grouped as previously described (Barker J. et al. BBMT 2010). Results: The characteristics of 513 units chosen for 136 CBT recipients by pt ancestry are shown (Table 1). Pts had highly diverse origins including 70 (51%) non-Europeans. The 513 units included 270 units infused as the graft (134 doubles & 2 singles) & 243 back-up units (109 pts had 2 back-ups, 25 pts had one & 2 had none). Thus, 4 best units were analyzed in 109 pts (all double unit recipients), 3 best in 25 pts (all doubles), & 1 unit in 2 pts (both singles). The median weight of the 136 pts was 81 kg. Asian pts (median 68 kg) had a lower weight than other groups. The median TNC content of units for the 66 European pts was higher than that for the 70 Non-Europeans (218 vs 196, p = 0.004). Units chosen for Northwestern (NW) Europeans had the highest median TNC content (235) with lower TNC content in units for Southern Europeans (202), Asian (193), African (191) & White Hispanic (189) pts. Units chosen for European pts also had a higher median CD34+ cell content (162) than Non-Europeans (138), p = 0.004. NW Europeans had units with a higher median CD34+ content (198) & the lowest CD34+ content were those for African (124) & Middle Eastern pts (124). When patient weight was considered, median TNC/kg dose per unit was similar in European and Non-European pts (2.7 vs 2.6, p = NS). Units for NW Europeans had the highest median TNC dose (3.0) whereas those for African pts had the lowest TNC dose (2.4). Units for Europeans had a higher median CD34+ dose (2.0) than Non-Europeans (1.7) although this difference was not significant (p = 0.15). Additionally, similar to TNC dose, median CD34+ dose was highest in units for NW European pts (2.2) & lowest in units chosen for African pts (1.5). 89% of chosen units were 4/6 HLA-matched with no differences between Europeans & non-Europeans. Furthermore, the median 8 allele HLA-match was 5/8 (range 2-8/8) with no overall differences between units for Europeans and Non-Europeans (p = NS). When only transplanted units were analyzed (Table 2), the median TNC & CD34+ contents were significantly lower in non-Europeans than Europeans (238 vs 216, p = 0.01 & 184 vs 160, p = 0.016). Overall, however, units received by Europeans vs non-European pts had similar TNC & CD34+ doses (p = NS). However, differences in the CD34+ content combined with differences in pt weights resulted in disparities in CD34+ doses by ancestry sub-group. NW Europeans (high weight, high CD34+ content) received the best CD34+ doses; lower CD34+ content in Asian pts was compensated for by their lower weight. African pts (high weight, low CD34+ content) received the lowest CD34+ doses. The median 8 allele HLA-match for all was 5/8 (range 3-8/8) with the exception of African pts [median 4/8 (range 3-7/8)]. Moreover, while 108 (40%) of transplanted units were 3-4/8 HLA-matched overall, there were marked differences between pt sub-groups with only 23% of units for NW Europeans being 3-4/8 vs 42% for southern Europeans, 46% for white Hispanics & 53% for Africans. Conclusions: While CB significantly extends transplant access to racial & ethnic minorities, differences in cellular content translates to many minority pts receiving lower dosed units. There are also marked racial/ ethnic differences in HLA-match grade with African pts the most likely to receive highly mismatched units. This data supports ongoing funding of public CB banks to further increase the inventory of high dosed & better matched units for all but especially racial & ethnic minority pts. Disclosures Shah: Janssen: Research Funding; Amgen: Research Funding. Kernan:National Cancer Institute: Research Funding.
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- 2018
283. Rash in Patients after T-Cell-Depleted Peripheral Blood Stem Cell Transplantation: Eosinophilia and Pruritus Do Not Distinguish Acute Graft-Versus-Host Disease from Drug Rash
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Margaret Hannum, Sean M. Devlin, Skylar Klager, Ann A. Jakubowski, and Alina Markova
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integumentary system ,medicine.diagnostic_test ,business.industry ,T cell ,medicine.medical_treatment ,Immunology ,Drug allergy ,Complete blood count ,Cell Biology ,Hematology ,Hematopoietic stem cell transplantation ,medicine.disease ,Biochemistry ,Rash ,surgical procedures, operative ,Clinical research ,Graft-versus-host disease ,medicine.anatomical_structure ,immune system diseases ,hemic and lymphatic diseases ,medicine ,Eosinophilia ,medicine.symptom ,business - Abstract
Background: The incidence and severity of acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (alloHSCT) is decreased with T-cell depletion. However, ~14% of these T-cell depleted (TCD) recipients will have aGVHD with skin involvement (Barba et al. 2017). Furthermore, alloHSCT recipients are at increased risk for drug eruptions and infectious exanthems (Byun et al. 2011). While histopathologic differences have been reported between aGVHD and non-aGVHD rash in TCD recipients (Fischer et al. 2015), skin biopsies alone are insufficient to determine rash etiology. As such, distinguishing inflammatory non-aGVHD rashes from aGVHD of the skin after TCD HSCT remains challenging and relies on clinical presentation. While peripheral eosinophilia is seen in both aGVHD and drug hypersensitivity, rashes that present with concomitant eosinophilia after HSCT are often suspected to have a drug-induced etiology. We sought to assess the incidence and features of aGVHD and non-aGVHD rashes within 1 year after TCD alloHSCT, as well as common etiologies of non-aGVHD rash. These findings may guide clinicians in earlier diagnosis and management of non-aGVHD rash. Methods: Using a clinical research database, 243 adult patients were identified who received alloTCD peripheral blood stem cell transplantation (PBSCT) at a single institution between 2008 and 2011. All patients had CD34+ hematopoietic progenitor cells selected using: the Isolex 300i Magnetic Cell, followed by additional T-cell rosetting with neuraminidase-treated sheep erythrocytes or using the CliniMACS CD34+ Reagent System (Table 1). Given decreased incidence of aGVHD with Isolex versus CliniMACS (Barba et al. 2017), we established Isolex and CliniMACS TCD groups and assessed aGVHD and non-aGVHD rash within these two CD34+ selection modalities. To identify non-aGVHD patients with skin rash, charts were reviewed from date of HSCT through 1 year post HSCT by review of dermatology visit notes or by extraction of International Classification of Diseases-9 (ICD-9) codes for skin lesion or rash (Table 2); skin infections and chronic GVHD rashes were excluded. Acute GVHD was diagnosed with histological confirmation when clinically indicated. Rash characteristics, including pruritus and peripheral eosinophilia at onset of rash, were collected from charts of both non-aGVHD and aGVHD rash patients. Results: Among 243 TCD PBSCT transplant recipients, 152 patients (63%) were identified with skin rash within 1 year after HSCT. Of these patients, 43 had aGVHD rash and 109 had non-aGVHD rash. The majority of aGVHD rashes had skin stage III aGVHD regardless of CD34+ selection method (Table 3). For patients with non-aGVHD rash, etiologies included inflammatory conditions (Table 4). TCD by Isolex led to non-aGVHD rash development at a median onset of 60 days and aGVHD rash at a median onset of 71 days; while TCD by CliniMACS led to non-aGVHD rash development at a median onset of 56.5 days and aGVHD rash at a median onset of 75 days. Of patients who had recorded complete blood counts at onset of rash, elevated percent eosinophilia (% eosinophils >7%) was present in 10% of Isolex and 5% of CliniMACS non-aGVHD rashes versus 3% of Isolex and 4% of CliniMACS aGVHD rashes. Peripheral eosinophilia was not associated with aGVHD versus non-aGVHD skin rash post TCD HSCT (p≥0.99) nor when separated by CD34+ selection method (Isolex p=0.673; CliniMACS p≥0.99). While non-aGVHD skin rash patients had higher incidence of pruritus compared to aGVHD skin rash, pruritus was not a significant predictor of aGVHD versus non-aGVHD skin rash (p=0.20) nor when separated by CD34+ selection modality (Isolex p=0.188; CliniMACS p=0.469). Conclusions: In our case series of 243 TCD PBSCT recipients of whom 152 had skin rashes, over three-quarters of all non-aGVHD skin rashes with clear etiologies were attributed to drug eruptions. Our results suggest that the commonly utilized feature of peripheral eosinophilia may not be helpful in differentiating between aGVHD and drug rashes after TCD alloHSCT. Additionally, pruritus at rash onset was not helpful in distinguishing cause of rash as due to aGVHD or non-aGVHD after TCD alloHSCT. Based on these data, if clinical scenario supports GVHD associated rash, the presence of peripheral eosinophilia or pruritus should not delay initiation of therapy for GVHD. Disclosures No relevant conflicts of interest to declare.
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- 2018
284. A High Degree of Engrafting Unit-Recipient HLA-Allele Mismatch Is Not Associated with an Increased Risk of Transplant-Related Mortality (TRM) or Inferior Progression-Free Survival (PFS) after Double Unit Cord Blood (CB) Transplantation (dCBT) in Adults with Hematologic Malignancies
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Kristine Naputo, Aishat Afuye, Andromachi Scaradavou, Ioannis Politikos, Doris M. Ponce, James W. Young, Sergio Giralt, Sean M. Devlin, Michael Scordo, Molly Maloy, Marcel R.M. van den Brink, Ann A. Jakubowski, Scott T. Avecilla, Miguel-Angel Perales, Hugo Castro-Malaspina, Christina Cho, Esperanza B. Papadopoulos, Juliet N. Barker, Christopher Mazis, Brian C. Shaffer, Boglarka Gyurkocza, Roni Tamari, Craig S. Sauter, Gunjan L. Shah, and Parastoo B. Dahi
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Oncology ,medicine.medical_specialty ,Univariate analysis ,business.industry ,Immunology ,Cell Biology ,Hematology ,Human leukocyte antigen ,ThioTEPA ,Transplant-Related Mortality ,Biochemistry ,Fludarabine ,Transplantation ,Cord blood ,Internal medicine ,Medicine ,Progression-free survival ,business ,medicine.drug - Abstract
Background : While incorporation of HLA-allele matching has highlighted high degrees of CB unit-recipient HLA-disparity, the less stringent HLA-match requirements extends allograft access to many patients without matched adult donors. The extent to which HLA-mismatch can adversely affect CBT outcomes, & the maximum permitted degree of HLA-mismatch, however, are not established. Methods : We analyzed TRM, relapse & PFS after intermediate intensity myeloablative cyclophosphamide 50 mg/kg, fludarabine 150 mg/m2, thiotepa 5-10 mg/kg, 400 cGy TBI double unit CBT in adults transplanted for hematologic malignancies. Eligible patients (pts) were first allograft recipients ≤ 65 years transplanted for acute leukemia/ MDS/ MPD (≤ 10% blasts pre-CBT), B-cell or T-cell lymphomas between 1/2014 - 12/2017. TNC & CD34+ dose were typically given priority over HLA-match in unit selection. Results : 102 pts [51 (50%) non-European, 59 (58%) CMV seropositive, median age 50 years (range 21-65), median weight 80 kg (range 36-137)] were transplanted. Diagnoses included 71 acute leukemias, 17 CML/ MPD/ MDS, 14 B- or T-cell NHLs. All received double unit grafts comprised of 2 (1%) 6/6 units, 21 (10%) 5/6, 181 (89%) 4/6 HLA-match, median unit-recipient 8-allele HLA-match 5/8 (range 3-7), & median infused viable CD34+ dose 1.3 x 105/kg/unit (range 0.2-8.6). Forty-eight (47%) CB grafts were supplemented with haplo-identical CD34+ cells as a myeloid bridge. The cumulative incidence of sustained CB engraftment was 97% (95%CI 90-99) with 2 pts having graft failure. A dominant (engrafting) unit was identified in all pts but 1 who died on day +14. Day 180 incidences of grades II-IV & III-IV aGVHD were 89% (95%CI 81-94) & 23% (95%CI 15-31), respectively. 1-yr cGVHD was 4% (95%CI 1-9). Cumulative incidence of TRM was 9% (95%CI 4-15) at day 180 & 14% (95%CI 8-22) at 2 yrs. 11% (95%CI 6-19) of pts relapsed by 2 yrs. With a median survivor follow-up of 2 yrs 3 months (range 6 - 51), the 2-yr overall survival is 82% (95%CI 75-90) & PFS is 74% (95%CI 66-84). Causes of death were transplant-related in 16 pts [6 aGVHD, 4 infection (2 viral, 1 bacterial, 1 fungal), 4 organ failure, 1 graft failure, 1 unknown] & due to relapse in 4 pts. By 2-yrs post-CBT, engrafting unit-recipient HLA-allele match had no association with TRM or PFS (Figure). Univariate analysis of the association between recipient variables [age, age adjusted hematopoietic cell transplant-comorbidity index (aaHCT-CI), revised disease risk index (rDRI)] & graft variables [engrafting unit-recipient HLA-allele match & infused CD34+ cell dose] & TRM, relapse & PFS are shown (Table). Age & aaHCT-CI were associated with 2-yr TRM with the 50 younger pts (< 50 years), & the 66 pts with aaHCT-CI 0-3, having especially low 2-yr TRM of 5% & 10%, respectively. Neither engrafting unit-recipient HLA-match nor CD34+ dose were associated with TRM. No pt or graft variable was associated with relapse. The only significant variable associated with 2-yr PFS was aaHCT-CI. The 66 pts with a lower aaHCT-CI score of 0-3 had a higher 2-year PFS [82% (95%CI 73-92)] than the 36 high score 4-9 pts [60% (95%CI 46-79)]. rDRI, engrafting unit-recipient 8-allele HLA-match & CD34+ cell dose had no effect. Multivariate analysis of TRM was precluded by too few events. Multivariate analysis of PFS including aaHCT-CI, rDRI & engrafting unit-recipient HLA-match showed high aaHCT-CI was associated with worse PFS [HR 2.82 (1.28-6.25) if score 4-9 vs 0-3, p = 0.01]; neither rDRI [HR 1.21 (0.54-2.69) if high-very high vs low-intermediate, p = 0.64] nor engrafting unit-recipient HLA-match [HR 2.06 (0.89-4.74) if 5-7/8 vs 3-4/8 matched (p = 0.09] were significant. Conclusions : Our finding that a high level of HLA-allele mismatch of the engrafting unit was not significantly associated with TRM or PFS in adult dCBT for hematologic malignancies has multiple implications. It supports the use of units with a relatively high degree of HLA-mismatch in the dCBT setting if needed in these pts. This facilitates extension of allograft access to the majority of pts including minorities. Moreover, the high PFS supports our centers unit selection strategy that gives unit quality & cell dose a priority in adults with malignancies to optimize engraftment. Finally, this data support CBT in many high-risk or urgent pts even if a well-matched CB graft cannot be identified. This is especially true in younger pts or those with a low 0-3 aaHCT-CI who had high 2-yr PFS. Disclosures Perales: Incyte: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees and Clinical trial support; Novartis: Other: Personal fees; Abbvie: Other: Personal fees; Merck: Other: Personal fees; Takeda: Other: Personal fees. Sauter:Juno Therapeutics: Consultancy, Research Funding; Sanofi-Genzyme: Consultancy, Research Funding; Spectrum Pharmaceuticals: Consultancy; Novartis: Consultancy; Precision Biosciences: Consultancy; Kite: Consultancy. Shah:Janssen: Research Funding; Amgen: Research Funding.
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- 2018
285. CD34+Selected Hematopoietic Stem Cell Transplants Conditioned with a Myeloablative Regimen Is Well Tolerated and Results in Good Outcomes in Patients with Myelofibrosis
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Miguel-Angel Perales, Craig S. Sauter, Sergio Giralt, Molly Maloy, Christina Cho, Esperanza B. Papadopoulos, Ann A. Jakubowski, Jessica Flynn, Jeong-Ok Lee, Sean M. Devlin, Roni Tamari, Hugo Castro-Malaspina, and Doris M. Ponce
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medicine.medical_specialty ,Acute leukemia ,business.industry ,medicine.medical_treatment ,Immunology ,Cell Biology ,Hematology ,Hematopoietic stem cell transplantation ,medicine.disease ,Biochemistry ,Chemotherapy regimen ,MAC Regimen ,Transplantation ,Regimen ,Graft-versus-host disease ,Internal medicine ,medicine ,Cumulative incidence ,business - Abstract
Background: Allogeneic hematopoietic stem cell transplantation (Allo-HSCT) remains the only curative treatment for myelofibrosis (MF). Due to high incidence of non-relapse mortality (NRM) in patients with MF who underwent allo-HCT with myeloablative conditioning (MAC), transplants in these patients are mostly done by utilizing a reduced intensity conditioning regimen with calcineurin inhibitors for graft versus host disease (GVHD) prophylaxis. We previously published very good outcomes in patients with acute leukemia (AML and ALL) and myelodysplastic syndrome (MDS) who underwent Ex- vivo CD34+-selected T-cell depleted (TCD) allo-HSCT following MAC regimens (Barba P et al. BBMT 2017; Tamari R et al. BBMT 2018). Aim: To study retrospectively the outcomes of patients with primary or secondary myelofibrosis (PMF or SMF) who underwent a CD34+ cell-selected Allo-HSCT. Methods: Twenty-one MF patients who underwent a CD34+-selected Allo-HSCT at a single center between October 2010 and November 2017 were included in this retrospective analysis. All patients received MAC regimen including busulfan, melphalan and fludarabine and antithymocyte globulin to prevent graft rejection. None of the patients received post-transplant GVHD prophylaxis. G-CSF mobilized peripheral blood stem cell grafts were depleted of T-cells using immunomagnetic CD34+ selection by CliniMACS device. Overall survival (OS), relapse free survival (RFS), relapse, NRM and the composite endpoint of GVHD-free/relapse-free survival (GFRS: defined as grade 3-4 acute GVHD, chronic GVHD requiring systemic treatment, relapse, or death) were estimated using the Kaplan-Meier and cumulative incidence method, with death considered a competing risk for relapse. Log-rank and Gray's tests were used to assess differences in patient and treatment characteristics. Results: Patient's and donor's characteristics are summarized in table 1. Neutrophils engraftment occurred in all patients at a median of 11 days (range: 8 - 14) and 90% (N = 19) achieved platelet engraftment at a median of 24 days (range, 14 - 77). Another patient achieved platelet engraftment only after splenectomy which was performed on post-transplant day 54. With a median follow-up of 54.06 months, the estimated 3-year OS and RFS were 84.4 % (95% CI, 69.6% to >99.9%) and 74.7% (95% CI, 57.6 to 96.9%), respectively (figure 1). The cumulative incidence of grade II-IV acute GVHD at day 100 was 33.3% (95% CI 11.2-54.1%); majority (N=5) had grade II and 2 patients had grade III (N=1) and grade IV (N=1) acute GVHD. Chronic GVHD developed in 2 patients including only 1 case requiring systemic treatment. The 3-year cumulative incidence rate of relapse was 9.5% (95% CI, Conclusions: In this analysis we demonstrate that CD34+ selected Allo-HSCT following a chemotherapy only based MAC regimen is well-tolerated and an effective treatment for patients with myelofibrosis. We noted higher incidence of acute GVHD when compared to our reported outcomes in patients with acute leukemia and MDS undergoing a CD34+ selected allo-HSCT and all cases of mortality in this analysis were secondary to GVHD. This may suggest differences in the biology of the diseases and a more inflammatory milieu in pts with MF. Relapse incidence was notably low and all patients who relapsed were salvaged with further cellular therapy suggesting a strong graft-versus-leukemia effect in this disease. Disclosures Sauter: Juno Therapeutics: Consultancy, Research Funding; Sanofi-Genzyme: Consultancy, Research Funding; Spectrum Pharmaceuticals: Consultancy; Novartis: Consultancy; Precision Biosciences: Consultancy; Kite: Consultancy. Perales:Incyte: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees and Clinical trial support; Novartis: Other: Personal fees; Merck: Other: Personal fees; Takeda: Other: Personal fees; Abbvie: Other: Personal fees.
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- 2018
286. HLA-a*0101 Expression Correlates with Increased Risk of Severe Cutaneous Acute Graft-Versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation
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Molly Maloy, Sergio Giralt, Samira Fatmi, Ann A. Jakubowski, Doris M. Ponce, Sean M. Devlin, James W. Young, Alina Markova, and Maira Fonseca
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Umbilical Cord Blood Transplantation ,business.industry ,medicine.medical_treatment ,Immunology ,Cell Biology ,Hematology ,Hematopoietic stem cell transplantation ,Human leukocyte antigen ,Biochemistry ,HLA-A ,Transplantation ,Increased risk ,HLA-A2 Antigen ,Acute graft versus host disease ,medicine ,business - Abstract
Introduction: Acute graft-versus-host disease (aGVHD) remains a substantial cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (alloHSCT). aGVHD most commonly affects the skin, for which there is a high treatment response after both unmodified and ex-vivo CD34+ selected/T-cell depleted (TCD) alloHSCT grafts. We identified a cluster of patients, however, who developed severe refractory cutaneous aGVHD and expressed MHC class I HLA-A*0101 allele. Although the effect of HLA polymorphisms on cutaneous aGVHD is unknown, we hypothesized that HLA-A*0101 expression correlates with worse cutaneous aGVHD after alloHSCT. Methods: We evaluated 831 patients who underwent either an unmodified or TCD allograft at a single institution between 03/2010 and 02/2017. We excluded patients who received Results: Most of the patients underwent alloHSCT after myeloablative conditioning for the treatment of hematologic malignancies or high-risk non-malignant hematologic disorders. A similar proportion received a TCD or an unmodified allograft. Because all patients had 8/8 HLA-identical donors, both donor and recipient either expressed HLA-A*0101 or did not. HLA-A*0101 was expressed in 206 (25%) patients (98 TCD, 108 unmodified) who had similar demographics to patients lacking HLA-A*0101 (Table 1). At day 180, patients expressing HLA-A*0101 had a higher incidence of grade II-IV cutaneous aGVHD when compared to patients lacking HLA-A*0101 expression in both the TCD (12% vs. 5%, p=0.02) and unmodified (16% vs. 9%, p=0.046) cohorts. Similarly, incidence of severe grade III-IV cutaneous aGVHD was higher in the HLA-A*0101 expressing group when compared to the non-expressing group after TCD (8% vs. 3%, p=0.027) and unmodified (11% vs. 4%, p=0.01) alloHSCT (Fig 1). In a multivariate cause-specific Cox model, HLA-A*0101 expression in the TCD alloHSCT cohort correlated with increased risk of grade III-IV cutaneous aGVHD [HR=2.79 (95% CI: 1.07-7.28), p=0.036] after adjusting for whether the donor was related or unrelated. In the unmodified alloHSCT cohort, HLA-A*0101 expression also correlated with an increased risk of grade III-IV cutaneous aGVHD [HR=2.68 (95% CI: 1.24-5.79), p = 0.012)] after adjusting for relationship status of the donor and the type of conditioning regimen. There was no statistically significant difference in OS or transplant-related mortality between HLA-A*0101 expressing vs. non-expressing patients after TCD or unmodified alloHSCT. Conclusions: Donor/recipient expression of HLA-A*0101 correlates with an increased incidence and severity of cutaneous aGVHD after both TCD and unmodified alloHSCT, including severe grade III-IV cutaneous aGVHD. These findings have potential practical implications in the development of cutaneous aGVHD prophylaxis or early therapeutic strategies targeting the skin in this high-risk population. These findings merit further investigation in a larger patient/donor population. Disclosures No relevant conflicts of interest to declare.
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- 2018
287. A Simple Geriatric Vulnerability Index for Older Patients Undergoing Allogeneic Hematopoietic Cell Transplantation
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Ann A. Jakubowski, Parastoo B. Dahi, Sean M. Devlin, Sergio Giralt, Miguel-Angel Perales, Molly Maloy, Brian C. Shaffer, Richard J. Lin, Theresa A. Elko, Juliet N. Barker, Beatriz Korc-Grodzicki, Esperanza B. Papadopoulos, Roni Tamari, Hugo Castro-Malaspina, Armin Shahrokni, and Craig S. Sauter
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Oncology ,medicine.medical_specialty ,Emotional vulnerability ,Hematopoietic cell ,Vulnerability index ,business.industry ,medicine.medical_treatment ,Immunology ,Cell Biology ,Hematology ,Hematologic Neoplasms ,Hematopoietic stem cell transplantation ,Biochemistry ,Transplantation ,03 medical and health sciences ,0302 clinical medicine ,Ferritin measurement ,Older patients ,030220 oncology & carcinogenesis ,Internal medicine ,Medicine ,030212 general & internal medicine ,business - Abstract
Older patients are at increased risk for complications and death following allogeneic hematopoietic cell transplantation (allo-HCT). Traditional transplant-specific prognostic indices such as hematopoietic cell transplant comorbidity index (HCT-CI) may not capture all underlying geriatric vulnerabilities, and in-depth evaluation by a geriatrician prior to transplant may not always be available. We hypothesize that routine pre-transplant assessments by interdisciplinary clinical providers including advanced practice providers, nursing staff, physical therapists, occupational therapists, and dietitians, as well as common laboratory tests, may uncover additional geriatric deficits. Using an institutional database and the electronic medical records of 406 adults age 60 years and older (range 60-78.7) who underwent first allo-HCT for hematological malignancies from 2010 to 2016, we examined the prevalence and the prognostic impact of pre-transplant geriatric deficits identified by interdisciplinary clinical providers including geriatric domains of functional activity, cognition, medication, nutrition, and mobility (Table 1), and by routine laboratory tests. With a median follow-up of 39 months for survivors, the 3-year probability of overall survival (OS) and progression-free survival was 47% (95% CI 42-53) and 40% (95% CI 35-45), respectively. The 2-year cumulative incidence of non-relapse mortality (NRM) was 26% (95% CI 22-29). Among pre-transplant geriatric and laboratory variables, we found that impairment in instrumental activities of daily living (IADL) and pre-transplant ferritin level ≥1200 was independently associated with increased NRM and inferior OS. In the multivariate analysis, HCT-CI ≥3, IADL impairment, ferritin level ≥1200, and Karnofsky Performance Scale (KPS) Most importantly, the combination of either IADL impairment or ferritin ≥1200 with HCT-CI further stratifies NRM and OS into distinct risk categories, including a group of highly vulnerable, high risk patients with high HCT-CI (≥3) plus IADL impairment and/or ferritin level ≥1200 (Figure 1). Detailed examination of non-relapse death among all vulnerable patients (≥2 risk factors) reveals a higher proportion of death from organ toxicities than patients with zero or 1 risk factor. Our findings establish a rapid and simple assessment tool to risk stratify older patients prior to allo-HCT. While requiring validation, the geriatric vulnerability index can be easily completed and integrated into outpatient clinics and the electronic medical record. It may also provide an entry point for prospective, interventional trials aimed at reducing non-relapse mortality and toxicities, and at improving survival and quality of life of older allo-HCT patients. Disclosures Perales: Takeda: Other: Personal fees; Merck: Other: Personal fees; Incyte: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees and Clinical trial support; Abbvie: Other: Personal fees; Novartis: Other: Personal fees. Sauter:Juno Therapeutics: Consultancy, Research Funding; Sanofi-Genzyme: Consultancy, Research Funding; Spectrum Pharmaceuticals: Consultancy; Novartis: Consultancy; Precision Biosciences: Consultancy; Kite: Consultancy.
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- 2018
288. V(D)J Sequence Capture for DNA-Based Minimal Residual Disease Detection in Multiple Myeloma
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Maria E. Arcila, Sean M. Devlin, Caleb Ho, Venkata Yellapantula, Ying Huang, Ola Landgren, Mikhail Roshal, Akshar Patel, Even H Rustad, Elli Papaemmanuil, Malin Hultcrantz, Theresia Akhlaghi, Jeffrey E. Miller, and Austin Jacobsen
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biology ,business.industry ,Immunology ,Cell Biology ,Hematology ,Plasma cell ,medicine.disease ,Immunoglobulin light chain ,Biochemistry ,Molecular biology ,Minimal residual disease ,medicine.anatomical_structure ,Plasma Cell Myeloma ,biology.protein ,Medicine ,Bone marrow ,Antibody ,business ,Kappa ,Multiple myeloma - Abstract
Introduction Minimal residual disease (MRD) negativity after initial therapy is a strong predictor of survival in multiple myeloma. Tracking of clonal immunoglobulin V(D)J rearrangements by next generation sequencing is highly sensitive for MRD and does not require immediate analysis of fresh samples. However, previous studies have found variable rates of baseline V(D)J sequence capture, which could limit tracking. In this study, we aimed to define the sample-related and disease-related factors that influence V(D)J capture. Methods We included 177 patients with plasma cell myeloma who had available stored mononuclear cells from a baseline bone marrow aspirate. Each sample was sequenced by two assays: The LymphoTrack® VDJ assays from Invivoscribe, and our in-house myeloma panel myTYPE, as a molecular control for detectable tumor derived DNA in the samples. MyTYPE positivity was defined by one or more single nucleotide variant, insertion, deletion, translocation or copy number variation that is known to occur in myeloma. Results and discussion The V(D)J capture rate in our whole cohort was 81 %, as compared with 95 % in the myTYPE positive samples, demonstrating the importance of tumor cell content for V(D)J capture. This was confirmed in multivariate logistic regression (Figure 1), where myTYPE positivity was a strong independent predictor of V(D)J capture success, with an odds ratio (OR) of 6.61 (95 % CI 2.22-24.81, p = 0.002). Plasma cell content estimated from bone marrow aspirate smears also contributed to the multivariate model, with an OR of 1.3 for each 10 % increase in plasma cell content (95 % CI 0.96-1.84, p=0.109), but this did not reach statistical significance after accounting for the strong effect of myTYPE. Finally, having lambda light chain restricted plasma cells was a strong predictor of V(D)J capture success (OR 6.91, 95 % CI 2.4-25.32, p = 0.001). Higher V(D)J capture rate in lambda-restricted myeloma as compared with kappa-restricted was mostly driven by a difference in immunoglobulin kappa gene (IGK) rearrangement capture (73 vs. 44 %, p < 0.001). As a potential explanation, we found up to 4 unique IGK rearrangements that are amenable to capture in lambda-restricted cases, as well as dramatically lower somatic hypermutation (SHM) of the IGK variable region in clonal rearrangements, as compared with kappa-restricted cases. SHM has previously been shown to cause V(D)J capture failure by interfering with PCR primer annealing. Both of these factors can be attributed to IGK inactivation by rearrangements involving the "kappa deleting element" region, affecting both IGK alleles in lambda-restricted plasma cells (Perfetti et al, Immunology, 2004). As an explanation for low plasma cell content in the samples used in this study, we describe how the tumor cell content of bone marrow aspirates decrease gradually in sequential pulls because of hemodilution: from the initial pull used for aspirate smear, to the final pull that is commonly used for research. Supporting the important role of hemodilution, we found V(D)J capture rates of 97 % in clinical samples (early pull aspirates) from our institution that were analyzed with the same NGS assays, as long as the bone marrow plasma cell infiltration was above 5 %. V(D)J capture probability appears to be determined by two factors: The abundance of clonal cells (i.e. tumor cell content), and the degree to which clonal sequences can be amplified by the assay (which is negatively affected by SHM). Thus, increasing the tumor cell content in samples as much as practically possible (i.e., optimal bone marrow aspirates and enrichment of CD138+ plasma cells) may compensate for SHM and improve V(D)J capture rates beyond 95 %. Conclusion V(D)J capture rates of at least 95 % are feasible in multiple myeloma using LymphoTrack® NGS assays, when the sample quality is good. The most important reason for V(D)J capture failure is low tumor cell content due to bone marrow aspirate hemodilution. Optimal performance depends on the use of early pull aspirates and/or subsequent tumor cell enrichment. Figure 1: Predicting V(D)J capture. Regression lines and individual data points are colored according to myTYPE status (red = positive; blue = negative); V(D)J capture probability on the y-axis (capture yes/no on the second y-axis) and bone marrow plasma cell percentage by aspirate smear on the x-axis; split into panels according to light chain restriction (right = lambda; left = kappa). Disclosures Ho: Invivoscribe, Inc.: Honoraria. Arcila:Invivoscribe, Inc.: Consultancy, Honoraria. Jacobsen:Invivoscribe, Inc.: Employment. Huang:Invivoscribe, Inc.: Employment. Miller:Invivoscribe, Inc.: Employment, Equity Ownership. Landgren:Pfizer: Consultancy; Karyopharm: Consultancy; Amgen: Consultancy, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.
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- 2018
289. Homebound Autologous Hematopoietic Cell Transplantation for Plasma Cell Disorders in an Urban Setting Is Safe for Patients and Preferred By Patients and Caregivers
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Melissa Cortes, Morgan Reeds, Alison J Applebaum, Christina Kiss, Heather Landau, Marci Andrejko, Jason Batalha, Sean M. Devlin, Sergio Giralt, Gunjan L. Shah, Naomi Cazeau, Nicole Lestrange, Dayna Palumbo, Kathleen Lynch, Elizabeth S. Rodriguez, Courtney McElrath, David J. Chung, Michael Scordo, Juliet Gerber Jenkelowitz, and Patrick Hilden
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medicine.medical_specialty ,Immunology ,Population ,Biochemistry ,Homebound Persons ,law.invention ,03 medical and health sciences ,0302 clinical medicine ,law ,Internal medicine ,Medicine ,Outpatient clinic ,education ,education.field_of_study ,business.industry ,Cell Biology ,Hematology ,medicine.disease ,Intensive care unit ,Transplantation ,Platelet transfusion ,030220 oncology & carcinogenesis ,business ,Febrile neutropenia ,Pegfilgrastim ,medicine.drug - Abstract
Background: Autologous hematopoietic stem cell transplantation (AHCT) is a mainstay of therapy for eligible patients with multiple myeloma (MM) and light chain (AL) amyloidosis and confers a progression free and overall survival benefit in most studies. Yet, AHCT requires specialized care at a transplant center and investment from patients and caregivers. To decrease the burden of therapy and increase access to AHCT, we studied the safety and feasibility of delivering transplant care in a homebound setting. Methods: Eligible MM and AL patients undergoing AHCT resided in designated zip codes, had 24hr caregiver support, adequate Wi-Fi connection, Sorror Co-morbidity index ≤ 3 and Karnofsky performance status ≥ 80. Following high-dose melphalan (day -2) and stem cell reinfusion (day 0) in the outpatient clinic, protocol-specific homecare commenced (day +1) until engraftment. Care included daily assessments by advanced practice providers and interventions were delivered by registered nurses in the afternoons. Attending physicians communicated through telemedicine daily. Due to regulation, blood products required infusion in the outpatient clinic. Patient and caregiver quality-of-life (QOL) and satisfaction were assessed using patient/caregiver reported outcome instruments (Functional Assessment of Cancer Therapy (FACT)-General and FACT-Bone Marrow Transplant (FACT-BMT) questionnaires, MD Anderson Symptom Inventory (MDASI), Caregiver QOL Index--Cancer (CQOL-C) and satisfaction surveys). Video diaries and one-on-one interviews provided detailed qualitative evaluations. The primary objective was feasibility defined by readmission within 21 days of AHCT. Descriptive statistics were used to describe the population, toxicities and QOL measures. Results: Between 2/2016 - 5/2018, 15 patients (60% MM; 40% AL) and caregivers met inclusion criteria. Patient median age was 62 years (range 40-71) with 80% male. AHCT was part of 1st line therapy in most patients (N=13); 2 with MM underwent 1st AHCT as part of salvage. Melphalan dose was 200mg/m2 (N=11) or less (N=4) in patients ≥70 or AL. All patients received pegfilgrastim 6mg on day +1; thereafter, intravenous fluids and electrolytes were the most common interventions administered at home. During homecare, a median of 2 (range 1-3) visits to clinic were required for platelet transfusions and only 1 patient required 1 red cell transfusion. Median time to neutrophil and platelet engraftment was 9 (range 8-10) and 18 (range 11-22) days, respectively. Overall 7/15 (47%) (95% CI; 0.21-0.73) of patients were admitted for a median of 4 (range 3-10) days. Admission occurred on day +7 (N=5), day +8 (N=1) and day +12(N=1). Reasons for admission included neutropenic fever (NF) (N=2), fever attributed to engraftment syndrome (N=2), diarrhea (N=2), and dehydration (N=1). Only 1 (7%) patient had a documented infection (C. difficile) and 1 admitted for NF required ICU care (2 days) for GI bleed. Overall, 47% of patients experienced grade ≥ 3 non-hematologic toxicities. There were no deaths on study. Results of thematic content analysis of transcripts for patient-caregiver dyads demonstrate that while feeling challenged, caregivers derived satisfaction from assisting with the patient's recovery through maintaining hygiene of the home environment, managing dietary needs and responding to symptoms. Caregivers reported that living with the patient during AHCT strengthened their relationship by being able to provide for one another in unanticipated ways. Patients reported positive support from the medical team, connection to the world and the ability to engage in relaxing activities and physical exercise as important during AHCT. Caregivers and patients unanimously described the homebound program as preferable to a hypothesized experience in the hospital and satisfaction surveys indicated favorable responses (Figure). Symptom burden and QOL data are being analyzed. Conclusion: Homebound AHCT is safe and feasible with less than half of patients requiring inpatient admission. Patients required an average of two outpatient visits while receiving homebound care for blood products. Qualitative evaluations of the program by patients and caregivers were overwhelmingly positive. Based on these results we intend to expand the homebound program and investigate other potential biologic (microbiota diversity preservation) and economic benefits. Disclosures No relevant conflicts of interest to declare.
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- 2018
290. Loss of Microbiota Diversity after Autologous Stem Cell Transplant Is Comparable to Injury in Allogeneic Stem Cell Transplant
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Sergio Giralt, Annelie Clurman, Miguel-Angel Perales, Molly Maloy, Gunjan L. Shah, Antonio L.C. Gomes, Ann E. Slingerland, Michael Scordo, Niloufer Khan, Craig S. Sauter, Carlos Rondon-Clavo, Robert R. Jenq, John B. Slingerland, Boglarka Gyurkocza, Nelson J. Chao, Anthony D. Sung, Eric G. Pamer, Doris M. Ponce, Heather Landau, Marcel R.M. van den Brink, Sean M. Devlin, Parastoo B. Dahi, and Jonathan U. Peled
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business.industry ,medicine.medical_treatment ,Immunology ,Cell Biology ,Hematology ,Hematopoietic stem cell transplantation ,medicine.disease ,Biochemistry ,Lymphoma ,Transplantation ,03 medical and health sciences ,0302 clinical medicine ,Intestinal mucosa ,030220 oncology & carcinogenesis ,Mucositis ,medicine ,Stem cell ,business ,Dysbiosis ,Multiple myeloma ,030215 immunology - Abstract
Introduction: We have previously reported that clinically relevant, dramatic reductions occur in intestinal bacterial diversity during allogeneic hematopoietic stem cell transplant (allo-HSCT). These are likely attributable to antibiotic exposure, nutritional alterations, and intestinal mucosa injury from high-dose chemotherapy. Patients undergoing autologous hematopoietic stem cell transplantation (AHCT) also receive antibiotics and experience nutritional alterations due to mucositis and other gastrointestinal toxicities. We hypothesized that the pattern of dysbiosis seen in AHCT patients would reflect the changes in allo-HSCT patients. Here, we present a novel analysis of microbiota diversity in AHCT patients from two independent institutions. Methods: We retrospectively identified a cohort of 365 patients (median age 60 years) who underwent AHCT for treatment of hematologic malignancy between May 2009 to February 2018 at two large-volume transplant centers in the US. The population was diverse in terms of histology, conditioning regimens and remission status prior to transplant, with 179 (49%) patients diagnosed with multiple myeloma, 153 (42%) patients diagnosed with lymphoma, and 33 (9%) patients with other diseases. Stool samples from the selected patients were collected approximately weekly during inpatient hospitalization. Sequencing of the V4-V5 region of the bacterial 16S rRNA genes from all samples was performed on the Illumina platform at a central site. Microbial diversity was measured by the Simpson reciprocal a-diversity index (S). We defined the pre-AHCT period as days -10 to 0, and computed median values for patients with multiple samples within that period. We additionally defined monodomination of the microbiota as a single operational taxonomic unit comprising >30% of bacterial abundance. For comparison, we sequenced samples from 17 healthy volunteers and used a public dataset of sequences from 313 healthy volunteers from the NIH Human Microbiome Project (HMP). Median pre-transplant microbial diversity in the healthy patient and AHCT groups was compared by a pairwise Wilcox test to a retrospective cohort of allo-HSCT patients. Results: We evaluated 857 samples from 365 adult patients undergoing AHCT, with 316 patients from Memorial Sloan Kettering Cancer Center (MSKCC) and 49 patients from Duke University Medical Center (DUMC). Median pre-transplant diversity in AHCT patients from both centers was significantly lower than in normal controls (Fig 1A) (HMP vs MSKCC AHCT, S=12.05 vs. 9.19, p50% by day 0 and was >75% by day +14. Conclusion: Microbial diversity is reduced prior to transplant in both AHCT and allo-HSCT patients. Loss of diversity after AHCT occurs across centers and the degree of injury is comparable to the dysbiosis in allo-HSCT patients. Preliminary analysis suggests that lower diversity may correlate with worse progression-free survival (PFS) in myeloma patients in our diverse AHCT cohort. Given the known associations of alterations in microbiota composition with toxicities and overall survival in allo-HSCT patients, further evaluation of microbiota injury and its associations with toxicities, PFS, and overall survival (OS) in AHCT patients is warranted. Figure 1: A: The median Simpson reciprocal a-diversity index (S) of pre-transplant (days -10 to 0) samples of AHCT and allo-HSCT patients from two centers, as well as two cohorts of healthy volunteers, was plotted and a pairwise Wilcox test was performed, with p-values as indicated. B: (S) was plotted against time relative to allo-HSCT (on L) and AHCT (on R), for samples collected from day -10 to day +30. Larger values indicate greater diversity. C: Microbiota composition and changes in bacterial monodominance after transplant (days -14 to +28); the most common genus post-transplant is Streptococcus. Figure 1. Figure 1. Disclosures Peled: Seres Therapeutics: Research Funding. Sauter:Juno Therapeutics: Consultancy, Research Funding; Sanofi-Genzyme: Consultancy, Research Funding; Spectrum Pharmaceuticals: Consultancy; Novartis: Consultancy; Precision Biosciences: Consultancy; Kite: Consultancy. Shah:Amgen: Research Funding; Janssen: Research Funding. Perales:Novartis: Other: Personal fees; Incyte: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees and Clinical trial support; Merck: Other: Personal fees; Takeda: Other: Personal fees; Abbvie: Other: Personal fees. Jenq:Ziopharm Oncology: Consultancy; Seres Therapeutics, Inc.: Membership on an entity's Board of Directors or advisory committees; MicrobiomeDx: Consultancy; Seres Therapeutics, Inc.: Patents & Royalties.
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- 2018
291. Safe and Effective Use of Rivaroxaban for Treatment of Cancer Associated Venous Thromboembolic Disease
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Jodi V. Mones, Simon Mantha, Eva S Haegler-Laube, Gemma Bendheim, Gerald A. Soff, Sean M. Devlin, Yimei Miao, Cy Wilkins, Debra M. Sarasohn, Jonathan Wills, and Jeanette Batista
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medicine.medical_specialty ,medicine.drug_class ,Immunology ,Low molecular weight heparin ,030204 cardiovascular system & hematology ,Biochemistry ,Gastroenterology ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Edoxaban ,Internal medicine ,Medicine ,Rivaroxaban ,business.industry ,Genitourinary system ,Surrogate endpoint ,Cancer ,Cancer Care Facilities ,Cell Biology ,Hematology ,medicine.disease ,Thrombosis ,chemistry ,030220 oncology & carcinogenesis ,business ,medicine.drug - Abstract
Introduction: Venous thromboembolism (VTE) is a common complication of cancer, associated with significant morbidity and mortality. Low-molecular weight heparin (LMWH), the most widely used anticoagulant in this setting, is expensive and burdensome. Rivaroxaban (Riva) was approved for treatment of VTE in 2012, but there is limited experience in cancer-associated thrombosis (CAT). In 2014, we established a Clinical Pathway (CP) to guide use of rivaroxaban (Riva) for CAT at Memorial Sloan Kettering Cancer Center. We were concerned that a direct oral anticoagulant (DOAC) would be more likely than LMWH to cause upper gastrointestinal (GI) bleeding in the presence of abnormal mucosa. DOACs have partial renal clearance and are active in the urine, in contrast to LMWH, and we also anticipated increased genitourinary (GU) tract bleeding in the presence of GU lesions. Therefore, the key to our CP has been to recommend against use of Riva or other DOAC in the setting of active (GI) or (GU) tract lesions. As the elderly are known to be at higher risk of bleeding from anticoagulation, the CP recommended reduced dose Riva in patients≥75 year old (yo), (10 mg bid X 3 wks., followed by 15 mg daily). Otherwise, we adhere to the standard FDA approved guidelines. We published a 200-patient cohort in 2016 demonstrating rates of recurrent VTE and bleeding that were at least as low as historical controls with LMWH. This past year, two randomized clinical trials were published comparing a DOAC with dalteparin ("Hokusai VTE Cancer" of edoxaban, Raskob G.E. et al, NEJM, 2017, and "Select-D" of Riva, Young A.M. et al, JCO 2018). Both studies showed a trend towards better efficacy with the DOAC, but with increased GI/GU bleeding. However, those studies did not exclude patients with known GI/GU lesions. We now report our expanded experience with Riva treatment of CAT, confirming the safety and efficacy of Riva treatment of CAT when guided by our CP. Methods: From 1/1/2014 through 10/31/2016, 2000 patients at MSKCC received Riva. 1072 had CAT, defined as a lower extremity DVT and/or PE in a patient with active cancer or receiving cancer therapy. (The other 928 patients did not have active cancer, or received Riva for other indication). All patients treated with Riva for CAT are included in this analysis, even in the presence of active GI/GU lesions. Recurrent VTE, major bleeding (MB), clinically relevant non-major bleeding (CRNMB) leading to discontinuation of Riva, and death were competing risk endpoints for the purpose of the analysis. We also evaluated the outcomes of the subgroup of patients ≥75 yo. Results: At 6 months, the cumulative incidence for the various endpoints estimated within a competing risks framework were; recurrent VTE (4.2%), MB (2.2%), CRNMB (5.5%). Overall, the 6-month incidence of death was 22.2%. In the elderly patients, the risks of recurrent VTE and bleeding were similar to the Conclusions: In our expanded experience of Riva therapy for CAT, applying our CP, we continue to maintain low rates of recurrent VTE and bleeding. Allowing for differences in methodology between a cohort study and randomized clinical trials, the rate of recurrent VTE was as low as the DOAC arm in Hokusai VTE Cancer and Select-D studies. Further, by applying the exclusion criteria in our CP, and not treating patients with known GI/GU lesions, we achieved a low rate of bleeding compared with the DOAC treatment arms in the two recent randomized clinical trials. Those two trials demonstrated bleeding rates greater than LMWH, particularly GI/GU bleeds. We saw no increased rates of recurrent VTE or bleeding in the elderly, which is reassuring, but we cannot conclude if reduced dose is of benefit. These new expanded observations further support the validity of our CP. The key to anticoagulation choice for CAT is not which anticoagulant is "better," but rather which anticoagulant to choose for a specific patient. In the absence of GI/GU contraindications, Riva provides effective and safe anticoagulation, at substantially lower cost and burden to the patient than LMWH. In contrast, we propose that LMWH is preferable in patients with GI/GU lesions. (We are now obtaining specific data for that subgroup). Disclosures Soff: Amgen: Research Funding; Janssen: Research Funding. Mantha:Heidell, Pittoni, Murphy & Bach, LLP: Consultancy; GLG: Consultancy; Janssen: Research Funding.
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- 2018
292. Intestinal Microbiota Composition Is Associated with Minimal Residual Disease Negativity in Patients with Multiple Myeloma
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Annelie Clurman, Ola Landgren, Emily Fontana, Elizabet Tavitian, Eric G. Pamer, Jonathan U. Peled, Ann E. Slingerland, Lilan Ling, Eric R. Littmann, Antonio L.C. Gomes, Donna Mastey, John B. Slingerland, Ying Taur, Aisara Chansakul, Alexander M. Lesokhin, Marcel R.M. van den Brink, Sean M. Devlin, Matthew J. Pianko, and Meghan Salcedo
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medicine.medical_specialty ,medicine.medical_treatment ,Immunology ,Faecalibacterium prausnitzii ,Hematopoietic stem cell transplantation ,Biochemistry ,Gastroenterology ,03 medical and health sciences ,0302 clinical medicine ,hemic and lymphatic diseases ,Internal medicine ,Medicine ,Eubacterium ,Multiple myeloma ,Neoadjuvant therapy ,Lenalidomide ,biology ,business.industry ,Cell Biology ,Hematology ,biology.organism_classification ,medicine.disease ,Minimal residual disease ,body regions ,Transplantation ,030220 oncology & carcinogenesis ,business ,030215 immunology ,medicine.drug - Abstract
Background: Multiple myeloma (MM) patients who achieve minimal residual disease (MRD) negative status after upfront treatment have prolonged progression-free and overall survival compared with those who remain MRD(+) (Landgren CO, Devlin SM et al. Bone Marrow Transplant. 2016;51(12):1565-8). Commensal intestinal microbial composition has been associated with treatment outcomes in cancer patients. We sought to evaluate whether the composition of the intestinal microbiota is associated with MRD status in patients with MM. Methods: Stool samples were collected prospectively from 34 patients after completion of upfront therapy for MM at the time of MRD testing. MRD was assessed with next-generation flow cytometry of bone marrow aspirates (sensitivity 10-5). Microbial analysis was performed via sequencing of 16S rRNA V4-V5 regions using the Illumina MiSeq platform and sequence data was analyzed using UPARSE (Edgar RC, Nature Methods 2013;10(10):996-8). The linear discriminant effect size method (LEfSe) (Segata N et al. Genome Biol. 2011;12(6):R60.) was used to compare detected clades among all groups and evaluate for associations with outcomes, using MRD as class and autologous stem cell transplant (ASCT) as subclass. Alpha diversity was calculated by the Inverse Simpson index and differential relative abundance were calculated using the phyloseq package and compared using the Wilcoxon rank sum test on the R statistical computing platform. Results: Among 34 patients evaluable for microbiota composition and MRD status, the median age was 62.5 years and 16 (47.1%) were MRD(-) at time of stool collection. 24 (70.6%) were treated with carfilzomib, lenalidomide, and dexamethasone as induction therapy (MRD(-): 14 (87.5%), MRD(+):10 (55.5%). 4 (28.5%) MRD(-) patients had autologous stem cell transplant(ASCT), compared with 10 (55.5%) who were MRD(+). In the cohort's samples, we observed 19 phyla, 315 genera, 654 species, and 1549 operational taxonomic units (OTUs). There was no significant difference in alpha diversity between MRD(-) (median 12.24, IQR = 8.76-13.98) and MRD(+) patients (median 12.44, IQR = 8.36 -16.23), p=0.6 by Wilcoxon rank sum test. A positive association with MRD negativity was noted with two butyrate-producing organisms, Eubacterium hallii (p=0.001) and Faecalibacterium prausnitzii (p= 0.006). To further evaluate these relationships, we performed a differential abundance analysis of these selected taxa in MRD(+) and MRD(-) patients at the genus and species level. The relative abundance of the genera Eubacterium and Faecalibacterium were higher in fecal samples from MRD(-) patients than MRD(+) patients (Eubacterium MRD(-): median 4.51% (IQR = 2.83 - 7.32%) vs. MRD(+): median 3.07% (IQR = 1.35 - 3.87%), p=0.0326; Faecalibacterium MRD(-): median 1.68% (IQR = 0.69 - 7.48%) vs. MRD(+): median 0.003% (IQR = 0 - 3.19%), p=0.022. The relative abundance of both species of interest were higher in MRD(-) patients than in MRD(+) patients: E. hallii MRD(-): median 2.67% (IQR = 2.11 - 3.98%) vs. MRD(+): median 1.01% (IQR = 0 - 2.16%), p=0.001; F. prausnitzii MRD(-): median 1.43% (IQR = 0.53 - 7.28%) vs. MRD(+): median 0.3%, (IQR = 0 - 2.54%), p=0.022. Other species of Eubacterium and Faecalibacterium were not significantly differentially abundant between the two groups. Conclusions: Intestinal microbiota containing several butyrate-producing anaerobes appear to be associated with MRD-negativity in patients with myeloma, with higher relative abundance of Eubacterium hallii and Faecalibacterium prausnitzii in MRD(-) patients compared with MRD(+) patients. Butyrate and other short-chain fatty acids are biologically active metabolites formed during microbial fermentation of dietary or host-derived carbohydrates, which supply the host with energy and also modulate immunity, including exerting anti-inflammatory functions. Microbes of the genus Eubacterium have been associated with reduced risk of relapse in several hematologic cancers after allogeneic hematopoietic cell transplantation, including MM (Peled JU, Devlin SM et al. J Clin Oncol 2017;35(15):1650-9). This is first study to our knowledge to suggest an association between gut microbiota and MRD status in patients with myeloma and supports further investigation of a potential role for intestinal microbiota in the natural history and treatment of myeloma. Disclosures Peled: Seres Therapeutics: Research Funding. Landgren:Karyopharm: Consultancy; Merck: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Lesokhin:Squibb: Consultancy, Honoraria; Genentech: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Serametrix, inc.: Patents & Royalties: Royalties; Takeda: Consultancy, Honoraria; Janssen: Research Funding.
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- 2018
293. Prognostic value of FDG-PET prior to autologous stem cell transplantation for relapsed and refractory diffuse large B-cell lymphoma
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Jessica Meikle, Patrick Hilden, Craig H. Moskowitz, Craig S. Sauter, Andrew D. Zelenetz, Jocelyn C. Migliacci, Heiko Schöder, Matthew J. Matasar, Sean M. Devlin, and Gary A. Ulaner
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Adult ,Oncology ,medicine.medical_specialty ,animal structures ,Time Factors ,medicine.medical_treatment ,Immunology ,Salvage therapy ,Kaplan-Meier Estimate ,Hematopoietic stem cell transplantation ,Transplantation, Autologous ,Biochemistry ,Disease-Free Survival ,Autologous stem-cell transplantation ,Refractory ,immune system diseases ,Fluorodeoxyglucose F18 ,Recurrence ,Risk Factors ,hemic and lymphatic diseases ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Outcome Assessment, Health Care ,medicine ,Humans ,Refractory Diffuse Large B-Cell Lymphoma ,neoplasms ,Retrospective Studies ,Salvage Therapy ,Transplantation ,Chemotherapy ,medicine.diagnostic_test ,business.industry ,Remission Induction ,Hematopoietic Stem Cell Transplantation ,Cell Biology ,Hematology ,Prognosis ,medicine.disease ,Combined Modality Therapy ,Lymphoma ,Surgery ,carbohydrates (lipids) ,Drug Resistance, Neoplasm ,Positron emission tomography ,Positron-Emission Tomography ,Lymphoma, Large B-Cell, Diffuse ,business - Abstract
High-dose chemotherapy (HDT) plus autologous stem cell transplantation (ASCT) is the standard of care for chemosensitive relapsed and refractory diffuse large B-cell lymphoma (rel/ref DLBCL). Interim restaging with functional imaging by positron emission tomography using (18)F-deoxyglucose (FDG-PET) has not been established after salvage chemotherapy (ST) and before HDT-ASCT by modern criteria. Herein, we evaluated 129 patients with rel/ref DLBCL proceeding to HDT-ASCT, with ST response assessment by FDG-PET according to the contemporary Deauville 5-point scale. At 3 years, patients achieving a Deauville response of 1 to 3 to ST experienced superior progression-free survival (PFS) and overall survival (OS) rates of 77% and 86%, respectively, compared with patients achieving Deauville 4 (49% and 54%, respectively) (P < .001). No other pre-HDT-ASCT risk factors significantly impacted PFS or OS. Despite achieving remission to ST, patients with Deauville 4 should be the focus of risk-adapted investigational therapies.
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- 2015
294. A Novel Reduced-Intensity Conditioning Regimen Induces a High Incidence of Sustained Donor-Derived Neutrophil and Platelet Engraftment after Double-Unit Cord Blood Transplantation
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Craig S. Sauter, Nancy A. Kernan, Sergio Giralt, Guenther Koehne, Miguel Perales, Esperanza B. Papadopoulos, Jenna D. Goldberg, Sean M. Devlin, Anne Marie Gonzales, Juliet N. Barker, Andromachi Scaradavou, James W. Young, Marissa Lubin, Ann A. Jakubowski, Doris M. Ponce, and Hugo Castro-Malaspina
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Adult ,Blood Platelets ,Male ,medicine.medical_specialty ,Transplantation Conditioning ,Comorbidity score ,Adolescent ,Platelet Engraftment ,Neutrophils ,Comorbidity ,ThioTEPA ,Gastroenterology ,Article ,Disease-Free Survival ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Humans ,Aged ,Preparative Regimen ,Acute leukemia ,Transplantation ,business.industry ,Incidence ,Cord blood ,Hematology ,Middle Aged ,Total body irradiation ,Survival Analysis ,Allogeneic transplant ,3. Good health ,Surgery ,Regimen ,Hematologic Neoplasms ,030220 oncology & carcinogenesis ,Female ,Cord Blood Stem Cell Transplantation ,business ,030215 immunology ,medicine.drug - Abstract
A preparative regimen of reduced intensity that can reliably engraft cord blood (CB) and can be used as an alternative to either high-dose myeloablative or nonmyeloablative conditioning is needed. We evaluated double-unit CB transplantation in 30 patients (median age, 56 years; range, 18 to 69) with acute leukemia or myelodysplasia using a regimen of cyclophosphamide 50 mg/kg, fludarabine 150 mg/m2, thiotepa 10 mg/kg, and 400 cGy total body irradiation with cyclosporine-A/mycophenolate mofetil immunosuppression. Ninety-seven percent of patients engrafted at a median of 26 days (range, 13 to 43), and 93% of patients had recovered platelets by day 180. Grades II to IV acute graft-versus-host disease (GVHD) incidence was 67% at day 180, and chronic GVHD was 10% at 1 year. Transplant-related mortality was 20% at day 180, and relapse was 11% at 2 years. Overall, 2-year disease-free survival (DFS) was 60% at 2 years. A hierarchy in DFS was seen according to the Sorror comorbidity score: 11 patients (median age, 55 years) with a score of 1 had a 2-year DFS of 82% compared with 62% in 9 patients (median age, 51 years) with a score of 2 to 3 and 40% in 11 patients (median age, 58 years) with a score of 4 to 5 (P = .13). This reduced-intensity regimen combined with double-unit CB transplantation reliably facilitates sustained donor engraftment without antithymocyte globulin. Although other approaches are needed in patients with high comorbidity scores, this regimen is highly effective in patients ≥50 years old who are otherwise reasonably fit. It also represents a promising alternative to high-dose conditioning in younger patients.
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- 2013
295. Hypoalbuminemia is significantly associated with increased clearance time of high dose methotrexate in patients being treated for lymphoma or leukemia
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Dan Douer, Larry W Buie, Samantha N Reiss, Nelly G. Adel, Sean M. Devlin, and Debra A. Goldman
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Adult ,Male ,medicine.medical_specialty ,Adolescent ,Lymphoma ,Metabolic Clearance Rate ,Serum albumin ,Gastroenterology ,Article ,Nephrotoxicity ,Cohort Studies ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Pharmacokinetics ,Internal medicine ,hemic and lymphatic diseases ,Ascites ,medicine ,Humans ,Hypoalbuminemia ,Serum Albumin ,Aged ,Retrospective Studies ,Aged, 80 and over ,Leukemia ,biology ,Dose-Response Relationship, Drug ,business.industry ,Albumin ,Hematology ,General Medicine ,Middle Aged ,medicine.disease ,Surgery ,Hospitalization ,Methotrexate ,Treatment Outcome ,030220 oncology & carcinogenesis ,Concomitant ,biology.protein ,Female ,medicine.symptom ,business ,Biomarkers ,030215 immunology ,medicine.drug - Abstract
As a weak acid, methotrexate (MTX) is bound to serum albumin and has variable protein binding. The purpose of this study was to assess serum albumin’s relationship with MTX pharmacokinetics by comparing MTX clearance and toxicities between patients with normal serum albumin to those with hypoalbuminemia. This single-center retrospective study included adult patients with leukemia or lymphoma who received their first MTX at a dose ≥ 1 gram/m2. Hypoalbuminemia was defined as serum albumin ≤ 3.4 g/dL. MTX clearance was defined as the first documented time the MTX level ≤ 0.05 micromolar. Fisher’s Exact tests and Wilcoxon Rank Sum tests were used to examine differences in toxicities and Cox proportional hazards regression was used to assess relationship with time to clearance. Of 523 patients identified, 167 patients were evaluable. One hundred thirty five patients had normal serum albumin and 32 had hypoalbuminemia. Hypoalbuminemia was associated with a higher proportion of patients experiencing edema, ascites or pleural effusions (34% vs. 12% p=0.006) and the concomitant use of nephrotoxic agents (41% vs. 20% p=0.021). Hypoalbuminemia was associated with a significantly longer time to methotrexate clearance (median: 96 hours vs 72 hour p=0.004). In addition, patients with hypoalbuminemia had a higher proportion of hyperbilirubinemia and significantly longer hospitalization (median 14 days vs. 5 days p
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- 2016
296. Hematopoietic Cell Transplantation Comorbidity Index Predicts Outcomes in Patients with Acute Myeloid Leukemia and Myelodysplastic Syndromes Receiving CD34
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Pere, Barba, Ravin, Ratan, Christina, Cho, Izaskun, Ceberio, Patrick, Hilden, Sean M, Devlin, Molly A, Maloy, Juliet N, Barker, Hugo, Castro-Malaspina, Ann A, Jakubowski, Guenther, Koehne, Esperanza B, Papadopoulos, Doris M, Ponce, Craig, Sauter, Roni, Tamari, Marcel R M, van den Brink, James W, Young, Richard J, O'Reilly, Sergio A, Giralt, and Miguel-Angel, Perales
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Adult ,Adolescent ,Hematopoietic Stem Cell Transplantation ,Antigens, CD34 ,Comorbidity ,Middle Aged ,Models, Theoretical ,Allografts ,Prognosis ,Survival Analysis ,Article ,Leukemia, Myeloid, Acute ,Young Adult ,surgical procedures, operative ,immune system diseases ,hemic and lymphatic diseases ,Myelodysplastic Syndromes ,Humans ,Transplantation, Homologous ,Aged ,Retrospective Studies - Abstract
To evaluate the association between the hematopoietic cell transplantation-comorbidity index (HCT-CI) and the recently developed age-adjusted HCT-CI (HCT-CI/age) and transplant outcomes in the setting of CD34-selected allogeneic HCT, we analyzed a homogeneous population of patients undergoing allogeneic HCT with CD34-selected grafts for acute myeloid leukemia and myelodysplastic syndrome (n = 346). Median HCT-CI and HCT-CI/age scores were 2 (percentile 25 to 75, 1 to 4) and 3 (percentile 25 to 75, 1 to 5), respectively. Higher HCT-CI and HCT-CI/age scores were associated with higher nonrelapse mortality (NRM) and lower overall survival (OS). The HCT-CI distinguished 2 risk groups (0 to 2 versus ≥3), whereas, with the HCT-CI/age, there was a progressive increase in NRM and decrease in OS with increasing scores in all 4 groups (0 versus 1 to 2 versus 3 to 4 versus ≥5). Higher scores in both models were associated with lower chronic graft-versus-host disease relapse-free survival but not with higher relapse. Both models showed a promising predictive accuracy for NRM (c- = .616 for HCT-CI and c- = .647 for HCT-CI/age). In conclusion, the HCT-CI and HCT-CI/age predict transplant outcomes in CD34-selected allo-HCT, including NRM, OS, and chronic graft-versus-host disease relapse-free survival and may be used to select appropriate patients for this approach.
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- 2016
297. Increased GVHD-related mortality with broad-spectrum antibiotic use after allogeneic hematopoietic stem cell transplantation in human patients and mice
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Silvia Caballero, Franck Rapaport, Hendrik Poeck, Ying Taur, Jennifer Tsai, Marco Calarfiore, Sophia R. Lieberman, Marcel R.M. van den Brink, Camilla Borges Ferreira Gomes, Ke Xu, Katya F. Ahr, Sean M. Devlin, Shannon B. Falconer, Chen Liu, Eric G. Pamer, Robert R. Jenq, George F. Murphy, Kori A. Porosnicu Rodriguez, Lauren F. Young, Jonathan U. Peled, Hillary V. Jay, Alan M. Hanash, Boglarka Gyurkocza, Jyotsna Gupta, Eli L. Moss, Ann E. Slingerland, Jarrod A Dudakov, Suelen M. Perobelli, Odette M. Smith, Ami S. Bhatt, Enrico Velardi, Yusuke Shono, and Melissa D. Docampo
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0301 basic medicine ,CD4-Positive T-Lymphocytes ,medicine.medical_treatment ,Antibiotics ,Cilastatin, Imipenem Drug Combination ,Graft vs Host Disease ,Penicillanic Acid ,Hematopoietic stem cell transplantation ,Aztreonam ,Interleukin-23 ,chemistry.chemical_compound ,Feces ,Mice ,immune system diseases ,polycyclic compounds ,Medicine ,Phylogeny ,biology ,Hematopoietic Stem Cell Transplantation ,General Medicine ,Flow Cytometry ,Anti-Bacterial Agents ,Drug Combinations ,surgical procedures, operative ,Piperacillin, Tazobactam Drug Combination ,Cilastatin ,Female ,Anaerobic bacteria ,Akkermansia muciniphila ,medicine.drug ,medicine.drug_class ,Colon ,Cefepime ,Article ,03 medical and health sciences ,Verrucomicrobia ,Animals ,Humans ,Transplantation, Homologous ,Piperacillin ,business.industry ,biology.organism_classification ,Mucus ,Gastrointestinal Microbiome ,Transplantation ,Mice, Inbred C57BL ,Imipenem ,030104 developmental biology ,chemistry ,Immunology ,business - Abstract
After allogeneic hematopoietic stem cell transplantation (allo-HSCT), intestinal bacteria modulate risks of infection and graft-versus-host disease (GVHD). Neutropenic fever is common and treated with a choice of clinically equivalent antibiotics that target obligately anaerobic bacteria (anaerobes) to varying degrees. We retrospectively examined 857 allo-HSCT recipients and found that treatment of neutropenic fever with imipenem-cilastatin and piperacillin-tazobactam was associated with increased GVHD-related mortality at 5 years (21.5% in imipenem-cilastatin-treated patients vs. 13.1% in untreated patients, p=0.025, and 19.8% in piperacillin-tazobactam-treated patients vs. 11.9% in untreated patients, p=0.007). However, two other antibiotics also used to treat neutropenic fever, aztreonam and cefepime, were not associated with GVHD-related mortality (p=0.78 and p=0.98, respectively). Analysis of stool microbiota composition showed that piperacillin-tazobactam administration was associated with increased compositional perturbation. Studies in mouse models demonstrated similar effects of these antibiotics, as well as aggravated GVHD mortality with imipenem-cilastatin or piperacillin-tazobactm compared to aztreonam (p
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- 2016
298. Role of MRD status in relation to clinical outcomes in newly diagnosed multiple myeloma patients: a meta-analysis
- Author
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Mathieu Boulad, Ola Landgren, Sham Mailankody, and Sean M. Devlin
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Melphalan ,Oncology ,medicine.medical_specialty ,Neoplasm, Residual ,Context (language use) ,Disease-Free Survival ,Article ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,hemic and lymphatic diseases ,medicine ,Humans ,Survival rate ,Multiple myeloma ,Transplantation ,Clinical Trials as Topic ,business.industry ,Hazard ratio ,Hematology ,medicine.disease ,Prognosis ,Minimal residual disease ,3. Good health ,Surgery ,Clinical trial ,Survival Rate ,Treatment Outcome ,030220 oncology & carcinogenesis ,business ,Multiple Myeloma ,030215 immunology ,medicine.drug - Abstract
Driven by access to better drugs, on average, newly diagnosed multiple myeloma patients have over 10 years overall survival. Using modern combination therapies – with or without the addition of high-dose melphalan and autologous stem cell transplantation – up to 80% of patients reach a complete response. As a logical and necessary step forward, clinical studies have explored strategies to detect minimal residual disease (MRD) and its correlation with clinical outcomes. In this context, MRD has been proposed as a regulatory endpoint for drug approval in newly diagnosed multiple myeloma. To better define the role of MRD negativity in relation to clinical outcomes, we undertook a meta-analysis including published clinical trials of newly diagnosed multiple myeloma patients. We applied a random effects model which weighted studies using the inverse-variance method. Studies were combined on the scale of the logarithm of the hazard ratio (HR) and the corresponding standard error. We found that remaining MRD positive was associated with worse progression-free survival (HR=2.85; 95% confidence interval (CI) 2.17–3.74; P
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- 2016
299. Near infrared spectroscopic imaging assessment of cartilage composition: Validation with mid infrared imaging spectroscopy
- Author
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Sean M. Devlin, Peter I. Lelkes, Arash Hanifi, Nancy Pleshko, Uday Palukuru, and Cushla McGoverin
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0301 basic medicine ,Cartilage, Articular ,Osteoarthritis ,Biochemistry ,Article ,Analytical Chemistry ,Absorbance ,03 medical and health sciences ,0302 clinical medicine ,Nuclear magnetic resonance ,Partial least squares regression ,medicine ,Transmittance ,Environmental Chemistry ,Animals ,Spectroscopy ,030203 arthritis & rheumatology ,Spectroscopy, Near-Infrared ,Chemistry ,Cartilage ,Near-infrared spectroscopy ,medicine.disease ,Imaging spectroscopy ,030104 developmental biology ,medicine.anatomical_structure ,Cattle - Abstract
Disease or injury to articular cartilage results in loss of extracellular matrix components which can lead to the development of osteoarthritis (OA). To better understand the process of disease development, there is a need for evaluation of changes in cartilage composition without the requirement of extensive sample preparation. Near infrared (NIR) spectroscopy is a chemical investigative technique based on molecular vibrations that is increasingly used as an assessment tool for studying cartilage composition. However, the assignment of specific molecular vibrations to absorbance bands in the NIR spectrum of cartilage, which arise from overtones and combinations of primary absorbances in the mid infrared (MIR) spectral region, has been challenging. In contrast, MIR spectroscopic assessment of cartilage is well-established, with many studies validating the assignment of specific bands present in MIR spectra to specific molecular vibrations. In the current study, NIR imaging spectroscopic data were obtained for compositional analysis of tissues that served as an in vitro model of OA. MIR spectroscopic data obtained from the identical tissue regions were used as the gold-standard for collagen and proteoglycan (PG) content. MIR spectroscopy in transmittance mode typically requires a much shorter pathlength through the sample (≤10 microns thick) compared to NIR spectroscopy (millimeters). Thus, this study first addressed the linearity of small absorbance bands in the MIR region with increasing tissue thickness, suitable for obtaining a signal in both the MIR and NIR regions. It was found that the linearity of specific, small MIR absorbance bands attributable to the collagen and PG components of cartilage (at 1336 and 856 cm−1, respectively) are maintained through a thickness of 60 μm, which was also suitable for NIR data collection. MIR and NIR spectral data were then collected from 60 μm thick samples of cartilage degraded with chondroitinase ABC as a model of OA. Partial least squares (PLS) regression using NIR spectra as input predicted the MIR-determined compositional parameters of PG/collagen within 6% of actual values. These results indicate that NIR spectral data can be used to assess molecular changes that occur with cartilage degradation, and further, the data provide a foundation for future clinical studies where NIR fiber optic probes can be used to assess the progression of cartilage degradation.
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- 2016
300. Treatment outcomes and secondary cancer incidence in young patients with hairy cell leukaemia
- Author
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Martin S. Tallman, Kaitlin M. Woo, Jae H. Park, Bartlomiej Getta, Alan Saven, Omar Abdel-Wahab, Sean M. Devlin, and Kanti R. Rai
- Subjects
0301 basic medicine ,Adult ,Male ,medicine.medical_specialty ,medicine.medical_treatment ,Disease ,Article ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Cumulative incidence ,Young adult ,Survival analysis ,Aged ,Aged, 80 and over ,Chemotherapy ,Leukemia, Hairy Cell ,business.industry ,Incidence (epidemiology) ,Incidence ,Age Factors ,Cancer ,Neoplasms, Second Primary ,Hematology ,Middle Aged ,medicine.disease ,Survival Analysis ,Surgery ,Clinical trial ,030104 developmental biology ,Treatment Outcome ,030220 oncology & carcinogenesis ,Female ,business ,Follow-Up Studies - Abstract
Repeated therapy of hairy cell leukaemia (HCL) with treatments that have potential long-term toxicities has raised concerns regarding increased risk for younger patients. We compared clinical outcomes and disease complications in 63 patients with HCL aged ≤40 years at diagnosis with 268 patients >40 years treated at Memorial Sloan Kettering Cancer Center. The rate of complete remission following initial therapy was 87% and 83% (P = 0·71) and estimated 10-year overall survival was 100% and 82% (P = 0·25) in younger and older patients, respectively. Younger patients required therapy earlier and had a significantly shorter time between first and second therapy (median: 63 months vs. 145 months) (P = 0·008). Younger patients required significantly more lines of therapy during follow-up. The 10-year cumulative incidence of secondary malignancies in young and old patients was 0·205 and 0·287, respectively (P = 0·22). The incidence of secondary cancers in patients aged >40 years at diagnosis increased with the number of treatments for HCL (P = 0·018). These results highlight that young patients with HCL have shorter responses to treatment and require more lines of therapy to maintain disease control, while attaining similar long-term survival. This has implications in the design of future clinical trials given our findings that secondary malignancies increase with more chemotherapy exposure.
- Published
- 2016
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