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1. Using a Modified Delphi Panel to Estimate Health Service Utilization for Patients with Advanced and Non-Advanced Systemic Light Chain Amyloidosis

Author

Gertz M, Abonour R, Gibbs SN, Finkel M, Landau H, Lentzsch S, Lin G, Mahindra A, Quock T, Rosenbaum C, Rosenzweig M, Sidana S, Tuchman SA, Witteles R, Yermilov I, and Broder MS

Subjects
consensus, hematology, outcomes research, mayo stage, cardiac failure, Medicine (General), R5-920, Therapeutics. Pharmacology, RM1-950
Abstract

Morie Gertz,1,* Rafat Abonour,2,* Sarah N Gibbs,3,* Muriel Finkel,4,* Heather Landau,5,* Suzanne Lentzsch,6,* Grace Lin,7,* Anuj Mahindra,8,* Tiffany Quock,9,* Cara Rosenbaum,10,* Michael Rosenzweig,11,* Surbhi Sidana,12,* Sascha A Tuchman,13,* Ronald Witteles,12,* Irina Yermilov,3,* Michael S Broder3,* 1Department of Medicine, Mayo Clinic, Rochester, MN, USA; 2Department of Medicine, Indiana University School of Medicine; Director, Multiple Myeloma, Waldenstrom’s Disease and Amyloidosis Program, Indianapolis, IN, USA; 3PHAR (Partnership for Health Analytic Research), Beverly Hills, CA, USA; 4Amyloidosis Support Groups Inc, Wood Dale, IL, USA; 5Memorial Sloan-Kettering Cancer Center, New York, NY, USA; 6Multiple Myeloma and Amyloidosis Program, Columbia University Medical Center, New York, NY, USA; 7Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA; 8Malignant Hematology, Scripps Clinic MD Anderson Cancer Center, La Jolla, CA, USA; 9Health Economics and Outcomes Research, Prothena Biosciences Ltd., South San Francisco, CA, USA; 10Department of Medicine, Hematology/Oncology, Weill Cornell Medical College, New York, NY, USA; 11Division of Multiple Myeloma, Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA, USA; 12Division of Cardiovascular Medicine, Stanford School of Medicine, Palo Alto, CA, USA; 13Division of Hematology, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA*These authors contributed equally to this workCorrespondence: Michael S Broder, PHAR (Partnership for Health Analytic Research), 280 S Beverly Drive, Suite 404, Beverly Hills, CA, 90212, USA, Tel +1 310 858 9555, Email mbroder@pharllc.comPurpose: Patients with diagnosed with systemic light chain (AL) amyloidosis at advanced Mayo stages have greater morbidity and mortality than those diagnosed at non-advanced stages. Estimating service use by severity is difficult because Mayo stage is not available in many secondary databases. We used an expert panel to estimate healthcare utilization among advanced and non-advanced AL amyloidosis patients.Patients and Methods: Using the RAND/UCLA modified Delphi method, expert panelists completed 180 healthcare utilization estimates, consisting of inpatient and outpatient visits, testing, chemotherapy, and procedures by disease severity and organ involvement during two treatment phases (the 1 year after starting first line [1L] therapy and 1 year following treatment [post-1L]). Estimates were also provided for post-1L by hematologic treatment response (complete or very good partial response [CR/VGPR], partial, no response or relapse [PR/NR/R]). Areas of disagreement were discussed during a meeting, after which ratings were completed a second time.Results: During 1L therapy, 55% of advanced patients had ≥ 1 hospitalization and 38% had ≥ 2 admissions. Rates of hematopoietic stem cell transplant (HSCT) in advanced patients were 5%, while pacemaker or implantable cardioverter defibrillator (ICD) placement were 15%. During post-1L therapy, rates of hospitalization in advanced patients remained high (≥ 1 hospitalization: 20-43%, ≥ 2 hospitalizations: 10-20%), and up to 10% of advanced patients had a HSCT. Ten percent of these patients underwent pacemaker/ICD placement.Conclusion: Experts estimated advanced patients, who would not be good candidates for HSCT, would have high rates of hospitalization (traditionally the most expensive type of healthcare utilization) and other health service use. The development of new treatment options that can facilitate organ recovery and improve function may lead to decreased utilization.Keywords: consensus, hematology, outcomes research, mayo stage, cardiac failure

Published
2023

2. Mapping Outcomes and Registries Used in Current Danish Pharmacoepidemiological Research

Author

Thor Petersen C, Jensen KJ, Rosenzweig M, von Osmanski BI, Ankarfeldt MZ, and Petersen J

Subjects
pharmacoepidemiology, registries, review, denmark, drugs, Infectious and parasitic diseases, RC109-216
Abstract

Charlotte Thor Petersen,1,2 Kristoffer Jarlov Jensen,1 Mary Rosenzweig,2 Benedikte Irene von Osmanski,1,2 Mikkel Zöllner Ankarfeldt,1 Janne Petersen1,3 1Copenhagen Phase IV Unit (Phase4CPH), Copenhagen University Hospital Bispebjerg and Frederiksberg, Copenhagen, Denmark; 2Life Science Insights Centre, DLI Market Intelligence, Copenhagen, Denmark; 3Section of Biostatistics, University of Copenhagen, Copenhagen, DenmarkCorrespondence: Charlotte Thor Petersen, Life Science Insights Centre, DLI Market Intelligence, Copenhagen, Denmark, Tel +45 30 35 20 43, Email ctp@dlimi.comPurpose: There is an increasing need for national and international pharmacoepidemiological studies based on high-quality real-world data of which the Danish registries are a valuable source. In lack of a complete overview of which data are used to assess real-world drug safety and effectiveness outcomes, we aimed to map the outcomes, data sources, and the reporting of outcome quality in recent pharmacoepidemiological studies.Methods: We conducted a systematic mapping review of pharmacoepidemiological studies based on Danish registries investigating drug safety and/or effectiveness, published in the period 2018– 2019, identified in PubMed and Scopus. Extraction included: Anatomical Therapeutic Chemical level 2 code for drug exposures, outcomes, outcome data sources, and quality of outcomes.Results: Of the 210 included studies, 96% used outcomes categorized as Clinical, 4% utilized outcomes categorized as Society-related, 5% used outcomes categorized as Healthcare cost and utilization, and 3% of the studies applied outcomes categorized as Patient-reported in which the percentages are not mutually exclusive. Diagnosis (66%) and Mortality (38%) were the two most utilized subcategories among those categorized as Clinical outcomes. Danish Health Data Authority and Statistics Denmark registries were the most reported outcome data sources (90%). Ninety-six studies (46%) reported one or more quality parameters related to their outcomes of interest with accuracy/validity being the most reported parameter (22%).Conclusion: The Danish registries support a wide range of outcomes. Across therapeutic areas, most studies investigate traditional clinical outcomes of disease and mortality based on data from a small number of available registries. In contrast, clinical and biochemical databases, despite potentially offering outcomes with high responsiveness, and the high-quality social and healthcare cost registries were rarely used as outcome data sources.Keywords: pharmacoepidemiology, registries, review, Denmark, drugs

Published
2022

3. Patients with NSCLCs Harboring Internal Inversions or Deletion Rearrangements of the ALK Gene Have Durable Responses to ALK Kinase Inhibitors

Author

Schrock AB, Madison R, Rosenzweig M, Allen JM, Erlich RL, Wang SY, Chidiac T, Reddy VS, Riess JW, Yassa AE, Shakir A, Miller VA, Alexander BM, Venstrom J, McGregor K, and Ali SM

Subjects
alk rearrangement, inversion, deletion, genomic profiling, targeted therapy, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Alexa B Schrock,1 Russell Madison,1 Mark Rosenzweig,2 Justin M Allen,2 Rachel L Erlich,2 Siao-Yi Wang,3 Tarek Chidiac,4 Vodur Suresh Reddy,5 Jonathan W Riess,6 Ahmet Ersin Yassa,6 Abdur Shakir,7 Vincent A Miller,1 Brian M Alexander,1 Jeffrey Venstrom,1 Kimberly McGregor,1 Siraj M Ali1 1Foundation Medicine, Department of Clinical Development, Cambridge, MA, USA; 2Foundation Medicine, Department of Translational Oncology and Clinical Reporting, Cambridge, MA, USA; 3Loyola University Medical Cancer, Department of Hematology and Oncology, Maywood, IL, USA; 4Zangmeister Cancer Center, Department of Hematology and Oncology, Columbus, OH, USA; 5Cancer Care Specialists, Department of Hematology and Oncology, Reno, NV, USA; 6UC Davis Comprehensive Cancer Center, Department of Hematology and Oncology Sacramento, CA, USA; 7Sarah Bush Lincoln Health System, Department of Medical Oncology, Mattoon, IL, USACorrespondence: Alexa B SchrockFoundation Medicine, 150 Second Street, Cambridge, MA 02141, USATel +1617-418-2200Email aschrock@foundationmedicine.comBackground: ALK fusions are targetable drivers in non-small-cell lung cancer (NSCLC). However, patients with NSCLC harboring ALK rearrangements without a fusion partner identified in DNA have also been shown to respond to ALK inhibitors. We aimed to characterize complex ALK variants that may predict sensitivity to multiple approved ALK inhibitors.Methods: Comprehensive genomic profiling (CGP) of DNA isolated from formalin‐fixed paraffin‐embedded (FFPE) tumor tissue or blood-based circulating tumor DNA was performed for 39,159 NSCLC patients during routine clinical care. For a subset of cases, RNA sequencing was performed, and prior ALK test results and clinical treatment information were collected from treating physicians.Results: We queried the Foundation Medicine NSCLC database and identified ALK internal inversions, as well as internal deletions, as the sole ALK rearrangements in 6 (0.02%) and 3 (0.01%) of cases, respectively. In cases with ALK internal inversions, RNA testing identified an EML4-ALK fusion in 2/2 cases evaluated, and 3/3 patients treated with ALK inhibitors had durable responses. A single patient with an ALK internal deletion and clinical data available responded to multiple ALK inhibitors. RNA data available for a subset of non-NSCLC cases suggest that ALK internal deletions removing a portion of the N-terminus are drivers themselves and do not result in ALK fusions. Fluorescence in situ hybridization (FISH) results were inconsistent for both classes of DNA events.Conclusion: Rare internal inversions of ALK appear to be indicative of ALK fusions, which can be detected in RNA, and response to ALK inhibitors in patients with NSCLC. In contrast, ALK internal deletions are not associated with ALK fusions in RNA but likely represent targetable drivers themselves. These data suggest that CGP of DNA should be supplemented with immunohistochemistry or RNA-based testing to further resolve these events and match patients to effective therapies.Keywords: ALK rearrangement, inversion, deletion, genomic profiling, targeted therapy

Published
2020

6. Phase I Study of Bortezomib, Fludarabine, and Melphalan, with or without Total Marrow Irradiation as Conditioning for Allogeneic Hematopoietic Stem Cell Transplantation in Patients with High-Risk or Relapsed/Refractory Multiple Myeloma

Author

Ladbury, C.J., primary, Sanchez, J.F., additional, Chowdhury, A., additional, Palmer, J., additional, Liu, A., additional, Stein, A., additional, Htut, M., additional, Farol, L., additional, Cai, J.L., additional, Somlo, G., additional, Rosenzweig, M., additional, Wong, J.Y.C., additional, and Sahebi, F., additional

Published
2023
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7. Recurrent hyperactive ESR1 fusion proteins in endocrine therapy-resistant breast cancer

Author

Hartmaier, R.J., Trabucco, S.E., Priedigkeit, N., Chung, J.H., Parachoniak, C.A., Vanden Borre, P., Morley, S., Rosenzweig, M., Gay, L.M., Goldberg, M.E., Suh, J., Ali, S.M., Ross, J., Leyland-Jones, B., Young, B., Williams, C., Park, B., Tsai, M., Haley, B., Peguero, J., Callahan, R.D., Sachelarie, I., Cho, J., Atkinson, J.M., Bahreini, A., Nagle, A.M., Puhalla, S.L., Watters, R.J., Erdogan-Yildirim, Z., Cao, L., Oesterreich, S., Mathew, A., Lucas, P.C., Davidson, N.E., Brufsky, A.M., Frampton, G.M., Stephens, P.J., Chmielecki, J., and Lee, A.V.

Published
2018
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14. Daratumumab-Based Treatment for Immunoglobulin Light-Chain Amyloidosis

Author

Kastritis E., Palladini G., Minnema M. C., Wechalekar A. D., Jaccard A., Lee H. C., Sanchorawala V., Gibbs S., Mollee P., Venner C. P., Lu J., Schonland S., Gatt M. E., Suzuki K., Kim K., Cibeira M. T., Beksac M., Libby E., Valent J., Hungria V., Wong S. W., Rosenzweig M., Bumma N., Huart A., Dimopoulos M. A., Bhutani D., Waxman A. J., Goodman S. A., Zonder J. A., Lam S., Song K., Hansen T., Manier S., Roeloffzen W., Jamroziak K., Kwok F., Shimazaki C., Kim J. -S., Crusoe E., Ahmadi T., Tran N., Qin X., Vasey S. Y., Tromp B., Schecter J. M., Weiss B. M., Zhuang S. H., Vermeulen J., Merlini G., Comenzo R. L., Bradley Augustson, Fiona Kwok, Peter Mollee, Simon Gibbs, Chantal Doyen, Greet Bries, Isabelle Vande Broek, Ka Lung Wu, Koen Theunissen, Koen Van Eygen, Michel Delforge, Nathalie Meuleman, Philip Vlummens, Angelo Maiolino, Breno Moreno de Gusmão, Carlos Eduardo Miguel, Edvan Crusoe, Fernanda Moura, Fernanda Seguro, Jandey Bigonha, Juliane Musacchio, Karla Zanella, Laura Garcia, Marcelo Eduardo Zanella Capra, Reijane Alves de Assis, Rosane Bittencourt, Vania Hungria, Walter Braga, Wolney Barreto, Christopher Venner, Donna Reece, Emilie Lemieux-Blanchard, Kevin Song, Michael Sebag, Selay Lam, Victor Zepeda, Haitao Zhang, Jianda Hu, Jin Lu, Juan Li, Songfu Jiang, Ting Niu, Wenming Chen, Xiaonong Chen, Zhen Cai, Zhou Fude, Maja Oelholm Vase, Morten Salomo, Niels Abildgaard, Alain Fuzibet, Anne-Marie Stoppa, Arnaud Jaccard, Bertrand Arnulf, Bruno Moulin, Bruno Royer, David Ghez, Denis Caillot, Dominique Chauveau, Franck Bridoux, Lauriane Clement-Filliatre, Lionel Karlin, Lotfi Benboubker, Mamoun Dib, Margaret Macro, Mohamad Mohty, Olivier Decaux, Olivier Hermine, Olivier Tournilhac, Philippe Moreau, Salomon Manier, Sylvain Choquet, Véronique Dorvaux, Alexander Carpinteiro, Axel Nogai, Britta Besemer, Christoph Roellig, Roland Fenk, Stefan Knop, Stefan Schönland, Timon Hansen, Argiris Symeonidis, Efstathios Kastritis, Gabor Mikala, Tamás Masszi, Zsolt Nagy, Celia Suriu, Hila Magen, Iuliana Vaxman, Lev Shvidel, Meir Preis, Moshe Gatt, Noa Lavi, Osnat Jarchowsky, Tamar Tadmor, Yael Cohen, Angelo Vacca, Giovanni Palladini, Mario Boccadoro, Maurizio Martelli, Maurizio Musso, Michele Cavo, Chihiro Shimazaki, Hiroyuki Takamatsu, Kazutaka Sunami, Kenshi Suzuki, Nagaaki Katoh, Shinsuke Iida, Takayuki Ikezoe, Tomoaki Fujisaki, Yuta Katayama, Chang Ki Min, Ho-Jin Shin, Jin Seok Kim, Jung Yong Hong, Ki Hyun Kim, Sung-Soo Yoon, Aline Ramirez, Alvaro Cabrera, Christian Ramos, David Gomez Almaguer, Deborah Martinez, Guillermo Ruiz, Helen Dayani Caballero, Juan Antonio Flores Jimenez, Annemiek Broijl, Laurens Nieuwenhuizen, Monique Minnema, Paula Ypma, Wilfried Roeloffzen, Dominik Dytfeld, Grzegorz Charlinski, Grzegorz Helbig, Krzysztof Jamroziak, Sebastian Grosicki, Wieslaw Jedrzejczak, Albert Oriol Rocafiguera, Elham Askari, Fernando Escalante Barrigon, Isabel Krsnik Castello, Javier De la Rubia Comos, Jesus Martin Sanchez, Joaquin Martinez Lopez, Jose Angel Hernandez Rivas, Luis Felipe Casado Montero, Maria Jesus Blanchard Rodriguez, Maria Teresa Cibeira Lopez, Maria Victoria Mateos Manteca, Marta Sonia Gonzalez Perez, Mercedes Gironella Mesa, Rafael Rios Tamayo, Ramon Lecumberri Villamediana, Ricarda Garcia Sanchez, Sunil Lakhwani, Yolanda Gonzalez, Hareth Nahi, Kristina Carlsson, Markus Hansson, Ulf-Henrik Mellqvist, Ali Unal, Burhan Ferhanoglu, Hayri Ozsan, Levent Undar, Mehmet Turgut, Mehmet Yilmaz, Meral Beksac, Muhlis Cem Ar, Muzaffer Demir, Sevgi Besisik, Ashutosh Wechalekar, Jamie Cavenagh, Jim Cavet, Mark Cook, Rachel Hall, Adam Waxman, Anuj Mahindra, Cesar Rodriguez Valdes, Christine Ye, Craig Reeder, Daphne Friedman, David Siegel, Divaya Bhutani, Edward Libby, Eva Medvedova, Frank Passero, Giada Bianchi, Giampaolo Talamo, Guido Tricot, Hans Lee, Heather Landau, Jan Moreb, Jason Valent, Jeffrey Matous, Jeffrey A Zonder, Jesus Berdeja, Jonathan Kaufman, Keith Stockerl-Goldstein, Keren Osman, Ketan Doshi, Kevin Barton, Larry Anderson, Manisha Bhutani, Mehmet Kocoglu, Michael Rosenzweig, Michael Schuster, Michaela Liedtke, Morie Gertz, Naresh Bumma, Natalie Callander, Raymond Comenzo, Robert Vescio, Roger Pearse, Sandy W Wong, Stacey A Goodman, Stefano Tarantolo, Taimur Sher, Tibor Kovacsovics, Tomer Mark, Vaishali Sanchorawala, William Bensinger, Role of intra-Clonal Heterogeneity and Leukemic environment in ThErapy Resistance of chronic leukemias (CHELTER), Université Clermont Auvergne (UCA), Kastritis E., Palladini G., Minnema M.C., Wechalekar A.D., Jaccard A., Lee H.C., Sanchorawala V., Gibbs S., Mollee P., Venner C.P., Lu J., Schonland S., Gatt M.E., Suzuki K., Kim K., Cibeira M.T., Beksac M., Libby E., Valent J., Hungria V., Wong S.W., Rosenzweig M., Bumma N., Huart A., Dimopoulos M.A., Bhutani D., Waxman A.J., Goodman S.A., Zonder J.A., Lam S., Song K., Hansen T., Manier S., Roeloffzen W., Jamroziak K., Kwok F., Shimazaki C., Kim J.-S., Crusoe E., Ahmadi T., Tran N., Qin X., Vasey S.Y., Tromp B., Schecter J.M., Weiss B.M., Zhuang S.H., Vermeulen J., Merlini G., and Comenzo R.L., Bradley Augustson, Fiona Kwok, Peter Mollee, Simon Gibbs, Chantal Doyen, Greet Bries, Isabelle Vande Broek, Ka Lung Wu, Koen Theunissen, Koen Van Eygen, Michel Delforge, Nathalie Meuleman, Philip Vlummens, Angelo Maiolino, Breno Moreno de Gusmão, Carlos Eduardo Miguel, Edvan Crusoe, Fernanda Moura, Fernanda Seguro, Jandey Bigonha, Juliane Musacchio, Karla Zanella, Laura Garcia, Marcelo Eduardo Zanella Capra, Reijane Alves de Assis, Rosane Bittencourt, Vania Hungria, Walter Braga, Wolney Barreto, Christopher Venner, Donna Reece, Emilie Lemieux-Blanchard, Kevin Song, Michael Sebag, Selay Lam, Victor Zepeda, Haitao Zhang, Jianda Hu, Jin Lu, Juan Li, Songfu Jiang, Ting Niu, Wenming Chen, Xiaonong Chen, Zhen Cai, Zhou Fude, Maja Oelholm Vase, Morten Salomo, Niels Abildgaard, Alain Fuzibet, Anne-Marie Stoppa, Arnaud Jaccard, Bertrand Arnulf, Bruno Moulin, Bruno Royer, David Ghez, Denis Caillot, Dominique Chauveau, Franck Bridoux, Lauriane Clement-Filliatre, Lionel Karlin, Lotfi Benboubker, Mamoun Dib, Margaret Macro, Mohamad Mohty, Olivier Decaux, Olivier Hermine, Olivier Tournilhac, Philippe Moreau, Salomon Manier, Sylvain Choquet, Véronique Dorvaux, Alexander Carpinteiro, Axel Nogai, Britta Besemer, Christoph Roellig, Roland Fenk, Stefan Knop, Stefan Schönland, Timon Hansen, Argiris Symeonidis, Efstathios Kastritis, Gabor Mikala, Tamás Masszi, Zsolt Nagy, Celia Suriu, Hila Magen, Iuliana Vaxman, Lev Shvidel, Meir Preis, Moshe Gatt, Noa Lavi, Osnat Jarchowsky, Tamar Tadmor, Yael Cohen, Angelo Vacca, Giovanni Palladini, Mario Boccadoro, Maurizio Martelli, Maurizio Musso, Michele Cavo, Chihiro Shimazaki, Hiroyuki Takamatsu, Kazutaka Sunami, Kenshi Suzuki, Nagaaki Katoh, Shinsuke Iida, Takayuki Ikezoe, Tomoaki Fujisaki, Yuta Katayama, Chang Ki Min, Ho-Jin Shin, Jin Seok Kim, Jung Yong Hong, Ki Hyun Kim, Sung-Soo Yoon, Aline Ramirez, Alvaro Cabrera, Christian Ramos, David Gomez Almaguer, Deborah Martinez, Guillermo Ruiz, Helen Dayani Caballero, Juan Antonio Flores Jimenez, Annemiek Broijl, Laurens Nieuwenhuizen, Monique Minnema, Paula Ypma, Wilfried Roeloffzen, Dominik Dytfeld, Grzegorz Charlinski, Grzegorz Helbig, Krzysztof Jamroziak, Sebastian Grosicki, Wieslaw Jedrzejczak, Albert Oriol Rocafiguera, Elham Askari, Fernando Escalante Barrigon, Isabel Krsnik Castello, Javier De la Rubia Comos, Jesus Martin Sanchez, Joaquin Martinez Lopez, Jose Angel Hernandez Rivas, Luis Felipe Casado Montero, Maria Jesus Blanchard Rodriguez, Maria Teresa Cibeira Lopez, Maria Victoria Mateos Manteca, Marta Sonia Gonzalez Perez, Mercedes Gironella Mesa, Rafael Rios Tamayo, Ramon Lecumberri Villamediana, Ricarda Garcia Sanchez, Sunil Lakhwani, Yolanda Gonzalez, Hareth Nahi, Kristina Carlsson, Markus Hansson, Ulf-Henrik Mellqvist, Ali Unal, Burhan Ferhanoglu, Hayri Ozsan, Levent Undar, Mehmet Turgut, Mehmet Yilmaz, Meral Beksac, Muhlis Cem Ar, Muzaffer Demir, Sevgi Besisik, Ashutosh Wechalekar, Jamie Cavenagh, Jim Cavet, Mark Cook, Rachel Hall, Adam Waxman, Anuj Mahindra, Cesar Rodriguez Valdes, Christine Ye, Craig Reeder, Daphne Friedman, David Siegel, Divaya Bhutani, Edward Libby, Eva Medvedova, Frank Passero, Giada Bianchi, Giampaolo Talamo, Guido Tricot, Hans Lee, Heather Landau, Jan Moreb, Jason Valent, Jeffrey Matous, Jeffrey A Zonder, Jesus Berdeja, Jonathan Kaufman, Keith Stockerl-Goldstein, Keren Osman, Ketan Doshi, Kevin Barton, Larry Anderson, Manisha Bhutani, Mehmet Kocoglu, Michael Rosenzweig, Michael Schuster, Michaela Liedtke, Morie Gertz, Naresh Bumma, Natalie Callander, Raymond Comenzo, Robert Vescio, Roger Pearse, Sandy W Wong, Stacey A Goodman, Stefano Tarantolo, Taimur Sher, Tibor Kovacsovics, Tomer Mark, Vaishali Sanchorawala, William Bensinger

Subjects
Male, Treatment outcome, Immunoglobulin Light-chain Amyloidosis/drug therapy, CD38, Dexamethasone, Cyclophosphamide/administration & dosage, Bortezomib, 0302 clinical medicine, Antineoplastic Combined Chemotherapy Protocols, Medicine, CRITERIA, Immunoglobulin Light-chain Amyloidosis, ComputingMilieux_MISCELLANEOUS, Aged, 80 and over, biology, Amyloidosis, Antibodies, Monoclonal, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, General Medicine, Middle Aged, 3. Good health, Treatment Outcome, 030220 oncology & carcinogenesis, Female, Antibody, Human, Adult, Dexamethasone/administration & dosage, ANTIBODY DARATUMUMAB, Immunoglobulin light chain, DIAGNOSIS, Antibodies, Monoclonal/administration & dosage, Disease-Free Survival, 03 medical and health sciences, Humans, Cyclophosphamide, Aged, Antineoplastic Combined Chemotherapy Protocol, business.industry, Antineoplastic Combined Chemotherapy Protocols/adverse effects, AL AMYLOIDOSIS, Daratumumab, Amyloid fibril, medicine.disease, Molecular biology, Immunoglobulin Light-chain Amyloidosi, biology.protein, Bortezomib/administration & dosage, business, 030215 immunology
Abstract

Systemic immunoglobulin light-chain (AL) amyloidosis is characterized by deposition of amyloid fibrils of light chains produced by clonal CD38+ plasma cells. Daratumumab, a human CD38-targeting antibody, may improve outcomes for this disease.We randomly assigned patients with newly diagnosed AL amyloidosis to receive six cycles of bortezomib, cyclophosphamide, and dexamethasone either alone (control group) or with subcutaneous daratumumab followed by single-agent daratumumab every 4 weeks for up to 24 cycles (daratumumab group). The primary end point was a hematologic complete response.A total of 388 patients underwent randomization. The median follow-up was 11.4 months. The percentage of patients who had a hematologic complete response was significantly higher in the daratumumab group than in the control group (53.3% vs. 18.1%) (relative risk ratio, 2.9; 95% confidence interval [CI], 2.1 to 4.1; P0.001). Survival free from major organ deterioration or hematologic progression favored the daratumumab group (hazard ratio for major organ deterioration, hematologic progression, or death, 0.58; 95% CI, 0.36 to 0.93; P = 0.02). At 6 months, more cardiac and renal responses occurred in the daratumumab group than in the control group (41.5% vs. 22.2% and 53.0% vs. 23.9%, respectively). The four most common grade 3 or 4 adverse events were lymphopenia (13.0% in the daratumumab group and 10.1% in the control group), pneumonia (7.8% and 4.3%, respectively), cardiac failure (6.2% and 4.8%), and diarrhea (5.7% and 3.7%). Systemic administration-related reactions to daratumumab occurred in 7.3% of the patients. A total of 56 patients died (27 in the daratumumab group and 29 in the control group), most due to amyloidosis-related cardiomyopathy.Among patients with newly diagnosed AL amyloidosis, the addition of daratumumab to bortezomib, cyclophosphamide, and dexamethasone was associated with higher frequencies of hematologic complete response and survival free from major organ deterioration or hematologic progression. (Funded by Janssen Research and Development; ANDROMEDA ClinicalTrials.gov number, NCT03201965.).

Published
2021
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16. P965: FOLLOW-UP ANALYSIS OF THE RANDOMIZED PHASE II TRIAL OF BORTEZOMIB, LENALIDOMIDE, DEXAMTHASONE WITH/WITHOUT ELOTUZUMAB FOR NEWLY DIAGNOSED, HIGH RISK MULTIPLE MYELOMA (SWOG-1211)

Author

Usmani, S., primary, Hoering, A., additional, Ailawadhi, S., additional, Sexton, R., additional, Lipe, B., additional, Valent, J., additional, Rosenzweig, M., additional, Zonder, J., additional, Dhodapkar, M., additional, Callander, N., additional, Zimmerman, T., additional, Voorhees, P., additional, Durie, B., additional, Rajkumar, S. V., additional, Richardson, P., additional, and Orlowski, R., additional

Published
2022
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17. Health-related quality of life in patients with light chain amyloidosis treated with bortezomib, cyclophosphamide, and dexamethasone ± daratumumab: Results from the ANDROMEDA study

Author

Sanchorawala, V. Palladini, G. Minnema, M.C. Jaccard, A. Lee, H.C. Gibbs, S. Mollee, P. Venner, C. Lu, J. Schönland, S. Gatt, M. Suzuki, K. Kim, K. Cibeira, M.T. Beksac, M. Libby, E. Valent, J. Hungria, V. Wong, S.W. Rosenzweig, M. Bumma, N. Chauveau, D. Gries, K.S. Fastenau, J. Tran, N.P. Qin, X. Vasey, S.Y. Weiss, B.M. Vermeulen, J. Ho, K.F. Merlini, G. Comenzo, R.L. Kastritis, E. Wechalekar, A.D.

Subjects
endocrine system, humanities
Abstract

In the phase 3 ANDROMEDA trial, patients treated with daratumumab, bortezomib, cyclophosphamide, and dexamethasone (D-VCd) had significantly higher rates of organ and hematologic response compared with patients who received VCd alone. Here, we present patient-reported outcomes (PROs) from the ANDROMEDA trial. PROs were assessed through cycle 6 using three standardized questionnaires. Treatment effect through cycle 6 was measured by a repeated-measures, mixed-effects model. The magnitude of changes in PROs versus baseline was generally low, but between-group differences favored the D-VCd group. Results were generally consistent irrespective of hematologic, cardiac, or renal responses. More patients in the D-VCd group experienced meaningful improvements in PROs; median time to improvement was more rapid in the D-VCd group versus the VCd group. After cycle 6, patients in the D-VCd group received daratumumab monotherapy and their PRO assessments continued, with improvements in health-related quality of life (HRQoL) reported through cycle 19. PROs of subgroups with renal and cardiac involvement were consistent with those of the intent-to-treat population. These results demonstrate that the previously reported clinical benefits of D-VCd were achieved without decrement to patients' HRQoL and provide support of D-VCd in patients with AL amyloidosis. © 2022 Wiley Periodicals LLC.

Published
2022

28. Daratumumab-Based Treatment for Immunoglobulin Light-Chain Amyloidosis

Author

Kastritis, E. Palladini, G. Minnema, M. C. Wechalekar, A. D. and Jaccard, A. Lee, H. C. Sanchorawala, V Gibbs, S. and Mollee, P. Venner, C. P. Lu, J. Schonland, S. Gatt, M. E. Suzuki, K. Kim, K. Cibeira, M. T. Beksac, M. and Libby, E. Valent, J. Hungria, V Wong, S. W. Rosenzweig, M. Bumma, N. Huart, A. Dimopoulos, M. A. Bhutani, D. and Waxman, A. J. Goodman, S. A. Zonder, J. A. Lam, S. Song, K. Hansen, T. Manier, S. Roeloffzen, W. Jamroziak, K. and Kwok, F. Shimazaki, C. Kim, J-S Crusoe, E. Ahmadi, T. Tran, N. P. Qin, X. Vasey, S. Y. Tromp, B. and Schecter, J. M. Weiss, B. M. Zhuang, S. H. Vermeulen, J. and Merlini, G. Comenzo, R. L. ANDROMEDA Trial Investigators

Abstract

Background Systemic immunoglobulin light-chain (AL) amyloidosis is characterized by deposition of amyloid fibrils of light chains produced by clonal CD38+ plasma cells. Daratumumab, a human CD38-targeting antibody, may improve outcomes for this disease. Methods We randomly assigned patients with newly diagnosed AL amyloidosis to receive six cycles of bortezomib, cyclophosphamide, and dexamethasone either alone (control group) or with subcutaneous daratumumab followed by single-agent daratumumab every 4 weeks for up to 24 cycles (daratumumab group). The primary end point was a hematologic complete response. Results A total of 388 patients underwent randomization. The median follow-up was 11.4 months. The percentage of patients who had a hematologic complete response was significantly higher in the daratumumab group than in the control group (53.3% vs. 18.1%) (relative risk ratio, 2.9; 95% confidence interval [CI], 2.1 to 4.1; P

Published
2021

30. Liver and Gastrointestinal Involvement: Update

Author

Rosenzweig, M. Kastritis, E.

Subjects
parasitic diseases, population characteristics, human activities
Abstract

The organs affected most commonly by AL amyloidosis are the kidneys and heart, however, liver and gastrointestinal (GI) tract are also commonly affected. Symptoms of GI amyloidosis often mimic those of other GI disorders; having a keen awareness of the need to evaluate for amyloidosis is critical in avoiding delay in diagnosis and intervention. GI and liver involvement is associated with significant complications, and challenges in symptomatic management. As with all AL-related organ disease, early systemic treatment can prevent progression of tissue damage and improve outcomes. © 2020 Elsevier Inc.

Published
2020

31. Daratumumab plus CyBorD for patients with newly diagnosed AL amyloidosis: Safety run-in results of ANDROMEDA

Author

Palladini, G. Kastritis, E. Maurer, M.S. Zonder, J. Minnema, M.C. Wechalekar, A.D. Jaccard, A. Lee, H.C. Bumma, N. Kaufman, J.L. Medvedova, E. Kovacsovics, T. Rosenzweig, M. Sanchorawala, V. Qin, X. Vasey, S.Y. Weiss, B.M. Vermeulen, J. Merlini, G. Comenzo, R.L.

Abstract

Although no therapies are approved for light chain (AL) amyloidosis, cyclophosphamide, bortezomib, and dexamethasone (CyBorD) is considered standard of care. Based on outcomes of daratumumab in multiple myeloma (MM), the phase 3 ANDROMEDA study (NCT03201965) is evaluating daratumumab-CyBorD vs CyBorD in newly diagnosed AL amyloidosis. We report results of the 28-patient safety run-in. Patients received subcutaneous daratumumab (DARA SC) weekly in cycles 1 to 2, every 2 weeks in cycles 3 to 6, and every 4 weeks thereafter for up to 2 years. CyBorD was given weekly for 6 cycles. Patients had a median of 2 involved organs (kidney, 68%; cardiac, 61%). Patients received a median of 16 (range, 1-23) treatment cycles. Treatment-emergent adverse events were consistent with DARA SC in MM and CyBorD. Infusion-related reactions occurred in 1 patient (grade 1). No grade 5 treatment-emergent adverse events occurred; 5 patients died, including 3 after transplant. Overall hematologic response rate was 96%, with a complete hematologic response in 15 (54%) patients; at least partial response occurred in 20, 22, and 17 patients at 1, 3, and 6 months, respectively. Renal response occurred in 6 of 16, 7 of 15, and 10 of 15 patients, and cardiac response occurred in 6 of 16, 6 of 13, and 8 of 13 patients at 3, 6, and 12 months, respectively. Hepatic response occurred in 2 of 3 patients at 12 months. Daratumumab-CyBorD was well tolerated, with no new safety concerns versus the intravenous formulation, and demonstrated robust hematologic and organ responses. This trial was registered at www.clinicaltrials.gov as #NCT03201965. © 2020 by The American Society of Hematology.

Published
2020

49. Enhancement of humoral and cellular immunity with an anti-glucocorticoid-induced tumour necrosis factor receptor monoclonal antibody

Author

Ponte, JF, Ponath, P, Gulati, R, Slavonic, M, Paglia, M, O'Shea, A, Tone, M, Waldmann, H, Vaickus, L, and Rosenzweig, M

Abstract

Adjuvants, including antibodies to tumour necrosis factor receptor superfamily members, augment immune responses. One member of this family, glucocorticoid-induced tumour necrosis factor receptor (GITR), is expressed at low levels on naive/resting T cells, B cells and macrophages, but at higher levels on T regulatory cells. The aim of this study was to determine the ability of a rat anti-mouse GITR monoclonal antibody, 2F8, to stimulate murine humoral and cellular immunity in a prime boost model with particular attention to posology and antigen-specific effects. 2F8 enhanced the humoral immune response to ovalbumin and haemagglutinin (HA) compared with controls and this enhancement was equal to or greater than that obtained in mice dosed with standard adjuvants. 2F8 F(ab')(2) fragments were as effective as intact antibody in boosting humoral immunity, indicating that FcR-mediated cross-linking of 2F8 is not required for efficacy. Moreover, the enhanced response was durable and antigen specific. Administration of 2F8 shifted the immune response towards a T helper type 1 response with significant enhancement of immunoglobulin G2a- and G2b-specific anti-HA antibodies, as well as enhanced cellular immunity as measured by ELISPOT. 2F8-treated mice also generated significantly more neutralizing antibodies to HA than control mice. Our findings show that anti-GITR is a robust, versatile adjuvant that, unlike commonly used adjuvants that primarily enhance humoral immunity, enhances both humoral and cellular immunity. These results support the continued development of anti-GITR for such indications as haematological and solid tumours, chronic viral infections, and as a vaccine adjuvant.

Published
2016

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