Fulminant Myocarditis with Combination Immune Checkpoint Blockade

被引：1773

作者：

Johnson, Douglas B. dbj ^{[1
]}

Balko, Justin M. jmb ^{[1
,2
,8
]}

Compton, Margaret L. mlc ^{[3
]}

Chalkias, Spyridon sc ^{[10
,11
]}

Gorham, Joshua jc ^{[14
]}

Xu, Yaomin yx ^{[4
,6
,9
]}

Hicks, Mellissa mh ^{[1
]}

Puzanov, Igor ip ^{[1
]}

Alexander, Matthew R. mra ^{[1
]}

Bloomer, Tyler L. tlb ^{[1
]}

Becker, Jason R. jrb ^{[1
]}

Slosky, David A. das ^{[1
,7
]}

Phillips, Elizabeth J. ejp ^{[1
]}

Pilkinton, Mark A. map ^{[1
]}

Craig-Owens, Laura lco ^{[3
]}

Kola, Nina nk ^{[16
]}

Plautz, Gregory gp ^{[16
]}

Reshef, Daniel S. dsr ^{[16
]}

Deutsch, Jonathan S. jsd ^{[16
]}

Deering, Raquel P. rpd ^{[17
]}

Olenchock, Benjamin A. bao ^{[12
]}

Lichtman, Andrew H. ahl ^{[13
]}

Roden, Dan M. dmr ^{[1
,5
,6
]}

Seidman, Christine E. ces ^{[12
,14
,15
]}

Koralnik, Igor J. ijk ^{[11
]}

Seidman, Jonathan G. jgs ^{[12
,14
]}

Hoffman, Robert D. rdh ^{[3
]}

Taube, Janis M. jmt ^{[18
,19
]}

Diaz, Luis A. Jr lad ^{[20
]}

Anders, Robert A. raa ^{[18
]}

Sosman, Jeffrey A. jas ^{[1
]}

Moslehi, Javid J. jjm ^{[1
,2
,7
]}

机构：

[1] Vanderbilt Univ, Med Ctr, Dept Med, Nashville, TN USA

[2] Vanderbilt Univ, Med Ctr, Dept Canc Biol, Nashville, TN USA

[3] Vanderbilt Univ, Med Ctr, Dept Pathol Microbiol & Immunol, Nashville, TN USA

[4] Vanderbilt Univ, Med Ctr, Dept Biostat, Nashville, TN USA

[5] Vanderbilt Univ, Med Ctr, Dept Pharmacol, Nashville, TN 37232 USA

[6] Vanderbilt Univ, Med Ctr, Dept Biomed Informat, Nashville, TN 37232 USA

[7] Vanderbilt Univ, Med Ctr, Cardiooncol Program, 2220 Pierce Ave, Nashville, TN 37232 USA

[8] Vanderbilt Univ, Med Ctr, Breast Canc Res Program, Nashville, TN 37232 USA

[9] Vanderbilt Univ, Med Ctr, Ctr Quantitat Sci, Nashville, TN 37232 USA

[10] Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02215 USA

[11] Beth Israel Deaconess Med Ctr, Div Neuroimmunol, Boston, MA 02215 USA

[12] Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA

[13] Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA

[14] Harvard Med Sch, Dept Genet, Boston, MA USA

[15] Howard Hughes Med Inst, Chevy Chase, MD USA

[16] Bristol Myers Squibb, New York, NY USA

[17] Neon Therapeut, Cambridge, MA USA

[18] Johns Hopkins Univ, Dept Pathol, Baltimore, MD USA

[19] Johns Hopkins Univ, Dept Dermatol, Baltimore, MD 21218 USA

[20] Johns Hopkins Univ, Dept Oncol, Baltimore, MD USA

来源：

NEW ENGLAND JOURNAL OF MEDICINE | 2016年 / 375卷 / 18期

基金：

美国国家卫生研究院;

关键词：

DILATED CARDIOMYOPATHY; UNTREATED MELANOMA; PD-1; BLOCKADE; IPILIMUMAB; NIVOLUMAB; PEMBROLIZUMAB; INFLAMMATION; AUTOPSY; HEART; RISK;

D O I：

10.1056/NEJMoa1609214

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Immune checkpoint inhibitors have improved clinical outcomes associated with numerous cancers, but high-grade, immune-related adverse events can occur, particularly with combination immunotherapy. We report the cases of two patients with melanoma in whom fatal myocarditis developed after treatment with ipilimumab and nivolumab. In both patients, there was development of myositis with rhabdomyolysis, early progressive and refractory cardiac electrical instability, and myocarditis with a robust presence of T-cell and macrophage infiltrates. Selective clonal T-cell populations infiltrating the myocardium were identical to those present in tumors and skeletal muscle. Pharmacovigilance studies show that myocarditis occurred in 0.27% of patients treated with a combination of ipilimumab and nivolumab, which suggests that our patients were having a rare, potentially fatal, T-cell-driven drug reaction. (Funded by Vanderbilt-Ingram Cancer Center Ambassadors and others.)

引用

页码：1749 / 1755

页数：7

共 24 条

[1] Using synthetic templates to design an unbiased multiplex PCR assay [J].

Carlson, Christopher S. ;

Emerson, Ryan O. ;

Sherwood, Anna M. ;

Desmarais, Cindy ;

Chung, Moon-Wook ;

Parsons, Joseph M. ;

Steen, Michelle S. ;

LaMadrid-Herrmannsfeldt, Marissa A. ;

Williamson, David W. ;

Livingston, Robert J. ;

Wu, David ;

Wood, Brent L. ;

Rieder, Mark J. ;

Robins, Harlan .

NATURE COMMUNICATIONS, 2013, 4

[2] Medical Progress: Myocarditis. [J].

Cooper, Leslie T., Jr. .

NEW ENGLAND JOURNAL OF MEDICINE, 2009, 360 (15) :1526-1538

[3] Dynamics of the Cytotoxic T Cell Response to a Model of Acute Viral Infection [J].

DeWitt, William S. ;

Emerson, Ryan O. ;

Lindau, Paul ;

Vignali, Marissa ;

Snyder, Thomas M. ;

Desmarais, Cindy ;

Sanders, Catherine ;

Utsugi, Heidi ;

Warren, Edus H. ;

McElrath, Juliana ;

Makar, Karen W. ;

Wald, Anna ;

Robins, Harlan S. .

JOURNAL OF VIROLOGY, 2015, 89 (08) :4517-4526

[4] Intestinal microbiome analyses identify melanoma patients at risk for checkpoint-blockade-induced colitis [J].

Dubin, Krista ;

Callahan, Margaret K. ;

Ren, Boyu ;

Khanin, Raya ;

Viale, Agnes ;

Ling, Lilan ;

No, Daniel ;

Gobourne, Asia ;

Littmann, Eric ;

Huttenhower, Curtis ;

Pamer, Eric G. ;

Wolchok, Jedd D. .

NATURE COMMUNICATIONS, 2016, 7

[5] Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial [J].

Eggermont, Alexander M. M. ;

Chiarion-Sileni, Vanna ;

Grob, Jean-Jacques ;

Dummer, Reinhard ;

Wolchok, Jedd D. ;

Schmidt, Henrik ;

Hamid, Omid ;

Robert, Caroline ;

Ascierto, Paolo A. ;

Richards, Jon M. ;

Lebbe, Celeste ;

Ferraresi, Virginia ;

Smylie, Michael ;

Weber, Jeffrey S. ;

Maio, Michele ;

Konto, Cyril ;

Hoos, Axel ;

de Pril, Veerle ;

Gurunath, Ravichandra Karra ;

de Schaetzen, Gaetan ;

Suciu, Stefan ;

Testori, Alessandro .

LANCET ONCOLOGY, 2015, 16 (05) :522-530

[6] Endothelial programmed death-1 ligand 1 (PD-L1) regulates CD8+ T-cell-mediated injury in the heart [J].

Grabie, Nir ;

Gotsman, Israel ;

DaCosta, Rosa ;

Pang, Hong ;

Stavrakis, George ;

Butte, Manish J. ;

Keir, Mary E. ;

Freeman, Gordon J. ;

Sharpe, Arlene H. ;

Lichtman, Andrew H. .

CIRCULATION, 2007, 116 (18) :2062-2071

[7] ANALYSIS OF FORMALIN-FIXED AND FROZEN MYOCARDIAL AUTOPSY SAMPLES FOR VIRAL GENOME IN CHILDHOOD MYOCARDITIS AND DILATED CARDIOMYOPATHY WITH ENDOCARDIAL FIBROELASTOSIS USING POLYMERASE CHAIN-REACTION (PCR) [J].

GRIFFIN, LD ;

KEARNEY, D ;

NI, JY ;

JAFFE, R ;

FRICKER, FJ ;

WEBBERS ;

DEMMLER, G ;

GELB, BD ;

TOWBIN, JA .

CARDIOVASCULAR PATHOLOGY, 1995, 4 (01) :3-11

[8] Improved Survival with Ipilimumab in Patients with Metastatic Melanoma [J].

Hodi, F. Stephen ;

O'Day, Steven J. ;

McDermott, David F. ;

Weber, Robert W. ;

Sosman, Jeffrey A. ;

Haanen, John B. ;

Gonzalez, Rene ;

Robert, Caroline ;

Schadendorf, Dirk ;

Hassel, Jessica C. ;

Akerley, Wallace ;

van den Eertwegh, Alfons J. M. ;

Lutzky, Jose ;

Lorigan, Paul ;

Vaubel, Julia M. ;

Linette, Gerald P. ;

Hogg, David ;

Ottensmeier, Christian H. ;

Lebbe, Celeste ;

Peschel, Christian ;

Quirt, Ian ;

Clark, Joseph I. ;

Wolchok, Jedd D. ;

Weber, Jeffrey S. ;

Tian, Jason ;

Yellin, Michael J. ;

Nichol, Geoffrey M. ;

Hoos, Axel ;

Urba, Walter J. .

NEW ENGLAND JOURNAL OF MEDICINE, 2010, 363 (08) :711-723

[9] Pituitary Expression of CTLA-4 Mediates Hypophysitis Secondary to Administration of CTLA-4 Blocking Antibody [J].

Iwama, Shintaro ;

De Remigis, Alessandra ;

Callahan, Margaret K. ;

Slovin, Susan F. ;

Wolchok, Jedd D. ;

Caturegli, Patrizio .

SCIENCE TRANSLATIONAL MEDICINE, 2014, 6 (230)

[10] Systemic inflammation in a melanoma patient treated with immune checkpoint inhibitors-an autopsy study [J].

Koelzer, Viktor H. ;

Rothschild, Sacha I. ;

Zihler, Deborah ;

Wicki, Andreas ;

Willi, Berenika ;

Willi, Niels ;

Voegeli, Michele ;

Cathomas, Gieri ;

Zippelius, Alfred ;

Mertz, Kirsten D. .

JOURNAL FOR IMMUNOTHERAPY OF CANCER, 2016, 4

← 1 2 3 →