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Immunomodulatory Treatment of Immune Checkpoint Inhibitor-Induced Myocarditis: Pathway Toward Precision-Based Therapy
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Immunomodulatory Treatment of Immune Checkpoint Inhibitor-Induced Myocarditis: Pathway Toward Precision-Based Therapy Dinu Valentin Balanescu MD , Teodora Donisan MD , Nicolas Palaskas MD , Juan Lopez-Mattei MD , Peter Y. Kim MD , Louis Maximilian Buja MD , Dennis M. McNamara MD , Jon A. Kobashigawa MD , Jean-Bernard Durand MD , Cezar A. Iliescu MD PII: DOI: Reference:
S1054-8807(20)30015-6 https://doi.org/10.1016/j.carpath.2020.107211 CVP 107211
To appear in:
Cardiovascular Pathology
Received date: Revised date: Accepted date:
11 November 2019 11 February 2020 11 February 2020
Please cite this article as: Dinu Valentin Balanescu MD , Teodora Donisan MD , Nicolas Palaskas MD , Juan Lopez-Mattei MD , Peter Y. Kim MD , Louis Maximilian Buja MD , Dennis M. McNamara MD , Jon A. Kobashigawa MD , Jean-Bernard Durand MD , Cezar A. Iliescu MD , Immunomodulatory Treatment of Immune Checkpoint Inhibitor-Induced Myocarditis: Pathway Toward Precision-Based Therapy, Cardiovascular Pathology (2020), doi: https://doi.org/10.1016/j.carpath.2020.107211
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Published by Elsevier Inc.
Title: Immunomodulatory Treatment of Immune Checkpoint Inhibitor-Induced Myocarditis: Pathway Toward Precision-Based Therapy Author list: Dinu Valentin Balanescu, MD,a Teodora Donisan, MD,a Nicolas Palaskas, MD,a Juan Lopez-Mattei, MD,a Peter Y. Kim, MD,a Louis Maximilian Buja, MD,b Dennis M. McNamara, MD,c Jon A. Kobashigawa, MD,d Jean-Bernard Durand, MD,a Cezar A. Iliescu, MDa Author affiliation list: a Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, Texas b Department of Pathology and Laboratory Medicine, McGovern Medical School at The University of Texas Health Science Center at Houston, Houston, Texas c University of Pittsburgh Medical Center Heart and Vascular Institute, Pittsburgh, Pennsylvania d Department of Cardiology, Cedars-Sinai Smidt Heart Institute, Los Angeles, California
Address for correspondence: Jean-Bernard Durand, MD, FACP, FCCP, FACC, FHFSA, FAHA Department of Cardiology, The University of Texas MD Anderson Cancer Center 1400 Pressler Street, Unit 1451, Houston, TX 77030 Phone: 713-792-6242 Fax: 713-745-1942 Email: [email protected] Funding: The University of Texas MD Anderson Cancer Center is supported in part by the National Institutes of Health through Cancer Center Support Grant P30CA016672.
Abstract Immune checkpoint inhibitor (ICI)-induced myocarditis carries a poor prognosis and is not fully understood. Similar to lymphocytic myocarditis and acute cellular rejection in heart transplant, ICI-induced myocarditis requires immune suppressive strategies. We aimed to describe ICI-induced myocarditis by presenting findings of comprehensive cardiovascular evaluations and outcomes of patients following a therapeutic approach similar to autoimmune disorders or allograft transplant rejection, and to discuss the molecular basis of the benefits of immune modulation and statins in ICI-myocarditis. Three patients with ICI-induced myocarditis (2 with positive biopsies and 1 based on cardiac magnetic resonance imaging with negative biopsy) underwent a complete cardiovascular workup, including cardiac catheterization
with
endomyocardial
biopsy.
Treatment
was
with
intravenous
immunoglobulins (IVIG) and statins in all cases, with additional colchicine (2 cases) or hydroxychloroquine (1 case). Immunohistochemical analysis demonstrated varied subsets of T cells involved in the inflammatory response. Therapy with IVIG and statins led to symptom resolution and cardiac function normalization at 1-month follow-up in all patients. Cancer therapy was resumed in all patients. One patient expired 10 months after the myocarditis episode due to advanced malignancy; two patients were alive, free of heart failure symptoms and cancer progression, at 1-year follow-up, and 1 patient was rechallenged with ICI. We suggest that treatment with IVIG and statins may allow for a prompt resumption of anticancer therapy (including ICI) and improve outcomes.
Key words: cardio-oncology; immune checkpoint inhibitors; immune-related adverse events; immunotherapy; myocarditis.
1.
Introduction
Immune checkpoint inhibitor (ICI) therapy has shown survival benefits for patients with various malignancies. The non-specific activation of the immune system caused by ICIs leads to a spectrum of immune-related adverse events which can affect multiple organs with ontarget and off-target injury and require treatment discontinuation in nearly 40% of patients [1]. ICI-induced myocarditis is a severe adverse event that occurs in 1% of patients, but it is believed that the incidence is underreported, given the lack of routine cardiac monitoring in most immunotherapy trials [2]. The efficacy of immunosuppressive agents over glucocorticoids in treating ICI-induced myocarditis has not yet been established [3]. Immunohistochemical analysis of endomyocardial biopsy (EMB) specimens allows for identification of the subtype of T-cells within the myocardial inflammatory response, potentially guiding therapy. We present the full cardiovascular evaluation and outcomes following a novel therapeutic approach of three cancer patients with ICI-induced myocarditis (Tables 1, 2).
2. Materials and Methods 2.1. Study population
From May to July 2017, three patients of The University of Texas MD Anderson Cancer Center, Houston, Texas, underwent EMB for clinically suspected ICI-induced myocarditis.
2.2. Comprehensive cardiovascular evaluation and management
Although ICI therapy is novel, a traditional approach is recommended for diagnostic evaluation [1], including cardiac biomarkers, chest X-ray (CXR), electrocardiogram (ECG), transthoracic echocardiogram (TTE), cardiac magnetic resonance (CMR) imaging, and cardiac catheterization (with or without EMB) upon appearance of cardiac signs/symptoms,
all of which were performed in our patients. Myocardial samples were examined by light microscopy following standard procedures. The diagnosis of myocarditis was confirmed by the presence of lymphocytic infiltrate on immunohistochemical analysis using the Dallas Criteria.
When
inflammatory
infiltrates
were
identified,
we
performed
immunohistochemistry, staining for leukocyte common antigen (CD45), T cell markers (CD3, CD4, CD8, FOXp3), B cell markers (CD20), macrophage markers (CD68), programmed death ligand 1 (PDL1), and capillary staining for complement (C3d, C4d). Once myocarditis was diagnosed, intravenous immunoglobulin (IVIG) 1g/kg/day for 3 days and either rosuvastatin 20 mg daily or atorvastatin 40 mg daily were administered. Colchicine 0.6 mg daily was added if initial ECG suggested pericarditis.
3. Results
Case 1. A 75-year-old man on day 33 of his first cycle of ipilimumab, nivolumab, and azacitidine for myelodysplastic syndrome, presented with fever, cough, dyspnea, and a rash. Serum cardiac troponin I cTnI peaked at 2.94 ng/ml and BNP at 1191 pg/ml. CXR revealed small bilateral pleural effusions (Fig. 1A). New-onset atrial flutter was discovered on ECG, possibly due to concomitant new-onset thyroiditis with hyperthyroidism (Fig. 1B). The left ventricular function and left atrial size were normal on TTE, which also revealed minimal pericardial effusion (Fig. 1, C-D). CMR suggested myopericarditis with anteroseptal mid myocardial late gadolinium enhancement and pericardial enhancement (Fig. 1, E1-E2). Intravenous immunoglobulin (1 mg/kg for 4 consecutive days) and rosuvastatin (20 mg daily) were initiated. Coronary angiography was normal (Fig. 1, F1-F2). EMB showed focal but dense interstitial and endocardial inflammatory infiltrate, predominantly CD68+ (Fig. 1 G1G7). Immunohistochemical staining for FOXp3 was negative. PDL1 staining was negative (although this analysis was performed on a deeper cut without cellular infiltrate), however,
C4d was positive (Fig. 1, G8-G9). At 1-month follow-up, the patient reported improved heart failure symptoms and had normal ECG and TTE. Chemotherapy with azacitidine and nivolumab (discontinued ipilimumab) was resumed after 6 weeks. The patient was alive 11 months after the event, without cardiovascular symptoms at last follow-up.
Case 2. A 78-year-old man with myelodysplastic syndrome treated with ipilimumab and azacitidine for 6 days was admitted for fever and pneumonia. CXR showed bilateral pleural effusions with overlying atelectasis and pulmonary edema (Fig. 2A). New-onset atrial fibrillation and diffuse ST elevations consistent with pericarditis were found on ECG (Fig. 2B). Peak cTnI was 12.45 ng/ml and BNP was 1988 pg/ml. The left ventricular ejection fraction (LVEF) assessed by TTE was 55%, 9% lower than the baseline evaluation 1 month prior. New regional wall motion abnormalities and decreased global longitudinal strain were also found (Fig. 2, C1-C2). Coronary angiography was initially deferred because of low platelet count (19,000/µl), therefore CMR was performed, with focal septal mid myocardial late gadolinium enhancement suggesting myocarditis (Fig. 2, D1-D2). IVIG, colchicine, and atorvastatin were initiated. Coronary angiogram one week later did not reveal significant lesions (Fig. 2, E1-E2). EMB at the time of coronary angiogram was not suggestive of myocarditis (Fig 2, F1-F6). Cardiac function normalized after 1 month and chemotherapy was restarted after 3 months, only with azacitidine. The patient survived for 10 months after the myocarditis episode, when he expired due to advanced malignancy.
Case 3. A 74-year-old woman with metastatic malignant melanoma treated with ipilimumab and evofosfamide for 28 days presented with dyspnea, fever, hypotension, and a rash that started immediately after her last chemotherapy infusion. CXR showed minor pleural effusions (Fig. 3A). She had cTnI elevation (3.72 ng/ml) and BNP was 193 pg/ml.
ECG revealed sinus tachycardia and diffuse low QRS voltage (Fig. 3B), with paroxysmal atrial fibrillation recorded on telemetry. TTE showed normal systolic function, with an LVEF of 51% (Fig. 3, C1-C2). CMR revealed global nonischemic cardiomyopathy, but was not suggestive of myocarditis (Fig. 3, D1-D2). IVIG, colchicine, rosuvastatin, and hydroxychloroquine (for severe rash and arthralgias) were initiated, based on clinical reasoning. No significant coronary artery lesions were found on coronary angiography (Fig. 3, E1-E2). EMB was performed, ultimately diagnosing lymphocytic myocarditis (predominantly CD8+) by the Dallas criteria (Fig. 3, F1-F8). Both PDL1 and C4d were positive (Fig. 3, F9-F10). The patient improved clinically, with repeat TTE revealing LVEF of 57% 1 month after the episode. Chemotherapy was restarted after 4 months, with a different regimen (dabrafenib and trametinib). The patient was alive 1 year after the event, asymptomatic at last follow-up.
4. Discussion
Myocarditis is heterogeneous and has patchy infiltration within myocardial tissue which can be missed on EMB due to sampling error. In these situations, CMR with gadolinium enhancement can help to increase the yield for diagnosing myocarditis. This is the likely cause of a negative EMB in Patient 2, with otherwise compelling evidence for myocarditis. However, EMB still remains the gold standard for diagnosing myocarditis [4]. The traditional definition for the histopathologic diagnosis of myocarditis is based on the Dallas criteria [5]. Although these criteria are still current and widely used, they are limited by high interobserver variability, significant sampling error, and inability to detect non-cellular inflammatory processes [6]. Novel techniques, such as immunohistochemistry, may fill some of these shortcomings and provide increased identification and understanding of novel entities, such as myocarditis induced by modern immunotherapies.
The similarities and differences between ICI-induced myocarditis versus viral myocarditis and acute allograft rejection are presently unknown. There are limited data suggesting the same T cell clones infiltrating the myocardium in ICI-induced myocarditis are also infiltrating the skeletal muscle and tumor, but direct comparison to T cells in viral myocarditis and acute allograft rejection has not been performed [2, 7, 8]. From a management perspective, the efficacy of immunosuppressive agents over glucocorticoids in treating ICI-induced myocarditis has not yet been established. Discontinuing ICI therapy is still the first step in managing ICI-induced myocarditis, however, poor prognoses demonstrate that this is not enough. Recent data suggest that fatality rates of ICI-induced myocarditis are as high as 36% with monotherapy and 67% with combination immunotherapy [9]. In a study based on a multicenter registry of patients with ICI-induced myocarditis, Mahmood et al. [10] reported that patients taking 1,000 mg of methylprednisolone daily still developed major adverse cardiac events. Several reports have declared the efficacy of immunotherapies such as rabbit anti-thymocyte globulin (ATG) and IVIG, along with advanced heart failure support [11-13]. Immune profiling in ICI-induced myocarditis is an innovative concept that may highlight specific patterns of inflammation. We speculate that there is commonality in T cell phenotypic profiles, such that a unifying mechanism that precipitates giant cell myocarditis or lymphocytic myocarditis can be isolated. Therefore, if an immune profile is created for myocarditis so that patients receive therapies based on their immuno-histo-clinicopathological profile, delivery of specific immune modulation can be established with the potential for survival benefit. Endomyocardial biopsies from patients with ICI myocarditis demonstrate dense infiltrates of macrophages and lymphocytes accompanied by CD3+, CD4+, CD8+, CD45+, and CD68+ cells on immunohistochemical evaluation [14, 15]. In one case report of two patients with ICI myocarditis, the pattern of infiltrate seen in both
malignant tissue and in cardiac and skeletal muscle showed similar T-cell populations suggesting a shared target of the immune response [2]. Heart transplant patients developing acute cellular rejection (ACR) demonstrate a similar pattern of immunohistochemistry as that seen in ICI-myocarditis [16]. Specifically, histology in ACR shows lymphocyte and macrophage infiltrates on endomyocardial biopsy samples, while samples from antibodymediated rejection (AMR) exhibit CD34+, CD68+ (intravascular macrophages) cells as well as complement deposition (C3d, C4d) within capillaries [16]. A treatment paradigm for ICImyocarditis drawing on elements of immunomodulatory treatment strategies successful in ACR and possibly AMR is therefore a logical next step. Most of the reports of ICI-induced myocarditis have not tested for an antibody-mediated process. Johnson et al’s two patients tested for IgG deposition in the myocardium were negative [2] but animal models have suggested there may also be an antibody-mediated process [17, 18]. This case series describes 3 patients who were successfully treated with IVIG, which is primarily targeting an antibodymediated process although does have some T cell activity. Two of our cases also tested positive for pericapillary C4d, which suggests that there may indeed be a role of antibodymediated injury in humans with ICI-induced myocarditis. Given the established immunomodulatory effects of statin therapy and its success in heart transplantation, adding this drug to the treatment paradigm for ICI-myocarditis may be reasonable. This effect has been attributed to 2 molecular pathways. First, statins indirectly decrease major histocompatibility complex-II (MHC-II) synthesis by inhibiting a promotor of transcription regulation [19, 20]. In turn, the lower expression of MHC-II down-regulates the immune response and decreases the proliferation and differentiation of T cells. More recently, it has been proposed that statins antagonize lymphocyte function-associated antigen1 (LFA-1), a β2 integrin with an important role in lymphocyte recirculation and T-cell activation [21]. Animal models have shown the benefit of LFA-1 inhibition for cardiac
allograft survival [22]. In addition to the above immunomodulatory effects, the benefit of statins as anti-inflammatory agents in the microvasculature may be mediated by isoprenoids and small GTPases [23, 24]. Lastly, this is the only case series to describe a patient successfully rechallenged with ICI after ICI-induced myocarditis. Patient 1 developed myocarditis with combination nivolumab and ipilimumab but after treatment with IVIG, steroids, and statins was able to reinitiate monotherapy with nivolumab in only 6 weeks. The patient tolerated this therapy and did not develop any cardiac complications for the follow-up period of 11 months. There is one case report in the literature currently in which a patient was reinitiated on ICI after myocarditis and recurrent myocarditis was described [25]. Identification of patients who will successfully tolerate reinitiating ICI after myocarditis is vital for this potentially life-saving cancer therapy. Based on the experience at our center, managing ICI-induced myocarditis as an autoimmune disorder may be justified. Our approach includes treating this condition with both cellular and antibody targeted immunomodulation. The three patients in our presentation were treated based on this premise, were discharged with LVEF improvement and class I NYHA, were symptom-free and in remission at 1-month follow-up, and were able to resume cancer therapy. These 3 patients do, however, represent the mild end of the spectrum of ICIinduced myocarditis and the efficacy of our approach in patients presenting with fulminant heart failure is currently unknown.
5. Conclusions
Histopathological characterization by EMB and immunohistochemistry is essential to advance the understanding of ICI-induced myocarditis and its management. ICI-induced myocarditis is a heterogeneous condition, involving varied subsets of T cells in the
myocardial inflammatory response. Treatment with IVIG and statins may be more effective than glucocorticoid therapy for improving outcomes and allowing for rechallenge. Guidelines for cardiovascular management of ICI-induced myocarditis are necessary and should rely on the evolving understanding of its underlying mechanisms. Conflicts of interest: None.
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Figure Legends
Figure 1. Myopericarditis in a 75-year-old man treated with azacitidine, ipilimumab, and nivolumab for myelodysplastic syndrome. Chest X-ray revealed small bilateral pleural effusions (A). Electrocardiogram (ECG) showed atrial flutter (B). Normal ventricular function and minimal pericardial effusion were seen on
transthoracic echocardiogram (C), with normal global longitudinal peak strain (D). Cardiac magnetic resonance imaging showed pericardial enhancement, and an enhancement pattern at the basal anteroseptal segment (mid-myocardial) and basal inferolateral segment (epicardial) (E1-E2). Coronary angiography did not reveal hemodynamically significant coronary artery disease (F1-F2). Hematoxylin and eosin (HE) stain (G1) showed focal and isolated (1/6 tissue specimens) inflammatory infiltrate with CD3+ cells (G2) involving the endocardium. There was an equal number of CD4+ and CD8+ cells (G3-G4) and of CD45+ lymphocytes and CD68+ histiocytes (G5-G6). CD20 was negative (G7), as was PDL1 (G8, although this analysis was done on a deeper cut without cellular infiltrate). C4d was positive (G9).
Figure 2. Myocarditis in a 78-year-old man treated with azacitidine and ipilimumab for myelodysplastic syndrome. CXR showed bilateral moderate sized pleural effusions with overlying atelectasis and pulmonary edema (A). ECG revealed atrial fibrillation and diffuse ST elevation (B). TTE revealed regional wall motion abnormalities and decreased global longitudinal strain (C1C2). CMR showed stable focal delayed myocardial enhancement in the mid septal wall suggestive of myocarditis (D1-D2). Coronary angiogram showed the right coronary artery with a patent stent and a mid-50% stenosis (E1) and a patent left anterior descending artery stent (E2). An endomyocardial biopsy was performed, without inflammatory infiltrate on HE stain (F1). No CD3+, CD4+, or CD8+ cells were present (F2-F4). There were <8/high-power field (40X objective) CD45+ and CD68+ inflammatory cells, within normal limits (F5-F6). Specimen was not suggestive of myocarditis.
Figure 3. Myocarditis in a 74-year-old woman treated with evofosfamide and ipilimumab for metastatic malignant melanoma. CXR showed blunting of bilateral posterior costophrenic angles (A). ECG revealed sinus tachycardia and low QRS voltage (B). TTE showed normal left ventricular systolic function (C1-C2). CMR revealed minimal pericardial effusion, global non-ischemic cardiomyopathy, and an LVEF of 41% (D1-D2). Coronary angiography showed no evidence of coronary artery disease (E1-E2). An endomyocardial biopsy was performed; HE stain is shown (F1). Most of the lymphocytes were CD3+ (F2) and CD8+ T-lymphocytes, with a small portion of CD4+ T-lymphocytes. CD4:CD8 ratio was approximately 1:20 (F3-F4). There were very few
CD20+ B-lymphocytes (F5) and few FOXp3 cells (F6). The number of CD68+ cells CD45+ lymphocytes was equal (F7-F8). PDL1 (F9) and C4d (F10) were positive.
Table 1. Clinical characteristics of 3 patients with myocarditis induced by immune checkpoint inhibitor therapy Patient ID
Age (years)
Sex
Cancer diagnosis
Chemotherapy and timing of AE Cycle 1, day 33: Azacitidine Ipilimumab Nivolumab
Immune-related AE
Cardiac findings
Treatment of cardiac AE
Outcome of cardiac AE at 1 month ECG: sinus rhythm, no AFL on loop recorder TTE: LVEF 59%
Chemotherapy rechallenged?
Survival after cardiac AE Alive after 11 months
ECG: new onset AFL Yes IVIG CXR: small bilateral pleural Rosuvastatin After 6 weeks effusions Nivolumab only TTE: minimal pericardial effusion, LVEF 57% CMR: myopericarditis, LVEF 51% CA: no significant lesions Biopsy: lymphocytic myocarditis 2 78 M MDS Cycle 1, day 6: Cardiac: ECG: new onset AF, diffuse IVIG ECG: sinus Yes Deceased ST elevation After 3 months after 10 Azacitidine Myocarditis Atorvastatin rhythm, biphasic CXR: bilateral pleural T waves, Different months Ipilimumab New onset AF Colchicine effusions, interstitial prolonged QT regimen (only (non-cardiac Others: pulmonary edema TTE: LVEF 62%, azacitidine) related Transaminitis TTE: LVEF 55%, new no wall motion death) regional wall abnormalities abnormalities CMR: myocarditis, LVEF 57% CA: patent LAD artery and RCA stents, no other significant lesions Biopsy: negative for myocarditis 3 74 F Metastatic Cycle 1, day 28: Cardiac: ECG: sinus tachycardia, ECG: paroxysmal Yes Alive after 1 IVIG melanoma Evofosfamide Myopericarditis diffuse low QRS voltage, After 4 months year Rosuvastatin AF paroxysmal AF TTE: LVEF 57% Different Ipilimumab Sinus Colchicine CXR: bilateral costophrenic HCQ regimen tachycardia, angle blunting (dabrafenib, paroxysmal AF TTE: minimal pericardial trametinib) Others: effusion, LVEF 51% Rash CMR: global non-ischemic Transaminitis cardiomyopathy, LVEF 41% CA: no significant lesions Biopsy: lymphocytic myocarditis Abbreviations: AE, adverse effect; AF, atrial fibrillation; AFL, atrial flutter; CA, coronary angiography; CMR, cardiac magnetic resonance imaging; CXR, chest X-ray; ECG, electrocardiogram; HCQ, hydroxychloroquine; IVIG, intravenous immunoglobulin; LAD, left anterior descending; LVEF, left ventricular ejection fraction; MDS, myelodysplastic syndrome; RCA, right coronary artery; TTE, transthoracic echocardiogram. 1
75
M
MDS
Cardiac: Myopericarditis New onset AFL Others: Hyperthyroidism Rash Transaminitis
Table 2. Endomyocardial biopsy findings in the 2 patients with positive biopsies for myocarditis.
H&E Trichrome CD45 (Leucocyte common antigen) T Lymphocytes CD3 CD4 CD8 FOXP3 B Lymphocytes CD20 Macrophages CD68 PDL1 Complement (capillary staining) C3d C4d
Patient 1 Large focus of cellular infiltrate with myocyte necrosis Associated collagen deposition 3+
Patient 3 Multiple foci of cellular infiltrate with myocyte necrosis Associated collagen deposition 4+
1+ 1+ 1+ 0
3+ 1+ 2+ 0
0
0
3+ 0 (deeper cut without cellular infiltrate)
2+ 1+
0 1+
0 1+
Immunomodulatory Treatment of Immune Checkpoint Inhibitor-Induced Myocarditis: Pathway Toward Precision-Based Therapy Dinu Valentin Balanescu MD , Teodora Donisan MD , Nicolas Palaskas MD , Juan Lopez-Mattei MD , Peter Y. Kim MD , Louis Maximilian Buja MD , Dennis M. McNamara MD , Jon A. Kobashigawa MD , Jean-Bernard Durand MD , Cezar A. Iliescu MD PII: DOI: Reference:
S1054-8807(20)30015-6 https://doi.org/10.1016/j.carpath.2020.107211 CVP 107211
To appear in:
Cardiovascular Pathology
Received date: Revised date: Accepted date:
11 November 2019 11 February 2020 11 February 2020
Please cite this article as: Dinu Valentin Balanescu MD , Teodora Donisan MD , Nicolas Palaskas MD , Juan Lopez-Mattei MD , Peter Y. Kim MD , Louis Maximilian Buja MD , Dennis M. McNamara MD , Jon A. Kobashigawa MD , Jean-Bernard Durand MD , Cezar A. Iliescu MD , Immunomodulatory Treatment of Immune Checkpoint Inhibitor-Induced Myocarditis: Pathway Toward Precision-Based Therapy, Cardiovascular Pathology (2020), doi: https://doi.org/10.1016/j.carpath.2020.107211
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Published by Elsevier Inc.
Title: Immunomodulatory Treatment of Immune Checkpoint Inhibitor-Induced Myocarditis: Pathway Toward Precision-Based Therapy Author list: Dinu Valentin Balanescu, MD,a Teodora Donisan, MD,a Nicolas Palaskas, MD,a Juan Lopez-Mattei, MD,a Peter Y. Kim, MD,a Louis Maximilian Buja, MD,b Dennis M. McNamara, MD,c Jon A. Kobashigawa, MD,d Jean-Bernard Durand, MD,a Cezar A. Iliescu, MDa Author affiliation list: a Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, Texas b Department of Pathology and Laboratory Medicine, McGovern Medical School at The University of Texas Health Science Center at Houston, Houston, Texas c University of Pittsburgh Medical Center Heart and Vascular Institute, Pittsburgh, Pennsylvania d Department of Cardiology, Cedars-Sinai Smidt Heart Institute, Los Angeles, California
Address for correspondence: Jean-Bernard Durand, MD, FACP, FCCP, FACC, FHFSA, FAHA Department of Cardiology, The University of Texas MD Anderson Cancer Center 1400 Pressler Street, Unit 1451, Houston, TX 77030 Phone: 713-792-6242 Fax: 713-745-1942 Email: [email protected] Funding: The University of Texas MD Anderson Cancer Center is supported in part by the National Institutes of Health through Cancer Center Support Grant P30CA016672.
Abstract Immune checkpoint inhibitor (ICI)-induced myocarditis carries a poor prognosis and is not fully understood. Similar to lymphocytic myocarditis and acute cellular rejection in heart transplant, ICI-induced myocarditis requires immune suppressive strategies. We aimed to describe ICI-induced myocarditis by presenting findings of comprehensive cardiovascular evaluations and outcomes of patients following a therapeutic approach similar to autoimmune disorders or allograft transplant rejection, and to discuss the molecular basis of the benefits of immune modulation and statins in ICI-myocarditis. Three patients with ICI-induced myocarditis (2 with positive biopsies and 1 based on cardiac magnetic resonance imaging with negative biopsy) underwent a complete cardiovascular workup, including cardiac catheterization
with
endomyocardial
biopsy.
Treatment
was
with
intravenous
immunoglobulins (IVIG) and statins in all cases, with additional colchicine (2 cases) or hydroxychloroquine (1 case). Immunohistochemical analysis demonstrated varied subsets of T cells involved in the inflammatory response. Therapy with IVIG and statins led to symptom resolution and cardiac function normalization at 1-month follow-up in all patients. Cancer therapy was resumed in all patients. One patient expired 10 months after the myocarditis episode due to advanced malignancy; two patients were alive, free of heart failure symptoms and cancer progression, at 1-year follow-up, and 1 patient was rechallenged with ICI. We suggest that treatment with IVIG and statins may allow for a prompt resumption of anticancer therapy (including ICI) and improve outcomes.
Key words: cardio-oncology; immune checkpoint inhibitors; immune-related adverse events; immunotherapy; myocarditis.
1.
Introduction
Immune checkpoint inhibitor (ICI) therapy has shown survival benefits for patients with various malignancies. The non-specific activation of the immune system caused by ICIs leads to a spectrum of immune-related adverse events which can affect multiple organs with ontarget and off-target injury and require treatment discontinuation in nearly 40% of patients [1]. ICI-induced myocarditis is a severe adverse event that occurs in 1% of patients, but it is believed that the incidence is underreported, given the lack of routine cardiac monitoring in most immunotherapy trials [2]. The efficacy of immunosuppressive agents over glucocorticoids in treating ICI-induced myocarditis has not yet been established [3]. Immunohistochemical analysis of endomyocardial biopsy (EMB) specimens allows for identification of the subtype of T-cells within the myocardial inflammatory response, potentially guiding therapy. We present the full cardiovascular evaluation and outcomes following a novel therapeutic approach of three cancer patients with ICI-induced myocarditis (Tables 1, 2).
2. Materials and Methods 2.1. Study population
From May to July 2017, three patients of The University of Texas MD Anderson Cancer Center, Houston, Texas, underwent EMB for clinically suspected ICI-induced myocarditis.
2.2. Comprehensive cardiovascular evaluation and management
Although ICI therapy is novel, a traditional approach is recommended for diagnostic evaluation [1], including cardiac biomarkers, chest X-ray (CXR), electrocardiogram (ECG), transthoracic echocardiogram (TTE), cardiac magnetic resonance (CMR) imaging, and cardiac catheterization (with or without EMB) upon appearance of cardiac signs/symptoms,
all of which were performed in our patients. Myocardial samples were examined by light microscopy following standard procedures. The diagnosis of myocarditis was confirmed by the presence of lymphocytic infiltrate on immunohistochemical analysis using the Dallas Criteria.
When
inflammatory
infiltrates
were
identified,
we
performed
immunohistochemistry, staining for leukocyte common antigen (CD45), T cell markers (CD3, CD4, CD8, FOXp3), B cell markers (CD20), macrophage markers (CD68), programmed death ligand 1 (PDL1), and capillary staining for complement (C3d, C4d). Once myocarditis was diagnosed, intravenous immunoglobulin (IVIG) 1g/kg/day for 3 days and either rosuvastatin 20 mg daily or atorvastatin 40 mg daily were administered. Colchicine 0.6 mg daily was added if initial ECG suggested pericarditis.
3. Results
Case 1. A 75-year-old man on day 33 of his first cycle of ipilimumab, nivolumab, and azacitidine for myelodysplastic syndrome, presented with fever, cough, dyspnea, and a rash. Serum cardiac troponin I cTnI peaked at 2.94 ng/ml and BNP at 1191 pg/ml. CXR revealed small bilateral pleural effusions (Fig. 1A). New-onset atrial flutter was discovered on ECG, possibly due to concomitant new-onset thyroiditis with hyperthyroidism (Fig. 1B). The left ventricular function and left atrial size were normal on TTE, which also revealed minimal pericardial effusion (Fig. 1, C-D). CMR suggested myopericarditis with anteroseptal mid myocardial late gadolinium enhancement and pericardial enhancement (Fig. 1, E1-E2). Intravenous immunoglobulin (1 mg/kg for 4 consecutive days) and rosuvastatin (20 mg daily) were initiated. Coronary angiography was normal (Fig. 1, F1-F2). EMB showed focal but dense interstitial and endocardial inflammatory infiltrate, predominantly CD68+ (Fig. 1 G1G7). Immunohistochemical staining for FOXp3 was negative. PDL1 staining was negative (although this analysis was performed on a deeper cut without cellular infiltrate), however,
C4d was positive (Fig. 1, G8-G9). At 1-month follow-up, the patient reported improved heart failure symptoms and had normal ECG and TTE. Chemotherapy with azacitidine and nivolumab (discontinued ipilimumab) was resumed after 6 weeks. The patient was alive 11 months after the event, without cardiovascular symptoms at last follow-up.
Case 2. A 78-year-old man with myelodysplastic syndrome treated with ipilimumab and azacitidine for 6 days was admitted for fever and pneumonia. CXR showed bilateral pleural effusions with overlying atelectasis and pulmonary edema (Fig. 2A). New-onset atrial fibrillation and diffuse ST elevations consistent with pericarditis were found on ECG (Fig. 2B). Peak cTnI was 12.45 ng/ml and BNP was 1988 pg/ml. The left ventricular ejection fraction (LVEF) assessed by TTE was 55%, 9% lower than the baseline evaluation 1 month prior. New regional wall motion abnormalities and decreased global longitudinal strain were also found (Fig. 2, C1-C2). Coronary angiography was initially deferred because of low platelet count (19,000/µl), therefore CMR was performed, with focal septal mid myocardial late gadolinium enhancement suggesting myocarditis (Fig. 2, D1-D2). IVIG, colchicine, and atorvastatin were initiated. Coronary angiogram one week later did not reveal significant lesions (Fig. 2, E1-E2). EMB at the time of coronary angiogram was not suggestive of myocarditis (Fig 2, F1-F6). Cardiac function normalized after 1 month and chemotherapy was restarted after 3 months, only with azacitidine. The patient survived for 10 months after the myocarditis episode, when he expired due to advanced malignancy.
Case 3. A 74-year-old woman with metastatic malignant melanoma treated with ipilimumab and evofosfamide for 28 days presented with dyspnea, fever, hypotension, and a rash that started immediately after her last chemotherapy infusion. CXR showed minor pleural effusions (Fig. 3A). She had cTnI elevation (3.72 ng/ml) and BNP was 193 pg/ml.
ECG revealed sinus tachycardia and diffuse low QRS voltage (Fig. 3B), with paroxysmal atrial fibrillation recorded on telemetry. TTE showed normal systolic function, with an LVEF of 51% (Fig. 3, C1-C2). CMR revealed global nonischemic cardiomyopathy, but was not suggestive of myocarditis (Fig. 3, D1-D2). IVIG, colchicine, rosuvastatin, and hydroxychloroquine (for severe rash and arthralgias) were initiated, based on clinical reasoning. No significant coronary artery lesions were found on coronary angiography (Fig. 3, E1-E2). EMB was performed, ultimately diagnosing lymphocytic myocarditis (predominantly CD8+) by the Dallas criteria (Fig. 3, F1-F8). Both PDL1 and C4d were positive (Fig. 3, F9-F10). The patient improved clinically, with repeat TTE revealing LVEF of 57% 1 month after the episode. Chemotherapy was restarted after 4 months, with a different regimen (dabrafenib and trametinib). The patient was alive 1 year after the event, asymptomatic at last follow-up.
4. Discussion
Myocarditis is heterogeneous and has patchy infiltration within myocardial tissue which can be missed on EMB due to sampling error. In these situations, CMR with gadolinium enhancement can help to increase the yield for diagnosing myocarditis. This is the likely cause of a negative EMB in Patient 2, with otherwise compelling evidence for myocarditis. However, EMB still remains the gold standard for diagnosing myocarditis [4]. The traditional definition for the histopathologic diagnosis of myocarditis is based on the Dallas criteria [5]. Although these criteria are still current and widely used, they are limited by high interobserver variability, significant sampling error, and inability to detect non-cellular inflammatory processes [6]. Novel techniques, such as immunohistochemistry, may fill some of these shortcomings and provide increased identification and understanding of novel entities, such as myocarditis induced by modern immunotherapies.
The similarities and differences between ICI-induced myocarditis versus viral myocarditis and acute allograft rejection are presently unknown. There are limited data suggesting the same T cell clones infiltrating the myocardium in ICI-induced myocarditis are also infiltrating the skeletal muscle and tumor, but direct comparison to T cells in viral myocarditis and acute allograft rejection has not been performed [2, 7, 8]. From a management perspective, the efficacy of immunosuppressive agents over glucocorticoids in treating ICI-induced myocarditis has not yet been established. Discontinuing ICI therapy is still the first step in managing ICI-induced myocarditis, however, poor prognoses demonstrate that this is not enough. Recent data suggest that fatality rates of ICI-induced myocarditis are as high as 36% with monotherapy and 67% with combination immunotherapy [9]. In a study based on a multicenter registry of patients with ICI-induced myocarditis, Mahmood et al. [10] reported that patients taking 1,000 mg of methylprednisolone daily still developed major adverse cardiac events. Several reports have declared the efficacy of immunotherapies such as rabbit anti-thymocyte globulin (ATG) and IVIG, along with advanced heart failure support [11-13]. Immune profiling in ICI-induced myocarditis is an innovative concept that may highlight specific patterns of inflammation. We speculate that there is commonality in T cell phenotypic profiles, such that a unifying mechanism that precipitates giant cell myocarditis or lymphocytic myocarditis can be isolated. Therefore, if an immune profile is created for myocarditis so that patients receive therapies based on their immuno-histo-clinicopathological profile, delivery of specific immune modulation can be established with the potential for survival benefit. Endomyocardial biopsies from patients with ICI myocarditis demonstrate dense infiltrates of macrophages and lymphocytes accompanied by CD3+, CD4+, CD8+, CD45+, and CD68+ cells on immunohistochemical evaluation [14, 15]. In one case report of two patients with ICI myocarditis, the pattern of infiltrate seen in both
malignant tissue and in cardiac and skeletal muscle showed similar T-cell populations suggesting a shared target of the immune response [2]. Heart transplant patients developing acute cellular rejection (ACR) demonstrate a similar pattern of immunohistochemistry as that seen in ICI-myocarditis [16]. Specifically, histology in ACR shows lymphocyte and macrophage infiltrates on endomyocardial biopsy samples, while samples from antibodymediated rejection (AMR) exhibit CD34+, CD68+ (intravascular macrophages) cells as well as complement deposition (C3d, C4d) within capillaries [16]. A treatment paradigm for ICImyocarditis drawing on elements of immunomodulatory treatment strategies successful in ACR and possibly AMR is therefore a logical next step. Most of the reports of ICI-induced myocarditis have not tested for an antibody-mediated process. Johnson et al’s two patients tested for IgG deposition in the myocardium were negative [2] but animal models have suggested there may also be an antibody-mediated process [17, 18]. This case series describes 3 patients who were successfully treated with IVIG, which is primarily targeting an antibodymediated process although does have some T cell activity. Two of our cases also tested positive for pericapillary C4d, which suggests that there may indeed be a role of antibodymediated injury in humans with ICI-induced myocarditis. Given the established immunomodulatory effects of statin therapy and its success in heart transplantation, adding this drug to the treatment paradigm for ICI-myocarditis may be reasonable. This effect has been attributed to 2 molecular pathways. First, statins indirectly decrease major histocompatibility complex-II (MHC-II) synthesis by inhibiting a promotor of transcription regulation [19, 20]. In turn, the lower expression of MHC-II down-regulates the immune response and decreases the proliferation and differentiation of T cells. More recently, it has been proposed that statins antagonize lymphocyte function-associated antigen1 (LFA-1), a β2 integrin with an important role in lymphocyte recirculation and T-cell activation [21]. Animal models have shown the benefit of LFA-1 inhibition for cardiac
allograft survival [22]. In addition to the above immunomodulatory effects, the benefit of statins as anti-inflammatory agents in the microvasculature may be mediated by isoprenoids and small GTPases [23, 24]. Lastly, this is the only case series to describe a patient successfully rechallenged with ICI after ICI-induced myocarditis. Patient 1 developed myocarditis with combination nivolumab and ipilimumab but after treatment with IVIG, steroids, and statins was able to reinitiate monotherapy with nivolumab in only 6 weeks. The patient tolerated this therapy and did not develop any cardiac complications for the follow-up period of 11 months. There is one case report in the literature currently in which a patient was reinitiated on ICI after myocarditis and recurrent myocarditis was described [25]. Identification of patients who will successfully tolerate reinitiating ICI after myocarditis is vital for this potentially life-saving cancer therapy. Based on the experience at our center, managing ICI-induced myocarditis as an autoimmune disorder may be justified. Our approach includes treating this condition with both cellular and antibody targeted immunomodulation. The three patients in our presentation were treated based on this premise, were discharged with LVEF improvement and class I NYHA, were symptom-free and in remission at 1-month follow-up, and were able to resume cancer therapy. These 3 patients do, however, represent the mild end of the spectrum of ICIinduced myocarditis and the efficacy of our approach in patients presenting with fulminant heart failure is currently unknown.
5. Conclusions
Histopathological characterization by EMB and immunohistochemistry is essential to advance the understanding of ICI-induced myocarditis and its management. ICI-induced myocarditis is a heterogeneous condition, involving varied subsets of T cells in the
myocardial inflammatory response. Treatment with IVIG and statins may be more effective than glucocorticoid therapy for improving outcomes and allowing for rechallenge. Guidelines for cardiovascular management of ICI-induced myocarditis are necessary and should rely on the evolving understanding of its underlying mechanisms. Conflicts of interest: None.
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Figure Legends
Figure 1. Myopericarditis in a 75-year-old man treated with azacitidine, ipilimumab, and nivolumab for myelodysplastic syndrome. Chest X-ray revealed small bilateral pleural effusions (A). Electrocardiogram (ECG) showed atrial flutter (B). Normal ventricular function and minimal pericardial effusion were seen on
transthoracic echocardiogram (C), with normal global longitudinal peak strain (D). Cardiac magnetic resonance imaging showed pericardial enhancement, and an enhancement pattern at the basal anteroseptal segment (mid-myocardial) and basal inferolateral segment (epicardial) (E1-E2). Coronary angiography did not reveal hemodynamically significant coronary artery disease (F1-F2). Hematoxylin and eosin (HE) stain (G1) showed focal and isolated (1/6 tissue specimens) inflammatory infiltrate with CD3+ cells (G2) involving the endocardium. There was an equal number of CD4+ and CD8+ cells (G3-G4) and of CD45+ lymphocytes and CD68+ histiocytes (G5-G6). CD20 was negative (G7), as was PDL1 (G8, although this analysis was done on a deeper cut without cellular infiltrate). C4d was positive (G9).
Figure 2. Myocarditis in a 78-year-old man treated with azacitidine and ipilimumab for myelodysplastic syndrome. CXR showed bilateral moderate sized pleural effusions with overlying atelectasis and pulmonary edema (A). ECG revealed atrial fibrillation and diffuse ST elevation (B). TTE revealed regional wall motion abnormalities and decreased global longitudinal strain (C1C2). CMR showed stable focal delayed myocardial enhancement in the mid septal wall suggestive of myocarditis (D1-D2). Coronary angiogram showed the right coronary artery with a patent stent and a mid-50% stenosis (E1) and a patent left anterior descending artery stent (E2). An endomyocardial biopsy was performed, without inflammatory infiltrate on HE stain (F1). No CD3+, CD4+, or CD8+ cells were present (F2-F4). There were <8/high-power field (40X objective) CD45+ and CD68+ inflammatory cells, within normal limits (F5-F6). Specimen was not suggestive of myocarditis.
Figure 3. Myocarditis in a 74-year-old woman treated with evofosfamide and ipilimumab for metastatic malignant melanoma. CXR showed blunting of bilateral posterior costophrenic angles (A). ECG revealed sinus tachycardia and low QRS voltage (B). TTE showed normal left ventricular systolic function (C1-C2). CMR revealed minimal pericardial effusion, global non-ischemic cardiomyopathy, and an LVEF of 41% (D1-D2). Coronary angiography showed no evidence of coronary artery disease (E1-E2). An endomyocardial biopsy was performed; HE stain is shown (F1). Most of the lymphocytes were CD3+ (F2) and CD8+ T-lymphocytes, with a small portion of CD4+ T-lymphocytes. CD4:CD8 ratio was approximately 1:20 (F3-F4). There were very few
CD20+ B-lymphocytes (F5) and few FOXp3 cells (F6). The number of CD68+ cells CD45+ lymphocytes was equal (F7-F8). PDL1 (F9) and C4d (F10) were positive.
Table 1. Clinical characteristics of 3 patients with myocarditis induced by immune checkpoint inhibitor therapy Patient ID
Age (years)
Sex
Cancer diagnosis
Chemotherapy and timing of AE Cycle 1, day 33: Azacitidine Ipilimumab Nivolumab
Immune-related AE
Cardiac findings
Treatment of cardiac AE
Outcome of cardiac AE at 1 month ECG: sinus rhythm, no AFL on loop recorder TTE: LVEF 59%
Chemotherapy rechallenged?
Survival after cardiac AE Alive after 11 months
ECG: new onset AFL Yes IVIG CXR: small bilateral pleural Rosuvastatin After 6 weeks effusions Nivolumab only TTE: minimal pericardial effusion, LVEF 57% CMR: myopericarditis, LVEF 51% CA: no significant lesions Biopsy: lymphocytic myocarditis 2 78 M MDS Cycle 1, day 6: Cardiac: ECG: new onset AF, diffuse IVIG ECG: sinus Yes Deceased ST elevation After 3 months after 10 Azacitidine Myocarditis Atorvastatin rhythm, biphasic CXR: bilateral pleural T waves, Different months Ipilimumab New onset AF Colchicine effusions, interstitial prolonged QT regimen (only (non-cardiac Others: pulmonary edema TTE: LVEF 62%, azacitidine) related Transaminitis TTE: LVEF 55%, new no wall motion death) regional wall abnormalities abnormalities CMR: myocarditis, LVEF 57% CA: patent LAD artery and RCA stents, no other significant lesions Biopsy: negative for myocarditis 3 74 F Metastatic Cycle 1, day 28: Cardiac: ECG: sinus tachycardia, ECG: paroxysmal Yes Alive after 1 IVIG melanoma Evofosfamide Myopericarditis diffuse low QRS voltage, After 4 months year Rosuvastatin AF paroxysmal AF TTE: LVEF 57% Different Ipilimumab Sinus Colchicine CXR: bilateral costophrenic HCQ regimen tachycardia, angle blunting (dabrafenib, paroxysmal AF TTE: minimal pericardial trametinib) Others: effusion, LVEF 51% Rash CMR: global non-ischemic Transaminitis cardiomyopathy, LVEF 41% CA: no significant lesions Biopsy: lymphocytic myocarditis Abbreviations: AE, adverse effect; AF, atrial fibrillation; AFL, atrial flutter; CA, coronary angiography; CMR, cardiac magnetic resonance imaging; CXR, chest X-ray; ECG, electrocardiogram; HCQ, hydroxychloroquine; IVIG, intravenous immunoglobulin; LAD, left anterior descending; LVEF, left ventricular ejection fraction; MDS, myelodysplastic syndrome; RCA, right coronary artery; TTE, transthoracic echocardiogram. 1
75
M
MDS
Cardiac: Myopericarditis New onset AFL Others: Hyperthyroidism Rash Transaminitis
Table 2. Endomyocardial biopsy findings in the 2 patients with positive biopsies for myocarditis.
H&E Trichrome CD45 (Leucocyte common antigen) T Lymphocytes CD3 CD4 CD8 FOXP3 B Lymphocytes CD20 Macrophages CD68 PDL1 Complement (capillary staining) C3d C4d
Patient 1 Large focus of cellular infiltrate with myocyte necrosis Associated collagen deposition 3+
Patient 3 Multiple foci of cellular infiltrate with myocyte necrosis Associated collagen deposition 4+
1+ 1+ 1+ 0
3+ 1+ 2+ 0
0
0
3+ 0 (deeper cut without cellular infiltrate)
2+ 1+
0 1+
0 1+