Immune-Checkpoint Inhibitor (ICI) resumption after severe graft injury in a heart transplant recipient with nivolumab-sensitive metastatic melanoma and renal cell carcinoma

While immune-checkpoint inhibitors (ICI) activate the immune system and have transformed cancer therapy, serious immune-related adverse events (irAE) including myocarditis may arise. ICI use in solid organ transplant recipients with cancer carries increased risks of alloreactivity and organ rejection.^1–4 We report a case of a cardiac transplant recipient treated with ICI therapy for 2 ICI sensitive malignancies who developed life-threatening graft injury but resumed successful ICI therapy after augmentation of immunosuppression.

A 77-year-old male was started on nivolumab for treatment of simultaneously discovered melanoma with pulmonary metastases and renal cell carcinoma. He had undergone heart transplantation 19 years earlier with no history of graft rejection. His immunosuppression regimen consisting of cyclosporine (CsA) 50 mg bid, mycophenolate mofetil (MMF) 250 mg bid, and prednisone 5 mg daily had been minimized to reduce progression of prior non-melanoma skin cancers. Before starting nivolumab, his cyclosporine (CsA) dose was reduced to 25 mg bid to minimize blunting ICI anti-tumor effects by his immunosuppressive therapy, while mycophenolate mofetil (MMF) and prednisone were continued at previous dosing (Table 1). After 6 nivolumab doses, he presented to the University of Kansas Hospital with syncope and an electrocardiogram showing complete heart block (CHB) with a ventricular rate of 34 bpm (Figure 1A). Transthoracic echocardiogram (TTE) showed left ventricular ejection fraction (LVEF) 35% to 40%, decreased from 55% 4 weeks earlier. Baseline LVEF was 60% prior to ICI therapy (Table S1). Labs were notable for troponin 0.06 ng/mL, B-type natriuretic peptide (BNP) 2,813 pg/mL, sodium 130 mmol/L, and creatinine 1.55 mg/dL (Table 1).

Table 1.

Summary of Key Laboratory, Echocardiogram, and Biopsy Findings, as Weii as Immunosuppression Regimen During notable Time Periods of Patient’s Clinical Course

	Baseline values prior to ICI initiation	irAE Following 6 cycles of ICI	After irAE recovery and prior to ICI rechallenge	Following 11 cycles of ICI rechallenge
Sodium (mmol/L)	140	130	135	139
Potassium (mmol/L)	3.8	5.1	4.6	4.6
Chloride (mmol/L)	104	100	103	105
Bicarbonate (mmol/L)	26	19	26	22
Blood Urea Nitrogen	24	21	36	30
(mg/dL)
Creatinine (mg/dL)	1.33	1.55	1.28	1.31
Glucose (mg/dL)	103	203	99	85
Calcium (mg/dL)	10.1	9.2	9.3	9.9
Magnesium (mg/dL)	2.1	2.1	2.2	1.8
B Type Natriuretic Pep-tide (pg/mL)	N/A	2813	440	1862
Troponin-I (ng/mL)	N/A	0.06	N/A	N/A
Cyciosporine Trough (ng/ml)	79	112a	143	238
Hemoglobin (gm/dL)	15.3	15.1	13.8	13.0
Hematocrit (%)	44.9	44.9	41.0	38.8
Platelet Count (K/uL)	222.0	172	171	198
White Blood Cells (K/uL)	7.7	9.3	10.0	7.3
Notable TTE Findings	• LVEF 60% • Mildly dilated RV with mildly reduced EF • Moderate-severe TR, Trace MR	• LVEF 35%–40% • Moderately dilated RV with moderately reduced EF • Moderate-severe MR, severe TR	• LVEF 55% • Mildly dilated RV with mildly reduced EF • Moderate-severe MR, moderate-severe TR	• LVEF 45% with new apical akinesis • LV thrombus • Moderately dilated RV with reduced EF • Mild-moderate MR, severe TR
Cardiac Biopsy ISHLT Grading	-	• ACR 3R • pAMR 0	• ACR 0R • pAMR 0	• ACR 0R • pAMR 0
Immunosuppression Regimen	• CsA 50mg bid • MMF 250mg bid • Prednisone 5mg daily	• CsA 25mg bid • MMF 250mg bid • Prednisone 5mg daily	• CsA 150mg bid • MMF 1g bid • Prednisone 10mg bid	• CsA 150mg bid • MMF 1g bid • Prednisone 10mg bid

Including the irAE (Graft Injury Due to Rejection vs ICI Myocarditis) Following 6 Cycles of Nivolumab, as Well When There was a New Decline in EF and Apical Akinesis Following 11 Post-Graft injury Doses of Nivolumab During ICI Rechallenge

irAE, immune-related adverse event;TTE, transthoracic echocardiogram;LVEF;left ventricular ejection fraction;RV, right ventricle;EF, ejection fraction;TR, tricuspid valve regurgitation;MR, mitral valve regurgitation;ACR, acute cellular rejection;pAMR, pathologic antibody mediated rejection; ISHLT, International Society for Heart and Lung Transplantation.

^acyclosporine level drawn on Day 2 of hospital admission after dose was increased from 25mg bid to 50mg bid on presentation.

Figure 1.

(A) EKG on initial presentation demonstrating bradycardia with third-degree AV conduction block. (B) Histopathologic examination of right ventricular endomyocardial biopsy was notable for myocardial necrosis and inflammatory infiltration (i-iii, staining with hematoxylin and eosin) consistent with ACR Grade 3R. The inflammatory infiltrate included CD3-positive (iv) T lymphocytes, which were predominantly CD8-positive (v). CD68-positive (vi) macrophages also represented a large component of the infiltrate. CD4-positive (vii) cells are present. There did not appear to be a significant number of Foxp3-positive (viii) T-regs. PD-L1 staining (ix) was unremarkable. Scale bars: (i) 500 μm, (ii - vii) 200 μm, (viii, ix) 50 μm.

Temporary pacemaker was placed for symptomatic CHB, inotropes begun, and solumedrol 1g IV daily was started due to concern for graft injury attributable to ICI mediated myocarditis vs acute cardiac allograft rejection. CsA was also empirically increased from 25 mg bid to 50mg bid on presentation. Cyclosporine level on day 2 of hospitalization was 112 ng/mL, compared to 41 ng/mL about 1 month prior (Table S1). RV biopsy (Figure 1B) was consistent with ISHLT Acute Cellular Rejection (ACR) grade 3R, evidenced by diffuse lymphocytic infiltration with multifocal myocyte damage. C4d and CD68 staining was performed which suggested only Pathologic Antibody-Mediated Rejection (pAMR) grade 0 as there were few intravascular CD68 positive cells present (<10%) and there was weak focal staining of capillaries for C4d. The patient was treated with 3 days of solumedrol 1g IV daily and then transitioned to oral prednisone 50mg bid on taper to 10mg bid. CsA was uptitrated to 150mg bid to maintain levels >100 ng/mL, and MMF dosing was increased to 1g bid. A permanent pacemaker was placed on the second day of hospitalization since the temporary pacemaker was not consistently capturing due to several instances of lead dislodgement. Patient had significant clinical improvement, including resolution of heart block, was weaned off inotropes, and was discharged home 10 days after admission.

RV biopsy 2 weeks later showed resolution of graft injury (ACR grade 0R, pAMR grade 0) and TTE showed LVEF 50% (Tables S1). Surveillance CT scan demonstrated regression of pulmonary nodules, although no change in renal cell tumor mass was noted. After consultation with cardiology and oncology, and discussion with patient and family, nivolumab was re-initiated at prior dose after it had been held for a total of 6 weeks (2 doses missed), with augmented immunosuppression regimen: CsA 150mg bid, MMF 1g bid, prednisone 10mg bid (Table 1). Over the next 6 months, serial TTE LVEFs ranged 55% to 70%, with monthly cardiac biopsies that were stable (ACR grades 0–1R, pAMR grades 0–1), and surveillance CT scans showed no progression in tumor burden. Cyclosporine levels of 150–250 ng/mL were also maintained during this period (Table S1). 11 post-graft injury doses of nivolumab were administered without evidence of recurrent graft injury or LVEF decline. Before the 12th post-graft injury dose of nivolumab, TTE revealed reduced LVEF to 40% to 45% and new LV apical akinesis with thrombus. Cardiac biopsy showed no graft injury (ACR grade 0R, pAMR grade 0). BNP was 1862 pg/mL, cyclosporine level 238 ng/ml, but chemistry labs and blood counts otherwise similar to baseline (Table 1). Coronary angiogram revealed severe diffuse 3-vessel disease and was deemed unsuitable for revascularization (Figure 2). Findings appeared consistent with cardiac allograft vasculopathy (CAV) and likely contributed to new TTE findings. Of note, patient did not have any prior history of CAV. His last angiogram was 19 years ago, and since that time, he had undergone annual TTE and myocardial perfusion imaging for surveillance. Oral anticoagulation was started for LV thrombus and guideline-directed medical therapy was initiated for systolic dysfunction. He proceeded with 12th dose of nivolumab but was found deceased 2 days later. Pacemaker interrogation and autopsy were not performed.

Figure 2.

Coronary angiogram displaying severe, diffuse disease consistent with severe arteriopathy in the left anterior descending, ramus intermedius, and left circumflex arteries. Lesions were not amenable for intervention.

ICI, which are monoclonal antibodies that lead to activation of the immune system, are potent therapies for many cancer types but can also lead to irAE including myocarditis whose presentation can be clinically indistinguishable from cardiac rejection.¹ irAE risks are magnified in transplant patients as malignancies demanding ICI therapy exist in patients whose where immune responses are medically attenuated. Balancing the opposing effects of transplant immunosuppression and ICI presented a challenge in this case. We addressed this initially by reducing CsA dosing in an attempt to increase the effectiveness of ICI due to an unequivocally elevated near term risk of death from metastatic melanoma while accepting some risk of facilitating graft injury. However, it is likely that the decrease in CsA and introduction of ICI both contributed to this patient’s episode of acute severe graft injury. The patient demonstrated clinical features common to both acute rejection and ICI myocarditis including complete heart block, which seems to occur more commonly with ICI myocarditis.^1,5 While the exact mechanism of this patient’s irAE is unknown, we believe acute rejection was more likely and was driven by increased alloreactivity from ICI therapy. In addition, the timing of his event from ICI initiation occurred later than would be expected of ICI myocarditis. Reports have shown that most cases of ICI-myocarditis present within 1 to 2 months after initiation of ICI, and 66% of cases develop within 1 to 2 doses.⁶ Treatment protocol with high-dose corticosteroids and augmentation of transplant immunosuppressants would have been reasonable for either disease and proved to be effective in this case.

Augmentation of immunosuppressive therapy in solid organ transplant patients after life-threatening ICI-associated irAE presents a unique circumstance in which escalation of immunosuppression may allow reintroduction of effective ICI therapy after life-threatening irAE, as our case demonstrates. The optimal balance between immune activation via ICI and immunosuppression in solid organ transplantation patients with cancer has yet to be defined. Restarting this patient on his previous dose of nivolumab for 12 doses after intensification of transplant immunosuppression regimen proved to be effective, as his malignancies remained stable and he did not experience additional episodes of graft injury until his demise from graft vasculopathy. Our experience may also suggest that increasing immunosuppression prior to initiation of ICI therapy in this patient may have prevented acute graft injury and still provided effective therapy for his malignancy.

While reports of ICI-related CAV in transplant patients are currently sparse, the development of graft vasculopathy in this patient is intriguing as there have been recent reports of atherosclerosis progression in patients treated with ICI, possibly because the same immune checkpoints being targeted in cancer therapy are also known negative regulators of atherosclerosis.⁷ As CAV contributed to our patient’s demise, it is critical to recognize ICI mediated acceleration of vasculopathy as another component of ICI cardiotoxicity in cardiac transplant patients treated with ICI. In addition, the potential role of CAV should be considered when transplant patients present with LV dysfunction and heart block.

As the role of ICI therapies in cardiac transplant patients represents the expanding intersection of oncology, immunology and cardiology, strategies in immunosuppression and ICI dosing at initiation of cancer therapy and after ICI immune mediated complications warrant further study, as well as continued efforts towards building ICI transplant registries to improve our understanding of using ICIs after cardiac transplant.⁸