Abstract

A male patient who underwent a pre-emptive renal allograft and, nine years after the transplant, was diagnosed with nodular melanoma in the left shoulder, developing a few months later metastases. After two cycles of combined therapy with anti-PD-1 and anti-CTLA4, the patient was confirmed with acute rejection of the transplanted kidney allograft. A review and discussion about renal allograft rejection and the use of immune checkpoint inhibitors to metastatic melanoma is reported.

Citation: Débora S, Erick S, Jéssica Z, Monique T. Immune checkpoint inhibitors to metastatic melanoma and renalallograft rejection: A case report. Open J Clin Med Images. 2022; 2(2): 1069.

Introduction

Metastatic melanoma is an aggressive disease that responds poorly to most standard chemotherapies, with less than 15% survival in 5 years. Immune checkpoint inhibitors (CPIs) and target therapy have revolutionized melanoma treatment with remarkable survival benefits [1].

Patients with Solid-Organ Transplantation (SOT) have an increased risk of developing cancer. Secondary malignancies have been reported as the second leading cause of death in this population, presumably because they receive chronic immunosuppressive therapy to maintain allograft tolerance and less aggressive cancer treatments [2].

As the indications for CPIs expand to many cancers, it is crucial to determine the risk-benefit ratio of CPI use in SOT recipients. However, safety and efficacy data lack CPIs in patients who have undergone Solid Organ Transplantation (SOT) because they have been excluded from clinical trials.

Case report

We report a case of a 68 years-old male, white, former smoker of 40 pack-years, intense sun exposure, type-2 diabetes mellitus, hypertension, and chronic renal failure that underwent a pre-emptive renal allograft. He had stable kidney function after the transplant.

Nine years after the transplant, he underwent resection of nodular melanoma in the left shoulder, with 4.5 mm Breslow, Clark’s level IV, with ulceration without the involvement of sentinel lymph nodes (pT4bN0M0 - 8ª ed AJCC).

Nine months after resection, he was diagnosed with metastases in the liver, lymph nodes, and bones, the biopsy of which was confirmed to be wild BRAF melanoma metastasis.

The case was discussed at the multidisciplinary tumor board and proposed combined therapy with anti-PD-1 (Nivolumab 3 mg/m²) and anti-CTLA4 (Ipilimumabe 1 mg/m²) every 21 days for four cycles, followed by maintenance Nivolumab 3 mg/m² until disease progression. There was a complete discussion involving graft loss risks with the patient, and he wished to proceed with the treatment.

Five days after the second cycle of the combined CPIs, he developed nausea, vomiting, fatigue, and abdominal pain. The transplanted kidney’s ultrasound doppler showed acute kidney disease findings and poor perfusion related to transplant dysfunction and a graft nephrectomy was performed. Shortly after surgical recovery, the patient agreed to restart immunotherapy.

After the fourth cycle of combined immunotherapy, the PET-CT showed a complete radiological response at all metastasis sites. Currently, the patient is asymptomatic, maintaining Nivolumab without limiting toxicities, undergoing a hemodialysis schedule, without evidence of melanoma.

Discussion

Melanoma and non-melanoma skin cancers after transplantation are common and are a cause of substantial mortality. Therefore, annual dermatological assessment is recommended for all renal transplant patients [3].

The studies suggest that the rejection rate may be higher with PD-1/L1 blockade because alloimmunity largely relies on an alloantigen-mediated response that resembles the mechanism of tumor immune rejection [4]. Besides, anti-PD-1/L1 has higher antitumor response rates than anti-CTLA-4 (CheckMate 067, Keynote 006) [5-8], and the differing allograft rejection rates may reflect this. Although anti-CTLA-4 demonstrated in retrospective studies show a lower risk of graft loss when compared to anti-PD-1, it also corresponds to a lower response rate [9,10]. Prospective studies are needed to answer whether the risk of alloimmunity with anti-PD-1 differs from anti-CTLA-4 [11].

In the institutional experience of MD Anderson Cancer Center, the median Overall Survival (OS) in melanoma patients with prior SOT was much lower (5 months 95% CI 1-9) than what has been recently reported in the interim analyses of the Keynote-006 trial and the 4-year updated safety analysis of the CheckMate-067 problem (12 months 95% CI 8-16). These data suggest that the occurrence of allograft rejection compromised OS in patients with prior SOT [5,7].

CPIs in SOT recipients have been previously reported in other reviews [12-14]. These previous reviews identified some patients with allograft rejection and others who tolerated treatment with no adverse events. However, they did not synthesize the evidence on allograft rejection frequency by type of SOT, class of CPI, and anti-rejection immunosuppressant used at CPI initiation. The tumor response to CPI and OS to the occurrence of allograft rejection and the type of anti-rejection immunosuppression was not specified. Besides, they did not provide information on how rejections were managed and whether they necessitated permanent discontinuation of CPIs [2].

No prospective observational cohort studies have been published; therefore, we could not ascertain allograft rejection incidence in patients with prior SOT.

The lack of knowledge on the safety and efficacy of CPIs in patients with prior SOT poses as a major oncologic challenge. There are no clear recommendations on how to intervene for these patients. Hence the risk of allograft rejection and the reduction in survival compared with CPIs metastatic melanoma without treatment or chemotherapy should be explicitly conveyed to the patients. Studies are also needed to enhance our understanding of the complex interactions between the immune system, cancer neoantigens, and alloantigens to establish the ideal therapeutic plan to maintain allograft tolerance and maximize antitumor therapeutic benefits.

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