Merkel Cell Carcinoma in Solid Organ Transplant Recipients: Prognosis and Response to Immunotherapy

Abstract

Background: Merkel cell carcinoma (MCC) is an aggressive skin cancer with an increased risk of occurrence in immunocompromised patients, including solid organ transplant recipients (SOTR). As the number of SOTR rises worldwide, MCC cases in this population are also expected to increase. While anti-programmed death-(ligand)1 (anti-PD-(L)1) immunotherapy generates durable tumor responses in ∼50% of immunocompetent (IC) patients with advanced MCC, its efficacy and safety in SOTR remain uncertain as these patients have been excluded from most clinical trials.

Objectives: To compare baseline characteristics and outcomes among SOTR and IC patients with MCC, and to evaluate efficacy and toxicity of anti-PD-(L)1 in SOTR.

Methods: We queried a MCC registry from our institution (April 1988-May 2024), extracting data on demographics, anti-PD-(L)1 response, immunosuppression regimens, and incidence of allograft rejection and failure for analysis.

Results: We identified 1214 MCC patients (37 SOTR and 1177 IC patients); 8 of 37 SOTR received anti-PD-(L)1. The median time from solid organ transplant to MCC diagnosis was 10 years (range 0.4-43). The proportion of patients with advanced MCC (≥ stage III) was 76% in SOTR compared to 51% in IC patients (p=0.004). SOTR status was associated with worse outcomes, including higher rates of disease progression (adjusted hazard ratio [aHR] 2.3), MCC-specific mortality (aHR 3.0), and overall mortality (aHR 3.9; all p<0.001). The median time to death due to MCC for SOTR was 2.7 years; 24% of SOTR died within one year of diagnosis, in contrast to just 4% of IC patients. The median time to MCC progression for SOTR was 8.6 months vs 12 years for IC patients. Among SOTR, 70% developed distant metastases within 2 years versus 25% of IC patients. All eight MCC SOTR treated with anti-PD-(L)1 were kidney transplant recipients, with 5 (63%) experiencing an objective response (CR: 2, PR: 3). However, 2 (29%) patients experienced irreversible graft failure within 9 weeks.

Conclusions: SOTR status is a significant independent risk factor of a worse prognosis for MCC. This study represents the largest cohort evaluating the efficacy and safety of anti-PD-(L)1 in SOTR with advanced MCC, highlighting the potential benefits in this population.

Figure 1

Flow chart for patients with Merkel cell carcinoma enrolled and analysed in the solid organ transplant (SOT) recipient and immunocompetent (IC) cohorts. ^aAmong the 35 SOT recipients studied, 25 developed distant metastases, eight of whom received immunotherapy with an anti-programmed cell death 1 ligand 1 agent.

Figure 2

Outcomes of solid organ transplant (SOT) and immunocompetent (IC) patients with Merkel cell carcinoma (MCC). (a) Median time to progression was 8.6 months in the SOT group and 12 years in the IC group. The proportion progression-free at 2 years was 21% vs. 59%, respectively. (b) Median MCC-specific survival time was 2.7 years in the SOT group (the median was not reached in the IC group). The proportion that did not die of MCC by 2 years was 58% vs. 87%, respectively. (c) Median overall survival time was 1.7 years in the SOT group and 11 years in the IC group. The proportion surviving for at least 2 years was 43% vs. 81%, respectively. (d) Among patients with locoregional stage, median time to distant metastasis was 1.1 years in the SOT group (the median was not reached in the IC group). The proportion of distant-metastasis-free at 2 years was 30% vs. 75%, respectively. Curves are not adjusted for stage or other covariates. The tick marks on each curve indicate censoring times.

Figure 3

Two patient cases with an objective response to immune checkpoint inhibitor therapy while maintaining their kidney transplant. (a) A 65-year-old man (patient 1 in Table 3) who underwent a kidney transplant in 1997 was diagnosed with seronegative Merkel cell carcinoma (MCC) of the right clavicular area with involvement of the axillary lymph nodes, in February 2021. Following an initial treatment of wide local excision and radiotherapy, he developed multiple in-transit recurrent lesions on the right chest wall in August 2021. After multidisciplinary tumour board discussion and shared decision making, we opted to initiate pembrolizumab with a modified immunosuppression regimen (tacrolimus 4 mg per day and prednisone 5 mg three times per week. while discontinuing mycophenolate). In December 2021, immunosuppression was further reduced to tacrolimus at 2 mg per day with prednisone at 5 mg three times per week due to disease progression. Throughout his pembrolizumab course, donor derived cell-free DNA (dd-cfDNA) was monitored to assess kidney allograft rejection risk. His dd-cfDNA remained below the threshold of graft rejection risk (< 1.0%) throughout. Circulating tumour DNA (ctDNA) was utilized to monitor MCC disease. The ctDNA level was 300 in November 2021 when he developed multiple recurrences but he has remained negative since February 2022, which is concordant with imaging studies. Notably, no side effects were observed during the immunotherapy treatment. The patient achieved a complete response (CR) after 25 weeks of pembrolizumab combined with adjuvant radiation therapy, as confirmed by positron emission tomography/computed tomography (PET/CT) scans. As of the data cutoff date in June 2024, he had an ongoing CR even after pembrolizumab, electing to discontinue pembrolizumab in March 2022 to minimize chances of developing side effects. (b) A 73-year-old man (patient 3 in Table 3) who underwent a kidney transplant in 2006 was diagnosed with seronegative MCC of the left cheek in December 2022. He was treated with surgery and radiation in December 2022. However, ctDNA increased significantly in February 2023, indicating progression of disease. Mycophenolate was stopped in April 2023. Pembrolizumab therapy was initiated in June 2023. Simultaneously, dd-cfDNA was tracked, with an increase in July 2023 (1.5%) that indicated an increased risk for rejection; sirolimus 2 mg daily and prednisone 60 mg taper was initiated to maintain the transplant while enabling antitumour response. Subsequently, dd-cfDNA decreased below the rejection risk threshold in late July 2023 and has remained below the threshold ever since while on sirolimus 0.5 mg daily and prednisone 2.5 mg daily. A partial response (PR) was first noted in August 2023 via PET/CT, with stable findings in October 2023. Several resistant bone lesions in the spine and hip were treated with radiation in December 2023. A new liver metastasis, noted on a February 2024 PET/CT scan, was treated with radiation in May 2024. Although his ctDNA has not reached a completely negative level, it has significantly dropped from 259 mean tumour molecules mL⁻¹ to below 1, indicating controlled, stable disease while preserving the kidney allograft.