Renal Allografts at Risk After ICIs for Subsequent Cancer

Pam Harrison

October 28, 2020

Rates of acute rejection are alarmingly high in kidney transplant recipients who are treated for cancer with immune checkpoint inhibitors (ICI), as are rates of subsequent allograft loss, an observational trial shows.

Naoka Murakami

"We strongly believe these data will help the multidisciplinary decision-making among patients, oncologists, and nephrologists. Our next steps will be to understand the mechanisms of rejection and find a way to 'uncouple' rejection from good tumor response," said Naoka Murakami, MD, PhD, from Harvard Medical School in Boston.

Murakami and her colleagues looked at the safety of ICIs in terms of risk for rejection, as well as the timing and clinical characteristics of acute rejection.

"ICIs are supposed to enhance the immune response to cancer, so it was expected that ICI therapy could provoke an immune response not only against the cancer, but also the allograft," she told Medscape Medical News.

The international study involved 69 kidney recipients from 23 different institutions. Median age at the initiation of ICI therapy was 65 years, and mean time between transplantation and ICI initiation was 9.3 years.

Mean creatinine level was 1.3 mg/dL at ICI initiation, and patients received a variety of ICIs, including anti-PD-1 inhibitors, anti-PD-L1 inhibitors, anti-CTLA-4 inhibitors. A small subset of patients received both an anti-PD-1 and an anti-CTLA-4 inhibitor.

The researchers evaluated tumor response to ICI therapy and compared overall survival rates in ICI-treated transplant recipients and 40 historic control kidney transplant patients.

In the ICI group, 24 patients had squamous cell carcinoma (cSCC), 22 had melanoma, and the remaining 23 patients had other types of cancer.

In the historic control group, 23 kidney transplant patients had advanced cutaneous cSCC and 17 had advanced melanoma. All would have met the criteria for ICI therapy had it been available.

Of the 69 patients in the ICI group, "29 experienced acute rejection," Murakami reported during her presentation at Kidney Week 2020. Importantly, the median time from ICI initiation to rejection was 24 days, and 80% of rejections occurred less than 13 weeks after initiation of ICI treatment.

Different types of rejection were observed: 13 patients had biopsy-proven rejection; six had T-cell-mediated rejection; and seven had mixed T-cell-mediated rejection and antibody-mediated rejection.

"Notably, once rejection occurred, 65% of patients eventually lost their allograft," said Murakami. The risk for rejection was one-quarter to one-third lower in patients treated with an mTOR inhibitor and a higher number of immunosuppressive agents.

Efficacy of ICI Therapy

Patients in the ICI and control groups were well matched for age, sex, and time to diagnosis.

In the subgroup of cSCC patients, the objective response rate was significantly better in the ICI group than in the control group (33.3% vs 8.6%). Median overall survival was also significantly better in the ICI group than in the control group (19.8 vs 10.6 months; log rank P = .016).

In the melanoma subgroup, the objective response rate was significantly better in the ICI group than in the control group (36.3% vs 14.2%). However, overall survival was not significantly different in the ICI and control groups (13.5 vs 11.4 months; log rank P = .34).

Rejection rates were higher in the ICI group than in the control group for patients with cSCC (40.0% vs 4.3%) and for those with melanoma (57.0% vs 12.0%).

"Some patients will not want to start ICI therapy because they don't want to risk rejection, whereas others may choose ICI therapy despite knowing the risk of having to return to dialysis," said Murakami.

"But the ICIs are an efficacious treatment option for advanced cancer in kidney transplant recipients, so a patient-centered, multidisciplinary risk–benefit discussion is essential before treatment initiation," she said.

"Huge Challenge"

The use of ICIs in solid organ transplant recipients poses a real dilemma, said session moderator Ala Abudayyeh, MD, from the M.D. Anderson Cancer Center in Houston.

"I see these patients a lot at the hospital, especially melanoma patients, and it's a huge challenge," she explained.

However, if the cancer is progressing — a patient has metastatic melanoma to the brain, for example — and there is nothing else left to treat it with, "then we have to say, 'get on immunotherapy as a last ditch effort to save your life, and then, if you end up on dialysis, we will see what we can do'," she said.

This is not a conversation she would have with a recipient of any other type of organ, such as a heart, liver, or lungs; if those patients reject their organ, "they will die," she explained. Those patients should not be offered ICIs "because if we treat them with an ICI and they do reject their organs, they have no recourse."

Abudayyeh and her colleagues documented findings similar to the ones Murakami presented in a retrospective review in which graft rejection occurred in 41% of 39 solid organ transplant recipients, and median time to rejection was 21 days.

Almost one-third of patients discontinued ICIs because of allograft rejection, but graft loss occurred in more than 80% of those who developed rejection because of ICI therapy, and 46% of patients died because of loss of their allograft.

The study was funded by the NIDDK and supported by a private foundation. Murakami and Abudayyeh have disclosed no relevant financial relationships.

Kidney Week 2020: American Society of Nephrology Annual Meeting: Abstract Th-OR34. Presented October 22, 2020.

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