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Background: High response rates of metastatic melanoma have been reported upon immune checkpoint inhibition by PD-1 blockade alone or in combination with CTLA-4 inhibitors. However, the majority of patients with a primary resistance to anti-PD-1 monotherapy is also refractory to a subsequent combined checkpoint inhibition. In BRAF wildtype patients with a primary resistance to PD-1 inhibitors, therapeutic options are therefore limited and immune-related adverse events (irAE) have to be taken into consideration when discussing a subsequent immunotherapy. Case presentation: We report the case of a 68-year-old male patient with metastatic melanoma who experienced an acute renal failure with nephrotic syndrome due to a minimal change disease developing after a single dose of the anti-PD-1 antibody pembrolizumab. A kidney biopsy revealed a podocytopathy without signs of interstitial nephritis. Renal function recovered to almost normal creatinine and total urine protein levels upon treatment with oral steroids and diuretics. Unfortunately, a disease progression (PD, RECIST 1.1) was observed in a CT scan after resolution of the irAE. In a grand round, re-exposure to a PD-1-containing regime was recommended. Consensually, a combined immunotherapy with ipilimumab and nivolumab was initiated. Nephrotoxicity was tolerable during combined immunotherapy and a CT scan of chest and abdomen showed a deep partial remission (RECIST 1.1) after three doses of ipilimumab (3 mg/kg) and nivolumab (1 mg/kg). Conclusion: This case illustrates that a fulminant response to combined checkpoint inhibition is possible after progression after anti-PD-1 monotherapy and a severe irAE. Keywords: PD-1, Immune-related adverse event, Minimal change disease, Ipilimumab, Nivolumab Background adverse events (irAE) related to monotherapy and pos- In prospective clinical trials response rates of up to ~ sible irAE during subsequent immunotherapy must be 40% to anti-PD-1 monotherapy and ~ 60% for com- taken into consideration when counselling these pa- bined checkpoint inhibition (ipilimumab plus nivolu- tients. Here, we report a case with a rare and severe mab) have been reported in patients with advanced or renal irAE due to pembrolizumab monotherapy and a metastatic melanoma . Unfortunately, treatment op- deep response to subsequent, well-tolerated ipilimumab tions for BRAF wildtype patients resistant to anti-PD-1 and nivolumab. monotherapy are limited. The majority of such patients are also refractory to subsequent combined checkpoint Case presentation inhibition [2, 3]. In addition, severe immune-related A 68-year old male was diagnosed with stage IV melan- oma (cM1c (0) AJCC 2017, BRAF wild type) with iliac * Correspondence: email@example.com lymph node, adrenal and splenic metastases (Fig. 1). Department of Dermatology, Venereology and Allergology, University Hospital Würzburg, Josef-Schneider-Str, 2, 97080 Würzburg, Germany Anti-PD-1 monotherapy with pembrolizumab was © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Glutsch et al. Journal for ImmunoTherapy of Cancer (2019) 7:181 Page 2 of 5 Fig. 1 Timeline: a-b CT scans of the abdomen with splenic metastases and a iliac lymph node metastasis before the first dose of pembrolizumab. c-d CT scans of the abdomen with splenic metastases and a iliac lymph node metastasis after one dose of pembrolizumab and acute kidney injury. e-f CT scans of the abdomen with a fulminant response of the splenic metastases and the iliac lymph node metastasis after three doses of ipilimumab/nivolumab. White arrows indicate metastases initiated (2 mg/kg q3w) as first-line therapy. Eighteen evident. Treatment with oral corticosteroids (100 mg days after the first application of pembrolizumab, the prednisolone qd) and diuretics was initiated. Renal func- patient reported a weight gain of 10 kg within 7 days tion recovered to creatinine levels around 1.5 mg/dl and and massive peripheral edema. Laboratory tests re- proteinuria decreased to 329 mg/l (Fig. 2). Prednisolone vealed an acute renal failure with nephrotic syndrome was tapered over approximately 6 weeks, diuretic treat- (creatinine 2.86 [0–1.17] mg/dl, urea 78.9 [10–50] mg/ ment with torasemid was reduced to a maintenance dose dl, potassium 5.2 [3.5–5] mmol/l, calcium 1.7 [2–2.7] of 25 mg qd. mmol/l, cholesterol 399 [130–220] mg/dl, total protein During irAE treatment, S100 serum levels increased 4.2 [6.6–8.7] g/dl, albumin 1.6 [3.5–5.5] g/dl). Prior to significantly and a computed tomography (CT) scan pembrolizumab, renal function tests were normal and of chest and abdomen 2 months after the single dose proteinuria was absent. The patient was hospitalized of pembrolizumab showed diesease progression (PD, and a kidney biopsy was performed. Light microscopy RECIST 1.1) (Fig. 1). A grand round recommended showed a tubular damage (presumably due to a preexis- re-exposure to a PD-1-based immunotherapy due to tent hypertensive nephropathy) without signs for inter- lacking effective therapy alternatives. The recommen- stitial nephritis. Amyloidosis, the presence of immune dation was discussed with the patient including the complexes or complement-mediated glomeruloneph- risk of an immunotherapy-related terminal dialysis- ritis were ruled out by immunohistochemistry. Ultim- dependent renal insufficiency. Finally, a combined ately, electron microscopy showed findings consistent checkpoint inhibition with ipilimumab (3 mg/kg) and with a minimal change disease. Based on these findings, nivolumab (1 mg/kg) was initiated. Proteinuria and an acute renal failure with nephrotic syndrome due to a blood pressure were monitored weekly. After two ap- minimal change disease related to pembrolizumab was di- plications of the combined immunotherapy, creatinine agnosed. Other risk factors for a minimal change disease levels increased to values ~ 2 mg/dl and the patient (e.g. non-steroidal anti-inflammatory drugs) were not once again showed massive proteinuria (total protein Glutsch et al. Journal for ImmunoTherapy of Cancer (2019) 7:181 Page 3 of 5 Fig. 2 Renal function tests: Serum creatinine and urine total protein throughout pembrolizumab and ipilimumab plus nivolumab therapy. Circles show serum creatinine while diamonds represent urine total protein at given time points. Upper limits of normal (ULN): Serum creatinine (ULN = 1.17 mg/l, indicated by dashed horizontal line) and urine total protein (ULN < = 120 mg/l). Black arrows indicate applications of ipilimumab/ nivolumab, black cross indicates application of pembrolizumab 18,200 mg/l) (Fig. 2). Fortunately, there were no signs predominant tubulointerstitial injury is the most common of peripheral edema and his body weight remained presentation of an acute kidney injury related to anti-PD- stable. To curtail proteinuria, oral treatment with the 1therapy [4, 7, 8], whereas an acute renal failure with ACE inhibitor ramipril was escalated to 5 mg qd. nephrotic syndrome due to a minimal change disease is Ipilimumab and nivolumab were continued without a rare. So far, only two cases of nephrotic syndrome with dose delay. Creatinine serum levels and proteinuria sta- minimal change disease secondary to therapy with an bilized (Fig. 2). Nevertheless, we abstained from the anti-PD-1 antibody have been reported [9, 10]. Both pa- fourth dose after another nephrological consultation and tients received pembrolizumab for Hodgkin’s lymphoma due to sonographic and serological signs for response (HL). In contrast to HL, malignant melanoma is not becoming evident. An ultrasound of the abdomen per- known to induce minimal change disease itself [11–13]. formed after two doses of ipilimumab and nivolumab Thus, the acute kidney injury in our patient was related to had already shown a shrinkage of the iliac lymph node pembrolizumab most likely. Consistent with the two cases metastasis and S100 serum levels were dropping (Fig. 3). reported and guidelines for managing irAE, immunother- A CT scan after three doses of combined checkpoint in- apy was stopped and both creatinine as well as proteinuria hibition confirmed a deep partial response (PR, RECIST improved after administering systemic glucocorticoids. In 1.1) with regression of all known visceral and lymph case of an immune-related acute kidney injury grade 3 ac- node metastases. There were no signs for new thoraco- cording to the Common Toxicity Criteria of Adverse abdominal or brain metastases (MRI). Due to the renal Events (CTCAE) treatment with methylprednisolone 0,5– irAE during anti-PD-1 monotherapy and a deep PR after 1 mg/kg daily is recommended and creatinine levels three doses of ipilimumab and nivolumab, we refrained should be monitored every 2 to 3 days . In case of un- from a maintenance treatment with nivolumab. clear clinical findings a kidney biopsy and a nephrology consultation are warranted . Most melanoma patients resistant to nivolumab or Discussions and conclusions pembrolizumab monotherapy are also refractory to a The frequency of renal adverse events related to anti-PD- subsequent combined immunotherapy with ipilimumab 1 therapy is very low [4–6]. Interstitial nephritis with plus nivolumab [2, 3]. However, there are case reports Glutsch et al. Journal for ImmunoTherapy of Cancer (2019) 7:181 Page 4 of 5 Fig. 3 Tumor markers: Course of lactate dehydrogenase (LDH) and S100B throughout pembrolizumab and ipilimumab plus nivolumab therapy. Diamonds show serum S-100 while circles indicate LDH levels at given time points. Upper limits of normal (ULN): LDH (ULN = 250 U/l) and S100 (ULN = 0.14 μg/l). Black arrows indicate applications of ipilimumab/nivolumab, black cross indicates application of pembrolizumab of fulminant responses to combined checkpoint inhib- Authors’ contributions VG, JW, FG and AG assessed and confirmed the accuracy of the details ition after failure of anti-PD-1 monotherapy despite un- relating to the patient’s oncologic history and treatment. VG and BS favorable predictive factors such as elevated lactate prepared figures. All authors took care of the patient. All authors contributed dehydrogenase (LDH) . Besides, there are reports to the writing and revising of the manuscript. All authors read and approved the final manuscript. that immunotherapy is safe in patients with an impaired renal function due to other underlying diseases . In Funding a process of participatory decision-making considering No specific funding was received. possible risks (e.g. dialysis-dependent renal failure) and Availability of data and materials alternative treatment options (PD-1 monotherapy with Not Applicable. nivolumab, CTLA-4 monotherapy with ipilimumab or Ethics approval and consent to participate chemotherapy with dacarbazine), combined checkpoint Not Appliclable. inhibition with ipilimumab and nivolumab was initiated and led to a deep response without new toxicites. Consent for publication Formal consent for anonymous publication of retrospective data from This unique case demonstrates that a response to routine care is not required by local laws. combined checkpoint inhibition is possible after disease progression after anti-PD-1 monotherapy and that appli- Competing interests cation of an anti-PD-1-based treatment after a severe Valerie Glutsch reports travel support from Novartis, Pierre Fabre Pharmaceuticals, Bristol-Myers Squibb (BMS) and Merck Sharp & Dohme irAE during anti-PD-1 monotherapy might be worth- (MSD). while. Keeping in mind that a response to ipilimumab Judith Weber reports travel support from BMS and MSD. plus nivolumab is still rare after disease progression after Anja Gesierich reports advisory roles for BMS, MSD, Novartis, Roche, Pfizer, Sanofi Genzyme, has received honoraria from MSD and BMS, and travel anti-PD-1 monotherapy [2, 3], this treatment sequence support from BMS, MSD, Novartis and Roche. should only be chosen in case of lacking effective treat- Bastian Schilling reports advisory roles for or has received honoraria from ment alternatives such as a targetable driver mutation. Pierre Fabre Pharmaceuticals, Incyte, Novartis, Roche, BMS and MSD, research funding from BMS, Pierre Fabre Pharmaceuticals and MSD, and travel support from Novartis, Roche, BMS, Pierre Fabre Pharmaceuticals and Acknowledgements Amgen. None. All other authors declare no conflicts of interest. Glutsch et al. 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Journal for ImmunoTherapy of Cancer – Springer Journals
Published: Jul 12, 2019
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