Fever reaction and haemophagocytic syndrome induced by immune checkpoint inhibitors

Fever reaction and haemophagocytic syndrome induced by immune checkpoint inhibitors We read with great interest Shah et al.’s [1] report on a case of severe fever and haemophagocytic syndrome triggered by anti-Programmed cell death 1 (PD1) treatment in a patient with bladder cancer. It is now well known that immune checkpoint inhibitors (ICIs) are associated with the occurrence of cutaneous, gastrointestinal, endocrine, and hepatic immune-related adverse events (irAEs) [2]. In view of the increasingly widespread use of ICIs, new types of irAEs are likely to be discovered; recent examples include myocarditis [3], polyradiculoneuropathy [4] and aplastic anaemia [5]. Shah et al. reported a first unexpected case of ICI-related fever with life-threatening haemophagocytic syndrome. In order to detect irAEs involving fever reaction and haemophagocytic syndrome such as that described by Shah et al., we screened the French pharmacovigilance database Registre des Effets Indésirables Sévères des Anticorps Monoclonaux Immunomodulateurs en Cancérologie (REISAMIC) [2]. This register was implemented in France at Gustave Roussy in October 2013 and collates for grade 2 CTCAEv4.03 or higher irAEs related to ICI use. For the period between October 2013 and July 2017, we identified one case of haemophagocytic syndrome in a patient being treated for metastatic melanoma with ipilimumab. Overall, 16 patients in REISAMIC had experienced an ICI-induced fever reaction (Table 1). Based on the number of patients having received anti-PD1, anti-PD-L1, or anti-CTLA4 treatments during this period (1212), the estimated incidences of haemophagocytic syndrome and fever reaction induced by ICI were 0.08% and 1.32%, respectively. Table 1 Characteristics of patients with grade 2 or higher ICI-related fever reaction or haemophagocytic syndrome, as recorded in the REISAMIC registry [2] Patient number  Type of event associated with fever  Anti-PD1 or PD-L1 treatment: dose and mode of administration  Causal link with immune- check-point inhibitor  Sex, age (years)  Indication by tumour type  Number of cycles of anti-PD1 or PD-L1 treatment  Time interval between infusion and fever  Maximum severity (CTCAEV4.03 grades)  Peak body temperature, °Celsius (°Fahrenheit)  Associated symptoms  Management of the fever reaction  Recurrence of fever at re-challenge  Other irAEs reported [grade (G) 2 or higher]  Best response to the immunotherapy  #1  HS  Pembrolizumab, 200 mg i.v. Q3W, followed by ipilimumab  Likely  Female, 63 y  Melanoma  Eight cycles pembro, followed by 1 cycle ipi  6 weeks after ipi  5  38.5 (100.4)  Hypotension, chills, DIC  Methylprednisolone, etoposide 150 mg/m2 i.v.  NA  Hepatitis G3  NA  #2  IRR  Anti-PDL1 (investigational drug)  Certain  Male, 59 y  Adenocarcinoma of the gastric cardia  1  1 h  2  38.4 (100.4)  Chills, flu-like symptoms  Methylprednisolone and Dexchlorpheniramine i.v.  NA  No  PD  #3  IRR  Pembrolizumab, 200 mg i.v. Q3W  Certain  Male, 62 y  Vesicular cancer  1  4 h  2  40.0 (104.0)  Chills, dyspnoea  Prednisolone, oral, 1 mg/kg  Yes  Rash G2, hepatitis G3, pneumonitis G2  PD  #4  IRR  Pembrolizumab, 10 mg/kg i.v. Q3W  Certain  Male, 53 y  Melanoma  2  1 h  2  39.6 (103.3)  NA  Dexchlorpheniramine i.v.  No  No  PD  #5  IRR  Atezolizumab, 1200 mg i.v. Q3W  Certain  Male, 61 y  CCR  1  4 h  2  39.0 (102.2)  Chills  Dexchlorpheniramine i.v.  Yes  No  PD  #6  IRR  Anti-PDL1 (experimental product)  Certain  Female, 69 y  Ovarian cancer  1  1 h  2  39.5 (103.1)  Chills  Dexchlorpheniramine i.v.  No  No  PD  #7  IRR  Atezolizumab, 1200 mg i.v. Q3W  Certain  Male, 41 y  NSCLC  1  1 h  2  39.5 (103.1)  NA  Prednisolone, oral, 0.5 mg/kg  NA  No  NA  #8  IRR  Pembrolizumab, 200 mg i.v. Q3W  Certain  Male, 29 y  Lymphoma (Hodgkin)  1  6 h  2  39.0 (102.2)  Chills, dyspnoea, tumour pain  Prednisolone, oral, 1 mg/kg, 2 days  No  No  SD  #9  Immune-related fever  Pembrolizumab, 200 mg i.v. Q3W  Likely  Female, 68 y  Lymphoma (DLBCL)  1  7 days  2  40.0 (104.0)  Rash  Solumedrol i.v. 1 mg/kg, 3 days  Yes  Rash G2  SD  #10  Immune-related fever  Nivolumab, 3 mg/kg i.v. Q2W  Certain  Female, 62 y  Lung cancer  1  4 days  3  40.1 (104.2)  Chills, Nausea,  Prednisolone, oral, 0.5 mg/kg, 7 days then tapering  No  Alopecia G2  PR  #11  Immune-related fever  Atezolizumab, 1200 mg i.v. Q3W  Certain  Female, 69 y  Breast cancer  1  6 days  2  39.0 (102.2)  Hyponatremia  Prednisolone, oral, 0.5 mg/kg  No  No  PD  #12  Immune-related fever  Pembrolizumab, 10 mg/kg i.v. Q3W  Certain  Male, 42 y  Melanoma  1  2 days  3  41.0 (105.8)  Diarrhoea  Ketoprofen oral  Yes  No  PD  #13  Immune-related fever  Anti-PDL-1 (experimentalproduct)  Certain  Male, 34 y  Merkel carcinoma  1  5 days  2  39.0 (102.2)  Flu-like syndrome  Prednisolone, oral, 1 mg/kg  Yes  No  PD  #14  Immune-related fever  Atezolizumab, 1200 mg i.v. Q3W  Certain  Male, 56 y  Urothelial cancer  1  10 days  2  39.0 (102.2)  NA  Resolved spontaneously  No  Mucositis G2, hepatitis G2  PD  #15  Immune-related fever  Pembrolizumab, 200 mg i.v. Q3W  Likely  Female, 88 y  Lymphoma (DLBCL)  1  1 day  2  39.0 (102.2)  Chills, diarrhoea, tumour pain  Prednisolone, oral, 0.5 mg/kg, 5 days  No  Colitis G2, rash G2  PR  #16  Immune-related fever  Nivolumab, 240 mg i.v. Q2W  Certain  Male, 64 y  Renal cancer  1  2 days  3  39.2 (102.6)  Chills, diarrhoea  Resolved spontaneously  No  No  PD  Patient number  Type of event associated with fever  Anti-PD1 or PD-L1 treatment: dose and mode of administration  Causal link with immune- check-point inhibitor  Sex, age (years)  Indication by tumour type  Number of cycles of anti-PD1 or PD-L1 treatment  Time interval between infusion and fever  Maximum severity (CTCAEV4.03 grades)  Peak body temperature, °Celsius (°Fahrenheit)  Associated symptoms  Management of the fever reaction  Recurrence of fever at re-challenge  Other irAEs reported [grade (G) 2 or higher]  Best response to the immunotherapy  #1  HS  Pembrolizumab, 200 mg i.v. Q3W, followed by ipilimumab  Likely  Female, 63 y  Melanoma  Eight cycles pembro, followed by 1 cycle ipi  6 weeks after ipi  5  38.5 (100.4)  Hypotension, chills, DIC  Methylprednisolone, etoposide 150 mg/m2 i.v.  NA  Hepatitis G3  NA  #2  IRR  Anti-PDL1 (investigational drug)  Certain  Male, 59 y  Adenocarcinoma of the gastric cardia  1  1 h  2  38.4 (100.4)  Chills, flu-like symptoms  Methylprednisolone and Dexchlorpheniramine i.v.  NA  No  PD  #3  IRR  Pembrolizumab, 200 mg i.v. Q3W  Certain  Male, 62 y  Vesicular cancer  1  4 h  2  40.0 (104.0)  Chills, dyspnoea  Prednisolone, oral, 1 mg/kg  Yes  Rash G2, hepatitis G3, pneumonitis G2  PD  #4  IRR  Pembrolizumab, 10 mg/kg i.v. Q3W  Certain  Male, 53 y  Melanoma  2  1 h  2  39.6 (103.3)  NA  Dexchlorpheniramine i.v.  No  No  PD  #5  IRR  Atezolizumab, 1200 mg i.v. Q3W  Certain  Male, 61 y  CCR  1  4 h  2  39.0 (102.2)  Chills  Dexchlorpheniramine i.v.  Yes  No  PD  #6  IRR  Anti-PDL1 (experimental product)  Certain  Female, 69 y  Ovarian cancer  1  1 h  2  39.5 (103.1)  Chills  Dexchlorpheniramine i.v.  No  No  PD  #7  IRR  Atezolizumab, 1200 mg i.v. Q3W  Certain  Male, 41 y  NSCLC  1  1 h  2  39.5 (103.1)  NA  Prednisolone, oral, 0.5 mg/kg  NA  No  NA  #8  IRR  Pembrolizumab, 200 mg i.v. Q3W  Certain  Male, 29 y  Lymphoma (Hodgkin)  1  6 h  2  39.0 (102.2)  Chills, dyspnoea, tumour pain  Prednisolone, oral, 1 mg/kg, 2 days  No  No  SD  #9  Immune-related fever  Pembrolizumab, 200 mg i.v. Q3W  Likely  Female, 68 y  Lymphoma (DLBCL)  1  7 days  2  40.0 (104.0)  Rash  Solumedrol i.v. 1 mg/kg, 3 days  Yes  Rash G2  SD  #10  Immune-related fever  Nivolumab, 3 mg/kg i.v. Q2W  Certain  Female, 62 y  Lung cancer  1  4 days  3  40.1 (104.2)  Chills, Nausea,  Prednisolone, oral, 0.5 mg/kg, 7 days then tapering  No  Alopecia G2  PR  #11  Immune-related fever  Atezolizumab, 1200 mg i.v. Q3W  Certain  Female, 69 y  Breast cancer  1  6 days  2  39.0 (102.2)  Hyponatremia  Prednisolone, oral, 0.5 mg/kg  No  No  PD  #12  Immune-related fever  Pembrolizumab, 10 mg/kg i.v. Q3W  Certain  Male, 42 y  Melanoma  1  2 days  3  41.0 (105.8)  Diarrhoea  Ketoprofen oral  Yes  No  PD  #13  Immune-related fever  Anti-PDL-1 (experimentalproduct)  Certain  Male, 34 y  Merkel carcinoma  1  5 days  2  39.0 (102.2)  Flu-like syndrome  Prednisolone, oral, 1 mg/kg  Yes  No  PD  #14  Immune-related fever  Atezolizumab, 1200 mg i.v. Q3W  Certain  Male, 56 y  Urothelial cancer  1  10 days  2  39.0 (102.2)  NA  Resolved spontaneously  No  Mucositis G2, hepatitis G2  PD  #15  Immune-related fever  Pembrolizumab, 200 mg i.v. Q3W  Likely  Female, 88 y  Lymphoma (DLBCL)  1  1 day  2  39.0 (102.2)  Chills, diarrhoea, tumour pain  Prednisolone, oral, 0.5 mg/kg, 5 days  No  Colitis G2, rash G2  PR  #16  Immune-related fever  Nivolumab, 240 mg i.v. Q2W  Certain  Male, 64 y  Renal cancer  1  2 days  3  39.2 (102.6)  Chills, diarrhoea  Resolved spontaneously  No  No  PD  The causal link with immune checkpoint inhibitor was assessed according to the Uppsala monitoring scale [6]. CCR, colorectal cancer; DIC, disseminated intravascular coagulation; DLBCL, diffuse large B-cell lymphoma; HS, haemophagocytic syndrome; i.v.: intravenous; irAE, immune-related adverse event; IRR, infusion-related reaction; NA, not available; NSCLC, non-small-cell lung carcinoma; PD, progressive disease; PR, partial response; SD, stable disease. The REISAMIC patient with haemophagocytic syndrome was a 52-year-old woman with metastatic melanoma with brain metastasis, classified T3b N1b M1c. Medical history found hematologic monoclonal immunoglobulin M gammopathy of indolent lymphoplasmocytic lymphoma confirmed by the presence of L265P mutation of MYD88, without treatment criteria. Patient was treated for melanoma with eight cycles of pembrolizumab treatment and had experienced progression of brain metastases. A cerebral stereotactic radiotherapy was performed, and she was then treated with ipilimumab intravenously at 3 mg/kg. After two cycles, the patient developed grade 3 immune-related hepatitis (confirmed by a liver biopsy). All screening tests for viruses were negative. Ipilimumab was withdrawn, and corticosteroid treatment was initiated. Although blood liver enzyme levels normalized progressively as the corticosteroids were tapered, the patient developed fever with pancytopenia and disseminated intravascular coagulation 8 weeks after the last ipilimumab cycle. Serum ferritin and triglyceride levels were elevated (37 times and 2 times the upper normal value, respectively). A bone marrow aspirate revealed no metastatic melanoma cells, numerous activated macrophages phagocyting lymphocytes, and an excess of small lymphocytes (40%) corresponding to the previous known indolent lymphoplasmocytic lymphoma. No viral, bacterial or fungal infections were detected. The entire body computerized tomography scan did not reveal any infection or adenomegaly. The final diagnosis was a drug-related haemophagocytic syndrome induced by ipilimumab. The patient was treated with high-dose corticosteroids and an intravenous infusion of etoposide (150 mg/m2). Unfortunately, the patient died after suffering a brain haemorrhage at the cerebral metastasis site. Our analysis of the 16 patients in REISAMIC that had experienced an ICI-induced fever reaction showed that fever reactions occurred mainly after the first infusion of anti-PD1 or anti-PD-L1 (Table 1). Of the 10 patients who resumed their ICI treatment, five experienced a fever reaction after the second infusion. Overall, seven cases were classified as ‘infusion-related reactions’ that occurred immediately after the infusion or within 24 h, while the eight other cases were classified as ‘immune-related fever’ that occurred 2 to 10 days after the infusion. The associated symptoms were typically chills and/or transient diarrhoea, although flares of tumour-related pain were noted in two patients with lymphoma. Corticosteroids were used to manage most of these cases of fever, and a low dose (0.5 mg/kg, for 2–5 days) was usually sufficient. In summary, we agree with Shah et al. that ICIs can induce rare but life-threatening cases of haemophagocytic syndrome. Furthermore, immune-related fever might be a new, rare irAE associated with anti-PD1 and anti-PD-L1 treatments (with an incidence of 1.2% in our registry) and usually be controlled with a short course of corticosteroids. Funding None declared. Disclosure The authors have declared no conflicts of interest. References 1 Shah D, Shrestha R, Ramlal R et al.   Pembrolizumab associated hemophagocytic lymphohistiocytosis. Ann Oncol  2017; 28( 6): 1403. Google Scholar CrossRef Search ADS PubMed  2 Michot JM, Bigenwald C, Champiat S et al.   Immune-related adverse events with immune checkpoint blockade: a comprehensive review. Eur J Cancer Engl  2016; 54: 139– 148. Google Scholar CrossRef Search ADS   3 Johnson DB, Balko JM, Compton ML et al.   Fulminant myocarditis with combination immune checkpoint blockade. N Engl J Med  2016; 375( 18): 1749– 1755. Google Scholar CrossRef Search ADS PubMed  4 de Maleissye M-F, Nicolas G, Saiag P. Pembrolizumab-induced demyelinating polyradiculoneuropathy. N Engl J Med  2016; 375( 3): 296– 297. Google Scholar CrossRef Search ADS PubMed  5 Michot J-M, Vargaftig J, Leduc C et al.   Immune-related bone marrow failure following anti-PD1 therapy. Eur J Cancer  2017; 80: 1– 4. Google Scholar CrossRef Search ADS PubMed  6 Hugman B. From the Uppsala monitoring centre: a review of viewpoint part 1 and part 2. Drug Saf  2005; 28( 7): 645– 646. Google Scholar CrossRef Search ADS   © The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For Permissions, please email: journals.permissions@oup.com. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Annals of Oncology Oxford University Press

Fever reaction and haemophagocytic syndrome induced by immune checkpoint inhibitors

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Abstract

We read with great interest Shah et al.’s [1] report on a case of severe fever and haemophagocytic syndrome triggered by anti-Programmed cell death 1 (PD1) treatment in a patient with bladder cancer. It is now well known that immune checkpoint inhibitors (ICIs) are associated with the occurrence of cutaneous, gastrointestinal, endocrine, and hepatic immune-related adverse events (irAEs) [2]. In view of the increasingly widespread use of ICIs, new types of irAEs are likely to be discovered; recent examples include myocarditis [3], polyradiculoneuropathy [4] and aplastic anaemia [5]. Shah et al. reported a first unexpected case of ICI-related fever with life-threatening haemophagocytic syndrome. In order to detect irAEs involving fever reaction and haemophagocytic syndrome such as that described by Shah et al., we screened the French pharmacovigilance database Registre des Effets Indésirables Sévères des Anticorps Monoclonaux Immunomodulateurs en Cancérologie (REISAMIC) [2]. This register was implemented in France at Gustave Roussy in October 2013 and collates for grade 2 CTCAEv4.03 or higher irAEs related to ICI use. For the period between October 2013 and July 2017, we identified one case of haemophagocytic syndrome in a patient being treated for metastatic melanoma with ipilimumab. Overall, 16 patients in REISAMIC had experienced an ICI-induced fever reaction (Table 1). Based on the number of patients having received anti-PD1, anti-PD-L1, or anti-CTLA4 treatments during this period (1212), the estimated incidences of haemophagocytic syndrome and fever reaction induced by ICI were 0.08% and 1.32%, respectively. Table 1 Characteristics of patients with grade 2 or higher ICI-related fever reaction or haemophagocytic syndrome, as recorded in the REISAMIC registry [2] Patient number  Type of event associated with fever  Anti-PD1 or PD-L1 treatment: dose and mode of administration  Causal link with immune- check-point inhibitor  Sex, age (years)  Indication by tumour type  Number of cycles of anti-PD1 or PD-L1 treatment  Time interval between infusion and fever  Maximum severity (CTCAEV4.03 grades)  Peak body temperature, °Celsius (°Fahrenheit)  Associated symptoms  Management of the fever reaction  Recurrence of fever at re-challenge  Other irAEs reported [grade (G) 2 or higher]  Best response to the immunotherapy  #1  HS  Pembrolizumab, 200 mg i.v. Q3W, followed by ipilimumab  Likely  Female, 63 y  Melanoma  Eight cycles pembro, followed by 1 cycle ipi  6 weeks after ipi  5  38.5 (100.4)  Hypotension, chills, DIC  Methylprednisolone, etoposide 150 mg/m2 i.v.  NA  Hepatitis G3  NA  #2  IRR  Anti-PDL1 (investigational drug)  Certain  Male, 59 y  Adenocarcinoma of the gastric cardia  1  1 h  2  38.4 (100.4)  Chills, flu-like symptoms  Methylprednisolone and Dexchlorpheniramine i.v.  NA  No  PD  #3  IRR  Pembrolizumab, 200 mg i.v. Q3W  Certain  Male, 62 y  Vesicular cancer  1  4 h  2  40.0 (104.0)  Chills, dyspnoea  Prednisolone, oral, 1 mg/kg  Yes  Rash G2, hepatitis G3, pneumonitis G2  PD  #4  IRR  Pembrolizumab, 10 mg/kg i.v. Q3W  Certain  Male, 53 y  Melanoma  2  1 h  2  39.6 (103.3)  NA  Dexchlorpheniramine i.v.  No  No  PD  #5  IRR  Atezolizumab, 1200 mg i.v. Q3W  Certain  Male, 61 y  CCR  1  4 h  2  39.0 (102.2)  Chills  Dexchlorpheniramine i.v.  Yes  No  PD  #6  IRR  Anti-PDL1 (experimental product)  Certain  Female, 69 y  Ovarian cancer  1  1 h  2  39.5 (103.1)  Chills  Dexchlorpheniramine i.v.  No  No  PD  #7  IRR  Atezolizumab, 1200 mg i.v. Q3W  Certain  Male, 41 y  NSCLC  1  1 h  2  39.5 (103.1)  NA  Prednisolone, oral, 0.5 mg/kg  NA  No  NA  #8  IRR  Pembrolizumab, 200 mg i.v. Q3W  Certain  Male, 29 y  Lymphoma (Hodgkin)  1  6 h  2  39.0 (102.2)  Chills, dyspnoea, tumour pain  Prednisolone, oral, 1 mg/kg, 2 days  No  No  SD  #9  Immune-related fever  Pembrolizumab, 200 mg i.v. Q3W  Likely  Female, 68 y  Lymphoma (DLBCL)  1  7 days  2  40.0 (104.0)  Rash  Solumedrol i.v. 1 mg/kg, 3 days  Yes  Rash G2  SD  #10  Immune-related fever  Nivolumab, 3 mg/kg i.v. Q2W  Certain  Female, 62 y  Lung cancer  1  4 days  3  40.1 (104.2)  Chills, Nausea,  Prednisolone, oral, 0.5 mg/kg, 7 days then tapering  No  Alopecia G2  PR  #11  Immune-related fever  Atezolizumab, 1200 mg i.v. Q3W  Certain  Female, 69 y  Breast cancer  1  6 days  2  39.0 (102.2)  Hyponatremia  Prednisolone, oral, 0.5 mg/kg  No  No  PD  #12  Immune-related fever  Pembrolizumab, 10 mg/kg i.v. Q3W  Certain  Male, 42 y  Melanoma  1  2 days  3  41.0 (105.8)  Diarrhoea  Ketoprofen oral  Yes  No  PD  #13  Immune-related fever  Anti-PDL-1 (experimentalproduct)  Certain  Male, 34 y  Merkel carcinoma  1  5 days  2  39.0 (102.2)  Flu-like syndrome  Prednisolone, oral, 1 mg/kg  Yes  No  PD  #14  Immune-related fever  Atezolizumab, 1200 mg i.v. Q3W  Certain  Male, 56 y  Urothelial cancer  1  10 days  2  39.0 (102.2)  NA  Resolved spontaneously  No  Mucositis G2, hepatitis G2  PD  #15  Immune-related fever  Pembrolizumab, 200 mg i.v. Q3W  Likely  Female, 88 y  Lymphoma (DLBCL)  1  1 day  2  39.0 (102.2)  Chills, diarrhoea, tumour pain  Prednisolone, oral, 0.5 mg/kg, 5 days  No  Colitis G2, rash G2  PR  #16  Immune-related fever  Nivolumab, 240 mg i.v. Q2W  Certain  Male, 64 y  Renal cancer  1  2 days  3  39.2 (102.6)  Chills, diarrhoea  Resolved spontaneously  No  No  PD  Patient number  Type of event associated with fever  Anti-PD1 or PD-L1 treatment: dose and mode of administration  Causal link with immune- check-point inhibitor  Sex, age (years)  Indication by tumour type  Number of cycles of anti-PD1 or PD-L1 treatment  Time interval between infusion and fever  Maximum severity (CTCAEV4.03 grades)  Peak body temperature, °Celsius (°Fahrenheit)  Associated symptoms  Management of the fever reaction  Recurrence of fever at re-challenge  Other irAEs reported [grade (G) 2 or higher]  Best response to the immunotherapy  #1  HS  Pembrolizumab, 200 mg i.v. Q3W, followed by ipilimumab  Likely  Female, 63 y  Melanoma  Eight cycles pembro, followed by 1 cycle ipi  6 weeks after ipi  5  38.5 (100.4)  Hypotension, chills, DIC  Methylprednisolone, etoposide 150 mg/m2 i.v.  NA  Hepatitis G3  NA  #2  IRR  Anti-PDL1 (investigational drug)  Certain  Male, 59 y  Adenocarcinoma of the gastric cardia  1  1 h  2  38.4 (100.4)  Chills, flu-like symptoms  Methylprednisolone and Dexchlorpheniramine i.v.  NA  No  PD  #3  IRR  Pembrolizumab, 200 mg i.v. Q3W  Certain  Male, 62 y  Vesicular cancer  1  4 h  2  40.0 (104.0)  Chills, dyspnoea  Prednisolone, oral, 1 mg/kg  Yes  Rash G2, hepatitis G3, pneumonitis G2  PD  #4  IRR  Pembrolizumab, 10 mg/kg i.v. Q3W  Certain  Male, 53 y  Melanoma  2  1 h  2  39.6 (103.3)  NA  Dexchlorpheniramine i.v.  No  No  PD  #5  IRR  Atezolizumab, 1200 mg i.v. Q3W  Certain  Male, 61 y  CCR  1  4 h  2  39.0 (102.2)  Chills  Dexchlorpheniramine i.v.  Yes  No  PD  #6  IRR  Anti-PDL1 (experimental product)  Certain  Female, 69 y  Ovarian cancer  1  1 h  2  39.5 (103.1)  Chills  Dexchlorpheniramine i.v.  No  No  PD  #7  IRR  Atezolizumab, 1200 mg i.v. Q3W  Certain  Male, 41 y  NSCLC  1  1 h  2  39.5 (103.1)  NA  Prednisolone, oral, 0.5 mg/kg  NA  No  NA  #8  IRR  Pembrolizumab, 200 mg i.v. Q3W  Certain  Male, 29 y  Lymphoma (Hodgkin)  1  6 h  2  39.0 (102.2)  Chills, dyspnoea, tumour pain  Prednisolone, oral, 1 mg/kg, 2 days  No  No  SD  #9  Immune-related fever  Pembrolizumab, 200 mg i.v. Q3W  Likely  Female, 68 y  Lymphoma (DLBCL)  1  7 days  2  40.0 (104.0)  Rash  Solumedrol i.v. 1 mg/kg, 3 days  Yes  Rash G2  SD  #10  Immune-related fever  Nivolumab, 3 mg/kg i.v. Q2W  Certain  Female, 62 y  Lung cancer  1  4 days  3  40.1 (104.2)  Chills, Nausea,  Prednisolone, oral, 0.5 mg/kg, 7 days then tapering  No  Alopecia G2  PR  #11  Immune-related fever  Atezolizumab, 1200 mg i.v. Q3W  Certain  Female, 69 y  Breast cancer  1  6 days  2  39.0 (102.2)  Hyponatremia  Prednisolone, oral, 0.5 mg/kg  No  No  PD  #12  Immune-related fever  Pembrolizumab, 10 mg/kg i.v. Q3W  Certain  Male, 42 y  Melanoma  1  2 days  3  41.0 (105.8)  Diarrhoea  Ketoprofen oral  Yes  No  PD  #13  Immune-related fever  Anti-PDL-1 (experimentalproduct)  Certain  Male, 34 y  Merkel carcinoma  1  5 days  2  39.0 (102.2)  Flu-like syndrome  Prednisolone, oral, 1 mg/kg  Yes  No  PD  #14  Immune-related fever  Atezolizumab, 1200 mg i.v. Q3W  Certain  Male, 56 y  Urothelial cancer  1  10 days  2  39.0 (102.2)  NA  Resolved spontaneously  No  Mucositis G2, hepatitis G2  PD  #15  Immune-related fever  Pembrolizumab, 200 mg i.v. Q3W  Likely  Female, 88 y  Lymphoma (DLBCL)  1  1 day  2  39.0 (102.2)  Chills, diarrhoea, tumour pain  Prednisolone, oral, 0.5 mg/kg, 5 days  No  Colitis G2, rash G2  PR  #16  Immune-related fever  Nivolumab, 240 mg i.v. Q2W  Certain  Male, 64 y  Renal cancer  1  2 days  3  39.2 (102.6)  Chills, diarrhoea  Resolved spontaneously  No  No  PD  The causal link with immune checkpoint inhibitor was assessed according to the Uppsala monitoring scale [6]. CCR, colorectal cancer; DIC, disseminated intravascular coagulation; DLBCL, diffuse large B-cell lymphoma; HS, haemophagocytic syndrome; i.v.: intravenous; irAE, immune-related adverse event; IRR, infusion-related reaction; NA, not available; NSCLC, non-small-cell lung carcinoma; PD, progressive disease; PR, partial response; SD, stable disease. The REISAMIC patient with haemophagocytic syndrome was a 52-year-old woman with metastatic melanoma with brain metastasis, classified T3b N1b M1c. Medical history found hematologic monoclonal immunoglobulin M gammopathy of indolent lymphoplasmocytic lymphoma confirmed by the presence of L265P mutation of MYD88, without treatment criteria. Patient was treated for melanoma with eight cycles of pembrolizumab treatment and had experienced progression of brain metastases. A cerebral stereotactic radiotherapy was performed, and she was then treated with ipilimumab intravenously at 3 mg/kg. After two cycles, the patient developed grade 3 immune-related hepatitis (confirmed by a liver biopsy). All screening tests for viruses were negative. Ipilimumab was withdrawn, and corticosteroid treatment was initiated. Although blood liver enzyme levels normalized progressively as the corticosteroids were tapered, the patient developed fever with pancytopenia and disseminated intravascular coagulation 8 weeks after the last ipilimumab cycle. Serum ferritin and triglyceride levels were elevated (37 times and 2 times the upper normal value, respectively). A bone marrow aspirate revealed no metastatic melanoma cells, numerous activated macrophages phagocyting lymphocytes, and an excess of small lymphocytes (40%) corresponding to the previous known indolent lymphoplasmocytic lymphoma. No viral, bacterial or fungal infections were detected. The entire body computerized tomography scan did not reveal any infection or adenomegaly. The final diagnosis was a drug-related haemophagocytic syndrome induced by ipilimumab. The patient was treated with high-dose corticosteroids and an intravenous infusion of etoposide (150 mg/m2). Unfortunately, the patient died after suffering a brain haemorrhage at the cerebral metastasis site. Our analysis of the 16 patients in REISAMIC that had experienced an ICI-induced fever reaction showed that fever reactions occurred mainly after the first infusion of anti-PD1 or anti-PD-L1 (Table 1). Of the 10 patients who resumed their ICI treatment, five experienced a fever reaction after the second infusion. Overall, seven cases were classified as ‘infusion-related reactions’ that occurred immediately after the infusion or within 24 h, while the eight other cases were classified as ‘immune-related fever’ that occurred 2 to 10 days after the infusion. The associated symptoms were typically chills and/or transient diarrhoea, although flares of tumour-related pain were noted in two patients with lymphoma. Corticosteroids were used to manage most of these cases of fever, and a low dose (0.5 mg/kg, for 2–5 days) was usually sufficient. In summary, we agree with Shah et al. that ICIs can induce rare but life-threatening cases of haemophagocytic syndrome. Furthermore, immune-related fever might be a new, rare irAE associated with anti-PD1 and anti-PD-L1 treatments (with an incidence of 1.2% in our registry) and usually be controlled with a short course of corticosteroids. Funding None declared. Disclosure The authors have declared no conflicts of interest. References 1 Shah D, Shrestha R, Ramlal R et al.   Pembrolizumab associated hemophagocytic lymphohistiocytosis. Ann Oncol  2017; 28( 6): 1403. Google Scholar CrossRef Search ADS PubMed  2 Michot JM, Bigenwald C, Champiat S et al.   Immune-related adverse events with immune checkpoint blockade: a comprehensive review. Eur J Cancer Engl  2016; 54: 139– 148. Google Scholar CrossRef Search ADS   3 Johnson DB, Balko JM, Compton ML et al.   Fulminant myocarditis with combination immune checkpoint blockade. N Engl J Med  2016; 375( 18): 1749– 1755. Google Scholar CrossRef Search ADS PubMed  4 de Maleissye M-F, Nicolas G, Saiag P. Pembrolizumab-induced demyelinating polyradiculoneuropathy. N Engl J Med  2016; 375( 3): 296– 297. Google Scholar CrossRef Search ADS PubMed  5 Michot J-M, Vargaftig J, Leduc C et al.   Immune-related bone marrow failure following anti-PD1 therapy. Eur J Cancer  2017; 80: 1– 4. Google Scholar CrossRef Search ADS PubMed  6 Hugman B. From the Uppsala monitoring centre: a review of viewpoint part 1 and part 2. Drug Saf  2005; 28( 7): 645– 646. Google Scholar CrossRef Search ADS   © The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

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Annals of OncologyOxford University Press

Published: Feb 1, 2018

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