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Table of Contents
CASE REPORT
Year : 2021  |  Volume : 11  |  Issue : 2  |  Page : 95-97

Cryoglobulinemia unmasked by nivolumab in a patient with hepatitis C-induced hepatocellular carcinoma: A case report and literature review


1 Department of Medical Education, Saint Michael's Medical Centre, New York Medical College, Newark, New Jersey, USA
2 Department of Medical Education; Department of Internal Medicine; Department of Hematology/Oncology, Saint Michael's Medical Centre, New York Medical College, Newark, New Jersey, USA

Date of Submission08-Mar-2020
Date of Acceptance15-May-2020
Date of Web Publication29-Jun-2021

Correspondence Address:
Dr. Amr Ramahi
Department of Medical Education, Saint Michael's Medical Centre, New York Medical College, Newark, New Jersey 07102
USA
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/IJCIIS.IJCIIS_11_20

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   Abstract 


Hepatocellular carcinoma (HCC) is ranked the fifth-most common cancer in men and ninth most common cancer in women. Immunotherapy has been shown effective in malignancies refractory to chemotherapy and has been used as a second-line therapies in many advanced cancers, including HCC. The advent of immunotherapy has resulted in a brand-new set of side effects, and it has been proposed that it was related to over activated immune system. Herein, we presented the case of 59-year-old African American gentlemen who was diagnosed with HCC caused by Hepatitis C virus, for which he was started on chemotherapy and immunotherapy. However, the patient developed cryoglobulinemia that prompted stopping both therapies and giving rituximab and steroids. We believe that the mixed cryoglobulinemia was unmasked by immunotherapy in our patient. To our knowledge, this is one of the few first cases to describe such adverse effect from immune checkpoint inhibitors.

Keywords: Cryoglobulinemia, hepatocellular carcinoma, immunotherapy, nivolumab


How to cite this article:
Ramahi A, Chan KH, Lim SL, Shaaban HS. Cryoglobulinemia unmasked by nivolumab in a patient with hepatitis C-induced hepatocellular carcinoma: A case report and literature review. Int J Crit Illn Inj Sci 2021;11:95-7

How to cite this URL:
Ramahi A, Chan KH, Lim SL, Shaaban HS. Cryoglobulinemia unmasked by nivolumab in a patient with hepatitis C-induced hepatocellular carcinoma: A case report and literature review. Int J Crit Illn Inj Sci [serial online] 2021 [cited 2022 Dec 9];11:95-7. Available from: https://www.ijciis.org/text.asp?2021/11/2/95/319775




   Introduction Top


Hepatocellular carcinoma (HCC) is ranked the fifth-most common cancer in men and ninth most common cancer in women.[1] HCC has high morbidity and mortality risk. HCC is common in areas where viral hepatitis is prevalent. In recent years, immune check point inhibitors (ICIs) have changed the landscape in the management of patients with advanced solid tumors. Immunotherapy has been shown effective in malignancies refractory to chemotherapy and has been used as second-line therapy in many advanced cancers, including HCC.

Despite the great advancement in the utilization of immunotherapy in cancer management, the advent of immunotherapy has resulted in a brand-new set of side-effects which were different from conventional chemotherapy, which has been proposed to be related to over activated immune system. This overactivation is comparable to the mechanism of autoimmune disease.[2]


   Case Report Top


A 59-year-old African American male with a past medical history of hypertension, asthma, obesity, and untreated Hepatitis C, 30-pack-year smoking history, daily alcohol and cocaine use, presented to the emergency department initially complaining of severe right upper quadrant abdominal pain associated with shortness of breath, generalized fatigue, and 20 lbs unintentional weight loss. Physical examination showed right upper quadrant tenderness and hepatomegaly. There were no stigmata of liver disease. Complete blood count was normal, and complete metabolic profile showed elevated liver enzymes. Hepatitis panel showed a reactive Hepatitis C antibody (unknown viral load), hepatitis A and B were otherwise negative. Computed tomography (CT) with angiogram showed numerous hepatic masses that were concerning for malignancy, followed by abdominal US that confirmed the masses, Alpha-fetoprotein was elevated, MRI of the abdomen revealed numerous masses compatible with HCC with positive pathologic lymph nodes in the peripancreatic region. Triple phase Liver CT scan confirmed HCC with satellite lesion, LI-RADS 5 score; nonetheless, based on the American Association for the Study of Liver Diseases guidelines, no biopsy was needed to confirm the diagnosis of HCC. Due to the size of the tumor and number of metastasis (Child Pugh score A), the patient was not a candidate for liver transplant.

The patient was started on nivolumab (anti PD-1 inhibitor) and chemotherapy (Gemcitabine and Oxaliplatin), he received a total of 12 cycles of nivolumab and 8 cycles of chemotherapy. Thereafter, the patient presented to the ED again complaining of abdominal pain, anasarca, intractable nausea, and vomiting. Elevated liver enzymes, blood urea nitrogen (BUN), and serum creatinine, CT abdomen did not show any significant change from the previous studies. The patient was admitted for the evaluation of glomerulonephritis, during which rheumatoid factor and cryoglobulins were positive and immunofixation showed IgM monoclonal protein with kappa light chain specificity, eventually, the patient was diagnosed with mixed cryoglobulinemia (type II cryoglobulinemia). The patient was treated with diuretics and was transfused 2 units of blood; afterwards, he was stabilized and discharged home. Chemotherapy and immunotherapy were held, and the MC was treated with steroids and rituximab that led to the resolution of MC symptoms. We believe that the MC was unmasked by immunotherapy treatment for HCC as the patient never had MC symptoms prior to receiving nivolumab.


   Discussion Top


The two most important risk factors for HCC are chronic liver disease (chronic Hepatitis C virus [HCV]) and cirrhosis. HCC is an aggressive and relatively chemotherapy resistant cancer that often diagnosed late in the setting of chronic liver disease.[3] To our knowledge, there is no effective chemotherapy for advanced-stage HCC or for those failing local therapies. However, systemic therapy using molecularly targeted agents such as sorafenib or regorafenib (multikinase inhibitor) has gained much interest and have shown to improve survival compared to supportive care alone. Other than that, immune checkpoint inhibitor, nivolumab, which is a monoclonal antibody against PD-1, has also demonstrated noninferiority to first-line sorafenib. These results have changed the treatment landscape for advanced HCC. In an open-label multicenter clinical trial using nivolumab in patients include advanced HCC with Child-Pugh A or B7, sorafenib untreated, intolerant with or without viral etiology.[4] Nivolumab was well tolerated with Grade III/IV adverse events in 25% patients in the dose-escalation phase. The overall safety profile of nivolumab in dose-expansion phase was comparable to dose-escalation phase. The objective response rate was 20% in dose-expansion phase and 15% in the dose-escalation phase.[4]

Patients with HCC treated with immune checkpoint inhibitors have also been reported to have an increase in transaminases as compared to patients with NSCLC and melanoma but this does not cause patients to come off therapy or cause death secondary to drug toxicity.[5] Patients on immune checkpoint inhibitors may have transient worsening of disease before it stabilizes and the response can take longer compared to cytotoxic therapy. As such, it was decided to start our patient on nivolumab with the addition of chemotherapy (Gemcitabine and Oxaliplatin). However, 5 months later, he presented with anasarca and significantly elevated BUN and serum creatinine. Although complements were within normal limits, he tested positive for rheumatoid factor and cryoglobulin. He had mixed cryoglobulinemia likely due to chronic Hepatitis C infection; however, since the patient never had symptoms of MC prior to receiving nivolumab, we believe that it was unmasked by immunotherapy.

Immunotherapy can lead to immune-related adverse events (irAEs) due to nonspecific activation of T-cells; however, the exact mechanism is still under investigation. Multiple irAEs such as inflammatory arthritis, various vasculitides, and sicca syndrome have been reported in literature.[6] Nevertheless, after an extensive literature review, we found two other cases of ICI related cryoglobulinemia [Table 1]. Pellegrino et al. reported a patient with non-small cell lung cancer that developed secondary cryoglobulinemia related to nivolumab treatment after taking one dose only.[7] While in Le Burel et al. study, they reported a patient with melanoma who developed Sjogren syndrome and cryoglobulinemia after receiving PD-L1 inhibitor.[8] In both cases, there was no underlying hepatitis C infection and the symptoms resolved after discontinuing the ICIs and giving corticosteroids.[7],[8] Moreover, there was no literature found on MC as an adverse effect of chemotherapy. In our case, we propose that the MC was unmasked by immunotherapy, as we believe that it is one of the irAEs. Our theory indicates that ICI might have triggered the autoantibody release, which led to secondary mixed cryoglobulinemia in our HCV-induced HCC patient.
Table 1: Characteristics of patients with immune checkpoint inhibitor-related cryoglobulinemia

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   Conclusion Top


When it comes to treating cancer patients with new treatments, uncommon adverse effects should be suspected. Our case should be added to the literature as it expands the horizon of adverse effects of ICIs, this should also prompt further retrospective studies to better understand this phenomenon.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient (s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initial s will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

Research quality and ethics statement

This case report did not require approval by the Institutional Review Board / Ethics Committee. The authors followed applicable EQUATOR Network (http://www.equator-network.org/) guidelines, specifically the CARE guideline, during the conduct of this research project.



 
   References Top

1.
Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin 2015;65:87-108.  Back to cited text no. 1
    
2.
Teufel A, Zhan T, Härtel N, Bornschein J, Ebert MP, Schulte N. Management of immune related adverse events induced by immune checkpoint inhibition. Cancer Lett 2019;456:80-7.  Back to cited text no. 2
    
3.
A new prognostic system for hepatocellular carcinoma: A retrospective study of 435 patients: The Cancer of the Liver Italian Program (CLIP) investigators. Hepatology 1998;28:751-5.  Back to cited text no. 3
    
4.
El-Khoueiry AB, Sangro B, Yau T, Crocenzi TS, Kudo M, Hsu C, et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): An open-label, non-comparative, phase ½ dose escalation and expansion trial. Lancet 2017;389:2492-502.  Back to cited text no. 4
    
5.
Brown ZJ, Heinrich B, Steinberg SM, Yu SJ, Greten TF. Safety in treatment of hepatocellular carcinoma with immune checkpoint inhibitors as compared to melanoma and non-small cell lung cancer. J Immunother Cancer 2017;5:93.  Back to cited text no. 5
    
6.
Cappelli LC, Gutierrez AK, Bingham CO 3rd, Shah AA. Rheumatic and musculoskeletal immune-related adverse events due to immune checkpoint inhibitors: A systematic review of the literature. Arthritis Care Res (Hoboken) 2017;69:1751-63.  Back to cited text no. 6
    
7.
Pellegrino B, Musolino A, Tiseo M. Anti-PD-1-related cryoglobulinemia during treatment with nivolumab in NSCLC patient. Ann Oncol 2017;28:1405-6.  Back to cited text no. 7
    
8.
Le Burel S, Champiat S, Routier E, Aspeslagh S, Albiges L, Szwebel TA, et al. Onset of connective tissue disease following anti-PD1/PD-L1 cancer immunotherapy. Ann Rheum Dis 2018;77:468-70.  Back to cited text no. 8
    



 
 
    Tables

  [Table 1]


This article has been cited by
1 Immune-Related Uncommon Adverse Events in Patients with Cancer Treated with Immunotherapy
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Diagnostics. 2022; 12(9): 2091
[Pubmed] | [DOI]



 

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