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Response to Treatment with an Anti-Interleukin-6 Receptor Antibody (Tocilizumab) in a Patient with Hemophagocytic Syndrome Secondary to Immune Checkpoint Inhibitors

Response to Treatment with an Anti-Interleukin-6 Receptor Antibody (Tocilizumab) in a Patient... Hindawi Case Reports in Oncological Medicine Volume 2021, Article ID 6631859, 5 pages https://doi.org/10.1155/2021/6631859 Case Report Response to Treatment with an Anti-Interleukin-6 Receptor Antibody (Tocilizumab) in a Patient with Hemophagocytic Syndrome Secondary to Immune Checkpoint Inhibitors 1,2 1,2 1,2 Alejandro Olivares-Hernández , Luis Figuero-Pérez , María A. Amores Martín, 1,2 3 1,2 Lorena Bellido Hernández, Laura Mezquita, María del Rosario Vidal Tocino , 4 5 2,6 Félix López Cadenas, Felipe Gómez-Caminero López , Roberto A. Escala-Cornejo, 1,2 and Juan Jesús Cruz Hernández Department of Medical Oncology, University Healthcare Complex of Salamanca, Paseo de San Vicente, 182, CP 37007 Salamanca, Spain Instituto de Investigación Biomédica de Salamanca (IBSAL), Paseo de San Vicente, 58-182, CP 37007 Salamanca, Spain Department of Medical Oncology, Hospital Clinic, Carrer de Villarroel, 170, CP 08036 Barcelona, Spain Hematology Department, University Healthcare Complex of Salamanca, Paseo de San Vicente, 182, CP 37007 Salamanca, Spain Nuclear Medicine Department, University Healthcare Complex of Salamanca, Paseo de San Vicente, 182, CP 37007 Salamanca, Spain Department of Medical Oncology, Ávila Healthcare Complex, Avenida Rey Juan Carlos I, CP 05004 Ávila, Spain Correspondence should be addressed to Alejandro Olivares-Hernández; aolivares@saludcastillayleon.es Received 26 December 2020; Revised 14 January 2021; Accepted 2 February 2021; Published 12 February 2021 Academic Editor: Raffaele Palmirotta Copyright © 2021 Alejandro Olivares-Hernández et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Background. Immunotherapy represents one of the fundamental treatments in the management of some types of cancer, especially malignant melanoma. Toxicity derived from increased immune system activity can manifest in multiple organs and systems. We present a case of hematological toxicity, manifested as hemophagocytic syndrome (HPS), which was successfully treated with an anti-interleukin-6 antibody (tocilizumab). Case Report. This case presents a 75-year-old woman diagnosed with metastatic choroidal melanoma, refractory to several lines of treatment. After the failure of the previous lines, ipilimumab was started. After the third dose, she developed grade 2 thrombocytopenia and anemia accompanied by elevated levels of ferritin, triglycerides, and decreased fibrinogen. Hemophagocytosis was observed in the bone marrow biopsy, and a PET-CT showed splenomegaly with increased metabolism. Treatment was based on high doses of corticosteroids and tocilizumab. Four days after the start of treatment, progressive clinical and analytical improvement was observed, achieving total remission of the condition. Discussion. HPS induced by immunotherapy is due to an immunorelated cytokine storm syndrome (CSS). The administration of the anti- interleukin-6 receptor antibody drug acted on this cytokine cascade, leading to stabilization and subsequent remission. For this reason, the use of tocilizumab should be part of the immunotherapy-induced HPS treatment algorithm. 1. Background signs and symptoms of excessive inflammation due to dys- function of the natural killer (NK) cells, which leads to the overstimulation, hyperproliferation, and ectopic migration Hemophagocytic syndrome (HPS) is a rare clinical entity of T1 cells [1]. The incidence is estimated at 1.2 per million characterized by hyperactivity and irregularity in the activa- cases per year. However, these values may be underestimated tion of the immune system induced by response to a specific due to low diagnostic suspicion in most cases [2]. trigger. This pathological immune activation manifests as 2 Case Reports in Oncological Medicine tal admission for study and determination of the appropriate HPS is not a single disease but a syndrome associated with a wide variety of underlying causes that lead to a charac- treatment. During admission, a PET-CT was performed, in teristic inflammatory phenotype [3]. The triggering causes which a partial response was observed in the liver. Splenomeg- can be classified as primary in the case of a mutation of the aly was also observed with a diffuse increase in the metabolic FLH gene or as secondary when they are due to infectious, activity of the entire splenic parenchyma. Suspecting primary neoplastic processes or other immunodeficiencies; in general, splenic B lymphoma, a bone marrow biopsy was performed, the secondary causes are observed most frequently [4]. The and abundant macrophages with compatible characteristics most common symptoms are fever and splenomegaly, of hemophagocytosis were observed (Figure 1). appearing in about 75% of patients at diagnosis, followed High levels of ferritin (>85,000 ng/mL), hypertriglyc- by liver failure, sepsis, Kawasaki disease, and neurological eridemia (maximum value of 389 mg/dL), low levels of fibrin- abnormalities. Diagnosis is based on a scale of eight diagnos- ogen (147 mg/dL), and normochromic normocytic anemia tic criteria, of which the patient must meet at least five: (1) (9.8 g/dL) were observed in the blood samples requested fever (>38 C); (2) splenomegaly; (3) cytopenias that affect during admission. Furthermore, the patient presented a fever at least two series; (4) hypertriglyceridemia (>265 mg/dL) of up to 38.5 C without elevation of acute phase reactants, and/or low fibrinogen levels (<150 mg/dL); (5) hemophago- such as c-reactive protein (CRP). Based on all of these signs cytosis in the bone marrow, spleen, lymph nodes, or liver; and symptoms, HPS was confirmed, and other possible (6) low or no activity of the NK cells; (7) high levels of ferritin causes were ruled out, including infections (negative viral (>500 ng/mL); and (8) high levels of soluble CD25 [5]. serologies, as well as negative urine and blood cultures, were Inhibition at the checkpoints of the immune system is collected), autoimmune diseases, hematological malignan- currently one of the cornerstones of cancer treatment in a wide cies, and bone marrow infiltration. variety of tumors, including melanoma [6]. Current treat- The patient met six of the eight diagnostic criteria for HPS. ments for B-RAF wild-type melanoma are based on two After ruling out other causes, secondary HPS was attributed to blocking points: (1) inhibition of the cytotoxic T lymphocyte an immunomediated adverse effect secondary to treatment antigen 4 (CTLA-4) receptor and (2) inhibition of the with the anti-CTLA-4, ipilimumab. Despite corticosteroid programmed cell death protein 1 (PD-1) receptor [7]. Mono- treatment (maximum doses of 2 mg/kg), no improvement clonal antibodies directed towards CTLA-4 inhibition, such as was observed, and it was decided to start treatment with an ipilimumab, and anti-PD-1, such as nivolumab, have changed anti-interleukin-6 receptor antibody (tocilizumab) at a dose the treatment and natural evolution of metastatic melanoma. of 8 mg/kg every eight hours for four doses [11]. Prior to the The immune-related adverse events (irAEs) from these treat- tocilizumab regimen, the IL-2 value was determined to dem- ments originate from excessive immune activation and can onstrate the existence of the cytokine storm secondary to affect any system or body function [8]. Hematological toxicity HPS. The IL-2 value was 1734 U/mL (158-623 U/mL). After appears in less than 1% of cases, with thrombocytopenia being the fourth dose of tocilizumab, there was clinical improvement the most frequently described [9]. The management of irAE is without fever and analytical improvement with progressive very complex, making the use of corticosteroids and immuno- normalization of the levels of hemoglobin, platelets, ferritin, suppressive treatments the mainstay. [10] We present a case of fibrinogen, and triglycerides (Table 1). a woman diagnosed with metastatic choroidal melanoma who Once the clinical process was corrected, a new bone mar- developed HPS secondary to treatment with ipilimumab. row biopsy was performed, and no signs compatible with hemophagocytosis were found. In addition, a PET-CT was performed (Figure 2), in which an absence of splenic meta- 2. Case Report bolic uptake was observed. For these reasons, the patient was discharged from the hospital and began outpatient follow- A 75-year-old woman diagnosed with choroidal melanoma in 1989 was treated by enucleation without adjuvant treatment. ups with the hematology and medical oncology departments. After 22 years of disease-free survival (DFS), in 2011, a CT scan revealed liver involvement, which was confirmed by biopsy and indicated the recurrence of the B-RAF wild-type 3. Discussion melanoma. She began treatment with dacarbazine (DTIC), which followed by nivolumab in 2016 due to tumor progres- Immune-related adverse effects are more frequently observed sion. With nivolumab, she maintained a progression-free with the use of anti-CTLA-4 (40%) than with anti-PD-1 or interval (PFI) of three years. When new liver progression anti-PD-L1. The most common irAEs are asthenia, anorexia, appeared, a third line of treatment with ipilimumab (3 mg/kg) and fever, appearing in up to 40-50% of cases. Hematologic was started, and she received three cycles. irAEs are poorly described in the literature due to their low Prior to the start of a fourth cycle of treatment with ipili- incidence (0.5%) [9]. mumab, grade 2 thrombocytopenia (platelets: 64,000/μL) It has been described that, in a small group of patients, was observed, suggesting hematological toxicity associated treatment with immune checkpoint inhibitors could induce with the immunotherapy treatment. Due to this suspicion, a cascade of cytokines, leading to the development of HPS. the treatment with anti-CTLA-4 was interrupted, and methyl- The cases reported in the literature suggest that HPS second- prednisolone was started at a dose of 1 mg/kg. Despite the ary to immunotherapy has been observed with the use of corticosteroid treatment, no clinical analytical improvement modified T cells (such as modified chimeric antigen receptor was observed; therefore, the patient was admitted to the hospi- T (CAR-T) cells), blinatumomab (monoclonal antibody Case Reports in Oncological Medicine 3 Figure 1: Pretreatment: (a) PET-CT: splenomegaly and increased metabolism in the spleen are observed at diagnosis; (b) bone marrow biopsy: macrophage phagocytosing erythrocytes and neutrophils (hemophagocyte). Table 1: Evolution of analytical values during the admission of the patient. HPS At time of Baseline steroid Baseline After 48 h of At time of Analytical values criteria admission therapy tocilizumab tocilizumab discharge Hemoglobin (g/dL) Yes 13.5 11.2 9.6 11.6 12.1 Platelets (/μL) Yes 64.000 45.000 48.000 74.000 113.000 Ferritin (ng/mL) Yes >74.150 >74.150 >89.918 12.019 1978 Fibrinogen (mg/dL) Yes 147 164 170 —— Triglycerides (mg/dL) Yes 271 327 265 234 172 Bone marrow Yes —— Yes — No findings – Not available. directed against CD3 and CD19) [12, 13], and immune In the case report, the use of tocilizumab was a novel checkpoint inhibitors. treatment in the field of immunotoxicity secondary to the Recently, the use of the anti-interleukin-6 receptor anti- anti-CTLA-4, introducing new hope into the treatment of body (tocilizumab) has been reported and approved for the this type of patient, with excellent results. In our center, the treatment of HPS secondary to the use of CAR-T cells and use of tocilizumab was based on the study carried out by blinatumomab. However, in patients treated with immune Dupré et al., in which the possible efficacy of tocilizumab in checkpoint inhibitors, such as anti-CTLA-4 or anti-PD-1/PD- the treatment of HPS secondary to immune checkpoint L1, tocilizumab is not typically used for HPS. In published cases inhibitors was postulated [17]. Our patient presented clinical of HPS as an irAE, immunomodulators have been used, such as improvement with the absence of fever and normalization of etoposide [14], mycophenolic acid [15], and tacrolimus [16], laboratory levels when four doses of tocilizumab were admin- and are always associated with corticosteroids in the interrup- istered. The benefit of the treatment and the short hospital tion of immune treatment. stay highlights the effectiveness and the role that anti- 4 Case Reports in Oncological Medicine Figure 2: Posttreatment. PET-CT: significant decrease in the metabolism in the spleen, after 4 doses of tocilizumab. interleukin-6 receptor antibodies could have in the treatment Authors’ Contributions of HPS induced by immune checkpoint inhibitors. The devel- AO-H was responsible for clinical management of the opment of a massive cytokine storm is the main determining patient, data collection, and preparation and design of the factor in HPS secondary to treatment with immune check- manuscript. LF-P was responsible for clinical management point inhibitors. For this reason, the decrease in endogenous of the patient, data collection, and preparation and design levels of interleukin-6 using tocilizumab could mitigate the of the manuscript. AA-M was responsible for clinical man- inappropriate activation of macrophages and improve the agement of the patient, data collection, and preparation and clinical situation. design of the manuscript. LB-H was responsible for clinical The treatment of any moderate or high grade irAEs, not management of the patient. LM was responsible for clinical only HPS, is based on the use of corticosteroids at high doses management of the patient and preparation and design of (1-2 mg/kg) [18]. Taking into account the current results on the manuscript. RV-T was responsible for clinical manage- the use of the anti-interleukin-6 receptor antibody, we ment of the patient. FL-C was responsible for clinical suggest that drugs, such as tocilizumab, could have a beneficial management of the patient. FG-C was responsible for per- use in severe cases of irAEs, as well as in patients for whom the forming the diagnostic imaging test. REC was responsible use of corticotherapy would be limited, such as those with type for writing and preparation of the manuscript. JJC-H was 1 diabetes mellitus secondary to immunotherapy [19]. responsible for clinical management of the patient and lead- In conclusion, our case and the review of the literature ership of the work team. Alejandro Olivares-Hernández and suggest that, at present, the anti-interleukin-6 antibodies Luis Figuero-Pérez contributed equally to this work. may be an appropriate treatment option for HPS induced by immune checkpoint inhibitors. Likewise, more studies are needed to determine the validity of these treatments References before being recommended in the clinical practice. [1] A. Hayden, S. Park, D. Giustini, A. Y. Lee, and L. Y. Chen, “Hemophagocytic syndromes (HPSs) including hemophago- Data Availability cytic lymphohistiocytosis (HLH) in adults: a systematic scop- ing review,” Blood Reviews, vol. 30, no. 6, pp. 411–420, 2016. The data provided for the case report can be found in the clin- ical record database of the University Hospital of Salamanca. [2] J. I. Henter, G. Elinder, O. Soder, and A. Ost, “Incidence in Sweden and clinical features of familial hemophagocytic lym- phohistiocytosis,” Acta Paediatrica Scandinavica, vol. 80, Conflicts of Interest no. 4, pp. 428–435, 1991. [3] R. Jaffe, “The histiocytoses,” Clinics in Laboratory Medicine, AO-H, LF-P, AA-M, LB-H, RV-T, FL-C, FG-C, and REC have vol. 19, no. 1, pp. 135–156, 1999. nothing to disclose. LM has the following disclosures: spon- [4] M. R. George, “Hemophagocytic lymphohistiocytosis: review sored research: Bristol-Myers Squibb and Boehringer Ingel- of etiologies and management,” Journal of Blood Medicine, heim; consulting and advisory roles: Roche Diagnostics and vol. 5, pp. 69–86, 2014. Takeda; lectures and educational activities: Bristol-Myers [5] K. Lehmberg, K. E. Nichols, J. I. Henter et al., “Consensus rec- Squibb, Tecnofarma, and Roche; travel, accommodations, ommendations for the diagnosis and management of hemopha- and expenses: Roche; and mentorship program with key opin- gocytic lymphohistiocytosis associated with malignancies,” ion leaders: funded by AstraZeneca. JJC-H has the following Haematologica, vol. 100, no. 8, pp. 997–1004, 2015. disclosures: consulting or advisory role: MSD Oncology and [6] P. Sharma and J. P. Allison, “The future of immune checkpoint Bristol-Myers Squibb; Merck Speakers’ Bureau: MSD Oncol- therapy,” Science, vol. 348, no. 6230, pp. 56–61, 2015. ogy, Bristol-Myers Squibb, Merck, Roche, Janssen Oncology, [7] M. A. Postow, M. K. Callahan, and J. D. Wolchok, “Immune and AstraZeneca; and travel, accommodations, and expenses: checkpoint blockade in cancer therapy,” Journal of Clinical MSD Oncology. Oncology, vol. 33, no. 17, pp. 1974–1982, 2015. Case Reports in Oncological Medicine 5 [8] L. Spain, S. Diem, and J. Larkin, “Management of toxicities of immune checkpoint inhibitors,” Cancer Treatment Reviews, vol. 44, pp. 51–60, 2016. [9] J. M. Michot, J. Lazarovici, A. Tieu et al., “Haematological immune-related adverse events with immune checkpoint inhibitors, how to manage?,” European Journal of Cancer, vol. 122, pp. 72–90, 2019. [10] E. Shiuan, K. E. Beckermann, A. Ozgun et al., “Thrombocyto- penia in patients with melanoma receiving immune check- point inhibitor therapy,” Journal for ImmunoTherapy of Cancer, vol. 5, no. 1, p. 8, 2017. [11] P. la Rosée, A. Horne, M. Hines et al., “Recommendations for the management of hemophagocytic lymphohistiocytosis in adults,” Blood, vol. 133, no. 23, pp. 2465–2477, 2019. [12] S. S. Neelapu, F. L. Locke, N. L. Bartlett et al., “Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lym- phoma,” The New England Journal of Medicine, vol. 377, no. 26, pp. 2531–2544, 2017. [13] H. Kantarjian, A. Stein, N. Gökbuget et al., “Blinatumomab versus chemotherapy for advanced acute lymphoblastic leuke- mia,” The New England Journal of Medicine, vol. 376, no. 9, pp. 836–847, 2017. [14] J. M. Michot, R. Pruvost, C. Mateus et al., “Fever reaction and haemophagocytic syndrome induced by immune checkpoint inhibitors,” Annals of Oncology, vol. 29, no. 2, pp. 518–520, [15] I. Satzger, P. Ivanyi, F. Länger et al., “Treatment-related hemo- phagocytic lymphohistiocytosis secondary to checkpoint inhi- bition with nivolumab plus ipilimumab,” European Journal of Cancer, vol. 93, pp. 150–153, 2018. [16] G. Lorenz, L. Schul, Q. Bachmann et al., “Hemophagocytic lymphohistiocytosis secondary to pembrolizumab treatment with insufficient response to high-dose steroids,” Rheumatol- ogy (Oxford, England), vol. 58, no. 6, pp. 1106–1109, 2019. [17] A. Dupré, J. M. Michot, A. Schoeffler et al., “Haemophagocytic lymphohistiocytosis associated with immune checkpoint inhibitors: a descriptive case study and literature review,” Brit- ish Journal of Haematology, vol. 189, no. 5, pp. 985–992, 2020. [18] J. Haanen, F. Carbonnel, C. Robert et al., “Management of tox- icities from immunotherapy: ESMO Clinical Practice Guide- lines for diagnosis, treatment and follow-up ,” Annals of Oncology, vol. 28, suppl_4, pp. iv119–iv142, 2017. [19] A. M. Stamatouli, Z. Quandt, A. L. Perdigoto et al., “Collateral damage: insulin-dependent diabetes induced with checkpoint inhibitors,” Diabetes, vol. 67, no. 8, pp. 1471–1480, 2018. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Case Reports in Oncological Medicine Hindawi Publishing Corporation

Response to Treatment with an Anti-Interleukin-6 Receptor Antibody (Tocilizumab) in a Patient with Hemophagocytic Syndrome Secondary to Immune Checkpoint Inhibitors

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Hindawi Publishing Corporation
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Copyright © 2021 Alejandro Olivares-Hernández et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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2090-6714
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10.1155/2021/6631859
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Abstract

Hindawi Case Reports in Oncological Medicine Volume 2021, Article ID 6631859, 5 pages https://doi.org/10.1155/2021/6631859 Case Report Response to Treatment with an Anti-Interleukin-6 Receptor Antibody (Tocilizumab) in a Patient with Hemophagocytic Syndrome Secondary to Immune Checkpoint Inhibitors 1,2 1,2 1,2 Alejandro Olivares-Hernández , Luis Figuero-Pérez , María A. Amores Martín, 1,2 3 1,2 Lorena Bellido Hernández, Laura Mezquita, María del Rosario Vidal Tocino , 4 5 2,6 Félix López Cadenas, Felipe Gómez-Caminero López , Roberto A. Escala-Cornejo, 1,2 and Juan Jesús Cruz Hernández Department of Medical Oncology, University Healthcare Complex of Salamanca, Paseo de San Vicente, 182, CP 37007 Salamanca, Spain Instituto de Investigación Biomédica de Salamanca (IBSAL), Paseo de San Vicente, 58-182, CP 37007 Salamanca, Spain Department of Medical Oncology, Hospital Clinic, Carrer de Villarroel, 170, CP 08036 Barcelona, Spain Hematology Department, University Healthcare Complex of Salamanca, Paseo de San Vicente, 182, CP 37007 Salamanca, Spain Nuclear Medicine Department, University Healthcare Complex of Salamanca, Paseo de San Vicente, 182, CP 37007 Salamanca, Spain Department of Medical Oncology, Ávila Healthcare Complex, Avenida Rey Juan Carlos I, CP 05004 Ávila, Spain Correspondence should be addressed to Alejandro Olivares-Hernández; aolivares@saludcastillayleon.es Received 26 December 2020; Revised 14 January 2021; Accepted 2 February 2021; Published 12 February 2021 Academic Editor: Raffaele Palmirotta Copyright © 2021 Alejandro Olivares-Hernández et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Background. Immunotherapy represents one of the fundamental treatments in the management of some types of cancer, especially malignant melanoma. Toxicity derived from increased immune system activity can manifest in multiple organs and systems. We present a case of hematological toxicity, manifested as hemophagocytic syndrome (HPS), which was successfully treated with an anti-interleukin-6 antibody (tocilizumab). Case Report. This case presents a 75-year-old woman diagnosed with metastatic choroidal melanoma, refractory to several lines of treatment. After the failure of the previous lines, ipilimumab was started. After the third dose, she developed grade 2 thrombocytopenia and anemia accompanied by elevated levels of ferritin, triglycerides, and decreased fibrinogen. Hemophagocytosis was observed in the bone marrow biopsy, and a PET-CT showed splenomegaly with increased metabolism. Treatment was based on high doses of corticosteroids and tocilizumab. Four days after the start of treatment, progressive clinical and analytical improvement was observed, achieving total remission of the condition. Discussion. HPS induced by immunotherapy is due to an immunorelated cytokine storm syndrome (CSS). The administration of the anti- interleukin-6 receptor antibody drug acted on this cytokine cascade, leading to stabilization and subsequent remission. For this reason, the use of tocilizumab should be part of the immunotherapy-induced HPS treatment algorithm. 1. Background signs and symptoms of excessive inflammation due to dys- function of the natural killer (NK) cells, which leads to the overstimulation, hyperproliferation, and ectopic migration Hemophagocytic syndrome (HPS) is a rare clinical entity of T1 cells [1]. The incidence is estimated at 1.2 per million characterized by hyperactivity and irregularity in the activa- cases per year. However, these values may be underestimated tion of the immune system induced by response to a specific due to low diagnostic suspicion in most cases [2]. trigger. This pathological immune activation manifests as 2 Case Reports in Oncological Medicine tal admission for study and determination of the appropriate HPS is not a single disease but a syndrome associated with a wide variety of underlying causes that lead to a charac- treatment. During admission, a PET-CT was performed, in teristic inflammatory phenotype [3]. The triggering causes which a partial response was observed in the liver. Splenomeg- can be classified as primary in the case of a mutation of the aly was also observed with a diffuse increase in the metabolic FLH gene or as secondary when they are due to infectious, activity of the entire splenic parenchyma. Suspecting primary neoplastic processes or other immunodeficiencies; in general, splenic B lymphoma, a bone marrow biopsy was performed, the secondary causes are observed most frequently [4]. The and abundant macrophages with compatible characteristics most common symptoms are fever and splenomegaly, of hemophagocytosis were observed (Figure 1). appearing in about 75% of patients at diagnosis, followed High levels of ferritin (>85,000 ng/mL), hypertriglyc- by liver failure, sepsis, Kawasaki disease, and neurological eridemia (maximum value of 389 mg/dL), low levels of fibrin- abnormalities. Diagnosis is based on a scale of eight diagnos- ogen (147 mg/dL), and normochromic normocytic anemia tic criteria, of which the patient must meet at least five: (1) (9.8 g/dL) were observed in the blood samples requested fever (>38 C); (2) splenomegaly; (3) cytopenias that affect during admission. Furthermore, the patient presented a fever at least two series; (4) hypertriglyceridemia (>265 mg/dL) of up to 38.5 C without elevation of acute phase reactants, and/or low fibrinogen levels (<150 mg/dL); (5) hemophago- such as c-reactive protein (CRP). Based on all of these signs cytosis in the bone marrow, spleen, lymph nodes, or liver; and symptoms, HPS was confirmed, and other possible (6) low or no activity of the NK cells; (7) high levels of ferritin causes were ruled out, including infections (negative viral (>500 ng/mL); and (8) high levels of soluble CD25 [5]. serologies, as well as negative urine and blood cultures, were Inhibition at the checkpoints of the immune system is collected), autoimmune diseases, hematological malignan- currently one of the cornerstones of cancer treatment in a wide cies, and bone marrow infiltration. variety of tumors, including melanoma [6]. Current treat- The patient met six of the eight diagnostic criteria for HPS. ments for B-RAF wild-type melanoma are based on two After ruling out other causes, secondary HPS was attributed to blocking points: (1) inhibition of the cytotoxic T lymphocyte an immunomediated adverse effect secondary to treatment antigen 4 (CTLA-4) receptor and (2) inhibition of the with the anti-CTLA-4, ipilimumab. Despite corticosteroid programmed cell death protein 1 (PD-1) receptor [7]. Mono- treatment (maximum doses of 2 mg/kg), no improvement clonal antibodies directed towards CTLA-4 inhibition, such as was observed, and it was decided to start treatment with an ipilimumab, and anti-PD-1, such as nivolumab, have changed anti-interleukin-6 receptor antibody (tocilizumab) at a dose the treatment and natural evolution of metastatic melanoma. of 8 mg/kg every eight hours for four doses [11]. Prior to the The immune-related adverse events (irAEs) from these treat- tocilizumab regimen, the IL-2 value was determined to dem- ments originate from excessive immune activation and can onstrate the existence of the cytokine storm secondary to affect any system or body function [8]. Hematological toxicity HPS. The IL-2 value was 1734 U/mL (158-623 U/mL). After appears in less than 1% of cases, with thrombocytopenia being the fourth dose of tocilizumab, there was clinical improvement the most frequently described [9]. The management of irAE is without fever and analytical improvement with progressive very complex, making the use of corticosteroids and immuno- normalization of the levels of hemoglobin, platelets, ferritin, suppressive treatments the mainstay. [10] We present a case of fibrinogen, and triglycerides (Table 1). a woman diagnosed with metastatic choroidal melanoma who Once the clinical process was corrected, a new bone mar- developed HPS secondary to treatment with ipilimumab. row biopsy was performed, and no signs compatible with hemophagocytosis were found. In addition, a PET-CT was performed (Figure 2), in which an absence of splenic meta- 2. Case Report bolic uptake was observed. For these reasons, the patient was discharged from the hospital and began outpatient follow- A 75-year-old woman diagnosed with choroidal melanoma in 1989 was treated by enucleation without adjuvant treatment. ups with the hematology and medical oncology departments. After 22 years of disease-free survival (DFS), in 2011, a CT scan revealed liver involvement, which was confirmed by biopsy and indicated the recurrence of the B-RAF wild-type 3. Discussion melanoma. She began treatment with dacarbazine (DTIC), which followed by nivolumab in 2016 due to tumor progres- Immune-related adverse effects are more frequently observed sion. With nivolumab, she maintained a progression-free with the use of anti-CTLA-4 (40%) than with anti-PD-1 or interval (PFI) of three years. When new liver progression anti-PD-L1. The most common irAEs are asthenia, anorexia, appeared, a third line of treatment with ipilimumab (3 mg/kg) and fever, appearing in up to 40-50% of cases. Hematologic was started, and she received three cycles. irAEs are poorly described in the literature due to their low Prior to the start of a fourth cycle of treatment with ipili- incidence (0.5%) [9]. mumab, grade 2 thrombocytopenia (platelets: 64,000/μL) It has been described that, in a small group of patients, was observed, suggesting hematological toxicity associated treatment with immune checkpoint inhibitors could induce with the immunotherapy treatment. Due to this suspicion, a cascade of cytokines, leading to the development of HPS. the treatment with anti-CTLA-4 was interrupted, and methyl- The cases reported in the literature suggest that HPS second- prednisolone was started at a dose of 1 mg/kg. Despite the ary to immunotherapy has been observed with the use of corticosteroid treatment, no clinical analytical improvement modified T cells (such as modified chimeric antigen receptor was observed; therefore, the patient was admitted to the hospi- T (CAR-T) cells), blinatumomab (monoclonal antibody Case Reports in Oncological Medicine 3 Figure 1: Pretreatment: (a) PET-CT: splenomegaly and increased metabolism in the spleen are observed at diagnosis; (b) bone marrow biopsy: macrophage phagocytosing erythrocytes and neutrophils (hemophagocyte). Table 1: Evolution of analytical values during the admission of the patient. HPS At time of Baseline steroid Baseline After 48 h of At time of Analytical values criteria admission therapy tocilizumab tocilizumab discharge Hemoglobin (g/dL) Yes 13.5 11.2 9.6 11.6 12.1 Platelets (/μL) Yes 64.000 45.000 48.000 74.000 113.000 Ferritin (ng/mL) Yes >74.150 >74.150 >89.918 12.019 1978 Fibrinogen (mg/dL) Yes 147 164 170 —— Triglycerides (mg/dL) Yes 271 327 265 234 172 Bone marrow Yes —— Yes — No findings – Not available. directed against CD3 and CD19) [12, 13], and immune In the case report, the use of tocilizumab was a novel checkpoint inhibitors. treatment in the field of immunotoxicity secondary to the Recently, the use of the anti-interleukin-6 receptor anti- anti-CTLA-4, introducing new hope into the treatment of body (tocilizumab) has been reported and approved for the this type of patient, with excellent results. In our center, the treatment of HPS secondary to the use of CAR-T cells and use of tocilizumab was based on the study carried out by blinatumomab. However, in patients treated with immune Dupré et al., in which the possible efficacy of tocilizumab in checkpoint inhibitors, such as anti-CTLA-4 or anti-PD-1/PD- the treatment of HPS secondary to immune checkpoint L1, tocilizumab is not typically used for HPS. In published cases inhibitors was postulated [17]. Our patient presented clinical of HPS as an irAE, immunomodulators have been used, such as improvement with the absence of fever and normalization of etoposide [14], mycophenolic acid [15], and tacrolimus [16], laboratory levels when four doses of tocilizumab were admin- and are always associated with corticosteroids in the interrup- istered. The benefit of the treatment and the short hospital tion of immune treatment. stay highlights the effectiveness and the role that anti- 4 Case Reports in Oncological Medicine Figure 2: Posttreatment. PET-CT: significant decrease in the metabolism in the spleen, after 4 doses of tocilizumab. interleukin-6 receptor antibodies could have in the treatment Authors’ Contributions of HPS induced by immune checkpoint inhibitors. The devel- AO-H was responsible for clinical management of the opment of a massive cytokine storm is the main determining patient, data collection, and preparation and design of the factor in HPS secondary to treatment with immune check- manuscript. LF-P was responsible for clinical management point inhibitors. For this reason, the decrease in endogenous of the patient, data collection, and preparation and design levels of interleukin-6 using tocilizumab could mitigate the of the manuscript. AA-M was responsible for clinical man- inappropriate activation of macrophages and improve the agement of the patient, data collection, and preparation and clinical situation. design of the manuscript. LB-H was responsible for clinical The treatment of any moderate or high grade irAEs, not management of the patient. LM was responsible for clinical only HPS, is based on the use of corticosteroids at high doses management of the patient and preparation and design of (1-2 mg/kg) [18]. Taking into account the current results on the manuscript. RV-T was responsible for clinical manage- the use of the anti-interleukin-6 receptor antibody, we ment of the patient. FL-C was responsible for clinical suggest that drugs, such as tocilizumab, could have a beneficial management of the patient. FG-C was responsible for per- use in severe cases of irAEs, as well as in patients for whom the forming the diagnostic imaging test. REC was responsible use of corticotherapy would be limited, such as those with type for writing and preparation of the manuscript. JJC-H was 1 diabetes mellitus secondary to immunotherapy [19]. responsible for clinical management of the patient and lead- In conclusion, our case and the review of the literature ership of the work team. Alejandro Olivares-Hernández and suggest that, at present, the anti-interleukin-6 antibodies Luis Figuero-Pérez contributed equally to this work. may be an appropriate treatment option for HPS induced by immune checkpoint inhibitors. Likewise, more studies are needed to determine the validity of these treatments References before being recommended in the clinical practice. [1] A. Hayden, S. Park, D. Giustini, A. Y. Lee, and L. Y. Chen, “Hemophagocytic syndromes (HPSs) including hemophago- Data Availability cytic lymphohistiocytosis (HLH) in adults: a systematic scop- ing review,” Blood Reviews, vol. 30, no. 6, pp. 411–420, 2016. The data provided for the case report can be found in the clin- ical record database of the University Hospital of Salamanca. [2] J. I. Henter, G. 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Published: Feb 12, 2021

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