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Immunocheckpoint Inhibitor- (Nivolumab-) Associated Hypereosinophilia in Non-Small-Cell Lung Carcinoma

Immunocheckpoint Inhibitor- (Nivolumab-) Associated Hypereosinophilia in Non-Small-Cell Lung... Hindawi Case Reports in Oncological Medicine Volume 2020, Article ID 7492634, 5 pages https://doi.org/10.1155/2020/7492634 Case Report Immunocheckpoint Inhibitor- (Nivolumab-) Associated Hypereosinophilia in Non-Small-Cell Lung Carcinoma 1 2 3 4 Navdeep Singh, Sandeep Singh Lubana , George Constantinou, and Andrea N. Leaf Medicine/Division of Hospice/Palliative Care, North Shore University Hospital, 300 Community Dr., Manhasset, NY 11030, USA Medicine/Division of Hematology/Oncology, SUNY Downstate Medical School, 450 Clarkson Ave., Brooklyn, NY 11203, USA Lafayette General Medical Center, 1214 Coolidge St., Lafayette, LA 70503, USA Medicine/Division of Hematology/Oncology, Brooklyn VA Medical Center, 800 Poly Pl., Brooklyn, NY 11209, USA Correspondence should be addressed to Sandeep Singh Lubana; sandeep_singh6517@yahoo.com Received 24 January 2020; Accepted 28 April 2020; Published 15 May 2020 Academic Editor: Jose I. Mayordomo Copyright © 2020 Navdeep Singh 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. Immunocheckpoint inhibitor (ICI) therapy has provided significant clinical improvements in the treatment of several malignancies. The purpose of this report is to increase awareness of hypereosinophilia associated with checkpoint inhibitors, a topic that has been rarely reported. Hypereosinophilia may need to be addressed especially if eosinophil counts increase to levels where hypereosinophilic visceral complications can occur. We are presenting a case of a 57-year-old male with hypereosinophilia that was seen in the setting of progression of metastatic non-small-cell lung cancer during and after nivolumab treatment. been postulated to be secondary to eosinophilia as a result 1. Introduction of immunotherapy [11]. Eosinophilia in patients with lung The use of immunotherapeutic agents has proven to be effec- cancer who received immunotherapy have been reported to tive for patients with many different types of cancers [1–3]. have had partial response to nivolumab [7]. Herein, we The antitumor function of T-cells is inhibited by PD-L1 report a case of hypereosinophilia with nivolumab therapy which is expressed on many malignant tumors. Nivolumab, in a patient with progression of metastatic NSCLC. The a fully human IgG4 monoclonal antibody against PD-1 role of eosinophilia as a biomarker requires additional receptors, blocks the interaction of PD-1 on the T-cell and investigation. PD-L1/PD-L2 on the tumor cell improving the antitumor function of the T-cells. The US FDA has approved nivolumab 2. Case Presentation for the treatment of several malignancies including non- small-cell lung cancer [1, 2, 4, 5]. The patient is a 57-year-old male with an extensive smoking Known toxicities for checkpoint inhibitors are typically history who underwent right upper lobe lobectomy in May immune-mediated, and guidelines have been published for 2012 for a clinical stage I adenocarcinoma of the lung. He the management of the immune-related adverse event (irAE) was found to have microscopic ipsilateral mediastinal adeno- [6]. irAEs are well known with nivolumab as well as other pathy. He received adjuvant chemotherapy with pemetrexed ICIs. Eosinophilia has also been reported with the use of ICIs. and cisplatin followed by radiation therapy for his pathologic [7] Although PD-L1 is widely used as a biomarker to predict stage IIIA (pT2aN2M0) adenocarcinoma of the lung. A pos- the response to ICIs, responses have been reported in itron emission tomography (PET) scan in February 2013 did patients having tumors without any PD-L1 expression [8]. not show any evidence of malignancy. Eosinophilia in patients with melanoma has been One year after completion of adjuvant chemotherapy, in reported as a biomarker for tumor response to ICIs [9, 10]. October 2013, the patient developed headaches. Magnetic The partial response of the tumor in metastatic disease has resonance imaging (MRI) of the brain was consistent with 2 Case Reports in Oncological Medicine Trend of WBC lines cile toxin. Serum IgG for Strongyloides and serum Quanti- FERON test were negative. Liver function tests, thyroid function tests, cortisol, and B12 levels were also normal. Echocardiogram, cardiac enzymes, and EKG did not reveal any abnormalities. Evaluation with bone marrow biopsy or molecular/cytogenetic testing was not pursued as it was felt that there was a clear temporal association of eosinophilia with nivolumab administration. MRI of the brain in February 2016 revealed continued mild progression of metastatic lesions and a new lesion in the left temporal lobe. The PET/CT at that time was consistent with systemic progres- sion in the bone and lung. Given the degree of eosinophilia and evidence of progression, the decision was made to hold further nivolumab therapy in March of 2016. As the eosinophilia (3:5×10 0 /L) was significant and per- sisted despite discontinuation of nivolumab, the patient was started on prednisone 10 mg daily in May 2016. Repeat MRI of the brain revealed an increase in the size of known intracranial metastases within the infratentorial and supra- ANC Mono tentorial regions. There was also a new area of edema and ALC Nivolumab discontinuation gyral-based enhancement with associated mass effect within Eos Corticosteroid initiation the superior posterior left temporal lobe; this pattern of Figure 1: Graph depicting various white cell lines following enhancement was considered atypical for metastatic disease. initiation of immunotherapy (nivolumab) in November 2015. The differential included radiation related necrosis, encepha- litis/cerebritis, or postinflammatory process. Given the concern for possible immune-mediated ence- four intracranial metastases. PET/CT scan revealed several phalitis/cerebritis, the patient was started on dexamethasone subcentimeter metastatic pulmonary nodules. EGFR/ALK/- 4 mg twice a day at that time which was later increased to ROS1 testing at that time did not reveal any targetable muta- 4 mg three times a day, with a resolution of eosinophilia in tions. He underwent whole brain radiation therapy. two weeks. Two weeks later, in June 2016, the patient started In the next two years, the patient had progression of developing thrombocytopenia. Evaluation of the peripheral disease (POD) in the lung through several lines of chemo- smear confirmed thrombocytopenia with myelocytes, meta- therapy. He also developed CNS progression with three myelocytes, few nucleated red cells, and teardrop cells which new lesions in December 2014, for which he underwent was felt to be consistent with a possible myelophthisic pro- stereotactic radiation therapy (SRS). Six months later, the cess from marrow infiltration of the tumor. A repeat MRI patient developed two more intracranial lesions for which of the brain two weeks later revealed a decrease in edema, he again received SRS. New intracranial subcentimeter meta- the mixed response of lesions with some increasing and some static disease was identified in September 2015 which was not decreasing in size, and the greater confluence of the left tem- amenable to further radiation. Immunotherapy with the poral lobe lesion which however remained stable in size. checkpoint inhibitor nivolumab was initiated in November The next day, the patient presented to the emergency 2015 (Figure 1 and Table 1). room with worsening shortness of breath. The computerized Eosinophil counts dating back to 1998 had always been tomography angiogram of the chest was consistent with within normal limits except for a brief period of mild marked progression of the disease. Despite treatment with increased eosinophilia after adjuvant chemotherapy in 2012 broad-spectrum antibiotics and aggressive treatment in the which spontaneously resolved. Four weeks after initiation of intensive care unit, the patient expired one week after his nivolumab, his absolute eosinophil count was noted to be ele- admission with the progression of the disease. An autopsy vated at 2:86 × 10 /L; all other hematopoietic cell lines not performed as per the family’s request. remained unaffected. He had denied any travel within the previous five years and denied any exposure to any known 3. Discussion allergens, new products, or new medications. He was asymp- Eosinophilia with PD-1/PD-L1 checkpoint inhibitors is a tomatic, and on physical examination, there was no evidence rarely reported adverse event. Absolute eosinophilic count of skin rash or splenomegaly. (AEC) of more 500 cells/μL in the peripheral blood is On a follow-up visit in April 2016, after eight cycles of eosinophilia, and based on the eosinophil count, it is further nivolumab, the peripheral blood smear revealed markedly 9 9 increased eosinophils, but no other significant findings. subdivided as mild 0:5‐1:5×10 /L, moderate 1:5‐5×10 /L, 9 9 Further work-up of the eosinophilia was performed and and severe >5 × 10 /L [12]. AEC > 1500 × 10 /L in the was unrevealing. Multiple stool samples were obtained, and peripheral blood on two separate occasions at least one testing for culture, ova, and parasites remained negative on month apart is defined as hypereosinophilia. Pathologic three separate occasions as was testing for Clostridium diffi- confirmation of tissue hypereosinophilia is also termed as 11/9/2015 12/9/2015 1/9/2016 2/9/2016 3/9/2016 4/9/2016 5/9/2016 6/9/2016 Case Reports in Oncological Medicine 3 Table 1 The prognostic significance of hypereosinophilia associ- ated with nivolumab in terms of overall survival and Timeline: ANC ALC Eos Mono Hg PLT progression-free survival remains largely undefined. There 11/09/2015 4220 1160 300 470 10.9 189 are reports of advanced lung adenocarcinoma with favorable 11/16/2015 3960 1300 1370 580 11.4 163 prognosis when eosinophilia was reported with nivolumab use [7, 14]. 11/23/2015 2990 1060 660 340 12 174 In some case reports, eosinophilia was noted as an 11/30/2015 3950 1740 1740 470 12.7 194 adverse event and as a prodrome in patients who were later 12/07/2015 3190 1360 2860 440 12.1 196 diagnosed with checkpoint-mediated immune complications 12/14/2015 3130 770 1260 330 10.8 169 such as adrenal insufficiency [11] systemic symptom syn- 12/21/2015 2560 1140 1540 460 12.5 157 drome and hypophysitis [16]. 12/28/2015 3400 1480 1920 590 13.5 204 Various studies related to tumor-associated tissue eosin- 12/31/2015 3180 1380 1920 410 13.1 198 ophilia (TATE) in many solid tumors (colorectal and esoph- 1/11/2016 2970 1380 1930 550 12.7 154 ageal squamous cell carcinoma) have revealed it to have good prognostic value, but in Hodgkin lymphoma, it is associated 1/19/2016 2220 1260 2100 420 12.1 147 with poor prognosis [17–19]. There has been some conflict- 2/01/2016 3110 1250 620 520 13.5 189 ing data [20] regarding oral SCC and cervical carcinoma 2/08/2016 2980 1170 690 490 13.1 163 where TATE has been shown to be associated with poor 2/16/2016 2960 1180 1710 490 13.6 164 prognosis. The mechanism that can explain these effects 2/22/2016 3890 1470 3200 870 14.4 186 remains unclear. Tumoricidal properties of eosinophils 2/29/2016 3330 1440 5770 550 13.1 181 remain unknown; however, one suggested possible mecha- 3/02/2016 2560 1460 4650 550 13.1 194 nism is the direct cytotoxic effect from degranulation of eosinophilic granules [20]. 3/07/2016 3660 1550 4740 580 12.5 168 The role of eosinophils in antitumor immune response 3/14/2016 3800 1350 2640 650 13.4 187 has been suggested. The various suggested mechanisms are 3/22/2016 3190 1420 1990 500 13.4 217 direct antitumor effects, dendritic cell activation and recruit- 3/28/2016 4210 1240 1500 540 12.8 171 ment, T-cell recruitment and polarization using chemokines 4/04/2016 2980 1460 1010 530 13 159 and enhanced immune surveillance, and normalization of 4/11/2016 3670 1480 1530 680 12.9 188 the tumor microenvironment vasculature [21–24]. Eosino- 4/18/2016 2740 1540 1360 480 12.5 170 philia which has been reported in acute or chronic graft- versus-host disease further points towards its immune- 4/25/2016 3220 1400 3100 530 12.3 179 related properties [20, 25]. 5/02/2016 3340 1330 3590 540 12.9 186 A retrospective study reported a correlation of enhanced 5/09/2016 4300 1540 2090 820 12.9 205 immune response, prolonged prostate cancer-specific sur- 5/12/2016 6950 1020 1210 740 12.8 204 vival, and trend towards improved overall survival in patients 5/16/2016 10210 1000 200 860 13.2 198 with eosinophilia. Eosinophilia was reported in 28% of 5/23/2016 12240 640 10 490 12.8 175 patients (105 of 377) following sipuleucel-T treatment at 6/14/2016 8420 840 30 880 13.5 106 week 6 with resolution by week 14 [26]. A prospective study of 73 patients with advanced mela- 6/29/2016 6230 620 20 200 13.3 111 noma treated with ipilimumab (anticytotoxic T lymphocyte- Abbreviations: ANC: absolute neutrophil count; ALC: absolute lymphocyte associated antigen [CTLA] 4 monoclonal antibody) demon- count; Eos: eosinophil count; Mono: monocyte count; Hg: hemoglobin in mg/dL; PLT: platelet count. strated correlation of improved overall survival with an increase in eosinophil count of more than 100 cells/μL [10]. Studies of anti-PD-1 monoclonal antibody (pembrolizumab hypereosinophilia. The term hypereosinophilic syndrome is used when eosinophilia is associated with tissue and organ and nivolumab) in patients with melanoma demonstrated a positive correlation between an elevated eosinophil count damage [13]. Early identification of drug-induced hypereosi- nophilia is critical, especially when deciding whether to con- and overall survival [27, 28]. The median eosinophil count tinue the drug and/or to treat with corticosteroids. peak (approximately 1000 cells/μL) has been correlated with an improved overall response rate [29]. There are studies Allergic or immunologic processes like asthma, eosino- philic granulomatosis with polyangiitis, bronchopulmonary contradicting the beneficial effect of eosinophilia. A study aspergillosis, and helminthic parasitic infections are associ- with 156 patients with advanced melanoma treated with ipi- ated with hypereosinophilia. Hematologic or neoplastic dis- limumab at a dose of 3 mg/kg manifested immune-related orders (adenocarcinomas, Hodgkin lymphoma, and T-cell adverse events including eosinophilia without overall sur- vival improvement [30]. T-cell-mediated antitumor response lymphoma) can also lead to hypereosinophilia, but are an uncommon cause [12]. could be affected by activated eosinophils via enhancing However, hypereosinophilia associated with immune- CD8-T-cell infiltration as demonstrated in a mouse model checkpoint inhibitors has rarely been reported. To date, only [23]. Therefore, some experts recommend that eosinophilia five reports of nivolumab-induced hypereosinophilia have should not be used as a prognostic factor due to its codepen- dence on T-cells. been reported in the literature [7, 11, 14, 15]. 4 Case Reports in Oncological Medicine Alternatively, eosinophilia could simply be due to an [2] S. L. Topalian, F. S. Hodi, J. R. Brahmer et al., “Safety, activity, and immune correlates of anti-PD-1 antibody in cancer,” The allergic drug reaction. There has been a reported case of New England Journal of Medicine, vol. 366, no. 26, pp. 2443– drug-related eosinophilia and systemic symptom (DRESS) 2454, 2012. syndrome in a patient with melanoma following ipilimumab [3] J. Larkin, V. Chiarion-Sileni, R. Gonzalez et al., “Combined and nivolumab administration [15]. nivolumab and ipilimumab or monotherapy in untreated mel- To determine the significance of eosinophils in immuno- anoma,” The New England Journal of Medicine, vol. 373, no. 1, therapy requires additional studies. To our knowledge, there pp. 23–34, 2015. are only two reports of hypereosinophilia associated with [4] R. Chen, P. L. Zinzani, M. A. Fanale et al., “Phase II study of nivolumab used in non-small-cell lung cancer where patients the efficacy and safety of pembrolizumab for relapsed/refrac- had a favorable response [7, 14]. However, in our case, the tory classic Hodgkin lymphoma,” Journal of Clinical Oncology, hypereosinophilia associated with nivolumab use is in the vol. 35, no. 19, pp. 2125–2132, 2017. treatment of lung adenocarcinoma resulted in progression [5] H. J. Hammers, E. R. Plimack, J. R. Infante et al., “Safety and of the disease. efficacy of nivolumab in combination with ipilimumab in met- In the case described here, the patient remained asymp- astatic renal cell carcinoma: the CheckMate 016 study,” Jour- tomatic despite a high eosinophil count (3:6×10 /L), and nal of Clinical Oncology, vol. 35, no. 34, pp. 3851–3858, 2017. no effects were noted on other leukocyte lineages. The signif- [6] J. R. Brahmer, C. Lacchetti, and J. A. Thompson, “Manage- icant and persistent hypereosinophilia was felt to be tempo- ment of immune-related adverse events in patients treated rally related to the administration of nivolumab. It is with immune checkpoint inhibitor therapy: American Society unclear whether the MRI changes in the brain were second- of Clinical Oncology clinical practice guideline Summary,” ary to immune cerebritis as there was also clear progression Journal of Oncology Practice, vol. 14, no. 4, pp. 247–249, of his metastatic disease. Given the progression of the disease and the potential toxicity of the drug, nivolumab was discon- [7] Y. Lou, J. A. Marin-Acevedo, P. Vishnu et al., “Hypereosino- tinued. The more challenging question is whether it is war- philia in a patient with metastatic non-small-cell lung cancer ranted to discontinue nivolumab in the setting of very treated with antiprogrammed cell death 1 (anti-PD-1) ther- apy,” Immunotherapy, vol. 11, no. 7, pp. 577–584, 2019. severe hypereosinophilia when a clinical response is being observed [14]. Notably, in this case after nivolumab was held, [8] X. J. Meng, Z. Q. Huang, F. F. Teng, L. G. Xing, and J. M. Yu, the eosinophilia did not resolve. As such, we decided to treat “Predictive biomarkers in PD-1/PD-L1 checkpoint blockade immunotherapy,” Cancer Treatment Reviews, vol. 41, no. 10, the patient with corticosteroids. Hypereosinophilia with pp. 868–876, 2015. nivolumab may be more common than reported, as it can [9] A. M. Hopkins, A. Rowland, G. Kichenadasse et al., “Predict- potentially be overlooked in an asymptomatic patient. It is ing response and toxicity to immune checkpoint inhibitors a complication, however, that may need to be addressed using routinely available blood and clinical markers,” British especially if eosinophil counts increase to levels where hyper- Journal of Cancer, vol. 117, no. 7, pp. 913–920, 2017. eosinophilic visceral immune-related complications occur. [10] J. Delyon, C. Mateus, D. Lefeuvre et al., “Experience in daily As it may be an early marker for later potential immune- practice with ipilimumab for the treatment of patients with related complications, it would also allow clinicians to have metastatic melanoma: an early increase in lymphocyte and increased vigilance for those patients. eosinophil counts is associated with improved survival,” Annals of Oncology, vol. 24, no. 6, pp. 1697–1703, 2013. 4. Conclusion [11] R. Ariyasu, A. Horiike, T. Yoshizawa et al., “Adrenal insuffi- ciency related to anti-programmed death-1 therapy,” Antican- The prognostic significance of hypereosinophilia associ- cer Research, vol. 37, no. 8, pp. 4229–4232, 2017. ated with nivolumab in terms of overall survival and [12] F. Roufosse and P. F. Weller, “Practical approach to the patient progression-free survival remains largely undefined. This is with hypereosinophilia,” The Journal of Allergy and Clinical the first case of a non-small-cell lung cancer (NSCLC) patient Immunology, vol. 126, no. 1, pp. 39–44, 2010. in which hypereosinophilia was associated with unfavorable [13] P. Valent, A. D. Klion, H. P. Horny et al., “Contemporary tumor response to an immune checkpoint inhibitor. Further consensus proposal on criteria and classification of eosino- investigations in a larger patient population is warranted philic disorders and related syndromes,” Journal of Allergy to demonstrate eosinophilia as a prognostic biomarker of and Clinical Immunology, vol. 130, no. 3, pp. 607–612.e9, immunotherapy. [14] H. Osawa, S. Okauchi, S. Taguchi, K. Kagohasi, and H. Satoh, “Immuno-checkpoint inhibitor associated hyper-eosinophilia Conflicts of Interest and tumor shrinkage,” Tuberkuloz ve Toraks, vol. 66, no. 1, The authors declare that they have no conflicts of interest. pp. 80–83, 2018. [15] S. Mirza, E. Hill, S. P. Ludlow, and S. 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J. Hammerling, “Eosinophils orchestrate cancer rejection by normalizing tumor vessels and enhancing infiltration of CD8 T cells,” Nature Immunology, vol. 16, no. 6, pp. 609–617, 2015. [24] S. Gatault, F. Legrand, M. Delbeke, S. Loiseau, and M. Capron, “Involvement of eosinophils in the anti-tumor response,” Cancer Immunology, Immunotherapy, vol. 61, no. 9, pp. 1527–1534, 2012. [25] D. McNeel, M. T. Rubio, G. Damaj et al., “Hypereosinophilia as a presenting sign of acute graft-versus-host disease after allogeneic bone marrow transplantation,” Transplantation, vol. 74, no. 12, pp. 1797–1800, 2002. [26] D. G. McNeel, T. A. Gardner, C. S. Higano et al., “A transient increase in eosinophils is associated with prolonged survival in men with metastatic castration-resistant prostate cancer who receive sipuleucel-T,” Cancer Immunology Research, vol. 2, no. 10, pp. 988–999, 2014. [27] A. Moreira, W. Leisgang, G. Schuler, and L. 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Immunocheckpoint Inhibitor- (Nivolumab-) Associated Hypereosinophilia in Non-Small-Cell Lung Carcinoma

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Copyright © 2020 Navdeep Singh 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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Abstract

Hindawi Case Reports in Oncological Medicine Volume 2020, Article ID 7492634, 5 pages https://doi.org/10.1155/2020/7492634 Case Report Immunocheckpoint Inhibitor- (Nivolumab-) Associated Hypereosinophilia in Non-Small-Cell Lung Carcinoma 1 2 3 4 Navdeep Singh, Sandeep Singh Lubana , George Constantinou, and Andrea N. Leaf Medicine/Division of Hospice/Palliative Care, North Shore University Hospital, 300 Community Dr., Manhasset, NY 11030, USA Medicine/Division of Hematology/Oncology, SUNY Downstate Medical School, 450 Clarkson Ave., Brooklyn, NY 11203, USA Lafayette General Medical Center, 1214 Coolidge St., Lafayette, LA 70503, USA Medicine/Division of Hematology/Oncology, Brooklyn VA Medical Center, 800 Poly Pl., Brooklyn, NY 11209, USA Correspondence should be addressed to Sandeep Singh Lubana; sandeep_singh6517@yahoo.com Received 24 January 2020; Accepted 28 April 2020; Published 15 May 2020 Academic Editor: Jose I. Mayordomo Copyright © 2020 Navdeep Singh 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. Immunocheckpoint inhibitor (ICI) therapy has provided significant clinical improvements in the treatment of several malignancies. The purpose of this report is to increase awareness of hypereosinophilia associated with checkpoint inhibitors, a topic that has been rarely reported. Hypereosinophilia may need to be addressed especially if eosinophil counts increase to levels where hypereosinophilic visceral complications can occur. We are presenting a case of a 57-year-old male with hypereosinophilia that was seen in the setting of progression of metastatic non-small-cell lung cancer during and after nivolumab treatment. been postulated to be secondary to eosinophilia as a result 1. Introduction of immunotherapy [11]. Eosinophilia in patients with lung The use of immunotherapeutic agents has proven to be effec- cancer who received immunotherapy have been reported to tive for patients with many different types of cancers [1–3]. have had partial response to nivolumab [7]. Herein, we The antitumor function of T-cells is inhibited by PD-L1 report a case of hypereosinophilia with nivolumab therapy which is expressed on many malignant tumors. Nivolumab, in a patient with progression of metastatic NSCLC. The a fully human IgG4 monoclonal antibody against PD-1 role of eosinophilia as a biomarker requires additional receptors, blocks the interaction of PD-1 on the T-cell and investigation. PD-L1/PD-L2 on the tumor cell improving the antitumor function of the T-cells. The US FDA has approved nivolumab 2. Case Presentation for the treatment of several malignancies including non- small-cell lung cancer [1, 2, 4, 5]. The patient is a 57-year-old male with an extensive smoking Known toxicities for checkpoint inhibitors are typically history who underwent right upper lobe lobectomy in May immune-mediated, and guidelines have been published for 2012 for a clinical stage I adenocarcinoma of the lung. He the management of the immune-related adverse event (irAE) was found to have microscopic ipsilateral mediastinal adeno- [6]. irAEs are well known with nivolumab as well as other pathy. He received adjuvant chemotherapy with pemetrexed ICIs. Eosinophilia has also been reported with the use of ICIs. and cisplatin followed by radiation therapy for his pathologic [7] Although PD-L1 is widely used as a biomarker to predict stage IIIA (pT2aN2M0) adenocarcinoma of the lung. A pos- the response to ICIs, responses have been reported in itron emission tomography (PET) scan in February 2013 did patients having tumors without any PD-L1 expression [8]. not show any evidence of malignancy. Eosinophilia in patients with melanoma has been One year after completion of adjuvant chemotherapy, in reported as a biomarker for tumor response to ICIs [9, 10]. October 2013, the patient developed headaches. Magnetic The partial response of the tumor in metastatic disease has resonance imaging (MRI) of the brain was consistent with 2 Case Reports in Oncological Medicine Trend of WBC lines cile toxin. Serum IgG for Strongyloides and serum Quanti- FERON test were negative. Liver function tests, thyroid function tests, cortisol, and B12 levels were also normal. Echocardiogram, cardiac enzymes, and EKG did not reveal any abnormalities. Evaluation with bone marrow biopsy or molecular/cytogenetic testing was not pursued as it was felt that there was a clear temporal association of eosinophilia with nivolumab administration. MRI of the brain in February 2016 revealed continued mild progression of metastatic lesions and a new lesion in the left temporal lobe. The PET/CT at that time was consistent with systemic progres- sion in the bone and lung. Given the degree of eosinophilia and evidence of progression, the decision was made to hold further nivolumab therapy in March of 2016. As the eosinophilia (3:5×10 0 /L) was significant and per- sisted despite discontinuation of nivolumab, the patient was started on prednisone 10 mg daily in May 2016. Repeat MRI of the brain revealed an increase in the size of known intracranial metastases within the infratentorial and supra- ANC Mono tentorial regions. There was also a new area of edema and ALC Nivolumab discontinuation gyral-based enhancement with associated mass effect within Eos Corticosteroid initiation the superior posterior left temporal lobe; this pattern of Figure 1: Graph depicting various white cell lines following enhancement was considered atypical for metastatic disease. initiation of immunotherapy (nivolumab) in November 2015. The differential included radiation related necrosis, encepha- litis/cerebritis, or postinflammatory process. Given the concern for possible immune-mediated ence- four intracranial metastases. PET/CT scan revealed several phalitis/cerebritis, the patient was started on dexamethasone subcentimeter metastatic pulmonary nodules. EGFR/ALK/- 4 mg twice a day at that time which was later increased to ROS1 testing at that time did not reveal any targetable muta- 4 mg three times a day, with a resolution of eosinophilia in tions. He underwent whole brain radiation therapy. two weeks. Two weeks later, in June 2016, the patient started In the next two years, the patient had progression of developing thrombocytopenia. Evaluation of the peripheral disease (POD) in the lung through several lines of chemo- smear confirmed thrombocytopenia with myelocytes, meta- therapy. He also developed CNS progression with three myelocytes, few nucleated red cells, and teardrop cells which new lesions in December 2014, for which he underwent was felt to be consistent with a possible myelophthisic pro- stereotactic radiation therapy (SRS). Six months later, the cess from marrow infiltration of the tumor. A repeat MRI patient developed two more intracranial lesions for which of the brain two weeks later revealed a decrease in edema, he again received SRS. New intracranial subcentimeter meta- the mixed response of lesions with some increasing and some static disease was identified in September 2015 which was not decreasing in size, and the greater confluence of the left tem- amenable to further radiation. Immunotherapy with the poral lobe lesion which however remained stable in size. checkpoint inhibitor nivolumab was initiated in November The next day, the patient presented to the emergency 2015 (Figure 1 and Table 1). room with worsening shortness of breath. The computerized Eosinophil counts dating back to 1998 had always been tomography angiogram of the chest was consistent with within normal limits except for a brief period of mild marked progression of the disease. Despite treatment with increased eosinophilia after adjuvant chemotherapy in 2012 broad-spectrum antibiotics and aggressive treatment in the which spontaneously resolved. Four weeks after initiation of intensive care unit, the patient expired one week after his nivolumab, his absolute eosinophil count was noted to be ele- admission with the progression of the disease. An autopsy vated at 2:86 × 10 /L; all other hematopoietic cell lines not performed as per the family’s request. remained unaffected. He had denied any travel within the previous five years and denied any exposure to any known 3. Discussion allergens, new products, or new medications. He was asymp- Eosinophilia with PD-1/PD-L1 checkpoint inhibitors is a tomatic, and on physical examination, there was no evidence rarely reported adverse event. Absolute eosinophilic count of skin rash or splenomegaly. (AEC) of more 500 cells/μL in the peripheral blood is On a follow-up visit in April 2016, after eight cycles of eosinophilia, and based on the eosinophil count, it is further nivolumab, the peripheral blood smear revealed markedly 9 9 increased eosinophils, but no other significant findings. subdivided as mild 0:5‐1:5×10 /L, moderate 1:5‐5×10 /L, 9 9 Further work-up of the eosinophilia was performed and and severe >5 × 10 /L [12]. AEC > 1500 × 10 /L in the was unrevealing. Multiple stool samples were obtained, and peripheral blood on two separate occasions at least one testing for culture, ova, and parasites remained negative on month apart is defined as hypereosinophilia. Pathologic three separate occasions as was testing for Clostridium diffi- confirmation of tissue hypereosinophilia is also termed as 11/9/2015 12/9/2015 1/9/2016 2/9/2016 3/9/2016 4/9/2016 5/9/2016 6/9/2016 Case Reports in Oncological Medicine 3 Table 1 The prognostic significance of hypereosinophilia associ- ated with nivolumab in terms of overall survival and Timeline: ANC ALC Eos Mono Hg PLT progression-free survival remains largely undefined. There 11/09/2015 4220 1160 300 470 10.9 189 are reports of advanced lung adenocarcinoma with favorable 11/16/2015 3960 1300 1370 580 11.4 163 prognosis when eosinophilia was reported with nivolumab use [7, 14]. 11/23/2015 2990 1060 660 340 12 174 In some case reports, eosinophilia was noted as an 11/30/2015 3950 1740 1740 470 12.7 194 adverse event and as a prodrome in patients who were later 12/07/2015 3190 1360 2860 440 12.1 196 diagnosed with checkpoint-mediated immune complications 12/14/2015 3130 770 1260 330 10.8 169 such as adrenal insufficiency [11] systemic symptom syn- 12/21/2015 2560 1140 1540 460 12.5 157 drome and hypophysitis [16]. 12/28/2015 3400 1480 1920 590 13.5 204 Various studies related to tumor-associated tissue eosin- 12/31/2015 3180 1380 1920 410 13.1 198 ophilia (TATE) in many solid tumors (colorectal and esoph- 1/11/2016 2970 1380 1930 550 12.7 154 ageal squamous cell carcinoma) have revealed it to have good prognostic value, but in Hodgkin lymphoma, it is associated 1/19/2016 2220 1260 2100 420 12.1 147 with poor prognosis [17–19]. There has been some conflict- 2/01/2016 3110 1250 620 520 13.5 189 ing data [20] regarding oral SCC and cervical carcinoma 2/08/2016 2980 1170 690 490 13.1 163 where TATE has been shown to be associated with poor 2/16/2016 2960 1180 1710 490 13.6 164 prognosis. The mechanism that can explain these effects 2/22/2016 3890 1470 3200 870 14.4 186 remains unclear. Tumoricidal properties of eosinophils 2/29/2016 3330 1440 5770 550 13.1 181 remain unknown; however, one suggested possible mecha- 3/02/2016 2560 1460 4650 550 13.1 194 nism is the direct cytotoxic effect from degranulation of eosinophilic granules [20]. 3/07/2016 3660 1550 4740 580 12.5 168 The role of eosinophils in antitumor immune response 3/14/2016 3800 1350 2640 650 13.4 187 has been suggested. The various suggested mechanisms are 3/22/2016 3190 1420 1990 500 13.4 217 direct antitumor effects, dendritic cell activation and recruit- 3/28/2016 4210 1240 1500 540 12.8 171 ment, T-cell recruitment and polarization using chemokines 4/04/2016 2980 1460 1010 530 13 159 and enhanced immune surveillance, and normalization of 4/11/2016 3670 1480 1530 680 12.9 188 the tumor microenvironment vasculature [21–24]. Eosino- 4/18/2016 2740 1540 1360 480 12.5 170 philia which has been reported in acute or chronic graft- versus-host disease further points towards its immune- 4/25/2016 3220 1400 3100 530 12.3 179 related properties [20, 25]. 5/02/2016 3340 1330 3590 540 12.9 186 A retrospective study reported a correlation of enhanced 5/09/2016 4300 1540 2090 820 12.9 205 immune response, prolonged prostate cancer-specific sur- 5/12/2016 6950 1020 1210 740 12.8 204 vival, and trend towards improved overall survival in patients 5/16/2016 10210 1000 200 860 13.2 198 with eosinophilia. Eosinophilia was reported in 28% of 5/23/2016 12240 640 10 490 12.8 175 patients (105 of 377) following sipuleucel-T treatment at 6/14/2016 8420 840 30 880 13.5 106 week 6 with resolution by week 14 [26]. A prospective study of 73 patients with advanced mela- 6/29/2016 6230 620 20 200 13.3 111 noma treated with ipilimumab (anticytotoxic T lymphocyte- Abbreviations: ANC: absolute neutrophil count; ALC: absolute lymphocyte associated antigen [CTLA] 4 monoclonal antibody) demon- count; Eos: eosinophil count; Mono: monocyte count; Hg: hemoglobin in mg/dL; PLT: platelet count. strated correlation of improved overall survival with an increase in eosinophil count of more than 100 cells/μL [10]. Studies of anti-PD-1 monoclonal antibody (pembrolizumab hypereosinophilia. The term hypereosinophilic syndrome is used when eosinophilia is associated with tissue and organ and nivolumab) in patients with melanoma demonstrated a positive correlation between an elevated eosinophil count damage [13]. Early identification of drug-induced hypereosi- nophilia is critical, especially when deciding whether to con- and overall survival [27, 28]. The median eosinophil count tinue the drug and/or to treat with corticosteroids. peak (approximately 1000 cells/μL) has been correlated with an improved overall response rate [29]. There are studies Allergic or immunologic processes like asthma, eosino- philic granulomatosis with polyangiitis, bronchopulmonary contradicting the beneficial effect of eosinophilia. A study aspergillosis, and helminthic parasitic infections are associ- with 156 patients with advanced melanoma treated with ipi- ated with hypereosinophilia. Hematologic or neoplastic dis- limumab at a dose of 3 mg/kg manifested immune-related orders (adenocarcinomas, Hodgkin lymphoma, and T-cell adverse events including eosinophilia without overall sur- vival improvement [30]. T-cell-mediated antitumor response lymphoma) can also lead to hypereosinophilia, but are an uncommon cause [12]. could be affected by activated eosinophils via enhancing However, hypereosinophilia associated with immune- CD8-T-cell infiltration as demonstrated in a mouse model checkpoint inhibitors has rarely been reported. To date, only [23]. Therefore, some experts recommend that eosinophilia five reports of nivolumab-induced hypereosinophilia have should not be used as a prognostic factor due to its codepen- dence on T-cells. been reported in the literature [7, 11, 14, 15]. 4 Case Reports in Oncological Medicine Alternatively, eosinophilia could simply be due to an [2] S. L. Topalian, F. S. Hodi, J. R. Brahmer et al., “Safety, activity, and immune correlates of anti-PD-1 antibody in cancer,” The allergic drug reaction. There has been a reported case of New England Journal of Medicine, vol. 366, no. 26, pp. 2443– drug-related eosinophilia and systemic symptom (DRESS) 2454, 2012. syndrome in a patient with melanoma following ipilimumab [3] J. Larkin, V. Chiarion-Sileni, R. Gonzalez et al., “Combined and nivolumab administration [15]. nivolumab and ipilimumab or monotherapy in untreated mel- To determine the significance of eosinophils in immuno- anoma,” The New England Journal of Medicine, vol. 373, no. 1, therapy requires additional studies. To our knowledge, there pp. 23–34, 2015. are only two reports of hypereosinophilia associated with [4] R. Chen, P. L. Zinzani, M. A. Fanale et al., “Phase II study of nivolumab used in non-small-cell lung cancer where patients the efficacy and safety of pembrolizumab for relapsed/refrac- had a favorable response [7, 14]. 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It is with immune checkpoint inhibitor therapy: American Society unclear whether the MRI changes in the brain were second- of Clinical Oncology clinical practice guideline Summary,” ary to immune cerebritis as there was also clear progression Journal of Oncology Practice, vol. 14, no. 4, pp. 247–249, of his metastatic disease. Given the progression of the disease and the potential toxicity of the drug, nivolumab was discon- [7] Y. Lou, J. A. Marin-Acevedo, P. Vishnu et al., “Hypereosino- tinued. The more challenging question is whether it is war- philia in a patient with metastatic non-small-cell lung cancer ranted to discontinue nivolumab in the setting of very treated with antiprogrammed cell death 1 (anti-PD-1) ther- apy,” Immunotherapy, vol. 11, no. 7, pp. 577–584, 2019. severe hypereosinophilia when a clinical response is being observed [14]. Notably, in this case after nivolumab was held, [8] X. J. Meng, Z. Q. Huang, F. F. Teng, L. G. Xing, and J. M. 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Case Reports in Oncological MedicineHindawi Publishing Corporation

Published: May 15, 2020

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