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Eosinophilic Asthma Secondary to Adjuvant Anti-PD-1 Immune Checkpoint Inhibitor Treatment in a Melanoma Patient

Eosinophilic Asthma Secondary to Adjuvant Anti-PD-1 Immune Checkpoint Inhibitor Treatment in a... Hindawi Case Reports in Oncological Medicine Volume 2022, Article ID 2658136, 6 pages https://doi.org/10.1155/2022/2658136 Case Report Eosinophilic Asthma Secondary to Adjuvant Anti-PD-1 Immune Checkpoint Inhibitor Treatment in a Melanoma Patient 1 2 2 2 2,3 2,3 P. Kissoonsingh, B. Sutton, Syed U. Iqbal, Lalit Pallan, Neil Steven, and L. Khoja College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital, Department of Oncology, Birmingham B15 2TH, UK Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK Correspondence should be addressed to L. Khoja; l.khoja@bham.ac.uk Received 6 January 2022; Revised 30 March 2022; Accepted 12 April 2022; Published 30 April 2022 Academic Editor: Mauro Cives Copyright © 2022 P. Kissoonsingh 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. Adjuvant immune checkpoint inhibitors are a new standard of care in melanoma. However, the immune related toxicity associated with these agents can be serious, and the long-term implications are yet to be defined especially in the adjuvant setting. We report, to our knowledge, the first case of anti-PD-1-induced eosinophilic asthma in a melanoma patient treated with adjuvant pembrolizumab. Case Presentation. A 72-year-old man commenced pembrolizumab in the adjuvant setting after resection of a stage IIIB cutaneous melanoma. The patient experienced episodes of breathlessness 4 weeks after cycle 1. These episodes were nocturnal and caused acute respiratory distress and cough, occasionally waking him up. The episodes progressed, and he was admitted after cycle 2 with a productive cough, wheeze, and breathlessness. Observations showed saturations on air of 94% and a respiratory rate of 19/min. The only laboratory abnormality was a raised eosinophil count of 1:1×10 . Spirometry showed a FEV1 of 2.57 (91% predicted), FVC of 4.04 (108% predicted), and ratio of 64%. Peak expiratory flow rate was 94% predicted, and corrected gas transfer was 6.29 (78% predicted) with KCO 1.18 (93% predicted). FeNO was raised at 129 indicating inflammation of his airways, and peak flow was 422 l/min. CT of the chest did not show pneumonitis or other lung pathology. A diagnosis of acute eosinophilic asthma was made. Treatment with steroids and beclometasone dipropionate and formoterol inhaler produced rapid resolution of symptoms and normalisation of the eosinophil count. Pembrolizumab was safely recommenced once steroids had discontinued and symptoms had resolved. Conclusions. Specialist respiratory input was needed for optimal patient management and is ongoing. Although a safe rechallenge with pembrolizumab was possible, treatment in the adjuvant setting is curative in intent and long-term safety follow-up is required to assess for delayed toxicity and long-term health implications. This is likely to require large regional/ national/international databases to detect, monitor, and educate the wider medical community as these patients are followed up in primary care following initial specialist follow-up. 1. Background majority of these toxicities resolve albeit with significant management in some instances. However, some toxicity Anti-PD-1 immune checkpoint inhibitor therapy is requires lifelong intervention. The longer-term implications approved for melanoma in the adjuvant (curative) setting of these toxicities and any further longer term health impli- after surgery [1, 2]. These agents alone and in combination cations are unknown. with ipilimumab (anti-CTLA-4 inhibitor) were first In the adjuvant setting, toxicity has reflected that of the approved in metastatic melanoma [3, 4], and their toxicity metastatic setting [7], but there is as yet a paucity of data profiles are well characterised in this setting [5, 6]. The on long-term outcomes in terms of both toxicity and any 2 Case Reports in Oncological Medicine dicted), and KCO 1.18 (93% predicted) (Figure 2(a)). He subsequent health issues and overall survival outcomes from melanoma. Moreover, the risk benefit ratio in the adjuvant also had a raised FeNO of 129 indicating inflammation of setting differs widely from that of metastatic disease. his airways and a peak flow of 422 l/min. CT of the chest Here, to our knowledge, we report the first case of anti- did not show pneumonitis or other lung pathology. PD-1-induced eosinophilic asthma in the adjuvant setting, An immune adverse event was suspected in this patient. in a melanoma patient treated with pembrolizumab. We dis- Pneumonitis secondary to immune check point inhibitor cuss the management and possible implications for the therapy would be the most common respiratory toxicity patient. and was the primary differential diagnosis, but the CT chest was clear. Immune-related myocarditis or pericarditis could have been less likely possibilities, but there the clinical signs 2. Case History were not consistent with these. The initial intermittent A 72-year-old male was referred for adjuvant therapy fol- nature of the breathlessness and the nocturnal timing of it, lowing resection of a stage IIIb malignant melanoma. The along with the history of dust exposure and progressive patient first presented 2 years earlier with a midscalp lesion; worsening of symptoms, made asthma the most likely diag- a punch biopsy of which showed an amelanotic SOX10 and nosis. The raised eosinophil counts over time added weight S100 positive melanoma (Breslow thickness unknown). The to an allergic and inflammatory process being the cause. A lesion had completely regressed by the time of referral for diagnosis of acute eosinophilic asthma was made, and treat- definitive treatment, and wide local excision did not show ment instigated with 40 mg prednisolone for 5 days and fos- malignancy. A year later, a skin lesion from the right tair (beclometasone dipropionate and formoterol) 100/6 two supra-auricular skin/occipital scalp was resected. This puffs twice daily. There was a rapid response to treatment proved to be a 13 mm subcutaneous nodule consistent with with improvement in all of his symptoms. The eosinophil metastatic melanoma. Histology revealed pleomorphic epi- count declined to a normal range within 2 days of predniso- thelioid and spindle-shaped cells with mitotic figures, posi- lone treatment, and peak flow improved to 590 l/min indi- tive for S100 protein and SOX10. Perineural invasion was cating reversibility of the acute obstruction. Repeat seen. A CT scan of the body did not show metastatic disease. spirometry 6 months later showed FEV1 2.61 (89% pre- Staging was Tx N2c M0 stage III. The patient had a back- dicted), FVC 3.65 (95% predicted), ratio of 93% (peak expi- ground of hypertension, previous MI, and coronary stent. ratory flow rate 97% predicted), and FeNo 17 ppb (Figure 2 There was no history of autoimmune or inflammatory con- (b)). ditions. There was no history of chronic obstructive airway Pembrolizumab was recommenced once steroids had disease, but he was an ex-cigar smoker having stopped 32 discontinued and symptoms had resolved, on schedule, 6 years ago. His medication consisted of atorvastatin 20 mg, weeks after cycle 2. The patient has not required any further latanoprost, lisinopril 10 mg, and rivaroxaban 20 mg. Adju- acute treatment for his asthma and continues on fostair vant 6 weekly pembrolizumab was commenced 6 weeks (beclometasone dipropionate and formoterol) 200/6 and sal- from surgery and planned to continue for one year in total. butamol as required (using them with a spacer). Peak expira- The patient started to have episodes of breathlessness 4 tory flow rate remains stable at an average of 500 l/min weeks after cycle 1/first dose of pembrolizumab. These epi- (which is within normal range for his age). His night time sodes tended to be at night and caused acute respiratory dis- breathlessness has completely resolved, and his exercise tol- tress and cough, occasionally waking him up at night. He erance is back to his baseline. During follow-up to date, he had some exposure to dust during this period as a result of has described some rhinitis, but this is mild and has not domestic building work. The episodes become more severe required further investigation or management. and prolonged, and he was admitted after cycle 2 of pembro- lizumab for further investigation. At that time, he had a pro- 3. Discussion ductive cough, wheeze, and breathlessness. On admission, his saturations were 94% on air and his Respiratory toxicity with checkpoint inhibitors is well docu- respiratory rate was 19. Blood tests showed normal renal mented with a wide range of toxicities reported including and liver function, a CRP count of 3 mg/l, and a full blood dyspnoea, pneumonitis, pleural effusion, pulmonary sar- count that revealed an isolated raised eosinophil count of coidosis, acute fibrinous organizing pneumonia, eosinophilic 1:1×10 . There was no evident rash, and the patient had pneumonia, adult respiratory distress syndrome, and lung not received any other new medications (excluding a possi- cavitation [8, 9]. The most common is pneumonitis with a ble diagnosis of DRESS (drug-related eosinophilia with sys- reported incidence of 1.7% of any grade in melanoma with temic symptoms)). On review of serial blood tests, an single-agent anti-PD-1 agents [6]. Exacerbation of asthma isolated raised eosinophil count of 0:47 × 10 first occurred has been reported and may be fatal [8, 10]. Predictive 3 weeks after cycle 1 pembrolizumab and peaked at 1:1× markers for immune checkpoint-related toxicity are lacking. 10 coinciding with his admission postcycle 2 of treatment Eosinophil counts have been proposed as a possible marker (Figures 1(a) and 1(b)) (autoantibody screen was not per- of increased inflammation and immune activation with sub- sequent improved survival outcomes [11–13] or increased formed either pre- or on immunotherapy). Spirometry dur- ing admission showed a FEV1 2.57 (91% predicted), FVC risk of toxicity [14]. 4.04 (108% predicted), ratio of 64% (peak expiratory flow Asthma is characterised by inflamed hyperresponsive rate 94% predicted), gas transfer corrected 6.29 (78% pre- bronchial airways and reversible airflow obstruction [15]. It Case Reports in Oncological Medicine 3 232 235 220 241 134 130 PLT HB 9.0 7.5 8.0 7.1 7.3 6.5 6.5 7.0 6.2 7.5 6.0 5.0 4.1 3.9 4.1 3.8 3.5 3.5 4.0 4.1 3.0 1.9 1.8 1.8 1.8 1.6 1.6 2.0 1.0 1.6 0.0 WBC NEUTS LYMPH 1.4 1.2 1.1 1.0 1.0 1.1 0.8 0.8 0.73 0.67 0.87 0.53 0.51 0.6 0.55 0.4 0.47 0.35 0.2 0.29 0.28 0.0 0123456789 10 11 12 13 14 15 16 17 18 Cycle 1 Cycle 2 Cycle 3 Cycle 4 WEEKS MONOS EOSIN Figure 1: Line graphs depicting serial full blood count values over time over cycles 1-4. Eosinophils were the only subset of cells that elevated above normal range after cycle 1 before returning to normal at time of cycle 3. Normal ranges for haemoglobin (130-162), white cell count (4.3-11.2), platelets (150-400), neutrophils (1.90-7.90), basophils (0.05-0.10), monocytes (0.30-0.90), eosinophils (0.03-0.44), and lymphocytes (0.50-4.00). is increasingly recognised that it is a heterogenous disease a typical finding of increased inflammatory cells and eosino- with different pathophysiologic mechanisms driving airway philia [15, 17]. inflammation and therefore subsequent differences in out- Our patient had a typical presentation of eosinophilic comes and effectiveness of treatments. Eosinophilic asthma asthma which occurred after the first dose of pembrolizu- represents approximately fifty percent of asthma with vary- mab. There was no history of preexisting respiratory condi- ing phenotypes [16]. It is frequently associated with “fixed” tions, and other diagnoses were excluded. The only possible airflow obstruction, decreased FVC, and increased residual causative agent was the pembrolizumab. The diagnosis was volume, with late (in life) onset and typical symptoms of made based on the clinical presentation, the reversible peak dyspnoea on exertion rather than wheeze [15, 17]. Exacerba- expiratory flow rate readings before, during, and after treat- tions can be severe with development of steroid reliance and ment, and the spirometry which has also improved with then resistance over time. A typical comorbidity at presenta- treatment. Furthermore, the patient during the acute presen- tion or one which subsequently develops is chronic rhinosi- tation had a high FeNo with evidence of variable airflow nusitis with nasal polyposis. Diagnostic tests include which also settled with treatment. These findings fit with demonstration of airflow variability, raised peripheral eosin- NICE criteria for diagnosis of asthma. Treatment was rap- ophil counts, raised FeNo, and induced sputum testing with idly successful in controlling his symptoms, and ⁎ ⁎ ⁎ 10 9/L 10 9/L 10 9/L 4 Case Reports in Oncological Medicine 14 14 Volume (L) Volume (L) 12 12 10 10 8 8 6 6 4 4 2 2 0 0 246 246 –2 –2 –4 –4 –6 –6 –8 –8 –10 –10 –12 –12 –14 –14 (a) (b) Figure 2: (a) Spirometry during acute admission with cough, wheeze, and shortness of breath. Spirometry indicates obstructive airways with raised FeNO supporting a process of inflammation in the airways. (b) Spirometry 6 months after acute episode requiring admission, values now normal including the FeNo. pembrolizumab rechallenge has been successful alongside told that the melanoma could recur, but if I had adjuvant regular inhaler use to control any asthma symptoms. treatment, meaning treatment to complement the surgery and prevent the melanoma from returning, the chances of The patient is halfway through the planned year of pem- brolizumab adjuvant therapy to date without further asthma this happening could be reduced. I opted to start pembroli- exacerbations. We found one reported case in the literature zumab treatment given intravenously every 6 weeks for of asthma induced by anti-PD-1 agent nivolumab in a stage one year. It was explained that this was an immunotherapy IV lung patient. This patient had a very similar presentation meaning it uses the immune system to attack the melanoma and diagnostic findings as our patient and symptoms cells. I was counselled about possible side effects which resolved with inhalers alone. Although not described as would be immune related as in an immune reaction in any such, that case was consistent with eosinophilic asthma [18]. part of my body. Treatment in the adjuvant setting is curative in intent, After the first cycle of treatment, I started to have short- and long-term safety follow-up is required to assess for ness of breath. This tended to be at night and made me feel delayed toxicity and long-term health implications following unwell lasting a few hours. I attended accident and emer- adjuvant immune checkpoint inhibitor therapy. This is likely gency and was told my CXR and oxygen saturations were to require large regional/national/international databases to fine and that I could take antihistamines as I may be having detect, monitor, and educate the wider medical community allergic reactions. I also consulted my GP who gave me an as these patients are followed up in primary care following inhaler to use if I had another episode. The shortness of initial specialist follow-up. Regarding our patient, subse- breath kept recurring. I had cycle 2 pembrolizumab, and quent follow-up postcompletion of the year’s therapy will the oncology doctor who assessed me beforehand told me reveal if exacerbations of our patient’s asthma develop and that the drug may have sensitized me to allergens, and this become problematic or indeed if he develops any other tox- could be causing the breathlessness. An opinion from the icity related to (pembrolizumab-induced) eosinophilia or respiratory physicians would be sought. After cycle 2, I kept pembrolizumab treatment in general. A multidisciplinary having the breathlessness and could not cope any more at approach with respiratory expertise was needed in our home; I phoned the red card for oncology emergencies and patient, and this should be the approach in managing and was admitted to hospital for assessment. Several tests were following up patients postadjuvant immune checkpoint done to assess my lungs; I had a CT scan which did not show inhibitor treatment. any inflammation (a possible side effect of the pembrolizu- mab) and lung function tests after which a respiratory doc- tor also assessed me. High-dose steroids and an inhaler 4. Patient Perspective treatment stopped my symptoms completely. I was dis- I first had a spot removed from my scalp in 2019. I was told charged home to finish the course of steroids but continue it was most likely a melanoma that had spontaneously disap- using the inhaler. The diagnosis for my breathlessness was found to be asthma. I was pleased to have a cause for the peared. In 2020, I noticed a lump behind my right ear which grew from a pea to almond sized. I was concerned as my sur- breathlessness found and for the treatment to have worked. gery was delayed due to the COVID pandemic, but the lump I was assessed in clinic after discharge to see if I could con- was completely removed and shown to be a melanoma. I was tinue with pembrolizumab. It was explained that there was a Flow (L/sec) Flow (L/sec) Case Reports in Oncological Medicine 5 risk of the breathlessness returning if I restarted treatment, [2] J. Weber, M. Mandala, M. Del Vecchio et al., “Adjuvant nivo- lumab versus ipilimumab in resected stage III or IV mela- and this could either be treated in the same way again, or noma,” The New England Journal of Medicine, vol. 377, if the attack was too severe, then the treatment would have no. 19, pp. 1824–1835, 2017. to be stopped. There was also a risk of other immune- [3] C. Robert, A. Ribas, J. Schachter et al., “Pembrolizumab versus related side effects if pembrolizumab restarted. I felt well ipilimumab in advanced melanoma (KEYNOTE-006): post- and am keen to finish my treatment as I do not want the hoc 5-year results from an open-label, multicentre, rando- melanoma to recur, so I opted to restart. So far everything mised, controlled, phase 3 study,” The Lancet Oncology, is going smoothly and I have had no further issues. I use vol. 20, no. 9, pp. 1239–1251, 2019. my inhaler when needed but as time as gone on, I have used it less and more recently not at all. I have seen the specialist [4] J. Larkin, V. Chiarion-Sileni, R. Gonzalez et al., “Five-year sur- asthma nurses in clinic who are pleased with my progress vival with combined nivolumab and ipilimumab in advanced and are going to repeat my lung function tests in a few melanoma,” The New England Journal of Medicine, vol. 381, months to compare to the ones done during my admission. no. 16, pp. 1535–1546, 2019. I discussed my side effect with the oncology doctor last [5] L. Khoja, D. Day, T. Wei-Wu Chen, L. L. Siu, and A. R. Han- time I was seen in clinic and asked about how long the pem- sen, “Tumour- and class-specific patterns of immune-related brolizumab remains in the body. She explained that the half- adverse events of immune checkpoint inhibitors: a systematic review,” Annals of Oncology, vol. 28, no. 10, pp. 2377–2385, life (time taken to reduce to half the amount) is ~30 days, and the time to completely clear the drug from the body from the last dose would be ~5 times this period. This means [6] J. S. Weber, F. S. Hodi, J. D. Wolchok et al., “Safety profile of nivolumab monotherapy: a pooled analysis of patients with that the antibody is not cleared quickly and that toxicity can advanced melanoma,” Journal of Clinical Oncology, vol. 35, therefore happen late into treatment and even after treat- no. 7, pp. 785–792, 2017. ment is stopped. I will have to have close monitoring for side [7] M. Mandala, J. Larkin, P. A. Ascierto et al., “Adjuvant nivo- effects for at least 6 months after finishing treatment, and I lumab for stage III/IV melanoma: evaluation of safety out- will have close monitoring by CT and assessment in person comes and association with recurrence-free survival,” by a doctor to test if my melanoma returns in the years to Journal for Immunotherapy of Cancer, vol. 9, no. 8, article come. My asthma may remain stable or it may worsen or e003188, 2021. recur. Treatment will be given to control it. [8] H. Bukamur, H. Katz, M. Alsharedi, A. Alkrekshi, Y. R. Shwei- hat, and N. J. Munn, “Immune checkpoint inhibitor-related Data Availability pulmonary toxicity: focus on nivolumab,” Southern Medical Journal, vol. 113, no. 11, pp. 600–605, 2020. Data are available on clinical records held in the hospital [9] H. Bukamur, A. Alkrekshi, H. Katz, M. Alsharedi, Y. R. Shwei- electronic database. hat, and N. J. Munn, “Immune checkpoint inhibitor-related pulmonary toxicity: a comprehensive review, part II,” South- Consent ern Medical Journal, vol. 114, no. 9, pp. 614–619, 2021. [10] H. Wang, J. Shi, X. Wang, H. Zhao, and H. Wang, “Acute exac- The patient was consented for his data to be used and erbation of asthma induced by combined therapy of pro- published. grammed death-1 blocker plus lenvatinib in a patient with advanced hepatocellular carcinoma,” European Journal of Conflicts of Interest Cancer, vol. 156, pp. 122–124, 2021. [11] A. Bernard-Tessier, P. Jeanville, S. Champiat et al., “Immune- The authors declare that they have no conflicts of interest. related eosinophilia induced by anti-programmed death 1 or death-ligand 1 antibodies,” European Journal of Cancer, vol. 81, pp. 135–137, 2017. Authors’ Contributions [12] S. C. S. Simon, X. Hu, J. Panten et al., “Eosinophil accumula- All authors contributed to the management of this case and tion predicts response to melanoma treatment with immune writing and review of the manuscript. checkpoint inhibitors,” Oncoimmunology., vol. 9, no. 1, p. 1727116, 2020. [13] B. Weide, A. Martens, J. C. Hassel et al., “Baseline biomarkers Acknowledgments for outcome of melanoma patients treated with pembrolizu- mab,” Clinical Cancer Research, vol. 22, no. 22, pp. 5487– We thank the patient who consented to reporting this case. 5496, 2016. [14] R. Kizawa, Y. Miura, Y. Oda et al., “Eosinophilia during treat- References ment of immune checkpoint inhibitors (ICIs) to predict suc- ceeding onset of immune-related adverse events (irAEs),” [1] A. M. M. Eggermont, C. U. Blank, M. Mandala et al., Journal of Clinical Oncology, vol. 37, article e14110, 15_suppl, “Adjuvant pembrolizumab versus placebo in resected stage III melanoma (EORTC 1325-MG/KEYNOTE-054): distant metastasis-free survival results from a double- blind, rando- [15] H. H. Walford and T. A. Doherty, “Diagnosis and manage- mised, controlled, phase 3 trial,” The Lancet Oncology, ment of eosinophilic asthma: a US perspective,” J Asthma vol. 22, no. 5, pp. 643–654, 2021. Allergy., vol. 7, pp. 53–65, 2014. 6 Case Reports in Oncological Medicine [16] S. E. Wenzel, “Asthma phenotypes: the evolution from clinical to molecular approaches,” Nature Medicine, vol. 18, no. 5, pp. 716–725, 2012. [17] J. C. de Groot, A. Ten Brinke, and E. H. Bel, “Management of the patient with eosinophilic asthma: a new era begins,” ERJ open research, vol. 1, no. 1, pp. 00024–02015, 2015. [18] K. Maeno, S. Fukuda, T. Oguri, and A. Niimi, “Nivolumab- induced asthma in a patient with non-small-cell lung cancer,” Annals of Oncology, vol. 28, no. 11, p. 2891, 2017. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Case Reports in Oncological Medicine Hindawi Publishing Corporation

Eosinophilic Asthma Secondary to Adjuvant Anti-PD-1 Immune Checkpoint Inhibitor Treatment in a Melanoma Patient

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Copyright © 2022 P. Kissoonsingh 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 2022, Article ID 2658136, 6 pages https://doi.org/10.1155/2022/2658136 Case Report Eosinophilic Asthma Secondary to Adjuvant Anti-PD-1 Immune Checkpoint Inhibitor Treatment in a Melanoma Patient 1 2 2 2 2,3 2,3 P. Kissoonsingh, B. Sutton, Syed U. Iqbal, Lalit Pallan, Neil Steven, and L. Khoja College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital, Department of Oncology, Birmingham B15 2TH, UK Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK Correspondence should be addressed to L. Khoja; l.khoja@bham.ac.uk Received 6 January 2022; Revised 30 March 2022; Accepted 12 April 2022; Published 30 April 2022 Academic Editor: Mauro Cives Copyright © 2022 P. Kissoonsingh 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. Adjuvant immune checkpoint inhibitors are a new standard of care in melanoma. However, the immune related toxicity associated with these agents can be serious, and the long-term implications are yet to be defined especially in the adjuvant setting. We report, to our knowledge, the first case of anti-PD-1-induced eosinophilic asthma in a melanoma patient treated with adjuvant pembrolizumab. Case Presentation. A 72-year-old man commenced pembrolizumab in the adjuvant setting after resection of a stage IIIB cutaneous melanoma. The patient experienced episodes of breathlessness 4 weeks after cycle 1. These episodes were nocturnal and caused acute respiratory distress and cough, occasionally waking him up. The episodes progressed, and he was admitted after cycle 2 with a productive cough, wheeze, and breathlessness. Observations showed saturations on air of 94% and a respiratory rate of 19/min. The only laboratory abnormality was a raised eosinophil count of 1:1×10 . Spirometry showed a FEV1 of 2.57 (91% predicted), FVC of 4.04 (108% predicted), and ratio of 64%. Peak expiratory flow rate was 94% predicted, and corrected gas transfer was 6.29 (78% predicted) with KCO 1.18 (93% predicted). FeNO was raised at 129 indicating inflammation of his airways, and peak flow was 422 l/min. CT of the chest did not show pneumonitis or other lung pathology. A diagnosis of acute eosinophilic asthma was made. Treatment with steroids and beclometasone dipropionate and formoterol inhaler produced rapid resolution of symptoms and normalisation of the eosinophil count. Pembrolizumab was safely recommenced once steroids had discontinued and symptoms had resolved. Conclusions. Specialist respiratory input was needed for optimal patient management and is ongoing. Although a safe rechallenge with pembrolizumab was possible, treatment in the adjuvant setting is curative in intent and long-term safety follow-up is required to assess for delayed toxicity and long-term health implications. This is likely to require large regional/ national/international databases to detect, monitor, and educate the wider medical community as these patients are followed up in primary care following initial specialist follow-up. 1. Background majority of these toxicities resolve albeit with significant management in some instances. However, some toxicity Anti-PD-1 immune checkpoint inhibitor therapy is requires lifelong intervention. The longer-term implications approved for melanoma in the adjuvant (curative) setting of these toxicities and any further longer term health impli- after surgery [1, 2]. These agents alone and in combination cations are unknown. with ipilimumab (anti-CTLA-4 inhibitor) were first In the adjuvant setting, toxicity has reflected that of the approved in metastatic melanoma [3, 4], and their toxicity metastatic setting [7], but there is as yet a paucity of data profiles are well characterised in this setting [5, 6]. The on long-term outcomes in terms of both toxicity and any 2 Case Reports in Oncological Medicine dicted), and KCO 1.18 (93% predicted) (Figure 2(a)). He subsequent health issues and overall survival outcomes from melanoma. Moreover, the risk benefit ratio in the adjuvant also had a raised FeNO of 129 indicating inflammation of setting differs widely from that of metastatic disease. his airways and a peak flow of 422 l/min. CT of the chest Here, to our knowledge, we report the first case of anti- did not show pneumonitis or other lung pathology. PD-1-induced eosinophilic asthma in the adjuvant setting, An immune adverse event was suspected in this patient. in a melanoma patient treated with pembrolizumab. We dis- Pneumonitis secondary to immune check point inhibitor cuss the management and possible implications for the therapy would be the most common respiratory toxicity patient. and was the primary differential diagnosis, but the CT chest was clear. Immune-related myocarditis or pericarditis could have been less likely possibilities, but there the clinical signs 2. Case History were not consistent with these. The initial intermittent A 72-year-old male was referred for adjuvant therapy fol- nature of the breathlessness and the nocturnal timing of it, lowing resection of a stage IIIb malignant melanoma. The along with the history of dust exposure and progressive patient first presented 2 years earlier with a midscalp lesion; worsening of symptoms, made asthma the most likely diag- a punch biopsy of which showed an amelanotic SOX10 and nosis. The raised eosinophil counts over time added weight S100 positive melanoma (Breslow thickness unknown). The to an allergic and inflammatory process being the cause. A lesion had completely regressed by the time of referral for diagnosis of acute eosinophilic asthma was made, and treat- definitive treatment, and wide local excision did not show ment instigated with 40 mg prednisolone for 5 days and fos- malignancy. A year later, a skin lesion from the right tair (beclometasone dipropionate and formoterol) 100/6 two supra-auricular skin/occipital scalp was resected. This puffs twice daily. There was a rapid response to treatment proved to be a 13 mm subcutaneous nodule consistent with with improvement in all of his symptoms. The eosinophil metastatic melanoma. Histology revealed pleomorphic epi- count declined to a normal range within 2 days of predniso- thelioid and spindle-shaped cells with mitotic figures, posi- lone treatment, and peak flow improved to 590 l/min indi- tive for S100 protein and SOX10. Perineural invasion was cating reversibility of the acute obstruction. Repeat seen. A CT scan of the body did not show metastatic disease. spirometry 6 months later showed FEV1 2.61 (89% pre- Staging was Tx N2c M0 stage III. The patient had a back- dicted), FVC 3.65 (95% predicted), ratio of 93% (peak expi- ground of hypertension, previous MI, and coronary stent. ratory flow rate 97% predicted), and FeNo 17 ppb (Figure 2 There was no history of autoimmune or inflammatory con- (b)). ditions. There was no history of chronic obstructive airway Pembrolizumab was recommenced once steroids had disease, but he was an ex-cigar smoker having stopped 32 discontinued and symptoms had resolved, on schedule, 6 years ago. His medication consisted of atorvastatin 20 mg, weeks after cycle 2. The patient has not required any further latanoprost, lisinopril 10 mg, and rivaroxaban 20 mg. Adju- acute treatment for his asthma and continues on fostair vant 6 weekly pembrolizumab was commenced 6 weeks (beclometasone dipropionate and formoterol) 200/6 and sal- from surgery and planned to continue for one year in total. butamol as required (using them with a spacer). Peak expira- The patient started to have episodes of breathlessness 4 tory flow rate remains stable at an average of 500 l/min weeks after cycle 1/first dose of pembrolizumab. These epi- (which is within normal range for his age). His night time sodes tended to be at night and caused acute respiratory dis- breathlessness has completely resolved, and his exercise tol- tress and cough, occasionally waking him up at night. He erance is back to his baseline. During follow-up to date, he had some exposure to dust during this period as a result of has described some rhinitis, but this is mild and has not domestic building work. The episodes become more severe required further investigation or management. and prolonged, and he was admitted after cycle 2 of pembro- lizumab for further investigation. At that time, he had a pro- 3. Discussion ductive cough, wheeze, and breathlessness. On admission, his saturations were 94% on air and his Respiratory toxicity with checkpoint inhibitors is well docu- respiratory rate was 19. Blood tests showed normal renal mented with a wide range of toxicities reported including and liver function, a CRP count of 3 mg/l, and a full blood dyspnoea, pneumonitis, pleural effusion, pulmonary sar- count that revealed an isolated raised eosinophil count of coidosis, acute fibrinous organizing pneumonia, eosinophilic 1:1×10 . There was no evident rash, and the patient had pneumonia, adult respiratory distress syndrome, and lung not received any other new medications (excluding a possi- cavitation [8, 9]. The most common is pneumonitis with a ble diagnosis of DRESS (drug-related eosinophilia with sys- reported incidence of 1.7% of any grade in melanoma with temic symptoms)). On review of serial blood tests, an single-agent anti-PD-1 agents [6]. Exacerbation of asthma isolated raised eosinophil count of 0:47 × 10 first occurred has been reported and may be fatal [8, 10]. Predictive 3 weeks after cycle 1 pembrolizumab and peaked at 1:1× markers for immune checkpoint-related toxicity are lacking. 10 coinciding with his admission postcycle 2 of treatment Eosinophil counts have been proposed as a possible marker (Figures 1(a) and 1(b)) (autoantibody screen was not per- of increased inflammation and immune activation with sub- sequent improved survival outcomes [11–13] or increased formed either pre- or on immunotherapy). Spirometry dur- ing admission showed a FEV1 2.57 (91% predicted), FVC risk of toxicity [14]. 4.04 (108% predicted), ratio of 64% (peak expiratory flow Asthma is characterised by inflamed hyperresponsive rate 94% predicted), gas transfer corrected 6.29 (78% pre- bronchial airways and reversible airflow obstruction [15]. It Case Reports in Oncological Medicine 3 232 235 220 241 134 130 PLT HB 9.0 7.5 8.0 7.1 7.3 6.5 6.5 7.0 6.2 7.5 6.0 5.0 4.1 3.9 4.1 3.8 3.5 3.5 4.0 4.1 3.0 1.9 1.8 1.8 1.8 1.6 1.6 2.0 1.0 1.6 0.0 WBC NEUTS LYMPH 1.4 1.2 1.1 1.0 1.0 1.1 0.8 0.8 0.73 0.67 0.87 0.53 0.51 0.6 0.55 0.4 0.47 0.35 0.2 0.29 0.28 0.0 0123456789 10 11 12 13 14 15 16 17 18 Cycle 1 Cycle 2 Cycle 3 Cycle 4 WEEKS MONOS EOSIN Figure 1: Line graphs depicting serial full blood count values over time over cycles 1-4. Eosinophils were the only subset of cells that elevated above normal range after cycle 1 before returning to normal at time of cycle 3. Normal ranges for haemoglobin (130-162), white cell count (4.3-11.2), platelets (150-400), neutrophils (1.90-7.90), basophils (0.05-0.10), monocytes (0.30-0.90), eosinophils (0.03-0.44), and lymphocytes (0.50-4.00). is increasingly recognised that it is a heterogenous disease a typical finding of increased inflammatory cells and eosino- with different pathophysiologic mechanisms driving airway philia [15, 17]. inflammation and therefore subsequent differences in out- Our patient had a typical presentation of eosinophilic comes and effectiveness of treatments. Eosinophilic asthma asthma which occurred after the first dose of pembrolizu- represents approximately fifty percent of asthma with vary- mab. There was no history of preexisting respiratory condi- ing phenotypes [16]. It is frequently associated with “fixed” tions, and other diagnoses were excluded. The only possible airflow obstruction, decreased FVC, and increased residual causative agent was the pembrolizumab. The diagnosis was volume, with late (in life) onset and typical symptoms of made based on the clinical presentation, the reversible peak dyspnoea on exertion rather than wheeze [15, 17]. Exacerba- expiratory flow rate readings before, during, and after treat- tions can be severe with development of steroid reliance and ment, and the spirometry which has also improved with then resistance over time. A typical comorbidity at presenta- treatment. Furthermore, the patient during the acute presen- tion or one which subsequently develops is chronic rhinosi- tation had a high FeNo with evidence of variable airflow nusitis with nasal polyposis. Diagnostic tests include which also settled with treatment. These findings fit with demonstration of airflow variability, raised peripheral eosin- NICE criteria for diagnosis of asthma. Treatment was rap- ophil counts, raised FeNo, and induced sputum testing with idly successful in controlling his symptoms, and ⁎ ⁎ ⁎ 10 9/L 10 9/L 10 9/L 4 Case Reports in Oncological Medicine 14 14 Volume (L) Volume (L) 12 12 10 10 8 8 6 6 4 4 2 2 0 0 246 246 –2 –2 –4 –4 –6 –6 –8 –8 –10 –10 –12 –12 –14 –14 (a) (b) Figure 2: (a) Spirometry during acute admission with cough, wheeze, and shortness of breath. Spirometry indicates obstructive airways with raised FeNO supporting a process of inflammation in the airways. (b) Spirometry 6 months after acute episode requiring admission, values now normal including the FeNo. pembrolizumab rechallenge has been successful alongside told that the melanoma could recur, but if I had adjuvant regular inhaler use to control any asthma symptoms. treatment, meaning treatment to complement the surgery and prevent the melanoma from returning, the chances of The patient is halfway through the planned year of pem- brolizumab adjuvant therapy to date without further asthma this happening could be reduced. I opted to start pembroli- exacerbations. We found one reported case in the literature zumab treatment given intravenously every 6 weeks for of asthma induced by anti-PD-1 agent nivolumab in a stage one year. It was explained that this was an immunotherapy IV lung patient. This patient had a very similar presentation meaning it uses the immune system to attack the melanoma and diagnostic findings as our patient and symptoms cells. I was counselled about possible side effects which resolved with inhalers alone. Although not described as would be immune related as in an immune reaction in any such, that case was consistent with eosinophilic asthma [18]. part of my body. Treatment in the adjuvant setting is curative in intent, After the first cycle of treatment, I started to have short- and long-term safety follow-up is required to assess for ness of breath. This tended to be at night and made me feel delayed toxicity and long-term health implications following unwell lasting a few hours. I attended accident and emer- adjuvant immune checkpoint inhibitor therapy. This is likely gency and was told my CXR and oxygen saturations were to require large regional/national/international databases to fine and that I could take antihistamines as I may be having detect, monitor, and educate the wider medical community allergic reactions. I also consulted my GP who gave me an as these patients are followed up in primary care following inhaler to use if I had another episode. The shortness of initial specialist follow-up. Regarding our patient, subse- breath kept recurring. I had cycle 2 pembrolizumab, and quent follow-up postcompletion of the year’s therapy will the oncology doctor who assessed me beforehand told me reveal if exacerbations of our patient’s asthma develop and that the drug may have sensitized me to allergens, and this become problematic or indeed if he develops any other tox- could be causing the breathlessness. An opinion from the icity related to (pembrolizumab-induced) eosinophilia or respiratory physicians would be sought. After cycle 2, I kept pembrolizumab treatment in general. A multidisciplinary having the breathlessness and could not cope any more at approach with respiratory expertise was needed in our home; I phoned the red card for oncology emergencies and patient, and this should be the approach in managing and was admitted to hospital for assessment. Several tests were following up patients postadjuvant immune checkpoint done to assess my lungs; I had a CT scan which did not show inhibitor treatment. any inflammation (a possible side effect of the pembrolizu- mab) and lung function tests after which a respiratory doc- tor also assessed me. High-dose steroids and an inhaler 4. Patient Perspective treatment stopped my symptoms completely. I was dis- I first had a spot removed from my scalp in 2019. I was told charged home to finish the course of steroids but continue it was most likely a melanoma that had spontaneously disap- using the inhaler. The diagnosis for my breathlessness was found to be asthma. I was pleased to have a cause for the peared. In 2020, I noticed a lump behind my right ear which grew from a pea to almond sized. I was concerned as my sur- breathlessness found and for the treatment to have worked. gery was delayed due to the COVID pandemic, but the lump I was assessed in clinic after discharge to see if I could con- was completely removed and shown to be a melanoma. I was tinue with pembrolizumab. It was explained that there was a Flow (L/sec) Flow (L/sec) Case Reports in Oncological Medicine 5 risk of the breathlessness returning if I restarted treatment, [2] J. Weber, M. Mandala, M. Del Vecchio et al., “Adjuvant nivo- lumab versus ipilimumab in resected stage III or IV mela- and this could either be treated in the same way again, or noma,” The New England Journal of Medicine, vol. 377, if the attack was too severe, then the treatment would have no. 19, pp. 1824–1835, 2017. to be stopped. There was also a risk of other immune- [3] C. Robert, A. Ribas, J. Schachter et al., “Pembrolizumab versus related side effects if pembrolizumab restarted. I felt well ipilimumab in advanced melanoma (KEYNOTE-006): post- and am keen to finish my treatment as I do not want the hoc 5-year results from an open-label, multicentre, rando- melanoma to recur, so I opted to restart. So far everything mised, controlled, phase 3 study,” The Lancet Oncology, is going smoothly and I have had no further issues. I use vol. 20, no. 9, pp. 1239–1251, 2019. my inhaler when needed but as time as gone on, I have used it less and more recently not at all. I have seen the specialist [4] J. Larkin, V. Chiarion-Sileni, R. Gonzalez et al., “Five-year sur- asthma nurses in clinic who are pleased with my progress vival with combined nivolumab and ipilimumab in advanced and are going to repeat my lung function tests in a few melanoma,” The New England Journal of Medicine, vol. 381, months to compare to the ones done during my admission. no. 16, pp. 1535–1546, 2019. I discussed my side effect with the oncology doctor last [5] L. Khoja, D. Day, T. Wei-Wu Chen, L. L. Siu, and A. R. Han- time I was seen in clinic and asked about how long the pem- sen, “Tumour- and class-specific patterns of immune-related brolizumab remains in the body. She explained that the half- adverse events of immune checkpoint inhibitors: a systematic review,” Annals of Oncology, vol. 28, no. 10, pp. 2377–2385, life (time taken to reduce to half the amount) is ~30 days, and the time to completely clear the drug from the body from the last dose would be ~5 times this period. This means [6] J. S. Weber, F. S. Hodi, J. D. Wolchok et al., “Safety profile of nivolumab monotherapy: a pooled analysis of patients with that the antibody is not cleared quickly and that toxicity can advanced melanoma,” Journal of Clinical Oncology, vol. 35, therefore happen late into treatment and even after treat- no. 7, pp. 785–792, 2017. ment is stopped. I will have to have close monitoring for side [7] M. Mandala, J. Larkin, P. A. Ascierto et al., “Adjuvant nivo- effects for at least 6 months after finishing treatment, and I lumab for stage III/IV melanoma: evaluation of safety out- will have close monitoring by CT and assessment in person comes and association with recurrence-free survival,” by a doctor to test if my melanoma returns in the years to Journal for Immunotherapy of Cancer, vol. 9, no. 8, article come. My asthma may remain stable or it may worsen or e003188, 2021. recur. Treatment will be given to control it. [8] H. Bukamur, H. Katz, M. Alsharedi, A. Alkrekshi, Y. R. Shwei- hat, and N. J. Munn, “Immune checkpoint inhibitor-related Data Availability pulmonary toxicity: focus on nivolumab,” Southern Medical Journal, vol. 113, no. 11, pp. 600–605, 2020. Data are available on clinical records held in the hospital [9] H. Bukamur, A. Alkrekshi, H. Katz, M. Alsharedi, Y. R. Shwei- electronic database. hat, and N. J. Munn, “Immune checkpoint inhibitor-related pulmonary toxicity: a comprehensive review, part II,” South- Consent ern Medical Journal, vol. 114, no. 9, pp. 614–619, 2021. [10] H. Wang, J. Shi, X. Wang, H. Zhao, and H. Wang, “Acute exac- The patient was consented for his data to be used and erbation of asthma induced by combined therapy of pro- published. grammed death-1 blocker plus lenvatinib in a patient with advanced hepatocellular carcinoma,” European Journal of Conflicts of Interest Cancer, vol. 156, pp. 122–124, 2021. [11] A. Bernard-Tessier, P. Jeanville, S. Champiat et al., “Immune- The authors declare that they have no conflicts of interest. related eosinophilia induced by anti-programmed death 1 or death-ligand 1 antibodies,” European Journal of Cancer, vol. 81, pp. 135–137, 2017. Authors’ Contributions [12] S. C. S. Simon, X. Hu, J. Panten et al., “Eosinophil accumula- All authors contributed to the management of this case and tion predicts response to melanoma treatment with immune writing and review of the manuscript. checkpoint inhibitors,” Oncoimmunology., vol. 9, no. 1, p. 1727116, 2020. [13] B. Weide, A. Martens, J. C. Hassel et al., “Baseline biomarkers Acknowledgments for outcome of melanoma patients treated with pembrolizu- mab,” Clinical Cancer Research, vol. 22, no. 22, pp. 5487– We thank the patient who consented to reporting this case. 5496, 2016. [14] R. Kizawa, Y. Miura, Y. Oda et al., “Eosinophilia during treat- References ment of immune checkpoint inhibitors (ICIs) to predict suc- ceeding onset of immune-related adverse events (irAEs),” [1] A. M. M. Eggermont, C. U. Blank, M. Mandala et al., Journal of Clinical Oncology, vol. 37, article e14110, 15_suppl, “Adjuvant pembrolizumab versus placebo in resected stage III melanoma (EORTC 1325-MG/KEYNOTE-054): distant metastasis-free survival results from a double- blind, rando- [15] H. H. Walford and T. A. Doherty, “Diagnosis and manage- mised, controlled, phase 3 trial,” The Lancet Oncology, ment of eosinophilic asthma: a US perspective,” J Asthma vol. 22, no. 5, pp. 643–654, 2021. Allergy., vol. 7, pp. 53–65, 2014. 6 Case Reports in Oncological Medicine [16] S. E. Wenzel, “Asthma phenotypes: the evolution from clinical to molecular approaches,” Nature Medicine, vol. 18, no. 5, pp. 716–725, 2012. [17] J. C. de Groot, A. Ten Brinke, and E. H. Bel, “Management of the patient with eosinophilic asthma: a new era begins,” ERJ open research, vol. 1, no. 1, pp. 00024–02015, 2015. [18] K. Maeno, S. Fukuda, T. Oguri, and A. Niimi, “Nivolumab- induced asthma in a patient with non-small-cell lung cancer,” Annals of Oncology, vol. 28, no. 11, p. 2891, 2017.

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Case Reports in Oncological MedicineHindawi Publishing Corporation

Published: Apr 30, 2022

References