Case Report

Nivolumab-induced aplastic anemia: A case report and literature review

J Oncol Pharm Practice 0(0) 1–5 ! The Author(s) 2017 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1078155217726159 journals.sagepub.com/home/opp

Rachel R Comito1, Lynette A Badu1 and Nicholas Forcello2

Abstract Directed immunotherapy at the programmed cell death-1 receptor has demonstrated efficacy in non-small-cell lung cancer, metastatic melanoma, and various other malignancies. Immune checkpoint inhibitors are innovative therapies producing some impressive clinical responses with a more manageable adverse effect profile when compared to traditional chemotherapy. The more common adverse effects associated with these agents include fatigue, rash, myalgia, pyrexia, and cough, but less common yet serious adverse effects have included immune-mediated colitis, pneumonitis, hepatitis, type 1 diabetes, and encephalitis. Here we present a case of a female patient with glioblastoma multiforme, who was treated with the programmed cell death-1 receptor inhibitor nivolumab and subsequently developed aplastic anemia.

Keywords Nivolumab, glioblastoma, aplastic anemia, immune checkpoint, programmed cell death-1 receptor Date received: 30 March 2017; accepted: 23 July 2017

Introduction Glioblastoma multiforme (GBM) is a type of localized, solid brain tumor arising from astrocytes found in the cerebral hemispheres or spinal cord. These heterogeneous tumors increase in frequency with age, affect men more than women, and represent approximately 15.4% of all primary brain tumors.1 Its aggressive, highly malignant nature is associated with a poor prognosis with an average five year survival rate of less than 5%.2 Common symptoms associated with glioblastomas including headache, nausea, vomiting, and drowsiness are typically due to the rapid tumor growth and resulting increased intracranial pressure. Patients may also experience hemiparesis, memory impairment, speech difficulties, and visual disturbances. The limited immunogenicity of glioma specific cancer cells and their immunosuppressive environment present various treatment challenges and novel GBM therapies are being further investigated.3 Existing treatments for GBM include surgery, radiation, targeted immunotherapies, and chemotherapy. Nivolumab is a humanized monoclonal, immunoglobulin G4 antibody with promising preliminary evidence against GBM. It works by antagonizing programmed cell death 1 (PD-1) proteins on the surface of activated

T-cells and serves as an immune checkpoint inhibitor that inhibits a pathway used by tumor cells to evade the immune system.4 CheckMate-143 was a multi cohort trial that included phase 1 component comparing nivolumab to nivolumab plus ipilimumabin patients with GBM and revealed 12-month overall survival (OS) rates of 40% (95% CI, 12.3–67) and 30% (95% CI: 7–58), respectively, with no grade 3/4 adverse events (AEs) reported.5 Tolerability profiles were consistent with experience in other tumor types. Nivolumab is also being studied in combination with or without radiotherapy in patients with newly diagnosed GBM.6 Efficacy results are pending, but preliminary prospective data suggest good tolerability and enhanced immune cell infiltration in some patients. Phase 2/3 trials have been initiated based on these results. Additionally, the Keynote-028 trial evaluated another PD-1 inhibitor, pembrolizumab, in patients with

1 2

Hartford Hospital, Hartford, CT, USA Smilow Cancer Hospital at Yale New Haven, New Haven, CT, USA

Corresponding author: Nicholas Forcello, Smilow Cancer Hospital at Yale New Haven, 20 York St, New Haven, CT 06510, USA. Email: [email protected]

2 bevacizumab-naı¨ ve, recurrent GBM and revealed a median progression free survival (PFS) of three months (95% CI, 2–9) with a 12-month PFS rate of 16%.7 The median, six month, and 12 month OS rates were 14 months, 85%, and 74%, respectively. Durable responses are still being seen in some patients showing over 80 weeks of PFS despite a median follow up of 60.9 weeks. The agent displayed acceptable tolerability with 15% of patients experiencing grade 3/4 AEs. The more common adverse effects associated with nivolumab and other immune checkpoint inhibitors include fatigue, rash, myalgia, nausea, vomiting, diarrhea, constipation, pyrexia, and cough, but less common yet serious adverse effects have included immune-mediated colitis, pneumonitis, hepatitis, type 1 diabetes, and encephalitis to name a few.8 Here we report a case of aplastic anemia in a patient with GBM attributed to therapy with nivolumab.

Case description A 57-year-old Caucasian female was admitted with a 2– 3 week history of worsening headaches, flashes of light in the right eye, and bouts of nausea and vomiting. Her medical and surgical histories were significant for hypothyroidism, depression, hypercholesterolemia, gastroesophageal reflux disease (GERD), obstructive sleep apnea (on continuous positive airway pressure therapy (CPAP)), glaucoma, mononucleosis, herpes zoster of the left forehead, and a cholecystectomy. She also reported an allergy (rash) to amoxicillin. Following her initial presentation, a CT scan and MRI of the brain showed necrotic, metastatic GBM of the right posterior temporal-parietal lobe extending from the gray-white matter interface measuring 4.5  4 cm. Pathology resulted as GBM with high cellularity, brisk mitoses, MIB-1 50%, glial fibrillary acidic protein (GFAP) positive, isocitrate dehydrogenase 1 (IDH-1) negative, and O6-methylguanine-DNA methyltransferase (MGMT) promoter methylated. The patient underwent a craniotomy for tumor resection that same month followed by chemoradiation with temozolomide. Every 28 days, she received temozolomide 200 mg orally daily for seven days and 100 mg orally on day 8 as the schedule of administration was adjusted due to profound nausea. Approximately one year later, a MRI of the brain showed tumor progression with multifocal subependymal nodular enhancement in the corpus callosum. The patient was evaluated for clinical trials, but deemed ineligible due to prior treatment with temozolomide. The recommendation by a peer physician group was to consider a PD-1 inhibitor pending patient agreement and insurance approval. The patient opted to try lomustine 200 mg orally at bedtime once

Journal of Oncology Pharmacy Practice 0(0) every six weeks first. After one dose of lomustine, a MRI revealed further tumor progression and concurrent myelotoxicity with grade 3 thrombocytopenia. Her platelet nadir was found to be 69  103/mL 34 days after starting lomustine. Twelve days after that, stereotactic radiosurgery and nivolumab were initiated at 3 mg/kg IV on day 1 every 14 days. After her second dose of nivolumab, she began to experience fevers (>101.4 F) along with intermittent headaches despite treatment with antipyretics and dexamethasone 2 mg orally twice daily. She was admitted with neutropenic fever, persistent pancytopenia, hyponatremia, Moraxella catarrhalis bacteremia, elevated liver function tests (LFTs), and choledocholithiasis. Her platelet counts decreased from 268  103/mL to a nadir of 5  103/mL (see Figure 1), white blood cell (WBC) counts decreased from 2.1  103/mL to a nadir of 0.1  103/mL (see Figure 2), and absolute neutrophil count decreased from 1.29  103/mL to a nadir of 0.00  103/mL (see Figure 3). Her prolonged episode of thrombocytopenia and leukopenia was a presumed immunologic reaction following nivolumab therapy. Further antineoplastic treatment was subsequently held. Six weeks after her first dose and one month after her second dose of nivolumab she was admitted again for neutropenic fever with a chief complaint of generalized weakness and fatigue for the preceding three days. She received packed red blood cells (PRBCs) for a hemoglobin of 6.8 g/dL (see Figure 4) and platelet transfusions for platelet count of 15  103/mL. Given the progressive nature of her pancytopenia, a bone marrow biopsy was conducted. Analysis showed markedly hypocellular marrow with a virtual absence of hematopoietic elements. Approximately 50% of the sample displayed properties of lymphocytes on flow cytometry, most of which were T-cells. Only one analyzable metaphase was found and was found to be chromosomally normal. A diagnosis of aplastic anemia was made with a presumed immunologic etiology secondary to nivolumab. Granulocyte-colony stimulating factor (G-CSF) was started on day 43 and continued until day 64. It was discontinued after 22 days as her WBC plateaued at 0.7  103/mL without further improvement. Eltrombopag 50 mg orally daily was initiated and subsequently increased to 100 mg orally daily. It was started on day 45 and continued until day 69 with no demonstrated improvement after five weeks of therapy. Hematopoietic stem cell transplantation and antithymocyte globulin were ruled out as options due to the patient’s prognosis and performance status. She remained transfusion dependent and continued on chronic levofloxacin prophylaxis. She was eventually discharged, but returned to the hospital two days later complaining of a syncopal episode with loss of

Comito et al.

3

Platelets (thousand/microliter)

300 250 200 150 100 50 –76 –74 –72 –70 –68 –66 –64 –62 –60 –58 –56 –54 –52 –50 –48 –46 –44 –42 –40 –38 –36 –34 –32 –30 –28 –26 –24 –22 –20 –18 –16 –14 –12 –10 –8 –6 –4 –2 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54 56 58 60 62 64 66 68 70 72 74 76 78 80 82 84

0 Days

Figure 1. Platelets. ¨ First dose of lomustine. # First dose of nivolumab (day 0).  Second dose of nivolumab. m Administration of irradiated platelets.

4 3 2 1 0

–76 –74 –72 –70 –68 –66 –64 –62 –60 –58 –56 –54 –52 –50 –48 –46 –44 –42 –40 –38 –36 –34 –32 –30 –28 –26 –24 –22 –20 –18 –16 –14 –12 –10 –8 –6 –4 –2 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54 56 58 60 62 64 66 68 70 72 74 76 78 80 82 84

White blood cells (thousand/microliters)

5

Days

Figure 2. White blood cells. ¨ First dose of lomustine. # First dose of nivolumab (day 0).  Second dose of nivolumab.

consciousness, likely neurocardiogenic in nature, and a diffuse morbilliform rash, presumably from the levofloxacin. The patient remained neurologically stable with no significant changes on MRI. Goals of care were eventually changed to comfort measures only during this admission and she passed away 73 days after her second dose of nivolumab.

Discussion Immune checkpoint inhibitors such as nivolumab have been associated with a wide spectrum of immunerelated adverse effects which include dermatologic, gastrointestinal, endocrine, and hepatic events. While less common, more severe events such as pancreatitis, neurologic toxicities, colitis, pneumonitis, and

thyroiditis can occur in up to 5% of patients.9 To date, the development of immune-mediated aplastic anemia related to checkpoint inhibitor therapy has not been reported in the literature or to the manufacturers of the commercially available agents. According to the Food and Drug Administration (FDA), lomustine has a Black Box Warning for delayed myelosuppression that is dose-related and cumulative.10 It typically occurs four to six weeks after drug administration and usually persists for one to two weeks.11 As the patient only received one dose of lomustine and the onset of symptoms occurred approximately 90 days after this dose, our suspicion of nitrosurea related myelosuppression is low. Nivolumab works by essentially cutting the brakes on T-cells and overcoming a mechanism of tumor

4

Journal of Oncology Pharmacy Practice 0(0)

Absolute neutrophil count (cells/microliter)

3000 2500 2000 1500 1000 500 –76 –74 –72 –70 –68 –66 –64 –62 –60 –58 –56 –54 –52 –50 –48 –46 –44 –42 –40 –38 –36 –34 –32 –30 –28 –26 –24 –22 –20 –18 –16 –14 –12 –10 –8 –6 –4 –2 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54 56 58 60 62 64 66 68 70 72 74 76 78 80 82

0 Days

Figure 3. Absolute neutrophil count. ¨ First dose of lomustine. # First dose of nivolumab (day 0).  Second dose of nivolumab.

14 12 10 8 6 4 2 0

–76 –74 –72 –70 –68 –66 –64 –62 –60 –58 –56 –54 –52 –50 –48 –46 –44 –42 –40 –38 –36 –34 –32 –30 –28 –26 –24 –22 –20 –18 –16 –14 –12 –10 –8 –6 –4 –2 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54 56 58 60 62 64 66 68 70 72 74 76 78 80 82 84

Hemoglobin (grams/deciliter)

16

Days

Figure 4. Hemoglobin. ¨ First dose of lomustine. # First dose of nivolumab (day 0).  Second dose of nivolumab. m Administration of packed red blood cells.

evasion from the host’s immune system. It antagonizes inhibitory signals on T-cells, allowing the cell to become activated against a given antigen.12 Once activated these cells attack and recruit the immune system against antigens on tumor cells, but also potentially against normal, healthy cells. The presence of T-cells in the bone marrow in the presence of hypocellular marrow strongly suggests an immune-mediated etiology precipitated by nivolumab. When assessing the probability of nivolumab causing this reaction in this patient with the Naranjo algorithm, a score of 5 resulted, indicating a probable adverse drug reaction.13 Several published cases exist that report on other hematologic AEs attributed to checkpoint inhibitors, including immune thrombocytic purpura, autoimmune

hemolytic anemia (AIHA), and acquired hemophilia.14 Palla et al. described a patient with metastatic adenocarcinoma of the lungs who developed AIHA after receiving two doses of nivolumab.15 Schwab et al. reported a case of AIHA in a patient with metastatic squamous cell cancer developing serious hemolysis after eight cycles of nivolumab that resolved following a two week course of steroids.16 Our patient did not display any signs of hemolysis during her course of care. Published literature on the use of checkpoint inhibitors in the setting of GBM is currently limited and several trials are currently ongoing to add to the existing body of literature.5–7,17,18 NCT02337491 is ongoing, but currently closed to enrollment and investigating the use of pembrolizumab in combination with

Comito et al. bevacizumab in patients with bevacizumab-naı¨ ve, recurrent GBM. The preliminary median OS is 6.8 months with no dose limiting or unexpected toxicities observed.18 A phase I trial by the University of Virginia is currently evaluating the safety and feasibility of nivolumab and valproate in patients with recurrent glioblastoma.19 A phase II study from the Universidad de Navarra is currently recruiting participants with primary and recurrent GBM that require surgery to receive neoadjuvant nivolumab.20 Unfortunately, it was recently announced that in a phase 3 trial, nivolumab did not show improved overall survival over bevacizumab in recurrent GBM.21 Here we report a serious case of aplastic anemia in a GBM patient receiving immunotherapy therapy with a PD-1 inhibitor. Increased vigilance for this potential adverse effect is warranted as experience with checkpoint inhibitors in this setting grows. Declaration of conflicting interests

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The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. 14.

Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.

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References 1. American Brain Tumor Association. Glioblastoma (GBM). 2014. Available at: http://www.abta.org/braintumor-information/types-of-tumors/glioblastoma.html (accessed 3 January 2017). 2. Tivnan A, Heilinger T and Lavelle EC. Advances in immunotherapy for the treatment of glioblastoma. J Neurooncol 2017; 131: 1–9. 3. National Cancer Institute. With immunotherapy, glimmers of progress against glioblastoma. 2016.Available at: http://www.cancer.gov/types/brain/research/ immunotherapy-glioblastoma (accessed 3 January 2017). 4. Vlahovic G, Fecci PE, Reardon D, et al. Programmed death ligand 1 (PD-L1) as an immunotherapy target in patients with glioblastoma. Neuro-Oncology 2015; 17: 1043–1045. 5. Reardon DA, Sampson JH, Sahebjam S, et al. Safety and activity of nivolumab (nivo) monotherapy and nivo in combination with ipilimumab (ipi) in recurrent glioblastoma (GBM): updated results from checkmate-143. J Clin Oncol 2016; 34(suppl 15): 2014. 6. Omuro A, Vlahovic G, Baehring J, et al. OS07.3 nivolumab in combination with radiotherapy with or without temozolomide in patients with newly diagnosed glioblastoma: updated results from CheckMate 143. Neuro Oncol 2017; 19(suppl 3): iii13. 7. Reardon DA, Kim T-M, Frenel J-S, et al. Results of the phase Ib KEYNOTE-28 multi-cohort trial of pembrolizumab monotherapy in patients with recurrent

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PD-L1-positive glioblastoma multiforme (GBM). Neuro-Oncology 2016; 18abstract ATIM-35. Available at: http://www.onclive.com/conference-coverage/sno2016/pembrolizumab-shows-durable-benefit-for-pdl1po sitive-recurrent-gbm (accessed 13 June 2017). OPDIVO (nivolumab) (package insert). Princeton, NJ: Bristol-Myers Squibb Company, 2014. Naidoo J, Page DB, Li BT, et al. Toxicities of the antiPD-1 and anti-PD-L1 immune checkpoint antibodies. Ann Oncol 2015; 26: 2375–2391. Food and Drug Administration. Gleostine (Lomustine) capsules. Available at: http://www.fda.gov/Safety/ MedWatch/SafetyInformation/ucm485677.htm (accessed 6 January 2017). Gerson SL, Bulgar AD, Weeks LD, et al. Classical alkylating agents. In: Chabner BA and Longo DL (eds) Cancer chemotherapy and biotherapy: principles and practice. 5th ed. Philadelphia, PA: Lippincott Williams and Wilkins, 2011. Ribas A. Releasing the brakes on cancer immunotherapy. NEJM 2015; 373: 1490–1492. US National Library of Medicine. Adverse drug reaction probability scale (Naranjo) in drug induced liver. Livertox. Available at: https://livertox.nih.gov/Narajo. html (accessed 23 June 2017). Friedman CF. Treatment of the immune-related adverse effects of immune checkpoint inhibitors: a review. JAMA Oncol 2016; 2: 1346–1353. Palla AR, Kennedy D, Mosharraf H, et al. Autoimmune hemolytic anemia as a complication of nivolumab therapy. Case Rep Oncol 2016; 9: 691–697. Schwab KS, Heinea A, Weimannb T, et al. Development of hemolytic anemia in a nivolumab-treated patient with refractory metastatic squamous cell skin cancer and chronic lymphatic leukemia. Case Rep Oncol 2016; 9: 373–378. Huang J, Liu F, Liu Z, et al. Immune checkpoint in glioblastoma: promising and challenging. Front Pharmacol 2017; 8: 242. Reardon DA, De Groot JF, Colman H, et al. Safety of pembrolizumab in combination with bevacizumab in recurrent glioblastoma (rGBM). J Clin Oncol 2016; 34(suppl 15): 2010. University of Virginia. Stereotactic radiosurgery with nivolumab and valproate in patients with recurrent glioblastoma. Available at: https://clinicaltrials.gov/ct2/ show/NCT02648633 (accessed 3 January 2017). Olivia Newton-John Cancer Research Institute. A phase II trial of ipilimumab and nivolumab for the treatment of rare cancers. Available at: https://clinicaltrials.gov/ct2/ show/study/NCT02923934?term¼nivolumab&rank¼18 (accessed 5 January 2017). Bristol-Meyers, S. Bristol-Myers Squibb announces results from CheckMate -143, a phase 3 study of Opdivo (nivolumab) in patients with glioblastoma multiforme. Available at: https://news.bms.com/press-release/ bmy/bristol-myers-squibb-announces-results-checkmate143-phase-3-study-opdivo-nivoluma (accessed 7 August 2017).

Nivolumab-induced aplastic anemia: A case report and literature review.

Directed immunotherapy at the programmed cell death-1 receptor has demonstrated efficacy in non-small-cell lung cancer, metastatic melanoma, and vario...
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