Unusual encephalopathy with Wernicke-Korsakoff syndrome-like features due to adjuvant nivolumab for malignant melanoma.

INTRODUCTION: Autoimmune encephalitis is a rare immune-related adverse event of PD-1 inhibitors, nivolumab and pembrolizumab. Autoimmune hypophysitis can also be seen with the use of these agents. The relationship between these two phenomena is currently unknown. CASE REPORT: We describe a 79-year-old man with anterior scalp melanoma who received adjuvant nivolumab therapy. Sixteen weeks after the completion of nivolumab therapy, the patient presented to the hospital with altered mental status, anterograde amnesia, and symptoms of nausea and vomiting. The patient's encephalopathy was associated with confabulations. Workup identified increased CSF protein without increased cellularity, along with decreased serum cortisol and ACTH levels. This was consistent with encephalitis and central adrenal insufficiency. MANAGEMENT AND OUTCOME: The patient had a robust clinical response to steroids, with resolution of mental status changes and normalization of blood pressure. He continues to receive maintenance steroid therapy without any further symptoms six months later. CONCLUSIONS: We report herein a unique case of encephalopathy in the setting of nivolumab use for the treatment of melanoma. The condition resembled Korsakoff psychosis seen in the setting of alcoholism and was associated with central adrenal insufficiency. A prompt response to steroids was both diagnostic and therapeutic in our case, suggesting the resolution of autoimmune phenomena related to nivolumab.

Ipilimumab with or without nivolumab in PD-1 or PD-L1 blockade refractory metastatic melanoma: a randomized phase 2 trial.

In this randomized phase 2 trial, blockade of cytotoxic T-lymphocyte protein 4 (CTLA-4) with continuation of programmed death protein 1 (PD-1) blockade in patients with metastatic melanoma who had received front-line anti-PD-1 or therapy against programmed cell death 1 ligand 1 and whose tumors progressed was tested in comparison with CTLA-4 blockade alone. Ninety-two eligible patients were randomly assigned in a 3:1 ratio to receive the combination of ipilimumab and nivolumab, or ipilimumab alone. The primary endpoint was progression-free survival. Secondary endpoints included the difference in CD8 T cell infiltrate among responding and nonresponding tumors, objective response rate, overall survival and toxicity. The combination of nivolumab and ipilimumab resulted in a statistically significant improvement in progression-free survival over ipilimumab (hazard ratio = 0.63, 90% confidence interval (CI) = 0.41-0.97, one-sided P = 0.04). Objective response rates were 28% (90% CI = 19-38%) and 9% (90% CI = 2-25%), respectively (one-sided P = 0.05). Grade 3 or higher treatment-related adverse events occurred in 57% and 35% of patients, respectively, which is consistent with the known toxicity profile of these regimens. The change in intratumoral CD8 T cell density observed in the present analysis did not reach statistical significance to support the formal hypothesis tested as a secondary endpoint. In conclusion, primary resistance to PD-1 blockade therapy can be reversed in some patients with the combination of CTLA-4 and PD-1 blockade. Clinicaltrials.gov identifier: NCT03033576 .

Unusual stroke-like symptoms with oxaliplatin use.

INTRODUCTION: Oxaliplatin has become the mainstay of treatment for many cancers, but its use can be accompanied by unusual side effects. CASE REPORT: We describe herein a 74-year-old patient with pancreatic cancer who developed severe motor weakness affecting lower extremities after starting treatment with oxaliplatin on three separate occasions. Our patient also experienced slurred speech, with decreased ability to phonate and word-finding difficulty. Brain imaging studies did not suggest recent brain ischemia, and the symptoms resolved within 15-20 h. MANAGEMENT AND OUTCOME: Oxaliplatin had to be discontinued due to suboptimal tolerance and a short-lived clinical response. After discontinuation of oxaliplatin, she did not experience any more similar symptoms. A score of 9 on the Naranjo nomogram supported a definite causality relationship between oxaliplatin and the observed neurologic toxicity. DISCUSSION: Rare reports of stroke-like events have previously been described with oxaliplatin. While the exact mechanism of these phenomena is not known, alterations in neuronal sodium channels might be involved. Clinicians, pharmacists, and patients need to be aware of these rare but important side effects of oxaliplatin. Nonetheless, work-up for a cerebrovascular accident is still warranted as hypercoagulability related to malignancy can also predispose the patients to strokes.

Immune checkpoint inhibitor-related adverse events: Real-world experience from a single veterans' affairs medical center.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are antineoplastic agents associated with a multitude of immune-related adverse events (irAEs). Available data from clinical trials include highly selective patient populations which may limit their applicability to real-world clinical practice. METHODS: We present a retrospective cohort study of cancer patients treated with ICI therapy at the Zablocki VA Medical Center between 2014 and 2021. Information on demographics, cancer diagnosis, type of therapy, treatment duration, comorbidities, irAE type, and overall survival were collected. RESULTS: We identified 187 patients who received at least one dose of ICI. About half the patients experienced at least one irAE, the most common categories being fatigue, pulmonary, and endocrine irAEs. Approximately half of the irAEs were diagnosed within the first three months of starting ICI therapy, and 60.38% of those who experienced irAEs discontinued ICI therapy. Patients who experienced endocrine or intestinal irAEs had a significantly longer overall survival. CONCLUSION: Immune-related complications due to ICI therapy are common and can frequently lead to treatment discontinuation in the real-world setting. Endocrine and intestinal irAEs may correlate with improved survival. The ICI-treated patients who received palliative radiation therapy to the bone had less irAEs, possibly due to immunogenic cell death.

Immune checkpoint inhibition in advanced colorectal cancer with inherited and acquired microsatellite instability: Current state and future directions.

OBJECTIVE: This paper reviews comprehensively the most relevant data on single-agent and combination therapies for advanced colorectal cancer with inherited and acquired microsatellite instability (MSI). DATA SOURCES: We performed a systematic search on PubMed and MEDLINE articles published from inception to December 2022. We have also searched independent websites including U.S. Food and Drug Administration and ClinicalTrials.gov. DATA SUMMARY: Performing microsatellite stability testing, tumor mutational burden (TMB), and germline mutation analysis could identify patients with metastatic colorectal cancer that benefit from immune checkpoint inhibitor (ICI) therapy. Single-agent pembrolizumab has proven superiority over traditional chemotherapy in these patients. The nivolumab-ipilimumab is the only combination ICI therapy approved in this space. Recently, the anti-PD-1 antibody dostarlimab was granted Food and Drug Administration approval in refractory tissue-agnostic advanced solid cancers with deficient mismatch repair (dMMR). ICIs are also being studied in the adjuvant/neoadjuvant setting in colon cancer patients with dMMR. Newer agents are being scrutinized in this space as well. More solid data on biomarkers predicting responses in patients with MSI-high or TMB-H to various therapies are needed. Given its both clinical and financial toxicity, it is imperative to determine the optimal duration of ICI therapy in individual patients. CONCLUSIONS: Overall, the outlook in advanced colorectal cancer patients with MSI appears optimistic as new and efficacious ICI drugs and combinations are being added to the existing therapeutic armamentarium.

Acquired angioedema late in the course of nivolumab treatment.

INTRODUCTION: Although programmed cell death-1 inhibitors have become the mainstay of treatment for many cancers, their use can at times be accompanied by unusual side effects. CASE REPORT: We describe herein a 43-year-old patient with Lynch syndrome and colon cancer who developed facial swelling 18 months after starting nivolumab therapy. Our patient also experienced a grade 1 maculopapular rash due to this agent. Naranjo nomogram assessment showed a probable causality between nivolumab and angioedema (score of 8). MANAGEMENT & OUTCOME: Given the modest intensity of symptoms and the excellent response of metastatic colon cancer to nivolumab, this agent was continued without interruptions. She was prescribed prednisone 20 mg orally daily as needed to be taken if the swelling progressed, or if respiratory symptoms developed. The patient experienced another two similar episodes over the next months; however, they were self-limiting and did not require steroids. Subsequently, she had no further similar symptoms. DISCUSSION: Rare reports of angioedema associated with immune checkpoint inhibitor (ICI) treatment have previously been described. The exact mechanism of these phenomena is unknown, but bradykinin release leading to increased vascular permeability might be involved. Clinicians, pharmacists, and patients should be aware of this rare side effect of ICIs as it can be life-threatening when involving the respiratory tract and causing impending airway obstruction.

Widespread vitiligo and poliosis following ipilimumab-nivolumab combination therapy.

INTRODUCTION: Combined immune checkpoint inhibitor therapy has been successfully used in the treatment of several malignancies. Adverse effects with the combination therapy may be more severe than the ones seen with single immune checkpoint inhibitors. CASE PRESENTATION: We report a unique case of a 59-year-old man of dark skin complexion who underwent treatment with intravenous ipilimumab-nivolumab every 3 weeks for metastatic malignant melanoma. After three cycles of this therapy, he developed extensive skin depigmentation that within 6 weeks, affected nearly the entire skin surface, along with progressive poliosis. MANAGEMENT AND OUTCOME: Ipilimumab-nivolumab therapy was subsequently discontinued due to grade 3 enterocolitis requiring high-dose steroids and intravenous infliximab. About six months later, imaging studies showed a relapse of malignant melanoma. At that juncture, vitiligo affected the total body surface area, resembling albinism, along with near-total poliosis and significant photosensitivity. Pembrolizumab was tried but had to be stopped after three cycles due to the reoccurrence of grade 3 enterocolitis. Progression of malignant melanoma with new brain, lung, liver, subcutaneous, and colonic metastases led to the patient's demise. CONCLUSION: We report a unique case of severe vitiligo and poliosis that involved total body surface area in a Caucasian man with dark complexion, resembling albinism. Further studies are warranted to evaluate the severity of dermatologic side effects with combination immune checkpoint inhibitor therapy.

Nivolumab-induced autoimmune diabetes mellitus presenting as diabetic ketoacidosis in a patient with metastatic mucosal melanoma.

INTRODUCTION: Nivolumab is an immune checkpoint inhibitor used in the treatment of several malignancies. A number of immune-related endocrinopathies have been linked to its use. CASE REPORT: We report a unique case of a 74-year-old man with well-controlled diabetes mellitus type 2 and metastatic mucosal anorectal melanoma who presented with diabetic ketoacidosis after receiving his third cycle of nivolumab 240 mg intravenous (IV) every 2 weeks. He was found to have autoantibodies against glutamic acid decarboxylase 65. Genotyping for human leukocyte antigens showed the presence of DQB1*02:01 and DRB1*03:01. MANAGEMENT AND OUTCOME: His presentation was complicated by acute renal failure. He required aggressive fluid resuscitation and insulin supplementation to reverse severe acid-base disturbance and multiple electrolyte abnormalities. After an 8-week interruption, the patient restarted nivolumab without any further evidence of adverse events over the next 12 weeks. He continues to require insulin replacement therapy. DISCUSSION AND CONCLUSION: Development of type 1 diabetes with the use of immune checkpoint inhibitors has been increasingly reported in the literature. The exact mechanism for autoimmune diabetes precipitated by nivolumab is yet to be elucidated. Patient education about the symptoms of diabetes and regular glucose monitoring cannot be overemphasized. Testing for antibodies against glutamic acid decarboxylase 65, insulin receptors, and islet cells may also prove useful. Human leukocyte antigen DQ and DR haplotyping prior to immune checkpoint inhibitor treatment might help determine susceptibility toward developing type 1 diabetes, and provide opportunities for earlier recognition, intervention, and possibly prevention.

Cycle-dependent eosinophilia due to adjuvant nivolumab for malignant melanoma.

INTRODUCTION: Immune checkpoint inhibitors (ICIs) have been widely used in the contemporary anticancer armamentarium. However, new side effects due to these agents have continued to emerge. CASE REPORT: We describe herein a 71-year-old patient who received nivolumab as adjuvant therapy for malignant melanoma of the skin. He developed eosinophilia starting at 4 weeks of therapy. Eosinophilia increased progressively during the first six nivolumab cycles, then stabilized. Cycle-dependent increments were observed. Subsequently, the patient experienced well-known side effects of ICIs such as grade 1 diarrhea, arthralgias, and erythematous papular rash. MANAGEMENT AND OUTCOME: Nivolumab was continued, and absolute eosinophil counts were monitored. Prednisone 10 mg PO daily was required for moderate gastroenteritis, dermatitis, and arthritis, which all subsequently improved. Eosinophil levels gradually downtrended after starting prednisone. Causality assessment between nivolumab and eosinophilia via adverse drug reaction (ADR) probability scale revealed a score of 9. DISCUSSION: Physicians and pharmacists need to be aware of this important side effect of ICI therapy. Eosinophilia in the context of ICI use has been previously reported in clinical trials. Our case is unique as eosinophilia was cumulative, showed increments every 8 weeks, and exhibited a trend toward cycle dependency. Extensive and expensive workup does not appear warranted, and simple monitoring of complete blood count is appropriate in most patients. Further studies are necessary to assess the true incidence, pattern, and severity of eosinophilia related to ICIs as well as its association with clinical outcomes.

Changing therapeutic landscape in advanced Kaposi sarcoma: Current state and future directions.

Kaposi sarcoma is a malignant neoplasm arising from the endothelial cell lining of blood and lymphatic vessels. Herein, we discuss etiopathogenesis, clinical presentation, diagnostic criteria, updated guideline-based approach to its management and newer experimental approaches. Given its efficacy and side effect profile, pegylated doxorubicin is the currently preferred first-line therapy in advanced disease. Paclitaxel remains an alternative first-line option. At the time of relapse, patients can be retreated with the same agents as they often maintain their clinical efficacy. New therapeutic options are on the rise, with pomalidomide being approved in 2020 as a second-line therapy. Optimal control of retroviral infection in human immunodeficiency virus (HIV) positive is instrumental in preventing disease occurrence in most patients. Suppressing human herpes virus type 8 (HHV-8) infection might also play a role in controlling Kaposi sarcoma growth, yet clinical trials are lacking. Unraveling the molecular and genetic intricacies of Kaposi sarcoma's pathogenesis might allow for the emergence of novel and effective therapeutic strategies. Clinical trials are currently underway to establish potential roles for various targeted agents, immune checkpoint inhibitors (ICIs) and experimental agents in the treatment of advanced Kaposi sarcoma.

A fatal disseminated cryptococcal infection in a patient treated with zanubrutinib for Waldenström's macroglobulinemia.

INTRODUCTION: Zanubrutinib is a second generation, irreversible small-molecule Bruton tyrosine kinase inhibitor (BTK) approved for the treatment of Waldenström's macroglobulinemia, mantle cell lymphoma, and marginal zone lymphoma. As a class, BTKs have been linked with an increased risk of respiratory infections in clinical trials. CASE REPORT: We describe a 75-year-old patient who presented with generalized weakness, fevers, dyspnea, and dry cough four months after starting zanubrutinib therapy for Waldenström's macroglobulinemia. He was subsequently diagnosed with pneumonia. Septic work-up led to diagnosis of disseminated cryptococcal infection, complicated by fungal pneumonia and meningitis. MANAGEMENT AND OUTCOME: Zanubrutinib was held on admission, and the patient was started on combination oral and intravenous antifungal therapy. Despite clearance of fungemia, aggressive resuscitation, and appropriate antimicrobial therapy, respiratory status deteriorated requiring intubation. His condition progressed to septic shock, multiorgan failure, and demise. DISCUSSION/CONCLUSION: We report herein a case of fatal disseminated cryptococcosis in the setting of zanubrutinib use for Waldenström's macroglobulinemia. At the time of diagnosis, his Waldenström's macroglobulinemia was in a partial response. The mechanism by which Bruton tyrosine kinase inhibitors (BTKs) lead to invasive fungal infections in these patients remains to be explored. T- and B-cell immune defects accompanying low-grade B-cell lymphomas may contribute to the severity of these infections.

Development of Monoclonal B-cell Lymphocytosis Shortly After Treatment with Nivolumab and Subsequent Progression to Chronic Lymphocytic Leukemia.

INTRODUCTION: Immune checkpoint inhibitors, such as programmed death (PD)-1 inhibitor nivolumab, are currently widely used in treatment of various malignancies. Due to their widespread application, any new potential adverse effects due to these agents necessitate careful assessment. CASE REPORT: We report a case of an 81-year-old man with recurrent high-risk malignant melanoma who underwent a 12-month adjuvant treatment with nivolumab. Shortly after the course of nivolumab, he developed monoclonal B-cell lymphocytosis (MBL) which subsequently progressed to chronic lymphocytic leukemia (CLL). MANAGEMENT AND OUTCOME: The patient is currently doing clinically well in Rai stage 0. Malignant melanoma remains in remission. CONCLUSION: Considering the pathophysiologic plausibility of nivolumab inducing B-cell dysregulation via PD-1 inhibition, we suggest further studies on potential association between nivolumab and B-cell malignancies.

Cecal volvulus associated with carfilzomib use for al amyloidosis.

INTRODUCTION: Proteasome inhibitors have emerged as quintessential therapies for light-chain (AL) amyloidosis and multiple myeloma in the last decade. While these agents are highly effective, reports have also documented toxicities affecting various organ systems. Whereas gastrointestinal (GI) toxicities are a relatively common occurrence with proteasome inhibitors, severe GI complications are exceedingly rare. CASE REPORT: We describe a unique case of a patient with AL amyloidosis who developed cecal volvulus after four weeks of treatment with carfilzomib. This severe GI manifestation has not been previously described in the literature. MANAGEMENT AND OUTCOME: The patient required right hemicolectomy. After clinical recovery, she restarted reduced-dose carfilzomib. She did not have any severe GI side effects following dose reduction, and continues with the current treatment regimen to the present day. DISCUSSION/CONCLUSION: The causality between volvulus and the treatment with carfilzomib was probable, with a documented score of 6 on the Naranjo probability nomogram. The exact mechanism behind this effect of carfilzomib has yet to be elucidated.

Necrotizing leg gangrene from invasive cutaneous Kaposi sarcoma, reversed by pegylated liposomal doxorubicin.

INTRODUCTION: Although rare, Kaposi sarcoma is the most common malignant neoplasm associated with human immunodeficiency virus (HIV) infection. Several agents have now been approved in the treatment of this malignancy and are used with varying degrees of success. CASE REPORT: We present a unique case of a 64-year-old man with well-controlled HIV infection who developed necrotizing leg gangrene from invasive cutaneous Kaposi sarcoma. He responded very well to systemic chemotherapy, thereby avoiding limb amputation. MANAGEMENT AND OUTCOME: Pegylated liposomal doxorubicin (PLD) at a dose of 20 mg/m2 every 3 weeks was utilized, with a near-complete response after six cycles of therapy. The patient continues to receive maintenance treatment with PLD. His HIV infection remains in excellent control, with a high-normal CD4 T-cell count. Periodic echocardiogram evaluations have not shown any decline in left ventricular ejection fraction (LVEF) over time. CONCLUSION: Most patients with Kaposi sarcoma achieve partial responses to treatment with PLD. Our case illustrates that near complete and complete responses are possible with this agent, leading to potential limb salvage in necrotizing gangrene.

Sustained erythrocytosis due to the use of Lenvatinib.

INTRODUCTION: Tyrosine kinase inhibitors have become the mainstay of treatment for many malignancies, but their use can be accompanied by unusual and often puzzling side effects. CASE REPORT: We describe herein a 64-year-old patient who developed a robust and sustained erythrocytosis shortly after starting treatment with lenvatinib. Our patient also experienced elevated blood pressure, mucositis, and hand-foot syndrome that are not uncommonly seen with this agent. The clinico-laboratory work-up suggested that lenvatinib was the likely culprit in this case. MANAGEMENT & OUTCOME: Lenvatinib had to be discontinued due to suboptimal tolerance and a short-lived response. With the discontinuation of lenvatinib, hemoglobin trended downwards and subsequently resolved. A score of 6 on the Naranjo nomogram supported a probable causality relationship between lenvatinib and the observed erythrocytosis. DISCUSSION: Erythrocytosis has previously been described with sunitinub, sorafenib and pazopanib. The exact mechanism of this phenomenon is not known. It might increase the risk of venous and arterial thromboses in cancer patients that are already in a hypercoagulable state due to cancer itself. In addition, laboratory work-up for polycythemia may prove extensive and costly. Therefore, clinicians need to be aware of this important side effect of tyrosine kinase inhibitors.

Acute gout flare of bilateral first metatarsophalangeal joints due to ibrutinib use in chronic lymphocytic leukemia.

INTRODUCTION: Bruton tyrosine kinase inhibitors represent important tools in the therapeutic armamentarium against chronic lymphocytic leukemia (CLL) and other B-lymphoproliferative disorders. CASE REPORT: We describe herein a unique 65-year-old patient who presented with bilateral foot pain four months after starting treatment with ibrutinib for CLL. Of note, the patient had previously been diagnosed with gout, and was taking allopurinol prophylactically at the time of the event. Compliance with allopurinol was in excess of 99%. Yet, he was diagnosed with acute gout flare of bilateral first metatarsophalangeal (MTP) joints.Management & Outcome: Ibrutinib dose was reduced by one third, and the patient's gout flare up was treated with ibuprofen as needed. After symptoms abated, ibrutinib was continued at 2/3rds of the dose, with an excellent CLL control. The patient tolerated this dose without any further adverse effects.Discussion/Conclusions: We have reported a unique side effect of acute bilateral first MTP joint gout flare likely triggered by ibrutinib use for CLL while the patient was taking a xanthine oxidase inhibitor. The mechanism by which ibrutinib caused this phenomenon remains to be elucidated.

Diabetic ketoacidosis as a hallmark of autoimmune diabetes occurring after two cycles of cemiplimab.

INTRODUCTION: Clinical indications of immune checkpoint inhibitors have expanded to a variety of malignancies. Nearly 50% of patients with advanced cutaneous squamous cell carcinoma, respond to the programmed-death 1 inhibitor cemiplimab. To date, insulin-dependent diabetes mellitus has been documented with the use of several immune checkpoint inhibitors but not cemiplimab. CASE REPORT: We report herein the first case of a patient with cutaneous squamous cell carcinoma who developed diabetic ketoacidosis and insulin-dependent diabetes mellitus following only two cycles of cemiplimab. A score of 6 on the Naranjo nomogram makes the causality relationship between cemiplimab use and the insulin-dependent diabetes mellitus probable. MANAGEMENT AND OUTCOME: The patient's developed diabetic ketoacidosis was managed with intravenous fluids and intravenous insulin, with a prompt resolution. Cemiplimab was discontinued, and the patient was discharged on long-acting and short-acting insulin therapy, with a follow-up with endocrinology. DISCUSSION/CONCLUSIONS: The mechanism by which cemiplimab caused insulin-dependent diabetes mellitus is most likely due to lack of endogenous insulin production in the setting of immune-mediated loss of pancreatic beta-cells. Patients may benefit from fasting blood glucose monitoring and early immune checkpoint inhibitor discontinuation where elevated serum glucose is detected.