Nivolumab and brentuximab vedotin with or without bendamustine for R/R Hodgkin lymphoma in children, adolescents, and young adults.

Children, adolescents, and young adults (CAYA) with relapsed/refractory (R/R) classic Hodgkin lymphoma (cHL) without complete metabolic response (CMR) before autologous hematopoietic cell transplantation (auto-HCT) have poor survival outcomes. CheckMate 744, a phase 2 study for CAYA (aged 5-30 years) with R/R cHL, evaluated a risk-stratified, response-adapted approach with nivolumab plus brentuximab vedotin (BV) followed by BV plus bendamustine for patients with suboptimal response. Risk stratification was primarily based on time to relapse, prior treatment, and presence of B symptoms. We present the primary analysis of the standard-risk cohort. Data from the low-risk cohort are reported separately. Patients received 4 induction cycles with nivolumab plus BV; those without CMR (Deauville score >3, Lugano 2014) received BV plus bendamustine intensification. Patients with CMR after induction or intensification proceeded to consolidation (high-dose chemotherapy/auto-HCT per protocol). Primary end point was CMR any time before consolidation. Forty-four patients were treated. Median age was 16 years. At a minimum follow-up of 15.6 months, 43 patients received 4 induction cycles (1 discontinued), 11 of whom received intensification; 32 proceeded to consolidation. CMR rate was 59% after induction with nivolumab plus BV and 94% any time before consolidation (nivolumab plus BV ± BV plus bendamustine). One-year progression-free survival rate was 91%. During induction, 18% of patients experienced grade 3/4 treatment-related adverse events. This risk-stratified, response-adapted salvage strategy had high CMR rates with limited toxicities in CAYA with R/R cHL. Most patients did not require additional chemotherapy (bendamustine intensification). Additional follow-up is needed to confirm durability of disease control. This trial was registered at www.clinicaltrials.gov as #NCT02927769.

[A Case of Thyroid Dysfunction and Isolated Adrenocorticotropin Deficiency after Nivolumab Therapy for Malignant Melanoma].

The patient was a 34-year-old woman. Surgical resection and chemotherapy had been performed on diagnosis of malignant melanoma in year X-9. Chronic thyroiditis was diagnosed in year X-8, but her thyroid function was normal. In November of the year X-1, the patient, who had metastasis to the left lung and the left main bronchus and radically unresectable metastases with distant metastases, was treated with the anti-PD-1 antibody nivolumab. In December X-1, we initiated levothyroxine sodium for hypothyroidism after the patient suffered indolent thyroiditis due to nivolumab. In March X, the nivolumab treatment was stopped because it proved to be ineffective, then in April, anorexia, fever, and general malaise were noted. Cortisol 5.0 and ACTH 17.5 were confirmed by blood test, and the patient was diagnosed with adrenal insufficiency and was admitted to the hospital. Head MRI showed no organic lesions, and a stress test showed abnormalities only in a CRH test (low response to both ACTH and cortisol). The patient was diagnosed with isolated ACTH deficiency due to nivolumab. Side effects of thyroid dysfunction due to nivolumab are frequently observed in Japan at a rate of 14.3%, and overseas at 5.9%. However, secondary adrenocortical dysfunction is observed in overseas clinical trials at a frequency of only about 0.3%. There are few reports of such complications, and we report this as a rare case.

DELIVER (JACCRO GC-08) trial: discover novel host-related immune-biomarkers for nivolumab in advanced gastric cancer.

Aim: Nivolumab has survival benefit in patients with previously treated advanced gastric cancer; however, about 60% of the patients did not respond to nivolumab, raising the necessity of its predictive biomarkers. Gut microbiome has been shown to be associated with efficacy of anti-PD-1 antibody in various types of cancers, but little is known about gastric cancer. Design: This is an observational/translational study to evaluate clinical outcomes of nivolumab and to discover novel immune-related biomarkers (gut microbiome, genetic polymorphism, gene expression and metabolome in plasma) in gastric cancer, using fecal and blood samples at two points before and after treatment. Candidate factors will be explored in first 200 patients and then validated in last 300 patients. Trial registration: UMIN000030850.

Combined immune checkpoint inhibitor therapy with nivolumab and ipilimumab causing acute-onset type 1 diabetes mellitus following a single administration: two case reports.

BACKGROUND: The use of immune checkpoint inhibitor (ICI) therapy is becoming a standard of care for several cancers. Monoclonal antibodies targeting cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed cell death protein 1 (PD-1) or its ligand (PD-L1) cause a broad spectrum of autoimmune adverse events. ICI-induced type 1 diabetes mellitus (T1DM) is extremely rare (< 1%) but potentially life-threatening. It appears to be more common with PD-1 blockade (or combination immunotherapy) than with anti-CTLA-4 therapy, often during the first three to six months of therapy. CASES PRESENTATION: We report an acute onset T1DM with severe inaugural diabetic ketoacidosis (DKA) and remarkably elevated Glutamic Acid Decarboxylase antibody (GADA) titres following a single administration of combined ICI therapy with nivolumab (anti-PD-1) and ipilimumab (anti-CTLA-4) in two adult patients with advanced metastatic melanoma. In these cases, the time to diabetes onset was remarkably short (two and five weeks), and one presented with fulminous T1DM in a previous long-standing type 2 diabetes mellitus. CONCLUSIONS: Oncological patients treated with combination therapy of anti-PD-1 and anti-CTLA-4 can develop a particular pattern of T1DM, with very rapid onset within a few weeks after starting ICI therapy, even in the presence of an existing type 2 diabetes. ICI-induced T1DM is a medical emergency in presence of severe inaugural DKA and requires a collaboration between specialists and primary care physicians, as well as patient education, for early diagnosis and supportive care.

Treatment of Immune Checkpoint Inhibitor Induced Colitis with Infliximab.

Several immunotherapeutic agents function against the T cell immune checkpoint inhibitor pathways thereby reestablishing immune response to elusive malignancies. Namely, the programmed death-1 co-receptor (PD-1) or ligand (PD-L1) and cytotoxic T lymphocyte- associated protein 4 (CTLA-4) are well known checkpoint targets of current FDA approved drugs. Among these drugs nivolumab, an IgG4 anti-PD-1 antibody, and ipilimumab, an anti-CTLA-4 antibody, are used to treat numerous malignancies but carry a large list of potential side effects termed immune-related adverse effects (irAEs). We describe the presentation, clinical course, and resolution of steroid-resistant immune checkpoint inhibitor-induced colitis secondary to administration of these two drugs in a 66-year-old female patient treated with infliximab.

Nivolumab plus Brentuximab vedotin +/- bendamustine combination therapy: a safe and effective treatment in pediatric recurrent and refractory classical Hodgkin lymphoma.

Introduction: Classical Hodgkin lymphoma (cHL) is the most common pediatric lymphoma. Approximately 10% of patients develop refractory or recurrent disease. These patients are treated with intensive chemotherapy followed by consolidation with radiotherapy or high-dose chemotherapy and autologous stem cell reinfusion. Although this treatment is effective, it comes at the cost of severe long-term adverse events, such as reduced fertility and an increased risk of secondary cancers. Recently, promising results of inducing remission with the immune checkpoint inhibitor nivolumab (targeting PD-1) and the anti-CD30 antibody-drug conjugate Brentuximab vedotin (BV) +/- bendamustine were published. Methods: Here we describe a cohort of 10 relapsed and refractory pediatric cHL patients treated with nivolumab + BV +/- bendamustine to induce remission prior to consolidation with standard treatment. Results and discussion: All patients achieved complete remission prior to consolidation treatment and are in ongoing complete remission with a median follow-up of 25 months (range: 12 to 42 months) after end-of-treatment. Only one adverse event of CTCAE grade 3 or higher due to nivolumab + BV was identified. Based on these results we conclude that immunotherapy with nivolumab + BV +/- bendamustine is an effective and safe treatment to induce remission in pediatric R/R cHL patients prior to standard consolidation treatment. We propose to evaluate this treatment further to study putative long-term toxicity and the possibility to reduce the intensity of consolidation treatment.

Nivolumab Hypersensitivity Reactions a Myth or Reality in Solid Tumors-A Systematic Review of the Literature.

Immune-checkpoint inhibitors (ICIs) are the most effective treatments nowadays. Nivolumab was the second ICI used for treating solid tumors with amazing results. Patients treated with Nivolumab may react differently to this treatment. Some people tolerate this treatment very well without experiencing any adverse reactions, whilst some may have mild symptoms and a part of them can present severe reactions. In our research, we sought to identify the answers to four questions: 1. what type of cancer has more severe hypersensitivity reactions to Nivolumab, 2. what is the time frame for developing these severe reactions to Nivolumab, 3. whether it is best to continue or stop the treatment after a severe hypersensitivity reaction to Nivolumab and 4. what severe hypersensitivity reactions are the most frequent reported along Nivolumab treatment. This review also highlights another problem with regard to the usage of concomitant and prior medications or other methods of treatment (e.g., radiation therapy), which can also lead to severe reactions. Treatment with Nivolumab is very well tolerated, but patients should also be warned of the possibility of severe hypersensitivity reactions for which they should urgently see a doctor for a personalized evaluation. There are some options for individuals with severe hypersensitivity reactions, for eg. switching the medication or applying a desensitization protocol.

Application of a patient-centered reverse translational systems-based approach to understand mechanisms of an adverse drug reaction of immune checkpoint inhibitors.

Immunotherapy became a key pillar of cancer therapeutics with the approvals of ipilimumab, nivolumab, and pembrolizumab, which inhibit either cytotoxic T-lymphocyte antigen-4 (CTLA-4) or programmed death-1 (PD-1) that are negative regulators of T-cell activation. However, boosting T-cell activation is often accompanied by autoimmunity, leading to adverse drug reactions (ADRs), including high grade 3-4 colitis and its severe complications whose prevalence may reach 14% for combination checkpoint inhibitors. In this research, we investigated how mechanistic differences between anti-CTLA-4 (ipilimumab) and anti-PD-1 (nivolumab and pembrolizumab) affect colitis, a general class toxicity. The data analytical platform Molecular Health Effect was utilized to map population ADR data from the US Food and Drug Administration (FDA) Adverse Event Reporting System to chemical and biological databases for hypothesis generation regarding the underlying molecular mechanisms causing colitis. Disproportionality analysis was used to assess the statistical relevance between adverse events of interest and molecular causation. We verified that the anti-CTLA-4 drug is associated with an approximately three-fold higher proportional reporting ratio associated with colitis than those of the anti-PD-1 drugs. The signal of the molecular mechanisms, including signaling pathways of inflammatory cytokines, was statistically insignificant to test the hypothesis that the severer rate of colitis associated with ipilimumab would be due to a greater magnitude of T-cell activation as a result of earlier response of the anti-CTLA-4 drug in the immune response. This patient-centered systems-based approach provides an exploratory process to better understand drug pair adverse events at pathway and target levels through reverse translation from postmarket surveillance safety reports.

The Effect and Tolerability of Second-line Chemotherapy Are Associated With Disease Control by Nivolumab Chemotherapy in Patients With Gastric Cancer.

BACKGROUND/AIM: Immune-related adverse events (irAEs) are associated with the efficacy of nivolumab. However, whether the tolerability of second-line chemotherapy is associated with the efficacy of nivolumab monotherapy (third-line chemotherapy) remains unclear. Our study aimed to investigate whether the results of second-line treatment were associated with the efficacy of nivolumab in patients with gastric cancer. PATIENTS AND METHODS: We enrolled Japanese patients aged ≥20 years with gastric cancer who were treated with nivolumab as a third-line chemotherapy at Fujita Health University Hospital from October 2017 to September 2021. Patients with the evaluations of complete response, partial response, and stable disease after third-line chemotherapy were included in the disease control (DC) group, while others were included in the progressive disease (PD) group. RESULTS: A total of 126 patients were enrolled. The population of patients aged over 65 years in the DC group was significantly higher than that in the PD group. The number of patients continuing second-line chemotherapy for >7 months was significantly higher in the DC than in the PD group. Age over 65 years [odds ratio (OR)=2.67], duration of second-line chemotherapy over 7 months (OR=3.10), and the occurrence of irAEs (OR=3.60) were detected as the factors associated with disease control after nivolumab chemotherapy. CONCLUSION: The effect and tolerability of second-line chemotherapy, and age over 65 years are the factors associated with DC after nivolumab chemotherapy. The control of tumour inflammatory status might be important for improving treatment outcomes.

Ipilimumab and nivolumab induced immune-related adverse events in metastatic mucosal melanoma.

Mucosal melanoma is a rare subtype of melanoma and represents a unique diagnosis and treatment challenge. Immune-checkpoint inhibitors (ICIs) have revolutionised metastatic melanoma treatment, and one of the leading regimens is the combination of ipilimumab (anti-cytotoxic T lymphocyte-associated antigen 4: CTLA4) and nivolumab (anti-programmed cell death protein 1: PD1). We report a case of a patient with metastatic mucosal melanoma treated with ipilimumab and nivolumab who developed multiple immune-related adverse events (irAEs) including uveitis, type I diabetes complicated by diabetic ketoacidosis, destructive thyroiditis, hepatitis and vitiligo. Endocrinopathies including type 1 diabetes and hypothyroidism were treated with insulin and levothyroxine. Hepatitis was responsive to steroids. She had sustained complete response 12 months after discontinuation of the combination therapy. With the wide usage of ICIs in multiple types of malignancies, it is important for general practioners to recognise common and serious irAEs due to ICIs.

Nivolumab-induced systemic capillary leak syndrome as an ultra rare life-threatening phenomenon of late toxicity and intravenous immunoglobulin efficacy.

Systemic capillary leak syndrome (SCLS) is a life-threatening disease. It is characterized by severe capillary hyperpermeability to proteins resulting in hemoconcentration, hypoalbuminemia and hypovolemic shock. Its treatment remains supportive, and the prognosis is generally poor. We report on a 51-year old male with melanoma treated with nivolumab for 1 year. 1 month following the completion of the treatment, the patient presented with signs of hypovolemic shock, anasarca, hemoconcentration and hypoalbuminemia. After excluding other diseases, a diagnosis of nivolumab-induced systemic capillary leak syndrome was made. A high dose of intravenous steroid therapy was promptly initiated without any significant clinical improvement. Intravenous immunoglobulin therapy was then administered with normalization of blood pressure, hemoconcentration and complete resolution of anasarca. Intravenous immunoglobulin should be considered a first-line treatment option for this rare phenomenon.

Lay abstract Systemic capillary leak syndrome (SCLS) is a life-threatening disease with a high fatality rate. Patients present with low blood pressure, widespread edema and rapid weight gain. Labs show low albumin levels with highly concentrated blood, seen as high hematocrit and hemoglobin levels. Current treatments aim to support the acute crisis. We are presenting on a 51-year old patient with melanoma, treated with nivolumab for 1 year who developed signs of SCLS 1-month following medication discontinuation. He was first treated with high-dose steroids without symptom resolution. He was then administered immune proteins called intravenous immunoglobulins, resolving all his symptoms. Due to the patient's complete response, we suggest intravenous immunoglobulins as the initial treatment in patients taking nivolumab presenting with SCLS.

A Case Report of Non-Bacterial Cystitis Caused by Immune Checkpoint Inhibitors.

We report a case of non-bacterial cystitis after treatment with programmed death-1 (PD-1) and programmed cell death-ligand 1 (PD-L1) antibodies, which was considered an immune-related adverse event (irAE). A 48-year-old male patient with intrahepatic cholangiocarcinoma (ICC) was treated with nivolumab after postoperative multi-line treatment. This patient recurred worsening of psoriasis and repeated urinary tract discomfort. The drug was discontinued and surgery was performed due to the recurrence of the tumor suggested by imaging. After receiving three cycles of chemotherapy treatment combined with atezolizumab, urinary tract discomfort reappeared. No bacteria were found in multiple urine cultures, and non-bacterial bladder inflammation was considered after cystoscopy biopsy. This is a report of non-bacterial inflammation of the urinary tract caused by immunotherapy.

Investigation of the Efficacy and Safety of Nivolumab in Recurrent and Metastatic Nasopharyngeal Carcinoma.

BACKGROUND/AIM: Nivolumab, an anti-PD-1 inhibitor, has demonstrated efficacy in patients with several types of recurrent and metastatic (R/M) squamous cell carcinoma of the head and neck. We evaluated patients with R/M-NPC receiving nivolumab. PATIENTS AND METHODS: Twelve patients with R/M-NPC were enrolled at 4 institutions. The primary endpoint was overall survival, and secondary endpoints were i) progression-free survival (PFS), ii) overall response rate (ORR), iii) disease control rate (DCR), and iv) treatment-related toxicity. RESULTS: The 1-year survival rate was 75.8%, the median PFS was 2.8 months, and the 1-year PFS rate was 33.3%. The best therapeutic response was complete response in 2, stable disease in 3 and progressive disease in 7 patients. The ORR of all patients was 16.7% and the DCR was 41.7%. CONCLUSION: Nivolumab is a useful and relatively safe second-line systemic therapy in patients with R/M-NPC, and even patients who do not respond to nivolumab may survive for a long time.

Psoriatic arthritis induced by anti-PD1 and treated with apremilast: a case report and review of the literature.

Immune checkpoint inhibitors targeting programmed cell death protein 1 pathways are generally well tolerated, but immune-related adverse events have been observed in more than 80% of all patients. Rheumatic and musculoskeletal immune related adverse events have to date not been widely recognized or well characterized. Psoriasic arthritis is a rare entity and it makes management of patients difficult due to the limited therapeutic possibilities and the strong impact on the quality of life. The majority of cases were treated with glucocorticoids, in some cases not enough. We present the case of a patient with psoriasic arthritis and report cases described in literature of patients treated with apremilast, a small oral molecule that inhibits of phosphodiestherase 4.

Concurrent Vogt-Koyanagi-Harada disease and impressive response to immune checkpoint blockade in metastatic melanoma.

Background: Vogt-Koyanagi-Harada disease (VKHD)-like symptoms have previously been reported in 11 melanoma patients treated with immune checkpoint inhibitors. Materials & methods: We report a female patient with multilocular metastatic melanoma who was treated with nivolumab. Results: Following the first nivolumab dose, she experienced bilateral blurry vision, hearing loss, vertigo and ataxia. Ocular ultrasound was consistent with the diagnosis of uveitis. Audiography revealed severe bilateral sensorineural hearing loss. A high-dose corticosteroid regimen was initiated under which the patient developed generalized vitiligo. Abdominal and thoracic CT scans showed an almost complete response to nivolumab therapy. This patient fulfilled all criteria of VKHD which is characterized pathogenetically by an antimelanocytic autoimmune process. Conclusion: The present case showed an impressive response to antimelanoma immunotherapy. Based on these data, the occurrence of VKHD in melanoma patients appears to be a strong indicator for immune checkpoint inhibitor efficacy.