Courses Of Ipilimumab Research Articles

Immune checkpoint inhibitor-associated sick sinus syndrome and cardiogenic shock.

Immune checkpoint inhibitors (ICI) represent a major advance in the treatment of cancer. Most studies of ICI have underestimated their cardiotoxicity; however, an increasing number of cases of cardiotoxicity are being reported. Herein we discussed a 67-year-old, male, Japanese patient who presented with cardiogenic shock accompanied by sick sinus syndrome 4days into his second course of ipilimumab plus nivolumab combination therapy. A temporary transvenous pacemaker was subsequently placed, and a permanent pacemaker was implanted for persistent, symptomatic, intermittent bradycardia. The permanent implantation of the pacemaker improved his symptoms and allowed him to continue his ICI therapy.

Retrospective Analysis of Rechallenge with Ipilimumab in Patients with Metastatic Melanoma.

Background Checkpoint inhibitors are effective in the treatment of several types of cancer, either being used separately or in combination. Ipilimumab pioneered the treatment of metastatic melanoma, and nowadays, it has been used more frequently in combination with anti-PD-1. Since the development of anti-PD1 for melanoma, rechallenge with ipilimumab has not been considered, although its use was considered in early trials. Cases In this study, we analyzed 22 patients with metastatic melanoma who had benefited from the first treatment with ipilimumab, but eventually had progressive disease. They received ipilimumab at the same dose as the first treatment. Most of the patients received the second course after six months or more from the first treatment with ipilimumab. The median progression-free survival (mPFS) of the treatment with ipilimumab was 8.9 months, and the median progression-free survival of the second course was 6.3 months. Conclusion There are limited data on rechallenge with ipilimumab addressing progression-free survival (PFS). In our analysis, twenty-two patients treated with a second course of ipilimumab were analyzed and most of them had a significant benefit. Despite the current alternatives for salvage therapies, rechallenging with ipilimumab might be an alternative to be considered in patients who had initial benefit.

Is the survival of patients treated with ipilimumab affected by antibiotics? An analysis of 1585 patients from the French National hospital discharge summary database (PMSI)

ABSTRACT Background: The gut microbiota has a key role in the regulation of the immune system. Disruption of the gut microbiota’s composition by antibiotics might significantly affect the efficacy of immune checkpoint inhibitors. In a study of patients treated with ipilimumab, we sought to assess the relationship between overall survival and in-hospital antibiotic administration. Methods: Patients having been treated with ipilimumab between January 2012 and November 2014 were selected from the French National Hospital Discharge Summary Database. Exposure to antibiotics was defined as the presence of a hospital stay with a documented systemic bacterial infection in the 2 months before or the month after initiation of the patient’s first ever course of ipilimumab. The primary outcome was overall survival. Results: We studied 43,124 hospital stays involving 1585 patients from 97 centers. All patients had received ipilimumab monotherapy for advanced melanoma. Overall, 117 of the 1585 patients (7.4%) were documented as having received systemic antibiotic therapy in hospital during the defined exposure period. The median overall survival time was shorter in patients with infection (6.3 months, vs. 15.4 months in patients without an infection; hazard ratio (HR) = 1.88, 95% confidence interval [1.46; 2.43], p = 10−6). In a multivariate analysis adjusted for covariates, infection was still significantly associated with overall survival (HR = 1.68, [1.30; 2.18], p = 10−5). Conclusions: In patients treated with ipilimumab for advanced melanoma, infection, and antibiotic administration in hospital at around the time of the patient’s first ever course of ipilimumab appears to be associated with significantly lower clinical benefit.

Severe hemophagocytic lymphohistiocytosis in a melanoma patient treated with ipilimumab + nivolumab

BackgroundTreatment of metastatic melanoma patients with immune checkpoint inhibitors is an important standard of care. Side effects are due to immune activation, can affect virtually all organ systems, and are occasionally severe. Although hematologic toxicity has been reported, we present a case of hemophagocytic lymphohistiocytosis (HLH) due to immune checkpoint inhibitor therapy.Case presentationA patient with metastatic melanoma was treated with one course of ipilimumab + nivolumab and presented 3 weeks later with severe anemia and hyperferritinemia. A bone marrow biopsy revealed necrotic tumor cells, infiltrating T cells, and hemophagocytosis. The patient was treated with high-dose steroids; 12 months later, the patient remains off all therapy and in complete remission of both HLH and metastatic melanoma.ConclusionsThe hemophagocytic syndromes are attributable to dysregulated immune activation and share pathophysiologic mechanisms with immune activation from checkpoint inhibitors. Increasing use of regimens that include immune checkpoint inhibition require vigilant monitoring for immune-activating side effects as they can occasionally be life threatening, as in this case of HLH.

Improved infield response rates and overall survival in patients with metastatic melanoma receiving higher biological equivalent doses of radiation with ipilimumab

There is a growing body of evidence that combining radiotherapy with ipilimumab might improve the survival and response rates in patients with metastatic melanoma. However, the patient and treatment variables that predict for improved outcomes have not been well defined. We conducted a retrospective analysis of 69 patients treated with ipilimumab and radiotherapy for metastatic melanoma at a single institution from May 2011 to June 2015. Demographic, clinical, and treatment factors were recorded, and end points of interest included infield and global complete response (CR) after the completion of radiation and ipilimumab based on the RECIST criteria (v1.1), and overall survival (OS). A bivariate and multivariate analysis was then performed to assess the relationship between outcomes and patient variables. In the multivariate analysis, infield CR was significantly associated with completing a full course of ipilimumab, a higher BED, and a smaller size of metastatic area treated. Global CR was significantly associated with increased age and giving radiotherapy to all areas of disease. OS was significantly associated with completing a full course of ipilimumab and a higher BED. Interestingly, after a multivariate analysis, higher BED was associated with an improved infield CR (p = 0.0281) and was not associated with an improved global CR (p = 0.5284) but was marginally associated with improved OS (p = 0.0545). Our findings suggest that the rate of a global CR is independent of the dose of radiation given, but the rate of infield CR and OS might improve with higher doses.

Short-term CTLA-4 blockade directly followed by PD-1 blockade in advanced melanoma patients: a single-center experience

Combination of T cell checkpoint blockade by CTLA-4- and PD-1-blockade is one of the most promising therapies in patients with advanced melanoma. It induces superior response rates when compared with single-agent therapy, but at the cost of a high percentage of grade 3 and 4 adverse events (AEs). This combination therapy was until July 2016 not available in the Netherlands, which prompted several physicians to treat patients with less than standard numbers of courses of ipilimumab followed directly by nivolumab or pembrolizumab. In this retrospective analysis, patients were included who were treated with two courses (day 0 and 21) anti-CTLA-4 (ipilimumab 3 mg/kg q3wk), directly followed by anti-PD-1 (starting at day 22 with nivolumab 3mg/kg q2wk or pembrolizumab 2 mg/kg q3wk). Data on treatment-related AEs were collected from electronic patient records and scored according to CTCAE 4.03 criteria. Overall response was evaluated using RECIST 1.1 for CT-scans and EORTC criteria for PET-scans. Forty advanced melanoma patients could be included (29/40 pembrolizumab, 11/40 nivolumab). Median follow-up (FU) was 51 weeks (range: 4-63 weeks) with a minimum FU of 26 weeks. Treatment-related AEs of grade 3 and 4 occurred in 38% of the patients. The best overall response rate (BORR) was 55% (95% CI 39-70) and disease control rate was 75% (95% CI 59-87). Ongoing responses were observed in 82% of responding patients. Treatment with short-term CTLA-4 blockade directly followed by PD-1 blockade may have similar efficacy but potentially lower toxicity when compared with concurrent therapy with anti-CTLA-4 and anti-PD-1. These results warrant further investigation in a prospective randomized controlled clinical trial.

Immunotherapy and Hypophysitis in the Clinical Practice: A Case Report

The reported frequency of ipilimumab-induced hypophysitis (IIH), a cytotoxic T-lymphocyte antigen 4 antibody, ranges from 0 to 17%, in contrast to the rarity of idiopathic autoimmune hypophysitis that has an estimated incidence of one in nine million people per year. Here we present the case of a patient with ipilimumab- induced hypophysitis (IIH). After his third course of ipilimumab, the patient began to present worsening asthenia and severe headache. A brain MRI scan showed the mild swelling of the anterior pituitary gland and thickening of the stalk. Haematological reports were consistent with hypophysitis diagnosis: in fact, ACTH and cortisol levels were very low. Then ipilimumab was interrupted and therapy with a large dose of glucocorticoids (dexamethasone) was promptly started. A rapid symptoms improvement was obtained by this therapeutic approach. The dose of dexamethasone was gradually decreased over 4 weeks and hydrocortisone replacement was started. Development of IIH is associated with the risk of acute adrenal insufficiency or adrenal crisis, so early recognition and therapeutic intervention are extremely relevant. Furthermore, in the absence of data demonstrating clinical benefit from high-dose glucocorticoid therapy, we wondered if, in absence of symptoms such as visual disturbances or other life-threatening simultaneous irAEs in other organs, there is the indication to start with hydrocortisone replacement therapy alone from the beginning. We also wondered if it was reasonable to administer ipilimumab during prolonged high-dose glucocorticoid therapy. Thus, guidelines for surveillance and management of IH are highly required.

Ipilimumab and craniotomy in patients with melanoma and brain metastases: a case series.

OBJECT In patients with large or symptomatic brain lesions from metastatic melanoma, the value of resection of metastases to facilitate administration of systemic ipilimumab therapy has not yet been described. The authors undertook this study to investigate whether craniotomy creates the opportunity for patients to receive and benefit from ipilimumab who would otherwise succumb to brain metastasis prior to the onset of regression. METHODS All patients with metastatic melanoma who received ipilimumab and underwent craniotomy for metastasis resection between 2008 and 2014 at the Massachusetts General Hospital were identified through retrospective chart review. The final analysis included cases involving patients who underwent craniotomy within 3 months prior to initiation of therapy or up to 6 months after cessation of ipilimumab administration. RESULTS Twelve patients met the inclusion criteria based on timing of therapy (median age 59.2). The median number of metastases at the time of craniotomy was 2. The median number of ipilimumab doses received was 4. Eleven of 12 courses of ipilimumab were stopped for disease progression, and 1 was stopped for treatment-induced colitis. Eight of 12 patients had improvement in their performance status following craniotomy. Of the 6 patients requiring corticosteroids prior to craniotomy, 3 tolerated corticosteroid dose reduction after surgery. Ten of 12 patients had died by the time of data collection, with 1 patient lost to follow-up. The median survival after the start of ipilimumab treatment was 7 months. CONCLUSIONS In this series, patients who underwent resection of brain metastases in temporal proximity to receiving ipilimumab had qualitatively improved performance status following surgery in most cases. Surgery facilitated corticosteroid reduction in select patients. Larger analyses are required to better understand possible synergies between craniotomy for melanoma metastases and ipilimumab treatment.

Single-center study under a French Temporary Authorization for Use (TAU) protocol for ipilimumab in metastatic melanoma: negative impact of baseline corticosteroids.

Ipilimumab is an anti-CTLA-4 antibody which has recently been approved in Europe as a monotherapy in the treatment of metastatic melanoma. We report a single-center study among patients treated within a Temporary Authorization for Use (TAU) protocol. We also performed a review of the literature involving expanded access program studies with a focus on factors associated with overall survival (OS). This retrospective, observational study included patients between June 2010 and July 2011 with a diagnosis of non-resectable stage III or IV melanoma with at least one previous line of chemotherapy. Treatment consisted of four courses of ipilimumab at a dose of 3mg/kg every three weeks. 45 patients were included, among whom 23 (51%) had brain metastases. 33 (71%) of the patients completed the induction phase. The best overall response rate (BORR) was 13% and median overall survival (OS) was 8 months (95%CI: 7 to 12). OS was not different between patients with brain metastases at baseline and those without (p = 0.10), regardless of BRAF V600E status (p = 0.61). OS was poorer in patients who were being treated with corticoids at baseline (p<0.001) or with LDH at baseline > 500 UI/ml (p = 0.008). A subset of patients most likely to benefit from ipilimumab should be defined. In our series we found a negative association of baseline corticosteroids with OS. Unlike high LDH levels, BRAF V600 E status and brain metastases should not be barriers to the initiation of treatment.

Experience in daily practice with ipilimumab for the treatment of patients with metastatic melanoma: an early increase in lymphocyte and eosinophil counts is associated with improved survival

BackgroundIpilimumab is a recently approved immunotherapy that has demonstrated an improvement in the overall survival (OS) of patients with metastatic melanoma. We report a single-institution experience in patients treated in a compassionate-use program. Patients and methodsIn this prospective study, patients were treated between June 2010 and September 2011. Inclusion criteria were a diagnosis of unresectable stage III or IV melanoma, at least one previous line of chemotherapy, and survival 12 weeks after the first perfusion. Four courses of ipilimumab were administered at a dose of 3 mg/kg every 3 weeks. ResultsSeventy-three patients were included. Median OS was 9.1 months (95% CI 6.4–11.3) from the start of ipilimumab. Immune-related adverse events were observed in 45 patients (62%), including 19 grade 3–4 events (26%). No drug-related death occurred. A lymphocyte count >1000/mm3 at the start of the second course and an increase in the eosinophil count >100/mm3 between the first and second infusions were correlated with an improved OS. ConclusionIpilimumab toxic effect is manageable in real life. Biological data such as lymphocyte and eosinophil counts at the time of the second ipilimumab infusion appear to be early markers associated with better OS.

Clinical and radiological response of leptomeningeal melanoma after whole brain radiotherapy and ipilimumab

Until recently, dacarbazine (DTIC) was the only registered chemotherapeutic drug for systemic treatment of metastatic melanoma. Patients with progressive disease during DTIC treatment can now also be treated with ipilimumab, a human monoclonal antibody directed against the cytotoxic T-lymphocyte antigen-4 (CTLA-4) receptor. Binding of ipilimumab to the CTLA-4 receptor enhances the immune response of T-lymphocytes, resulting in an offensive against the tumor and an increased median survival of patients with metastatic melanoma [1]. Few data are available on the effect of ipilimumab on central nervous system (CNS) metastases of melanoma [2, 3]. Here, we report a patient with stage IV melanoma, who showed a remarkable response of leptomeningeal metastases (LM) after whole brain radiotherapy (WBRT) and ipilimumab treatment. In January 2009, a 63-year-old woman was diagnosed with lung metastases of a melanoma. DTIC (800 mg/m, q3 weeks) was initiated. In May 2010, after 17 courses, treatment was discontinued due to progression of lung metastases. Concurrently, the patient complained of morning headache, nausea and vomiting. Neurological examination showed no abnormalities. MRI of the brain demonstrated a hyperintense signal in the cerebellar foliae on FLAIR images (Fig. 1a) and slight contrast enhancement of the leptomeninges on T1 images with gadolinium (Fig. 1b). No brain metastases were detected. According to the Dutch guidelines, LM was diagnosed [4–8]. The patient received WBRT (5 9 4 Gy) and low dose dexamethasone. However, her neurological symptoms did not diminish. In June 2010 ipilimumab (3 mg/kg, q3 weeks, four courses) was initiated. After the first course morning headache, nausea, and vomiting disappeared. After three courses the patient developed low grade dermatitis and diarrhea, which both recovered spontaneously. Repeated neurological examination after four courses of ipilimumab showed a slight dexamethasone-induced myopathy and some hearing loss due to the WBRT. The radiological signs of LM on MRI of the brain had disappeared and the CT-thorax showed regression of the lung metastases. On last followup, in October 2011, there were no signs of CNS recurrence on MRI (Fig. 1c, d) and lung metastases were stable. The patient had no complaints and she was near fully active in daily life (WHO 1). This is the first case report describing a metastatic melanoma patient with LM demonstrating a complete clinical and radiological response of LM after WBRT and four courses of ipilimumab. One should consider that, following the USA National Comprehensive Cancer Network (NCCN) CNS tumors section guidelines, CSF examination and MRI of the spine I. Bot (&) D. Brandsma Department of Neuro-oncology, Antoni van Leeuwenhoek Hospital, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands e-mail: i.bot@neuro.umcn.nl