Immune checkpoint inhibitors (ICPIs) have recently emerged as a novel treatment for cancer. These agents, transforming the field of oncology, are not devoid of toxicity and cause immune-related side ...effects which can involve any organ including the nervous system. In this study, we present 9 patients (7 men and 2 women) with neurologic complications secondary to ICPI treatment. These included meningoencephalitis, limbic encephalitis, polyradiculitis, cranial polyneuropathy, myasthenic syndrome and myositis. Four patients received dual ICPI therapy comprised of programmed cell death-1 and cytotoxic lymphocyte associated protein-4 blocking antibodies. Median time to onset of neurologic adverse event during immune checkpoint inhibitor treatment was 8 weeks (range 5 days–19 weeks). In all patients ICPIs were stopped and corticosteroids were initiated, resulting in a marked improvement in seven out of nine patients. Two patients, one with myositis and one with myasthenic syndrome, died. In two patients ICPI therapy was resumed after resolution of the neurological adverse event with no additional neurologic complications. This series highlights the very broad spectrum of neurological complications of ICPIs, emphasizes the need for expedited diagnosis and suggests that withholding treatment early, accompanied with steroid therapy, carries the potential of complete resolution of the neurological immune-mediated condition. Thus, a high level of suspicion and rapid initiation of corticosteroids are mandatory to prevent uncontrolled clinical deterioration, which might be fatal.
Paraneoplastic neurological syndromes (PNS) are a group of syndromes that affect the central and peripheral neuromuscular system in association with cancer. Specific antibodies may assist in the ...diagnosis of PNS. The antibodies tested can be classified into those directed against intracellular neuronal proteins (“well characterized” PNS: Hu, Yo, RI, CV2, amphiphysin, Ma1, Ma2) and those directed against neural surface antigens (autoimmune encephalitis syndromes: NMDA, AMPA, LGI1, CASPR2, GABAR). We aimed to characterize patients with unexplained neuropsychiatric symptoms, in whom positive PNS antibodies were detected in the Sheba medical center, a large referral hospital.
Clinical and demographic data of patients with positive PNS antibodies were collected during the years 2002–2016. Antibodies were tested by either Line immunoassay or by cell-based indirect immunofluorscent assay.
During the follow up of 14 years, 4010 PNS tests were performed in patients with unexplained neuropsychiatric symptoms. Seventy-two were found to be positive; among them we had full clinical data access to 44. The most frequent antibodies were anti-Hu (31.8%), anti-Yo (18.2%), anti-CV2 (13.6%), and anti-NMDA (9.1%), and the most common cancers were small-cell lung (SCLC) and ovarian cancers. In the well characterized paraneoplastic group, cancer was diagnosed in 55.9% of the patients, and in the autoimmune encephalitis group, 40.0% were diagnosed with cancer. A positive correlation between antibody titer and the presence of cancer was found. Ninety percent of the tests in patients who were found positive were ordered by a neurologist or neuro-oncologist.
The titers of PNS auto-antibodies can predict cancer in patients whom anti-PNS antibodies are tested. In addition, consultation with a specialist should be considered before this test is ordered.
Neurologic immune-related adverse events (n-irAEs) reportedly occur in up to 8% of patients treated with immune checkpoint inhibitors (ICIs) of all age groups. We investigated the association between ...age and n-irAEs in patients treated with ICIs and examined the effect of n-irAEs on survival outcomes in a large cohort of patients with melanoma.
We conducted a retrospective analysis of patients with advanced melanoma treated with ICIs at Ella Institute for Immuno-oncology and Melanoma between January 1, 2015, and April 20, 2022. The outcomes of interest were defined as the investigation of age-related frequency and severity of n-irAEs, the need for ICI interruption, the treatment required for n-irAE management, the safety of ICI reintroduction, and n-irAE's effect on survival.
ICI was administered to 937 patients. At least one irAE occurred in 73.5% (n = 689) of them. Among the study population, 8% (n = 76) developed a n-irAE, with a median age of 66 years in female and 68 years in male patients at onset. The median follow-up after n-irAE was 1,147 days (IQR: 1,091.5 range: 3,938). Fewer irAEs occurred in patients older than 70 years (median: 3 events,
= 0.04, CI 2.5-4.7) while specifically colitis and pneumonitis were more common in the 18-60 age group (
= 0.03, 95% CI 0.8-0.38,
= 0.009, 95% CI 0.06-0.2). Grade ≥ 3 toxicity was seen in 35.5% of patients across age groups. The median time from ICI administration to n-irAE development was 48 days across age groups. Common n-irAE phenotypes were myositis (44.7%), encephalitis (10.5%), and neuropathy (10.5%). N-irAE required hospitalization in 40% of patients and steroids treatment in 46% with a median of 4 days from n-irAE diagnosis to steroids treatment initiation. Nine patients needed second-line immunosuppressive treatment. Rechallenge did not cause additional n-irAE in 71% of patients. Developing n-irAE (HR = 0.4, 95% CI 0.32-0.77) or any irAE (HR = 0.7195% CI 0.56-0.88) was associated with longer survival.
N-irAEs are a relatively common complication of ICIs (8% of our cohort). Older age was not associated with its development or severity, in contrast with non-n-irAEs which occurred less frequently in the elderly population. Rechallenge did not result in life-threatening AEs. Development of any irAEs was associated with longer survival; this association was stronger with n-irAEs.
Background
Elderly patients account for nearly 70% of all primary central nervous system lymphoma (PCNSL) cases. They cannot tolerate aggressive treatment and have poor prognosis with a median ...overall survival (OS) of less than 2 years and progression‐free survival (PFS) of 6–16 months. Ibrutinib penetrates the blood–brain barrier and has shown activity in PCNSL.
Methods
This prospective study investigated whether ibrutinib maintenance is feasible, and whether it can benefit elderly PCNSL patients in terms of expected 2‐year PFS. It is an open label, phase 2 study in newly diagnosed PCNSL patients 60–85 years old who responded to first‐line high‐dose methotrexate (HDMTX)‐based treatment with partial or complete response. Ibrutinib maintenance (560 mg/d) was continued until disease progression or intolerable toxicity.
Results
Twenty patients were enrolled, with a median age of 72 years (range, 61–80). Median time on ibrutinib maintenance was 12.5 (range, 2–46) months. Twelve patients stopped treatment: five due to central nervous system relapse and seven due to adverse events that were mainly grade 2. Five patients died (25%) all due to relapse. The 1‐ and 2‐year PFS are 90% and 72.6%, respectively, and the 2‐year OS is 89%.
Conclusions
The study reached its primary end points and also showed that ibrutinib maintenance is tolerated reasonably well by the elderly. Therefore, this study supports the concept that ibrutinib maintenance should be further evaluated as an optional consolidation measure in the elderly.
Ibrutinib maintenance following first‐line high dose methotrexate‐based chemotherapy in elderly patients with primary central nervous system lymphoma is feasible and probably also effective.
Primary central nervous system lymphoma (PCNSL) is a rare disease with an incidence of 0.4/per 100,000 person‐years. As there is a limited number of prospective randomized trials in PCNSL, large ...retrospective studies on this rare disease may yield information that might prove useful for the future design of randomized clinical trials. We retrospectively analyzed the data of 222 newly diagnosed PCNSL patients treated in five referral centers in Israel between 2001 and 2020. During this period, combination therapy became the treatment of choice, rituximab has been added to the induction therapy, and consolidation with irradiation was largely laid off and was mostly replaced by high‐dose chemotherapy with or without autologous stem cell transplantation (HDC‐ASCT). Patients older than 60 comprised 67.5% of the study population. First‐line treatment included high‐dose methotrexate (HD‐MTX) in 94% of patients with a median MTX dose of 3.5 g/m2 (range 1.14–6 g/m2) and a median cycle number of 5 (range 1–16). Rituximab was given to 136 patients (61%) and consolidation treatment to 124 patients (58%). Patients treated after 2012 received significantly more treatment with HD‐MTX and rituximab, more consolidation treatments, and autologous stem cell transplantation. The overall response rate was 85% and the complete response (CR)/unconfirmed CR rate was 62.1%. After a median follow‐up of 24 months, the median progression‐free survival (PFS) and overall survival (OS) were 21.9 and 43.5 months respectively with a significant improvement since 2012 (PFS: 12.5 vs. 34.2 p = 0.006 and OS: 19.9 vs. 77.3 p = 0.0003). A multivariate analysis found that the most important factors related to OS were obtaining a CR followed by rituximab treatment and Eastern Cooperative Oncology Group performance status. The observed improvement in outcomes may be due to multiple components such as an intention to treat all patients regardless of age with HD‐MTX‐based combination chemotherapy, treatment in dedicated centers, and more aggressive consolidation with the introduction of HDC‐ASCT.
Abstract
INTRODUCTION
TRAMs calculated from delayed-contrast MRI enable reliable (sensitivity/specificity>70%) differentiation between tumor (blue in the TRAMs) and non-tumoral tissues (red). The ...TRAMs are calculated by subtracting 3D T1-MRIs acquired 5min (early time point) post-contrast injection from those acquired 60-105min (late point) later. Here we studied the sensitivity to tumor/treatment-effects as a function of the early T1-MRI acquisition time.
METHODS
7 patients with high grade glioma and 6 with brain metastases were scanned by the standard TRAMs protocol with the addition of a rapid 3D T1-MRI sequence (20 sec) acquired 2, 5, 12, 17, 20, 24 and 70 min post-contrast. Rapid-TRAMs were calculated using the rapid T1-MRIs, where the late time point was fixed at 70 min and the early time point changed from 2 to 24 min post-contrast. Enhancing volumes were determined on the T1-MRIs and copied to the TRAMs. Blue/tumor and red/treatment-effects volumes were calculated within the enhancing regions.
RESULTS
The blue/tumor volumes, calculated from the rapid-TRAMs, increased by a factor of 4.4 ± 2.6 when moving the early time point from 2min to 15.7 ± 2.2min, where they plateaued. The increase between 5min (standard) and 15.7min was by 1.5 ± 0.3. In contrast, when moving from 2 min to 15.7min the red/treatment-effects volumes decreased by 0.7 ± 0.2, and by 0.8 ± 0.1 when moving from 5min. CONCLUSIONS: The TRAMs were shown to provide reliable differentiation between tumor/treatment-effects. The early time point is fixed at 5min post-contrast. Using shorter delays may significantly decrease the sensitivity to tumor. Still, increasing the delay to 15min may increase the sensitivity to tumor. This over-estimation of the tumor volume may be explained by the tumor vasculature clearing contrast diffusing into further brain regions surrounding the tumor. An additional 3D-T1 acquired at 15min may be applied for calculating additional TRAMs with higher sensitivity to tumor, for depicting small tumor regions.
Abstract
BACKGROUND
TTFields are low intensity, intermediate frequency alternating electric fields, delivered through a portable, non-invasive device (Optune, NovocureTM). The EF-14 phase III trial ...showed significant prolongation of both progression-free and overall survival in newly diagnosed glioblastoma (GBM) patients. This is the first report on clinical experience with 110 patients treated with TTFields in Israel, focusing on safety and patient acceptance in our country.
METHODS
Patients received Optune-prescription in 6 neuro-oncology centers in Israel and used the device for at least one month. The cohort included both newly diagnosed (n=53) and recurrent GBM (rGBM, n=57) patients. The male/female ratio was 74/36 with a median age of 58.0 (18–82) years at start of treatment. Of patients with rGBM, 51% were treated at first progression.
RESULTS
Our data shows a high acceptance, with a compliance rate (monthly usage of the device) within the first 3 months of 80% for newly diagnosed GBM and 66% for rGBM. Median treatment compliance was independent of age, sex and stage of disease. In addition, our data indicates that the compliance is not negatively correlated with time on treatment, as the median compliance for newly diagnosed GBM patients was still at 79% within the first 6 months. With regards to device-related side effects, data shows that in total 30 patients (27%) experienced mild-moderate skin irritations that were usually manageable with local steroid creams and did not cause significant treatment breaks despite the warm climate in Israel. Other side effects related to the device were heat sensation in 10 patients (9%) and electric sensation in 9 patients (8%) that did not cause significant treatment interruption.
CONCLUSIONS
The accumulating clinical experience shows that TTFields are well-tolerated by patients in Israel without any major deviation from reported treatment-related side effects. Treatment compliance remains stable during a 6-month period.
BACKGROUND: Concurrent radiation (RT) and temozolomide (TMZ) has been accepted as standard first-line therapy for glioblastoma since publication of results of the phase III EORTC/NCIC trial in 2005. ...In the same NEJM issue, data were presented which showed the prognostic significance of MGMT methylation status in these patients. Trials for first-line treatment of anaplastic (grade III) glioma are currently underway, but until these trials complete accrual and mature, the role of concurrent chemotherapy and the prognostic significance of MGMT methylation status for patients with anaplastic glioma is unclear. METHODS: We hypothesized that methylated MGMT promoter may be a prognostic factor for anaplastic astrocytomas treated with chemoradiation (RT+ TMZ). We retrospectively reviewed data from 53 patients with anaplastic astrocytoma tested for MGMT methylation status by Methylation-Specific PCR (MSP) in our Neuro-oncology laboratory from 2007- 2014. Most patients were treated with concurrent TMZ and RT as first-line therapy (with a few selected cases treated with radiation alone). Survival curves of the groups of methylated and unmethylated tumors were compared using Logrank test. RESULTS: Twenty-one of 53 patients (39%) had MGMT methylation. The median survival in patients with MGMT methylation was 32.2 months and for unmethylated tumors, 23.7 months (p = 0.0947). Patients 45 years and younger showed more favorable prognosis with a median survival of 33.9 months compared to 24.3 in patients older than 45. CONCLUSIONS: The results of this study support the hypothesis that patients with anaplastic astrocytoma who have MGMT methylation have a more favorable prognosis when treated with concomitant TMZ and RT than do their unmethylated counterparts. Further analysis regarding progression- free survival; the effect of other chemotherapy or biologic agents given as second-line or adjuvant therapy; the pattern of response in anaplastic gliomatosis; and the impact of 1p19q and IDH status in these patients will be presented.
BACKGROUND: Concurrent radiation (RT) and temozolomide (TMZ) has been accepted as standard first-line therapy for glioblastoma since publication of results of the phase III EORTC/NCIC trial in 2005. ...In the same NEJM issue, data were presented which showed the prognostic significance of MGMT methylation status in these patients. Trials for first-line treatment of anaplastic (grade III) glioma are currently underway, but until these trials complete accrual and mature, the role of concurrent chemotherapy and the prognostic significance of MGMT methylation status for patients with anaplastic glioma is unclear. METHODS: We hypothesized that methylated MGMT promoter may be a prognostic factor for anaplastic astrocytomas treated with chemoradiation (RT+ TMZ). We retrospectively reviewed data from 53 patients with anaplastic astrocytoma tested for MGMT methylation status by Methylation-Specific PCR (MSP) in our Neuro-oncology laboratory from 2007- 2014. Most patients were treated with concurrent TMZ and RT as first-line therapy (with a few selected cases treated with radiation alone). Survival curves of the groups of methylated and unmethylated tumors were compared using Logrank test. RESULTS: Twenty-one of 53 patients (39%) had MGMT methylation. The median survival in patients with MGMT methylation was 32.2 months and for unmethylated tumors, 23.7 months (p = 0.0947). Patients 45 years and younger showed more favorable prognosis with a median survival of 33.9 months compared to 24.3 in patients older than 45. CONCLUSIONS: The results of this study support the hypothesis that patients with anaplastic astrocytoma who have MGMT methylation have a more favorable prognosis when treated with concomitant TMZ and RT than do their unmethylated counterparts. Further analysis regarding progression- free survival; the effect of other chemotherapy or biologic agents given as second-line or adjuvant therapy; the pattern of response in anaplastic gliomatosis; and the impact of 1p19q and IDH status in these patients will be presented.
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