Abstract
Advanced molecular and pathophysiologic characterization of primary central nervous system lymphoma (PCNSL) has revealed insights into promising targeted therapeutic approaches. Medical ...imaging plays a fundamental role in PCNSL diagnosis, staging, and response assessment. Institutional imaging variation and inconsistent clinical trial reporting diminishes the reliability and reproducibility of clinical response assessment. In this context, we aimed to: (1) critically review the use of advanced positron emission tomography (PET) and magnetic resonance imaging (MRI) in the setting of PCNSL; (2) provide results from an international survey of clinical sites describing the current practices for routine and advanced imaging, and (3) provide biologically based recommendations from the International PCNSL Collaborative Group (IPCG) on adaptation of standardized imaging practices. The IPCG provides PET and MRI consensus recommendations built upon previous recommendations for standardized brain tumor imaging protocols (BTIP) in primary and metastatic disease. A biologically integrated approach is provided to addresses the unique challenges associated with the imaging assessment of PCNSL. Detailed imaging parameters facilitate the adoption of these recommendations by researchers and clinicians. To enhance clinical feasibility, we have developed both “ideal” and “minimum standard” protocols at 3T and 1.5T MR systems that will facilitate widespread adoption.
Purpose
The role of maintenance immunotherapy with anti-CD20 monoclonal antibody rituximab in primary central nervous system lymphoma (PCNSL) is unclear. We retrospectively reviewed the medical ...records of all immunocompetent adults with newly diagnosed PCNSL treated at our institution between1996 and 2017.
Methods
We identified 66 patients who attained complete response (CR) after completion of first-line regimen; 20 received maintenance therapy (maintenance therapy group) and 46 were observed with serial MRI scans without maintenance therapy (no-maintenance therapy group).
Results
Compared to the surveillance group, there was a significant increase in duration of survival (HR 0.27, 95% CI 0.08–0.98,
P
= 0.046) in the maintenance therapy group while the reduction in the risk of progression was not significant (HR: 0.61, 95% CI 0.26–1.43,
P
= 0.259).
Conclusion
We are evaluating the effectiveness of maintenance immunotherapy in PCNSL in a prospective multicenter randomized clinical trial.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
•Focal epilepsy from oligodendrogliomas can be very treatment resistant.•IDH1/2 mutation can lower seizure threshold by D2HG production.•Ivosidenib, an IDH1 inhibitor, significantly improved seizures ...in our patient.•In our patient, seizure improvement was seen with stable tumor appearance on MRI.
Compared to high grade gliomas, low grade gliomas such as oligodendrogliomas are often more epileptogenic. Epilepsy develops in 70–90% of patients with oligodendrogliomas and 40% of these are resistant to anti-seizure medications and surgery 3. IDH1/2 mutation is one defining feature of oligodendrogliomas and confers improved prognosis when found in astrocytomas 7. One possible etiology of the high rate of epileptogenicity in oligodendrogliomas is D-2-Hydroxyglutarate (D2HG), an oncometabolite seen in IDH mutation 8. D2HG can mimic the effect of glutamate at the NMDA receptor and increase the seizure risk 11. In this case report, we present a patient with drug resistant focal epilepsy from IDH1 mutant oligodendroglioma with markedly improved seizure frequency after starting Ivosidenib, an IDH1 inhibitor, in the absence of any changes to traditional anti-seizure medications. Our case suggests the possibility that IDH1 inhibitors may help reduce seizure burden in patients with difficult to control epilepsy from IDH1 mutant oligodendrogliomas. This is significant because we show that a targeted cancer therapy is able to improve seizure frequency through a unique pathway, and suggests that research into similar targeted, precision medicine therapies in brain lesions associated with epilepsy may be beneficial.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPUK, ZAGLJ, ZRSKP
The radiologic features and patterns of primary central nervous system lymphoma (PCNSL) at initial presentation are well described. High response rates can be achieved with first-line high-dose ...methotrexate (HD-MTX) based regimens, yet many relapse within 2 years of diagnosis. We describe the pattern of relapse and review the potential mechanisms involved in relapse.
We identified 78 consecutive patients who attained complete radiographic response (CR) during or after first-line treatment for newly diagnosed PCNSL (CD20+, diffuse large B cell type). Patients were treated with HD-MTX based regimen in conjunction with blood-brain barrier disruption (HD-MTX/BBBD); 44 subsequently relapsed. Images and medical records of these 44 consecutive patients were retrospectively reviewed. The anatomical location of enhancing lesions at initial diagnosis and at the time of relapse were identified and compared.
37/44 patients fulfilled inclusion criteria and had new measureable enhancing lesions at relapse; the pattern and location of relapse of these 37 patients were identified. At relapse, the new enhancement was at a spatially distinct site in 30 of 37 patients. Local relapse was found only in seven patients.
Unlike gliomas, the majority of PCNSL had radiographic relapse at spatially distinct anatomical locations within the brain behind a previously intact neurovascular unit (NVU), and in few cases outside, the central nervous system (CNS). This may suggest either (1) reactivation of occult reservoirs behind an intact NVU in the CNS (or ocular) or (2) seeding from bone marrow or other extra CNS sites.
Recognizing patterns of relapse is key for early detection and may provide insight into potential mechanisms of relapse as well as help develop strategies to extend duration of complete response.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
2077
Background: Osmotic blood-brain barrier disruption (BBBD) uses intra-arterial (IA) mannitol to open the neuro-vascular unit to enhance delivery of therapeutic agents to the brain. We report the ...results of a multi-institutional, single arm, phase 2 study evaluating the efficacy and safety of BBBD-enhanced chemotherapy in combination with immunotherapy in patients with newly diagnosed primary central nervous system lymphoma (PCNSL). PCNSL is a rare non-Hodgkin’s lymphoma that is limited to the brain, cerebrospinal fluid, spinal cord and/or the vitreoretinal compartment. Methods: Non-immunocompromised subjects with newly diagnosed PCNSL received rituximab IV over 5 hours on day 1. On days 2 and 3, under general anesthesia in the angiography suite, subjects received IA mannitol immediately followed by IA methotrexate over 10 minutes, and then IA carboplatin over 10 minutes. Subjects received sodium thiosulfate IV for hearing protection at 4 and 8 hours after each carboplatin dose. Treatment was repeated every month for up to 12 courses in the absence of disease progression or unacceptable toxicity. Per institutional recommendations, further accrual was terminated during the COVID-19 pandemic. Contrast MRI was used for response assessment based on IPCG criteria. Results: Twenty subjects (10 F, 10 M, Median KPS = 80; range 40-100) received a median of 8 cycles at 3 US institutions. Sixteen radiographic complete responses (80%) and 1 partial response were documented, 3 subjects were not evaluable (2 withdrew consent and 1 unrelated death). Median PFS was 55.2 months (95% CI :10.3 – not reached) and Median Overall survival was 82.8 months (95% CI :19.8-145.8). Fourteen patients (82% of evaluable patients) had grade 3 or 4 adverse events (AE). Grade 4 AEs (n = 14 in n = 7 patients) included neurologic toxicities (ischemia, cervical cord inflammation, neuropathy) and blood/bone marrow toxicities (lymphopenia, neutropenia, granulocytopenia). There were no treatment-related deaths. Conclusions: We demonstrate the feasibility of performing BBBD in a multi-institutional setting with excellent PFS and OS in patients without whole brain radiation or autologous transplant. Our CR rates, PFS and OS are comparable to other IV high-dose MTX regimens, with acceptable toxicity profile and no documented treatment-related deaths. Clinical trial information: NCT00293475 .
Chemotherapeutics play a significant role in the management of most brain tumors. First pass effect, systemic toxicity, and more importantly, the blood-brain barrier pose significant challenges to ...the success of chemotherapy. Over the last 80 years, different techniques of intraarterial chemotherapy delivery have been performed in many studies but failed to become standard of care. The purpose of this article is to review the history of intraarterial drug delivery and osmotic blood-brain barrier disruption, identify the challenges for clinical translation, and identify future directions for these approaches.
Abstract
Glioblastoma is the most common and aggressive form of primary brain tumor in adults. Standard of care gadolinium-enhanced MRI (Gd-MRI) fails to capture hypoxia, a disease-defining feature ...of glioblastoma. Hypoxia potentiates resistance to chemo-radiation therapy (CRT) but is not extensively observed with therapy-induced pseudoprogression (PSP). This neuroinflammatory response to CRT occurs in approximately 40% of patients and is indistinguishable from disease progression by Gd-MRI, potentially causing unnecessary termination of effective therapy in patients with PSP. Additionally, delayed second line-therapy can occur in patients with resistance to CRT. This research evaluated whether 18F-fluoromisonidazole (FMISO) positron emission tomography (PET), a noninvasive metric of tissue hypoxia, improves diagnostic accuracy in this context. Clinically, PET quantification employs the standardized uptake value (SUV), representing summed counts over an acquisition period. To add accuracy to this assessment, static 40-minute PET data acquired starting 90 minutes after FMISO injection was reconstructed into 20x2-minute frames and a relative Patlak model was applied. This technique forgoes blood sampling and extensive examination times required by traditional dynamic PET studies. The model produces two parameters that separately characterize the FMISO relative influx rate (Ki') and blood volume (VB'). In a cohort of 16 patients (3 IDH-mutated) imaged at a time of presumed disease progression, results showed that Ki' within the Gd-MRI enhancing lesion predicts future diagnosis of true progression (n = 11) or inflammation (n =5 ) with a sensitivity and specificity of 91% and 80% respectively. This outperforms diagnosis made with Gd-MRI alone, achieving ~70% for the same metrics. A t-test assuming unequal variance of cohort-wide mean Ki' tended toward significance (p = 0.07) for differentiating progressive disease (0.0036 ± 0.0016 min-1) from PSP (0.0011 ± 0.0017 min-1). RESULTS: from this study suggest relative Patlak analysis adds specificity to Gd-MRI and provides clinically relevant information regarding disease status.
Abstract
Intra-arterial (IA) infusion of hypertonic mannitol transiently opens the blood-brain barrier (BBB) to improve drug delivery to intracerebral tumors. The aim of this study was to evaluate ...the safety of osmotic BBB disruption (BBBD) followed by administration of IA chemotherapy. We performed a retrospective chart review of all malignant brain tumor patients who underwent BBBD on six IRB approved treatment protocols or off protocol at Oregon Health and Science University between 1997 and 2017. Toxicities and adverse events (AEs), including death within 30 days of treatment, were assessed. A total of 4018 BBBD procedures were performed on 268 patients (mean 15 BBBD procedures per patient). The most common pathologies were primary central nervous system lymphoma (32%) and anaplastic oligodendroglioma (12%). Most AEs were chemotherapy-related. Only 5% of AEs were attributable to the BBBD procedure, and only 0.42% of these were associated with permanent neurological damage (Grade 3 or 4 SAE). Four SAEs were due to ischemia as detected on magnetic resonance imaging and had minimal impact on quality of life. Four SAEs were due to anterior cord syndrome subsequent to iatrogenic laminar flow of the chemotherapy and were partially responsive to steroids. Subsequently this toxicity was eliminated by procedures to avoid laminar flow. Focal seizures, largely responsive to medical intervention, occurred within 24 hours after 257 (6.4%) BBBD procedures. Most seizures (229, 89%) followed IA administration of methotrexate and were transient and without sequelae. Five patient deaths occurred within 30 days; 1 due to a brain stem stroke related to BBBD, 1 due to a pulmonary embolus, and 3 due to disease progression. We conclude that although the BBBD procedure is invasive, permanent toxicities or death are rare. These results show that osmotic BBBD can be performed safely in brain tumor patients.
OBJECTIVE:To evaluate the efficacy of rituximab (R) when added to high-dose methotrexate (HD-MTX) in patients with newly diagnosed immunocompetent primary CNS lymphomas (PCNSLs).
...METHODS:Immunocompetent adults with newly diagnosed PCNSL treated at The Johns Hopkins Hospital between 1995 and 2012 were investigated. From 1995 to 2008, patients received HD-MTX monotherapy (8 g/m initially every 2 weeks and after complete response CR monthly to complete 12 months of therapy). From 2008 to 2012, patients received the same HD-MTX with rituximab (375 mg/m) with each HD-MTX treatment. CR rates and median overall and progression-free survival were analyzed for each patient cohort in this single-institution, retrospective study.
RESULTS:A total of 81 patients were identified54 received HD-MTX (median age 66 years) while 27 received HD-MTX/R (median age 65 years). CR rates were 36% in the HD-MTX cohort and 73% in the HD-MTX/R cohort (p = 0.0145). Median progression-free survival was 4.5 months in the HD-MTX cohort and 26.7 months in the HD-MTX/R cohort (p = 0.003). Median overall survival was 16.3 months in the HD-MTX cohort and has not yet been reached in the HD-MTX/R cohort (p = 0.01).
CONCLUSIONS:The addition of rituximab to HD-MTX appears to improve CR rates as well as overall and progression-free survival in patients with newly diagnosed PCNSL. Comparisons of long-term survival in the 2 cohorts await further maturation of the data.
CLASSIFICATION OF EVIDENCE:This study provides Class III evidence that in immunocompetent patients with PCNSL, HD-MTX plus rituximab compared with HD-MTX alone improves CR and overall survival rates.
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