Central Nervous System Irradiation Research Articles

Intracranial outcomes of 1L selpercatinib in advanced RET fusion-positive NSCLC: LIBRETTO-431 study.

199 Background: Selpercatinib is a highly selective and potent CNS active RET inhibitor approved for treatment of advanced RET fusion-positive ( RET+) NSCLC. Treatment or prevention of CNS disease is critical in RET+ NSCLC patients (pts), who have nearly a 50% lifetime prevalence of brain metastases (mets) (Drilon et al. JTO 2018). LIBRETTO-431 is the first study to compare intracranial (IC) efficacy of a targeted therapy to chemo/IO in pts with oncogene driven NSCLC. Methods: LIBRETTO-431 (NCT04194944) is a randomized, open-label, phase 3 trial comparing 1L selpercatinib vs chemotherapy (cisplatin/carboplatin + pemetrexed) +/- pembrolizumab. As previously reported, the study met its primary endpoint of PFS by blinded independent central review (BICR) at the pre-planned interim analysis. IC analyses included CNS and non-CNS PD, IC PFS and IC responses by BICR per RECIST 1.1 in all pts who had a baseline and one or more post-baseline CNS scans (CNS-evaluable) and were designated to receive pembrolizumab if randomized to the control arm (CNS-pembro population). Adverse events were evaluated in the CNS safety population. Results: A total of 192 of 261 pts enrolled were CNS-evaluable (selpercatinib: 120, control: 72). Baseline characteristics were generally balanced with the selpercatinib arm having a slightly lower proportion of pts with BICR-assessed baseline brain mets (21% vs 25%) and prior CNS radiotherapy (RT; 6% vs 10%) compared to the control arm. Selpercatinib delayed CNS PD as evidenced by a lower 12 mo cumulative incidence rate (CIR) for CNS PD, as well as delaying non-CNS PD compared to control in pts with and without brain mets (Table). In pts with measurable brain mets at baseline (n=29), median time to IC response per RECIST 1.1 was similar between selpercatinib and control (1.4 mo [range: 1.2-2.9] vs 1.6 mo [range: 1.2-2.9]); however, as previously reported the IC response rates were higher (82% vs 58%) and more durable (12 mo DOR rate 76% vs 63%) with selpercatinib vs control (Zhou et al. NEJM 2023). IC responses to selpercatinib were more common in pts without prior CNS RT (14/15, 93%) than with prior CNS RT (3/6, 50%). Conclusions: Selpercatinib delayed IC progression in advanced RET+ NSCLC pts with or without baseline brain mets and achieved higher IC response rates compared to chemotherapy + pembrolizumab. LIBRETTO-431 is the first study to demonstrate IC efficacy improvement of a targeted therapy vs chemo/IO in a biomarker selected NSCLC population. These data further support selpercatinib as the preferred 1L regimen in pts with advanced RET+ NSCLC. Clinical trial information: NCT04194944 . [Table: see text]

A Case-based Guide for World Health Organization (WHO) Grade 2 Meningioma Radiosurgery and Radiation Therapy from The Radiosurgery Society

Meningiomas represent the most common primary tumor of the central nervous system. Current treatment options include surgical resection with or without adjuvant radiation therapy (RT), definitive RT, and observation. However, the radiation dose, fractionation, and margins used to treat patients with WHO grade 2 meningiomas, which account for approximately 20% of all meningiomas, are not clearly defined, and deciding on the optimal treatment modality can be challenging owing to the lack of randomized data. In this manuscript, 3 cases of patients with WHO grade 2 meningiomas are presented with descriptions of treatment options after gross total resection, subtotal resection, and previous irradiation. Treatment recommendations were compiled from 9 central nervous system radiation oncology and neurosurgery experts from The Radiosurgery Society, and the consensus of treatment recommendations is reported. Both conventional and stereotactic RT are treatment options for WHO grade 2 meningiomas. The majority of prospective data in the setting of WHO grade 2 meningiomas involve larger margins. Stereotactic radiosurgery/hypofractionated stereotactic RT are less appropriate in this setting. Conventionally fractionated RT to at least 59.4 Gy is considered standard of care with utilization of preoperative and postoperative imaging to evaluate the extent of disease and possible osseous involvement. After careful discussion, stereotactic radiosurgery/hypofractionated stereotactic RT may play a role for the subset of patients who are unable to tolerate the standard lengthy conventionally fractionated treatment course, for those with prior RT, or for small residual tumors. However, more studies are needed to determine the optimal approach. This case-based evaluation of the current literature seeks to provide examples for the management of grade 2 meningiomas and give examples of both conventional and stereotactic RT.

Tyrosine kinase inhibitors with and without upfront CNS radiation for brain metastases in oncogene-driven non-small cell lung cancer (TURBO-NSCLC).

2019 Background: Newer generation tyrosine kinase inhibitors (TKI) for NSCLC with EGFR mutations and ALK rearrangements have demonstrated encouraging central nervous system (CNS) activity with CNS objective response rates, greatly improved from 1st generation TKIs. In response to these data, guideline statements have acknowledged a strategy of CNS-penetrant TKI +/- upfront stereotactic radiosurgery (SRS) for the treatment of select patients with BM. However, optimal use of upfront SRS for BM in these patients is controversial since upfront CNS radiation has been the historical standard of care, and there are limited data guiding patient management with upfront TKI alone. Additionally, results from a large multi-institutional series reported inferior overall survival (OS) with the omission of SRS in patients with EGFR-mutated NSCLC treated with first-generation TKI. Methods: Data on TKI-naïve patients with EGFR- and ALK-driven NSCLC with BM treated with CNS-penetrant TKIs +/- upfront SRS were retrospectively collected from 7 centers in the United States. Time to CNS progression (PD), local CNS PD, and OS were analyzed, with multivariable adjustment (MVA) in Fine and Gray and Cox proportional hazards models for baseline factors including age, sex, performance status, mutation, extracranial metastases, prior therapy, neurologic symptoms, and number and size of BM. Results: We identified 317 patients (200 TKI only and 117 TKI+SRS). 250 (79%) and 61 (19%) patients received osimertinib and alectinib, respectively. Patients who received TKI+SRS were more likely to have BM ≥1 cm (p<0.001) and neurologic symptoms (p<0.001) at baseline. The median follow-up from treatment of BM was 23 months and 26 months in the TKI and TKI+SRS groups, respectively. Median OS was similar between the TKI and TKI+SRS groups (median 41 months [95% CI: 35-NR] vs 40 months [95% CI: 40-NR], respectively; p=0.5). On MVA, TKI+SRS was associated with a significant improvement in time to CNS PD (HR 0.63; 95% CI: 0.42-0.96; p=0.033). Local CNS control was significantly improved with TKI+SRS (HR 0.30, 95% CI: 0.16-0.55; p<0.001), whereas no significant differences were observed in distant CNS control. Subgroup analyses demonstrated greater CNS control benefits with TKI+SRS in patients with BM ≥1 cm. Conclusions: This is the largest multi-institutional study comparing strategies of CNS-penetrant TKIs +/- upfront SRS in TKI-naïve patients with oncogene-driven NSCLC. The addition of SRS improved time to CNS PD and local CNS control but not OS. Patients with BM ≥1 cm may benefit the most from upfront integration of SRS. [Table: see text]

Abstract PO4-20-11: Excellent Response to Trastuzumab Deruxtecan in “HER-2 Low” Leptomeningeal Breast Cancer and Diagnostic and Monitoring Utility of CNSide Assay

Abstract A 72-year-old female presented to the emergency department with sudden onset of imbalance and cognitive decline. Two years ago, she was diagnosed with stage III estrogen receptor (ER) positive, progesterone receptor (PR) negative and human epidermal growth factor receptor 2 (HER2) negative (immunohistochemistry score: 0) invasive breast cancer. She subsequently underwent lumpectomy, adjuvant radiation and chemotherapy. She had been taking adjuvant letrozole at the time of presentation. Magnetic resonance imaging (MRI) of the brain showed obstructive hydrocephalus without any parenchymal lesion or leptomeningeal enhancement. MRI of spine, computerized tomography of chest/abdomen/pelvis and bone scan were unrevealing except a left adrenal mass which was equivocal for metastasis. Cerebrospinal fluid (CSF) analysis showed rare malignant cells. Based on the morphology of malignant cells and the patient’s prior history of breast cancer, the diagnosis of leptomeningeal disease with breast primary was made. There were insufficient cells for additional studies. CNSide, a microfluidic platform that uses antibody capture method to detect CSF tumor cells, showed 4678 tumor cells per milliliter (ml) of CSF. Immunocytochemistry of these cells showed that the cells were ER negative (criterion: < 2.6% ER positive cells) and programmed cell death ligand 1 (PD-L1) negative (criterion: < 3.4% PD-L1 positive cells). Fluorescence in situ hybridization (FISH) testing showed 22% of tumor cells with HER2 amplification (either HER2 to CEP17 ratio >/= 2.0 or HER2 copy number >/= 6). She underwent ventriculoperitoneal (VP) shunt placement with complete recovery of her neurological symptoms. Five weeks later, she was started on trastuzumab deruxtecan (T-DXd) mainly because of the HER2 FISH results from CNSide. She did not receive central nervous system(CNS) irradiation due to complete resolution of neurological symptoms with VP shunt placement. After two cycles of T-DXd, MRI brain showed mild leptomeningeal enhancement along bilateral superior cerebellar sulci. Positron emission tomography/computed tomography(PET/CT) scan showed a new sclerotic rib focus, thought to represent treatment response. It also showed decrease in size of the adrenal mass. The adrenal mass was hypermetabolic on PET, consistent with malignancy. CSF cytology was negative, while CSF tumor cell count significantly reduced to 6.72 cells/ml using CNSide. There were no new neurological symptoms. Despite MRI brain findings, she was continued on T-DXd given overall favorable clinical, radiological and CSF data. After 7th cycle of T-DXd, repeat CSF cytology continued to remain negative, CNSide CSF tumor cell count decreased further to 6.27 cells/ml, MRI brain showed interval resolution of prior leptomeningeal enhancement, CT scan showed further decrease in size of the adrenal mass (baseline 5.4cm to 3cm), stable rib sclerotic lesion and no additional metastatic lesion. To date, she has undergone eight cycles of T-DXd which has effectively controlled her disease for a period of seven months. She has not needed VP shunt revision and continues to do well. To our knowledge, this is the first case demonstrating the activity of T-DXd against CSF tumor cells where a small subset exhibited HER2 amplification. This case also highlights the benefits of using advanced and highly sensitive CSF assays to diagnose and surveil leptomeningeal disease and to assess HER2 signaling. This case is well-timed especially in the era of next-generation, CNS penetrating, potent HER2-directed antibody-drug conjugate like T-DXd which can mount antitumor activity even with minimal HER2 expression in tumors. Citation Format: Sarah Stanford, Zeni Kharel, Lauryn Hemminger, Tyler Schmidt, Sara Hardy, Jason Zittel, Nimish Mohile, Ajay Dhakal. Excellent Response to Trastuzumab Deruxtecan in “HER-2 Low” Leptomeningeal Breast Cancer and Diagnostic and Monitoring Utility of CNSide Assay [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-20-11.

Abstract PS11-02: Clinical risk factors of Central Nervous System (CNS)-related death in patients with HER2-positive metastatic breast cancer

Abstract Background: Central nervous system (CNS) relapse represents a challenge in the management of patients with HER2-positive (+) metastatic breast cancer. Data regarding the impact of brain metastases (BrM) and CNS involvement on mortality are sparse. In this study we sought to determine the proportion of HER2+ MBC patients in which CNS disease is the cause of death and identify risk factors associated with CNS-related mortality. Methods: We reviewed medical records of 294 consecutive patients with HER2+ MBC and diagnosis of CNS disease including parenchymal BrM, leptomeningeal disease (LMD) or dural metastases (DM), treated at Memorial Sloan Kettering Cancer Center between August 2010 and April 2022. HER2-positivity was assessed at the first diagnosis of metastatic disease (any site). Clinicopathologic characteristics including disease burden at presentation, timing of CNS disease and extracranial metastases (ECM), neurologic complications, and local and systemic treatments were collected. CNS-related death was defined as any death caused by BrM or LMD or DM progression or CNS treatment-associated complications. CNS-related death was estimated using cumulative incidence in the competing risks setting (with death due to other causes as a competing event) and overall survival (OS) was estimated using Kaplan Meier methodology. Risk factors associated with CNS-related death were assessed using sub-distribution hazards regression modeling. Treatments given after CNS disease diagnosis were treated as time-varying variables. Tests were two-sided with statistical significance < 0.05. Results: After excluding 19 patients (11 for discordant HER2 status, 5 for concomitant second solid tumor, and 3 for missing data), 275 patients were included in these analyses (258 patients with parenchymal BrM +/- LMD, 8 patients with DM only, 2 patients with DM concomitantly with LMD, and 6 patients with LMD only). Overall, 63/275 (23%) presented with CNS as first and only site of metastasis, 210 (76%) patients developed CNS disease synchronously with or following ECM, and 2 had unknown timing. 125/275 (45%) had de novo MBC, and nearly all patients were treated with CNS local therapies (92% ≥1 radiation treatment and 28% underwent ≥1 BrM resection). The median number of lines of systemic therapy after CNS disease diagnosis was 1 (range: 0-14); 105/275 (38%) patients received a HER2 tyrosine kinase inhibitor (lapatinib: 21%, neratinib: 4.4%, and tucatinib: 12%). The median follow-up was 3.6 years for survivors (range: 0.22 years-12 years). 193/275 (70%) patients died, of whom 105 (54%) died of CNS-related cause. The 3-year OS rate was 40% (95% CI=34%-46%), which varied for patients with BrM only at the diagnosis of metastatic disease [56% (95% CI=43%-69%] compared to patients with ECM +/- BrM [35% (95% CI=28%-42%] (p=0.05). The cumulative incidence of CNS-related death at 3 years was 33% (95% CI=27%-39%). Upon univariable modeling, LMD and CNS radiation treatment (RT) were associated with CNS-related death, and these associations remained statistically significant in a multivariable model [LMD: HR=2.49 (95% CI=1.62-3.83), p< 0.0001, and RT: HR=2.91 (95% CI=1.27-6.64), p=0.01]. Conclusions: Greater than half of patients with HER2+ with CNS involvement suffered of CNS-related death, with greatest risk among patients with LMD. We hypothesize that the association between radiotherapy and CNS-related death may reflect upfront response to systemic cancer-directed treatments of those in patients with DM only or limited CNS disease extension. CNS-only relapse at metastatic presentation portended improved survival than intra- plus extracranial progression, supporting an approach of aggressive local therapy for selected patients. Multimodality approaches using HER2-directed agents effective against parenchymal BrM, LMD along with extracranial metastases, in combination with local CNS-directed therapies need to be optimized. Citation Format: Emanuela Ferraro, Rabih Bou Nassif, Anne Reiner, Samantha Brown, Umberto Tosi, Katherine Panageas, Chau Dang, Andrew D Seidman, Nelson Moss. Clinical risk factors of Central Nervous System (CNS)-related death in patients with HER2-positive metastatic breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS11-02.

The study protocol of the winners project: a randomized and controlled trial using a videogame-based training program in pediatric cancer survivors

IntroductionChildhood cancer survivors have neurocognitive sequelae that in most survivor follow-up programs are underdiagnosed and for which there is usually no treatment plan.Video games have demonstrated various psychological and neurocognitive benefits in different subpopulations, such as patients with organic neurological deficits or children with ADHD. However, few studies have been carried out using video games-based interventions in the paediatric oncology population.ObjectivesThe aim of this work is to present the WINNERS study protocol, the objectives of which are to diagnose the neurological and cognitive sequelae in child cancer survivors, and to demonstrate the benefit in these areas of a training program based on video games.MethodsA randomized controlled and unblinded trial is presented. Fifty-six patients aged 8 to 17 years stratified into two age groups (8-12 and 13-17) who had received any of the following treatments 1 to 6 years before the enrolment will be selected: high-dose chemotherapy with blood-brain barrier crossing, intrathecal or intraventricular chemotherapy, CNS radiotherapy or hematopoietic stem cell transplantation. A neuropsychological evaluation will be performed consisting of a battery of neuropsychological tests to assess parameters such as attention, memory, visuospatial ability or speed of response, as well as a neuroimaging evaluation by structural and functional magnetic resonance imaging. The evaluation will be repeated 3 months and 6 months after the enrolment. Patients will be randomized to a treatment group or to a recycled waiting group. Intervention will consist on a 12-week training at home using 3 video games: a brain training game, an exergaming game and a skill training game.ResultsAccording to the hypotheses of this study, it is expected that the proposed program of videogame-based interventions will improve neurocognitive and other wellbeing parameters in the intervention group.ConclusionsThis study aims to improve the quality of care for patients who have survived a cancer disease by detecting sequelae that have so far been poorly attended, and by proposing a gamification-based intervention program that is effective and attractive for this population.Disclosure of InterestNone Declared

Abstract 6472: Response to PARP inhibitors in patients with breast cancer metastatic to the central nervous system

Abstract Background: Central nervous system (CNS) metastasis from breast cancer can be challenging to treat due to the limited blood brain barrier penetration of many systemic therapies. PARP inhibitors (PARPi) block single-strand DNA break repairs and have activity in cancers with homologous recombination repair deficiency; they are FDA approved for patients with metastatic HER2 negative breast cancer with germline BRCA1/2 mutations. While preclinical studies suggest that PARPi have CNS penetration, clinical data is limited. The goal of our study is to describe the clinical benefit of PARPi in patients with breast cancer CNS metastasis. Methods: This retrospective case series was conducted at three academic cancer centers (Johns Hopkins, Dana-Farber, and Duke) and included patients with the following criteria: (1) age≥18 years with a breast cancer diagnosis (any subtype); (2) diagnosis of parenchymal brain metastasis or leptomeningeal disease (LMD); and (3) received PARPi (olaparib, talazoparib) for CNS metastasis. Clinical and pathologic information were analyzed with descriptive statistics (median, range) and Kruskal-Wallis rank sum tests. Survival analysis was performed using Kaplan-Meier curves with log-rank p-values. Results: Although this analysis includes one center’s experience, we will present a combined dataset (N = 45) at the main conference. 11 patients were identified at Johns Hopkins. 4 (36.4%) were Black and 6 (54.5%) were White; 6 (54.5%) had ER+HER2- disease and 5 (45.5%) had TNBC at time of brain metastasis; 5 (45.5%) had BRCA1 mutations, 5 (45.5%) had a BRCA2 mutations, and 1 patient (9%) had a BARD1 mutation; 7 (63.6%) had brain metastasis and 4 (36.4%) had LMD. Median lines of therapy prior to PARPi was 6 [1 - 11]; 8 patients (72.7%) had previous CNS radiation (5 SRS and 3 WBRT) and 3 (27.3%) had previous CNS surgery. On average, patients remained on PARPi for 5 months [0.5 - 66], and overall survival (OS) time from PARPi to death was 16 months [2 - 66]. Time on PARPi was 5 months [2 - 66] for patients with brain metastasis and 3 months [0.5 - 10] for those with LMD (p=0.22). Duration of PARPi and OS did not differ significantly between ER+HER2- and TNBC (p=0.74 and 0.69, respectively), BRCA 1 and 2 (p=0.78 and 0.72, respectively), or brain and LMD metastasis (p=0.22 and 0.91, respectively). Black patients had significantly shorter PARPi duration and survival than White patients (PARPi 2 vs. 8 months, p=0.028 and OS 4 vs 18 months, p=0.028). Prior CNS radiation was significantly associated with longer PARPi duration and survival (PARPi 5 vs 1 month, p=0.02 and OS 17 vs. 3 months, p=0.032). Prior CNS surgery was significantly associated with longer PARPi duration, but not overall survival (PARPi 18 vs 3 months, p=0.05 and OS 28 vs. 7 months, p=0.14). Conclusions: PARPi are associated with significant clinical benefit in patients with breast cancer CNS metastasis. Larger data series will help confirm these observations. Citation Format: Seoho Lee, Rani Bansal, Melissa E. Hughes, Amanda E. Van Swearingen, Heather N. Moore, David O. Kamson, Solmaz Sahebjam, Greg Kirkner, Anna Gorfinkel, Sarah Sammons, Nancy U. Lin, Carey Anders, Cesar A. Santa-Maria. Response to PARP inhibitors in patients with breast cancer metastatic to the central nervous system [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6472.

Breast lymphoma mimicking benign breast lesions: A diagnostic challenge

Abstract: NHL Primary of the breast is rare accounting 0.1% of the total malignancy. DLBCL is the most common histology for Primary NHL breast. It presentation is similar to carcinoma breast so biopsy followed by IHC is only method to differentiate between both. Due to rarity of the tumor there is lack of literature on proper diagnosis and treatment. RCHOP is the chemotherapy regime used and radiotherapy role is not clear. Some studies suggest role of CNS irradiation in high risk patient because of high chances of CNS spread in advance stage patient. In this paper we aim to highlight the diagnostic difficulties we faced and the treatment we followed. Here we bring to the knowledge of the reader about the review over diagnosis, clinical feature and treatment of NHL breast along side with two clinical cases to enhance clinical interest of the reviewer.

Multicenter Pilot Trial of Intrathecal Liposomal Cytarabine Combined with FAB Chemoimmunotherapy with Reduced Doxorubicin in CAYA with Mature De-Novo B-NHL

Background: Children, adolescents, and young adults (C-AYA) with newly diagnosed advanced Mature B Non-Hodgkin Lymphoma (MB-NHL), specifically Burkitt Lymphoma (BL) and Diffuse Large B Cell Lymphoma (DLBCL), have achieved ≥ 90% overall survival with multi-agent chemotherapy and intrathecal chemotherapy (IT) without central nervous system (CNS) radiation (Cairo et al., Blood 2007; Goldman/Cairo et al., BJH 2014; Frazier/Cairo, et al., BJH 2014; Minard-Colin, et al., NEJM 2020). Standard therapy includes short but intensive courses of multiagent chemotherapy including CNS-penetrating high dose methotrexate and cytarabine for CNS penetration as well as vincristine, prednisone, doxorubicin, and cyclophosphamide with or without etoposide. Patients also receive 9, 10 and 13 IT doses of intrathecal chemotherapy when treated according to FAB Group B, FAB Group C (CNS -) and FAB Group C (CNS +) protocols, respectively. While this approach has effectively eliminated need for CNS radiation for disease control, the need for sedation of patients during these procedures results in the need for repeated episodes of patient fasting, increased healthcare costs, and most importantly, general anesthesia is associated with long-term late effects in cognitive development (Banerjee et al., JAMA Oncol, 2019). Liposomal cytarabine (LC) is a formulation of cytarabine encapsulated in spherical multivesicular, biodegradable particles known as DepoCyt® which has a maximum-tolerated intrathecal dose of 35 mg in patients between the ages of 3 and 21 years (Bomgaars et al., JCO, 2004). This liposomal formulation has a half-life of 100-263 hours compared with only 3.4 hours of standard cytarabine. As an s-phase specific agent, prolonged exposure may increase its efficacy in controlling CNS disease while decreasing the total number of intraventricular doses required for treatment. Objective: To determine the safety and efficacy of reduction of IT therapy and substitution of LC within modified FAB group B and C backbones of systemic immunochemotherapy. Methods: LC was incorporated into the multiagent chemotherapy regimen in a unique manner to mitigate the risk of possible CNS toxicity. A total of 2 doses of LC were administered as part of the prophylaxis IT therapy for Group B and CNS negative group C patients. A total of 4 doses of LC were administered as part of the treatment of Group C CNS + patients (Table 1). The LC was given only in phases of therapy in which no systemic cytarabine was administered. When Methotrexate was given, the LC was only given after clearance. Dexamethasone replaced prednisone for all patients to mitigate potential CNS toxicities from LC. Results: This trial enrolled 33 patients with newly diagnosed MB-NHL (25 Group B, 8 Group C with 7 CNS+). Median age was 12 (Range 3-25). Males comprised 64% of patients and 52% had Burkitt Lymphoma/Leukemia. The CNS was involved in 21% of patients, and a total of 78 doses of LC was given. Twenty-six patients received 2 prophylactic doses (25 Group B and 1 Group C CNS negative). Six of seven CNS + patients received all 4 planned doses of LC. The median days from the start of the induction cycles until LC administration (post methotrexate clearance) was 3 days. Of the 33 patients, only 1 (3%) had a transient Grade 3 adverse event (facial nerve palsy). With dexamethasone prophylaxis, there were minimal adverse events and no toxic deaths reported. There were no other serious adverse events, such as seizure, headaches, nausea, vomiting, fever, somnolence, confusion, or asthenia that have been previously reported. The 2-year EFS and OS of LC when added to an FAB backbone for MB-NHL, was 94.5% and 97.2%, respectively (Figure 1). Conclusions: By utilizing dexamethasone prophylaxis and waiting for systemic methotrexate clearance, we were able to demonstrate that IT LC in C-AYAs with MB-NHL who received FAB chemoimmunotherapy with HD MTX was feasible, safe, and did not compromise event free and overall survival. We were also able to reduce the total number of IT injections without apparent compromise to CNS prophylaxis and treatment.

CNS Radiotherapy As Bridging Prior to CAR T-Cell Therapy for Non-Hodgkin B-Cell Lymphoma

Introduction: Up to 80% of patients who receive CAR T-cell therapy (CAR T) for central nervous system lymphoma (CNSL) require bridging therapy, yet optimal regimens remain undefined. Radiotherapy is an established strategy for extracranial lymphoma that provides beneficial cytoreduction. However, CNS bridging radiotherapy (CNS-BRT) prior to CAR T is controversial due to concerns of potential enhanced neurotoxicity. We explored the safety and response profiles in patients treated with CNS-BRT prior to CAR T. Methods: We identified patients with non-hodgkin B-cell lymphoma who received CNS-BRT at our institution prior to commercial CAR T infusion. CNS-BRT was defined as treatment delivered between apheresis and CAR T infusion or within 30 days prior to apheresis, targeting the CNS parenchyma, leptomeninges, or epidural spine. Patients with epidural spine disease were included since the adjacent spinal cord is part of the treatment field. Safety was evaluated by rate of cytokine release syndrome (CRS) and immune effector associated neurotoxicity syndrome (ICANS) after CAR T. Best CNS response post CAR T was evaluated using the International Primary CNS Lymphoma Collaborative Group (IPCG) or Response Assessment in Neuro-Oncology (RANO) for parenchymal or leptomeningeal lesions, respectively. Cytoreduction from CNS-BRT was estimated by calculating the change in lesion size (sum of product diameter) from before and after CNS-BRT, but before CAR T infusion. Risk of any CNS relapse after CAR T was estimated using the Gray's method with death as a competing risk. Patients with epidural spine disease were not evaluate for CNS response or relapse. Results: 12 patients received CNS-BRT with median follow up of 8.5 months (range: 3.2 - 30.2), median age of 60 (30-76), median Karnofsky Performance Status (KPS) of 80 (range: 50 - 90). Histologies included diffuse large B cell (DLBCL) (n = 9), mantle cell (n = 2), and Burkitt lymphoma (n = 1), with disease localizing to the brain parenchyma (n = 6), leptomeninges (n = 4), and epidural spine (n = 2). 9 patients had secondary CNSL and 1 patient had primary CNSL. Prior to CNS-BRT, 11/12 patients had progressive disease. 5/12 patients had disease outside of the CNS. 5/12 patients received prior autologous hematopoietic stem cell transplantation. 9/12 patients received prior high dose methotrexate with median 46-day interval to CNS-BRT (range: 0 - 393). RT targets included whole brain (n = 3), involved site (partial) brain (n = 4), involved site spine (n = 4), and orbits (n = 1) with median dose 24 Gy (range: 15 - 33). CAR T products included Tisagenlecleucel (n = 4), Lisocabtagene maraleucel (n = 7), and Axicabtagene ciloleucel (n = 1). Among 10 patients with available toxicity grading, 6/10 experienced CRS (n = 1 grade (G) 1, n = 4 G2, and n = 1 G3), and 3/10 experienced ICANS (n = 1 G1, n = 1 G3, n = 1 G4). 6/10 patients required tocilizumab and/or steroids. CNS-BRT achieved a 74.4% (95% CI, 62.9 - 85.9) mean reduction in lesion size prior to CAR T infusion. Best CNS response after CAR T infusion included 3 complete responses (CR), 6 partial responses (PR), and 1 progressive disease (PD). The patients who achieved PR remained in PR at last follow up. The 12-month estimated risk of CNS progression after CNS-BRT and CAR T infusion was 20.0% (95% CI, 3- 49). CNS progression was not observed in patients who received involved site brain RT. Conclusion: Preliminary data suggest CNS-BRT achieves rapid cytoreduction prior to CAR T therapy and is associated with a favorable CNS response profile. While overall numbers are limited to date, the rate of severe CRS and ICANS is similar to that of historical series of CNSL patients treated with CAR T. However, a larger cohort will be required to determine the safety of CNS-BRT. These data support further study of RT, and exploration of involved site brain RT, as an effective bridging modality for CAR T-cell therapy in CNSL.

CNS Irradiation in Adult De Novo B-Precursor ALL / Lbl: Results of the Randomized GMALL T rial 08/2013 Indicate Potential Antileukemic Efficacy

In the past decade outcome of adult ALL was improved significantly using pediatric-based chemotherapy. The GMALL Trial 08/2013 (NCT02881086) for patients (pts) aged 18-55 years (yrs) with newly diagnosed ALL/LBL is a pediatric based regimen with MRD based treatment stratification and risk adapted stem cell transplantation (SCT) (Gökbuget et al, ASH 2021). CNS prophylaxis consisted of three doses i.th. MTX during induction II, 11 doses of triple i.th. for standard risk (SR) in consolidation (C)/maintenance and 1 dose before SCT in high risk (HR); 7 vs 1 cycle of HDMTX (1.5 g/m 2 as 24h infusion) were scheduled in SR and HR resp. Prophylactic fractionated CNS irradiation (RAD) with 24 Gy during induction II (IP2) was part of all previous GMALL trials. The trial incorporated a randomization for Ph/BCR::ABL1 negative (Ph-) B-precursor ALL/LBL without initial CNS involvement and treated until C1 in order to compare standard IP2 with i.th. MTX with vs without CNS RAD. The key endpoint was the time from start of induction to start of C1 in CR pts, reasoning that less toxicities and treatment delays would occur without CNS RAD. Further endpoints were remission duration (RD), event-free survival (EFS) and cognitive disturbances (DemTect Test). The statistical assumption was that it is possible to detect a shortening of time to C1 from 74 to 69 days with a power of more than 90% with 215 pts per arm with a two-sided α-niveau of 5%. Between 8/2016-8/2022 1023 pts from 78 centers were included. 512 pts had Ph- B-precursor ALL/LBL (497/15). 31 pts had initial CNS involvement (N=20) or were not randomized due to other reasons (N=11). 241 pts were randomized in arm A (RAD) and 241 in arm B (NoRAD). The median age was 33.5 (18-55) yrs; c/pre B-ALL versus pro B-ALL was present in 83% vs 17%. 191 were HR vs 291 SR. No significant differences were observed between both arms. 477 pts were randomized (ITT population) and 422 were eligible (analysis population) since they achieved CR and were treated until C1. Reasons for non-eligibility were protocol violation (N=5), early death (ED) (N=15), withdrawal (N=12), no CR before C1 (N=18) and late withdrawals in CR before C1 (N=10). 207 pts in the RAD-arm (86%) vs 215 pts in the NoRAD-arm (89%) were eligible. In the analysis population treatment per randomization was 97% in NoRAD and 95% in RAD arm. CR rates before C1 (95% RAD vs 96% NoRAD), ED rates (5% vs 4%), rates of grade III/IV leukopenia in IP2 (14% vs 16%) and infections (29% vs 29%) were similar. The median time to C1 was similar too (75 vs 76 days; p=0.34). Relapse rates (RR) were lower in RAD (13%) vs NoRAD (18%) (p=0.14). Whereas CNS relapses were infrequent in both arms (N=1 vs N=3 i.e. 1% vs 1%; p=0.62), the rate of BM±other relapses (11% vs 15%; p=0.15) was lower in the RAD arm. The cumulative incidence of CNS relapse at 3 yrs was 1% vs 1% and of all relapses 14% vs 20% (p=0.13). The EFS at 3 yrs was higher for the RAD (79% [95%-CI: 72% - 85%]) vs NoRAD (72% [95%-CI: 65% - 78%])(p=0.10) in the analysis population and 74% vs 67% (p=0.13) in the ITT population. In the ITT population the impact was statistically significant (p=0.05) in SR pts whereas no difference was detected in HR (i.e. pts with indication for SCT) (figure 1); differences did not reach significance in the analysis population. We further analyzed the impact of randomization arm on cognitive function (analysis population). After C1 results were available in 264 pts. In the RAD vs NoRAD arm 2% vs 2% resp. had low scores (0-8) and 10% vs 8% intermediate scores (9-12) indicating a relevant or limited cognitive disturbance. At the end of therapy (week 130), results are available in 53 pts treated in SR arm. 0% vs 4% had low and 4% vs 4% intermediate scores. Thus, relevant cognitive limitations were present in both arms. The primary endpoint (time to C1) was not met. Pts with RAD did have a trend towards better EFS and RD. The CNS RR was overall low but CNS RAD might have an impact on the systemic relapse rate in SR pts. We recorded no significant negative impact of CNS RAD on DemTect results, but this requires further observation. Results must be interpreted in the context of adult pts with potentially lower risks for cognitive disturbances compared to children and - on the other hand - a relatively low dose of systemic HDMTX. Overall, no clear negative effects of CNS RAD were detected whereas a trend towards positive impact on EFS was observed. GMALL 08/2013 is an independent academic trial funded by the Deutsche Krebshilfe.

Pituitary Metastasis Clinical Presentation of Diabetes Insipidus Six Years after Invasive Breast Carcinoma Diagnosis: Case Report

Introduction: Breast carcinomas are the major cause of death in women with cancer worldwide, mainly in metastatic cases. The pituitary gland stands for only 6-8% of the secondary sites of distant metastasis and it is usually asymptomatic. When symptomatic, these lesions can mimic primary pituitary diseases. Case report: A 43-year-old woman underwent a left mastectomy with axillary lymph node dissection in April 2013 due to a luminal, invasive ductal carcinoma with nodal metastasis. Six years later, she started complaining of myalgia, bone pain, dizziness and decreased visual acuity, in addition to polydipsia and polyuria. Laboratory tests showed hyperprolactinemia and diabetes insipidus suggestive of panhypopituitarism. Magnetic resonance imaging of the brain showed a sellar tumor with extension to adjacent structures which was removed on November 2019. A pathology report of an epithelial neoplasm of unknown origin and an immunohistochemical study showed positivity for estrogen, progesterone receptors and GATA 3, and negativity for pituitary hormones. This set of findings and the histological morphology were consistent with a metastatic mucinous adenocarcinoma of mammary origin without HER-2 overexpression. The patient underwent ovarian ablation, central nervous system radiotherapy, chemotherapy and oncological follow-up. Conclusion: The patient's young age and clinical presentation of visual impairment and sudden development of diabetes insipidus diverges from the current data, since these findings are usually present in asymptomatic women over sixty-years-old. The varied clinical presentation can lead to a delay in diagnosis of pituitary metastasis, which reinforces the importance of reporting cases like this.

Selected-Lesion Stereotactic Radiosurgery in Treatment of Patients with Multiple Brain Metastases: A Single Institution Retrospective Study

Stereotactic Radiosurgery (SRS) has been increasingly used as first and subsequent-line treatments for brain metastases. While the appropriate cut-off number of lesions for SRS is still being debated nationally in patients with multiple brain metastases, some institutions use an alternate approach particularly for patients with >10-15 lesions. Selected-lesion SRS (SL-SRS) is where only a subset of lesions are chosen for initial SRS treatment leaving small and clinically inconsequential lesions for treatment using alternate or delayed treatments. This study aims to investigate the patient selection criteria, patient and tumor characteristics and analyze the outcomes in patients receiving SL-SRS for brain metastases at our institution. Clinical data from patients treated using the SL-SRS approach from 2012-2022 at our institution were retrospectively reviewed. Patients were divided into cohorts based on overall survival from time of SL-SRS treatment and indications for using SL-SRS. We compared the patient characteristics (age, histology, KPS, dsGPA), tumor characteristics (cumulative tumor volumes, tumor dose, number of brain metastases found, number of metastases treated), treatment characteristics (chemotherapy, immunotherapy, previous SRS/ radiation, previous WBRT) and the reason for decision to recommend SL-SRS across these cohort. A total of 102 patients were treated using the SL-SRS approach. Indications for using SL-SRS were immunotherapy trial (n = 40), CNS penetrating drug options available (n = 18), patient refusing WBRT (n = 6), palliative after prior WBRT/SRS (n = 28), WBRT planned to follow SRS (n = 9). 31 patients were alive at 12 months and 21 patients at 24 months. In patients surviving <12 months - the most common indications for SL-SRS were CNS palliation in the setting of progressive disease after prior WBRT or SRS. Patients in this group had median KPS< = 60 and had predominantly non-small cell carcinoma primary diagnosis. In those patients surviving >12 months - the most common indication for SL-SRS was participation in CNS-penetrant agent clinical trials without WBRT. Patients in this group were more likely to be female, had a median KPS of 90, had predominantly diagnoses of melanoma. Following the SL-SRS treatment, 14 patients required further SRS and 4 patients went on to WBRT in the >12-month survival group. No patients died of CNS progression alone. 10 patients survived 24 months without requiring further CNS radiation. In our institution, SL-SRS has predominantly been used either as palliative treatment at time of disease progression or to facilitate entry onto clinical trial with immunotherapy or potentially CNS-penetrant agents. The latter indication resulted in 47.6% patients surviving >24 month without the need for additional radiation to the CNS and therefore SL-SRS should be considered a feasible, safe and effective alternative to either WBRT or SRS treatment of all radiographically visible brain metastases.

Real World Utilization of Cranial or Craniospinal Radiation in Adult Acute Lymphoid Leukemia Patients: Data from the Center for International Blood and Marrow Transplant Research

Though CNS involvement at diagnosis in adult acute lymphoid leukemia (ALL) is relatively rare (3-7%), >50 % of patients will develop CNS relapse without CNS-directed therapy. Radiation therapy is commonly used as part of stem cell transplant (SCT) conditioning. Historically, a cranial boost was given to reduce risk of CNS relapse. While a CNS boost is not a universal part of prophylaxis, CNS directed RT is used in patients at highest risk for CNS relapse following transplantation, typically those with CNS disease at diagnosis or after induction. There is little data on real world utilization of CNS directed radiation as part of SCT for adult ALL patients. The Center for International Blood and Marrow Transplant Research (CIBMTR) database was queried for adult ALL patients undergoing SCT between 2013 - 2019 who received TBI as part of their regimen where data was available on CNS directed RT. Patient demographics, pre-transplant response to induction, CNS status pre/post-transplant, and overall survival information were collected. Results were stratified by cranial irradiation (CNS-RT), craniospinal irradiation (CSI), or no cranial RT (nCRT). Radiation dose is not collected by the CIBMTR. The data presented here are preliminary and were obtained from the Statistical Center of the Center for International Blood and Marrow Transplant Research. The analysis has not been reviewed or approved by the Advisory or Scientific Committees of the CIBMTR. A total of 1240 patients were identified, of which 59 (5%) received CNS-RT, 2 (0.2%) received CSI, 989 (80%) received nCRT, and 190 (15%) had unknown CNS RT status. Median age was younger in patients receiving CNS-RT (26y, range 19-66y) or CSI (34y, 22-46y) compared to patients receiving nCRT (42y, 18-79y). Patients receiving CNS radiation had more advanced disease at time of transplant (17% requiring 3+ lines of induction before CR vs 50% vs 5%, respectively). 24% of CNS-RT patients and 50% of CSI patients had CNS disease at diagnosis compared to 7% of nCRT patients. 37% of CNS-RT patients and 100% of CSI patients had CNS disease prior to transplant compared to 11% of nCRT patients. Overall survival at 1-5 years was numerically higher with CNS-RT compared to no RT, though 95% confidence intervals overlapped at each follow up point. Data from the CIBMTR on real world utilization of CNS-RT or CSI in adult ALL patients suggest inconsistent practice patterns with 11% of patients without any cranial RT having CNS disease prior to transplant and 57% of CNS-RT patients having no CNS disease prior to transplant. These data offer an interesting analysis of current CNS radiation practice patterns in the past 10 years for adult ALL patients, though interpretation is limited by the retrospective nature of the study and by significant limitations of available data.

Stereotactic Radiotherapy or Whole Brain Radiotherapy Combined with Pyrotinib and Capecitabine in HER2-Positive Advanced Breast Cancer Patients with Brain Metastases (BROPTIMA): A Prospective, Phase Ib/II Single-Arm Clinical Study

Approximately half of patients with advanced HER2-positive breast cancer (BC) will develop brain metastases (BM) over time. Local therapy including stereotactic radiotherapy (SRT) and whole brain radiotherapy (WBRT) is the main initial treatment in malignant tumor patients with BM. However, more than 50% patients after radiotherapy in one year suffered intracranial recurrence. Pyrotinib, a small molecule, irreversible, pan-ErbB receptor tyrosine kinase inhibitor (TKI), has a high potency for controlling BM and reducing the occurrence of brain metastases in advanced HER2-positive BC patients. We hypothesized that SRT or WBRT combined with pyrotinib and capecitabine could decrease intracranial progression in HER2 positive BC with newly diagnosed BM. In this prospective single-arm phase Ib/II trial (NCT04582968), eligible patients were assigned to either fractionated stereotactic radiotherapy (FSRT) or whole-brain radiation therapy (WBRT), combined with pyrotinib and capecitabine. The primary endpoint was one-year CNS progression-free survival (PFS) rate. Secondary endpoints included intracranial objective response rate (IC-ORR) according to RANO-BM criteria, progression-free survival (PFS), overall survival (OS) and evaluation of safety and neurocognitive function. From January 2020 to August 2022, 40 patients were enrolled. Twenty-nine patients were treated with FSRT in 8 Gy per fraction with 3 to 5 fractions and 11 were treated with WBRT in 3 Gy per fraction with 10 fractions, and then received chemotherapy in a time frame starting from 0 to 7 days after radiotherapy. At a median follow-up of 17.3 months, 1-year CNS-PFS rate was 74.9% (95% CI 61.9-90.7%) and median CNS-PFS was 18 months (95% CI, 15.5 to NA months). One-year PFS rate was 66.9% (53.1-84.2%) and median PFS time was 17.6 months (95% CI 12.8-34.1 months). The best intracranial response rate (IC-ORR: complete response and partial response) was 92.5% (37/40). The most common grade 3 or worse toxicity was diarrhea (7.5%) and asymptomatic radiation necrosis was detected in 4 of 67(6.0%) lesions treated with FSRT. No differences of neurocognitive function evaluated by MMSE (Mini-Mental State Exam) were observed between different groups at any time point. Radiotherapy combined with pyrotinib and capecitabine resulted in a promising efficacy that crossed the pre-specified boundary in patients with HER2-positive advanced breast cancer with brain metastases. This is the first prospective study showing the efficacy and safety of CNS radiotherapy concurrent with pyrotinib and capecitabine in patients with BM from HER2-positive breast cancer. Further investigation in a randomized controlled study is warranted.

Therapy of childhood acute lymphoblastic leukemia in resource-poor geospaces.

The therapy of children with acute lymphoblastic leukemia (ALL) in limited resource geospaces is challenging and must balance safety, efficacy, availability, and affordability. We modified the control arm of the St. Jude Total XI protocol for outpatient delivery including once-weekly daunorubicin and vincristine in initial therapy, postponing intrathecal chemotherapy until day 22, prophylactic oral antibiotics/antimycotics, use of generic drugs, and no central nervous system (CNS) radiation. Data were interrogated from 104 consecutive children ≤12 years (median, 6 years [interquartile range (IQR), 3, 9 years]. All therapies were given in an outpatient setting in 72 children. Median follow-up is 56 months (IQR 20, 126 months). A total of 88 children achieved a hematological complete remission. Median event-free survival (EFS) is 87 months [95% confidence interval (CI), 39, 60], 7.6 years in low-risk children (3.4, 8 years) whereas 2.5 years (1, 10 years) in high-risk children. The 5-year cumulative incidence of relapse (CIR) is 28% (18, 35%), 26% (14, 37%) in low-risk children and 35% (14, 52%) in high-risk children. Median survival for all subjects is not reached but must exceed 5 years. A total of 36 children relapsed at a median of 12 months (5, 23 months). Outcomes were comparable to those reported in the control arm of the Total Therapy XI study, but inferior to current treatment protocols in high-income countries. The average cost of the first 2 years of therapy was $28,500 USD compared with an average cost of approximately $150,000 USD in the US, an 80% saving. In conclusion, using an outpatient-based modification of the St. Jude Total XI protocol, we obtained good results with relatively few hospitalizations or adverse events and at a substantial saving. This model can be applied in other resource-poor geospaces.

Targeted Central Nervous System Irradiation with Proton Microbeam Induces Mitochondrial Changes in Caenorhabditis elegans.

Fifty percent of all patients with cancer worldwide require radiotherapy. In the case of brain tumors, despite the improvement in the precision of radiation delivery with proton therapy, studies have shown structural and functional changes in the brains of treated patients with protons. The molecular pathways involved in generating these effects are not completely understood. In this context, we analyzed the impact of proton exposure in the central nervous system area of Caenorhabditis elegans with a focus on mitochondrial function, which is potentially implicated in the occurrence of radiation-induced damage. To achieve this objective, the nematode C. elegans were micro-irradiated with 220 Gy of protons (4 MeV) in the nerve ring (head region) using the proton microbeam, MIRCOM. Our results show that protons induce mitochondrial dysfunction, characterized by an immediate dose-dependent loss of the mitochondrial membrane potential (ΔΨm) associated with oxidative stress 24 h after irradiation, which is itself characterized by the induction of the antioxidant proteins in the targeted region, observed using SOD-1::GFP and SOD-3::GFP strains. Moreover, we demonstrated a two-fold increase in the mtDNA copy number in the targeted region 24 h after irradiation. In addition, using the GFP::LGG-1 strain, an induction of autophagy in the irradiated region was observed 6 h following the irradiation, which is associated with the up-regulation of the gene expression of pink-1 (PTEN-induced kinase) and pdr-1 (C. elegans parkin homolog). Furthermore, our data showed that micro-irradiation of the nerve ring region did not impact the whole-body oxygen consumption 24 h following the irradiation. These results indicate a global mitochondrial dysfunction in the irradiated region following proton exposure. This provides a better understanding of the molecular pathways involved in radiation-induced side effects and may help in finding new therapies.

CNS radiotherapy as bridging prior to CAR T‐cell therapy for hematologic malignancies

Introduction: Up to 80% of patients who receive CAR T-cell therapy for central nervous system lymphoma (CNSL) require bridging therapy, yet optimal regimens remain undefined. Bridging radiotherapy (BRT) is an established strategy for extracranial lymphoma that provides beneficial cytoreduction. However, BRT for CNSL (CNS-BRT) is controversial due to concerns of potential enhanced neurotoxicity. We explored the safety and response profiles for CNS-BRT prior to CAR T therapy. Methods: We identified CAR T patients with hematologic malignancy at MSKCC who received CNS-BRT, defined as treatment delivered between cell collection and infusion to targets in CNS parenchyma, leptomeninges, or epidural space. Safety was evaluated by cytokine release syndrome (CRS), immune effector associated neurotoxicity syndrome (ICANS), and immune effector cell encephalopathy (ICE) scores, as documented by primary physician. Response was evaluated within the RT field for patients with baseline measurable disease using the International Primary CNS Lymphoma Collaborative Group (IPCG), Response Assessment in Neuro-Oncology (RANO), and Response Evaluation Criteria in Lymphoma (RECIL) radiographic criteria for parenchymal, leptomeningeal, and epidural lesions, respectively. Results: 11 patients received CNS-BRT with median follow up of 10.1 months (range: 1.1–25.9). At RT, median age was 51 (25–79), median KPS was 80 (50–90), and 9/11 patients had progressive CNS disease. 8/11 patients received prior methotrexate (high dose n = 7, intrathecal n = 1) with median 39-day interval to RT (0–179). Disease was localized to the brain parenchyma (n = 6), leptomeninges (n = 2), and epidural spine (n = 3). RT targets included whole brain (n = 3), involved site (partial) brain (n = 4), and involved site spine (n = 4), with median dose 24 Gy (20–30). Patient and CAR T cell characteristics are shown in Table 1. 4/10 patients experienced ICANS (n = 1 grade (G) 1, n = 1 G2, n = 1 G3, and n = 1 G4). 8/10 patients experienced CRS (n = 2 G1, n = 5 G2, and n = 1 G3). 6/11 patients required tocilizumab and/or steroids. Patients with G3/4 ICANS had decreased baseline ICE scores of 5 and 6, respectively. Median change in lesion size prior to CAR T infusion was -43.6% (-3.1% to -74.5%) among 7 evaluable patients. Best response included 6 partial responses (PR) and 4 complete responses (CR) at median 4.2 months (0.5–10.4). There were 3 CNS treatment failures, 1 in the leptomeninges and 2 in the paraspinal/epidural space. Keywords: Aggressive B-cell non-Hodgkin lymphoma, Cellular therapies, Radiation Therapy Conflicts of interests pertinent to the abstract. R. Shouval Other remuneration: Medexus Pharmaceuticals, Inc., MyBiotics P. B. Dahi Other remuneration: Curio Science LLC, Kite Pharmaceuticals, OncLive, Targeted Oncology R. J. Lin Consultant or advisory role: Kite, A Gilead Company M. L. Palomba Other remuneration: BeiGene, Ltd., Mustang Bio, Novartis, Synthekine, Inc. M. Perales Stock ownership: NexImmune, Omeros, Orca Biosystems, Inc. Other remuneration: ADC Therapeutics, Bristol-Myers Squibb, Cidara Therapeutics, Inc., CoImmune, Inc., Equillium, Inc., Incyte, Jazz Pharmaceuticals, Karyopharm, Kite Pharmaceuticals, Merck & Co Inc., Miltenyi Biotec Incorporated, MorphoSys AG, Novartis, Partners Therapeutics Inc., VectivBio AG, Vor Biopharma Inc. G. Salles Stock ownership: Owkin, Inc. Other remuneration: AbbVie, Aptitude Health, Bayer, BeiGene, Ltd., Bio Ascend, Bristol-Myers Squibb, Celgene, Epizyme, Everest Clinical Research Corporation, GenMab, Genentech, Gilead Pharmaceutical, Incyte, Ipsen, Janssen Pharmaceuticals, Inc., Loxo Oncology, Miltenyi Biotec Incorporated, MorphoSys AG, Nordic Nanovector ASA, Novartis, Physicians' Education Resource, RAPT Therapeutics, Regeneron Pharmaceuticals, Inc., Roche, Scientific Education Support Ltd., Takeda Millennium L. Falchi Consultant or advisory role: Genmab, Abbvie, Genentech, ADC therapeutics, Astrazeneca, Seagen, Roche Research funding: Genmab, Abbvie, Roche, Genentech Educational grants: Genmab C. Grommes Other remuneration: BTG International, Ono Pharma, Roche M. Scordo Consultant or advisory role: McKinsey & Company, Angiocrine Bioscience, Inc., Omeros Corporation, Kite – A Gilead Company Honoraria: i3Health, Medscape Research funding: Angiocrine Bioscience, Inc., and Omeros Corporation J. Yahalom Other remuneration: Convergent R.N.R Ltd. B. S. Imber Other remuneration: GT Medical Technologies, Inc.

Safety and preliminary efficacy of intrathecal (IT) and intravenous (IV) nivolumab (N) for patients (pts) with leptomeningeal disease (LMD).

9554 Background: Pts with LMD have a dismal prognosis, with median overall survival (OS) &lt; 3 months, no approved therapies and extremely limited clinical trial options. We previously reported initial safety findings from the dose escalation of an open label, single arm, single center phase I/IB trial (NCT03025256) for pts with metastatic melanoma (MM), in which IT/IV N were well tolerated, without any CNS-specific or unexpected toxicity. Here we report an update on safety, maximum tolerated dose (MTD), and dose expansion cohort (including 2 pts with NSCLC) and preliminary efficacy. Methods: Pts aged ≥18 with evidence of LMD by MRI and/or CSF cytology, ECOG PS ≤2 were treated with IT/IV N. Dexamethasone (dexa) ≤4mg/daily and concurrent BRAF/MEK inhibitor(i) therapy (tx) were allowed. For cycle 1, IT N was administered via ommaya reservoir on day (D)1. For subsequent cycles (every 14 days) pts received IT N on D1, followed by IV N 240 mg on D2. IT N doses evaluated were 5, 10, 20, and 50 mg. Blood and CSF were collected at multiple time points for translational research. The primary objectives were to determine safety and/or recommended dose/MTD of IT N given with IV N in pts with LMD and the safety of the MTD in an expansion cohort. OS was a secondary objective. Bayesian mTPI methodology was used to define the MTD. Results: 50 pts were treated: 17 in the dose escalation (2 at 5; 3 at 10; 6 at 20; 6 at 50 mg IT N), 8 in the initial expansion of 20mg, and 25 at the MTD 50 mg IT N. 48 pts had a diagnosis of MM, 2 NSCLC. Median age at LMD was 49 (19-74); 27 pts are male. All pts had radiographic evidence of LMD; 26 pts had positive baseline CSF cytology. 46 pts received prior systemic tx including checkpoint inhibitors (n = 42) and targeted tx (n = 34). 39 pts had prior CNS radiation (RT), including whole brain RT (n = 14). 18 pts used concurrent steroid, with a median dose of 2mg (0.9-4) dexa equivalent and 27 pts used concurrent targeted tx with BRAF/MEKi. The median number of IT N doses was 6 (1- 92). The combination regimen was well tolerated by all evaluable pts (n = 50), with 9 pts (18%) experiencing grade (gr) 3 AEs and no reported gr 4 or 5 toxicities. Rash (58%), nausea (44%), vomiting (34%), and dizziness (22%) were the most common AEs. Thirty pts (60%) experienced AEs after IT N administration, all gr 1/2 and 1 gr 3 (vasogenic edema). At a median follow-up of 4.6 months (mths) (0, 54.8 mths), median OS was 7.0 mths. OS was 66.6% at 3 mths, 53.1% at 6 mths and 34.8% at 12 mths. Conclusions: IT + IV nivo was safe and well-tolerated in MM pts with LMD, with no unexpected toxicities of the 50 mg MTD of IT N. OS rates at 6 and 12 mths are encouraging and support further evaluation of IT immunotherapy for LMD, including in other tumor types. Overall results also demonstrate the feasibility of prospective clinical trials in pts with LMD. Final presentation will also include immunological analysis of longitudinally collected CSF samples collected in the trial. Clinical trial information: NCT03025256 .

PD-0656 Evaluation of an interactive, multi-language, neurocognitive app in CNS radiation oncology

PD-0656 Evaluation of an interactive, multi-language, neurocognitive app in CNS radiation oncology