Median Karnofsky Performance Status Research Articles

Abstract CT019: Biological mechanisms underlying objective responses in recurrent GBM patients treated with sequential bortezomib and temozolomide: An interim analysis of NCT03643549 Phase IB/II trial

Abstract Background: Glioblastoma (GBM) has dismal prognosis, where median survival is approximately 12 months for patients harboring unmethylated O6−methylguanine DNA methyltransferase (MGMT) promoter (uMGMT) due to temozolomide (TMZ) chemotherapy resistance. In preclinical studies, we showed that sequential administration of bortezomib (BTZ) prior to TMZ depleted MGMT protein, abrogated autophagic flux and sensitized uMGMT GBM cells to TMZ. Thus, a phase I/II was launched to investigate clinical benefit. An interim analysis based on Simon´s MinMax design (where at least 2 patients should show clinical benefit amongst the first 15 evaluable patients) would allow the study to continue to full recruitment. Clinical benefit, was defined by progression free survival and or objective radiological complete (CR), partial (PR) responses or stable disease (SD) based on RANO criteria at 6 months and 1-year follow-up. This study aimed to identify the biological mechanisms underlying the objective responses in the initial 15 recurrent GBM patients treated in this trial. Methods: Adult recurrent GBM patients with uMGMT promoter, progressing ≥12 weeks after radiotherapy, Karnofsky performance status (KPS) ≥70 and with measurable lesions were enrolled. They received BTZ 1.3mg/m2 IV on days 1,4,7, during each 4-week cycle starting on day 3 with per oral TMZ at 200mg/m2 5 days/week. The sample size was powered for n=63 patients. Quantitative LC-MS/MS was used to identify novel biomarkers that correlate with objective treatment responses by determining proteomic changes in plasma collected on days 1,4,7,11,15 and 22 during first cycle of treatment. Targeted sequencing of 360 cancer genes and whole exome sequencing (WES) of tumor DNA were conducted to identify associated molecular genetic changes. Results: The 15 patients had median age 52 yrs (range 25-62 yrs), 10 male and 5 female treated at Haukeland University Hospital in Norway. Median KPS was 90 (70-100) and median NANO score was 1 (0-7). 27% (n=4/15) of patients obtained objective radiological responses, where 2/4 (50%) obtained PR and 2/4 (50%) had SD. LC-MS/MS revealed significantly increased (p<0.05) levels of proteins important for regulation of cell death and apoptosis (ADAMTS13, HPR, HBD, CLU and APOE) in objective responders compared to the rest of the patients. Sequential BTZ+ TMZ therapy was safe, tolerated and platelet nadirs consistently normalized by day 22 of each cycle. Proteins associated with platelet activation, aggregation and degranulation (ACTN1, ITGB3, PLEK, PPBP, THBS1, TF, TAGLN2, TLN1, PFN1, VCL and FERMT3) were significantly upregulated (1.6-4.8 fold, p<0.05) on day 15 and 22 compared to baseline in patient plasma. Preliminary analysis of sequencing data identified EGFR gain-of-function mutation in 3 of the 4 responder patients; potentially distinguishing this as a molecular biomarker for the objective treatment responders. Conclusion: Sequential BTZ+TMZ therapy is safe and effective as indicated by objective radiological response. Activation of tumor cell death and apoptosis pathways was observed specifically in objective responders. The interim criteria were fulfilled as 4 amongst the first 15 patients showed clinical benefit. The study is currently recruiting. Citation Format: Mohummad Aminur Rahman, Dorota Goplen, Andreas Waha, Leif Oltedal, Judit Haasz, Surendra Kumar, Even Birkeland, Hrvoje Miletic, Frode Selheim, Martha Chekenya. Biological mechanisms underlying objective responses in recurrent GBM patients treated with sequential bortezomib and temozolomide: An interim analysis of NCT03643549 Phase IB/II trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT019.

Treatment Outcomes after Dose-Escalated Moderately Hypofractionated Radiotherapy for Frail Patients with High-Grade Glioma.

For high-grade glioma (HGG) patients with old age or poor performance status, hypofractionated radiotherapy (hypoRT) in 10-15 fractions is recommended. Also, limited data exist on the impact of salvage treatment after progression in frail patients. We retrospectively analyzed the outcomes of dose-escalated hypoRT in 40 frail HGG patients who were treated with hypoRT between 2013 and 2021. With a median biologically effective dose of 71.7 Gy, a total dose of 56 Gy in 20 fractions was the most frequently used regimen (53.7%). The median age and Karnofsky Performance Status of patients were 74 years and 70, respectively. Most patients (n = 31, 77.5%) were diagnosed with glioblastoma, IDH-wildtype, CNS WHO grade 4. Only 10 (25.0%) patients underwent surgical resection, and 28 (70.0%) patients received concurrent temozolomide during hypoRT. With a median follow-up of 9.7 months, the median overall survival (OS) was 12.2 months. Of the 30 (75.0%) patients with disease progression, only 12 patients received salvage treatment. The OS after progression differed significantly depending on salvage treatment (median OS, 9.6 vs. 4.6 months, p = 0.032). Dose-escalated hypoRT in 20 fractions produced survival outcomes outperforming historical data for frail patients.

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.

Germinal Center B-Cell-like (GCB) Phenotype Predicts Improved Outcomes in Central Nervous System Diffuse Large B-Cell Lymphoma Patients Receiving Stereotactic Radiosurgery (SRS)

Background: Diffuse large B cell lymphoma (DLBCL) constitutes most cases of both primary and secondary central nervous system lymphoma (CNSL). They represent a highly aggressive subset of non-Hodgkin lymphoma and prognosis varies depending on the cell of origin. Immunohistochemistry using antibodies for CD10, BCL-6, and MUM-1, also known as the Hans algorithm, is the most common method for determining the cell of origin and predicting outcomes in DLBCL. The study by Hans et al. found that the germinal center B-cell-like (GCB) group had a much better prognosis compared to the non-GCB group, with 5-year overall survival (OS) of 76% and 34% respectively. Despite chemotherapy, recurrence is common in these patients, and up to 40-50% do not achieve durable remission. It is important to identify who may benefit from more aggressive or experimental therapy at diagnosis. Stereotactic radiosurgery (SRS) is the administration of a localized, high dose of ionizing radiation and limited studies exist exploring SRS as a treatment modality in relapsed/refractory (r/r) CNSL or prognostic implications of the Hans algorithm in these patients. Aim/Objective: To perform a retrospective analysis of outcomes of patients with CNSL, phenotypes determined by the Hans algorithm, treated with SRS at a single comprehensive cancer center. Methods: We studied the demographic, clinical, pathological, and treatment characteristics of r/r CNSL patients (N=27), age ≥ 18 years, who received SRS at Roswell Park Comprehensive Cancer Center between 01/2000 and 01/2023. The Hans algorithm was used to group the patients into non-GCB (N=17) and GCB (N=10) cohorts. Overall survival (OS) and progression-free survival (PFS) were calculated and reported using Kaplan-Meier analyses and log-rank tests. Cox regression models were used to describe cross-cohort comparisons of survival. Results: The median Karnofsky performance status at diagnosis was 70 for both groups. The overall response rate (ORR) to SRS in GCB-type was 80% (7 complete response and 1 partial response; CR, PR). The ORR in non-GCB type was 58% (6 CR and 4 PR). Post-SRS, stem cell transplant (SCT) was avoided in 100% of the patients in the GCB group, while 17% of the patients in the non-GCB group received SCT. The 6-month overall survival (OS) rate was 100% and 46% for the GCB-type and non-GCB type respectively (p=0.096, Figure 1A). The 6-month progression-free survival (PFS) rate was 80% for the GCB-type and 33% for the non-GCB type (p=0.024, Figure 1B). In the GCB group, the median OS was 18.0 months while the median PFS was 13.8 months. In the non-GCB group, the median OS was 4.9 months while the median PFS was 3.6 months. The median time from chemotherapy completion to SRS administration was 8.0 months in the GCB-type and 2.0 months in the non-GCB type. Conclusion: Our data support that the GCB-type predicts a more favorable outcome in CNSL, with improved OS and PFS rates compared to the non-GCB type. In addition, the non-GCB type patients required earlier SRS administration and had a lower ORR to SRS. Classifying CNSL into GCB and non-GCB phenotypes using the Hans algorithm might help characterize patients into groups with different prognoses.

Radiotherapy As an Effective Bridge for Relapsed/Refractory Secondary CNS Lymphoma

Introduction: Secondary CNS lymphoma (SCNSL) is observed in 2-5% of patients with diffuse large B cell lymphoma (DLBCL). Progression of SCNSL after first line CNS-directed systemic therapy is particularly challenging to treat, without a clear standard of care. Brain radiotherapy (RT) is used for progressive SCNSL in either the chemo-refractory or palliative setting. Historically, the RT field included the whole brain due to concerns about diffuse intracranial involvement. However, treatment fields limited to just involved site(s) (partial brain RT) may provide a favorable balance of disease control and reduced treatment toxicity, particularly in an era of improved CNS-directed systemic therapies. We hypothesized that RT would confer a high rate of intracranial response among patients with chemo-refractory SCNSL. Methods: We identified DLBCL patients with SCNSL who received brain RT at our institution for radiographic or clinical progression after at least 1 line of SCNSL-directed therapy. SCNSL-directed therapy was defined as systemic therapy for active SCNSL (as opposed to prophylaxis). Overall survival (OS) was determined from RT start to death from any cause using the Kaplan-Meier method. OS comparing subsequent therapy was landmarked 2 months post RT to minimize immortal time bias. RT response was evaluated with contrast MRI or CT using International Primary CNS Lymphoma Collaborative Group (IPCG) or Response Assessment in Neuro-oncology (RANO) radiographic criteria for parenchymal or leptomeningeal disease (LMD), respectively. LMD was assessed by cytology and/or imaging. Results: Between 1999-2023, 55 patients received brain RT for progressive SCNSL with median follow up of 3.2 months. At the time of RT, median age was 64 (interquartile range (IQR) 49 - 71), median Karnofsky Performance Status was 70 (IQR, 60 - 80), and 85% had neurologic symptoms. Patients had received a median of 2 lines of SCNSL-directed therapy prior to RT (IQR, 1 - 3), 91% received a methotrexate-based regimen with median interval of 21 days (IQR, 10 - 67) between methotrexate and RT. Median RT dose was 30 Gy in 10 fractions delivered to whole brain (n = 44), partial brain (n = 9), or craniospinal axis (n = 2). 38 patients were evaluable for response; the remainder were lost to follow up/hospice (n = 8), lacked suitable imaging (n = 4), died with progressive neurologic symptoms (n = 4) or other cause (n = 1). The overall response rate was 79%, including a 24% complete response rate. Median time to best response was 60 days (IQR, 30 - 145). 32/55 patients (58%) were successfully bridged to subsequent systemic therapy (n = 22), hematopoietic stem cell transplantation (autologous n = 4, allogeneic n = 1), or CAR T (n = 5), after a median of 34 days from RT (IQR, 20 - 57). Median OS for the entire cohort was 3.5 months, and was improved for those who were bridged to subsequent therapy (no subsequent therapy 0.7 months, subsequent systemic therapy 4.0 months, subsequent cell therapy 8.9 months, p = 0.006). Among patients who received partial brain RT, 7/7 evaluable patients had at least a partial response and 7/9 patients were successfully bridged to subsequent therapy. Conclusion: Patients referred to RT for progressive SCNSL represent a high-risk cohort characterized by rapidly progressive, symptomatic, treatment-resistant disease. RT confers a high response rate in this chemo-resistant population, and can facilitate bridging to subsequent therapy. Preliminary data suggest that partial brain radiotherapy may be an effective bridging strategy among select patients, however a larger sample size will be required to determine this.

British Columbia Experience in Allogeneic Stem Cell Transplantation for Myelofibrosis with or without Pre-Transplant Ruxolitinib

Introduction Allogeneic stem cell transplantation (AlloHSCT) remains the only potentially curative treatment for myelofibrosis (MF). It confronts many challenges stemming from the older age of the typical patients and their age-related comorbidities, as well as disease-specific factors such as splenomegaly and hostile marrow microenvironment, which raise concerns for delayed engraftment and graft failure. Methods We performed a retrospective review of the 58 adult patients who received AlloHSCT for MF in British Columbia, Canada, in the 20-year period between January 2001 and December 2020. Data pertaining to patient demographics, disease characteristics, treatment/transplant details and clinical outcomes were gathered from the available paper and electronic records. Relapse-free survival (RFS) was defined as the time between the day of the transplant and the day of disease relapse or death from any cause. Overall survival (OS) was defined as the time between the day of the transplant and death from any cause. Patients who did not have an event during follow up were censored at the time of the last known follow up. Survival analysis was performed by Kaplan-Meier survival estimator and log-rank test, using Stata version 16.1 (Texas, USA). Results The median age of the cohort was 56 years (range 26-68), with 36% being 60 years old or older. The male to female ratio was 1.6:1. The median Karnofsky Performance Status index was 80 (range 70-100) and the median age-adjusted HCT-specific Comorbidity Index was 2 (range 0-5). The pre-transplant DIPPS plus risk category was: high in 13 patients (22%); intermediate-2 in 29 (50%); intermediate-1 in 15 (26%); and low in 1 (2%). 19/58 (33%) had a peripheral blast percentage greater than 2%. 51/58 (88%) had grade 3 fibrosis seen on the pre-AlloHSCT bone marrow biopsy. 27/57 (47%) patients were transfusion-dependent for pRBC and/or platelets. 28/54 (52%) evaluable patients had a normal karyotype and 6/54 (11%) a complex karyotype. Sixteen patients (28%) had a myeloid gene panel performed by PCR; the most commonly seen variants were ASXL1 (10 patients) and TET2 (5 patients). The median number of variants seen in a single patient was 3 (range 0-5). 42/58 (72%) patients received myeloablative conditioning before AlloHSCT. The donor type was: a volunteer unrelated donor in 54%; a matched sibling in 42%; and an alternative source (double cord or haploidentical donor) in 4%. Peripheral blood stem cells were used in 93% of the AlloHSCT. 24/58 (41%) patients received ruxolitinib pre-AlloHSCT (starting in June 2012) for a median duration of 10 months (range 1-44); 17/24 (71%) of the recipients had a clinical response to ruxolitinib but 3 had lost the response before their AlloHSCT. One patient had stopped ruxolitinib due to cytopenia. During a median follow up period of 41.7 months (range 0.5-260.7), 24/58 (41%) experienced acute graft-versus-host disease (GVHD) and 33/49 (67%) evaluable patients developed chronic GVHD. Graft failure was seen in 2 patients - one primary and the other secondary. MF relapse was seen in 13/58 (22%) after a median time of 1.1 years post-AlloHSCT (IQR 0.7-2.4). The transplant-related mortality (TRM) was 25% at 1 year and 28% at 3 years post-AlloHSCT. The most common causes of death were infection (7 patients), disease relapse (6 patients), and multiorgan failure (5 patients). Transfusion independence was achieved in 45/58 (78%) patients by day +100 and in 40/44 (90%) by 1-year post-AlloHSCT. 17/48 (35%) evaluable patients had persistent grade 3 fibrosis on their day+100 bone marrow biopsy. The estimated 1-year, 5-year and 10-year RFS rates were 66% (95% CI 52-76), 55% (95% CI 41-67) and 47% (95% CI 42-61) respectively. The estimated 1-year, 5-year and 10-year OS rates were 72% (95% CI 59-82), 63% (95% CI 49-74) and 54% (95% CI 37-68) respectively. There were no differences in RFS (p=0.40) and OS (p=0.23) between those who received ruxolitinib pre-transplant vs. those who did not. Conclusion In our cohort, approximately half the AlloHSCT recipients achieved long-term survival, many in remission (10-year OS 54%; 10-year RFS 47%). TRM was seen in 25% within the first year after AlloHSCT, with patients most commonly succumbing to infections. The graft failure rate was low at 3%. An increasing number of patients received pre-AlloHSCT ruxolitinib in the recent years but we were unable to demonstrate improved transplant outcomes with its use in this single centre cohort.

Peripheral Blood Haploidentical Allogeneic Stem Cell Transplantation in Older Adults with Acute Myeloid Leukemia and Myelodysplastic Syndromes Demonstrates Long Term Survival, Results from Australia and New Zealand Transplant and Cellular Therapies

There is a limited body of evidence for haploidentical hematopoietic stem cell transplantation (haplo-HSCT) in older patients. Previous studies have used a high proportion of bone marrow–derived grafts and a variety of conditioning regimens. In Australia and New Zealand, haplo-HCST is predominantly performed using peripheral blood (PB) with universal use of post-transplantation cyclophosphamide (PTCy). To characterize the outcomes of older recipients undergoing haplo-HSCT for acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). Data were collected through the Australasian Bone Marrow Transplant Recipient Registry (ABMTRR) for patients aged 65 or older receiving a PB haplo-HSCT for AML/MDS between January 2010 and July 2020. A total of 44 patients were included in the analysis. The median follow-up time was 377 days. The median age was 68 (range 65-74) with a median Karnofsky performance status of 90. Thirty patients (68.2%) had AML, whereas 14 (31.8%) had MDS. The median donor age was 40. The most common conditioning regimen was nonmyeloablative fludarabine, cyclophosphamide, and total body irradiation (75%); the remainder of the patients received either melphalan- or busulfan-based regimens, and the majority were reduced intensity, with only 2 patients undergoing myeloablative conditioning. All patients received post-transplantation cyclophosphamide and mycophenolate mofetil, with the majority also receiving tacrolimus (90.5%) and the remainder receiving cyclosporine (9.5%). No patients received anti-thymocyte globulin. Neutrophil engraftment was achieved in 97.6% of patients at a median of 18 days, whereas platelet engraftment was achieved in 92.7% of patients at a median of 28 days. The cumulative incidences of cytomegalovirus (CMV) reactivation and CMV disease were 52.5% and 5.1% at 1 year. The incidence of grade 2-4 acute Graft Versus Host Disease (GVHD) was 18.2%. The incidence of chronic GVHD at 2 years was 40.7%, with extensive chronic GVHD occurring in 17.7% of patients. The incidences of relapse and non-relapse mortality (NRM) at 2 years were 8.8% and 20.7% respectively. The leading causes of death were infection (64.7%) followed by relapse (14.2%). The 2-year overall survival was 74%. Relapse free survival and GVHD free, relapse free survival at 2 years was 70% and 48%. Haplo-HSCT using a peripheral blood graft and PTCy GVHD prophylaxis demonstrates long-term disease control with acceptable rates of NRM for older patients with AML/MDS.

SURG-32. EFFICACY OF LASER INTERSTITIAL THERMAL THERAPY (LITT) FOR BIOPSY-PROVEN RADIATION NECROSIS IN RADIOGRAPHICALLY RECURRENT BRAIN METASTASES

Abstract BACKGROUND Evidence is growing for the efficacy of laser interstitial thermal therapy (LITT) for radiation necrosis (RN) following stereotactic radiosurgery (SRS) for patients with brain metastases. Questions remain regarding local control, symptom control, and concurrent use of therapies. METHODS Demographics, intraprocedural data, safety, Karnofsky performance status (KPS) and survival data were prospectively collected from the LAANTERN multi-center registry (NCT02392078) then analyzed on patients consented between 2016-2020 and who were undergoing LITT for biopsy-proven RN at one of 14 U.S. centers. Data was monitored for accuracy. Statistical analysis included individual variable summaries, multivariable Fine and Gray analysis, and Kaplan Meier estimated survival. RESULTS Ninety patients met inclusion criteria. Median hospitalization time was 32.5hrs. Median time to corticosteroid cessation after LITT was 13 days (range 0 - 1229) and cumulative incidence of lesional progression was 19% at 1-year. Median post-procedure overall-survival was 2.6 years [1.7, NR] and 77% at one year as estimated by Kaplan Meier. Median KPS remained 80 through 2-year follow-up. Seizure prevalence improved from 34.4% pre-procedure to 12% 1-month post-LITT and 7.9% at 3-months. There was no significant difference in risk of radiographic progression in total and near-total ablations (91% or greater ablative coverage) versus sub-total ablations (< 90%). Lesion size was not a significant predictor of future radiographic progression. CONCLUSIONS LITT is an effective, minimally invasive, safe treatment for RN, in terms of both local control and symptom management. LITT is effective in the management of lesion-related seizures in addition to averting expected neurological death. LITT facilitates ongoing systemic therapy (particularly immunotherapy) by enabling the rapid cessation of corticosteroids. Effective management options for RN could facilitate the more aggressive use of combined systemic and radiotherapeutic treatment options for brain metastases patients in order to avoid failure due to tumor recurrence and extend survival.

Post-Hoc Analysis of the Final, Three-Year Follow-up Results of a Phase I/II Study on Tirabrutinib (ONO-4059) in Patients with Relapsed or Refractory Primary Central Nervous System Lymphoma

[Background] Tirabrutinib (TIR; ONO-4059) is a second-generation inhibitor of Bruton's tyrosine kinase with high kinase selectivity. Based on the results of study ONO-4059-02 in patients with relapsed or refractory (r/r) primary central nervous system lymphoma (PCNSL) (Phase I/II study, jRCT: 2080223590), TIR was approved in Japan, Korea, and Taiwan. We have reported the results of 3-year follow-up (median follow-up: 37.1 months) of study ONO-4059-02, in which the overall response rate (ORR), the primary endpoint, was 63.6% and median duration of response was 9.2 months. The 3-year PFS and OS rates were 13.9% and 56.7%, respectively (Asai et al. ASCO 2023, Abstract 7548). Several clinical questions still remained to be addressed, including the proportion of patients who received subsequent treatment after discontinuation of TIR, and their treatment types; the characteristics of patients with higher efficacy of TIR; and the impact of long-term TIR treatment on Karnofsky Performance Status (KPS) and the Quality of Life (QoL). Here, we report the results of post-hoc analyses of the 37-month follow-up data of study ONO-4059-02. [Methods] In study ONO-4059-02, 44 patients with r/r PCNSL, age ≥20, and KPS≥70 were treated with TIR once daily at doses of 320 mg (n=20), 480 mg (n=7), or 480 mg (n=17) under a fasted condition. TIR was administered in 28-day cycles, and treatment was continued until disease progression or clinically unacceptable toxicity was observed. We assessed the number of patients who received subsequent treatment after discontinuation of TIR and their treatment types. ORR was assessed in patient subgroups according to their characteristics. In addition, patient characteristics associated with 12-month PFS rates were identified using univariate/multivariate logistic regression analysis. The time course of KPS and QoL during the TIR treatment was also assessed. QoL was evaluated using the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30, EORTC QLQ-BN20, and EuroQol 5 dimensions. [Results] Of the 44 patients, 6 patients were treated for 3 years. At the time of last visit, 2 patients (4.5%) continued the TIR treatment, 10 (22.7%) discontinued the TIR treatment but had not received subsequent treatment, and 32 (72.7%) received subsequent treatment after discontinuation of TIR. The subsequent treatments included systemic therapy, radiotherapy, hematopoietic stem cell transplantation, and surgery. Major subsequent treatments were MTX-based therapy (n=18) and radiotherapy (n=10) with the 3-year OS rate of 61.1% and 40.0%, respectively. The subgroup analyses of ORR by patient characteristics showed that response to TIR was observed in all patient subgroups; ORR was low in those refractory to the treatment just before TIR (33.3%), those receiving ≥ 4 previous treatments (33.3%), those receiving hematopoietic stem cell transplantation (28.6%), those with high tumor burden (42.9%), and those having mutations in CD79B and MYD88 (40.0%). The univariate/multivariate analyses for the 12-month PFS rate identified that baseline KPS 90-100 was significantly associated with long-term response (odds ratio 5.99, P=0.0289). The median baseline KPS was 80.0 (range: 70~100) and was maintained during the TIR treatment (max: 49 cycles). QoL scores were generally maintained. [Conclusion] The majority of patients were able to receive subsequent treatment, including MTX, after TIR. TIR responses were observed in all patient subpopulations, and the baseline KPS was suggested to be associated with long-term response. KPS and QoL were generally maintained during the long-term observation period.

Rapid Passive Gamma Mapping as an Adjunct to Electrical Stimulation Mapping for Functional Localization in Resection of Primary Brain Neoplasms

We examined the utility of passive high gamma mapping (HGM) as an adjunct to conventional awake brain mapping during glioma resection. We compared functional and survival outcomes before and after implementing intraoperative HGM. This was a retrospective cohort study of 75 patients who underwent a first-time, awake craniotomy for glioma resection. Patients were stratified by whether their operation occurred before or after the implementation of a U.S. Food and Drug Administration-approved high-gamma mapping tool in July2017. The preimplementation and postimplementation cohorts included 28 and 47 patients, respectively. Median intraoperative time (261 vs. 261 minutes, P= 0.250) and extent of resection (97.14% vs. 98.19%, P= 0.481) were comparable between cohorts. Median Karnofsky performance status at initial follow-up was similar between cohorts (P= 0.650). Multivariable Cox regression models demonstrated an adjusted hazard ratio for overall survival of 0.10 (95% confidence interval: 0.02-0.43, P= 0.002) for the postimplementation cohort relative to the preimplementation cohort. Progression-free survival adjusted for insular involvement showed an adjusted hazard ratio of 1.00 (95% confidence interval: 0.49-2.06, P= 0.999) following HGM implementation. Falling short of statistical significance, prevalence of intraoperative seizures and/or afterdischarges decreased after HGM implementation as well (12.7% vs. 25%, P=0.150). Our results tentatively indicate that passive HGM is a safe and potentially useful adjunct to electrical stimulation mapping for awake cortical mapping, conferring at least comparable functional and survival outcomes with a nonsignificant lower rate of intraoperative epileptiform events. Considering the limitations of our study design and patient cohort, further investigation is needed to better identify optimal use cases for HGM.

Clinical Outcomes of Patients with Brain Metastases from Colorectal Cancer Treated with Stereotactic Radiosurgery

Prior studies have demonstrated that brain metastases from gastrointestinal (GI) primary cancers have a poorer response to stereotactic radiosurgery (SRS) when compared to patients with other primary sites, with reported local control of 62-74%. We report our institutional outcomes for patients with colorectal primary cancer who were treated with SRS for brain metastases. Patients with colorectal primary cancer who underwent SRS for brain metastases between 1989 and 2021 were retrospectively reviewed from a single institutional IRB-approved database. The primary endpoint was local failure (LF) and secondary endpoint was overall survival (OS). LF was estimated using the Cumulative Incidence Function with death as a competing risk. Survival analysis was performed using the Kaplan-Meier Method. Predictors of cumulative incidence of LF were assessed using competing risk regression. The study population comprised of 109 patients with primary colorectal adenocarcinoma with 207 brain metastases. The median follow-up was 5.2 months (range: 0.4-124 months) and median OS was 5.8 months (range: 0.5-71.2 months). Fifty-two patients (48%) were male and median Karnofsky Performance Status at the time of treatment was 80 (range: 40-100). The median tumor diameter was 1.55 cm (range: 0.17-5.48 cm). The median prescription dose and number of fractions were 24 Gy (range: 11-36 Gy) and 1 fraction (range: 1-3 fractions), respectively. The cumulative incidence of LF at 3, 6, and 12 months was 9.7% (95% CI: 6.1-14%), 22% (95% CI: 16-28%), and 25% (95% CI: 20-31%), respectively. Overall survival at 3, 6, and 12 months was 81% (95% CI: 76-87%), 49% (95% CI: 42-56%) and 24% (95% CI: 18-31%), respectively. On univariate analysis, age was a significant predictor (HR = 0.96, 95% CI: 0.94-0.98), p < 0.001) of LF. Tumor size (HR = 0.80, p = 0.13) and prescription dose (HR = 1.02, p = 0.54) did not predict for LF. To our knowledge, this is the largest series of patients with brain metastases from colorectal primary cancer treated with SRS. Compared to historical data, LF and OS in our cohort of patients was favorable. Our data confirms relatively higher rates of LF when compared to brain metastases from other primary disease sites. Further studies are warranted to identify factors that predict for LF following SRS and to develop models that predict which patients with colorectal brain metastases may be at higher risk of failure.

Immune Checkpoint Inhibition and Single Fraction Stereotactic Radiosurgery in Non-Small Cell Lung Cancer Brain Metastases: An International Multicenter Study of 395 Patients

Brain metastases most commonly arise from non-small cell lung cancer (NSCLC). In recent years, immune checkpoint inhibitors (ICI) have demonstrated improvements in overall survival (OS) in NSCLC. However, concerns remain about the risk of radiation necrosis (RN) when ICI are administered with stereotactic radiosurgery (SRS). Logistic regression was used to evaluate prognostic factors associated with the development of any grade RN and symptomatic RN. Cumulative incidence of RN was evaluated using competing risks analysis and the Fine and Gray model, where the null hypothesis was rejected for p < 0.05. There were 395 patients with 2,513 brain metastases treated across 11 international institutions included in the analysis. The median follow-up was 14.2 months. Median patient age was 67 years (Interquartile Range [IQR]: 61-73), 53.4% were male, the median Karnofsky Performance Status was 80 (IQR: 80-90), and 88.6% has active extracranial disease at the time of SRS. The median margin dose was 19 Gy (IQR: 18-20), 97.5% of patients were treated on the Gamma Knife ®, 3.8% underwent prior whole brain radiation therapy (WBRT). The median V12 Gy was 5.2 cm3 and 36.5% of patients had a V12 Gy ≥ 10 cm3, anti-PD-1 agents were administered in 91.6% of patients. A V12 Gy ³ 10 cm3 was associated with an increased risk of developing any grade RN; odds ratio (OR): 2.12, p = 0.04 and OR: 2.18; p = 0.03 on univariable and multivariable analysis, respectively. Similarly, a V12 Gy ≥ 10 cm3 was associated with an increased risk of developing symptomatic RN; OR: 3.80, p = 0.003 and OR: 3.95; p = 0.003 on univariable and multivariable analysis, respectively. Receipt of concurrent ICI and prior WBRT were not statistically significant. At 1-year, the cumulative incidence of any grade and symptomatic RN was 4.8% and 3.8%, respectively. The cumulative incidence of any grade RN was 3.8% vs. 5.3% for the concurrent and non-concurrent groups at 1-year, respectively (p = 0.35). The cumulative incidence of symptomatic RN was 3.8% vs. 3.6% for the concurrent and non-concurrent groups at 1-year, respectively (p = 0.95). The risk of any grade and symptomatic RN following SRS and ICI administration for NSCLC brain metastases increases as the V12 Gy exceeds 10 cm3. Concurrent ICI and SRS does not appear to increase this risk. Radiosurgical planning techniques should aim to minimize the V12 Gy.

Long-Term Outcomes of Non-Vestibular Cranial Nerve Schwannomas Treated with Fractionated Stereotactic Radiotherapy and Stereotactic Radiosurgery

Non-vestibular cranial nerve schwannomas (NVCNS) are rare tumors that account for approximately 10% of cranial nerve schwannomas. They are commonly treated with radiation therapy (XRT) due to their location often precluding safe resection. We examined the long-term outcomes of NVCNS treated with XRT as primary management and for post-operative salvage. We conducted a retrospective review of patients with NVCNS treated with fractionated stereotactic radiation therapy (FSRT) or Gamma Knife Stereotactic Radiosurgery (GK-SRS) from 1996 to 2018 at our institution. We examined patient demographics, cranial nerve (CN) involvement, CN function pre-/post-XRT, treatment volume (TV), toxicity, surgery pre-XRT, and local control. Kaplan-Meier analysis was performed for evaluation of local control. We identified 66 patients (38 female, 28 male) with NVCNS, a portion of whom had tumors involving more than one cranial nerve. Forty-six (69.7%) were treated with FSRT (median dose 50.4 Gy in 1.8 Gy/fraction; range 45-54 Gy), and 20 (30.3%) with GK-SRS (median dose 12 Gy; range 12-15 Gy). Median follow-up time was 92.5 months (5-306). Median Karnofsky Performance Status was 90 (70-100). Median age at start of XRT was 45 years old (15-92). Prior to XRT, 34.8% (23) of patients had surgical resection, with median time from surgery to XRT of 4.25 months (0.5-130 months). Median treatment volume was 4.72 cc (0.26-29). The cranial nerve most commonly involved was CN V (48.4%), followed by CN X (15.2%), CN VII (13.6%), CN VI (6.1%), CN XII (6.1%), CN III (6.1%), and CN IX (3%). Twenty-nine (43.9%) patients experienced grade 1 acute toxicity during treatment. Six (9%) patients experienced grade 1 chronic toxicity. No grade 2 or higher acute or chronic toxicity was observed. No significant difference in rates of acute or chronic toxicity was observed between patients treated with GK-SRS vs. FSRT. Post-XRT, 37 patients (56.1%) had improvement in CN function/symptom, 24 patients (36.3%) had stable function/symptoms, and 5 patients (7.6%) had worsening function/symptoms. Local control at one and five years was 100%. In-field recurrence was observed in one patient (1.5%), at 9 years post-XRT. For salvage this patient was treated with a second course of FSRT to the recurrent tumor. Our large institutional series with long term follow up showed excellent local control of NVCNS treated with FSRT or GK-SRS both for primary management and post-operative salvage. Treatment is well tolerated, with high rates of preservation or improvement of CN function, and minimal acute and chronic toxicity.

Five-Fraction Proton Therapy for Chordomas and Chondrosarcomas of the Skull Base: Preliminary Results of a Prospective Series

To describe the first series of patients with clival chordomas and chondrosarcomas treated with extremely hypofractionated proton therapy in a single institution with focus on acute tolerance and dosimetric parameters. A total of 11 consecutive patients with biopsy proven chordomas and chondrosarcomas were prospectively included in a five-fraction proton therapy protocol between June 2022 and January 2023. The inclusion criteria for this protocol were: Age > 18 yo., Karnofsky Performance Status (KPS) ≥ 70%, absence of metastases, no previous radiation courses, clinical target volume (CTV) up to 50 cc and CTV location relative to organs at risk that allowed compliance with the necessary dose restrictions for hypofractionated treatments in 5 fractions, according to the international guidelines. Treatment was delivered with a Proteus®ONE cyclotron using Pencil Beam Scanning (PBS) Intensity-Modulated Proton Therapy (IMPT). Patient setup was performed with CBCT imaging at isocenter and X-Ray obliques, allowing a robust planning with 1 mm setup uncertainty and 3.5% range uncertainty. IMPT plans were obtained with RayStation employing 4 to 6 non-coplanar beams. In 7 patients' apertures were used in 2 of the beams, to reduce lateral penumbra and to optimize dose gradient. A total of 11 patients (7 males and 5 females) with an age range between 29 and 79 yo, were included. 6 patients with classic chordomas and 5 patients with grade I-II chondrosarcomas were treated with a total dose of 37.5 GyRBE and 35 GyRBE, respectively, in 5 daily fractions. All the patients had received previous surgery with complete resection in 2 patients, subtotal resection in 7 patients and partial resection in 2 patients. Most common symptoms at diagnosis were diplopia and headache and baseline median KPS after surgery was 90% (70 - 100%). Median CTV was 30.62 cc (10.56 - 47.47 cc). Median CTV coverage was V95% = D95.5%. Median maximal dose for the brainstem was 26.5 GyRBE (30 - 24.7 GyRBE) and for the optic pathway was 20.7 GyRBE (8.9 - 23.6 GyRBE). Median follow-up was 3 months (8 - 1 months). Acute toxicity during follow-up was mild, with grade I - II headache (64%), grade I asthenia (45%), grade I nausea (27%), grade I dysphagia (18%) and reversible alopecia (45%). Only one patient showed nystagmus and mild loss of strength in left lower limb related with an ischemic brainstem lesion, in a low dose region, not clearly radiation related. 8 patients had a 3-month follow-up MRI with no signs of progression. Five-fraction proton therapy for the treatment of clival chordomas and chondrosarcomas is dosimetrically feasible and well tolerated for selected patients. Proton therapy remains a limited resource, consequently, reducing treatment time can have significant financial and psychosocial implications. Longer follow up is needed to validate these results.

P03.15.B SURGICALLY TARGETED RADIATION THERAPY (START) FOR RECURRENT GLIOBLASTOMA: INITIAL OUTCOMES FROM A PROSPECTIVE MULTICENTER REGISTRY

Abstract BACKGROUND Surgically targeted radiation therapy (STaRT), using a novel bioresorbable collagen brachytherapy device containing 4 Cesium-131 sources, is FDA-cleared for use as adjuvant radiation therapy (RT) post-resection in both newly diagnosed and recurrent intracranial neoplasms. Intraoperative initiation of brachytherapy potentially minimizes post-resection tumor regrowth with a favorable dosimetric profile compared to external beam radiation. This work sought to determine early patterns of care and the safety of this approach in recurrent glioblastoma (GBM). MATERIAL AND METHODS This prospective multi-institutional observational study (NCT04427384) included recurrent GBM patients who underwent maximum safe resection (MSR) and permanent implantation of the device(s) (GammaTile, GT Medical Technologies, Tempe, AZ, US). Descriptive and comparative analyses regarding patient characteristics and early clinical outcomes were performed. Toxicities were categorized using the CTCAE v5.0 adverse event (AE) criteria. RESULTS During 10/2020-01/2023, 14 participating sites enrolled 45 patients with recurrent GBM for STaRT; 2 patients had two sites treated for a total of 47 implants. 67% of patients were treated at the first recurrence, 24% at the second, and 13% at the third, respectively. The median age was 61 (range 28-75), 36% were female, and 23% were &amp;gt;65 years. 85% of patients received prior same-site RT with the median time from last RT to implantation of 14.6 months (range 3.5-57). The median maximum preoperative size was 4.2 cm (range 1.6-7.0), and the median volume was 20.8 cm3 (range 0.8-130). 68% of resections were gross-total, 17% near-total, and 15% sub-total; the median time needed for device implantation was 5 minutes (range 1.0-13). Median follow-up was 5.2 months (range 0.6-23.2). Median Karnofsky performance status (KPS) at screening, at initial postoperative assessment, and 3 months were all 80 (range 40-100). 7 attributed AEs occurred in 13% (6/45) of patients, all grade 3 AEs: 2 CSF leaks, 2 seizures, 1 cerebral edema, 1 pseudomeningocele, and 1 left hemiparesis. All except one were coded as related to both radiation and surgery; the patient with pseudomeningocele experienced a seizure at 47 days that was considered related to radiation alone. CONCLUSION Early data from this prospective registry demonstrate the feasibility and safety of STaRT in recurrent GBM. Data on 6-month progression-free survival will be presented at the conference. A prospective randomized trial of adjuvant systemic therapy (AST)+MSR+STaRT versus MSR+AST is planned for initiation in 2023.

KS01.6.A UCPVAX-GLIO: A PHASE II TRIAL EVALUATING THE IMMUNOGENICITY AND EFFICACY OF AN ANTI-TELOMERASE VACCINE IN PATIENTS WITH NEWLY DIAGNOSED GBM

Abstract BACKGROUND The Telomerase Reverse Transcriptase (TERT) is activated in 85%-90% of cancers, and glioblastomas (GBM) harbor the highest incidence of activating mutations within its promoter (over 85% of patients). This high expression of TERT in cancers and its role in oncogenesis make TERT a very promising tumor antigen for immunotherapy, especially in GBM. UCPvax is a therapeutic vaccine in which two CD4 helper peptides derived from TERT are mixed with the Montanide adjuvant. This phase IIa trial was designed to test the immunogenicity, safety and efficacy of UCPvax in patients with newly diagnosed GBM. PATIENTS AND METHODS In this first cohort of the UCPvax-glio trial (NCT04280848), patients with unmethylated MGMT non-mutated IDH1 GBM were included if they had a Karnofsky Performance status (KPS) ≥ 70%, a steroid treatment &amp;lt; 10mg/ day equivalent prednisone, and lymphocytes count ≥ 0.8 x 109/L. One month after completion of radiation/ temozolomide (TMZ), patients started UCPvax vaccinations on days 1, 8, 15, 29, 36 and 43, then every two months until tumor progression. Patients did not receive any additional cure of TMZ because of the unmethylated MGMT promoter status. Peripheral blood mononuclear cells were collected before treatment, at 1 and 2 months after treatment, and at each vaccination boost. The primary endpoint was the anti-TERT specific CD4 T-cell response at 2 months using IFN-gamma ELISPOT. Secondary endpoints included safety, progression-free survival (PFS) and overall survival (OS). RESULTS All the 31 patients (median age 60-yr old, median KPS 90%) included in this study received at least one vaccination. Vaccinations were given for 4.5 months on average (min 2- max 14). At baseline, only one patient had a pre-existing anti-TERT CD4 T-cell response (3%). After immunizations, de novo induction and/or amplification of an anti-TERT response were found in 29/30 patients (97%). An epitope spread response against other tumor-associated antigens was detected in 12/25 patients (48%). All patients developed local skin reactions (≤ grade 2), 16 patients complained of transient asthenia (≤grade 2), and 13 patients experienced local pain (≤grade 2). No severe (grade 3-4) toxicity was attributable to the vaccination. In the intent-to-treat population (n = 31), the PFS was 8.9 months (95% CI: 7.6-10.6) and the median OS was 17.9 months (95% CI: 16-23). Two years after diagnosis, 26% of the patients were still alive. OS was significantly improved in the patients developing an epitope spread response vs the others (20.8 versus 14.1 months, respectively, p = 0.03). CONCLUSION s: In this population of unmethylated MGMT GBM patients, UCPVax is highly immunogenic and provides an interesting OS rate. These data strongly support the completion of the second ongoing cohort, assessing UCPvax in combination with TMZ for GBM patients with methylated MGMT promoter status.

Stereotactic radiosurgery for sarcoma metastases to the brain: a single-institution experience.

Brain metastases (BMs) secondary to sarcoma are rare, and their incidence ranges from 1% to 8% of all bone and soft tissue sarcomas. Although stereotactic radiosurgery (SRS) is widely used for BMs, only a few papers have reported on SRS for sarcoma metastasizing to the brain. The purpose of this study was to evaluate the safety and effectiveness of SRS for sarcoma BM. The authors retrospectively reviewed the clinical and radiological outcomes of patients with BM secondary to histopathologically confirmed sarcoma treated with SRS, either as primary treatment or as adjuvant therapy after surgery, at their institution between January 2005 and September 2022. They also compared the outcomes of patients with hemorrhagic lesions and of those without. Twenty-three patients (9 females) with 150 BMs secondary to sarcoma were treated with CyberKnife SRS. Median age at the time of treatment was 48.22 years (range 4-76 years). The most common primary tumor sites were the heart, lungs, uterus, upper extremities, chest wall, and head and neck. The median Karnofsky Performance Status on presentation was 73.28 (range 40-100). Eight patients underwent SRS as a primary treatment and 15 as adjuvant therapy to the resection cavity. The median tumor volume was 24.1 cm3 (range 0.1-150.3 cm3), the median marginal dose was 24 Gy (range 18-30 Gy) delivered in a median of 1 fraction (range 1-5) to a median isodose line of 76%. The median follow-up was 8 months (range 2-40 months). Median progression-free survival and overall survival were 5.3 months (range 0.4-32 months) and 8.2 months (range 0.1-40), respectively. The 3-, 6-, and 12-month local tumor control (LTC) rates for all lesions were respectively 78%, 52%, and 30%. There were no radiation-induced adverse effects. LTC at the 3-, 6-, and 12-month follow-ups was better in patients without hemorrhagic lesions (100%, 70%, and 40%, respectively) than in those with hemorrhagic lesions (68%, 38%, and 23%, respectively). SRS, both as a primary treatment and as adjuvant therapy to the resection cavity after surgery, is a safe and relatively effective treatment modality for sarcoma BMs. Nonhemorrhagic lesions show better LTC than hemorrhagic lesions. Larger studies aiming to validate these results are encouraged.

Neurotoxicity in patients with CNS lymphomas treated with CAR‐T cell therapy. A LOC network study

Introduction: CAR-T cell therapy represents one of the major progress of the last years in aggressive B-cell lymphomas. Its use in central nervous system (CNS) lymphomas has been limited due to the fear of neurotoxicity but several recent studies have showed promising efficacy in this setting. The aim of this study was to focus on neurotoxicity in CNS lymphoma patients treated with CAR-T cells. Methods: Patients with isolated CNS relapse of DLBCL treated with commercial CAR-T cells at Pitié-Salpêtrière hospital were retrospectively selected. We considered only neurological deterioration for which other causes than CAR-T cell toxicity had been reasonably ruled out. Results: Thirty patients (median age: 65, 17 women, 19 primary, 11 secondary CNS lymphomas, median of 3 previous lines) received CAR-T cells (Tisa-cel: N = 23, axi-cel, N = 7) between May 2020 and December 2022. At the time of CAR-T, 15 (50%) had stable or progressive disease, median Karnofsky Performance Status (KPS) was 70, median Montreal Cognitive Assessment (MoCA) score was 22 and median immune effector cell-associated encephalopathy (ICE) score was 10. Twelve (40%) patients didn’t experience any neurotoxicity after CAR-T, whereas 9 (30%), 3 (10%), 2 (7%), 4 (13%) patients experienced grade 1, 2, 3 or 4 toxicity according to ASTCT classification. The signs of neurotoxicity began at a median of 5 days after CAR-T. The most common symptoms were cognitive disorders (N = 18), motor deficit (N = 4), balance disorders (N = 8), consciousness disorders (N = 5), seizures (N = 3) and movement disorders (N = 3). Among cognitive symptoms, there was predominantly a worsening of pre-existing symptoms regarding memory impairment (12/15 patients) or dysexecutive syndrome (11/13), while dysgraphia or dyscalculia were most frequently new symptoms (in 14/15 and 7/11 patients). Brain MRI showed pseudo-progression in 4 cases. On lumbar puncture, median IL-6 level and median cellularity were higher in patients with grade 2 to 4 neurotoxicity compared to other patients (243 vs. 41 pg/ml, 15 vs. 3 cells/mm3). We found no association between risk of neurotoxicity and age, gender, pre-CART KPS, MoCA or ICE score, primary vs. secondary CNS lymphoma or type of CAR-T. Twelve patients (40%) received steroids, for a median of 10 days, leading to an improvement in a median of 5 days; one received anakinra. Median duration with neurological impairment was 13 days, but was >3 months in 3 patients, including one who finally died from neurotoxicity. Conclusions: The majority of CNS lymphoma patients didn’t experience severe neurotoxicity following CAR-T cells, so that this treatment shouldn’t be contraindicated in this population. However, the percentage of severe and prolonged neurotoxicity is probably higher than in systemic lymphomas and a close neurological follow-up is warranted in these complex situations. Further studies are needed to better predict severe neurotoxicity. Keyword: Cellular therapies Conflicts of interests pertinent to the abstract. S. Choquet Consultant or advisory role: Kite-Gilead, Novartis

Outcomes of stereotactic radiosurgery in central nervous system lymphoma: A single institution experience.

e14061 Background: Primary or systemic high-grade B-cell lymphoma with secondary central nervous system lymphoma (PCNSL or SCNSL) are currently treated with high-dose methotrexate (HD-MTx) based chemo-immunotherapy regimens with/without whole brain radiation therapy (WBRT). CNS relapse can occur in up to 50% of patients with PCNSL or SCNSL. WBRT has been used as a salvage therapy for those patients. However, long-term neurological toxicities significantly reduce its clinical benefit. Stereotactic radiosurgery (SRS) is the administration of a localized, high dose of ionizing radiation. Limited studies exist exploring SRS as a treatment modality in relapsed/refractory (r/r) PCNSL/SCNSL. Methods: We conducted a retrospective single-center study evaluating the clinical efficacy of SRS in r/r PCNSL/SCNSL. Demographic, clinical, pathological, and treatment characteristics were collected in 29 r/r PCNSL (N=17)/SCNSL (N=12) patients, age ≥ 18 years, who received SRS between 01/2000 and 01/2023. Progression-free survival (PFS) and overall survival (OS) were calculated and reported using Kaplan-Meier analyses and log-rank tests. Results: Baseline characteristics are summarized (Table). The median Karnofsky performance status and Charlson comorbidity index were 70 and 5 respectively. For patients with PCNSL (N=17), the most common prior chemotherapy regimen administered was rituximab (R) in combination with the DeAngelis regimen (N=12), followed by the MATRIX regimen (N=3). In patients with SCNSL, the most common systemic chemotherapy regimen used was R + CHOP (N=9). Few patients received temozolomide (N=2). 5/29 (17%) of patients received WBRT before SRS. The overall response rate (ORR) to SRS in r/r PCNSL was 60% (7 CR and 2 PR). The ORR in r/r SCNSL was 83% (7 CR and 3 PR). The median OS of the overall cohort was 7.0 months (95% CI 5.1-8.9), while the median PFS was 5.0 months (95% CI 1.2-8.7). For patients with PCNSL, the median OS was 10.0 months (95% CI 2.2-17.7), and only 7 months (95% CI 1.8-12.1) for patients with SCNSL. Prior WBRT was associated with worse survival outcomes. Of interest, WBRT was avoided in 24/24 patients (100%). Conclusions: Our data support that CNSL patients can benefit from SRS therapy, with acceptable OS and PFS. In addition, the disease control spared patients from WBRT and therefore, mitigated neurological complications associated with that modality. [Table: see text]

Surgically targeted radiation therapy (STaRT) for recurrent glioblastoma: Initial outcomes from a prospective multicenter registry.

2038 Background: Surgically targeted radiation therapy (STaRT), using a novel bioresorbable collagen brachytherapy device containing 4 Cesium-131 sources, is FDA-cleared for use as adjuvant radiation therapy (RT) post-resection in both newly diagnosed and recurrent intracranial neoplasms. Intraoperative initiation of brachytherapy potentially minimizes post-resection tumor regrowth with a favorable dosimetric profile compared to external beam radiation. This work sought to determine early patterns of care and the safety of this approach in recurrent GBM. Methods: This prospective multi-institutional observational study (NCT04427384) included recurrent GBM patients who underwent maximum safe resection (MSR) and permanent implantation of the device(s) (GammaTile, GT Medical Technologies, Tempe, AZ, US). Descriptive and comparative analyses regarding patient characteristics and early clinical outcomes were performed. Toxicities were categorized using the CTCAE v5.0 adverse event (AE) criteria. Results: During 10/2020–01/2023, 14 participating sites enrolled 45 patients with recurrent GBM for STaRT; 2 patients had two sites treated for a total of 47 implants. 67% of patients were treated at the first recurrence, 24% at the second, and 13% at the third, respectively. The median age was 61 (range 28-75), 36% were female, and 23% were &gt; 65 years. 85% of patients received prior same-site RT with the median time from last RT to implantation of 14.6 months (range 3.5-57). The median maximum preoperative size was 4.2 cm (range 1.6-7.0) and the median volume was 20.8 cm3 (range 0.8-130). 68% of resections were gross-total, 17% near-total, and 15% sub-total; the median time needed for device implantation was 5 minutes (range 1.0-13). Median follow-up was 5.2 months (range 0.6-23.2). Median Karnofsky performance status (KPS) at screening, at initial postoperative assessment, and 3 months were all 80 (range 40-100). 7 attributed AEs occurred in 13% (6/45) of patients, all grade 3 AEs: 2 CSF leaks, 2 seizures, 1 cerebral edema, 1 pseudomeningocele, and 1 left hemiparesis. All except one were coded as related to both radiation and surgery; the patient with pseudomeningocele experienced a seizure at 47 days that was considered related to radiation alone. Conclusions: Early data from this prospective registry demonstrate the feasibility and safety of STaRT in recurrent GBM. Data on 6-month progression-free survival will be presented at the conference. A prospective randomized trial of adjuvant systemic therapy (AST) +MSR+STaRT versus MSR+AST is planned for initiation in 2023.