Breen, William G.

Abstract Purpose: Axicabtagene ciloleucel (axi-cel) is an anti-CD19 chimeric antigen receptor T-cell (CAR-T) therapy utilized for patients with non-Hodgkin lymphoma (NHL) refractory to at least 2 lines of therapy. F-18 fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) is used to evaluate disease extent prior to CAR-T infusion at two time points: pre-leukapheresis (pre-leuk) approximately 6 weeks prior to CAR-T infusion, and pre-lymphodepletion chemotherapy (pre-LD) approximately 1 week prior to CAR-T infusion. We hypothesized that PET/CT characteristics beyond Lugano criteria, such as metabolic tumor volume (MTV), total lesion glycolysis (TLG), SUV maximum (SUVMax), and changes in these parameters from pre-leuk to pre-LD, may predict for progressive disease (PD), death, and treatment toxicity after CAR-T infusion. Methods: Patients with NHL who received axi-cel on a prospective registry at Mayo Clinic Rochester were included. Lesions on pre-leuk and pre-LD PET/CT scans were segmented with a fixed absolute SUVMax threshold of 2.5 using a semi-automated workflow (LesionID, MIM Software Inc.) with manual modification to exclude physiologic uptake as needed. MTV, TLG, SUVMax, number of lesions, and other lesion characteristics were assessed for each PET/CT, and changes from pre-leuk to pre-LD were calculated. Lesions were categorized as either nodal, spleen, bone, parenchymal (i.e. liver, lung), or soft tissue (i.e. subcutaneous, muscle), and MTV was calculated for each category. Univariate Cox modeling was used to associate relative and directional change in metabolic and volumetric PET/CT characteristics with PD and death, after adjusting for bridging therapy. LASSO method was used for multivariable model selection. Pre-LD PET/CT characteristics were also assessed for association with presence and duration of cytokine release syndrome (CRS), grade 3+ immune effector cell-associated neurotoxicity syndrome (ICANS), tocilizumab (toci) use, and corticosteroid use. Results: From 2018-2020, axi-cel was delivered to 69 patients. Histology included diffuse large B-cell lymphoma (57%), transformed follicular lymphoma (23%), or high-grade lymphoma (19%). Pre-leuk and pre-LD PET/CT scans were performed a median of 46 days and 7 days prior to CAR-T infusion, respectively. Forty patients (58%) received bridging therapy between scans, including 9 (13%) receiving radiotherapy. At a median follow-up of 13 months, 39 (57%) had died and 46 (67%) had PD. Sixty patients (87%) developed CRS following CAR-T infusion for a median duration of 5 days. Presence of pre-LD parenchymal disease was associated with longer duration CRS (p=0.032). Thirty-seven patients (54%) developed ICANS for a median duration of 4.5 days, including 12 (32%) with grade 3+ ICANS. Greater pre-LD total MTV was associated with higher risk of grade 3+ ICANS (p=0.042). Greater pre-LD SUVMax was associated with longer duration ICANS (p=0.032). Nineteen (28%) patients required toci. Greater pre-LD total MTV, SUVMax, TLG, and volume of the largest lesion were associated with increased use of toci (p<0.05 for all). Greater pre-LD total MTV and TLG of the largest lesion were associated with increased use of corticosteroid (p<0.05 for each). While no individual pre-leuk or pre-LD PET/CT characteristics were associated with risk of PD or death, increases from pre-leuk to pre-LD in total MTV, total TLG, parenchymal MTV, and nodal MTV were associated with increased risk of PD (Figure 1). Similarly, increases from pre-leuk to pre-LD in parenchymal MTV, nodal MTV, TLG of the largest lesion, and total number of lesions were associated with increased risk of death (p<0.05 for all). LASSO analysis identified increasing extranodal MTV (≥25% increase) and increasing TLG of the largest lesion (≥10% increase) as strong predictors of death (AUC 0.74, Table 1). Kaplan-Meier plots were generated for overall and progression-free survival using these risk factors (Figure 2). Additional patients and follow-up will be presented. Conclusions: Patients with greater pre-LD MTV had higher risk of grade 3+ ICANS and use of toci or corticosteroids. Increasing metabolic disease burden during CAR-T manufacturing is associated with increased risk of PD and death. A two variable risk score using increasing extranodal disease and increasing TLG of the largest lesion may stratify prognosis prior to CAR-T and inform treatment paradigms. Figure 1 Figure 1. Disclosures Bennani: Verastem: Other: Advisory Board; Purdue Pharma: Other: Advisory Board; Daichii Sankyo Inc: Other: Advisory Board; Kyowa Kirin: Other: Advisory Board; Vividion: Other: Advisory Board; Kymera: Other: Advisory Board. Paludo: Karyopharm: Research Funding. Wang: Genentech: Research Funding; LOXO Oncology: Membership on an entity's Board of Directors or advisory committees, Research Funding; Eli Lilly: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; InnoCare: Research Funding; Novartis: Research Funding; MorphoSys: Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees. Ansell: Bristol Myers Squibb, ADC Therapeutics, Seattle Genetics, Regeneron, Affimed, AI Therapeutics, Pfizer, Trillium and Takeda: Research Funding. Lin: Gamida Cell: Consultancy; Janssen: Consultancy, Research Funding; Legend: Consultancy; Novartis: Consultancy; Celgene: Consultancy, Research Funding; Sorrento: Consultancy; Bluebird Bio: Consultancy, Research Funding; Takeda: Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Merck: Research Funding; Vineti: Consultancy; Juno: Consultancy.

Abstract Medulloblastoma is a posterior fossa tumor rarely diagnosed in adults. Treatment includes craniospinal irradiation (CSI). Proton CSI is increasingly utilized to decrease radiation dose to normal tissues, despite the lack of randomized data demonstrating decreased toxicity compared to photon CSI. This single institution retrospective study of 39 adult medulloblastoma patients includes nineteen patients treated with photon CSI prior to 2015, and twenty treated with proton CSI thereafter. Median age was 28 years (range 18-66). Molecular subtype was most commonly sonic hedgehog (68%). The most common fractionation schedule was 36 Gy CSI in 20 fractions (85% of photon and 58% of proton patients) with a boost to 54-55.8 Gy (92%). Proton CSI delivered significantly lower mean doses to the cochleae (median 32 Gy vs. 44 Gy), lacrimal glands (8 vs. 36 Gy), lens (2 vs. 28 Gy), parotid glands (3 vs. 26 Gy), pharyngeal constrictors (6 vs. 15 Gy), esophagus (2 vs. 29 Gy), heart (0 vs. 14 Gy), lungs (1 vs. 7 Gy), liver (0.1 vs. 7 Gy), and skin (38 vs. 51 Gy) (all p< 0.001). Patients receiving proton CSI had significantly lower rates of acute dysphagia of any grade (5% vs. 35%, p= 0.044) and decreased median weight loss during radiation (+1.0 vs. -2.8 kg, p= 0.011). Acute hospitalization was associated with increased weight loss (p= 0.009). Median follow-up was 2.9 and 12.9 years for proton and photon patients, respectively, limiting late toxicity and outcome comparisons. At last follow-up five photon patients had died (two of progressive disease, three without recurrence ages 41-63) and 21% had experienced major cardiovascular events. At 10 years, 89% were alive and 82% were recurrence free. In conclusion, this study demonstrates dosimetric improvements with proton CSI, potentially leading to decreased acute toxicity including dysphagia and weight loss during treatment.

Abstract While dose escalation of radiotherapy (DERT) has failed to improve overall survival (OS) or progression-free survival (PFS) for glioblastoma in previous studies, a recent phase II clinical trial utilizing 18F-DOPA-PET-directed DERT demonstrated improved PFS in MGMT-unmethylated patients and OS in MGMT-methylated patients compared to historical controls. This planned secondary analysis sought to determine 1) how 18F-DOPA-PET changes RT volumes beyond standard MRI-planning, 2) which patients benefit most and least from this protocol, 3) which are mostly likely to experience clinically significant radionecrosis after DERT, and 4) patterns of failure after DERT. For 69 evaluable patients, median MRI-defined, PET-defined, and combined low-dose gross tumor volumes (GTV51) were 54 cc (range 9-248), 23 cc (0.4-179), and 62 cc (10-260), respectively. Median MRI-defined, PET-defined, and combined high-dose GTVs (GTV76) were 32 cc (range 4-136), 6 cc (0.1-138), and 34 cc (4-162), respectively. 18F-DOPA-PET resulted in a median volumetric expansion of 13% (0-243%) and 5% (0-217%) from MRI-defined low-dose and high-dose GTV’s, respectively. Central failures ( >95% of recurrence tumor volume) occurred within the 76 Gy, 60 Gy, and 51 Gy isodose lines in 32 (46%), 60 (87%), and 64 (93%) patients, respectively. Recursive partitioning analysis stratified patients by OS and PFS. Patients with 18F-DOPA-PET-defined GTV76 > 7.8cc, MRI-defined GTV76 > 42.7cc, and MGMT promotor-unmethylated tumors had the shortest OS, while patients with smaller PET and MRI-defined tumors had the longest OS (median 10.4 vs. 64.6 months, p< 0.001). Similarly, PFS was worst in patients with 18F-DOPA-PET-defined GTV76 > 2.17 cc who had biopsy only (median PFS 3.2 months, p< 0.001). Patients with 18F-DOPA-PET-defined GTV51 > 50 cc had the highest risk of grade 3+ radionecrosis (p< 0.001). In conclusion, larger 18F-DOPA-PET and MRI-defined tumor volumes were associated with worse outcomes, and 18F-DOPA-PET-directed DERT appears to reduce risk of central recurrence in high-dose volumes.

e17535 Background: Androgen Deprivation Therapy (ADT) is commonly used to treat prostate cancer (PC), but has been associated with cardiac morbidity and mortality. The exact mechanisms of this association are unclear. We sought to use an artificial intelligence (AI) enabled algorithm to identify ECG changes in PC patients who received ADT compared to PC patients who did not receive ADT. Methods: From 1,000,000 ECGs performed on 210,414 patients between 1993 and 2017 at our institution, a convolutional neural network was developed to detect predictive signatures for cardiac pathologies. During this process, the ability to predict “estimated sex” of the patient was developed, with output values ranging from 0 (female) to 1 (male). We applied this algorithm to 8,619 ECGs performed on 1,057 men age 75 or younger treated with radiation for high-risk or recurrent PC at our institution, and compared estimated sex after receiving ADT (n = 1,065) to ADT-naive ECGs (n = 7,554). We correlated ECG-identified estimated sex with serum testosterone levels using Spearman rank correlation. Results: Patients who had received ADT had a mean (SD) estimated sex value of 0.81 (0.26) compared to 0.92 (0.17) for those who did not (p < 0.001). Difference between estimated sex in post-ADT ECGs and ADT-naive ECGs remained significant across age groups (Table). Decreased serum total testosterone correlated with decreased estimated sex values in men receiving ADT (R = .57, p < 0.001). Conclusions: ADT for prostate cancer is associated with changes in AI-identified ECG parameters, including lower estimated male sex after receiving ADT. Lower ECG male sex estimate was associated with decreased serum testosterone. In this study, we provide preliminary proof of concept for a potential non-invasive means of monitoring treatment effect and physiologic change using ECGs. [Table: see text]

2524 Background: Postoperative radiosurgery (SRS) has been associated with up to 30% risk of subsequent leptomeningeal disease (LMD). We previously demonstrated that radiographic pattern of LMD (classical “sugarcoating” [cLMD] vs. nodular [nLMD]) in this setting is prognostic. The association between radiographic pattern of LMD, type of salvage treatment (tx), and neurologic death (ND) has not been well described. Methods: The records of patients (pts) with brain metastases (BM), of which 1 was resected and treated with adjunctive SRS, and who subsequently developed LMD were combined from 7 tertiary care centers. Pts with classically radiosensitive tumors or prior or planned whole brain radiotherapy (WBRT) were excluded. ND was defined as symptomatic CNS progression around the time of death without life threatening systemic symptoms or progression. Salvage radiotherapy (RT) for LMD was categorized according to use of WBRT vs. focal cranial RT. Results: The study cohort consisted of 147 pts, of which 125 had died with known cause, 107 also received LMD salvage tx, and 82 also had cranial MRI follow-up. The ND rate in the 125 pts who died with known cause was 79%; the rate in pts who underwent LMD salvage tx (n = 107) was 76%. Univariate logistic regression demonstrated radiographic pattern of LMD (cLMD vs. nLMD, odds ratio [OR] 2.9, p = 0.04) and 2nd LMD failure after salvage tx (OR 3.9, p = 0.02) as significantly associated with ND. The ND rate was 86% for cLMD vs. 68% for nLMD pattern. WBRT was used in 95% of pts with cLMD vs. 52% of pts with nLMD. In the nLMD cohort (n = 58), there was no difference in ND rate based on type of salvage RT (WBRT: 67% vs. focal cranial RT: 68%, p = 0.92). Second LMD failure (vs. not) was associated with higher ND in the nLMD cohort (77% vs. 52%, p = 0.02). Of the 26 pts with nLMD who experienced 2nd LMD failure, 7 had classical 2nd LMD, of which 100% experienced ND, and 19 had nodular 2nd LMD, of which 68% experienced ND (p = 0.09). Conclusions: LMD after surgery and SRS for brain metastases is a clinically significant event with high rates of neurologic death. Classical LMD pattern (vs. nodular) and 2nd LMD failure after salvage tx were significantly associated with higher risk of neurologic death. In the nodular LMD cohort, radiographic pattern of 2nd LMD may be associated with risk of subsequent neurologic death. Pts with nodular LMD treated with salvage focal cranial RT or WBRT had similar risk of neurologic death. Methods to decrease LMD and the subsequent high risk of neurologic death in this setting warrant investigation.

409 Background: For patients with metastatic renal cell carcinoma (RCC), metastasis-directed local therapies can delay progression and need to initiate/switch systemic therapy. We examined our experience treating lung or mediastinal metastases from RCC with radiotherapy (RT). Methods: We reviewed patients with lung or mediastinal metastases from RCC treated with RT. Overall survival (OS) and local control (LC) was measured from the start of RT using the Kaplan-Meier method. Results: Seventy-one patients were treated with RT for 89 lung or mediastinal metastases. Median follow-up was 2.0 years (range 0.02-11.4 years) after RT for surviving patients. Most patients were male (n=53, 74.6%). Median age was 58.4 years at initial diagnosis. Histology was most frequently clear cell carcinoma (n=62, 89.9%). At the time of treatment, 18 patients (25.4%) had 1-3 metastases, and the remainder (74.6%) had 4 or more metastases. Forty-one patients (57.5%) received systemic therapy prior to thoracic radiation. Initial systemic therapy was most commonly sunitinib (45%) or pazopanib (32.5%). Median time from starting systemic therapy to initiation of radiation was 2.0 years. Fifty-eight lung metastases and 31 mediastinal metastases were treated with a median 5 fractions (range 1-40), to a median total dose of 4800 cGy (range 400-7000), with a median fraction size of 500 cGy (range 150-2000). Thirty-three lesions were treated with concurrent systemic therapy, which was most commonly nivolumab (n=16). Of 89 treated lesions, 11 (12%) had local tumor recurrence, at a median of 1.6 years (range 0.4-2.9 years) after initiation of radiation. 1, 3, and 5 year MC (metastasis control) were 96.6%, 83.5% and 67.9%, respectively. Nine patients were treated with radiation in order to delay initiation of systemic therapy. Of these, 3 eventually received systemic therapy, initiated at a median 2.5 years after radiation. At last follow-up, 41 patients (57.7%) had died. Median OS was 2.6 years. Survival at 1, 3, and 5 years was 65.2%, 48.5%, and 38%, respectively. Conclusions: Radiation achieves high metastasis control rates for lung and mediastinal metastases from RCC, potentially delaying the need for systemic therapy.

204 Background: More than 50% of colorectal cancer (CRC) patients will develop metastatic disease. Brain metastasis (BM) from colorectal cancer is uncommon (0.6-1.36%). This study aims to investigate the patient characteristics, treatment modalities and prognostic factors in this rare population. Methods: 104 patients with brain metastasis disease from CRC were identified from over 30,000 colorectal cancer patients at the Mayo Clinic Rochester between 1/1994 and 6/2019. A retrospective review was conducted by using data from electronic medical records (EMR). Statistical analysis utilized the Kaplan-Meier method, Log-rank test, and Cox proportional hazards models. Results: Among the 104 patients, 62 were male (59.6%) and 42 were female (40.4%). Median age at CRC diagnosis was 58.4 and at BM diagnosis was 61. Thirty-three patients had right-sided colon cancers, 27 patients had left-sided colon cancers and 39 patients had rectal cancer. Median time from CRC diagnosis to BM was 30.7 months. The majority of patients (58.7%) presented with a solitary brain lesion. Eighty-six patients (82.7%) had extracranial metastatic disease at BM diagnosis. Median survival was 7.0 months (95% CI 2.6-16.9) from BM diagnosis. Age <70, solitary BM, surgery, radiation, and chemotherapy were associated with statistically significant improved survival on univariate and multivariate analysis. Multi-modality treatment including surgical brain lesion resection, postoperative stereotactic radiation (SRS) with/without whole brain radiation (WBRT), and chemotherapy significantly improved median overall survival (Table). Conclusions: Although BM from CRC carries poor prognosis, multi-modality treatment (surgery, radiation and systemic chemotherapy) for patients with limited BM improves clinical outcome. [Table: see text]

AbstractBackgroundThe optimal radiation dose for adult supratentorial low-grade glioma is unknown. The aim of this study was to provide a final update on oncologic and cognitive outcomes of high-dose versus low-dose radiation for low-grade glioma.MethodsBetween 1986 and 1994, 203 patients with supratentorial low-grade glioma were randomized (1:1) to 50.4 Gy in 28 fractions versus 64.8 Gy in 36 fractions after any degree of resection.ResultsFor all patients, median overall survival (OS) was 8.4 years (95% CI: 7.2–10.8). Median progression-free survival (PFS) was 5.2 years (95% CI: 4.3–6.6). Median follow-up is 17.2 years for the 33 patients still alive. High-dose radiation did not improve 15-year OS (22.4%) versus low-dose radiation (24.9%, log-rank P = 0.978) or 15-year PFS (high dose, 15.2% vs low dose, 9.5%; P = 0.7142). OS was significantly better for patients with preoperative tumor diameter &lt;5 cm and baseline Mini-Mental State Examination (MMSE) &gt;27 and who underwent gross total resection. PFS was improved for patients with oligodendroglioma versus astrocytoma, preoperative tumor diameter &lt;5 cm, patients who had gross total resection, and patients with baseline MMSE &gt;27. For patients who had normal MMSE at baseline, at 7 years only 1 patient (5%) had a clinically significant decrease in MMSE from the previous time point, with the remainder (95%) stable. None had decrease in MMSE at 10, 12, or 15 years.ConclusionsLong-term follow-up indicates no benefit to high-dose over low-dose radiation for low-grade gliomas. Cognitive function appeared to be stable after radiation as measured by MMSE.

Abstract PURPOSE To provide a final update on oncologic and cognitive outcomes of high dose versus low dose radiation for low-grade glioma. METHODS Between 1986 and 1994, 203 patients with supratentorial low grade glioma were randomized to 50.4 Gy in 28 fractions versus 64.8 Gy in 36 fractions after any degree of resection. Histologic subtype was oligodendroglioma (71%) or astrocytoma (29%). Primary outcome was overall survival (OS). Cognitive status was followed using Folstein Mini-Mental State Examination (MMSE). RESULTS For the entire cohort of 203 patients, median OS was 8.4 years (95% CI: 7.2 – 10.8). Median progression-free survival (PFS) was 5.2 years (95% CI: 4.3 – 6.6). Median follow-up is 17.2 years for the 33 patients still alive. High-dose radiation did not improve OS (15-yr OS: 22.4% vs. 24.9%, log rank p=0.978) or PFS (15-yr PFS: 15.2% vs. 9.5%, p=0.7142). OS was significantly better for patients with pre-operative tumor diameter < 5 cm (15-yr OS: 39.4% vs. 15.2%, p< 0.001), baseline MMSE > 27 (15-yr OS: 27.3% vs. 9.8%, p=0.001), and for patients who underwent gross total resection (GTR) (15-yr OS: 39.3% GTR vs. 16.4% subtotal resection vs. 24.5% biopsy only, p=0.0119). PFS was improved for patients with oligodendroglioma versus astrocytoma (15-yr PFS: 13.8% vs. 8.6%, p=0.0221). PFS was also improved for patients with pre-operative tumor diameter < 5 cm, patients who had GTR, and patients with baseline MMSE > 27. For patients who had normal MMSE at baseline, at 7 years only 1 patient (5%) had a clinically significant decrease in MMSE from the previous time point, with the remainder (95%) stable. None had decrease in MMSE at 10, 12, or 15 years. CONCLUSIONS Long-term follow-up indicates no benefit to high-dose over low-dose radiation for low-grade gliomas. Minimal late decline in cognitive function after radiation was seen by MMSE. SUPPORT: U10CA180821,U10CA180882. https://acknowledgments.alliancefound.org