Citations

Abstract Background: ZUMA-1 is a pivotal, multicenter trial of axi-cel, an autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy, for the treatment of patients with refractory, aggressive NHL. The objective response rate (ORR) was 82% with a 54% rate of complete response and 44% of responses were ongoing at the time of the primary analysis (Locke et al. AACR 2017. #9986). Grade ≥ 3 cytokine release syndrome (CRS) and neurologic events (NE) occurred in 13% and 28% of patients, respectively. A safety expansion cohort was added to further characterize mechanisms underlying CRS and NE associated with CAR T cell therapy and to evaluate the impact of prophylactic use of tocilizumab and levetiracetam on the rates of these adverse events (AEs). Methods: Patients (≥ 18 years) must have had an Eastern Cooperative Oncology Group performance status of 0-1 and refractory or relapsed transplant ineligible disease. Patients received low-dose conditioning of 500 mg/m2 cyclophosphamide and 30 mg/m2 fludarabine for 3 days followed by axi-cel at a target dose of 2 × 106 CAR T cells/kg. Patients also received prophylactic treatment with 750 mg of levetiracetam twice a day on day 0 and 8 mg/kg of tocilizumab on day 2 post axi-cel infusion. To evaluate the mechanisms of NE, paired serum and cerebrospinal fluid (CSF) were obtained for all patients prior to conditioning chemotherapy and after axi-cel infusion (day 5). Results: As of April 26, 2017, 31 patients received axi-cel. Median age was 51 years (range, 21-74), 52% were male, 65% had stage III-IV disease, 74% were refractory to ≥ second-line therapy, and 19% relapsed ≤ 12 months after autologous stem cell transplant. Most patients (97%) experienced at least 1 grade ≥ 3 AE. The most common grade ≥ 3 AEs were neutropenia/neutrophil count decreased (71%), anemia (55%), thrombocytopenia/platelet count decreased (52%), leukopenia/white blood cell count decreased (35%), febrile neutropenia (29%), encephalopathy (23%), and hypotension (23%). One patient (3%) experienced a grade ≥ 3 (grade 4) CRS. Grade 3 and 4 NE occurred in 29% and 6% of patients, respectively. One patient died of cerebral edema; there were no other deaths due to AE. Updated efficacy, safety, subgroups, and paired blood/serum/CSF biomarker associative analyses will be presented. Conclusions : Early use of tocilizumab may reduce the incidence of severe CRS but not NE in patients treated with CAR T cell therapy. These data provide evidence that the underlying pathophysiology of NE may differ from that of CRS. Understanding the mechanisms of NE may help to further improve the benefit:risk profile for CAR T cell therapy. Drs Locke and Neelapu contributed equally to this work. Disclosures Locke: Kite Pharma: Consultancy; Cellular Biomedicine Group Inc: Consultancy. Neelapu: Kite Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Poseida: Research Funding; Cellectis: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees. Jacobson: Pharmacyclics, LLC: Consultancy; Kite Pharma: Consultancy. Braunschweig: Kite Pharma: Equity Ownership. Oluwole: Kite Pharma: Consultancy. Siddiqi: Seattle Genetics: Speakers Bureau; Juno: Other: Steering committee for JCAR017; Pharmacyclics, an AbbVie Company: Other: Steering committee for ibrutinib, Speakers Bureau. Timmerman: Celgene: Consultancy; Seattle Genetics: Consultancy; Kite Pharma: Research Funding; ImmuneGene: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Other: Travel expenses, Research Funding; Genmab: Consultancy, Equity Ownership. Reagan: Seattle Genetics: Research Funding. Bot: Kite Pharma: Employment, Equity Ownership. Rossi: Kite Pharma: Employment, Equity Ownership. Sherman: Kite Pharma: Employment, Equity Ownership. Navale: Kite Pharma: Employment, Equity Ownership. Jiang: Kite Pharma: Employment, Equity Ownership. Aycock: Kite Pharma: Employment, Equity Ownership. Elias: Kite Pharma: Employment, Equity Ownership. Wiezorek: Kite Pharma: Employment, Equity Ownership. Go: Kite Pharma: Employment, Equity Ownership. Miklos: Pharmacyclics, LLC: Consultancy, Other: Travel expenses, Patents & Royalties, Research Funding; Kite Pharma: Consultancy, Other: Travel expenses, Research Funding; Adaptive Biotechnologies: Consultancy, Other: Travel expenses; Roche: Research Funding; Genentech: Research Funding; Novartis: Research Funding; Janssen: Consultancy, Honoraria, Other: Travel expenses; Sanofi: Honoraria.

ABSTRACT Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare genetic disorder characterized by progressive heterotopic ossification (HO), often heralded by flare-ups, leading to reduced movement and life expectancy. This placebo-controlled, double-blind trial (NCT02190747) evaluated palovarotene, an orally bioavailable selective retinoic acid receptor gamma agonist, for prevention of HO in patients with FOP. Patients experiencing a flare-up were enrolled in two cohorts: (1) patients ≥15 years were randomized 3:1 to palovarotene 10/5 mg (weeks 1–2/3–6) or placebo; (2) patients ≥6 years were randomized 3:3:2 to palovarotene 10/5 mg, palovarotene 5/2.5 mg (weeks 1–2/3–6), or placebo. Cohort data were pooled. The primary endpoint was the proportion of responders (no/minimal new HO at flare-up body region by plain radiograph) at week 6. Change from baseline in HO volume and new HO incidence were assessed by computed tomography (CT) at week 12. Tissue edema was assessed by magnetic resonance imaging (MRI) or ultrasound. Forty patients (aged 7–53 years) were enrolled (placebo: n = 10; palovarotene 5/2.5 mg: n = 9; palovarotene 10/5 mg: n = 21). Disease history was similar between groups. In the per-protocol population, the proportion of responders at week 6 by plain radiograph was 100% with palovarotene 10/5 mg; 88.9% with palovarotene 5/2.5 mg; 88.9% with placebo (Cochran-Armitage trend test: p = 0.17). At week 12, the proportions were 95.0% with palovarotene 10/5 mg; 88.9% with palovarotene 5/2.5 mg; 77.8% with placebo (Cochran-Armitage trend test: p = 0.15). Week 12 least-squares mean (LSmean) new HO volume, assessed by CT, was 3.8 × 103 mm3 with palovarotene 10/5 mg; 1.3 × 103 mm3 with palovarotene 5/2.5 mg; 18.0 × 103 mm3 with placebo (pairwise tests versus placebo: p ≤ 0.12). Palovarotene was well-tolerated. No patients discontinued treatment or required dose reduction; one patient had dose interruption due to elevated lipase. Although these findings were not statistically significant, they support further evaluation of palovarotene for prevention of HO in FOP in larger studies. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Abstract In this secondary analysis of Hispanic adolescents and young adults (AYA) with acute lymphoblastic leukemia (ALL) treated on Cancer and Leukemia Group B (CALGB) 10403, we evaluated outcomes and geographic enrollment patterns relative to US population data. We used demographic, clinical, and survival data on AYAs enrolled on CALGB 10403 (N = 295, 2007-2012). Surveillance, Epidemiology, and End Results registries provided overall survival (OS) for US AYA ALL by ethnicity/race. North American Association of Cancer Registries provided AYA ALL incidence overall and proportion among Hispanics by US state. Of AYAs enrolled on CALGB 10403, 263 (89%) reported ethnicity/race: 45 (17%) Hispanic, 172 (65%) non-Hispanic White (NHW), 25 (10%) non-Hispanic Black (NHB), and 21 (8%) other. Compared with NHWs, Hispanic and NHB patients had lower household income, and Hispanic patients were more likely to harbor high-risk CRLF2 aberrations. Relative to US estimates, where Hispanic patients represented 46% of newly diagnosed AYA ALL patients and experienced inferior OS compared with NHW (P < .001), Hispanic AYAs on CALGB 10403 did as well as NHW patients (3 year OS, 75% vs 74%; P = NS). Hispanic patients also had higher rates of protocol completion (P = .05). Enrollments on CALGB 10403 differed relative to the distribution of Hispanic AYA ALL in the United States: enrollment was highest in the Midwest; t and only 15% of enrollees were from states with a high proportion of Hispanic AYA ALL patients. In summary, Hispanic patients treated on CALGB 10403 did as well as NHWs and better than population estimates. Geographical misalignment between trial sites and disease epidemiology may partially explain the lower-than-expected enrollment of Hispanic AYA ALL patients.

Background: Lytic or malpositioned tunnels may require bone grafting during revision anterior cruciate ligament reconstruction (rACLR) surgery. Patient characteristics and effects of grafting on outcomes after rACLR are not well described. Purpose: To describe preoperative characteristics, intraoperative findings, and 2-year outcomes for patients with rACLR undergoing bone grafting procedures compared with patients with rACLR without grafting. Study Design: Cohort study; Level of evidence, 3. Methods: A total of 1234 patients who underwent rACLR were prospectively enrolled between 2006 and 2011. Baseline revision and 2-year characteristics, surgical technique, pathology, treatment, and patient-reported outcome instruments (International Knee Documentation Committee [IKDC], Knee injury and Osteoarthritis Outcome Score [KOOS], Western Ontario and McMaster Universities Osteoarthritis Index, and Marx Activity Rating Scale [Marx]) were collected, as well as subsequent surgery information, if applicable. The chi-square and analysis of variance tests were used to compare group characteristics. Results: A total of 159 patients (13%) underwent tunnel grafting—64 (5%) patients underwent 1-stage and 95 (8%) underwent 2-stage grafting. Grafting was isolated to the femur in 31 (2.5%) patients, the tibia in 40 (3%) patients, and combined in 88 patients (7%). Baseline KOOS Quality of Life (QoL) and Marx activity scores were significantly lower in the 2-stage group compared with the no bone grafting group ( P≤ .001). Patients who required 2-stage grafting had more previous ACLRs ( P < .001) and were less likely to have received a bone–patellar tendon–bone or a soft tissue autograft at primary ACLR procedure ( P≤ .021) compared with the no bone grafting group. For current rACLR, patients undergoing either 1-stage or 2-stage bone grafting were more likely to receive a bone–patellar tendon–bone allograft ( P≤ .008) and less likely to receive a soft tissue autograft ( P≤ .003) compared with the no bone grafting group. At 2-year follow-up of 1052 (85%) patients, we found inferior outcomes in the 2-stage bone grafting group (IKDC score = 68; KOOS QoL score = 44; KOOS Sport/Recreation score = 65; and Marx activity score = 3) compared with the no bone grafting group (IKDC score = 77; KOOS QoL score = 63; KOOS Sport/Recreation score = 75; and Marx activity score = 7) ( P≤ .01). The 1-stage bone graft group did not significantly differ compared with the no bone grafting group. Conclusion: Tunnel bone grafting was performed in 13% of our rACLR cohort, with 8% undergoing 2-stage surgery. Patients treated with 2-stage grafting had inferior baseline and 2-year patient-reported outcomes and activity levels compared with patients not undergoing bone grafting. Patients treated with 1-stage grafting had similar baseline and 2-year patient-reported outcomes and activity levels compared with patients not undergoing bone grafting.

Abstract Brain metastases are a challenging manifestation of renal cell carcinoma. We have a limited understanding of brain metastasis tumor and immune biology, drivers of resistance to systemic treatment, and their overall poor prognosis. Current data support a multimodal treatment strategy with radiation treatment and/or surgery. Nonetheless, the optimal approach for the management of brain metastases from renal cell carcinoma remains unclear. To improve patient care, the authors sought to standardize practical management strategies. They performed an unstructured literature review and elaborated on the current management strategies through an international group of experts from different disciplines assembled via the network of the International Kidney Cancer Coalition. Experts from different disciplines were administered a survey to answer questions related to current challenges and unmet patient needs. On the basis of the integrated approach of literature review and survey study results, the authors built algorithms for the management of single and multiple brain metastases in patients with renal cell carcinoma. The literature review, consensus statements, and algorithms presented in this report can serve as a framework guiding treatment decisions for patients. CA Cancer J Clin. 2022;72:454‐489.

LBA7564 Background: Patients with r/r B-NHL have a dismal prognosis. DIAL (Dual Immunomodulation in Aggressive Lymphoma) was a multi-center randomized phase II study testing the efficacy of nivolumab (PD-1 inhibitor) plus varlilumab (CD27 agonist) in this population. Methods: Patients were randomized (1:1) to nivolumab (240 mg IV every 2 weeks for 4 months, 480 mg IV monthly thereafter; group 1) alone or combined with varlilumab (3 mg/kg IV monthly; group 2). Cross-over (group 1 to 2) was allowed for progression. Primary endpoint was overall response (ORR) per LYRIC criteria. A sample size of 48 patients per arm would provide 80% power to detect increase in ORR from 25% to 45% using a one-sided test (p = 0.15). Pre-specified interim analysis occurred after half of the patients completed first radiologic assessment. Secondary endpoints included overall survival (OS), progression-free survival (PFS), and adverse events (AEs). Exploratory endpoints included tumor genomic assessment and immune profiling of blood and tumor. Results: 53 patients were enrolled (27 in group 1; 26 in group 2). Interim analysis included 24 patients from each arm. Mean age was 65.2 years, 34 (70.8%) were male, and 36 (75%) received prior CAR-T cell therapy. Baseline characteristics were balanced between arms. Grade ≥ 3 AEs were observed in 8 (33.3%) and 7 (30.4%) of patients in groups 1 and 2, respectively. Common AEs (> 5%) of any grade included fatigue, lymphopenia, diarrhea, rash. There were no treatment-associated deaths. Toxicity profile was similar between arms. Table summarizes efficacy outcomes. ORR was achieved in 6 patients (12.5%), not statistically different between arms; 4 responses were complete. Seven patients crossed over (1 responded after crossing). Median OS (8.6 vs 7.3 months; p = 0.39) and PFS (2.7 vs 1.4 months; p = 0.06) were similar between arms. Subgroup analysis of patients with prior CAR-T cell therapy showed similar ORR (5/36; 14%), not statistically different between arms. Correlative analysis results will be presented at conference. The trial met futility criterion on interim analysis and enrollment ceased based on pre-specified stopping rule. Conclusions: Dual immunomodulatory therapy did not enhance anti-tumor activity in patients with aggressive B-NHL compared to nivolumab alone. Response rates were low and consistent with previous data using PD-1 inhibitors in this population. Prior therapy with CAR-T cell does not seem to sensitize patients to PD-1 blockade. Toxicity profile was acceptable and dual therapy did not increase the rate of AEs. Clinical trial information: NCT03038672. [Table: see text]