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Background: Autologous CD19-targeted chimeric antigen receptor-modified (CAR) T-cell therapy leads to complete responses (CR) in patients (pts) with (w/) relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL, >80% CR rate) and diffuse large B-cell lymphoma (DLBCL, ~40-55% CR rate). However, following fludarabine/cyclophosphamide (Flu/Cy) conditioning and CAR T-cell therapy w/ a CD28 costimulatory domain (e.g. 19-28z CAR T-cells), rates of grade ≥3 ICANS and grade ≥3 cytokine release syndrome (CRS) in pts w/ R/R DLBCL and morphologic R/R B-ALL exceed 30%. CRS and ICANS are associated w/ considerable morbidity, including increased length of hospitalization, and may be fatal. Host monocytes appear to be the major reservoir of cytokines driving CRS and ICANS post-CAR T-cell therapy (Giavradis et al. and Norelli et al., Nature Medicine, 2018). Circulating monocytic myeloid-derived suppressor cells (MDSCs) may also blunt efficacy of 19-28z CAR T-cells in R/R DLBCL (Jain et al., Blood, 2021). The CD45-targeted antibody radioconjugate (ARC) 131-I apamistamab is being investigated at myeloablative doses as conditioning prior to hematopoietic cell transplantation in pts w/ R/R acute myeloid leukemia. However, even at low doses (4-20 mCi), transient lymphocyte and blast reduction are observed. Preclinical studies in C57BL/6 mice demonstrate low-dose anti CD45 radioimmunotherapy (100 microCi) transiently depletes >90% lymphocytes, including CD4/CD8 T-cells, B-cells, NK cells, and T-regs, as well as splenocytes and MDSCs, w/ negligible effect on bone marrow (BM) hematopoietic stem cells (Dawicki et al., Oncotarget, 2020). We hypothesized a higher, yet nonmyeloablative dose of 131-I apamistamab may achieve more sustained, but reversible depletion of lymphocytes and other CD45 + immune cells, including monocytes thought to drive CRS/ICANS. We additionally hypothesized this approach (vs Flu/Cy) prior to CAR T-cell therapy would promote CAR T-cell expansion while reducing CSF levels of monocyte-derived cytokines (e.g. IL-1, IL-6, and IL-10), thus lowering the risk of severe ICANS (Fig 1A). Study design and methods: We are conducting a single-institution pilot study of 131-I apamistamab in lieu of Flu/Cy prior to 19-28z CAR T-cells in adults w/ R/R BALL or DLBCL (NCT04512716; Iomab-ACT); accrual is ongoing. Pts are eligible for leukapheresis if they are ≥18 years-old w/ R/R DLBCL (de novo or transformed) following ≥2 chemoimmunotherapy regimens w/ ≥1 FDG-avid measurable lesion or B-ALL following ≥1 line of multi-agent chemotherapy (R/R following induction/consolidation; prior 2 nd/3 rd gen TKI required for pts w/ Ph+ ALL) w/ ≥5% BM involvement and/or FDG-avid extramedullary disease, ECOG performance status 0-2, and w/ appropriate organ function. Active or prior CNS disease is not exclusionary. Pts previously treated w/ CD19-targeted CAR T-cell therapy are eligible as long as CD19 expression is retained. See Fig 1B/C: Post-leukapheresis, 19-28z CAR T-cells are manufactured as previously described (Park et al., NEJM, 2018). Bridging therapy is permitted at investigator discretion. Thyroid blocking is started ≥48h pre-ARC. 131-I apamistamab 75 mCi is administered 5-7 days pre-CAR T-cell infusion to achieve total absorbed marrow dose ~200 cGy w/ remaining absorbed dose The primary objective is to determine safety/tolerability of 131-I apamistamab 75 mCi given prior to 19-28z CAR T-cells in pts w/ R/R B-ALL/DLBCL. Secondary objectives include determining incidence/severity of ICANS and CRS, anti-tumor efficacy, and 19-28z CAR T-cell expansion/persistence. Key exploratory objectives include describing the cellular microenvironment following ARC and 19-28z CAR T-cell infusion using spectral cytometry, as well as cytokine levels in peripheral blood and CRS. The trial utilizes a 3+3 design in a single cohort. If dose-limiting toxicity (severe infusion-related reactions, treatment-resistant severe CRS/ICANS, persistent regimen-related cytopenias, among others defined in protocol) is seen in 0-1 of the first 3 pts treated, then up to 6 total (up to 3 additional) pts will be treated. We have designed this study to provide preliminary data to support further investigation of CD45-targeted ARCs prior to adoptive cellular therapy. Figure 1 Figure 1. Disclosures Geyer: Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Actinium Pharmaceuticals, Inc: Research Funding; Amgen: Research Funding. Geoghegan: Actinium Pharmaceuticals, Inc: Current Employment. Reddy: Actinium Pharmaceuticals: Current Employment, Current holder of stock options in a privately-held company. Berger: Actinium Pharmaceuticals, Inc: Current Employment. Ludwig: Actinium Pharmaceuticals, Inc: Current Employment. Pandit-Taskar: Bristol Myers Squibb: Research Funding; Bayer: Research Funding; Clarity Pharma: Research Funding; Illumina: Consultancy, Honoraria; ImaginAb: Consultancy, Honoraria, Research Funding; Ymabs: Research Funding; Progenics: Consultancy, Honoraria; Medimmune/Astrazeneca: Consultancy, Honoraria; Actinium Pharmaceuticals, Inc: Consultancy, Honoraria; Janssen: Research Funding; Regeneron: Research Funding. Sauter: Genmab: Consultancy; Celgene: Consultancy, Research Funding; Precision Biosciences: Consultancy; Kite/Gilead: Consultancy; Bristol-Myers Squibb: Research Funding; GSK: Consultancy; Gamida Cell: Consultancy; Novartis: Consultancy; Spectrum Pharmaceuticals: Consultancy; Juno Therapeutics: Consultancy, Research Funding; Sanofi-Genzyme: Consultancy, Research Funding. OffLabel Disclosure: 131-I apamistamab and 19-28z CAR T-cells are investigational agents in treatment of ALL and DLBCL

Identification of prognostic factors for patients with relapsed/refractory Hodgkin lymphoma (HL) is essential for optimizing therapy with risk-adapted approaches. In our phase 2 study of positron emission tomography (PET)-adapted salvage therapy with brentuximab vedotin (BV) and augmented ifosfamide, carboplatin, and etoposide (augICE), we assessed clinical factors, quantitative PET assessments, and cytokine and chemokine values. Transplant-eligible patients with relapsed/refractory HL received 2 (cohort 1) or 3 (cohort 2) cycles of weekly BV; PET-negative patients (Deauville score ≤2) proceeded to autologous stem cell transplantation (ASCT) whereas PET-positive patients received augICE before ASCT. Serum cytokine and chemokine levels were measured at baseline and after BV. Metabolic tumor volume (MTV) and total lesion glycolysis were measured at baseline, after BV, and after augICE. Sixty-five patients enrolled (45, cohort 1; 20, cohort 2); 49 (75%) achieved complete response and 64 proceeded to ASCT. Three-year overall survival and event-free survival (EFS) were 95% and 82%, respectively. Factors predictive for EFS by multivariable analysis were baseline MTV (bMTV) (P < .001) and refractory disease (P = .003). Low bMTV (