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Summary: The success of CD19 Chimeric antigen receptor (CAR) T‐cell therapy in large B‐cell lymphoma (LBCL) has been partially offset by toxicity and logistical challenges, which off‐the‐shelf agents like CD20xCD3 bispecific antibodies might potentially overcome. However, when using CAR T outcomes as the ʽstandard‐of‐care comparator̕ for relapsed/refractory (r/r) LBCL, a potential learning curve with implementing a novel, complex therapy like CAR T needs to be considered. To address this, we analysed 726 UK patients intended to be treated with CD19 CAR T for r/r LBCL and compared outcomes between the first year of the national CAR T programme (Era 1; 2019) and the more recent treatment era (Era 2; 2020–2022). We identified significant improvements for Era 2 versus Era 1 in dropout rate (17% vs. 27%, p = 0.001), progression‐free survival (1‐year PFS 50% vs. 32%, p < 0.001) and overall survival (1‐year OS 60% vs. 40%, p < 0.001). We also observed increased use of bridging therapy, improvement in bridging outcomes, more tocilizumab/corticosteroid use, reduced high‐grade cytokine release syndrome (4% vs. 9%, p = 0.01) and intensive care unit admissions (20% vs. 32%, p = 0.001). Our results demonstrate significant improvement in CAR T outcomes over time, highlighting the importance of using up‐to‐date clinical data when comparing CAR T against new treatment options for r/r LBCL. [ABSTRACT FROM AUTHOR]

Claire Roddie, Karl S Peggs UCL Cancer Institute, Department of Hematology, London, UK Abstract: Ipilimumab is a fully human immunoglobulin subclass G1 anticytotoxic-T-lymphocyte-antigen-4 monoclonal antibody. It has been approved by the US Food and Drug Administration (FDA) and the European Medicines Agency for use in advanced melanoma following clear evidence of survival benefit in randomized Phase III studies. It is also under investigation as a treatment for other solid tumors such as renal cell, lung, and prostate cancers. The purported mechanism of antitumor activity of ipilimumab is through T-cell activation, and the side effect profile reflects this. Immune-related adverse events (irAEs) affect 60% of treated patients and 15% are defined as severe. Fortunately, most irAEs are reversible with early diagnosis and correct management. FDA approval of ipilimumab is dependent on the careful execution of a risk evaluation and mitigation strategy, with the aim of increasing awareness amongst patients and clinicians of the immunological risks of treatment, and providing algorithms for management of irAEs as they develop. Ipilimumab is one of the first immunotherapies to become widely available in the setting of solid tumors, and ongoing research aims to elucidate optimal dosing, optimal scheduling, and expanded access to ipilimumab as an adjuvant or maintenance therapy where appropriate. The identification of clinical correlates or biomarkers to identify those likely to benefit from this high-cost therapy is a top priority. Keywords: ipilimumab, cytotoxic-T-lymphocyte-antigen-4, advanced melanoma, metastatic, overall survival

High-precision, individualised RT protocols allowed successful tumour de-bulking with limited toxicity, providing the basis to develop specific RT bridging protocols in lymphoma. RADIOTHERAPY BRIDGING IN LARGE B-CELL LYMPHOMA PATIENTS RECEIVING CD19 CAR-T - THE UK EXPERIENCE B Background: b Radiotherapy (RT) has potential synergistic effects with CAR T but is not widely used as bridging therapy for lymphoma patients due to logistical challenges, uncertainty about patient selection and lack of standardised protocols. [Extracted from the article]

Radiotherapy (RT) is an effective treatment for residual lymphoma early after CD19 chimeric antigen receptor T cell therapy (CAR T). However, there are concerns regarding the effect of RT on CAR T. We investigated the effect of different RT planning techniques on the dose to circulating blood to develop CAR T sparing RT using a published computational framework to compute hematological doses (HEDOS) We analyzed 33 RT treatment plans for 11 lesions. Each lesion was planned with 3 RT techniques. Technique A: a conventional VMAT plan, B: a blood sparing technique with lower number of arcs and dose optimization for blood vessels (BV) and blood rich organs (BRO) and C: the same as B but delivered with Flattening Filter Free (FFF) beams to increase dose rate (DR) and reduce beam on time (BOT). Fractional blood doses were calculated using HEDOS, which simulates individual blood particles as they travel through the body, dictated by intra- and inter-organ blood flow. The % of blood volume that received 0, 0.05 and 0.5 Gy was estimated for each RT technique. Wilcoxon test was used to test for significance. BV dose was reduced by B & C, with wide variation between different cases. However, the differences between the mean BV dose of the whole group did not reach statistical significance. Techniques B & C reduced BOT, especially C due to its higher DR (1400 vs 600 MU/min). BOT reduction had the largest influence on the volume of irradiated blood and thus C significantly reduced the blood dose compared to A & B (Table 1). The % blood volume receiving 0 Gy was highest for C. C also reduced the blood volume that received > 0.05 Gy / fraction, a dose level that can induce cell death/inactivation due to the highly radiosensitive nature of lymphocytes. This is the first study to develop a blood sparing (and potentially CAR T sparing) RT by modifying treatment parameters to account for the circulating nature of the blood. Using a dynamic dose calculation method, BOT has a large effect compared to other modifications. Reducing BOT to < 60 seconds had the greatest blood dose-sparing effect. This blood sparing RT could have other potential applications such as reducing risk for lymphopenia after RT. [ABSTRACT FROM AUTHOR]

Radiotherapy is an accepted bridging prior to CD19 CAR T in large B cell lymphoma (LBCL) and is sometimes used post CAR T for residual disease. However, consolidation (cRT) is not well established and there is no agreed standard for patient selection, timing, doses or techniques. Concern also exists regarding effect on circulating CAR T in responding patients. We initiated a prospective protocol for the use of RT with CAR T to: (1) standardize the selection of patients, (2) promote the use of RT consolidation post CAR T according to pre defined criteria, and (3) optimize the use of CAR T sparing RT in the consolidation setting. The eligibility criteria included LBCL patients approved for CD19 CAR T and no contraindication for RT. Patients were selected for pathway A (Bridging RT alone) if most sites of disease can be covered with RT. Pathway B (bridging systemic therapy ± cRT) was selected for rapidly progressing disease, wide-spread extranodal disease (e.g. liver, lung, bone, peritoneum) or LDH >2xULN. Baseline PET CT was reviewed and sites at high risk for local recurrence (≥5cm or SUVmax ≥15) were recorded. cRT post CAR T was given to high-risk lesions which on D28 PET CT showed a Deauville score (DS) 3-4 or 5 (but partial response). RT was planned 6-8 weeks post CAR T, with CAR T sparing technique. 28 patients were entered between Nov 2021 – Oct 2023, 10 in pathway A & 18 in pathway B. Median age was 55 years. 51.7% had stage 4 (20% vs. 68.4% in A vs. B). 44.8% had bulky disease, 24.1% ≥2 extranodal sites, and 48.2% high LDH. 1 patient in pathway A did not receive CAR T due to PD. RT dose was 20-36Gy (10-12#) in pathway A, all delivered with VMAT and with no gaps. Pathway B doses were 25-37.5Gy / 5-15# (23/26 sites treated with VMAT) and with no gaps. Planning modifications for early cRT post CAR T included: (1) contouring and dose-optimisation of blood vessels (BV) and blood-rich OARs (BR-OAR) to reduce doses to blood, and (2) measures to reduce beam-on time to account for the circulating nature of blood; hypofractionation (2.5 – 5 Gy/#, median = 3), limited beam angles (e.g. partial single arcs) avoiding BV and BR-OAR, and flattening filter free (FFF) beams. Overall response rate at 1 month was 86.2% (41.4% DS 1-3) and 48.2% at 6 months. With a median follow-up of 180 days, 9 patients progressed (4 in pathway A and 5 in pathway B) and 5 died, all due to disease progression. Data on local disease control, progression-free and overall survival will be provided at the meeting. Significant toxicity included 2 G3 ICANS but no CRS G≥ 3. No G≥3 toxicity reported after cRT. Implementing a comprehensive protocol of RT bridging and post CAR T RT consolidation with selection of patients based on pre-defined criteria was feasible. All patients but one completed treatment according to protocol. The disease control outcomes and the toxicity are promising, particularly in the RT consolidation setting. [ABSTRACT FROM AUTHOR]

Chimeric Antigen Receptor T-cell therapy (CAR-T) targeting CD19 has transformed the management of relapsed/refractory (r/r) B-Acute Lymphoblastic Leukemia (B-ALL), with FDA approval of tisagenlecleucel (tisa-cel) for pediatric/young adult patients and brexucabtagene autoleucel (brexu-cel) for adults. Efficacy is contingent upon several factors including disease burden. Emerging data suggests that bridging therapy, lymphodepletion and for some patients, consolidation therapy have an important role in the success of treatment. Further, strategies to define and manage immunotoxic side effects including hematotoxicity is critical to safe delivery. Advancements in CAR-T design beyond CD19 represent an ongoing therapeutic evolution. Overall, CAR-T therapy signifies a paradigm shift in B-ALL management, with the potential for improved remission and survival in a historically challenging patient population., (Copyright © 2024 American Society of Hematology.)