Outcomes for Anti-CD19+ Chimeric Antigen Receptor T (CAR-T) Cell Therapy for Non Hodgkin Lymphoma (NHL) across a Large Community Transplant and Cellular Therapy Network

Background: The Sarah Cannon Transplant and Cellular Therapy Network (SCTCTN), which offers community access to transplant and cell therapy, implemented a coordinated approach to deliver CAR-T therapy through 5 programs. We conducted a retrospective review of clinical outcomes after FDA-approved anti-CD19+ CAR-T in B-cell NHL. Method(s): All patients referred for evaluation within SCTCTN were tracked in our prospective registry (Stafa-CT). We identified 110 patients who received FDA-approved anti-CD19+ CAR-T for NHL within the network between 12/10/2018 and 3/7/2022. All patients received care through standardized eligibility criteria, process, care pathways, toxicity management protocols, and a single quality plan. Result(s): The median age at referral was 60 years (range 23-82), 63% were male, the referral indication was diffuse large B-cell lymphoma (70%), mantle cell lymphoma (7%), follicular lymphoma (15%), or other B-NHL (8%). 35% had received a prior autologous transplant. The median time from referral to infusion was 143 days (range 89- 224), and from collection to infusion was 32 days. The infusion year was 2018 (1), 2019 (20), 2020 (31), 2021 (48), 2022 (10). The CAR-T cell products were Axi-cel (70), Tisa-cel (27), Brexu-cel (9), and Liso-cel (4). 16 patients (15%) were infused as outpatient, of which 10 patients were subsequently hospitalized at a median of 8 days (range 1-26) after infusion. Of the 94 patients (85%) infused as inpatient, the median length of stay was 15 days (range 6 to 85). Cytokine release syndrome (CRS) was observed in 78% with a median maximum grade 1. Maximum grade CRS was none, grade 1, grade 2, grade 3, grade 4, grade 5 in 22%, 36%, 32%, 7%, 2 % and <1%, respectively. The median times to onset and resolution of symptoms were day 3 and 8, respectively. Tocilizumab was administered to 39% for a median of 2 doses. Neurotoxicity was observed in 55% with a median maximum grade 1. Maximum grade neurotoxicity was none, grade 1, grade 2, grade 3, grade 4, grade 5 in 45%, 19%, 13%, 18%, 4 % and 0%, respectively. The median times to onset and resolution of symptoms were day 7 and 13, respectively. Neutropenia (<0.5/ muL) and thrombocytopenia (<20K/muL) at day 30 were reported in 11% and 12%, respectively. 18% required ICU stay. 37 deaths (34%) were reported from disease progression (23), infections (7, including 5 from COVID), CRS (2) and other causes (5).(Figure Presented) Conclusion(s): Administration of anti-CD19+ CAR-T is feasible in specialized community hospitals with outcomes similar to registrational clinical trials. Outpatient administration is feasible in selected patients, but subsequent hospitalization needs to be anticipated. CRS, neurotoxicity, cytopenias and infection remain challenges, while disease progression was the commonest cause of deathCopyright © 2023 American Society for Transplantation and Cellular Therapy

CLADRIPLAS: Does cladribine Target CNS plasma cells and reduce neuro-axonal damage in people with MS?

Introduction: Cladribine is a CNS penetrant disease-modifying treatment, which - in an oral preparation (Mavenclad) - was licensed for people with highly active relapsing MS in August 2017. Our experience with cladribine dates back to 2014 when we started using subcutaneously injected cladribine as a compassionate immunotherapy in people with MS (pwMS) off-label. This programme enabled us to embed CLADRIPLAS, a mechanistic study of the effect on intrathecal B cell and plasma cell function and axonal damage focussing on progressive MS (PMS) (IRAS # 240360). Objective(s): To study the effect of cladribine on peripheral and intrathecal B and plasma cells. Aim(s): To study the effect of cladribine on oligo-clonal bands (OCB) and the level of neurofilament light (NfL) chain. Method(s): Observational study involving two lumbar punctures and phlebotomies, 6-12 months apart, to collect B cell subsets, and intrathecal plasma cell as well as neurofilament light chain (NfL) level in pwMS eligible and not eligible for cladribine treatment based on cerebro-spinal fluid (CSF) NfL, clinical and/or MRI evidence of inflammatory disease activity. Here, we report baseline cohort characteristics. Result(s): Thirty-eight pwMS were recruited (19 women, 19 men) and had their first sample collections. Eight pwMS were eligible for cladribine treatment (7 based on elevated NfL, 1 due to MRI activity). Follow-up samples have been collected in 21. Mean age at baseline was 55 years (40-76). Fourteen had primary, 24 secondary PMS. Median EDSS=6.5 (3.5-8). Twenty-one pwMS had been treated with DMT before consideration of cladribine, 17 were immunotherapy-naive. Mean CSF-NfL level was 552 (176- 2072) pg/ml. Conclusion(s): Despite restrictions due to COVID-19, 38 of 40 planned pwMS were enrolled. 7/8 were eligible based on CSFNfL level indicating the importance of using biomarkers other than MRI to establish disease activity in PMS. We expect our cohort to enable meaningful comparison between groups. CLADRIPLAS will finish in early 2023.

Did it hurt? COVID-19 vaccination experience in people with multiple sclerosis.

BACKGROUND: Current guidelines recommend vaccination against SARS-CoV2 for people with multiple sclerosis (pwMS). The long-term review of the safety and effectiveness of COVID-19 vaccines in pwMS is limited. METHODS: Service re-evaluation. PwMS using the MS service at Barts Health National Health Service Trust were sent questionnaires via email to report symptoms following first and second COVID-19 vaccinations (n = 570). A retrospective review of electronic health records was conducted for clinical and safety data post-vaccination(s); cut-off was end of September 2021. Separate logistic regressions were carried out for symptoms experienced at each vaccination. Two sets of regressions were fitted with covariates: (i) Disease-modifying therapy type and (ii) patient characteristics for symptoms experienced. RESULTS: 193/570 pwMS responded. 184 pwMS had both vaccinations. 144 received the AZD1222 and 49 the BNT162b2 vaccine. 87% and 75% of pwMS experienced any symptoms at first and second vaccinations, respectively. The majority of symptoms resolved within a short timeframe. No severe adverse effects were reported. Two pwMS subsequently died; one due to COVID-19 and one due to aspiration pneumonia. Males were at a reduced risk of reporting symptoms at first vaccination. There was evidence that pwMS in certain treatment groups were at reduced risk of reporting symptoms at second vaccination only. CONCLUSIONS: Findings are consistent with our preliminary data. Symptoms post-vaccination were similar to the non-MS population and were mostly temporary. It is important to inform the MS community of vaccine safety data.

Up to 6 years follow-up of people with MS (n=250) receiving cladribine

Introduction: Oral cladribine is a licensed disease-modifying treatment (DMT) for highly active relapsing multiple sclerosis (RMS). We report clinical and paraclinical data collected as part of ongoing follow-up of our cohort of people with MS (pwMS) treated with subcutaneous (s.c.) cladribine personalised dosing (CPD). Objectives and Aims: To report follow-up data in pwMS treated using CPD (adjusted for weight and total lymphocyte count, TLC). Methods: CPD was offered to pwMS with signs of disease activity irrespective of their disease course. Cladribine 10 mg s.c. was given on three consecutive days (four in pwMS & gt;90kg) during week 1. Based on TLC at week 4, patients were given another 0-3 doses at week 5. A second cycle of CPD was administered 11 months later. Follow-up included recording of adverse events, relapses, annual EDSS, 9-hole peg, timed 25-foot walking, and symbol digit modalities tests. MRI (gadolinium enhancing T1 and T2 lesions), cerebrospinal fluid (CSF) neurofilament light chain (NfL) measurements and full blood counts were obtained. Results: 250 pwMS (113 RMS, 137 PMS) received CPD. 211/250 completed a second cycle. Baseline age 45 (17-72) years and baseline EDSS 0-8.5. The safety and tolerability profile of CPD was generally very good. Six severely disabled pwMS died (one each from influenza, encephalitis, hypoxic brain injury due to choking, COVID19 pneumonia, haemopericardium and dissecting aortic aneurysm and unknown [prior EDSS 9.5]). One myocardial infarction, two breast cancers, one pulmonary embolism occurred, and three severe allergic skin reactions without long term sequelae. Severe lymphopenia (WHO grade 3-4) occurred in 7% despite personalised dosing. In 74/155 pwMS (47.7% of those with EDSS data available), EDSS remained stable or improved at follow up (median 2.9 years). In n=37, mean pre- and post-treatment CSF-NfL measurements at -4.4 and 11.3 months, respectively, were 1079pg/ml (CI 557, 1601) and 508pg/ml (CI 330, 686). Conclusions: Our ongoing observations of this uncontrolled real world cohort suggests CPD is a safe, well tolerated treatment for pwMS with disease activity. Efficacy of cladribine in preserving upper limb function in advanced MS (EDSS 6.5-8.5) will be tested in the ChariotMS trial.

Managing an adult CF population in the COVID-19 pandemic-1 year on.

BACKGROUND: The advent of the COVID-19 pandemic in 2020 required an alteration in the routine care of people with CF (pwCF), deemed to be extremely vulnerable. AIM: We wished to report the alterations in clinical practice, including the introduction of remote video-assisted clinics, made to manage the adult pwCF attending our large centre. METHODS: We studied clinical records over a period of 2 years (March 2019 to February 2021) by comparing 19th March to 20th February (Y1) with 20th March to 21st February (Y2). RESULTS: We have shown out of hospital Multi Disciplinary Team (MDT) support increased and a greater proportion of IV therapy was administered at home. The VAC model of care increased clinical activity while reducing clinic non-attendance rates, suggesting more individuals engage with their carers. CONCLUSIONS: This new model of care has allowed greater engagement with pwCF.

Experience with the COVID-19 AstraZeneca vaccination in people with multiple sclerosis.

BACKGROUND: Some people with multiple sclerosis (pwMS) are at increased risk of severe Coronavirus disease 19 (COVID-19) and should be rapidly vaccinated. However, vaccine supplies are limited, and there are concerns about side-effects, particularly with the ChAdOx1nCoV-19 (AstraZeneca) vaccine. OBJECTIVES: To report our first experience of pwMS receiving the AstraZeneca vaccine. METHODS: Service evaluation. pwMS using the MS service at Barts Health NHS Trust were sent questionnaires to report symptoms following vaccination. RESULTS: Thirty-three responses were returned, 29/33 pwMS received a first dose of AstraZeneca vaccine, the remaining four received a first dose of BioNTech/Pfizer vaccine. All but two patients (94%) reported any symptoms including a sore arm (70%), flu-like symptoms (64%), fever (21%), fatigue (27%), and headache (21%). In more than 2/3 patients, symptoms lasted up to 48 hours, and with the exception of two pwMS reporting symptom duration of 10 and 12 days, respectively, symptoms in the remainder resolved within seven days. No severe adverse effects occurred. CONCLUSIONS: pwMS report transient symptoms following AstraZeneca vaccination, characteristics of which were similar to those reported in the non-MS population. Symptoms may be more pronounced in pwMS due to the temperature-dependent delay in impulse propagation (Uhthoff's phenomenon) due to demyelination.

Clinical prioritisation of revision knee surgical procedures: BASK working group consensus document.

BACKGROUND: Elective orthopaedic surgery during the Covid-19 pandemic requires careful case prioritisation. We aimed to produce consensus-based guidelines on the prioritisation of revision total knee arthroplasty (TKA) procedures. METHOD: Twenty-three revision TKA scenarios were assigned priority (NHS England/Royal College of Surgeons scale) by the British Association for Surgery of the Knee (BASK) Revision Knee Working Group (n = 24). Consensus agreement was defined as ≥70% respondents (18/24) giving the same prioritisation. Two voting rounds were undertaken; procedures achieving <70% agreement were given their most commonly assigned priority. RESULTS: 18/23 procedures achieved ≥70% agreement. Three were P1a (surgery within <24 h); DAIR for sepsis, peri-prosthetic fracture (PPF) fixation and PPF-revision TKA. Three were P1b (<72 h); debridement, antibiotics and implant retention (DAIR) for a stable patient, flap coverage for an open knee, and acute extensor mechanism rupture. Eight were P2 (<4 weeks), including aseptic loosening at risk of collapse, inter-stage patients with poor functioning spacers. Five were P3 (<3 months), including second stage revision for infection, revision for instability with limited mobility. Four were P4 (can wait >3 months) e.g. aseptic loosening. CONCLUSION: Sepsis and PPF surgery are the most urgent procedures. Although most procedures should be undertaken within one to three months (P2/3), these cases represent a small revision practice volume; P4 cases (e.g. aseptic loosening without risk of collapse) make up most surgeons' caseload. These recommendations are a guideline; patient co-morbidities, Covid-19 pathways, availability of support services and multi-disciplinary team discussion within the regional revision network will dictate prioritisation.