IBRUTINIB AND RITUXIMAB AS FIRST LINE THERAPY FOR MANTLE CELL LYMPHOMA: A MULTICENTRE, REAL-WORLD UK STUDY

Background: Ibrutinib (IBR) is an oral covalent Bruton tyrosine kinase inhibitor (BTKi), licensed for treatment of relapsed or refractory mantle cell lymphoma (MCL). Under NHS interim Covid-19 agreements in England, IBR with or without rituximab (R) was approved for the frontline treatment for MCL patients (pts) as a safer alternative to conventional immunochemotherapy. Although recent phase 2 studies have reported high response rates in low-risk patients for this combination in the frontline setting, randomised phase 3 and real-world data are currently lacking. Aims: To describe the real-world response rates (overall response rate (ORR), complete response (CR) rate) and toxicity profile of IBR +/-R in adult patients with previously untreated MCL. Methods: Following institutional approval, adults commencing IBR +/-R for untreated MCL under interim Covid-19 arrangements were prospectively identified by contributing centres. Hospital records were interrogated for demographic, pathology, response, toxicity and survival data. ORR/CR were assessed per local investigator according to the Lugano criteria using CT and/or PET-CT. Results: Data were available for 66 pts (72.7% male, median age 71 years, range 41-89). Baseline demographic and clinical features are summarised in Table 1. 23/66 pts (34.8%) had high-risk disease (defined as presence of TP53 mutation/deletion, blastoid or pleomorphic variant MCL, or Ki67%/MiB-1 ≥30%). IBR starting dose was 560mg in 56/62 pts (90%) and was given with R in 22/64 pts (34%). At a median follow up of 8.7 months (m) (range 0-18.6), pts had received a median of 7 cycles of IBR. 19/60 pts (32%) required a dose reduction or delay in IBR treatment. New atrial fibrillation and grade ≥3 any-cause toxicity occurred in 3/59 pts (5.8%) and 8/57 (14.0%) respectively. For the whole population and high-risk pts only, ORR was 74.4% and 64.7% respectively (p=0.2379), with a median time to response of 3.8m, coinciding with the first response assessment scan. Seven pts (16.7%), of whom 2 had highrisk disease, attained CR at a median of 6.0m. ORR for pts receiving vs not receiving R were 84.2% and 66.7% respectively (p=0.1904). IBR was discontinued in 20/61 pts (32.8%) at a median time to discontinuation of 4.1m, due to progressive disease (PD, 19.7%), toxicity (4.9%), death (3.3%;1 pt each of Covid-19 and E. coli infection), pt choice (3.3%) and other unspecified reasons (1.6%). 15/66 pts (22.7%) overall and 7/23 (30.4%) with high-risk disease progressed on IBR at a median time to PD of 4.0m. No pts underwent autologous stem cell transplantation consolidation during the study period. 12/57 pts (21.1%) received second line treatment (R-chemotherapy n=7, Nordic MCL protocol n=2, VR-CAP n=2, pirtobrutinib n=1). Response to second line treatment was CR in 4/11 pts, PD in 7/11. Of the 2 Nordic-treated patients, 1 had CR after cycle 2 and 1 PD. Fourteen pts (21.2%) died during the follow up period, due to MCL (n=11), Covid-19 (n=2) and congestive cardiac failure (n=1). Overall survival was lower for patients with high-risk disease (HR 0.55, p=0.038). Image: Summary/Conclusion: In this real-world UK cohort of pts receiving first-line IBR +/-R for MCL, including older and high-risk pts, we report high ORR rates in a similar range to the phase II Geltamo IMCL-2015 study of combination IBR-R in an exclusively low-risk population. Documented CR rates were lower, possibly reflecting a low usage of rituximab in the Covid-19 pandemic as well as CT assessment of response. Treatment was generally well tolerated, with low rates of toxicityrelated treatment discontinuation. The study is ongoing.

Longitudinal characterisation of haematological and biochemical parameters in cancer patients prior to and during COVID-19 reveals features associated with outcome.

BACKGROUND: Cancer patients are at increased risk of death from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Cancer and its treatment affect many haematological and biochemical parameters, therefore we analysed these prior to and during coronavirus disease 2019 (COVID-19) and correlated them with outcome. PATIENTS AND METHODS: Consecutive patients with cancer testing positive for SARS-CoV-2 in centres throughout the United Kingdom were identified and entered into a database following local governance approval. Clinical and longitudinal laboratory data were extracted from patient records. Data were analysed using Mann-Whitney U test, Fisher's exact test, Wilcoxon signed rank test, logistic regression, or linear regression for outcomes. Hierarchical clustering of heatmaps was performed using Ward's method. RESULTS: In total, 302 patients were included in three cohorts: Manchester (n = 67), Liverpool (n = 62), and UK (n = 173). In the entire cohort (N = 302), median age was 69 (range 19-93 years), including 163 males and 139 females; of these, 216 were diagnosed with a solid tumour and 86 with a haematological cancer. Preinfection lymphopaenia, neutropaenia and lactate dehydrogenase (LDH) were not associated with oxygen requirement (O2) or death. Lymphocyte count (P < 0.001), platelet count (P = 0.03), LDH (P < 0.0001) and albumin (P < 0.0001) significantly changed from preinfection to during infection. High rather than low neutrophils at day 0 (P = 0.007), higher maximal neutrophils during COVID-19 (P = 0.026) and higher neutrophil-to-lymphocyte ratio (NLR; P = 0.01) were associated with death. In multivariable analysis, age (P = 0.002), haematological cancer (P = 0.034), C-reactive protein (P = 0.004), NLR (P = 0.036) and albumin (P = 0.02) at day 0 were significant predictors of death. In the Manchester/Liverpool cohort 30 patients have restarted therapy following COVID-19, with no additional complications requiring readmission. CONCLUSION: Preinfection biochemical/haematological parameters were not associated with worse outcome in cancer patients. Restarting treatment following COVID-19 was not associated with additional complications. Neutropaenia due to cancer/treatment is not associated with COVID-19 mortality. Cancer therapy, particularly in patients with solid tumours, need not be delayed or omitted due to concerns that treatment itself increases COVID-19 severity.

Longitudinal analysis of biochemical and haematological features of cancer patients with COVID-19

Background: Cancer patients (pts) are at increased risk of severe COVID-19 infection and death. Older pts, men and those with haematological malignancies and receiving anti-tumour therapy within 14 days appear to be at highest risk for poor outcomes. In general populations, severe COVID-19 infection has been associated with neutrophilia, raised lactate dehydrogenase (LDH) and C-reactive protein (CRP). Cancer and its treatment affect many haematological and biochemical parameters. We examined whether COVID-19 infection affected these compared to pts’ baseline parameters by longitudinal tracking. We also investigated whether changes were associated with poor outcome. Methods: Consecutive pts with solid or haematological malignancies presenting with index symptoms and testing positive for SARS-CoV-2 at a tertiary oncology centre were identified following institutional board approval. Clinical and laboratory data were extracted from the pt record. Paired T-tests were used for longitudinal sampling and ANOVA/Chi squared for outcomes. Results: 52 pts tested positive (27 male, 25 female;median age 63). 80.5% had solid cancers, and 19.5% haematological. 31/52 pts were lymphopenic prior to infection. Comparing mean pre-infection counts (6 months-14 days=PRE) with mean counts from the 5 days following positive test (DURING) lymphocyte counts significantly decreased during infection (p<0.0001). Platelets were significantly reduced DURING vs. PRE COVID-19 (p=0.0028). 17/52 pts developed transient (median 2 days) neutropenia (<2x109/L) DURING infection (6 pts <1x109/L, 2 pts <0.5x109/L), 8/17 attributed to cancer/cancer therapy, the rest had no underlying cause. 8/17 pts received growth factor support. Reduced lymphocytes/neutrophils/platelets at diagnosis were not associated with oxygen requirement (O2) or death. Different CRP trajectories were observed when comparing pts grouped by discharge/ O2/death. Higher CRP and LDH at diagnosis were associated with admission (p=0.02 CRP/0.2 LDH), O2 (p=0.0002 CRP/p<0.01 LDH) and death (p=0.069 CRP/p=0.04 LDH). Updated analysis will be presented. Conclusions: Infection with SARS-CoV-2 commonly affects haematological parameters in cancer pts. High CRP and LDH are associated with poor outcomes. Legal entity responsible for the study: The Christie NHS Foundation Trust. Funding: Has not received any funding. Disclosure: R. Lee: Speaker Bureau/Expert testimony, Research grant/Funding (self): Bristol Myers Squibb;Speaker Bureau/Expert testimony: Astra Zeneca. A. Armstrong: Shareholder/Stockholder/Stock options, Husband has shares: Astra Zeneca. T. Cooksley: Speaker Bureau/Expert testimony: Bristol Myers Squibb. All other authors have declared no conflicts of interest.

Development of a model to predict hospital admission and severe outcome in cancer patients with COVID-19

Background: Patients (pts) with cancer are at increased risk of severe COVID-19 infection and death. Due to the heterogeneity of manifestations of COVID-19, accurate assessment of patients presenting to hospital is crucial. Early identification of pts who are likely to deteriorate allows timely discussions regarding escalation of care. It is equally important to identify pts who could be safely managed at home. To aid clinical decision making, we developed a model to determine which pts should be admitted vs. discharged at presentation to hospital. Methods: Consecutive pts with solid or haematological malignancies presenting with symptoms who tested positive for SARS-CoV-2 at 10 UK hospitals from March-May 2020 were identified following institutional board approval. Clinical and laboratory data were extracted from pt records. Clinical outcome measures were discharge within 24 hours, requirement for oxygen at any stage during admission and death. The associations between clinical features and outcomes were examined using ANOVA or Chi-squared tests. A logistic model was developed using clinical features with p<0.05 to predict patients who need hospital admission. Results: 52 pts were included (27 male, 25 female;median age 63). 80.5% pts had solid cancers, 19.5% haematological. Association analysis indicated that smoking status, prior cancer therapy and comorbidities had no significant association with outcomes. A number of other factors presented in the table had significant associations. A multivariate logistic regression model was generated to predict need for admission to hospital. Of note, age and male sex lost significance in the multivariate model (p>0.8). Using haematological cancer, NEWS2 score, dyspnoea, CRP and albumin, the model predicted requirement for admission with an area under the curve of 0.88. [Formula presented] Conclusions: We have developed a model to predict which pts require hospital admission. Further refinement and validation in larger cohorts of pts will be presented. Legal entity responsible for the study: The Christie NHS Foundation Trust. Funding: Has not received any funding. Disclosure: R. Lee: Honoraria (self): Bristol Myers Squibb;Honoraria (self): Astra Zeneca;Research grant/Funding (institution): Bristol Myers Squibb. M.P. Rowe: Travel/Accommodation/Expenses: Astellas Pharma. L. Horsley: Travel/Accommodation/Expenses: Lilly. C. Wilson: Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony: Pfizer;Amgen;Novartis. T. Cooksley: Speaker Bureau/Expert testimony: Bristol Myers Squibb. A. Armstrong: Shareholder/Stockholder/Stock options, husband had shares now sold: Astra Zeneca. All other authors have declared no conflicts of interest.