Mucosa-Associated Lymphoid Tissue Lymphoma of the Rectum Incidentally Found in a Patient with Ulcerative Colitis

Introduction: Mucosa-associated lymphoid tissue (MALT) lymphomas are extra-nodal marginal zone B-cell lymphomas, most commonly found in the stomach, associated with Helicobacter pylori infections, and generally not linked with inflammatory bowel disease. Rectal MALT lymphoma is very uncommon and often associated with painful defecation, change in bowel habits, or rectal pressure/prolapse. Here, we present a rare case of an asymptomatic female with ulcerative colitis (UC) found to have benign-appearing rectal polyps during a routine screening colonoscopy. Case Description/Methods: The patient is a 56-year-old female with a history of left-sided UC, diagnosed in 1993, with one flare after receiving the 2nd dose of the Moderna COVID-19 vaccine, taking oral Olsalazine 500 mg twice daily, low-dose Prednisone, and mesalamine suppositories as needed presenting for screening colonoscopy. The patient was asymptomatic, citing regular non-bloody bowel movements and normal stool consistency. Colonoscopy revealed two 7 mm sessile, non-bleeding rectal polyps, surrounded by congested, erythematous, friable, and ulcerated mucosa in the rectosigmoid colon. Cold forceps biopsies were taken. Hematopathology evaluation of the routine colon biopsy samples revealed chronic nonspecific colitis while pathology of the rectal polyps showed marked lymphoplasmacytic infiltrate and extra-nodal marginal zone lymphoma of MALT. Ancillary studies, immunohistochemistry, and molecular studies for B-cell gene rearrangement confirmed extra-nodal marginal zone lymphoma of MALT with prominent plasmacytic differentiation. The patient was informed and close follow-up in Gastroenterology clinic was arranged. (Figure) Discussion: Rectal MALT lymphoma is rare with unclear management options. Treatments of UC include watchful waiting, surgical resection, endoscopic mucosal resection, radiation, and/or chemotherapy. Helicobacter pylori infections, though strongly linked with gastric MALT lymphoma, have not been shown to be strongly correlated with rectal MALT lymphoma. Given that patients with UC have chronic UCassociated colonic inflammation, lymphoma is often difficult to distinguish visually during colonoscopy, frequently masked by ulcerations and pseudo-polyps. In cases like these, more definitive treatments such as surgical resection could therefore be warranted. Long-term follow-up data is sparse and definitive management remains a clinical conundrum, thus these patients require reliable long-term multidisciplinary close follow-up. (Figure Presented).

COVID-19 vaccination-related [18F]FDG-avid lymph node in a patient with marginal zone B-cell lymphoma

The [18F]FDG PET/CT is a crucial tool in the diagnostic process and monitoring of neoplastic diseases. Currently, during the global program of vaccination against COVID-19 and the possibility of axillary lymphadenopathy after this injection, the correct interpretation of PET/CT images is vitally significant and may create some difficulties. We present a case of increased uptake of [18F]FDG in an axillary lymph node in a PET/CT scan performed 2 days after the Pfizer BioNTech COVID-19 vaccine in a 48-year-old patient newly diagnosed with marginal zone B-cell lymphoma.Copyright © 2023 Via Medica.

Long-Term Efficacy and Safety of Zanubrutinib in Patients with Relapsed/Refractory (R/R) Marginal Zone Lymphoma (MZL): Final Analysis of the Magnolia (BGB-3111-214) Trial

Introduction: Advanced MZL is generally incurable, with periods of remission and relapse. Zanubrutinib (BGB-3111), a potent and highly specific next-generation Bruton tyrosine kinase (BTK) inhibitor, was approved in the US and Canada for R/R MZL based on the MAGNOLIA primary analysis (BGB- 3111-214;NCT03846427);here, the final MAGNOLIA analysis is presented. Method(s): This was a phase 2, multicenter, single-arm study of adult patients (pts) with R/R MZL (>=1 prior CD20-directed therapy). Zanubrutinib (160 mg twice daily) was given until disease progression or unacceptable toxicity. The primary endpoint was overall response rate (ORR) by independent review committee (IRC) per Lugano classification. Secondary endpoints were investigator-assessed ORR, duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Efficacy was assessed by positron emission tomography (PET)-based Lugano criteria for IRC-confirmed fluorodeoxyglucose (FDG)-avid disease at baseline;non-avid disease was assessed by computed tomography (CT)-based criteria. Result(s): As of May 4, 2022, 68 pts were treated (median age=70 y [range 37-95];>=75 y=27.9%). MZL subtypes included extranodal (38.2%), nodal (38.2%), splenic (17.6%), and unknown (5.9%). The median number of prior therapies was 2 (range 1-6);32.4% of pts had disease refractory to last therapy, most (89.7%) had prior chemoimmunotherapy, and 7 (10.3%) had rituximab monotherapy as their only prior treatment. Sixty-one pts (89.7%) had FDG-avid disease. After a median follow-up of 28.0 mos (range 1.6-32.9) and a median treatment duration of 24.2 mos (range 0.9-32.9), 66 pts were efficacy- evaluable. IRC-assessed ORR (complete response [CR]+partial response [PR]) was 68.2% (CR=25.8%). By subtype, (Figure Presented)(Figure Presented)ORR/CR rates were 64.0%/40.0% (extranodal), 76.0%/20.0% (nodal), 66.7%/8.3% (splenic), and 50.0%/25.0% (unknown). Median DOR, PFS, and OS were not reached. Over 70.0% of pts were alive or progression-free after 2 years (Figure). Sensitivity analysis using only CT-based criteria (n=66) showed an ORR of 66.7% and CR of 24.2%. The most common treatment-emergent AEs were bruising (23.5%), diarrhea (22.1%), and constipation (17.6%). Neutropenia (8.8%) and COVID-19 pneumonia (5.9%) were the most common Grade >=3 AEs. Five pts (7.4%) died due to unrelated AEs: COVID-19 pneumonia=2, acute myeloid leukemia=1, myocardial infarction=1, septic encephalopathy=1. Hypertension occurred in 3 pts (4.4%), atrial fibrillation and atrial flutter in 1 pt (1.5%) each;none led to treatment withdrawal. One pt (1.5%) had a Grade 3 gastrointestinal hemorrhage while receiving rivaroxaban. None of the pts required dose reduction. Conclusion(s): In this final analysis with over 2 years of median follow-up, zanubrutinib continues to demonstrate durable disease control and was generally well tolerated, with no new safety signals observedCopyright © 2023 American Society for Transplantation and Cellular Therapy

Zanubrutinib for the treatment of lymphoid malignancies: Current status and future directions.

Zanubrutinib (BGB-3111, Brukinsa®, BeiGene) is a next-generation irreversible inhibitor of Bruton's tyrosine kinase (BTK), developed by BeiGene in 2012 for the treatment of B-cell malignancies. It was designed to minimize off-target inhibition of TEC- and EGFR-family kinases. Zanubrutinib is more selective than ibrutinib for BTK versus EGFR, FGR, FRK, HER2, HER4, ITK, JAK3, LCK, BLK and TEC. In addition, compared to ibrutinib, zanubrutinib has improved oral absorption and better target occupancy. Zanubrutinib demonstrated a lower incidence of off-target toxicities and reduced severity than ibrutinib. Moreover, zanubrutinib is similar to acalabrutinib, with less activity against TEC and ITK. The preliminary phase 1 results suggest that zanubrutinib has clinical activity and the drug is well tolerated in patients with B-cell lymphoid malignancies. Recent clinical trials have found it to demonstrate excellent efficacy and good tolerability in patients with chronic lymphocytic leukemia (CLL), Waldenstrom macroglobulinemia (WM) and mantle cell lymphoma (MCL). In recent phase 3 studies, zanubrutinib was compared with ibrutinib in patients with relapsed/refractory (R/R) MW and RR CLL. In both trials, zanubrutinib was found to demonstrate clinically meaningful advantages in safety and tolerability over ibrutinib; in particular, it was associated with a lower risk of atrial fibrillation/flutter and major bleeding events. In the recent SEQUOIA study, comparing zanubrutinib with bendamustine and rituximab (BR) in patients with previously untreated CLL, zanubrutinib significantly improved progression-free survival versus BR, with an acceptable safety profile consistent with previous studies. Zanubrutinib also demonstrated good activity and tolerability in patients with R/R MCL, marginal zone lymphoma and follicular lymphoma. Trials examining the efficacy and safety of the combination of zanubrutinib with obinutuzumab venetoclax and other drugs are ongoing. This review summarizes the clinical efficacy and safety of zanubrutinib in lymphoid malignancies.

[Warm autoimmune hemolytic anemia and IgM-monoclonal gammopathy following BNT162b2 COVID-19 vaccine in a patient with splenic marginal zone lymphoma].

There is currently no evidence that a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccine might be associated with the development of autoimmune hemolytic anemia or disease progression in patients with mature B-cell neoplasm. Our patient was a 71-year-old man with indolent mature B-cell neoplasm who had been monitored for many years without treatment. After receiving the second dose of the BNT162b2 mRNA COVID-19 vaccine, he developed severe warm autoimmune hemolytic anemia. Although steroid therapy improved his anemia, he continued to develop IgM-monoclonal gammopathy, renal insufficiency, and splenomegaly. He was diagnosed with splenic marginal zone lymphoma after undergoing splenectomy. The splenectomy improved the patient's symptoms. We assessed his SARS-CoV-2 specific antibody response, but the patient's serologic response to the vaccine was impaired. In patients with mature B-cell neoplasm, a non-specific immune response after vaccination might be associated with paraneoplastic syndromes.

SARS-COV-2 INFECTION WITH RITUXIMAB THERAPY

SESSION TITLE: COVID-19 Case Report Posters 3 SESSION TYPE: Case Report Posters PRESENTED ON: 10/19/2022 12:45 pm - 01:45 pm INTRODUCTION: Exposure to anti-CD20 treatment affects B cell functions involved in anti-COVID immunity and impacts the clinical course of infection. We present two patients with persistent respiratory symptoms and persistent SARS-COv-2 PCR positivity months after initial infection. The aim of presenting these cases is to highlight how exposure to Rituximab can result in patients having significantly prolonged SARS-CoV-2 infections that may require special treatment compared to immunocompetent patients. CASE PRESENTATION: Patient A is a 46-year-old man with a history of marginal zone lymphoma, who was treated with six cycles of bendamustine with rituximab and monthly maintenance rituximab. He has been hypoxic for 7 months after COVID infection with ground glass opacities on imaging, elevated CRP of 58.4, positive PCR, undetectable CD3/CD4 and low cycle threshold of 28, suggesting rapid active viral replication. COVID IGG was negative. T cell subsets counts were undetectable. IgG 351, IgA 59, IgM less than 10. He was treated with a 10-day course of Remdesevir and steroids. Given lack of humoral immunity, he was given convalescent plasma. At discharge he developed positive COVID IgG and remained COVID positive by PCR. He had complete resolution of hypoxia. Patient B is a 68-year-old man with a history of chronic lymphocytic leukemia, who was treated with six years of rituximab maintenance therapy, last rituximab was three years ago. He was diagnosed with SARS-CoV-2 three months prior to admission with worsening hypoxia. He remained PCR positive with persistent respiratory symptoms. At readmission his imaging showed ground glass opacities, CRP 6.6 and cycle threshold was 27.8. The follow studies were abnormally low:IgG 541, IgA 25, IgM 14, absolute CD3 171, absolute CD4 68. He was treated with remdesivir, steroids, granulocyte colony stimulating factor and sotrovimab. Despite these therapies, his hypoxia worsened, and he pursued comfort care. DISCUSSION: There are reports of patients receiving B cell depleting therapy who have persistent shedding of viable SARS-CoV. Persistent viral infection may be suspected in patients with relapsing symptoms, elevated CRP, D-dimer and active ground glass changes imaging. Low T cell subsets and low immunoglobulin levels indicate a CD20 related impairment of adaptive immunity. Time to viral clearance appears to be prolonged compared to general population in immunocompromised patients. There is some published experience using convalescent plasma in this setting. SARS-CoV-2 viremia has been demonstrated to predict adverse outcomes. Median cycle threshold has been shown to be lower, reflecting a high viral load comparable with acute infectious phase of COVID. CONCLUSIONS: To achieve stable clinical responses this subset of patients may benefit from early administration of combination regimens, including both passive immunotherapy and prolonged antiviral treatment. Reference #1: Furlan A, Forner G, Cipriani L, Vian E, Rigoli R, Gherlinzoni F, Scotton P. COVID-19 in B Cell-Depleted Patients After Rituximab: A Diagnostic and Therapeutic Challenge. Front Immunol. 2021 Nov 3;12:763412. doi: 10.3389/fimmu.2021.763412. PMID: 34804051;PMCID: PMC8595333. DISCLOSURES: No relevant relationships by Cheryl Augenstein Primary Investigator relationship with Boehringer Ingelheim Please note: 2/2022-2/2024 Added 04/01/2022 by A. Thanushi Wynn, value=Grant/Research Support

ZANUBRUTINIB IN OLDER PATIENTS (PTS) WITH RELAPSED/REFRACTORY (R/R) MARGINAL ZONE LYMPHOMA (MZL): SUBGROUP ANALYSIS OF THE MAGNOLIA STUDY

Background: MZL is the second most common lymphoma in older pts. Choosing an optimal treatment can be challenging because of patient-or disease-related risk factors and treatment-related toxicities (Curr Opin Oncol. 2019;31(5):386-393). Zanubrutinib is a potent, irreversible next-generation Bruton tyrosine kinase (BTK) inhibitor designed to maximize BTK occupancy and minimize off-target kinase inhibition, which may improve efficacy outcomes and minimize toxicities, such as cardiac arrythmias and bleeding events. Zanubrutinib received accelerated approval from the United States FDA for the treatment of pts with R/R MZL (Haematologica . 2022;107(1):35-43). Aims: We aim to present a subgroup analysis of efficacy and safety of zanubrutinib in pts aged ≥65 years with R/R MZL enrolled in MAGNOLIA (BGB-3111-214;NCT03846427). Methods: MAGNOLIA is a phase 2, multicenter, single-arm study of adults with R/R MZL who had received ≥1 line of therapy including ≥1 CD20-directed regimen. All were treated with zanubrutinib 160 mg twice daily until disease progression or unacceptable toxicity. Use of long-term antiplatelet and anticoagulation agents was permitted. The primary endpoint was overall response rate (ORR;complete response [CR] and partial response [PR]) determined by an independent review committee (IRC) in accordance with the Lugano classification. Secondary endpoints include ORR by investigator assessment (INV), duration of response (DOR), progression-free survival (PFS), and safety. All pts gave informed consent. Results: As of 18 January 2021, a total of 68 pts were enrolled (Table). Forty (61%) pts were ≥65 years old with a median age of 73 (range, 65-85);18 pts were ≥75 years old. Median number of prior therapies was 2 (range, 1-6) and 10 (25%) pts were refractory to last therapy. Most pts received prior rituximab + cyclophosphamide + vincristine + prednisone (48%) or bendamustine + rituximab (30%), while 5 (13%) pts received rituximab monotherapy. MZL subtypes included extranodal (n=17, 43%), nodal (n=14, 35%), and splenic (n=8, 20%). Median duration of treatment was 14.4 months (mo;range, 0.9-19.6). At a median follow-up of 15.8 mo (range, 2.8-21.8), ORR by IRC was 75% (CR 25%, PR 50%;Table). Responses were observed in all subtypes, with an ORR of 71%, 86%, and 75% in extranodal, nodal, and splenic subtypes, respectively (CR 41%, 21%, and 0%, respectively). Median DOR and PFS were not reached;15-month PFS was 87% and 12-month DOR was 93%. Most (63%) pts are continuing zanubrutinib. Treatment discontinuation due to disease progression was 28% by INV. Most common treatmentemergent adverse events (AEs) observed in ≥20% of pts include contusion (28%), diarrhea (25%), and constipation (20%). Grade ≥3 neutropenia occurred in 5% of pts. The most common infection was upper respiratory tract infection (10%). Two (5%) pts discontinued zanubrutinib due to unrelated fatal AEs (COVID-19 pneumonia and myocardial infarction in a patient with pre-existing coronary artery disease). Atrial fibrillation/flutter and hypertension occurred in 2 (5%) pts each and did not lead to treatment discontinuation. No pts required dose reductions, or experienced major or serious hemorrhage. Image: Summary/Conclusion: The safety profile of zanubrutinib observed in older pts was consistent with previously published results (Clin Cancer Res . 2021;27(23):6323-6332). Zanubrutinib was well tolerated and effective, as demonstrated by a high response rate and durable disease control in older pts with R/R MZL.

CELLULAR IMMUNE RESPONSE TO THE BNT162B2 VACCINE IN LYMPHOMA PATIENTS

Background: In most individuals, protective humoral and cellular immunity develops after two doses of the BNT162b2 Pfizer vaccine. In patients with lymphoma, humoral response is weaker and almost universally abrogated in patients who received anti-CD20 monoclonal antibodies. Whether cellular immune response is also abrogated is unknown. Aims: To determine whether patients with lymphoma develop specific T-cell mediated cellular response to BNT162b2 Pfizer vaccine. Methods: We included patients with lymphoma above the age of 18 years who received two doses of the BNT162b2 Pfizer vaccine and collected clinical and demographics data. T-cell immune response to the vaccine was analysed in patients' blood samples stimulated by spike antigen and quantified by two methods: (1) Interferon-gamma (IFNg)- release assay (IGRA, EuroImmun, Germany)- IFNg was quantified by ELISA (DuoSet, R and D Systems, Minneapolis, Minnesota, USA) and response above 50 pg/ml was considered positive. (2) Flow cytometry- Quantification of the T cell activation markers, CD134+ CD25+CD4+ T-cells was performed (Act-T4 CellTM kit, Cytognos, Spain), and any response above 0 was considered positive. Humoral response was measured by SARS-CoV-2 IgG II Quant (Abbott©) assay. The positive cut-off was set at 50AU/ml. Blood samples were drawn approximately 4 months after the second vaccination. Results: Sixty-nine lymphoma patients, treated with two vaccine doses, were included in this study. Median age was 66 (range: 30-84) and 39 (57%) were males. Sixty-two patients (90%) had non-Hodgkin lymphoma (NHL) including 18 with DLBCL, 26 with follicular lymphoma and 14 with marginal zone lymphoma. Seven (10%) patients had Hodgkin lymphoma. In this cohort, 70% (n=49) of the patients received anti CD20 MoAb, and 35% of them (n=27) were still on anti CD20 treatment. Thirteen patients received bendamustine-based immunochemotherapy. At the time of assessment (median 4.8 months after the 2nd vaccine) anti-spike antibodies were detected in only 42% (N = 29) of patients. In comparison, there was an increase in specific T cell response by any assay (IGRA and Flow) in 49% of patients (n = 34). The correlation between the IGRA and flow data was 0.7 (pearson correlation, P = 0.01). However, no correlation between humoral (qualitative and quantitative) and T cell response was shown, regardless of the assay applied. Cellular response was not corelated with the time elapsing from last immunochemotherapy. In the anti-CD20 MoAb treated cohort, of which 27 patients were still on active treatment at the time of vaccination, only 2 patients (7%) developed a humoral immune response, while cellular immunity was elicited in 52% (N = 15) patients (ELISA assay). In the Bendamustine treated cohort, with a median time from end of treatment to vaccination of 23 months (1-106 months), humoral but not cellular response correlated positively with the time from treatment completion to vaccination (p=0.04). Summary/Conclusion: The rate of cellular and humoral response to two doses of the BNT162b2 Pfizer vaccine in lymphoma patients was found to be significantly abrogated. In this small cohort, 49% of patients developed a cellular response despite a severely abrogated humoral immunity. These findings suggest that vaccine administration should be considered even early after anti CD20 therapy despite the reduced humoral immunity. These findings should be validated in studies with a higher number of patients.

CLINICAL COURSE and OUTCOMES of COVID-19 INFECTION in PATIENTS with SJOGREN'S SYNDROME TREATED with RITUXIMAB

Background: Data from multiple rheumatological cohorts have shown that treatment with rituximab (RTM) is associated with higher COVID-19 morbidity and mortality. Information about the course of COVID-19 in patients (pts) with Sjogren's syndrome (SjS) is still lacking. Objectives: To compare clinical course of COVID-19 in pts with SjS treated with anti-CD20 monoclonal antibody (RTM) and treated with synthetic disease-modifying antirheumatic drugs and low doses of glucocorticoids. Methods: Single center observational study. Pts with SjS were screened for SARS-CoV-2 infection anamnesis via telephone interview. Diagnosis of SjS was based on ECR/EULAR 2016 criteria. COVID-19 diagnosis was based on positive PCR test and typical clinical features (CT signs, fever and anosmia). RTM was administered as two infusions of 1000 mg each 2 weeks apart, and then 500 mg every 6 months. Results: 387 pts with SjS were interviewed, 142 of them with confrmed SARS-CoV-2 were included in the study and divided into 2 groups. The frst group (gr) consisted of 86 pts (79 women and 7 men) receiving RTM (gr R), median age was 56 years (33-66,5 years), and median rituximab treatment duration was 36 months (12-42 months). Pts in the control gr (gr C), 56 pts did not receive RTM (55 women and 1 man), their median age was 50 years (35-69 years). Median time from last RTM administration to COVID-19 symptoms onset was 4 months (2-6 months). Ten pts had concomitant RA, 4 pts-SLE, 5 pts-Systemic sclerosis. Fifteen pts had MALT-lymphoma anamnesis. Additionally, 15 pts (10.5%) had pulmonary involvement secondary to rheumatic disease. In total 37 pts had chronic ischemic heart disease and/or severe arterial hypertension, diabetes mellitus type 2. In gr R 31 pts (36%), and in gr C 13 (23%) required hospitalization due to marked shortness of breath and long febrile period (p=0,1). Anti-IL6 treatment or/and Jak inhibitors were prescribed to 17 of 31 pts (54.8%) in gr R and to 5 of 13 (38%) in gr C (p=0,1). The risk of hospitalization was slightly higher in pts with comorbidity (p=0.06) and with a history of lymphoma (p=0.056) and didn't correlate with the following parameters: age, the duration of RTM therapy, lung damage. A high rate of hospitalization correlated with a shorter period between the administration of the RTM and the development of COVID-19 (R=0,387, Spearmaǹs Rank Correlation). Anti-SARS-CoV-2 IgG were measured in 66 pts, 47 (71%) of them were positive. Positive Anti-SARS-CoV-2 IgG were signifcantly more often detected in gr C (84% vs. 57,6%). No correlation was found between the formation of antibodies and the duration of RTM therapy or the time from the last RTM administration. Conclusion: According to our data anti-CD20 therapy doesn't predispose SjS pts to severe course of COVID-19. Lymphoma anamnesis, cardiovascular diseases and diabetes have greater impact on COVID-19 severity. Obviously, anti-CD20 therapy negatively affected the formation of specifc anti-SARS-CoV-2 humoral immunity.

INDICATIONS AND DIAGNOSTIC YIELD OF SINGLE-BALLOON ASSISTED ENTEROSCOPY: AN EXPERIENCE IN A TERTIARY CARE CENTER OF A LOW INCOME COUNTRY

AIM: Enteroscopy is an endoscopic procedure to approach the small intestine in order to diagnose and treat various pathologies. The aim of this study is to share the experience of our center with this modality and highlight the main indications and diagnostic yield pf the procedure. METHODS: This is a single center retrospective study at Aga Khan University Hospital Karachi, Pakistan in which we included all the enteroscopies done in last five years. RESULTS: A total of 37 enteroscopies were done in past five years, the numbers has reduced significantly in the Covid-19 era. The mean age was 50.4 ± 16.5 years with 19 (51.4%) females and 18 (48.6%) males. The most common indications were jejunal thickening on CT scan 17 (45.9%) followed by obscure gastrointestinal bleeding 7 (18.9%) and chronic diarrhea 5 (13.5%). Most of the enteroscopies showed no gross pathology 17 (45.9%). However, jejunal ulcers 6 (16.2%), arteriovenous malformations 4 (10.8%), jejunal polyps 3 (8.1%), erythematous mucosa 2 (5.4%), pale mucosa 2 (5.4%), jejunal mass 2 (5.4%) and gastric polyp 1 (2.7%) are the findings noticed in rest of the enteroscopies performed. In 18 (48.6%) no biopsies were taken due to normal findings. 12 (32.4%) had nonspecific chronic inflammation in the jejunum. The remaining seven patient's histopathology showed giardiasis, MALTOMA, high grade B cell lymphoma, moderately differentiated adenocarcinoma, inflammatory polyp, hamartomatous polyp and adenomatous polyp. CONCLUSIONS: We shared the five year experience of enteroscopies done in our center which belongs to a low income country. The number of enteroscopies has greatly affected by the cost, low socioeconomic status of patients. Covid-19 has further reduced the number of diagnostic procedures in general. Most of the enteroscopies didn't reveal significant findings however there are cases where lymphoma and adenocarcinoma has been diagnosed.

Marginal lymphoma and COVID-19: features of clinical presentation and outcome

There is now sufficient evidence to show conclusively that, together with various comorbidities, the presence of a malignancy, especially of haematopoietic nature, significantly worsens the course and prognosis of the new coronavirus infection COVID-19 caused by SARSCoV-2. It has been shown that of great importance for the outcome of COVID-19 is the variant of the disease, the type of antitumour treatment and its stage (primary diagnosis, remission, relapse). The national and international literature presents generalised data, which combine large cohorts of patients with tumour and COVID-19, without detailing individual immunomorphological variants and peculiarities of the course of the viral infection. An analysis of the course of COVID-19 in patients with a previous immunodeficiency state caused by another viral infection, in particular viral hepatitis C and associated non-Hodgkin lymphoma, seems to us a particularly relevant and understudied problem. The aim of our study was to assess the incidence and impact of COVID-19 on the course and outcome in patients with hepatitis C-associated marginal zone lymphoma (HCV+MZL) and patients with marginal zone lymphoma (MZL). Materials and methods: A total of 27 patients with HCV+MZL and 32 patients with MZL were included in the study. The HCV+MZL group of 27 patients (group 1) received interferon and ribavirin therapy for an average of 24 months (12-36 months). The MZL group of patients (group 2) 32 received immunochemotherapy. Clinical characteristics of patients in groups 1 and 2 differed significantly: median age was 43 and 58 years ( p = 0.005), 74% and 52%, respectively, had advanced stage III-IV disease ( p = 0.01). The incidence of splenic form was 54% in group 1 and 27% in group 2 ( p = 0.005). Results: In HCV+MZL patients treated with interferon (group 1), COVID-19 infection was diagnosed in two cases during the pandemic and in one patient was found to have a high titre of antibodies to COVID-19 (3 of 27 -11% total). The age of the patients was 47 and 76 years. Both patients developed COVID-19 infection on the background of relapsed HCV+MZL, which required administration of rituximab. One patient, due to the severity of the respiratory syndrome and the extent of lung tissue damage, was hospitalized and died on day 7 against the background of increasing respiratory failure. All MZL group 2 patients had completed immunochemotherapy by the time of the COVID-19 pandemic. During the pandemic, COVID-19 infection was diagnosed in 21 patients, and two patients had a high titre of antibodies to COVID-19 at routine examination (23 of 32 patients = 72%). The age ranged from 33 to 76 years (median age 61 years). Fifteen patients (47%) were hospitalized for 10 to 23 days (median 14 days) because of severity of respiratory syndrome, extent of lung tissue involvement and comorbidities. Of 23 patients with COVID-19 seven patients died against the background of increasing respiratory failure (22%). Thus the incidence of infection with COVID-19 was 11% and 72% respectively ( p > 0.001), with a moderate and severe course of infection in 4% and 47% ( p > 0.005), the mortality rate of COVID-19 was 4% and 22% respectively ( p = 0.01). Conclusion: Patients with marginal zone lymphoma have a high risk of morbidity and a severe course of the new coronavirus infection COVID-19. In a pandemic setting, interferon alpha therapy is the safest and preferred treatment option in this patient population..

Utilization and cost effectiveness of first-line yttrium-90 ibritumomab tiuxetan in lowgrade follicular and marginal zone lymphomas compared to standard of care bendamustine plus rituximab: A real-world experience

Background Yttrium-90 ibritumomab tiuxetan [(90)Y-IT;Zevalin] is a radio-immunoconjugate (RIC) which targets CD20. This study evaluates the utilization and cost-effectiveness of (90)Y-IT in the first line treatment for patients with previously untreated low-grade FL (UFL) and marginal zone lymphoma (UMZL) treated at our institution with (90)Y-IT. Methods We utilized the Advanced Text Explorer (ATE) and the Lymphoma SPORE databases to identify two groups of patients with UFL, WHO grade 1-2, and UMZL who received treatment with either (90)Y-IT or bendamustine plus rituximab (BR) at Mayo Clinic Cancer Center between January 2003 and December 2019. We excluded all patients who had >25% bone marrow involvement with lymphoma for the BR group as this was a requirement for (90)Y-IT treatment. Inverse propensity weighting was utilized to balance the groups for baseline patients and disease characteristics. We use progression-free survival (PFS) as a denominator for the cost effectiveness/utilization evaluation. We identified meaningful and retrospectively measurable outcomes to compare between the groups. we extracted the following data;number of clinic visits in the first year after therapy, emergency room visits, number of hospital admissions, number of hospitalization days, numbers of days on the floor and ICU, number of infections, number of neutropenic fever hospitalizations, number of C-difficile events, number of blood products transfusions, overall use of growth factors due to therapy induced neutropenia, average number of times a growth factor was used, and the number of therapeutic use days. We defined days of therapeutic use as the number of days a treatment was administered on. We also calculated the average cost of the induction treatment when utilizing either (90)Y-IT or BR. The therapeutic cost included only the cost of the medications/therapies and their administration. Results Our cohort consists of a total of 143 patients - 64% (92/143) received BR and 36% (51/143) received (90)Y-IT (see Table-1 for clinical characteristics).The median follow-up from the time of therapeutic administration for the (90)Y-IT group was 5.3 years (95% CI;4.2, 6.2) with one death and 4.7 years (95% CI;3.9, 4.9) for the BR group with 6 deaths. The ORR was 100% in (90)Y-IT group with 94% achieving complete response (CR) while ORR in the BR group was 98% with 95% achieving CR. Rituximab maintenance was utilized in 33% of BR patients compared to only 6% in patients who received (90)Y-IT, p=0.002. After utilizing inverse propensity weighting (Figure-1), 5 years PFS was 76% for the (90)Y-IT group and 75% for the BR group, p=0.63 (Figure-2). We evaluated the average treatment effect of (90)Y-IT compared to BR on utilization outcomes, Table-2. (90)Y-IT required an average of 4.5 clinic visits less within the first year after treatment compared to BR group, p<0.001. (90)Y-IT patients had an average of 10 days less of therapeutic use days compared to the BR group, p<0.001. Patienta had similar admission rates to the hospital in both groups. However, when patients were admitted to the hospital in the first year after treatment, those who received (90)Y-IT spent an average of 1.5 days less in the hospital compared to the BR group, p=0.046. The overall use of growth factors was 40% less in the (90)Y-IT group as compared to the BR group, p<0.001. The therapeutic cost of induction of (90)Y-IT was 54% less than that of 6 cycles of BR. Transformation to a high grade of lymphoma was seen in 4 patients in the BR group and 2 patients in the (90)Y-IT group. There was only one case of myelodysplastic syndrome in the BR group and none in the (90)Y-IT group. Conclusion Radio-immunoconjugate therapy with (90)Y-IT is a very convenient and cost-effective treatment for low-grade UFL and UMZL. This is especially important amidst the COVID-19 pandemic as it requires less contact with the health system with decreased number of therapeutic days, clinic visits, use of growth factors and number of hospitalization days. The cost of the therapeutic agents and heir administration was also significantly lower for the (90)Y-IT which could help reducing the burden on the health system. (Figure Presented).

Zanubrutinib in patients with B-cell malignancies intolerant to ibrutinib and/or acalabrutinib

Introduction: Bruton tyrosine kinase inhibitor (BTKi) therapy is remarkably effective in a number of B-cell malignancies;however, its continuous use is limited by adverse events (AE) leading to discontinuation. Zanubrutinib is a potent and selective BTKi with the potential to be a safe and effective therapy after intolerance to previous BTKi therapy. Here, we report preliminary results of a phase 2 study of zanubrutinib in patients with B-cell malignancies intolerant to ibrutinib and/or acalabrutinib based on a median follow-up of 6 months. Methods: Patients meeting protocol criteria for intolerance to ibrutinib, acalabrutinib, or both (without documented progressive disease on ibrutinib or acalabrutinib) were given zanubrutinib monotherapy (160mg twice daily or 320mg once daily at investigator's discretion). Recurrence of adverse events that led to intolerance to prior BTKi and additional safety measures were assessed based on the Common Terminology Criteria for AEs v5.0. Investigators determined responses using disease status at study entry as baseline and standard established disease response criteria. Results: As of 1 March 2021 (cutoff), 64 patients (n=48 chronic lymphocytic leukemia/small lymphocytic lymphoma, n=10 Waldenström macroglobulinemia, n=3 mantle cell lymphoma, n=3 marginal zone lymphoma) were enrolled, received ≥1 dose of zanubrutinib, and were analyzed for safety. The median age was 71 y (range, 49-91);the median duration of treatment was 5.9 months (range, 0.6-16.6). The median number of prior regimens was 2 (range, 1-12). Regarding prior BTKi, 55 patients had received ibrutinib monotherapy, eight had received ibrutinib combination therapy, and seven had received acalabrutinib monotherapy. The median number of ibrutinib- or acalabrutinib-intolerant adverse events per patient was 2 (range, 1-5). Most ibrutinib- (75%) and acalabrutinib-intolerant events (75%) did not recur with zanubrutinib (Table 1). A majority (90%) of the recurrent ibrutinib-intolerant events were less severe with zanubrutinib than with ibrutinib. Ibrutinib intolerance events present in >1 patient that did not recur on zanubrutinib were alanine aminotransferase increased, aspartate transaminase increased, neutropenia, and pain in extremity. The ibrutinib-intolerant events that recurred were diarrhea, dizziness, insomnia, nausea, constipation, myalgia, stomatitis, arthralgia, headache, muscle spasm, rash, atrial fibrillation, fatigue, hemorrhage, and hypertension. One-third of the recurrent acalabrutinibintolerant events were less severe with zanubrutinib than with acalabrutinib. The acalabrutinib-intolerant events that recurred were myalgia and arthralgia. Two events of arthralgia that induced acalabrutinib intolerance did not recur with zanubrutinib. No ibrutinib- or acalabrutinib-intolerant events recurred at a higher severity while patients were on zanubrutinib. At cutoff, 57 patients remained on treatment;one withdrew consent due to zanubrutinib-unrelated grade 3 syncope. Grade ≥3 adverse events were reported in 14 patients (21.9%), serious adverse events in five patients (7.8%;pain in jaw;COVID-19 pneumonia;anemia;febrile neutropenia and salmonella infection [occurred in the same patient]), adverse events requiring dose interruptions in 15 patients (23.4%), and adverse events leading to dose reduction in three patients (4.7%). Adverse events led to zanubrutinib discontinuation for three patients (4.7%). One death was reported (COVID-19 pneumonia). Among efficacy evaluable patients (n=48), the disease control rate was 89.6% and the overall response rate was 50.0%. Conclusions: In patients with B-cell malignancies intolerant to ibrutinib and/or acalabrutinib, zanubrutinib therapy was effective and controlled patient's disease or induced responses to therapy, and was well-tolerated;most adverse events that led to discontinuation of previous BTKi therapy did not recur while patients were on zanubrutinib.

Immunocompromised Patients with Prolonged Viral Shedding of SARS-COV-2

Background. Most individuals diagnosed with mild to moderate COVID-19 are no longer infectious after day 10 of symptom onset and those with severe or critical illness from COVID are typically not infection after day 20 day of symptom onset. Recovered persons can continue to test positive for SARS-CoV-2 by PCR via detection of non-viable RNA in nasopharyngeal specimens for up to three months (or longer) after illness onset. It is also know known that severely immunocompromised patients may produce replication-competent virus greater than 20 days from symptom onset and may require, per CDC recommendations, "additional testing and consultation with infectious diseases specialists and infection control experts". We aim to discuss four case studies of severely immunocompromised patients who exhibited signs of persistent COVID-19 infection of COVID and how we managed transmission-based precautions in our hospital through sequencing and evaluation of cycle thresholds (CT) values and subgenomic RNA detection. Methods. Residual nasopharyngeal (NP) samples were collected on patients exhibiting persistent COVID like symptoms. These samples underwent N gene and N gene subgenomic RNA (sgRNA) real-time reverse transcription polymerase chain reaction (rRT-PCR) testing. Results. Analysis of longitudinal SARS-CoV-2 sequence data demonstrated within-patient virus evolution, including mutations in the receptor binding domain and deletions in the N-terminal domain of the spike protein, which have been implicated in antibody escape. See Figures 1 and 2. Figure 1. Timelines of Identified Patients 1 and 2 Patient 1: 46-year-old woman with recently diagnosed stage IV diffuse large B-cell lymphoma for which she was treated with 2 cycles of R-CHOP. Patient 2: 38-year-old woman with history of myelodysplastic syndrome, peripheral blood stem cell transplant with chronic graft versus host disease of the GI tract, skin, and eyes as well as CMV enteritis, and she was maintained on rituximab, mycophenolate mofetil, prednisone, and monthly IVIG without recent changes to her immunosuppression. Figure 2. Timeline of Identified Patients 3 and 4 Patient 3: 44 year-old man with prior history of thymoma s/p thymectomy Patient 4: 46 year-old man who was initially diagnosed with marginal zone lymphoma approximately 2.5 years ago. He was initially treated with bendamustine and rituximab and achieved remission. He was then continued on maintenance rituximab without significant complications for a planned two years. Conclusion. Differentiating between prolonged viral shedding of non-infectious RNA and persistent replicating viable virus can be difficult to determine without full evaluation of a patient's clinical picture and timeline. Consultation between laboratory, infectious diseases, and infection prevention experts to provide appropriate level of guidance for precautions and treatment may be warranted. Testing by PCR and analysis of CT values may provide key findings of viral replication in immunocompromised hosts, indicating the need for evaluation of additional treatment and maintaining isolation status in healthcare settings.

Glofitamab Plus R-CHOP Induces High Response Rates with Minimal Cytokine Release Syndrome (CRS) in Patients (pts) with Relapsed/Refractory (R/R) Non-Hodgkin Lymphoma (NHL) and Previously Untreated (1L) Diffuse Large B-Cell Lymphoma (DLBCL): Preliminary Results from a Dose-Escalation and Safety Run-in Phase Ib Study

Background: Over a third of pts with 1L DLBCL do not respond to, or relapse after, rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP;[Sarkozy and Sehn. Ann Lymphoma 2019]). Despite recent advances, pts with R/R NHL have limited curative options. Glofitamab (Glofit) is a novel, T-cell-engaging bispecific antibody with a 2:1 molecular configuration that allows bivalent binding to CD20 on B cells and monovalent binding to CD3 on T cells. Unlike other CD20xCD3 bispecific antibodies, this format uniquely enables combination with anti-CD20 antibodies, including rituximab. Glofit monotherapy induces high response rates in R/R B-cell NHL (Hutchings et al. J Clin Oncol 2021). We present results of the ongoing NP40126 study (NCT03467373), designed to assess the feasibility and safety of Glofit + R-CHOP in R/R NHL (dose-escalation phase) and 1L DLBCL (safety run-in phase). Methods: R/R NHL dose-escalation: Pts (Eastern Cooperative Oncology Group performance status [ECOG PS] 0-2) received increasing Glofit doses in separate cohorts (70µg, 1800µg, 10mg and 30mg) plus standard R-CHOP for 6-8 cycles (each 21-day). To mitigate CRS risk, R- or obinutuzumab (G)-CHOP was given in Cycle (C)1, with the aim of tumor debulking. Glofit was given from C2 onwards. For 70µg and 1800µg cohorts, fixed-dose Glofit was given on C2 Day (D)8 and onwards. For 10mg and 30mg cohorts, step-up dosing was used to further mitigate CRS risk (2.5mg C2D8, 10mg C2D15, target dose C3D8 and onwards). Optional Glofit maintenance was permitted (every 2 months for <2 years;dose-escalation phase only). 1L DLBCL safety run-in: Pts (ECOG PS 0-3) received Glofit 30mg plus standard R-CHOP for 6-8 cycles (each 21-day). Pts received R-CHOP in C1;Glofit step-up dosing began in C2 (2.5mg C2D8, 10mg C2D15, 30mg C3D8 and onwards). Response rates were assessed by PET-CT (Lugano criteria;[Cheson et al. J Clin Oncol 2014]). CRS events were graded by ASTCT criteria [Lee et al. Biol Blood Marrow Transplant 2019]. Results: R/R NHL dose-escalation: At data cut-off (June 10, 2021), 31 pts (23 follicular lymphoma [FL];6 transformed FL;1 marginal-zone lymphoma;1 mantle-cell lymphoma) had received Glofit with R/G-CHOP. Median age was 62 years, median prior lines of therapy was 2 (range: 1-5). In efficacy-evaluable pts (n=31), after a median 9.0 months' (range: 0-29) follow-up, the overall response rate (ORR) was 90% (n=28) and complete response rate (CRR) was 77% (n=24). Median duration of response was not reached. The Figure shows change in tumor size. Grade (Gr) ≥3 adverse events (AEs) occurred in 28 (90%) pts, serious AEs in 21 (68%) pts and CRS in 17 (55%) pts (mostly low grade;majority after the first 2.5mg Glofit dose;Table). One (3%) pt had a Gr 5 AE (COVID-19 pneumonia not related to study treatment). AEs led to Glofit dose modification/interruption in 2 (6%) pts and Glofit withdrawal in 1 (3%) pt. Neurologic AEs (NAEs) occurred in 20 (65%) pts: Gr 1-2 (16 pts, 52%);Gr 3 (4 pts, 13%). Immune effector cell-associated neurotoxicity syndrome (ICANS)-like AEs were uncommon;a serious AE was reported in 1 pt only (Gr 3 epilepsy during the maintenance phase;resolved in 3 days). Neutropenia occurred in 24 (77%) pts. Median dose intensity was 100% for all R-CHOP components. 1L DLBCL safety run-in: At data cut-off, 13 pts were enrolled (safety population);of these, 4 pts received Glofit 30mg with R-CHOP and were efficacy-evaluable. Median age was 68 years, all pts had Ann Arbor Stage 3/4 disease. At interim assessment (C3), CRR was 100% (4/4). Of 13 pts, 1 (8%) had a CRS event (Gr 1 with fever only) after the first 2.5mg Glofit dose;no other CRS events observed. Gr ≥3 AEs occurred in 8 (62%) pts and Gr ≥3 AEs related to Glofit in 1 (8%) pt only. One (8%) pt had a serious AE and 1 (8%) pt had a Gr 5 AE (infusion-related reaction related to rituximab on C1D1). No AEs led to Glofit or R-CHOP dose interruptions. NAEs occurred in 3 (23%) pts (all Gr 1-2;none were ICANS-like). Neutropenia occurred in 6 (46%) pts. Median dose intensity was 10 % for all R-CHOP components. Conclusions: Initial data show that Glofit + R-CHOP has tolerable safety in R/R NHL and 1L DLBCL. R-CHOP dose intensity was maintained in all pts. The very low CRS rate and no neurotoxicity in 1L DLBCL may render Glofit particularly suitable for the outpatient setting without the need for hospitalization. Updated data, including end-of-treatment responses from the 1L DLBCL safety run-in phase, will be presented. [Formula presented] Disclosures: Ghosh: Seattle Genetics: Consultancy, Honoraria, Speakers Bureau;Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau;Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding, Speakers Bureau;AbbVie: Honoraria, Speakers Bureau;Karyopharma: Consultancy, Honoraria;AstraZeneca: Consultancy, Honoraria, Speakers Bureau;ADC Therapeutics: Consultancy, Honoraria;Adaptive Biotech: Consultancy, Honoraria;TG Therapeutics: Consultancy, Honoraria, Research Funding;Genmab: Consultancy, Honoraria;Bristol Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau;Epizyme: Honoraria, Speakers Bureau;Incyte: Consultancy, Honoraria;Janssen: Consultancy, Honoraria, Speakers Bureau;Genentech: Research Funding. Townsend: Celgene (Bristol-Myers Squibb): Consultancy, Honoraria;F. Hoffmann-La Roche Ltd: Consultancy, Honoraria. Dickinson: Amgen: Honoraria;Celgene: Research Funding;Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau;Takeda: Research Funding;Gilead Sciences: Consultancy, Honoraria, Speakers Bureau;MSD: Consultancy, Honoraria, Research Funding, Speakers Bureau;Janssen: Consultancy, Honoraria;Bristol-Myers Squibb: Consultancy, Honoraria;Roche: Consultancy, Honoraria, Other: travel, accommodation, expenses, Research Funding, Speakers Bureau. Topp: Celgene: Consultancy, Research Funding;Janssen: Consultancy;Universitatklinikum Wurzburg: Current Employment;Kite, a Gilead Company: Consultancy, Research Funding;Novartis: Consultancy;Roche: Consultancy, Research Funding;Gilead: Research Funding;Regeneron: Consultancy, Research Funding;Macrogeniecs: Research Funding;Amgen: Consultancy, Research Funding. Santoro: Sandoz: Speakers Bureau;Eli-Lilly: Speakers Bureau;Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;AstraZeneca: Speakers Bureau;Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Celgene: Speakers Bureau;Amgen: Speakers Bureau;AbbVie: Speakers Bureau;Roche: Speakers Bureau;BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Eisai: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Takeda: Speakers Bureau;Sanofi: Consultancy;Arqule: Consultancy, Speakers Bureau;Novartis: Speakers Bureau;Bayer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;MSD: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Crump: Novartis: Membership on an entity's Board of Directors or advisory committees;Kyte/Gilead: Membership on an entity's Board of Directors or advisory committees;Epizyme: Research Funding;Roche: Research Funding. Morschhauser: Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees;Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees;Genentech, Inc.: Consultancy;Genmab: Membership on an entity's Board of Directors or advisory committees;Roche: Consultancy, Speakers Bureau;BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees;Chugai: Honoraria;Incyte: Membership on an entity's Board of Directors or advisory committees;Servier: Consultancy;AstraZenenca: Membership on an entity's Board of Directors or advisory committees;Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees;F. Hoffmann-La Roch Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;Celgene: Membership on an entity's Board of Directors or advisory committees;AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees;Janssen: Honoraria. Mehta: Kite/Gilead;Roche-Genetech;Celgene/BMS;Oncotartis;Innate Pharmaceuticals;Seattle Genetics;Incyte;Takeda;Fortyseven Inc/Gilead;TG Therapeutics;Merck;Juno Pharmaceuticals/BMS: Research Funding;Seattle Genetics;Incyte;TG Therapeutics: Consultancy;Seattle Genetics;Incyte;TG Therapeutics: Membership on an entity's Board of Directors or advisory committees. Panchal: F. Hoffmann-La Roche Ltd: Current Employment. Wu: F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company. Barrett: Roche Products Ltd: Current Employment;F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company. Humphrey: Roche: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Qayum: F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company. Hutchings: Novartis: Research Funding;Janssen: Honoraria, Research Funding;Incyte: Research Funding;Genentech: Honoraria, Research Funding;Celgene: Research Funding;Takeda: Consultancy, Honoraria, Research Funding;Roche: Consultancy, Honoraria, Research Funding;Genmab: Consultancy, Honoraria, Research Funding. OffLabel Disclosure: Glofitamab is a full-length, humanized immunoglobulin G1 bispecific antibody with a 2:1 molecular format that facilitates bivalent binding to CD20 on B-cells, and monovalent binding to CD3 on T-cells. Glofitamab redirects T cells to engage and eliminate malignant B cells. Glofitamab is an investigational agent. Rituximab (Rituxan) is aCD20-directed cytolytic antibody indicated for the treatment of adult pts with: relapsed or refractory, low grade or follicular, CD20-positive, B-cell NHL as a single agent;previously untreated follicular, CD20-positive, B-cell NHL in combination with first-line chemotherapy (chemo) and, in pts achieving a CR or PR to a rituximab product in combination with chemo, as single-agent maintenance therapy;non-progressing (including stable disease), low-grade, CD20 positive, B-cell NHL as a single agent after first-line CVP chemo;previously untreated diffuse large B-cell, CD20-positive, NHL in combination with CHOP or other anthracycline-based chemo regimens;previously untreated and previously treated CD20-positive CLL in combination with fludarabine and cyclophosphamide.

Selinexor in Combination with R-GDP for Patients with Relapsed/Refractory B-Cell Lymphoma: Results of the Selinda Phase Ib Lysa Study

Background: Salvage chemotherapy followed by high-dose therapy (HDT) and autologous stem-cell transplantation (ASCT) is the standard treatment of young patients (pts) with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL). A complete remission before ASCT is the most important prognosis factor for a better outcome. Selinexor is a first-in-class, oral selective inhibitor of nuclear export compound, an exportin 1 [XPO1] inhibitor, which, through XPO1 blockade, causes nuclear accumulation and activation of tumor suppressor proteins, reduction in oncoproteins and cancer cell apoptosis. Selinexor has been approved by the US Food and Drug Administration for the treatment of R/R DLBCL, de novo or transformed from follicular lymphoma (FL) pts after ≥2 therapies. The phase Ib SELINDA (EUDRACT 2015-005612-15) study assessed safety and efficacy of selinexor, in combination with R-GDP for pts with R/R B-cell lymphoma. Patients & methods: Eligible pts < 70 years with R/R B-cell lymphoma after first or second treatment failure received every 21 days (d) 3 cycles of rituximab 375 mg/m² on d1, dexamethasone 40 mg on d1 to 4, cisplatin 75 mg/m² d1 and gemcitabine 1 gr/m² on d1 and 8 (R-GDP) in combination with escalating doses of selinexor. The starting dose (dose level 1, DL1) 40 mg was given on days 1, 3, 8, 10 (Cohort A), and from December 2017 on days 1, 8 and 15 (Cohort B). The dose-variation scheme followed a traditional “3+3” design (DL1: 40 mg;DL2: 60 mg). The primary endpoint of SELINDA was the determination of the recommended phase 2 dose of selinexor in combination with R-GDP. Secondary and exploratory endpoints were safety, efficacy, and feasibility of ASCT after selinexor-R-GDP. Results: The R2PD for selinexor in combination with R-GDP was established as 40 mg on days 1, 8, and 15 (Maerevoet, IMCL 2021#176). Between January 2017 and January 2021, 32 pts received selinexor-R-GDP. We focused on the 18 pts who received the R2PD: 15 had DLBCL, 2 FL, 1 marginal zone lymphoma. In this cohort, median age was 61 years (range 44-69);14 pts (78%) has stage III/IV. Thirteen pts received 1 previous line before inclusion, 5 pts received 2 previous lines. At inclusion, 6 pts had refractory disease and 12 relapsed. Four pts prematurely discontinued treatment: 2 for thrombocytopenia, 1 for COVID, 1 for progression. Major adverse events (AEs) in >10% of pts were reversible neutropenia (50%), thrombocytopenia (39%), and nausea (22%). No AEs leading to death were observed. Seven pts (39%) achieved a complete metabolic response (CMR), 5 pts (28%) partial metabolic response (PMR). Overall response rate (CMR+PMR) assessed at the end of treatment according to Lugano classification was 67% (12 of 18). Nine of the 15 pts (60 %) with DLBCL had metabolic response (CMR:4, PMR:5). Per protocol, peripheral stem cell collection and ASCT were optional, 4 pts of this RP2D cohort proceeded to high dose therapy (BEAM) and ASCT. Conclusion: This study established the safety profile of weekly 40mg of Selinexor in combination with R-GDP for R/R B cell lymphoma with an ORR of 67%. Reversible AEs are expected for platinum-based regimen. An ongoing randomized phase 2 study comparing R-GDP and R-GDP plus selinexor in pts with R/R DLBCL will now establish the safety and efficacy of the combination. Disclosures: Casasnovas: Janssen: Consultancy;BMS: Consultancy;Gilead/Kite: Consultancy, Research Funding;TAKEDA: Consultancy, Research Funding;ROCHE: Consultancy, Research Funding;Amgen: Consultancy. Morschhauser: Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees;F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;Roche: Consultancy, Speakers Bureau;AstraZenenca: Membership on an entity's Board of Directors or advisory committees;BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees;Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees;Janssen: Honoraria;Genen ech, Inc.: Consultancy;Chugai: Honoraria;Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees;Incyte: Membership on an entity's Board of Directors or advisory committees;Celgene: Membership on an entity's Board of Directors or advisory committees;AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees;Servier: Consultancy;Genmab: Membership on an entity's Board of Directors or advisory committees. Thieblemont: Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding;Gilead Sciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses;Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses;Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees;Bristol Myers Squibb/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses;Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees;Kyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses;Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees;Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses;Cellectis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses;Hospira: Research Funding;Bayer: Honoraria;Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses. Feugier: Amgen: Honoraria;Janssen: Consultancy, Honoraria;Gilead: Consultancy, Honoraria;Abbvie: Consultancy, Honoraria;Astrazeneca: Consultancy, Honoraria.

Antibody and T-Cell Responses to Covid-19 mRNA Vaccines in Patients with B-Cell Lymphomas and Chronic Lymphocytic Leukemia (CLL)

Introduction: While the approval of three commercial vaccines for the SARS-CoV-2 virus has provided upwards of 95% protection against the coronavirus for healthy subjects, the efficacy among patients with hematologic malignancies remains unknown. Immune dysfunction and impaired humoral responses to other vaccines are well documented in patients with CLL and B-cell lymphomas. Furthermore, they suffer increased risk of morbidity and mortality with Covid-19 infections compared to healthy controls. As such, the immune response elicited by the available Covid-19 vaccines in these patients is of utmost importance to investigate. Methods: We performed a prospective exploratory analysis in CLL and B-cell lymphoma patients to evaluate humoral and T-cell responses to the commercially available mRNA Covid-19 vaccines. The objective was to obtain samples at baseline and 2-3 weeks post-vaccination, although some samples were obtained outside of this timeframe. IgG to the SARS-CoV-2 spike receptor-binding domain (RBD) was quantified using the ImmunoCAP platform (Thermo Fisher);results were compared to data from 167 subjects in a healthy vaccine cohort at the University of Virginia. T-cell responses to spike protein of SARS-CoV-2 were measured in 3 NHL patients and 3 matched healthy controls at 2-3 weeks post-2nd vaccine dose, by T cell receptor dependent activation-induced marker (AIM) assay using pooled peptides spanning spike protein. Results: Among 18 patients currently evaluable, median age is 67 y and 72% are male. Diagnoses include CLL (5), marginal zone lymphoma (MZL;4), diffuse large B-cell lymphoma (3), follicular lymphoma (1), mantle cell lymphoma (MCL;4), and Waldenstrom's macroglobulinemia (1). All patients except 1 MZL patient are currently receiving or have received systemic treatment for their hematologic malignancy. Treatments include immunochemotherapy in 5 patients, Bruton's tyrosine kinase inhibitors (BTKi) with or without anti-CD20 monoclonal antibody therapy in 5, single agent anti-CD20 monoclonal antibody in 4, and other targeted therapy in 4 patients including venetoclax, lenalidomide, and bortezomib. Two patients had received prior autologous stem cell transplantation, 1 patient allogeneic transplantation, and 1 patient chimeric antigen receptor T-cell therapy. Among patients on therapy (n=10), median time from start of current treatment to Covid-19 vaccine was 136 days (range 13 - 829d). In patients who had completed therapy (n=8), median time from end of last treatment to vaccine was 153 days (range 37 - 355d). Seven patients had a blood sample drawn between 1 week and 1 month post-second mRNA vaccine dose. IgG antibody levels to spike RBD were markedly lower in NHL/CLL patients compared to those observed in the control cohort (median 2.1 µg/mL [IQR 0.23-7.6 µg/mL] versus 60.3 µg/mL [IQR 42.5-87.0 µg/mL], Mann-Whitney P<0.001, Figure 1). Of the 16 samples that were obtained post-vaccine dose 2, nine had IgG levels less than 2 µg/mL (manufacturer lower threshold of detection), whereas only 5 of 252 samples from the control cohort were less than this level (Chi-square P<0.001, RR =39.6 (95%CI 15.1-100)). Antibody responses were independent of type of therapy (Figure 2). The percentage of total lymphocytes and T cells was generally reduced in NHL patients versus controls;however, CD4+ T cells responding to spike protein were readily detected, despite the absence of antibody responses in 2 of these patients, both of whom had MCL. Curiously, 2 patients (1 MZL with and 1 MCL patient without antibodies) displayed a higher percentage of activated CD4+ T cells compared to controls, and CD8+ T cells also responded in each of these patients. T-cell responses were specific for spike protein as evidenced by no response to peptides of whole nucleoprotein. Conclusions: Compared to a reference cohort, patients with B-cell malignancies, both treatment-naïve and on treatment, have impaired antibody response to the commercially available mRNA Covid-19 vaccines. Despite this, virus-responsive T-cells can be readil detected, even in the absence of antibodies. Further research is needed to determine whether antibody levels can be used as a biomarker for vaccine efficacy, whether the presence of virus-specific T-cells confers protection in the absence of antibodies, and to determine the effect of booster doses of vaccine on immune response. [Formula presented] Disclosures: Wilson: Thermo-Fisher Phadia: Research Funding. Woodfolk: Regeneron: Other: Salary Support, Research Funding;NIH/NIAID: Other: Salary support, Research Funding;University of Virginia: Other: Salary Support;Regeneron: Other: research sponsor and salary support;FDA: Membership on an entity's Board of Directors or advisory committees;Clinical and Experimental Allergy: Other: Editorial Board. Portell: Abbvie: Research Funding;Aptitude Health: Honoraria;Merck: Honoraria, Research Funding;Xencor: Research Funding;Pharmacyclics: Honoraria;BeiGene: Honoraria, Research Funding;Targeted Oncology: Honoraria;Morphosys: Honoraria;SeaGen: Research Funding;TG Therapeutics: Honoraria, Research Funding;Acerta/AstraZeneca: Research Funding;Kite: Honoraria, Research Funding;Genentech: Research Funding;VelosBio: Research Funding. Williams: Janssen: Consultancy, Research Funding;Pharmacyclics: Research Funding.

Phase 2 Study of Zanubrutinib in BTK Inhibitor-Intolerant Patients (Pts) with Relapsed/Refractory B-Cell Malignancies

Background: Bruton tyrosine kinase inhibitors (BTKis) are important tools to treat B-cell malignancies. However, duration of treatment may be limited by adverse events (AEs). Zanubrutinib (zanu) is a BTKi approved for mantle cell lymphoma (MCL) and is in development for other hematologic malignancies. Data from phase 3 head-to-head trials of zanu vs ibrutinib (ibr) in pts with Waldenström macroglobulinemia (WM) or chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) demonstrated that pts treated with zanu showed lower rates of AEs leading to discontinuation (Blood 2020;136(18):2038-50;EHA 2021 LB1900). Preliminary results from BGB-3111-215 (NCT04116437) show that zanu was well-tolerated in pts who discontinued ibr and/or acalabrutinib (acala) treatment due to AEs (EHA 2021 EP642). Here, we report updated results from the BGB-3111-215 study with a median follow-up of 9 months. Methods: This study is an ongoing US, phase 2, multicenter, single-arm, open-label study. The safety and efficacy of zanu monotherapy (160 mg twice daily or 320 mg once daily) were evaluated in pts with B-cell malignancies who met criteria for continued treatment after having become intolerant to prior BTKi therapy. Pts were divided into cohort 1 (pts who were intolerant to ibr only) and cohort 2 (pts who were intolerant to acala alone/and ibr). Pts with documented progressive disease (PD) on prior BTKi therapy were excluded. Efficacy and safety, including recurrence of intolerant AEs to the prior BTKi, were evaluated. AEs were assessed for severity, seriousness, and relation to zanu;as well as dose reductions, holds, or discontinuations. Response was assessed by investigators based on response criteria for their respective indications (Blood 2008;131:2745;J Clin Oncol 2012;30:2820;J Clin Oncol 2014;32:3059;Br J Haemtol 2013;160:171). Disease parameters from study entry were the baseline for response assessment. Mutational analysis was performed on pts who discontinued treatment, and data will be shared once available. To support clinical findings, kinase selectivity was assessed using Kinome profiling at 100X IC50 (against BTK) for zanu, ibr, acala and its major metabolite, M27 (Reaction Biology Corp). Results: As of 7 June 2021 (data cutoff), 57 pts (n=44 CLL/SLL;n=9 WM;n=2 MCL;n=2 marginal zone lymphoma [MZL]) were enrolled in cohort 1, and 7 pts were enrolled in cohort 2 (n=4 CLL;n=1 WM;n=1 MCL;n=1 MZL). All received ≥1 dose of zanu and were analyzed for safety. The median age was 71 years (range, 49-91) in cohort 1 and 71 years (range, 65-76) in cohort 2;median duration of treatment was 8.7 months (range, 0.6-17.9) in cohort 1 and 8.2 months (range, 6.4-11.4) in cohort 2;median number of prior regimens was 1 (range, 1-12) in cohort 1 and 3 (range, 2-5) in cohort 2. Within cohort 2, 5 pts were intolerant to both ibr and acala. Median number of intolerant events per pt for both cohorts 1 and 2 was 2 (range, 1-5). Overall, 73% of pts did not experience recurrence of their ibr or acala intolerant events and 79% of recurrent events recurred at a lower severity (Figure 1). At cutoff, 54 pts remained on treatment. Reasons for treatment discontinuation were AEs (n=4), PD (n=4), physician's decision (n=1), and consent withdrawal (n=1). Grade ≥3 AEs were reported in 18 pts (28%), and serious AEs occurred in 7 pts (11%). AEs requiring dose interruptions occurred in 17 pts (27%), and AEs leading to dose reduction occurred in 3 pts (5%). One death, due to COVID-19, was reported. Pts demonstrated maintained (41%) and improved (53%) response with zanu treatment from their reported best overall response on prior BTKis for a total disease control rate of 94% (including a 42% partial response rate in pts with CLL/SLL, 30% in pts with WM, and a 20% very good partial response rate in pts with WM). Zanu also demonstrated good selectivity by kinase profiling. It showed >50% inhibition on 7/370 kinases, while ibr, acala, and M27 had more off-target binding (17, 15 and 23 kinases, respectively) at their respective 100X IC50 (BTK) c ncentrations (Figure 2). Conclusion: In pts with B-cell malignancies intolerant to ibr and/or acala, zanu treatment resulted in continued disease control or improved response. Zanu was well-tolerated, and most AEs that led to discontinuation of previous BTKi therapy did not recur or recurred at a lower grade. In support of clinical findings, differentiation between BTKi selectivity profiles favor zanu over ibr and acala. [Formula presented] Disclosures: Shadman: Abbvie, Genentech, AstraZeneca, Sound Biologics, Pharmacyclics, Beigene, Bristol Myers Squibb, Morphosys, TG Therapeutics, Innate Pharma, Kite Pharma, Adaptive Biotechnologies, Epizyme, Eli Lilly, and Atara Biotherapeutics, Adaptimmune: Consultancy;Mustang Bio, Celgene, Bristol Myers Squibb, Pharmacyclics, Gilead, Genentech, Abbvie, TG Therapeutics, Beigene, AstraZeneca, Sunesis, Atara Biotherapeutics, GenMab: Research Funding;Abbvie, Genentech, AstraZeneca, Sound Biologics, Pharmacyclics, Beigene, Bristol Myers Squibb, Morphosys, TG Therapeutics, Innate Pharma, Kite Pharma, Adaptive Biotechnologies, Epizyme, Eli Lilly, and Atara Biotherapeutics, Adaptimmune: Membership on an entity's Board of Directors or advisory committees. Flinn: Nurix Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute;Seagen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding;MorphoSys: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding;Forty Seven: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding;Calithera Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding;Verastem: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding;Curis: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding;Takeda: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding;Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute;IGM Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding;AbbVie: Consultancy, Other: All Consultancy and Research Funding payments made to Sarah Cannon Research Institute, Research Funding;Portola Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding;Trillium Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding;Rhizen Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding;Incyte: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding;Acerta Pharma: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding;Agios: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding;Kite, a Gilead Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding;Gilead Sciences: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding;Pharmacyclics LLC, an AbbVie Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding;Karyopharm Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding;Forma Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding;Genentech: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding;ArQule: Other: All research funding payments mad to Sarah Cannon Research Institute, Research Funding;Triphase Research & Development Corp.: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding;Roche: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding;Pfizer: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding;Teva: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding;Infinity Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding;Unum Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding;Celgene: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding;Constellation Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding;Juno Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding;AstraZeneca: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding;Iksuda Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute;Loxo: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding;Merck: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding;Novartis: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding;Great Point Partners: Consultancy, Other: All consultancy payments made toSarah Cannon Research Institute;BeiGene: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding;Janssen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding;TG Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding;Century Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute;Hutchison MediPharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute;Vincerx Pharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute;Sarah Cannon Research Institute: Current Employment;Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute;Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute;Seagen: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute;Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute;Unum Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute, Research Funding;Johnson & Johnson: Current holder of individual stocks in a privately-held company;Seattle Genetics: Research Funding. Levy: Epizyme: Consultancy, Other: Promotional speaker;Amgen Inc.: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau;Gilead Sciences, Inc.: Consultancy, Honoraria, Speakers Bureau;GSK: Consultancy, Other: Promotional speaker;Morphosys: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau;AbbVie: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau;Beigene: Consultancy, Honoraria, Speakers Bureau;Karyopharm: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau;AstraZeneca: Consultancy, Honoraria, Speakers Bureau;Takeda: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau;Novartis: Consultancy, Other: Promotional speaker;Dova: Consultancy, Other: Promotional speaker;TG Therapeutics: Co sultancy, Honoraria, Speakers Bureau;Bristol Myers Squibb: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau;Seattle Genetics: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau;Jazz Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau;Janssen Pharmaceuticals: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau. Burke: SeaGen: Consultancy, Speakers Bureau;Beigene: Consultancy, Speakers Bureau;MorphoSys: Consultancy;Bristol Myers Squibb: Consultancy;AstraZeneca: Consultancy;Epizyme: Consultancy;Verastem: Consultancy;Kura: Consultancy;Kymera: Consultancy;AbbVie: Consultancy;Adaptive Biotechnologies: Consultancy;Roche/Genentech: Consultancy;X4 Pharmaceuticals: Consultancy. Cultrera: Beigene: Research Funding. Yimer: Astrazeneca: Speakers Bureau;Karyopharm: Current equity holder in publicly-traded company, Speakers Bureau;Janssen: Speakers Bureau;Beigene: Speakers Bureau;GSK: Speakers Bureau;Sanofi: Speakers Bureau;Amgen: Speakers Bureau;Pharmacyclics: Speakers Bureau;Texas Oncology: Current Employment. Chaudhry: Medical Oncology Associates, PS (dba Summit Cancer Centers): Current Employment;Novartis, Immunomedics: Current holder of individual stocks in a privately-held company. Gandhi: TG Therapeutics: Honoraria;Karyopharm Therapeutics: Honoraria;GlaxoSmithKline: Honoraria. Kingsley: Comprehensive Cancer Centers of Nevada: Current Employment. Tumula: Texas Oncology: Current Employment. Manda: Morphosys: Honoraria;Genmab: Current equity holder in publicly-traded company. Chen: BeiGene: Current Employment, Divested equity in a private or publicly-traded company in the past 24 months. Cohen: BeiGene: Current Employment, Current equity holder in publicly-traded company, Other: Travel, Accommodations, Expenses. By: BeiGene, Ltd: Current Employment. Xu: Beigene: Current Employment;AstraZeneca: Ended employment in the past 24 months. Liu: BeiGene Co., Ltd: Current Employment, Current equity holder in publicly-traded company. Sharman: TG Therapeutics: Consultancy;Centessa: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees;Pharmacyclics LLC, an AbbVie Company: Consultancy;BMS: Consultancy;AbbVie: Consultancy;BeiGene: Consultancy;AstraZeneca: Consultancy;Lilly: Consultancy.