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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
ABSTRACT
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.
ABSTRACT
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.
ABSTRACT
Background: BCR signaling mediated through Bruton's tyrosine kinase (BTK) plays a critical role in the development and maintenance of marginal zone lymphoma (MZL). BTK inhibitors have established activity in relapsed/refractory (R/R) MZL with the phase 2 study of ibrutinib demonstrating an objective response rate (ORR) of 48% (Noy et al. Blood. 2017;129:2224-2232). Zanubrutinib is a potent and highly specific next-generation BTK inhibitor designed with greater selectivity for BTK vs TEC- and EGFRfamily kinases, which are thought to be related to off-target toxicities. Therapeutic activity of zanubrutinib was established in an early-phase study (BGB-3111-AU-003) of 20 patients (pts) with R/R MZL demonstrating an ORR of 80%, with a complete response (CR) rate of 15%, and partial response (PR) rate of 65% (Tedeschi et al. EHA 2020, abstract 2804). Aims: To present initial efficacy and safety results in pts with R/R MZL enrolled in MAGNOLIA (BGB-3111-214). 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 end point was ORR determined by an independent review committee in accordance with the Lugano classification. Secondary end points include ORR by investigator assessment, duration of response (DOR), progression-free survival (PFS), and safety. Results: As of January 11, 2021, 68 pts were enrolled and treated. Median age was 70 years (range, 37-95), with 28% aged ≥75 years. Subtypes included extranodal (mucosa-associated lymphoid tissue;38%), nodal (38%), splenic (18%), and indeterminate (6%) MZL. Median number of prior therapies was 2 (range, 1-6) and 32% of pts had disease that was refractory to last therapy. Median duration of drug exposure was 59.1 weeks (range, 3.7-84.1). Sixty-six pts were evaluable for efficacy. At a median study follow-up of 15.5 months (range, 1.6-21.7), investigator-assessed ORR (CR + PR) was 74% (CR 24%, PR 50%, stable disease 17%). Responses were observed in all subtypes, with an ORR of 68%, 84%, 75%, and 50% in extranodal, nodal, splenic, and indeterminate subtypes, respectively. CR rate was 36% for extranodal MZL, 20% for nodal, 8% for splenic, and 25% for indeterminate subtype. Median DOR and PFS were not reached;15-month PFS was 68% and 12-month DOR was 81%. IRC review is ongoing. Twenty-eight (41%) pts discontinued treatment: 20 due to disease progression, 1 withdrew consent, 3 required prohibited medications, 4 due to adverse events (AEs;2 due to COVID-19 pneumonia, 1 due to pyrexia attributed to disease transformation, and 1 due to myocardial infarction [MI]). The most common (≥10%) treatment-emergent AEs reported were diarrhea (22%), bruising (21%), constipation (15%), pyrexia (13%), abdominal pain (12%), upper respiratory tract infection (12%), back pain (10%), and nausea (10%). Most AEs were grade 1 or 2. Neutropenia was the most common grade ≥3 AE (10%). Two pts died from COVID-19 pneumonia and 1 pt with pre-existing coronary artery disease died from MI. No fatal AEs were considered related to zanubrutinib. All-grade AEs of interest included neutropenia (13%), thrombocytopenia (13%), atrial fibrillation/flutter (3%), and hypertension (3%). No major/serious hemorrhage was reported. No AEs led to dose reductions. Summary/Conclusion: Zanubrutinib demonstrated high response rates and durable disease control with a favorable safety profile in pts with R/R MZL.