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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
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Aims: People with haematological malignancies (HM) are at increased risk of severeCOVID-19 infection and death due to underlying immune deficiency and impaired vaccine responses. FromMarch 2021,COVID- 19 vaccination was offered to patients with HM, as part of the Australian COVID-19 vaccination rollout program. This study sought to ascertain whether vaccine hesitancy was a barrier to optimal vaccine uptake and explored the attitudes of people with HM towards COVID-19 vaccination. Method(s): Between June and October 2021, an online survey was distributed to adults with HM at nine Australian health services. The survey collected sociodemographic and clinical characteristics, and attitudes towards COVID-19 and COVID-19 vaccination using the Oxford COVID-19 Vaccine Hesitancy Scale, the Oxford COVID-19 Vaccine Confidence and Complacency Scale, and the Disease Influenced Vaccine Acceptance Scale-Six (DIVAS-6). Result(s): Of the 869 survey participants (mean age 64.2 years, 43.6% female), 741 (85.3%) reported receiving at least oneCOVID-19 vaccine dose. Unvaccinated status was significantly associated with younger age, English as a non-dominant language, and shorter duration since diagnosis. Participants who were female or spoke English as their nondominant language reported more negative attitudes towards vaccine side-effects. Unvaccinated participants were more likely to report greater concerns about the vaccine impacting on their HM and treatment (DIVAS-6 Vaccine Vulnerability subscale score: B (SE) = 2.71 (0.35), p < 0.001). They were also more likely to report greater vaccine complacency (DIVAS-6 Disease Complacency subscale score: B (SE) = 1.79 (0.28), p < 0.001). Conclusion(s): People with HM reported high vaccine uptake, however, participantswho are recently diagnosed with malignancy, female, younger age or for whom English is a non-dominant language may benefit from targeted education strategies to address their vaccine concerns. Clinicians are well-positioned to address their patients' specific vaccine concerns and support the decision-making process, particularly with the need for COVID-19 vaccine boosters.
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Background: Adults and childrenwith cancer are susceptible to severe SARS-CoV-2 disease. Vaccination is protective;data beyond initial response and regarding effect of booster doses are lacking in cancer patients. Method(s): The SerOzNET study assesses SARS-CoV-2 vaccine response in haematological and solid cancer patients aged 5 and older. Patients are recruited pre dose 1 and receive standard BNT162b2 (Pfizer) or ChadOx1-S (AstraZeneca) vaccine. Blood is taken at baseline and after each dose. Neutralizing antibody (NAb) titre, absolute antibody titre (Abbott), T cell response (IFN-gamma) and epigenetics are analysed. Clinical data are collected. Patients are followed for up to 3 months beyond dose 5. Result(s): 105 children (64% haem, 36% solid cancers) and 399 adults (35% haem, 65% solid cancers) were enrolled. In adults, NAb response rate increased after dose 3 (Post 2: 40% haem, 87%solid;Post 3:70%haem,97%solid). Post dose 2, predictors of nonresponse were ChadOx1-S vaccine (OR 3 p = .02), haem cancer (OR 14 p < .001), ECOG >=1 (OR 2.6 p = .01) and steroids (OR 5 p = .01). Post dose 3, only haem cancer predicted non-response (OR 16). IFN-gamma response is available for a subset, detectable in 41/90 (46%) postdose 1, 78/96 (81%) post-dose 2 and 35/42 (83%) post-dose 3;without significant difference between haem and solid cancer. In children, NAb response post dose 2 is available for 50 patients. Response rate between haem (19/31, 61%) and solid patients (13/19, 68%) was similar. IFN-gamma response post dose 2 was also similar: (14/22, 63%) vs solid patients (12/14, 85%) (p = .25). Analysis is ongoing. Conclusion(s): Response to two doses of SARS-CoV-2 vaccine is suboptimal in patients with cancer. The third priming dose is integral, with significantly higher response rates observed. 36% of children did not develop neutralizing antibodies post dose 2;subsequent doses are likely to be important for young patients.
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Background: COVID-19 disease is more severe in unvaccinated cancer patients compared with the general population. There is limited data regarding clinical efficacy of vaccination in these patients. Method(s): SerOzNET (ACTRN12621001004853) is a prospective observational cohort study of adults and children with cancer receiving COVID-19 vaccination. The primary endpoint is serological response. An important secondary endpoint is outcome of COVID-19 infection after vaccination. We report self- and clinician reported COVID-19 infections. Result(s): Of 395 adults (20 years +), 74 (19%) reported COVID-19 infection over mean duration on study of 259 days. 71 (97%) had received 2 vaccine doses, 51 (69%) received 3+ doses. 21 (28%) had antiviral treatment. 62 (84%) had symptoms, 7 (9%) required hospitalisation, 0 required ICU admission or died due to COVID-19. Of 113 children/adolescents (5-19 years), 31 (27%) reported COVID-19 infection over mean duration on study of 215 days. 28 (90%) had received 2 vaccination doses, and 12 (39%) received 3+ doses. 23 (74%) had symptoms, 8 (25%) required hospitalisation, 2 (6%) had antiviral therapy, 0 required ICU admission or died due to COVID-19. Pediatric pts with COVID-19 infection had increased risk of hospitalisation compared with adults (p=0.03). Hematological cancer pts had non-significant but numerically higher rates of hospitalisation (Table). [Formula presented] Conclusion(s): Pts with cancer are likely to be exposed to COVID-19, with infection rates similar to the wider population. Vaccination appears to protect against ICU admission in cancer patients. However, 9% of adults and 25% of children with cancer required hospitalisation for COVID-19, demonstrating increased severity of symptoms compared to the general population. Higher rates of infection and hospitalisation in pediatric pts may be partly attributable to the lower proportion of children who had received a 3rd vaccination dose at the time of infection. Clinical trial identification: ACTRN12621001004853. Legal entity responsible for the study: Monash Health. Funding(s): Cancer Australia (Australian Federal Government) Victorian Cancer Agency (Victorian State Government, Australia) Leukaemia Foundation (Foundation, Australia). Disclosure: All authors have declared no conflicts of interest. Copyright © 2022
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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.
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Background: COVID-19 infection has poor outcomes for patients (pts) with cancer. Understanding vaccine response as a correlate of protection from severe infection is essential to advise pts regarding protective behaviours and optimal vaccine schedule. This Australian cohort is unique due to low rates of COVID-19 exposure at study entry (July-November 2021). and use of a 3 dose schedule. Pts initially received 2 doses of either BNT162b2 (Pf) at a 3 week interval, or ChadOx1-S (AZ) at a 6 week interval, all then received a 3rd dose, either mRNA-1273 (Mod) or Pf after 2-4 months, and finally a 4th dose at an interval of a further 3 months, for a subset. Methods: SerOzNET (ACTRN12621001004853) has enrolled pts with solid and haematological (haem) cancers prior to initial vaccination. Serial blood samples were processed for serum, PBMC and PMN at timepoints: 0, then 3-4 weeks post dose 1 then 2 then 3 then 4 (where administered). We report here neutralizing antibodies (nAb) against wild type (wt) and delta and omicron variants of concern (VOC);quantitative S-protein IgG antibody (Abbott);Tcell correlates measured by levels of interferon-g (IFN g), tumour necrosis factor-a, interleukins (IL-) 2/ 4/5/13;and epigenetic profiling of T cells. Results: The cohort consists of 401 pts with median age 58 (range 18-85);59% female;128 (32%) haem cancers. 377 (94%) are on current or recent (< 12 months) systemic therapy: 162 (43%) chemotherapy, 62 (16%) immunotherapy, 40 (10%) combined chemo/immunotherapy, 113 (29%) hormonal or targeted therapy. 42 (10%) received anti-CD20 therapy < 12 months, 6 (1.4%) had allogeneic stem cell transplant. NAb levels against wt are available for 256 pts post dose 1, 245 pts post dose 2 and 159 pts post dose 3 (will be updated). Response rates post dose were respectively 27%, 77% and 88%. Pts with haem cancer were less likely to respond to vaccination at any time compared to pts with solid cancer (p < 0.001, chi-squared test). After 3 doses, 3.8% of pts with solid cancer and 27.8% with haem cancer lacked NAb. NAb results to VOC delta are available for 92 pts post dose 2: 25/92 (27%) were negative, compared with a non-response rate to wt of 15% at same time in same pts. IFN-γ-Spike response was detectable in 18/31 (58%) and 24/30 (80%) pts post dose 1 and 2 respectively. 101 pts to date have received a 4th dose;data will be available at the meeting, as will epigenetic profiles and detailed clinicopathological correlations. Conclusions: This interim analysis shows that a significant proportion of pts with haem cancers (27.8%) lack protective Sars-CoV-2 antibodies following 3 vaccinations, whereas only 3.8% of solid cancer pts lack detectable response. Results from other B and T cell parameters may also be important in identifying pts less well protected by vaccination. Follow up is ongoing, response rate post 4th dose will be presented at the meeting.
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Background: Defining cancer and treatment-related factors which influence protection against COVID-19 following vaccination are important given the worse outcomes following infection in this group. Sophisticated and detailed studies which go beyond a single measure are required particularly with correlation to multiple disease and treatment factors. This study cohort is unique due to (a) very low prior COVID-19 infection at time of sampling (July-Nov 2021), (b) vaccines studied were BNT162b2 (Pf) given 3 weeks apart or ChAdOx1 (AZ) spaced 12 weeks (dose 1, 2) (c) most participants then received a third dose 2 months later (heterologous for AZ). Methods: SerOzNET (ACTRN12621001004853) enrols Australian blood and solid cancer patients prior to vaccination, with serial blood analyses and qualitative measures. We measured neutralizing antibodies (nAb) against SARS-CoV-2 wild type (wt) and variants of concern delta and omicron, quantitative S-protein IgG antibody level (Abbott), and T-cell correlates (interferon-g, tumour necrosis factor-a, interleukins 2/4/5/13) and epigenetic profiling at baseline and 3-4 weeks post dose 1, 2 +/- 3.Results: 379 participants were included, median age 58 years (IQR 47-66) and 60% female. 30% participants had hematological malignancies with the remainder solid organ cancers. 90% patients were on current systemic cancer treatment (most commonly chemotherapy in 41%, chemoimmunotherapy or immunotherapy in 20%). In 331 patients where treatment intent was recorded, 47% was palliative. Only one patient had known prior COVID-19 infection. Of the initial 94 participants who received Pf vaccination, median (IQR) neutralizing antibody titre 4 weeks following dose 2 was 80 (40-160) for SARS-CoV-2 wt and 40 (0-80) for delta variant. Conclusion: Neutralizing antibody titres in this Australian cancer population following Pf vaccination appear lower than those reported elsewhere such as CAPTURE study (Fendler et al, 2021), possibly related to shorter interdose interval. Preliminary data highlights low nAb titres as expected in haematology patients but also in some cases with treatment not traditionally associated with immunosuppression such as hormonal therapy. These results will be updated in February 2022 with third dose, AZ and omicron variant data.
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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.