Brentuximab vedotin plus cyclophosphamide, doxorubicin, etoposide, and prednisone (Chep-BV) followed by bv consolidation in patients with cd30-expressing peripheral tcell lymphomas

Introduction: Peripheral T-cell lymphomas (PTCL) are a heterogeneous group of lymphomas associated with poor outcomes following anthracycline-based chemotherapy, even when consolidative autologous stem cell transplantation (ASCT) is used. CD30 expression is universal in anaplastic large cell lymphoma (ALCL) and is frequently expressed in other PTCL subtypes. Brentuximab vedotin (BV) is a CD30-directed antibody drug conjugate that prolongs progression-free survival (PFS) and overall survival (OS) when combined with cyclophosphamide, doxorubicin, and prednisone (CHP) as compared to CHOP chemotherapy (Horwitz, 2020). Although a majority of pts treated with BV-CHP remained in durable remission (5y PFS 51%), there is room for improvement. Based on retrospective studies that demonstrated improved outcomes in younger pts, the addition of etoposide to CHOP (CHOEP) is commonly used as initial therapy for PTCL. We performed a multicenter phase 2 trial to evaluate the safety and efficacy of adding etoposide to BV-CHP (CHEP-BV) followed by BV consolidation in pts with newly diagnosed CD30-expressing PTCL. Methods: Adults with newly diagnosed CD30+ (≥ 1% of tumor cells by local pathology) PTCL were eligible, including pts with ALK+ ALCL and IPI score ≥ 2, ALK-negative ALCL, PTCL not otherwise specified (NOS), angioimmunoblastic T-cell lymphoma (AITL), adult Tcell leukemia/lymphoma (ATLL), among others. After accrual of 28 pts, the protocol was amended to allow enrollment of 20 additional pts with CD30+ non-ALCL PTCL (with ALCL allowed in Canada). Pts could receive prephase steroids and/or 1 cycle of CHOPequivalent chemotherapy prior to study entry. 6 pts were treated in a safety lead-in cohort and all pts received CHEP-BV at the recommended phase 2 dose: 6 x 21-day cycles of CHP+BV (1.8mg/kg) on d1 and etoposide 100mg/m2 on d1-3. G-CSF prophylaxis was mandatory. Pts in response after CHEP-BV could receive BV consolidation (1.8mg/kg q3w) for up to 10 additional cycles (16 total BV cycles) either after ASCT or CHEP-BV if no ASCT was performed. The co-primary endpoints were safety and the CR rate (Deauville score 1-3) by PET-CT after CHEP-BV assessed by investigators according to the 2014 Lugano classification. Secondary endpoints were PFS and OS. Results: Accrual has completed and 48 pts were enrolled;all were evaluable for toxicity, 46 were evaluable for efficacy. 16 pts had ALCL (13 ALK+, 3 ALK-) and 32 had non-ALCL PTCL subtypes, including 18 with AITL, 11 with PTCL NOS, 2 with T-follicular helper PTCL, and 1 with ATLL. Baseline characteristics are shown in Table. 43 pts completed CHEP-BV, 2 had progressive disease (PD) prior to completion, 1 pt discontinued CHEP-BV early (MD discretion), 1 pt died due to COVID-19, and 1 remains on CHEP-BV. Of 43 pts who completed CHEP-BV, 24 proceeded to ASCT and 19 did not. 33 (74%) pts received BV consolidation (20 after ASCT, 13 directly after CHEP-BV) and completed a median 8 of the planned 10 cycles (range, 1-10). 13 pts completed all cycles of consolidation;19 pts discontinued early-12 due to adverse events (AE), 5 due to PD, and 2 due to patient/physician choice. The most frequent CHEP-BV related AEs (all grades, G) include fatigue (73%), peripheral sensory neuropathy (67%), anemia (62.5%), nausea (56%), neutropenia (50%), lymphopenia (44%), leukopenia (42%), thrombocytopenia (40%), elevated transaminases (33%). The most common G3+ AEs were neutropenia (37.5%), febrile neutropenia (23%), lymphopenia (21%), anemia (19%), thrombocytopenia (19%). There were 5 deaths, 4 due to PD and 1 due to COVID-19 infection during C3 of CHEP-BV. The interim (n=46) ORR and CR rates (after 3 CHEP-BV cycles, except 1 pt after 2) were 96% and 59% (27 CR, 17 PR), respectively. At completion of CHEP-BV (n=46), the ORR was 91% with 80% CR (37 CR, 5 PR, 4 PD). The ORR/CR rates in ALCL (n=16) vs non-ALCL (n=30) pts were 94%/94% vs 90%/73%, respectively. The ORR/CR rates in pts with CD30 expression 1-9% (n=15) vs 10+% (n=31) were 93%/67% and 90%/87%, respectively. The median follow-up in surviving pts is 1 .1 months (range, 0.9-32.5). The overall 18mo PFS and OS were 61% and 89%;18mo PFS by subgroup: ALCL 81%, non-ALCL 49%, CD30 1-9% 48%, CD30 10+% 67%. Landmark 1y PFS from end of CHEP-BV in responding pts (n=41) was 82% in pts who underwent ASCT vs 48% in pts who did not Conclusions: In a cohort of pts with mostly non-ALCL CD30-expressing PTCL, CHEP-BV (+/-ASCT) followed by BV consolidation was tolerable and effective.

A phase 2 study evaluating the addition of ublituximab and umbralisib (U2) to ibrutinib in patients with chronic lymphocytic leukemia (CLL): A minimal residual disease (MRD)-driven, time-limited approach

Background: While time-limited novel agent combinations have demonstrated high overall response rates and durable responses for patients with chronic lymphocytic leukemia (CLL), they also have high rates of adverse events and possibly overtreat many favorable risk patients. Meanwhile, patients receiving indefinite ibrutinib monotherapy are at risk for cumulative toxicity and acquired resistance with continuous exposure. To address these challenges, we utilized an 'add-on' approach to combination therapy after a period of ibrutinib monotherapy exposure. We examined the addition of umbralisib (a selective PI3Kδ and casein kinase-1epsilon [CK1ϵ] inhibitor) and ublituximab (a novel anti-CD20 monoclonal antibody glycoengineered for enhanced antibody-dependent cellular cytotoxicity;U2) to ibrutinib in CLL patients with detectable minimal residual disease (MRD) after an initial period of treatment with ibrutinib monotherapy. With this strategy, we aimed to induce undetectable MRD (uMRD), minimize the risk of developing BTKi resistance mutations, stop all CLL-directed therapy, and achieve a durable treatment-free observation (TFO) period in CLL patients who would most benefit from combination therapy. Methods: This is a phase II, multicenter, open label clinical trial (NCT04016805). Eligible patients were receiving ongoing ibrutinib, in any line of therapy, for a minimum duration of 6 months and had detectable residual CLL in the peripheral blood via MRD assay (flow cytometry with a cutoff of 10

A Multi-Center Retrospective Review of COVID-19 Outcomes in Patients with Lymphoid Malignancy

Background: Early reports suggested that cancer patients have a 1.7-fold increased risk of contracting SARS-CoV-2 and higher rates of severe events and mortality compared with general population. Patients with hematologic malignancies may have worse COVID-19 outcomes, due to an impaired humoral immune response from their underlying malignancy and concurrent anticancer therapy. In this multi-center, retrospective, observational study, we evaluate the associations of COVID-19 outcomes with patient and lymphoma disease characteristics. Methods: EMRs at 10 study centers across the USA identified 519 patients with a diagnosis of lymphoma, CLL, or other lymphoid malignancies, who had a documented positive result of SARS-CoV-2 PCR or nucleocapsid antibody testing. Descriptive statistics were used to summarize the demographic and clinical characteristics. Logistic regression was used to evaluate the associations of individual characteristics with COVID-19 outcomes, adjusted for center (NYU vs. other). The interactions between each of the variables was also included in these models;since the interactions were generally small and non-significant, only the main effect of center was included. Two-sided p-values ≤0.05 were considered significant;there were no adjustments for multiple variables or endpoints. Each analysis was based on complete data for that analysis. Results: Tables 1 and 2 provide demographic and clinical characteristics, respectively, of the 519 patients. The mean age was 61.9 years, with 296 (57%) male and 374 (72%) white patients. NYU had the largest cohort (318 patients), with the remaining centers contributing a range of 3 to 69 patients (median 14). Logistic regression models for the association of each COVID-19 outcome with individual clinical and patient characteristics included adjustments for the center (NYU/other). While center effects were statistically significant, center by covariate interaction effects were not and are not included in the final models. The odds ratio (OR) estimates and p-values for each patient and CLL/lymphoma clinical variable are shown in Tables 3 and 4, respectively. The risks of experiencing a severe event, death, and hospital admission increased with age;for each 10 years of age increase, the ORs were 1.58 for experiencing severe events, 1.78 for death, and 1.65 for hospital admission. The risks of poor outcome were higher in males than in females (OR 1.93 for severe events, 1.85 for death, and 1.47 for hospital admission). Patients with Charlson Comorbidity Index (CCI) >5 had a higher risk of severe events (OR 2.46), mortality (3.30) and hospital admission (2.73) compared to patients with CCI ≤5. Compared to patients with HL, patients with aggressive NHL had a higher risk of severe events (OR 4.05), mortality (4.68) and hospital admission (4.65). Patients with CLL similarly had a higher risk of severe events (OR 4.64), mortality (4.65) and hospital admission (5.93) compared to HL patients. Patients with indolent NHL had a higher risk of hospital admission (OR 3.95) but not a higher risk of mortality compared to HL. Patients in remission at the time of COVID-19 diagnosis had a lower risk of severe events (OR 0.42), mortality (0.36) and hospital admission (0.40) relative to those who were not in remission. Patients who received cytotoxic chemotherapy within 28 days of their COVID-19 diagnosis had a higher risk of severe events (OR 2.54), mortality (2.79), and hospital admission (2.31). Patients who received an anti-CD20 monoclonal antibody within 6 months of COVID-19 diagnosis had a higher risk of severe events (OR 2.60), mortality (2.17) and hospital admission (3.28). Conclusions: In addition to demographic and comorbidity risk factors identified in previous studies, our study shows that patients with aggressive NHL and CLL, or patients who have received recent cytotoxic chemotherapy or anti-CD20 mAB, may be at risk for poor COVID-19 outcome. The difference in risk between NHL and HL patients is likely associated with young age of HL patients but may also be related o differences in underlying innate and adaptive immune defects. Patients at high risk for poor outcome should be a priority for studies of monoclonal antibody prophylaxis. If defects in humoral immunity are at the root of poor outcome, this may be compounded by poor response to vaccination. Multivariate analysis of this data will be completed in advance of the meeting. [Formula presented] Disclosures: Olszewski: Celldex Therapeutics: Research Funding;PrecisionBio: Research Funding;TG Therapeutics: Research Funding;Acrotech Pharma: Research Funding;Genentech, Inc.: Research Funding;Genmab: Research Funding. Barta: Daiichi Sankyo: Honoraria;Seagen: Honoraria;Acrotech: Honoraria;Kyowa Kirin: Honoraria. Hernandez-Ilizaliturri: AbbVie: Other: Advisory Boards;Incyte: Other: Advisory Boards;Celgene: Other: Advisory Boards;BMS: Other: Advisory Boards;Pharmacyclics: Other: Advisory Boards;Amgen: Other: Advisory Boards;Kite: Other: Advisory Boards;Gilead: Other: Advisory Boards;Epyzime: Other: Advisory Boards. Leslie: Janssen: Consultancy, Speakers Bureau;Merck: Consultancy;Abbvie: Consultancy, Honoraria;Epizyme: Consultancy, Honoraria, Speakers Bureau;PCYC/Janssen: Consultancy, Honoraria, Speakers Bureau;Seagen: Consultancy, Honoraria, Speakers Bureau;TG Therapeutics: Consultancy, Honoraria, Speakers Bureau;Celgene/BMS: Consultancy, Honoraria, Speakers Bureau;Kite, a Gilead Company: Consultancy, Honoraria, Speakers Bureau;ADC Therapeutics: Consultancy;BeiGene: Consultancy, Honoraria, Speakers Bureau;Karyopharm Therapeutics: Honoraria, Speakers Bureau;AstraZeneca: Consultancy, Honoraria, Speakers Bureau;Pharmacyclics: Consultancy, Honoraria, Speakers Bureau. Diefenbach: Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding;Merck Sharp & Dohme: Consultancy, Honoraria, Research Funding;Morphosys: Consultancy, Honoraria, Research Funding;Genentech, Inc./ F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding;Perlmutter Cancer Center at NYU Langone Health: Current Employment;Incyte: Research Funding;AbbVie: Research Funding;Trillium: Research Funding;IGM Biosciences: Research Funding;IMab: Research Funding;Janssen: Consultancy, Honoraria, Research Funding;Gilead: Current equity holder in publicly-traded company;MEI: Consultancy, Research Funding;Celgene: Research Funding;Seattle Genetics: Consultancy, Honoraria, Research Funding.

Production of Anti-Spike Antibodies in Response to COVID Vaccine in Lymphoma Patients

Background Patients with hematologic malignancies have poor outcomes from COVID infection with associated mortality of up to 30-40%. Studies have shown that these patients are less likely to mount an antibody response after COVID infection 1. The Pfizer-BioNTech and Moderna COVID mRNA vaccines have been shown to be 94% effective in preventing severe disease in the general population. There is limited data on the efficacy of these vaccines in lymphoma patients, and to suggest the optimal timing of vaccination to elicit immunity in patients receiving immunochemotherapy. Methods This is a retrospective study of adult lymphoma patients who received the COVID vaccine between 12/2020 and 04/2021. The primary endpoint was a positive anti-COVID spike protein antibody titer following 2 doses of the COVID mRNA vaccines or 1 dose of the COVID adenovirus vaccine. Additional outcomes of interest included key variables, such as lymphoma subtype and treatment with anti-CD20 monoclonal antibodies. Subgroups were compared using Fisher's exact test, and unadjusted and adjusted logistic regression models were used for univariate (UVA) and multivariate (MVA) analyses. Results One-hundred thirty-seven patients were identified with baseline characteristics as shown in Table 1. Overall, the study population was older at a median age of 69 (IQR 59-78) years old, 52% of patients were male, and 72% of patients were white. The most frequent comorbidities were cardiovascular disease (39%) and former smoking history (34%), and 45 (33%) patients were obese (BMI >= 30). Testing for anti-COVID spike protein antibodies occurred at a median 48 (IQR 25-62) days [range 6-120] after second vaccination. Lymphoma subtypes in our cohort were: indolent lymphomas (35%), CLL/SLL (20%), 27 (20%) patients with Burkitt's, DLBCL, PMBCL combined, and 25 (18%) patients with Hodgkin's and T-cell lymphomas (HL/TCL) combined. Majority of patients received COVID mRNA vaccines, and we were able to confirm the specific type in 71 (52%) patients. Only 1 person received the COVID adenovirus vaccine. Ninety-two patients (67.2%) developed anti-COVID spike protein antibodies after receiving a COVID vaccine. Of 27 patients who received an anti-CD20 monoclonal antibody-containing regimen in the last 12 months prior to vaccination, 14 (52%) patients produced antibodies. This rate was numerically lower than 72% (26/36) of those who developed antibodies and received an anti-CD20 antibody greater than 12 months prior to vaccination. There were differences observed in the ability to produce serology towards the COVID vaccine amongst lymphoma subtypes. Of 28 patients with CLL, 12 (43%) produced antibodies. There were 6 CLL patients receiving anticancer treatment at the time of vaccination, of which 2 patients produced antibodies. CLL/SLL patients were less likely to mount an antibody response to the COVID vaccine when compared to those with other types of lymphoma, and this difference was significant on UVA (OR 0.270, 95% CI 0.112-0.648), p=0.003) and MVA (OR 0.259, 95% CI 0.104-0.643, p=0.004). For patients with HL/TCL, 22 of 25 (88%) patients produced antibodies. Among the 3 HL/TCL patients that did not produce antibodies, 1 patient had HIV/AIDS post-transplant, 1 had relapsed AITL, and 1 received rituximab. All HL/TCL patients who received anticancer treatment in the last 6 months (10 of 10) produced antibodies at a median titer of 120 AU/mL (reference >=15 AU/mL), with 4 patients having a robust response of antibody titers >400 AU/mL. On statistical analysis, HL/TCL patients were more likely to elicit an antibody response to the COVID vaccine when compared to those with other types of lymphoma, and this response was significant on UVA (OR 4.084, 95% CI 1.149-14.515, p=0.03) and MVA (OR 4.442, 95% CI 1.219-16.191, p=0.024). Conclusion Lymphoma patients are capable of mounting a humoral response to the COVID mRNA vaccines. CLL/SLL appears predictive of a negative antibody response to the COVID vaccine, while HL/TCL histologies appeared to correlate to a positive antibody response even with treatment within 6 months of vaccination. Our study suggests anti-CD20 monoclonal antibody therapy in the last 12 months may affect the ability to produce serology towards a COVID vaccine. Further studies are required to confirm our findings, including whether T-cell immunity would be of clinical relevance in this patient population. 1. Passamonti et al, Br J Haematol 2021 [Formula presented] Disclosures: Leslie: Kite, a Gilead Company: Consultancy, Honoraria, Speakers Bureau;Abbvie: Consultancy, Honoraria;BeiGene: Consultancy, Honoraria, Speakers Bureau;PCYC/Janssen: Consultancy, Honoraria, Speakers Bureau;TG Therapeutics: Consultancy, Honoraria, Speakers Bureau;Janssen: Consultancy, Speakers Bureau;AstraZeneca: Consultancy, Honoraria, Speakers Bureau;Seagen: Consultancy, Honoraria, Speakers Bureau;Epizyme: Consultancy, Honoraria, Speakers Bureau;Karyopharm Therapeutics: Honoraria, Speakers Bureau;Celgene/BMS: Consultancy, Honoraria, Speakers Bureau;Merck: Consultancy;Pharmacyclics: Consultancy, Honoraria, Speakers Bureau;ADC Therapeutics: Consultancy. Goy: Acerta: Consultancy, Research Funding;Bristol Meyers Squibb: Membership on an entity's Board of Directors or advisory committees;AstraZeneca: Membership on an entity's Board of Directors or advisory committees;Genentech/Hoffman la Roche: Research Funding;AbbVie/Pharmacyclics: Membership on an entity's Board of Directors or advisory committees;Gilead: Membership on an entity's Board of Directors or advisory committees;Kite Pharma: Membership on an entity's Board of Directors or advisory committees;Janssen: Membership on an entity's Board of Directors or advisory committees;Vincerx pharma: Membership on an entity's Board of Directors or advisory committees;Rosewell Park: Consultancy;LLC(Targeted Oncology): Consultancy;Elsevier's Practice Update Oncology, Intellisphere, LLC(Targeted Oncology): Consultancy;Michael J Hennessey Associates INC: Consultancy;Hoffman la Roche: Consultancy;Xcenda: Consultancy;Medscape: Consultancy;Physicians' Education Resource: Consultancy, Other: Meeting/travel support;Vincerx: Honoraria, Membership on an entity's Board of Directors or advisory committees;AbbVie/Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;Bristol Meyers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;Incyte: Honoraria;MorphoSys: Honoraria, Other;Novartis: Consultancy, Honoraria;OncLive Peer Exchange: Honoraria;Xcenda: Consultancy, Honoraria;AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;Elsevier PracticeUpdate: Oncology: Consultancy, Honoraria;Celgene: Consultancy, Honoraria, Research Funding;Genomic Testing Cooperative: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Other: Leadership role;COTA (Cancer Outcome Tracking Analysis): Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Other: Leadership role;Hackensack Meridian Health, Regional Cancer Care Associates/OMI: Current Employment;Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;Infinity/Verastem: Research Funding;Janssen: Research Funding;Karyopharm: Research Funding;Phamacyclics: Research Funding;Constellation: Research Funding. Feldman: Alexion, AstraZeneca Rare Disease: Honoraria, Other: Study investigator.