ABSTRACT
Objective: Assess the SARS-CoV2 Spike antibody response in multiple sclerosis (MS) patients on high efficacy immunotherapies. Background: There is limited knowledge about SARS-CoV2 mRNA vaccine response in MS patients on immunotherapy. Design/Methods: Patients with MS, aged 18-65, on fingolimod, siponimod, ofatumumab, or ocrelizumab for at least 3 months prior to first mRNA SARS-CoV2 vaccine (Pfizer or Moderna) were offered enrollment. A cohort of healthy controls who received the mRNA vaccines were also enrolled. Blood samples for the SARS-CoV2 Spike antibody (Anti-SARS-CoV2 S, RocheElecsys) were collected 2-3 months after the second mRNA vaccine. The proportion who seroconverted (antibody>0.4 U/ml), and SARS-CoV2 Spike antibody levels were assessed. Results: A total of 39 MS patients (6 fingolimod, 33 ocrelizumab) and 31 controls were included in this interim analysis. 33%(13/39) of MS patients seroconverted, compared to 100%(31/31) in the control group, with an estimated risk difference of -0.67,(95% confidence interval: -0.81, -0.52;Fisher's exact test, p=9.0∗10-10 ). There was no difference in seroconversion rates between MS patients who received the Pfizer (34%, 10/29) versus the Moderna vaccine (30%, 3/10) (95% confidence interval -0.38, 0.29;Fisher's exact test=1). Seroconversion was found in 100% (31/31) of controls, 66.7% (4/6) of fingolimod-treated patients, and 27.3% (9/33) of ocrelizumab-treated patients (three group comparison, Fisher's exact test p-value =2.7∗10 -10). The median Spike antibody level was <0.4 U/ml in MS patients, and 1,663 U/ml in controls (Wilcoxon rank sum test, p-value= 1.0∗10-12 ). The median Spike antibody level in the ocrelizumab group was <0.4 U/ml, 3.45 U/ml in the fingolimod group, and 1,663 U/ml in the control group (Kruskal Wallis test, p-value=5.9∗10-12 ). Total IgG correlated with Spike antibody levels in the ocrelizumab-treated group only (Spearman correlation, p=0.025). Conclusions: MS patients on ocrelizumab and fingolimod have significantly lower rates of seroconversion, and lower median Spike antibody levels in response to the mRNA SARS-CoV2 vaccines compared to controls.
ABSTRACT
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.
ABSTRACT
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.
ABSTRACT
Introduction: While most patients (pts) with cutaneous T-cell lymphoma (CTCL) have an indolent course, survival for stages ≥IIB is usually less than 5 years (Kim YH et al, Arch Dermatol 2003). When an aggressive approach of combination cytotoxic therapies and radiation in CTCL was compared to conservative sequential therapies in newly diagnosed pts, the increase in response rate with combination therapy was offset by toxicities, and no benefit in disease-free or overall survival was seen (Kaye FS et al, NEJM, 1989). Since then several novel agents have been approved in CTCL, including the CD30-directed antibody-drug conjugate brentuximab vedotin (BV) [in relapsed primary cutaneous ALCL and CD30-expressing mycosis fungoides (MF)], and HDAC inhibitors (HDACi). However, response rates of single agents are modest. Tolerable and more efficacious therapies are needed, including rational combinations of active biological agents. Evidence suggests that HDAC inhibition may upregulate CD30 expression (Hasanali ZS et al, Sci Transl Med 2015), supporting the combination of the HDACi romidepsin (R) with Brentuximab vedotin (BV) in pts with CTCL. Methods: In this multicenter phase I clinical trial, pts age ≥18 with stage ≥IB CTCL, good organ function, ECOG PS≤2, <G2 neuropathy, who require systemic treatment, are enrolled, irrespective of CD30 expression. A traditional “3+3” design with 4 dose levels (DL -2, -1, 0, and 1) was used to define the maximum tolerated dose (MTD). Prior HDACi or BV use is allowed. Enrollment started at dose level (DL) 0, where R is given at 10mg/m2 on days (D) 1, 8 & 15, with BV at 1.2mg/kg (max. 120mg) on D1 & 15 of a 28 day cycle for up to 16 cycles. Dose level 1 dosing is R 14mg/m2 and BV 1.2mg/kg, both on D1 & 15. Dosing in the de-escalation cohorts -1 and -2 is as follows: R 10mg/m2 and BV 1.2mg/kg D1 & D15 (DL-1) or R 10mg/m2 D1, 8 & 15 with BV 0.9mg/kg D1&15 (DL-2). Once the MTD had been established, 9-12 additional pts are being enrolled in an expansion cohort to better define toxicities and efficacy. Response is measured during treatment using the mSWAT for skin assessment with every cycle, and flow cytometry and CT imaging after every 3rd cycle for extracutaneous sites. The Global Response Score is used for response assessment. There is a “run-in” phase of treatment with R alone given 14 days prior to D1 (D-14). Skin biopsies are taken at baseline and prior to D1 of cycle 1 to assess changes in CD30 expression after a single dose of R. The trial is registered in clinicaltrials.gov as NCT02616965. Results: At the time of abstract submission, 7 pts have been enrolled (DL0: n=3;DL1: n=3;expansion cohort: n=1). No pt experienced a cycle 1 DLT and DL1 was deemed the MTD. No pts were enrolled in the de-escalation cohorts. Enrollment in the expansion cohort is ongoing. Median age of pts was 64 years (range 51-79);72% (n=5) were male;median ECOG PS 1 (0-2);median prior lines of systemic therapy were 4 (0-4), including 1 pt with prior HDACi, and 1 pt with prior BV and R exposure. All pts had MF. Stage at enrollment was stage IIB in 5 (72%), IB and IVA2 in 1 each (14% each). No pts have experienced G4 or 5 adverse events (AE). The only G3 AEs observed during treatment were transaminitis and fever (n=1 each), both resolved spontaneously. The most common AEs were nausea (71%), vomiting (43%), gastro-esophageal reflux, constipation, peripheral sensory neuropathy, anorexia, fatigue, and thrombophlebitis (29% each;see Table 1). Response assessment is available for 5 of 7 pts. The overall response rate was 80% (4/5), all of which partial responses, including 1 pt who had received both prior R and BV. The median change in mSWAT was a decrease of 59% from baseline (range -19.5 to -81.8%). After a median follow up of 6.1 months, median estimated progression-free survival was 12 months (PFS probability 0.42;95%CI 0.1-1.0). Four pts came off treatment: 2 due to progression, 1 due to non-adherence related to COVID-19 concerns, 1 because of recurrent thrombophlebitis;3 pts remain on treatmen . Conclusion: Preliminary findings from this phase I study exploring the combination of R+BV indicate that R+BV is well tolerated at a dose of R 14mg/m2 and BV 1.2mg/kg given every 2 weeks and appears efficacious in CTCL. Updated results will be presented at the time of the meeting. Enrollment in the expansion cohort and correlative studies, including analysis of changes in CD30 expression after 1 dose of R, and association of response with CD30 expression, are ongoing. [Formula presented] Disclosures: Barta: Atara: Honoraria;Monsanto: Consultancy;Seattle Genetics: Honoraria, Research Funding;Janssen: Honoraria;Pfizer: Honoraria. Feldman: AstraZeneca: Consultancy;Janssen: Speakers Bureau;Portola: Research Funding;Pfizer: Research Funding;Kyowa Kirin: Consultancy, Research Funding;Eisai: Research Funding;Cell Medica: Research Funding;Amgen: Research Funding;Pharmacyclics: Honoraria, Other, Speakers Bureau;Abbvie: Honoraria;Bayer: Consultancy, Honoraria;Trillium: Research Funding;Viracta: Research Funding;Rhizen: Research Funding;Corvus: Research Funding;BMS: Consultancy, Honoraria, Research Funding;Kite: Honoraria, Other: Travel expenses, Speakers Bureau;Celgene: Honoraria, Research Funding;Takeda: Honoraria, Other: Travel expenses;Seattle Genetics, Inc.: Consultancy, Honoraria, Other: Travel expenses, Research Funding, Speakers Bureau. DeSimone: Sanofi/Genzyme: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Soligenix: Other: Investigator;Helsinn: Speakers Bureau. Fung: Genentech: Honoraria, Other: speakers' bureau, travel support;Sanotif: Honoraria, Other: speakers' bureau, travel support;AstraZeneca: Honoraria, Other: speakers' bureau, travel support;Kite, a Gilead Company: Honoraria, Other: speakers' bureau, travel support;Takeda: Honoraria, Other: speakers' bureau, travel support;Janssen Oncology: Honoraria, Other: speakers' bureau, travel support;AbbVie: Honoraria, Other: speakers' bureau, travel support. Khan: Celgene: Research Funding;Seattle Genetics: Research Funding;Janssen: Honoraria;Pharmacyclics: Honoraria;Bristol Myers Squibb: Research Funding. OffLabel Disclosure: Combination of romidepsin and brentuximab vedotin.