ABSTRACT
Background: Patients (pts) with Hodgkin lymphoma (HL) may be at an increased risk from COVID-19- related complications due to immunosuppression and common therapies with pulmonary toxicities (e.g. bleomycin, radiation). Additionally, they may experience unexpected adverse events (AEs) from the novel SARS-CoV-2 vaccines due to the intrinsic abnormalities in cellular immunity. Exploring their perspective on the COVID-19 pandemic and subjective AEs from the novel vaccines may ultimately allow providers to develop improved services based on needs of this specific population. Methods: We conducted a single-institution, questionnaire-based study in pts treated after 1/1/2015, for diagnosis of HL. Pts were identified through the electronic medical records at our institution. After signing an informed consent, pts answered 19 questions designed to reflect on their COVID-19 pandemic experience. An additional section aimed to determine the percentage of pts with a local or systemic AEs within 7 days of novel SARS-CoV-2 vaccine dose. Results: We enrolled 30 pts with median age 28.5 years (18-66);16 (53%) were male, and 26 (87%) were on active HL therapy. With data cutoff 1/28/ 2022, 27 pts (90%) completed the questionnaire. A total of 8 (27%) patients had COVID-19 infection with 75% of those occurring after the vaccination. None required hospitalization and none reported residual pulmonary issues. Eighteen (67%) had a member of their household test positive for COVID-19. Most pts (67%) did not require cancellation of their appointments due to COVID-19-related issues during the pandemic. 85% of pts participated in at least 1 telehealth medical appointment and the majority (72%) were satisfied with their telehealth experience for cancer care. A total of 24 (80%) pts received the novel SARS-CoV-2 vaccines (58% had Pfizer-BioNTech BNT162b2, 38% Moderna mRNA-1273, 4% Ad26.COV2.S) and 23 pts completed the AE section of the questionnaire. The vaccines were generally well-tolerated. Six pts (26%) reported at least one grade 3 AE, but none had grade 4 local or systemic AEs. The most common AE was pain at injection site (65% after dose 1, 55% after dose 2, 69% after dose 3). AEs that occurred in over 25% of pts during any of the injections included redness/swelling/pain at the injection site, fatigue, headache, muscle pain, and fever. Of 23 eligible pts, 13 (57%) received 3rd dose of the vaccine. No unexpected toxicities or autoimmune issues were noted by participants in this study following vaccination with a median follow up of 10 months after the 1st vaccine dose. Conclusions: Based on responses from our study, HL pts adjusted to the challenges of the COVID-19 pandemic with minimal disruptions to their cancer care, showed positive attitudes toward telehealth, and appear without any unexpected toxicities from the novel vaccines.
ABSTRACT
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.
ABSTRACT
Background: Patients (pts) with cancer are at higher risk for complications and mortality related to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Although mRNA vaccines have been granted Food and Drug Administration emergency use authorization (EUA) for prevention of COVID-19, the pivotal trials largely excluded pts with active cancer. Emerging data suggests suboptimal efficacy of these vaccines in pts with hematologic malignancies. There are also theoretical concerns that programmed cell death protein 1 inhibitors (PD-1i) could potentiate vaccine-related adverse events (AEs);conversely, these vaccines could activate the immune system, increasing the risk for immune-related reactions (IRRs) after PD-1i treatment. Pts with classic Hodgkin lymphoma (cHL) receiving PD-1i represent a unique cohort and should be investigated for safety and efficacy issues with SARS-CoV-2 vaccines. Methods: We conducted a retrospective analysis of pts with cHL who were treated with PD-1i within the past 12 months. Our primary objective was to determine the frequency of vaccine-related AEs and also subsequent IRRs to PD-1i after vaccination as reported in the medical records. Our secondary objective was to determine efficacy based on post-vaccine COVID-19 infection rates and by presence of adequate receptor binding domain (RBD) IgG antibody level to the SARS-CoV-2 spike protein. This assay was a clinically available institutional assay developed under EUA. While the level of antibody that is associated with immune protection has not yet been defined, we used RBD IgG > 0.700 AU as positive since it was previously correlated with virus neutralization titer in vitro. Results: From July 1, 2020 through June 31, 2021, we identified 27 pts who received PD-1i for cHL and were seen at the University of Pennsylvania. Seventeen (63%) pts received nivolumab and 10 (37%) received pembrolizumab. The median age was 42 years (23-86), median number of therapies was 4 (2-15), and 7 (26%) had prior history of COVID-19 infection (none required hospitalization). Twenty-three pts (85% of total) were vaccinated: 17 (74%) received Pfizer-BioNTech BNT162b2 and 6 (26%) had Moderna mRNA-1273 formulations. Of 19 (83%) pts who received at least one dose of PD-1i prior vaccine, the median time between last PD-1i infusion and first vaccine administration was 20 days (2-157). Of 19 (83%) pts who received any PD-1i after vaccine, the median time to infusion was 18 days (4-89). In pts who had prior COVID-19 infection, the median time between the prior infection and vaccine was 91 days (range 78-350). There were no unexpected toxicities noted and no severe adverse events or hospitalizations directly related to vaccination. No patient discontinued the vaccination series due to side effects. In 12 vaccinated pts who had vaccine-related AEs solicited by the medical provider, 7 (58%) developed injection site reaction/pain: grade 1 (6/12) and grade 2 (1/12). Six (50%) pts had systemic AEs: grade 1 fatigue (4/12), grade 2 fatigue (1/12), transient generalized lymphadenopathy (1/12), fever (1/12). No new IRRs occurred in pts receiving subsequent PD-1i after vaccination. Two weeks after second vaccination, 1 patient developed worsening cough with imaging suggestive of pneumonitis but improved with antibiotics. There were no post-vaccine COVID-19 infections noted. RBD IgG antibody levels were available in 12/23 (52%) of all vaccinated pts;11/12 (92%) pts had positive antibody titers. The only patient who did not mount positive RBD IgG antibody titers received brentuximab vedotin concurrently with PD-1i prior to vaccination. There were insufficient events to correlate pre-vaccine factors with AEs or efficacy. Conclusion: Pts with relapsed/refractory cHL on PD-1i who received SARS-CoV-2 vaccines had no unexpected toxicities and tolerated subsequent PD-1i without new IRRs. The efficacy based on post-vaccination COVID-19 rates and RBD IgG levels is encouraging in these heavily pretreated pts. We plan an additional prospective component of this study using atient reported outcomes and long-term safety and efficacy follow-up. Disclosures: Svoboda: Incyte: Research Funding;Genmab: Consultancy;Merck: Research Funding;Pharmacyclics: Consultancy, Research Funding;BMS: Consultancy, Research Funding;TG: Research Funding;Imbrium: Consultancy;Seattle Genetics: Consultancy, Research Funding;Astra Zeneca: Consultancy, Research Funding;Atara: Consultancy;Adaptive: Consultancy, Research Funding. Dwivedy Nasta: Roche: Research Funding;Merck: Other: Data safety monitoring board;Incyte: Membership on an entity's Board of Directors or advisory committees;AstraZeneca: Membership on an entity's Board of Directors or advisory committees;Pharmacyclics: Research Funding;ATARA: Research Funding;Millenium: Research Funding;Rafael: Research Funding;Debiopharm: Research Funding. Ruella: AbClon: Consultancy, Research Funding;BMS, BAYER, GSK: Consultancy;Novartis: Patents & Royalties;Tmunity: Patents & Royalties;viTToria biotherapeutics: Research Funding. Landsburg: Triphase: Research Funding;Takeda: Research Funding;Curis: Research Funding;ADCT: Membership on an entity's Board of Directors or advisory committees;Incyte: Membership on an entity's Board of Directors or advisory committees;Karyopharm: Membership on an entity's Board of Directors or advisory committees, Other: DSMB member;Morphosys: Membership on an entity's Board of Directors or advisory committees. Barta: Seagen: Honoraria;Daiichi Sankyo: Honoraria;Acrotech: Honoraria;Kyowa Kirin: Honoraria. Gerson: TG Therapeutics: Consultancy;Kite: Consultancy;Abbvie: Consultancy;Pharmacyclics: Consultancy. Schuster: Loxo Oncology: Consultancy;Nordic Nanovector: Consultancy;Genentech/Roche: Consultancy, Research Funding;Novartis: Consultancy, Honoraria, Patents & Royalties, Research Funding;Celgene: Consultancy, Honoraria, Research Funding;Acerta Pharma/AstraZeneca: Consultancy;BeiGene: Consultancy;Juno Theraputics: Consultancy, Research Funding;Tessa Theraputics: Consultancy;Pharmaclyclics: Research Funding;Abbvie: Consultancy, Research Funding;Alimera Sciences: Consultancy;Adaptive Biotechnologies: Research Funding;Merck: Research Funding;Incyte: Research Funding;TG Theraputics: Research Funding;DTRM: Research Funding.
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.