ABSTRACT
Background:COVID-19 adversely affects individuals with cancer. Several studies have found that seroconversion rates among patients with hematologic malignancies are suboptimal when compared to patients without cancer. Among patients with hematologic malignancies, seroconversion rates also appear to be influenced by recent treatment and the type of treatment they have received. Patients with non-Hodgkin lymphoma (NHL) and multiple myeloma (MM) are immunocompromised due to impaired humoral and cellular immunity in addition to prescribed immunosuppressive therapy. Chimeric antigen receptor T-cell (CAR T) therapy is now widely used for NHL and MM, but little is known about seroconversion rates after COVID-19 vaccination among these populations. Current national guidelines recommend COVID-19 vaccination to be offered to CAR T recipients as early as three months thereafter. We retrospectively evaluated SARS-CoV-2 spike-binding IgG antibody levels following COVID-19 vaccination among NHL and MM CAR T therapy recipients. Methods:This retrospective study was conducted at three Mayo Clinic sites on NHL and MM patients that received CAR T infusions from Sept 2016 to June 2021. Baseline characteristics were ascertained from medical records. All NHL and MM patients who had received CAR T at any point and were alive at the time that the COVID-19 vaccine first became available were eligible for inclusion for antibody response evaluation. For antibody response to vaccination, antibody spike values > 0.80 U/mL were considered positive. Results: Out of 104 CAR T infusions, 73 patients are alive at the time of this submission. We have had 7 patients with known COVID-19 pre-CAR T and all 7 are currently alive (5 have antibody titers and 2 have not been tested yet). Nineteen patients developed known COVID infection post-CAR T (13 alive and 6 deceased). The mortality of COVID post-CAR T in our sample was 31.5%. Furthermore, of the 13 patients that survived COVID-19, they received CAR T an average of 416 days prior to COVID-19 infection (median = 337, range = 54 - 1406);the 6 patients who died from COVID-19 had received CAR T an average of 250 days prior to COVID-19 infection (median = 164, range = 7 - 846). All 6 deceased patients did not receive COVID-19 vaccination pre-CAR T. Out of 17 CAR T patients tested for antibody spike titers post COVID-19 vaccination, 76.4% were able to mount an antibody response. More patients with MM had a higher titer response to the vaccine (>250 U/mL) compared to the NHL counterparts (0.80-249 U/mL). All patients that received the vaccine, regardless of antibody response, were alive at the time of this submission. Conclusions:The majority of CAR T recipients with NHL and MM are able to mount an antibody response following COVID-19 vaccination in our relatively small sample. The frequency of seroconversion among CAR T recipients seems to be similar to patients with hematologic malignancy who had received a hematopoietic cell transplant reported elsewhere. These findings are limited by our small sample size and may be influenced by the timing of vaccination relative to CAR T. Furthermore, almost half of our patients received IVIG post CAR T which could potentially cause false positive antibody results as pooled immunoglobulin preparations may contain COVID-19 antibodies from vaccinated healthy donors. To better understand the characteristics of the immunologic response against SARS-CoV-2 in patients post-CAR T, larger multicenter studies exploring both humoral and cellular immunity will be needed. JEWN, MI and JM are co-first authors and PV, HM and AR are co-senior authors. [Formula presented] Disclosures: Munoz: Physicians' Education Resource: Honoraria;Seattle Genetics: Honoraria;Bayer: Research Funding;Gilead/Kite Pharma: Research Funding;Celgene: Research Funding;Merck: Research Funding;Portola: Research Funding;Incyte: Research Funding;Genentech: Research Funding;Pharmacyclics: Research Funding;Seattle Genetics: Research Funding;Janssen: Research Funding;Millennium: Research Funding;Gilea /Kite Pharma, Kyowa, Bayer, Pharmacyclics/Janssen, Seattle Genetics, Acrotech/Aurobindo, Beigene, Verastem, AstraZeneca, Celgene/BMS, Genentech/Roche.: Speakers Bureau;Pharmacyclics/Abbvie, Bayer, Gilead/Kite Pharma, Pfizer, Janssen, Juno/Celgene, BMS, Kyowa, Alexion, Beigene, Fosunkite, Innovent, Seattle Genetics, Debiopharm, Karyopharm, Genmab, ADC Therapeutics, Epizyme, Beigene, Servier: Consultancy;Targeted Oncology: Honoraria;OncView: Honoraria;Kyowa: Honoraria. Bergsagel: Oncopeptides: Consultancy, Honoraria;Novartis: Consultancy, Honoraria, Patents & Royalties: human CRBN mouse;Pfizer: Consultancy, Honoraria;Celgene: Consultancy, Honoraria;Janssen: Consultancy, Honoraria;Genetech: Consultancy, Honoraria;GSK: Consultancy, Honoraria. Wang: Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding;LOXO Oncology: Membership on an entity's Board of Directors or advisory committees, Research Funding;Genentech: Research Funding;InnoCare: Research Funding;Novartis: Research Funding;MorphoSys: Research Funding;Eli Lilly: Membership on an entity's Board of Directors or advisory committees;TG Therapeutics: Membership on an entity's Board of Directors or advisory committees. Fonseca: Juno: Consultancy;Kite: Consultancy;Aduro: Consultancy;OncoTracker: Consultancy, Membership on an entity's Board of Directors or advisory committees;GSK: Consultancy;AbbVie: Consultancy;Patent: Prognosticaton of myeloma via FISH: Patents & Royalties;Caris Life Sciences: Membership on an entity's Board of Directors or advisory committees;Scientific Advisory Board: Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees;BMS: Consultancy;Amgen: Consultancy;Sanofi: Consultancy;Merck: Consultancy;Mayo Clinic in Arizona: Current Employment;Celgene: Consultancy;Takeda: Consultancy;Bayer: Consultancy;Janssen: Consultancy;Novartis: Consultancy;Pharmacyclics: Consultancy. Palmer: Sierra Oncology: Consultancy, Research Funding;CTI BioPharma: Consultancy, Research Funding;Protagonist: Consultancy, Research Funding;Incyte: Research Funding;PharmaEssentia: Research Funding. Dingli: Novartis: Research Funding;GSK: Consultancy;Apellis: Consultancy;Alexion: Consultancy;Sanofi: Consultancy;Janssen: Consultancy. Kapoor: Sanofi: Research Funding;AbbVie: Research Funding;Takeda: Research Funding;Karyopharm: Consultancy;Cellectar: Consultancy;BeiGene: Consultancy;Pharmacyclics: Consultancy;Sanofi: Consultancy;Amgen: Research Funding;Ichnos Sciences: Research Funding;Regeneron Pharmaceuticals: Research Funding;Glaxo SmithKline: Research Funding;Karyopharm: Research Funding. Kumar: Roche-Genentech: Consultancy, Research Funding;Oncopeptides: Consultancy;Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;BMS: Consultancy, Research Funding;Beigene: Consultancy;Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding;Novartis: Research Funding;Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding;Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Tenebio: Research Funding;Merck: Research Funding;Carsgen: Research Funding;KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Amgen: Consultancy, Research Funding;Bluebird Bio: Consultancy;Antengene: Consultancy, Honoraria;Sanofi: Research Funding. Paludo: Karyopharm: Research Funding. Bennani: Kymera: Other: Advisory Board;Vividion: Other: Advisory Board;Kyowa Kirin: Other: Advisory Board;Daichii Sankyo Inc: Other: Advisory Board;Purdue Pharma: Other: Advisory Board;Verastem: Other: Advisory Board. Ansell: Bristol Myers Squibb, ADC Therapeutics, Seattle Genetics, Regeneron, Affimed, AI Therapeutics, Pfizer, Trillium and Takeda: Research Funding. Lin: Kite, a Gilead Company: Consultancy, Research Funding;Merck: Research Funding;Gamida Cell: Consultancy;Takeda: Research Funding;Juno: Consultancy;Bluebird Bio: Consultancy, Research Funding;Celgene: Consultancy, Research Funding;Novartis: Consultancy;Janssen: Consultancy, Research Funding;Sorrento: Consultancy;Legend: Consultancy;Vineti: Consultancy. Murthy: CRISPR Therapeutics: Research Funding.
ABSTRACT
Introduction: Acquired thrombotic thrombocytopenic purpura (aTTP) due to an acquired deficiency in the enzyme ADAMTS13 leads to ultra-large von Willebrand multimers, thrombocytopenia and microangiopathic hemolytic anemia. Complications include microvascular and macrovascular thrombosis. We present an unusual case of a patient with a history of refractory aTTP who experienced relapsed aTTP following COVID-19 vaccine. Case Description: A 57-year-old African-American male with a history of refractory aTTP experienced a relapse following 3 years of remission after receiving COVID-19 vaccination. The patient was initially diagnosed with aTTP in 2016, after presenting with symptoms of dark urine, mild headaches and transient episodes of aphasia and paresthesia. Due to symptoms and persistently low ADAMTS13 levels, he required prolonged and extensive treatment including over 5 weeks of daily therapeutic plasma exchange (TPE), followed by gradual reduction in frequency of TPE sessions, as well as trials of rituximab, eculizumab, steroids, mycophenolate mofetil and bortezomib. Ultimately, he achieved remission after 9 months of intermittent TPE, 3 months of weekly bortezomib 1 mg/m 2, mycophenolate mofetil up-titrated to 1,750 mg twice daily, and then slowly tapered off over a 2-year period. The patient was doing well for 3 years without manifestations of aTTP (2 years off all therapeutics), until he developed a petechial rash 7 weeks after receiving the second dose of the Moderna COVID-19 vaccine. He was found to have acute thrombocytopenia with platelets of 38 x 10 9/L (normal range 135-317 x 109/L), from a baseline of 200-300 x 10 9/L. He was referred to the emergency department, where additional labs were notable for mildly elevated LDH of 508 U/L (normal range 122-222 U/L), hemoglobin of 12.4 g/dL (normal range 13.2-16.6 g/dL), creatinine at baseline, and peripheral blood smear showing 1-3 schistocytes per high-powered field. ADAMTS13 activity level was t <5% (normal >/= 70%), with positive ADAMTS13 inhibitor screen and titer of 1.5 (normal <0.4), consistent with relapsed aTTP. The patient was admitted to the hospital, and initiated on daily TPE, with steroids and diphenhydramine prior to each TPE session. He quickly improved with TPE alone, but given his history of refractory aTTP, he was discharged on weekly rituximab for 4 weeks and caplacizumab 11 mg daily for 30 days. His platelets remained stable within the upper limit of normal during his 30 day course of caplacizumab. However, 3 weeks after completion of caplacizumab, he had an acute drop in his platelets to 23 x 10 9/L. His ADAMTS13 level was again found to be <5%, and inhibitor level was the highest that it had ever been at 11.4. He was again hospitalized and underwent 8 sessions of daily TPE, as well as re-initiation of caplacizumab, mycophenolate mofetil 500 mg bid (with increasing taper), and a prednisone taper. Intravenous Cyclophosphamide 750 mg/m 2 was also added every 3 weeks. With this regimen, patient's platelet count normalized and remain stable, and his ADAMTS13 activity level has reached 52-59%. Discussion: Cases of vaccine-induced immune thrombotic thrombocytopenia (VITT) have been described as a complication following vaccination with formulations containing replication-defective adenoviral vectors (AstraZeneca-Oxford and Johnson&Johnson COVID-19 vaccines)(Arepally and Ortel 2021, Simpson, Shi et al. 2021). VITT and aTTP are both immune-mediated, however, VITT is distinct and pathogenically linked to autoimmune heparin-induced thrombocytopenia (HIT), given the presence of anti-platelet factor 4 antibodies in these patients, whereas aTTP is due to reduction in ADAMTS13 level, secondary to an antibody inhibitor of ADAMTS13 (Arepally and Ortel 2021). Recently, cases have been reported of de novo aTTP developing shortly after COVID-19 vaccination with all available vaccines, except the Moderna (mRNA-1273) vaccine (Al-Ahmad, Al-Rasheed et al. 2021, de Bruijn, Maes et al. 2021, Maayan, Kirgner et al. 2021, Ruhe, Schnetzke et al. 2021, Waqar, Khan et a . 2021, Yocum and Simon 2021). Additionally, cases of relapsed aTTP have been described following only the BNT162B2 (Pfizer-BioNTech) vaccine (Maayan, Kirgner et al. 2021, Sissa, Al-Khaffaf et al. 2021). This is the first case, to our knowledge, reported in the literature of aTTP following vaccination with Moderna's mRNA-1273 vaccine. Disclosures: No relevant conflicts of interest to declare.