SUBPOPULATION COMPOSITION OF PERIPHERAL BLOOD LYMPHOCYTES IN COVID-19.

The pathogenesis of severe coronavirus infection COVID-19 is associated with activation of immune system, cytokine storm, impaired blood clotting, microvascular thrombosis, organ ischemia and multiple organ dysfunction syndrome. The role of various lymphocyte subpopulations in COVID-19 is still debated. The aim of our study was to analyze the subpopulational profile of peripheral blood lymphocytes in COVID-19 patients as compared with healthy donors. The study included 20 COVID-19 patients (11 males and 9 females,) and 26 healthy donors. Average age of the patients was 52 and 56 years, respectively. Clinical examinations were performed by standard laboratory methods. Peripheral blood lymphocytes were isolated in the Ficoll gradient. The cells were stained with antibodies to specific antigens of main lymphocyte populations, endothelial cells, and apoptotic cell markers. The analysis was performed by flow cytometry. The results showed that all patients had elevated C-reactive protein (14- to 35-fold), ferritin (1.2- to 13-fold), D-dimers (1.2- to 90-fold). 55% of men had a decrease in the absolute number of lymphocytes, in women this index was at the low normal limit. Cytometric analysis showed that, among peripheral blood lymphocytes, the proportion of functional cells expressing the CD45 marker ranged from 2 to 12% in 70% of patients, as compared with 80-99% among the donors. The proportion of CD45+ lymphocytes significantly correlated with the level of hemoglobin, but not with the levels of inflammatory biochemical markers. Among the functional lymphocytes of patients, there was a decrease in the proportion of CD3+, CD4+, CD8+T cells, increased proportion of natural killer CD56+ and the apoptotic (AnnexinV+) cell contents, but the proportion of CD19 and HLA-DR+B cells was not changed. Analysis of the lymphocyte (LC) subpopulations that did not express CD45 marker showed that this fraction contained different lymphocyte subsets with reduced expression of CD4, CD8, CD19, CD56 etc. in the blood of patients and donors. Higher percentage of endothelial cells expressing CD62P marker made the difference between patients and donors. Laboratory determination of lymphocyte subsets in blood samples of COVID-19 patients does not reflect the real severity pattern of the disease, thus requiring studies of the CD45-expressing functional cell populations.Copyright © Svirshchevskaya E.V. et al., 2023 The article can be used under the Creative Commons Attribution 4.0 License.

FEATURES OF POST-VACCINATION HUMORAL IMMUNE RESPONSE IN THE PERSONS WHO UNDERWENT COVID-19 OF VARIOUS SEVERITY.

The studies on humoral immune response in the individuals who have undergone COVID-19 and vaccinated with anti-COVID vaccines allows us to assess the development of "hybrid" immunity, which contributes to understanding the mechanisms of its formation from the effector phase to the step of immunological memory. We assessed the relative and absolute contents of B cell populations and subpopulations, development of humoral immunity in the patients who suffered with COVID-19 of varying severity being thereafter vaccinated with "KoviVak" and "Sputnik V". The study involved volunteers (age 47.3+/-14.5 years) who beared COVID-19 asymptomatically (n = 32), at moderate severity (n = 21), or had severe form of the disease (n = 12), then being vaccinated with "KoviVak" and "Sputnik V" 6-9 months after their recovery. The groups of vaccinated persons consisted of those who beared severe disease being vaccinated with "KoviVak" (n = 6) or "Sputnik V" (n = 6);moderate cases, vaccinated with "KoviVak" (n = 10) and "Sputnik V" (n = 11);asymptomatic cases vaccinated with "KoviVak" (n = 10) and "Sputnik V" (n = 22). We have determined relative and absolute numbers of B lymphocytes (CD45+CD19+), B1 lymphocytes (CD45+CD5+CD19-CD27-), B2 lymphocytes (CD45+CD19+CD5-CD27-), total population of memory B cells (CD45+CD19+CD5-CD27+), non-switched (CD45+CD19+IgD+CD27+), and switched (CD45+CD19+IgD-CD27+) memory B cells;mature naive B lymphocytes (CD45+CD19+CD27-IgD+), plasmoblasts (CD45+CD19+ CD38+++IgD-CD27+), as well as presence of IgG to S(RBD)-SARS-CoV-2 protein. We have found that the humoral immunity among survivors of COVID-19 of varying severity is expressed for up to nine months. The largest number of volunteers who raised antibodies to SARS-CoV-2 S-protein was registered in the group of seriously ill patients. As soon as 1 month after "Sputnik V" vaccination and until the end of the observation, all the examined subjects in this group became seropositive. 4-5 months after injection of this vaccine, specific immunoglobulins were present in all patients who had asymptomatic or average-severity infection. All volunteers who received "KoviVak" had antibodies to the COVID-19 viral S protein from the beginning to the end of the study. Vaccination, especially with "KoviVak", contributed to the highest increase, both in relative and absolute numbers of memory B lymphocytes in asymptomatic patients. Less pronounced changes in the content of B lymphocytes in COVID-19 patients who had severe and moderate clinical course may be associated with higher levels of these cells prior to injection of the vaccines. A positive correlation was found between the number of memory B cells and presence of immunoglobulins to the S protein SARS-CoV-2 in all examined patients.Copyright © 2023 Russian Association of Allergologists and Clinical Immunologists, St. Petersburg Regional Branch (SPb RAACI). All rights reserved.

FEATURES OF POST-VACCINATION HUMORAL IMMUNE RESPONSE IN THE PERSONS WHO UNDERWENT COVID-19 OF VARIOUS SEVERITY.

The studies on humoral immune response in the individuals who have undergone COVID-19 and vaccinated with anti-COVID vaccines allows us to assess the development of "hybrid" immunity, which contributes to understanding the mechanisms of its formation from the effector phase to the step of immunological memory. We assessed the relative and absolute contents of B cell populations and subpopulations, development of humoral immunity in the patients who suffered with COVID-19 of varying severity being thereafter vaccinated with "KoviVak" and "Sputnik V". The study involved volunteers (age 47.3+/-14.5 years) who beared COVID-19 asymptomatically (n = 32), at moderate severity (n = 21), or had severe form of the disease (n = 12), then being vaccinated with "KoviVak" and "Sputnik V" 6-9 months after their recovery. The groups of vaccinated persons consisted of those who beared severe disease being vaccinated with "KoviVak" (n = 6) or "Sputnik V" (n = 6);moderate cases, vaccinated with "KoviVak" (n = 10) and "Sputnik V" (n = 11);asymptomatic cases vaccinated with "KoviVak" (n = 10) and "Sputnik V" (n = 22). We have determined relative and absolute numbers of B lymphocytes (CD45+CD19+), B1 lymphocytes (CD45+CD5+CD19-CD27-), B2 lymphocytes (CD45+CD19+CD5-CD27-), total population of memory B cells (CD45+CD19+CD5-CD27+), non-switched (CD45+CD19+IgD+CD27+), and switched (CD45+CD19+IgD-CD27+) memory B cells;mature naive B lymphocytes (CD45+CD19+CD27-IgD+), plasmoblasts (CD45+CD19+ CD38+++IgD-CD27+), as well as presence of IgG to S(RBD)-SARS-CoV-2 protein. We have found that the humoral immunity among survivors of COVID-19 of varying severity is expressed for up to nine months. The largest number of volunteers who raised antibodies to SARS-CoV-2 S-protein was registered in the group of seriously ill patients. As soon as 1 month after "Sputnik V" vaccination and until the end of the observation, all the examined subjects in this group became seropositive. 4-5 months after injection of this vaccine, specific immunoglobulins were present in all patients who had asymptomatic or average-severity infection. All volunteers who received "KoviVak" had antibodies to the COVID-19 viral S protein from the beginning to the end of the study. Vaccination, especially with "KoviVak", contributed to the highest increase, both in relative and absolute numbers of memory B lymphocytes in asymptomatic patients. Less pronounced changes in the content of B lymphocytes in COVID-19 patients who had severe and moderate clinical course may be associated with higher levels of these cells prior to injection of the vaccines. A positive correlation was found between the number of memory B cells and presence of immunoglobulins to the S protein SARS-CoV-2 in all examined patients.Copyright © 2023 Russian Association of Allergologists and Clinical Immunologists, St. Petersburg Regional Branch (SPb RAACI). All rights reserved.

Unusual Myositis of the Temporalis Muscle Occurring with Acute Covid-19

Background. SARS-CoV-2 infection can be accompanied by neuromuscular disorders. Rhabdomyolysis and Guillain-Barre syndrome have been described repeatedly. There are case reports of inflammatory myopathies manifesting during COVID-19, presenting as dermatomyositis, polymyositis or immune-mediated necrotizing myopathy, with dermatomyositis-like presentations most commonly reported. Larger cases series are from postmortem examinations of COVID-19 patients, where variable inflammatory pathology of the skeletal muscle has been found frequently but without local detection of the actual virus. Thus, autoimmune mechanisms or the systemic interferon response are discussed as causes. We report a case of focal inflammatory myopathy with perimysial pathology of the temporalis muscle occurring with acute, but mild COVID-19. Methods. Case report of clinical observations, cranial MRI, histopathological, and laboratory findings. 3T cranial MRI was performed with gadolinium contrast. Open temporalis muscle biopsy was performed. The sample underwent standard cryohistological studies as well as immunohistochemistry with antibodies against MHC-I and II, CD3, CD4, CD19, CD68, anti-MAC, p62 and MxA. Testing for auto-antibodies was based on immunoblots or ELISA. RT-PCR for SARS-CoV-2 was run with RNA extracted from cryopreserved muscle. Results. A Caucasian woman in her 60s with no history of autoimmune or muscle complaints developed swelling and pain of the right jaw musculature five days after testing positive for SARS-CoV-2 due to respiratory tract symptoms. In addition, she experienced trismus, but no further neuromuscular complaints. The course of respiratory tract symptoms stayed mild. She had been vaccinated previously with single shot SARS-CoV-2 vector vaccine. Due to persistent swelling and complaints, giant cells arteritis was excluded by unresponsiveness to five days oral steroids and sonography of the temporal artery. Cranial MRI was performed nearly four weeks after the SARS-CoV-2 infection and showed marked swelling and oedema of the temporalis muscle. Its biopsy showed numerous CD68 and acid phosphatase positive cells infiltrating from perimysial perivascular foci towards the endomysium with perimysial damage but little damage of adjacent, perifascicular muscle fibres. Muscle fibres did not react with anti-MHC-II, anti-MAC or -MxA. Capillaries did not react with anti-MAC or -MxA. SARS-CoV-2 RNA was not detected in muscle tissue. Serum creatine kinase was not elevated in the subacute phase. Slightly elevated ANA titre led to detection of autoantibodies against proliferating cell nuclear antigen (PCNA). No pathological results for other autoantibodies, including myositis-specific antibodies and anti-ds-DNA, were found in blood. Neither were antibodies against hepatitis C and B viruses. Retesting 15 weeks after infection, anti-PCNA immunoblot was still positive, but ELISA did not indicate a pathologic titre. The swelling, myalgia and trismus regressed spontaneously a month after onset, yet the latter still persists at the time of reporting. Conclusion. Our case diverges from the majority of COVID-19 associated my-ositis reports in the unusual location of the focal myositis and the histopathological pattern of predominantly perimysial damage and histiocytic infiltration. It concurs with the literature as no SARS-CoV2 RNA could be detected in the muscle. Anti-PCNA is associated very rarely with myositis. Other associated disorder (systemic lupus erythematosus, chronic viral hepatitis B or C) were not found. Increased levels of autoantibodies are reported in COVID-19 and mostly attributed to loss of self-tolerance during the acute disease phase. Interestingly, the structural protein M of SARS-CoV-2 appears to interact notably with PCNA in infected cells. Still, the causal connection between the myositis and COVID-19 in this case is based on the close temporal association in the absence of alternative, competing explanations from the medical history and findings.

Hairy Cell Leukemia in a Filipino Male during the COVID-19 Pandemic - Report of a Rare Case

Hairy cell leukemia (HCL) is a rare, chronic, mature B-cell lymphoproliferative disorder accounting for 2% of all leukemias. In this paper, we would like to present our experience in the management of HCL in a financially limited setting where other diagnostic tests and chemotherapy are unavailable. The case report aims to emphasize the recognition of the distinctive morphology of hairy cells in the peripheral blood in the consideration of the initial diagnosis. A 60-year-old Filipino male was incidentally found to have anemia, thrombocytopenia and an absolute neutrophilic count below 1,000 in a pre-operative clearance for elective herniorrhaphy. Blood smear revealed atypical lymphocytes with hair like cytoplasmic projections. CT-scan of the abdomen showed splenomegaly and prominent paraaortic nodes. Flow cytometry of the bone marrow aspirate was consistent with an involvement of a Mature B cell neoplasm markers CD19, CD20, CD22 and surface immunoglobulin lambda and hairy cell leukemia markers CD11c, CD103 and CD25. He responded to six-weekly sessions of Cladribine with remission of the bone marrow and hematologic parameters. HCL is a rare type of a mature B cell neoplasm characterized by pancytopenia, splenomegaly, bone marrow fibrosis and the presence of atypical lymphoid cells with hairy projections in blood, bone marrow and spleen. Immunophenotyping express CD11c, CD103, CD123, and CD25. BRAF V600E mutation is the disease defining genetic event. Cladribine and Pentostatin are the first line of treatment. Cases of leukemia can be easily overlooked because of the mild derangement in the complete blood count. A meticulous differential review of the atypical lymphocyte, is the first step in the diagnosis of this rare disease.Copyright © 2022, Philippine College of Physicians. All rights reserved.

SUBPOPULATION COMPOSITION OF PERIPHERAL BLOOD LYMPHOCYTES IN COVID-19.

The pathogenesis of severe coronavirus infection COVID-19 is associated with activation of immune system, cytokine storm, impaired blood clotting, microvascular thrombosis, organ ischemia and multiple organ dysfunction syndrome. The role of various lymphocyte subpopulations in COVID-19 is still debated. The aim of our study was to analyze the subpopulational profile of peripheral blood lymphocytes in COVID-19 patients as compared with healthy donors. The study included 20 COVID-19 patients (11 males and 9 females,) and 26 healthy donors. Average age of the patients was 52 and 56 years, respectively. Clinical examinations were performed by standard laboratory methods. Peripheral blood lymphocytes were isolated in the Ficoll gradient. The cells were stained with antibodies to specific antigens of main lymphocyte populations, endothelial cells, and apoptotic cell markers. The analysis was performed by flow cytometry. The results showed that all patients had elevated C-reactive protein (14- to 35-fold), ferritin (1.2- to 13-fold), D-dimers (1.2- to 90-fold). 55% of men had a decrease in the absolute number of lymphocytes, in women this index was at the low normal limit. Cytometric analysis showed that, among peripheral blood lymphocytes, the proportion of functional cells expressing the CD45 marker ranged from 2 to 12% in 70% of patients, as compared with 80-99% among the donors. The proportion of CD45+ lymphocytes significantly correlated with the level of hemoglobin, but not with the levels of inflammatory biochemical markers. Among the functional lymphocytes of patients, there was a decrease in the proportion of CD3+, CD4+, CD8+T cells, increased proportion of natural killer CD56+ and the apoptotic (AnnexinV+) cell contents, but the proportion of CD19 and HLA-DR+B cells was not changed. Analysis of the lymphocyte (LC) subpopulations that did not express CD45 marker showed that this fraction contained different lymphocyte subsets with reduced expression of CD4, CD8, CD19, CD56 etc. in the blood of patients and donors. Higher percentage of endothelial cells expressing CD62P marker made the difference between patients and donors. Laboratory determination of lymphocyte subsets in blood samples of COVID-19 patients does not reflect the real severity pattern of the disease, thus requiring studies of the CD45-expressing functional cell populations.Copyright © Svirshchevskaya E.V. et al., 2023 The article can be used under the Creative Commons Attribution 4.0 License.

Novel heterozygous PLCG2 variant presenting with very early-onset perianal abscess

Case report Background: Mutations in the PLCG2 gene can cause PLCG2-associated antibody deficiency and immune dysregulation (PLAID) or auto-inflammation with PLCG2-associated antibody deficiency and immune dysregulation (APLAID). PLAID is characterized by urticarial eruptions triggered by evaporative cooling along with cutaneous granulomas. APLAID may present with early-onset skin inflammation and non-infectious granulomas, uveitis, and colitis. Method(s): Case report and literature review. We performed in silico analysis for variants of uncertain significance (VUS). Result(s): A 29-day-old boy presented to emergency department for failure to thrive. He was found to be SARS-CoV2 positive, had an E. coli UTI in the setting of bilateral perinephric masses which subsequently resolved. He also had a perianal soft tissue abscess measuring 4cm in diameter. Mom reported a similar infection when she was age 2. She also reported intermittent diffuse urticaria triggered following perspiration evaporation.Abscess wall histology showed diffuse neutrophil and lymphocytic infiltration, with cultures growing polymicrobial enteric flora. His serum immunoglobulins G, A, M, and E were within reference range. Naive and memory CD4, CD8, CD19 lymphocyte subsets (including NK cells) were also within age-appropriate reference range. He had a normal neutrophil oxidative burst measured using dihydrorhodamine (DHR) flow cytometry following PMA stimulation, which ruled out a diagnosis of chronic granulomatous disease. On evaporative cooling, the patient had a 2mm wheal with surrounding erythema which resolved rapidly with warming. A targeted primary immunodeficiency panel showed a heterozygous VUS in PLCG2, c.688C > G (p.Leu230Val). The variant was absent from major databases and had a calculated CADD score of 17.77. He had symptomatic resolution after completing 3 weeks of ceftriaxone and metronidazole antimicrobials. Given the concern for PLCG2-associated very early-onset inflammatory bowel disease (VEO-IBD), a fecal calprotectin was obtained at 3 months and found to be elevated (157 mcg/g [ < = 49 mcg/g]). However, he had no symptomatic or macroscopic evidence for VEO-IBD. Conclusion(s): Presence of very early onset abscesses has not been previously described in patients with heterozygous PLCG2 deficiency. This case adds to the expanding variable phenotype of PLCG-2-associated immune dysregulation.

Characterization of Mesenchymal Cell from BAL of post COVID-19 patient whit fibrosis

Increasing number of severe COVID 19 patients develop pulmonary Fibrosis, but the management of this complication is still unclear due to a lack of clinical trials. Aim of this study was to characterize mesenchymal cells (MC) isolated from 10 broncho-alveolar lavage (BAL, at 2 months after discharge) from patients with COVID19 fibrosis (COVID19-f) and to compare them with those isolated from 8 patients with collagen tissue diseaseassociated interstitial fibrosis(CTD-ILD). BAL fluid (BALf) levels of TGFbeta, VEGF, TIMP2, RANTES, IL6, IL8, and PAI1 were assessed by ELISA. Primary MC foci were cultured and expanded in D-MEM +10% FBS, characterized by flow cytometry and osteogenic and adipogenic differentiation. Collagen 1 production (+/-TGF-beta) was tested by WB and mRNA expression. BALf cytokine and GF levels were comparable in the two groups. Efficiency of MC isolation from BAL was 100% in COVID-f compared to 65% in CTD-ILD. MC antigen surface expression of CD105, CD73, CD90 (>90%, respectively), CD45, CD34, CD19 and HLA-DR (<5%, respectively) was comparable. None of MC samples differentiated in adipocytes, while COVID19-f were positive for calcium deposition. COVID19-f MC showed at WB, higher Collagen 1 production with respect to CTD-ILD with TGF-beta stimulation. Our preliminary data suggest MC from COVID19-f share several features with CTD-ILD but might have a higher response to fibrogenic and differentiation signals.

Infections by varicella zoster virus in patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED)

Rationale: APECED is a life-threatening monogenic disorder characterized by multiorgan autoimmunity. Most patients harbor autoantibodies (auto-abs) to type-1 interferons (IFNs), which are important mediators of viral defense. Auto-abs to type-1 IFNs are associated with severe COVID-19 and may play a role in other viral infections including by varicella zoster virus (VZV). A recent study of 44 European APECED patients reported increased susceptibility to VZV, and a correlation between VZV recurrence and auto-abs to IFN-α. The clinical, immunophenotypic, and auto-ab characteristics of APECED patients in the USA with VZV are described. Methods: Data was obtained from 103 participants on a prospective, natural history study after informed consent. Auto-abs to IFN-α, IFN-β or IFN-ω were measured using a multiplex particle-based assay. Unpaired t tests or U Mann Whitney tests were used, with Holm correction for multiple comparisons, where appropriate. Results: Twenty-six patients reported childhood chickenpox (mean onset 5.6 years) and 2 (7.7%) required hospitalization for severe disease. Nineteen patients (18%) had at least one episode of shingles (median onset 13 years;range, 4-55 years) and 4 had >1 episode. Fifteen of the 19 patients with shingles (79%) were not receiving immunosuppressive medications during their first infection. VZV IgG levels;total and percent CD3, CD8, CD4, CD19, NK cells;and auto-abs to IFN-α, IFN-β and IFN-ω did not significantly differ between patients with or without recurrent shingles. Conclusions: A subset of APECED patients develop early-onset, recurrent VZV infections even in the absence of immunosuppression. The mechanisms underlying susceptibility to VZV in APECED require further study.

CASE REPORT: A RARE CASE OF ALVEOLAR HEMORRHAGE AFTER COVID-19 VACCINATION IN A PATIENT WITH RENAL-LIMITED ANTINEUTROPHIL CYTOPLASMIC ANTIBODYASSOCIATED VASCULITIS

The coronavirus disease 2019 (COVID-19) vaccination campaign has progressed worldwide. Rare but severe adverse events of COVID-19 vaccination such as anaphylaxis and myocarditis have begun to be noticed. Of note, several cases of new-onset antineutrophil cytoplasmic antibody-associated vasculitis (AAV) after COVID-19 mRNA vaccination have been reported. In contrast, relapse of AAV in remission has not been recognized enough as an adverse outcome of COVID-19 vaccination. We report, to the best of our knowledge, a first case of renal-limited AAV in remission using every 6-month rituximab administration that relapsed with pulmonary hemorrhage, but not glomerulonephritis, following the first dose of the COVID-19 vaccine. Notably, the patient received the COVID-19 vaccine more than 6 months after the last dose of rituximab according to the recommendations. Ironically, his CD19 positive B cell counts were found to be increased after admission, indicating that our case might have been prone to relapse after COVID-19 vaccination. Although our case cannot establish causality between AAV relapse and COVID-19 mRNA vaccination, a clinical vigilance for relapse of AAV especially in patients undergoing rituximab maintenance therapy following COVID-19 vaccination should be maintained. Furthermore, the elapsed time between rituximab administration and COVID-19 mRNA vaccination should be carefully adjusted based on AAV disease-activity (Nishioka et al. Front Med 2022. in press).

Leucemia Aguda De Fenotipo Misto - Apresentacao Inicial Atipica - Um Relato De Caso

Introducao: Com desafiador tratamento e de diagnostico criterioso, a leucemia aguda de fenotipo misto (LAFM) e uma entidade rara dentro do espectro das leucemias agudas. Requer a presenca imunofenotipica de marcadores de linhagem B (CD19, CD22, CD79a), T (CD3) em conjunto com a linhagem mieloide (mieloperoxidase e diferenciacao monocitica - CD11c, CD14, CD64 ou lisozima). Relato de caso: Paciente masculino, 30 anos, obeso e diabetico tipo 2, hipertrigliceridemia, inicia com febre (38C), dor abdominal em hipocondrio direito e fadiga. Com dois dias de sintomas procura atendimento sendo liberado com sintomaticos. No quarto dia de sintomas houve piora da febre (39degreeC) e da dor, surgindo maculas hiperemiadas pruriginosas pelo corpo, ictericia e coluria. Retornou ao hospital de sua cidade sendo prescrito azitromicina e liberado com suspeita de influenza. No sexto dia de sintomas notou piora da ictericia, procurando, novamente, atendimento. Encaminhado, entao ao servico de referencia da regiao. Interna inicialmente na equipe da gastroenterologia como suspeita de hepatite viral. Na chegada: Hb 14,9, leucocitos 6140 com 2793 neutrofilos, 442 monocitos e 2812 linfocitos, 53 mil plaquetas;AST 57, ALT 733, hiperbilirrubinemia as custas de bilirrubina direta. Com todos os marcadores virais negativos, prosseguiu a investigacao de hepatite. No dia em que realiza ressonancia magnetica, que indicava processo infiltrativo/inflamatorio em figado e rim esquerdo, alem de testar positivo para COVID-19, ha evolucao no hemograma: Hb 10,7, leucocitos 7450 com 1192 blastos, 60 neutrofilos, 2012 monocitos e 4187 linfocitos, 23 mil plaquetas. Com o aparecimento de blastos, piora dos niveis de bilirrubinas e das lesoes de pele, foi realizado imunofenotipagem de sangue periferico que indicava leucemia monocitica aguda. Transferido a equipe da hematologia, sendo realizada biopsia de medula e iniciado protocolo 7 + 3 com substituicao das antraciclinas em falta no mercado por doxorrubicina 45 mg/m2. No terceiro dia da inducao, foi liberado o resultado da imunofenotipagem que confirmava o diagnostico de leucemia aguda de fenotipo misto B/mieloide, marcando CD19, CD22 e CD79a, com diferenciacao monocitica (CD14 e CD64). Cariotipo nao houve crescimento e PCR BCR/ABL negativo. Optado por seguir tratamento com 7 + 3, apresentando medula no D14 aplasiada e medula no D28 com doenca residual minima (DRM) negativa. Realiza tres consolidacoes com altas doses de citarabina (3g/m2). Paciente sustenta DRM negativa, estando em remissao completa. Iniciado manutencao com vincristina, mercaptopurina, metotrexato e prednisona. Aguarda transplante de celulas tronco hematopoieticas (TCTH). Discussao: Com o diagnostico de LAFM, o tratamento requer o maior numero de quimioterapicos, sendo sugerido o uso de protocolos para leucemia linfoblastica aguda. Como ja havia sido instituido o tratamento com doxorrubicina e citarabina, foi optado por seguir protocolo e, na manutencao da remissao completa, terminar as consolidacoes e iniciar a manutencao prevista pelo protocolo HyperCVAD. Devido a ser uma leucemia de alto risco, a realizacao do TCTH e necessaria e, neste caso relatado, a manutencao sera mantida ate a realizacao do transplante. Conclusao: Contudo, por se tratar de doenca rara e com poucos estudos publicados, requer compartilhamento de conhecimentos e condutas para melhora da abordagem. Copyright © 2022

Infiltracao Do Sistema Nervoso Central: Desafio Terapeutico Nas Doencas Linfoproliferativas B Cronicas

Introducao: O acometimento do sistema nervoso central (SNC) e raro nas doencas linfoproliferativas B cronicas, sendo mais frequente a recaida nos linfomas nao-Hodgkin agressivos, porem a era pos Rituximab promoveu um ganho para esse perfil de pacientes. Objetivo: Relatar o envolvimento de SNC em 04 pacientes com doencas linfoproliferativas B cronicas e indolentes e revisar a literatura. Relato de caso: Caso 1: Homem, 53 anos, com leucemia linfoide cronica (LLC) Binet A desde 2012 e delecao 17p, apresentou crise convulsiva e rebaixamento neurologico em 12/2021. O liquor mostrou 18,3% de celulas B CD5+, CD19+, CD200+, recebeu imunoquimio intratecal e ibrutinibe sem resposta, LCR ainda infiltrado. Caso 2: Homem, 56 anos, com LLC Binet A desde 07/2021 evoluiu com abrupta piora cognitiva, RNM encefalica previa normal, novo exame em 02/2022 mostrou lesoes expansivas infiltrativas e nodulares intra-axiais bilaterais, compativeis com LNHDGCB (BCL-2+, CD20+, c-Myc+, Ki-67+, MUM1+), LCR normal, tratado com metotrexate (MTX) em altas doses, sem resposta. Caso 3: Mulher, 56 anos, com LNH folicular EC IVA em 2019, recebeu 06 ciclos de R-CHOP e manutencao por 02 anos, em remissao clinica. Em 04/2022 cursou com rapido agravo neurologico. A RNM mostrou lesoes na substancia branca nos hemisferios cerebrais, LCR infiltrado por celulas CD19, CD23, CD20, CD10 positivas, tratada com Ara C em altas doses, regressao das lesoes encefalicas, LCR ainda infiltrado. Caso 4 - Homem, 64 anos, com linfocitose, assintomatico desde 2011, IF de SP CD5- CD20+, CD22+, CD79b+, CD200+, evoluiu em 01/2022 subitamente com rebaixamento neurologico, entubado, LCR com 52,8% de linfocitos B CD19+, CD 20+, CD200+. Intercorreu com infeccao pelo SARS-Cov 19, complicacoes clinicas e obito. Discussao: O envolvimento do SNC nas doencas linfoproliferativas, tanto na apresentacao inicial ou na recidiva, e raro, podendo ser leptomeningeo disseminado e/ou parenquimatoso. Raramente descrito, o acometimento meningeo na LLC e objeto de discussao quanto ao impacto prognostico e ao tratamento. A infiltracao do SNC e mais descrita nos linfomas agressivos em cerca de 5% dos casos. Descrevemos 04 casos com envolvimento SNC em patologias de comportamento tipicamente indolente. Lemma et al. exploraram o papel dos marcadores biologicos que podem conferir as celulas do linfoma tropismo pelo SNC, altos niveis de Integrina alpha 10 e PTEN em amostras de tecido foram associadas a este tropismo, enquanto a expressao de CD44 e caderina-11 parecem ser protetivas, estes dados sao preliminares e precisam de validacao. A apresentacao clinica e heterogenea, desde alteracao comportamental, cefaleia, meningismo, hidrocefalia, e hipertensao intracraniana. No tratamento do linfoma primario de SNC o MTX e fundamental, mas ainda nao ha consenso em relacao a profilaxia e ao protocolo padrao nas recaidas. Fica claro que a dose de MTX IT parece insuficiente para tratar as formas parenquimatosas. Quando ha envolvimento meningeo, a via IT pode ser usada, mas os dados sobre os resultados nao sao conclusivos. Conclusao: O tratamento dos pacientes que apresentam infiltracao SNC permanece um desafio principalmente nos linfomas indolentes, considerando a dificuldade de padronizar tratamento eficaz, de menor toxicidade e a gravidade das sequelas por vezes irreversiveis. O mecanismo associado a invasao e a predilecao de alguns casos pelo SNC permanece incerto. Copyright © 2022

Defects in the interferon system associated with a deficiency of natural killers and T-cells in patients with COVID-19

Objective. To clarify the features of the defect in the function of NK cells, T lymphocytes, the interferon system in patients with moderate and severe COVID-19. Patients and methods. Tests of the peripheral blood of 50 COVID-19 patients aged 61(57–71) and having the moderate and severe disease were performed. The following parameters were measured: the quantity of CD3+CD19–, CD3+CD4+, CD3+CD8+ T lymphocytes, NK – (CD3–CD16+CD56+), and TNK – CD3+CD16+CD56+ with expression density considered membrane receptors (MFI) (FC 500 Beckman Coulter, USA), the levels of IFN-α, IFN-γ, IL-6, TNF-α cytokines (IFA). Results. Combined immunodeficiency associated with quantitative and functional defects in NK, T lymphocytes and their subsets was revealed in moderate and severe COVID-19. An imbalance of cytokines has been established: blockade of the production of IFN-α and IFN-γ against the background of a significant increase in IL-6 and TNF-α, which negatively affects both the number and functionality of the participants in the immune response and is associated with a severe course and poor prognosis of COVID-19. Conclusion. The data obtained demonstrate the need to develop new strategies and tactics for the treatment of COVID-19, including replacement systemic therapy with recombinant IFN-α2b in combination with antioxidants (Viferon®) in adequate therapeutic doses, aimed at restoring the normal functioning of T lymphocytes, NK and the interferon system.

Synergistic anti-tumor effect of Allocetra-OTS in combination with immune checkpoint inhibitors (ICI)/chemotherapy/CAR T, through in-vivo reprogramming of macrophages

Background: ICI revolutionized solid tumor treatment, however, in many tumors only partial response is achieved. Here we investigated the anti-tumoral effect of Allocetra—OTS cellular therapy, in solid tumor models. Methods: Allocetra-OTS is manufactured from enriched mononuclear fractions and induced to undergo early apoptosis.Balb/c mice were inoculated in the peritoneal cavity with AB12 (mesothelioma) stably transduced with pLenti-PGK-V5-Luc-Neo for IVIS visualization and treated with anti-CTLA4, anti-PD1, or cisplatin, with or without Allocetra-OTS (also administered as monotherapy). Kaplan-Meier log rank test was done for survival. CAR T model was induced in SCID-Bg mice were inoculated intraperitoneally with human HeLa-CD19, followed by treatment with 10×109 cells of Allocetra-OTS or vehicle, and 1×107 CD19-CAR T cells or mock T cells. Results: Anti-CTLA4 therapy significantly improved survival from mean 34±9 to 44.9 ±20 days (p<0.05). However, Allocetra-OTS monotherapy improved survival to 52.3 ±20 days (p<0.02) and anti-CTLA4 + Allocetra-OTS combination therapy to 86.7±20 days (p<0.0001) with complete cancer remission in 60-100% of mice. Similar results were seen in combination therapy with either anti-PD1 or cisplatin. In the CAR-T model, SCID-Bg mice survived 30±5 days (range 27–37) and were sacrificed or died from tumor progression. Results were verified using IVIS of intraperitoneal HeLaCD19-Luc cells. CAR T cell therapy significantly improved survival to 55±11 days (p < 0.05 vs MOCK) but Alloctra-OTS further improved survival to 75±10 (p < 0.001) with 20-40% complete remission. Conclusions: During intraperitoneal tumor progression, Allocetra-OTS as monotherapy or in combination with ICI, cisplatin or CAR-T therapy, significantly reduced tumor size and resulted in complete remission in up to100% treated mice. Based on excellent safety profile in > 40 patients treated in prior clinical trials for sepsis and COVID-19, phase I/II clinical trial of Allocetra-OTS plus chemotherapy is planned for Q3 2022, and a second phase I/II clinical trial of Allocetra-OTS plus anti-PD1, as a second- and third-line therapy in various cancers, is planned for Q4 2022. Legal entity responsible for the study: The authors. Funding: Enlivex Therapeutics Ltd. Disclosure: D. Mevorach: Financial Interests, Personal, Royalties, Founder & CSO: Enlivex Therapeutics LTD. E. Yalon, E. Regev, C. Ankri, O. Hershkovitz, Y. Shabat, B. Reicher: Financial Interests, Personal, Full or part-time Employment: Enlivex Therapeutics LTD.

Haematological Malignancy Presenting in an Unusual Manner

Chronic lymphocytic leukaemia is a haematological malignancy that occurs due to an increased proliferation of mature B lymphocytes. It is considered to be the most common leukaemia in adults. Hyponatremia is commonly seen in such patients. This case report is about a 75-year-old male, who presented with giddiness, followed by altered sensorium. However, the patient had no motor weakness or sensory loss. Initially, a diagnosis of posterior circulation stroke was made but Magnetic Resonance Imaging (MRI) brain did not show associated signs. The routine investigations showed highly elevated total leukocyte count and hyponatremia. The patient was worked up for malignancy and diagnosed with Chronic lymphocytic leukaemia. Oncology reference was taken and treated with tablet Ibrutinib. On discharge, the patient's mentation improved, and he is on regular follow-up.

SAFETY AND EFFICACY FINDINGS OF AUTO1, A FAST-OFF RATE CD19 CAR, IN RELAPSED/REFRACTORY B-CELL NON-HODGKIN'S LYMPHOMA (B-NHL), AND CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) / SMALL LYMPHOCYTIC LYMPHOMA (SLL)

Background: We have previously described AUTO1, a CD19 CAR with a fast off-rate CD19 binding domain, designed to reduce CAR T-cell immune toxicity and improve engraftment. Its clinical activity has been tested in r/r paediatric and adult B-ALL (Ghorashian S et al., Nat Med 2019;Roddie C et al., JCO 2021). This data confirms the intended function of the receptor, with low levels of CRS/ICANS and long-term engraftment of CAR T-cells observed in both patient groups. Aims: We have initiated testing of AUTO1 in the setting of B-NHL and CLL/SLL (NCT02935257). Methods: Manufacturing: CAR T-cell products were generated using a semi-automated closed process from non-mobilised patient leukapheresate. Study design: Subjects ≥ 16y underwent lymphodepletion with fludarabine (30mg/m x3) and cyclophosphamide (60mg/kg x1) prior to AUTO1 infusion, with the exception of the DLBCL cohort who additionally received a single dose of pembrolizumab (200mg) on day -1 to potentiate CAR-T expansion. AUTO1 dose varies based on the indication. Split dosing of 230 x106 CD19 CAR T-cells at day 0 and day 9 is employed in the CLL cohort. A single dose of 200 x106 CD19 CAR T-cells is delivered to patients with B-NHL. Study endpoints include feasibility of manufacture, grade 3-5 toxicity and remission rates at 1 and 3 months. Results: As of 8th February 2022, we enrolled 23 patients: 11 low grade NHL (LG-NHL:7 with FL and 3 with MCL), 7 DLBCL and 5 CLL. Apheresis was successful in all 23 patients and product manufacture was successful in 22 (pending in the last). 19 patients were infused: 10 with LG-NHL, 6 with DLBCL and 3 with CLL. 1 CLL patient was pending infusion at time of data cut-off and 2 patients died pre-infusion: 1 MCL patient, from COVID-19 and 1 CLL patient, from intracerebral haemorrhage. Patients treated with AUTO1 had a median age of 60 years (range 39-79), had received a median of 3 prior lines of treatment (range 2-8). Grade 1 CRS was reported in 6/19 and Grade 2 CRS in 3/19. No ICANS was observed in the B-NHL and CLL cohorts. CAR engraftment was observed in 13/13 patients evaluated by qPCR with ongoing persistence in 12/13 patients at last follow-up. In the LG-NHL and DLBCL cohorts 10/10 and 4/5 evaluable patients respectively were in CMR by 18FDG PET-CT post-treatment. Responses were ongoing in 9/10 LG-NHL at 12 months and in 4/4 DLBCL at months 1, 3, 3 and 6. In the CLL cohort, 2/3 evaluable patients achieved MRD negative remission in the bone marrow with residual small volume lymph nodes by CT at 6 and 3 months of follow-up respectively. 1 CLL patient did not engraft and had SD at month 1. Summary/Conclusion: AUTO1 has a tolerable safety profile in patients with r/r B-NHL and CLL despite high disease burden. Early data shows excellent complete remission rates and excellent CAR engraftment/expansion. Additional patients, updated data and longer follow up will be presented.

DEPLETION AND RECOVERY OF NORMAL B-CELLS DURING AND AFTER TREATMENT WITH CHEMOIMMUNOTHERAPY, IBRUTINIB OR VENETOCLAX

Background: Infectious complications are a major cause of morbidity and mortality in Chronic Lymphocytic Leukaemia (CLL). Therapeutic approaches that deplete CLL cells also affect normal B-cells. Optimal treatment would result in eradication of CLL cells and recovery of normal immune function. FLAIR (ISRCTN01844152) is a phase III trial for previously untreated CLL comparing ibrutinib plus rituximab (IR) with fludarabine, cyclophosphamide and rituximab (FCR) and subsequently amended to also compare ibrutinib plus venetoclax (I+V) and ibrutinib alone (I) with FCR. Measurable residual disease (MRD) and normal B-cell levels were assessed at multiple timepoints. Aims: To assess the depletion of normal B-cells during treatment and recovery after end of treatment. Methods: Participants aged under 75 years with <20% TP53-deleted cells were initially randomised to FCR or IR and subsequently to FCR, IR, I+V or I with the IR arm closed after randomisation of 771 participants to FCR/IR. FCR was given for 6 cycles, while treatment in the IR, I and I+V arms continued for up to 6 years except in participants attaining <0.01% MRD who continued treatment for the time taken to achieved MRD <0.01% and then stopped if MRD remained <0.01%. Month (M) 24 was earliest permitted stopping point. MRD flow cytometry was performed according to ERIC guidelines (panel: CD19/5/20/43/79/81+ROR1, acquisition of 0.5-2.2 million cells, BD Biosciences Lyric). Additional analysis of normal B-cell subsets was performed in a cohort of >500 patients (panel: CD19 to identify B-cells, CD20/5/79b+ROR1 and CD3 to exclude CLL & contaminating cells, with CD27/ 38/IgD/IgM to characterise normal B-cell subsets using a Coulter Cytoflex LX). Results: Normal B-cells were undetectable during FCR treatment and only rarely detectable until 12 months after last FCR cycle. Circulating normal B-cells were reduced in number or undetectable in participants receiving ibrutinibcontaining regimens with greater depletion in the I+V and IR arms relative to I monotherapy. B-progenitors persist through FCR treatment but were depleted during I, I+R or I+V treatment. Normal B-cell levels at 24 and 36 months after randomisation, with time off-treatment if applicable, are shown in Figure 1. In the ibrutinib-containing arms (IR, I, and I+V), there was a trend towards fewer COVID-associated SAE at any time point for participants with detectable B-cells at 24M (4/181, 2.2%) compared to those with no detectable B-cells (14/344, 4.1%) and COVID-associated SAEs were not observed in FCR-treated participants who had recovered any level of normal B-cells by 24M (0/215). However, the data on COVID infections are limited and there was no apparent association between normal B-cell levels at 24M with the proportion of participants experiencing an infectious SAE overall. Assessment of normal B-cell subsets during ibrutinib-based treatment demonstrated a mix of naïve and memory B-cells. Serological response to COVID infection/vaccination in this cohort is currently being performed. Participants stopping I+V treatment at 24-30 months post-randomisation due to MRD eradication showed rapid recovery of normal naive B-cells within 6-12 months after end of treatment in the vast majority (>95%) of evaluable cases. Summary/Conclusion: Normal circulating B-cells are depleted during treatment with rituximab but can persist at a low level during I, IR or I+V treatment. Most patients in remission after treatment with FCR or I+V show recovery of normal B-cells at 12 months of stopping treatment.

HIGH COMPLETE RESPONSE RATE FOLLOWING POINT-OF-CARE ANTI CD19 CAR T-CELL THERAPY IN PATIENTS WITH RELAPSED/REFRACTORY FOLLICULAR LYMPHOMA

Background: Patients with relapsed/refractory follicular lymphoma (R/R FL) often experience multiple relapses and require various lines of therapy. The ELARA and ZUMA-5 trials demonstrated high response rates along with acceptable safety profiles. We perform a phase 1b/2 single-center clinical trial of autologous point-of-care (POC) academic anti-CD19 chimeric antigen receptor (CAR) T-cells for patients with R/R FL treated with at least 2 lines of systemic therapy (NCT02772198). Aims: To report outcomes of POC CAR T-cell therapy in patients with R/R FL. Methods: Adults with R/R FL underwent a single leukapheresis procedure. Fresh peripheral blood mononuclear cells were isolated, activated, and transduced with a gammaretrovirus encoding for a CD19 CAR (based on an FMC63-derived ScFv, a CD28 costimulatory domain, and a CD3-ζ signaling domain). Lymphodepletion included fludarabine 25 mg/m2 over 3 days (days-4 to-2) and cyclophosphamide 900 mg/m2 once (day-2), followed by infusion of 1×106/kg CAR T-cells in the inpatient setting. Primary endpoints were response (by PET-CT, per Lugano criteria) at day 28, best response, and safety. Secondary endpoints included overall survival, progression-free survival (PFS), and production feasibility. Last follow-up was as of 02/2022. Results: All 19 patients enrolled received CAR T-cell infusion in a median of 11 days (IQR 10-11) after leukapheresis. The median age was 61 years (IQR 52-66). Five (26%) patients had Karnofsky performance status < 90%. Disease stage at enrollment was III-IV in 16 (84%) patients. Two (11%) patients had bulky disease;8 (42%) had LDH > upper limit of normal;and 16 (84%) had Follicular Lymphoma International Prognostic Index ≥ 3. Disease status at enrollment was progressive disease (n=14, 74%), stable disease (n=3, 16%), or partial response (PR;n=2, 11%). Twelve patients (64%) were refractory to last treatment. Disease grade at most recent lymph node biopsy was 1 (n=3, 16%), 2 (n=11, 58%), or 3a (n=5, 26%). The median time from FL diagnosis was 3.9 years (IQR 2.5-4.6). Sixteen (84%) patients had progression of disease within 24 months of initial therapy. The number of prior therapies was ≥ 4 in 6 (32%) patients;and 5 (26%) patients underwent prior autologous transplantation. Grade III-IV cytokine release and immune effector cell-associated neurotoxicity syndromes occurred in 1 (5%) and 4 (21%) patients, respectively. One patient was infected with COVID-19 on the 5th day following cell infusion and was admitted to the intensive care unit. One patient had grade 3 atrial fibrillation. Severe neutropenia (absolute neutrophil count <500/μL), thrombocytopenia (platelets <50K/μL) and anemia (hemoglobin <10g/dl) occurred in 15 (79%), 5 (26%), and 7 (37%) patients, respectively. No bleeding events or death were recorded following cell infusion. Response was evaluated in all patients. Overall response rate on day 28 was 84% (79% complete response [CR]). One patient with PR on day 28 achieved a CR after a year of follow-up. Three patients (16%) continued to progress following CAR infusion. All patients were alive at the last follow-up (median follow-up, 11.5 months [IQR 4-21]). One-year PFS was 74% (95% CI, 53-100). The median duration of response (DOR) was not reached (95% CI, 12.5-not reached). Estimated DOR at 1-year was 89% (95% CI, 71-100). Image: Summary/Conclusion: Point-of-Care anti-CD19 CAR T-cell therapy, performed following a very short production time, induced high CR rate with an acceptable safety profile in a cohort of patients with high-risk R/R FL.

A phase 1b study of blinatumomab with the anti-programmed cell death (PD)-1 antibody AMG 404 in adults with relapsed/refractory (R/R) B-cell precursor acute lymphoblastic leukemia (ALL)

Background: Preclinical data indicate that anti-PD-1 agents can facilitate activity of bispecific T-cell engager (BiTE) molecules. Here we assess the combination of the anti-CD19 BiTE molecule blinatumomab with the anti-PD-1 antibody AMG 404 in adults with R/R ALL (NCT04524455). Methods: Eligible adults with R/R ALL (Ph+ disease included) received 2-5 treatment cycles. Each cycle was 42 days, consisting of 4 weeks of cIV blinatumomab and a 2-week treatment-free interval as per label. In Cohort 1, AMG 404 was dosed IV at 240 mg every 4 weeks (Q4W);first dose was Day (D) 11 of Cycle (C) 1. Primary endpoints were dose-limiting toxicities (DLTs) and other adverse events (AEs). Results: As of 20 Dec 2021, patients (pts) from Cohort 1 (n=8) had median age of 57 (range: 24-73) y, 6/ 8 male, 6/8 Caucasian, 1 with extramedullary disease (duodenum), 2 with prior blinatumomab, and a median of 5 (2-15) prior treatment lines. Two pts remain on study and 2 completed the study;4 pts discontinued the study due to death (n=3) or consent withdrawn (n=1). No DLTs were reported for the 3 evaluable pts. Of the 5 pts not evaluable for DLTs, in C1, 4 had disease progression and 1 an unrelated fatal pneumonia. Treatment-related grade (Gr) ≥3 and/or serious AEs in all 8 pts included cytokine release syndrome (CRS) (1 pt Gr 2, 1 pt Gr 1 and 3), Gr 3 increases in ALT and AST, Gr 3 fever, Gr 3-4 neutropenia, Gr 4 neutropenia/Gr 3-4 thrombocytopenia (same pt), Gr 2 sensorimotor polyneuropathy, Gr 3 hypertension, Gr 3 encephalopathy, and in 1 pt Gr 3-4 decreases in white blood cells, lymphocytes, and neutrophils. One pt developed Gr 3 SARS-COV-2 pneumonia on C2D25, resolving without clinical sequelae. C3 start was delayed by 12 days but protocol treatment resumed uneventfully. All 3 DLT-evaluable pts had a complete response (CR) or CR with partial hematologic recovery (CRh), 2/3 without measurable residual disease (MRD), within 2 cycles;the 3rd pt had an MRD response at the end of C3. Preliminary pharmacokinetic results for the combination of blinatumomab and AMG 404 demonstrated that their exposures were consistent with those observed for each as monotherapy and did not indicate any drug-drug interactions. To date, all samples tested for anti-blinatumomab antibodies have been negative. Conclusions: In this ongoing phase 1b study, the combination of blinatumomab with AMG 404 was tolerated with a manageable safety profile. No DLTs were reported. Enrollment continues in Cohort 2 in which AMG 404 is dosed Q4W at 480 mg starting on C1D1, 48 hours prior to blinatumomab.

Impact of cancer diagnosis, stage, and systemic therapies on immunogenicity after COVID-19 vaccination in patients with cancer: A systematic review and metaanalysis

Background: Patients (pts) with cancer are at increased risk of severe COVID-19. Both underlying malignancy and anti-cancer treatments influence the immune system, potentially impacting the level of vaccine protection achieved. Methods: A systematic literature search of PubMed, Embase, CENTRAL and conference proceedings (ASCO annual meetings and ESMO congress) up to 28/09/21, was conducted to identify studies reporting anti-SARS-CoV-2 spike protein immunoglobulin G seroconversion rates (SR) at any time point after complete COVID-19 immunization (mRNA- or adenoviral-based vaccines) in cancer pts. Complete immunization was defined as 1 dose of JNJ-78436735 vaccine or 2 doses of BNT162b2, mRNA-1273 or ChAdOx1 nCoV-19 vaccines. Subgroup analyses were performed to examine the impact of cancer diagnosis, disease stage, and anticancer therapies on the SR. Overall effects were pooled using random-effects models and reported as pooled SR with 95% confidence intervals (CI). Results: Of 1,548 identified records, 64 studies were included in this analysis reporting data from 10,511 subjects. The Table shows the SR in the overall population and specific subgroups. In pts with solid malignancies (SM), disease stage and primary site did not significantly impact the SR. In pts with hematologic malignancies (HM), SR were significantly lower in pts with chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL) compared to acute lymphoblastic leukemia (ALL), Hodgkin lymphoma (HL), and multiple myeloma (MM). Concerning the impact of cancer therapies on SR, pts with SM undergoing chemotherapy had numerically lower SR (N = 1,234, SR 87%, CI 81-92) compared to those treated with immune checkpoint inhibitors (N = 574, SR 94%, CI 88-97) or endocrine therapy (N = 326, SR 94%, CI 86-97) with or without another targeted therapy. Pts with HM treated with anti-CD20 therapy (within the last 12 months: N = 360, SR 7%, CI 2-20;or more than 12m: N = 175, SR 59%, CI 35-80), immune-modulating agents (BTK or BCL2 inhibitors) (N = 462, SR 47%, CI 32-64%) or other immunotherapies (anti-CD19/CART or anti-CD38) (N = 293, SR 37%, CI 23-53) had lower SR compared to pts treated with autologous (N = 353, SR 77%, CI 67- 85) or allogenic stem cell transplantation (N = 509, SR 77%, CI 68-84). Conclusions: SR varies between cancer types and anticancer therapies with some cancer pts having low protection against COVID- 19 even after complete vaccination.