Obstructed hemivagina with ipsilateral renal agenesis (OHVIRA) syndrome: Typical presentation of a rare syndrome.

Obstructed hemivagina with ipsilateral renal agenesis (OHVIRA) syndrome is a rare congenital malformation of the Mullerian duct. We report on a 34-year-old female who presented to the emergency department for cramping lower abdominal pain and pelvic pressure with vaginal spotting. Physical exam showed marked swelling in the right adnexa, and laboratory exams were within normal limits except for positive Coronavirus disease 2019 (COVID-19) status. Transvaginal ultrasound revealed 3 well circumscribed, round hypoechoic complex cystic lesions with arterial doppler detected within the peripheral walls. Magnetic resonance imaging of the abdomen and pelvis showed a right hemivagina, right hematosalpinx, right hematometra and right renal agenesis, compatible with OHVIRA syndrome. The patient was informed of elective surgical procedure but was unable to undergo surgery at this time secondary to COVID status. The patient was therefore recommended oral contraceptive therapy for suppression of menses and protection of endometrial lining.

Exacerbation of autoimmune hemolytic anemia associated with pure red cell aplasia after COVID-19: A case report.

Autoimmune hemolytic anemia (AIHA) and pure red cell aplasia (PRCA) are rare complications of coronavirus disease 2019 (COVID-19). Herein, we report the case of a 28-year-old Japanese man who showed severe AIHA exacerbation associated with PRCA after COVID-19. AIHA was diagnosed and maintained for 5 years. Approximately 4 weeks after COVID-19, the patient developed severe anemia (hemoglobin level, 3.4 g/dL). Laboratory test results confirmed hemolytic exacerbation of IgG-mediated warm-type AIHA. Despite the hemolysis phase, the bone marrow revealed extreme hypoplasia of erythroblasts with a decreased reticulocyte count, similar to that observed in patients with PRCA. During oral prednisolone treatment, the patient recovered from anemia and showed increased reticulocyte count and reduced hypoplasia of marrow erythroblasts. Exacerbation of AIHA and PRCA was triggered by COVID-19 because other causes were ruled out. Although this case report highlights that COVID-19 could lead to hematological complications such as AIHA and PRCA, the exact mechanisms remain unclear.

Aplasia cutis congenita in dizygotic twin infants

Aplasia cutis congenita (ACC) is often sporadic, but familial cases have been reported. We report a case of a dichorionic diamniotic twin pregnancy in which both the male and female twins had matching areas of aplasia cutis on their scalps. An Irish couple sought fertility treatment using a donor egg and paternal sperm. Successful in vitro fertilization (IVF) and the transfer of two embryos resulted in a diamniotic dichorionic twin pregnancy. Two fetal poles were noted at the 12-week ultrasound (US) scans. The mother suffered from a minor urinary tract infection during the first trimester but had no other history of infection, including herpes simplex virus or COVID- 19. She was known to be varicella immune prior to pregnancy. The twins were born by elective caesarean section owing to breech presentation. Twin one was female and twin two was male. Both infants were born with scarring on the crown of their head, which was consistent with ACC. Cranial US showed no underlying bony abnormality. The rest of the cutaneous examination was normal and there were no other congenital anomalies. ACC is a rare, heterogeneous group of disorders characterized by the congenital absence of skin, which can be focal or widespread. It is thought to affect 1-3 per 10 000 live births. The exact cause of ACC is unclear. Various hypotheses have been suggested, including defective closure of the neural tube or embryonic fusion lines, intrauterine trauma, placental insufficiency, fetus papyraceus, amniotic membrane adhesions, intrauterine infections, teratogens and genetic mutations. The classification of ACC is based on the area affected, type of skin irregularity, associated congenital defects and mode of inheritance. Scalp ACC without multiple anomalies (category 1) is generally associated with an autosomal dominant or sporadic pattern of inheritance. These twins may have an autosomal dominant mutation that led to this phenotype. ACC can also be associated with fetus papyraceus or placental infarct. This is less likely in this case as only two embryos were transferred, and the pregnancy was dichorionic. Most cases of ACC associated with fetus papyraceus occur in monozygotic pregnancies. ACC lesions often heal spontaneously by re-epithelialization resulting in a hairless superficial scar. Twin one had a slightly smaller area affected by ACC and overlying eschar resolved several weeks after birth. Twin two has had no hair growth in the area. This case highlights the difficulties in ascertaining the aetiology of this rare condition in twin pregnancies.

Intestinal ischemia secondary to Covid-19.

With the wide spread of the current SARS-Cov (Covid-19), It was found that about 2% of children was affected according to several studies, it should be mentioned that Those children are most often asymptomatic, but the current concern is about a vascular inflammatory disease which is similar to Kawasaki disease observed in children with Covid-19. we report a case of a 9-year-old girl, known to have idiopathic medullar aplasia, admitted to the emergency department for a pseudo appendicular syndrome with shock, neurological abnormalities and skin lesions. She underwent an emergency surgery; the peroperative exploration suggested an ischemic bowel lesion of the ileal loop and a healthy appendix. The link involving a Covid-19 infection was well established (RT-PCR +). We shared in common our clinical, radiological, biological and pathological data to draw attention towards the intestinal vasculitis that can be a part in the MIS-C related to Covid 19. To our best knowledge, this is the first case encountered of combination between Covid-19 with intestinal ischemic in children.

[Analysis of anti-SARS-CoV-2 IgG antibody titers after mRNA booster vaccination in patients with nonmalignant hematological disorders].

In our facility, anti-SARS-CoV-2 mRNA vaccines were given to 21 patients, including 8 with aplastic anemia (AA), 3 with pure red cell aplasia (PRCA), and 10 with immune thrombocytopenic purpura (ITP), and IgG antibody titers were assessed one month after vaccinations. After receiving both a second vaccine and a booster shot, all patients with AA/PRCA treated with cyclosporine A aside from one, had IgG titers that were lower than the median levels of healthy controls. Even if prednisolone (PSL) doses did not go over 10 mg/day, ITP patients receiving PSL therapy were unable to achieve adequate levels of IgG after booster immunizations.

A fatal SARS-coronavirus-2 induced bone marrow aplasia complicated with invasive fungal infection and severe neutropenic enterocolitis.

BACKGROUND: Immunization against the coronavirus disease 2019 (COVID-19) began in January 2021 in Iran; nonetheless, due to a lack of vaccination among children under 12, this age group is still at risk of SARS-CoV-2 infection and its complications. CASE PRESENTATION: SARS-CoV-2 infection was diagnosed in a 6-year-old girl who had previously been healthy but had developed a fever and pancytopenia. The bone marrow aspiration/biopsy demonstrated just hypocellular marrow without signs of leukemia. She was worked up for primary and secondary causes of pancytopenia. Except for a repeated reactive HIV antibody/Ag P24 assay, all test results were inconclusive. After a thorough diagnostic investigation, the cross-reactivity of the HIV antibody/Ag P24 test with SARS-CoV-2 antibodies was confirmed. The patient did not develop any COVID-19-related signs and symptoms, but she did get a severe invasive fungal infection and neutropenic enterocolitis. She died as a result of disseminated intravascular coagulopathy. CONCLUSION: It is critical to recognize children infected with SARS-CoV-2 who exhibit atypical clinical manifestations of COVID-19, such as persistent pancytopenia. SARS-CoV-2 infection can cause severe and deadly consequences in children; thus, pediatricians should be aware of COVID-19's unusual signs and symptoms mimicking other conditions such as aplastic anemia.

Acquired pure red cell aplasia after severe acute respiratory syndrome corona virus 2 infection: a case report.

BACKGROUND: Coronavirus disease 2019, caused by severe acute respiratory coronavirus 2, has been responsible, since December 2019, for a severe pandemic resulting in millions of deaths worldwide, and the number is still increasing. Although coronavirus disease 2019 is mostly a respiratory syndrome, it is considered a multisystemic disease and shows clinical diversity with a wide range of manifestations including hematological features. CASE PRESENTATION: We present the case of an Arab male, 77 years old, who developed severe anemia 8 weeks after acute infection with severe acute respiratory coronavirus 2. The investigations revealed acquired pure red cell aplasia. Workup for an associated underlying disorder was negative, ruling out secondary causes. The patient received corticosteroids as the standard treatment of primary acquired pure red cell aplasia, and he had a good response to treatment. CONCLUSION: This case illustrates that acquired pure red cell aplasia might occur weeks after severe acute respiratory coronavirus 2 infection, suggesting that it might be considered a delayed complication of coronavirus disease 2019. The most relevant hypothesis of the pathogenesis of acquired pure red cell aplasia, in this case, is an immune mechanism triggered by infection with severe acute respiratory coronavirus 2 resulting in interruption of normal erythroid differentiation. We highlight the importance of follow-up care after the acute phase of coronavirus disease 2019 to spot late complications in order to successfully manage the secondary burden of the pandemic.

The efficacy and safety of second allogeneic hematopoietic stem cell transplantation

Background: Second allogeneic hematopoietic cell transplant (sAHCT) might be indicated following a graft failure or disease relapse after the first one;although it might emerge with high rates of morbidities and mortality. Currently, there is a limited number of publications on this matter in the literature, here we aimed to share our sAHCT experience from a single center. Methods: Data from 51 patients who were eligible for sAHCT between 2001 and 2021 was evaluated retrospectively. All data was obtained from the Ankara University Faculty of Medicine, Department of Hematology and Bone Marrow Transplant Unit. Results: 51 patients were included in the present study. Median age at sAHCT was 34 (18- 65) and female/ male ratio 19/ 32 (37.3% / 62.7%). The same donor from the first transplant was eligible for sAHCT for most patients (n= 46, 90.2 %). sAHCT indication was graft failure for 11 patients (21.6 %) whereas 40 (78.4 %) patient went on sAHCT for disease relapse. Patients' diagnoses were as follows: acute myeloid leukemia (n= 26, 50.9 %), acute lymphoblastic leukemia (n=9, 17.6 %), myelodysplastic syndrome (n= 6, 11.8 %), aplastic anemia (n= 6, 11.8 %) and others (CMML, CML, biphenotypic leukemia). Median number of transplanted CD34+ hematopoietic cells was 5.77 x x106/ kg (1.11- 8.29). Stem cell source was either bone marrow (n= 5, 9.8%) or peripheral blood (n= 46, 90.2 %). Myeloablative conditioning regimens were used for most sAHCTs (n= 30, 58.8%). Median overall survival (OS) rates for graft failure and disease relapse groups were 12.8 and 18.7 months, respectively (p= 0.63). During early transplant phase, 20 patients (39.2 %) died due to bone marrow aplasia, transplant failure or other complications. 1 year OS of the entire cohort was 33.3 % whereas 2-y- OS was 21.6% (95% CI= 25-45). 2 patients (3.9 %) died due to COVID19 during transplant process. On univariate analysis, sex, time from the first transplant (<12 months/ ≥12 months), conditioning intensity, sAHCT indication did not statistically significantly influence OS. Multivariate analysis confirmed a lower ECOG score (<2) at sAHCT significantly increased OS (p= 0.001). Conclusions: Based on this single center study, sAHCT is an efficacious treatment modality especially for patients with lower ECOG scores. sAHCT may offer long term survival for both graft failure and disease relapse states.

Peritoneal Rupture of Hematocolpos in Distal Vaginal Atresia

An adolescent girl with vaginal atresia, massive hematocolpos and bilateral hydroureteronephrosis presented with an acute abdomen secondary to spontaneous rupture of the hematocolpos into the cul-de-sac. Diagnosis, treatment, postoperative course and complications of this unique case are briefly summarized. Spontaneous rupture of hematocolpos into the abdominal cavity is an extremely rare manifestation of vaginal atresia. Tertiary care management, which involves a multidisciplinary team of experienced gynecologists, plastic surgeons, urosurgeons, and critical care physicians, is recommended for optimal management of these patients. Patient education is also crucial;regular follow-ups visits and strict adherence to the postoperative vaginal dilatation schedule can reduce risk of stenosis after vaginoplasty.

The burden of SARS-CoV-2 in patients receiving chimeric antigen receptor T cell immunotherapy: everything to lose.

INTRODUCTION: Chimeric antigen receptor T (CAR-T) cell immunotherapy has revolutionized the prognosis of refractory or relapsed B-cell malignancies. CAR-T cell recipients have immunosuppression generated by B-cell aplasia, leading to a higher susceptibility to respiratory virus infections and poor response to vaccination. AREAS COVERED: This review focuses on the challenge posed by B-cell targeted immunotherapies: managing long-lasting B-cell impairment during the successive surges of a deadly viral pandemic. We restricted this report to data regarding vaccine efficacy in CAR-T cell recipients, outcomes after developing COVID-19 and specificities of treatment management. We searched in MEDLINE database to identify relevant studies until 31 March 2022. EXPERT OPINION: Among available observational studies, the pooled mortality rate reached 40% in CAR-T cell recipients infected by SARS-CoV-2. Additionally, vaccine responses seem to be widely impaired in recipients (seroconversion 20%, T-cell response 50%). In this setting of B-cell depletion, passive immunotherapy is the backbone of treatment. Convalescent plasma therapy has proven to be a highly effective curative treatment with rare adverse events. Neutralizing monoclonal antibodies could be used as pre-exposure prophylaxis or early treatment but their neutralizing activity is constantly challenged by new variants. In order to reduce viral replication, direct-acting antiviral drugs should be considered.

Warm Autoimmune Hemolytic Anemia and Pure Red Cell Aplasia during a Severe COVID-19 B.1.1.7 Infection.

Warm autoimmune hemolytic anemia (AIHA) is a rare complication of COVID-19 infection. We report a case of warm AIHA in a patient with COVID-19 pneumonia treated with methylprednisolone and several red blood cell transfusions. Despite treatment of the warm AIHA, the patient's reticulocyte count remained low, and his biochemical markers were suggestive of pure red cell aplasia, which was later attributed to a concurrent parvovirus B19 infection. This case highlights an unusual situation of two separate hematological processes caused by two separate and simultaneous viral infections.

RELATO DE CASO: APLASIA MEDULAR SECUNDÁRIA A COVID-19

Introdução: Desde de dezembro de 2019, temos enfrentado a infecção pelo novo coronavírus (SARS-COV-2), causando repercussões diversas, que vão de síndrome respiratória aguda grave até formas assintomáticas. Uma hiperativação inflamatória parece estar associada a fenômenos autoimunes associada ao SARS-COV2. Se tratando de uma afecção emergente pouco se sabe dos fenômenos autoimunes induzidos pela infecção, sobretudo, patologias autoimunes hematológicas. Com esse intuito, o presente estudo vem relatar uma aplasia medular transitória em paciente internado pela infecção. Relato: Trata-se de paciente adulto, sexo masculino,52 anos, apresentando sintomas gripais e teste positivo para COVID-19, vinha em seguimento ambulatorial em uso de moxifloxacino, quando no 12°dia de sintomas foi internado em leito de terapia intensiva, após evolução com síndrome respiratória aguda grave (SRAG) e intubação orotraqueal. Iniciada terapia com dexametasona 10mg/dia, enoxaparina 40 mg de 12/12h SC, Ceftriaxona 1 g 12/12h. Intercorrendo após 10 dias de internação com disfunção renal, necessitando suporte dialítico. No 18°dia evoluindo com pancitopenia, sem sangramentos e sendo suspenso a profilaxia para tromboembolismo venoso (nesse momento era feita com heparina não fracionada devido a disfunção renal) e acionado o serviço de hematologia. Realizando seguimento diário com exames de sangue, e evoluindo para pancitopenia grave, com agranulocitose (neutrófilos: < 200). Exames Hb:7,90 Htc:22% VCM: 84,3 HCM: 30,30 GB:487 (Seg:194 — Lin:243 — Mon:49) Plaquetas: 50000. Havendo troca de esquema de antimicrobianos para Meropenem, Vancomicina e após 3 dias sem melhora clínica, introduzido Anfotericina B, e ampliado esquema antimicrobiano com associação de Polimixina B. Realizada biopsia de medula óssea com achados corroborando para hipótese de Aplasia de medula óssea. Afastados critérios para linfohistiocitose hemofagocítica e com sorologias negativas para outras infecções virais que sabidamente poderiam apresentar esse quadro. Após o 26°dia paciente iniciou melhora clínica e resolução espontânea da neutropenia, persistindo até o 30°dia com anemia e necessidade transfusional em raras ocasiões. Evolui com desmame ventilatório e recuperação da função renal, tendo alta após 45 dias de internação. Discussão: Acreditamos que a aplasia medular nesse caso foi associada a infecção pelo SARS-COV2, paciente que intercorreu com doença grave, necessidade de suporte ventilatório e acometimento sistêmico pela infecção. Dados da literatura trazem descrição de fenômenos imunes associados a infecção, como trombocitopenia imune, sem associação com linfohistiocitose ou coagulação intravascular disseminada. O mecanismo pelo qual os fenômenos imunes hematológicos ocorrem não estão claros.

LINFOMA PRIMÁRIO DE SISTEMA NERVOSO CENTRAL EM PACIENTE PEDIÁTRICO HIV POSITIVO: RELATO DE CASO

Relato: Paciente de 6 anos, HIV+, iniciou quadro com crise de ausência em jan/2021. Recebeu tratamento para encefalite com melhora clínica temporária. Evoluiu com cefaleia frontal de forma progressiva, desenvolvendo ataxia, afasia, vômitos em jato e novo episódio convulsivo após 1 mês da alta. RNM de crânio evidenciou lesão expansiva em hemisfério cerebral direito com compressão do 4° ventrículo e pequenas imagens nodulares difusas com edema cerebral. Realizou cirurgia para derivação ventricular externa e biópsia das lesões. Descartadas causas infecciosas, foi diagnosticado em mar/2021 com linfoma de células B de alto grau através de exame histopatológico. Estadiamento não evidenciou doença em outros sítios. Iniciou tratamento em mar/2021 com o protocolo NHL BFM 2012 associado a rituximabe. Após o bloco AAZ1 apresentou mucosite grau IV. Após BBZ1, evoluiu com mucosite grau III precoce, íleo paralítico, tiflite e infecção leve pelo SARS-CoV-2. RNM após 2 blocos de tratamento apresentando expressiva redução das lesões previamente identificadas. Após CCZ1 apresentou íleo paralítico e pneumonia, evoluindo com quadro de insuficiência respiratória grave e óbito. Discussão: Linfoma primário do SNC (LPSNC) é um tipo raro e agressivo de LNH, mais comum em pacientes imunodeficientes, que corresponde a 0,5–2% dos tumores primários de SNC e 0,7–0,8% de todos os linfomas. A incidência desse tipo de neoplasia na população pediátrica é desconhecida devido a raridade de casos reportados. Seu subtipo mais frequente é o linfoma difuso de grandes células B. O paciente em questão foi diagnosticado com Linfoma de células B de alto grau estádio IV, duplo expressor (myc e bcl2) através do histopatológico e imuno-histoquímica com Ki67 >95%, padrão menos comum em crianças. A co-expressão das proteínas MYC e BCL2 está associada a um pior prognóstico. Pacientes duplo-expressores têm idade média de 71 anos, apresentam pior performance-status, doença mais avançada e maior índice de proliferação Ki-67. O cenário ideal seria o rastreio de MYC, BCL2 e BCL6 em todos os pacientes com linfoma de alto grau no diagnóstico e, se positivo, a complementação por FISH para avaliação de double-hit, que já confere novas abordagens prognósticas e terapêuticas em adultos. Os principais fatores prognósticos do LPSNC são idade e performance status. O tratamento de primeira linha em crianças é baseado em quimioterapia (QT) com HD-MTX. O papel da radioterapia (RT) nesses pacientes é questionável. O estudo com maior número de casos pediátricos (29) mostrou sobrevida de 82% em 3 anos, apresentando melhores taxas que dos adultos (20–40% em 5 anos) e a maioria dos casos não fez RT. A adição do anticorpo monoclonal anti-CD20, Rituximabe, ao tratamento, foi baseada em estudos recentes realizados com crianças e adolescentes com LNH de células B maduras de alto grau. Houve remissão em 95% dos pacientes que usaram a terapia combinada (rituximabe e QT) com uma maior taxa de sobrevida livre de eventos em 3 anos quando comparado àqueles que receberam somente QT (95,1% vs. 87,3%). Devido a agressividade da doença, a intensificação do tratamento se faz necessária. O uso combinado do rituximabe com a poliquimioterapia, gera maior risco de toxicidade, principalmente mielotoxicidade. O paciente em questão teve boa resposta parcial ao tratamento, porém apresentou intercorrências graves durante os 3 períodos de aplasia pós QT, o que levou ao seu óbito.

Immune Responses to SARS-CoV-2 Vaccination in Young Patients with Anti-CD19 Chimeric Antigen Receptor T Cell-Induced B Cell Aplasia.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines are capable of inducing combined humoral and cellular immunity. Which effect is more relevant for their potent protective effects is unclear, but isolated T cell responses without seroconversion in healthy household members of individuals with Coronavirus disease 19 (COVID-19) suggest that T cell responses effectively protect against clinical infection. Oncologic patients have an outsize risk of unfavorable outcomes after SARS-CoV-2 infection and therefore were prioritized when vaccines first became available, although the quality of their immune response to vaccination was expected to be suboptimal, as has been confirmed in subsequent studies. Inherently, patients with anti-CD19 chimeric antigen receptor (CAR) T cell therapy-mediated B cell aplasia would be incapable of generating humoral responses, so that assessment of the vaccine-induced cellular immunity is all the more important to gauge whether the vaccine can induce meaningful protection. A salient difference between T cell and humoral responses is the former's relative impassiveness to mutations of the antigen, which is more relevant than ever since the advent of the omicron variant. The objective of this study was to assess the immune cell composition and spike protein-specific T cell responses before and after the first and second doses of SARS-CoV-2 mRNA vaccine in a cohort of juvenile CD19 CAR T cell therapy recipients with enduring B cell aplasia. The prospective study included all patients age >12 years diagnosed with multiply relapsed B cell precursor acute lymphoblastic leukemia and treated with anti-CD19 CAR T cell (CAR-T19) therapy in our center. The primary endpoint was the detection of cell-mediated and humoral responses to vaccine (flow cytometry and anti-S immunoglobulin G, respectively). Secondary endpoints included the incidence of vaccine-related grade 3 or 4 adverse events, exacerbation of graft-versus-host disease (GVHD), relapse, and the influence of the vaccine on CAR T cells and lymphocyte subsets. Even though one-half of the patients exhibited subnormal lymphocyte counts and marginal CD4/CD8 ratios, after 2 vaccinations all showed brisk T-cell responsiveness to spike protein, predominantly in the CD4 compartment, which quantitatively was well within the range of healthy controls. No severe vaccine-related grade 3 or 4 adverse events, GVHD exacerbation, or relapse was observed in our cohort. We posit that SARS-CoV-2 mRNA vaccines induce meaningful cellular immunity in patients with isolated B cell deficiency due to CAR-T19 therapy.

APLASIA GRAVE DE MEDULA ÓSSEA EM REMISSÃO COMPLETA APÓS TRANSPLANTE DE MEDULA ÓSSEA COM DOADOR HAPLOIDÊNTICO (PAI)- RELATO DE CASO

Introdução: A aplasia de medula óssea grave (AAG) adquirida é uma doença rara e de origem desconhecida (80% dos casos). É caracterizada por pancitopenia e medula óssea (MO) hipocelular na ausência de infiltração anormal de células na medula ou aumento da trama de reticulina. Trata-se de doença com alta mortalidade e necessidade de intervenção precoce em serviço especializado. Para o diagnóstico de AAG faz-se necessário avaliação da celularidade da MO por biópsia (<25–30% celularidade);além de 2 de 3 critérios no sangue periférico: Neutrófilos <500/uL;plaquetas <20.000/uL e reticulócitos <60.000/uL(1%). O transplante de MO com doador aparentado (irmão) deve ser inicialmente indicado para todos os pacientes com AAG adquirida. Na ausência desse doador é recomendado terapia imunossupressora;e naqueles pacientes sem resposta ou com perda de resposta uma das opções é a escolha de doador alternativo. Relato do caso: J.F.S., 15 anos, atendida em 05/03/2017 no pronto atendimento com queixa de dor abdominal difusa e astenia. Hemograma da admissão com pancitopenia e USG abdominal total com esplenomegalia leve. Dosagens de vitamina B12, ácido fólico, ferritina, DHL, sorologias virais e triagem reumatológica normais. Realizada Biópsia de MO que revelou intensa hipocelularidade geral (<5 % de tecido hematopoético). Cariótipo: 46 XX sem anormalidade. Pesquisa de HPN e Deb test para anemia de fanconi negativos. HLA do irmão não revelou compatibilidade sendo imediatamente inscrita no Rereme (Registro Nacional de Receptores de Medula Óssea). Paciente evoluiu com piora da pancitopenia (Hb 6,0, neutrófilos 483, Plaq 16mil) e alta necessidade transfusional. Em 5/07/2017 foi submetida ao protocolo de imunosupressão com Thymoglobulina de coelho /corticoide /Ciclosporina. Após 2 meses apresentou resposta parcial com neutrófilos >500 e plaquetas >20mil e independência transfusional. A Ciclosporina foi mantida até março de 2019. Paciente ficou estável até out de 2019 quando progrediu com pancitopenia e necessidade transfusional principalmente de plaquetas, porém evoluiu com reações anafiláticas à transfusão de plaquetas além de pouco incremento plaquetário, mantendo plaquetas <10 mil. Em 12/02/2020, diante desse cenário de dificuldade transfusional (refratariedade e reação anafilática) e manutenção de plaquetopenia grave, optou-se por Eltrombopag, com dose máxima de 250mg/dia também com reposta insatisfatória após 11 meses (mantinha plaquetas <10 mil). Neste momento (pandemia COVID-19) nos foi sinalizado pelo Rereme doador compatível 9×10. O serviço de transplante, convocou o pai da paciente e optou-se pelo transplante de MO alogênico com doador haploidêntico (pai) que ocorreu em 12/03/2021. A paciente evoluiu com remissão completa da doença e atualmente apresenta-se assintomática com hemograma normal (Hb 12,5, Neutrófilos 3500, Plaq 274 mil). Discussão e considerações finais: O transplante de MO através de doador irmão HLA compatível é o tratamento de escolha para paciente com AAG. Esse relato nos mostra que dentro as duas opções disponíveis (pai haploidêntico e doador Rereme não aparentado 9×10) o pai foi o escolhido como doador e obtivemos remissão completa da doença. Uma das hipóteses para tal escolha também inclui a dificuldade de viabilizar a medula de doador não aparentado em um momento pandemia mundial de COVID-19.

Transient erythroblastopenia of childhood and COVID-19 infection: a case report

Aim: Emphasize the importance of including transient erythroblastopenia of childhood in the differential diagnosis of anemia in a previously healthy young child, aiming to avoid unnecessary diagnostic and therapeutic interventions, and describe the influence of SARS-CoV-2 virus infection on the course and outcome of the disease. Case report: A two-and-a-half-year-old girl was referred to the emergency hospital department due to severe anemia. On admission, she was in good general condition, asymptomatic, with pale skin and mucous membranes, and no other abnormalities. Previous and family history were negative. Repeated findings confirmed isolated severe normocytic normochromic anemia. Spontaneous recovery was observed. Intercurrent COVID-19 infection with associated neutropenia and thrombocytopenia the course but not the favorable outcome of the disease. Transient erythroblastopenia of childhood was diagnosed, with complications due to COVID-19 infection. The treatment was supportive. She was followed up on an outpatient basis, until complete recovery of anemia two months after hospitalization. Conclusion: Transient erythroblastopenia of childhood is an acquired self-limiting disorder, characterized by anemia and reticulocytopenia due to temporary suppression of erythropoiesis in a previously healthy child. The evaluation should be focused on excluding other causes of anemia. COVID-19 infection does not affect a favorable outcome of the disease. © 2022, Croatian Medical Association. All rights reserved.

Impaired mRNA Based COVID-19 Vaccine Response in Patients with B-Cell Malignancies after CD19 Directed CAR-T Cell Therapy

Introduction: Patients with hematologic malignancies are at an increased risk of morbidity and mortality from COVID-19 disease (Vijenthira, Blood 2020). This is likely a result of combination of immunodeficiency conferred by the disease and the therapeutics. The immunogenicity of the COVID-19 vaccines in patients with exposure to CD19 directed Chimeric Antigen Receptor (CAR)-T cell therapy is not established. CD19 CAR-T cell therapies cause B-cell aplasia, which in turn can affect humoral immune response against novel antigens. Herein, we present results from our prospectively conducted clinical study to evaluate immune responses against mRNA based COVID-19 vaccines in patients with lymphoma who have received CD19 directed CAR-T cell therapy. Methods: All patients and healthy controls were enrolled in a prospective clinical study evaluating immune responses against commercial COVID-19 RNA vaccines in patients with hematologic malignancies. Plasma samples were generated from heparinized peripheral blood of 4 heathy controls (HCs) receiving the same vaccines and 19 B cell lymphoma patients treated with CD19 CAR- T cells. Samples from ~4 weeks post second dose of the vaccine (d56) were available for 14 CAR-T patients, for 5 CAR-T patients samples were available from ~4 weeks after the first dose (d28). Plasma samples were analyzed in an enzyme-linked immunosorbent assay (ELISA) using different full-length recombinant SARS-CoV-2 proteins and control proteins. Neutralizing activity was measured using the cPass Neutralization Antibody Detection Kit (GenScript Biotech). Results: Results from 4 healthy controls and 19 patients (12 males and 7 females) with lymphoma are reported. Median age for the lymphoma patients is 65 years. Eleven patients had large B cell lymphoma, 5 had follicular lymphoma and 3 had mantle cell lymphoma as primary diagnoses. Seventeen patients had advance stage disease (III/IV stage) and had received a median of 3 prior lines of therapy. All patients received CD19 directed CAR-T cell therapy. Ten patients received Moderna vaccine and 9 received Pfizer vaccine. Median time between CAR-T infusion and first COVID-19 vaccine was 258 days. While the peripheral blood plasma from 3/4 HCs already showed substantial SARS-CoV-2 neutralizing activity at ~4 weeks after the first dose of COVID-19 mRNA vaccine, none of the 5 CD19 CAR-T patients analyzed evidenced any antibody-mediated neutralizing activity in their blood at the same point in time (Figure 1A). Around 4 weeks after receiving the second dose of the vaccine, all 4 HCs tested evidenced complete or almost complete neutralizing activity (Figure 1B). In marked contrast, only 1 out of 14 CAR-T patients analyzed evidenced any relevant antibody-mediated SARS-CoV-2 neutralizing activity in their blood (Figure 1B). Interestingly, when we asked whether a globally insufficient antibody-mediated immunity was the underlying cause of the lack of a response to the COVID-19 vaccine in our CAR-T patients, we found that that was clearly not the case since anti-Flu, -TT, and -EBV responses were equivalent to the ones observed in HCs (Figure 2A). However, while at ~4 weeks post second dose of the vaccine the HCs showed marked antibody titers against all the viral spike proteins including their “delta” variants (Figure 2B), that was not the case for our CAR-T patients. The vast majority of our CAR-T patients did not evidence IgG antibody responses against any of the SARS-CoV-2 proteins analyzed such as S1, S1 delta, RBD, RBD delta, or S2 (Figure 2B). Conclusion: In this prospectively conducted clinical study, 18 of 19 patients with lymphoma who have received CD19 CAR-T therapy had poor immunogenicity against mRNA based COVID-19 vaccines as measured by neutralization assays and antibody titers. The antibody titers against B.1.617.2 (delta variant, S1 and RBD protein) were also demonstrably poor. The antibody response to common pathogens (flu, EBV, TT) were preserved, suggesting impaired immune response against novel antigens. Long-term follow-up of this study is ongoin . APR and DJ contributed equally [Formula presented] Disclosures: Dahiya: Kite, a Gilead Company: Consultancy;Atara Biotherapeutics: Consultancy;BMS: Consultancy;Jazz Pharmaceuticals: Research Funding;Miltenyi Biotech: Research Funding. Hardy: American Gene Technologies, International: Membership on an entity's Board of Directors or advisory committees;InCyte: Membership on an entity's Board of Directors or advisory committees;Kite/Gilead: Membership on an entity's Board of Directors or advisory committees.

A Comparative Outcome Analysis of COVID-19 and Influenza Infection in Patients with Hematological Malignancies

Introduction: Patients with hematological malignancies and concomitant SARS-CoV-2 infection suffer from a more severe course of their infection than patients without underlying concomitant disease. Similar observations have been made for concomitant influenza infections. The aim of this retrospective study is to compare the clinical courses of COVID-19 and seasonal influenza in patients with hematological malignancies. Methods: In this retrospective, single center analysis all patients with hematological malignancies aged 18 years and older were included with a laboratory confirmed SARS-CoV-2 or influenza A or B infection who were admitted or were already under treatment at the Department of Oncology and Hematology or at the Department of Stem Cell Transplantation at the University Medical Center Hamburg-Eppendorf, Germany, between January 2012 and January 2021. Primary and secondary endpoints of this study are the rate of acute respiratory distress syndrome (ARDS) and virus-associated 30- and 90-day mortalities. The retrospective data collection was performed in accordance with local legal requirements and was reviewed and approved by the Ethics Committee of the Medical Council of Hamburg. Results: A total of 79 patients were included in this study. 29 patients had laboratory confirmed SARS-CoV-2 infection and 50 patients had influenza A or B infection. 69% in the COVID-19 group and 68% in the influenza group were male. Median age in the COVID-19 group were 59 years vs 58.5 years in the influenza group. Distribution of hematological malignancies in the COVID-19 group was as follows: 59% had acute leukemia (AL), 24% malignant lymphoma, 14% multiple myeloma (MM) and 3% myelodysplastic syndrome (MDS). 89% of the patients with concomitant SARS-CoV-2 diagnosis were currently under treatment with chemotherapy, CD20 or CD38 antibody-therapy, underwent allogeneic stem cell transplantation (SCT) or received CAR-T-cells shortly before (< 2 months) or during SARS-CoV-2 positivity. In the influenza group, 60% had AL, 8% lymphoma, 24% MM and 8% MDS or myeloproliferative neoplasm. 84% of these patients were under treatment with chemotherapy, CD33-, CD38- or SLAMF7-directed antibodies or underwent allogeneic SCT shortly before or during infection with seasonal influenza. At the time of infection, 41% of all SARS-CoV-2 positive patients were in refractory or relapsed setting compared to 42% in the influenza group whereas 28% in the COVID-19 and 36% in the influenza cohort were in complete remission. At the time of SARS-CoV-2 detection 38% of patients had grade IV neutropenia (defined as neutrophil count <0.5 x 10 9/L) with a median duration of 3.5 days which is comparable to 33% of patients and a median neutropenia duration of three days in the influenza group. The incidence of ARDS was significantly higher in the COVID-19 group compared to the influenza group (48% vs. 14%, p = 0.001). Furthermore, virus infection related 30-day and 90-day mortality was significantly higher in the COVID-19 group (28% vs. 8%, p = 0.026 and 41% vs. 12%, p = 0.005). In the COVID-19 group, a duration of aplasia ≥ 7 days had no negative impact on 90-day mortality or development of an ARDS (p = 0.599 and 0.982 respectively) whereas in the patients infected with influenza A or B, an aplasia ≥ 7 days had a negative impact on 90-day mortality and development of ARDS (p < 0.001 each). Conclusion: Based on our results, we conclude that comparable to the general population, infections with SARS-CoV-2 result in a significantly higher rate of ARDS and a significantly higher 30- and 90-day mortality compared to influenza A or B infections in patients with underlying hematological malignancies. Disclosures: Weisel: Adaptive: Consultancy, Honoraria;Amgen: Consultancy, Honoraria, Research Funding;BMS: Consultancy, Honoraria;Celgene: Consultancy, Honoraria, Research Funding;Janssen: Consultancy, Honoraria, Research Funding;GSK: Consultancy, Honoraria;Karyopharm: Consultancy, Honoraria;Takeda: Consultancy, Honoraria;Sanofi: Consultancy, Honoraria, Resear h Funding. Bokemeyer: Gilead Sciences: Research Funding;Bayer Schering Pharma: Consultancy;Merck Serono: Consultancy, Other: Travel accomodation;AOK Health insurance: Consultancy;Alexion Pharmaceuticals: Research Funding;Agile Therapeutics: Research Funding;ADC Therapeutics: Research Funding;Abbvie: Research Funding;GSO: Consultancy;Lilly/ImClone: Consultancy;Amgen: Research Funding;Apellis Pharmaceuticals: Research Funding;Astellas: Research Funding;BerGenBio: Research Funding;Blueprint Medicine: Research Funding;Boehringer Ingelheim: Research Funding;Celgene: Research Funding;Daiichi Sankyo: Research Funding;Eisai: Research Funding;Gylcotope GmbH: Research Funding;GlaxoSmithKline: Research Funding;Inside: Research Funding;IO Biotech: Research Funding;Isofol Medical: Research Funding;Janssen-Cilag: Research Funding;Sanofi: Consultancy, Honoraria, Other: Travel accomodation;Merck KGaA: Honoraria;Roche: Honoraria, Research Funding;Merck Sharp Dohme: Consultancy, Honoraria;AstraZeneca: Honoraria, Research Funding;BMS: Honoraria, Other: Travel accomodation, Research Funding;Bayer: Honoraria, Research Funding;Karyopharm Therapeutics: Research Funding;Lilly: Research Funding;Millenium: Research Funding;MSD: Research Funding;Nektar: Research Funding;Rafael Pharmaceuticals: Research Funding;Springworks Therapeutics: Research Funding;Taiho Pharmaceutical: Research Funding;Pfizer: Other. Fiedler: Novartis: Honoraria;Pfizer: Consultancy, Honoraria, Research Funding;Daiichi Sanyko: Consultancy, Other: Meeting attendance, Preparation of information material;Stemline: Consultancy;Servier: Consultancy, Other: Meeting attendance, Preparation of information material;MorphoSys: Consultancy, Honoraria;Jazz: Consultancy, Honoraria, Other: Meeting attendance, Preparation of information material;Celgene: Consultancy, Honoraria;Ariad/Incyte: Honoraria;Amgen: Consultancy, Honoraria, Other: Meeting attendance, Preparation of information material, Patents & Royalties, Research Funding;Abbvie: Consultancy, Honoraria, Other: Meeting attendance, Preparation of information material. Modemann: Teva: Other: Travel accomodation;Novartis: Other: Travel accomodation;Jazz Pharmaceuticals: Other: Travel accomodation;Gilead: Other: Travel accomodation;Incyte: Other: Travel accomodation;Servier: Honoraria, Other: Travel accomodation;Pfizer: Other: Travel accomodation;Amgen: Other: Travel accomodation;Daiichi Sankyo: Research Funding;Abbvie: Honoraria, Other: Travel accomodation.

Profound B-Cell Lymphopenia Is a Major Factor Predicting Poor Humoral Response after BNT162b2 mRNA Sars-Cov-2 Vaccines in Recipients of Allogeneic Hematopoietic Stem Cell Transplantation

Background Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection results in poor outcome in patients with hematologic malignancies. Moreover, the efficacy of anti-SARS-CoV-2 mRNA vaccines appears lower in immunocompromised patients, including recipients of allogeneic stem cell transplantation (Allo-HSCT). In this population, data are scarce regarding factors predicting the response to mRNA vaccines. Methods This retrospective study aimed to decipher which factors, including immune status at time of vaccine and recipient/donor blood groups, might influence the antibody response after two injections (V1 and V2) of BNT162b2 (Pfizer-BioNTech) vaccine in a cohort of allografted patients with no previous symptomatic nor asymptomatic COVID-19 infection. Possible previous asymptomatic COVID-19 infection was investigated in pre-V1 samples by testing for anti-nucleocapsid (N) antibodies (anti-SARS-CoV-2 immunoassay, Roche Elecsys®, Rotkreuz, Switzerland). Antibody response to the SARS-CoV-2 spike protein receptor-binding domain was tested post-V2 (Roche Elecsys®). As recommended by the manufacturer, titers ≥0.8 U/mL were considered positive, the highest value being >250 U/mL. Blood samples were also collected before V1 and at distance from V2 to evaluate, by flow cytometry, total lymphocyte (Ly) counts and quantitative Ly subsets (CD3, CD4 and CD8 T cells, B and NK cells). Statistical analyses were performed on R (version 4.0.3). Patient characteristics were compared by using the Χ² test for discrete variables and the Wilcoxon test for continuous variables. Generalized linear models were used to conduct multivariate analyses. Results Samples were available from 117 Allo-HSCT patients who had been vaccinated between January 20 and April 17, 2021. Patient characteristics are provided in Table 1. The average interval from Allo-HSCT day 0 (D0) to V1 (D0-V1) was 654 (IQR: 372-1367) days (d). S-antibody response rate post-V2 was 82.9% for the entire cohort. Non-humoral responders (NHR) post-V2 (n = 20) had a lower D0-V1 interval (median 271 vs 914 d, p <10 -5) and a lower pre-V1 median total Ly count (0.62 vs 1.61x10 9/L, p < 10 -4). Lymphocyte subsets possibly predictive of antibody response were then investigated. NHR were associated with lower median CD3 (0.39 vs 0.97 x10 9/L, p = 0.01), CD4 (0.13 vs 0.35 x10 9/L, p=<10 -3), and B-cell (0.00 vs 0.28 G/L, p <10 -6) counts. NK and T CD8 counts were not statistically different between NHR and HR (respectively p=0.14 and p=0.06). No influence either was observed when considering the age of donors (p=0.39) or recipients (p=0.55), underlying disease (p=1), Allo-HSCT conditioning (p=0.11), blood groups (donor, p=0.55;receiver, p=0.39) or a previous history of graft versus host disease (GVHD;83.1 vs 83.6%, p=1). Conversely, ongoing immunosuppressive (IS)/chemotherapy treatment and a haploidentical source of graft were associated with lower responses to vaccination (respectively 62.5 vs 90.5%, p<10 -3, and 69.4 vs 88.6% for patients with matched donors, p=0.02). In multivariate analysis (Fig.1) also including D0-V1 interval, donor source, current IS/chemotherapy treatment and TCD4 Ly count, only B cell aplasia remained statistically associated with lack of antibody response after two vaccine injections (OR 0.01, 95%CI [0.00 - 0.10], p <10 -3). The possible modification in terms of lymphocyte counts between pre-V1 and post-V2 times has been also investigated showing that only CD4 lymphocytes counts improved significantly (0.31 vs 0.34 x10 9/L, p=0.01) between this interval. Conclusion B cell aplasia appears as a major predictor of anti SARS-CoV-2 mRNA vaccine failure after Allo-HSCT. It may be suggested from this result that a close immune monitoring should be proposed after allotransplant to propose the vaccine at the most appropriate time, meaning after of B cell detection, regardless of the delay from Allo-SCT or the presence of an IS/chemotherapy treatment. The possibility for these patients to have mounted a cellular response should also be considered, which was not investigated here. [Formula presented] Disclosures: Moreau: Celgene BMS: Honoraria;Sanofi: Honoraria;Abbvie: Honoraria;Oncopeptides: Honoraria;Amgen: Honoraria;Janssen: Honoraria.

COVID-19 in Children, Adolescents and Young Adults with Hematological Malignancies

Background: COVID-19 in adults with cancer results in substantial rates of severe infection (>25%) and death (13%) that are more than two-fold those in adults without cancer. Data from a few cohorts of COVID-19 in children with cancer, most of whom had leukemia, suggest low hospitalization rates (<10%) for COVID-19 in pediatric cancer. However, among pediatric patients with hematological cancers, there is a paucity of data regarding COVID-19 in adolescent and young adults (AYA) or recipients of hematopoietic stem cell transplantation (HSCT) or chimeric antigen receptor T-cell (CAR-T) therapies. This study aims to define outcomes in COVID-19 in children and AYA with hematologic cancers receiving HSCT, CAR-T, or chemotherapy. Methods: We retrospectively reviewed medical records of patients aged 25 years and younger treated at Children's Hospital Los Angeles for a hematological cancer between March 2020 and March 2021. These patients underwent COVID-19 nasopharyngeal (NP) PCR prior to any sedation, hospitalization, or in case of symptoms suggestive of COVID-19 infection. COVID-19 related hospitalizations were defined as hospital stays due to COVID-19 manifestations that necessitated inpatient care and excluded those that were solely for febrile neutropenia. Results: We identified a cohort of 56 patients with PCR positive COVID-19 infection. The infected cohort had a median age of 11.5 years (2-24 years). A majority of the cohort was of Hispanic ethnicity (n=38, 67%), and 40% (n=22) were overweight or obese. 53 had leukemia (49 lymphoid, 2 acute myeloid, and 2 chronic myeloid), and 3 had lymphoma. Anti-cancer therapy included chemotherapy only (n=40), CAR-T (n=6), HSCT (n=6) or both HSCT and CAR-T (n=4).The median time from malignancy diagnosis to COVID-19 for the chemotherapy cohort was 11 months (0-119 months.) Median time from HSCT or CAR-T was 15 months (2-59 months.) 29 patients were in a highly immunosuppressive phase of anti-cancer therapy. 44 (79%) had symptomatic COVID-19. 18 (32%) patients required inpatient care for COVID-19 (COVID-19 related hospitalization.) 6 had critical/severe, 6 had moderate, and 44 had mild infection (WHO Criteria.) For patients with non-severe infection, the reasons for hospitalization were dehydration and tachycardia requiring intravenous fluids. All patients with critical/severe infection developed hypoxia;5 required intensive care admission. One required invasive ventilation. Two patients had multisystem inflammatory syndrome;both had received CAR-T. Only one patient developed a new thrombus during COVID-19 infection. COVID-19 therapies included Remdesivir (n=9), steroids (n=5), convalescent plasma (n=3), azithromycin (n=2), hydroxychloroquine (n=1), and monoclonal antibodies (n=1.) 4 patients underwent multiple (2-6) COVID related hospitalizations. Factors associated with a higher risk for COVID related hospitalization included recent steroid exposure (p=0.006), neutropenia (p=0.04), and lymphopenia (p=0.005.) Obesity or HSCT were not associated with a higher risk for hospitalization. 3 of 6 CAR-T recipients with B-cell aplasia had severe/critical infection, one of whom required 6 hospitalizations for COVID-19 and was COVID-19 PCR positive for 212 days. COVID-19 resulted in chemotherapy delays in 11 of 40 patients (delays ranged 2-39 days, median=14 days.) Conclusions: While there was no mortality from COVID-19, in contrast to other pediatric cancer studies, several patients required recurrent hospitalizations, and there was a substantially higher COVID-19 related hospitalization rate in our cohort. Differences in demographics and immunosuppression between our and other studies may account for this discrepancy. Neutropenia, lymphopenia, and exposure to steroids were predictive of higher risk for hospitalization. Our data suggest higher severity of COVID-19 infections in CAR-T recipients with B-cell aplasia raising the possibility of an increased risk for COVID-19 morbidity in the setting of hypogammaglobulinemia. In contrast to studies reported from the general population, obes ty was not associated with worse COVID-19 outcomes in our cohort of pediatric patients with cancer. Ongoing studies entail collection of retrospective clinical data and prospective clinical and immune biomarker data from additional patients. Disclosures: Parekh: Amgen: Other: spouse is employee and owns stock;PLUTO: Other: early investor.