Preliminary safety of Bcl-2 inhibitor BGB-11417 in relapsed/refractory multiple myeloma Harbouring t(11,14): Phase 1b/2 study

Background: B-cell lymphoma-2 (Bcl-2) proteins play an important role in multiple myeloma (MM) cell survival and represent an attractive therapeutic target. In prior trials, a subgroup analysis of patients with t(11;14)-positive relapsed/refractory (R/R) MM showed the combination of a Bcl-2 inhibitor, a proteasome inhibitor, and dexamethasone improved progression-free survival with no increased mortality. BGB-11417, a Bcl-2 inhibitor, is more potent and selective than venetoclax. BGB-11417- 105 (NCT04973605) is a phase 1b/2 study assessing the safety and efficacy of BGB-11417 monotherapy, in combination with dexamethasone, or with dexamethasone+carfilzomib in patients with t(11;14)-positive R/R MM. Preliminary safety results for the combination of BGB-11417 + dexamethasone are presented. Method(s): Eligible patients had t(11;14)-positive R/R MM and had been exposed to a proteasome inhibitor, immunomodulatory agent, and anti-CD38 therapy. Patients received 80-, 160-, 320-, or 640-mg BGB-11417 daily with 40-mg dexamethasone weekly until death, intolerability, or disease progression. Dose escalation was guided by a mTPI-2 design and overall review by a safety monitoring committee. Pharmacokinetics (PK) were also assessed. Result(s): As of 1 July 2022, 10 patients were enrolled in the 80-, 160-, and 320-mg (3 patients each) and 640-mg (1 patient) dose-escalation cohorts of BGB-11417 + dexamethasone. The median age was 69 years (range, 52-81) and median prior lines of therapy was 3 (range, 1-5). The median treatment duration was 3.2 months (range, 0.5-6.5). No patients experienced dose-limiting toxicity at any dose level. Three patients died whilst on study: 1 due to COVID-19 complications 157 days after treatment discontinuation (day 208), 1 due to progressive disease 50 days after treatment discontinuation (day 89), and 1 due to COVID-19 whilst on study treatment (day 78). No deaths were associated with study treatment. Two patients experienced Grade >= 3 treatment-emergent adverse events (TEAEs). One patient in the 160-mg cohort experienced Grade 3 increase in liver enzymes and lymphopenia. One patient in the 320-mg cohort experienced Grade 3 lymphopenia. The most common TEAEs were insomnia (50%), fatigue (30%), arthralgia (20%), back pain (20%), lymphopenia (20%), and nausea (20%). BGB-11417 exposure increased dose-dependently from 80 mg to 320 mg with high interpatient PK variability. BGB-11417 exposures after single and multiple doses appeared similar, indicating limited accumulation. Conclusion(s): BGB-11417 plus dexamethasone was generally well-tolerated in patients with R/R MM harbouring t(11;14) at doses <=640 mg. Efficacy data are forthcoming. Recruitment is ongoing in the US, Australia, and New Zealand;the BGB-11417, dexamethasone, and carfilzomib combination arm will open in the future.

Combinacao Bem Sucedida De Azacitidina E Venetoclax: Mudando Paradigmas No Tratamento De Leucemia Mieloide Aguda E Sindrome Mielodisplasica

Objetivos: O Venetoclax tem como alvo a proteina BCL-2. Aprovado para LLC, mostrou eficacia tambem LMA em combinacao com agentes hipometilantes como a Azacitidina. No ultimo ano, tivemos experiencias bem-sucedidas com a utilizacao desta associacao. Selecionamos 4 casos representativos de LMA e SMD para relatar nossa experiencia com este protocolo e desfechos obtidos. Material e Metodos: As informacoes foram obtidas por meio de revisao do prontuario. Resultados: Caso 1 - E.Q.O., 42 anos, sexo feminino, diagnosticada em janeiro de 2019 com LMA, evoluiu com 3 recidivas, quando foi optado pela associacao de Azacitidina e Venetoclax. Realizou ciclos com boa evolucao. Caso 2 - F.G.S., 72 anos, sexo feminino, historico de Linfoma Folicular EIIA em 2003. Em janeiro de 2021 recebeu diagnostico de LMA. Houve associacao de Azacitidina e Venetoclax como tratamento. Foram realizados 2 ciclos sem intercorrencias. Entretanto, antes do terceiro ciclo, a paciente relatou sindrome gripal, com diagnostico de COVID-19 e evoluiu a obito. Caso 3 - J.W.L.L., 37 anos, sexo masculino, em agosto de 2020 foi diagnosticado com SMD. Evolui com remissao e melhora significativa das citopenias de base. Foi submetido a TCTH nao aparentado com sucesso em julho de 2021, com enxertia no D+16 e internacao sem intercorrencias. Caso 4 - Paciente de 72 anos, sexo masculino, com diagnostico de SMD com excesso de blastos. Iniciou protocolo com Azacitidina associado a Venetoclax, persistia com elevada necessidade transfusional. Houve reducao das dosagens no segundo ciclo. O paciente evoluiu com melhor tolerabilidade, mantendo padrao transfusional. Manteve dose de Azacitidina e ajustada novamente dose de Venetoclax. Apos o quarto e quinto ciclos, paciente retornou com melhora significativa de indices hematimetricos O mielograma estava normal, bem como a imunofenotipagem e o cariotipo. Discussao: Apresentamos aqui 4 casos distintos de indicacao bem-sucedida da associacao entre Azacitidina e Venetoclax. A dose padrao utilizada foi de 75 mg/m2/dia de Azacitidina, do D1 ao D7 e 100 mg/dia de Venetoclax, com escalonamento progressivo ate atingir 400 mg/dia, do D1 ao D28. O caso 1 descreve paciente com doenca refrataria. Na literatura, esse perfil de pacientes tem beneficio importante com essa combinacao. Em nossa pratica clinica, o ajuste de dose ou duracao do Venetoclax e/ou espacamento entre os ciclos tem se mostrado uma alternativa viavel para minimizar os impactos da neutropenia. O caso 2 refere-se a paciente idosa, com mutacao do NPM1, sem status performance para quimioterapia intensiva, em primeira linha de tratamento. O impacto favoravel da mutacao NPM1 tende a reduzir em pacientes idosos (>65 anos). Nos casos 3 e 4 relatamos pacientes com SMD. Os bons resultados de Azacitidina e Venetoclax em LMA levaram os pesquisadores a avaliar a combinacao em pacientes com SMD de alto risco. Conclusao: A escolha do tratamento depende em grande parte da idade do paciente, status performance, remissao, caracteristicas geneticas e moleculares.A quimioterapia de baixa intensidade, em especial a associacao de Azacitidina com Venetoclax e uma opcao viavel, mesmo em pacientes com recidiva multipla/doenca refrataria ou naqueles com baixo status performance. Tambem aparenta ser promissora nos casos de SMD de alto risco. Os efeitos adversos mais frequentes dizem respeito as infeccoes decorrentes da neutropenia prolongada, mas nos 4 casos relatados, os pacientes evoluiram com estabilidade. Copyright © 2022

Eficacia Do Tratamento Baseado Em Venetoclax Em Paciente Jovem Com Leucemia Mieloide Aguda Recidivada Candidato a Transplante De Medula Ossea Alogenico

Introducao: A Leucemia Mieloide Aguda (LMA) e uma doenca agressiva, e em geral, de prognostico reservado. O tratamento com intuito curativo e realizado com altas doses de quimioterapia, seguido ou nao por transplante de medula ossea (TMO) alogenico. Porem, a recidiva ainda representa um desafio a ser superado, levando a busca de novas opcoes terapeuticas, como o inibidor de bcl-2, Venetoclax. Objetivo: Relatar o caso de um paciente jovem com LMA recidivada com resposta ao tratamento baseado em Venetoclax, seguido por TMO alogenico. Metodo: Levantamento de dados do prontuario e revisao da literatura. Relato do caso: VSV, sexo masculino, 21 anos, diagnosticado com LMA em 18/02/2020, mielograma com 60,4% blastos, com fenotipo CD45+ intermediario;CD34+;CD13+;CD33 parcial;CD64 parcial;HLA-DR parcial;MPO parcial e cariotipo 46, XY [20]. Sem possibilidade de avaliacao molecular da doenca. O paciente recebeu tratamento de inducao padrao (D3A7) atingindo remissao completa apos um ciclo e seguindo com consolidacao com 3 ciclos de ARA-C 3g/m2 ate maio de 2020 (optou-se por nao realizar o 4ciclo devido a pandemia por COVID19). Apresentava doenca residual minima (DRM) negativa em reavaliacao medular de agosto de 2020, mantendo-se ate junho de 2021, quando apresentou recidiva com 33,8% de blastos em imunofenotipagem de reavaliacao. Internado em julho de 2021 para QT de resgate com FLAG, evoluiu com choque septico e insuficiencia respiratoria, sendo necessario suporte em unidade de terapia intensiva. Apos recuperacao clinica, obteve novamente DRM negativa, sendo encaminhado para TMO alogenico aparentado (irma "full match"). Entretanto, enquanto aguardava o transplante, apresentou nova recidiva (IF com 5,4% de blastos), sendo optado por tratamento com Venetoclax + Azacitidina, com reducao de DRM para 1,5%. Recebeu o segundo ciclo de Venetoclax combinado com citarabina, devido a indisponibilidade da Azacitidina, seguido por DRM negativa. O paciente foi submetido ao TMO alogenico em 31/03/22, com avaliacao medular no D+60 com quimerismo de 100%, mantendo DRM negativa no D+120. Discussao: O uso do inibidor de BCL-2 (Venetoclax), em combinacao com agentes hipometilantes ou doses baixas de citarabina, foi aprovado para pacientes recem-diagnosticados com LMA inelegiveis para quimioterapia intensiva, revolucionando o tratamento da doenca. Publicacoes recentes vem demonstrando novos beneficios dessa associacao, tanto previamente ao TMO (em primeira linha ou com doenca recidivada), como na terapia de resgate para recidiva pos-TMO. Tambem tendo sido evidenciado sucesso terapeutico em faixas etarias menores (incluindo criancas). Esses novos estudos motivaram o uso de terapia baseada em venetoclax nesse paciente jovem, com doenca recidivada, conseguindo atingir e manter DRM negativa. Conclusao: O caso relatado demonstra eficacia do Venetoclax (em combinacao com hipometilante ou citarabina) em promover remissao profunda da doenca, tornando o paciente habil para o transplante e aumentando a probabilidade de sobrevida a longo prazo. Copyright © 2022

Uso De Acalabrutinib Em Paciente Transplantado Renal Com Linfoma Do Manto R/R

Introducao: Linfoma de celulas do manto (MCL) e uma doenca rara, mais frequente em homens, com idade media ao diagnostico de 68 anos. A terapia para MCL nao e curativa e praticamente todos os pacientes terao doenca refrataria ou recorrente. Quimioimunoterapia e a principal modalidade de tratamento de 1 linha, combinada a consolidacao com transplante autologo de medula ossea nos pacientes elegiveis. Mais recentemente, com a incorporacao de novas drogas na pratica clinica, ha mais opcoes de tratamento a partir da 2 linha, como os inibidores de tirosina quinase de Bruton (iBTK) e inibidor de bcl-2. Objetivos: Relatar um caso de paciente com MCL R/R, com historico de transplante renal e uso de imunossupressores, tratado com acalabrutinib com necessidade de ajuste de dose. Relato de caso: RCM, masculino, 70 anos, coronariopata, transplantado renal de doador cadaver em janeiro de 2018 devido a doenca renal cronica dialitica por sindrome hemolitico-uremica atipica em 2014, em uso de tacrolimus, micofenolato de mofetila e prednisona. Poucos meses apos o transplante apresentou linfocitose (14.900) e esplenomegalia, sem sintomas B. Biopsia de medula ossea mostrou infiltracao por MCL, positivo para CD20, BCL-2 e ciclina-D1. Na ocasiao, o paciente encontrava-se assintomatico e a doenca foi caracterizada como MCL leucemizado e indolente, foi optado por acompanhamento ambulatorial. Apos dois anos, apresenta linfocitose progressiva, aumento da esplenomegalia e trombocitopenia. Realizou tratamento com 6 ciclos de R-CHOP (ate 29/10/2020), atingindo resposta parcial. Apresentava 2,73% de linfocitos B monoclonais ao final do tratamento. Devido ao uso concomitante de imunossupressores para profilaxia de rejeicao do enxerto renal, durante a pandemia de COVID-19, optou-se por nao realizar manutencao com rituximabe. Apresentou recaida precoce, novamente com linfocitose progressiva e esplenomegalia 6 meses apos o termino do tratamento de 1 linha. Em junho de 2021 iniciou tratamento de 2 linha com iBTK de 2geracao - acalabrutinibe 200 mg/dia. Atingiu resposta hematologica com rapida normalizacao da linfocitose e resolucao da esplenomegalia, porem evoluiu com diarreia cronica, perda de peso e desnutricao, com prejuizo a qualidade de vida. Diante dos possiveis diagnosticos diferenciais - infeccao oportunista em paciente severamente imunossuprimido, infiltracao colonica por linfoma ou toxicidade medicamentosa, foi submetido a colonoscopia, com resultado normal, tornando toxicidade medicamentosa a principal hipotese. A dose do acalabrutinibe foi reduzida para 100 mg/dia em 20/04/22. Desde entao houve melhora da diarreia, o paciente voltou a ganhar peso e mantem resposta hematologica completa. Discussao e conclusao: Nao ha descricao de interacao entre acalabrutinib e inibidores de calcineurina, sirolimus e micofenolatomofetil. A posologia recomendada de acalabrutinibe e 100 mg de 12/12h, de forma universal. Pacientes transplantados em uso de imunossupressores nao foram incluidos nos estudos clinicos que levaram a aprovacao da droga para uso na pratica clinica. Esse caso ilustra que em cenarios especificos pode ser necessario realizar ajuste de dose para reduzir o risco de efeitos colaterais, sem prejuizo na eficacia do tratamento. Copyright © 2022

INHIBITION OF PROTEIN KINASE CK2 AND BCL-2: A NOVEL THERAPEUTIC STRATEGY TO ANTAGONIZE MANTLE CELL LYMPHOMA CELL GROWTH

Background: Mantle cell lymphoma (MCL) is a B-cell tumor which often relapses. BCR inhibitors (Ibrutinib, Acalabrutinib) and antiapoptotic BCL2-family members blockers BH3-mimetics (Venetoclax, ABT-199) are effective drugs to fight MCL. However, the disease remains incurable, due to therapy resistance, even to the promising Venetoclax and Ibrutinib combination. Therefore, there is a profound need to explore novel useful therapeutic targets. CK2 is a S/T kinase overexpressed in several solid and blood tumors. We demonstrated that CK2, operating through a 'non-oncogene addiction' mechanism promotes tumor cell survival, and counteracts apoptosis, by activating pro-survival signaling cascades, such as NF-κ B, STAT3 and AKT. CK2 could regulate also BCL2 family members. The CK2 chemical inhibitor CX-4945 (Silmitasertib, Sil) is already under scrutiny in clinical trials in relapsed multiple myeloma, solid tumors and COVID-19. Aims: In this work, we tested the effect of CK2 chemical inhibition or knock down on Venetoclax (Ven)-induced cytotoxicity in MCL pre-clinical models to effectively reduce MCL cell growth and clonal expansion. Methods: CK2 expression and BCR/BCL2 related signaling components were analyzed in MCL cells and control cells by Western blotting. CK2 and BCL2 inhibition was obtained with Sil and Ven, respectively and with CK2 gene silencing through the generation of anti-CK2 shRNA IPTG-inducible MCL cell clones. Survival, apoptosis, mitochondrial membrane depolarization and proliferation were investigated by FACS analysis of AnnexinV/PI and JC-10 staining. The synergic action of Ven and Sil was analyzed by the Chou-Talalay combination index (CI) method. CK2 knock down in vivo was obtained in xenograft NOD-SCID mouse models Results: CK2 inactivation (with Sil or CK2 silencing) determined a reduction in the activating phosphorylation of S529 p65/RelA and S473 and S129 AKT, important survival cascades for MCL. Sil or CK2 silencing caused BCL2 and related MCL1 protein reduction, causing cell death. Importantly, we confirmed these results also in an in vivo xenograft mouse model of CK2 knockdown in MCL. Sil +Ven combination increased MCL cell apoptosis, as judged by the augmented frequency of Annexin V positive cells and expression of cleaved PARP protein, and JC-10 mitochondrial membrane depolarization, with respect to the single treatments. Captivatingly, Sil or CK2 gene silencing led to a substantial reduction of the Ven-induced increase of MCL-1, potentially counteracting a deleterious Ven-induced drawback. Analysis of cell cycle distribution confirmed an increased frequency of apoptotic cells in the sub G1 phase in CK2-silenced cells and a modulation of the other phases of the cell cycle. Remarkably, the calculated CI less than 1 suggested a strong synergic cell-killing effect between Sil and Ven, on all the cell lines tested, including those less sensitive or resistant to Ven Summary/Conclusion: We demonstrated that the simultaneous inhibition/knock down of CK2 and BCL2 synergistically cooperates in inducing apoptosis and cell cycle arrest of MCL malignant B-lymphocytes and has the potential of reducing MCL clonal growth, also counterbalancing mechanism of resistance that may arise with Ven. Therefore, CK2 is a rational therapeutic target for the treatment of MCL to be tested in combination with Ibrutinib or Ven.

B-CELL MALIGNANCIES TREATED WITH TARGETED DRUGS AND SARS-COV-2 INFECTION. A EUROPEAN HEMATOLOGY ASSOCIATION SURVEY (EPICOVIDEHA)

Background: Patients with lymphoproliferatie diseases (LPD) appear particularly ulnerable to SARS-CoV-2 infection, partly because of the effects of the anti-neoplastic regimens (chemotherapy, signaling pathway inhibitors, and monoclonal antibodies) on the immune system. The real impact of COVID-19 on the life expectancy of patients with different subtypes of lymphoma and targeted treatment is still unknown. Aims: The aim of this study is to describe and analyse the outcome of COVID-19 patients with underlying LPD treated with targeted drugs such as monoclonal antibodies (obinutuzumab, ofatumumab, brentuximab, niolumab or pembrolizumab), BTK inhibitors (ibrutinib, acalabrutinib), PI3K inhibitors (idelalisib), BCL2 inhibitors (enetoclax) and IMIDs, (lenalidomide). Methods: The surey was supported by EPICOVIDEHA registry. Adult patients with baseline CLL or non-Hodgkin Lymphoma (NHL) treated with targeted drugs and laboratory-confirmed COVID-19 diagnosed between January 2020 and January 2022 were selected. Results: The study included 368 patients (CLL n=205, 55.7%;NHL n=163, 44.3%) treated with targeted drugs (Table 1). Median follow-up was 70.5 days (range 19-159). Most used targeted drugs were ITKs (51.1%), anti-CD20 other than rituximab (16%), BCL2 inhibitors (7.3%) and lenalidomide (7.9%). Of note, only 16.0% of the patients were accinated with 2 or more doses of accine at the onset of COVID-19. Pulmonary symptoms were present at diagnosis in 244 patients (66.2%). Seere COVID-19 was obsered in 47.8 % patients while 21.7% were admitted to to intensie care unit (ICU), being 55 (26.8%) CLL patients and 25 (15.3%) NHL patients. More comorbidities were reported in patients with seere-critical COVID-19 compared to those with mild- asymptomatic infection (p=0.002). This difference was releant in patients with chronic heart diseases (p=0.005). Oerall, 134 patients (36.4%) died. Primary cause of death was COVID-19 in 92 patients (68.7%), LPD in 14 patients (10.4%), and a combination of both in 28 patients (20.9%).Mortality was 24.2% (89/368) at day 30 and 34.5%(127/368) at day 200. After a Cox multiariable regression age >75 years (p<0.001, HR 1.030), actie malignancy (p=0.011, HR 1.574) and admission to ICU (p<0.00, HR 4.624) were obsered as risk factors. Surial in patients admitted to ICU was 33.7% (LLC 38.1%, NHL 24%). Mortality rate decreased depending on accination status, being 34.2% in not accinated patients, 15.9-18% with one or two doses, decreasing to 9.7% in patients with booster dose (p<0.001). There was no difference in OS in NLH s CLL patients (p=0.344), nor in ITKs s no ITKs treated patients (p=0.987). Additionally, mortality rate dropped from the first semester 2020 (41.3%) to last semester 2021 (25%). Summary/Conclusion: - Our results confirm that patients with B--mallignancies treatted with targeted drugs hae a high risk off seere infection (47.8%) and mortality (36.4%) from COVID-19. - Pressence of comorbidities,, especially heart disease,, is a risk factor for seere COVIID--19 infection in ourr series. - Age >75 years,, actie mallignancy att COVIID--19 onset and ICU admission were mortality risk factors. - COVIID--19 acination was a protectie factor for mortality,, een iin this popullation wiitth humorall immunity impairment. - The learning cure in the management of the infection throughout the pandemiic and the deelopmentt off COVIID--19 treatments showed benefit in this partticullarlly ullnerablle popullation? (Table Presented).

PEDIATRIC-TYPE FOLLICULAR LYMPHOMA - A NEW PARADIGM IN DIAGNOSIS?

Background: Recognized as an entity in the 2016 WHO Classification of Tumors of Hematopoietic and Lymphoid Tissues, Pediatric-Type Follicular Lymphoma (PTFL) is a rare nodular follicular lymphoma that affects primarily children and young adults. The clinical presentation is characterized by the sudden appearance of an isolated lymphadenopathy, with a predilection for the head and neck region, without systemic symptoms. The incidence is higher in men. It has an excellent prognosis with the excision of the affected ganglion. By definition, diagnosis is histological, immunocytochemical and molecular. There are no known risk factors or any described association with immunodeficiency or viral infections. Aims: We report two clinical cases. Methods: Case 1 - a previously healthy 18-year-old boy with an isolated, non-painful, cervical lymphadenopathy of approximately 20 mm, which was incidentally found. Case 2 - a 13-year-old boy without relevant personal history, who, after the second dose of vaccination against COVID-19, developed multiple adenomegalies that spontaneously regressed. However, one month later, a right submandibular adenomegaly appeared. It was analysed by ultrasound and was described as suspicious. In both cases, a fine-needle lymph node biopsy was performed for cytological diagnosis and material was sent for immunophenotyping by flow cytometry and molecular cytogenetics by FISH. Results: Immunophenotyping suggested a large-cell B-lymphoma with a phenotype compatible with Burkitt's Lymphoma (BL). In the cytology of both cases, the population observed was more consistent with diffuse large B cell lymphoma (DLBCL) or possibly high-grade follicular lymphoma (FL). In the FISH study, no rearrangements in the MYC, BCL2, BCL6 or IRF4 genes were detected in the samples of the two cases. The lymphadenopathies were excised with a probable diagnosis of PTFL or DLBCL. Histological examination confirmed the PTFL diagnosis. Summary/Conclusion: We did not find in the literature any reference to clear causal relationship between vaccination against COVID-19 and the onset of lymphoproliferative diseases. The cytological/immunophenotypic/molecular approach of this entity in both cases seems to define a characteristic pattern, which may eventually allow, in a first approach, to suspect this diagnosis. More extensive studies will be needed to establish the role of these methodologies in the diagnosis of this pathology.

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.

Annual Conference of National Cancer Institute - Cairo University “Bridging Gaps in Oncology”

The proceedings contain 12 papers. The topics discussed include: prognostic implication of MYC/BCL2 expressions in patients with diffuse large B-cell NHL;clinical outcomes of pediatric-inspired chemotherapy protocol in adolescent and young adults (AYAs) acute lymphoblastic leukemia patients;effect of nutritional status on survival of Egyptian patients with gastrointestinal malignancies;characterization of COVID-19 disease in cancer patients, single institute experience, low income setting;malignant obstructive jaundice;review of 232 patients;determining resectability in pancreatic tumors;review of 70 cases;Inhibition of dynamins restricts the survival of vasopressin stimulated and PI3K/Akt/mTOR inhibited breast cancer cells;and complete mesocolic excision and central vascular ligation in colon cancer surgery, feasibility and outcome.

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.

SARS-COV-2 INDUCED REMISSION OF DIFFUSE LARGE B-CELL LYMPHOMA: A CASE REPORT

Introduction: Diffuse Large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma, which accounts for approximately 30% of all non-Hodgkin lymphoma cases. Spontaneous remission of DLBCL is exceedingly rare, with only a handful of case reports that describe the phenomenon present in the literature. Specialists are investigating similar cases to find out whether the SARS-CoV-2 infection triggered an antitumor immune response, as has been described with other infections in the context of high-grade non-Hodgkin lymphoma. We report one case of an elderly woman with EBV positive DLBCL diagnosed with PCR-positive SARS-CoV-2 pneumonia in the course of the disease and their outcomes. Case report: A 81 years-old woman, was referred to the consult ambulatory of intern medicine with progressive cervical, axillary and inguinal lymphadenopathy with local pain, fever and weight loss. The biopsy of an axillary lymph node demonstrated diffuse atypical lymphoid infiltrate. Immunohistochemistry stains showed positive CD20, CD30, Bcl-2 and MUM-1. It was negative for CD3, CD10, Bcl-6, c-Myc and CMV. The Ki-67 proliferation index was 80%. Epstein-Barr virus (EBV) stain were positive. These findings were consistent with DLBCL, EBV positive, clinical Stage IIIB and R-IPI 4 (poor prognosis and high risk). Since PET-CT was unavailable, thorax and abdomen computed tomographies were performed and revealed enlarged lymph node on pulmonary hilum, pathological lymph node enlargement in the axillary and supraclavicular chains bilaterally and peri aortocaval adenomegaly, extending along the bilateral femoral iliac vessels (larger lymph nodes of 2.5cm). She was treated with 4 cycles of R-CVP (rituximab with cyclophosphamide, vincristine and prednisone). When an interim PET-CT was performed, disease progression was revealed (Lugano score 5). Therefore, considering patient age and clinical status, treatment scheme was changed to R-mini-CHOP (rituximab with reduced doses of cyclophosphamide, doxorubicin, vincristine and prednisone), achieving partial response after 4 cycles (Lugano score 4). A month after this evaluation, she was admitted to the Emergency Department with diarrhea, fever and was diagnosed with PCR-positive SARS-CoV-2 pneumonia. After 6-days hospitalization with no significant ventilatory impairment, she was discharged. No corticosteroid or immunochemotherapy was administered. Two months later, she had no palpable lymphadenopathy and a PET/CT scan revealed widespread resolution of the lymphadenopathy and reduced metabolic uptake throughout (Lugano score 1). After a 7-months follow-up, the patient still has no clinical relapse. Discussion: The putative mechanisms of action include cross-reactivity of pathogen-specic T cells with tumour antigens and natural killer cell activation by inammatory cytokines produced in response to infection. It is important to consider that the more cases of SARS-CoV-2 infection in patients with non-Hodgkin lymphoma, the more likely it is to analyze lymphoma remissions and demonstrate the exact mechanism of pathogen-specific T cells with tumor antigens. Conclusion: Because spontaneous remission of DLBCL associated with SARS-CoV-2 infection is a new event, careful investigation of these cases is important, because the information gained may lead to new therapeutic targets or treatment strategies for future patients.

LINFOMA GÁSTRICO DOUBLE HIT: RELATO DE CASO

Introdução: O linfoma não-Hodgkin (LNH) é a neoplasia hematológica mais comum, mais frequente em homens e em países subdesenvolvidos. De acordo com estudo do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HCFMUSP), o LNH corresponde à 80% dos linfomas, destes 50% linfoma difuso de grandes células B (LDGCB), com idade média de 59,6 anos, 33% de acometimento extranodal, 62% de doença avançada, IPI (Índice Internacional de Prognóstico) intermediário alto de 24% e alto de 19% para portadores de LDGCB. Objetivos: Relatar caso de paciente diagnosticada com LNHDGCB double hit gástrico durante investigação ambulatorial de síndrome dispéptica e sua abordagem. Materiais e métodos: Levantamento de prontuário, descrição e discussão de relato de caso clínico, por meio de uma revisão integrativa utilizando bases de dados PUBMED, MEDLINE, BVS e SCIELO. Relato de caso: Feminina, 47 anos, sem comorbidades, com queixa de epigastralgia pós-prandial há 9 meses e perda ponderal de 15 kg no período, sem outros sinais e sintomas. Há 2 meses, em investigação com gastroenterologista foi realizada EDA com biópsia de lesão gástrica associada a painel imuno-histoquímico (BCL6, CD20, CD30, MYC e Ki-67 positivos) compatíveis com LNHDGCB gástrico com alto índice proliferativo, além de tomografia de abdome total com contraste, evidenciando infiltração em lobo hepático esquerdo e hilo esplênico (estádio IV), sendo encaminhada ao serviço de hematologia há aproximadamente 15 dias. Atualmente, paciente segue em programação de quimioterapia com R-da-EPOCH após término de isolamento contactante Covid. Discussão: O linfoma double-hit (LDH) é uma neoplasia de alto grau e agressiva, que integra o subgrupo de LDGCB e se traduz na translocação do gene MYC combinada à translocação gênica adicional de BCL2, BCL3, BCL6 ou CCND1. Nesses casos, há maior tendência de infiltração de medula óssea e sistema nervoso central, além de prognóstico reservado associado ao alto índice de proliferação celular, elevação de DHL sérica, acometimento acima de 70 anos, apresentação clínica em estádio avançado e má resposta terapêutica. O diagnóstico é realizado por meio de biópsia excisional do local suspeito, estudo imuno-histoquímico, e, preferencialmente, acrescido da pesquisa FISH (hibridação in situ por Fluorescência) para MYC, BCL2 e BCL6. O estadiamento obedece a classificação Lugano, baseada no antigo sistema Ann Arbor: envolvimento de região linfonodal única (I);duas ou mais regiões linfonodais do mesmo lado do diafragma (II);regiões linfonodais em ambos lados do diafragma (III);sítio extranodal fora do sistema linfático (IV). O tratamento quimioterápico envolve ciclos de R-da-EPOCH (rituximabe, dose ajustada de etoposídeo, prednisona, doxorrubicina, ciclofosfamida e vincristina) a cada 21 dias. A Associação Brasileira de Hematologia, Hemoterapia e Terapia Celular (ABHH) considera R-da-EPOCH o tratamento padrão-ouro, porém, durante a pandemia Covid, diante da indisponibilidade de leitos e/ou bombas de infusão portáteis para tratamento ambulatorial, orienta levar em consideração a terapia com R-CHOP, seguido de estratégias de consolidação, que incluem TCTH, a fim de não atrasar o tratamento. Conclusão: O LNHDGCB double hit pode acometer jovens, em sítio extranodal e exige abordagem diferenciada por sua agressividade e alto grau associados a prognóstico reservado. Apesar disso, com as novas terapêuticas e estadiamento clínico precoce é uma neoplasia potencialmente tratável e curável, cujo tratamento pode se beneficiar do uso de técnicas citogenéticas para pesquisa de translocações gênicas.

AVALIAÇÃO DE DNA CIRCULANTE TUMORAL EM UMA COORTE PROSPECTIVA DE PACIENTES COM LINFOMA DIFUSO DE GRANDES CÉLULAS B: ANÁLISE PRELIMINAR

Objetivos: implementar a biópsia líquida em linfoma difuso de grandes células B (LDGCB) ao diagnóstico e seguimento prospectivamente. Relacionar seus achados com características clínicas e patológicas. Material e métodos: foram incluídos pacientes com LDGCB, sem disfunção orgânica tratados com RCHOP ou RminiCHOP. Antes do início do tratamento e 2 meses após seu término foram coletados 20 mL de sangue, para análise de DNA livre circulante. Desse material foi feita a pesquisa de DNA circulante tumoral (DNAct). Além disso, foi feita a extração do DNA tumoral da biópsia diagnóstica para comparação com o DNAct. A pesquisa de mutações foi feita por NGS com um painel de genes (KMT2D, TP53, CREBBP, PIM1, MYD88, PCLO, EZH2, B2M, CARD11, CD79B e HIST1H1E). A amostra inicial foi chamada de DNA1 e a final de DNA2. Resultados: Até agora foram incluídos 22 pacientes na pesquisa. Idade mediana ao diagnóstico: 61 anos (26-88), 40% do sexo masculino. Sintomas B em 50% e 32% com lesão bulky. Acometimento extranodal em 17 pacientes (77%), sendo 7 com acometimento gástrico. A maioria tinha IPI-NCCN 2-3 (40%) e nenhum teve infiltração de medula óssea. Até agora 20 pacientes completaram o tratamento e 1 destes ainda fará PET de fim de terapia para atestar resposta. São 11 pacientes em remissão completa (RC), 2 refratários, 2 recaídas e 6 óbitos (2 por progressão de doença, 1 de causa desconhecida e 3 por infecção). Mediana de seguimento dos pacientes vivos: 23.5 meses (3-33). Análise de DNAct completa em 5 casos. Desses, na pesquisa de célula de origem pelo algoritmo de Hans, 4 são do tipo ABC. Nenhum paciente era duplo expressor de MYC e BCL2. A média de mutações detectadas presumivelmente somáticas no DNA1 foi de 35. O gene mais frequentemente mutado foi o PCLO, na sua maioria mutações missense. Apenas 1 teve aumento do número de mutações detectadas entre o DNA1 e DNA2. A média de redução de mutações foi de 20 entre o DNA1 e DNA2. Em 2 pacientes com doença localizada, as mutações encontradas no material de biópsia não foram vistas no DNA circulante. Todos esses 5 casos analisados seguem em remissão completa. Discussão: A população avaliada foi similar à literatura em relação a idade, com uma proporção um pouco maior de pacientes com doença extranodal e acometimento gástrico. Houve um excesso de mortes por causas infecciosas, notadamente no período da pandemia por Covid-19. Nos 5 casos com análise de DNAct, o teste foi factível e correlacionou com os achados clínicos. A maioria dos pacientes teve redução substancial da quantidade de mutações, congruente com a remissão completa. Na doença localizada, em amostra reduzida e com avaliação preliminar, o DNAct não detectou todas as mutações vistas na biópsia. Conclusão: Nessa avaliação preliminar com poucos casos, a biópsia líquida em LDGCB teve correlação com a evolução clínica e se mostrou factível.

Successful retreatment of CLL with venetoclax following clonal evolution during 37 months of tirabrutinib and idelalisib

The BCL2-specific inhibitor, venetoclax, has demonstrated remarkable clinical activity in the treatment of chronic lymphocytic leukemia (CLL), either alone or in combination with CD20 antibodies. Nevertheless, patients who fail to attain a complete remission relapse, and require further therapy. Data on retreatment with venetoclax at disease progression are currently limited. Here, we report patterns of clonal evolution in an R/R CLL patient that has demonstrated successful retreatment. A 57 year-old lady with chemotherapy- refractory (FCR, RCHOP, high dose methyl prednisolone) TP53 mutant CLL was treated for 21 months with single-agent venetoclax in 2014 (NCT01889186). She attained an MRD positive CR with the resolution of massive lymphadenopathy and with only low-level (0.01%) disease in the bone marrow. However, she subsequently progressed rapidly with a lymphocyte doubling time of only 4 weeks and was treated with tirabrutinib and idelalisib in combination (NCT02968563) from December 2015 for 37 months before progressing December 2019. She was retreated with venetoclax and rituximab but died of COVID-19-induced respiratory failure in March 2020. To study the clonal evolution underlying these events, in vitro drug sensitivity assays and whole exome sequencing (WES) were used to study peripheral blood mononuclear (PBMC) and bone marrow samples. WES of sample 1 showed multiple mutations in CLL driver genes: SF3B1 R625C, KMT2C R4434Q, and TP53 R110L at VAFs of 37, 17, 35%, respectively. Mutations in other genes associated with CLL included FANCA L217F (47%) and SPEN P3402S (46%). At disease progression (sample 2), following venetoclax, there was the loss of detectable (WES at 100× coverage) TP53 R110L (with loss of 17p deletion on interphase FISH and analysis of copy number) but maintenance of SF3B1 R625C (44%), KMT2C R4434Q 30%), FANCA L217F (47%), and SPEN P3402S (55%). These data, therefore, suggest the TP53 mutant subclone was largely lost during therapy. No other mutations were identified as possible resistance mediators. There were no detectable BCL2 mutations. In vitro drug sensitivity testing to venetoclax showed an EC50 of 228nM (CLL EC50 usually 3-5 nM). The patient was then treated with the BTK inhibitor tirabrutinib in combination with idelalisib, with an excellent clinical response. After 10 months (sample 3, during the lymphocytosis induced by BTKi/PI3Kdi) SF3B1, KMT2C, FANCA, and SPEN mutations were detected at VAFs of 26, 30, 54, and 56%, respectively. At this point the TP53 R110L mutation was detected again at a VAF of 4%, indicating that stopping venetoclax allowed the clone to re-emerge. At this time, there were no detectable BTK or PLCG2 mutations. The patient then responded for a further 37 months before disease progression. At progression (sample 4), SF3B1, KMT2C, FANCA, and SPEN mutations were still detected in the peripheral blood at VAFs of 43, 31, 48, and 50%, respectively. The VAF of the TP53 R110L mutation had increased to 33%. Additionally, a BTK mutation (T474I) was identified with a VAF of 16%. Identical results were obtained using a bone marrow sample. Now, however, in vitro analysis demonstrated a high degree of sensitivity to venetoclax (EC50 0.72 nM). The patient was, therefore, retreated with venetoclax and rituximab. At the point of re-treatment, VAFs were maintained, with the emergence of a new subclonal NOTCH1 G1001D mutation at a VAF of 3%. The patient, unfortunately, died 4 months after commencing therapy due to COVID-19 associated pneumonitis. A full disease reassessment was not made but the patient's blood count had normalized, with rapid clearance of CLL cells from the peripheral blood, recovery of normal hematological indices, resolution of splenomegaly, and partial resolution of lymphadenopathy on CT scan. These data, therefore, suggest that re-treatment with venetoclax in CLL can be successful. Regaining sensitivity to venetoclax may largely depend on shifting clonal dynamics. The molecular basis of venetoclax resistance in this case is currently being investigated. A so in this particular case, it appears that the TP53 mutant subclone was more sensitive to BCL2 inhibition than TP53 wild-type subclone(s), and was largely eliminated by initial venetoclax treatment, contrasting with recently published data suggesting resistance of TP53 mutant hematological malignancies to BCL2 inhibition due to increased thresholds for BAX/BAK activation (Thijssen et al., 2021).

Longitudinal antibody levels and T-cell response following BNT162b mRNA COVID19 vaccine in patients with chronic lymphocytic leukemia on behalf of the Israeli CLL Study Group

We investigated the safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine in patients with CLL as part of the collaborative work of the Israeli CLL study group. Aims and methods: Our study included analysis of both humoral and cellular immune response. Blood samples for immune response evaluation to the above vaccine were assessed in two-time points: after 3 weeks, and 100 days following the second dose using anti-spike antibody tests. Neutralizing antibodies were analyzed for 40 patients with CLL. For analysis of cellular response: Interferon-gamma secretion was measured using Elispot and comparing blood sample from a patient and a matched control. Results: In total 400 patients were included, of which 373 were found to be eligible for the analysis of the first time point analysis;antibody response was detected in 43% of the cohort. In treatment-naïve patients, 61% responded to the vaccine, while only 18, 9, and 5% of patients with CLL previously treated with, BTKi, BCL2i, or recent anti CD20 antibody developed responses, respectively. In 40 patients we also analyzed neutralizing antibodies for demonstrated high concordance with positive serologic response to spike (S) protein. longitudinally report of antibody production was performed in a cohort of 84 patients;First analysis was 22 days (17-36) after the second dose of the vaccine and the second test was performed after a median of 100 (74-131) days following the second dose of COVID19 vaccine. Antibody decay rates and half-life were calculated using an exponential model. We demonstrated that after a median of 100 days decay of IgG levels is similar to that of the elderly healthy controls indicating that although the efficacy of the vaccine is lower, patients who respond to the vaccine are able to maintain their immune response. The cellular response was evaluated in 55 patients and data will be presented for different subgroups including treatment naïve patients as well as patients following anti CD20 antibody treatment or BCL, BTKi. Our work summarized the available data in terms of immune response to the covid19 vaccine in patients with CLL.

Safety and Efficacy of Azacitidine with Venetoclax for Newly Diagnosed Intensive Chemotherapy Ineligible, and Relapsed or Refractory Acute Myeloid Leukemia in Arab Population: A Single-Center, Retrospective Study

Background: Venetoclax combined with hypomethylating agents is a new standard of care for newly diagnosed patients with acute myeloid leukemia (AML) 75 years or older, or unfit for intensive chemotherapy. As precision therapy in AML expanded with the addition of venetoclax among others in the therapeutic armamentarium of AML, efficacy and safety reports in ethnic minorities are limited, with a background of well recognized inter-ethnic differences in drug response. Phase III data from VIALE-A, as well as VIALE-C, was limited for the Arab population as no site opened in the Arab world. We herein report our experience on the use of venetoclax with azacitidine in patients with newly diagnosed or relapsed/refractory AML in the Arab population. Methods: Retrospective-single center review on the use of Azacitidine with venetoclax in older patients (aged ≥60 years) with newly diagnosed AML, not eligible for intensive chemotherapy;secondary AML and relapsed or refractory AML. All patients self-identified of Arabic ethnicity. Patients who received previous BCL2-inhibitor therapy were excluded. Patients who received at least one dose of treatment (Azacitidine ≥3 days, >14 days of venetoclax) were included in the intention to treat analysis. Patients typically received azacitidine 75 mg/m2 intravenously for 7 days with oral venetoclax 400 mg daily for induction, with appropriate dose adjustment for concomitant use of azoles. This is followed by the same regimen in consolidation, with adjustment according to response and side effects at the treating physician's discretion. The primary endpoint was overall survival. The secondary endpoints include response rate, safety, and relapse-free survival. Results: Between July 2019, and July 2021, we identified 19 patients;13 (68%) had newly diagnosed AML (ND-AML), and 6 (32%) had relapsed or refractory AML (R/R AML). The median age was 70 years (17-82). In the ND-AML, most patients had an adverse ELN 2017 AML (69%) with 23% having either intermediate or adverse AML (Negative for CBF, NPM1, FLT3-ITD and biCEBPA, but missing NGS data for adverse mutations Tp53/ASXL1 and RUNX1). Only one patient was classified as intermediate-risk AML. The overall response rate in the ND-AML was 77%, with 46% achieving complete remission (CR), and 23% CR with incomplete count recovery (CRi) [Table]. One patient achieved PR after the first cycle (blast 7% by morphology and 1.5% by flow cytometry) and did not have a subsequent bone marrow evaluation, however had a full count recovery. Among the responders in the ND-AML cohort, 4 deaths were noted. One death was related to COVID-19 associated pneumonia, one due to graft failure (at day 42 post Haplo-SCT), one due to septic shock, and one was related to relapse disease. The overall survival and relapse-free survival for ND-AML were 5.6 months for both [Figure]. In the R/R AML, 66% had prior HMA exposure, and all patients did receive high-intensity chemotherapy. The median number of prior treatments was 3 (1-5). the response rate was 80% (4/5), with 60% achieving CR. All patients are still alive with a median follow-up of 7.6 months. One patient had progressive disease. One patient is early to evaluate and was not included in the response analysis [Table]. The 30-day mortality was zero in both ND-AML and R/R AML cohorts. Conclusions: In a majority of adverse risk ND-AML, and in heavily pretreated R/R AML, the response rate and overall survival is comparable to what has been previously reported. Our data support the use of this regimen in older patients with newly diagnosed AML, patients with relapsed or refractory disease, and those with adverse-risk features. This analysis is limited by the small number of patients, and by the lack of ELN 2017 favorable-risk AML. Future prospective and randomized studies are needed to clarify activity and safety in the Arab population, as well as in the high-risk AML subset. [Formula presented] Disclosures: No relevant conflicts of interest to declare.

Seroconversion Rates after COVID-19 Vaccination Amongst Patients with Hematologic Malignancies: Results of a Rapid Vaccination and Evaluation Program in a Minority Rich, Ethnically Diverse Inner City Cohort

It is well established that COVID-19 carries a higher risk of morbidity and mortality in patients (pts) with hematologic malignancies. Emerging data suggests that despite the 3 COVID-19 vaccines with emergency use authorization (EUA) by the FDA inducing high levels of immunity in the general population, pts with hematologic malignancies have lower rates of seroconversion for the SARS-CoV-2 Spike antibody (Spike IgG) and thus possibly lower protection against severe COVID-19. We established a program of rapid vaccination and evaluation of response in an inner city minority population to help determine the factors that contribute to the poor seroconversion to COVID-19 vaccination in pts with hematologic malignancies. We conducted a cross-sectional cohort study of pts with hematologic malignancies seen at Montefiore Medical Center between March 29, 2021 and July 8, 2021 who completed their vaccination series with 1 of the 3 FDA EUA COVID-19 vaccines, Moderna, Pfizer, or Johnson & Johnson (J&J). We qualitatively measured Spike IgG production in all pts using the AdviseDx Spike IgG assay and performed quantitative analysis on pts who completed their vaccination series with at least 14 days (d) after the 2 nd dose of the Moderna or Pfizer vaccines or 28d after the single J&J vaccine. Safety data was collected via questionnaires or as part of the electronic medical record. We analyzed the characteristics of these pts using standard descriptive statistics and associations between pts characteristics, cancer subtypes, treatments, and vaccine response using a Fisher Exact test, Kruskal-Wallis Rank Sum test, or Kendall Tau-b test. A total of 121 pts with hematologic malignancies were enrolled and another 10 pts were included by retrospective chart review. Five pts did not have a Spike IgG performed after consent and excluded. Ten patients had Spike IgG testing before completion of their vaccination series and excluded from quantitative analyses. A total of 116 pts were included in immunogenicity analysis and 106 pts in quantitative analysis. Baseline characteristics and representative malignancies are listed in Table 1. Seventy pts (60%) received Pfizer, 36 pts (31%) Moderna, and 10 pts (9%) J&J. Median time from vaccination completion to Spike IgG was 40d. We observed a high-rate of seropositivity (86%) with 16 pts (14%) having a negative Spike IgG. Percent positivity was not statistically significant between vaccine types (p=0.50). We observed significantly lower seroconversion rates in pts with Non-Hodgkin lymphoma (p=0.005) and pts who received: cytotoxic chemotherapy (p=0.002), IVIG (p=0.01), CAR-T cell therapy (p=0.00002), and CD20 monoclonal antibodies (Ab) (p=0.0000008) especially within 6 mo of Spike Ab evaluation (p=0.01). All pts who received anti-CD19 (Axi-cel) CAR-T therapy (0/6) were seronegative, and 1 pt that received BCMA directed CAR-T (Cilta-cel) was seropositive with no association between timing CAR-T cell infusion and seroconversion/titer. Use of BCL2 inhibitors (p=0.04), CD20 monoclonal Ab (p=0.0009), CAR-T cell therapy (p=0.01), BTK inhibitors (p=0.04), current steroid use (p=0.002), and IVIG (p=0.003) also correlated with significantly lower Ab titers with a trend toward lower Ab titers in pts on any active cancer therapy at time of vaccination (p=0.051). Immunomodulatory drugs (p=0.01) and proteasome inhibitors (p=0.01) had significantly higher seroconversion rates, and pts with history prior COVID-19 (12/106) had significantly higher Ab titers (p=0.0003). Of 47 pts who received stem cell transplant, 43 received an autologous (37 seropositive, 6 seronegative) and 4 an allogeneic transplant (3 seropositive, 1 seronegative), with no significant association with seroconversion, Ab titer, or time since transplant (greater or less than 1 year). The majority of pts, 64% and 53%, reported no adverse effects (AE) to the 1 st and 2 nd dose respectively. The most common AE were mild in severity and included sore arm, muscle aches, fatigue, and fever. No life-threatening AE were observed. Our findings indicate hat vaccination is safe, effective, and well tolerated in the majority of pts with hematologic malignancies. We observed that pts receiving B-cell depleting therapies are unable to mount an effective serological response to COVID-19 vaccines and remain vulnerable to the disease. Novel immunization strategies (active or passive) are urgently needed in this population. [Formula presented] Disclosures: Gritsman: iOnctura: Research Funding. Shastri: Onclive: Honoraria;Kymera Therapeutics: Research Funding;Guidepoint: Consultancy;GLC: Consultancy. Halmos: Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding;Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding;Astra-Zeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding;Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding;AbbVie: Research Funding;Boehringer-Ingelheim: Membership on an entity's Board of Directors or advisory committees, Research Funding;Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding;GSK: Research Funding;Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding;Mirati: Research Funding;Elevation: Research Funding;Blueprint: Research Funding;Advaxis: Research Funding;Eli-Lilly: Research Funding;TPT: Membership on an entity's Board of Directors or advisory committees;Apollomics: Membership on an entity's Board of Directors or advisory committees;Guardant Health: Membership on an entity's Board of Directors or advisory committees. Verma: BMS: Research Funding;GSK: Research Funding;Novartis: Consultancy;Stelexis: Consultancy, Current equity holder in publicly-traded company;Eli Lilly: Research Funding;Curis: Research Funding;Medpacto: Research Funding;Incyte: Research Funding;Acceleron: Consultancy;Stelexis: Current equity holder in publicly-traded company;Celgene: Consultancy;Throws Exception: Current equity holder in publicly-traded company.

Geriatric oncological patients in the pandemic: What are we currently doing differently in practice as compared to the past?

Patients with multiple myeloma (MM), monoclonal gammopathies (MGUS/SMM) and other hemato-oncological (hem-onc) diseases frequently present with disease- and treatment related immunosuppression and bear an increased risk for infections and infection-related mortality. Measures to reduce the infection risk, such as antibiotic and antiviral prophylaxis as well as vaccinations are important elements in the management of these pts. During the COVID-19 pandemic many hem-onc pts have been infected with the SARS-CoV-2 virus, and a large proportion had to be hospitalized. Many required intensive care treatment. Mortality rates were higher compared to those of the general population, highlighting the need to boost pts' immune system against SARS-CoV-2. Although millions of people have already been vaccinated with one of the several COVID-19 vaccines, data on the immune response in MM and other hem-onc pts are limited. First reports indicate suboptimal antispike protein or neutralizing antibody response, leaving several pts potentially unprotected. Yet, the immunological correlates of protection are incompletely understood. Factors associated with poor humoral immune response to the vaccine against SARS-CoV-2 were active or relapsing/progressive disease as well as concomitant therapy. A diminished antibody response in MM pts treated with daratumumab or lymphoma patients undergoing treatment with CD20-antibody or BTK-/bcl2-inhibitors was shown. These data mandate monitoring of humoral and cellular immune response to SARS-Cov-2-vaccination in our pts in order to define the correlates of protection in this pt population. Eventually, it is necessary to assure sufficient protection or to consider additional measures such as discontinuation of MM/lymphoma therapy, if possible, and/or additional doses with the same or other COVID-19 vaccines. In those failing to respond, prophylactic treatment with neutralizing monoclonal antibody cocktails, which is not yet approved, may be considered. However, pts lacking adequate immune response to SARS-CoV-2 will be required to adhere to measures for infection risk reduction until the end of the pandemic is reached. At this meeting, we will report our experiences with COVID-19 in hemonc pts at our center and data on the immune response of pts with certain hem-onc diseases after vaccination against SARS-CoV-2. Furthermore, we will discuss current recommendations regarding this vulnerable pt population during the COVID-19 pandemic.

Phase I Study of Novel SYK Inhibitor TAK-659 in Combination with R-CHOP for Front-Line Treatment of High Risk Diffuse Large B-Cell Lymphoma

Background: DLBCL is highly heterogeneous in underlying biology and clinical behavior. Several high-risk disease features and poor prognostic factors are associated with a higher propensity for refractory disease or relapse after standard R-CHOP therapy;these subset patients require novel strategies to improve upon outcomes. Single-agent TAK-659, a novel oral SYK inhibitor, has demonstrated efficacy in heavily pre-treated DLBCL (Gordon et al., Clin Cancer Res, 2020). We report results of a phase I single institution, single arm dose escalation study that assessed safety of 1 st line treatment with R-CHOP and adjunctive TAK-659 for treatment naïve high-risk DLBCL. Methods: Patients aged ≥18 years, ECOG 0-2 with untreated stage I-IV DLBCL with high-risk features defined as, ABC/non-GCB subtype, high-intermediate or high-risk NCCN-IPI (score ≥4), MYC gene rearranged by FISH including double hit lymphoma (DHL), double expressing DLBCL (DEL;overexpression of MYC ≥40% AND BCL2 ≥50% by IHC respectively), or previously treated transformed low-grade lymphoma without prior exposure to anthracycline, were eligible. Patients were treated with R-CHOP for 1 cycle on or off study followed by combined treatment with R-CHOP and TAK-659 for an additional 5 cycles on study. TAK-659 was dosed daily with dosing escalated from 60mg (dose level 1), to 80mg (dose level 2) to 100mg (dose level 3) based on a 3+3 design. The primary objective was to determine the safety and establish the maximum tolerated dose of TAK-659 when combined with R-CHOP in the front-line treatment of high-risk DLBCL. Secondary objectives were to assess preliminary efficacy of this combination as determined by overall response rate (ORR) by PET-CT (Lugano 2014 criteria), progression free survival (PFS), overall survival (OS) and establish the pharmacokinetics of TAK-659 according to dose. Results: 12 pts were enrolled from Dec 2019 to Nov 2021. The median age was 64 yrs (range 25-75);8 (67%) had stage III/IV disease, 4 (33%) with high risk NCCN-IPI ≥ 4. Histology included 7 (58%) with de novo DLBCL (4 GCB, 3 non-GCB subtype DLBCL) including 7 (58%) with DEL, 3 (25%) with transformed FL, 1 (8%) with Richter's and 1 (8%) with DHL. Dose level 3 (100 mg) was established as the MTD. PKs were measured pre- and post-dose D1 and D15 of cycle 2;Cuzick's test signaled an increase in AUC by dose level on D1 (p = 0.01) but not on D15 (Fig 1). ORR was 100% (CR 92%;Fig 2). With a median follow-up of 14.2 months, 1 pt had primary refractory disease (ABC and DEL), 2 pts with CR subsequently progressed (1 non-GC DLBCL, 1 Richter's) and 1 died of cardiogenic shock unrelated to study drug. The 12-month PFS and OS rates were 82% and 90% respectively with estimated 18-month PFS and OS rates of 68% and 90% respectively. The most common treatment related adverse events (TRAEs) attributed to TAK-659 were lymphopenia (n=12, 100%), infection (6=, 50%), AST elevation (n = 12, 100%) and ALT elevation (n = 10, 83%) (Table). Incidence and severity of transaminitis was consistent with prior reports for this agent. Most common grade 3/4 toxicities were hematologic. Median number of cycles of TAK-659 delivered was 5 (range 3-5). TRAEs led to TAK-659 dose modifications in 8 (67%) pts, though none at dose level 1: 2 (17%) required permanent dose reductions (both for lung infections), while 5 (42%) required discontinuation (4 for infection, and 1 for febrile neutropenia). R-CHOP administration was delayed in 2 pts because of TAK-659 related TRAEs. Aside from dose modifications of vincristine for peripheral neuropathy, no additional dose modifications for R-CHOP were needed. Infections encountered included bacterial and opportunistic infections (1 each for PJP, CMV and aspergillosis) and 1 case of COVID. Growth factor prophylaxis and anti-fungal therapy were not mandated;PJP prophylaxis was advised for CD4 counts < 200 at initial diagnosis. Conclusion: TAK-659, a novel SYK inhibitor combined with R-CHOP in pts with newly diagnosed high-risk DLBCL including DLBCL transformed from follic lar lymphoma and DEL produces high CR rates;survival at 12 months appears promising. A dose of 60 mg was well tolerated, did not require dose modifications and maintained a similar AUC to the MTD of 100 mg with ongoing treatment. Opportunistic infections were noted with this treatment combination suggesting that patients should receive aggressive anti-microbial prophylaxis with future evaluation of this combination. [Formula presented] Disclosures: Karmali: BeiGene: Consultancy, Speakers Bureau;Morphosys: Consultancy, Speakers Bureau;Kite, a Gilead Company: Consultancy, Research Funding, Speakers Bureau;Takeda: Research Funding;Karyopharm: Consultancy;EUSA: Consultancy;Janssen/Pharmacyclics: Consultancy;AstraZeneca: Speakers Bureau;BMS/Celgene/Juno: Consultancy, Research Funding;Genentech: Consultancy;Epizyme: Consultancy;Roche: Consultancy. Ma: Beigene: Research Funding, Speakers Bureau;Juno: Research Funding;AstraZeneca: Honoraria, Research Funding, Speakers Bureau;Loxo: Research Funding;Janssen: Research Funding, Speakers Bureau;Abbvie: Honoraria, Research Funding;TG Therapeutics: Research Funding;Pharmacyclics: Research Funding, Speakers Bureau. Winter: BMS: Other: Husband: Data and Safety Monitoring Board;Agios: Other: Husband: Consultancy;Actinium Pharma: Consultancy;Janssen: Other: Husband: Consultancy;Epizyme: Other: Husband: Data and Safety Monitoring Board;Gilead: Other: Husband: Consultancy;Ariad/Takeda: Other: Husband: Data and Safety Monitoring Board;Karyopharm (Curio Science): Honoraria;Merck: Consultancy, Honoraria, Research Funding;Novartis: Other: Husband: Consultancy, Data and Safety Monitoring Board. Gordon: Zylem Biosciences: Patents & Royalties: Patents, No royalties;Bristol Myers Squibb: Honoraria, Research Funding. OffLabel Disclosure: TAK-659 will be discussed for the treatment of DLBCL (not FDA approved for this indication)