ABSTRACT
Introduction: IgA vasculitis is more commonly seen in the pediatric population than in adults. Rarely IgA vasculitis is associated with malignancy, most commonly solid tumor malignancies, although there are case reports of association with hematologic malignancies. We report a case of large B-cell lymphoma mimicking IgA vasculitis in a 33-year-old immunosuppressed male with a prior history of IgA vasculitis. Case Description/Methods: A 33-year-old Caucasian male post renal transplant from reflux nephropathy on chronic immunosuppression was hospitalized for postprandial epigastric abdominal pain, nausea, vomiting and diarrhea. Two years prior, he was admitted for the same symptoms, palpable purpura of the lower extremities and elevated serum IgA. Enteroscopy had shown duodenal and jejunal ulceration with biopsies staining positive for IgA, confirming IgA vasculitis. He had complete resolution with a steroid taper. His current presentation had resulted in multiple hospital admissions, but empiric trial of steroids failed to alleviate symptoms. Vitals were normal and exam was notable for epigastric tenderness. Labs were notable for WBC 19.00 x103/cmm with normal differential, hemoglobin 9.2 gm/dL (prior 11.0 gm/dL), CRP 20.7 mg/L, serum creatinine 2.7 mg/dL (prior 1.5 mg/dL), and urinalysis with proteinuria, sterile pyuria, and hematuria. CTA abdomen/pelvis revealed thickening of the duodenum with shotty mesenteric lymph nodes without ischemia. Enteroscopy revealed an erythematous duodenum and jejunum (figure A). Jejunal biopsy (figure B) revealed CD20 positive cells consistent with DLCBL (figure C). He was seen by oncology and treated with R-CHOP but later unfortunately expired due to COVID-19 complications. Discussion(s): Non small cell lung cancer and renal cell carcinoma are most commonly associated with IgA vasculitis. It may also be seen in both Hodgkin and Non-Hodgkin lymphomas in adult patients. If IgA vasculitis occurs after a malignancy is diagnosed, it may indicate that metastasis has occurred. Malignancy associated IgA vasculitis is more likely to have an incomplete response to steroids and requires treatment of the underlying malignancy to achieve remission. Our case illustrates posterior probability error and premature closure cognitive biases. We should consider alternative diagnoses rather than anchor on prior diagnoses even when presentations are similar. Our case also highlights the importance of considering occult malignancy in adults with diagnosis of IgA vasculitis.
ABSTRACT
Case report Background: Association of chronic spontaneous urticaria (CSU) with malignancies and worsening of urticaria during COVID-19 have been reported. The efficacy of treatment of CSU with omalizumab in the context of malignancies or COVID-19 is not well established. Method(s): Case report of a patient followed for 9 years with CSU. Data collected from Medical Records and interviews during consultations. Result(s): Female, 29 years-old, came to clinic in 2013 for investigation, diagnosed with CSU. She also presented mild asthma, allergic rhinitis and history of urticaria after taking amoxicillin. She had a positive autologous serum skin test, and positive skin tests to dust mite, cat, cockroach, peanut and milk. Her total IgE was 227IU/ mL. Anti-nuclear and anti-thyroid antibodies were negative;ERS 13mm, blood eosinophils 300/mm3, and stool exam negative for parasites. She showed no response to second generation antihistamines up to fourfold doses, with UCT < 6 and CU-QoL = 89. After 6 months, omalizumab was added at 300 mg subcutaneously, every 4 weeks. The patient showed immediate reactions after the two applications of omalizumab: first, diffuse pruritus and throat tightness;second, worsening of urticaria and pruritus, requiring iv medications. Treatment with omalizumab was stopped, she was kept on fourfold dose of bilastine with partial control of symptoms. In 2016, she presented worsening of urticaria (UCT = 1), weight loss of 6kg/2 months, daily fever and enlarged cervical lymph nodes, and was diagnosed with diffuse large B-cell non-Hodgkin's lymphoma. Following chemotherapy with cyclophosphamide, doxorubicin, vincristine, prednisone and rituximab, she presented complete resolution of urticaria. Two years after remission of the lymphoma, in 2019, she presented recurrence of urticaria, and treatment with fourfold dose of bilastine was reinitiated with control of symptoms (UCT = 16). Investigation ruled out recurrence of lymphoma. In May 2021, she was diagnosed with SARS-CoV- 2 infection. Symptoms of COVID-19 were runny nose and low grade fever, however urticaria got worse and no longer responsive to bilastine. Treatment with omalizumab was attempted, with no reactions and good efficacy after the first dose, with an UCT = 15, and urticaria remains controlled on treatment with omalizumab to present. Conclusion(s): In this report, we highlight the efficacy and safety of using omalizumab in a patient with refractory CSU associated with neoplasia and SARS-CoV- 2 infection.
ABSTRACT
Introducao: O linfoma da celula do manto (LCM) e uma doenca rara e agressiva com poucas alternativas terapeuticas. Mas com a introducao de inibidores de tirosina kinase de Bruton tem mudado a sobrevida a longo prazo. Objetivo: descricao de um caso clinico em portadora da doenca com insuficiencia renal cronica. Material e metodos: Descricao do caso clinico: Paciente feminina, 65 anos de idade, queixa de cansaco, dor abdominal, hepatoesplenomegalia, presenca de linfonodomegalias, emagrecimento de 5 kg em 6 meses, sudorese noturna, Hb = 8.8 g/dL, plaquetopenia de 118.000/mm3, albumina = 2.5 g/dL. Antecedente de HAS e DPOC. Diagnostico de Linfoma de celulas do manto em maio de 2021 por biopsia de adenomegalia inguinal. Tratamento instituido foi R-CHOP e RDHAP em meses alternados, porem apos o segundo ciclo evoluiu com edema agudo de pulmao volumoso, insuficiencia renal com necessidade dialitica diaria (IRA- KDIGO III multifatorial), intubacao orotraqueal e tratamento em unidade intensiva por quadro de choque septico (KPC). Realizou terceiro ciclo de QT com RCHOP, mas com a piora clinica foi aventada hipotese de cuidados paliativos. Mas com a melhora recebeu mais 3 tratamentos com rituximabe mensal, persistiu com falencia renal e necessidade de hemodialise. Recebeu alta hospitalar e introduzido ibrutinibe 560 mg ao dia em 09/11/2021 sem muitos efeitos adversos. Resultados: PETScan do diagnostico 26/05/2021 mostra linfonodos axilares, volumosa esplenomegalia, linfonodos mediastinais, retroperitoneais e inguinais, area focal de intensa concentracao na transicao retossigmoide e na pelve (SUVmax:12.5), moderado derrame pleural bilateral. PETScan antes da introducao do ibrutinibe 10/11/202: reducao do metabolismo dos linfonodos axilares bilaterais, das dimensoes do baco, mas persistencia da area focal na transicao do retossigmoide (SUVmax:10.15). 6 meses apos o tratamento: 23/06/2022, nao se observam areas focais de atividade metabolica glicolitica anomala (Score 1 de Deauville), persiste com esplenomeagalia homogenea. A paciente segue em tratamento, no momento com ibrutinibe e em hemodialise de segunda a sexta. Apresentou infeccao pelo coronavirus em janeiro de 2022 sem sequelas. Atualmente clinicamente assintomatica, ECOG=0 e exames laboratoriais normais exceto pelo aumento de ureia e creatinina. Discussao: A causa da insuficiencia renal desenvolvida durante a internacao pode ser explicada por varios fatores como a sindrome de lise tumoral, uso da medicamento cisplatina, historia de HAS previa e ao quadro septico. A paciente evoluiu com regressao do quadro de esplenomegalia, adenomegalias e da massa em retrossigmoide ao longo dos 6 primeiros meses e atualmente se encontra sem evidencia de doenca em uso de ibrutinibe ha 10 meses. A dose da medicacao nao foi ajustada em vigencia de realizacao de hemodialise se acreditando que a droga apresenta depuracao renal minima. Ha poucos casos descritos na literatura do uso de ibrutinibe em pacientes com insuficiencia renal grave com clearance < 30 mL/minuto avaliando a seguranca e eficacia de tratamento. Conclusao: Tratamento em paciente portador de Linfoma de celulas do manto com insuficiencia renal grave pode ser tratado com ibrutinibe. Em nosso caso houve sucesso terapeutico, mas e imprescindivel acompanhar a resposta pois o tratamento e continuo ate a progressao da doenca ou eventos adversos graves. Copyright © 2022
ABSTRACT
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
ABSTRACT
Background: Optimal consolidation for young R/R FL in the rituximab age remains uncertain and the benefit of ASCT is not clearly established. Aims: The FIL FLAZ12 trial (NCT01827605) is a prospective, multicenter, randomized, phase 3 trial, comparing RIT versus ASCT, as consolidation after chemoimmunotherapy, both followed by R maintenance in R/R FL. Methods: Pts aged 18-65 yrs, with R/R FL after 1 or 2 lines of chemoimmunotherapy, without significant comorbidities were enrolled. Patients received 3 courses of therapy chosen by the investigator among RCHOP, R-DHAP, R-FM, R-ICE, R-IEV or R-B. Pts achieving at least PR (according to Cheson et al. 2007) were randomized 1:1 to either RIT or ASCT before CD34+ collection. Conditioning for ASCT was BEAM or TEAM. RIT was given as previously described (Morschhauser et al., 2008). After consolidation, pts received R maintenance every 3 months for eight courses. Primary endpoint was PFS. Considering ASCT toxicity, it was hypothesized to be a superior choice, if capable of increasing 3-years PFS from 40% to 60% (two-side log-rank test with alpha of 5% and a power of 85%). Clinical secondary endpoints were ORR, CRR, OS, EFS and TTF. Results: Between Aug 2012, and Sep 2019, 164 pts were screened and 159 enrolled by 38 FIL Centers (enrolled population). Unfortunately, the study was prematurely closed due to low accrual. The data were analyzed on an ITT basis on May 2, 2021 with a median follow-up (mFU) from enrollment of 43 months and 75 PFS events. The two arms were clinically well balanced, with median age of 57 yrs (IQR 49-62), 55% male, 57% stage IV, 20% bulky disease. Tumor re-biopsy was performed in 79% pts. POD-24, retrospectively assessed was observed in 32% of pts. Two pts (1%) did not start treatment (non-confirmed histology and withdrawal). Sixteen (10%) pts discontinued before randomization (7 SD, 3 PD, 3 AE, 1 withdrawal, 2 poor compliance) and 141 (89%) were randomized to either RIT (71) or ASCT (70) (randomized population). Of these 19 (13%) (RIT 8, ASCT 11) did not receive the planned consolidation due to 7 PD, 4 AE, 1 medical decision, 2 poor mobilization, 2 withdrawals, 1 poor compliance, 2 protocol breaches, while 63 (89%) received RIT and 59 (84%) ASCT. After RIT, 61% of pts achieved CR and 23% PR, while after ASCT these were 70% and 9%. Estimated PFS at 3 yrs was 60% (95% CI: 46%-71%) in the RIT arm vs. 59% (95% CI:45%-70%) in the ASCT arm, p = 0.8613 (HR 0.96, 95%CI: 0.57,1.59). (Figure 1) 3yrs-OS was again superimposable in the two arms: 83% (95%CI: 69%-91%) in the RIT vs 85% (95% CI: 72%-91%) in the ASCT, p = 0.8310 (HR 1.10, 95%CI: 0.45,2.72). Grade ≥ 3 hematological toxicity was 46% in the RIT vs 94% in the ASCT arm (p < 0.001). For ASCT vs RIT grade ≥3 neutropenia occurred in 94% vs 41% of pts (p < 0.001). During follow-up, 4 pts died in remission: 1 AML (RIT), 2 SARS-COV2 infections (RIT) and 1 pneumonia (ASCT). Second cancers occurred in 3 pts after RIT and 7 after ASCT (p = 0.480). Multivariable analysis for PFS indicated POD-24, male sex, LDH and refractory disease as adverse parameters. Subgroup analysis for PFS including gender, age, LDH, POD-24 and extranodal disease show no subgroup favoring RIT nor ASCT. Image: Summary/Conclusion: Even if prematurely interrupted, our study demonstrated no meaningful difference in efficacy between ASCT and RIT, but ASCT was more toxic and more demanding for pts and health service. Both strategies induced a similar and favorable long-term outcome suggesting that consolidation programs milder than ASCT require further investigation in R/R FL.
ABSTRACT
Introduction: The Fungitell assay is an in vitro diagnostic test for the qualitative detection of (1-3)-beta-D-Glucan (BDG) in serum. It can be particularly useful in early diagnosis of fungal infections that would otherwise take weeks to finalize in culture.Description:This is a case of a 73 year old Filipino female with a history of diffuse large B-cell lymphoma status post RCHOP therapy, currently maintained on Ritixumab, and rheumatoid arthritis treated with Methotrexate who was admitted to the hospital with increasing shortness of breath for several weeks. In the Emergency Department she was hypoxic and required 2 liters of oxygen via nasal cannula and with 92% oxygen saturation. Her vital signs were otherwise normal. She was afebrile and WBC was 9.4. She had a negative respiratory viral PCR which included COVID-19. Infectious work up including sputum culture and urine antigens were also sent. A CT chest was performed and showed bilateral ground glass opacities suspicious for atypical pneumonia.There was concern for drug toxicity from Methotrexate which was subsequently suspended. A bronchoscopy and bronchoalveolar lavage (BAL) was performed to rule out infection prior to starting steroids for suspected pneumonitis. Cell count from the BAL revealed low neutrophils. There was negative growth over the next 48 hours. Steroids were initiated at 1 mg/kg daily and patient was discharged home with close outpatient follow up scheduled. A fungitell (serum beta D glucan) that was collected from the BAL had resulted after the patient was discharged home. The level returned very elevated (>500). The patient was contacted and she reported that her symptoms did not improve with the steroids. She was still requiring up to four liters of oxygen at home. She was asked to return to the hospital to work up an undiagnosed fungal or PJP pneumonia. A repeat bronchoscopy was performed and a PJP PCR was tested on the BAL. This returned positive. She was started on Bactrim for 14 days to treat PJP pneumonia. She was weaned down to 2 liters of oxygen and was doing well from a pulmonary standpoint at her outpatient follow up visit 2 weeks later. Discussion: The Fungitell assay test in this case was crucial to help guide us to the correct diagnosis. In patients who are immunocompromised, physicians should utilize specialty testing such as Fungitell when it is available. Compared to microbial fungal culture, Fungitell results faster, has a higher sensitivity and a higher negative predictive value. (Figure Presented).
ABSTRACT
Diffuse Large B-cell Lymphoma (DLBCL) is the most common form of non Hodgkin lymphoma, involving multiple organ system including lymph node, bone marrow, spleen etc. Among overall cases of DLBCL, 40% are extranodal in origin and stomach being the most common site. While most of the (60%) are not diagnosed until the disease reach stage 3 or 4. While in the present case, patient had predominant involvement of neck lymph nodes. Following the final diagnosis, patient was given first line treatment in the form of Rituximab, Cyclophosphamide, Hydroxydaunorubicin hydrochloride (doxorubicin hydrochloride), vincristine (Oncovin) and Prednisone (R-CHOP) regimen, to which patient didn’t respond and further the patient was given Rituximab, Ifosfamide, Carboplatin, and Etoposide (R-ICE)regimen, to which patient responded quickly. With Coronavirus Disease 2019 (COVID-19) pandemic, the patient encountered infection with its associated complication. The following case report is all about the timely management of DLBCL and patient’s survival with COVID-19 and its related complication. Haematological malignancy such as lymphomas, leukaemias, myelomas cause severe myelosuppression and lymphodepletion increasing the risk for development of COVID-19. Studies have shown that patients with malignancy had an estimated two-fold increased risk of contracting Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2) than the general population. The survival rates strongly depend on COVID-19 stage and other factors such as immune (neutropenia) status and systemic inflammation.
ABSTRACT
A Síndrome de Richter (SR) é uma condição rara caracterizada pela transformação da leucemia linfocítica crônica (LLC) mais frequentemente em linfoma difuso de grandes células B (LDCBG);todavia, menos comumente podendo se transformar em linfoma das células do manto blastoides (LCMB). A etiologia da SR é desconhecida até o momento;ainda não foram identificadas predisposições genéticas ou uma única alteração responsável por essa transformação da LLC em LCMB. Sua incidência é rara, ocorrendo transformação de LLC em 2% a 6% dos casos, e, destes, acredita-se que ocorra em < 3% dos casos por falta de evidências na literatura. O diagnóstico é realizado pela biópsia de medula óssea, por biópsia de linfonodos alterados e pelos marcadores imunohistoquímicos. O tratamento é baseado na quimioterapia e pode-se incluir o transplante de células-tronco. Esse estudo objetiva relatar e discutir a transformação da LCC em LCMB. Visto que, apesar de sua rara incidência, possui curso agressivo e de alto grau, o diagnóstico precoce se faz necessário para melhor prognóstico do paciente. Relata-se caso de paciente masculino, 63 anos, ex-tabagista pesado, ex-etilista pesado, com diagnóstico de LLC em 2011 em tratamento. Iniciada quimioterapia com 1 ciclo de rituximab em 2017, não respondendo à terapêutica. Tentou-se terapia de resgate em 2018 com rituximab + dexametasona + ciclofosfamida, sem sucesso. Iniciado em 2019 clorambucil, com resposta por 7 ciclos. Na admissão em 2020, para acompanhamento com o serviço de hematologia em hospital geral para sequência de tratamento de LLC, paciente mostra-se refratário. À ectoscopia massa bulky em região cervical à esquerda. Exames laboratoriais mostraram anemia macrocítica, leucopenia e plaquetopenia. Exames de imagem e biópsia de medula óssea revelaram esplenomegalia, linfonodomegalia paraesofágica, retrocural, mesentérica e os seguintes marcadores bioquímicos: CD20+;PAX-5+;CD5+;ciclina+;BCL2+;Ki67+;CD43+;CD3+;SOX-11+;MUM-1+;CD23-;CD10-;BCL6-;Tdt-. Conclui-se diagnóstico de síndrome de Richter com transformação LLC para LCMB, uma rara condição potencialmente relacionada à imunossupressão provocada pela doença linfoproliferativa crônica de etiologia ainda desconhecida. A evolução do paciente à nova terapêutica, o protocolo quimioterápico R-CHOP, mostrou melhora do quadro clínico no primeiro ciclo. No ínterim até o segundo ciclo, paciente contrai SARS-CoV-2 e evolui a óbito devido à infecção.
ABSTRACT
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.
ABSTRACT
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.
ABSTRACT
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).
ABSTRACT
Background. Most individuals diagnosed with mild to moderate COVID-19 are no longer infectious after day 10 of symptom onset and those with severe or critical illness from COVID are typically not infection after day 20 day of symptom onset. Recovered persons can continue to test positive for SARS-CoV-2 by PCR via detection of non-viable RNA in nasopharyngeal specimens for up to three months (or longer) after illness onset. It is also know known that severely immunocompromised patients may produce replication-competent virus greater than 20 days from symptom onset and may require, per CDC recommendations, "additional testing and consultation with infectious diseases specialists and infection control experts". We aim to discuss four case studies of severely immunocompromised patients who exhibited signs of persistent COVID-19 infection of COVID and how we managed transmission-based precautions in our hospital through sequencing and evaluation of cycle thresholds (CT) values and subgenomic RNA detection. Methods. Residual nasopharyngeal (NP) samples were collected on patients exhibiting persistent COVID like symptoms. These samples underwent N gene and N gene subgenomic RNA (sgRNA) real-time reverse transcription polymerase chain reaction (rRT-PCR) testing. Results. Analysis of longitudinal SARS-CoV-2 sequence data demonstrated within-patient virus evolution, including mutations in the receptor binding domain and deletions in the N-terminal domain of the spike protein, which have been implicated in antibody escape. See Figures 1 and 2. Figure 1. Timelines of Identified Patients 1 and 2 Patient 1: 46-year-old woman with recently diagnosed stage IV diffuse large B-cell lymphoma for which she was treated with 2 cycles of R-CHOP. Patient 2: 38-year-old woman with history of myelodysplastic syndrome, peripheral blood stem cell transplant with chronic graft versus host disease of the GI tract, skin, and eyes as well as CMV enteritis, and she was maintained on rituximab, mycophenolate mofetil, prednisone, and monthly IVIG without recent changes to her immunosuppression. Figure 2. Timeline of Identified Patients 3 and 4 Patient 3: 44 year-old man with prior history of thymoma s/p thymectomy Patient 4: 46 year-old man who was initially diagnosed with marginal zone lymphoma approximately 2.5 years ago. He was initially treated with bendamustine and rituximab and achieved remission. He was then continued on maintenance rituximab without significant complications for a planned two years. Conclusion. Differentiating between prolonged viral shedding of non-infectious RNA and persistent replicating viable virus can be difficult to determine without full evaluation of a patient's clinical picture and timeline. Consultation between laboratory, infectious diseases, and infection prevention experts to provide appropriate level of guidance for precautions and treatment may be warranted. Testing by PCR and analysis of CT values may provide key findings of viral replication in immunocompromised hosts, indicating the need for evaluation of additional treatment and maintaining isolation status in healthcare settings.
ABSTRACT
Background: Over a third of pts with 1L DLBCL do not respond to, or relapse after, rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP;[Sarkozy and Sehn. Ann Lymphoma 2019]). Despite recent advances, pts with R/R NHL have limited curative options. Glofitamab (Glofit) is a novel, T-cell-engaging bispecific antibody with a 2:1 molecular configuration that allows bivalent binding to CD20 on B cells and monovalent binding to CD3 on T cells. Unlike other CD20xCD3 bispecific antibodies, this format uniquely enables combination with anti-CD20 antibodies, including rituximab. Glofit monotherapy induces high response rates in R/R B-cell NHL (Hutchings et al. J Clin Oncol 2021). We present results of the ongoing NP40126 study (NCT03467373), designed to assess the feasibility and safety of Glofit + R-CHOP in R/R NHL (dose-escalation phase) and 1L DLBCL (safety run-in phase). Methods: R/R NHL dose-escalation: Pts (Eastern Cooperative Oncology Group performance status [ECOG PS] 0-2) received increasing Glofit doses in separate cohorts (70µg, 1800µg, 10mg and 30mg) plus standard R-CHOP for 6-8 cycles (each 21-day). To mitigate CRS risk, R- or obinutuzumab (G)-CHOP was given in Cycle (C)1, with the aim of tumor debulking. Glofit was given from C2 onwards. For 70µg and 1800µg cohorts, fixed-dose Glofit was given on C2 Day (D)8 and onwards. For 10mg and 30mg cohorts, step-up dosing was used to further mitigate CRS risk (2.5mg C2D8, 10mg C2D15, target dose C3D8 and onwards). Optional Glofit maintenance was permitted (every 2 months for <2 years;dose-escalation phase only). 1L DLBCL safety run-in: Pts (ECOG PS 0-3) received Glofit 30mg plus standard R-CHOP for 6-8 cycles (each 21-day). Pts received R-CHOP in C1;Glofit step-up dosing began in C2 (2.5mg C2D8, 10mg C2D15, 30mg C3D8 and onwards). Response rates were assessed by PET-CT (Lugano criteria;[Cheson et al. J Clin Oncol 2014]). CRS events were graded by ASTCT criteria [Lee et al. Biol Blood Marrow Transplant 2019]. Results: R/R NHL dose-escalation: At data cut-off (June 10, 2021), 31 pts (23 follicular lymphoma [FL];6 transformed FL;1 marginal-zone lymphoma;1 mantle-cell lymphoma) had received Glofit with R/G-CHOP. Median age was 62 years, median prior lines of therapy was 2 (range: 1-5). In efficacy-evaluable pts (n=31), after a median 9.0 months' (range: 0-29) follow-up, the overall response rate (ORR) was 90% (n=28) and complete response rate (CRR) was 77% (n=24). Median duration of response was not reached. The Figure shows change in tumor size. Grade (Gr) ≥3 adverse events (AEs) occurred in 28 (90%) pts, serious AEs in 21 (68%) pts and CRS in 17 (55%) pts (mostly low grade;majority after the first 2.5mg Glofit dose;Table). One (3%) pt had a Gr 5 AE (COVID-19 pneumonia not related to study treatment). AEs led to Glofit dose modification/interruption in 2 (6%) pts and Glofit withdrawal in 1 (3%) pt. Neurologic AEs (NAEs) occurred in 20 (65%) pts: Gr 1-2 (16 pts, 52%);Gr 3 (4 pts, 13%). Immune effector cell-associated neurotoxicity syndrome (ICANS)-like AEs were uncommon;a serious AE was reported in 1 pt only (Gr 3 epilepsy during the maintenance phase;resolved in 3 days). Neutropenia occurred in 24 (77%) pts. Median dose intensity was 100% for all R-CHOP components. 1L DLBCL safety run-in: At data cut-off, 13 pts were enrolled (safety population);of these, 4 pts received Glofit 30mg with R-CHOP and were efficacy-evaluable. Median age was 68 years, all pts had Ann Arbor Stage 3/4 disease. At interim assessment (C3), CRR was 100% (4/4). Of 13 pts, 1 (8%) had a CRS event (Gr 1 with fever only) after the first 2.5mg Glofit dose;no other CRS events observed. Gr ≥3 AEs occurred in 8 (62%) pts and Gr ≥3 AEs related to Glofit in 1 (8%) pt only. One (8%) pt had a serious AE and 1 (8%) pt had a Gr 5 AE (infusion-related reaction related to rituximab on C1D1). No AEs led to Glofit or R-CHOP dose interruptions. NAEs occurred in 3 (23%) pts (all Gr 1-2;none were ICANS-like). Neutropenia occurred in 6 (46%) pts. Median dose intensity was 10 % for all R-CHOP components. Conclusions: Initial data show that Glofit + R-CHOP has tolerable safety in R/R NHL and 1L DLBCL. R-CHOP dose intensity was maintained in all pts. The very low CRS rate and no neurotoxicity in 1L DLBCL may render Glofit particularly suitable for the outpatient setting without the need for hospitalization. Updated data, including end-of-treatment responses from the 1L DLBCL safety run-in phase, will be presented. [Formula presented] Disclosures: Ghosh: Seattle Genetics: Consultancy, Honoraria, Speakers Bureau;Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau;Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding, Speakers Bureau;AbbVie: Honoraria, Speakers Bureau;Karyopharma: Consultancy, Honoraria;AstraZeneca: Consultancy, Honoraria, Speakers Bureau;ADC Therapeutics: Consultancy, Honoraria;Adaptive Biotech: Consultancy, Honoraria;TG Therapeutics: Consultancy, Honoraria, Research Funding;Genmab: Consultancy, Honoraria;Bristol Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau;Epizyme: Honoraria, Speakers Bureau;Incyte: Consultancy, Honoraria;Janssen: Consultancy, Honoraria, Speakers Bureau;Genentech: Research Funding. Townsend: Celgene (Bristol-Myers Squibb): Consultancy, Honoraria;F. Hoffmann-La Roche Ltd: Consultancy, Honoraria. Dickinson: Amgen: Honoraria;Celgene: Research Funding;Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau;Takeda: Research Funding;Gilead Sciences: Consultancy, Honoraria, Speakers Bureau;MSD: Consultancy, Honoraria, Research Funding, Speakers Bureau;Janssen: Consultancy, Honoraria;Bristol-Myers Squibb: Consultancy, Honoraria;Roche: Consultancy, Honoraria, Other: travel, accommodation, expenses, Research Funding, Speakers Bureau. Topp: Celgene: Consultancy, Research Funding;Janssen: Consultancy;Universitatklinikum Wurzburg: Current Employment;Kite, a Gilead Company: Consultancy, Research Funding;Novartis: Consultancy;Roche: Consultancy, Research Funding;Gilead: Research Funding;Regeneron: Consultancy, Research Funding;Macrogeniecs: Research Funding;Amgen: Consultancy, Research Funding. Santoro: Sandoz: Speakers Bureau;Eli-Lilly: Speakers Bureau;Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;AstraZeneca: Speakers Bureau;Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Celgene: Speakers Bureau;Amgen: Speakers Bureau;AbbVie: Speakers Bureau;Roche: Speakers Bureau;BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Eisai: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Takeda: Speakers Bureau;Sanofi: Consultancy;Arqule: Consultancy, Speakers Bureau;Novartis: Speakers Bureau;Bayer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;MSD: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Crump: Novartis: Membership on an entity's Board of Directors or advisory committees;Kyte/Gilead: Membership on an entity's Board of Directors or advisory committees;Epizyme: Research Funding;Roche: Research Funding. Morschhauser: Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees;Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees;Genentech, Inc.: Consultancy;Genmab: Membership on an entity's Board of Directors or advisory committees;Roche: Consultancy, Speakers Bureau;BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees;Chugai: Honoraria;Incyte: Membership on an entity's Board of Directors or advisory committees;Servier: Consultancy;AstraZenenca: Membership on an entity's Board of Directors or advisory committees;Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees;F. Hoffmann-La Roch Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;Celgene: Membership on an entity's Board of Directors or advisory committees;AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees;Janssen: Honoraria. Mehta: Kite/Gilead;Roche-Genetech;Celgene/BMS;Oncotartis;Innate Pharmaceuticals;Seattle Genetics;Incyte;Takeda;Fortyseven Inc/Gilead;TG Therapeutics;Merck;Juno Pharmaceuticals/BMS: Research Funding;Seattle Genetics;Incyte;TG Therapeutics: Consultancy;Seattle Genetics;Incyte;TG Therapeutics: Membership on an entity's Board of Directors or advisory committees. Panchal: F. Hoffmann-La Roche Ltd: Current Employment. Wu: F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company. Barrett: Roche Products Ltd: Current Employment;F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company. Humphrey: Roche: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Qayum: F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company. Hutchings: Novartis: Research Funding;Janssen: Honoraria, Research Funding;Incyte: Research Funding;Genentech: Honoraria, Research Funding;Celgene: Research Funding;Takeda: Consultancy, Honoraria, Research Funding;Roche: Consultancy, Honoraria, Research Funding;Genmab: Consultancy, Honoraria, Research Funding. OffLabel Disclosure: Glofitamab is a full-length, humanized immunoglobulin G1 bispecific antibody with a 2:1 molecular format that facilitates bivalent binding to CD20 on B-cells, and monovalent binding to CD3 on T-cells. Glofitamab redirects T cells to engage and eliminate malignant B cells. Glofitamab is an investigational agent. Rituximab (Rituxan) is aCD20-directed cytolytic antibody indicated for the treatment of adult pts with: relapsed or refractory, low grade or follicular, CD20-positive, B-cell NHL as a single agent;previously untreated follicular, CD20-positive, B-cell NHL in combination with first-line chemotherapy (chemo) and, in pts achieving a CR or PR to a rituximab product in combination with chemo, as single-agent maintenance therapy;non-progressing (including stable disease), low-grade, CD20 positive, B-cell NHL as a single agent after first-line CVP chemo;previously untreated diffuse large B-cell, CD20-positive, NHL in combination with CHOP or other anthracycline-based chemo regimens;previously untreated and previously treated CD20-positive CLL in combination with fludarabine and cyclophosphamide.
ABSTRACT
TYPE: Case Report TOPIC: Chest Infections INTRODUCTION: Irpex lacteus is a basidiomycete found on decaying wood. Known uses include the saccharification of wheat for ethanol production;decolorization of textile effluent wastewater;and detoxification of effluents from the debittering process of olives. Rarely found to cause a human mycosis, and ours is the first adult pulmonary case that is reported. CASE PRESENTATION: 61 yr old male with Stage 4ae B cell lymphoma and bcl6 amplification s/p RCHOP, presented with recurrent right effusions. The patient yielded 500mL of transudative effusion. No prior COVID infections and he was fully vaccinated. He worked by cutting down wood in the forests. No complaints of hemoptysis, night sweats, or weight loss. PET scan revealed anterior mediastinal calcifications, a large right effusion, and a LLL nodule. The LLL nodule was biopsied, and pathology revealed necrotizing granulomas. Bronchoscopy with EBUS did not reveal granulomas within the mediastinal lymph nodes. BAL from the LLL revealed a fungal culture positive for I. lacteus. The patient did not undergo further treatment for the positive fungal culture. Follow up PET scan did not reveal progression of his lymphoma. DISCUSSION: The two documented cases of I. lacteus were within a 9 yr old with ALL and pulmonary abscess;and a 73 yr old with sarcoidosis and fungal meningitis. Due to his clinical stability, he did not require amphotericin B, as was needed in the two prior cases. CONCLUSIONS: I.lacteus is a rare cause of a human mycosis. Further investigation would be warranted in terms of treatment, as there are so few cases. DISCLOSURE: Nothing to declare. KEYWORD: fungal
ABSTRACT
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)
ABSTRACT
Background The biosimilar rituximab (Redditux) was approved in Turkey for all indications of the reference molecule (MabThera) in March 2018. Large clinical trials and real-life experiences are lacking in hematological malignancies. Aims We aimed to evaluate the efficacy and safety of Redditux in de-novo diffuse large B-cell lymphoma (DLBCL). Methods Our institution decided to provide Redditux for hematological indications since February 2019. We retrospectively analyzed medical records of 51 consecutive de-novo DLBCL patients (pts) diagnosed between February 2019 and September 2019 in the hematology department of Istanbul University Istanbul Medical Faculty. We compared the response rates with historical controls treated with MabThera-CHOP at Cerrahpaşa Medical Faculty. Our study was approved by I.U. Istanbul Medical Faculty Ethical Committee (2019/1454). Results A total of 51 pts without CNS involvement received Redditux-CHOP. Median follow-up was 24 months (range: 8-31). A median of 6 cycles of biosimilar (range: 4-8) was administered. Four pts with high CNS-IPI score received four intrathecal methotrexate injections and 13 pts had additional radiotherapy for their initial bulky disease. The patient characteristics and response rates of the Redditux and historical MabThera cohorts are summarized in Table 1. Apart from 6 cases who were refractory to Redditux-CHOP, 8 pts had progressive disease (6 with CR, 1 with PR and 1with SD) in the follow-up. The median time to relapse was 11.5 months for 6 cases who had CR following first-line treatment. Five of 8 cases with PD experienced CNS relapse. Their CNS-IPI score (Schmitz et al. J Clin Oncol 2016) were low in 2 pts, intermediate in 2 pts and high in 1 patient. Of 11 pts with bone involvement at the time of diagnosis, three cases had CNS relapse (p=0.028). Two pts with CNS relapse were treated with intrathecal chemotherapy only due to their poor performance status. Eight pts received salvage combination chemotherapy [R-ICE (n=3);R-benda (n=3);R-DHAP (n=1);MATRix (n=1)] and two of them responded. One of these 2 cases underwent auto-SCT and the other proceeded to allo-SCT;however, he died during conditioning treatment. Ten pts died in the follow-up. Causes of death were progressive disease (n=7, two cases with CNS involvement), infection during allo-conditioning (n=1), post-COVID herpes zoster infection (n=1) and unknown (n=1). The 24 month PFS and OS rates were 75.8% (95% CI: 0.61-0.85) and 80.3% (95% CI: 0.67-0.89) for Redditux cohort, respectively. In the historical MabThera group, the 24 month PFS and OS rates were 85.2 (95% CI: 0.79-0.90) and 81.4% (95% CI: 0.75-0.86), respectively. For pts with high R-IPI score in the Redditux cohort (3-5);the 24-month PFS and OS rates were 54.2% (95% CI: 0.29-0.74) and 55.6% (95% CI: 0.31-0.75), respectively. In the historical Mabthera group, the 24-month PFS and OS rates were 68.7% (95% CI: 0.53-0.80) and 59.4% (95% CI: 0.47-0.70), respectively. Although the PFS rates seems to be worse in high R-IPI cases receiving Redditux, the difference was not significant (p=0.18;Figure 1). AEs were reported in 51% (n=26) of patients. Most common AE was grade 2 infusion reactions (shivering, nausea, fever) requiring medical intervention in 20% of pts, accompanied with rash in half of them. Grade 3&4 AEs were leucopenia (n=2;4%), neutropenia (n=20;39%) febrile in 2 cases, anemia (n=6;12%), thrombocytopenia (n=3;6%). Grade 2 pneumonia (n=2) and urinary tract infections (n=2) were other infectious complications. Conclusion Although the PFS rate at 24 months in high-IPI group treated with Redditux seems to be lower compared to MabThera treated historical control group, survival rates were not significantly different. Our results should be cautiously evaluated due to small sample size. Compared to the original trial of MabThera added to CHOP based regimen, (Coiffier et al N Eng J Med. 2002), our CR rates in stage 2-4 pts seem to be slightly lower (70.7% vs 76%), although the OS rates are quite similar (86.3% vs 82%). Grade 3&4 neutrop nia requiring empirical administration of G-CSF was 39% in our cohort. Infusion reactions were observed in 20% of pts, which was reported to be around 30% with original molecule (Patel et al. Clin Lymphoma Myeloma Leuk 2019). The CNS relapse rate was relatively high (9.8%) in our cohort. Prospective randomized clinical trials are needed to determine the efficacy and safety profile of Redditux. [Formula presented] Disclosures: Ferhanoglu: Takeda Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees;Roche: Membership on an entity's Board of Directors or advisory committees;Janssen: Membership on an entity's Board of Directors or advisory committees;Abbvie: Membership on an entity's Board of Directors or advisory committees.
ABSTRACT
Background: Waldenström macroglobulinemia (WM) is a rare, indolent B-cell lymphoproliferative disorder. After the STiL-1 trial (Rummel MJ. Lancet. 2013;381(9873):1203-1210) demonstrated significant benefit in a subgroup analysis as well as reduced toxicity using bendamustine and rituximab (BR) compared to R-CHOP (N=41 enrolled WM patients), BR became the preferred immunochemotherapy (IC) regimen for all patients with symptomatic treatment naïve (TN) WM in British Columbia (BC) since 2014. Prior to the introduction of BR, the combination of rituximab, cyclophosphamide, vincristine, and prednisone (RCVP), was the standard of care in BC for this population since 2004, given its widespread use across a broad range of indolent B-cell lymphomas. We report a population-based analysis evaluating outcomes in TN-WM patients comparing BR with RCVP. Methods: The BC Cancer Centre for Lymphoid Cancer Database was used to identify TN-WM patients treated with BR or RCVP as their first systemic therapy between August 1, 2004 - August 1, 2020. A period of observation but no prior to systemic therapy was permitted. All patients had clinicopathologically confirmed lymphoplasmacytic lymphoma and measurable monoclonal IgM. Event-free survival (EFS) was defined as time from start of IC to progression, relapse, initiation of alternative therapy, histologic transformation, or death due to any cause. Early progression (POD24) was defined as relapse or progression, death from lymphoma, or treatment toxicity within 24 months of initiation of systemic therapy. Outcomes were compared with a historical cohort of patients treated with frontline RCVP. Responding patients were eligible to receive maintenance rituximab (MR) every 3 months for 2 years since 2006;however this was discontinued in 2020 when a subgroup analysis of the MAINTAIN trial (Rummel MJ. Blood 2019;134 (Supplement_1): 343), showed a lack of PFS benefit after BR, coupled with safety and vaccine response concerns during the COVID-19 pandemic. Results: A total of 111 patients with WM were identified;57 treated with BR, 54 treated with RCVP. Median age was 69 years (range 33-89) and baseline characteristics (Table 1), were well-balanced. A higher proportion of RCVP-treated patients received >4 cycles of chemotherapy (81% vs 65%, p=0.049). After IC, 75 (68%) received MR, with 36 (63%) and 39 (72%) in the BR and RCVP groups respectively (p=0.3). Median follow-up from diagnosis for all living patients was 5.9 years (range 0.8-19.2), with median 4.4y vs 9.8y for BR and RCVP respectively. EFS estimates at 4-years achieved with BR were 57% (95% CI 40-71%) compared to RCVP 60% (95% CI 45-72%), p=0.5 (Figure 1). Median EFS was established for RCVP due to longer duration of follow up at 6.3 years (95% CI 3.6-11.8y). Overall survival (OS) estimates at 4-years were 74% (95% CI 57-85%) and 81% (95% CI 67-89%) for BR and RCVP patients respectively, p=0.6. Worse performance status (≥2) was the only pre-treatment factor identified as significant for inferior EFS. A sub-analysis limited to patients that received >4 cycles of IC also showed no clear difference in outcomes between BR and RCVP. Median time to transformation was 6.5y (5.5-13y), with only 3 late biopsy-proven events. Early progression (POD24) has occurred in 19 (18%) patients, with inferior survival observed in patients that had an early event compared with a reference cohort (2-years event free), however this did not reach statistical significance (p=0.3) (Figure 1). Conclusion: This population-based analysis of TN-WM patients treated with upfront IC confirms the excellent outcomes that can be achieved with a finite course of therapy. In contrast to prior studies, similar outcomes were observed with RCVP and BR. Further, regardless of front-line therapy, POD24 may be associated with inferior outcome but larger studies are needed. To our knowledge, this study is the first to make a direct comparison between BR and RCVP, and one of the largest restricted to IC-treated TN-WM. This data supports RCVP as a viable option, and should ser e to inform clinicians, patients, and policy makers in decision-making when considering upfront therapeutic options, and when considering indefinite alternative regimens such as BTK inhibitors. [Formula presented] Disclosures: Gerrie: AbbVie: Honoraria, Research Funding;Janssen: Honoraria, Research Funding;Astrazeneca: Honoraria, Research Funding;Sandoz: Honoraria;Roche: Research Funding. Savage: Servier: Consultancy, Honoraria;Astra-Zeneca: Consultancy, Honoraria;BMS: Consultancy, Honoraria, Other: Institutional clinical trial funding;Seattle Genetics: Consultancy, Honoraria;Merck: Consultancy, Honoraria, Other: Institutional clinical trial funding;Takeda: Other: Institutional clinical trial funding;AbbVie: Consultancy, Honoraria;Roche: Research Funding;Beigene: Other: Institutional clinical trial funding;Genentech: Research Funding. Villa: Roche: Honoraria;Janssen: Honoraria;Lundbeck: Honoraria;Celgene: Honoraria;Seattle Genetics: Honoraria;AbbVie: Honoraria;AstraZeneca: Honoraria;Gilead: Honoraria;NanoString Technologies: Honoraria. Scott: BC Cancer: Patents & Royalties: Patent describing assigning DLBCL COO by gene expression profiling–licensed to NanoString Technologies. Patent describing measuring the proliferation signature in MCL using gene expression profiling.;Abbvie: Consultancy;Janssen: Consultancy, Research Funding;AstraZeneca: Consultancy;Rich/Genentech: Research Funding;Celgene: Consultancy;Incyte: Consultancy;NanoString Technologies: Patents & Royalties: Patent describing measuring the proliferation signature in MCL using gene expression profiling. Craig: Bayer: Consultancy. Slack: Seagen: Consultancy, Honoraria. Sehn: Debiopharm: Consultancy;Novartis: Consultancy;Genmab: Consultancy. Freeman: Amgen: Honoraria;Celgene: Honoraria;Sanofi: Honoraria, Speakers Bureau;Incyte: Honoraria;Abbvie: Honoraria;Teva: Research Funding;Roche: Research Funding;Bristol Myers Squibb: Honoraria, Speakers Bureau;Janssen: Honoraria, Speakers Bureau;Seattle Genetics: Honoraria.
ABSTRACT
Introduction Tafasitamab is a humanized, Fc-modified, anti-CD19 monoclonal antibody (mAb) shown to enhance antibody-dependent cellular cytotoxicity and phagocytosis. It is approved by the FDA under accelerated approval (July 2020) in combination with lenalidomide (LEN) for treatment of relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) in adult patients ineligible for autologous stem cell transplantation. To evaluate if newly diagnosed DLBCL patients would also benefit from this regimen, this Phase Ib study (First-MIND;NCT04134936) was designed to first assess the safety and tolerability of tafasitamab ± LEN in addition to rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) in newly diagnosed DLBCL patients. Methods Eligible patients were ≥18 years old, with treatment-naïve DLBCL, international prognostic index (IPI) 2-5 and Eastern Cooperative Oncology Group performance status (ECOG PS) 0-2. Patients with known double- or triple-hit and transformed lymphoma were excluded. Patients were randomized 1:1 to either six 21-day [D] cycles of R-CHOP (R-CHO, D1;P, D1-5) + tafasitamab (12 mg/kg IV, D1, 8, 15) (Arm A) or R-CHOP + tafasitamab + LEN (25 mg orally, D1-10) (Arm B). Granulocyte colony-stimulating factor and venous thromboembolism prophylaxis was mandatory. The primary safety endpoint was incidence of treatment-emergent adverse events (TEAEs);secondary endpoints included overall response rate (ORR), positron emission tomography (PET)-complete response (CR) rate, and partial response (PR) rate at end of treatment (EOT). Tumor measurements by PET/CT or PET/MRI at EOT were performed according to Lugano 2014 criteria within 6±2 weeks after Day 21 of the last treatment cycle the patient started. Results From December 2019 to August 2020, 83 patients were screened in nine countries across 34 sites in Europe and the US;66 were randomized (Arm A, n=33;Arm B, n=33). Data cut-off for this analysis: 13 March 2021. Median age was 64.5 years (range 20-86). Many patients had high-risk disease: IPI 2: 24/66 (36.4%), IPI 3: 29/66 (43.9%), IPI 4: 11/66 (16.7%), IPI 5: 2/66 (3.0%);ECOG PS ≥2: 6/66 (9.1%). Most patients had Stage III/IV disease 62/66 (93.9%);29/66 (43.9%) had bulky disease. All patients experienced at least one TEAE. The most frequent Grade ≥3 TEAEs by system organ class were blood and lymphatic disorders (81.8% patients overall), experienced by 24 patients (72.7%) in Arm A and 30 patients (90.9%) in Arm B. Grade ≥3 neutropenia and thrombocytopenia occurred in 19/33 (57.6%) and 4/33 (12.1%) (Arm A), and 28/33 (84.8%) and 12/33 (36.4%) (Arm B) patients, respectively;Grade ≥3 febrile neutropenia was experienced by 6/33 (18.2%) patients in each arm. Grade ≥3 infusion-related reactions to both rituximab and tafasitamab occurred in no patients in Arm A and one patient (3.0%) in Arm B, and 7/33 (21.2%) (Arm A) and 9/33 (27.3%) (Arm B) patients had a Grade ≥3 infection and/or infestation (Figure 1). Serious TEAEs occurred in 14/33 (42.4%) patients in Arm A and 17/33 (51.5%) patients in Arm B. Two out of 33 (6.1%) and one out of 33 (3.0%) patients discontinued study treatment due to TEAEs in Arms A and B, respectively. There were four deaths unrelated to tafasitamab and/or LEN (COVID-19 pneumonia, sepsis, and urosepsis). The average relative dose intensity of R-CHOP in each cycle was maintained in both arms. ORR at EOT was observed in 25/33 patients (75.8%;95% confidence interval [CI]: 57.7-88.9) in Arm A and 27/33 patients (81.8%;95% CI: 64.5-93.0) in Arm B. Conclusion These data suggest that both regimens are tolerable and do not impair dosing and scheduling of R-CHOP. Toxicities were similar to those expected with R-CHOP with or without LEN. With tumor follow-up still ongoing, the ORR at EOT suggests that patients with treatment-naïve DLBCL may achieve clinically meaningful efficacy tafasitamab and LEN in addition to standard treatment. A Phase III, multicenter, randomized, double-blind, placebo-controlled trial will assess efficacy and safety of R-CHOP + t fasitamab + LEN vs R-CHOP in newly diagnosed patients with high intermediate and high risk DLBCL, and is currently recruiting (frontMIND study;NCT04824092). Funding: MorphoSys AG. [Formula presented] Disclosures: Belada: Roche: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding;Gilead Sciences: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding;Janssen-Cilag: Consultancy, Research Funding;Takeda: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding;MorphoSys AG: Consultancy, Research Funding;Debiopharm Group: Consultancy;Pharmacyclics: Research Funding;Archigen Biotech: Research Funding;Reddys: Research Funding. André: Johnson & Johnson: Research Funding;Roche: Other: Travel/accomodation/expenses, Research Funding;Incyte: Consultancy;Gilead: Consultancy, Other: Travel/Accommodations/Expenses;Karyopharm: Consultancy;Bristol-Myers-Squibb: Consultancy, Other: Travel/Accommodations/Expenses;Takeda: Consultancy, Research Funding;Celgene: Other: Travel/accomodation/expenses;AbbVie: Other: Travel/accomodation/expenses. Pérez Persona: Amgen: Consultancy, Other: Support for attending meetings and/or travel, Speakers Bureau;BMS/Celgene: Consultancy, Other: Support for attending meetings and/or travel, Speakers Bureau;AbbVie: Other: Support for attending meetings and/or travel, Speakers Bureau;Takeda: Speakers Bureau;Sanofi: Consultancy, Speakers Bureau;AstraZeneca: Speakers Bureau;GSK: Consultancy;Incyte: Consultancy. Staber: Roche: Consultancy, Honoraria, Research Funding;AbbVie: Consultancy, Honoraria;Gilead: Consultancy, Honoraria;Janssen: Consultancy, Honoraria;Astra Zeneca: Consultancy, Honoraria;Takeda: Consultancy, Research Funding;MSD: Consultancy, Honoraria;BMS: Consultancy, Honoraria;Incyte: Consultancy, Honoraria, Research Funding;Beigene: Consultancy, Honoraria. Trneny: AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses;Amgen: Consultancy, Honoraria;Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses;Gilead Sciences: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses;Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses;MorphoSys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses;Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses;Celgene: Consultancy;1st Faculty of Medicine, Charles University, General Hospital in Prague: Current Employment;Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;Portola: Honoraria, Membership on an entity's Board of Directors or advisory committees;AstraZeneca: Honoraria. Brackertz: MorphoSys AG: Current Employment. Shah: MorphoSys AG: Current Employment. Sporchia: MorphoSys AG: Current Employment. Burke: MorphoSys: Consultancy;Adaptive Biotechnologies: Consultancy;Verastem: Consultancy;AstraZeneca: Consultancy;Bristol Myers Squibb: Consultancy;Kymera: Consultancy;X4 Pharmaceuticals: Consultancy;AbbVie: Consultancy;SeaGen: Consultancy, Speakers Bureau;Kura: Consultancy;Roche/Genentech: Consultancy;Epizyme: Consultancy;Beigene: Consultancy, Speakers Bureau. Nowakowski: Celgene, NanoString Technologies, MorphoSys: Research Funding;Celgene, MorphoSys, Genentech, Selvita, Debiopharm Group, Kite/Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Tafasitamab is a humanized Fc-modified cytolytic CD19 targeting monoclon l antibody. In combination with lenalidomide (LEN), it received accelerated approval in July 2020 for adult patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) not otherwise specified (NOS), including arising from lowâ€'grade lymphoma, who are ineligible for autologous stem cell transplant (ASCT). Following FDA approval, we are now evaluating the safety and efficacy of tafasitamab in combination with LEN as an add-on to first-line therapy with R-CHOP in newly diagnosed patients with DLBCL.
ABSTRACT
COVID-19, caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has become a global pandemic. Patients with hematological disorders are known to be at high risk of morbidity and mortality from COVID-19, and vaccines against SARS-CoV-2 have been rapidly developed. Although mRNA vaccines against SARS-CoV-2 are reported to be effective, efficacy in patients with hematological malignancies who have received anti-CD20 antibody treatment remains unclear. Here, we prospectively evaluated the efficacy of BNT162b2 mRNA COVID-19 vaccine in patients with B-cell malignancies treated with anti-CD20 antibody. We first evaluated antibody titers in 12 healthy volunteers (median age 75.5 years, range 57-82) and three lymphoma patients undergoing R-CHOP therapy (73, 81, and 81 years old) who had received 2 vaccine doses of BNT162b2 at pre-vaccination, 21 days after the first dose and 14 days after the second dose of vaccination. IgG antibody titers for S1 protein were measured in serum samples by ELISA. In healthy control subjects, titers were clearly increased. In contrast, no patient treated with R-CHOP developed antibodies even after the second vaccination (Figure A). To determine the SARS-CoV-2-specific T-cell reactivity in these three patients, we evaluated interferon (IFN)-γ response to the SARS-CoV-2 spike peptide before and after the second vaccination dose, and detected IFN-γ responses after vaccination in all three patients (Figure B). Next, to investigate the duration of the effect of anti-CD20 antibody on antibody production to BNT162b2, we enrolled 36 patients (median age 74 years, range 50-87) who had received the final dose of anti-CD20 antibody 48-1320 (median 571) days before vaccination. S1 antibody titers were measured 14 days after the second dose of vaccination. Diagnoses included diffuse large B-cell lymphoma (n = 21), follicular lymphoma (n = 9), lymphoplasmacytic lymphoma/Waldenström's macroglobulinemia (n = 3), and mantle cell lymphoma (n = 3). Thirty-four patients had received rituximab-based and 2 had received obinutuzumab-based therapy, with a median of 6 (range 3-20) courses. No patient had received any chemotherapy after the last anti-CD20 antibody dose. No patient vaccinated within close to one year or sooner after the last anti-CD20 antibody administration showed an increase in titers. Furthermore, titers in most patients were lower than in healthy volunteers even among those vaccinated more than three years after the last administration (Figure C). Finally, we investigated surrogate markers of antibody production ability. We found no relationship between the percent of B-cells (CD19-positive cells) and S1 antibody titers (Figure D), whereas all patients (n = 9) with total IgG level below lower normal limit (< 870 mg/dl) had low S1 antibody titers (< 0.16), below the lowest optical density (O.D.) value in healthy donors (Figure E). These findings indicate that the antibody-mediated response to vaccination in patients following treatment with anti-CD20 antibody was considerably impaired for an extended time. Alternative protection strategies for these patients are therefore warranted. Although T-cell responses were detected, we recommend that these patients continue to wear a face mask and wash their hands to prevent COVID-19 even after vaccination. [Formula presented] Disclosures: Yakushijin: Chugai pharmaceutical Co. Ltd.: Research Funding;Jazz pharmaceuticals: Research Funding;Nippon Shinyaku: Honoraria. Kiyota: Bristol-Myers Squibb: Honoraria, Research Funding;Ono Pharmaceutical: Honoraria, Research Funding;Astra-Zeneca: Honoraria, Research Funding;Roche Phamaceuticals: Research Funding;Merck Biopharma: Honoraria;Merck Sharp & Dohme: Honoraria;Eisai: Honoraria;Bayer: Honoraria. Matsuoka: Takeda Pharmaceutical Company: Research Funding;Sysmex: Research Funding. Minami: Behring: Research Funding;CSL: Research Funding;Yakult Honsha: Research Funding;Nippon Shinyaku: Research Funding;Astellas Pharma: Research Funding;Asahi-Kasei Pharma: Research Funding;Eli Lilly: H noraria, Research Funding;Taiho Pharmaceutical: Honoraria, Research Funding;Takeda Pharmaceutical: Honoraria, Research Funding;Sanofi: Honoraria, Research Funding;Pfizer: Honoraria, Research Funding;Ono Pharmaceutical: Honoraria, Research Funding;Novartis: Honoraria, Research Funding;MSD: Honoraria, Research Funding;Merck Serono: Honoraria, Research Funding;Kyowa-Kirin: Honoraria, Research Funding;Eisai: Honoraria, Research Funding;DaiichiSankyo: Honoraria, Research Funding;Chugai Pharmaceutical: Honoraria, Research Funding;Bristol-Myers Squibb: Honoraria, Research Funding;Boehringer Ingelheim: Honoraria, Research Funding;Bayer Yakuhin: Honoraria, Research Funding;Nippon Kayaku: Research Funding;Celgene: Honoraria;Ohtsuka Pharmaceutical: Honoraria;Shire Japan: Honoraria;Genomic Health: Honoraria;Abbvie: Honoraria.