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Introducao: O acometimento do sistema nervoso central (SNC) e raro nas doencas linfoproliferativas B cronicas, sendo mais frequente a recaida nos linfomas nao-Hodgkin agressivos, porem a era pos Rituximab promoveu um ganho para esse perfil de pacientes. Objetivo: Relatar o envolvimento de SNC em 04 pacientes com doencas linfoproliferativas B cronicas e indolentes e revisar a literatura. Relato de caso: Caso 1: Homem, 53 anos, com leucemia linfoide cronica (LLC) Binet A desde 2012 e delecao 17p, apresentou crise convulsiva e rebaixamento neurologico em 12/2021. O liquor mostrou 18,3% de celulas B CD5+, CD19+, CD200+, recebeu imunoquimio intratecal e ibrutinibe sem resposta, LCR ainda infiltrado. Caso 2: Homem, 56 anos, com LLC Binet A desde 07/2021 evoluiu com abrupta piora cognitiva, RNM encefalica previa normal, novo exame em 02/2022 mostrou lesoes expansivas infiltrativas e nodulares intra-axiais bilaterais, compativeis com LNHDGCB (BCL-2+, CD20+, c-Myc+, Ki-67+, MUM1+), LCR normal, tratado com metotrexate (MTX) em altas doses, sem resposta. Caso 3: Mulher, 56 anos, com LNH folicular EC IVA em 2019, recebeu 06 ciclos de R-CHOP e manutencao por 02 anos, em remissao clinica. Em 04/2022 cursou com rapido agravo neurologico. A RNM mostrou lesoes na substancia branca nos hemisferios cerebrais, LCR infiltrado por celulas CD19, CD23, CD20, CD10 positivas, tratada com Ara C em altas doses, regressao das lesoes encefalicas, LCR ainda infiltrado. Caso 4 - Homem, 64 anos, com linfocitose, assintomatico desde 2011, IF de SP CD5- CD20+, CD22+, CD79b+, CD200+, evoluiu em 01/2022 subitamente com rebaixamento neurologico, entubado, LCR com 52,8% de linfocitos B CD19+, CD 20+, CD200+. Intercorreu com infeccao pelo SARS-Cov 19, complicacoes clinicas e obito. Discussao: O envolvimento do SNC nas doencas linfoproliferativas, tanto na apresentacao inicial ou na recidiva, e raro, podendo ser leptomeningeo disseminado e/ou parenquimatoso. Raramente descrito, o acometimento meningeo na LLC e objeto de discussao quanto ao impacto prognostico e ao tratamento. A infiltracao do SNC e mais descrita nos linfomas agressivos em cerca de 5% dos casos. Descrevemos 04 casos com envolvimento SNC em patologias de comportamento tipicamente indolente. Lemma et al. exploraram o papel dos marcadores biologicos que podem conferir as celulas do linfoma tropismo pelo SNC, altos niveis de Integrina alpha 10 e PTEN em amostras de tecido foram associadas a este tropismo, enquanto a expressao de CD44 e caderina-11 parecem ser protetivas, estes dados sao preliminares e precisam de validacao. A apresentacao clinica e heterogenea, desde alteracao comportamental, cefaleia, meningismo, hidrocefalia, e hipertensao intracraniana. No tratamento do linfoma primario de SNC o MTX e fundamental, mas ainda nao ha consenso em relacao a profilaxia e ao protocolo padrao nas recaidas. Fica claro que a dose de MTX IT parece insuficiente para tratar as formas parenquimatosas. Quando ha envolvimento meningeo, a via IT pode ser usada, mas os dados sobre os resultados nao sao conclusivos. Conclusao: O tratamento dos pacientes que apresentam infiltracao SNC permanece um desafio principalmente nos linfomas indolentes, considerando a dificuldade de padronizar tratamento eficaz, de menor toxicidade e a gravidade das sequelas por vezes irreversiveis. O mecanismo associado a invasao e a predilecao de alguns casos pelo SNC permanece incerto. Copyright © 2022
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Background: RET fusions are found in 1-2% of patients (pts) with advanced non-small cell lung cancer (aNSCLC). Targeted therapy with RET inhibitors (RETi) significantly improved prognosis. Molecular mechanisms of resistance are still incompletely characterized. Methods: This multicentric retrospective study included 24 centres. Eligible pts had a RET+ aNSCLC, were treated with a RETi and had at least one molecular profile by next-generation sequencing (NGS), performed before and/or after RETi, on tissue and/or plasma samples. Primary resistance under RETi was defined as disease progression (PD) within 6 months of therapy. Results: 95 patients were included with 112 biopsies: 93 at baseline, 19 at PD. 17 patients had paired NGS (baseline and PD). Median age was 65 years (range 56-72);62% were female, 54% were never smokers, 17% had brain metastasis (BM) at diagnosis. 55 patients received pralsetinib, 36 selpercatinib, 4 other RETi. Overall, median PFS under RETi was 17.1 months (95%CI 12.6-28). Primary resistance to RETi occurred in 22 (23%) patients. Primary resistant versus durable responders to RETi had non-adenocarcinoma histology in 9% vs 46% (p=0.61), smoking history in 57% vs 40% (p=0.21), BM in 5% vs 21% (p=0.1), TP53 mutations in 37% vs 22% (p=0.23). KRAS G12V mutation and SMARCA4 alterations were found only in poor responders (4.5% vs 0%, p=0.2;and 25% vs 0%, p=0.04, respectively). Among biopsies at PD (N=19, 13 liquid and 6 tissue biopsies), 7/13 (54%) liquid biopsies failed due to insufficient ctDNA. In 12 evaluable pts, 3 (25%) acquired secondary RET mutations (2 G810S and 1 S904F), 3 (25%) had novel RET rearrangements (2 in intron 11, 1 RET-DOCK1, 1 RET-CSGALNACT2) and 3 (25%) pts had off-target alterations (2 MET and 1 MYC amplification). Three pts (25%) developed novel TP53 mutations, while 3 (25%) had no novel identifiable alterations at PD. Conclusions: SMARCA4 and KRAS co-mutations may have a role in primary resistance to RETi. Secondary RET mutations, novel RET rearrangements and MET/MYC amplifications were identified after treatment with RETi. More than half of pts had insufficient ctDNA at PD, making tissue biopsy essential to identify resistance mechanisms. Legal entity responsible for the study: Institut Gustave Roussy. Funding: Has not received any funding. Disclosure: V. Fallet: Financial Interests, Personal, Advisory Board: AstraZeneca, BMS, Takeda, Roche, Pfizer, Sanofi, Sandoz, Jansen;Financial Interests, Personal, Invited Speaker: AstraZeneca, BMS, Takeda, Pfizer, MSD;Financial Interests, Personal, Expert Testimony: GSK, Boehringer. C. Audigier-Valette: Financial Interests, Personal, Advisory Role: AbbVie, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Ipsen, Eli Lilly, Novartis, Pfizer, and Roche. A. Russo: Financial Interests, Personal, Advisory Board: Pfizer, AstraZeneca, MSD, Novartis;Financial Interests, Personal, Writing Engagements: AstraZeneca, Novartis. A. Calles Blanco: Financial Interests, Personal, Advisory Board: AstraZeneca, Boehringer Ingelheim, Pfizer, Roche, Lilly, Merck Sharp & Dohme, Novartis, Bristol-Myers Squibb, Takeda, Sanofi;Financial Interests, Personal, Other, Speaker honoraria: Bayer;Financial Interests, Institutional, Research Grant, Drug-only for Investigator-initiated trial: Merck Sharp & Dohme. P. Iranzo Gomez: Financial Interests, Personal, Advisory Role: Bristol-Myers Squibb Recipient, F. Hoffmann, La Roche AG, Merck Sharp & Dohme, Boehringer Ingelheim, MSD Oncology, Rovi, Yowa Kirin, Grunenthal Pharma S.A., Pfizer. M. Tagliamento: Financial Interests, Personal, Other, medical writer: Novartis, Amgen;Financial Interests, Personal, Invited Speaker, travel/accommodation: Roche, Bristol-Myers Squibb, AstraZeneca, Takeda. L. Mezquita: Financial Interests, Personal, Advisory Board: Takeda, AstraZeneca, Roche;Financial Interests, Personal, Invited Speaker: Roche, BMS, AstraZeneca, Takeda;Financial Interests, Personal, Research Grant, SEOM Beca Retorno 2019: BI;Financial Interests, Personal, Research Grant, ESMO TR Research Fellowship 2019: BMS;Financial Interests, Institutional, Research Grant, COVID research Grant: Amgen;Financial Interests, Institutional, Invited Speaker: Inivata, Stilla. C. Lindsay: Financial Interests, Institutional, Principal Investigator: Roche, Amgen, BI;Financial Interests, Personal, Advisory Role: CBPartners, Amgen. S. Ponce: Financial Interests, Institutional, Principal Investigator: Merck Sharp and Dohme, F. Hoffmann-La Roche, Foundation Medicine, PharmaMar. Personal fees: Merck Sharp and Dohme, Bristol-Myers Squibb, F. Hoffmann-La Roche, Foundation Medicine, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Pfizer, Amgen, Celgene.;Financial Interests, Personal, Advisory Board: Merck Sharp and Dohme, Bristol-Myers Squibb, F. Hoffmann-La Roche, Foundation Medicine, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Pfizer, Amgen, Celgene.;Non-Financial Interests, Personal, Other: Merck Sharp and Dohme, Bristol-Myers Squibb, F. Hoffmann-La Roche. M. Aldea: Financial Interests, Personal, Invited Speaker, travel/accommodation: Sandoz. All other authors have declared no conflicts of interest.
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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.
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Introduction: Following initial response to TKI, advanced NSCLC patients with actionable mutations ultimately develop treatment resistance. In a proportion of patients (15-40%), initial, limited progression (≤5 lesions) is observed, termed oligoprogressive disease (OPD). SBRT offers hypofractionated, targeted radiotherapy treatment hypothesised to prolong clinical benefit from TKI prior to widespread disease development. With limited evidence to date, and poor clinical/biological selection criteria, the potential benefit offered by SBRT to ablate OPD sites prior to change in systemic therapy is an important question to address. Methods: HALT is a randomised, multi-centre, phase II/III international trial with seamless transition to phase III incorporated. Eligible patients (stage IV NSCLC, actionable mutation, TKI response prior to OPD) are randomised 2:1 to SBRT/continued TKI or continued TKI alone. Eligibility is confirmed by a virtual MDT (vMDT) comprising trial clinicians and radiologists (confirmation of OPD, SBRT suitability). Follow-up assessments are aligned with routine care at 3-monthly intervals until change in systemic therapy is clinically indicated, with imaging and toxicity assessment at each visit. Results: Recruitment commenced November 2017 with 25 centres (17 UK;8 non-UK) open to date. Following the COVID-19 pandemic, recruitment is recovering with 129 registered and 74 randomised patients. Over the last 4 years, little evidence has emerged to confirm any potential benefit of SBRT in this patient group and the impact on patient toxicity remains unknown. Therefore, with persisting questions around clinical equipoise, HALT remains highly relevant. With an 18-month extension and a recent amendment to the HALT inclusion criteria (≤5 OPD lesions, ≤7cm and OPD assessments by PET-avidity), the target of 110 randomised patients remains achievable. Conclusions: As the first randomised trial assessing SBRT benefit in this mutation-positive NSCLC patient population, HALT will provide valuable treatment efficacy and safety information, informing subsequent trial design and contribute to the development of international guidelines for the identification and clinical management of oligoprogression in mutation positive lung cancer. Keywords: Stereotactic body radiotherapy, NSCLC, Phase II
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Background: Pathological complete response (pCR) is associated with improved prognosis in triple-negative breast cancer (TNBC). Anlotinib, a novel multi-target tyrosine kinase inhibitor that effectively inhibits VEGFR, FGFR, c-KIT, c-MET, and RET, monotherapy has been proven effective in HER-2 negative metastatic breast cancer, but its efficacy in early-stage TNBC is unknown. This phase 2 study aims to evaluate the efficacy and safety of adding anlotinib to neoadjuvant chemotherapy in patients (pts) with primary TNBC. Methods: Pts with clinical stage II/III TNBC were to be treated with 5 cycles of anlotinib (12mg, d1-14, q3w) plus 6 cycles of taxanes (docetaxel 75 mg/m2 or nab-paclitaxel 260 mg/m2, d1, q3w) and lobaplatin (30 mg/m2, d1, q3w), followed by surgery. The primary endpoint was the total pCR (tpCR;ypT0/is ypN0). A Simon's two-stage optimum design was used, and > 5 of 11 pts were required to achieve tpCR in the first stage, with a pre-specified tpCR rate of 54.5% before proceeding to the second stage. A total of 31 participants was required for the study. Results: Six out of 11 pts achieved tpCR in the first stage, reaching the threshold for the second stage. From Jan 2021 to Jan 2022, a total of 22 pts were enrolled and 12 received surgery after the completion of neoadjuvant therapy, but a total of 2 pts withdrew from the study due to the COVID-19 pandemic or serious adverse events. Of the 22 eligible pts, the median age was 49 years (range, 29-64), 64% were postmenopausal, and 73% were nodal involved. At the time of surgery, 58.3% (7/12) achieved tpCR. Of the 9 pts with the node-positive disease at diagnosis, 88.9% (8/9) became ypN0. The results of FUSCC TNBC classification (IHC-based) revealed the tpCR rates were 57.1% (4/7), 100% (3/3), and 0% (0/2) for BLIS subtype, IM subtype and LAR/unknown subtypes, respectively. Biomarker analysis showed the tpCR rates were 100% (3/3) and 100% (4/4) in patients with gBRCA1 mutation and MYC amplification, respectively. The most common grade 3 or 4 treatment-related adverse events were leucopenia (6/22, 27%), neutropenia (6/22, 27%), anemia (5/22, 23%), decreased appetite (5/22, 23%), hypertension (2/22, 9%), ALT increased (1/22, 5%) and oral mucositis (1/22, 5%). No treatment-related deaths occurred. The trial is ongoing. Conclusions: The addition of anlotinib to neoadjuvant chemotherapy showed manageable toxicity and promising antitumor activity for patients with early-stage TNBC.
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Background: An important but insufficient aspect of care in people with infam-matory arthritis (IA) is empowering them to acquire good understanding of their disease and build ability to deal effectively with the practical, physical and psychological impacts of it. This extends beyond drug therapy and emphasises the ability to self-manage, with the right support, as an essential component of care. Good self-efficacy and coping skills reduce health and fnancial burden to the individual as well as the health service, beneftting society overall. Provision of excellent supported self-management education is at the heart of what NRAS does and it was due to the difficulty of getting Commissioners to fund our face-to-face group self-management that led to our building an e-learning programme to expand on and replace our 6-week programme. Objectives: To co-create an intuitive, easy to use, modular e-learning programme, free for all and which health professionals (HCPs) could refer their patients to. This makes supported self-management and evidence-based education accessible to all, wherever they live. SMILE enables HCPs to meet both NICE guideline and quality standards in RA against which rheumatology units in England and Wales are currently audited, as well as EULAR Recommendations for self-management strategies in infammatory arthritis. Methods: In 2019 with initial funding in place, we worked with our provider to help us realise our goal of developing a state-of-the art e-learning experience in a modular format for people with RA. The programme had to be 1) simple to use;2) interactive;3) innovative and engaging;4) able to measure impact through achievement of learning objectives and use of a validated patient reported outcome measure. The programme also had to be integrable with our Salesforce database enabling us to collect data and target resources to individuals, driven by identifed need. Results: Delayed by COVID, we launched with 4 modules on 17/09/2021. The 4 modules comprise: Foundation Module covering the importance of self-management which has the RA Impact of Disease PROM embedded;Newly Diagnosed;Meet the Team and Managing Pain and Flares. A ffth module on Medicines in RA will be launched 1st quarter 2022 and 4 further modules will be uploaded in 2022. To date (26/01/22), 760 people have registered, of which 313 have completed a baseline RAID and this reveals that <50% are achieving minimal acceptable state of 3 or less. Over 78% of registrants are not NRAS members, and 634 modules have been completed. Early indications are that almost all are achieving learning objectives. More data will be available by June 2022. Conclusion: Early indications demonstrate that people are successfully engaging with the programme and we have marketing activity lined up to raise further awareness of the value of SMILE with both potential users and rheumatology teams in 2022. Massive workforce issues together with signifcant backlogs of existing patients caused by the pandemic, have restricted the ability of Teams to provide education and self-management support for their patients. SMILE offers high quality, evidence-based learning opportunities for their patients and has been co-created with health professionals and people with RA at every step. With remote consultations here to stay, the importance of patients having access to evidence based online learning which they can tailor to their specifc needs and improve their self-efficacy is even more critical.
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Background/Aims NRAS Groups have long provided an opportunity for those with RA to meet others in a similar situation for mutual benefit. Attendees have told us how they enjoy meeting in a non-clinical environment to learn more about the condition and receive encouragement from others. When COVID-19 hit and NRAS groups were unable to meet in person and most people living with RA had to shield this intensified the feelings of isolation. NRAS responded to this need by establishing online regional groups and JoinTogether virtual groups. Methods 1. NRAS offered training and support to facilitate online group meetings to its regional groups' leaders. Volunteers were provided with a dedicated NRAS email address, access to an Office 365 portal and Zoom account and GDPR training. NRAS colleagues attended introductory meetings to support the Group Leaders and continue to provide technical support, promotion via website and social media as well as general advice. 2. Recognising a need to reach a wider audience who were not accessing the regional groups - i.e. younger and perhaps 'time poor' due to working etc. - NRAS took advantage of the move to online engagement and also initiated the exclusively online JoinTogether topic-based groups, using a Volunteer Lead model. Results Regional Groups: Almost half of the regional groups signed up to the online training. Many found that the online meetings brought very positive benefits e.g. they were able to reach a wider audience as attendees were not put off by having to travel and could still attend if they were feeling fatigued. Many reported it was easier to attract NHS rheumatology health professionals to give talks as they did not have to travel and could even join meetings from home in the evenings. Some groups in adjoining areas joined forces so they could expand their offerings. JoinTogether Groups: Volunteer Lead, with NRAS support, has now set up 5 topic-based groups, each led by two co-ordinators. Topics are: Exercise and Back to Sport;Parenting With Inflammatory Arthritis;18-35 year olds with RA or JIA: Working with Inflammatory Arthritis and Parents with children with JIA. These groups are thriving and attracting new audiences. They are very much volunteer led and attendees play a key role in directing the development of the JoinTogether groups to suit their needs. Conclusion NRAS virtual groups have allowed those living with RA or JIA to maintain contact with a community, with shared experiences, throughout the pandemic. They have also been instrumental in attracting attendees from audiences NRAS had traditionally found harder to access. The Volunteer Lead model that has been successfully implemented for the JoinTogether groups can now be expanded to other areas, enabling NRAS to increase capacity for delivering vital services.
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Background/Aims NRAS understands that inflammatory arthritis affects people of all ages. In early 2020 NRAS decided that a voice of the JIA community was needed to inform and provide guidance on a framework for JIA services at NRAS. The group would also empower younger people with RA, who are often frustrated by the perception that the condition 'only affects elderly people'. Methods NRAS recruited a group of young people with lived experience of JIA and RA to reflect the target population of the JIA service age range. The group were drawn from diverse backgrounds and now it includes representation from the Cabinet office, health care professionals and experts in youth engagement and digital marketing together with PhD students and creative professionals. Results Throughout the last 12 months the Young Voices Panel have developed and prioritised the service framework for young people with inflammatory arthritis and JIA-at-NRAS. One of the main priorities was peer-topeer support and now having the JIA Parents online group we can offer this to parents, alongside our other new JoinTogether online groups as well (e.g. 18 to 35year olds, Working with inflammatory arthritis, Parenting with inflammatory arthritis and Exercise and Back to Sport with inflammatory arthritis). The Young Voices have shared their stories and experiences in Facebook Live sessions during RAAW, Wear Purple for JIA in November 2020 and recently for the new #WearPurpleForJIA Wellbeing Week in June 2021. Some of the Young Voices were also part of the focus group for the new Medicines in JIA booklet which has now been launched. They spoke with parents during our zoom event Coping with JIA during COVID-19 in March to show parents that their children can thrive in life whilst learning to manage to the ups and downs that RA/ JIA has. They also shared their experiences with young people at the young person's event Navigating your future with inflammatory arthritis in April discussing how to tell friends and partners about their disease and where to find support at university and explain to employers about the conditions. They have also helped NRAS focus on what young people may want from the new JIA digital membership and participated in raising awareness for young people with JIA/RA podcasts and articles for Enable magazine. Conclusion The Young Voices Panel have been an integral part of NRAS and will continue to develop the service framework and be the voice of young people with JIA/RA. Feedback from events: 'Thank you for sharing your stories and experiences, you are inspirational'. 'I am so glad that young people are getting of a voice with regard to being diagnosed with arthritis'.
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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.
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The proceedings contain 170 papers. The topics discussed include: circular RNAs in pediatric t-cell acute lymphoblastic leukemia: new biomarkers;microRNAs in B cell precursor acute lymphoblastic leukemia: strict cooperation with oncogenes and tumor suppressors;metabolic strategies of myeloid blast survival;SARS-COV2 coagulopathy: an intricated puzzle;role of the microenvironment in the pathogenesis of myelodysplastic syndromes;the tumor microenvironment in Hodgkin lymphoma: clinical implications;liquid biopsy provides complementary information to tissue biopsies for the molecular classification of DLBCL patients;and prognostic value of immune cells in the multiple myeloma bone marrow microenvironment: a meta-analysis with in silico and in vitro validation.
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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.
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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.
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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.
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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.
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Background - The WINDOW-1 regimen introduced first-line ibrutinib with rituximab (IR) followed by 4 cycles of R-HCVAD for younger mantle cell lymphoma (MCL) patients (pts) demonstrating 90% CR on IR alone and we aimed to improve the CR rate with the addition of venetoclax. We therefore investigated the efficacy and safety of IR and venetoclax (IRV) followed by risk-stratified observation or short course R-HCVAD/MTX-ARA-C as consolidation in previously untreated young patients with mantle cell lymphoma (MCL). Our aim was to use a triplet chemotherapy-free induction to reduce the toxicity, complications and minimize chemotherapy exposure in MCL pts. Methods - We enrolled 50 previously untreated pts in this single institution, single arm, phase II clinical trial - NCT03710772. Pts received IR induction (Part-1) for initial 4 cycles. Pts were restaged at cycle 4 and received IRV for up to eight cycles (Cycle 5 to Cycle 12) starting with ramp up venetoclax dosing in Cycle 5. All pts who achieved CR prior to cycle 12 continued to receive IRV for 4 cycles (maximum 12 cycles) and then moved to part 2. Pts were stratified into three disease risk groups: high, moderate and low risk categories from the baseline data for assignment to R-HCVAD/MTX-ARA-C as consolidation in part 2 (4 cycles, 2 cycles, or no chemotherapy for high, medium and low risk pts respectively). Briefly, low risk pts were those with Ki-67 ≤30%, largest tumor mass <3 cm, low MIPI score and no features of high risk disease (Ki-67 ≥50%, mutations in the TP53, NSD2 or in NOTCH genes, complex karyotype or del17p, MYC positive, or largest tumor diameter >5 cm or blastoid/pleomorphic histology or if they remain in PR after 12 cycles of part 1. Medium risk are pts which did not belong to low or high-risk category. Those who experienced progression on part 1 went to part 2 and get 4 cycles of part 2. Patient were taken off protocol but not off study, if they remained in PR after 4 cycles of chemotherapy, these patients were followed up for time to next treatment and progression free survival on subsequent therapies. After part 2 consolidation, all pts received 2 years of IRV maintenance. The primary objective was to assess CR rates after IRV induction. Adverse events were coded as per CTCAE version 4. Molecular studies are being performed. Results - Among the 50 pts, the median age was 57 years (range - 35-65). There were 20 pts in high-risk group, 20 pts in intermediate-risk group and 10 pts in low-risk group. High Ki-67 (≥30%) in 18/50 (36%) pts. Eighteen (36%) had high and intermediate risk simplified MIPI scores. Six (12%) pts had aggressive MCL (blastoid/pleomorphic). Among the 24 TP53 evaluable pts, eight pts (33%) had TP53 aberrations (mutated and/or TP53 deletion by FISH). Forty-eight pts received IRV. Best response to IRV was 96% and CR of 92%. After part 2, the best ORR remained unaltered, 96% (92% CR and 4% PR). The median number of cycles of triplet IRV to reach best response was 8 cycles (range 2-12). Fifteen pts (30%) did not receive part 2 chemotherapy, two pts (4%) received 1 cycle, 16 pts (32%) 2 cycles and 13 pts (26%) got 4 cycles of chemotherapy. With a median follow up of 24 months, the median PFS and OS were not reached (2 year 92% and 90% respectively). The median PFS and OS was not reached and not significantly different in pts with high and low Ki-67% or with/without TP53 aberrations or among pts with low, medium or high-risk categories. The median PFS and OS was inferior in blastoid/pleomorphic MCL pts compared to classic MCL pts (p=0.01 and 0.03 respectively). Thirteen pts (26%) came off study - 5 for adverse events, 3 for on study deaths, and 2 for patient choice, 2 patients lost to follow up and one for disease progression. Overall, 5 pts died (3 on trial and 2 pts died off study, one due to progressive disease and another due to COVID pneumonia). Grade 3-4 toxicities on part 1 were 10% myelosuppression and 10% each with fatigue, myalgia and rashes and 3% mucositis. One pt developed grade 3 atrial flutter on part 1. None had grade 3-4 bleeding/bruising. Conclusions - Chemotherapy-free induction with IRV induced durable and deep responses in young MCL pts in the frontline setting. WINDOW-2 approach suggests that pts with low risk MCL do not need chemotherapy but further follow up is warranted. This combined modality treatment approach significantly improves outcomes of young MCL pts across all risk groups. Detailed molecular analyses will be reported. (Figure Presented).
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Cytogenetic abnormalities involving chromosome 16 are found in 5– 8% of acute myeloid leukemia (AML). These are typically a pericentric inversion inv(16)(p13.1q22) or a translocation, t(16;16)(p13.1;q22), involving the MYH11 and CBFB genes localized to chromosome 16p13.1 and 16q22, respectively. In addition, less common rearrangements include deletion of the long arm of chromosome 16, del(16) (q22), and cryptic insertions involving the MYH11 and the CBFB genes with otherwise normal karyotypes. In this report, we present the first AML case with a new translocation involving the CBFB gene. The more common CBFB - MYH11 fusion product resulting from the inversion and/or translocation of chromosome(s) 16 leads to an AML with monocytic and granulocytic differentiation and abnormal eosinophil component with large, purple to violet color eosinophilic granules. This entity typically corresponds to the adult AML-M4Eo in French-American- British (FAB) Classification and now called AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22);CBFB-MYH1 in the new 2017 WHO Classification. Patients may present with myeloid sarcoma at initial diagnosis or at relapse. We present a case of an 80-year-old male with a history of prostate cancer post radiotherapy who was referred for COVID-19 testing. A complete blood count with differential revealed neutropenia and a macrocytic anemia. A bone marrow biopsy and a bone marrow aspirate confirmed a diagnosis of AML with 33% blasts including myeloblasts and promonocytes. Interphase fluorescence in situ hybridization (FISH) analysis with a break-apart probe for CBFB showed an abnormal hybridization pattern consistent with rearrangement of CBFB in 66% of nuclei. Chromosome analysis revealed an abnormal karyotype with two related clones: 47,XY, t(10;16)(p13;q22),+22[4]/48,idem,+8[16]. Sequential GTG-FISH confirmed that the 3’ region of CBFB was translocated to 10p13 in the t(10;16) and the 5’ region remained on 16q. Based on the karyotype, the patient’s bone barrow exhibits clonal evolution having acquired additional chromosome abnormalities (trisomy 22 and trisomy 8). Molecular studies by next generation sequencing showed NRAS p.Gln61Lys mutation with a VAF of 11.21%. No genomic alterations were detected in KIT, KRAS or FLT3 genes. AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22) is associated with a high rate of complete remission and favorable overall survival when treated with intensive consolidation therapy. However, their prognostic advantage may be affected by additional cytogenetic abnormalities and/or other gene mutations. Specifically, trisomy 22, is a frequent abnormality additional to inv(16) detected as a secondary finding which has been associated with an improved outcome when compared to the prognosis associated with inv(16) alone. Furthermore, KIT (in 30–40%), FLT3 (in 14%), NRAS (in 45%) and KRAS (in 13%) mutations are common in this AML type. The prognostic implications of KIT mutation (especially involving exon 8) do not appear to be significantly poor prognostic compared to other AML types. On the other hand FLT3-TKD mutations and trisomy 8 are associated with a worse outcome. The patient is currently receiving Vidaza 75 mg/m2, days 1–7 of a 28 days cycle with Venetoclax mg daily of a 28-day cycle and his clinical prognosis is currently unclear. Further analysis by DNA sequencing may help to characterize the molecular nature of the fusion gene product resulting from the novel t(10;16)(p13;q22). To the best of our knowledge, this is the first reported case of an AML patient with translocation t(10;16)(p13;q22) involving the CBFB gene. Given the rarity and lack of additional information regarding the effects of this abnormality, the prognosis and survival cannot be predicted.
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Background: Coronavirus disease 19 (COVID-19) tends to be milder in children, but severe cases have been reported. We described a case report of a toddler admitted to our department with additional findings, highlighting the importance of assessing the patient as a whole. Case Presentation: A previously healthy, 15-month-year-old girl presented with fever and dry cough for 10 days, respiratory distress and PCR SARS-CoV-2 was positive. At admission, she presented with hypoxemia (SpO2 89-90% in room air), global retraction and bilateral bronchospasm. She was treated with bronchodilators, methylprednisolone, remdesivir and also amoxicillin/clavulanic acid. Her complete blood count revealed leucocytosis 16,160x109/L, 41% lymphocytes, C-reactive protein 57,9 mg/L, procalcitonin 0,13 ng/mL, sedimentation rate 44 mm/h, ferritin 218,4 ng/mL. Chest computed tomography (CT) scan revealed bilateral peripheral areas of ground glass, coexisting consolidation areas at inferior lobes but also revealed a 6 cm supra-renal mass. Abdominal ultrasound and CT confirmed an heterogeneous right supra-renal gland mass of 5,5cm along the greatest diameter with diffuse calcifications, evolving the inferior vena cava and the renal vascular pedicle, no signs of liver, bone, cutaneous or ganglionic metastization. These features were suggestive of neuroblastoma in stage L2. Vanillylmandelic acid, normetanephrine/creatinine ratio and metanephrine/creatinine ratio were elevated. The metaiodobenzylguanidine (Mibg) scan showed a localized disease. The total excision of the tumour mass was performed, and the histology confirmed neuroblastoma with no N-myc oncogene amplification, nor other bad prognosis chromosomal abnormalities. She is currently under oncological surveillance, with no signs of recurrence. Learning Points Discussion: Neuroblastoma is the most common extracranial solid tumour of childhood. It is known for its broad spectrum of clinical behaviour and outcome. In this case, although this toddler was admitted due to COVID-19 pneumonia, it allowed to identify a localized tumour, perform excision and due to the favourable biology tumour, she has a very good chances of being cured and free of disease.
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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: High-risk LBCL is associated with poor prognosis after first-line anti-CD20 mAb-containing regimens, highlighting the need for novel treatments. Axi-cel, an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, is approved for treatment of relapsed/refractory (R/R) LBCL after ≥2 lines of systemic therapy. Here we report the primary analysis of ZUMA-12, a Phase 2, multicenter, single-arm study of axi-cel as part of first-line therapy in patients with high-risk LBCL. Methods: Eligible adults had high-risk LBCL, defined by histology (double- or triple-hit status [MYC and BCL2 and/or BCL6 translocations] per investigator) or an IPI score ≥3, plus a positive interim PET per Lugano Classification (Deauville score [DS] 4/5) after 2 cycles of an anti-CD20 mAb and anthracycline-containing regimen. Patients underwent leukapheresis and received conditioning chemotherapy (cyclophosphamide and fludarabine) followed by a single axi-cel infusion at 2×10 6 CAR T cells/kg. Non-chemotherapy bridging could be administered before conditioning per investigator discretion. The primary endpoint was investigator-assessed complete response (CR) rate per Lugano. Secondary endpoints included objective response rate (ORR;CR + partial response), duration of response (DOR), event-free survival (EFS), progression-free survival (PFS), overall survival (OS), incidence of adverse events (AEs), and levels of CAR T cells in blood and cytokines in serum. The primary analysis occurred after all treated patients had ≥6 months of follow-up. Results: As of May 17, 2021, 42 patients were enrolled and 40 were treated with axi-cel. Median age was 61 years (range, 23-86);68% of patients were male, 63% had ECOG 1, 95% had stage III/IV disease, 48% had DS4, 53% had DS5, 25% had double- or triple-hit status per central assessment, and 78% had IPI score ≥3. A total of 37 patients had centrally confirmed double- or triple-hit histology or an IPI score ≥3 and were evaluable for response, with 15.9 months of median follow-up (range, 6.0-26.7). The CR rate was 78% (n=29;95% CI, 62-90);89% of patients had an objective response, and median time to initial response was 1 month. Among all 40 treated patients, 90% had an objective response (80% CR rate). At data cutoff, 73% of response-evaluable patients had ongoing responses. Medians for DOR, EFS, and PFS were not reached;12-month estimates were 81%, 73%, and 75%, respectively. The estimated OS at 12 months was 91%. All 40 treated patients had AEs of any grade;85% of patients had Grade ≥3 AEs, most commonly cytopenias (68%). Grade ≥3 cytokine release syndrome (CRS) and neurologic events (NEs) occurred in 3 patients (8%) and 9 patients (23%), respectively. Median times to onset of CRS and NEs were 4 days (range, 1-10) and 9 days (range, 2-44), with median durations of 6 days and 7 days, respectively. All CRS and most NEs (28/29) of any grade resolved by data cutoff (1 ongoing Grade 1 tremor);39/40 CRS events resolved by 14 days post-infusion and 19/29 NEs resolved by 21 days post-infusion. Tocilizumab was administered to 63% and 3% of patients for management of CRS or NEs, respectively;corticosteroids were administered to 35% and 33% of patients for CRS and NE management. One Grade 5 event of COVID-19 occurred (Day 350). Median peak CAR T-cell level in all treated patients was 36 cells/µL (range, 7-560), and median expansion by AUC 0-28 was 495 cells/µL × days (range, 74-4288). CAR T-cell levels peaked at a median of 8 days post-infusion (range, 8-37). Higher frequency of CCR7+CD45RA+ T cells in axi-cel product, previously associated with greater expansion of CAR T cells (Locke et al. Blood Adv. 2020), was observed in ZUMA-12, compared with the ZUMA-1 study in R/R LBCL (Neelapu et al. New Engl J Med. 2017). Conclusion: In the primary analysis of ZUMA-12, axi-cel demonstrated a high rate of rapid and complete responses in patients with high-risk LBCL, a population with high unmet need. With 15.9 months of median follow-up, responses were durable as medians for DOR, EFS, nd PFS were not yet reached and over 70% of patients remained in response at data cutoff. No new safety signals were reported with axi-cel in an earlier line. Overall, axi-cel may benefit patients exposed to fewer prior therapies, and further trials in first-line high-risk LBCL are warranted to assess axi-cel in this setting. [Formula presented] Disclosures: Neelapu: Kite, a Gilead Company, Merck, Bristol Myers Squibb, Novartis, Celgene, Pfizer, Allogene, Kuur, Incyte, Precision BioSciences, Legend, Adicet Bio, Calibr, and Unum Therapeutics: Other: personal fees;Kite, a Gilead Company, Bristol Myers Squibb, Merck, Poseida, Cellectis, Celgene, Karus Therapeutics, Unum Therapeutics (Cogent Biosciences), Allogene, Precision BioSciences, Acerta and Adicet Bio: Research Funding;Takeda Pharmaceuticals and related to cell therapy: Patents & Royalties;Kite, a Gilead Company, Merck, Bristol Myers Squibb, Novartis, Celgene, Pfizer, Allogene Therapeutics, Cell Medica/Kuur, Incyte, Precision Biosciences, Legend Biotech, Adicet Bio, Calibr, Unum Therapeutics and Bluebird Bio: Honoraria. Dickinson: Janssen: Consultancy, Honoraria;Takeda: Research Funding;Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau;Amgen: Honoraria;Celgene: Research Funding;Bristol-Myers Squibb: Consultancy, Honoraria;MSD: Consultancy, Honoraria, Research Funding, Speakers Bureau;Roche: Consultancy, Honoraria, Other: travel, accommodation, expenses, Research Funding, Speakers Bureau;Gilead Sciences: Consultancy, Honoraria, Speakers Bureau. Munoz: Kite, a Gilead Company, Kyowa, Bayer, Pharmacyclics/Janssen, Seagen, Acrotech/Aurobindo, Beigene, Verastem, AstraZeneca, Celgene/BMS, Genentech/Roche.: Speakers Bureau;Bayer, Gilead/Kite Pharma, Celgene, Merck, Portola, Incyte, Genentech, Pharmacyclics, Seattle Genetics, Janssen, and Millennium: Research Funding;Pharmacyclics/Abbvie, Bayer, Kite, a Gilead Company, Pfizer, Janssen, Juno/Celgene, Bristol Myers Squibb, Kyowa Kirin, Alexion, Fosun Kite, Innovent, Seagen, BeiGene, Debiopharm, Epizyme, Karyopharm, ADC Therapeutics, Servier, and Genmab: Consultancy, Other: advisory role;Alexion, AstraZeneca Rare Disease: Other: Study investigator;Targeted Oncology, OncView, Kyowa Kirin, Physicians' Education Resource, and Seagen: Honoraria. Thieblemont: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses;Gilead Sciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses;Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees;Kyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses;Bristol Myers Squibb/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses;Takeda: 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, Research Funding;Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees;Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses;Cellectis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses;Hospira: Research Funding;Bayer: Honoraria;Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses. Oluwole: Pfizer: Consultancy;Curio Science: Consultancy;Janssen: Consultancy;Kite, a Gilead Company: Consultancy, Research Funding. Herrera: Takeda: Consultancy;Genentech: Consultancy, Research Funding;Merck: Consultancy, Research Funding;Seagen: Consultancy, Research Fundi g;AstraZeneca: Consultancy, Research Funding;Kite, a Gilead Company: Research Funding;Gilead Sciences: Research Funding;Tubulis: Consultancy;ADC Therapeutics: Consultancy, Research Funding;Bristol Myers Squibb: Consultancy, Research Funding;Karyopharm: Consultancy. Ujjani: Loxo: Research Funding;AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees;Janssen: Consultancy;TG Therapeutics: Honoraria;Gilead: Honoraria;ACDT: Honoraria;Kite, a Gilead Company: Honoraria;Adaptive Biotechnologies: Research Funding;Atara Bio: Consultancy;AbbVie: Consultancy, Research Funding;Pharmacyclics: Consultancy, Research Funding. Lin: Sorrento: Consultancy;Legend: Consultancy;Novartis: Consultancy;Bluebird Bio: Consultancy, Research Funding;Gamida Cell: Consultancy;Janssen: Consultancy, Research Funding;Celgene: Consultancy, Research Funding;Juno: Consultancy;Vineti: Consultancy;Takeda: Research Funding;Merck: Research Funding;Kite, a Gilead Company: Consultancy, Research Funding. Riedell: Bayer: Honoraria;Karyopharm Therapeutics: Consultancy, Honoraria;Morphosys: Research Funding;Celgene/Bristol-Myers Squibb Company: Consultancy, Honoraria, Research Funding;Verastem Oncology: Honoraria;Kite, a Gilead Company: Honoraria, Research Funding, Speakers Bureau;Novartis: Consultancy, Honoraria, Research Funding;Takeda: Consultancy;BeiGene: Consultancy;Calibr: Research Funding;Xencor: Research Funding;Tessa Therapeutics: Research Funding. Kekre: Gilead: Consultancy, Honoraria;Novartis: Consultancy, Honoraria;Celgene: Consultancy, Honoraria. Lui: Gilead Sciences: Other: stock or other ownership;Kite, a Gilead Company: Current Employment, Other: travel support. Milletti: Kite, aGilead company: Current Employment;Gilead Sciences: Other: stock or other ownership. Dong: Kite, a Gilead Company: Current Employment;Gilead Sciences: Other: stock or other ownership;GliaCure/Tufts: Consultancy, Other: advisory role, Patents & Royalties. Xu: Kite, A Gilead Company: Current Employment;Gilead Sciences: Other: stock or other ownership. Chavez: MorphoSys, Bayer, Karyopharm, Kite, a Gilead Company, Novartis, Janssen, AbbVie, TeneoBio, and Pfizer: Consultancy;ADC Therapeutics: Consultancy, Research Funding;Merk: Research Funding;AstraZeneca: Research Funding;MorphoSys, AstraZeneca, BeiGene, Genentech, Kite, a Gilead Company, and Epizyme: Speakers Bureau;BMS: Speakers Bureau.
ABSTRACT
Background: De novo nucleotide synthesis is necessary to meet the enormous demand for nucleotides, other macromolecules associated with acute myeloid leukemia (AML) progression 1, 2, 34. Hence, we hypothesized that targeting de novo nucleotide synthesis would lead to the depletion of the nucleotide pool, pyrimidine starvation and increase oxidative stress preferentially in leukemic cells compared to their non-malignant counterparts, impacting proliferative and differentiation pathways. Emvododstat (PTC299) is an inhibitor of dihydroorotate dehydrogenase (DHODH), a rate-limiting enzyme for de novo pyrimidine nucleotide synthesis that is currently in a clinical trial for the treatment of AML. Objectives: The goals of these studies were to understand the emvododstat-mediated effects on leukemia growth, differentiation and impact on Leukemia Stem Cells(LSCs). Comprehensive analyses of mitochondrial function, metabolic signaling in PI3K/AKT pathways, apoptotic signatures, and DNA damage responses were carried out. The rationale for clinical testing emvododstat was confirmed in an AML-PDX model. Results: Emvododstat treatment in cytarabine-resistant AML cells and primary AML blasts induced apoptosis, differentiation, and reduced proliferation, with corresponding decreased in cell number and increases in annexin V- and CD14-positive cells. Indeed, the inhibition of de novo nucleotide synthesis compromises the dynamic metabolic landscape and mitochondrial function, as indicated by alterations in the oxygen consumption rate (OCR) and mitochondrial ROS/membrane potential and corresponding differentiation, apoptosis, and/or inhibition of proliferation of LSCs. These effects can be reversed by the addition of exogenous uridine and orotate. Further immunoblotting and mass cytometry (CyTOF) analyses demonstrated changes in apoptotic and cell signaling proteins (cleaved PARP, cleaved caspase-3) and DNA damage responses (TP53, γH2AX) and PI3/AKT pathway downregulation in response to emvododstat. Importantly, emvododstat treatment reduced leukemic cell burden in a mouse model of AML PDX ( Complex karyotype, mutation in ASXL1, IDH2, NRAS), decreased levels of leukemia stem cells frequency (1 in 522,460 Vs 1 in 3,623,599 in vehicle vs emvododstat treated mice), and improved survival. The median survival 40 days vs. 30 days, P=0.0002 in primary transplantation and 36 days vs 53.5 days, P=0.005 in secondary transpantation in a PDX mouse model of human AML. This corresponded with a reduction in the bone marrow burden of leukemia and increased expression of differentiation markers in mice treated with emvododstat (Fig. 1). These data demonstrate effect of emvododstat on mitochondrial functions. Conclusion: Inhibition of de novo pyrimidine synthesis triggers differentiation, apoptosis, and depletes LSCs in AML models. Emvododstat is a novel dihydroorotate dehydrogenase inhibitor being tested in a clinical trial for the treatment of myeloid malignancies and COVID-19. Keywords: AML, emvododstat, DHODH, apoptosis, differentiation References: 1 Thomas, D. & Majeti, R. Biology and relevance of human acute myeloid leukemia stem cells. Blood 129, 1577-1585, doi:10.1182/blood-2016-10-696054 (2017). 2 Quek, L. et al. Genetically distinct leukemic stem cells in human CD34- acute myeloid leukemia are arrested at a hemopoietic precursor-like stage. The Journal of experimental medicine 213, 1513-1535, doi:10.1084/jem.20151775 (2016). 3 Villa, E., Ali, E. S., Sahu, U. & Ben-Sahra, I. Cancer Cells Tune the Signaling Pathways to Empower de Novo Synthesis of Nucleotides. Cancers (Basel) 11, doi:10.3390/cancers11050688 (2019). 4 DeBerardinis, R. J. & Chandel, N. S. Fundamentals of cancer metabolism. Sci Adv 2, e1600200, doi:10.1126/sciadv.1600200 (2016). [Formula presented] Disclosures: Weetall: PTC therapeutics: Current Employment. Sheedy: PTC therapeutics: Current Employment. Ray: PTC therapeutics: Current Employment. Andreeff: Karyopharm: Research Funding;AstraZeneca: Research Funding;Oxford Biomedica UK: Research Funding;Aptose: Consultancy;Daiich -Sankyo: Consultancy, Research Funding;Syndax: Consultancy;Breast Cancer Research Foundation: Research Funding;Reata, Aptose, Eutropics, SentiBio;Chimerix, Oncolyze: Current holder of individual stocks in a privately-held company;Novartis, Cancer UK;Leukemia & Lymphoma Society (LLS), German Research Council;NCI-RDCRN (Rare Disease Clin Network), CLL Foundation;Novartis: Membership on an entity's Board of Directors or advisory committees;Senti-Bio: Consultancy;Medicxi: Consultancy;ONO Pharmaceuticals: Research Funding;Amgen: Research Funding;Glycomimetics: Consultancy. Borthakur: ArgenX: Membership on an entity's Board of Directors or advisory committees;Protagonist: Consultancy;Astex: Research Funding;University of Texas MD Anderson Cancer Center: Current Employment;Ryvu: Research Funding;Takeda: Membership on an entity's Board of Directors or advisory committees;Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees;GSK: Consultancy.