Background: Targeted therapies including ibrutinib, acalabrutinib and venetoclax (ven) have fundamentally changed the treatment of patients (pts) with chronic lymphocytic leukemia (CLL) leading to improved outcomes and durable remissions for many pts. However, CLL remains an incurable disease and a subset of pts will ultimately have progressive CLL following treatment with a covalent Bruton's Tyrosine Kinase inhibitor (cBTKi, e.g., ibrutinib, acalabrutinib) and ven. Data on efficacy of therapies for "double exposed" pts (i.e., pts exposed to both a cBTKi and ven) are extremely limited. Available approved options include chemoimmunotherapy (CIT) and phosphatidylinositol 3-kinase inhibitors (PI3Ki). However, the landmark clinical trials leading to the approvals of CIT and PI3Kis did not include pts treated with either cBTKi or ven (Furman et al. NEJM 2014, Flinn et al. Blood 2018). Non-covalent BTKis (ncBTKi) and chimeric antigen receptor (CAR) T-cell therapy have demonstrated promising clinical activity in double exposed CLL pts in clinical trials (Mato et al. Lancet 2021, Siddiqi et al. ASH 2020), but have not yet been compared to other novel agents or CIT in clinical trials or real-world analyses. We sought to describe outcomes of therapies for "double exposed" CLL pts. Methods: A retrospective, international, multicenter study was conducted. CLL pts were included if they received a cBTKi and ven and then a subsequent CLL-directed therapy. Therapies for Richter Transformation were excluded. Investigators identified pts at each site and collected data on demographics, disease characteristics, prior therapies, subsequent therapies and response assessments. Information was collected on up to three subsequent lines of therapy (LOT 1-3) per patient. The primary study endpoint was investigator-assessed overall response rate (ORR) per iwCLL 2018 criteria to therapies (LOT 1-3) following both cBTKi and ven. Kaplan-Meier method was used to estimate progression free survival (PFS). All other analyses were descriptive. Analyses were performed using STATA 17.0. Results: We report outcomes on 125 CLL pts who had prior cBTKi and ven and received a subsequent LOT. Baseline characteristics are presented in Table 1. ORR to prior cBTKi was 84.7% and 69.6% to prior ven. The most common reason for discontinuation of prior cBTKi and ven was CLL progression (71.1% cBTKi, 68.8% ven) followed by toxicity (25.6% cBTKi, 16.8% ven). Most common treatment strategies included ncBTKi (n=45), cBTKi (n=43), CIT (n=23), PI3Ki (n=24), alloSCT (n=17), CAR T-cell therapy (n=9), ven re-treatment (n=6), and other (n=44). ORR for selected agents following cBTKi and ven are presented in Table 2. ORR and PFS estimates were as follows: CAR T-cell therapy (85.7%, median PFS 4 months), alloSCT (76.5%, median PFS 11 months), ncBTKi (75.0%, median PFS not reached), PI3Ki (40.9%, median PFS 5 months), CIT (31.8%, median PFS 3 months) and ven re-treatment (ORR 40%, median PFS 14 months). ORR to cBTKi was 53.7%; however, median PFS for pts who discontinued a previous cBTKi for PD was 1 month versus 7 months for pts who discontinued due to AE. Figure 1 shows Kaplan-Meier estimated PFS for ncBTKi, PI3Ki, alloSCT, and CIT. Conclusions: In the largest series of "double exposed" CLL pts, several key findings warrant further investigation and discussion. Practice patterns are variable and no standard of care exists for CLL pts previously treated with a cBTKi and ven. Additionally, approved standard therapies including CIT combinations and PI3Kis yield poor outcomes with responses which are not durable. The low response rates and short PFS for PI3Ki and CIT call into question the use of these therapies as standard comparator arms in planned randomized trials. At this time, ncBTKi has a high ORR with durable responses (median PFS not reached). There appears to be a promising role for alloSCT in select, fit patients (ORR 76.5%, median PFS 11 months), and CAR T-cell therapy should be further explored in this population (ORR 85.7%, median PFS 4 months). Overall, this study highlights a continued unmet need for therapies for "double exposed" CLL pts. Figure 1 Figure 1. Disclosures Thompson: MJH Life Sciences: Honoraria; VJHemOnc: Honoraria; Curio Science: Honoraria. Roeker: Abbot Laboratories: Current equity holder in publicly-traded company; Pharmacyclics: Consultancy; Loxo Oncology: Consultancy; TG Therapeutics: Consultancy; AbbVie, AstraZeneca, Janssen, LOXO, Pharmacyclics, TG Therapeutics, Vaniam Group, Verastem: Consultancy; Pfizer: Consultancy, Research Funding. Coombs: LOXO: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; AstraZeneca: Honoraria; AbbVie: Honoraria; Genentech: Honoraria; MEI Pharma: Honoraria. Kamdar: AbbVie: Consultancy; TG Therapeutics: Research Funding; SeaGen: Speakers Bureau; ADC Therapeutics: Consultancy; Adaptive Biotechnologies: Consultancy; AstraZeneca: Consultancy; Celgene: Other; Celgene (BMS): Consultancy; Kite: Consultancy; KaryoPharm: Consultancy; Genentech: Research Funding; Genetech: Other. Pagel: Epizyme: Consultancy; Incyte/MorphoSys: Consultancy; BeiGene: Consultancy; Pharmacyclics/AbbVie: Consultancy; Actinium Pharmaceuticals: Consultancy; AstraZeneca: Consultancy; Gilead: Consultancy; Kite, a Gilead Company: Consultancy; MEI Pharma: Consultancy. Jacobs: MEI Pharma: Research Funding; Adaptive Biotechnologies: Consultancy; Genentech: Consultancy; TG Therapeutics: Research Funding, Speakers Bureau; Verastem: Consultancy; AstraZeneca: Consultancy, Speakers Bureau; ADC Therapeutics: Consultancy; TeneoBio: Research Funding; AbbVie: Consultancy, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding, Speakers Bureau; Jannsen: Speakers Bureau; SecuraBio: Consultancy, Speakers Bureau. Hill: Gentenech: Consultancy, Honoraria, Research Funding; Epizyme: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Incyte/Morphysis: Consultancy, Honoraria, Research Funding; Celgene (BMS): Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Beigene: Consultancy, Honoraria, Research Funding; AstraZenica: Consultancy, Honoraria; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel Support, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding. Brander: AbbVie: Consultancy, Other: informCLL registry steering committee, Research Funding; AstraZeneca: Research Funding; BeiGene: Research Funding; ArQule: Research Funding; DTRM: Research Funding; LOXO: Research Funding; Verastem: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Juno Therapeutics/Celgene/Bristol Myers Squibb: Research Funding; Novartis: Research Funding; Ascentage: Research Funding; MEI Pharma: Research Funding; Genentech: Consultancy, Research Funding; NCCN: Other: panel member; Pfizer: Consultancy, Other: Biosimilars outcomes research panel; ArQule/Merck: Consultancy. Shadman: Mustang Bio, Celgene, Bristol Myers Squibb, Pharmacyclics, Gilead, Genentech, Abbvie, TG Therapeutics, Beigene, AstraZeneca, Sunesis, Atara Biotherapeutics, GenMab: Research Funding; Abbvie, Genentech, AstraZeneca, Sound Biologics, Pharmacyclics, Beigene, Bristol Myers Squibb, Morphosys, TG Therapeutics, Innate Pharma, Kite Pharma, Adaptive Biotechnologies, Epizyme, Eli Lilly, Adaptimmune , Mustang Bio and Atara Biotherapeutics: Consultancy. Ujjani: AbbVie: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Loxo: Research Funding; Adaptive Biotechnologies: Research Funding; Atara Bio: Consultancy; 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. Battiato: Abbvie: Honoraria; Janssen: Honoraria. Rhodes: AbbVie, Genentech, Pharmacyclics, TG Therapeutics: Other: Consultant; Conquer Cancer Foundation Young Investigator Award: Other: Grant/Research Support. Fakhri: Loxo/Lilly: Research Funding. Barr: Morphosys: Consultancy; Gilead: Consultancy; Seattle Genetics: Consultancy; TG Therapeutics: Consultancy; Janssen: Consultancy; AstraZeneca: Consultancy; Beigene: Consultancy; Bristol Meyers Squibb: Consultancy; Abbvie/Pharmacyclics: Consultancy; Genentech: Consultancy. Portell: TG Therapeutics: Honoraria, Research Funding; SeaGen: Research Funding; Kite: Honoraria, Research Funding; Xencor: Research Funding; Abbvie: Research Funding; Pharmacyclics: Honoraria; Merck: Honoraria, Research Funding; BeiGene: Honoraria, Research Funding; Acerta/AstraZeneca: Research Funding; Aptitude Health: Honoraria; Targeted Oncology: Honoraria; Morphosys: Honoraria; Genentech: Research Funding; VelosBio: Research Funding. Lamanna: AbbVie: Consultancy, Research Funding; Verastem Oncology: Research Funding; BeiGene: Consultancy; Pharmacyclics: Consultancy; Celgene Corporation: Consultancy; Oncternal Therapeutics: Research Funding; Janssen Pharmaceuticals, Inc.: Consultancy; Gilead Sciences, Inc.: Consultancy; MingSight Pharmaceuticals, Inc.: Research Funding; Genentech, Inc.: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; TG Therapeutics, Inc: Research Funding; Juno Therapeutics, Inc.: Research Funding. Zelenetz: MorphoSys: Honoraria; Verastem: Honoraria; LFR: Other; Gilead: Honoraria, Research Funding; NCCN: Other; AstraZeneca: Honoraria; MEI Pharma: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Janssen: Honoraria; Gilead: Honoraria; Pharmacyclics: Honoraria; BMS/Celgene/JUNO: Honoraria, Other; Novartis: Honoraria; SecuraBio: Honoraria; Genentech/Roche: Honoraria, Research Funding; MethylGene: Research Funding; Amgen: Honoraria; Beigene: Honoraria, Other, Research Funding. Schuster: Abbvie: Consultancy, Research Funding; Acerta Pharma: Consultancy; AstraZeneca: Consultancy; Adaptive Biotechnologies: Research Funding; BeiGene: Consultancy; Celgene: Consultancy, Honoraria, Research Funding; DTRM: Research Funding; Genetech: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Incyte: Research Funding; Juno Theraputics: Consultancy, Research Funding; Loxo Oncology: Consultancy; Merck: Research Funding; Nordic Nanovector: Consultancy; Novartis: Consultancy, Honoraria, Patents & Royalties, Research Funding; Pharmaclcyclics: Research Funding; Tessa Theraputics: Consultancy; TG Theraputics: Research Funding. Eyre: Secura Bio: Consultancy, Honoraria; Loxo Oncology: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria, Research Funding; Incyte: Consultancy; Beigene: Honoraria, Research Funding; Roche: Consultancy, Honoraria; Gilead/KITE: Honoraria, Other: Travel support for conferences, Research Funding, Speakers Bureau; Janssen: Honoraria; Abbvie: Consultancy, Honoraria, Other: Travel to conferences. Mato: MSKCC: Current Employment; AstraZeneca: Consultancy; Genmab: Research Funding; LOXO: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy, Research Funding; TG Therapeutics: Consultancy, Other: DSMB, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Johnson and Johnson: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; DTRM BioPharma: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Acerta/AstraZeneca: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Nurix: Research Funding.
flare should not discourage vaccination, provided a close clinical and laboratory monitoring.
Lung cancer remains the leading cause of cancer-related mortality worldwide. Non-small-cell lung cancer (NSCLC) is the most common type and is still incurable for most patients at the advanced stage. Targeted therapy is an effective treatment that has significantly improved survival in NSCLC patients with actionable mutations. However, therapy resistance occurs widely among patients leading to disease progression. In addition, many oncogenic driver mutations in NSCLC still lack targeted agents. New drugs are being developed and tested in clinical trials to overcome these challenges. This review aims to summarize emerging targeted therapy that have been conducted or initiated through first-in-human clinical trials in the past year.
transcraniana e aplicabilidade clínica: perspectivas na conduta terapêutica neuropsiquiátrica/ Transcranial magnetic stimulation and clinical applicability: perspectives in neuropsychiatric therapeutics. Rev Med (São Paulo). 2011 jan.-mar.;90(1):3-14.RESUMO: Estimulação magnética transcraniana (EMT) é uma técnica conhecida desde o começo dos anos 90 e que atualmente tem ganhado destaque devido a sua segurança e possível aplicabilidade para tratar diversas patologias neuropsiquiátricas refratárias. A fim de clarificar os possíveis usos da EMT e suas variações no campo da clínica como forma de tratamento, procedemos à revisão da literatura selecionando os artigos nas áreas em que a técnica de EMT já tem sido largamente utilizada, a saber: AVC, Dor, Doença de Parkinson e Depressão. Essas doenças possuem elevada morbidade, possuindo grandes implicações na qualidade de vida devido ao elevado grau de incapacidade associado e ao fato de ainda carecerem de métodos terapêuticos totalmente eficientes. Nesse contexto, a EMT emerge como ferramenta promissora, apresentando bons resultados, os quais fornecem margem para aplicações diretas na prática clínica. É necessário, todavia, o desenvolvimento de mais estudos randomizados, para se padronizar e aperfeiçoar as abordagens dessa técnica no tratamento de tais patologias. DESCRITORES: Estimulaçãomagnética transcraniana; Acidente cerebral vascular; Dor/terapia; Doença de Parkinson/terapia; Depressão/patologia.
Background Although the clinical outcomes of patients with TP53‐mutated acute myeloid leukemia (AML) are dismal, subsets of patients eligible for curative‐intent therapies may fare better. Because racial disparities are known to affect outcome in hematologic malignancies, the authors sought to explore disparities among patients with TP53‐mutated AML. Methods A multicenter, retrospective study was conducted in a cohort of 340 patients who had TP53‐mutated AML (275 non‐Hispanic White [NHW] and 65 non‐Hispanic Black [NHB]) to analyze differences in treatment and outcome among NHW and NHB patients. Results The median patient age was comparable between NHW and NHB patients (p = .76). A higher proportion of NHB patients had therapy‐related AML (31% vs. 20%; p = .08) and had co‐mutations (74% vs. 61%; p = .06). A higher proportion of NHW patients received intensive chemotherapy compared with NHB patients (47% vs. 31%; p = .02). Conversely, a higher proportion of NHB patients received low‐intensity chemotherapy (9% vs. 5.5%; p = .02) or best supportive care (22% vs. 7%; p < .001). The complete response rate (including complete responses with or without complete count recovery) was 31% versus 24.5% (p = .39) in NHW and NHB patients, respectively. Only 5% of NHB patients received allogeneic stem cell transplantation compared with 15.5% of NHW patients (p = .02). The proportion of patients who were event‐free (18.5% vs. 8.5%; p = .49) or who remained alive (24.9% vs. 8.3%; p = .13) at 18 months was numerically higher in NHW versus NHB patients, respectively, but was not statistically significant. Conclusions The current study highlights disparities between NHW and NHB patients with TP53‐mutated AML. Efforts are warranted to eliminate treatment disparities in minority populations.
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