Acalabrutinib, a highly selective, potent, Bruton tyrosine kinase inhibitor, was evaluated in this global, multicenter, randomized, open-label, phase III study in patients with relapsed/refractory ...(R/R) chronic lymphocytic leukemia (CLL).
Eligible patients, aged ≥ 18 years with R/R CLL, were randomly assigned 1:1 centrally and stratified by del(17p) status, Eastern Cooperative Oncology Group performance status score, and number of prior lines of therapy. Patients received acalabrutinib monotherapy or investigator's choice (idelalisib plus rituximab I-R or bendamustine plus rituximab B-R). The primary end point was progression-free survival (PFS) assessed by an independent review committee (IRC) in the intent-to-treat population. Key secondary end points included IRC-assessed overall response rate, overall survival, and safety.
From February 21, 2017, to January 17, 2018, a total of 398 patients were assessed for eligibility; 310 patients were randomly assigned to acalabrutinib monotherapy (n = 155) or investigator's choice (n = 155; I-R, n = 119; B-R, n = 36). Patients had received a median of two prior therapies (range, 1-10). After a median follow-up of 16.1 months (range, 0.03-22.4 months), median PFS was significantly longer with acalabrutinib monotherapy (PFS not reached) compared with investigator's choice (16.5 months 95% CI, 14.0 to 17.1 months; hazard ratio, 0.31 95% CI, 0.20 to 0.49;
< .0001). Estimated 12-month PFS was 88% (95% CI, 81% to 92%) for acalabrutinib and 68% (95% CI, 59% to 75%) for investigator's choice. Serious adverse events occurred in 29% of patients (n = 44 of 154) treated with acalabrutinib monotherapy, 56% (n = 66 of 118) with I-R, and 26% (n = 9 of 35) with B-R. Deaths occurred in 10% (n = 15 of 154), 11% (n = 13 of 118), and 14% (n = 5 of 35) of patients receiving acalabrutinib monotherapy, I-R, and B-R, respectively.
Acalabrutinib significantly improved PFS compared with I-R or B-R and has an acceptable safety profile in patients with R/R CLL.
Certain cytogenetic abnormalities are known to adversely impact outcomes in patients with multiple myeloma (MM). The phase 3 TOURMALINE-MM1 study demonstrated a significant improvement in ...progression-free survival (PFS) with ixazomib-lenalidomide-dexamethasone (IRd) compared with placebo-lenalidomide-dexamethasone (placebo-Rd). This preplanned analysis assessed the efficacy and safety of IRd vs placebo-Rd according to cytogenetic risk, as assessed using fluorescence in situ hybridization. High-risk cytogenetic abnormalities were defined as del(17p), t(4;14), and/or t(14;16); additionally, patients were assessed for 1q21 amplification. Of 722 randomized patients, 552 had cytogenetic results; 137 (25%) had high-risk cytogenetic abnormalities and 172 (32%) had 1q21 amplification alone. PFS was improved with IRd vs placebo-Rd in both high-risk and standard-risk cytogenetics subgroups: in high-risk patients, the hazard ratio (HR) was 0.543 (95% confidence interval CI, 0.321-0.918; P = .021), with median PFS of 21.4 vs 9.7 months; in standard-risk patients, HR was 0.640 (95% CI, 0.462-0.888; P = .007), with median PFS of 20.6 vs 15.6 months. This PFS benefit was consistent across subgroups with individual high-risk cytogenetic abnormalities, including patients with del(17p) (HR, 0.596; 95% CI, 0.286-1.243). PFS was also longer with IRd vs placebo-Rd in patients with 1q21 amplification (HR, 0.781; 95% CI, 0.492-1.240), and in the “expanded high-risk” group, defined as those with high-risk cytogenetic abnormalities and/or 1q21 amplification (HR, 0.664; 95% CI, 0.474-0.928). IRd demonstrated substantial benefit compared with placebo-Rd in relapsed and/or refractory MM (RRMM) patients with high-risk and standard-risk cytogenetics, and improves the poor PFS associated with high-risk cytogenetic abnormalities. This trial was registered at www.clinicaltrials.gov as #NCT01564537.
•IRd was associated with a consistent PFS benefit vs placebo-Rd in RRMM patients with high-risk and standard-risk cytogenetics.•The addition of ixazomib to Rd overcomes the poor PFS associated with high-risk cytogenetics in patients with RRMM.
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Acalabrutinib is a Bruton tyrosine kinase inhibitor approved for patients with chronic lymphocytic leukemia (CLL). ASCEND is the pivotal phase 3 study of acalabrutinib versus investigator's choice of ...idelalisib plus rituximab (IdR) or bendamustine plus rituximab (BR) in patients with relapsed/refractory (R/R) CLL. In the primary ASCEND analysis (median 16.1‐month follow‐up), acalabrutinib showed superior efficacy with an acceptable tolerability profile versus IdR/BR; here, we report final ~4 year follow‐up results. Patients with R/R CLL received oral acalabrutinib 100 mg twice daily until progression or unacceptable toxicity, or investigator's choice of IdR or BR. A total of 310 patients (acalabrutinib, n = 155; IdR, n = 119; BR, n = 36) were enrolled. At median follow‐up of 46.5 months (acalabrutinib) and 45.3 months (IdR/BR), acalabrutinib significantly prolonged investigator‐assessed progression‐free survival (PFS) versus IdR/BR (median, not reached NR vs 16.8 months; P < 0.001); 42‐month PFS rates were 62% (acalabrutinib) versus 19% (IdR/BR). Median overall survival (OS) was NR (both arms); 42‐month OS rates were 78% (acalabrutinib) versus 65% (IdR/BR). Adverse events led to drug discontinuation in 23%, 67%, and 17% of patients in the acalabrutinib, IdR, and BR arms, respectively. Events of clinical interest (acalabrutinib vs IdR/BR) included all‐grade atrial fibrillation/flutter (8% vs 3%), all‐grade hypertension (8% vs 5%), all‐grade major hemorrhage (3% vs 3%), grade ≥3 infections (29% vs 29%), and second primary malignancies excluding nonmelanoma skin cancer (7% vs 2%). At ~4 years follow‐up, acalabrutinib maintained favorable efficacy versus standard‐of‐care regimens and a consistent tolerability profile in patients with R/R CLL.
Celem artykułu jest zwrócenie uwagi na kicz jako kategorię z zakresu nauk społecznych i hu-manistycznych o odpowiednich implikacjach dla dyscypliny pedagogicznej Zagadnienie kiczu osadzam w ramach ...swoiście rozumianej i uprawianej refleksji kulturoznawczej. Układ pojęć niezbędnych do tego osadzenia przedstawiam w następującym porządku: kultura – sztuka – uczestnictwo w kulturze (sztuce) – wprowadzanie do uczestnictwa w kulturze (sztuce). W przyjętej perspektywie nakreślanie granic pomiędzy „sztuką”, „złą sztuką”, „antysztuką”, „kiczem” jest mało atrakcyjne. Problem ten zostaje uwolniony od niepotrzebnych napięć. Kluczem jest tutaj sposób rozumienia pojęcia kultura, który implikuje odpowiedni sposób rozumienia sztuki, a w konsekwencji uczestnictwa w kulturze (sztuce) oraz wprowadzania doń (co jest prymarną funkcją edukacji). Publikacja ma na celu zapoznanie Czytelnika z różnorodnymi sposobami myślenia na temat kiczu oraz zaproszenie go do dyskusji na jego temat.
The aim of the article is to draw attention to kitsch as a category in the field of social sciences and humanities with appropriate implications for the pedagogical discipline I place the problem of ...kitsch within a specifically understood and cultivated cultural studies reflection. The system of concepts necessary for this embedding is presented in the following order: culture –art –participation in culture (art) –introduction to participation in culture (art). In the adopted perspective, delin-eating the boundaries between “art”, “bad art”, “anti-art”, “kitsch”is not very attractive. This prob-lem is relieved of unnecessary tensions. The key here is the way of understanding the concept of culture, which implies an appropriate way of understanding art and, consequently, participation in and introduction to culture (art) (which is the primary function of education). The aim of the publication is to familiarize the reader with various ways of thinking about kitsch and to invite him to discuss it.
The aim of the article is to draw attention to kitsch as a category in the field of social sciences and humanities with appropriate implications for the pedagogical discipline I place the problem of ...kitsch within a specifically understood and cultivated cultural studies reflection. The system of concepts necessary for this embedding is presented in the following order: culture – art – participation in culture (art) – introduction to participation in culture (art). In the adopted perspective, delineating the boundaries between “art”, “bad art”, “anti-art”, “kitsch” is not very attractive. This problem is relieved of unnecessary tensions. The key here is the way of understanding the concept of culture, which implies an appropriate way of understanding art and, consequently, participation in and introduction to culture (art) (which is the primary function of education). The aim of the publication is to familiarize the reader with various ways of thinking about kitsch and to invite him to discuss it.
Background: Myelofibrosis (MF), which comprises primary MF (PMF), post-polycythemia vera MF (post-PV-MF), and post-essential thrombocythemia MF (post-ET-MF), is a clonal myeloproliferative neoplasm ...characterized by progressive bone marrow fibrosis, ineffective erythropoiesis, dysplastic megakaryocyte hyperplasia, and extramedullary hematopoiesis. Patients typically have heterogeneous clinical presentation marked by splenomegaly, progressive anemia and constitutional symptoms and are at increased risk of leukemic transformation. Hematopoietic stem cell transplant is the only potentially curative therapy but is associated with high morbidity and mortality. Approved therapies for MF are limited to the Janus kinase inhibitors (JAKi) ruxolitinib and fedratinib which have been shown to reduce spleen volume (≥35% from baseline at week 24) in 32% - 42% of patients and to improve constitutional symptoms, with no clear impact on bone marrow fibrosis. Several studies have shown a correlation between the degree of week 24 spleen response to JAKi treatment and survival outcomes in MF (Vannucchi, et al. Haematologica. 2015; Palandri et al. Leuk Res. 2018), demonstrating the need for novel treatment strategies in patients with a suboptimal response to ruxolitinib treatment.
KRT-232 is a potent, selective, orally available, small molecule drug that binds to MDM2, a key negative regulator of the tumor suppressor protein p53. MDM2 blocks p53 activity via ubiquitination, nuclear export and direct inhibition of transcriptional activity. In MF, somatic driver mutations such as JAK2 V617F are associated with MDM2 overexpression in the circulating CD34+ cells that are a characteristic feature of the disease (Lu, et al. Blood. 2017). The first clinical proof-of-concept study of KRT-232 monotherapy showed promising efficacy and tolerability in patients with MF relapsed or refractory (R/R) to prior JAKi treatment (Al-Ali et al. EHA 2020). It is hypothesized that KRT-232 may deliver synergistic efficacy and disease modification when combined with ruxolitinib by targeting a complementary mechanism that promotes apoptosis in malignant MF clones. Further, by combining ruxolitinib with KRT-232 to inhibit both the aberrant JAK/STAT signaling and the upregulation of MDM2-mediated survival pathways, this combination has the potential to lower the apoptotic threshold of malignant cells that are deprived of growth factor and cytokine support.
Study Design/Methods: KRT-232 in combination with ruxolitinib is being evaluated in an open-label, global, multicenter phase 1b/2 study in patients with MF (PMF/post-PV-MF/post-ET-MF) who have a suboptimal response after ≥18 weeks of ruxolitinib treatment (Figure). Patients aged ≥18 years, on stable dose of ruxolitinib for at least 8 weeks prior to enrollment and with ECOG performance status of 0-2 will be enrolled. Patients with TP53 mutations, spleen response or progressive disease during ruxolitinib treatment per European LeukemiaNet criteria (Tefferi, et al. Blood. 2013), or prior JAKi treatment other than ruxolitinib are excluded. In the phase 1b portion of the study, patients will be randomly assigned to arm 1 (KRT-232 once daily qd on days D 1-7 of 28-day cycle) or arm 2 (KRT-232 qd on D1-5 of 28-day cycle). KRT-232 will be administered in a 3+3 dose-escalation design with doses starting at KRT-232 120 mg, increasing to 180 mg, followed by 240 mg in combination with the patient’s pre-study stable dose of ruxolitinib to determine the maximum tolerated dose (MTD) of KRT-232 + ruxolitinib. The phase 2 portion will evaluate the MTD reached in arm 1 and arm 2 as expansion arms, assessing the safety and efficacy of the combinations to determine a recommended phase 2 dose (RP2D).
The primary end point of the study is to determine the RP2D of KRT-232 + ruxolitinib. Secondary end points include spleen response (≥35% spleen volume reduction from baseline), change in Myelofibrosis Symptom Assessment Form version 4.0 Total Symptom Score, duration of response, spleen size reduction, red blood cell transfusion usage and independence, overall response rate (complete response + partial response), overall survival, progression-free survival, leukemia-free survival, safety/tolerability, and pharmacokinetics. This trial is enrolling at approximately 40 global sites (NCT04485260).
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Mascarenhas:Incyte, Kartos, Roche, Promedior, Merck, Merus, Arog, CTI Biopharma, Janssen, and PharmaEssentia: Other: Research funding (institution); Celgene, Prelude, Galecto, Promedior, Geron, Constellation, and Incyte: Consultancy. Vannucchi:Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees; Blueprint: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Mead:Gilead: Consultancy; CTI: Consultancy; Abbvie: Consultancy; Celgene/BMS: Consultancy, Honoraria, Other: travel, accommodations, expenses, Research Funding; Novartis: Consultancy, Honoraria, Other: travel, accommodations, expenses, Research Funding, Speakers Bureau. Pluta:Janssen-Cilag, Kartos Therapeutics, Iqvia, Roche, Acerta Pharma, Pharmacyclics, BeiGene, Takeda: Research Funding; Celgene, Servier, Takeda, Novartis: Honoraria; Celgene: Other: Travel, Accommodations, Expenses. Qamoos:Kartos Therapeutics: Current Employment, Current equity holder in private company. Uyei:Kartos Therapeutics: Current Employment. Gandhi Laurent:Abbevie, Pfizer, Takeda, Roche: Other: Travel; Roche, Takeda, Iqone, Accord: Consultancy; Roche, Takeda, Accord: Honoraria. Al-Ali:AOP Orphan: Other: travel, accommodations, expenses; Incyte: Research Funding; Pfizer: Consultancy, Honoraria; Celgene/BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel, accommodations, expenses, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.
Yes, KRT-232 is an investigational small molecule MDM2 inhibitor. This trial-in-progress abstract describes a clinical trial that will evaluate the safety and efficacy of KRT-232 + ruxolitinib for patients with myelofibrosis with suboptimal response to ruxolitinib.
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