A matching-adjusted indirect comparison of acalabrutinib versus zanubrutinib in relapsed or refractory chronic lymphocytic leukemia

Video abstract for our matching-adjusted indirect comparison of acalabrutinib versus zanubrutinib in relapsed or refractory chronic lymphocytic leukemia</p

Health-related quality of life in treatment-naive CLL/SLL patients treated with zanubrutinib versus bendamustine plus rituximab

Zanubrutinib is a highly selective, next-generation Bruton’s tyrosine kinase inhibitor. In the phase 3 SEQUOIA trial (NCT03336333), treatment with zanubrutinib resulted in significantly improved progression-free survival compared to bendamustine plus rituximab (BR) in adult patients with treatment-naïve chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) without del(17p). The current analysis compared the effects of zanubrutinib versus BR on patients’ health-related quality of life (HRQoL). In the SEQUOIA trial, patient-reported outcomes (PROs) were assessed at baseline and every 12 weeks (3 cycles) using the EORTC QLQ-C30 and EQ-5D-5L. Descriptive analyses were performed on all the questionnaires’ scales and a mixed model for repeated measures was performed using the key QLQ-C30 endpoints of global health status/QoL (GHS/QoL), physical and role functioning, and symptoms of fatigue, pain, diarrhea, and nausea/vomiting at Weeks 12 and 24. Compared with BR-treated patients, those in the zanubrutinib arm experienced greater improvements in HRQoL outcomes at both Weeks 12 and 24. By Week 24, mean change differences (95% confidence interval) between the arms were significant for GHS/QoL (4.9 [0.9, 9.0]), physical functioning (3.8 [0.8, 6.7]), diarrhea (-6.2 [-10.0, -2.5]), fatigue (-4.5 [-8.9, -0.1]), and nausea/vomiting (-4.5 [-8.9, -0.1]); role functioning (4.8 [-0.2, 9.7]) was marginally better in the zanubrutinib arm and there were no differences in pain symptoms (-0.4 [-4.3, 5.1]) between the arms. During the first 24 weeks of treatment, zanubrutinib was associated with better HRQoL outcomes in patients with treatment-naive CLL/SLL without del(17p) compared to BR.</p

(a) WB analysis of PCL12 cells, basal (-) and after IgM stimulation (+), for BCR signaling pathway proteins activation and expression.

<p>On the right a schematic representation of the BCR signaling pathway analyzed. (b) WB analysis after treatment with ibrutinib (5’, 30’, 1 hour, 24 hour) for BTK activation.(c) Transwell PCL12 migration assay of migration with and without SDF-1 stimulation. (d F-actin polymerization index on PCL12 cells in basal conditions and after IgM stimulation (e) confocal analysis of PCL12 cells stained for HS1 protein in green and DAPI in blue.</p

(a) PCL12 cells images acquired with Nikon TS100 microscope after 4 weeks of culture (20x magnification objective in the left panel), dark arrow indicating nurse like cells, and 6 weeks of culture (4x magnification objective on the right).

<p>(b) Haematoxylin and Eosin staining (c) WB analysis for LMP1 protein on PCL12 cells, Positive control JY cell line and negative RL cell line. (d) PCL12 immunophenotype dot plot acquired by Flow cytometry.</p

(a) Graph showing the subcutaneous tumor volume grow (b) CD19+ PCL12 cells infiltrating lymphoid organs quantified by flow cytometry in PB, SP, PE and BM.

<p>(c) Flow cytometric analysis of PCL12 cells in PB, surface CD19, CD5 and CD23 are represented. (d) images of the representative spleen from 1 mouse injected with PCL12 cells (1) and a WT (2). Histopathological examination of different tissues and IHC analysis.</p

(a) VH and VL CDR3 amino acid composition and junction analysis.

<p>(b) Frequency analysis for the IG genes and the length of the CDR3 of the heavy and light chain of the BcR IG, respectively. Analysis performed on IG data from the largest up-to-date CLL cohorts [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0130195#pone.0130195.ref023" target="_blank">23</a>].</p

DataSheet_1_T cell receptor gene repertoire profiles in subgroups of patients with chronic lymphocytic leukemia bearing distinct genomic aberrations.pdf

BackgroundMicroenvironmental interactions of the malignant clone with T cells are critical throughout the natural history of chronic lymphocytic leukemia (CLL). Indeed, clonal expansions of T cells and shared clonotypes exist between different CLL patients, strongly implying clonal selection by antigens. Moreover, immunogenic neoepitopes have been isolated from the clonotypic B cell receptor immunoglobulin sequences, offering a rationale for immunotherapeutic approaches. Here, we interrogated the T cell receptor (TR) gene repertoire of CLL patients with different genomic aberration profiles aiming to identify unique signatures that would point towards an additional source of immunogenic neoepitopes for T cells.Experimental designTR gene repertoire profiling using next generation sequencing in groups of patients with CLL carrying one of the following copy-number aberrations (CNAs): del(11q), del(17p), del(13q), trisomy 12, or gene mutations in TP53 or NOTCH1.ResultsOligoclonal expansions were found in all patients with distinct recurrent genomic aberrations; these were more pronounced in cases bearing CNAs, particularly trisomy 12, rather than gene mutations. Shared clonotypes were found both within and across groups, which appeared to be CLL-biased based on extensive comparisons against TR databases from various entities. Moreover, in silico analysis identified TR clonotypes with high binding affinity to neoepitopes predicted to arise from TP53 and NOTCH1 mutations.ConclusionsDistinct TR repertoire profiles were identified in groups of patients with CLL bearing different genomic aberrations, alluding to distinct selection processes. Abnormal protein expression and gene dosage effects associated with recurrent genomic aberrations likely represent a relevant source of CLL-specific selecting antigens.</p

DataSheet_1_Obinutuzumab plus chlorambucil versus ibrutinib in previously untreated chronic lymphocytic leukemia patients without TP53 disruptions: A real-life CLL campus study.docx

One of the main issues in the treatment of patients with chronic lymphocytic leukemia (CLL) deals with the choice between continuous or fixed-duration therapy. Continuous ibrutinib (IB), the first-in-class BTK inhibitor, and obinutuzumab-chlorambucil (G-CHL) are commonly used therapies for elderly and/or comorbid patients. No head-to-head comparison has been carried out. Within the Italian campus CLL network, we performed a retrospective study on CLL patients without TP53 disruption treated with IB or G-CHL as first-line therapy. Patients in the G-CHL arm had a higher CIRS score and the worst renal function. The overall response rates between the G-CHL and IB arms were similar, but more complete remissions (CRs) were achieved with G-CHL (p = 0.0029). After a median follow-up of 30 months, the progression-free survival (PFS, p = 0.0061) and time to next treatment (TTNT, p = 0.0043), but not overall survival (OS, p = 0.6642), were better with IB than with G-CHL. Similar results were found after propensity score matching and multivariate analysis. While PFS and TTNT were longer with IB than with G-CHL in IGHV unmutated patients (p = 0.0190 and 0.0137), they were superimposable for IGHV mutated patients (p = 0.1900 and 0.1380). In the G-CHL arm, the depth of response (79% vs. 68% vs. 38% for CR, PR and SD/PD; p < 0.0001) and measurable residual disease (MRD) influenced PFS (78% vs. 53% for undetectable MRD vs. detectable MRD, p = 0.0203). Hematological toxicities were common in the G-CHL arm, while IB was associated with higher costs. Although continuous IB provides better disease control in CLL, IGHV mutated patients and those achieving an undetectable MRD show a marked clinical and economic benefit from a fixed-duration obinutuzumab-based treatment.</p