Zanubrutinib versus acalabrutinib indirect treatment comparison in relapsed or refractory mantle cell lymphoma.

Zanubrutinib and acalabrutinib have demonstrated efficacy in separate single-arm clinical trials in patients with relapsed/refractory (R/R) mantle cell lymphoma (MCL). Given these single-arm trials lacked a common comparator, an unanchored indirect treatment comparison was conducted to assess the comparative efficacy of zanubrutinib versus acalabrutinib using a simulated treatment comparison (STC) method. In the base case analysis (adjusted for all covariates), zanubrutinib treatment was associated with significantly improved progression-free survival (hazard ratio [HR], 0.

Zanubrutinib in the treatment of patients with del(17p) and/or TP53 CLL/SLL: analysis across clinical studies.

Patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) who harbor del(17p) and/or tumor protein p53 (TP53) mutations represent a high-risk population with a historically poor prognosis. To assess zanubrutinib efficacy and safety outcomes in patients with CLL/SLL with del(17p) and/or TP53 mutations (N=301; n=132, treatment-naive; n=169, relapsed/refractory), data from SEQUOIA (phase 3; treatment-naive; zanubrutinib; NCT03336333), ALPINE (phase 3; relapsed/refractory; zanubrutinib versus ibrutinib; NCT03734016) and AU-003 (phase 1/2; zanubrutinib) were evaluated. In SEQUOIA (n=127; median follow-up, 64.

Neurotoxicity associated with chimeric antigen receptor T-cell therapy.

Chimeric antigen receptor T cell (CAR-T) therapy involves reengineering patient-derived or donor-derived T cells to express a synthetic CAR that can recognise specific cell-surface antigens, independently of major histocompatibility complex molecules. As of March 2025, six autologous CAR-T cell products have received regulatory approval from the United States Food and Drug Administration (FDA) for B-cell derived haematological malignancies and multiple myeloma, delivering effective and durable treatment responses. All currently approved CAR-T cell therapy products target either CD19 or B-cell maturation antigen (BCMA).

Elucidating novel immune profiles for predicting infection in high-risk cohorts: a pilot study in patients with relapsed and refractory chronic lymphocytic leukaemia.

Objectives: Chronic lymphocytic leukaemia (CLL) patients are at increased risk for infection, with the risk even higher for relapsed and refractory patients. Clinical assessment of infection risk is increasingly challenging in the era of immune-based therapies, such as Bruton's tyrosine kinase inhibitors. A pilot study was conducted to elucidate possible predictive immune markers.

CLOX and neurotox: Utility of the clock drawing task in monitoring for immune effector cell-associated neurotoxicity syndrome following chimeric antigen receptor T-cell therapy.

Immune effector cell-associated neurotoxicity syndrome (ICANS)-associated cognitive impairment is common in patients who receive chimeric antigen receptor T-cell (CAR-T) therapy. This study evaluated the utility of the clock drawing task (CDT) in detecting ICANS in patients with haematological cancers following CAR-T therapy. Data were collected from CAR-T patients at The Alfred Hospital, Melbourne, Australia.

Efficacy of zanubrutinib versus acalabrutinib for relapsed or refractory chronic lymphocytic leukemia (R/R CLL): a matching-adjusted indirect comparison (MAIC).

Background: There are no head-to-head studies comparing the efficacy of the Bruton tyrosine kinase inhibitors, zanubrutinib and acalabrutinib, in relapsed or refractory chronic lymphocytic leukemia (R/R CLL).

Objective: To compare the relative efficacy of zanubrutinib and acalabrutinib in R/R CLL using indirect treatment comparison.

Design: An unanchored matching-adjusted indirect comparison (MAIC) was performed.

Evaluation of in vivo CAR transgene levels in tisagenlecleucel-treated patients with relapsed/refractory B-ALL and DLBCL.

Tisagenlecleucel is a CD19-directed autologous chimeric antigen receptor (CAR) T-cell therapy. Quantitative polymerase chain reaction assays are highly sensitive in defining in vivo kinetics by measuring CAR transgene in peripheral blood. This study aimed to identify clinically meaningful CAR T-cell blood levels that correlated with response/relapse.

Zanubrutinib and Venetoclax for Patients With Treatment-Naïve Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma With and Without Del(17p)/ Mutation: SEQUOIA Arm D Results.

Purpose: Several chronic lymphocytic leukemia (CLL) studies have demonstrated promising efficacy with the combination of BCL2 and Bruton tyrosine kinase inhibitors; however, patients with CLL with del(17p) and/or mutation (mut) comprised a small percentage of study populations or were excluded entirely. The purpose of the SEQUOIA Arm D cohort was to evaluate the combination of zanubrutinib + venetoclax in treatment-naïve (TN) patients with CLL/small lymphocytic lymphoma (SLL), in a large population of patients with -aberrant disease.

Patients And Methods: Arm D is a nonrandomized cohort of patients aged 65 years and older (or 18-64 years with comorbidities).

Enhanced Disease Detection of Hairy Cell Leukaemia Through Next-Generation Sequencing Based and Phased Variant Analysis.

Introduction: Longitudinal disease assessment by molecular techniques is not routine in hairy cell leukaemia (HCL). Combining and other genomic targets through next-generation sequencing (NGS) with phased variant analysis is a novel approach for disease detection in this setting.

Results: digital droplet PCR of paired peripheral blood and cell-free DNA (cfDNA) specimens detected residual disease in 15/48 and 6/48 specimens respectively from patients with HCL.

International consensus statement on diagnosis, evaluation, and research of Richter transformation: the ERIC recommendations.

Richter transformation (RT) is defined as an aggressive lymphoma emerging in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL). Despite novel therapeutics developed in CLL, RT is associated with poor outcomes. In light of recent progress regarding the diagnostic procedures and therapeutic concepts of RT, an international group of experts, under the coordination of the European Research Initiative on CLL, has developed consensus recommendations for clinical procedures and future research on this disease.

Comparative efficacy of Bruton tyrosine kinase inhibitors in high-risk relapsed/refractory CLL: a network meta-analysis.

Bruton tyrosine kinase inhibitors (BTKis) have led to changes in the treatment algorithm for patients with high-risk relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL), defined based on the presence of genetic mutations. Given the lack of head-to-head trials comparing next-generation BTKis used to treat high-risk R/R disease, a network meta-analysis (NMA) was performed to estimate their relative efficacy. High-risk populations were defined based on the prespecified definitions within each trial, including patients with del(17p) and/or TP53 mutations in the ALPINE (n = 150) and ASCEND (n = 86) trials, and del(17p)/del(11q) in the ELEVATE-RR (n = 533) trial.

The mutational landscape and functional effects of noncoding ultraconserved elements in human cancers.

The mutational landscape of phylogenetically ultraconserved elements (UCEs), especially those in noncoding DNAs (ncUCEs), and their functional relevance in cancers remain poorly characterized. Here, we perform a systematic analysis of whole-genome and in-house targeted UCE sequencing datasets from more than 3000 patients with cancer of 13,736 UCEs and demonstrate that ncUCE somatic alterations are common. Using a multiplexed CRISPR knockout screen in colorectal cancer cells, we show that the loss of several altered ncUCEs significantly affects cell proliferation.

Ibrutinib plus venetoclax in relapsed or refractory mantle cell lymphoma (SYMPATICO): a multicentre, randomised, double-blind, placebo-controlled, phase 3 study.

Background: The combination of ibrutinib and venetoclax leverages complementary mechanisms of action and has shown promising clinical activity in mantle cell lymphoma (MCL). This study evaluated the efficacy and safety of ibrutinib-venetoclax compared with ibrutinib-placebo in patients with relapsed or refractory MCL.

Methods: SYMPATICO is a multicentre, randomised, double-blind, placebo-controlled, phase 3 study performed at 84 hospitals in Europe, North America, and Asia-Pacific.

Acquired mutations in patients with relapsed/refractory CLL who progressed in the ALPINE study.

Some patients with chronic lymphocytic leukemia who develop progressive disease (PD) during covalent Bruton tyrosine kinase (BTK) inhibitor treatment acquire resistance mutations in BTK or PLCG2. Here, we report gene mutation data from paired baseline and PD peripheral blood samples from 52 patients (zanubrutinib, n = 24; ibrutinib, n = 28) who, at an early median follow-up of 25.7 months, progressed on zanubrutinib or ibrutinib treatment in ALPINE.

Novel mechanisms of resistance in CLL: variant BTK mutations in second-generation and noncovalent BTK inhibitors.

Bruton tyrosine kinase inhibitors (BTKis) are an established standard of care in chronic lymphocytic leukemia. The covalent BTKis ibrutinib, acalabrutinib, and zanubrutinib bind to BTK C481 and are all susceptible to the C481S mutation. Noncovalent BTKi, including pirtobrutinib, overcome C481S resistance but are associated with multiple variant (non-C481) BTK mutations, including those associated with resistance to acalabrutinib and zanubrutinib (T474 codon and L528W mutations).

Zanubrutinib Versus Bendamustine and Rituximab in Patients With Treatment-Naïve Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma: Median 5-Year Follow-Up of SEQUOIA.

JCO SEQUOIA (ClinicalTrials.gov identifier: NCT03336333) is a phase III, randomized, open-label trial that compared the oral Bruton tyrosine kinase inhibitor zanubrutinib to bendamustine plus rituximab (BR) in treatment-naïve patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). The initial prespecified analysis (median follow-up, 26.

Peripheral neuropathy in the phase 3 ASPEN study of Bruton tyrosine kinase inhibitors for Waldenström macroglobulinemia.

Peripheral neuropathy (PN) is a significant cause of morbidity associated with Waldenström macroglobulinemia (WM). The phase 3 ASPEN study compared the efficacy and safety of zanubrutinib with ibrutinib in patients with WM. This ad hoc analysis examined treatment outcomes with zanubrutinib or ibrutinib on PN symptoms associated with WM in patients enrolled in ASPEN.

Evaluation of bleeding risk in patients who received pirtobrutinib in the presence or absence of antithrombotic therapy.

Clinical bleeding events are reported here from 773 patients with B-cell malignancies receiving pirtobrutinib monotherapy from the phase 1/2 BRUIN study (ClinicalTrials.gov identifier: NCT03740529), either in the presence or absence of antithrombotic therapy (antithrombotic exposed [AT-E],  = 216; antithrombotic nonexposed [AT-NE],  = 557). Among the AT-E cohort, 51.

Sustained benefit of zanubrutinib vs ibrutinib in patients with R/R CLL/SLL: final comparative analysis of ALPINE.

The ALPINE trial established the superiority of zanubrutinib over ibrutinib in patients with relapsed/refractory chronic lymphocytic leukemia and small lymphocytic lymphoma; here, we present data from the final comparative analysis with extended follow-up. Overall, 652 patients received zanubrutinib (n = 327) or ibrutinib (n = 325). At an overall median follow-up of 42.

Seven-year outcomes of venetoclax-ibrutinib therapy in mantle cell lymphoma: durable responses and treatment-free remissions.

In the phase 2 clinical trial (AIM) of venetoclax-ibrutinib, 24 patients with mantle cell lymphoma (MCL; 23 with relapsed/refractory [R/R] disease) received ibrutinib 560 mg and venetoclax 400 mg both once daily. High complete remission (CR) and measurable residual disease negative (MRD-negative) CR rates were previously reported. With median survivor follow-up now exceeding 7 years, we report long-term results.