Marginal zone lymphoma (MZL) is a group of indolent B-cell malignancies that have a natural history that follows a remitting and relapsing course. For systemic disease, available first-line therapies include anti-CD20 antibody as monotherapy with or in combination with chemotherapy (chemoimmunotherapy), with second-line options such as covalent (c) Bruton tyrosine kinase inhibitors (BTKi). However, management of relapsed and refractory (R/R) MZL remains a challenge. Pirtobrutinib, a highly selective, non-covalent BTKi has shown promising efficacy and tolerability in patients with poor-prognosis B-cell malignancies following prior therapy, including cBTKi. Here we report the safety and efficacy of pirtobrutinib in patients with MZL from the phase 1/2 BRUIN study. Endpoints included investigator assessed ORR by Lugano 2014 criteria, DOR, PFS, OS, and safety. Among 36 R/R MZL patients (EMZL: n=6; NMZL: n=17; SMZL: n=13), median age was 68 years (range, 22-83) and median prior lines of therapy were 3 (range, 2-10) including anti-CD-20 antibody (100%), chemotherapy (86%) and cBTKi therapy (72%). The ORR was 55.6% (95% confidence interval [CI], 38.1- 72.1) including 3 (8.3%) complete responses and 17 (47.2%) partial responses. Median DOR was 17.8 months (95%CI, 7.4-non-estimable [NE]), and median PFS was 16.6 months (95%CI, 9.0-22.1). With median follow-up of 32.4 months (IQR, 28.0, 41.3), median OS was NE (95%CI, 29.5-NE). The ORR for patients with prior cBTKi therapy was 53.8% (95%CI, 33.4-73.4). Pirtobrutinib was well-tolerated with dose reductions in 4 patients (11.1%) and permanent discontinuation due to TEAEs in 4 (11.1%). Pirtobrutinib showed promising efficacy and safety in patients with heavily pre-treated R/R MZL, including prior cBTKi. NCT03740529

Background: There are multiple effective treatment options for patients diagnosed with chronic lymphocytic leukemia and small lymphocytic lymphoma (hereafter, simply CLL). In 2025, two phase 3 randomized clinical trials of pirtobrutinib, a non-covalent BTK inhibitor, were reported, demonstrating improved outcomes versus comparator therapies in the treatment-naïve setting (NCT05254743 and NCT05023980). Methods: A systematic literature review was conducted to identify RCTs in the first-line setting for CLL. A Bayesian NMA was performed to compare overall response rate (ORR) and progression-free survival (PFS) of pirtobrutinib versus treatments recommended by the National Comprehensive Cancer Network in the first-line setting, with a focus on BTKi monotherapy. Results: Eight unique trials were identified for comparison versus pirtobrutinib. Eligible RCTs formed two disconnected networks (pirtobrutinib, ibrutinib and zanubrutinib were in Network 1; acalabrutinib was in Network 2). Results from Network 1 for ORR showed an odds ratio (OR) = 0.56 (95% credible interval [CrI], 0.28, 1.12) for ibrutinib versus pirtobrutinib and OR = 0.50 (95% CrI, 0.20, 1.27) for zanubrutinib versus pirtobrutinib. The PFS of ibrutinib was inferior to pirtobrutinib (hazard ratio (HR) = 1.89, 95% CrI, 1.13, 3.19); the PFS HR comparing zanubrutinib with pirtobrutinib was 1.51 (95% CrI, 0.84, 2.72). Conclusions: This NMA shows that pirtobrutinib has better PFS outcomes than ibrutinib. While PFS outcomes suggest that pirtobrutinib is comparable to second-generation covalent BTKi monotherapies, uncertainty exists in the interpretation of the treatment effect, as evidenced by wide credible intervals. These findings suggest the value of pirtobrutinib as a future treatment option for patients in the first-line setting.

ABSTRACT:Pirtobrutinib, a noncovalent, reversible Bruton tyrosine kinase inhibitor (BTKi), demonstrated efficacy in patients with chronic lymphocytic leukemia (CLL), resistant to covalent BTKi (cBTKi). We analyzed genomic correlations with response and resistance to pirtobrutinib in relapsed/refractory (R/R) patients with CLL pretreated with cBTKi enrolled in the phase 1/2 BRUIN trial. DNA sequencing was performed on peripheral blood mononuclear cells at baseline, on treatment, and at progressive disease (PD). Common alterations at baseline included mutations in BTK (43%), TP53 (38%), SF3B1 (25%), NOTCH1 (23%), ATM (19%), XPO1 (11%), PLCG2 (9%), BCL2 (8%), and 17p deletion (28%). Common baseline BTK mutations included C481S (85%), C481R (10%), C481F (6%), and C481Y (4%). At PD, 60 of 88 patients (68%) acquired ≥1 mutation, including 44% with acquired BTK mutations and 24% with other acquired mutations. A total of 55 acquired BTK mutations were detected in 39 patients, including gatekeeper mutations (T474I/F/S/Y/L, 26%), kinase-impaired L528W (16%), C481S/R/Y (5%), V416L (2%), and A428D (1%) and others proximal to the adenosine triphosphate-binding pocket, D539A/G/H (1%) and Y545N (1%). Decrease or complete clearance of BTK C481x was observed at PD in 36 of 43 patients (84%). Using a more sensitive assay, 37% (18/49) of acquired BTK mutations were detected at baseline at low allele frequency. Using a highly sensitive assay at progression, a similar frequency of acquired BTK mutations (39%) was detected, and all patients had detectable acquired mutations. This study highlights the complex clonal dynamics of BTK mutations in patients with R/R CLL undergoing pirtobrutinib treatment, and the extent of resistance without an obvious genomic driver. Trial registration: #NCT03740529 at www.ClinicalTrials.gov.

PURPOSE:In large B-cell lymphoma (LBCL), use of high-dose methotrexate (HD-MTX) to prevent CNS relapse (so-called CNS prophylaxis) remains controversial. International guidelines continue to recommend HD-MTX in patients deemed ultra high risk (UHR) because of a lack of robust data specific to these subgroups. This study was designed to examine the impact of HD-MTX specifically in UHR patients. METHODS:Data from two previous retrospective analyses were combined to produce a cohort of UHR patients (≥1 of the following criteria: CNS international prognostic index score 5-6; testicular, renal/adrenal, or breast involvement; ≥3 extranodal sites), treated with or without HD-MTX. The primary outcome was CNS relapse rate (isolated or concurrent with systemic relapse) measured from diagnosis with additional landmark analysis of all responding patients with no progression event at 6 months. RESULTS:Analyses were performed on 1,923 patients meeting UHR criteria. No significant difference in 3-year CNS relapse rate was observed between no HD-MTX (n = 1,051) versus HD-MTX patients (n = 872), including in multivariable analyses adjusting for baseline characteristics (3-year rate, 9.3% v 8.1%; adjusted hazard ratio [HR], 1.13 [95% CI, 0.82 to 1.57]). Analyses restricted to isolated CNS relapse also confirmed no difference (5.9% v 5.7%; adjusted HR, 1.03 [95% CI, 0.69 to 1.53]). In the landmark analysis (no HD-MTX n = 782, HD-MTX n = 773), no difference in 3-year CNS relapse was observed (6.7% v 6.6%, adjusted HR, 0.95 [95% CI, 0.62 to 1.44]). CONCLUSION:To our knowledge, this is the largest international comparative data set of patients with LBCL with UHR features showing no significant reduction in CNS relapse with HD-MTX in all UHR or in any individual subgroup. Despite inherent limitations of retrospective analyses, the data strongly support previous studies in suggesting HD-MTX prophylaxis has no meaningful benefit for most patients.

COMMENTARY ON:Wang et al. Ibrutinib plus venetoclax for relapsed/refractory mantle cell lymphoma: Final analysis of the phase 3 SYMPATICO study. Br J Haematol 2026; 209(2): 734-739.

OBJECTIVE:No head-to-head trials have compared the efficacy of zanubrutinib versus ibrutinib in relapsed/refractory mantle-cell lymphoma (R/R MCL). METHODS:Following a systematic literature review, individual patient data from trials of zanubrutinib (n = 118) and aggregate data from a pooled analysis of ibrutinib trials (n = 370) were analyzed using an unanchored matching-adjusted indirect comparison (MAIC). RESULTS:After matching selected covariates, statistically significant differences were observed with zanubrutinib versus ibrutinib for progression-free survival (hazard ratio [HR] = 0.63; 95% confidence interval [CI] 0.46-0.87, p = .0044) and overall survival (HR, 0.46; 95% CI 0.30-0.71, p = .0005). CONCLUSION:These MAIC analyses demonstrate that zanubrutinib may be more effective than ibrutinib at delaying disease progression and death in R/R MCL.

PURPOSE:Mantle cell lymphoma (MCL) is a rare and typically aggressive B-cell non-Hodgkin lymphoma characterized by recurrent relapse after short remissions. Sonrotoclax (BGB-11417) is a next-generation B-cell lymphoma 2 inhibitor with greater selectivity and potency than venetoclax, a shorter half-life, and no drug accumulation. Sonrotoclax monotherapy was evaluated in Bruton tyrosine kinase inhibitor-pretreated patients with relapsed/refractory (R/R) MCL. METHODS:BGB-11417-201 (ClinicalTrials.gov identifier: NCT05471843) is an ongoing global, open-label, phase I/II trial. Sonrotoclax was orally administered once daily with gradual, 4-week ramp-up to 160 mg or 320 mg to mitigate tumor lysis syndrome (TLS). The primary end point was overall response rate by the independent review committee (ORR-IRC) per Lugano classification; secondary end points included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. RESULTS:Overall, 125 patients were enrolled and assigned to receive sonrotoclax 160 mg (n = 10) or 320 mg (n = 115) target doses once daily. Most patients had advanced disease (stage IV, 78.3%) and were heavily pretreated (median prior therapies, 3). In efficacy-evaluable patients (n = 103), the ORR-IRC was 52.4% (95% CI, 42.4 to 62.4), a statistically significant increase versus the historic control ORR (30%; P < .0001); the complete response rate was 15.5%. Responses were seen across high-risk subgroups, including patients with TP53 mutation (59.1%). With a median study follow-up of 14.2 months, the median DOR-IRC was 15.8 months, and the median PFS-IRC was 6.5 months. Median OS was not reached. The most common all-grade/grade ≥3 treatment-emergent adverse events were neutropenia (35.7%/19.1%), thrombocytopenia (24.3%/9.6%), and anemia (24.3%/7.8%). TLS occurred in 7.0% of patients; all cases resolved without sequelae. CONCLUSION:Sonrotoclax demonstrated rapid, durable responses and manageable safety in heavily pretreated patients with R/R MCL, including high-risk subgroups, supporting its further clinical evaluation as an oral therapy for R/R MCL.

Cellular therapies, namely autologous hematopoietic cell transplantation (autoHCT), allogeneic HCT (alloHCT) and more recently, chimeric antigen receptor T-cell therapies (CART), play a major role in state-of-the-art treatment of mantle cell lymphoma (MCL). With numerous therapeutic innovations currently entering the MCL treatment landscape, guidance for indication, sequencing and application of cellular therapies is of key importance. To address this practical need, the European Society for Blood and Marrow Transplantation (EBMT) Practice Harmonisation and Guidelines Committee convened an international expert meeting in Berlin on Sept 29/30, 2025. EBMT provided funding and logistical support. Two appointed chairpersons invited experts in MCL and cellular therapy, who completed three work packages devoted to the three types of cellular therapy. A literature search was performed beforehand and suitable published evidence was considered collectively in structured discussions and consensus-building exercises. The recommendations developed as a result of this process provide a sound basis for practical counseling and decision-making in the care of patients with treatment-naïve and relapsed/refractory MCL.

BACKGROUND:This study presents patient-reported outcomes (PROs) from the phase 1/2 BRUIN (NCT03740529) trial of pirtobrutinib monotherapy for the treatment of B-cell malignancies, including chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and mantle cell lymphoma (MCL). METHODS:PROs were collected at each cycle using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire and item library (IL) sets for CLL/SLL- and MCL-related symptoms and an Expanded Fatigue measure. Prespecified analyses included descriptive change from baseline, time to worsening (TTW) using Kaplan-Meier method, and longitudinal analyses using a mixed model for repeated measures. RESULTS:A total of 263 patients with CLL/SLL and 124 with non-blastoid MCL who received pirtobrutinib monotherapy after prior BTKi were included in the final PRO analysis. The proportion of patients with CLL/SLL who improved or remained stable from baseline through Cycle 31 remained above 80% for physical function (PF), CLL/SLL-related symptoms, fatigue, and global health status/quality of life (GHS/QoL). The proportion of patients with MCL who improved or remained stable through Cycle 20 remained above 70% for PF, MCL-related symptoms, fatigue, and GHS/QoL. Median TTW was not reached in either CLL or MCL. Longitudinal analyses for PF, CLL/SLL-related symptoms, fatigue, and GHS/QoL consistently met statistically significant and clinically-meaningful improvement from baseline for CLL. PRO assessments remained stable over time for MCL. CONCLUSIONS:The final analysis from the BRUIN trial demonstrates stability in PROs throughout the duration of treatment with pirtobrutinib. Most patients with CLL/SLL and MCL reported stable or improved outcomes throughout the study.

Abstract Clinical trials indicate that acalabrutinib, a second-generation Bruton tyrosine kinase inhibitor, is safe and effective for treating patients with chronic lymphocytic leukemia (CLL), but real-world evidence on its clinical effectiveness is limited. This ongoing multicenter retrospective chart review included UK adults with previously untreated CLL who received acalabrutinib monotherapy as part of a UK-wide early access program. These patients received their first dose of acalabrutinib between 1 April 2020 and 1 April 2021. Data from 282 patients (male patients, n = 156 [55%]) collected from 29 sites across the United Kingdom revealed a median age of 73.9 years (interquartile range [IQR], 68.6-79.4) at acalabrutinib initiation (index date) and a median time of 3.0 years (IQR, 1.2-5.7; n = 281) from CLL diagnosis to treatment. The median follow-up was 48.9 months (IQR, 45.0-52.3). At the 3-year landmark, real-world progression-free survival was 82.5% (95% confidence interval [CI], 78.2-87.1), and real-world overall survival was 84.3% (95% CI, 80.2-88.7). Additionally, 72.3% of patients (95% CI, 67.3-77.8) remained on acalabrutinib treatment. The most common reasons for acalabrutinib discontinuation were adverse events (AEs; 31/87 [36%]), death (16/87 [18%]), and disease progression (14/87 [16%]). Of the 270 patients with recorded information, 99 patients (37%) experienced ≥1 prespecified AE, of which the most frequent were upper respiratory tract infection (n = 21 patients [8%]), rash (n = 13 [5%]), and neutropenia (n = 12 [4%]). This study adds to a body of clinical trial and further postmarketing evidence demonstrating the effectiveness and safety of acalabrutinib within routine UK clinical practice.

BACKGROUND:Venetoclax-rituximab (VR) following covalent Bruton tyrosine kinase (BTK) inhibitor therapy is the fixed-duration standard of care for patients with chronic lymphocytic leukaemia (including small lymphocytic lymphoma). Pirtobrutinib, a non-covalent BTK inhibitor, is approved for use after treatment with a covalent BTK inhibitor as a continuous therapy option. We aimed to evaluate the addition of pirtobrutinib to VR as a fixed-duration regimen in patients with relapsed or refractory chronic lymphocytic leukaemia. METHODS:This open-label, multicentre, randomised, controlled, phase 3 trial was conducted at 152 sites (comprising community hospitals and academic centres) across 22 countries. Eligible patients were aged 18 years or older, had a confirmed diagnosis of chronic lymphocytic leukaemia (including small lymphocytic lymphoma), and had previously been treated with at least one line of therapy that could include a covalent BTK inhibitor. Patients who had previously received a non-covalent BTK inhibitor, venetoclax, or another BCL2 inhibitor were not eligible. Enrolled patients were randomly assigned (1:1) using an interactive web-based randomisation system, stratified by del(17p) status and previous exposure to covalent BTK inhibitors, and assigned to receive either pirtobrutinib plus VR (PVR) or VR. Both groups received oral venetoclax (25 cycles) and intravenous rituximab (six cycles); the PVR group also received oral pirtobrutinib for 28 cycles, with a three-cycle pirtobrutinib-rituximab lead-in before venetoclax initiation. For this prespecified interim analysis, the primary endpoint was progression-free survival in the intention-to-treat population, assessed by a masked independent review committee (IRC) as per 2018 International Workshop on Chronic Lymphocytic Leukemia guidelines. Safety analyses were conducted in the safety population, defined as all randomly assigned patients who took at least one dose of any study treatment. All analyses were based on a data cutoff date of Feb 2, 2026. The trial is registered at ClinicalTrials.gov, NCT04965493, and is ongoing but no longer recruiting. FINDINGS:Between Oct 13, 2021, and Oct 28, 2024, 784 patients were screened, of whom 639 were randomly assigned: 321 to the PVR group and 318 to the VR group. The median age of patients was 68·0 years (IQR 60·0-74·0), of whom 439 (69%) were male and 200 (31%) were female. The median number of previous therapies was 2 (IQR 1-3); 510 (80%) of 639 patients had previous exposure to covalent BTK inhibitors, of whom 362 (71%) discontinued their most recent drug of this class owing to progressive disease. At a median follow-up of 27·3 months (IQR 19·5-38·7), PVR showed a significant improvement in IRC-assessed progression-free survival compared with VR (hazard ratio 0·547 [95% CI 0·400-0·748]; p=0·0001). The median 24-month progression-free survival rate was 87% (95% CI 82·3-90·4) in the PVR group versus 72% (65·7-77·0) in the VR group, and the median progression-free survival was not reached (IQR 31·7-not estimable) in the PVR group versus 39·7 months (21·5-50·0) in the VR group. This benefit was consistent across prespecified subgroups, including patients with previous exposure to covalent BTK inhibitors. The most frequent treatment-emergent adverse event of any grade in both groups was diarrhoea, reported in 106 (34%) of 316 patients in the PVR group and 110 (35%) of 311 patients in the VR group. The frequency of treatment-emergent adverse events of grade 3 or higher was similar in both groups (249 [79%] of 316 patients in the PVR group vs 227 [73%] of 311 patients in the VR group); the rate of tumour lysis syndrome of grade 3 or higher was lower in the PVR group (1%; three of 316) than in the VR group (4%; 12 of 311). Rates of atrial fibrillation or flutter of any grade were low (11 [3%] of 316 patients in the PVR group vs eight [3%] of 311 patients in the VR group). Rates of treatment discontinuation owing to treatment-emergent adverse events deemed as related to any of the study drugs were similar: 5% (17 of 316 patients) in the PVR group versus 5% (16 of 311 patients) in the VR group. There were five treatment-related deaths: one in the PVR group and four in the VR group. INTERPRETATION:In patients with previously treated chronic lymphocytic leukaemia, PVR showed significant improvement in progression-free survival compared with VR, with consistent results in patients who had previously received covalent BTK inhibitors and no new safety signals. To our knowledge, these results represent the first randomised phase 3 evidence comparing a novel fixed-duration regimen to the current standard of VR in relapsed or refractory chronic lymphocytic leukaemia, supporting PVR as a potential new standard of care. FUNDING:Eli Lilly and Company.

Mantle cell lymphoma (MCL) is a biologically and clinically heterogeneous B-cell malignancy with variable prognosis, ranging from indolent, asymptomatic forms to aggressive subtypes with early treatment failure. Contemporary management emphasizes risk-adapted strategies that integrate patient characteristics, clinical disease burden, and tumor biology. Prognostic tools such as the MCL International Prognostic Index (MIPI) and its biologically integrated variant (combined MIPI), alongside assessment of Ki-67 proliferation, TP53 status, and blastoid morphology, help guide treatment selection. In younger, fit patients, first-line therapy traditionally involves dose-intensified chemoimmunotherapy with high-dose cytarabine and autologous stem-cell transplantation (ASCT). The incorporation of Bruton tyrosine kinase inhibitors (BTKi), such as ibrutinib, into induction regimens has improved survival outcomes, with emerging evidence that may limit the use of ASCT to high-risk subsets. Maintenance therapy, particularly rituximab, remains crucial for durable disease control. In older or transplant-ineligible patients, bendamustine-rituximab remains a backbone therapy, with chemotherapy-free combinations incorporating BTKi, BCL2 inhibitors, and anti-CD20 antibodies offering effective, well-tolerated alternatives. High-risk patients, including those with TP53 mutations, may benefit from targeted triplet regimens or early cellular therapies. Relapsed/refractory MCL is increasingly managed with covalent and noncovalent BTKi, BCL2 inhibitors, and T-cell-redirecting therapies including chimeric antigen receptor T-cell therapy and bispecific antibodies. Ongoing trials are evaluating optimal sequencing and combination strategies to improve outcomes, particularly in high-risk and cBTKi-exposed patients. Overall, modern MCL management emphasizes individualized therapy based on biological risk, functional status, and treatment tolerability, with novel targeted and cellular approaches reshaping the frontline and relapsed treatment landscape.

BACKGROUND:Covalent Bruton tyrosine kinase (BTK) inhibitors have advanced the treatment of Waldenström macroglobulinaemia; however, the occurrence of progression, intolerance, and acquired resistance are not fully understood. We aim to report on the safety and activity of pirtobrutinib (a highly selective, non-covalent BTK inhibitor) in patients with relapsed or refractory Waldenström macroglobulinaemia, including those who received previous covalent BTK inhibitors as part of the phase 1/2 BRUIN trial. METHODS:The BRUIN study was an open-label, multicentre, phase 1/2 trial that enrolled patients with relapsed or refractory B-cell malignancies from 29 sites across eight countries. Patients aged 18 years or older who previously received BTK inhibitor-containing regimens, had an Eastern Cooperative Oncology Group performance status of 0-2, and histologically confirmed Waldenström macroglobulinaemia were eligible. In phase 1, patients received 100-300 mg oral pirtobrutinib once a day in 28-day cycles and the recommended phase 2 dose (RP2D) of 200 mg pirtobrutinib once a day was determined. The phase 2 primary endpoint was antitumour activity of pirtobrutinib based on objective response rate as assessed by an investigator in patients with chronic lymphocytic leukaemia, small lymphocytic leukaemia, or mantle cell lymphoma. In patients with Waldenström macroglobulinaemia, response was evaluated using the Sixth International Workshop on Waldenström Macroglobulinemia (IWWM-6) criteria. BRUIN is registered with ClinicalTrials.gov, NCT03740529 (completed). FINDINGS:BRUIN recruited patients from Aug 12, 2019, to March 14, 2022, and 778 patients received pirtobrutinib. 80 patients had relapsed or refractory Waldenström macroglobulinaemia (n=18 in phase 1 and n=62 in phase 2), with a median age of 68·5 years (IQR 61·0-75·0). 52 (65%) patients were male and 28 (35%) were female. The median number of previous lines of systemic therapy was 3·0 (2·0-5·0). 63 (79%) patients received previous covalent BTK inhibitors. 73 (91%) received 200 mg pirtobrutinib once per day (the RP2D). Using IWWM-6 criteria, the objective response rate was 82·5% (95% CI 72·4-90·1), with one (1·3%) patient reaching complete response, eight (10·0%) reaching very good partial response, 49 (61·3%) reaching partial response, and eight (10·0%) reaching minor response. The median study follow-up was 35·0 months (17·7-47·7). The objective response rate was 81·0% (69·1-89·8) for those who received previous covalent BTK inhibitors and 88·2% (63·6-98·5) for covalent BTK inhibitor-naive patients. Grade 3 or higher treatment-emergent adverse events occurred in 57 (71%) patients, with the most common being neutropenia or neutrophil count decreased (15 [19%]) and anaemia (19 [24%]). Treatment-emergent deaths were reported in five (6%) patients (bacterial sepsis, intracranial haemorrhage, COVID-19 pneumonia, hypertensive cardiomegaly and pneumonia [n=1 each unrelated to treatment], and treatment-related necrotising pneumonia [n=1]). Treatment-emergent adverse events leading to dose reductions occurred in four (5%) patients and pirtobrutinib discontinuation in 12 (15%). INTERPRETATION:Pirtobrutinib was highly active and well tolerated, regardless of previous exposure to covalent BTK inhibitors, and might be a promising new therapeutic option for patients with relapsed or refractory Waldenström macroglobulinaemia, particularly in those previously exposed to covalent BTK inhibitors, for whom durable and effective treatments are needed. FUNDING:Eli Lilly and Company.

ABSTRACT Background The treatment landscape for relapse/refractory chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) has evolved with recent novel agents. With the availability of novel agents that slow disease progression, managing treatment side effects and monitoring response in patients with these hematologic malignancies may present a challenge for healthcare providers. The imperative to engage patients in the management of their condition demands that specialists are knowledgeable about new treatment options and are skilled and confident in educating patients to manage and monitor for potential side effects. Aims This study aimed to establish the current knowledge, skills and confidence levels of oncologists, hematologists and hematologist‐oncologists (ONC/HEM) and identify the challenges they experience when managing and monitoring treatment and engaging patients with CLL or MCL in shared decision‐making. The long‐term aim is to inform evidence‐based continuing medical education to optimize ONC/HEM competencies. Methods and Results This cross‐sectional study employed a quantitative survey, completed by 285 ONC/HEM practicing in academic or community settings in Brazil, France, Germany, the United Kingdom, and the United States. Using 5‐point Likert‐type scales, participants reported their knowledge/skills/confidence levels, and their agreement with selected statements. Sub‐optimal levels of knowledge/skills to identify and manage side effects associated with treatments for CLL or MCL were reported. Challenges with patient risk stratification and engaging patients in shared decision‐making were reported, with a greater proportion reported by those in community settings. Of note, 31% of participants reported sub‐optimal skills identifying patients at higher risk for progression and using stratification to plan and manage treatment, and 58% never/rarely/sometimes considered patients' concerns about treatment safety. Conclusion Continuing medical education activities to improve knowledge of new treatments and associated pathways for patients with CLL or MCL, and to develop skills/confidence to engage in shared decision‐making are recommended. Setting‐specific issues should be integrated into interventions to ensure relevant educational support for the ONC/HEM.