A Review of Selected Presentations From ASH 2025 • December 6-9, 2025 • Orlando, Florida
Post Hoc Safety Analysis and Exploratory Analysis of Impact of Prognostic Mutations on Outcomes of Fixed-Duration Acalabrutinib-Venetoclax Combinations vs Chemoimmunotherapy: Results From the Phase 3 AMPLIFY Trial
The phase 3 AMPLIFY trial compared fixed-duration acalabrutinib plus venetoclax with or without obinutuzumab against chemoimmunotherapy in fit patients with previously untreated chronic lymphocytic leukemia (CLL) without del(17p) or TP53 mutations. As previously reported, the acalabrutinib-containing regimens were associated with a significant progression-free survival (PFS) benefit over chemoimmunotherapy; estimated 3-year PFS rates were 76.5% with acalabrutinib-venetoclax (AV), 83.1% with acalabrutinib, venetoclax, and obinutuzumab (AVO), and 66.5% with chemoimmunotherapy.1
Post Hoc Safety Analysis
At the 67th American Society of Hematology Annual Meeting and Exposition (henceforth referred to as ASH 2025), Seymour and colleagues presented results of a post hoc safety analysis from AMPLIFY further assessing the safety of AV, AVO, and chemoimmunotherapy.2 The trial enrolled 834 patients who were randomly assigned and received at least 1 dose of AV (n=291), AVO (n=284), or chemoimmunotherapy (n=259). Patients assigned to AV received acalabrutinib in cycles 1 through 14 and venetoclax in cycles 3 through 14; patients assigned to AVO also received obinutuzumab in cycles 2 through 7. Chemoimmunotherapy consisted of investigator’s choice of fludarabine, cyclophosphamide, and rituximab (FCR) or bendamustine-rituximab (BR) administered for 6 cycles.
Treatment exposure varied across arms, with a median duration of acalabrutinib exposure of 12.9 months in the AV and AVO arms, compared with a median treatment exposure of 5.6 months in the FCR/BR arm.
The incidence of any-grade events of clinical interest was 76.3% with AV, 85.2% with AVO, and 71.4% with FCR/BR. Exposure-adjusted event rates (EAERs) were 25.3, 36.1, and 57.8 events per 100 person-months, respectively (Table 1). Rates of any-grade cardiac events were higher with AV (9.3%) or AVO (12.0%) compared with FCR/BR (3.5%), with both comparisons reaching significance (P=.0063 and P=.0003). However, the EAER was similar across arms, at 0.83, 1.11, and 0.86 events per 100 person-months with AV, AVO, and FCR/BR, respectively. Grade 3 or greater cardiac events were infrequent across arms, with EAERs of 0.126, 0.211, and 0.285 events per 100 person-months, respectively.
The incidence of infection was higher with AV (50.9%) and AVO (53.9%) compared with FCR/BR (31.7%; P<.0001 for both comparisons); however, EAERs were similar across arms, at 6.47, 8.38, and 8.77 events per 100 person-months with AV, AVO, and FCR/BR, respectively. EAERs for grade 3 or greater infections were 1.032, 2.193, and 2.138 events per 100 person-months, respectively, indicating a lower adjusted incidence of grade 3 or greater infections in the AV arm. Requirements for granulocyte colony-stimulating factor were lower with AV and AVO (30.9% and 42.6%, respectively) compared with FCR/BR (57.1%).
In subgroup analysis, the rate of grade 3 or greater infection was increased in the AVO arm among patients with a baseline immunoglobulin G (IgG) level of at least 600 mg/dL (above the lower limit of normal) but was similar across arms among patients with a baseline IgG of 400 mg/dL or less. Cumulative rates of second primary malignancies were similar across arms, with basal cell carcinoma being the most frequently reported across arms. The rate of grade 5 treatment-emergent adverse events (TEAEs) was 3.4% with AV, 6.0% with AVO, and 3.5% with FCR/BR; these were primarily attributed to COVID-19.
Overall, 91.6% of patients in the AV arm and 94.9% of patients in the AVO arm completed treatment. The incidence of premature discontinuation of all study drugs or death was lower with AV vs FCR/BR (8.4% vs 18.6%; hazard ratio [HR] for time to an event, 0.07; P<.0001) and with AVO vs FCR/BR (5.1% vs 18.6%; HR for time to an event, 0.16; P<.0001). Adverse events (AEs) were the most common cause of discontinuation of all study drugs, reported in 5.9%, 4.3%, and 10.5% of patients in the AV, AVO, and FCR/BR arms, respectively. The incidence of AEs leading to withholding and reduction of doses was 49.8% and 14.1%, respectively, in the AV arm; 64.8% and 20.8%, respectively, in the AVO arm; compared with 31.3% and 11.2%, respectively, in the FCR/BR arm.
An efficacy analysis including patients who completed treatment and had at least 14 months of follow-up found that dose modifications did not appear to negatively affect efficacy of the acalabrutinib-containing regimens. Among patients receiving AV, the estimated 24-month PFS rate from the end of treatment was 77.0% in patients with dose modifications (n=125) and 80.1% in patients without dose modifications (n=127). Among patients receiving AVO, estimated 24-month PFS rates from the end of treatment were 91.2% in patients with dose modifications (n=124) and 94.4% in patients without dose modifications (n=93). Similar patterns were noted for the time to next treatment (TTNT).
Investigators also reported the incidence of tumor lysis syndrome (TLS) and the effect of the acalabrutinib lead-in period on TLS risk. At baseline, 93 patients in the AV arm (32.0%), 75 patients in the AVO arm (26.4%), and 86 patients in the FCR/BR arm (33.2%) had a high risk of TLS. At cycle 3, most patients with high TLS risk had moved to the medium-risk category (60.2%, 21.3%, and 8.1%, respectively) or to the low-risk category (19.4%, 61.3%, and 77.9%, respectively). TLS occurred in 1 patient receiving AV during the venetoclax ramp-up and in 1 patient receiving AVO during the acalabrutinib lead-in; both were laboratory events with no clinical TLS reported.
Exploratory Analysis of Impact of Prognostic Mutations on Outcomes
In the GAIA/CLL13 trial, established prognostic factors including unmutated IGHV (uIGHV) and the presence of NOTCH1 mutations were associated with shorter PFS after either chemoimmunotherapy or venetoclax-based targeted therapy.3 At ASH 2025, Ghia and colleagues presented an exploratory analysis from the AMPLIFY trial evaluating the association between prognostic genetic factors and clinical outcomes with acalabrutinib-containing regimens vs chemoimmunotherapy in patients with treatment-naive CLL.4 Using next-generation sequencing (NGS), investigators evaluated the prognostic significance of 6 genes with established prognostic value in the context of chemoimmunotherapy: ATM, SF3B1, NOTCH1, BIRC3, MYD88, and CARD11, and IGHV status.5,6
The overall prevalence of uIGHV was 59%. Approximately one-half of patients had at least 1 key mutation, with mutations most commonly occurring in ATM (20%-24% across arms), SF3B1 (15%-16%), and NOTCH1 (14%-17%). Mutations were more commonly found in patients with uIGHV than in patients with mutated IGHV (mIGHV) except for MYD88 mutations, which occurred more frequently in patients with mIGHV. Co-mutations included ATM/SF3B1, detected in 10% to 12% of patients, ATM/NOTCH1, detected in 6% to 10%, and NOTCH1/SF3B1, detected in 5% to 9%.
In the intention-to-treat (ITT) population, 36-month PFS rates were higher with AV (76.5%) and AVO (83.1%) compared with FCR/BR (66.5%). Among patients with uIGHV, the HR for PFS with AV vs FCR/BR was 0.69 (95% CI, 0.48-0.97) and the HR for PFS with AVO vs FCR/BR was 0.35 (95% CI, 0.23-0.53). The PFS benefit with AV or AVO vs FCR/BR was consistently maintained across prespecified mutation status subgroups.
Among patients receiving AV, NOTCH1 mutations were associated with a lower 36-month PFS rate (57.1% vs 79.0% in patients without NOTCH1 mutations). However, NOTCH1 mutations were not prognostic in the AVO arm. Mutations in ATM and SF3B1 were not prognostic in the AV or AVO arms.
In the AV arm, PFS rates in the uIGHV subgroup were higher among patients without a co-occurring NOTCH1 mutation than in patients with a co-occurring NOTCH1 mutation (36-month PFS, 72.9% vs 48.7%); conversely, in the mIGHV subgroup, 36-month PFS rates were 85.4% and 80%, respectively (Figure 1). However, investigators cautioned that the mIGHV, NOTCH1-mutated subgroup had a small patient population.
In the AVO arm, the presence of NOTCH1 mutations did not appear to affect PFS outcomes across IGHV status. In the FCR/BR arm, PFS rates were lower in the NOTCH1-mutated uIGHV subgroup vs the NOTCH1-mutated mIGHV subgroup, although number of patients in each subgroup was low.
Acalabrutinib-containing regimens were also associated with an improvement in TTNT compared with chemoimmunotherapy, with 36-month TTNT rates of 88.5% with AV, 85.4% with AVO, and 75.2% with FCR/BR, yielding HRs of 0.46 (95% CI, 0.32 to 0.64) with AV or AVO vs FCR/BR. In subgroup analyses, the TTNT benefit with AV or AVO vs BR was consistent regardless of the presence of key mutations and was observed in the uIGHV and mIGHV subgroups. Among patients receiving AV or FCR/BR with uIGHV, there was a trend toward shorter TTNT in patients with a NOTCH1 mutation. TTNT did not appear to be affected by NOTCH1 status in the mIGHV subgroup, but those patient populations were small.
In a univariate Cox regression analysis, genetic alterations that were significantly prognostic for PFS varied by arm and included IGHV status in the AV and FCR/BR arms, BIRC3 and NOTCH1 in the AV arm, and SF3B1 in the FCR/BR arm. In a multivariate Cox regression analysis, factors that were significantly prognostic for PFS included NOTCH1 and the presence of bulky disease in the AV arm, bulky disease and age in the AVO arm, and IGHV status and del(11q) in the FCR/BR arm.
References
1. Brown JR, Seymour JF, Jurczak W, et al. Fixed-duration acalabrutinib combinations in untreated chronic lymphocytic leukemia. N Engl J Med. 2025;392(8):748-762.
2. Seymour J, Aw A, Ribrag V, et al. A post hoc safety analysis of fixed-duration acalabrutinib-venetoclax combinations vs chemoimmunotherapy: results from the phase 3 AMPLIFY trial. Presented at: 67th American Society of Hematology Annual Meeting and Exposition; December 6-9, 2025; Orlando, Florida, USA. Abstract 2118.
3. Tausch E, Schneider C, Furstenau M, et al. Genetic markers and front line FCR/BR vs RVe, GVe and GIVe treatment – outcome results from the CLL13/GAIA trial. Blood. 2020;140(Supplement 1):839-841.
4. Ghia P, Eichhorst B, Wróbel TM, et al. Impact of prognostic mutations on outcomes with fixed-duration acalabrutinib-venetoclax combinations vs chemoimmunotherapy: an exploratory analysis from AMPLIFY. Presented at: 67th American Society of Hematology Annual Meeting and Exposition; December 6-9, 2025; Orlando, Florida, USA. Abstract 3898.
5. Arcari A, Morello L, Borotti E, Ronda E, Rossi A, Vallisa D. Recent advances in the molecular biology of chronic lymphocytic leukemia: how to define prognosis and guide treatment. Cancers (Basel). 2024;16(20):3483.
6. Kou Z, Mao M, Liu H, et al. CARD11 is a novel target of miR-181b that is upregulated in chronic lymphocytic leukemia. Biomark Med. 2021;15(9):623-635.
Fixed-Duration vs Continuous Targeted Treatment for Previously Untreated CLL: Results From the Randomized CLL17 Trial
Current options for first-line CLL therapy include a continuous Bruton tyrosine kinase (BTK) inhibitor and a fixed-duration regimen of a BCL2 inhibitor in combination with an anti-CD20 antibody or a BTK inhibitor.1 These approaches have not been compared in a head-to-head randomized trial. To prospectively evaluate the efficacy and safety of these 2 approaches, the investigator-initiated, randomized, phase 3 CLL17 trial was undertaken to compare indefinite ibrutinib against fixed-duration venetoclax-obinutuzumab or venetoclax-ibrutinib in patients with previously untreated CLL. Results from CLL17 were presented at ASH 2025 and published concurrently in the New England Journal of Medicine.2,3
Between February 2021 and November 2022, 976 patients were screened across 174 sites in 13 countries. Patients were stratified 1:1:1 according to fitness, del(17p)/TP53 mutation, and IGHV status, and randomly assigned to ibrutinib 420 mg daily until progression (n=301), venetoclax 400 mg daily (cycle 1 day 22 to cycle 12) plus obinutuzumab 1000 mg intravenous (IV) (cycle 1 day 1/2, 8, and 15, and cycles 2-6 day 1) (n=303), or venetoclax 400 mg daily (cycle 4 day 1 to cycle 15) plus ibrutinib 420 mg daily (cycle 1 day 1 to cycle 15) (n=305).
After a median follow-up of 34.2 months, the trial met its primary objective, demonstrating a noninferior PFS with fixed-duration venetoclax-obinutuzumab vs continuous ibrutinib (HR, 0.87; 98.3% CI, 0.54-1.41), and with fixed-duration venetoclax-ibrutinib vs continuous ibrutinib (HR, 0.84; 98.0% CI, 0.53-1.32) (Table 2). The 3-year PFS rates were 81.1% with venetoclax-obinutuzumab, 79.4% with venetoclax-ibrutinib, and 81.0% with ibrutinib. Investigators noted that additional follow-up is needed to assess differences in PFS between arms across clinical and biologic subgroups.
Rates of undetectable minimal residual disease (MRD) at the end of treatment were 73.3% with venetoclax-obinutuzumab, 47.2% with venetoclax-ibrutinib, and 0% with ibrutinib; 3-year overall survival (OS) rates were 91.5%, 96.0%, and 95.7%, respectively. Frequent AEs included neutropenia (52.5%, 36.3%, and 16.4% of patients receiving venetoclax-obinutuzumab, venetoclax-ibrutinib, and ibrutinib, respectively), infections (76.3%, 80.2%, and 79.9%, respectively), and diarrhea (27.1%, 47.2%, and 34.9%, respectively). Rates of atrial fibrillation were 3.7%, 12.5%, and 16.8%, respectively. Grade 3 or greater infections were reported in 34.9% of patients receiving venetoclax-obinutuzumab (15.9% with COVID-19), 25.1% of patients receiving venetoclax-ibrutinib (8.6% with COVID-19), and 24.8% of patients receiving ibrutinib (6.7% with COVID-19).
Investigators noted that all CLL therapies, and particularly anti-CD20 antibodies, are associated with a risk of infection, and that safety outcomes were consistent with the established safety profiles of these regimens. They concluded that fixed-duration treatment is a primary option for most patients with previously untreated CLL.
References
1. National Comprehensive Cancer Network (NCCN) guidelines: chronic lymphocytic leukemia/small lymphocytic lymphoma. Version 2.2026. Revised December 22, 2025. https://www.nccn.org/professionals/physician_gls/pdf/cll.pdf. Accessed December 29, 2025.
2. Al-Sawaf O, Stumpf J, Zhang C, et al. Fixed-duration vs continuous targeted treatment for previously untreated CLL: results from the randomized CLL17 Trial. Presented at: 67th American Society of Hematology Annual Meeting and Exposition; December 6-9, 2025; Orlando, Florida, USA. Abstract 1.
3. Al-Sawaf O, Stumpf J, Zhang C, et al. Fixed-duration vs continuous treatment for chronic lymphocytic leukemia. N Engl J Med. Published online December 6, 2025.
Pirtobrutinib vs Bendamustine + Rituximab in Patients With CLL/SLL: First Results From a Randomized Phase 3 Study Examining a Non-covalent BTK Inhibitor in Untreated Patients
Pirtobrutinib is a noncovalent BTK inhibitor that is approved by the US Food and Drug Administration for use in adults with CLL or small lymphocytic lymphoma (SLL) who have received at least 2 prior lines of therapy, including a covalent BTK inhibitor and a BCL2 inhibitor.1 Previously, the efficacy and safety of noncovalent BTK inhibitors including pirtobrutinib had not been directly compared against current standard therapies for the initial treatment of CLL. Two recent prospective trials directly compared pirtobrutinib against current therapies in patients with treatment-naive CLL. BRUIN CLL-314 compared pirtobrutinib with ibrutinib in previously untreated and relapsed/refractory (R/R) CLL. In the subset of patients with previously untreated CLL (n=225), the overall response rate (ORR) as assessed by independent review committee (IRC) was 92.9% with pirtobrutinib and 85.9% with ibrutinib; investigator-assessed PFS favored pirtobrutinib over ibrutinib (HR, 0.24; 95% CI, 0.10-0.59).2
At ASH 2025, Jurczak and colleagues presented results from the randomized, open-label, global, phase 3 BRUIN CLL-313 trial comparing pirtobrutinib with BR in patients with previously untreated CLL/SLL.3 The trial enrolled 282 patients with treatment-naive CLL/SLL without del(17p) who were stratified by IGHV mutation status and Rai stage (0-II vs III-IV) and randomly assigned them to pirtobrutinib (200 mg once daily) (n=141) or BR (bendamustine 90 mg/m2 IV plus rituximab 375-400 mg/m2 IV) for 6 cycles (n=141). Crossover from BR to pirtobrutinib was allowed upon disease progression confirmed by IRC.
In the pirtobrutinib arm, 140 patients (99.3%) started treatment and 11.3% discontinued treatment, primarily owing to AEs (4.3%), with the remaining 87.9% continuing treatment. In the BR arm, 132 patients (93.6%) started treatment, 102 patients (72.3%) completed treatment, and 30 patients (21.3%) discontinued early, primarily owing to AEs (12.7%). The median time on treatment was 32.3 months for pirtobrutinib and 5.6 months for BR. Of the 34 patients with disease progression on the BR arm, 18 patients (52.9%) crossed over to pirtobrutinib.
After a median follow-up of 28 months, pirtobrutinib was associated with a significant reduction in risk of progression or death compared with BR; the 24-month PFS rate was 93.4% with pirtobrutinib vs 70.7% with BR (HR, 0.20; 95% CI, 0.11-0.37; P<.0001) (Figure 2). Subgroup analyses favored pirtobrutinib in all prespecified groups, including in patients with mIGHV and uIGHV, in patients with complex karyotype, and in patients with TP53 mutations. The IRC-assessed ORR was 94.3% with pirtobrutinib (13.5% complete response [CR] or incomplete CR [CRi]) and 80.9% with BR (20.6% CR/CRi).
OS outcomes were immature, but investigators noted a nonsignificant trend toward improved OS with pirtobrutinib vs BR (24-month OS rate, 97.8% vs 93.0%; HR, 0.26; 95% CI, 0.07-0.93; stratified log-rank 2-sided P=.0261), despite the 52.9% crossover rate.
The most frequent TEAEs reported with pirtobrutinib were COVID-19 (21.4%; 0.7% grade ≥3), upper respiratory tract infection (17.9%; 0.7% grade ≥3), and neutropenia (12.1%; 7.1% grade ≥3). The most frequent TEAEs reported with BR were neutropenia (38.6%; 34.8% grade ≥3), nausea (23.5%; 0.8% grade ≥3), pyrexia (18.9%; 0% grade ≥3), anemia (15.9%; 7.6% grade ≥3), and infusion-related reaction (15.2%; 3.0% grade ≥3).
Exposure-adjusted incidence rates were lower with pirtobrutinib compared with BR across AEs, including for neutropenia (5.2 vs 110.0 per 100 person-years), upper respiratory tract infection (7.7 vs 15.7 per 100 person-years), and COVID-19 (9.9 vs 20.9 per 100 person-years). Pirtobrutinib was also associated with reductions over BR in rates of discontinuation owing to TEAEs (4.3% vs 15.4%) and dose reduction owing to TEAEs (3.6% vs 31.1%).
Atrial fibrillation and flutter occurred in 1.4% of patients on the pirtobrutinib arm (0.7% grade ≥3) and 1.5% of patients on the BR arm (0.8% grade ≥3) and remained low in the subset of patients aged 75 years or older, with an overall incidence of 5.0% with pirtobrutinib and 4.3% with BR, and no grade 3 or greater events reported.
Investigators concluded that in patients with treatment-naive CLL/SLL, pirtobrutinib was associated with superior PFS vs BR, a trend toward longer OS, and a good tolerability profile, suggesting that pirtobrutinib may be considered a new standard of care for the initial treatment of CLL, particularly for older patients who may receive only a single line of therapy.
References
1. U.S. Food & Drug Administration. FDA grants traditional approval to pirtobrutinib for chronic lymphocytic leukemia and small lymphocytic lymphoma. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-traditional-approval-pirtobrutinib-chronic-lymphocytic-leukemia-and-small-lymphocytic. Accessed January 2, 2026.
2. Woyach JA, Qiu L, Grosicki S, et al. Pirtobrutinib vs ibrutinib in treatment-naïve and relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma. J Clin Oncol. Published online December 7, 2025.
3. Jurczak W, Kwiatek M, Czyz J, et al. Pirtobrutinib vs bendamustine + rituximab in patients with CLL/SLL: first results from a randomized phase III study examining a non-covalent BTK inhibitor in untreated patients. Presented at: 67th American Society of Hematology Annual Meeting and Exposition; December 6-9, 2025; Orlando, Florida, USA. Abstract LBA-3.
Pirtobrutinib vs Ibrutinib in Treatment-Naïve and Relapsed/Refractory CLL/SLL: Results From the First Randomized Phase 3 Study Comparing a Non-covalent and Covalent BTK Inhibitor
The first-generation BTK inhibitor ibrutinib and the second-generation BTK inhibitors acalabrutinib and zanubrutinib have improved outcomes and transformed the care of patients with CLL. However, these agents are associated with limitations including toxicities, short half-lives, and the development of resistance mutations, in particular C481S.1
Pirtobrutinib is a noncovalent BTK inhibitor that binds reversibly but with a long half-life, allowing for sustained BTK inhibition.2 In the BRUIN CLL-321 trial, pirtobrutinib demonstrated improved PFS and a favorable safety profile compared with chemoimmunotherapy in patients with CLL/SLL previously treated with a covalent BTK inhibitor.3 The efficacy and safety of pirtobrutinib in treatment-naive patients has not been established.
The randomized, phase 3 BRUIN CLL-314 trial was undertaken to compare pirtobrutinib with ibrutinib in 2 population of patients with CLL: treatment-naive patients and patients with R/R CLL not previously treated with a BTK inhibitor. Results were presented at ASH 2025 and concurrently published in the Journal of Clinical Oncology (Table 3).4,5 The trial enrolled 662 patients who were stratified by the presence of del(17p) and the number of prior lines of therapy (0 vs 1 vs ≥2) and randomly assigned to pirtobrutinib 200 mg once daily (n=331) or ibrutinib 420 mg once daily (n=331). Overall, 34% of patients were treatment naive.
In a blinded IRC analysis, pirtobrutinib demonstrated a numerically higher and statistically noninferior ORR compared with ibrutinib in the ITT population (87.0% vs 78.5%; nominal P=.0035) and the R/R population (84.0% vs 74.8%; nominal P=.0175). In the treatment-naive subgroup, the ORR with pirtobrutinib and ibrutinib was 92.9% and 85.8%, respectively (nominal P=.0886). ORRs were generally higher with pirtobrutinib over ibrutinib across key clinical and demographic subgroups and in high-risk subsets, including patients with del(17p), uIGHV, and complex karyotype.
PFS outcomes favored pirtobrutinib over ibrutinib in the treatment-naive subgroup (18-month PFS, 95.3% vs 87.6%; HR, 0.239; 95% CI, 0.098-0.586; nominal P=.0007) and in the R/R subgroup (18-month PFS, 81.7% vs 79.2%; HR, 0.729; 95% CI, 0.471-1.128; nominal P=.1563).
In the safety analysis, the most common grade 3 or greater AEs with pirtobrutinib and ibrutinib were neutropenia (17.3% and 13.2%, respectively), pneumonia (6.4% and 8.6%, respectively), and anemia (5.8% and 3.7%, respectively). Atrial fibrillation occurred in 2.4% of patients receiving pirtobrutinib (0.9% grade ≥3) compared with 13.5% of patients receiving ibrutinib (4.0% grade ≥3). In patients aged 75 years or older, rates of atrial fibrillation/flutter were 4.5% with pirtobrutinib (1.5% grade ≥3) and 21.4% with ibrutinib (7.1% grade ≥3). Pirtobrutinib was also associated with a lower rate of dose reductions than ibrutinib (7.9% vs 18.2%) and a lower rate of discontinuation (9.4% vs 10.8%).
Investigators noted that this trial was the first to compare a noncovalent BTK inhibitor with a covalent BTK inhibitor in CLL and the first to compare 2 BTK inhibitors head-to-head in treatment-naive patients with CLL. Pirtobrutinib demonstrated noninferior ORR to ibrutinib in the ITT and R/R populations, a trend toward a PFS benefit in the R/R and treatment-naive populations, and a favorable tolerability profile.
References
1. Tam C, Thompson PA. BTK inhibitors in CLL: second-generation drugs and beyond. Blood Adv. 2024;8(9):2300-2309.
2. Gomez EB, Ebata K, Randeria HS, et al. Preclinical characterization of pirtobrutinib, a highly selective, noncovalent (reversible) BTK inhibitor. Blood. 2023;142(1):62-72.
3. Sharman JP, Munir T, Grosicki S, et al. Phase III trial of pirtobrutinib vs idelalisib/rituximab or bendamustine/rituximab in covalent Bruton tyrosine kinase inhibitor-pretreated chronic lymphocytic leukemia/small lymphocytic lymphoma (BRUIN CLL-321). J Clin Oncol. 2025;43(22):2538-2549.
4. Woyach J, Qiu L, Grosicki S, et al. Pirtobrutinib vs ibrutinib in treatment-naïve and relapsed/refractory CLL/SLL: results from the first randomized phase III study comparing a non-covalent and covalent BTK inhibitor. Presented at: 67th American Society of Hematology Annual Meeting and Exposition; December 6-9, 2025; Orlando, Florida, USA. Abstract 683.
5. Woyach JA, Qiu L, Grosicki S, et al. Pirtobrutinib vs ibrutinib in treatment-naïve and relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma. J Clin Oncol. Published online December 7, 2025.
Efficacy of Second-Line Treatment in CLL After Venetoclax-Based First-Line Treatment: Results From the GAIA/CLL13 Trial
Outcomes with second-line therapy after first-line venetoclax-based therapy have not been well characterized, as most clinical trial data in R/R CLL have been derived from patients who have received chemoimmunotherapy in prior lines of therapy. In a substudy of the MURANO trial, retreatment with fixed-duration venetoclax-rituximab in 25 patients with relapsed CLL was associated with a median PFS of 23 months and an ORR of 72%.1 Retrospective data from 23 patients with R/R CLL who received a BTK inhibitor after developing disease progression on venetoclax-based therapy reported a median PFS of 34 months after starting a BTK inhibitor.2
The randomized, open-label, phase 3 GAIA/CLL13 trial compared 3 first-line venetoclax-containing combinations in 926 fit patients with CLL without TP53 mutations: rituximab-venetoclax (RV), venetoclax-obinutuzumab (VO), and venetoclax, obinutuzumab, and ibrutinib (VOI), and compared these against chemoimmunotherapy (CIT). As previously reported, venetoclax-obinutuzumab with or without ibrutinib was associated with superior PFS and higher rates of MRD compared with chemoimmunotherapy.3
At ASH 2025, Niemann and colleagues reported efficacy outcomes for 177 patients from the GAIA/CLL13 trial who received second-line treatment after developing progressive disease on their assigned first-line regimens (Table 4).4 The median time from disease progression to the start of second-line therapy or death ranged from 10.1 months after first-line CIT to 14.5 months after first-line VOI.
Among 65 patients who had received first-line CIT, the most common second-line regimens included BTK inhibitor-based therapy (52%) and venetoclax-based therapy (34%), followed by venetoclax plus a BTK inhibitor (8%) and CIT (2%). Among 63 patients who had received first-line RV, second-line regimens included BTK inhibitor–based therapy (56%), venetoclax-based therapy (22%), venetoclax plus a BTK inhibitor (17%), and CIT. Among 32 patients who had received first-line VO, second-line therapy included venetoclax plus a BTK inhibitor (47%), BTK inhibitor–based therapy (34%), venetoclax-based therapy (13%), and CIT (6%). Among 17 patients who had received first-line VOI, second-line therapy included BTK inhibitor–based therapy (65%), venetoclax-based therapy (29%), and CIT (6%).
The proportion of patients alive and not requiring third-line treatment, reported as treatment-free survival 2 (TFS2), across second-line treatments was numerically higher in patients who had received first-line venetoclax-based therapy vs those who had received first-line CIT, with 2-year TFS2 rates of 81.5% and 77.6%, respectively.
Evaluating second-line treatments independent of first-line therapy, TFS2 rates at 2 years were 88.5% with second-line venetoclax plus a BTK inhibitor, 90.5% with second-line venetoclax-based therapy, 76.6% with second-line BTK inhibitor–based therapy, and 21.4% with second-line CIT.
In the subset of patients who had received venetoclax-based first-line therapy, 2-year TFS2 rates were 100% with second-line venetoclax plus a BTK inhibitor, 81.4% with second-line venetoclax-based therapy, 77.9% with second-line BTK inhibitor–based therapy, and 27.8% with CIT (Table 4).
OS from second-line treatment (OS2) rates at 2 years were 92.4% with second-line venetoclax plus a BTK inhibitor, 100% with second-line venetoclax-based therapy, 91.3% with second-line BTK inhibitor–based therapy, and 60% with second-line CIT.
The investigators concluded that venetoclax-based retreatment is feasible following progression after first-line venetoclax-based first-line treatment in patients with TP53-wild type CLL, with 2-year TFS2 rates exceeding 80%. They added that venetoclax plus a BTK inhibitor should be an option for second-line therapy after venetoclax plus an anti-CD20 antibody, and noted that there is no role for CIT in the second-line treatment of CLL.
References
1. Kater AP, Harrup R, Kipps TJ, et al. The MURANO study: final analysis and retreatment/crossover substudy results of VenR for patients with relapsed/refractory CLL. Blood. 2025;145(23):2733-2745.
2. Lin VS, Lew TE, Handunnetti SM, et al. BTK inhibitor therapy is effective in patients with CLL resistant to venetoclax. Blood. 2020;135(25):2266-2270.
3. Eichhorst B, Niemann CU, Kater AP, et al. First-line venetoclax combinations in chronic lymphocytic leukemia. N Engl J Med. 2023;388(19):1739-1754.
4. Niemann C, Fürstenau M, Zhang C, et al. Efficacy of second-line treatment in CLL after venetoclax-based first-line treatment: results from the GAIA/CLL13 trial. Presented at: 67th American Society of Hematology Annual Meeting and Exposition; December 6-9, 2025; Orlando, Florida, USA. Abstract 795.
Time-Limited Acalabrutinib Monotherapy in Frail Patients With Previously Untreated CLL: Primary Endpoint Analysis of the Randomized STAIR trial
Continuous treatment with a covalent BTK inhibitor is a guideline-recommended initial treatment option for patient with CLL.1 However, indefinite use of BTK inhibitors is associated with a risk of resistance and cumulative toxicity that can be particularly challenging in older or frail adults.2,3
Fixed-duration combination therapies have emerged as an alternative to indefinite BTK inhibitor therapy; guideline-recommended combination options include a BTK inhibitor plus a BCL2 inhibitor (eg, venetoclax).1 However, toxicity is a consideration with this approach; in the GLOW trial, 75.5% of older patients receiving ibrutinib and venetoclax developed grade 3 or greater AEs.4 The combination of acalabrutinib and venetoclax was evaluated in the AMPLIFY trial, which enrolled patients with a median age of 61 years, thus the tolerability of this approach in older patients is not well established.5
At ASH 2025, Guièze and colleagues presented results of the investigator-sponsored, randomized, phase 2 STAIR trial comparing indefinite vs fixed-duration acalabrutinib in older patients with previously untreated CLL/SLL.6 The trial enrolled patients aged over 70 years requiring treatment per the iwCLL2 018 criteria, who all received acalabrutinib 100 mg twice daily for 18 months; patients were randomly assigned to stop acalabrutinib after the 18-month treatment period, with the options to restart acalabrutinib for an unlimited period upon progression or to continue acalabrutinib indefinitely. The trial was conducted at 32 French centers and enrolled 159 evaluable patients between October 2021 and June 2023.
Patients were required to have a Cumulative Illness Rating Scale (CIRS) score greater than 6 and/or impaired creatinine clearance (31-69 mL/min) and were stratified by the presence of complex karyotype and TP53 disruption. The primary endpoint was PFS; secondary endpoints included TTNT, OS, ORR at retreatment, quality of life, safety, and tolerability.
The median age of enrolled patients was 77.0 years (range, 70-96 years); 33% of patients were older than 80 years. Most patients had an Eastern Cooperative Oncology Group performance status of 0 (35.8%) or 1 (57.2%). Comorbidities included a history of cancer in 23.9%, a CIRS score greater than 6 in 58.5%, and a creatinine clearance less than 70 mL/min in 78%. Key genetic features include uIGHV in 59.1% of patients, complex karyotype in 28.7%, del(17p) in 11.9%, and TP53 mutations in 11.9%.
Of the 159 patients who started acalabrutinib, 38 discontinued, primarily owing to AEs (n=13) or progressive disease (n=10). The remaining 121 patients were randomly assigned to continue acalabrutinib (indefinite treatment; n=41) or discontinue acalabrutinib (fixed duration; n=80).
After a median follow-up of 14.2 months from randomization (at the end of the 18-month treatment period), the 1-year PFS rate was 53.1% with fixed-duration acalabrutinib vs 96.3% with continuous treatment. The 1-year TTNT in the fixed-duration arm was 74.0%. Of the 25 patients who restarted treatment, 24 received acalabrutinib per protocol and 1 received venetoclax. The ORR for retreatment with acalabrutinib was 87.5% (79% partial response).
IGHV mutational status was significantly associated with outcomes, with mIGHV associated with superior outcomes vs uIGHV as assessed by 1-year PFS rate (90.4% vs 34.0%; P<.001) and 1-year TTNT (100% vs 62.4%; P<.001). At 1 year, OS rates were similar with indefinite vs fixed-duration acalabrutinib, at 100% and 96.8%, respectively.
During the overall treatment period, serious AEs occurred in 30.8% of patients. The most frequent grade 3/4 AEs were neutropenia (12%), thrombocytopenia (3%), anemia (2.5%), increased alanine aminotransferase (2.5%), and fracture (2.5%). Any-grade atrial fibrillation developed in 6.9% of patients. Rates of grade 3/4 hypertension and bleeding were 2.5% and 1.9%, respectively. Infections of any grade developed in 40.9% of patients, with 8.2% grade 3/4. Second primary malignancies were reported in 35 patients (22%), including 23 nonmelanoma skin cancers. During the post-randomization treatment period, AEs of any severity occurred in 68.3% of patients continuing acalabrutinib and in 43.8% of those discontinuing acalabrutinib.
Investigators concluded that administering acalabrutinib for a fixed duration of 18 months was associated with a significant reduction in PFS, and that the effect of acalabrutinib discontinuation was strongly dependent on IGHV mutational status. They added that additional follow-up is needed to confirm the durability of responses after stopping acalabrutinib in patients with mIGHV, observed reductions in AEs over time, observed lack of effect on OS, and the efficacy of acalabrutinib retreatment.
References
1. National Comprehensive Cancer Network (NCCN) guidelines: chronic lymphocytic leukemia/small lymphocytic lymphoma. Version 2.2026. Revised December 22, 2025. https://www.nccn.org/professionals/physician_gls/pdf/cll.pdf. Accessed December 29, 2025.
2. Skånland SS, Mato AR. Overcoming resistance to targeted therapies in chronic lymphocytic leukemia. Blood Adv. 2021;5(1):334-343.
3. Lipsky A, Lamanna N. Managing toxicities of Bruton tyrosine kinase inhibitors. Hematology Am Soc Hematol Educ Program. 2020;2020(1):336-345.
4. Kater AP, Owen C, Moreno C, et al. Fixed-duration ibrutinib-venetoclax in patients with chronic lymphocytic leukemia and comorbidities. NEJM Evid. 2022;1(7):EVIDoa2200006.
5. Brown JR, Seymour JF, Jurczak W, et al. Fixed-duration acalabrutinib combinations in untreated chronic lymphocytic leukemia. N Engl J Med. 2025;392(8):748-762.
6. Guièze R, Ferrant E, Merabeh F, et al. Time-limited acalabrutinib monotherapy in frail patients with previously untreated CLL: primary endpoint analysis of the randomized STAIR trial. Presented at: 67th American Society of Hematology Annual Meeting and Exposition; December 6-9, 2025; Orlando, Florida, USA. Abstract 684.
Long-Term Immune Reconstitution and Final 1-Year Follow-up After Fixed-Duration Venetoclax-Obinutuzumab in First-Line CLL: Results From the Phase 3 CRISTALLO trial
The combination of venetoclax and obinutuzumab (VO) as first-line therapy for CLL was evaluated in the CLL14 trial, which demonstrated superior PFS with VO compared with CIT in unfit patients with previously untreated CLL, and the phase 3 CRISTALLO trial, which demonstrated higher rates of MRD negativity with VO compared with CIT in fit patients with previously untreated CLL.1,2
At ASH 2025, Jin and colleagues reviewed updated findings from the CRISTALLO trial and presented results of an analysis evaluating immune dynamics during and after VO and their associations with treatment efficacy.3 Investigators also evaluated correlations between immune recovery and infection outcomes, given that infections are a primary contributor to morbidity and mortality in patients with CLL.4
In the CRISTALLO trial, 166 patients with previously untreated CLL, a CIRS score of 6 or less, and a creatinine clearance of at least 70 mL/min without del(17p) or TP53 mutations were stratified by Binet stage, IGHV mutation status, and age, and randomly assigned to 6 cycles of VO followed by 6 cycles of venetoclax (n=80) or 6 cycles of FCR/BR (n=86). Venetoclax was administered using a 5-week ramp-up period, reaching 400 mg starting at cycle 3 day 1. Obinutuzumab was administered IV for 6 cycles on cycle 1 day 1/2, 8, and 15, and on day 1 of subsequent cycles.
In the primary efficacy analysis, VO was associated with a significant improvement in the rate of undetectable MRD (uMRD) (10-4) over FCR/BR at 15 months (81.3% vs 54.7%; P=.0004). The trial was not powered to detect significant differences in PFS, but after a median follow-up of 41 months, there were fewer instances of progression or death with VO vs FCR/BR (14 vs 18; P=.3999), and fewer patients had started a new CLL treatment (3 vs 13).
No new safety findings were noted with this additional follow-up. Rates of grade 3 or greater neutropenia were 48.1% with VO and 38.8% with FCR/BR, and rates of grade 3 or greater febrile neutropenia were 6.5% and 8.2%, respectively. The most frequent grade 3 or greater infections were COVID-19, reported in 7.8% of patients receiving VO and 7.1% receiving FCR/BR, and COVID-19 pneumonia, reported in 9.1% and 5.9%, respectively.
The biomarker analysis found that median CD4+ and CD8+ T-cell counts decreased during VO treatment but remained within the normal range. These trends were observed regardless of MRD status. Transient depletion of natural killer cells was observed at 12 months, with subsequent gradual reconstitution. Absolute numbers of CD19+ CLL cells declined during VO treatment, depleting substantially by the 12-month follow-up. In the uMRD group, CD19+ CLL cells remained suppressed out to 36 months, whereas in the detectable MRD group, CD19+ CLL cells were not fully depleted at 12 months and increased by 10-fold by 18 months.
Nonmalignant B cells were not depleted to the same extent as CLL cells and their counts returned to a normal range by 24 months of follow-up. Serum Ig levels recovered in a similar pattern, particularly IgA and IgM levels. In contrast, Ig recovery was slower and less complete in the MRD-positive group.
Light chain restriction was detected at baseline and resolved over time in the uMRD group, reaching and remaining within normal levels through 42 months of follow-up. In contrast, light chains did not normalize in the MRD-detectable group.
Based on their findings, investigators concluded that immune reconstitution can occur with deep remissions in the context of a fixed-duration VO regimen.
References
1. Fischer K, Al-Sawaf O, Bahlo J, et al. Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med. 2019;380(23):2225-2236.
2. Sharman JP, Laurenti L, Ferrant E, et al. CRISTALLO: results from a phase III trial of venetoclax-obinutuzumab vs fludarabine, cyclophosphamide and rituximab or bendamustine-rituximab in patients with untreated chronic lymphocytic leukemia without del(17p) or TP53 mutations. Blood. 2024;144(Supplement 1):3237.
3. Jin HY, Sharman JP, Laurenti L, et al. Long-term immune reconstitution and final 1-year follow-up after fixed-duration venetoclax-obinutuzumab in first-Line CLL: results from the phase III CRISTALLO trial. Presented at: 67th American Society of Hematology Annual Meeting and Exposition; December 6-9, 2025; Orlando, Florida, USA. Abstract 682.
4. Dhalla F, Lucas M, Schuh A, et al. Antibody deficiency secondary to chronic lymphocytic leukemia: Should patients be treated with prophylactic replacement immunoglobulin? J Clin Immunol. 2014;34(3):277-282.
MRD-Guided Ibrutinib + Venetoclax Improves Outcomes in CLL Patients With TP53, ATM, or NOTCH1 Aberrations Compared to Ibrutinib and FCR: Results From the Phase 3 NCRI FLAIR Trial
The UK National Cancer Research Institute (NCRI) FLAIR trial is a randomized, open-label, adaptive, phase 3 platform trial with a design that has evolved based on emerging evidence on first-line approaches for the treatment of CLL.
The FLAIR trial initially compared ibrutinib plus rituximab (IR) against FCR as first-line therapy in 771 patients 18 to 75 years of age with previously untreated CLL. In this comparison, IR was associated with significant improvements in PFS over FCR (HR, 0.44; 95% CI, 0.23-0.60; P<.0001) but no improvements in OS, and there were 8 sudden unexplained or cardiac deaths in the IR arm vs 2 in the FCR arm.1
Subsequently the trial was adapted to include single-agent ibrutinib and ibrutinib-venetoclax, with therapy duration guided by MRD. In the ibrutinib-venetoclax arm, patients received 2 months of ibrutinib with venetoclax added for up to 6 years. Therapy duration was defined as the time to achieve uMRD in peripheral blood and bone marrow multiplied by 2. After a median of 43.7 months, MRD-guided ibrutinib-venetoclax was associated with a significant improvement over FCR in PFS (HR, 0.13; 95% CI, 0.07-0.24; P<.001) and longer OS (HR, 0.31; 95% CI, 0.15-0.67).2 After a median follow-up of 62.2 months, 5-year PFS rates were 93.9% with ibrutinib-venetoclax, 79.0% with ibrutinib alone, and 58.1% with FCR. The proportion of patients attaining uMRD in the bone marrow within 2 years was higher with ibrutinib-venetoclax vs ibrutinib (66.2% vs 0%; P<.001) and vs FCR (48.3%).
At ASH 2025, Dalal and colleagues presented additional results from the FLAIR trial, focusing on the effect of baseline gene alterations on clinical outcomes across the 4 treatment arms (ibrutinib, IR, ibrutinib-venetoclax, and FCR).3 Molecular analyses included NGS (n=1474) to identify 33 recurrently mutated genes, fluorescence in situ hybridization (n=1479) using targeted probes for 11q, 17p, 13p, and 12, and analysis of IGHV somatic hypermutation status for 1373 patients.
At baseline, 36% of patients had mIGHV, 36.8% had del(13q), 26.1% had a normal karyotype, 16.1% had del(11q), 14.4% had trisomy 12, and 0.3% of patients had del(17p); the trial excluded patients with more than 20% cells testing del(17p)-positive. Other mutations present at baseline in at least 10% of patients included SF3B1 in 17.0%, ATM in 14.4%, NOTCH1 in 11.7%.
MRD-guided treatment with ibrutinib-venetoclax was associated with improvements over the other 3 regimens (ibrutinib, IR, and FCR) as assessed by PFS and OS in most genetic subgroups, including patients with uIGHV, ATM aberrations, stereotyped subset #2, SF3B1, NOTCH1, and TP53 mutations. Across subgroups, 5-year PFS rates with ibrutinib/venetoclax ranged from 90% to 100%, and 5-year OS rates ranged from 92% to 100%.
Approximately two-thirds of patients in these groups—including 66% of patients with uIGHV, 60% of patients with stereotyped subset #2, 65% of patients with ATM aberrations, and 66% of patients with NOTCH1 mutations—and 50% of patients with TP53 mutations, attained MRD negativity and stopped treatment within 3 years of starting ibrutinib-venetoclax.
Investigators concluded that MRD-guided ibrutinib plus venetoclax is highly effective in overcoming adverse prognostic factors including uIGHV, stereotyped set #2, and recurrent genetic alterations.
References
1. Hillmen P, Pitchford A, Bloor A, et al. Ibrutinib and rituximab vs fludarabine, cyclophosphamide, and rituximab for patients with previously untreated chronic lymphocytic leukaemia (FLAIR): interim analysis of a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2023;24(5):535-552.
2. Munir T, Cairns DA, Bloor A, et al. Chronic lymphocytic leukemia therapy guided by measurable residual disease. N Engl J Med. 2024;390(4):326-337.
3. Dalal S, Shingles J, Girvan S, et al. MRD-guided ibrutinib + venetoclax improves outcomes in CLL patients with TP53, ATM, or NOTCH1 aberrations compared to ibrutinib and FCR: results from the phase III NCRI FLAIR trial. Presented at: 67th American Society of Hematology Annual Meeting and Exposition; December 6-9, 2025; Orlando, Florida, USA. Abstract 679.