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Cited by 6Chronic Lymphocytic Leukemia ResearchLymphoma Diagnosis and TreatmentAcute Lymphoblastic Leukemia research

The DOI matches its Crossref record; 94 of the 94 references it cites were found in a registry or an index; 81 of the 102 sources its claims cite were checked for support.

Resistance Mechanisms and Approach to Chronic Lymphocytic Leukemia after BTK Inhibitor Therapy

Open access
Gruessner, Christine, Wiestner, Adrian, Sun, Clare·2025·Leukemia & Lymphoma
DOI 10.1080/10428194.2025.2466101PMC PMC12221821
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Abstract

Bruton tyrosine kinase (BTK), an essential component of the B-cell receptor (BCR) signaling pathway, is a validated target in chronic lymphocytic leukemia. Ibrutinib, acalabrutinib, and zanubrutinib are covalent BTK inhibitors (cBTKi) that bind to residue C481, leading to sustained target inhibition. A significant proportion of patients develop resistance to continuous cBTKi therapy, predominantly via mutations in BTK and its immediate downstream effector, PLCG2. The noncovalent BTKi pirtobrutinib does not require binding to C481 and can restore BTK inhibition after progression on a cBTKi. However, non-C481 BTK mutations conferring resistance to pirtobrutinib have been identified. Furthermore, the scaffolding function of BTK, activation of bypass signaling pathways, and the tumor microenvironment may contribute to BTKi resistance. Targeting BTK for degradation is an emerging strategy that appears effective against multiple BTK mutations, and inhibitors of downstream BCR signaling proteins are under development. This review addresses BTKi resistance mechanisms and therapeutic approaches after cBTKi failure.

Overview

AI snapshot

Written from the paper’s full text.

TL;DR

This review summarizes mechanisms of resistance to covalent BTK inhibitors in CLL, including BTK C481 and PLCG2 mutations, bypass signaling, and tumor microenvironment effects, and discusses subsequent therapies such as venetoclax, noncovalent BTK inhibitors, CAR-T, PI3K inhibitors, BTK degraders, and bispecific antibodies. It emphasizes that resistance is often polyclonal and that optimal sequencing after BTKi failure remains uncertain.

Key findings

  • Resistance to covalent BTK inhibitors is predominantly via BTK and PLCG2 mutations; in published progression studies, approximately 35% of patients had a BTK mutation alone, 10% had coexisting PLCG2 mutation, 5% had PLCG2 mutation alone, and 50% were wild-type for both. About 20% of ibrutinib-resistant patients have no BTK or PLCG2 mutations even with highly sensitive testing.
  • After 4 years of ibrutinib, up to 40% of patients experience treatment failure due to resistance or intolerance. The noncovalent BTKi pirtobrutinib in the BRUIN phase 1/2 study produced an ORR of 73.3% and median PFS of 19.6 months, but non-C481 BTK mutations such as L528W, A428D, V416L, M437R, and T474I can confer acquired resistance.
  • Venetoclax monotherapy after covalent BTKi therapy in a phase 2 study had an ORR of 65%, CR rate of 9%, and median PFS of 21.9 months in patients with known BTK and/or PLCG2 mutations. Liso-cel in TRANSCEND CLL 004 achieved a CR rate of 18%, ORR of 43%, and median PFS of 11.9 months.
  • Emerging strategies include BTK degraders, with NX-2127 achieving >80% BTK degradation and clinical responses in 79% of evaluable patients, and bispecific antibodies, with epcoritamab producing an ORR of 82% and CR of 33% in a cohort of 23 patients.

Methods

  • Narrative review; no primary patient cohort or experimental data are reported. It synthesizes published literature and clinical trial results on BTKi resistance mechanisms and therapeutic approaches after cBTKi failure.
  • Sources include phase 1/2/3 trials and retrospective series such as BRUIN, TRANSCEND CLL 004, CAPTIVATE, GLOW, and ELEVATE-TN, as well as preclinical studies.
  • Main analysis is qualitative synthesis; no systematic search, meta-analysis, or formal risk-of-bias assessment is described.

Limitations

  • Stated: the optimal sequencing of novel agents after BTKi failure is a matter of debate and needs further clinical investigation; a head-to-head randomized trial of pirtobrutinib is underway (NCT05254743).
  • Stated: CAR-T durable remissions appear limited to patients who achieve CR, and little is known about clonal stability and long-term persistence of infused cells.
  • Evident from the text: as a narrative review, it lacks systematic search/selection criteria and quantitative pooling; reported mutation prevalence depends on assay sensitivity and may under-report rare baseline mutations.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1080/10428194.2025.2466101

Cites

94 of 94 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Verification

Claims the paper makes

81 of 102 cited sources checked · 28 supported · 5 flagged · accuracy not yet measured

  • Premisecitation

    BTK T316A affect a binding residue for B-cell like linker protein, preventing activation of the downstream PLCγ2.

    “BTK T316A affect a binding residue for B-cell like linker protein, preventing activation of the downstream PLCγ2(28).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [28] Sharma S, Galanina N, Guo A, Lee J, Kadri S, Van Slambrouck C, Identification of a structurally novel BTK mutation that drives ibrutinib resistance in CLL. Oncotarget. 2016; 7(42): 68833– 41. Epub 2016/09/15. doi: 10.18632/oncotarget.11932. 27626698 PMC5356593 source

      The Discussion places T316A in BTK’s SH2 domain and predicts that it may lessen binding to B-cell linker protein. But it reports that stimulated PLCG2 activity was comparable in cells with wild-type and mutant BTK, contrary to the claim that T316A prevents downstream PLCγ2 activation. (LLM, conf=0.90)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
  • Premisecitation

    There has been no indication that BTKi therapy, in contrast to PI3Kδ inhibition, increases genomic instability in B cells.

    “Further, there has been no indication that BTKi therapy, in contrast to PI3Kδ inhibition, increases genomic instability in B cells (33).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [33] Compagno M, Wang Q, Pighi C, Cheong TC, Meng FL, Poggio T, Phosphatidylinositol 3-kinase delta blockade increases genomic instability in B cells. Nature. 2017; 542(7642): 489– 93. doi: 10.1038/nature21406. 28199309 PMC5382874 source

      The paper reports that the BTK inhibitor ibrutinib increased AID expression and translocation junctions in mouse and human B cells, although less potently than PI3Kδ inhibitors (passage 4, labeled Abstract). It separately reports no increased AID off-target SHM in patients treated with ibrutinib (passage 1, labeled Abstract), but that narrower patient finding does not support the claim that there was no indication of increased genomic instability in B cells. (LLM, conf=0.90)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
  • Premisecitation

    Duration of response with a BTKi is longer in settings where clonal complexity and evolutionary potential are lower, such as in treatment-naïve cases.

    “Duration of response with a BTKi is longer in settings where clonal complexity and evolutionary potential are lower, such as in treatment-naïve cases(12, 14, 17).”
    Quote in the paperNot a substantial claim3 of 3 sources checked
    • cites [12] Ahn IE, Underbayev C, Albitar A, Herman SE, Tian X, Maric I, Clonal evolution leading to ibrutinib resistance in chronic lymphocytic leukemia. Blood. 2017; 129(11): 1469– 79. Epub 2017/01/05. doi: 10.1182/blood-2016-06-719294. 28049639 PMC5356450 source

      The Progression-free survival section reports significantly shorter time to progression on ibrutinib in relapsed/refractory CLL than in treatment-naïve CLL, supporting longer disease control in the latter group. The paper does not establish that treatment-naïve cases have lower clonal complexity or evolutionary potential, or that those factors explain the difference. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [14] Ahn IE, Farooqui MZH, Tian X, Valdez J, Sun C, Soto S, Depth and durability of response to ibrutinib in CLL: 5-year follow-up of a phase 2 study. Blood. 2018; 131(21): 2357– 66. doi: 10.1182/blood-2017-12-820910. 29483101 PMC5969380 source

      The Results (Disease progression and survival; page not available in our copy) report more favorable progression-free survival with first-line ibrutinib than with treatment after relapse, supporting the longer-durability comparison for treatment-naïve CLL. The paper does not establish that lower clonal complexity or evolutionary potential explains that difference; the Discussion identifies prior treatment history and TP53 aberration as determinants of progression-free survival. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [17] Landau DA, Sun C, Rosebrock D, Herman SEM, Fein J, Sivina M, The evolutionary landscape of chronic lymphocytic leukemia treated with ibrutinib targeted therapy. Nat Commun. 2017; 8(1): 2185. Epub 2017/12/21. doi: 10.1038/s41467-017-02329-y. 29259203 PMC5736707 source

      The Results section, “Early clonal shifts associate with adverse clinical outcome,” links clonal shifts to shorter time to progression on ibrutinib. The Discussion says clonal complexity is expected to be lower in treatment-naïve CLL and proposes studying ibrutinib in that setting. It does not establish that treatment-naïve patients have a longer duration of response; that part of the claim turns the paper’s rationale into a demonstrated outcome. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
  • Premisecitation

    The first reported BTK mutation in CLL patients with progressive disease on ibrutinib was a missense mutation changing C481 to serine (C481S).

    “The first reported BTK mutation in CLL patients with progressive disease on ibrutinib (19, 35)was a missense mutation changing C481 to serine (C481S)(19).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [19] Woyach JA, Furman RR, Liu TM, Ozer HG, Zapatka M, Ruppert AS, Resistance mechanisms for the Bruton’s tyrosine kinase inhibitor ibrutinib. N Engl J Med. 2014; 370(24): 2286– 94. Epub 2014/05/30. doi: 10.1056/NEJMoa1400029. 24869598 PMC4144824 source

      The Results section reports that relapse samples from five patients with progressive CLL on ibrutinib had a BTK mutation changing cysteine 481 to serine (C481S). The paper does not establish that this was the first reported BTK mutation in that setting. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
  • Premisecitation

    In vitro studies have shown that cell lines transfected with both C481 and T474 mutations are insensitive to exponentially higher pharmacological serum concentrations of ibrutinib, acalabrutinib, and zanubrutinib.

    “Invitro studies have shown thatcell lines transfected with both C481 and T474mutations are insensitive to exponentially higher pharmacological serum concentrations of ibrutinib, acalabrutinib, and zanubrutinib(40).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [40] Estupinan HY, Wang Q, Berglof A, Schaafsma GCP, Shi Y, Zhou L, BTK gatekeeper residue variation combined with cysteine 481 substitution causes super-resistance to irreversible inhibitors acalabrutinib, ibrutinib and zanubrutinib. Leukemia. 2021; 35(5): 1317– 29. Epub 20210201. doi: 10.1038/s41375-021-01123-6. 33526860 PMC8102192 source

      The Results report that transfected cells carrying T474I/C481S or T474M/C481S were highly resistant to ibrutinib, acalabrutinib, and zanubrutinib at elevated concentrations. But the claim does not specify which substitutions: the Results also report that T474A/C481S was sensitive and T474S/C481S was partially sensitive to ibrutinib at a pharmacological concentration. Zanubrutinib also overcame the tested double variants at 64 μM, rather than leaving them wholly insensitive. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
  • It may state two separate claims as one. 38
  • Probably not a substantial claim. 12

  • It may state two separate claims as one.

    Premisecitation

    In published studies of disease progression during BTKi therapy, approximately 35% of patients were found to have a BTK mutation alone, an additional 10% had coexisting mutations in PLCG2, 5% had a PLCG2 mutation alone, and the remaining 50% were wild-type for BTK and PLCG2.

    “In published studies of disease progression during BTKi therapy,approximately 35% of patients were found to have aBTK mutation alone, an additional 10% had a coexisting mutations in PLCG2, 5% of cases had a PLCG2mutation alone, and the remaining 50% were wild-type (WT) for BTK and PLCG2 (Figure 2)(12, 19, 21–31).”
    Quote in the paperNot a substantial claim10 of 10 sources checked
    • cites [12] Ahn IE, Underbayev C, Albitar A, Herman SE, Tian X, Maric I, Clonal evolution leading to ibrutinib resistance in chronic lymphocytic leukemia. Blood. 2017; 129(11): 1469– 79. Epub 2017/01/05. doi: 10.1182/blood-2016-06-719294. 28049639 PMC5356450 source

      In “Resistance mutations at disease progression” (page unavailable), the paper reports BTK and/or PLCG2 mutations in 8 of 10 patients with progressive CLL, leaving 2 of 10 without detectable mutations—not the claimed 50% wild-type. Table 3 shows 5 of those 10 had both mutations, 1 had BTK alone, and 2 had PLCG2 alone. These proportions differ substantially from the percentages attributed to this source. (LLM, conf=0.88)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
    • cites [19] Woyach JA, Furman RR, Liu TM, Ozer HG, Zapatka M, Ruppert AS, Resistance mechanisms for the Bruton’s tyrosine kinase inhibitor ibrutinib. N Engl J Med. 2014; 370(24): 2286– 94. Epub 2014/05/30. doi: 10.1056/NEJMoa1400029. 24869598 PMC4144824 source

      The Results section (page unavailable) reports BTK-only, PLCγ2-only, and coexisting mutations among six patients with progressive CLL during ibrutinib therapy. It does not report the claimed 35%/10%/5%/50% distribution across published studies; all six patients in this study had at least one of the two mutations at relapse. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [21] Woyach JA, Jones D, Jurczak W, Robak T, Illes A, Kater AP, Mutational profile in previously treated patients with chronic lymphocytic leukemia progression on acalabrutinib or ibrutinib. Blood. 2024; 144(10): 1061– 8. doi: 10.1182/blood.2023023659. 38754046 PMC11406168 source

      The Results (section 63; page not provided) report BTK and PLCG2 mutations, including co-occurrence, among 77 patients whose CLL progressed on acalabrutinib or ibrutinib. The reported counts imply about 5% had PLCG2 mutations alone, but they do not support the claimed 35% BTK-only, 10% co-mutated, and 50% wild-type breakdown; the paper also does not present those figures as a summary of published studies. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [22] Blombery P, Thompson ER, Lew TE, Tiong IS, Bennett R, Cheah CY, Enrichment of BTK Leu528Trp mutations in patients with CLL on zanubrutinib: potential for pirtobrutinib cross-resistance. Blood Adv. 2022; 6(20): 5589– 92. doi: 10.1182/bloodadvances.2022008325. 35901282 PMC9647719 source

      The Results and discussion report BTK variants in 37 selected patients and compare a specific BTK mutation between treatment groups. Our copy does not report the claimed 35%/10%/5%/50% breakdown across BTK mutations alone, coexisting BTK and PLCG2 mutations, PLCG2 mutations alone, and wild-type cases (searched for those percentages and mutation categories). (LLM, conf=0.75)

      Experimental — accuracy not yet measured
    • cites [23] Burger JA, Landau DA, Taylor-Weiner A, Bozic I, Zhang H, Sarosiek K, Clonal evolution in patients with chronic lymphocytic leukaemia developing resistance to BTK inhibition. Nat Commun. 2016; 7: 11589. doi: 10.1038/ncomms11589. 27199251 PMC4876453 source

      The Discussion reports BTK-C481S or PLCG2 mutations in two of five subjects, while the other three had different mutations associated with progression. The Results also report no BTK or PLCG2 mutations in Patients 2 and 3. These passages support the existence of mutation-positive and mutation-negative cases, but this paper does not report the cited 35%/10%/5%/50% distribution across published studies. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [24] Woyach JA, Ruppert AS, Guinn D, Lehman A, Blachly JS, Lozanski A, BTK(C481S)-Mediated Resistance to Ibrutinib in Chronic Lymphocytic Leukemia. J Clin Oncol. 2017; 35(13): 1437– 43. doi: 10.1200/JCO.2016.70.2282. 28418267 PMC5455463 source

      The Results section reports mutations in both BTK and PLCG2 in 6 of 46 patients (13%) and PLCG2 alone in 3 of 46 (7%), roughly consistent with two of the claimed proportions. But it reports BTK alone in 31 of 46 (67%), leaving 6 of 46 (13%) with neither mutation—not the claimed 35% and 50%. These are findings from this paper's ibrutinib cohort, not an aggregate of published BTKi studies. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [25] Gango A, Alpar D, Galik B, Marosvari D, Kiss R, Fesus V, Dissection of subclonal evolution by temporal mutation profiling in chronic lymphocytic leukemia patients treated with ibrutinib. Int J Cancer. 2020; 146(1): 85– 93. Epub 20190625. doi: 10.1002/ijc.32502. 31180577 source

      The Subclonal dynamics section reports BTK and PLCG2 mutations, including co-occurrence, in a 20-patient ibrutinib cohort. It does not establish the quoted four-part distribution among patients whose disease progressed, or present those percentages as a summary of published studies. The Clinical outcome section also says the patient with a PLCG2-only variant died without CLL progression. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [26] Quinquenel A, Fornecker LM, Letestu R, Ysebaert L, Fleury C, Lazarian G, Prevalence of BTK and PLCG2 mutations in a real-life CLL cohort still on ibrutinib after 3 years: a FILO group study. Blood. 2019; 134(7): 641– 4. Epub 20190626. doi: 10.1182/blood.2019000854. 31243043 source

      The Results and discussion (page not provided) report BTK-only and coexisting BTK/PLCG2 mutations among two patients profiled at relapse, so the paper supports those mutation patterns during progression. It does not report the claimed 35%/10%/5%/50% distribution across published studies; its main prevalence figures concern patients still on ibrutinib after three years, not a pooled group of patients progressing during therapy. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
    • cites [27] Maddocks KJ, Ruppert AS, Lozanski G, Heerema NA, Zhao W, Abruzzo L, Etiology of Ibrutinib Therapy Discontinuation and Outcomes in Patients With Chronic Lymphocytic Leukemia. JAMA Oncol. 2015; 1(1): 80– 7. doi: 10.1001/jamaoncol.2014.218. 26182309 PMC4520535 source

      The Results section on BTK and PLCγ2 mutations reports BTK-only, PLCγ2-only, and coexisting mutations among patients with progressive CLL; all 11 sequenced CLL progressions had at least one of these mutations. It also reports patients with Richter’s transformation who had neither mutation. The paper does not give the cited 35%/10%/5%/50% distribution across published studies, and its progressive-CLL cohort does not support a 50% wild-type figure. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [28] Sharma S, Galanina N, Guo A, Lee J, Kadri S, Van Slambrouck C, Identification of a structurally novel BTK mutation that drives ibrutinib resistance in CLL. Oncotarget. 2016; 7(42): 68833– 41. Epub 2016/09/15. doi: 10.18632/oncotarget.11932. 27626698 PMC5356593 source

      The Introduction identifies BTK and PLCG2 mutations in ibrutinib resistance, and the Discussion says some relapsed CLL patients carry neither. The Results describe a BTK mutation in the patient studied. No passage gives the claimed 35%/10%/5%/50% breakdown or establishes the frequencies of coexisting and PLCG2-only mutations. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • It may state two separate claims as one.

    Premisecitation

    There is a tendency for T747I mutations with acalabrutinib and L528W mutations with zanubrutinib among others.

    “There is a tendency for T747I mutations with acalabrutinib and L528W mutations with zanubrutinib among others (Figure 3)(20–22).”
    Quote in the paperNot a substantial claim3 of 3 sources checked
    • cites [20] Brown JR, Li J, Eichhorst B, Lamanna N, O’Brien SM, Tam CS, Acquired Mutations in Patients with Relapsed/Refractory Cll Who Progressed in the Alpine Study. Blood Adv. 2025. Epub 20250124. doi: 10.1182/bloodadvances.2024014206. PMC12008693 39853273 source

      The Results (BTK/PLCG2 mutations in patients without RT; page unavailable) report L528W in 2 of 24 patients who progressed on zanubrutinib. The Introduction and Discussion associate acalabrutinib with T474 mutations, not the claimed T747I; the study itself included no acalabrutinib-treated patients. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [21] Woyach JA, Jones D, Jurczak W, Robak T, Illes A, Kater AP, Mutational profile in previously treated patients with chronic lymphocytic leukemia progression on acalabrutinib or ibrutinib. Blood. 2024; 144(10): 1061– 8. doi: 10.1182/blood.2023023659. 38754046 PMC11406168 source

      The results in section 63 report L528W and A428D co-mutations in one ibrutinib-treated patient, not a tendency with zanubrutinib. The paper compares acalabrutinib with ibrutinib and does not report T747I with acalabrutinib. (LLM, conf=0.82)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
    • cites [22] Blombery P, Thompson ER, Lew TE, Tiong IS, Bennett R, Cheah CY, Enrichment of BTK Leu528Trp mutations in patients with CLL on zanubrutinib: potential for pirtobrutinib cross-resistance. Blood Adv. 2022; 6(20): 5589– 92. doi: 10.1182/bloodadvances.2022008325. 35901282 PMC9647719 source

      The Results and discussion report enrichment of BTK Leu528Trp (L528W) mutations in patients with CLL treated with zanubrutinib versus ibrutinib. The paper does not support the sentence’s T747I–acalabrutinib association; it states that no patients in its cohort had received acalabrutinib. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

  • It may state two separate claims as one.

    Interpretationcitation

    BTK inhibitors increase the efficacy of CD19/CD3 bispecific antibody irrespective of ITK inhibition, an effect of ibrutinib but not acalabrutinib.

    “suggesting that BTKi increases efficacy of CD19/CD3 bsAb irrespective of interleukin-2 inducible T-cell kinase (ITK) inhibition, an effect of ibrutinib but not acalabrutinib (95).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [95] Mhibik M, Gaglione EM, Eik D, Kendall EK, Blackburn A, Keyvanfar K, BTK inhibitors, irrespective of ITK inhibition, increase efficacy of a CD19/CD3-bispecific antibody in CLL. Blood. 2021; 138(19): 1843– 54. doi: 10.1182/blood.2020009686. 34046681 PMC8586964 source

      The Discussion says BTK inhibitors improve the bispecific antibody’s cytotoxic response irrespective of ITK inhibition. But the Results explicitly report no difference between ibrutinib and acalabrutinib, contrary to the claim that the effect occurs with ibrutinib but not acalabrutinib. (LLM, conf=0.94)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured

  • It may state two separate claims as one.

    Premisecitation

    BTK is a non-receptor tyrosine kinase that amplifies upstream BCR signaling and is essential for B-cell development and maturation.

    “Bruton tyrosine kinase (BTK) is a non-receptor tyrosine kinase that amplifiesupstream B-cell receptor (BCR) signaling and is essential for B-cell development and maturation(1, 2).”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [1] Pal Singh S, Dammeijer F, Hendriks RW. Role of Bruton’s tyrosine kinase in B cells and malignancies. Mol Cancer. 2018; 17(1): 57. Epub 20180219. doi: 10.1186/s12943-018-0779-z. 29455639 PMC5817726 source

      The Background and BTK structure sections identify BTK as a non-receptor tyrosine kinase downstream of the BCR. The Abstract states that it is essential for B-cell development and mature B-cell function, and the peripheral-development section describes impaired maturation without BTK. The paper describes BTK transmitting signals to downstream targets, but does not say it amplifies upstream BCR signaling. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [2] Burger JA, Wiestner A. Targeting B cell receptor signalling in cancer: preclinical and clinical advances. Nat Rev Cancer. 2018; 18(3): 148– 67. doi: 10.1038/nrc.2017.121. 29348577 source

  • It may state two separate claims as one.

    Premisecitation

    Continuous BTKi therapy exerts a strong selective pressure, with resistant subclones often emerging after years of treatment.

    “Likewise, continuous BTKi therapy exerts a strong selective pressure, with resistant subclones often emerging after years of treatment(12, 17, 18).”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [12] Ahn IE, Underbayev C, Albitar A, Herman SE, Tian X, Maric I, Clonal evolution leading to ibrutinib resistance in chronic lymphocytic leukemia. Blood. 2017; 129(11): 1469– 79. Epub 2017/01/05. doi: 10.1182/blood-2016-06-719294. 28049639 PMC5356450 source
    • cites [17] Landau DA, Sun C, Rosebrock D, Herman SEM, Fein J, Sivina M, The evolutionary landscape of chronic lymphocytic leukemia treated with ibrutinib targeted therapy. Nat Commun. 2017; 8(1): 2185. Epub 2017/12/21. doi: 10.1038/s41467-017-02329-y. 29259203 PMC5736707 source
    • cites [18] Woyach JA, Jones D, Jurczak W, Robak TP, Illes A, Kater AP, Mutational profile of previously treated chronic lymphocytic leukemia patients progressing on acalabrutinib or ibrutinib. Blood. 2024. Epub 20240516. doi: 10.1182/blood.2023023659. PMC11406168 38754046 source

  • It may state two separate claims as one.

    Premisecitation

    Primary resistance, where a cBTKi fails to provide benefit, is uncommon and most often associated with Richter transformation.

    “Primary resistance,where a cBTKi fails to provide benefit, is uncommon and most often associated with Richter transformation(12, 13).”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [12] Ahn IE, Underbayev C, Albitar A, Herman SE, Tian X, Maric I, Clonal evolution leading to ibrutinib resistance in chronic lymphocytic leukemia. Blood. 2017; 129(11): 1469– 79. Epub 2017/01/05. doi: 10.1182/blood-2016-06-719294. 28049639 PMC5356450 source

      The Discussion says transformation accounted for most early progression, and the Abstract reports transformation in 5 of 84 patients (6.0%). But the paper studies ibrutinib, not all covalent BTK inhibitors, and does not establish that these early progressions were primary resistance—failure to obtain benefit from treatment. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [13] Sun C, Nierman P, Kendall EK, Cheung J, Gulrajani M, Herman SEM, Clinical and biological implications of target occupancy in CLL treated with the BTK inhibitor acalabrutinib. Blood. 2020; 136(1): 93– 105. Epub 2020/03/24. doi: 10.1182/blood.2019003715. 32202637 PMC7332900 source

      The Efficacy section reports an 87.5% overall response rate in 48 patients treated with acalabrutinib and three Richter transformations, consistent with lack of benefit being uncommon in this study. It does not identify those transformations as cases of primary resistance or establish that primary resistance to covalent BTK inhibitors is most often associated with Richter transformation. (LLM, conf=0.83)

      Experimental — accuracy not yet measured

  • It may state two separate claims as one.

    Premisecitation

    Inhibition of BTK abrogates BCR-driven survival and proliferation, and is an effective therapeutic strategy against several B-cell malignancies, particularly CLL/SLL.

    “As a result, inhibition of BTK abrogatesBCR-driven survival and proliferation, and is an effective therapeutic strategyagainst several B-cell malignancies, particularly chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL)(3).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [3] Nakhoda S, Vistarop A, Wang YL. Resistance to Bruton tyrosine kinase inhibition in chronic lymphocytic leukaemia and non-Hodgkin lymphoma. Br J Haematol. 2023; 200(2): 137– 49. Epub 20220827. doi: 10.1111/bjh.18418. 36029036 PMC9839590 source

      The Introduction says BTK inhibition disrupts BCR signaling, and the Conclusion describes it as pivotal in treating B-cell malignancies; the Chronic Lymphocytic Leukemia section says ibrutinib has drastically changed CLL management. But the Introduction specifies that BCR inhibition primarily slows proliferation rather than directly kills cells, so saying it 'abrogates' survival and proliferation overstates the source. Page numbers are not provided in our copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • It may state two separate claims as one.

    Premisecitation

    Ibrutinib-resistant CLL often harbors several subclones with BTK C481 and PLCG2 mutations; different growth rates of these subclones are most consistent with each mutation arising in an independent ancestor.

    “Ibrutinib-resistant CLL often harbors several subclones with BTK C481 and PLCG2mutations; different growth rates of these subclones aremost consistent with each mutation arising in an independent ancestor (12).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [12] Ahn IE, Underbayev C, Albitar A, Herman SE, Tian X, Maric I, Clonal evolution leading to ibrutinib resistance in chronic lymphocytic leukemia. Blood. 2017; 129(11): 1469– 79. Epub 2017/01/05. doi: 10.1182/blood-2016-06-719294. 28049639 PMC5356450 source

  • It may state two separate claims as one.

    Premisecitation

    Mechanisms of resistance are tumor intrinsic due to mutations in signaling components or activation of bypass pathways, or extrinsic due to cytokine signaling or cell-cell interactions within the tumor microenvironment.

    “We distinguish between mechanisms of resistance that aretumor intrinsic due tomutations in signaling componentsor activation of bypass pathways, or extrinsic due to cytokine signaling or cell-cell interactionswithin the tumor microenvironment (TME)(15).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [15] Polcik L, Dannewitz Prosseda S, Pozzo F, Zucchetto A, Gattei V, Hartmann TN. Integrin Signaling Shaping BTK-Inhibitor Resistance. Cells. 2022; 11(14). Epub 20220718. doi: 10.3390/cells11142235. PMC9322986 35883678 source

      Section 4 (page unavailable) identifies BTK and PLCγ2 mutations, microenvironmental interactions, and bypass signaling as possible causes of BTK-inhibitor resistance in CLL. It also describes a supportive cytokine environment and direct cell-cell contact in lymphoid organs. The paper does not classify bypass pathways as tumor-intrinsic, and its discussion is centered on CLL rather than resistance across tumors generally. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • It may state two separate claims as one.

    Premisecitation

    Ibrutinib, acalabrutinib, and zanubrutinib bind covalently to residue C481 of BTK, and thus are susceptible to mutations changing C481 to another amino acid, most commonly C481S.

    “Ibrutinib, acalabrutinib, and zanubrutinib bind covalently to residue C481 of BTK, and thus are susceptible to mutations changing C481 to another amino acid, most commonly C481S(19–21).”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites [19] Woyach JA, Furman RR, Liu TM, Ozer HG, Zapatka M, Ruppert AS, Resistance mechanisms for the Bruton’s tyrosine kinase inhibitor ibrutinib. N Engl J Med. 2014; 370(24): 2286– 94. Epub 2014/05/30. doi: 10.1056/NEJMoa1400029. 24869598 PMC4144824 source

      The Results report C481S in five patients at relapse and show that it prevents irreversible binding of ibrutinib, conferring relative resistance. Our copy does not address acalabrutinib or zanubrutinib, so it does not establish that those drugs bind C481 or are susceptible to this mutation. The five-patient finding also does not establish that C481S is the most common C481 substitution across all three drugs. (LLM, conf=0.90)

      Experimental — accuracy not yet measured
    • cites [20] Brown JR, Li J, Eichhorst B, Lamanna N, O’Brien SM, Tam CS, Acquired Mutations in Patients with Relapsed/Refractory Cll Who Progressed in the Alpine Study. Blood Adv. 2025. Epub 20250124. doi: 10.1182/bloodadvances.2024014206. PMC12008693 39853273 source
    • cites [21] Woyach JA, Jones D, Jurczak W, Robak T, Illes A, Kater AP, Mutational profile in previously treated patients with chronic lymphocytic leukemia progression on acalabrutinib or ibrutinib. Blood. 2024; 144(10): 1061– 8. doi: 10.1182/blood.2023023659. 38754046 PMC11406168 source

      In section 63 (page not given), the Introduction describes acalabrutinib as a covalent BTK inhibitor, and the Results report BTK C481S, C481Y, and C481R mutations in both the acalabrutinib and ibrutinib groups at progression. The copy does not discuss zanubrutinib, explicitly identify C481 as the binding residue, or establish that C481S is the most common substitution. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • It may state two separate claims as one.

    Premisecitation

    Additional genetic mechanisms of resistance to BTKi in CLL include PLCG2 mutations as well as chromosome 8p deletion (del [8p]).

    “Additional genetic mechanisms of resistance to BTKi in CLL include,PLCG2 mutations as well as chromosome 8p deletion (del [8p])(23).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [23] Burger JA, Landau DA, Taylor-Weiner A, Bozic I, Zhang H, Sarosiek K, Clonal evolution in patients with chronic lymphocytic leukaemia developing resistance to BTK inhibition. Nat Commun. 2016; 7: 11589. doi: 10.1038/ncomms11589. 27199251 PMC4876453 source

      The Results report PLCG2 mutations expanding during ibrutinib treatment alongside CLL progression. They also identify del(8p) in relapse clones, but the Discussion calls its contribution a potential resistance mechanism and suggests that additional lesions may be needed to achieve ibrutinib resistance. The claim presents del(8p) more definitively than the paper does (page numbers unavailable in our copy). (LLM, conf=0.87)

      Experimental — accuracy not yet measured

  • It may state two separate claims as one.

    Premisecitation

    The C481S mutation disrupts the covalent binding of ibrutinib to BTK and results in a weak and reversible interaction (affinity [KD], 0.2 nM vs. 10.4 nM).

    “The C481S mutation disrupts the covalent binding of ibrutinib to BTK and results in a weak and reversible interaction (affinity [KD], 0.2 nM vs. 10.4 nM) (19).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [19] Woyach JA, Furman RR, Liu TM, Ozer HG, Zapatka M, Ruppert AS, Resistance mechanisms for the Bruton’s tyrosine kinase inhibitor ibrutinib. N Engl J Med. 2014; 370(24): 2286– 94. Epub 2014/05/30. doi: 10.1056/NEJMoa1400029. 24869598 PMC4144824 source

  • It may state two separate claims as one.

    Premisecitation

    In contrast to C481S, which retains the enzymatic activity of BTK, C481Y/R/F cause steric hindrance and structural clashing within the ATP binding pocket, preventing BTK Y223 autophosphorylation.

    “In contrast to C481S, which retains the enzymatic activity of BTK, C481Y/R/F cause steric hindrance and structural clashing within the ATP binding pocket, preventing BTK Y223 autophosphorylation (34, 37).”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [34] Hamasy A, Wang Q, Blomberg KE, Mohammad DK, Yu L, Vihinen M, Substitution scanning identifies a novel, catalytically active ibrutinib-resistant BTK cysteine 481 to threonine (C481T) variant. Leukemia. 2017; 31(1): 177– 85. Epub 2016/06/11. doi: 10.1038/leu.2016.153. 27282255 PMC5220130 source

      The Results sections on differential catalytic activity and structure–function correlation (pages not provided) support retained activity for C481S, severely compromised Y223 phosphorylation for C481F/R/Y, and structural clashes for the bulky F and Y substitutions. They do not support the proposed mechanism for C481R: the paper says its flexible side chain can be accommodated in the structure, rather than causing a structural clash. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [37] Thompson PA, Tam CS. Pirtobrutinib: a new hope for patients with BTK inhibitor-refractory lymphoproliferative disorders. Blood. 2023; 141(26): 3137– 42. doi: 10.1182/blood.2023020240. 37156004 PMC10646821 source

      The mechanism-of-action section reports kinase inhibition in C481S-mutated BTK, and the resistance section says many non-C481S mutants are kinase-dead and cannot autophosphorylate Y223. Table 1 lists C481Y and C481R among kinase-dead mutations. Our copy does not identify C481F or say that steric hindrance and structural clashing in the ATP pocket cause the loss of autophosphorylation. Page numbers are unavailable in our copy. (LLM, conf=0.82)

      Experimental — accuracy not yet measured

  • It may state two separate claims as one.

    Premisecitation

    Sonrotoclax is a second-generation BCL2 inhibitor under clinical investigation with activity against BCL2 mutations, and superior potency and selectivity compared with venetoclax.

    “Sonrotoclaxis a second-generation BCL2 inhibitor under clinical investigation with activity againstBCL2 mutations, and superior potency and selectivity compared with venetoclax(63).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [63] Liu J, Li S, Wang Q, Feng Y, Xing H, Yang X, Sonrotoclax overcomes BCL2 G101V mutation-induced venetoclax resistance in preclinical models of hematologic malignancy. Blood. 2024; 143(18): 1825– 36. doi: 10.1182/blood.2023019706. 38211332 PMC11076911 source

  • It may state two separate claims as one.

    Premisecitation

    Studies have shown that mutant PLCG2 protein can be activated via kinases LYN and SYK and also suggest functional dependency of PLCG2 on LYN and SYK.

    “Studies have shown that mutant PLCG2 protein can be activated via kinases LYN and SYK and also suggest functional dependency of PLCG2 on LYN and SYK (46).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [46] Liu TM, Woyach JA, Zhong Y, Lozanski A, Lozanski G, Dong S, Hypermorphic mutation of phospholipase C, gamma2 acquired in ibrutinib-resistant CLL confers BTK independency upon B-cell receptor activation. Blood. 2015; 126(1): 61– 8. Epub 2015/05/15. doi: 10.1182/blood-2015-02-626846. 25972157 PMC4492196 source

  • It may state two separate claims as one.

    Premisecitation

    BTK degraders eliminate both the enzymatic activity and the scaffolding function of BTK, unlike BTK inhibitors.

    “In contrast to BTKi, BTK degraders eliminate both the enzymatic activity and scaffolding function of BTK (41).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [41] Montoya S, Bourcier J, Noviski M, Lu H, Thompson MC, Chirino A, Kinase-impaired BTK mutations are susceptible to clinical-stage BTK and IKZF1/3 degrader NX-2127. Science. 2024; 383(6682): eadi5798. Epub 20240202. doi: 10.1126/science.adi5798. 38301010 PMC11103405 source

  • It may state two separate claims as one.

    Premisecitation

    Treatment with BTKi does not completely block VLA-4 activation, leading to pro-survival and activation signals.

    “Treatment with BTKidoes not completely block this mechanism, leading to pro-survival and activation signals (49).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [49] Alsadhan A, Chen J, Gaglione EM, Underbayev C, Tuma PL, Tian X, CD49d Expression Identifies a Biologically Distinct Subtype of Chronic Lymphocytic Leukemia with Inferior Progression-Free Survival on BTK Inhibitor Therapy. Clin Cancer Res. 2023; 29(18): 3612– 21. doi: 10.1158/1078-0432.CCR-22-3217. 37227160 PMC10524232 source

  • Probably not a substantial claim.

    Premisecitation

    A targeted protein degrader is a chimeric small molecule that recruits a target protein into proximity of an E3 ubiquitin ligase, promoting polyubiquitylation and degradation of the target via the ubiquitin proteasome system.

    “A targeted protein degrader is a chimeric small molecule that recruits target protein into the proximity of an E3 ubiquitin ligase, which then promotes polyubiquitylation of the target, triggering its degradation via the ubiquitin proteasome system (88, 89).”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [88] Lai AC, Crews CM. Induced protein degradation: an emerging drug discovery paradigm. Nat Rev Drug Discov. 2017; 16(2): 101– 14. Epub 20161125. doi: 10.1038/nrd.2016.211. 27885283 PMC5684876 source
    • cites [89] Zhang D, Harris HM, Chen J, Judy J, James G, Kelly A, NRX-0492 degrades wild-type and C481 mutant BTK and demonstrates in vivo activity in CLL patient-derived xenografts. Blood. 2023; 141(13): 1584– 96. Epub 2022/11/15. doi: 10.1182/blood.2022016934. M.C.C., S.Y., D.W.R., and M.N. were or currently are full-time employees and shareholders of Nurix Therapeutics. A.W. received research funding from Pharmacyclics, Acerta Pharma, Merck, Verastem, Genmab, and Nurix Therapeutics. C.S. received research funding from Genmab. The remaining authors declare no competing financial interests. 36375120 PMC1 source

  • It may state two separate claims as one.

    Premisecitation

    In a phase 1 first-in-human trial of NX-2127 in patients with CLL, more than 80% BTK degradation was achieved and clinical responses occurred in 79% of evaluable patients.

    “Preliminary results of a phase 1, first-in-human clinical trial of NX-2127 in patients with CLL have demonstrated that >80% BTK degradation was achieved, and clinical responses were seen in 79% of evaluable patients (41, 90).”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [41] Montoya S, Bourcier J, Noviski M, Lu H, Thompson MC, Chirino A, Kinase-impaired BTK mutations are susceptible to clinical-stage BTK and IKZF1/3 degrader NX-2127. Science. 2024; 383(6682): eadi5798. Epub 20240202. doi: 10.1126/science.adi5798. 38301010 PMC11103405 source

      The Clinical benefit section (page not provided) describes a first-in-human phase 1 trial in patients with CLL and reports >90% BTK degradation in one patient. It also reports improvement in target-lesion measurements in 11 of 14 evaluable patients (79%), but does not establish that all 11 had clinical responses; it identifies a formal partial response in one patient. (LLM, conf=0.83)

      Experimental — accuracy not yet measured
    • cites [90] Mato AR WW, Ai WZ, Flinn IW, Tees M, Patel MR, NX-2127–001, a First-in-Human Trial of NX-2127, a Bruton’s Tyrosine Kinase-Targeted Protein Degrader, in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia and B-Cell Malignancies. Blood. 2022; 140. source

  • It may state two separate claims as one.

    Premisecitation

    Venetoclax is the only BCL2 inhibitor currently approved by the U.S. FDA, but drug resistance driven, in part, by BCL2 mutations, has been reported.

    “Venetoclax is the only BCL2 inhibitor currently approved by the U.S. FDA, but drug resistance driven, in part, byBCL2 mutations, has been reported(62).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [62] Blombery P, Anderson MA, Gong JN, Thijssen R, Birkinshaw RW, Thompson ER, Acquisition of the Recurrent Gly101Val Mutation in BCL2 Confers Resistance to Venetoclax in Patients with Progressive Chronic Lymphocytic Leukemia. Cancer Discov. 2019; 9(3): 342– 53. Epub 20181204. doi: 10.1158/2159-8290.CD-18-1119. 30514704 source

      The paper’s title, reproduced in our copy’s bibliographic listing, states that a recurrent BCL2 mutation confers resistance to venetoclax in patients with progressive chronic lymphocytic leukemia. The available passages do not address whether venetoclax is the only BCL2 inhibitor approved by the U.S. FDA (searched: FDA approval and BCL2-mutation resistance). (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • It may state two separate claims as one.

    Premisecitation

    NX-2127 is an orally bioavailable small-molecule BTK degrader effective against both wild-type and mutant forms of BTK.

    “NX-2127 is an orally bioavailable, small molecule BTK degrader that is effective against both WT and mutant forms of BTK (41).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [41] Montoya S, Bourcier J, Noviski M, Lu H, Thompson MC, Chirino A, Kinase-impaired BTK mutations are susceptible to clinical-stage BTK and IKZF1/3 degrader NX-2127. Science. 2024; 383(6682): eadi5798. Epub 20240202. doi: 10.1126/science.adi5798. 38301010 PMC11103405 source

  • It may state two separate claims as one.

    Premisecitation

    Within the TME, the integrin very late antigen 4 (VLA-4) has a major role in B-cell development and function and is a master regulator of cell-cell and cell-matrix interactions via binding to vascular cell adhesion molecule-1 (VCAM-1) and fibronectin.

    “Within the TME, the integrin very late antigen 4 (VLA-4) has a major role in B-cell development and function and isa master regulator of cell-cell and cell-matrix interactions via binding to vascular cell adhesion molecule-1 (VCAM-1) and fibronectin(49).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [49] Alsadhan A, Chen J, Gaglione EM, Underbayev C, Tuma PL, Tian X, CD49d Expression Identifies a Biologically Distinct Subtype of Chronic Lymphocytic Leukemia with Inferior Progression-Free Survival on BTK Inhibitor Therapy. Clin Cancer Res. 2023; 29(18): 3612– 21. doi: 10.1158/1078-0432.CCR-22-3217. 37227160 PMC10524232 source

      Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

  • It may state two separate claims as one.

    Interpretationcitation

    Bispecific antibodies represent a promising therapeutic strategy for relapsed/refractory CLL and a potential combination partner to deepen responses in patients on targeted therapy, especially with BTK inhibitors and venetoclax.

    “Overall, bsAb represent a promising therapeutic strategy for relapsed/refractory CLL, and as a potential combination partner to deepen responses in patients on targeted therapy, especially in conjunction with BTKi and venetoclax (94, 95, 98).”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [94] Robinson HR, Qi J, Cook EM, Nichols C, Dadashian EL, Underbayev C, A CD19/CD3 bispecific antibody for effective immunotherapy of chronic lymphocytic leukemia in the ibrutinib era. Blood. 2018; 132(5): 521– 32. Epub 2018/05/11. doi: 10.1182/blood-2018-02-830992. 29743179 PMC6073325 source
    • cites [95] Mhibik M, Gaglione EM, Eik D, Kendall EK, Blackburn A, Keyvanfar K, BTK inhibitors, irrespective of ITK inhibition, increase efficacy of a CD19/CD3-bispecific antibody in CLL. Blood. 2021; 138(19): 1843– 54. doi: 10.1182/blood.2020009686. 34046681 PMC8586964 source

      The Discussion (page not available) calls bispecific antibodies combined with BTK inhibitors a promising strategy to consolidate remissions and overcome drug resistance in CLL. The Results include samples from patients with relapsed CLL, but the paper does not establish efficacy in relapsed/refractory patients or address a combination with venetoclax. Its BTK-inhibitor findings are from in vitro experiments and, as the Discussion notes, need clinical testing. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [98] Mhibik M, Gaglione EM, Eik D, Herrick J, Le J, Ahn IE, Cytotoxicity of the CD3xCD20 bispecific antibody epcoritamab in CLL is increased by concurrent BTK or BCL-2 targeting. Blood Adv. 2023; 7(15): 4089– 101. doi: 10.1182/bloodadvances.2022009517. 37219524 PMC10388733 source

  • Probably not a substantial claim.

    Premisenone given

    Secondary resistance is seen in patients who initially respond then progress on continued therapy.

    “Secondary resistance is seen in patients who initially respond then progress on continued therapy.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Premisereasoning

    The noncovalent BTKi pirtobrutinib does not require binding to C481 and can restore BTK inhibition after progression on a cBTKi.

    “The noncovalent BTKi pirtobrutinib does not require binding to C481 and can restore BTK inhibition after progression on a cBTKi.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Interpretationnone given

    The scaffolding function of BTK, activation of bypass signaling pathways, and the tumor microenvironment may contribute to BTKi resistance.

    “Furthermore, the scaffolding function of BTK, activation of bypass signaling pathways,and the tumor microenvironment maycontribute to BTKi resistance.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper may give no reason why it holds. It may state two separate claims as one.

    Premisenone given

    Targeting BTK for degradation is an emerging strategy that appears effective against multiple BTK mutations, and inhibitors of downstream BCR signaling proteins are under development.

    “Targeting BTK for degradation is an emerging strategy that appears effective against multipleBTK mutations,and inhibitors of downstream BCR signaling proteins are under development.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. It may state two separate claims as one.

    Premisenone given

    Ibrutinib, acalabrutinib, and zanubrutinib are covalent BTK inhibitors that bind to residue C481, leading to sustained target inhibition.

    “Ibrutinib, acalabrutinib, and zanubrutinib are covalent BTK inhibitors (cBTKi) that bind toresidue C481, leading to sustained target inhibition.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Interpretationreasoning

    Since the reported prevalence of mutations depends on assay sensitivity, it is likely that rare mutations at baseline will not be detected by most next-generation sequencing methods; consequently, mutations are likely under-reported in older studies utilizing less sensitive assays.

    “Since the reported prevalence of mutations depends on assay sensitivity, it is likely that rare mutations at baseline will not be detected by most next-generation sequencing methods; consequently, mutations are likely under-reported in older studies utilizing less sensitive assays.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Premisereasoning

    While mutations at C481 are the common mechanism of resistance to cBTKi, other mutations of BTK outside C481 may arise.

    “While mutations at C481 are the common mechanism of resistance to cBTKi, other mutations of BTK outside C481 may arise.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim.

    Premisenone given

    PLCG2 is an effector phospholipase immediately downstream of BTK that connects BCR signaling to NF-kB activation.

    “PLCG2 is an effector phospholipase immediately downstream of BTK that connects BCR signaling to NF-kB activation.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim.

    Interpretationreasoning

    These observations are consistent with the hypothesis that these resistance mutations are pre-existing and expand under therapeutic pressure.

    “These observations are consistent with the hypothesis that these resistance mutations are pre-existingand expand under therapeutic pressure.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Premisecitation

    Of 21 patients evaluated for mutations, BTK or PLCG2 mutations were present in 17 (81%), with VAF ranging widely from 1.2% to 98.8%.

    “Of 21 patients evaluated for mutations, BTK or PLCG2mutations were present in 17 (81%), with VAF ranging widely from 1.2%to 98.8%(60).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [60] Roberts AW, Ma S, Kipps TJ, Coutre SE, Davids MS, Eichhorst B, Efficacy of venetoclax in relapsed chronic lymphocytic leukemia is influenced by disease and response variables. Blood. 2019; 134(2): 111– 22. Epub 2019/04/27. doi: 10.1182/blood.2018882555. 31023700 PMC6624969 source

  • It may state two separate claims as one.

    Premisecitation

    In a retrospective international observational study, 184 patients discontinued cBTKi and initiated venetoclax-based therapy; ORR was 78.0% (CR 43.3%) and median PFS was 43.2 months.

    “Of 127 (69.0%)patients evaluable for response, the ORR was 78.0% (CR rate 43.3%) and the median PFS was 43.2 months (95% CI, 31.9 to NR).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [61] Ghosh N LN, Eyre TA, Coombs CC, Manzoor BS, Brown JR, Treatment Effectiveness with Venetoclax-Based Therapy after Bruton Tyrosine Kinase Inhibitors in Chronic Lymphocytic Leukemia: An International Real-World Study. Blood. 2023; 142: 1908. PMC11803543 39698781 source

  • It may state two separate claims as one.

    Premisecitation

    In a cohort of 23 patients in the EPCORE CLL-1 trial, epcoritamab produced an overall response rate of 82%, a complete response rate of 33%, and 83% of responders remained in response at 9 months.

    “In a cohort of 23 patients, responses were seen early, with an ORR of 82%, CR of 33%, and 83% of responders remained in response at 9 months(96).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [96] Kater AP. Epcoritamab in patients with relapsed or refractory chronic lymphocytic leukemia: results from the phase 1b/2 EPCORE CLL-1 trial expansion cohort.. Presented at: 2023 International Workshop on CLL; October 6–9, 2023; Boston, MA Abstract 1546171.

  • It may state two separate claims as one.

    Premisenone given

    Pirtobrutinib has demonstrated clinical efficacy and appears in clinical trials to have lower rates of cardiac adverse events, major bleeding, bruising, and arthralgias compared to covalent BTK inhibitors.

    “Pirtobrutinib has demonstrated clinical efficacy, and in clinical trialsappears to havelower rates of cardiac AEs,major bleeding episodes, bruising,and arthralgias compared to cBTKi.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper may give no reason why it holds.

    Premisenone given

    Mutations in BTK and PLCG2 are the most common and best understood mechanism leading to BTK inhibitor resistance.

    “Mutations in BTKand PLCG2 are the most common and best understood mechanism leading to BTKi resistance.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds. It may state two separate claims as one.

    Interpretationnone given

    CAR-T may be an effective option for patients with high-risk CLL, but its toxicity is considerable and durable remissions are achieved only in a small subset of patients.

    “CAR-T may be an effective option for patients with high-risk CLL, but toxicity is considerable and durable remissions are only achieved in a small subset of patients.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Interpretationnone given

    BTK degraders that utilize the cellular proteasome to degrade BTK are currently under investigation and show early promise.

    “BTK degraders utilizing the cellular proteasome to degrade BTK are currently under investigation and show early promise.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisenone given

    Other mechanisms of BTK inhibitor resistance, including bypass mechanisms and clonal evolution, have been described and may have implications for selection of subsequent treatment.

    “Other mechanisms, including bypass mechanisms and clonal evolution, have been described, and may have implications for selection of subsequent treatment.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Interpretationreasoning

    Preliminary results from T-cell engaging bispecific antibodies suggest a role for harnessing the host immune system to overcome refractory CLL or possibly augment response with BTK inhibitors or venetoclax.

    “Preliminary results from T-cell engaging bsAb suggest a role for harnessing the host immune system to overcome refractory CLL or possibly augment response with BTKi or venetoclax.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Premisenone given

    Venetoclax has improved progression-free survival in cases of BTK inhibitor resistance, but remissions remain shorter than in BTK inhibitor-naive patients.

    “The introduction of venetoclax has improved PFS in cases of BTKi resistance, butremissions remain shorter compared to patients who are BTKi-naive”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper may give no reason why it holds.

    Premisenone given

    The optimal sequencing of therapies has not been systematically tested.

    “The optimal sequencing of therapieshas not been systematically test, and should be tailored to the individual patient.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper may give no reason why it holds.

    Premisenone given

    A significant percentage of patients need to discontinue treatment with covalent BTK inhibitors due to toxicity or progression.

    “However, a significant percentage of patients need to discontinue treatment with cBTKi due to toxicity or progression.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisenone given

    Novel drugs targeting BTK and immunotherapy are being developed for patients refractory to BTK inhibitors.

    “Novel drugs targeting BTK and immunotherapy are being developed for patients refractory to BTKi.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Premisecitation

    With optimized step-up dosing of epcoritamab and corticosteroid prophylaxis, there were no CRS events greater than grade 2 and no reports of immune effector cell-associated neurotoxicity syndrome.

    “Furthermore, with optimized step-up dosing of epcoritamab and corticosteroid prophylaxis,there were no CRS events greater than grade 2 in severity and no reports of immune effector cell-associated neurotoxicity syndrome (97).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [97] Danilov A FB, Awan FT, Bentzen HH, Eradat HA, Niemann CU, Epcoritamab Monotherapy in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia: Results from CLL Expansion and Optimization Cohorts of Epcore CLL-1. Blood. 144: 883.

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

46 of 46

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

  • BTK C481 mutation percentage uses an inconsistent denominator

    Minor

    The text says 84 of 247 patients had a known BTK C481 mutation, but 84/247 is 34.0%, not 37.8%.

    Reported 37.8 · recomputed 34.008097

1 of 1

Citations

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Kater AP. Epcoritamab in patients with relapsed or refractory chronic lymphocytic leukemia: results from the phase 1b/2 EPCORE CLL-1 trial expansion cohort. In Presented at: 2023 international workshop on CLL; October 6-9. Boston (MA); 2023. p. 1546171.

Cited by

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Related

Metadata

Authors
Gruessner, C., Wiestner, A., & Sun, C.
Affiliations
National Institutes of Health (US)
Corresponding author
Sun, Clare
ORCID
Sun, Clare
Venue
Leukemia & Lymphoma
Publisher
Informa UK Limited
Published
2025-02-19
Volume
66
Issue
7
Pages
1176-1188
ISSN
  • 1026-8022 (ISSN-L)
  • 1042-8194
  • 1029-2403
DOI
10.1080/10428194.2025.2466101
PMC
PMC12221821
OpenAlex
W4407798781
Semantic Scholar
154fc272e6f7459511824db19628ee0e1a3d5c91
Cited by
6
References
92
Citations by year
2026: 2 · 2025: 4
FWCI
3.14
Type
journal article
Language
en
Open access
Locations
  • Leukemia & lymphoma/Leukemia and lymphoma (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion)
Funders
National Institutes of Health (Z99 HL999999)
Topics
  • Health Sciences › Medicine › Hematology › Chronic Lymphocytic Leukemia Research
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Lymphoma Diagnosis and Treatment
  • Health Sciences › Medicine › Hematology › Acute Lymphoblastic Leukemia research
Keywords
chronic lymphocytic leukemia, Bruton's tyrosine kinase, BTK inhibitors, ibrutinib, acalabrutinib, zanubrutinib, pirtobrutinib, drug resistance, PLCG2 mutations, B cell receptor signaling, bypass signaling pathways, tumor microenvironment
MeSH terms
Agammaglobulinaemia Tyrosine Kinase, Antineoplastic Agents, Humans, Mutation, Piperidines, Receptors, Antigen, B-Cell, Signal Transduction, Leukemia, Lymphocytic, Chronic, B-Cell, Drug Resistance, Neoplasm, Protein Kinase Inhibitors, Molecular Targeted Therapy, Tumor Microenvironment

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

A language model drew the claims from the paper on 2026-10-19, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).

A second model labelled each claim on 2026-10-19 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).

Cited sources are checked with a language model’s help (gpt-6-sol).

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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