The DOI matches its Crossref record; 34 of the 34 references it cites were found in a registry or an index; 17 of the 19 sources its claims cite were checked for support.
Resistance Mechanisms for the Bruton's Tyrosine Kinase Inhibitor Ibrutinib
Open accessAbstract
BACKGROUND: Ibrutinib is an irreversible inhibitor of Bruton's tyrosine kinase (BTK) and is effective in chronic lymphocytic leukemia (CLL). Resistance to irreversible kinase inhibitors and resistance associated with BTK inhibition have not been characterized. Although only a small proportion of patients have had a relapse during ibrutinib therapy, an understanding of resistance mechanisms is important. We evaluated patients with relapsed disease to identify mutations that may mediate ibrutinib resistance. METHODS: We performed whole-exome sequencing at baseline and the time of relapse on samples from six patients with acquired resistance to ibrutinib therapy. We then performed functional analysis of identified mutations. In addition, we performed Ion Torrent sequencing for identified resistance mutations on samples from nine patients with prolonged lymphocytosis. RESULTS: We identified a cysteine-to-serine mutation in BTK at the binding site of ibrutinib in five patients and identified three distinct mutations in PLCγ2 in two patients. Functional analysis showed that the C481S mutation of BTK results in a protein that is only reversibly inhibited by ibrutinib. The R665W and L845F mutations in PLCγ2 are both potentially gain-of-function mutations that lead to autonomous B-cell-receptor activity. These mutations were not found in any of the patients with prolonged lymphocytosis who were taking ibrutinib. CONCLUSIONS: Resistance to the irreversible BTK inhibitor ibrutinib often involves mutation of a cysteine residue where ibrutinib binding occurs. This finding, combined with two additional mutations in PLCγ2 that are immediately downstream of BTK, underscores the importance of the B-cell-receptor pathway in the mechanism of action of ibrutinib in CLL. (Funded by the National Cancer Institute and others.).
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Written from the paper’s full text.
TL;DR
Acquired resistance to ibrutinib in CLL often involves BTK C481S or PLCγ2 mutations that restore B-cell–receptor signaling. Functional studies show C481S prevents irreversible BTK binding, while PLCγ2 R665W/L845F are gain-of-function and BTK-independent.
Key findings
- Whole-exome sequencing of six patients with acquired ibrutinib resistance identified BTK C481S in five patients and PLCγ2 mutations in two patients: R665W in Patient 6, and R665W, L845F, plus S707Y in one patient who also had low-frequency BTK C481S.
- C481S BTK had lower ibrutinib affinity than nonmutant BTK (dissociation constant, 0.2 nM vs. 10.4 nM) and was only reversibly inhibited by ibrutinib; washout experiments in patient cells showed inhibition required continuous drug exposure.
- PLCγ2 R665W and L845F showed enhanced anti-IgM–mediated calcium flux that was not inhibited by ibrutinib, indicating potential gain-of-function mutations allowing BTK-independent B-cell–receptor signaling.
- No BTK or PLCγ2 mutations were found in nine patients with prolonged lymphocytosis (≥12 months) on ibrutinib; sequencing depth was >700 reads for BTK C481 and PLCγ2 R665/S707 and >100 reads for PLCγ2 L845.
Methods
- Whole-exome sequencing was performed on baseline and relapse samples from six patients with acquired resistance to ibrutinib; relapse-specific nonsynonymous mutations were verified by Sanger or Ion Torrent sequencing.
- Ion Torrent sequencing was used to test for BTK and PLCγ2 mutations in nine patients with prolonged lymphocytosis during ibrutinib therapy.
- Functional analyses included in vitro kinase assays, flow cytometry, immunoblot assays, and stable transfection into DT40 or HEK 293T cells; statistical methods were detailed in the Supplementary Appendix.
Limitations
- The paper states that inability to identify small numbers of mutant clones in the presence of large numbers of nonmutant clones may mean such variants were present but not identified; the clinical significance of very low baseline R665W variant reads is unknown and more patients need evaluation.
- The paper states that other resistance mechanisms are likely present in a subgroup of patients without B-cell–receptor pathway mutations, and work is ongoing to identify alternative mechanisms.
- Evident from the text: the study is based on a small number of patients (six with acquired resistance and nine with prolonged lymphocytosis), limiting generalizability and statistical power.
Model-written summary. Check it against the paper before relying on it.
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Claims the paper makes
17 of 19 cited sources checked · 4 supported · 0 flagged · accuracy not yet measured
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“In patients treated with ibrutinib, a characteristic lymphocytosis develops as CLL cells are mobilized from lymph nodes and the spleen.”
§ Resistance Mechanisms for the Bruton’s Tyrosine Kinase Inhibitor Ibrutinib > RESULTS > ABSENCE OF BTK OR PLCγ2 MUTATIONS IN PATIENTS WITH PROLONGED LYMPHOCYTOSIS DURING IBRUTINIB THERAPY
What the sources say
- Partly supportedcites [24] sourceExperimental — accuracy not yet measured
The Results report that lymphocytosis occurred in 77% of patients treated with ibrutinib, and the Introduction describes cell mobilization from nodal and marrow sites as a possible mechanism. Our copy does not identify the spleen as a source of the mobilized CLL cells, so that part of the claim is unsupported. (LLM, conf=0.85)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Although lymphocytosis typically resolves within 8 months, a subgroup of patients have lymphocytosis that lasts longer than 12 months in the presence of a continued response to ibrutinib.24”
§ Resistance Mechanisms for the Bruton’s Tyrosine Kinase Inhibitor Ibrutinib > RESULTS > ABSENCE OF BTK OR PLCγ2 MUTATIONS IN PATIENTS WITH PROLONGED LYMPHOCYTOSIS DURING IBRUTINIB THERAPY
What the sources say
- Supportedcites [24] source
The Results (page not specified) report a median time to lymphocyte normalization of 6.2 months and identify patients who still had lymphocytosis at 12 months but otherwise met criteria for a partial response. A second Results passage reports that their progression-free survival was not inferior to that of patients with a conventional partial or complete response. (LLM, conf=0.91)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“whereas dasatinib, a reversible inhibitor of BTK,23 inhibited nonmutant and mutant BTK with similar efficacy.”
§ Resistance Mechanisms for the Bruton’s Tyrosine Kinase Inhibitor Ibrutinib > RESULTS > REVERSIBLE INHIBITION OF MUTANT BTK BY IBRUTINIB IN VITRO AND IN PATIENTS
What the sources say
- Partly supportedcites [23] sourceExperimental — accuracy not yet measured
The citation is attached to the description of dasatinib as a reversible BTK inhibitor. The Results establish that dasatinib inhibits BTK, but our copy does not establish that its inhibition is reversible. It also does not test C481S or support the sentence’s comparison of C481S with nonmutant BTK; the mutant it tests is T474I, which was resistant. (LLM, conf=0.83)
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Ibrutinib is an irreversible inhibitor of Bruton’s tyrosine kinase (BTK) and is effective in chronic lymphocytic leukemia (CLL).”
§ Resistance Mechanisms for the Bruton’s Tyrosine Kinase Inhibitor Ibrutinib > Abstract > BACKGROUND
What the sources say
- Partly supportedcites [6] sourceExperimental — accuracy not yet measured
The section on PCI-32765-induced cytotoxicity states that PCI-32765 is an irreversible BTK inhibitor. Our copy does not name ibrutinib or establish that it is the same compound, so it does not fully support the claim as worded. (LLM, conf=0.78)
- Partly supportedcites [8] sourceExperimental — accuracy not yet measured
The Introduction states that PCI-32765 binds irreversibly to BTK, supporting the inhibitor property. Our copy does not identify PCI-32765 as ibrutinib, so it does not establish that the named drug has that property. (LLM, conf=0.76)
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“At 26 months, the estimated progression-free survival rate among patients treated with ibrutinib is 75%.9”
§ Resistance Mechanisms for the Bruton’s Tyrosine Kinase Inhibitor Ibrutinib > Abstract > CONCLUSIONS
What the sources say
- Supportedcites [9] source
The Results > Efficacy passage reports that the 26-month estimated progression-free survival rate during ibrutinib treatment was 75%, exactly as claimed. This estimate concerns the patients in the cited study. (LLM, conf=0.95)
Strength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Ibrutinib irreversibly binds BTK at the C481 residue, rendering it kinase-inactive”
§ Resistance Mechanisms for the Bruton’s Tyrosine Kinase Inhibitor Ibrutinib > Abstract > CONCLUSIONS
What the sources say
- Partly supportedcites [6] sourceExperimental — accuracy not yet measured
The Introduction and Discussion describe PCI-32765 as an irreversible BTK inhibitor, and the section on BCR-dependent signaling reports reduced BTK phosphorylation consistent with inhibited kinase activity. Our copy does not identify PCI-32765 as ibrutinib or state that it binds BTK at C481, so those specifics are not established by this source. (LLM, conf=0.84)
- Partly supportedcites [8] sourceExperimental — accuracy not yet measured
The Introduction (page not provided) says PCI-32765 binds irreversibly to a cysteine residue in BTK and inhibits its enzymatic activity. It does not identify that residue as C481; a search for “C481” found no matching passage. The copy calls the drug PCI-32765 rather than ibrutinib. (LLM, conf=0.87)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Partly supported
The cited sources that could be checked couldn’t confirm or dispute this claim.
In the paper
“At relapse, none of the patients had mutations in other kinases containing a cysteine residue homologous to C481 in BTK that are irreversibly inhibited by ibrutinib”
§ Resistance Mechanisms for the Bruton’s Tyrosine Kinase Inhibitor Ibrutinib > RESULTS > MUTATIONS IN BTK AND PLCγ2 REVEALED BY WHOLE-EXOME SEQUENCING
What the sources say
- Could not verifycites [7] sourceExperimental — accuracy not yet measured
The Results and Discussion describe PCI-32765 binding to BTK at Cys-481 and note that a small subset of other kinases has a homologous cysteine. Neither section reports sequencing patients at relapse or whether any had mutations in those kinases; searches for relapse and patient mutations found no such result in our copy. (LLM, conf=0.76)
- Could not verifycites [22] sourceExperimental — accuracy not yet measured
The Introduction and Results describe cysteine-dependent irreversible inhibition of BTK and ITK, but do not report mutation testing at relapse. A search for relapsed patients, six patients, and mutations in other kinases found no passage addressing the claim. (LLM, conf=0.75)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Could not verify
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“mutations have not been observed in these other targets, findings that suggest that BTK is its critical target.”
§ Resistance Mechanisms for the Bruton’s Tyrosine Kinase Inhibitor Ibrutinib > DISCUSSION
What the sources say
- Partly supportedcites [7] sourceExperimental — accuracy not yet measured
The Discussion reports that BTK inhibition correlated with efficacy in a mouse arthritis model, consistent with BTK being a relevant target in vivo. It does not report acquired-resistance mutations in patients or establish that mutations were absent from ITK, BLK, or other targets. It also says a role for other cysteine-containing kinases cannot be ruled out. (LLM, conf=0.80)
- Could not verifycites [22] sourceExperimental — accuracy not yet measured
The Results describe ITK-C442A engineered in Jurkat cells to test ibrutinib binding, not mutations observed in patients with acquired resistance. Searches for acquired-resistance mutations in ITK, BLK, and other targets found no passage addressing whether such mutations were observed; our copy therefore cannot verify the attributed claim. (LLM, conf=0.73)
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“We have previously documented by immunoblot analysis24 that BTK and PLCγ2 are inhibited in these patients”
§ Resistance Mechanisms for the Bruton’s Tyrosine Kinase Inhibitor Ibrutinib > DISCUSSION
What the sources say
- Supportedcites [24] source
The Results report immunoblot analysis of samples from patients with prolonged lymphocytosis at baseline and six months into ibrutinib therapy. BTK autophosphorylation was down-regulated in 8 of 8 patients, and PLCγ2 phosphorylation was diminished in 7 of 9; the authors conclude that both remain inhibited in most patients with persistent lymphocytosis. (LLM, conf=0.95)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Although ibrutinib inhibits other similar kinases that contain C481, including ITK and BLK,7,22”
§ Resistance Mechanisms for the Bruton’s Tyrosine Kinase Inhibitor Ibrutinib > DISCUSSION
What the sources say
- Partly supportedcites [7] sourceExperimental — accuracy not yet measured
The Discussion (page unavailable) says PCI-32765 binds BTK at Cys-481 and that inhibition of other cysteine-containing kinases, including BLK, cannot be ruled out. It does not establish BLK inhibition or identify ITK as a kinase inhibited by PCI-32765, so the claim is stronger and more specific than this paper supports. (LLM, conf=0.86)
- Partly supportedcites [22] sourceExperimental — accuracy not yet measured
The Results confirm that ibrutinib binds and inhibits ITK, but identify its covalent binding residue as C442, not C481. The passages searched for BLK do not report BLK inhibition, so the source does not support that part of the claim. (LLM, conf=0.88)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Partly supported
- It may state two separate claims as one. 11
- The quote only partly states this claim. 2
- Probably not a substantial claim. 1
Every source the paper cites for this claim was checked and supports it.
In the paper
“Ibrutinib has been shown to have clinically significant activity in patients with relapsed CLL, with 71% of patients having an objective complete or partial response and an additional 15 to 20% of patients having a partial response with persistent lymphocytosis.”
§ Resistance Mechanisms for the Bruton’s Tyrosine Kinase Inhibitor Ibrutinib > Abstract > CONCLUSIONS
What the sources say
- Supportedcites [9] source
The Results > Efficacy passage reports a 71% response rate by standard criteria in each dose cohort. It also reports an additional partial response with persistent lymphocytosis in 20% of the 420-mg cohort and 15% of the 840-mg cohort, matching the cited claim about patients with relapsed CLL. (LLM, conf=0.94)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Supported
The cited sources that could be checked couldn’t confirm or dispute this claim.
In the paper
“This mutation is not known to cause the X-linked agammaglobulinemia phenotype31 but instead results in retained catalytic activity.”
§ Resistance Mechanisms for the Bruton’s Tyrosine Kinase Inhibitor Ibrutinib > DISCUSSION
What the sources say
- Could not verifycites [31] sourceExperimental — accuracy not yet measured
The citation is attached to the claim that C481S is not known to cause the X-linked agammaglobulinemia phenotype. The Mutation Statistics section discusses tolerated substitutions generally, but our copy does not address C481S specifically (searched: C481S, 481, and the phenotype claim). The retained-catalytic-activity clause falls after the citation and is not assessed as attributed to this source. (LLM, conf=0.72)
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Could not verify
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In Patients 3, 5, and 6, Ion Torrent sequencing was performed, and no mutation was identified in more than 0.2% of reads”
§ Resistance Mechanisms for the Bruton’s Tyrosine Kinase Inhibitor Ibrutinib > RESULTS > MUTATIONS IN BTK AND PLCγ2 REVEALED BY WHOLE-EXOME SEQUENCING
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesThe quote only partly states this claim.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In Patient 6, the decrease in BTK phosphorylation at the time of the relapse was similar to the decrease at 11 months of therapy, when the patient was having a response to the drug (Fig. 3A), whereas PLCγ2 showed enhanced phosphorylation at the time of relapse”
§ Resistance Mechanisms for the Bruton’s Tyrosine Kinase Inhibitor Ibrutinib > RESULTS > IDENTIFIED MUTATIONS IN PLCγ2 AS RESISTANCE MECHANISMS IN VITRO AND IN PATIENTS
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Ibrutinib washout experiments showed that the C481S mutation allows reversible, but not irreversible, inhibition of BTK by ibrutinib”
§ Resistance Mechanisms for the Bruton’s Tyrosine Kinase Inhibitor Ibrutinib > RESULTS > REVERSIBLE INHIBITION OF MUTANT BTK BY IBRUTINIB IN VITRO AND IN PATIENTS
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“At baseline, BTK phosphorylation was completely abrogated by ibrutinib with either washout or continuous exposure to ibrutinib. At the time of relapse, however, ibrutinib inhibited BTK phosphorylation only with continuous exposure”
§ Resistance Mechanisms for the Bruton’s Tyrosine Kinase Inhibitor Ibrutinib > RESULTS > REVERSIBLE INHIBITION OF MUTANT BTK BY IBRUTINIB IN VITRO AND IN PATIENTS
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“After ibrutinib was discontinued, ibrutinib still inhibited BTK phosphorylation (Fig. 3C) but not PLCγ2 phosphorylation (Fig. 3D).”
§ Resistance Mechanisms for the Bruton’s Tyrosine Kinase Inhibitor Ibrutinib > RESULTS > IDENTIFIED MUTATIONS IN PLCγ2 AS RESISTANCE MECHANISMS IN VITRO AND IN PATIENTS
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The intrinsic affinity of ibrutinib for nonmutant BTK was significantly higher than for mutant BTK (dissociation constant, 0.2 nM vs. 10.4 nM)”
§ Resistance Mechanisms for the Bruton’s Tyrosine Kinase Inhibitor Ibrutinib > RESULTS > REVERSIBLE INHIBITION OF MUTANT BTK BY IBRUTINIB IN VITRO AND IN PATIENTS
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesThe quote only partly states this claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These data show that the R665W and L845F mutations in PLCγ2 are potentially gain-of-function mutations in the presence of B-cell–receptor stimulation and could be relevant as mutations conferring resistance to ibrutinib in patients.”
§ Resistance Mechanisms for the Bruton’s Tyrosine Kinase Inhibitor Ibrutinib > RESULTS > IDENTIFIED MUTATIONS IN PLCγ2 AS RESISTANCE MECHANISMS IN VITRO AND IN PATIENTS
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The sequencing depth for BTK at C481 and for PLCγ2 at R665 and S707 was more than 700 reads, and the sequencing depth for PLCγ2 at L845 was more than 100 reads.”
§ Resistance Mechanisms for the Bruton’s Tyrosine Kinase Inhibitor Ibrutinib > RESULTS > ABSENCE OF BTK OR PLCγ2 MUTATIONS IN PATIENTS WITH PROLONGED LYMPHOCYTOSIS DURING IBRUTINIB THERAPY
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Unlike the mutations in this group, however, the C481S mutation in BTK is not a second mutation in a previously mutated gene, but rather a primary mutation in a gene that is not recurrently mutated in CLL, and it is mutated at the amino acid required for drug binding.”
§ Resistance Mechanisms for the Bruton’s Tyrosine Kinase Inhibitor Ibrutinib > DISCUSSION
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“In a recent preliminary study involving three patients with ibrutinib resistance, sequencing revealed the S707Y mutation in PLCγ2 that we identified in Patient 5 in our study but did not reveal BTK mutations.32”
§ Resistance Mechanisms for the Bruton’s Tyrosine Kinase Inhibitor Ibrutinib > DISCUSSION
What the sources say
- Not checked — no full text of the sourcecites [32] Burger JA, 2013, Blood source
Strength:plain· not yet calibratedn = 3Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“However, we recognize that our inability to identify small numbers of mutant clones in the presence of large numbers of nonmutant clones may mean that such variants were present but were not identified.”
§ Resistance Mechanisms for the Bruton’s Tyrosine Kinase Inhibitor Ibrutinib > DISCUSSION
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This pattern of a mutation localized to the irreversible binding site of ibrutinib and the immediate downstream kinase is not commonly seen with reversible kinase inhibitors and may be a result of continuous (rather than intermittent) pressure on the drug target.”
§ Resistance Mechanisms for the Bruton’s Tyrosine Kinase Inhibitor Ibrutinib > DISCUSSION
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Furthermore, many mutations discovered in PLCγ2 have been linked to the development of complex immune disorders as well as resistance to ibrutinib treatment in chronic lymphocytic leukaemia.”
From Characterisation of molecular mechanisms for PLCγ2 disease-linked variants (2024) · cites this paper as Woyach et al., 2014
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“whole-exome sequencing of six CLL patients with late relapses revealed C481S mutations in BTK of five patients and three distinct mutations in PLCG2 of two patients as follows: L845F, R665W, and S707Y in one patient with tumor cells also harboring a BTK C481S mutation and PLCG2 R665W representing the sole mutation in the other patient (29).”
From The Phospholipase Cγ2 Mutants R665W and L845F Identified in Ibrutinib-resistant Chronic Lymphocytic Leukemia Patients Are Hypersensitive to the Rho GTPase Rac2 Protein (2016) · cites this paper as [29]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“the R665W and L845F mutants of PLC␥ 2 appeared to be functionally normal in reconstituted DT40 chicken B cells in the absence of BCR stimulation, but to mediate moderately enhanced and markedly prolonged ibrutinib-resistant increases in [Ca 2ϩ ] i following BCR ligation with anti-IgM (29).”
From The Phospholipase Cγ2 Mutants R665W and L845F Identified in Ibrutinib-resistant Chronic Lymphocytic Leukemia Patients Are Hypersensitive to the Rho GTPase Rac2 Protein (2016) · cites this paper as [29]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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).”
From Resistance Mechanisms and Approach to Chronic Lymphocytic Leukemia after BTK Inhibitor Therapy (2025) · cites this paper as [19]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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).”
From Resistance Mechanisms and Approach to Chronic Lymphocytic Leukemia after BTK Inhibitor Therapy (2025) · cites this paper as [19]
Experimental — accuracy not yet measured
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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).”
From Resistance Mechanisms and Approach to Chronic Lymphocytic Leukemia after BTK Inhibitor Therapy (2025) · cites this paper as [19]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“PLCG2 S707Y, R665W, and L845F are gain-of-function missense mutations which prolong activation of BCR‐mediated downstream signaling, independent of BTK (19).”
From Resistance Mechanisms and Approach to Chronic Lymphocytic Leukemia after BTK Inhibitor Therapy (2025) · cites this paper as [19]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Specifically, genomic deletions (exon 19 or exons 20 through 22) or somatic mutations (R665W or S707Y) within the regulatory domain of PLCG2 constitutively activate PLCG2 and lead to BTK inhibitor resistance in leukemia patients 20,21 .”
From Genetic variants of phospholipase C-γ2 alter the phenotype and function of microglia and confer differential risk for Alzheimer’s disease (2023) · cites this paper as [21]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“Mutations in the gene encoding phospholipase C-␥ 2 (PLC␥ 2 ) have been shown to be associated with resistance to targeted therapy of chronic lymphocytic leukemia (CLL) with the Bruton's tyrosine kinase inhibitor ibrutinib.”
The cited source says what the claim attributes to it.
In the citing paper
“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).”
From Resistance Mechanisms and Approach to Chronic Lymphocytic Leukemia after BTK Inhibitor Therapy (2025) · cites this paper as [19]
The cited source says what the claim attributes to it.
In the citing paper
“Mutations of PLCG have been observed to co-occur with BTK mutations in the same patient (12, 19, 24).”
From Resistance Mechanisms and Approach to Chronic Lymphocytic Leukemia after BTK Inhibitor Therapy (2025) · cites this paper as [19]
In the citing paper
“the resistance to ibrutinib emerges due to a cysteine to serine mutation (C418S) at the ibrutinib binding site in BTK [113, 114].”
From Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies (2020) · cites this paper as [114]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
ALK resistance claim cites a ROS1 mutation study
MinorThe text cites reference 27 as an example of resistance through an ALK mutation, but reference 27 is titled as a report of resistance from a CD74-ROS1 mutation.
“EGFR25,26 and ALK27 in lung cancer”
“27. Awad MM Katayama R McTigue M Acquired resistance to crizotinib from a mutation in CD74–ROS1 N Engl J Med 2013 368 2395 2401 23724914 PMC3878821”
Citations
Cites
Fast and accurate short read alignment with Burrows-Wheeler transform
Li, H., & Durbin, R. (2009) · Bioinformatics · doi:10.1093/bioinformatics/btp324 · Cited by 58,607
The Genome Analysis Toolkit: A MapReduce framework for analyzing next-generation DNA sequencing data
McKenna, A., Hanna, M., Banks, E., Sivachenko, A., Cibulskis, K., Kernytsky, A., Garimella, K., Altshuler, D., Gabriel, S., Daly, M., et al. (2010) · Genome Research · doi:10.1101/gr.107524.110 · Cited by 27,895
Cingolani, P., Platts, A., Wang, L. L., Coon, M., Nguyen, T., Wang, L., Land, S. J., Lu, X., & Ruden, D. M. (2012) · Fly · doi:10.4161/fly.19695 · Cited by 11,816
Sensitive detection of somatic point mutations in impure and heterogeneous cancer samples
Cibulskis, K., Lawrence, M. S., Carter, S. L., Sivachenko, A., Jaffe, D. B., Sougnez, C. L., Gabriel, S., Meyerson, M. M., Lander, E. S., & Getz, G. A. (2013) · Nature Biotechnology · doi:10.1038/nbt.2514 · Cited by 4,965
EGFR Mutation and Resistance of Non–Small-Cell Lung Cancer to Gefitinib
Kobayashi, S., Boggon, T. J., Dayaram, T., Jänne, P. A., Kocher, O., Meyerson, M., Johnson, B. E., Eck, M. J., Tenen, D. G., & Halmos, B. (2005) · New England Journal of Medicine · doi:10.1056/nejmoa044238 · Cited by 3,964
O’Brien, S. G., Guilhot, F., Larson, R. A., Gathmann, I., Baccarani, M., Cervantes, F., Cornelissen, J. J., Fischer, T. H., Hochhaus, A., Hughes, T. P., et al. (2003) · New England Journal of Medicine · doi:10.1056/nejmoa022457 · Cited by 3,550
Pao, W., Miller, V. A., Politi, K. A., Riely, G. J., Somwar, R., Zakowski, M. F., Kris, M. G., & Varmus, H. (2005) · PLoS Medicine · doi:10.1371/journal.pmed.0020073 · Cited by 3,527
Clinical Resistance to STI-571 Cancer Therapy Caused by BCR-ABL Gene Mutation or Amplification
Gorre, M. E., Mohammed, M., Ellwood, K., Hsu, N., Paquette, R., Rao, P. N., & Sawyers, C. L. (2001) · Science · doi:10.1126/science.1062538 · Cited by 3,104
Targeting BTK with Ibrutinib in Relapsed Chronic Lymphocytic Leukemia
Byrd, J. C., Furman, R. R., Coutre, S. E., Flinn, I. W., Burger, J. A., Blum, K. A., Grant, B., Sharman, J. P., Coleman, M., Wierda, W. G., et al. (2013) · New England Journal of Medicine · doi:10.1056/nejmoa1215637 · Cited by 2,270
Self-citationChiorazzi, N., Rai, K. R., & Ferrarini, M. (2005) · New England Journal of Medicine · doi:10.1056/nejmra041720 · Cited by 1,684
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Feasibility and clinical utility of comprehensive genomic profiling of hematological malignancies
Fukuhara, S., Oshikawa‐Kumade, Y., Kogure, Y., Shingaki, S., Kariyazono, H., Kikukawa, Y., Koya, J., Saito, Y., Tabata, M., Yoshifuji, K., et al. (2022) · Cancer Science · doi:10.1111/cas.15427 · Cited by 32
Non-Covalent Bruton’s Tyrosine Kinase Inhibitors in the Treatment of Chronic Lymphocytic Leukemia
Montoya, S., & Thompson, M. C. (2023) · Cancers · doi:10.3390/cancers15143648 · Cited by 32
Gaudio, E., Tarantelli, C., Kwee, I., Barassi, C., Bernasconi, E., Rinaldi, A., Ponzoni, M., Cascione, L., Targa, A., Stathis, A., et al. (2016) · Annals of Oncology · doi:10.1093/annonc/mdw131 · Cited by 33
Targeting BTK through microRNA in chronic lymphocytic leukemia
Bottoni, A., Rizzotto, L., Lai, T.-H., Liu, C., Smith, L. L., Mantel, R., Reiff, S. D., El‐Gamal, D., Larkin, K. T. M., Johnson, A. J., et al. (2016) · Blood · doi:10.1182/blood-2016-07-727750 · Cited by 31
Self-citationNext-generation sequencing in chronic lymphocytic leukemia: recent findings and new horizons
Rodríguez‐Vicente, A. E., Bikos, V., Hernández‐Sánchez, M., Malčíková, J., Hernández‐Rivas, J. M., & Pospı́šilová, Š. (2017) · Oncotarget · doi:10.18632/oncotarget.19525 · Cited by 32
Kozaki, R., Vogler, M., Walter, H. S., Jayne, S., Dinsdale, D. D., Siebert, R., Dyer, M. J. S., & Yoshizawa, T. (2018) · Cancers · doi:10.3390/cancers10040127 · Cited by 31
Cosimo, E., Tarafdar, A., Moles, M. W., Holroyd, A. K., Malik, N., Catherwood, M. A., Hay, J., Dunn, K. M., Macdonald, A. M., Guichard, S. M., et al. (2018) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-18-2036 · Cited by 30
Acalabrutinib for mantle cell lymphoma
Witzig, T. E., & Inwards, D. J. (2019) · Blood · doi:10.1182/blood.2019852368 · Cited by 32
New Means and Challenges in the Targeting of BTK
Nawaratne, V., Sondhi, A. K., Abdel-Wahab, O. I., & Taylor, J. (2024) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-23-0409 · Cited by 37
Salvaris, R., Brennan, J., & Lewis, K. L. (2025) · Cancers · doi:10.3390/cancers17030557 · Cited by 39
Bruton tyrosine kinase inhibition in chronic lymphocytic leukemia
Maddocks, K. J., & Jones, J. A. (2016) · Seminars in Oncology · doi:10.1053/j.seminoncol.2016.02.008 · Cited by 32
Li, J., Wang, X., Xie, Y., Ying, Z., Liu, W., Ping, L., Zhang, C., Pan, Z., Ding, N., Song, Y., et al. (2017) · International Journal of Cancer · doi:10.1002/ijc.31044 · Cited by 30
Qin, H., Wei, G., Sakamaki, I., Dong, Z., Cheng, W. A., Smith, D. L., Wen, F., Sun, H., Kim, K., Cha, S.-C., et al. (2017) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-17-1193 · Cited by 31
Estrogen Receptor Covalent Antagonists: The Best Is Yet to Come
Furman, C., Hao, M., Prajapati, S., Reynolds, D. J., Rimkunas, V. M., Zheng, G. Z., Zhu, P., & Korpal, M. (2019) · Cancer Research · doi:10.1158/0008-5472.can-18-3634 · Cited by 33
Chronic Lymphocytic Leukaemia in 2020: the Future Has Arrived
Milne, K. M., Sturrock, B. R., & Chevassut, T. J. T. (2020) · Current Oncology Reports · doi:10.1007/s11912-020-0893-0 · Cited by 33
Small-molecule PROTACs: Novel Agents for Cancer Therapy
Wan, Y., Yan, C., Gao, H. J., & Liu, T. (2020) · Future Medicinal Chemistry · doi:10.4155/fmc-2019-0340 · Cited by 32
Self-citationLim, Y. S., Yoo, S.-M., Patil, V., Kim, H. W., Kim, H.-H., Suh, B., Park, J. Y., Jeong, N.-R., Park, C. H., Ryu, J. H., et al. (2022) · Blood Advances · doi:10.1182/bloodadvances.2022008121 · Cited by 32
Pro‐survival signal inhibition by CDK inhibitor dinaciclib in Chronic Lymphocytic Leukaemia
Chen, Y., Germano, S., Clements, C., Samuel, J., Shelmani, G., Jayne, S., Dyer, M. J. S., & Macip, S. (2016) · British Journal of Haematology · doi:10.1111/bjh.14285 · Cited by 31
Resisting the Resistance: Navigating BTK Mutations in Chronic Lymphocytic Leukemia (CLL)
Chirino, A., Montoya, S., Safronenka, A., & Taylor, J. (2023) · Genes · doi:10.3390/genes14122182 · Cited by 30
Herriott, A., Tudhope, S. J., Junge, G., Rodrigues, N., Patterson, M. J., Woodhouse, L. C., Lunec, J., Hunter, J. E., Mulligan, E. A., Cole, M. F., et al. (2015) · Oncotarget · doi:10.18632/oncotarget.6287 · Cited by 30
Rozovski, U., Benjamini, O., Jain, P., et al. (2015) · Journal of Clinical Oncology · doi:10.1200/jco.2014.58.6750 · Cited by 30
Albitar, A., Ma, W., DeDios, I., Estella, J. J., Ahn, I. E., Farooqui, M. Z. H., Wiestner, A. U., & Albitar, M. X. (2017) · Oncotarget · doi:10.18632/oncotarget.15316 · Cited by 30
Tibaldi, E. V., Pagano, M. A., Frezzato, F., Trimarco, V., Facco, M., Zagotto, G., Ribaudo, G., Pavan, V., Bordin, L., Visentin, A., et al. (2017) · Haematologica · doi:10.3324/haematol.2016.155747 · Cited by 30
Acalabrutinib and its Use in Treatment of Chronic Lymphocytic Leukemia
Khan, Y., & O'Brien, S. M. (2018) · Future Oncology · doi:10.2217/fon-2018-0637 · Cited by 30
Clonal dynamics in chronic lymphocytic leukemia
Gutierrez, C., & Wu, C. J. (2019) · Blood Advances · doi:10.1182/bloodadvances.2019000367 · Cited by 30
Song, Y., Sun, M. Y., Qi, J., Xu, W., Zhou, J., Li, D., Li, J., Qiu, L., Du, C., Guo, H., et al. (2022) · British Journal of Haematology · doi:10.1111/bjh.18162 · Cited by 29
Self-citationIbrutinib in mantle cell lymphoma patients: glass half full? Evidence and opinion
Stephens, D. M., & Spurgeon, S. E. F. (2015) · Therapeutic Advances in Hematology · doi:10.1177/2040620715592569 · Cited by 32
Combinatorial BTK and MALT1 inhibition augments killing of CD79 mutant diffuse large B cell lymphoma
Nagel, D., Bognar, M., Eitelhuber, A. C., Kutzner, K., Vincendeau, M., & Krappmann, D. (2015) · Oncotarget · doi:10.18632/oncotarget.6273 · Cited by 31
Tailored Treatment Strategies for Chronic Lymphocytic Leukemia in a Rapidly Changing Era
Brander, D. M., Islam, P., & Barrientos, J. C. (2019) · American Society of Clinical Oncology Educational Book · doi:10.1200/edbk_238735 · Cited by 29
Self-citationAcquired resistance to tyrosine kinase targeted therapy: mechanism and tackling strategies
Wu, D., Sun, Q., Tang, H., Xiao, H., Luo, J., Ouyang, L., & Sun, Q. (2024) · Drug Resistance Updates · doi:10.1016/j.drup.2024.101176 · Cited by 32
Management of Chronic Lymphocytic Leukemia
Stilgenbauer, S., Furman, R. R., & Zent, C. S. (2015) · American Society of Clinical Oncology Educational Book · doi:10.14694/edbook_am.2015.35.164 · Cited by 29
Self-citationFront-line treatment of CLL in the era of novel agents
Robak, T., Stilgenbauer, S., & Tedeschi, A. (2016) · Cancer Treatment Reviews · doi:10.1016/j.ctrv.2016.12.007 · Cited by 28
Self-citationZhang, Z., Zhang, D., Liu, Y., Yang, D., Ran, F., Wang, M. L., & Zhao, G. (2018) · Archiv der Pharmazie · doi:10.1002/ardp.201700369 · Cited by 33
The Evolving Landscape of Chronic Lymphocytic Leukemia on Diagnosis, Prognosis and Treatment
Carretero, C. P., González-Gascón-y-Marín, I., Rodríguez‐Vicente, A. E., Quijada‐Álamo, M., Hernández‐Rivas, J., Hernández‐Sánchez, M., & Hernández‐Rivas, J. M. (2021) · Diagnostics · doi:10.3390/diagnostics11050853 · Cited by 33
Yang, G., Wang, J., Tan, L., Munshi, M. N., Liu, X., Kofides, A., Chen, J. G., Tsakmaklis, N., Demos, M. G., Guerrera, M. L., et al. (2021) · Blood · doi:10.1182/blood.2021011405 · Cited by 30
Structure of BTK kinase domain with the second-generation inhibitors acalabrutinib and tirabrutinib
Lin, D. Y.-W., & Andreotti, A. H. (2023) · PLoS ONE · doi:10.1371/journal.pone.0290872 · Cited by 30
Klempner, S. J., Mehta, P., Schrock, A. B., Ali, S. M., & Ou, S. I. (2017) · Lung Cancer Targets and Therapy · doi:10.2147/lctt.s147129 · Cited by 30
Metabolic rewiring beyond Warburg in chronic lymphocytic leukemia: How much do we actually know?
Galicia-Vázquez, G., & Aloyz, R. S. (2018) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2018.12.003 · Cited by 30
Eyre, T. A., & Riches, J. C. (2023) · Cancers · doi:10.3390/cancers15092596 · Cited by 29
Famà, R., Bomben, R., Rasi, S., Bo, M. D., Ciardullo, C., Monti, S. M., Rossi, F. M., D’Agaro, T., Zucchetto, A., Gattei, V., et al. (2014) · Blood · doi:10.1182/blood-2014-08-592725 · Cited by 28
Bruton tyrosine kinase inhibitor ONO/GS-4059: from bench to bedside
Wu, J., Zhang, M., & Liu, D. (2016) · Oncotarget · doi:10.18632/oncotarget.12786 · Cited by 28
Treating EGFR mutation resistance in non-small cell lung cancer – role of osimertinib
Mazza, V., & Cappuzzo, F. (2017) · The Application of Clinical Genetics · doi:10.2147/tacg.s103471 · Cited by 28
Zhang, C., Pei, H., He, J., Zhu, J., Li, W., Niu, T., Xiang, M., & Chen, L. (2019) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2019.02.077 · Cited by 30
Bruscaggin, A., di Bergamo, L. T., Spina, V., Hodkinson, B. P., Forestieri, G., Bonfiglio, F., Condoluci, A., Wu, W., Pirosa, M. C., Faderl, M., et al. (2021) · Blood Advances · doi:10.1182/bloodadvances.2021004528 · Cited by 28
Jebaraj, B. M. C., Müller, A., Dheenadayalan, R. P., Endres, S., Roessner, P. M., Seyfried, F., Walliser, C., Wist, M., Qi, J., Tausch, E., et al. (2021) · Blood · doi:10.1182/blood.2021011516 · Cited by 28
Self-citationRecent development of BTK-based dual inhibitors in the treatment of cancers
Ran, F., Liu, Y., Xu, Z., Meng, C., Yang, D., Qian, J., Deng, X., Zhang, Y., & Ling, Y. (2022) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2022.114232 · Cited by 31
Amengual, J. E., Prabhu, S. A., Lombardo, M., Zullo, K. M., Johannet, P. M., Gonzalez, Y., Scotto, L., Serrano, X. O. J., Wei, Y., Duong, J., et al. (2016) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-16-2022 · Cited by 28
Phospholipase Cγ2 regulates endocannabinoid and eicosanoid networks in innate immune cells
Jing, H., Reed, A., Ulanovskaya, O. A., Grigoleit, J.-S., Herbst, D. M., Henry, C. L., Li, H., Barbas, S., Germain, J., Masuda, K., et al. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2112971118 · Cited by 24
Roeker, L. E., Woyach, J. A., Cheah, C. Y., Coombs, C. C., Shah, N. N., Wierda, W. G., Patel, M. R., Lamanna, N., Tsai, D. E., Nair, B. C., et al. (2024) · Blood · doi:10.1182/blood.2024024510 · Cited by 30
Self-citationBruton's tyrosine kinase inhibitors in B‐cell non‐Hodgkin's lymphomas
Alinari, L., Quinion, C. D., & Blum, K. (2015) · Clinical Pharmacology & Therapeutics · doi:10.1002/cpt.65 · Cited by 28
Self-citationThe genomic landscape of chronic lymphocytic leukaemia: biological and clinical implications
Strefford, J. C. (2014) · British Journal of Haematology · doi:10.1111/bjh.13254 · Cited by 27
Österborg, A., Udvardy, M., Zaritskey, A. Y., Andersson, P., Grosicki, S., Mazur, G. J., Kaplan, P., Steurer, M., Schuh, A., Montillo, M., et al. (2016) · Leukemia & lymphoma/Leukemia and lymphoma · doi:10.3109/10428194.2015.1122783 · Cited by 27
Inhibition of the Bruton Tyrosine Kinase Pathway in B-Cell Lymphoproliferative Disorders
Castillo, J. J., Treon, S. P., & Davids, M. S. (2016) · The Cancer Journal · doi:10.1097/ppo.0000000000000170 · Cited by 30
Engaging Cytotoxic T and NK Cells for Immunotherapy in Chronic Lymphocytic Leukemia
Hofland, T., Eldering, E., Kater, A. P., & Tonino, S. H. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20174315 · Cited by 27
Thompson, E. R., Nguyen, T., Kankanige, Y., Markham, J. F., Anderson, M. A., Handunnetti, S. M., Thijssen, R., Yeh, P. S.-H., Tam, C. S. L., Seymour, J. F., et al. (2021) · Blood Advances · doi:10.1182/bloodadvances.2021006211 · Cited by 28
Ibrutinib-A double-edge sword in cancer and autoimmune disorders
Kokhaei, P., Jadidi‐Niaragh, F., Jahromi, A. S., Österborg, A., Mellstedt, H., & Hojjat‐Farsangi, M. (2015) · Journal of drug targeting · doi:10.3109/1061186x.2015.1086357 · Cited by 27
Type I Cytokines Synergize with Oncogene Inhibition to Induce Tumor Growth Arrest
Acquavella, N., Clever, D. C., Yu, Z., Parker, M. R., Palmer, D. C., Xi, L., Pflicke, H., Ji, Y., Gros, A., Hanada, K., et al. (2014) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-14-0122 · Cited by 27
Phosphodiesterase 4 inhibitors have wide-ranging activity in B-cell malignancies
Cooney, J. D., & Aguiar, R. C. T. (2016) · Blood · doi:10.1182/blood-2016-09-737676 · Cited by 29
Tavakoli, G. M., Yazdanpanah, N., & Rezaei, N. (2024) · Revista Brasileira de Reumatologia · doi:10.1186/s42358-024-00401-y · Cited by 33
Tam, C. S. L., Balendran, S., & Blombery, P. A. (2025) · Blood · doi:10.1182/blood.2024026672 · Cited by 29
Blombery, P. A., Chatzikonstantinou, T., Gerousi, M., Rosenquist, R., Gaïdano, G., Pospíšilová, Š., Roberts, A. W., Birkinshaw, R. W., Rossi, D., Scarfò, L., et al. (2025) · Leukemia · doi:10.1038/s41375-025-02662-y · Cited by 30
Self-citationMorabito, F., Gentile, M., Seymour, J. F., & Polliack, A. (2015) · Leukemia & lymphoma/Leukemia and lymphoma · doi:10.3109/10428194.2015.1061193 · Cited by 27
Ibrutinib in Chronic Lymphocytic Leukemia
Reddy, N. M., & Sethi, T. K. (2015) · International Journal of Hematologic Oncology · doi:10.2217/ijh.15.15 · Cited by 26
Advances in the treatment of relapsed/refractory chronic lymphocytic leukemia
Shustik, C., Bence‐Bruckler, I., Delage, R., Owen, C., Toze, C. L., & Coutre, S. E. (2017) · Annals of Hematology · doi:10.1007/s00277-017-2982-1 · Cited by 28
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Chen, Y., & Jin, J. (2020) · Acta Biochimica et Biophysica Sinica · doi:10.1093/abbs/gmaa053 · Cited by 29
Cuesta‐Mateos, C., Brown, J. R., Terrón, F., & Muñoz‐Calleja, C. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.662866 · Cited by 28
Vollbrecht, C., Mairinger, F. D., Koitzsch, U., Peifer, M., Koenig, K., Heukamp, L. C., Crispatzu, G., Wilden, L., Kreuzer, K., Hallek, M. J., et al. (2015) · PLoS ONE · doi:10.1371/journal.pone.0129544 · Cited by 29
Flinn, I. W., Panayiotidis, P. G., Afanasyev, B. V., Janssens, A. M., Grosicki, S., Homenda, W., Smolej, L., Kuliczkowski, K., Doubek, M., Domnikova, N. P., et al. (2016) · American Journal of Hematology · doi:10.1002/ajh.24430 · Cited by 25
Role of Specific B-Cell Receptor Antigens in Lymphomagenesis
Thurner, L., Hartmann, S., Neumann, F., Hoth, M., Stilgenbauer, S., Küppers, R., Preuss, K., & Bewarder, M. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2020.604685 · Cited by 26
Self-citationDose Finding Study of Ibrutinib and Venetoclax in Relapsed or Refractory Mantle Cell Lymphoma
Portell, C. A., Wages, N. A., Kahl, B. S., Budde, L. E., Chen, R. W., Cohen, J. B., Varhegyi, N., Petroni, G. R., & Williams, M. E. (2021) · Blood Advances · doi:10.1182/bloodadvances.2021005357 · Cited by 25
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Bühler, M. M., Martín-Subero, J. I., Pan‐Hammarström, Q., Campo, E., & Rosenquist, R. (2021) · Journal of Internal Medicine · doi:10.1111/joim.13423 · Cited by 28
Aronson, J. H., Skånland, S. S., Roeker, L. E., Thompson, M. C., & Mato, A. R. (2022) · American Journal of Hematology · doi:10.1002/ajh.26682 · Cited by 27
NF-κB Mutations in Germinal Center B-Cell Lymphomas: Relation to NF-κB Function in Normal B Cells
Pasqualucci, L., & Klein, U. (2022) · Biomedicines · doi:10.3390/biomedicines10102450 · Cited by 26
SF3B1 Mutations in Hematological Malignancies
Cilloni, D., Itri, F., Bonuomo, V., & Petiti, J. (2022) · Cancers · doi:10.3390/cancers14194927 · Cited by 26
Acquired BTK mutations associated with resistance to noncovalent BTK inhibitors
Qi, J., Endres, S., Yosifov, D. Y., Tausch, E., Dheenadayalan, R. P., Gao, X., Müller, A., Schneider, C., Mertens, D., Gierschik, P., et al. (2023) · Blood Advances · doi:10.1182/bloodadvances.2022008955 · Cited by 28
Self-citationSchmid, V., & Hobeika, E. (2024) · Frontiers in Oncology · doi:10.3389/fonc.2024.1339620 · Cited by 27
Pandey, M. K., Gowda, K., Sung, S., Abraham, T., Budak-Alpdoǧan, T., Talamo, G., Dovat, S., & Amin, S. (2017) · Experimental Hematology · doi:10.1016/j.exphem.2017.06.003 · Cited by 26
Metabolic Detection of Bruton's Tyrosine Kinase Inhibition in Mantle Cell Lymphoma Cells
Lee, S., Shestov, A. A., Guo, L., Zhang, Q., Roman, J. C., Liu, X., Wang, H. Y., Pickup, S., Nath, K., Lu, P., et al. (2019) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-18-0256 · Cited by 26
Secondary Resistant Mutations to Small Molecule Inhibitors in Cancer Cells
Hamid, A. B., & Petreaca, R. C. (2020) · Cancers · doi:10.3390/cancers12040927 · Cited by 29
Koenig, K. L., Huang, Y., Dotson, E. K., Sheredy, S., Bhat, S. A., Byrd, J. C., Desmond, E., Ford, J., Iarocci, S., Jones, J. A., et al. (2020) · Blood Advances · doi:10.1182/bloodadvances.2020002593 · Cited by 24
Self-citationDesign of next-generation covalent inhibitors: Targeting residues beyond cysteine
Jones, L. H. (2020) · Annual reports in medicinal chemistry · doi:10.1016/bs.armc.2020.10.001 · Cited by 28
Siglec-6 is a target for chimeric antigen receptor T-cell treatment of chronic lymphocytic leukemia
Kovalovsky, D., Yoon, J. H., Cyr, M. G., Simon, S., Voynova, E., Rader, C. M., Wiestner, A. U., Alejo, J. C., Pittaluga, S., & Gress, R. E. (2021) · Leukemia · doi:10.1038/s41375-021-01188-3 · Cited by 24
How I treat chronic lymphocytic leukemia after venetoclax
Lew, T. E., Tam, C. S. L., & Seymour, J. F. (2021) · Blood · doi:10.1182/blood.2020008502 · Cited by 26
Kawahata, W., Asami, T., Kiyoi, T., Irie, T., Kashimoto, S., Furuichi, H., & Sawa, M. (2021) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.1c01279 · Cited by 27
BTK kinase activity is dispensable for the survival of diffuse large B-cell lymphoma
Yuan, H., Zhu, Y., Cheng, Y., Hou, J., Jin, F., Li, M., Jia, W. Q., Cheng, Z., Xing, H., Liu, M., et al. (2022) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2022.102555 · Cited by 24
Treatment Refractoriness in Chronic Lymphocytic Leukemia: Old and New Molecular Biomarkers
Maher, N., Mouhssine, S., Matti, B. F., Alwan, A., & Gaïdano, G. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241210374 · Cited by 26
Rule, S. A., & Tucker, D. L. (2015) · Therapeutics and Clinical Risk Management · doi:10.2147/tcrm.s73559 · Cited by 24
UGT2B17 modifies drug response in chronic lymphocytic leukaemia
Allain, E. P., Rouleau, M., Vanura, K., Tremblay, S., Vaillancourt, J., Bat, V., Caron, P., Villeneuve, L., Labriet, A., Turcotte, V., et al. (2020) · British Journal of Cancer · doi:10.1038/s41416-020-0887-6 · Cited by 24
Woyach, J. A., Qiu, L., Grosicki, S., et al. (2025) · Journal of Clinical Oncology · doi:10.1200/jco-25-02477 · Cited by 23
Self-citationPietryga, I. F., Maciejewski, H., Ostrowska, K., et al. (2016) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2016.03.021 · Cited by 23
Cavallari, M., Cavazzini, F., Bardi, A., Volta, E., Melandri, A., Tammiso, E., Saccenti, E., Lista, E., Quaglia, F. M., Urso, A., et al. (2018) · Oncotarget · doi:10.18632/oncotarget.26146 · Cited by 25
Guo, X., Yang, D., Fan, Z., Zhang, N., Zhao, B., Huang, C., Wang, F., Ma, R., Meng, M., & Deng, Y. (2019) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2019.06.035 · Cited by 24
The Role of BTK Inhibition in the Treatment of Chronic Lymphocytic Leukemia: A Clinical View
Tambaro, F. P., Novellis, D. D., & Wierda, W. G. (2021) · Journal of Experimental Pharmacology · doi:10.2147/jep.s265284 · Cited by 23
Das, D., Wang, J., & Hong, J. (2022) · Current Topics in Medicinal Chemistry · doi:10.2174/1568026622666220801101706 · Cited by 23
Zent, C. S., & Burack, R. (2014) · Hematology · doi:10.1182/asheducation-2014.1.119 · Cited by 24
Voltan, R., Rimondi, E., Melloni, E., Rigolin, G. M., Casciano, F., Arcidiacono, M. V., Celeghini, C., Cuneo, A., Zauli, G., & Secchiero, P. (2016) · Oncotarget · doi:10.18632/oncotarget.12139 · Cited by 24
Guo, A., Lü, P., Lee, J. C., Zhen, C., Chiosis, G., & Wang, Y. L. (2017) · Oncogene · doi:10.1038/onc.2016.494 · Cited by 25
Cosialls, A. M., Pomares, H., Iglesias‐Serret, D., Saura‐Esteller, J., Núñez‐Vázquez, S., González‐Gironès, D. M., de la Banda, E., Preciado, S., Alberício, F., Lavilla, R., et al. (2017) · Haematologica · doi:10.3324/haematol.2016.162958 · Cited by 24
Lukas, M., Velten, B., Sellner, L., Tomska, K., Hüellein, J., Walther, T., Wagner, L., Muley, C., Wu, B., Oleś, M., et al. (2020) · Leukemia · doi:10.1038/s41375-020-0846-5 · Cited by 25
Schaff, L. R., Nayak, L., & Grommes, C. (2024) · Leukemia & lymphoma/Leukemia and lymphoma · doi:10.1080/10428194.2024.2333985 · Cited by 24
Metadata
- Authors
- Woyach, J. A., Furman, R. R., Liu, T.-M., Ozer, H. G., Zapatka, M., Ruppert, A. S., Xue, L., Li, D. H.-H., Steggerda, S. M., Versele, M., Dave, S. S., Zhang, J., Yilmaz, A. S., Jaglowski, S. M., Blum, K. A., Lozanski, A., Lozanski, G., James, D. F., Barrientos, J. C., Lichter, P., Stilgenbauer, S., Buggy, J. J., Chang, B. Y., Johnson, A. J., & Byrd, J. C.
- Affiliations
- German Cancer Research Center (DE)
- Weill Cornell Medicine (US)
- Pharmacyclics (United States) (US)
- Janssen (Belgium) (BE)
- Duke University (US)
- The Ohio State University (US)
- Northwell Health (US)
- Universität Ulm (DE)
- ORCID
- Woyach, Jennifer A.
- Furman, Richard R.
- Zapatka, Marc
- Ruppert, Amy S.
- Li, Daniel Hsieh-Hsin
- Versele, Matthias
- Zhang, Jenny
- Yilmaz, Ayse Selen
- Jaglowski, Samantha M.
- Blum, Kristie A.
- Lozanski, Gerard
- James, Danelle F.
- Barrientos, Jacqueline C.
- Lichter, Peter
- Stilgenbauer, Stephan
- Chang, Betty Y.
- Johnson, Amy J.
- Byrd, John C.
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2014-06-12
- Volume
- 370
- Issue
- 24
- Pages
- 2286-2294
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- PMC
- PMC4144824
- OpenAlex
- W2067064694
- Cited by
- 1,275
- References
- 34
- Citations by year
- 2026: 50 · 2025: 77 · 2024: 91 · 2023: 99 · 2022: 102 · 2021: 143 · 2020: 122 · 2019: 99 · 2018: 98 · 2017: 126 · 2016: 118 · 2015: 108 · 2014: 39
- FWCI
- 58.67
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (submittedVersion)
- Funders
- National Institutes of Health (4p01ca081534-16, 5k12ca133250-17, 2p30ca014236-51)
- National Cancer Institute (P30‐CA014236, R01CA183444, P01CA095426, K12‐CA133250, P50CA140158, K23 CA178183, R01CA177292, P30CA016058, P01-CA-081534)
- Topics
- Health Sciences › Medicine › Hematology › Chronic Lymphocytic Leukemia Research
- Health Sciences › Medicine › Pathology and Forensic Medicine › Lymphoma Diagnosis and Treatment
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Keywords
- ibrutinib, Bruton's tyrosine kinase, chronic lymphocytic leukemia, drug resistance, B cell receptor signaling, irreversible kinase inhibitors, relapsed disease
- MeSH terms
- Agammaglobulinaemia Tyrosine Kinase, Adenine, Aged, Binding Sites, Humans, Middle Aged, Piperidines, Protein-Tyrosine Kinases, Pyrazoles, Pyrimidines, Receptors, Antigen, B-Cell, Recurrence, Leukemia, Lymphocytic, Chronic, B-Cell, Point Mutation, Sequence Analysis, DNA, Drug Resistance, Neoplasm, Phospholipase C gamma, Exome
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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