CoChat
Sign Up
Cited by 585Chronic Lymphocytic Leukemia ResearchLymphoma Diagnosis and TreatmentAcute Lymphoblastic Leukemia research

Etiology of ibrutinib therapy discontinuation and outcomes in patients with chronic lymphocytic leukemia

Open access
Maddocks, Kami J., Ruppert, Amy S., Lozanski, Gerard, Heerema, Nyla A., Zhao, Weiqiang, Abruzzo, Lynne, Lozanski, Arletta, Davis, Melanie +13 more·2015·JAMA Oncology
DOI 10.1001/jamaoncol.2014.218PMC PMC4520535
Open this paper in CoChat — free account

Abstract

IMPORTANCE: The Bruton tyrosine kinase (BTK) inhibitor ibrutinib is effective in patients with chronic lymphocytic leukemia (CLL). Reasons for discontinuing therapy with this drug and outcomes following discontinuation have not been evaluated outside of clinical trials with relatively short follow-up. OBJECTIVE: To determine features associated with discontinuation of ibrutinib therapy and outcomes. DESIGN, SETTING, AND PARTICIPANTS: A total of 308 patients participating in 4 sequential trials of ibrutinib at The Ohio State University Comprehensive Cancer Center were included. These clinical trials accrued patients included in this analysis from May 2010 until April 2014, and data were locked in June 2014. MAIN OUTCOMES AND MEASURES: Patients were evaluated for time to therapy discontinuation, reasons for discontinuation, and survival following discontinuation. For patients who discontinued therapy because of disease progression, targeted deep sequencing was performed in samples at baseline and time of relapse. RESULTS: With a median follow-up of 20 months, 232 patients remained on therapy, 31 had discontinued because of disease progression, and 45 had discontinued for other reasons. Disease progression includes Richter's transformation (RT) or progressive CLL. Richter's transformation appeared to occur early and CLL progressions later (cumulative incidence at 12 months, 4.5% [95% CI, 2.0%-7.0%] and 0.3% [95% CI, 0%-1.0%], respectively). Median survival following RT was 3.5 months (95% CI, 0.3-6.0 months) and 17.6 months (95% CI, 4.7 months-"not reached") following CLL progression. Sequencing on peripheral blood from 8 patients with RT revealed 2 with mutations in BTK, and a lymph node sample showed no mutations in BTK or PLCG2. Deep sequencing on 11 patients with CLL progression revealed BTK or PLCG2 mutations in all. These mutations were not identified before treatment in any patient. CONCLUSIONS AND RELEVANCE: This single-institution experience with ibrutinib confirms it to be an effective therapy and identifies, for the first time, baseline factors associated with ibrutinib therapy discontinuation. Outcomes data show poor prognosis after discontinuation, especially for those patients with RT. Finally, sequencing data confirm initial reports associating mutations in BTK and PLCG2 with progression and clearly show that CLL progressions are associated with these mutations, while RT is likely not. TRIAL REGISTRATIONS: clinicaltrials.gov Identifiers:NCT01105247, NCT01217749, NCT01589302, and NCT01578707.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1001/jamaoncol.2014.218

Cites

21 of 21 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

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?

  • 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).”

    From Resistance Mechanisms and Approach to Chronic Lymphocytic Leukemia after BTK Inhibitor Therapy (2025) · cites this paper as [27]

    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

  • Two separate studies observed no PLCγ2 or BTK mutations detected in patients with CLL before Ibrutinib treatment.

    “Interestingly, two separate studies observed that there were no PLCγ2 or BTK mutations detected in patients with CLL before Ibrutinib treatment (127, 128).”

    From The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration (2021) · cites this paper as [128]

  • The most common ibrutinib-resistant BTK mutant is C481S; other mutants include C481R, C481F, C481Y, T474I, and T474S.

    “While the most common ibrutinib-resistant BTK mutant is C481S, other mutants observed in patients include C481R, C481F, C481Y, T474I, and T474S.33”

    From Bruton tyrosine kinase degradation as a therapeutic strategy for cancer (2019) · cites this paper as [33]

Self-check

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

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Cited by

Sorted by citations

Related

Authors
Maddocks, K. J., Ruppert, A. S., Lozanski, G., Heerema, N. A., Zhao, W., Abruzzo, L., Lozanski, A., Davis, M., Gordon, A., Smith, L. L., Mantel, R., Jones, J. A., Flynn, J. M., Jaglowski, S. M., Andritsos, L. A., Awan, F., Blum, K. A., Grever, M. R., Johnson, A. J., Byrd, J. C., & Woyach, J. A.
Affiliations
The Ohio State University (US)
Corresponding author
Woyach, Jennifer A.
ORCID
Venue
JAMA Oncology
Publisher
American Medical Association (AMA)
Published
2015-04-01
Volume
1
Issue
1
Pages
80
ISSN
2374-2437 (ISSN-L)
DOI
10.1001/jamaoncol.2014.218
PMC
PMC4520535
OpenAlex
W1999128869
Cited by
584
References
21
Citations by year
2026: 13 · 2025: 29 · 2024: 35 · 2023: 38 · 2022: 47 · 2021: 59 · 2020: 65 · 2019: 72 · 2018: 60 · 2017: 85 · 2016: 64 · 2015: 16
FWCI
41.98
Type
journal article
Language
en
Open access
Locations
  • JAMA Oncology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health (4p01ca081534-16)
  • National Cancer Institute (P01CA095426, U10CA180861, P50CA140158, R01CA183444, P01CA95426, K23CA178183, R01CA177292, P01-CA-081534)
Topics
  • Health Sciences › Medicine › Genetics › Chronic Lymphocytic Leukemia Research
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Lymphoma Diagnosis and Treatment
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Acute Lymphoblastic Leukemia research
Keywords
chronic lymphocytic leukemia, BTK inhibitors, treatment discontinuation, Richter transformation, BTK mutations, PLCG2 mutations, relapse, deep sequencing, prognostic factors, sequential clinical trials, targeted therapy resistance
MeSH terms
Agammaglobulinaemia Tyrosine Kinase, Adenine, Adult, Aged, Aged, 80 and over, Clinical Trials as Topic, DNA Mutational Analysis, Female, Humans, Male, Middle Aged, Mutation, Ohio, Piperidines, Protein-Tyrosine Kinases, Pyrazoles, Pyrimidines, Recurrence, Risk Factors, Time Factors, Biomarkers, Tumor, Leukemia, Lymphocytic, Chronic, B-Cell, Treatment Outcome, Disease Progression, Protein Kinase Inhibitors, Phospholipase C gamma, Kaplan-Meier Estimate, Molecular Targeted Therapy, High-Throughput Nucleotide Sequencing

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.

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 ›

Are you an author, or do you see a problem with this page? Request a review