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Cited by 23Chronic Lymphocytic Leukemia ResearchLymphoma Diagnosis and TreatmentAcute Lymphoblastic Leukemia research

CD49d Expression Identifies a Biologically Distinct Subtype of Chronic Lymphocytic Leukemia with Inferior Progression-Free Survival on BTK Inhibitor Therapy

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Alsadhan, Anfal, Chen, Jonathan, Gaglione, Erika M., Underbayev, Chingiz, Tuma, Pamela L., Tian, Xin, Freeman, Lita A., Baskar, Sivasubramanian +9 more·2023·Clinical Cancer Research
DOI 10.1158/1078-0432.ccr-22-3217PMC PMC10524232

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Abstract

Purpose: To determine the role of CD49d for response to Bruton's tyrosine kinase inhibitors (BTKi) in patients with chronic lymphocytic leukemia (CLL). Patients and Methods: In patients treated with acalabrutinib (n = 48), CD49d expression, VLA-4 integrin activation, and tumor transcriptomes of CLL cells were assessed. Clinical responses to BTKis were investigated in acalabrutinib- (n = 48; NCT02337829) and ibrutinib-treated (n = 73; NCT01500733) patients. Results: In patients treated with acalabrutinib, treatment-induced lymphocytosis was comparable for both subgroups but resolved more rapidly for CD49d+ cases. Acalabrutinib inhibited constitutive VLA-4 activation but was insufficient to block BCR and CXCR4–mediated inside–out activation. Transcriptomes of CD49d+ and CD49d− cases were compared using RNA sequencing at baseline and at 1 and 6 months on treatment. Gene set enrichment analysis revealed increased constitutive NF-κB and JAK–STAT signaling, enhanced survival, adhesion, and migratory capacity in CD49d+ over CD49d− CLL that was maintained during therapy. In the combined cohorts of 121 BTKi-treated patients, 48 (39.7%) progressed on treatment with BTK and/or PLCG2 mutations detected in 87% of CLL progressions. Consistent with a recent report, homogeneous and bimodal CD49d-positive cases (the latter having concurrent CD49d+ and CD49d− CLL subpopulations, irrespective of the traditional 30% cutoff value) had a shorter time to progression of 6.6 years, whereas 90% of cases homogenously CD49d− were estimated progression-free at 8 years (P = 0.0004). Conclusions: CD49d/VLA-4 emerges as a microenvironmental factor that contributes to BTKi resistance in CLL. The prognostic value of CD49d is improved by considering bimodal CD49d expression. See related commentary by Tissino et al., p. 3560

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  • Positive or bimodal CD49d expression portends inferior PFS compared to cases entirely negative for CD49d.

    “Positive or bimodal CD49d expression portends inferior PFS compared to cases entirely negative for CD49d(49, 52).”

    From Resistance Mechanisms and Approach to Chronic Lymphocytic Leukemia after BTK Inhibitor Therapy (2025) · cites this paper as [49]

    The Results section reports shorter time to progression for positive or bimodal CD49d cases than for uniformly negative cases in patients receiving BTK inhibitors. The claim omits that treatment setting and calls the measured outcome PFS rather than time to progression, so it is broader than the paper’s direct finding. No page number is available in our copy. (LLM, conf=0.84)

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  • 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).”

    From Resistance Mechanisms and Approach to Chronic Lymphocytic Leukemia after BTK Inhibitor Therapy (2025) · cites this paper as [49]

    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

  • 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).”

    From Resistance Mechanisms and Approach to Chronic Lymphocytic Leukemia after BTK Inhibitor Therapy (2025) · cites this paper as [49]

  • CD49d is a strong prognostic factor in patients with CLL treated with ibrutinib or acalabrutinib.

    “CD49d is a strong prognostic factor in patients with CLL treated with ibrutinib or acalabrutinib(49).”

    From Resistance Mechanisms and Approach to Chronic Lymphocytic Leukemia after BTK Inhibitor Therapy (2025) · cites this paper as [49]

  • Bimodal CD49d expression correlates with shorter PFS in ibrutinib and acalabrutinib-treated patients.

    “Moreover, bimodal CD49d expression correlates with shorter PFS in ibrutinib and acalabrutinib-treated patients(49).”

    From Resistance Mechanisms and Approach to Chronic Lymphocytic Leukemia after BTK Inhibitor Therapy (2025) · cites this paper as [49]

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Authors
Alsadhan, A., Chen, J., Gaglione, E. M., Underbayev, C., Tuma, P. L., Tian, X., Freeman, L. A., Baskar, S., Nierman, P., Soto, S., Itsara, A., Ahn, I. E., Sun, C., Bibikova, E., Hartmann, T. N., Mhibik, M., & Wiestner, A.
Affiliations
  • National Institutes of Health (US)
  • Catholic University of America (US)
  • 5AstraZeneca South San Francisco, California.
  • University of Freiburg (DE)
Corresponding author
Wiestner, Adrian
ORCID
Venue
Clinical Cancer Research
Publisher
American Association for Cancer Research (AACR)
Published
2023-05-09
Volume
29
Issue
18
Pages
3612-3621
ISSN
  • 1078-0432 (ISSN-L)
  • 1557-3265
DOI
10.1158/1078-0432.ccr-22-3217
PMC
PMC10524232
OpenAlex
W4375955361
Cited by
23
References
3
Citations by year
2026: 4 · 2025: 8 · 2024: 7 · 2023: 4
FWCI
3.99
Type
journal article
Language
en
Open access
Locations
  • Clinical Cancer Research (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
NHLBI Division of Intramural Research (HL002346-15)
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
CD49d, VLA-4 integrin, chronic lymphocytic leukemia, BTK inhibitors, acalabrutinib, ibrutinib, BTK inhibitor resistance, progression-free survival, tumor microenvironment, NF-κB signaling, JAK/STAT signaling, PLCG2 mutations, tumor transcriptome, cell adhesion and migration
MeSH terms
Agammaglobulinaemia Tyrosine Kinase, Progression-Free Survival, Clinical Relevance, Benzamides, Humans, Pyrazines, Leukemia, Lymphocytic, Chronic, B-Cell, Integrin alpha4beta1, Protein Kinase Inhibitors

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