ArticleClinical cancer research : an official journal of the American Association for Cancer Research2023
CD49d Expression Identifies a Biologically Distinct Subtype of Chronic Lymphocytic Leukemia with Inferior Progression-Free Survival on BTK Inhibitor Therapy.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to 2 registered trials, which are not on this map. Cited by 14 papers.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
A Phase II Study of PCI-32765 for Patients With Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL) Who Need Therapy and Are Older Than 65 or Have a 17p Deletion
A Phase II Study Using ACP-196 (Acalabrutinib) in Patients With Relapsed/Refractory and Treatment-naïve Deletion 17p CLL/SLL: Pharmacodynamic Assessment of BTK Inhibition and Antitumor Response.
Who cites it
14 citing papers in PubMed, 20 citations in OpenAlex.
- Clinical Flow Cytometric Testing in Chronic Lymphocytic Leukemia.Methods in molecular biology (Clifton, N.J.) · 2027Article
- From Time-Limited Therapy to Treatment-Free Observation: The Evolving Role of MRD in CLL Management.European journal of haematology · 2026Review
- CD49d governs immune synapse formation through actin rearrangements and synchronizes BCR signaling in CLL.Blood · 2026Article
- Real-world safety and effectiveness of zanubrutinib vs ibrutinib in CLL: the CLL-ZANU2024 Italian cohort.Blood advances · 2026Article
- Mechanisms of resistance to bruton's tyrosine kinase inhibitors: synergistic effects of tumor microenvironment regulation and signaling pathways.Annals of hematology · 2026Review
- Review
- The cytoskeletal control of B cell receptor and integrin signaling in normal B cells and chronic lymphocytic leukemia.FEBS letters · 2025Review
- Resistance mechanisms and approach to chronic lymphocytic leukemia after BTK inhibitor therapy.Leukemia & lymphoma · 2025Review
- Co-expression of CD69, CD49d, CD279 and CD20 in chronic lymphocytic leukemia cells is a new biomarker of active disease before or under therapy.Haematologica · 2025Article
- The contribution of BTK signaling in myeloid cells to neuroinflammation.Frontiers in immunology · 2025Article
- Article
- CXCR4 overexpression in chronic lymphocytic leukemia associates with poorer prognosis: A prospective, single-center, observational study.Genes and immunity · 2024Observational
- Ibrutinib and the chemotactic lymph node choreography.Haematologica · 2024Article
- The Role of the Microenvironment and Cell Adhesion Molecules in Chronic Lymphocytic Leukemia.Cancers · 2023Review
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Authors and funding
17 authors at 4 institutions in 3 countries.
Funding
Abstract
purposeTo determine the role of CD49d for response to Bruton's tyrosine kinase inhibitors (BTKi) in patients with chronic lymphocytic leukemia (CLL). PATIENTS AND
methodsIn 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.
resultsIn 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).
conclusionsCD49d/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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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.