BIOLOGICAL FEATURES of B-CLL and RESIDUAL IMMUNITY at TREATMENT INITIATION DETERMINE IMMUNITY on BTKI THERAPY.
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All Authors
Hodges, M.
Darcy, J.
Bruton, R.
Roberts, T.
Croft, W.
Moss, P.
Pugh, M.
Lane, P.
Cook, J.
Pratt, G.
LTHT Author
Munir, Talha
Rawstron, Andy
Rawstron, Andy
LTHT Department
Oncology
Haematology
Leeds Cancer Centre
Haematological Malignancy Diagnostic Service
Haematology
Leeds Cancer Centre
Haematological Malignancy Diagnostic Service
Contributor Profession (Non Medical)
Healthcare Scientist
Publication Date
2025
Item Type
Conference Abstract
Language
Subject
Subject Headings
Abstract
Background Impaired immunity on continuous BTKi therapy is associated with substantial infection related morbidity/mortality and poor response to vaccination. The UK IMPROVE RCT (ISRCTN14197181) investigated vaccine immunity for patients taking BTKi and reported heterogeneity in patient humoral immunity. An appreciation of the biological determinants of poor immunity during covalent BTKi therapy and an improved understanding of why such variability exists amongst patients, is an important unmet need. Aims To determine the biological features of CLL and humoral immunity that influence infection risk and vaccine responsiveness during covalent BTKi therapy. Methods Using participant samples from IMPROVE, immunophenotyping of peripheral blood B cells was undertaken in vaccine responders versus non-responders to identify CLL and non-CLL B cell phenotype, followed by detection and phenotypic analysis of antigen-specific B cells amongst responders. Calcium flux and signalling pathways by CyTOF analysis following IgM stimulation, along with mRNA sequencing of detectable B cells in antibody responders versus non-responders, was next investigated. An assessment of pre-treatment bone marrow samples by immunohistochemistry and spatial transcriptomics was also performed. Finally, serial immunophenotypic analysis of peripheral blood samples from therapy initiation to >1 year on BTKi were used to corroborate findings and the association with infection admission risk assessed. Results Of 99 patients with controlled CLL, following >1 year of BTKi therapy (mean age 70.5, SD 8.8), 32 participants (32%) demonstrated no SARS-CoV-2 Ab response despite a median of 5 (IQR 5-6) SARS-COV-2 vaccine doses. No difference in antibody titre was observed between: first or subsequent therapy line, acalabrutinib or ibrutinib therapy, pausing or continuing BTKi for 3 weeks at the time of vaccination (p=0.772). Importantly, the number of non-CLL CD19+ B cells differed between responders (8.23 cells/ul (IQR 4.4-20.9)) and non-responders (3.4 cells/ul (IQR 1.4-5.2); p=0.02), with the greatest differences observed in IgM+ IgD+, CD27- naive cells (responders:1.09 (IQR 0.3-3.1) Vs non-responders: 0.01(IQR 0-0.06) cells/ ul; p<0.0001). Amongst antibody responders, B cell klickmers revealed a class switched IgG antigen-specific response and an intact calcium flux following BCR stimulation amongst non-CLL naive B cells, despite continuous covalent BTK inhibition. Detectable CLL cells were evident in both responders and non-responders and no difference in total B cell number was observed (p=0.55). Non-responders strongly associated with a C2 transcription factor profile (p adj: 3.3e-35), whilst IGHV status did not. Immunohistochemistry and spatial transcriptomics demonstrated a heterogeneous degree of marrow infiltration by CLL at therapy initiation, contributing to the variability in normal B and plasma cell numbers. Serial analysis of peripheral immunophenotyping found the presence of normal B cells pre-treatment impacts the B cell immune repertoire >1 year post therapy. Summary/Conclusion Current IWCLL criteria for treatment initiation leads to heterogeneity in patient immunity, with heavy marrow infiltration associated with the poor prognostic C2 transcriptional profile of CLL and impaired immunity. The depletion of naive and memory B cells in pre-treatment work up, provides a tool for identifying those at risk of poor antigen-specific Ab responses during long term BTKi and where antimicrobial prophylaxis may be beneficial.
Journal
HemaSphere