Amanda Goh^1,2, Josephine Campbell,^3,4 Christina MacMillan,³ Jodie Fitness,³ Ryan Droney,¹ Polly Higgins¹

¹QML Pathology
²Faculty of Medicine, The University of Queensland
³Genomic Diagnostics
⁴School of Health and Medical Sciences, University of Southern Queensland

This is a case report of a 69 year old male who presented with asymptomatic lymphocytosis (15.5x10^9/L) and a serum IgG kappa paraprotein (20g/L). 

Bone marrow examination revealed a hypercellular marrow with preserved trilineage haematopoiesis and marked lymphocytosis (63%) of small, mature lymphocytes. A heavy lymphoid infiltrate, nodular and interstitial in distribution, was described. Together with flow cytometry findings of a CD5+ monoclonal B cell population (CD19+,CD20+weak,CD23+,CD43+,CD200+,FMC7-,CD79b-), these findings were classic for Chronic Lymphocytic Leukaemia (CLL). No clonal nor aberrant plasma cell population was demonstrated. 

Molecular karyotyping detected a deletion in chromosome 13q, which is associated with lower risk disease.¹ No copy number changes in MYB, ATM or TP53 were found. 

Interestingly, lymphoid NGS identified a single, unexpected variant in the CXCR4 gene p.(Thr342Argfs*3) at a VAF of 12.2%. According to WHO 5th edition, CXCR4 mutations are unique to lymphoplasmacytic lymphoma (LPL), with only rare reports in marginal zone lymphoma and DLBCL.² They have not been reported in CLL.

CXCR4 facilitates the migration and survival of CLL cells. Although the significance of this truncating variant is not yet established, CXCR4 overexpression in CLL correlates with a poorer prognosis based on RNASeq studies,³ and a resistance to ibrutinib therapy in LPL.²

The submission of this work was the original idea of Dr Amanda Goh and Dr Polly Higgins. The primary work, abstract and poster was created by Dr Amanda Goh with the assistance of Josephine Campbell and contributions from Christina MacMillan, Jodie Fitness and Dr Ryan Droney.

References:

^1. Chun K, Wenger GD, Chaubey A, Dash DP, Kanagal-Shamanna R, Kantarci S, Kolhe R, Van Dyke DL, Wang L, Wolff DJ, Miron PM. Assessing copy number aberrations and copy-neutral loss-of-heterozygosity across the genome as best practice: An evidence-based review

^2. World Health Organization. (2024). WHO classification of tumours: Haematolymphoid tumours. 5th edition.

^3. Xue X, Wen Z, Zhang X, Yang Y, Li Y, Liao R, Zheng Q, Fu Y, Liu Y, Liao H. CXCR4 overexpression in chronic lymphocytic leukemia associates with poorer prognosis: A prospective, single-center, observational study. Genes Immun. 2024 Apr;25(2):117-123.