CXCR4 allelic Variations Influence Hematological Recovery Following Autologous Stem Cell Transplantation,

The ability to achieve rapid and sustained myeloid and platelet engraftment is a major determinant for outcome in patients undergoing autologous stem cell transplantation (ASCT). The CXCR4 chemokine receptor, present in hematopoietic progenitors (HPs), and its ligand, stromal cell-derived factor 1 (SDF-1) play a pivotal role in retaining HPs within the bone marrow microenvironment in the adult. Recently, the intronic single nucleotide polymorphism (SNP) rs2680880 in CXCR4 located close to a region implicated in alternative splicing that generates 2 variants, has been associated with peripheral blood progenitor cell (PBPC) mobilization success among healthy donors (Haematologica 2011; 96: 102–109). Aim. To evaluate the influence of rs2680880 polymorphism in CXCR4 on engraftment of PBPC in patients undergoing ASCT. Patients and Methods. A total of 144 ASCT patients were included (60 lymphoma, 60 multiple myeloma, 24 acute leukemia). The median dose of PBPC infused was 2.6 x10⁶ CD34+ cells/kg. Myeloid and platelet recovery after transplant were evaluated by daily CBC. The rs2680880 polymorphism was genotyped by allelic discrimination polymerase chain reaction (PCR) assays using TaqMan®Genotyping Assays (Applied Biosystems). Results. Allelic frequencies were 0.64 for A allele and 0.36 for T allele, being 13% of patient TT homozygous. Notably, when analyzing the subgroup of 136 patients that had been infused with a yield of CD34+ cells below the 95th percentile (<6.8×10⁶/kg CD34+ cells) the presence of the T variant in homocygosis was related with a significant delayed myeloid and platelet engraftment compared to AA+AT genotypes. Thus, TT homozygotes exhibited slower leukocyte recovery, (neutrophils >0.5×10⁹/L [15 vs. 12 days, p=0.022], neutrophils >1×10⁹/L [16 vs. 13 days, p=0.023). Platelet engraftment was similarly delayed (>20 × 10⁹/L and >50 × 10⁹/L [18 vs. 13 days, p=0.038; 23 vs. 17 days, p=0.016, respectively]). The T allele in heterozygosity did not have any influence on these variables. A multivariate analysis considering age, disease, low platelet/leukocyte count before mobilization, rs2680880 polymorphism in CXCR4 and number of CD34+ cells infused, showed that the best predictive factors for delayed platelet recovery were the number of infused CD34+ cells and the presence of the T variant in homozygosis. Remarkably, homozygosis for T allele in CXCR4 was found to be the main and only predictive factor for neutrophil engraftment. Discussion. Some patients exhibit delayed recoveries after ASCT despite a sufficient number of CD34+ cells administered in a clinically stable situation. We find that a homozygous common variant (rs2680880[T]) that could modulate the alternative splicing in CXCR4 to produce shorter transcripts, is a strong predictor of engraftment. A high number of CD34+ infused cells probably disguise or lessen the effect of the TT allelic variant of CXCR4 gene on PBPC homing. Because the migration of hematopoietic stem cells is a complex process that involves the CXCR4/SDF-1 axis, we speculate that this genetic marker could be associated to poorer mobilization responses to plerixafor. This is the first study, to our knowledge, to describe a genetic variable as a potential predictive factor in the hematological recovery after ASCT. Funding. This study was supported in part by a research grants 04515/GERM/06; RECAVA RD06/0014/0039, and FIS 10/02594.

No relevant conflicts of interest to declare.