Plasma B-Cell Maturation Antigen Levels Are Elevated and Correlate with Disease Activity in Patients with Chronic Lymphocytic Leukemia

Background: B-cell maturation antigen (BCMA) serves as one of the receptors for B-cell activating factor (BAFF) or a proliferation-inducing ligand (APRIL), which are members of the tumor necrosis factor (TNF) family that promote survival of B-cells, including neoplastic B cells from chronic lymphocytic leukemia (CLL) patients (pts).  We have found that BCMA is increased in plasma or serum from patients with multiple myeloma (MM).  The level of serum BCMA found among MM pts associates with clinical status and predicts overall survival (OS).  However, it is not known whether plasma (p) BCMA levels are elevated in pts with other B-cell malignancies, such as CLL.  We examined plasma from healthy adults and pts with CLL for pBCMA and associated the observed levels in CLL pts with disease characteristics and/or known prognostic markers, such as white blood cell counts (WBC), serum β2-M, CLL-cell expression of mutated (M) or unmutated (U) immunoglobulin heavy-chain variable region (IGHV) or ZAP‑70, or CLL-cytogenetic markers.  We also examined the relationship between pBCMA and time from diagnosis (DX) or sample collection (SC) to initial treatment (treatment‑free survival (TFS)) or OS.

Methods: We examined the archived, plasma samples of 171 pts with CLL that were collected upon initial presentation to UCSD for studies on factors that could associate with disease outcome.  Pts received therapy if they satisfied International Workshop on CLL (IWCLL) criteria for treatment.  We examined serial plasma samples from a subset of these pts (n = 21) collected soon after DX, prior to first treatment, after treatment, and at relapse after therapy.  We also assessed plasma samples of 76 healthy adults.  We determined the pBCMA levels using a polyclonal anti-BCMA antibody in an ELISA available from R&D Systems (Minneapolis, MN).  We used Mann-Whitney analysis to assess for associations between the relative pBCMA levels and disease characteristics assessed at the time of SC and Kaplan-Meier analysis to assess the relationship between measured pBCMA and TFS (median 4.1 years) and OS (median follow-up 7.8 years).

Results: The median level of pBCMA in pts with CLL obtained from pts that were untreated at the time of first determination of pBCMA levels, regardless of whether they subsequently received therapy (n = 166; 58.54 ng/mL), was higher than that of healthy adults (n = 76; 6.32 ng/mL, P < 0.0001).  The median pBCMA levels of samples from pts with CLL-cells that used M-IGHV (n = 87; median 42.13 ng/mL), or that lacked expression of ZAP-70 (n = 88; median 42.59 ng/mL), was lower than that of pts with CLL-cells that used U-IGHV (n = 84; 87.46 ng/mL, P < 0.0001), or that expressed ZAP-70 (n = 83; median 87.38 ng/mL, P < 0.0001).  The median pBCMA level of pts with CLL cells that had del(13q) (n = 83; 46.57 ng/mL) was lower than that of pts with CLL cells that did not have detectable del(13q) (n = 77; 73.8 ng/mL; P = 0.0002).  The median pBCMA of pts with CLL cells with del(17p) (n = 16; 77.23 ng/mL) appeared lower than that of pts without detectable del(17p) (n = 144; 51.77 ng/mL), but did not reach significance (P = 0.09).  The TFS was longer (overall median time from SC to treatment: 2.36 years) among pts with pBCMA levels in the lowest three quartiles (median 3.72 years; range of pBCMA 13.21 – 104.69 ng/mL) when compared to patients with pBCMA in the highest quartile (median 0.67 years; range of pBCMA 110.1 - 782.97 ng/mL; P < 0.0001).  Serial pBCMA levels consistently correlated with changes in clinical status among pts (n = 21) who had a pBCMA sample taken within three months of the determination of their clinical status.  CLL pts with a pBCMA in the highest quartile had a significantly shorter OS when compared to pts with pBCMA levels in the lower three quartiles (P = 0.023).

Conclusions: This is the first study to show that BCMA levels are increased in the plasma of CLL pts.  We also demonstrate that the pBCMA levels correlate with other known prognostic indicators of CLL, such as IGHV mutational status, ZAP‑70 expression and chromosomal abnormalities.  CLL pts with higher pBCMA levels have a shorter TFS and OS.  Furthermore, changes in pBCMA levels show consistent correlation with changes in the pts’ clinical status during treatment.  In summary, pBCMA appears to be a new plasma biomarker to monitor the disease course of CLL patients and determine their outcome.