Serum B-Cell Maturation Antigen As a Biomarker for Chronic Lymphocytic Leukemia Treated with Ibrutinib

INTRODUCTION: Early assessment of tumor response in chronic lymphocytic leukemia (CLL) can be difficult during ibrutinib therapy due to treatment-related lymphocytosis and concern for radiation exposure that limits the frequency of computed tomography (CT). B-cell maturation antigen (BCMA), a member of the tumor necrosis factor super family receptors, is overexpressed in CLL. In another mature B-cell malignancy, multiple myeloma, elevated serum (s) BCMA has been associated with inferior therapeutic response and survival. It was previously shown that sBCMA levels are increased in CLL and correlated with time to first treatment and overall survival. To evaluate its utility as a biomarker in the context of targeted therapy, we assessed sBCMA in CLL patients during treatment with ibrutinib.

METHODS: BCMA levels were measured in the serum of 46 patients enrolled on a phase 2 study of ibrutinib for CLL (NCT01500733). The following time points were evaluated: baseline, day 2, and 1, 2, 6, 12, 24, 36, 48 months (M) after starting ibrutinib, as well as at the time of progressive disease (PD), if available. sBCMA was measured using a sandwich ELISA (R&D Systems). Lymphadenopathy was measured by the sum of the product of the diameters (SPD). Signed-rank test, rank-sum test and Spearman correlation were performed to compare sBCMA between categorical and continuous variables.

RESULTS: Baseline disease characteristics included relapsed or refractory CLL in 15 patients (33%), 17p deletion in 31 (67%), unmutated IGHV in 33 (72%), and advanced Rai stage in 32 (70%). The median age was 67 years (range 39-81) and 26 patients (57%) were male. At baseline, the median sBCMA was 145 ng/mL (range 24-376) and significantly higher among patients with 17p deletion than those without (median 179.6 versus 75.8, P = 0.033). sBCMA was not different with respect to prior treatment status, IGHV mutation, or Rai stage. A weak correlation between sBCMA and known serologic indicators of tumor burden and activity, β2-microglobulin (r = 0.36, P = 0.02) and lactate dehydrogenase (r = 0.41, P = 0.006), was also observed.

sBCMA decreased as early as day 2 (median decrease 15%, P = 0.003) and progressively decreased during the first year of ibrutinib therapy (median decrease 79%, P < 0.0001 at 12M). To assess whether early changes in sBCMA predict tumor response, we compared lymph node response at 12M between patients dichotomized by the median decrease in sBCMA at 1M. Patients with a decrease in sBCMA above the median of 65% at 1M showed a greater reduction in lymph node SPD at 12M (median reduction 84% versus 74%, P = 0.0487). However, the decrease in sBCMA at 1M was not different between patients who achieved partial remission (n = 29) and those in complete remission (n = 16) at best response per modified iwCLL criteria.

Next, we retrospectively measured sBCMA in 13 patients from whom serum was collected within 3M of PD to evaluate whether it could be used to predict PD. Baseline sBCMA was not significantly different between patients who later developed PD and those who did not. Among patients who developed PD, sBCMA reached a nadir after a median of 12M on ibrutinib therapy before gradually increasing until the time of PD (median increase 153% [interquartile range, IQR 81%-314%] from nadir). The initial increase in sBCMA was observed at a median of 8.4M (range 0-20.2) before clinical progression. In contrast, patients who remained in remission experienced lesser fluctuations in sBCMA (median increase 20% [IQR 0%-43%] from nadir). The increase in sBCMA from nadir among PD cases was significantly greater than non-PD cases (P < 0.0001).

CONCLUSION: sBCMA rapidly decreased during treatment with ibrutinib. Decrease in sBCMA was associated with reduction in lymphadenopathy, while an increase in sBCMA from nadir often preceded clinical PD. sBCMA represents a potential biomarker for monitoring response and detecting disease progression in CLL patients treated with ibrutinib.

This research was supported by the Intramural Research Program of NHLBI. Pharmacyclics, an Abbvie company provided ibrutinib and research support.