Post-transplantation B cell activating factor and B cell recovery before onset of chronic graft-versus-host disease

Abstract

Excessive levels of B cell activating factor (BAFF) are found in patients with active chronic graft-versus-host disease (cGVHD). In mice, BAFF has been shown to be essential for B cell recovery after myeloablation. To assess how BAFF levels relate to transplantation factors and subsequent development of cGVHD, we prospectively monitored 412 patients in the first year after allogeneic peripheral blood or bone marrow hematopoietic stem cell transplantation (HSCT) and censored data at time of cGVHD onset. In patients who did not develop cGVHD, we affirmed a temporal pattern of gradually decreasing BAFF levels as B cell numbers increase after myeloablative conditioning. In contrast, after reduced-intensity conditioning, BAFF levels remained high throughout the first post-HSCT year, suggesting that the degree of myeloablation resulted in delayed B cell recovery associated with persistence of higher BAFF levels. Given that high BAFF/B cell ratios have been associated with active cGVHD, we examined differences in early BAFF/B cell ratios and found significantly different BAFF/B cell ratios at 3 months post-HSCT only after myeloablative conditioning in patients who subsequently developed cGVHD. In addition to HSCT conditioning type, the use of sirolimus was significantly associated with higher BAFF levels after HSCT, and this also was potentially related to lower B cell numbers. Taken together, our results are important for interpreting BAFF measurements in cGVHD biomarker studies.

Keywords: B cell; B cell activating factor; Chronic graft-versus-host disease.

Figure 1. BAFF levels and B cells recovery after allogeneicstem cell transplantation

Patients who received either myelablative (MAC) or reduced intensity conditioning (RIC) are shown separately according to subsequent cGVHD development. A) BAFF levels (squares) and B cell numbers (triangles) after MAC in patients who never developed cGVHD. B) BAFF levels (squares) and B cell numbers (triangles) after MAC in patients who developed cGVHD. C) BAFF levels (squares) and B cell numbers (triangles) after RIC in patients who never developed cGVHD. D) BAFF levels (squares) and B cell numbers (triangles) after RIC in patients who subsequently cGVHD. *Indicates differences that are statistically significant (p<0.05). Note: Blood samples after the clinical onset of cGVHD were excluded from analysis.

Figure 2. Patterns of BAFF levels, B-cells and BAFF/B-cell ratios after stem cell transplantation before cGVHD onset

Serial values during the first year after transplant for patients who received eitherMAC (three left panels, A, C, and E) or RIC (three right panels, B, D, and F) prior to HSCT. Patients who later developed cGVHD (triangles) are compared to patients who did not develop cGVHD (squares). *Indicates differences that are statistically significant (p<0.05). Median values and ranges (in parentheses) are listed for those that were significantly different after MAC are as follows: 6 months: yes cGVHD 9.79 (0.62-58.43) vs no cGVHD 5.71 (0.08-34.49) ng/mL, p=0.025; 9 months: yes cGVHD 12.3 (1.75-37.38) vs. no cGVHD 3.99 (0.83-31.82) ng/mL, p=0.004; 12 months: yes cGVHD 8.68 (2.37-22.17) vs. no cGVHD 4.3 (3.48-25.3) ng/mL, p=0.02); or after RIC are as follows: 6 months: yes cGVHD 7.09 (0-26.01] vs no cGVHD 9.92 (0-80.49) ng/mL, p=0.05). Significant differences in total B cell numbers (median values with range in parentheses) are listed as follows: 3 months after MAC: yes cGVHD 10 (0- 631.41) versus no cGVHD 37 (0-434.64) cells/uL, p=0.008; BAFF/B-cell ratios were calculatedas previously described and are depicted on a log scale. Significant difference was determined at the 3 month timepoint after MAC with median values and ranges (in parentheses) as follows: yes cGVHD 1.11 (0.05-20.07)vs No-cGVHD 0.37 (0.03-10.75), p=0.01.

Figure 3. Changes in BAFF levels and B-cell recoveryin patients receiving sirolimus for GVHD prophylaxis after stem cell transplantation

Serial median BAFF levels (left y-axis, squares) are compared to B cell numbers (right y-axis, triangles) in patients at 1, 3, 6, 9, and 12 months post-transplantation. A) Patients who received sirolimus after transplant. B) Patients who did not receive sirolimus after transplant. Note: All patients studied after HSCT, before cGVHDdevelopment, were combined in this analysis.