Donor HLA-specific Abs: to BMT or not to BMT?

Abstract

The engraftment failure associated with Abs to donor-specific HLA (DSA) limits options for sensitized BMT candidates. Fourteen of fifteen patients with no other viable donor options were desensitized and transplanted using a regimen of plasmapheresis and low-dose i.v. Ig modified to accommodate pre-BMT conditioning. DSA levels were assessed by solid-phase immunoassays and cell-based crossmatch tests. DSA levels were monitored throughout desensitization and on day -1 to determine if there was any DSA rebound that would require additional treatment. A mean reduction in DSA level of 64.4% was achieved at the end of desensitization, with a subsequent reduction of 85.5% after transplantation. DSA in 11 patients was reduced to levels considered negative post-BMT, whereas DSA in three patients remained at low levels. All 14 patients achieved donor engraftment by day +60; however, seven patients suffered disease relapses. Four patients experienced mild, grade 1 GVHD. Factors influencing the response to desensitization include initial DSA strength, number, specificity, DSA rebound and a mismatch repeated from a prior transplant. While desensitization should be reserved for patients with limited donor options, careful DSA assessment and monitoring can facilitate successful engraftment after BMT.

Figure 1

The desensitization course for patient no. 9 who had DSA to HLA-DR4 and -DR53. Arrows indicate the timing and number of PP/IVIG treatments. The course of the strongest DSA to HLA-DR4 is given as a ratio of the MFI values normalized to the positive control to account for the day-to-day variation in the solid-phase immunoassays.

Figure 2

The desensitization course for patient no. 13 who had DSA to HLA-A26 and -DP2. The trend of the DSA to HLA-A26 is illustrated by the solid line and the DSA to HLA-DP2 is shown as a dashed line. The DSA values are given as ratios of the MFI values normalized to their respective positive controls. The solid arrows indicate the timing and number of PP/IVIG treatments and the dashed arrow indicates when the patient experienced a neutropenic fever.

Figure 3

Evaluation of BMT candidates for desensitization. The algorithm is illustrated for donor selection and evaluation of relative DSA levels for possible desensitization. For patients lacking an HLA fully matched donor, partially mismatched haploidentical, unrelated registry donors or umbilical cord blood units become options. Whether desensitization is considered is based on the DSA level. Moderate levels of DSA to HLA class I Ags can range from borderline FCXM positive to low-titer CDC XM positive. Lower thresholds are used for DSA to HLA class II Ags, generally no more than FCXM positive. Low levels of DSA are below a positive FCXM. CDC = complement-dependent cytotoxicity; DSA = donor HLA-specific antibody; TX = transplant.