Desensitization for Mismatched Hematopoietic Stem Cell Transplantation (HSCT)

Sensitization to donor HLA antigens is associated with an increased risk of engraftment failure in HLA mismatched hematopoietic stem cell transplantation (HSCT). However, the use of partially mismatched donors is increasing since, at best, only 30% of patients have an HLA identical sibling donor available for transplantation, and many are unable to find a matched unrelated donor in a timely fashion. A non-myeloablative, T cell replete regimen for HSCT that utilizes post-transplant high dose, cyclophosphamide for graft-versus-host-disease (GVHD) prophylaxis was pioneered at Johns Hopkins and has permitted transplantation of over 200 patients with HLA-haploidentical related donors. The use of HLA haplo-identical donors greatly increases the numbers of potential donors for most HSCT candidates. Review of the evaluations of 148 consecutive candidates for haplotransplantation revealed that 95% had at least one haplo-identical donor with an average of 2.7 donors/patient. However donor specific HLA antibody (DSHA) was observed in 10.8% of patients. We report here, successful desensitization of (DHSA) to levels safe for HSCT in six broadly sensitized patients who had poor-risk hematologic malignancies and for whom there were no other donors for whom HLA specific antibodies were not an issue.

The desensitization protocol was modified from that developed for renal transplant patients at the Johns Hopkins University Comprehensive Transplant Center and included alternate day, single volume plasmapheresis (PP) with low dose, 100mg/kg, anti-CMV hyper immune immunoglobulin (IVIg) under immunosuppression with tacrolimus and mycophenolate mofetil. Varying numbers of PP/IVIg treatments were scheduled prior to the non-myeloablative conditioning regimen according to each patient's DHSA level. PP/IVIg was stopped during conditioning. All but one patient received one additional PP/IVIg at transplant day −1. HLA antibodies were assessed by solid phase immunoassays using panels of pooled HLA antigens, HLA phenotypes, and single HLA antigens in microbead suspension array immunoassays (GenProbe Lifecodes Inc., San Diego, CA; One Lambda, Inc., Canoga Park, CA)

All six patients prior to desensitization had DHSA at levels sufficient to yield positive flow cytometric crossmatch (FCXM) tests defined as 12K molecules of equivalent soluble fluorochromes (MESFs). The donor specific antibodies were reduced to levels well below a positive FXCM in all six patients by the end of the PP/IVIG treatments and before transplantation through an average of 4.2 PP/IVIg treatments. The average reduction in the donor specific antibody strength was 71.5% (range: 52–91%). In three patients, the DHSA levels were reduced to negative by time of transplant. A fourth patient was transplanted with a DHSA level just below that consistent with a positive FCXM, but by three months post-transplant had completely eliminated the DHSA. Two patients received one additional post-transplant PP/IVIg, resulting in stable DSA levels well below a +FCXM. Sufficient post-transplant follow-up of more than four months was available for four patients of which 3 received grafts from haploidentical donors and 1 from an HLA-mismatched unrelated donor. All four of these fully engrafted with no acute GVHD episodes. These results demonstrate that desensitization can extend the opportunity for HSCT to sensitized patients with no other donor options.

Luznik:Otsuka Pharmaceuticals: Research Funding.