Allogeneic Stem Cell Transplantation (SCT) Using Rabbit-ATG (Thymoglobulin®) and Low Dose Total Body Irradiation (TBI): Favorable Outcomes with Unrelated Donors (URD).

Non-myeloablative allogeneic SCT is associated with acute GVHD rates similar to conventional allografting which adversely impacts the survival of elderly patients typically receiving this therapy. In an attempt to modify the incidence of GVHD, we have developed conditioning regimens combining Thymoglobulin (THY) with low dose TBI in patients with hematologic malignancies. We report outcomes of two patient cohorts transplanted using either THY 2.5 mg/kg/day (day −4 to −1) with 2-Gy TBI on day 0 in cohort 1 (n=16) or THY 2.5 mg/kg/day (day−10 to −7) with 4.5-Gy TBI (day -1 to 0; 1.5 Gy fractions) in cohort 2 (n=7). This later modification was instituted because of early relapse and/or graft rejection seen in some patients in cohort 1. The patients received SCT from either matched sibling (MSD; n=14, all GCSF mobilized) or URD (n=9, marrow in 6). GVHD prophylaxis consisted of tacrolimus + methotrexate (day 1,3 & 6) in cohort 1 and tacrolimus + mycophenolate mofetil (day 0–30) in cohort 2. There were 8 female patients; median age was 57 years (range 70–43). Diseases treated were MM (9), NHL (6), CLL/SLL (3), AML (2) and other (3). A median of 3 (range 1–5) prior therapies had been given; 12 (52%) patients had failed a prior autograft. Disease status at transplant was, CR (4), Persistent disease (13) untreated relapse (6). No treatment-related grade IV or V toxicities were seen. Combined overall day-100 survival in the two cohorts is 87% (95% confidence interval 72–100%); and 1-year survival is 81% (95% CI 62–100%) in cohort 1. With a median follow-up of 32 months (range 44–13 mo) in cohort 1 and 6 mo (9–2 mo) in cohort 2, 16/23 (70%) patients are alive (6 died of progression and one of infection; 5 deaths were seen in cohort 1). 15/16 (93%) surviving patients are without disease progression (10 in CR). 11/23 (48%) are event-free (DLI, relapse or death), 8 of these were transplanted with URD. Only 3/23 patients (all receiving URD-PBSCT) developed steroid responsive GII–III AGVHD. Chronic GVHD developed in 7 patients undergoing URD-SCT. Graft rejection was seen in cohort 1 (3; all with disease relapse) but not in cohort 2. Hematopoietic chimerism as measured by PCR for STR loci in blood at day 30 was 95% (range 53–100) donor derived in all patients; 95% (68–100) at day 60, 95% (25–100) at day 90 and 95% around day 180 (1–100). The surviving patients are >90% donor chimeric in blood (8 URD, 7 MSD). WBC subset chimerism analysis at 30, 60 and 90 days showed similar neutrophil (96, 94, 96 vs. 96, 95, 98 %; P= 0.40) but superior T cell (96, 100, 99 vs. 85, 86, 71; P= 0.018) engraftment in cohort 2 when compared with cohort 1. There was rapid normalization of NK cell (CD3−, 56+) counts in patients with URD BMT compared with T cells (CD3+, 56−); median 46/μ L & 140 vs. 20 & 240 at 4 and 8 weeks. Ten patients (all MSD; 9 in cohort 1) received DLI, for mixed chimerism (4) or persistent disease (6). Six patients had increased donor chimerism following DLI, however only 4 developed GVHD requiring therapy. In conclusion, selected patients conditioned with reduced intensity TBI in combination with THY achieve rapid and sustained engraftment with minimal acute GVHD, especially when an URD is used.