Poster Board III-259
Failure to achieve high levels of donor T-cell chimerism in the early period after RICT may be associated with eventual graft rejection, disease relapse and poor disease-free survival [Maris et al Blood 102:2021-2030 (2003); Saito et al Biol Blood Marrow Transplant 14:1148-1155 (2008)]. We hypothesized that pre-administration of reduced-dose rATG two weeks prior to stem cell transplant (SCT) would produce selective in-vivo depletion of host but not donor T-cells due to in-vivo decay of active rATG levels.
Twenty-two pts with HLA-identical sibling donors were enrolled on this study. The median age 57 yrs (24-68); F (n=10) M (n=12); NHL (n=9), MDS (n= 7), MPS (n=2), AML (n=2), HD (n=1), MM (n=1). Seven pts had a prior auto transplant. Disease status at transplant was CR (n=8), PR (n=4), HI (n=3), not in remission (n=5), untreated (n=2). CIBMTR risk stratification was high (n=12), intermediate (n=6) and low (n=4). RIC consisted of rATG 1 mg /kg d-16 & 3.5 mg/kg d-15, fludarabine 30 mg/m2/d (d-7 to -3), busulfan 130 mg/m2 IV (d -4, -3), and cylophosphamide 1.5 g/m2 d-2. Mobilized PBSC were infused on d 0. GVHD prophylaxis consisted of tacrolimus and methotrexate. All pts were admitted on d -16,-15 for rATG administration and were then discharged to receive the remaining therapy in the outpatient clinic.
Median active rATG levels at day -14, -7, and 0 were 4.4 mcg/mL (1.37-12.2), 1.35 mcg/mL (0.2-2.6), and 0.5 mcg/mL (0-3.2). Fifteen evaluable pts (83%) had a sub therapeutic active ATG level (<1 mcg/mL) on day 0. Of evaluable pts, the median (range) peripheral blood CD 3+ cell chimerism on day 15, 30, 60, 90 & 360 was 93% (75-100%), 95% (75-100%), 100% (87-100%), 100 (88-100%) and 100% (93-100%) respectively. Median CD 33+ cell chimerism was consistently > 95% (range 90-100%) at all time points. Readmission prior to d 100 occurred in 17 pts and was most commonly due to febrile neutropenia (n=7), GI toxicity (n=6) and acute GVHD (n=4). The median length of hospitalization was 5 days (range 1-34 days). Post transplant infections included CMV reactivation (n=5), Adenovirus (n=1), BK virus (n=3), Parainfluenza (n=1), HSV oral (n=1), Candida Parapsilosis (n=1), C.Difficile (n=3), Pseudomonas (n=4) Giardia (n=1), MRSE (n=17), MRSA (n=1) Gram positive organisms (other; n=9) and other bacteria (n=5). Estimated cumulative incidence of treatment related mortality (TRM) at d 100 and 1 year was 0% and 17.9%.The maximum cumulative incidence of aGVHD grade II-III and grade III-IV was 44% and 5% respectively. Chronic GVHD (all stages) developed in 70% of evaluable patients but was extensive severe for only 8%. One patient developed steroid refractory GVHD. Estimated probability of 2 year overall survival & progression-free survival are 59.9% and 39.8%. Cause of death included progression of malignancy (n=2), chronic GVHD (n=1), bacterial infection (n=1), pulmonary failure (n=1).
Pre-administration of rATG (on d-16 and -15) with this RIC regimen results in sub-therapeutic serum active rATG levels on d 0 in the majority of patients thus avoiding significant in-vivo donor T-cell depletion. It produces high levels of early and sustained donor T-cell chimerism without an apparent increase in TRM or GVHD.
Off Label Use: Anti-thymocyte globulin off label use for stem cell transplant. Bashey:Genzyme: Research Funding.
Asterisk with author names denotes non-ASH members.