AbstractAbstract 2236Intense immunosuppression therapy (IST) using a combination of ATG and cyclosporine A (CsA) produces responses in 60–70% of patients (pts) with severe aplastic anemia (sAA). Until recently, horse ATG (hATG, ATGAM) has been the primary preparation used upfront for sAA. Relapsed or refractory pts may be treated with rabbit ATG (rATG, Thymoglobulin) a second course of IST. However, only limited efficacy data are available for rATG used as initial therapy in sAA. For both ATG preparations, recognition of the biomarkers and clinical parameters predictive of response has been a major focus of research in AA. A significant minority of patients remains refractory to IST and these patients may benefit from an early application of alternative therapeutic approaches such as bone marrow transplantation.We performed a phase II study of rATG/CsA combination (3.5 mg/kg/day × 5 days followed by CsA, dosing based on blood levels) as first line therapy for sAA. We then compared these pts to historical controls who received hATG (40 mg/kg/day × 4 days/CsA) as an initial therapy. sAA was defined according to well established criteria (cellularity <30%, with at least 2 of the following: absolute neutrophil count (ANC) <0.5 × 109/l, absolute reticulocyte count (ARC) <60 × 109/l, platelet count < 20 × 109/l. Responses (as previously defined by Rosenfeld, 2003) were assessed at 3, 6 and 12 months, as were early death rates and overall survival. Immunologic parameters that could potentially predict responses were also assessed.A total of 22 patients with sAA treated initially with rATG (770 days median f/u) were compared to 67 control pts (1165 days median follow-up) who received hATG as initial IST. There were no significant differences in most hematologic characteristics prior to IST administration: age (55 vs 49, p=.34), platelets (14K vs. 14K, p=.35), median ANC (0.60 vs. 0.60, p=.99), median ALC (1.46 vs. 1.42, p=.81), presence of PNH clone >1% (11 versus 21, p=.45) and presence of HLA-DR15 (9 vs. 21 p=1.00), median absolute reticulocyte count (0.020 vs. 0.028, p=.09). Response was similar for pts treated with rATG compared to hATG at 3, 6 and 12 months: 41% vs. 52% (p=.15), 50% vs. 59% (p=.62) and 54% vs 59% (p=.66), respectively. The number of early deaths also did not differ between the ATG preparations, with 2 (9%) for rATG and 6(9%) for hATG (p=.98). Similarly, no difference in overall survival was observed (log rank test p=0.32). Both groups also showed similar relapse rates (14% vs 16%, p=.81) in the observation interval. We then performed a retrospective analysis of patients who received a second course of different ATG preparations (i.e. rATG after hATG and hATG after rATG). 18/67 (26%) patients initially treated with hATG had second treatment with rATG and 6/22 (27%) patients who initially received rATG were retreated hATG. There was no statistically significant difference of response at 12 months between these groups at 50% vs. 56% (p=.88). As rATG and hATG had similar baseline and response characteristics, we performed a combined analysis of all 89 patients for predictor of response at 6 months. The presence of a PNH clone and a higher reticulocyte count were the only variables found to be independent prognostic factors for response (p=.004 and .009, respectively). Similarly, multivariable models (cox proportion hazards) showed that age (p=.003), ALC (p=.02), and ANC (p=.03) were found to be independent predictors for survival. At 5 years, pts with >2 poor prognostic features (i.e. higher age, lower ANC and ALC) had a 16% survival rate compared to 67% for patients with <2 poor prognostic features (p=.001). We also analyzed cytokine gene polymorphisms, particularly TGF-β codons 10/25 and IFN-γ. Our analysis did not show any significant association between a specific genotype and response or survival. Analysis of TCR V beta repertoire by flow cytometry prior to initiation of IST revealed that patients with an expanded CD4 T cell clone were more likely to respond at 3 months to ATG (12/15, 80%) than those without (19/40, 47%, p=.037) indicating that CD4 TCR V beta skewing may be a marker of immune-mediated disease. Conclusion:Our study demonstrates that rATG shows a comparable efficacy to hATG for upfront treatment as well as salvage of sAA in a relapsed and refractory setting. Disclosures:Kalaycio: Genzyme: Speakers Bureau; Genetech: Speakers Bureau; Cephalon: Speakers Bureau. Maciejewski: Genzyme: Research Funding.
Read full abstract
Jul 21, 2021
Shabaldin Na + 4
Open Access
