The Impact of Body Mass Index (BMI) in Patients with Aplastic Anemia Receiving Weight-Adjusted Horse Anti-Thymocyte Globulin (hATG) on Outcome, Response and Relapse Rate

Introduction: Immunosuppressive therapy (IST) with anti-thymocyte globulin (ATG), cyclosporine A (CsA), and Eltrombopag (Epag) is the standard of care for adult patients (pts) with aplastic anemia (AA) who are ≥ 40-50 years of age and those ineligible for allogeneic transplantation. Horse ATG (hATG) is administered for 4 days at a dosage of 40 mg/kg/day based on the patient's current body weight (BW). Thus, obese pts, defined by a body mass index (BMI) ≥ 30, receive much higher absolute hATG dosages than do non-obese pts (BMI < 30). To date, it is unknown whether the administration of higher hATG dosages in obese pts has beneficial or adverse effects in AA treatment. To address the impact of obesity on the outcome of AA, we analyzed the overall survival (OS), response, and relapse rates of obese and non-obese AA pts in (1) a retrospective registry cohort (RC) and (2) an independent prospective clinical trial cohort (CTC).

Methods: The retrospective cohort (RC) was from the German Registry for AA and Bone Marrow Failure Syndromes and consisted of 78 AA pts (44 SAA, 17 VSAA, 17 AA NOS; both 39 male and female, resp.) with a median age of 55 (range 17-76) years treated with hATG/CsA (50 pts) or hATG/CsA/ Epag (28 pts). The prospective clinical trial cohort (CTC) was provided by the National Institutes of Health (NIH) and consisted of 143 AA pts (66 male, 77 female) with a median age of 40 (range 18-82) years, all treated with hATG/CsA/Epag (NCT 01623167). BMI was distributed as follows: RC: median BMI of 25.3 (range: 18.2-40.8), BMI < 30: 64/78 (82%) vs. BMI ≥ 30: 14/78 (18%); CTC: median BMI of 25.6 (range: 16.1-56.5), BMI < 30: 109/143 (76%) vs. BMI ≥ 30: 34/143 (24%).

Results: In both cohorts, pts received 40 mg/kg/day of hATG adjusted to their current BW. In relation to the idealized BW (IBW), the median applied hATG dosage for non-obese pts (BMI < 30) was 43.8 mg/kg IBW (range: 31.1-57.6) in the RC and 44.3 mg/kg IBW (range: 15.2-68.1) in the CTC, while obese pts (BMI ≥ 30) received 64.8 mg/kg IBW (range: 46.3-79.3) in the RC and 61.5 mg/kg IBW (range: 54.7-111.3) in the CTC. Regarding 4-year OS, no significant difference was observed between obese and non-obese pts in either cohort (BMI ≥ 30 vs. < 30: 84% vs. 81% in RC and 93% vs. 92% in CTC, all p-values >0.6). Hematological response after 6 months (partial or complete) in obese pts was achieved in 71% (10/14 pts) in the RC and in 79% (27/34 pts) in the CTC. Non-obese pts responded in 66% (42/64 pts) in the RC and in 94% (102/109) in the CTC. Among responders in the RC, a significantly lower relapse rate was observed in obese compared to non-obese pts after 4 years of follow-up (0% vs. 68%, p=0.029). In the CTC, the relapse rate after 4 years tended to be slightly lower in obese compared to non-obese pts (40% vs. 53%, p=0.126). To further analyze the impact of BMI and hATG dosage on relapse, we combined the data from the CTC and RC. In the pooled analysis, pts with BMI < 25 showed relapse rates of 38% and 51% after 2 and 4 years, while pts with BMI 25-30 showed relapse rates of 47% and 59%, respectively. In contrast, pts with BMI ≥ 30 showed significantly lower relapse rates with 15% and 35% after 2 and 4 years of follow-up compared to both subgroups (BMI < 25, p=0.036; BMI 25-30, p=0.012) as well as compared to all pts with BMI < 30 (p=0.015).

Conclusion: Pts with BMI ≥ 30 received a 1.5-fold higher median hATG dose relative to the idealized BW compared to pts with BMI < 30. Overall survival in obese and non-obese pts was comparable in the independent retrospective and prospective cohorts. However, a higher total hATG dose may have had a beneficial impact on relapse rates in obese compared to non-obese patients.