In Landmark Analysis the Severity of Day 100 Acute Graft-Versus-Host Disease (aGVHD) Has No Impact on Long-Term Progression-Free Survival (PFS) after Double-Unit Cord Blood Transplantation (DCBT)

Introduction: While DCBT has been associated with high PFS in both children & adults, rates of grade II-IV aGVHD are significant in patients transplanted with calcineurin inhibitor/ mycophenolate mofetil (CNI/MMF) immunosuppression (IS) without anti-thymocyte globulin. However, GVHD biology in DCBT recipients appears distinct from that of adult donor allografts with a high incidence of corticosteroid responsiveness & low rates of chronic GVHD. Consequently, the impact of aGVHD upon long-term PFS in DCBT may be different to that of adult donor allografts & is not established. Methods: We analyzed the time to systemic (sys.) IS cessation, transplant-related mortality (TRM), relapse, & PFS in a day 100 landmark analysis of DCBT recipients transplanted for hematologic malignancies who were engrafted & progression-free according to the incidence & severity of their aGVHD by day 100. Results: 129 day 100 progression-free DCBT survivors (median age 36 years, range 0.9-70) were evaluated. Of this cohort, 80 (62%) had grade II-IV aGVHD (55 grade II, 21 grade III, & 4 grade IV disease), & all 129 patients were on sys.IS at day 100. With a median follow-up of 4.8 years (range 1.2-9.0) in this cohort, the cumulative incidence of achieving sustained sys.IS cessation was 33% (95%CI: 25-42) at 1-year, 55% (95%CI: 45-63) at 2-years, & 61% (95%CI: 51-69) at 3-years with a median time to sys.IS cessation of 1.2 years (range 0.5-5.6) post-DCBT. Of 103 progression-free survivors at 1-year, 26 (25%) were on high, 26 (25%) on intermediate, 18 (17%) on low dose sys.IS, & 33 (32%) were on no sys.IS. The number of patients on any sys.IS decreased to 30% in evaluable progression-free survivors at 2-years, & 18% at 3-years. A total of 84/129 (65%) patients survive progression-free to date from the day 100 landmark with 24 having died of TRM (17 GVHD-related), 1 from relapsed sarcoma, & 20 have relapsed/ progressed. The 3-year incidence of TRM according to maximum day 100 aGVHD grade was 11% (95%CI: 4-22) in grade 0-I & 24% (95%CI: 15-34) in grade II-IV patients, p = 0.14. The 3-year incidence of relapse was 20% (95%CI: 10-34) in grade 0-I & 11% (95%CI: 6-20) in grade II-IV patients, p = 0.54. Overall, there was no difference in the 3-year PFS of 69% (95%CI: 56-84) in those whose day 100 aGVHD grade was 0-I when compared to the 65% (95%CI: 55-76) PFS in patients whose aGVHD grade was II-IV (Figure). Conclusions: In patients alive at day 100, most will achieve sustained cessation of sys.IS despite initial aGVHD. Moreover, while the contribution of aGVHD to TRM is significant, there was no statistical difference in overall TRM in the GVHD groups. Finally, grade 0-I versus II-IV aGVHD had no impact on long-term PFS. Thus, despite an approximate 50% incidence of grade II-IV aGVHD in DCBT recipients at our center (Ponce et al, BBMT 2013), long-term PFS is not impacted in day 100 survivors & the majority of patients are off IS after 2 years post-allograft.