Late Mortality Following Allogeneic Stem Cell Transplantation Is Closely Associated with Chronic Graft Versus Host Disease but Not with Donor Type.
Authors:   on behalf of the Late Effects Working party of the EBMT, Hows Jill , Nunn Ann , Passweg Jakob , Tichelli Andre , Locasciulli Anna , Bradley Benjamin , Socie Gerard 
Published: April 2020

Abstract
The International Unrelated Search and Transplant (IMUST) Study included 42 European centers and prospectively accrued 345 unrelated donor (URD) and 699 matched sibling donor (MSD) SCT between 1989 and 19921. We now compare the incidence and severity of late events occurring in the 108 URD and 355 MSD recipients surviving more than 2 years, range 2.0–13.9 years after SCT. In this late surviving cohort 11/108 URD and 37/355 MSD recipients were transplanted for non-malignant disease, and 97/108 URD and 318/355 MSD recipients for haematological malignancy. In the URD cohort 85 recipients received TBI conditioning and 33 T-cell depletion. In the MSD cohort 259 received TBI conditioning and 68 T-cell depletion. In patients surviving more than 2 years after SCT the Karnofsky score was 90–100 in 262, 80 or less in 104 and unknown in 77. The Karnofsky score was similar in the URD and MSD SCT cohorts. One hundred and five late deaths occurred amongst the 463 patients surviving more than 2 years. Deaths were relapse related in 60 cases, transplant related in 29, due to second malignancy in 4, other causes in 6 and unknown causes in 6. Extensive CGVHD was present in 84 recipients surviving more than 2 years, limited CGVHD in 179 and no CGVHD in 200. The cumulative incidence (CI) for survival at 12 years in patients surviving more than 2 years with CGVHD was 49% (44–55) in the MSD cohort and 59% (51–70) in the URD cohort. The CI for extensive CGVHD was slightly higher in the URD than MSD recipients, 49% (44–55) versus 30% (22–42), p=0.1. Twelve year survival was 77+/−5% for the MSD and 67+/−11% for the URD cohort, p=0.1. For patients surviving more than 2 years with extensive CGVHD subsquent survival at 12 years was poor at 49+/−14%, compared with 80+/−7% for limited CGVHD, and 82+/−6% for no CGVHD, p=0.0001. In the presence of extensive CGVHD 12 year survival was similar after MSD 43+/−20% and URD transplants 51+/−20%, p=0.89. A multivariate Cox regression model showed CGVHD was the only variable significantly associated with survival beyond 2 years, p=&lt;0.0001. We also investigated the 12-year CI of cataract formation, failure of endocrine organs, bone necrosis and second malignancies in MSD and URD cohorts. Cataracts and endocrine failure were frequently reported in survivors beyond 2 years. CI for cataracts at 12 years was 43% (33–57) in the URD cohort and 28% (24–34) in the MSD cohort; endocrine failure 28% (19–40) in the URD and 29% (23–35) MSD cohort. Cataract formation was positively associated with TBI conditioning, p=0.0001, but endocrine failure was not. The CI at 12 years for bone necrosis and second malignancy was reported as less than 8% in both cohorts. We conclude that late mortality following allogeneic SCT is closely associated with CGVHD but not with donor type. Cataract formation and endocrine failure are frequently reported in long-term survivors of both URD and MSD SCT but bone necrosis and second malignancy are less prevalent.