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G. Fatobene et al.
requiring dilation), the duration of immunosuppressive therapy and resumption of pretransplant activities (e.g., work/school) may serve as better measures of outcome after HCT.
The aim of this study was to analyze chronic GvHD manifestations most likely to be associated with disability, requirement of secondary systemic treatment, discontinu- ation of systemic immunosuppressive therapy and func- tional outcomes among recipients of grafts from alterna- tive HCT donors. Differences in these clinical outcomes could help inform patients about outcomes after HCT from alternative donors.
Methods
Patients and donors
This retrospective study included all consecutive adult patients who received a first alternative donor HCT for any underlying diagnosis at Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance between 2006 and 2015 and subsequently developed chronic GvHD that required systemic treatment. The alternative grafts included unrelated 4-6/6-HLA-matched single or double umbilical cord blood units (UCB), related HLA-haploiden- tical bone marrow or mobilized peripheral blood stem cells plus post-transplant cyclophosphamide (Haplo/PTCY), and mobilized peripheral blood stem cells from unrelated donors with a single HLA allele mismatched at an A, B, C or DRB1 locus by high reso- lution typing (1-mMUD), regardless of whether the mismatch resulted in antigen disparity at the locus. Patients had given writ- ten consent allowing the use of medical records for research in accordance with the Declaration of Helsinki, and the institutional review board approved the study.
Clinical assessments and definitions
Involved sites and types of treatment at the onset of first sys- temic teraphy of chronic GvHD and treatment changes after initial teraphy were recorded prospectively via the Long-Term Follow- Up Program through medical records from our outpatient clinic and local clinics that provided primary care for patients. All patients were screened for evidence of chronic GvHD between days 80 and 100 after HCT, at 1 year after HCT, and whenever clinically indicated to establish the diagnosis of chronic GvHD or to determine treatment.
Acute GVHD was graded according to previously described cri- teria.4 Chronic GvHD was diagnosed using the 2014 National Institutes of Health consensus criteria.5 Disability related to chron- ic GvHD was defined as 2014 National Institutes of Health con- sensus grade 2 or 3 keratoconjunctivitis sicca, grade 2 or 3 sclero- derma, any grade of bronchiolitis obliterans, grade 2 or 3 joint/fas- ciae involvement, or grade 3 esophageal stricture requiring dila- tion. While vulvovaginal chronic GvHD can result in fibrosis, this manifestation is under reported and unlikely to result in disability by itself, and thus not included in our study. National Institutes of Health score 2 or 3 gastrointestinal, oral or hepatic manifestations reflect GvHD activity but are less likely to cause irreversible dam- age and were also not included in our study. Return to work or school was considered only for patients who were working or in school before the HCT indication was diagnosed and had not resumed those activities before the onset of chronic GvHD. Treatment change was defined as any additional systemic treat- ment not used for the initial treatment of chronic GvHD. An increase in steroid dose in patients who were initially treated with steroid was not considered as a treatment change, because tempo- rary increases in steroid doses or resumption of steroid treatment
are often necessary during the initial treatment of chronic GvHD.6 Discontinuation of systemic immunosuppression was defined as cessation of treatment for at least 6 months after resolution of chronic GvHD.
Statistical analysis
The main endpoints of this study were chronic GvHD manifes- tations associated with disability and impaired functional out- comes (i.e., return to work/school after the diagnosis of chronic GvHD, discontinuation of systemic immunosuppressive therapy, and change in Karnovsky Performance Status). We also compared the overall severity of chronic GvHD at initial diagnosis and the incidences of avascular necrosis, new systemic immunosuppres- sion or treatment after first-line therapy for chronic GvHD, non- relapse mortality and overall survival after chronic GvHD diagno- sis.
The chronic GvHD characteristics between donor groups were compared using a c2 test for categorical variables and Wilcoxon rank-sum test for continuous variables. Overall survival was esti- mated by the Kaplan-Meier method. Cumulative incidences of chronic GvHD and of events after the onset of chronic GvHD were estimated by methods for competing risks, as previously described.7 Death was a competing event for all risks except non- relapse mortality; relapse was a competing event for non-relapse mortality. All comparisons of time-to-event endpoints were per- formed using Cox regression. The analysis of return to work or school was restricted to patients who were working or in school before HCT, and had not returned to work or school before the onset of chronic GvHD. The analysis of high morbidity was based on the first defining complication. All P-values are two-sided and unadjusted for multiple comparisons.
Results
We identified 396 alternative donor HCT recipients who received a first allogeneic transplant for any disease between 2006 and 2015 at our center. The median age at HCT was 42 years (range, 18-73) for UCB, 48 years (range, 18-75) for Haplo/PTCY, and 55 years (range, 22-77) for 1- mMUD HCT recipients. Acute myeloid leukemia and myelodysplastic syndrome were the most common diag- noses at HCT, 64% and 65% among the UCB and 1- mMUD HCT recipients, respectively, while lymphomas were the most common diagnosis (52%) among the Haplo/PTCY HCT recipients. Other demographic charac- teristics are summarized in Table 1.
Chronic graft-versus-host disease
Of the 396 alternative donor HCT recipients, 129 devel-
oped chronic GvHD that required systemic treatment and were included in this study. The cases of treatment-requir- ing chronic GvHD were diagnosed in 29 of the 163 UCB HCT recipients, 21 of 88 Haplo/PTCY HCT recipients and 79 of 145 1-mMUD HCT recipients, for 3-year cumu- lative incidences of 18%, 24% and 55%, respectively. The rate of chronic GvHD was significantly lower in UCB and Haplo/PTCY recipients than in 1-mMURD recipients [hazard ratio (HR)=0.23; 95% confidence interval (95% CI): 0.2-0.4), P<0.0001, and HR=0.29 (95% CI: 0.2-0.5), P<0.0001, respectively] (Figure 1A). The incidence of chronic GvHD was comparable between patients who received 1-mMUD grafts with either allelic or antigenic mismatches (data not shown). Progression-free survival after HCT did not differ among the three donor groups
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haematologica | 2019; 104(4)