Improved outcome of patients with graft-versus-host disease after allogeneic hematopoietic cell transplantation for hematologic malignancies over time: an EBMT mega-file study

Abstract

Acute graft-versus-host disease (aGvHD) remains a major threat to successful outcome following allogeneic hematopoietic cell transplantation though advances in prophylaxis and supportive care have been made. The aim of this study is to test whether the incidence and mortality of aGvHD have decreased over time. 102,557 patients with a median age of 47.6 years and with malignancies after first allogeneic sibling or unrelated donor (URD) transplant were studied in the following periods: 1990-1995, 1996-2000, 2001-2005, 2006-2010 and 2011-2015. Findings: 100-day incidences of aGvHD grades II-IV decreased from 40% to 38%, 32%, 29% and 28%, respectively, over calendar time (P<0.001). In multivariate analysis URD, not in complete remission (CR) at transplant or untreated, and female donor for male recipient were factors associated with increased risk whereas the use of ATG/alemtuzumab decreased aGvHD incidence. Median follow-up was 214, 169, 127, 81 and 30 months, respectively, for the periods analyzed. Three-year-survival after aGvHD grades II-IV increased significantly from 38% to 40%, 43%, 44%, and 45%, respectively. In multivariate analysis URD, not in CR at transplant, peripheral blood as stem cell source, female donor for male recipient, and the use of ATG/alemtuzumab were associated with increased mortality whereas reduced-intensity conditioning was linked to lower mortality. Mortality increased with increasing patient age but decreased in the recent cohorts. Our analysis demonstrates that aGvHD has decreased over recent decades and also that the survival rates of patients affected with aGvHD has improved.

Figure 1.

Incidences of aGvHD grades II-IV and grades III-IV over time. (A) Incidences of aGvHD grades II-IV over time. Cumulative incidence estimates were calculated for aGvHD grades II-IV with mortality considered as a competing event. The endpoint aGvHD grades II-IV was estimated from the date of first transplantation. Data are shown according to transplantation periods 1990-1995, 1996-2000, 2001-2005, 2006-2010 and 2011-2015. (B) Incidences of aGvHD grades III-IV over time. Cumulative incidence estimates were calculated for aGvHD grades III-IV with mortality considered as a competing event. The endpoint aGvHD grades III-IV was estimated from the date of first transplantation. Data are shown according to transplantation periods 1990-1995, 1996-2000, 2001-2005, 2006-2010 and 2011-2015.

Figure 2.

Three-year overall survival over time for the whole patient cohort. The probability of OS for all patients was calculated using the Kaplan Meier estimator. Data are shown according to transplantation periods 1990-1995, 1996-2000, 2001-2005, 2006-2010 and 2011-2015.

Figure 3.

Three-year overall survival over time. (A) Three-year overall survival after aGvHD grades II-IV over time. The probability of OS for patients experiencing aGvHD grades II-IV was calculated using the Kaplan Meier estimator. Data are shown according to transplantation periods 1990-1995, 1996-2000, 2001-2005, 2006-2010 and 2011-2015. (B) Three-year overall survival after aGvHD grades III-IV over time. The probability of OS for patients experiencing aGvHD grades III-IV was calculated using the Kaplan Meier estimator. Data are shown according to transplantation periods 1990-1995, 1996-2000, 2001-2005, 2006-2010 and 2011-2015.

Figure 4.

Three-year non-relapse mortality after aGvHD grades II-IV over time. Cumulative incidence estimates were calculated for NRM in a competing risks framework with relapse as a competing risk for estimation of NRM. Data are shown according to transplantation periods 1990-1995, 1996-2000, 2001-2005, 2006-2010 and 2011-2015.

Figure 5.

Three-year relapse incidence after aGvHD grades II-IV over time. Cumulative incidence estimates were calculated for relapse in a competing risks framework with NRM as a competing risk in the estimation of malignancy relapse.