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Graft-versus-host disease and outcome in HLA-identical sibling transplantations for chronic myeloid leukemia
Alois Gratwohl1, Ronald Brand, Jane Apperley
1Division of Hematology, Department of Internal Medicine, Kantonsspital Basel, Basel, Switzerland. hematology@uhbs.ch
Insights
Graft-versus-host disease (GvHD) after allogeneic stem cell transplants impacts survival by increasing mortality but reducing relapse. Limited chronic GvHD offers the best long-term survival outcomes.
Area of Science:
- Hematopoietic Stem Cell Transplantation
- Immunology
- Oncology
Background:
- Graft-versus-host disease (GvHD) is a critical factor influencing outcomes after allogeneic hematopoietic stem cell transplantation (HSCT).
- GvHD presents in acute (aGvHD) and chronic (cGvHD) forms, with discordant effects on transplantation-related mortality (TRM) and relapse risk (RI).
- Understanding the net effect of GvHD on survival is crucial for optimizing HSCT protocols, especially when leveraging graft-versus-leukemia (GVL) effects.
Purpose of the Study:
- To analyze the impact of aGvHD and cGvHD severity on TRM, RI, and overall survival after HSCT for chronic myeloid leukemia.
- To determine the optimal GvHD profile for maximizing long-term survival by balancing TRM and RI.
- To clarify the role of GvHD in posttransplantation outcomes and inform clinical decision-making.
Main Methods:
- Analysis of 4174 HLA-identical sibling transplantations for chronic myeloid leukemia in first chronic phase.
- Landmark analysis to assess the influence of aGvHD and cGvHD presence and severity on TRM and RI.
- Calculation of hazard ratios (HRs) for TRM and RI across different grades of aGvHD and cGvHD.
- Estimation of 10-year survival rates based on initial aGvHD grade and subsequent cGvHD status.
Main Results:
- During the first 100 days post-HSCT, only severe aGvHD (grades III and IV) significantly impacted TRM.
- Between 100 days and 3 years, increasing aGvHD severity correlated with higher TRM and lower RI (e.g., HR for TRM grade IV = 14.7; HR for RI grade IV = 0.14).
- Beyond 3 years, cGvHD determined outcomes; limited cGvHD reduced RI without increasing TRM, yielding the best survival (HR = 0.48). Initial aGvHD grade I was associated with the highest likelihood of limited cGvHD and best 10-year survival (63%).
Conclusions:
- The severity of acute GvHD significantly influences TRM and RI in a time-dependent manner after HSCT.
- Chronic GvHD, particularly limited cGvHD, plays a crucial role in long-term survival by reducing relapse risk without increasing mortality.
- Optimizing HSCT outcomes requires considering the long-term effects of GvHD, balancing the trade-off between TRM and RI, with limited cGvHD offering the most favorable survival prognosis.
Abstract:
Graft-versus-host disease in its acute (aGvHD) or chronic form (cGvHD) remains the most important posttransplantation factor influencing outcome after allogeneic hematopoietic stem cell transplantation (HSCT). It increases transplantation-related mortality (TRM) but reduces risk of relapse. The net effect of these 2 discordant effects determines survival. In view of current interests to exploit graft-versus-leukemia (GVL) effects, we analyzed 4174 HLA-identical sibling transplantations for chronic myeloid leukemia in first chronic phase, depending on the presence or absence and severity of GvHD with a landmark analysis. During the first 100 days, only aGvHD grades III and IV had an impact on TRM. During the time period day 100 to 3 years increasing severity of aGvHD is associated with increased TRM and decreased relapse incidence (RI) with hazard ratios (HRs) for TRM as follows: grade 0, HR = 1.0; grade I, HR = 1.52 (1.19-1.96); grade II, HR = 2.48 (1.95-3.14); grade III, HR = 5.76 (4.44-7.48); grade IV, HR = 14.7 (10.9-19.9) and likewise for RI: grade I versus 0, HR = 0.94 (0.76-1.16); grade II, HR = 0.60 (0.46-0.77); grade III, HR = 0.48 (0.29-0.81); grade IV, HR = 0.14 (0.02-0.99). Beyond 3 years, TRM and RI are determined by cGvHD. Limited cGvHD reduces RI to the same extent as extensive cGvHD but has no impact on TRM and, hence, results in best survival with an HR = 0.48 (0.32-0.71). aGvHD grade I has the highest likelihood of subsequent limited cGvHD, which results in cumulative incidence estimates of survival at 10 years being best for patients with initial aGvHD grade I: survival at 10 years grade 0 = 59%, I = 63%, II = 56%, III = 26%, IV = not applicable. These data clarify the role of GvHD in posttransplantation outcome. Considerations for long-term outcome are essential when short-term data of interventions on GvHD are analyzed.
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