Reduced intensity conditioning increases risk of severe cGVHD: identification of risk factors for cGVHD in a multicenter setting

Chronic GVHD remains the major cause of morbidity and mortality in long-term survivors after allogeneic stem cell transplantation. However, it is also correlated with a strong graft-versus-tumor effect. Thus, proper management of patients should be based on individualized strategies taking into account the notion that the absence of cGVHD might hamper relapse-free survival while severe cGVHD leads to increased mortality due to infectious complications and organ failure [15‐18].

In the current study, we identified risk factors with regard to developing severe cGVHD, including female donor-to-male donor recipient, prior aGVHD and use of reduced intensity conditioning. While the first two risk factors have previously been described, the latter requires further clarification. In this regard, the finding of a higher risk of cGVHD among patients receiving RIC is somewhat surprising, since previous studies have not been able to show a difference in terms of cGVHD incidence depending on the type of conditioning regimen [19, 20]. Mechanisms involved in the development of acute and chronic GVHD are not entirely congruent. In this regard, cGVHD is not simply the end stage of acute GVHD [21]. In accordance with this hypothesis, use of RIC might, in fact, decrease the risk of acute and increase the risk of chronic GVHD. It could be speculated that acute GVHD is mostly dependent on the cytokine storm mediated by the tissue injury induced by the high doses of chemoradiotherapy, which is avoided in the RIC setting. On the other hand, chronic GVHD would be more dependent on the persistence of host–origin antigen-presenting cells that might trigger an alloresponse in donor T cells. The use of RIC favors the persistence of a mixed chimerism for a longer period post-transplant as compared to myeloablative conditioning. It could also be argued that since many centers show a preference toward treating older patients with RIC mainly due to comorbidities, the median age in this patient group is higher compared to those treated with myeloablative conditioning (MAC). This is also true in our study, and therefore, RIC patients are a higher-risk subpopulation for the development of cGVHD compared to MAC.

In the present study, we have shown that the addition of ATG decreases the overall incidence of cGVHD without hampering relapse-free survival, which is consistent with previous studies [6, 11, 17, 22‐25].

Langston et al. showed that the addition of ATG to fludarabine–melphalan in the RIC regimen for patients receiving partially matched URD transplants does not increase the rates of relapse or infection. The same study did not show any difference with regards to cGVHD incidence in the two groups with Fu–Mel–ATG versus Flu–Mel [26]. One recent report shows that a fludarabine-containing RIC regimen with the addition of ATG is effective and safe for adults up to the age of 69 [27]. Investigation of the effect of ATG in a matched related donor myeloablative setting has shown beneficial effects with reduction in both severe aGVHD and cGVHD, which translated into higher survival [28].

Nevertheless, the use of pretransplant ATG as GVHD prophylaxis in patients receiving grafts from URD has been discussed for years, and although most studies have shown a significant reduction in acute GVHD and cGVHD, they have lacked evidence concerning a potential benefit on overall survival [11, 13, 24, 25, 29]. A GITMO group showed a significant reduction in the incidence of grades III–IV aGVHD and extensive cGVHD, but this positive effect was counterbalanced by the increased risk of infections. In a follow-up analysis of this study, encouraging results included a reduced risk of chronic lung dysfunction, protection against extensive chronic GVHD, and an improved quality of life [21]. In this prospective setting, there was no significant difference between the two groups regarding relapse and long-term survival.

These data contrast with a recent report from CIBMTR describing lower overall survival, lower disease-free survival, and an increased risk of relapse in patients receiving in vivo T-cell depletion [30]. This difference might be due to the heterogeneous nature of the population included in the CIBMTR study, in which patients received different preparations of ATG, dosage, conditioning regimens and donor types. In addition, the type of conditioning determines the effect of the antibody therapy since, according to Soiffer et al., there is a deleterious effect of in vivo T cell depletion among patients undergoing RIC. Furthermore, both the dosage and the preparation of ATG seem to be important in terms of transplant outcomes [13, 24, 25, 31]. In this regard, most studies have shown that an intermediate dose of rabbit-ATG (Thymoglobulin, Genzyme) ranging from 5 to 8 mg/kg leads to a positive reduction in severe aGVHD and cGVHD without impairing relapse or long-term survival.

In addition, in the current study, we show that increasing patient age significantly influences the incidence of cGVHD, but only up to 50 years, which is consistent with a recent study including 206 patients who underwent RIC allo-HSCT plus 5 mg/kg r-ATG. In this study, there was no difference in the incidence of extensive cGVHD in patient groups younger or older than 60 years [32].

Most importantly, the current study allowed us to develop a scoring system with clearly identifiable subgroups of patients at different risk of developing overall or severe cGVHD. Remarkably, both severe cGVHD and no cGVHD had a similar adverse impact on outcome. Based on these data, mild or moderate cGVHD show a desirable GvL effect without increasing the mortality from the procedure. Interestingly we found that in patients with more advanced disease stages the difference in RFS became less prominent, perhaps suggesting that this patient group relapses before a significant GvL effect is obtained. All together, these data suggest that patients at higher risk of severe cGVHD should be identified in order to have a favorable influence on long-term outcomes via the use of more intense immunosuppressive strategies, such as the use of ATG. In this regard, the lack of conclusive data regarding the impact of the use of ATG on survival in most previously reported randomized studies could be attributed to the lack of selection criteria, such that, according to our data, older males with female donors receiving RIC transplants would benefit the most from receiving this prophylaxis. Pretransplant identification of patients at risk of developing graft-versus-host disease remains an unmet medical need. In this regard, even among patients receiving transplantation from HLA-identical donors, the risk of GVHD varies greatly among individuals. Recently, Sorror et al. [33] reported that the pretransplant comorbidity index predicts the risk of severe aGVHD and subsequent mortality. In the current study, we developed a scoring system for cGVHD including risk factors known at the time of transplant: RIC, female-to-male donation and patient age > 45 years. Patients with these three risk factors had an incidence of severe cGHD of 40% at 5 years, while the same patients had a cumulative incidence of 7% at 5 years when they received ATG. Accordingly, the scoring system allows the tailoring of strategies to prevent cGVHD in the early post-transplant period and in the long-term follow-up. Furthermore, we also identified RIC, female-to-male donation, prior acute GVHD and not receiving ATG as GVHD prophylaxis as risk factors for developing severe cGVHD. This information would be of the greatest use for modifying immunosuppression during the post-transplant follow-up period. In this regard, these patients should be carefully monitored and might benefit from receiving early treatment once signs or symptoms of cGVHD appear.

In conclusion, in the current study, we identified subgroups of patients with different risk of cGVHD; these parameters might help to tailor GVHD prophylaxis and manage immunosuppression in the long term.