After allogeneic stem cell transplantation, graft-versus-host disease (GvHD) occurs through recognition of histocompatibility mismatches by donor T lymphocytes. The same mechanism operates in eliminating malignant cells (the graft-versus-tumor or GvT effect). We hypothesized that comparing the correlation between GvHD and relapse might provide a surrogate marker for the susceptibility of diseases to allo-immune effects. We studied 48 111 first allogeneic transplants performed between 1998 and 2007. In chronic myeloid leukemia (CML), the relapse risk declined clearly and proportionally to severity of acute and chronic GvHD. Acute lymphoblastic leukemia and BCR-ABL-negative myeloproliferative neoplasias were comparably sensitive to GvHD as CML, whereas myelodysplastic syndromes and lymphoproliferative disorders showed intermediate sensitivity. GvHD was only associated with modest reductions in relapse risk in acute myeloid leukemia (AML) and plasma cell disorders (PCDs). Except for PCD, hazard rates for relapse decreased to almost 0 at 48 months of follow-up in all diseases. These data confirm observations of potent GvT effects associated with GvHD. The strength of the GvHD/GvT correlation differs significantly between hematological malignancies. The parallel drop of relapse rates in different diseases despite differences in GvHD/GvT ratios suggests that GvT effects might operate in the absence of GvHD, particularly in AML.
Graft-versus-host disease (GvHD) is the major complication after allogeneic hematopoietic stem cell transplantation (HSCT). GvHD occurs through recognition of mismatched minor or major histocompatibility antigens by donor-derived T lymphocytes. The same mechanism operates in the elimination of residual malignant cells (the graft-versus-tumor (GvT) effect). Although it is difficult to measure GvT directly, previous studies have shown that incidence and severity of GvHD correlate inversely with relapse/progression rates.1, 2, 3 The relative reduction in relapse/progression incidence might therefore be used as a surrogate endpoint to measure the strength of GvT effects associated with GvHD.4 Previous studies performed in the 1990s have analyzed patients treated for acute myeloid (AML), acute lymphoid (ALL) and chronic myeloid leukemia (CML), the prevailing diseases treated with allogeneic transplantation at that time. Transplant indications have since changed significantly. Tyrosine kinase inhibitors have replaced allogeneic transplantation as primary treatment of CML;5 today, besides more standard indications such as acute leukemias, significant numbers of patients are allografted for diseases such as plasma cell myeloma, lymphoma, or myelodysplastic syndrome (MDS).6 For these diseases, the existence and strength of GvT reactions is still a matter of debate.7, 8, 9, 10
In addition to the change of the spectrum of diseases treated with allografting, transplant characteristics have significantly evolved over the past two decades. Increasing numbers of patients are transplanted after reduced intensity conditioning regimens, from unrelated rather than family donors, and with stem cells collected from peripheral blood rather than bone marrow. Last but not least, the age of recipients and of family donors has increased remarkably, which might interact with the strength of GvT reactions. By correlating GvHD incidence with post-transplant relapse/progression rates, we aimed to study the sensitivity of different malignant hematological conditions to allo-immune effects. Moreover, the large cohort analyzed in this study allowed comparing GvT effects of more modern to those of traditional treatment regimens.
Materials and methods
This retrospective study is based on 48 111 first allogeneic transplants carried out for malignant hematological diseases in adult patients (⩾18 years at time of transplant) between 1998 and 2007, and reported to the European Group for Blood and Marrow Transplantation by standardized questionnaire or electronic data management system. Seven thousand eight hundred and eighty nine patients had previously undergone autologous transplantation. Patients were included if information was available on: patient age, disease, disease stage, type of donor, source of stem cells, incidence and date of relapse/progression. Five thousand six hundred and seven patients were excluded due to missing information.
Patient population and definitions
Analysis was restricted to patients treated with an allogeneic HSCT for AML or ALL, chronic myelogenous leukemia, lymphoproliferative disorder (LPD), MDS or secondary acute leukemia, BCR-ABL-negative myeloproliferative neoplasm, or plasma cell disorder (PCD). Patients transplanted for solid tumors and bone marrow failure syndromes were excluded, as were those receiving autologous or syngeneic transplants.
Disease stage was defined as follows: in acute leukemia, MDS or myeloproliferative neoplasm, patients transplanted in first complete remission were considered to have early-stage disease, those in any other complete remission have intermediate stage and all other patients have advanced disease. In CML, patients transplanted in chronic phase were considered to have early-stage disease, those in blast crisis have advanced diseaseand all others have intermediate stage. In patients with LPD, those in complete remission were considered to have early-stage disease, those in partial remission and those untreated were considered to have intermediate-stage disease and all others were considered advanced stage. In PCD, patients in complete remission were considered to have early-stage disease, those in partial and those untreated were considered to have intermediate-stage disease and all other patients were considered advanced stage disease. Details of the 48 111 patients are listed in Table 1.
The endpoint of this analysis was the incidence of disease relapse/progression after allogeneic stem cell transplantation. Outcome data were compiled from the date of first allogeneic transplantation through the date of relapse/progression or death or date of last contact. All outcome data were artificially censored 48 months after transplantation. Patients were also censored if they underwent a second allogeneic transplant procedure (N=1297), unless they had already developed a disease relapse/progression after the first and before the second transplant (N=1465).
Relapse/progression, acute and chronic GvHD (aGvHD and cGvHD) cumulative incidences were calculated in a competing risks framework, in which non-relapse mortality, death without prior aGvHD and death without prior cGvHD, respectively, were considered as the competing events. The cumulative incidence of chronic GvHD was estimated in the population alive at 100 days after transplantation.
Hazard ratios (HRs) adjusted for pre-transplant risk factors (disease stage, graft source, intensity of conditioning regimen, type of donor, T-cell depletion of the graft and year of transplant) were calculated using the Cox proportional hazards models for the cause-specific hazards for relapse/progression for each disease separately. Pre-transplant factors included in the multivariable models were age of the patient at transplant, year of transplant, donor type (matched related versus matched unrelated versus mismatched), stem cell source and type of conditioning regimen (myeloablative versus reduced intensity). aGvHD and cGvHD were graded according to standard definitions.11, 12 The impact of GvHD on relapse/progression incidence as measured by the HRs was assessed by including aGvHD and cGvHD as time-dependent covariates in the Cox models. Both aGvHD and cGvHD were modeled as states in which patients remained once GvHD developed, even if clinical data suggested that GvHD had resolved, as the biological effects of GvHD regarding relapse/progression protection may extend beyond the period when GvHD is active. Limited and extensive chronic GvHD were modeled as separate variables, thus allowing patients to progress from limited to extensive cGvHD. As aGvHD is a risk factor for the development of cGvHD, the impact of aGvHD was assessed in models that did not incorporate cGvHD, to measure the total impact of aGvHD. The impact of cGvHD was assessed in models starting at day 100 and adjusted for preceding a GvHD to measure the net impact of cGvHD. As information on cGvHD was missing in a substantial portion of patients (N=8880, 23% of patients alive at day 100), we performed sensitivity analyses coding these patients as (A) having cGvHD of unknown severity, as (B) being free from cGvHD, or (C) by excluding these patients from the analysis of cGvHD. Model A produced HRs for this category for outcome disease relapse/progression above 1.0 and was clearly different from HRs for patients with known limited or extensive cGvHD, rendering this assumption unlikely. In models B and C, HRs were nearly identical (Supplementary Figure 1). We therefore excluded these patients from the analysis on cGvHD.
To analyze the relationship between transplant characteristics and the effect of GvHD on relapse/progression incidence, we performed Cox analysis on subgroups of patients (for example, early versus intermediate versus advanced disease) incorporating disease type as a stratification variable and adjusting for the same covariables as in the main analysis. HRs and confidence intervals (CIs) were then subjected to a fixed effects meta-analysis to produce Forest plots and interaction P-values. If the P-values were <0.05, we considered the interaction significant.
Incidence of aGvHD, cGvHD, survival, relapse/progression and non-relapse mortality
Cumulative incidence of grade I–IV aGvHD was 49% at 100 days after transplantation, with grade II–IV aGvHD occurring in 30% of patients. Four years after allogeneic HSCT, the estimated cumulative incidences of limited and extensive cGvHD and of chronic GvHD of unknown severity were 23%, 27% and 2%, respectively (percentages referring to the total number of patients with information on cGvHD). Overall survival and relapse-free survival at 1, 2 and 4 years after transplantation amounted to 61%, 53% and 46%, respectively, for overall survival, and 53%, 44% and 38%, respectively, for RFS. Incidence of disease relapse/progression was 22%, 28% and 31% at 1, 2 and 4 years, respectively. Cumulative incidence of non-relapse mortality was 25%, 28% and 31% at 1, 2 and 4 years, respectively.
Influence of GvHD on relapse/progression incidence
As shown in previous analyses, development of GvHD was associated with a reduction in the risk of disease relapse/progression after allogeneic stem cell transplantation. In CML, the clearest reduction of relapse/progression risk was evident with HRs declining proportionally to severity of both aGvHD and cGvHD (Figure 1, corresponding HRs and CIs in Supplementary Table 1). The protective effect of severe acute (grade III–IV) GvHD was similar to that of extensive cGvHD, whereas the protective effect of mild acute (grade I–II) GvHD was comparable to that of limited cGvHD. cGvHD was more effective in reducing relapse risk, if occurring ‘de novo’, that is, without preceding cGvHD (HR: 0.75, 95% CI: 0.60–0.92 for limited cGvHD; HR: 0.37, 95% CI: 0.27–0.51) compared with patients with preceding aGvHD (HR: 0.80, 95% CI: 0.6–0.97 for limited cGvHD; HR: 0.61, 95% CI: 0.50–0.75), presumably due to larger numbers of patients with residual leukemia at the time of cGvHD onset in the absence of preceding aGvHD. ALL and myeloproliferative neoplasm were almost equally sensitive to GvHD as CML, MDS and LPD showed intermediate sensitivity (Figure 1). Both AML and PCD showed only modest sensitivity to aGvHD and limited cGvHD. and relevant reductions in relapse/progression rates were only seen in patients experiencing extensive cGvHD.
The limited sensitivity of PCD to allo-immune effects was also evident in the analysis of unadjusted relapse/progression hazard rates, which failed to drop to values near zero during follow-up in patients with PCD (Figure 2, upper panel), resulting in a lack of plateau in the progression-free survival curve in this disease (Figure 2, lower panel). Interestingly, despite a relatively poor correlation of GvHD and relapse/progression risk observed in patients transplanted for AML, the relapse/progression risk of these patients dropped along that of patients transplanted for other diseases during post-transplant follow-up and the progression-free survival curve developed a plateau during follow-up.
Influence of patient and transplant factors on graft-versus-host-mediated relapse protection
To assess conditions favoring beneficial graft-versus-host effects, we analyzed the relationship of transplant characteristics with the effects of aGvHD and cGvHD on disease relapse/progression. Extensive cGvHD was associated with an HR for disease relapse/progression that was significantly lower after reduced intensity compared with myeloablative transplants (P=0.03), a trend that was also seen for limited cGvHD and for all grades of aGvHD without reaching the level of statistical significance (Figure 3, panel ‘Conditioning’, corresponding HRs and CIs in Supplementary Table 2).
The strongest protective effects associated with GvHD development were noted for patients transplanted in earlier phases of their disease for all grades of aGvHD and for limited cGvHD, consistent with a decline of GvT effects in patients with more advanced disease (Figure 3, panel ‘Stage’). The effect of stage was significant in aGvHD (P<0.05 for grades II, III and IV aGvHD) but not in cGvHD (P=0.85 and 0.83 for limited and extensive cGvHD, respectively). Transplants of bone marrow and of peripheral blood stem cells were not associated with significantly different effects if patients developed GvHD (Figure 3, panel ‘Source’). Cord blood transplants were not analyzed separately, due to the relatively small number of such treatments in this cohort. Finally, no consistent pattern regarding differences in the correlation between GvHD and graft-versus-leukemia effects between human leukocyte antigen-identical sibling, matched unrelated, or human leukocyte antigen-mismatched donor emerged (Figure 3, panel ‘Donor type’).
Influence of disease stage and conditioning intensity in transplants for AML
Possible explanations for the apparent paradox of a low correlation between GvHD and GvT in AML patients and the comparably low relapse/progression risk in this disease include the possibilities that a large fraction of patients might already be cured at the time of GvHD onset (by preceding treatment or by the conditioning regimen); or that GvT effects that occur independently from GvHD (such as natural killer cell immunity or T-cell-based recognition of tumor-specific antigens) are more important in AML than in other diseases. To analyze these possibilities, we performed subgroup analyses of AML patients to estimate the impact of disease stage and intensity of conditioning regimens, respectively. If a large fraction of patients transplanted in CR1 were already cured, effects of GvHD on relapse/progression rate would be diluted, resulting in HRs near 1.0 in early-stage AML. However, GvHD-associated GvT effects were comparable in patients transplanted in an early disease stage, arguing against a major proportion of patients already cured at the time of transplant (Supplementary Figure 2). Similarly, a higher susceptibility of AML to the conditioning regimen would lead to lower GvT effects in myeloablative compared with reduced intensity conditioning regimens. Indeed, reduced intensity conditioning transplants were associated with a stronger GvT effect particularly of cGvHD, suggesting that myeloablative conditioning has relevant role in disease eradication in AML (Supplementary Figure 2).
The data of this study comprehensively demonstrate the effect of GvHD on disease relapse/progression within the first 4 years after HSCT in patients transplanted for hematological malignancies. They confirm earlier observations of a potent GvT effect associated with GvHD. Because of the higher number of patients analyzed in the current study, we were able to dissect with greater detail the differential effects of aGvHD and cGvHD.
We confirmed that the relapse/progression risk in patients transplanted for CML gradually decreases proportionally to the degree of aGvHD and cGvHD. Although the introduction of tyrosine kinase inhibitors has rendered early-phase CML an infrequent transplant indication, this subgroup of patients still allows comparison of the GvHD/relapse association found here with earlier studies of similar design.3, 4 ALL also proved to be highly sensitive to GvHD, confirming previous analyses,4, 13 as was the disease category of BCR-ABL-negative myeloproliferative neoplasm. The strong protection from relapse associated with GvHD in ALL patients stands in some contrast to the low rates of success of **donor lymphocyte infusions for relapse in this disease,14 suggesting that GvT effects occurring after transplantation are more effective than those induced by donor lymphocyte infusion, perhaps due to differences in the quantity of tumor cells in these two settings. Regarding more recent transplant indications, both MDS and LPD appeared to have a clear susceptibility to GvHD, which was however lower than that of CML. These data are in agreement with recent analyses of the outcome of patients treated with allogeneic HSCT for these indications.10, 15
As a major finding of this study, the relapse/progression risk in AML and PCD appeared largely refractory to development of any aGvHD and or limited cGvHD. Regarding AML, these results are in contrast to early reports4 but in line with more recent studies,16 suggesting that changes in transplantation procedures and patient selection may have influenced the relationship between GvHD and relapse/progression risk. In addition, a recent study analyzing the effect aGvHD and cGvHD on relapse/progression risk after reduced intensity transplantation for AML found only relatively mild protective effects of aGvHD and cGvHD of any grade.17 The lack of correlation of GvHD and GvT in AML did not appear to be the result of an increased proportion of patients already cured at the onset of GvHD. Alternatively, non-T-cell-based alloreactivity occurring in the absence of GvHD may operate beneficially and preferentially in AML. In particular, polymorphisms in natural killer cell receptors and their ligands have been shown to affect the survival of patients transplanted for AML, suggesting that this subset may have a role in eradication of this disease.18, 19, 20 Natural killer cell-mediated GvT effects have previously been shown to be more effective in AML than in ALL, which is compatible with the results of this analysis.18, 21 The low relapse/progression rates in AML despite a relative lack of correlation with GvHD are further in line with the excellent results of T-cell-depleted allogeneic transplantation in this disease for patients transplanted early in their disease course,22, 23, 24 and with previous studies showing that patients not developing GvHD after allogeneic transplantation have a better survival compared with recipients of autografts, suggesting the existence of a GvHD-independent GvT effect.25
Regarding PCD, our analysis suggests that this type of disease is largely refractory to aGvHD and to limited cGvHD and shows only limited susceptibility to extensive GvHD. Results of this analysis are compatible with hazard rates of disease relapse/progression, suggesting that allogeneic HSCT is not curative in the majority of patients with PCD, even though long-term follow-up of randomized trials comparing allogeneic with autologous HSCT suggest some GVT efficacy in PCD.8, 26 Comparing relapse hazard rate curves between AML and PCD patients demonstrates that a significant fraction of AML but not PCD patients are cured despite only a weak GvHD/relapse correlation in both diseases, suggesting that GvHD-independent GvT effects, which likely operate in AML, may not be as efficient in PCD.
Finally, we attempted to define transplant-associated factors favoring beneficial aspects of GvHD. We confirm previous observations that GvHD is associated with stronger GvT effects in reduced intensity compared with myeloablative transplants.16 This is in agreement with a relatively more potent GvT effect after less intensive conditioning regimens, possibly through a diluting effect of myeloablative conditioning regimens, which may by themselves be curative in a fraction of patients. Furthermore, in agreement with previous data we find stronger GvT effects in transplants performed at an earlier stage of the disease.27, 28 However, all types of transplants studied were found to induce GvT effects, and donor or transplant characteristics had a lower influence on the balance between GvHD and GvT than underlying disease.
The main strength of this analysis lies in the large population analyzed and the distribution of diseases and transplant types that reflect current practice in Europe.29 Its main weakness lies in the substantial proportion of patients with missing information of cGvHD. As detailed in the Methods section, we undertook sensitivity analyses, which produced very little variation in HRs of patients with known cGvHD status in the different models. However, we still cannot definitively rule out that excluding patients with missing cGvHD status from the analysis may have introduced some bias. An additional limitation associated with the design of the study is that the approach taken here allows comparison of relapse rates in patients with or without GvHD only. As demonstrated by the outcome of patients with AML, such a distinction may be inadequate for diseases where relevant GvT effects occur in the absence of GvHD. Finally, due to the nature of this registry study, we had no information on cytogenetics and on minimal residual disease transplant, two factors shown in many studies to be of significant importance in assessing the risk of disease relapse.30
In conclusion, we show that development of GvHD is associated with potent GvT effects in a wide variety of hematological malignant diseases, with the crucial exception of PCD, which appear to be relatively resistant to beneficial effects of GvHD. AML appears to differ from the other diseases analyzed by being associated with a low post-transplant relapse/progression risk despite only a weak correlation of GvHD and GvT. In all diseases, GvT effects appear to operate consistently across the different types of transplant regimens analyzed.
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MS was supported by the Swiss National Science Foundation (grant PPOOP3_128461/1).
The authors declare no conflict of interest.
Supplementary Information accompanies this paper on the Leukemia website
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Stern, M., de Wreede, L., Brand, R. et al. Sensitivity of hematological malignancies to graft-versus-host effects: an EBMT megafile analysis. Leukemia 28, 2235–2240 (2014). https://doi.org/10.1038/leu.2014.145
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