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We studied GVHD on relapse, transplant-related mortality (TRM), disease-free (DFS) and survival (OS) after allogeneic transplantation for AML (n=4224) and MDS (n=1517) in four groups: without GVHD, acute GVHD alone, chronic GVHD alone, and acute + chronic GVHD. Examining GVHD as time dependent covariate, after myeloablative conditioning (MAC), chronic and acute + chronic GVHD were associated with lower relapse (p<0.002). TRM was higher in all GVHD groups (p<0.0001); DFS and OS were lower with acute ± chronic GVHD (p<0.0001). After reduced intensity conditioning (RIC), relapse was lower in all GVHD groups (p<0.0001); TRM was increased and DFS and OS were reduced with GVHD (p<0.0001). In those surviving disease-free (≥1-year) following MAC, relapse risks were similar in all groups and TRM higher with any GVHD (p<0.0001). DFS and OS were lower with chronic and acute + chronic GVHD (p<0.0006). After RIC, relapse was lower (p=0.009) and TRM higher (p=0.002) only with acute + chronic GVHD. DFS was similar in all groups and OS worse with acute + chronic GVHD. After MAC, GVHD has an adverse effect on TRM with early modest augmentation of GVHD-associated graft-versus-leukemia (GVL). With RIC, GVHD-associated GVL may be important in limiting both early and late leukemia recurrence.
Graft vs. host disease (GVHD) can complicate allogeneic hematopoietic cell transplantation (HCT) by inducing substantial morbidity or transplant related, non-relapse mortality (TRM). It can also, however, be associated with augmented antineoplastic potency thus limiting risks of relapse by this association with the graft vs. leukemia (GVL) effect [1,2]. The net impact on survival represents a differential in potency between these two parallel immunologic influences. In recent years, as older patients, or those with pre-HCT comorbidities, receive allografts following reduced intensity conditioning (RIC), the strength of the GVL effect has become more critical in limiting the hazards of relapse. Because older patients may also be more vulnerable to acute and/or chronic GVHD, we studied the effect of GVHD on relapse, TRM, disease-free survival (DFS) and overall survival (OS) following allogeneic HCT for acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). The study goal was to identify any differential GVHD-associated GVL influences following transplants using either myeloablative (MAC) or RIC regimens. We report the impact of these immunologic influences on mortality and relapse in these two settings where less potent antineoplastic conditioning might allow persistence of more minimal residual disease (MRD) and render the need for extra GVL more critical for survival.
The Center for International Blood and Marrow Transplant Research (CIBMTR) is a voluntary working group of more than 450 transplantation centers worldwide that contribute detailed data on consecutive allogeneic and autologous hematopoietic cell transplantation to a Statistical Center at the Medical College of Wisconsin in Milwaukee and the National Marrow Donor Program Coordinating Center in Minneapolis. Participating centers are required to report all transplants consecutively; compliance is monitored by on-site audits. Patients are followed longitudinally. All patients provided written informed consent. The Institutional Review Boards of the Medical College of Wisconsin and the National Marrow Donor Program approved this study.
Patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) who received allogeneic HCT from 1997 to 2006 were eligible (N=5741). Recipients of MAC and RIC regimens were eligible while children under 16 years were excluded as were cases with ex vivo T-cell depleted grafts. Transplant regimens were defined as reduced intensity for busulfan dose <9 mg/kg and melphalan dose <150 mg/m2 and total body irradiation dose ≤500 cGy.
Transplant-related mortality (TRM) was defined as death not related to disease recurrence or progression and relapse was defined as disease recurrence based on morphological evaluation. Patients who received a second transplant or donor leukocyte infusion were censored at time of event. Disease-free survival (DFS) was defined as survival in continuous complete remission. Treatment failure was defined as either relapse or death from any cause; the inverse of DFS. OS was calculated from the date of transplant with censoring at the time of last contact for survivors.
The characteristics of patients, their disease and transplantation are shown in Table 1. Variables related to patients, disease and transplantation were compared among the groups using the chi-square statistic. Incidences of grade II–IV acute GVHD and chronic GVHD were based on reports from each transplant center. Patients were divided into four groups: 1) those without GVHD, 2) those with acute GVHD alone, 3) those with chronic GVHD alone and 4) those with acute and chronic GVHD. To examine the influence of acute and chronic GVHD on TRM, relapse, DFS and OS, we conducted two separate analyses and all analyses were performed separately for recipients of MAC and RIC regimens. Cox regression models  were built to adjust for effects of other patient, disease and treatment variables for both analyses. The first analysis included all patients (N = 5791) and acute and chronic GVHD were treated as time dependent covariates. The second analysis was a landmark analysis which included patients who survived at least one-year disease-free after their transplantation (N= 2369). For the landmark analysis of one-year disease-free survivors, acute and/or chronic GVHD status was evaluated at one year by which time all acute and 95% of chronic GVHD had developed. The landmark analysis allowed us to examine any late effect of GVHD on those who were disease-free for at least one year while the analysis with all patients allowed examination of any early effect of GVHD, within one year. The results of multivariate analysis are expressed as hazard ratio with the 95% confidence interval. Factors considered in the multivariate models included age, gender, diagnosis and disease/remission status, donor type and HLA matching, CMV serostatus, performance status, year of transplant and GVHD prophylaxis along with the primarily analysis variables of acute and chronic GVHD. The probabilities of TRM and relapse were calculated using cumulative incidence [4–6]. In all analyses, data on patients without an event were censored at last follow-up. Probability of DFS and OS was calculated with the Kaplan-Meier estimator . Analyses used SAS version 9.2 (Carey, NC).
Details of patients’ demographics and disease characteristics pre-transplantation are shown including all patients, the one-year disease-free survivors included in the landmark analysis and those excluded from the landmark analysis by death, relapse or duration of follow-up < 1 year (Table 1). Forty-three percent (1739 of 4022) of MAC transplants and 37% (630 of 1719) of RIC recipients were alive and disease-free at one year after HCT. The median time to acute GVHD onset after MAC was 23 days and after RIC, 28 days. The median times to chronic GVHD onset were 4.7 months and 4.9 months after MAC and RIC transplants, respectively. Clinical characteristics were similar across all groups except that MAC recipients were younger than those receiving RIC. Approximately 75% of patients had AML and the remaining, MDS. A third of patients were in first complete remission (CR), 15%, in second CR and the remaining patients, in relapse at transplantation. Median follow-up was 4 years.
Results of multivariate analysis of the entire cohort with acute and chronic GVHD modeled as time-dependent covariates are shown in Table 2. Among recipients of MAC transplants, compared to patients without GVHD, relapse risks were significantly lower in patients with chronic GVHD either alone or with acute plus chronic GVHD. Relapse risks were similar in patients without GVHD or with only acute GVHD. However, compared to patients without GVHD, TRM was significantly higher in patients with any GVHD. Consequently, treatment failure and survival risks were significantly higher in patients with acute ± chronic GVHD.
Among recipients of RIC transplants, compared to patients without GVHD, patients with any GVHD had significantly lower relapse risks. TRM risks were also significantly higher in patients with any GVHD. In contrast to the findings after MAC transplants following RIC, compared to patients without GVHD patients with acute GVHD alone had significantly more treatment failure. Treatment failure risks were similar in patients without GVHD and those with chronic GVHD with or without preceding acute GVHD. Overall survival was worse in those with either acute or chronic GVHD.
Multivariate analyses of the one-year disease free survivor cohort are shown in Table 3. Following MAC transplants, subsequent relapse risks among one-year disease free survivors were not significantly different amongst all four GVHD groups (Figure 1A). In contrast, TRM was higher in patients with any GVHD (Figure 1B), leading to higher subsequent treatment failure and lower DFS in those with chronic GVHD and with acute + chronic GVHD compared to those with no GVHD (Figure 1C). Similarly, overall survival was worse with chronic or with acute + chronic GVHD. Following RIC transplants, subsequent relapse risks among one-year disease free survivors were not significantly influenced by isolated acute or chronic GVHD, but risks were significantly lower in those with both acute and chronic GVHD (Figure 1D). TRM (Figure 1E) was also higher only in those both acute and chronic GVHD. Consequently, treatment failure and DFS were similar in all groups (Figure 1F) while survival was impaired only in those with both acute and chronic GVHD.
The potency of allogeneic HCT in preventing relapse has long been attributed to a T cell-mediated antitumor effect targeting histocompatibility or tumor-associated antigens expressed on the target neoplastic cells [1,2,8]. A second contention, that GVHD was directly associated with the antineoplastic effect was reported in a landmark paper which included only a modest number of patients with leukemia . In 1990, Horowitz et al., described a stepwise, more evident protection against relapse associated with acute, chronic or acute plus chronic GVHD. All transplants with GVHD were found to associate with more potent GVL than either syngeneic or GVHD-free transplantation in a population that included sibling donor MAC transplantation for patients with AML, chronic myeloid leukemia and acute lymphoblastic leukemia but not MDS . Additionally, only a minority of patients in that early report received double agent therapy for post-transplant immune suppression, which might potentially alter the GVL effect. Despite these differences, after MAC, the findings in the early study are similar to the MAC transplants in the current study with a statistically significant GVL effect associated with acute plus chronic GVHD, but no significant effect of isolated acute GVHD. However, no protection against relapse had been seen with isolated chronic GVHD, although only few (n=54) patients were in that group. In the current analysis, chronic GVHD alone or with acute GVHD was associated with relapse protection, but only in the first post transplant year. In patients receiving RIC regimens, the situation is different as both acute and chronic GVHD, alone or in combination, had protective effects on relapse.
The current analysis, by including a landmark analysis of one-year disease free survivors, allowed us to specifically examine later effects on relapse, beyond 1 year. Here we observed further divergence between GVHD and GVL with MAC and RIC regimens. After MAC we observed substantial higher late TRM risks with any GVHD, but no greater protection against relapse, suggesting that any GVL effects have already been manifest in the first year. GVHD, therefore, led to a substantially higher risk of late treatment failure. In contrast, among patients who had received RIC regimens, one-year disease free survivors with both acute and chronic GVHD continue to have a significant GVL benefit, suggesting an ongoing active anti-leukemia process. The increase in late TRM associated with GVHD was restricted to patients with both acute and chronic GVHD and, although statistically significant, was of a lesser magnitude in the cohort receiving RIC versus MAC regimens. Consequently, there was no higher risk of late treatment failure associated with any GVHD in patients receiving RIC. These data suggest that following RIC, a setting where late GVHD-associated mortality is ameliorated, its potent association with GVL might improve outcomes and increase the fraction of leukemia patients surviving disease-free.
It is difficult to predict, however, the effect GVHD on overall relapse and survival. Several recent reports could not document augmented antineoplastic protection with either partially matched related or unrelated donor transplantation compared to HLA matched sibling transplantation, circumstances where greater histoincompatibility leads to more GVHD [[9–12]. This suggests that the clinical consequences of GVHD might not always be accompanied by sufficiently potent GVL effects to improve disease control and survival in patients with AML or MDS. These observations do not illuminate the mechanism underlying the immunologic cytolytic effects that may be coordinately operative in GVHD and GVL. T cell, NK cell or pro-apoptotic inflammatory responses may all limit persistence of neoplastic cells, yet not induce clinically uncontrollable or fatal GVHD [13–16]. What, therefore, are the clinical implications of these findings? One might infer that using RIC [17–20], where a greater residual tumor burden may persist following conditioning, clinically limited GVHD may convey a profound and important GVL response. Indeed, in vivo T cell depletion using anti-thymocyte globulin or alemtuzumab with RIC transplants has been reported to compromise GVL and overall survival . In patients with no manifestations of GVHD, additional interventions including, for example, adoptive cellular therapy or antitumor vaccination might be warranted to limit the risks of leukemia recurrence. Conversely, following MAC, with an expectedly lower post-transplant residual disease burden, more stringent measures to limit GVHD might be of net clinical benefit [22,23]. Clinical strategies to balance these two effects, perhaps best combined with measures to better detect persisting post-transplant MRD, might be integrated to identify those most likely to benefit from additional post-transplant anti-leukemic interventions.
Supported by a Public Health Service grant (U24-CA76518) from the National Cancer Institute, the National Heart Lung and Blood Institute and the National Institute of Allergy and Infectious Diseases and a contract (SCTOD#HHSH234200637015C) from the Health Services and Resource Administration. The authors acknowledge the participation of numerous transplant and donor centers who collect and submit data to the CIBMTR.
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These data were presented in part at the 2011 American Society of Hematology meeting, San Diego, California.
Authorship ContributionsDW, MJZ and ME designed the study and completed the analysis.
All authors wrote the paper and approved the final submission.
Conflict of Interest
The authors all report no conflict of interest for any submitted information in this manuscript.