Graft-Versus-Host Disease

Clinical impact of graft-versus-host disease against leukemias not in remission at the time of allogeneic hematopoietic stem cell transplantation from related donors. The Japan Society for Hematopoietic Cell Transplantation Working Party

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Summary:

Acute graft-versus-host disease (GVHD) increases post-transplant mortality and morbidity, but exerts a potent graft-versus-leukemia (GVL) effect. To clarify the impact of GVHD on outcome after transplant in aggressive diseases, patients with acute myeloid or lymphoblastic leukemia (AML, n=366 or ALL, n=255) in nonremission states, or chronic myelogenous leukemia (CML, n=180) in accelerated phase (AP) or blastic crisis (BC), who received allogeneic hematopoietic stem cell transplantation (HSCT) from a related donor between 1991 and 2000, were analyzed. Significant improvement in overall and disease-free survival (DFS) was detected with grade I acute GVHD in AML (P=0.0002 for overall survival and 0.0009 for DFS, respectively) and in CML (P=0.0256 and 0.0366, respectively), while the trend towards improved survival was observed in ALL. Relapse rate was lower in grade I acute GVHD than in grade II in all three diseases, suggesting that treatment for grade II GVHD may compromise the GVL effect associated with GVHD. Chronic GVHD was found to suppress relapse in CML and ALL, but not in AML, although no improvement in survival was observed in any disease category. Our results suggest that treatment for grade II acute GVHD may need to be attenuated in transplant for refractory leukemias.

Main

Refractory or relapsed acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and chronic myelogenous leukemia (CML) in accelerated phase (AP) or blastic crisis (BC) have poor prognosis, and conventional salvage chemotherapy does not yield satisfactory survival benefit for patients with these refractory and/or advanced leukemias. If a suitable donor for allogeneic hematopoietic stem cell transplantation (HSCT) is available and the patient's general condition permits, high-dose chemo-radiotherapy followed by allogeneic HSCT is indicated for the advanced stage of these diseases. In spite of high incidence of transplant-related mortality (TRM) and morbidity, including regimen-related toxicity (RRT), infection, and other complications,1, 2 allogeneic HSCT during the nonremission state seems to contribute toward prolonged disease-free survival (DFS). Indeed, clinical evidence shows its potential of curing these highly aggressive diseases.1, 2, 3, 4 It has been shown that allogeneic HSCT overcomes chemo-refractoriness not only by increasing the dose of chemotherapeutic agents by several fold, but also by exerting a potent graft-versus-leukemia (GVL) effect which cannot be achieved with high-dose therapy followed by autologous HSCT.5, 6, 7, 8, 9 It is assumed that both graft-versus-host disease (GVHD) and GVL, being observed together and considered to be inseparable at this point, are mediated by specific or nonspecific allo-cellular immunity.10, 11, 12 Thus, the grade of GVHD may be considered as a surrogate marker for the GVL effect, and an appropriate level of GVL (or GVHD) should be sought according to the condition of the underlying disease. It is a general understanding that grade I acute GVHD may be associated with an improved post-transplant outcome.13, 14 In cases of grade II acute GVHD or above, its beneficial aspect of suppressing leukemic relapse is overwhelmed by the deleterious effect of acute GVHD, and overall survival (OS) may be worse than that without GVHD.15, 16, 17 However, this observation is mainly based on the results with standard risk patients or patients whose disease is relatively well controlled at the time of transplant. It is not known whether more GVL/GVHD is appropriate or justified if the disease is not in remission at the time of transplant.

To clarify this point, we investigated, in the present study, a relationship between the severity (grade) of acute GVHD and overall DFS, as well as relapse in patients with refractory or advanced leukemia receiving allogeneic HSCT from related donors. In addition, the effect of the presence or absence of chronic GVHD was also analyzed.

Patients and methods

Study design and data collection

The present study was based on the collected data from a 2001 nationwide survey conducted by the Japan Society for Hematopoietic Cell Transplantation (JSHCT). All of the data were collected from 396 participating institutions, which provided detailed information about patients, donors, procedures, and outcomes of all HSCT. The database was updated annually. In this study, patients transplanted between 1991 and 2000 were analyzed. Acute GVHD was graded according to the Seattle criteria.18 In CML and ALL, grade III and IV acute GVHD were put together into one group, as the number of patients were not sufficient.

Statistical analysis

OS curves with regard to each grade of acute GVHD in individual diseases were generated according to the Kaplan–Meier method. Cox proportional hazards regression model was employed as a multivariate analysis with all continuous variables dichotomized. The choice of covariates to be analyzed and cut points of continuous covariates were made in concordance with previous reports.6, 14, 19 All statistical analyses were performed with the StatView version 5.0 (SAS Institute Inc., CA, USA). To minimize the effect of competing risks, day 100 landmark analysis was performed for analysis of acute GVHD effect on relapse.

Results

Patients

A total of 801 patients with either AML (n=366), ALL (n=255) in nonremission state, or CML (n=180) in AP or BC at the time of either bone marrow transplantation (BMT) or peripheral blood stem cell transplantation (PBSCT) from related donors between 1991 and 2000 were analyzed. In patients who underwent two or more transplantations, the data of the last one were assessed. Table 1 summarized the characteristics of patients and transplantation. Sex, age, disease status, donor source, type of transplant, number of transplant, prophylaxis for acute GVHD, preparative regimens, year of transplant, and interval from diagnosis to transplant were extracted from the database. FAB classification in acute leukemias and the presence of Philadelphia chromosome (Ph) in ALL were also analyzed.

Table 1 Patient characteristics

Acute and chronic GVHD

The incidence and severity of acute GVHD were similar among all the three categories of leukemias. Acute GVHD grade II–IV was observed in less than half of the patients. Chronic GVHD was observed slightly more than half of the patients in all the three diseases.

Transplant outcome and acute and chronic GVHD

At the time of this analysis, 84 (23%) of 366 patients with AML, 47 (18%) of 255 with ALL, and 61 (34%) of 180 with CML were alive. OS, DFS, and relapse according to the grade of acute GVHD in AML, CML, and ALL are shown in Figures 1, 2 and 3, respectively. Same analyses according to the presence or absence of chronic GVHD in each disease are shown in Figures 4, 5 and 6, respectively.

Figure 1
figure1

OS (a), DFS (b), and relapse (c) in AML not in remission at the time of transplant, by the grade of acute GVHD. Grade 0 (solid line), grade I (interrupted line), grade II (thin line), grade III (gray line), and grade IV (dotted line). Relapse was shown by landmark analysis at day 60.

Figure 2
figure2

OS (a), DFS (b), and relapse (c) in CML in AP or BC at the time of transplant, by the grade of acute GVHD. Grade 0 (solid line), grade I (interrupted line), grade II (thin line), and grade III–IV (gray line). Relapse was shown by landmark analysis at day 60.

Figure 3
figure3

OS (a), DFS (b), and relapse (c) in ALL not in remission at the time of transplant, by the grade of acute GVHD. Grade 0 (solid line), grade I (interrupted line), grade II (thin line), and grade III–IV (gray line). Relapse was shown by landmark analysis at day 60.

Figure 4
figure4

OS (a), DFS (b), and relapse (c) in AML not in remission at the time of transplant, by the presence (thin line) or absence (thick line) of chronic GVHD.

Figure 5
figure5

OS (a), DFS (b), and relapse (c) in CML in AP or BC at the time of transplant, by the presence (thin line) or absence (thick line) of chronic GVHD.

Figure 6
figure6

OS (a), DFS (b), and relapse (c) in ALL not in remission at the time of transplant, by the presence (thin line) or absence (thick line) of chronic GVHD.

In AML, grade I acute GVHD and grade IV acute GVHD were associated with significantly better (P=0.0002 for OS and 0.0009 for DFS) and worse (P<0.0001 for both OS and DFS) survival compared to other grades of acute GVHD, respectively (Figure 1). In CML, grade I acute GVHD was again associated with a better survival than others (P=0.0256 for OS and 0.0366 for DFS, Figure 2). However, in ALL, the trend was observed that acute GVHD grade I is associated with a better survival, but not significant (P=0.0620 for OS and 0.0938 for DFS, Figure 3).

In all the three diseases, grade I acute GVHD was associated with lower relapse rate than grade 0 or grade II acute GVHD. Relapse rate with grade II acute GVHD was as high as with grade 0 acute GVHD, whereas that with grade I acute GVHD was close to that with grade III acute GVHD in all disease categories (Figures 1c, 2c, 3c). The relative risk of relapse in each disease with each grade of acute GVHD is summarized in Table 2.

Table 2 Relative risk of relapse compared to patients with grade 0 acute GVHD

Multivariate analysis for factors on OS

Multivariate analyses were performed to estimate the significance of risk factors other than acute or chronic GVHD for OS in each disease. Table 3 shows the results of the analysis.

Table 3 Result of multivariate analysis

Adult patients showed worse outcome compared to children with AML (RR=2.451, 95% CI (1.332–4.509)). The post-transplant outcome of CML in BC was worse than that in AP (RR=2.640, 95% CI (1.607–4.335)). HLA disparity between a donor–recipient pair showed a significantly unfavorable influence on only CML (RR=2.497, 95% CI (1.276–4.887)). T-cell depletion was a significant risk factor for AML (RR=9.887, 95% CI (2.097–46.628)) and ALL (RR=23.930, 95% CI (4.560–125.590)), but it was not for CML (RR=0.263, 95% CI (0.049–1.414)). PBSCT demonstrated lower RR compared to BMT in ALL (RR=0.433, 95% CI (0.234–0.801)). However, the opposite result was found in CML (RR=3.057, 95% CI (1.450–6.447)). No significant differences were found in survival according to sex, karyotypic abnormalities, preparative regimens, and intervals from diagnosis to transplantation in all diseases.

Discussion

Development of acute GVHD has been demonstrated to contribute to suppress leukemic relapse after allogeneic HSCT and to be associated with longer leukemia-free and OS.5, 6, 7, 8, 9, 14, 19, 20, 21, 22 This is considered as one of the evidences to confirm the existence of GVL effect, as well as the efficacy of donor lymphocyte infusion (DLI), for relapsed leukemia after allogeneic HSCT.23, 24 Some reports claim that there may be GVL without GVHD,25 but it is still debatable whether GVL effect is separable from GVHD. On the other hand, moderate to severe acute GVHD had been believed to have deleterious effects on the transplant outcome.15 Therefore, grade I GVHD is not usually treated, but grade II and higher GVHD is treated with steroid in a standard manner. If the disease status is different at the time of allogeneic HSCT, the appropriate level of acute GVHD may be different. If there is any occasion that more than slight (grade I) acute GVHD may be desirable, patients who have extremely high risk for relapse of leukemia after transplantation may be those patients who receive more benefit from ‘more than slight’ GVHD. In this study, we dealt with only those who have an extremely high risk for post-transplant disease progression; patients with AML, CML and ALL in advanced or refractory stages only were analyzed in order to clarify the influence of GVHD on more aggressive diseases.

Our results indicate that patients who developed grade I acute GVHD showed significantly improved overall and DFS compared to those who did not develop acute GVHD at all or developed grade II–IV acute GVHD in AML and CML. The same trend was observed in ALL, although not statistically significant. It has been reported that grade I acute GVHD is associated with the best survival.13, 14 In addition, our analyses show that grade I acute GVHD was associated with a lower relapse rate than grade II acute GVHD. As far as we know, this is the first time that this observation has been reported. The same trend was observed in all the three disease categories, independently. Usually, grade I acute GVHD is not treated, but grade II and higher grade acute GVHD are treated with steroids, 2 mg/kg of prednisolone most of the time. Apparently, the treatment of acute GVHD compromised a GVL effect. Among the nontreated group (grade 0 and I), grade 0 GVHD is associated with a higher relapse rate than grade I, whereas in the treated group (grade II, III and IV) the relapse rate was higher in grade II, and lower in grades III and IV. The relapse rate with grade II acute GVHD was as high as with grade 0, whereas that with grade I acute GVHD was as low as that with grade III acute GVHD. In other reports, the patients had standard risk diseases, such as CML or AML with standard risks.13, 14 Thus, attenuation of the GVL effect by the treatment for acute GVHD may not have had such a deleterious effect. In addition, the relapse rate in standard risk diseases is up to 20%; thus, the small increase in the relapse rate may not have been detected. In this series, the relapse rate was between 40 and 80% in most of the disease categories as the patient population was associated with very high relapse risk. Thus, the increase in relapse was readily detected. We conclude that, at least in most aggressive diseases, treatment of acute GVHD may compromise the GVL effect.

The time course of acute GVHD was not taken into account in this study, as well as in any other studies; that is, only the maximum grade of acute GVHD was reported. It has been disregarded whether acute GVHD was still active when the disease relapsed. There is a possibility that duration of GVHD may be as important as the maximum grade of acute GVHD to suppress disease relapse. The current database did not allow us to analyze the effect of the duration of acute GVHD, but hereafter this also should be taken into account.

It has been known that grade I acute GVHD is associated with the best survival because transplant-related morbidity and mortality may increase with higher grade acute GVHD. In this series, however, increased relapse was the obvious reason for poorer survival in grade II acute GVHD compared to grade I. Grade II acute GVHD usually does not increase transplant-related mortality by itself.14 Thus, it may be possible that withholding or attenuating the treatment of acute GVHD in cases of grade II acute GVHD may improve the survival of the patients, particularly in aggressive diseases. It has to be noted, however, that high-grade acute GVHD may, if not appropriately treated, progress rapidly into more advanced disease, particularly in the case of gut GVHD. In addition, if not properly treated early, particularly gut GVHD may become more resistant to steroid treatment. Acute GVHD refractory to steroid treatment dictates dismal prognosis.26 If there is any factor which may predict whether GVHD in a particular patient will be steroid refractory or not, it will be very useful to ‘tailor’ the treatment for acute GVHD. Research to find such factors should be encouraged. Practically, as we do not have such predictive factors at present, acute GVHD treatment may be attenuated only in the cases of skin-only grade II GVHD, as skin-only diseases rarely progress to lethal stage. Alternatively, initial GVHD treatment may be started with standard dose steroid, and if responsiveness to steroid is prompt, treatment can be rapidly attenuated, that is, relatively fast steroid taper after initial response. If grade II or higher acute GVHD is treated, not as much as to completely suppress GVHD, but to ‘titrate’ the GVHD treatment so that GVHD similar to grade I disease can be seen for a longer period of time, the survival may be improved in aggressive diseases. In addition to facilitating possible relapse, an intensive therapy for acute GVHD may result in severe immunosuppression and many complications associated with it, including severe infections. Thus, it may not always be true that one has to completely suppress GVHD by strong immunosuppression. However, since acute GVHD is not always controllable once developed, there is a significant risk of inducing ‘severe’ GVHD unintentionally as discussed above. Thus, acute GVHD is really a ‘double-edged sword’.

Particular attention should be paid to the genetic homogeneity among the Japanese population and a decreased incidence and severity of acute GVHD as compared to the incidence and severity in the Caucasians.27 Thus, there is a possibility that attenuation of acute GVHD treatment in the Caucasian population may not be as safe as in the Japanese population.

It is generally described that a GVL effect is less apparent in ALL. Our results may indicate that GVL effect carried by acute GVHD may be effective even in ALL. On the other hand, it was unexpected that the positive role of acute GVHD was not more distinct in CML, compared to AML or ALL, given the established efficacy of DLI for post-transplant relapse as a method of delivering a direct GVL effect after allogeneic HSCT.23, 24 It is possible that, even in CML, when leukemic proliferation is active, such as in AP or BC, the GVL effect may not be more effective than in AML or ALL.

In the analysis of chronic GVHD, neither overall, nor DFS, was affected by the presence or absence of chronic GVHD in any of the diseases. In CML and ALL, the advantage of chronic GVHD in relapse rate was counterbalanced by the negative effect of chronic GVHD on survival. However, in AML, even the relapse rate was similar with or without chronic GVHD. The reason for this observation is not known.

The influence of other covariates was demonstrated in this study. Sex, age, disease status, karyotypic abnormality, donor source, type of transplant, number of transplants, prophylaxis of acute GVHD, preparative regimen, year of transplant, and interval from diagnosis to transplant were assessed (Table 3). It is of interest that T-cell depletion (TCD) was the strongest risk factor among all covariates in AML and ALL. It is again unexpected that TCD was not a significant risk factor in CML.

In summary, we have shown that the grade of acute GVHD has an effect on post-transplant outcome in patients with refractory or advanced leukemias. We found that grade I acute GVHD is at least beneficial for survival. Even patients with grade II–III acute GVHD may have comparable survival to patients without GVHD if the underlying diseases were not in remission at the time of transplant. We have also shown that the relapse rate of the disease is higher in patients with grade II acute GVHD than in grade I acute GVHD, most likely due to the immunosuppressive treatment for acute GVHD. Particular attention should be paid to determine the optimal way of treating, or ‘not treating’, GVHD in patients with the most aggressive leukemias. Further studies in this direction are warranted to clarify issues which were not conclusive in the present study.

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Kataoka, I., Kami, M., Takahashi, S. et al. Clinical impact of graft-versus-host disease against leukemias not in remission at the time of allogeneic hematopoietic stem cell transplantation from related donors. The Japan Society for Hematopoietic Cell Transplantation Working Party. Bone Marrow Transplant 34, 711–719 (2004) doi:10.1038/sj.bmt.1704659

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Keywords

  • acute graft-versus-host disease
  • allogeneic transplantation
  • leukemia
  • nonremission

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