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.
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.
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.
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.
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.
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.
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.
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.
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.
Forman SJ, Schmidt GM, Nademanee AP et al. Allogeneic bone marrow transplantation as therapy for primary induction failure for patients with acute leukemia. J Clin Oncol 1991; 9: 1570–1574.
Biggs JC, Horowitz MM, Gale RP et al. Bone marrow transplants may cure patients with acute leukemia never achieving remission with chemotherapy. Blood 1992; 80: 1090–1093.
Martin PJ, Clift RA, Fisher LD et al. HLA-identical marrow transplantation during accelerated-phase chronic myelogenous leukemia: analysis of survival and remission duration. Blood 1988; 72: 1978–1984.
Copelan EA, Grever MR, Kapoor N, Tutschka PJ . Marrow transplantation following busulfan and cyclophosphamide for chronic myelogenous leukaemia in accelerated or blastic phase. Br J Haematol 1989; 71: 487–491.
Sullivan KM, Storb R, Buckner CD et al. Graft-versus-host disease as adoptive immunotherapy in patients with advanced hematologic neoplasms. N Engl J Med 1989; 320: 828–834.
Sullivan KM, Weiden PL, Storb R et al. Influence of acute and chronic graft-versus-host disease on relapse and survival after bone marrow transplantation from HLA-identical siblings as treatment of acute and chronic leukemia. Blood 1989; 73: 1720–1728.
Weisdorf DJ, Nesbit ME, Ramsay NK et al. Allogeneic bone marrow transplantation for acute lymphoblastic leukemia in remission: prolonged survival associated with acute graft-versus-host disease. J Clin Oncol 1987; 5: 1348–1355.
Weiden PL, Flournoy N, Thomas ED et al. Antileukemic effect of graft-versus-host disease in human recipients of allogeneic-marrow grafts. N Engl J Med 1979; 300: 1068–1073.
Horowitz MM, Gale RP, Sondel PM et al. Graft-versus-leukemia reactions after bone marrow transplantation. Blood 1990; 75: 555–562.
Grebe SC, Streilein JW . Graft-versus-host reactions: a review. Adv Immunol 1976; 22: 119–221.
Korngold R, Sprent J . T cell subsets and graft-versus-host disease. Transplantation 1987; 44: 335–339.
Ferrara JL, Deeg HJ . Graft-versus-host disease. N Engl J Med 1991; 324: 667–674.
Ringden O, Hermans J, Labopin M et al. The highest leukaemia-free survival after allogeneic bone marrow transplantation is seen in patients with grade I acute graft-versus-host disease. Acute and Chronic Leukaemia Working Parties of the European Group for Blood and Marrow Transplantation (EBMT). Leuk Lymphoma 1996; 24: 71–79.
Gratwohl A, Brand R, Apperley J et al. Graft-versus-host disease and outcome in HLA-identical sibling transplantations for chronic myeloid leukemia. Blood 2002; 100: 3877–3886.
Weisdorf D, Haake R, Blazar B et al. Treatment of moderate/severe acute graft-versus-host disease after allogeneic bone marrow transplantation: an analysis of clinical risk features and outcome. Blood 1990; 75: 1024–1030.
Paulin T, Ringden O, Nilsson B et al. Variables predicting bacterial and fungal infections after allogeneic marrow engraftment. Transplantation 1987; 43: 393–398.
Miller W, Flynn P, McCullough J et al. Cytomegalovirus infection after bone marrow transplantation: an association with acute graft-versus-host disease. Blood 1986; 67: 1162–1167.
Glucksberg H, Storb R, Fefer A et al. Clinical manifestations of graft-versus-host disease in human recipients of marrow from HL-A-matched sibling donors. Transplantation 1974; 18: 295–304.
Gratwohl A, Hermans J, Apperley J et al. Acute graft-versus-host disease: grade and outcome in patients with chronic myelogenous leukemia. Working Party Chronic Leukemia of the European Group for Blood and Marrow Transplantation. Blood 1995; 86: 813–818.
Barrett AJ, Horowitz MM, Gale RP et al. Marrow transplantation for acute lymphoblastic leukemia: factors affecting relapse and survival. Blood 1989; 74: 862–871.
Grigg AP, Szer J, Beresford J et al. Factors affecting the outcome of allogeneic bone marrow transplantation for adult patients with refractory or relapsed acute leukaemia. Br J Haematol 1999; 107: 409–418.
Ringden O, Sundberg B, Lonnqvist B et al. Allogeneic bone marrow transplantation for leukemia: factors of importance for long-term survival and relapse. Bone Marrow Transplant 1988; 3: 281–290.
Shiobara S, Nakao S, Ueda M et al. Donor leukocyte infusion for Japanese patients with relapsed leukemia after allogeneic bone marrow transplantation: lower incidence of acute graft-versus-host disease and improved outcome. Bone Marrow Transplant 2000; 26: 769–774.
Kolb HJ, Schattenberg A, Goldman JM et al. Graft-versus-leukemia effect of donor lymphocyte transfusions in marrow grafted patients. European Group for Blood and Marrow Transplantation Working Party Chronic Leukemia. Blood 1995; 86: 2041–2050.
Ringden O, Labopin M, Gorin NC et al. Is there a graft-versus-leukaemia effect in the absence of graft-versus-host disease in patients undergoing bone marrow transplantation for acute leukaemia? Br J Haematol 2000; 111: 1130–1137.
Locatelli F, Zecca M, Rondelli R et al. Graft versus host disease prophylaxis with low-dose cyclosporine-A reduces the risk of relapse in children with acute leukemia given HLA-identical sibling bone marrow transplantation: results of a randomized trial. Blood 2000; 95: 1572–1579.
Morishima Y, Kodera Y, Hirabayashi N et al. Low incidence of acute GVHD in patients transplanted with marrow from HLA-A,B,DR-compatible unrelated donors among Japanese. Bone Marrow Transplant 1995; 15: 235–239.
About this article
Cite this article
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
- acute graft-versus-host disease
- allogeneic transplantation
Blood Advances (2019)
Immune stimulation during chemotherapy increases incidence of acute graft versus host disease in acute myeloid leukemia: A study on behalf of SFGM-TC and ALFA
Leukemia Research (2017)
Impacts of graft-versus-host disease on outcomes after allogeneic hematopoietic stem cell transplantation for chronic myelomonocytic leukemia: A nationwide retrospective study
Leukemia Research (2016)
Improved outcome of children transplanted for high-risk leukemia by using a new strategy of cyclosporine-based GVHD prophylaxis
Bone Marrow Transplantation (2016)
Impact of pre-transplant disease burden on the outcome of allogeneic hematopoietic stem cell transplant in refractory and relapsed acute myeloid leukemia: a single-center study
Leukemia & Lymphoma (2015)