Abstract

The incidence, characteristics, risk factors for, and impact of chronic graft-vs-host disease (GVHD) were evaluated in a consecutive series of 116 evaluable HLA-identical blood stem cell transplant recipients. Minimum follow-up was 18 months. Limited chronic GVHD occurred in 6% (95% confidence interval [CI], 0%-13%), and clinical extensive chronic GVHD in 71% (95% CI, 61%-80%). The cumulative incidence was 57% (95% CI, 48%-66%). In univariate analyses, GVHD prophylaxis other than tacrolimus and methotrexate, prior grades 2 to 4 acute GVHD, use of corticosteroids on day 100, and total nucleated cell dose were significant risk factors for clinical extensive chronic GVHD. On multivariate analysis, GVHD prophylaxis with tacrolimus and methotrexate was associated with a reduced risk of chronic GVHD (hazard ratio [HR], 0.35; P = .001), whereas the risk was increased with prior acute GVHD (HR, 1.67;P = .046). When adjusted for disease status at the time of transplantation, high-risk chronic GVHD had an adverse impact on overall mortality (HR, 6.6; P < .001) and treatment failure (HR, 5.2; P < .001) at 18 months. It was concluded that there is a substantial rate of chronic GVHD after HLA-identical allogeneic blood stem cell transplantation, that clinical factors may alter the risk of chronic GVHD, and that high-risk chronic GVHD adversely affects outcome.

Introduction

Transplantation of mobilized blood stem cells from HLA-identical sibling donors has been explored extensively. In the initial reports comparing early outcome measures for allogeneic blood stem cell recipients with those for historical or concurrent control marrow recipients, the use of blood stem cells was associated with less regimen-related toxicity,1,2 earlier hematopoietic recovery,2-9 a reduction in transfusion requirements,3,4,10 fewer days of hospitalization,2,3,10 and lower initial cost11 without an increase in acute graft-vs-host disease (GVHD). Subsequent randomized trials have confirmed these benefits of blood stem cell grafts for allogeneic transplantation.12-16 

In contrast, the question of whether the use of blood stem cells alters the risk of chronic GVHD in allograft recipients has been controversial; several centers have reported no impact,3,4,7,14,16,17 whereas other centers related a trend toward,2,6,13 or statistically significant,5,8,9,15,18 increase in the rate of chronic GVHD. Moreover, there is a substantial variation in the rates of chronic GVHD reported to occur after allogeneic blood stem cell transplantation.2-18 In addition, it is unclear whether relapse is altered with the use of allogeneic blood stem cells, and some researchers have suggested that the risk of relapse may depend on the occurrence of chronic GVHD in these patients.19 To address some of these inconsistencies, we evaluated the incidence, characteristics, risk factors for, and impact of chronic GVHD in a consecutive series of HLA-identical blood stem cell transplant recipients.

Patients and methods

Patients

Over a consecutive 45-month period, 168 adults received a myeloablative preparative regimen and an unmanipulated blood stem cell graft from an HLA-matched related donor. Recipients of T-cell–depleted blood stem cell transplants and those receiving minitransplant preparative regimens were not included. One hundred sixteen patients survived at least 100 days after transplantation and were evaluable for chronic GVHD (Table 1). One additional patient left the country after day 100, and follow-up data were insufficient for inclusion in this study. The medical records were reviewed retrospectively for date of onset of chronic GVHD, staging, organ involvement, and outcome. Details of blood stem cell collection and administration, peritransplant care, and GVHD prophylaxis have been described previously.20 Patients received 1 of 3 GVHD prophylaxis regimens depending on the standard at the time of transplantation or the requirement of the transplantation protocol as designated by the standard at the time the protocol was instituted.20 Patients were not assigned to a GVHD prophylaxis regimen on the basis of risk of GVHD. Written informed consent was obtained from each patient, and all protocols were approved by the Institutional Review Board of the MD Anderson Cancer Center.

Table 1.

Patient, donor, and graft characteristics

No. patients 116* 
Median patient age (range) 38 yrs (17-61)  
Patient sex (male/female) 58/58 
Diagnosis  
 Leukemia/myelodysplastic syndrome 66 
 Lymphoma/Hodgkin disease/myeloma 42  
 Solid tumor 
Disease status  
 First remission or chronic phase 12 
 Second remission or accelerated phase 31  
 Relapse or blast crisis 73  
Preparative regimen  
 Total body irradiation–based 30  
 Chemotherapy alone 86  
GVHD prophylaxis  
 Cyclosporine/methylprednisolone 32 
 Tacrolimus/methylprednisolone 45 
 Tacrolimus/methotrexate 39  
Prior grades 2-4 acute GVHD 33  
On steroids at day 100 46  
Median donor age (range) 39 yrs (8-64)  
Donor sex (male/female) 57/59  
Pair cytomegalovirus-seronegative 12  
Total nucleated cells infused (range) 8.7 × 108/kg (1.1-26.3) 
CD34+ cells infused (range) 5.7 × 106/kg (1.9-20.9)  
CD3+ cells infused (range) 2.3 × 108/kg (0.3-6.9)  
CD56+cells infused (range) 2.6 × 107/kg (1.0-8.1) 
No. patients 116* 
Median patient age (range) 38 yrs (17-61)  
Patient sex (male/female) 58/58 
Diagnosis  
 Leukemia/myelodysplastic syndrome 66 
 Lymphoma/Hodgkin disease/myeloma 42  
 Solid tumor 
Disease status  
 First remission or chronic phase 12 
 Second remission or accelerated phase 31  
 Relapse or blast crisis 73  
Preparative regimen  
 Total body irradiation–based 30  
 Chemotherapy alone 86  
GVHD prophylaxis  
 Cyclosporine/methylprednisolone 32 
 Tacrolimus/methylprednisolone 45 
 Tacrolimus/methotrexate 39  
Prior grades 2-4 acute GVHD 33  
On steroids at day 100 46  
Median donor age (range) 39 yrs (8-64)  
Donor sex (male/female) 57/59  
Pair cytomegalovirus-seronegative 12  
Total nucleated cells infused (range) 8.7 × 108/kg (1.1-26.3) 
CD34+ cells infused (range) 5.7 × 106/kg (1.9-20.9)  
CD3+ cells infused (range) 2.3 × 108/kg (0.3-6.9)  
CD56+cells infused (range) 2.6 × 107/kg (1.0-8.1) 
*

No. patients unless indicated otherwise.

Chronic GVHD grading and other study definitions

The diagnosis of GVHD was based on clinical evidence with histologic confirmation whenever possible.21 GVHD was graded as limited (localized skin or single organ involvement) or clinical extensive (generalized skin or multiple organ involvement), and platelet count was used to categorize the risk as high (platelet count less than 100 × 109/L) or low (platelet count exceeding 100 × 109/L).22 Disease status was considered early for patients in first remission or first chronic phase, intermediate for those in second remission or accelerated phase, and advanced for those in later remission, relapse, or blast crisis.

Statistical considerations

Minimum follow-up at the time of analysis was 18 months after transplantation. The actuarial rates of chronic GVHD and disease-free survival were calculated by the method of Kaplan and Meier.23 The cause-specific cumulative incidence of chronic GVHD was also calculated24 with relapse and death without relapse or chronic GVHD as competing risks. In the association of GVHD rates with continuously measured covariates, patients were initially grouped into quartiles based on covariate values (age, log cell dose). Proportional hazards regression modeling was used for univariate and multivariate analyses of chronic GVHD.25Factors found to be significant (P < .05) in the univariate analysis were included in the multivariate analysis. Factors that remained significant were retained in the final model. Factors that correlated with each other were not entered into the model simultaneously. An association was found between CD34+ cell dose group and use of methotrexate (Fisher exact test,P = .001), between CD3+ cell dose group and total nucleated cell dose group (Fisher exact test,P < .0001), and between prior acute GVHD and use of steroids at day 100 (Fisher exact test, P < .0001). Proportional hazards regression modeling with chronic GVHD entered as a time-dependent covariate was used to determine the effect of chronic GVHD on relapse, survival, and disease-free survival. A 2-sidedP < .05 was considered significant.

Results

Incidence of chronic GVHD

Three patients had limited chronic GVHD (actuarial rate, 6%; 95% confidence interval [CI], 0%-13%). One of these patients had only elevated liver enzymes, and 2 had only mild oral mucosal abnormalities. The actuarial rate of clinical extensive chronic GVHD at 18 months was 71% (95% CI, 61%-80%). The cumulative incidence of clinical extensive chronic GVHD at 18 months was 57% (95% CI, 48%-66%) (Figure 1). Onset was progressive in 5 patients (7%), quiescent in 20 (29%), and de novo in 43 (63%).

Fig. 1.

Clinical extensive chronic GVHD after allogeneic blood stem cell transplantation.

The cumulative risk of chronic GVHD was 57% at 18 months. Patients surviving more than 1 year without chronic GVHD are indicated by the tick marks. Competing risks were relapse without chronic GVHD (cumulative incidence, 24%) and death without relapse or chronic GVHD (cumulative incidence, 4%).

Fig. 1.

Clinical extensive chronic GVHD after allogeneic blood stem cell transplantation.

The cumulative risk of chronic GVHD was 57% at 18 months. Patients surviving more than 1 year without chronic GVHD are indicated by the tick marks. Competing risks were relapse without chronic GVHD (cumulative incidence, 24%) and death without relapse or chronic GVHD (cumulative incidence, 4%).

Risk factors for clinical extensive chronic GVHD

A number of demographic characteristics were evaluated as potential risk factors for clinical extensive chronic GVHD. When age was assessed by quartile, there was no trend for increasing risk of chronic GVHD with increasing age. When age was assessed dichotomously, there was no significant difference in chronic GVHD in patients above or below the median age of the group (Table2). Factors that were significant on univariate analysis were the GVHD prophylaxis regimen (P < .001), prior grades 2 to 4 acute GVHD (P = .013), and whether the patient was on corticosteroids at day 100 after transplantation (P = .027) (Table 2). There was no significant difference in the risk of chronic GVHD between the groups receiving cyclosporine or tacrolimus in addition to corticosteroids for GVHD prophylaxis (P = .55), so these 2 groups were combined for the multivariate analysis.

Table 2.

Univariate analysis of demographic risk factors for clinical extensive chronic graft-versus-host disease

Factor No. patients Chronic GVHD HR (95% CI)* P 
Patient age    
 Younger than 38 years 55 1.0  
 38 years or older 61 1.4  (0.8-2.2) .2  
Patient sex    
 Male 58 1.0  
 Female 58 0.9  (0.6-1.5) .8  
Diagnosis    
 Leukemia/myelodysplastic syndrome 66 1.0  
 Lymphoma/Hodgkin disease/myeloma 42 1.0  (0.6-1.6) .9  
 Solid tumor 0.9  (0.3-3.0) .9  
Disease status    
 First remission or chronic phase 12 1.0  
 Second remission or accelerated phase 31 1.4  (0.5-3.7) .5  
 Relapse or blast crisis 73 1.4  (0.6-3.6) .5  
Preparative regimen    
 Total body irradiation–based 30 1.0  
 Chemotherapy alone 86 0.97  (0.6-1.7) .9  
GVHD prophylaxis    
 Cyclosporine/methylprednisolone 32 1.0  
 Tacrolimus/methylprednisolone 45 0.8  (0.5-1.5) .6  
 Tacrolimus/methotrexate 39 0.3  (0.2-0.6) < .001  
Grades 2-4 acute GVHD    
 No 83 1.0  
 Yes 33 1.9  (1.1-3.1) .013  
On steroids at day 100    
 No 70 1.0  
 Yes 46 1.7  (1.1-2.8) .027  
Cytomegalovirus serology before transplant    
 Patient and donor seronegative 12 1.0  
 Patient or donor seropositive 104 0.5  (0.2-1.1) .07 
Factor No. patients Chronic GVHD HR (95% CI)* P 
Patient age    
 Younger than 38 years 55 1.0  
 38 years or older 61 1.4  (0.8-2.2) .2  
Patient sex    
 Male 58 1.0  
 Female 58 0.9  (0.6-1.5) .8  
Diagnosis    
 Leukemia/myelodysplastic syndrome 66 1.0  
 Lymphoma/Hodgkin disease/myeloma 42 1.0  (0.6-1.6) .9  
 Solid tumor 0.9  (0.3-3.0) .9  
Disease status    
 First remission or chronic phase 12 1.0  
 Second remission or accelerated phase 31 1.4  (0.5-3.7) .5  
 Relapse or blast crisis 73 1.4  (0.6-3.6) .5  
Preparative regimen    
 Total body irradiation–based 30 1.0  
 Chemotherapy alone 86 0.97  (0.6-1.7) .9  
GVHD prophylaxis    
 Cyclosporine/methylprednisolone 32 1.0  
 Tacrolimus/methylprednisolone 45 0.8  (0.5-1.5) .6  
 Tacrolimus/methotrexate 39 0.3  (0.2-0.6) < .001  
Grades 2-4 acute GVHD    
 No 83 1.0  
 Yes 33 1.9  (1.1-3.1) .013  
On steroids at day 100    
 No 70 1.0  
 Yes 46 1.7  (1.1-2.8) .027  
Cytomegalovirus serology before transplant    
 Patient and donor seronegative 12 1.0  
 Patient or donor seropositive 104 0.5  (0.2-1.1) .07 
*

Hazard ratio (95% CI) at 18 months in comparison with the reference group with a hazard ratio of 1.0.

No significant difference was found when chronic GVHD was assessed across quartiles of the total nucleated cell count or the cell subsets in the grafts. When assessed dichotomously, however, the rate of chronic GVHD was significantly higher in the highest quartile of total nucleated cell dose (P = .02), and there was a trend for increasing chronic GVHD in the highest quartile of CD34+cell dose (P = .08) (Table3).

Table 3.

Univariate analysis of graft characteristics as risk factors for clinical extensive chronic graft-versus-host disease

Factor No. patients Chronic GVHD HR (95% CI)3-150 P 
Total nucleated cells    
 Less than 1 × 109/kg 73 1.0 .02  
 At least 1 × 109/kg 43 1.8  (1.1-2.9)  
CD34+ cells    
 Less than 8 × 106/kg 84 1.0  
 At least 8 × 106/kg 32 1.6  (0.9-2.7) .08  
CD3+cells    
 Less than 3 × 108/kg 84 1.0  
 At least 3 × 108/kg 32 1.2  (0.7-2.0) .4  
CD56+cells    
 Less than 4 × 107/kg 87 1.0  
 At least 4 × 107/kg 29 1.1  (0.6-1.8) .8 
Factor No. patients Chronic GVHD HR (95% CI)3-150 P 
Total nucleated cells    
 Less than 1 × 109/kg 73 1.0 .02  
 At least 1 × 109/kg 43 1.8  (1.1-2.9)  
CD34+ cells    
 Less than 8 × 106/kg 84 1.0  
 At least 8 × 106/kg 32 1.6  (0.9-2.7) .08  
CD3+cells    
 Less than 3 × 108/kg 84 1.0  
 At least 3 × 108/kg 32 1.2  (0.7-2.0) .4  
CD56+cells    
 Less than 4 × 107/kg 87 1.0  
 At least 4 × 107/kg 29 1.1  (0.6-1.8) .8 
F3-150

See Table 2 footnote.

On multivariate analysis, 2 factors remained in the optimal model. Methotrexate in the GVHD prophylaxis regimen was associated with a significant reduction in risk of chronic GVHD (P = .001), and a history of grades 2 to 4 acute GVHD was associated with an increased risk of chronic GVHD (P = .046) (Table4). As there was a strong association between prior acute GVHD and use of corticosteroids at day 100, these 2 factors could not be included in the same model. When use of corticosteroids was included instead of history of acute GVHD, methotrexate in the GVHD prophylaxis remained a significant risk factor (hazard ratio [HR], 0.35; 95% CI, 0.2-0.6; P < .001), and use of corticosteroids at day 100 was associated with an increased risk of chronic GVHD (HR, 1.6; 95% CI, 1.0-2.6; P = .05). Although there was also an association between a low CD34+cell dose and use of methotrexate, grouping by CD34+ cell dose did not substitute for use of methotrexate as a significant prognostic factor in the model.

Table 4.

Summary of regression model for extensive chronic graft-versus-host disease

Risk factor HR (95% CI) P 
Methotrexate in GVHD prophylaxis 0.35  (0.2-0.6) .001  
Prior acute GVHD 1.67  (1.0-2.8) .046 
Risk factor HR (95% CI) P 
Methotrexate in GVHD prophylaxis 0.35  (0.2-0.6) .001  
Prior acute GVHD 1.67  (1.0-2.8) .046 

We reported previously that the risk of acute GVHD after allogeneic blood stem cell transplantation was lowest in patients receiving tacrolimus and methotrexate as GVHD prophylaxis and a CD34+cell dose lower than 8 × 106/kg.20 For the 37 patients in the current series who fulfill these criteria, the actuarial rate of chronic GVHD was 51% (95% CI, 32%-68%), and the cumulative risk was 43% (95% CI, 27%-61%). Of the affected individuals, 81% had low-risk chronic GVHD.

Characteristics of chronic GVHD

Twenty-five patients had high-risk chronic GVHD, and 43 had low-risk chronic GVHD (Table 5). There were several differences between the 2 groups clinically. Patients with high-risk chronic GVHD most commonly had abnormalities of the liver, skin, gut, and mouth, whereas in patients with low-risk disease, the skin, mouth, liver, and eyes were most commonly affected (Table 5). Eosinophilia occurred more frequently in the low-risk group. In addition, for patients with high-risk chronic GVHD, the median time from transplantation to onset of chronic GVHD was significantly shorter (P = .004) and 1-year progression-free survival was significantly less (P < .001).

Table 5.

Clinical characteristics of patients with extensive chronic graft-versus-host disease

 All patients
(n = 68) 
High-risk chronic GVHD (n = 25) Low-risk chronic GVHD (n = 43) 
Organ involvement    
 Rash/scleroderma 52  (75%)* 17  (68%) 35  (81%)  
 Oral mucositis 33  (49%) 8  (32%) 25  (58%)  
 Ocular sicca 17  (25%) 3  (12%) 14  (33%)  
 Pulmonary disease 6  (9%) 0  (0%) 6  (14%)  
 Liver abnormalities 45  (66%) 21  (84%) 24  (56%) 
 Esophagitis 3  (4%) 1  (4%) 2  (5%) 
 Nausea/vomiting 10  (15%) 6  (24%) 4  (9%) 
 Diarrhea 20  (29%) 13  (52%) 7  (16%) 
 Arthralgias/arthritis 6  (9%) 2  (8%) 4  (9%) 
 Myositis 2  (3%) 0  (0%) 2  (5%) 
 Eosinophilia 23  (34%) 3  (12%) 20  (47%) 
 Effusions 3  (4%) 0  (0%) 3  (7%)  
Median day of onset after transplantation (range) Day 209 (90-655) Day 135 (90-383) Day 229 (98-655) 
1-year progression-free survival from diagnosis of chronic GVHD (95% CI) 47%  (35%-59%) 16%  (0%-30%) 64%  (50%-79%) 
 All patients
(n = 68) 
High-risk chronic GVHD (n = 25) Low-risk chronic GVHD (n = 43) 
Organ involvement    
 Rash/scleroderma 52  (75%)* 17  (68%) 35  (81%)  
 Oral mucositis 33  (49%) 8  (32%) 25  (58%)  
 Ocular sicca 17  (25%) 3  (12%) 14  (33%)  
 Pulmonary disease 6  (9%) 0  (0%) 6  (14%)  
 Liver abnormalities 45  (66%) 21  (84%) 24  (56%) 
 Esophagitis 3  (4%) 1  (4%) 2  (5%) 
 Nausea/vomiting 10  (15%) 6  (24%) 4  (9%) 
 Diarrhea 20  (29%) 13  (52%) 7  (16%) 
 Arthralgias/arthritis 6  (9%) 2  (8%) 4  (9%) 
 Myositis 2  (3%) 0  (0%) 2  (5%) 
 Eosinophilia 23  (34%) 3  (12%) 20  (47%) 
 Effusions 3  (4%) 0  (0%) 3  (7%)  
Median day of onset after transplantation (range) Day 209 (90-655) Day 135 (90-383) Day 229 (98-655) 
1-year progression-free survival from diagnosis of chronic GVHD (95% CI) 47%  (35%-59%) 16%  (0%-30%) 64%  (50%-79%) 

Data presented as no. patients (with percentage of group in column in parentheses) unless indicated otherwise.

Effect of clinical extensive chronic GVHD on relapse, survival, and progression-free survival

For all patients, survival at 18 months was 55% (95% CI, 46%-64%), and progression-free survival was 45% (95% CI, 36%-54%). The cumulative incidence of relapse was 29% (95% CI, 21%-39%). On multivariate analysis with chronic GVHD entered as a time-dependent covariate and with adjustment for disease status at the time of transplantation (early, intermediate, or advanced), development of chronic GVHD did not have a significant impact on relapse (HR, 0.6; 95% CI, 0.2-1.4; P = .2), and neither low-risk nor high-risk chronic GVHD was an independent risk factor for relapse (Table 6).

Table 6.

Summary of effect of chronic graft-versus-host disease on outcomes

Outcome Low-risk chronic GVHD, HR
(95% CI) 
P High-risk chronic GVHD, HR
(95% CI) 
P 
Relapse 0.6  (0.2-1.6) .3 0.6  (0.1-2.4) .4 
Overall mortality 1.4  (0.6-3.2) .4 6.6  (3.5-12.4) < .001  
Treatment failure6-150 1.7  (0.8-3.3) .1 5.2  (2.9-9.4) < .001 
Outcome Low-risk chronic GVHD, HR
(95% CI) 
P High-risk chronic GVHD, HR
(95% CI) 
P 
Relapse 0.6  (0.2-1.6) .3 0.6  (0.1-2.4) .4 
Overall mortality 1.4  (0.6-3.2) .4 6.6  (3.5-12.4) < .001  
Treatment failure6-150 1.7  (0.8-3.3) .1 5.2  (2.9-9.4) < .001 

Hazard ratio (95% CI) at 18 months is in comparison with no chronic GVHD, when chronic GVHD is entered as a time-dependent covariate and there is adjustment for disease status at the time of transplantation.

For abbreviations, see footnote to Table 2.

F6-150

Treatment failure defined as relapse or death without relapse.

In contrast, high-risk chronic GVHD was a strong adverse factor for survival and progression-free survival when entered as a time-dependent covariate (Table 6). Moreover, when calculatations were done from the time of transplantation, patients who developed high-risk chronic GVHD had a relatively short progression-free survival (Figure2). For patients with high-risk chronic GVHD, the causes of death were GVHD-related in 85%, relapse in 10%, and other in 5%. For those with low-risk GVHD, 80% of the deaths were GVHD-related, 10% were due to relapse, and 10% were from other causes. For those who died without developing chronic GVHD, 77% of the deaths were due to relapse, and 23% to other causes. Thus, although the impact of GVHD on survival differs between the low-risk and high-risk chronic GVHD groups, GVHD was still the major cause of death within the first 18 months in both groups.

Fig. 2.

Progression-free survival from time of transplantation.

Long-term progression-free survival was 31% for patients without chronic GVHD (solid line), 51% for patients with low-risk chronic GVHD (dotted line), and 16% for patients with high-risk chronic GVHD (dashed line). All patients surviving in remission are indicated by the tick marks.

Fig. 2.

Progression-free survival from time of transplantation.

Long-term progression-free survival was 31% for patients without chronic GVHD (solid line), 51% for patients with low-risk chronic GVHD (dotted line), and 16% for patients with high-risk chronic GVHD (dashed line). All patients surviving in remission are indicated by the tick marks.

Discussion

The reported rates of chronic GVHD after allogeneic blood stem cell transplantation have varied from 38% to 95%.2-9,13-18,26-29 In our series, the actuarial rate of chronic GVHD was 77%, and almost all of our patients with chronic GVHD had clinical extensive disease. This predominance of clinical extensive over limited chronic GVHD after allogeneic blood stem cell transplantation in our study is consistent with the findings of others.5,8,13,15,27,29 Although the incidence of chronic GVHD in our patients is higher than that reported for marrow transplant recipients, the multivariate analysis identified a number of factors associated with an increased risk of chronic GVHD.

We noted that prior acute GVHD or use of corticosteroids at day 100 were prognostic factors for development of clinical extensive chronic GVHD. The late use of corticosteroids is likely to represent patients still completing treatment for acute GVHD, accounting for the association between these 2 prognostic factors. Prior acute GVHD and persistent use of corticosteroids have also been reported as risk factors for chronic GVHD after HLA-identical marrow transplantation30-35 and in one small series of allogeneic blood stem cell transplant recipients.8 Pavletic et al17 also reported cytomegalovirus (CMV) seropositivity as a risk factor for chronic GVHD in the stem cell recipients; we did not find this to be so in our series, but the number of CMV-seronegative patient-donor pairs in our study may have been too small for an accurate assessment of this risk factor.

T-cell depletion has been the only known method of GVHD prophylaxis consistently associated with a reduction in chronic GVHD after HLA-identical marrow transplantation.32 More recently, methotrexate-containing GVHD prophylaxis regimens were associated with a lower incidence of chronic GVHD after marrow transplantation,36,37 but this relationship was not confirmed by others.38 In our study, patients receiving methotrexate for GVHD prophylaxis also had a lower risk of chronic GVHD after allogeneic blood stem cell transplantation than those who received corticosteroid-based GVHD prophylaxis. However, patients in the methotrexate group had also received the lower doses of CD34+ cells, known predictors of acute GVHD, so it is unclear if use of methotrexate is an actual risk factor or a surrogate for another factor in our data set.

Several reports have suggested that the graft-vs-leukemia (GVL) effect is increased with use of blood stem cells in place of marrow for allogeneic transplantation.15,16,39 Others have noted specifically that fewer relapses occurred in patients with chronic GVHD after allogeneic blood stem cell transplantation.19,40,41In the current analysis, using chronic GVHD entered as a time-dependent covariate, chronic GVHD did not have a significant effect on the risk of relapse. However, the power of the analysis may be compromised by the small number of patients in the series, the heterogeneity of the diagnoses, and the relatively short follow-up.

The potential benefits of the GVL effect of allogeneic marrow transplantation are often blunted by the GVHD-related mortality.42-45 In fact, for the marrow transplant recipients, chronic GVHD was found to have an adverse impact on survival for patients at low risk for relapse.43 In our series, however, the adverse impact of chronic GVHD on survival was significant only for patients who developed high-risk chronic GVHD.

Chronic GVHD has been associated with excessive Th2 activity in humans.46,47 Th2 and DC2 polarization were found in healthy volunteers treated with filgrastim in vivo or in peripheral blood incubated with filgrastim in vitro,48-50 supporting the expectation that the risk of chronic GVHD would be increased with the use of filgrastim-mobilized blood stem cells for allogeneic transplantation. We here describe a population of patients with chronic GVHD, the high-risk subgroup, some of whom had typical manifestations of both acute (eg, maculopapular rash and inflammatory diarrhea) and chronic (eg, lichenoid changes of the oral mucosa) GVHD. In some cases, this has been associated with early withdrawal of GVHD prophylaxis.51 Whether the high-risk syndrome represents true chronic GVHD or a delayed form of acute GVHD is not known, as the biologic correlates have not been studied in this subgroup specifically. However, the intensity of the clinical disease in patients with high-risk chronic GVHD warrants aggressive treatment similar to that used for acute GVHD.

Although our patients had a substantial rate of clinical extensive chronic GVHD after allogeneic blood stem cell transplantation, for those using tacrolimus and methotrexate for GVHD prophylaxis and who received a conservative CD34+cell dose, the risk of chronic GVHD (51%) was similar to that reported previously for HLA-identical marrow transplant recipients using tacrolimus and methotrexate.52 The ability to optimize these prognostic variables in clinical practice suggests that the benefits of blood stem cells for allografting might be achieved without exacerbating acute or chronic GVHD, and this hypothesis should be tested in a randomized study. Whether the risk factors for chronic GVHD identified here will also apply in other clinical settings, such as with nonmyeloablative preparative regimens or CD34-selected allografts, remains to be determined.

Supported in part by The Tony Anderson Fund and Cancer Center Core grant CA 16672 from the National Institutes of Health.

The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked “advertisement” in accordance with 18 U.S.C. section 1734.

References

References
1
Przepiorka
D
Ippoliti
C
Khouri
I
et al. 
Allogeneic transplantation for advanced leukemia.
Transplantation.
62
1996
1806
1810
2
Lemoli
RM
Bandini
G
Leopardi
G
et al. 
Allogeneic peripheral blood stem cell transplantation in patients with early-phase hematologic malignancy: a retrospective comparison of short-term outcome with bone marrow transplantation.
Haematologica.
83
1998
48
55
3
Russell
JA
Brown
C
Bowen
T
et al. 
Allogeneic blood cell transplants for haematological malignancy: preliminary comparison of outcomes with bone marrow transplantation.
Bone Marrow Transplant.
17
1996
703
708
4
Bensinger
WI
Clift
R
Martin
P
et al. 
Allogeneic peripheral blood stem cell transplantation in patients with advanced hematologic malignancies: a retrospective comparison with marrow transplantation.
Blood.
88
1996
2794
2800
5
Kalayoglu-Besisik
S
Budak-Alpdogan
T
Nuri Yenerel
M
Sargin
D
Tangun
Y
High risk of chronic graft-versus-host disease in unmanipulated allogeneic peripheral blood stem cell transplantation.
Blood.
92
1998
2973
2975
6
Scott
MA
Gandhi
MK
Jestice
HK
et al. 
A trend towards an increased incidence of chronic graft-versus-host disease following allogeneic peripheral blood progenitor cell transplantation: a case controlled study.
Bone Marrow Transplant.
22
1998
273
276
7
Bacigalupo
A
Zikos
P
Van Lint
M-T
et al. 
Allogeneic bone marrow or peripheral blood cell transplants in adults with hematologic malignancies: a single-center experience.
Exp Hematol.
26
1998
409
414
8
Solano
C
Martinez
C
Brunet
S
et al. 
Chronic graft-versus-host disease after allogeneic peripheral blood progenitor or bone marrow transplantation from matched related donors: a case-control study.
Bone Marrow Transplant.
22
1998
1129
1135
9
Ustun
C
Arslan
O
Beksac
M
et al. 
A retrospective comparison of allogeneic peripheral blood stem cell and bone marrow transplantation results from a single center: a focus on the incidence of graft-vs-host disease and relapse.
Biol Blood Marrow Transplant.
5
1999
28
35
10
Przepiorka
D
Anderlini
P
Ippoliti
C
et al. 
Allogeneic blood stem cell transplantation in advanced hematologic cancers.
Bone Marrow Transplant.
19
1997
455
460
11
Bennett
C
Waters
T
Stinson
T
et al. 
Valuing clinical strategies early in development: a cost analysis of allogeneic peripheral blood stem cell transplantation.
Bone Marrow Transplant.
24
1999
555
560
12
Schmitz
N
Bacigalupo
A
Hasenclever
D
et al. 
Allogeneic bone marrow transplantation vs filgrastim-mobilised peripheral blood progenitor cell transplantation in patients with early leukaemia: first results of a randomised multicentre trial of the European Group for Blood and Marrow Transplantation.
Bone Marrow Transplant.
21
1998
995
1003
13
Vigorito
AC
Azevedo
WM
Marques
JFC
et al. 
A randomised, prospective comparison of allogeneic bone marrow and peripheral blood progenitor cell transplantation in the treatment of haematological malignancies.
Bone Marrow Transplant.
22
1998
1145
1151
14
Bensinger
WI
Martin
PJ
Storer
B
et al. 
Transplantation of bone marrow as compared with peripheral-blood cells from HLA-identical relatives in patients with hematologic cancers.
Blood.
344
2001
175
181
15
Blaise
D
Kuentz
M
Fortanier
C
et al. 
Randomized trial of bone marrow versus lenogratim-primed blood cell allogeneic transplantation in patients with early-stage leukemia: a report from the Societe Francaise de Greffe de Moelle.
J Clin Oncol.
18
2000
537
546
16
Powles
R
Mehta
J
Kulkarni
S
et al. 
Allogeneic blood and bone-marrow stem-cell transplantation in haematological malignant diseases: a randomised trial.
Lancet.
355
2000
1231
1237
17
Pavletic
SZ
Tarantolo
S
Oria
N
et al. 
Allogeneic peripheral blood stem cell transplantation is not associated with a high risk of chronic graft-versus-host disease (cGVHD) [abstract].
Blood.
92
1998
456a
18
Storek
J
Gooley
T
Siadak
M
et al. 
Allogeneic peripheral blood stem cell transplantation may be associated with a high risk of chronic graft-versus-host disease.
Blood.
90
1997
4705
4709
19
Elmaagacli
AH
Beelen
DW
Opalka
B
et al. 
The risk of residual molecular and cytogenetic disease in patients with Philadelphia-chromosome positive first chronic phase chronic myelogenous leukemia is reduced after transplantation of allogeneic peripheral blood stem cells compared with bone marrow.
Blood.
94
1999
384
389
20
Przepiorka
D
Smith
TL
Folloder
J
et al. 
Risk factors for acute graft-versus-host disease after allogeneic blood stem cell transplantation.
Blood.
94
1999
1465
1470
21
Snover
DC
Biopsy interpretation in bone marrow transplantation.
Pathology Annual, Part 2.
Rosen
PP
Fechner
RE
1989
63
101
Appleton & Lange
Hartford, CT
22
Sullivan
KM
Witherspoon
RP
Storb
R
et al. 
Prednisone and azathioprine compared with prednisone and placebo for treatment of chronic graft-v-host disease: prognostic influence of prolonged thrombocytopenia after allogeneic marrow transplantation.
Blood.
72
1988
546
554
23
Kaplan
EL
Meier
P
Nonparametric estimation from incomplete observations.
J Am Stat Assoc.
53
1958
457
481
24
Gooley
TA
Leisenring
W
Crowley
J
et al. 
Estimation of failure probabilities in the presence of competing risks: new representaitons of old estimators.
Stat Med.
18
1999
695
706
25
Cox
DR
Regression models and life tables.
J Royal Stat Soc.
34
1972
187
220
26
Schmitz
N
Bacigalupo
A
Labopin
M
et al. 
Transplantation of peripheral blood progenitor cells from HLA-identical sibling donors.
Br J Haematol.
95
1996
715
723
27
Urbano-Ispizua
A
Garcia-Conde
J
Brunet
S
et al. 
High incidence of chronic graft versus host disease after allogeneic peripheral blood progenitor cell transplantation.
Haematologica.
82
1997
683
689
28
Miflin
G
Russell
NH
Hutchinson
RM
et al. 
Allogeneic peripheral blood stem cell transplantation for haematological malignancies: an analysis of kinetics of engraftment and GVHD risk.
Bone Marrow Transplant.
19
1997
9
13
29
Brown
RA
Adkins
D
Khoury
H
et al. 
Long-term follow-up of high-risk allogeneic peripheral-blood stem-cell transplant recipients: graft-versus-host disease and transplant-related mortality.
J Clin Oncol.
17
1999
806
812
30
Storb
R
Prentice
RL
Sullivan
KM
et al. 
Predictive factors in chronic graft-versus-host disease in patients with aplastic anemia treated by marrow transplantation from HLA-identical siblings.
Ann Intern Med.
98
1983
461
466
31
Ringden
O
Paulin
T
Lonnqvist
B
Nilsson
B
An analysis of factors predisposing to chronic graft-versus-host disease.
Exp Hematol.
13
1985
1062
1067
32
Atkinson
K
Horowitz
MM
Gale
RP
et al. 
Risk factors for chronic graft-versus-host disease after HLA-identical sibling bone marrow transplantation.
Blood.
75
1990
2459
2464
33
Bostrom
L
Ringden
O
Jacobsen
N
et al. 
A European multicenter study of chronic graft-versus-host disease: the role of cytomegalovirus serology in recipients and donors, acute graft-versus-host disease, and splenectomy.
Transplantation.
49
1990
1100
1105
34
Ochs
LA
Miller
WJ
Filipovich
AH
et al. 
Predictive factors for chronic graft-versus-host disease after histocompatible sibling donor bone marrow transplantation.
Bone Marrow Transplant.
13
1994
455
460
35
Wagner
JL
Flowers
MED
Longton
G
et al. 
The development of chronic graft-versus-host disease: an analysis of screening studies and the impact of corticosteroid use at 100 days after transplantation.
Bone Marrow Transplant.
22
1998
139
146
36
Shaji Kumar
KR
Litzow
M
Chen
M
et al. 
Prophylaxis of graft-versus-host disease (GVHD) with cyclosporine-prednisone (CSP-PRED) is associated with an increased risk of chronic GVHD (cGVHD) [abstract].
Blood.
92
1998
347b
37
Copelan
EA
Penza
SL
Theil
KS
et al. 
The influence of early transplantation, age, GVHD prevention regimen, and other factors on outcome of allogeneic transplantation for CML following BuCy.
Bone Marrow Transplant.
26
2000
1037
1043
38
Ross
M
Schmidt
GM
Niland
JC
et al. 
Cyclosporine, methotrexate, and prednisone compared with cyclosporine and prednisone for prevention of acute graft-vs-host disease: effect on chronic graft-vs-host disease and long-term survival.
Biol Blood Marrow Transplant.
5
1999
285
291
39
Russell
JA
Larratt
L
Brown
C
et al. 
Allogeneic blood stem cell and bone marrow transplantation for acute myelogenous leukemia and myelodysplasia: influence of stem cell source on outcome.
Bone Marrow Transplant.
24
1999
1177
1183
40
Brunet
S
Urbano-Ispizua
A
Ojeda
E
et al. 
Evidence of graft-versus-tumor (GVT) effect in 136 patients with advanced hematologic malignancies receiving unmanipulated peripheral blood stem cell allografts (allo-PSCT): the Spanish experience [abstract].
Blood.
94
1999
165a
41
Miflin
G
Russell
NH
Franklin
I
et al. 
An analysis of the effect of chronic GVHD on relapse and survival following allogeneic PBSC transplantation.
Cytotherapy.
2
2000
423
428
42
Weiden
PL
Sullivan
KM
Fluornoy
N
et al. 
Antileukemic effect of chronic graft-versus-host disease: contribution to improved survival after allogeneic marrow transplantation.
New Engl J Med.
304
1981
1529
1533
43
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.
73
1989
1720
1728
44
Horowitz
MM
Gale
RP
Sondel
PM
et al. 
Graft-versus-leukemia reactions after bone marrow transplantation.
Blood.
75
1990
555
562
45
Ringden
O
Labopin
M
Gluckman
E
et al. 
Strong antileukemic effect of chronic graft-versus-host disease in allogeneic marrow transplant recipients having acute leukemia treated with methotrexate and cyclosporine.
Transplant Proc.
29
1997
733
734
46
Tanaka
J
Imamura
M
Kasai
M
et al. 
Th2 cytokines (IL-4, IL-10 and IL-13) and IL-12 mRNA expression by concanavalin A-stimulated peripheral blood mononuclear cells during chronic graft-versus-host disease.
Eur J Haematol.
57
1996
111
113
47
Guenther
C
Schregelmann
M
Holler
E
Kolb
HJ
Imbalance of T-helper cell subsets in patients with chronic graft versus host disease [abstract].
Blood.
94
1999
158a
48
Hartung
T
Doecke
W-D
Bundschuh
D
et al. 
Effect of filgrastim treatment on inflammatory cytokines and lymphocyte functions.
Clin Pharmacol Ther.
66
1999
415
424
49
Sloand
EM
Kim
S
Maciejewski
JP
et al. 
Pharmacologic doses of granulocyte colony-stimulating factor affect cytokine production by lymphocytes in vitro and in vivo.
Blood.
95
2000
2260
2274
50
Arpinati
M
Green
CL
Heimfeld
S
et al. 
Granulocyte-colony stimulating factor mobilizes T helper 2-inducing dendritic cells.
Blood.
95
2000
2484
2490
51
Elmaagacli
AH
Beelen
DW
Trenn
G
Schmidt
O
Nahler
M
Schaefer
UW
Induction of a graft-versus-leukemia reaction by cyclosporine A withdrawal as immunotherapy for leukemia relapsing after allogeneic bone marrow transplantation.
Bone Marrow Transplant.
23
1999
771
777
52
Ratanatharathorn
V
Nash
RA
Przepiorka
D
et al. 
Phase III study comparing methotrexate and tacrolimus (Prograf, FK506) with methotrexate and cyclosporine for graft-versus-host disease prophylaxis after HLA-identical sibling bone marrow transplantation.
Blood.
92
1998
2303
2314

Author notes

Donna Przepiorka, Baylor College of Medicine, Center for Cell and Gene Therapy, 6565 Fannin St, M964, Houston, TX 77030; e-mail: donnap@bcm.tmc.edu.