Acute graft-versus-host disease (AGVHD) complicates donor lymphocyte infusion (DLI) treatment in 40% to 60% of cases.1,2 Although factors predictive of GVHD after allogeneic stem cell transplantation (SCT) could also be valid after DLI, patients receiving DLI are a select group, having survived the GVHD after transplantation and relapsed. We therefore investigated the role of possible factors in the development of AGVHD after DLI.

Sixty-three consecutive patients with BCR-ABL–positive chronic myeloid leukemia (CML) who relapsed after allogeneic SCT (31 from their respective HLA-identical siblings and 32 from volunteer-matched unrelated donors) were started on treatment with DLI between August 1990 and April 1999. At the time of DLI, 7 patients were in molecular relapse, 15 were in cytogenetic relapse, and 26 were in hematologic relapse (19 in chronic phase, 7 in accelerated phase). Twenty-seven patients received a single infusion of donor lymphocytes (bulk-dose regimen [BDR]), and 36 patients received lymphocytes according to our escalating-dose regimen (EDR).3 Molecular remission was defined as the absence of detectable BCR-ABL transcripts by reverse transcriptase–polymerase chain reaction (RT-PCR) analysis of peripheral blood on 2 consecutive occasions.4 AGVHD was graded according to the Glucksberg criteria.5 Grades II to IV were deemed of clinical significance.

Forty-five patients (71%) treated with DLI achieved molecular remission. Fifteen patients (24%) developed grade II to IV AGVHD, 48 patients (76%) showed no or minimal AGVHD. Results of the univariate analyses are presented in Table 1. No association was found between AGVHD after DLI and AGVHD after transplantation. The vast majority of patients who developed AGVHD following DLI treatment did not have a history of AGVHD after their original transplantation. Recipient-donor sex mismatch, patient-donor CMV seropositivity, and increasing patient age (> 35 years) were found to be significantly associated with AGVHD in the DLI setting. In accord with previous observations,1,2 patients who received T-cell–replete allografts suffered less AGVHD after DLI compared to those who received a T-cell–depleted stem cell preparation. We did not observe any association between achievement of complete remission and development of AGVHD. This finding contrasts with the results reported by other groups, whereby 89% of the responders suffered AGVHD.6 Such a difference may be attributed to the high proportion of patients receiving DLI according to an EDR in our study. In fact, the influence of method of administration was highly significant. In a multivariate logistic analysis, any positive patient-donor CMV serostatus (relative risk [RR] = 19.5,P = .013), BDR (RR = 9.4, P = .008), and T-cell depletion (TCD) at transplantation (RR = 21.9,P = .011) were found to be independent predictors of GVHD after DLI. Although there is more AGVHD associated with patient-donor sex mismatch, in the mismatch-only group there is considerably more AGVHD associated with the use of BDR than with EDR (9 of 16 patients vs 2 of 11 patients, P = .048); this explains why sex mismatch is not significant in the multivariate analysis.

Table 1.

Incidence of AGVHD in 63 patients receiving DLI for relapse after allogeneic SCT for CML: univariate analysis of potential factors

Variable AGVHD Grade P* 
0 to I II to IV  
AGVHD after SCT    
 0 to I 28 .43  
 II to IV 20  
Patient-donor sex    
 Matched 32 .003 
 Mismatched 16 11  
Patient-donor CMV serostatus    
 Negative 20 .016 
 Positive 28 13  
GVHD prophylaxis at SCT    
 Non-TCD 19 .017 
 TCD 29 14  
Patient age at time of DLI    
 Younger than 36 y 28 .032  
 Older than 36 y 20 11  
Type of DLI regimen    
 BDR 16 11 .006 
 EDR 32  
Molecular remission after DLI    
 Yes 35 13 .64 
 No 10  
Donor type    
 Identical sibling 24 .82  
 Matched unrelated 24  
Type of relapse at time of DLI    
 Molecular .40 
 Cytogenetic 15  
 Hem-CP 19  
 Hem-AP  
Interval SCT to relapse    
 Shorter than 12 mo 24 .50 
 12 mo or longer 24  
Interval relapse to DLI    
 Shorter than 12 mo 23 .59  
 12 mo or longer 25  
Interval SCT to DLI    
 Shorter than 24 mo 22 .33  
 24 mo or longer 22  
Variable AGVHD Grade P* 
0 to I II to IV  
AGVHD after SCT    
 0 to I 28 .43  
 II to IV 20  
Patient-donor sex    
 Matched 32 .003 
 Mismatched 16 11  
Patient-donor CMV serostatus    
 Negative 20 .016 
 Positive 28 13  
GVHD prophylaxis at SCT    
 Non-TCD 19 .017 
 TCD 29 14  
Patient age at time of DLI    
 Younger than 36 y 28 .032  
 Older than 36 y 20 11  
Type of DLI regimen    
 BDR 16 11 .006 
 EDR 32  
Molecular remission after DLI    
 Yes 35 13 .64 
 No 10  
Donor type    
 Identical sibling 24 .82  
 Matched unrelated 24  
Type of relapse at time of DLI    
 Molecular .40 
 Cytogenetic 15  
 Hem-CP 19  
 Hem-AP  
Interval SCT to relapse    
 Shorter than 12 mo 24 .50 
 12 mo or longer 24  
Interval relapse to DLI    
 Shorter than 12 mo 23 .59  
 12 mo or longer 25  
Interval SCT to DLI    
 Shorter than 24 mo 22 .33  
 24 mo or longer 22  

TCD indicates in vitro or in vivo T-cell depletion with Campath monoclonal antibodies; EDR, escalating-dose regimen; BDR, bulk-dose regimen; Hem, hematologic; CP, chronic phase; AP, accelerated phase.

*

Chi-squared or Fisher exact test.

CMV serostatus negative: when both donor and recipient were negative; CMV serostatus positive if only donor or only recipient or both were positive.

GVHD prophylaxis at time of transplantation.

Our findings demonstrate that most of the factors known to be associated with AGVHD after allogeneic SCT are not predictive of AGVHD following DLI. Our data reinforce the notion that DLI can be safe if the effective cell dose is administered late after transplantation3,7; this has important practical implications for the use of DLI in the context of reduced-intensity conditioning SCT.

References

References
1
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.
86
1995
2041
2050
2
Sehn
LH
Alyea
EP
Weller
E
et al. 
Comparative outcomes of T-cell-depleted and non-T-cell-depleted allogeneic bone marrow transplantation for chronic myelogenous leukemia: impact of donor lymphocyte infusion.
J Clin Oncol.
17
1999
561
568
3
Dazzi
F
Szydlo
RM
Craddock
C
et al. 
Comparison of single-dose and escalating-dose regimens of donor lymphocyte infusion for relapse after allografting for chronic myeloid leukemia.
Blood.
95
2000
67
71
4
Dazzi
F
Szydlo
RM
Cross
NC
et al. 
Durability of responses following donor lymphocyte infusions for patients who relapse after allogeneic stem cell transplantation for chronic myeloid leukemia.
Blood.
96
2000
2712
2716
5
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.
18
1974
295
304
6
Porter
DL
Collins
RH
Jr
Shpilberg
O
et al. 
Long-term follow-up of patients who achieved complete remission after donor leukocyte infusions.
Biol Blood Marrow Transplant.
5
1999
253
261
7
Johnson
BD
Truitt
RL
Delayed infusion of immunocompetent donor cells after bone marrow transplantation breaks graft-host tolerance allows for persistent antileukemic reactivity without severe graft-versus-host disease.
Blood.
85
1995
3302
3312