Abstract

Grade I acute GVHD (a-GVHD) has been traditionally considered to have limited or even positive impact on the outcome of hematopoietic stem cell transplantation. Thus, most transplant centers defer systemic treatment until patients present with higher grades. This deferral may preclude early intervention in cases of grade I a-GVHD progressing to more severe forms. Patients and Methods: We evaluated the risk and predictors of progression of grade I a-GVHD retrospectively among 815 consecutive recipients of allogeneic stem cell transplantation at our institution between 1998 and 2002. Patient characteristics are summarized in Table 1. Acute GVHD was graded prospectively according to the modified Glucksberg criteria (

Bone Marrow Transplantation
, (
1995
),
15
:
825
–28
). Prognostic factors were evaluated using Cox’s regression analysis. Results: 80 of 194 (41%) patients presenting with grade I a-GVHD progressed to grades II–IV (60%, 19% and 21% to grades II, III and IV respectively) within a median of 10 days since diagnosis of grade I (range 2–66). These progressive cases represent one third of all grade II–IV (80/265) and grade III–IV (32/113) a-GVHD diagnosed in this cohort (n=815). GI and liver were the sites of progression in 40% (33/80) and 20% (16/80), respectively. The occurrence of hyperacute GVHD (GVHD by day 14 post transplantation) (HR=2.8, p value <0.001) and a-GVHD prior to neutrophil engraftment (HR=2.5, p value 0.01) were the only significant predictors for progression to higher grades among the 194 patients. These factors are highly correlated and their independent effects could not be evaluated. There was no effect for patient age, cell type, underlying malignancy, disease status at transplant, donor type, patient/donor sex, preparative regimen (reduced intensity, TBI, high dose intensity without TBI), or the number of prior chemoregimens. Response to first line systemic therapy (CR) was lower in the progressive grade I cases (40% vs 80%, p value <0.001). Non relapse mortality (NRM) since diagnosis of grade I was significantly higher at 1 and 2 years post transplant in the progressive group (HR at 2 years =2.9, p value <0.001). Patient and disease characteristics which may impact NRM were comparable in both groups. Acute GVHD was the primary cause for 18% of deaths in the progressive group versus 5% in the non progressive group. Both groups had a significantly higher NRM compared to patients who did not develop a-GVHD in a landmark analysis starting at day 30 post transplantation. Conclusions: In this cohort, a substantial proportion of patients with grade II–IV a-GVHD presented initially with grade I. The most important predictor for progression is hyperacute GVHD, which occurs primarily prior to neutrophil engraftment. Patients developing grade I a-GVHD early post transplantation may potentially benefit from systemic therapy. This recommendation requires prospective validation.

Table 1.

Patient’s characteristics

N(%)
 815  
Median age (range) 47 (18–75)  
Sex mismatch 359 44 
Diagnosis   
Lymphoid 308 38 
Myeloid 429 53 
Multiple Myeloma (MM) 31 
Solid organ 35 
Other 12 
Disease status at transplant   
Active disease 545 67 
No disease 270 33 
Donor type   
Matched related 490 60 
Mismatched related 71 
Matched unrelated 252 31 
Preparative regimen   
Reduced intensity 381 47 
High dose TBI 102 12 
High dose non-TBI 332 41 
N(%)
 815  
Median age (range) 47 (18–75)  
Sex mismatch 359 44 
Diagnosis   
Lymphoid 308 38 
Myeloid 429 53 
Multiple Myeloma (MM) 31 
Solid organ 35 
Other 12 
Disease status at transplant   
Active disease 545 67 
No disease 270 33 
Donor type   
Matched related 490 60 
Mismatched related 71 
Matched unrelated 252 31 
Preparative regimen   
Reduced intensity 381 47 
High dose TBI 102 12 
High dose non-TBI 332 41 

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