Abstract

IL-1α is a pro-inflammatory cytokine implicated in initiation and maintenance of graft versus host disease (GVHD) and the immune response to infection. A cytosine (C) to thymine (T) transition at codon -889 is believed to influence gene transcription. Previously we showed that the presence of at least one IL-1α T allele in the donor was associated with improved survival after unrelated donor (URD) BMT (survival at 1 year 40% C/C donor, 68% T/C donor, 75% T/T donor, p <0.01). Multiple regression analysis showed reduced treatment related mortality (TRM) if the donor and recipient each possessed the IL-1α T allele (RR 0.2, 95% CI 0.05–0.6, p<0.01). In the present study we sought to confirm these results in a larger more homogeneous patient population. The study included 426 adult patients (age > 18 years) with CML transplanted in first chronic phase between 1990 and 2002 with a cyclophosphamide/TBI preparative regimen. Patients receiving peripheral blood stem cells, a second transplant, or a graft with > 1 HLA antigen mismatch were excluded. Donors and recipients were genotyped for the IL-1α polymorphism using a high throughput PCR assay. Donor recipient pairs were categorized into 4 groups according to the presence or absence of a T-allele in donor and in recipient (only recipient has T-allele, only donor has T-allele, both have T-allele and neither have a T-allele). Median patient age was 38 years (range 18–59); 57% were male; median donor age was 38 years (range 18–57 years) and 64% were HLA-matched at 6 antigens. Genotype categories were not significantly different in recipient and donor age, gender, year of transplant, performance status, GVH prophylaxis, HLA-match, interval from diagnosis to transplant, CMV serology and donor-recipient sex match. The impact of IL-1a genotype on univariate outcomes is shown below.

Table 1
Endpoint Recipient has T-allele Donor has T-allele Both have T-allele Neither have T-allele p-value 
TRM @ 1 yr 41% 43% 43% 43% 0.99 
Acute GVHD 64% 67% 68% 72% 0.80 
Chronic GVHD 50% 57% 52% 52% 0.81 
Relapse@1yr 7% <1% 3% 1% 0.14 
Relapse@2yrs 7% 4% 3% 3% 0.63 
LFS @ 2yrs 46% 51% 47% 47% 0.90 
Survival@2yrs 49% 52% 48% 48% 0.95 
Endpoint Recipient has T-allele Donor has T-allele Both have T-allele Neither have T-allele p-value 
TRM @ 1 yr 41% 43% 43% 43% 0.99 
Acute GVHD 64% 67% 68% 72% 0.80 
Chronic GVHD 50% 57% 52% 52% 0.81 
Relapse@1yr 7% <1% 3% 1% 0.14 
Relapse@2yrs 7% 4% 3% 3% 0.63 
LFS @ 2yrs 46% 51% 47% 47% 0.90 
Survival@2yrs 49% 52% 48% 48% 0.95 

The data show no impact of IL-1α genotype on survival or TRM. Multivariate analysis including donor and recipient age, performance status, year of transplant, CMV status, HLA disparity and donor patient sex mismatch confirmed that IL-1α genotype did not impact survival, LFS, GVHD or TRM. Survival (and LFS) was significantly reduced in recipients of marrow with an allele or antigen level HLA-mismatch (RR 1.9, 95% CI 1.4–2.7; p< 0.0001) and T-depleted marrow (RR 1.43, 95% CI 1.07–1.92; p=0.017). Relapse was notably increased in recipients of T-cell depleted grafts (RR 4.1 95%CI 1.79–9.37; p=0.0008) and TRM increased in recipients of an allele or antigen mismatched graft (RR 2.05 95% CI 1.44–2.91; p< 0.0001). In conclusion these data from a large and relatively homogeneous population do not support a role for IL-1α genotype on outcome of unrelated donor transplant for CML.

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