Abstract

Abstract 4182

Introduction and methods:

In two different study populations with sibling (SIB) or unrelated (URD) HLA-identical donors we evaluated the role of 48 different genes (table1) reported to have influence on the outcome of allogeneic transplant and compared them between the transplant settings. 314 patients and their HLA identical URD and 285 patients and their HLA-identical SIB donors were analyzed after T cell repleted myeloablative transplantation and use of GVHD-prophylaxis with only MTX and CSA or CSA and MMF. Patients were transplanted for acute leukemia, CML, MDS, lymphoma and MM between Jan. 2000 and June 2011 at our center.

Results:

In the URD-cohort the occurrence of acute GVHD grade 2–4 was influenced adversely by gene variants on recipient side of LTA (40% vs 28%, P=0.013), MBL2 codon550 (47% vs 31%, P= 0.03), MCP1 (69% vs 42%, p=0.03) and NFKBIL1 (51% vs 34%, P=0.02). Further, the occurrence of severe aGVHD 3–4 was influenced adversely by gene variants of MBL codon 550 (10% vs 23%, P= 0.025), MBL2 codon 4 (10% vs 36% P=0.04), LCT13910 (9% vs 26%, P= 0.04) and CYP1B1 (8% vs 20%; P=0.05). Favorable effect was induced by a gene variant of IL6 on aGVHD 3–4 (4% vs 19%, P=0.04) in the URD setting, whereas NOD2 gene variants, but none of these gene variants had influence on aGVHD in the SIB cohort.

Further, we found that the rate of 5-year none-relapse mortality (NRM) was associated adversely with the detection of variants of IL16 (60% vs 34%, P=0.01) and MCP1 (58% vs 27%, P=0.02), which influenced the 5-year estimate for overall survival (OS) of patients (MCP1 40% vs 53%, P=0.01 and IL16 46% vs 28%, P=0.03) in the URD setting.

On donor side the occurrence of aGVHD grade 2–4 was influenced by MBL2 codon4 (69% vs 32%, P= 0.007), TLR2 (66% vs 41%, P=0.02), TLR5 (75% vs 42%, P=0.041). AGVHD 3–4 was influenced by IL23R favorably (0% vs 20%, p=0.01) and adversely by IL18 (10% vs 36%; p= 0.01) in the URD setting.

The 5-year NRM was associated with the detection of gene variants at donor side of CCR5 (53% vs 27%, p=0.01), CTLA4 (23% vs 44%, P=0.02), CYP1B1 (14% vs 26%, P=0.045), TLR2 (34% vs 66%, P=0.025). Also, IL10 gene variants at donor side influenced the 5-year OS significantly (23% vs 54%, p=0.03) as well as the gene variants TLR2 (28% vs 50%, P= 0.04), IL18 Rap (40% vs 72%, P= 0.03) and FAS (60% vs 36%, P=0.04).

In SIB cohort the 5-year TRM was influenced by MTHFR677 (30% vs 19%, p=0.05) at recipient side, and at donor side by the genes IL18 Rap (39% vs 19%, p=0.046) and CYP1B1 (29% vs 16%,p=0.07). IL10 gene variants at recipients side influenced the 5-year OS, too. At donor side the 5-year OS was influenced by IL23R (54% vs 72%, p=0.04) and MBL2CD55 49% vs 65% p=0.02).

In conclusion we report here that except IL23R and IL10 different panels of gene variants have influence on outcome of transplants from SIB donors compared to transplants from URD.

CCL5 28 promotor G/C rs1800825 MBL2 Codon220 rs7096206 
CCR5 2086 A/G rs1800023 MBL2 Codon4 rs7095891 
CCR5 2554 G/T rs2734648 MBL2 Codon550 rs11003125 
CP2C19*2 rs4244285 MBL2[G54D] rs1800450 
CP2C19*3 rs4986893 MBL2[G57E] rs1800451 
CTLA4 A/G pos.49 rs231775 MBL2[R55C] rs5030737 
CYP1B1 432 rs1056836 MCP1 1543 C/T rs13900 
CYP2C9*2 rs1799853 mdr1 C3435T rs1045642 
CYP2C9*3 rs1057910 MTHFR1298 rs1801131 
CYP2D6*3 rs4986774 MTHFR677 rs1801133 
CYP2D6*4, rs1800716 NFKBIL1 rs2857605 
CYP2D6*6 rs5030655 NOD2 G908R rs2066847 
CYP3A4*1B  NOD2 L1007F insC rs2066847 
CYP3A5*3  NOD2 R702W rs2066844 
FAS 670 G/A rs4934436 TLR2 R753Q rs5743708 
GSTA1 A567T, 69C 52G rs3957356 TLR3 rs3775291 
GSTP1 313A/G rs1695 TLR4 [D299G] rs4986790 
IL10 -1082 rs1800896 TLR4 [T399I] rs4987233 
IL10 592 C/A rs1800872 TLR5 rs764535 
IL23R  TLR6 745C>T rs5743810 
IL18 137 G/C rs187238 TLR9 C-1237T rs5743836 
IL18 RAP rs917997 TLR9 T-1486C rs187084 
IL6 G174C rs1800795 TNF alpha 238 A/G rs361525 
LTA rs2844484 VEGF 405G/C rs833061 
CCL5 28 promotor G/C rs1800825 MBL2 Codon220 rs7096206 
CCR5 2086 A/G rs1800023 MBL2 Codon4 rs7095891 
CCR5 2554 G/T rs2734648 MBL2 Codon550 rs11003125 
CP2C19*2 rs4244285 MBL2[G54D] rs1800450 
CP2C19*3 rs4986893 MBL2[G57E] rs1800451 
CTLA4 A/G pos.49 rs231775 MBL2[R55C] rs5030737 
CYP1B1 432 rs1056836 MCP1 1543 C/T rs13900 
CYP2C9*2 rs1799853 mdr1 C3435T rs1045642 
CYP2C9*3 rs1057910 MTHFR1298 rs1801131 
CYP2D6*3 rs4986774 MTHFR677 rs1801133 
CYP2D6*4, rs1800716 NFKBIL1 rs2857605 
CYP2D6*6 rs5030655 NOD2 G908R rs2066847 
CYP3A4*1B  NOD2 L1007F insC rs2066847 
CYP3A5*3  NOD2 R702W rs2066844 
FAS 670 G/A rs4934436 TLR2 R753Q rs5743708 
GSTA1 A567T, 69C 52G rs3957356 TLR3 rs3775291 
GSTP1 313A/G rs1695 TLR4 [D299G] rs4986790 
IL10 -1082 rs1800896 TLR4 [T399I] rs4987233 
IL10 592 C/A rs1800872 TLR5 rs764535 
IL23R  TLR6 745C>T rs5743810 
IL18 137 G/C rs187238 TLR9 C-1237T rs5743836 
IL18 RAP rs917997 TLR9 T-1486C rs187084 
IL6 G174C rs1800795 TNF alpha 238 A/G rs361525 
LTA rs2844484 VEGF 405G/C rs833061 
Disclosures:

No relevant conflicts of interest to declare.

Author notes

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Asterisk with author names denotes non-ASH members.