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10 Match Unrelated Donor (MUD) Hematopoietic Cell Transplant (HCT) for Hematological Malignancies
Abstracts / Biol Blood Marrow Transplant 22 (2016) S19eS481
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at day 100 patients with grade II-IV aGVHD had significantly higher VEGF-A, PlGF, sVEGFR1, and sVEGFR1/VEGF-B, but lower VEGF-B levels. Among patients with grade III-IV aGVHD, day 100 levels of VEGF-A, sVEGFR1, and TNF were significantly increased (p<0.01, <0.01, and 0.03). NRM: In multivariate analysis, higher day 28 sVEGFR1 levels (>2301 pg/ml) were associated with a 5.2-fold increased risk of NRM (p<0.001, Figure 2), independent of GVHD prophylaxis and other factors. Conclusions: Our results suggest that multiple angiogenic factors and their soluble receptors are altered post-HCT and tightly associated with clinical outcomes. We also identified a pre-HCT angiogenic signature (elevated VEGF-A and PlGF, decreased sVEGFR1/VEGF-A) that may be associated with the subsequent development of aGVHD, and identified an independent association of elevated day 28 sVEGFR1 with NRM. Further studies are needed to elucidate the pathophysiology of alterations in VEGF ligands and receptor binding in HCT, the role of soluble receptors as an angiogenic factor ‘sink’, and methods of manipulating these pathways to reduce risks of both aGVHD and NRM.
71 Deleterious Effect of High-Expression HLA-DPB1 Allele Mismatch in Patients (pts) Undergoing 10/10 Match Unrelated Donor (MUD) Hematopoietic Cell Transplant (HCT) for Hematological Malignancies Monzr M. Al Malki 1, Ketevan Gendzekhadze 2, Andy Dagis3, Joycelynne Palmer 3, Chatchada Karanes 1, Pablo Parker 1, David Senitzer 2, Stephen J. Forman 1, Auayporn Nademanee 1. 1 Hematology/Hematopoietic Cell Transplant, City of Hope National Medical Center, Duarte, CA; 2 HLA, City of Hope National Medical Center, Duarte, CA; 3 Information Sciences, City of Hope National Medical Center, Duarte, CA
We quantified plasma levels of the VEGFR1 ligands (VEGF-A, PlGF, and VEGF-B), the soluble forms of the VEGFR1 and VEGFR2 receptors (sVEGFR1, sVEGFR2), as well as tumor necrosis factor-alpha (TNFa) at day 0 (pre-HCT), day 28, and day 100 post-HCT. Results: 247 patients had plasma samples available for analysis, with tacrolimus/methotrexate (Tac/MTX) GVHD prophylaxis in 126 (51%) and tacrolimus/sirolimus (Tac/Sir) in 121 (49%). Longitudinal changes: At day 28, sVEGFR1 levels were elevated 3-fold compared to day 0 and day 100, especially in recipients of Tac/Sir (Figure 1, p¼0.02). GVHD: Patients who developed grade II-IV aGVHD had higher levels of both VEGF-A and PlGF at day 0, as well as a lower sVEGFR1/VEGF-A ratio (p¼0.02, 0.03, and 0.04). While there was no significant correlation with day 28 levels of any factor,
Background: HLA mismatch at DP locus (mmDP) has been associated with significant increase in the incidence of acute graft versus host disease (aGvHD) and decrease in relapse rate (RR) in myeloablative HCT using 10/10 MUD. Lately, DP mismatch with high protein expression (based on SNP rs9277534G vs. A) in pts was described to be an independent predictor of increased risk of aGVHD but no impact on overall survival (OS). We evaluate the impact of DP mismatch and the expression of HLA-DPB1 allele on the outcome of 10/10 MUD in patients with hematological malignancies undergoing myeloablative (MAC) or reduced conditioning regimen (RIC). Patients and Methods: 264 pts who underwent (10/10 HLAA, B, C, DR, and DQ) MUD HCT at City of Hope from 2006 to 2012 were included. HLA DPB1 alleles were grouped based on linkage disequilibrium reported between rs9277534 and HLA-DPB1 alleles (Petersdorf et al. 2015). 23% (n¼61) of pts were 12/12 matched DP (mDP), 77% (n¼203) were mmDP (at single or double alleles), 21% (n¼57) pts had high expression mismatched allele (HmmDP), and 30% (n¼80) low expression mismatched allele (LmmDP). Median age was 54.5 years (range: 18-73). Seventy-eight percent received Tacrolimus/Sirolimus-based GVHD prophylaxis; Mini-methotrexate or ATG was added in 22% (n¼60). Conditioning regimen used was MAC (39%, n¼103) and RIC (61%, n¼161). Diseases included acute leukemia (n¼166), MDS/MPN (n¼44), NHL (n¼32), HL (n¼2), CLL (n¼7), CML (n¼10), and multiple myeloma (n¼3). Disease risk was low in 40% (n¼106), intermediate in 11% (n¼30) and high in 44% pts (n¼115). With the exception of disease risk (p¼0.04), patient/disease characteristics were similar in all groups.
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Abstracts / Biol Blood Marrow Transplant 22 (2016) S19eS481
Results: With median follow-up of 3.8 years (range: 1.4 to 8.2 years) for surviving pts 51% were alive and 31% had relapsed. In univariate analysis, mmDP had lower RR compared to mDP (HR¼0.62, [95% CI: 0.39-1.00] p¼0.05), which translates to better EFS (HR¼0.68, [95% CI: 0.47-0.98] p¼0.04). This was confirmed in a multivariable analysis after adjusting for age, disease risk, and conditioning regimen used. However, no significant effect was found on the incidence of aGvHD, NRM or OS. In multivariable analysis, pts with HmmDP had increased incidence of II-IV aGvHD (HR¼1.74, [95% CI: 1.04-2.9] p¼0.03) as well as III-IV aGVHD (HR¼2.96, [95% CI: 1.2-7.3] p¼0.02) when compared to pts with LmmDP. This was adjusted for age, disease risk and intensity of conditioning (p¼0.03). This has led to a trend in increased overall mortality (HR¼1.62, [95% CI: 0.96-2.76] p¼0.07). No significant effect was found on RR or NRM. Conclusions: In pts undergoing 10/10 MUD HCT, mmDP improved RR when compared to mDP. Among patients with mismatch, those with HmmDP had higher risk of II-IV and IIIIV aGVHD. Selecting donor with DP mismatch may result in a better outcome, however donor-patient mismatched for high-expression DPB1 allele should be avoided. *MMA and KG contributed equally
Figure 1a. Overall survival by rs3135006 genotype, cohort 1
72 Functional Single Nucleotide Polymorphisms (SNPs) in the Major Histocompatibility Complex (MHC) Class II Region Are Associated with Overall Survival (OS) after HLA Matched Unrelated Donor BMT: Results from the Discovery-BMT Study Lara Sucheston-Campbell 1, Leah Preus 1, Stephen Spellman 2, Marcelo C. Pasquini 3, Philip L. McCarthy 4, Kenan Onel 5, Xiaochun Zhu 6, Christoper Haiman 7, Daniel O. Stram 7, Loreall Pooler 7, Xie Sheng 7, Qianqian Zhu 8, Li Yan 8, Qian Liu 9, Qiang Hu 8, Song Liu 8, Alyssa Clay 1, Sebastiano Battaglia 10, Theresa E. Hahn 4. 1 Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY; 2 Center for International Blood and Marrow Transplant Research, National Marrow Donor Program, Minneapolis, MN; 3 CIBMTR, CIBMTR (Center fo, Milwaukee, WI; 4 Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY; 5 Pediatrics, University of Chicago, Chicago, IL; 6 Department of Medicine, CIBMTR (Center for International Blood and Marrow Transplant Research), Medical College of Wisconsin, Milwaukee, WI; 7 Preventive Medicine, University of Southern California, Los Angeles, CA; 8 Biostatistics & Bioinformatics, Roswell Park Cancer Institute, Buffalo, NY; 9 Biostatistics, State University of New York at Buffalo, Buffalo, NY; 10 Pharmacology & Therapeutics, Roswell Park Cancer Institute, Buffalo, NY The MHC region, 6p22.1-21.3, is the most polymorphic region of the human genome. MHC class I and II contain genes for HLA, while MHC class III genes relate to the complement cascade, cytokines and heat shock proteins. We performed a genome-wide association study, Determining the Influence of Susceptibility COnveying Variants Related to one-Year mortality after BMT (DISCOVeRY-BMT), of 1-year survival in 3,532 AML, ALL or MDS patients reported to CIBMTR from 2000-2011 and their 8/8 HLA-matched URD using the Illumina HumanOmniExpress-24 Chip. After quality control, almost 9 million typed and imputed SNPs were available on donor-recipient pairs in cohorts 1 (N1 ¼2,111) and 2 (N2¼779). Due to the small number of non-Europeans, we report results of European American donors and recipients only. Survival analyses were conducted using Cox proportional hazard models adjusting for age, disease (AML, ALL, MDS), disease status, and graft source. Combined P-values
were determined using METAL software weighted by sample-size (Pmeta). In donor-recipient pairs, 10/10 matched at HLA-A, -B, -C, -DRB1 and DQB1 (n1¼2111, n2¼632), both the recipient and donor T allele of rs3135006 associates with increased hazard of death in the first year post-BMT; rs4947344 shows similar effect size and P values (Table 1). Recipient and donor genotypes were identical at both SNPs and thus we present
Figure 1b. Overall survival by HLA-DQB1*06 allele count, cohort 1
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at day 100 patients with grade II-IV aGVHD had significantly higher VEGF-A, PlGF, sVEGFR1, and sVEGFR1/VEGF-B, but lower VEGF-B levels. Among patients with grade III-IV aGVHD, day 100 levels of VEGF-A, sVEGFR1, and TNF were significantly increased (p<0.01, <0.01, and 0.03). NRM: In multivariate analysis, higher day 28 sVEGFR1 levels (>2301 pg/ml) were associated with a 5.2-fold increased risk of NRM (p<0.001, Figure 2), independent of GVHD prophylaxis and other factors. Conclusions: Our results suggest that multiple angiogenic factors and their soluble receptors are altered post-HCT and tightly associated with clinical outcomes. We also identified a pre-HCT angiogenic signature (elevated VEGF-A and PlGF, decreased sVEGFR1/VEGF-A) that may be associated with the subsequent development of aGVHD, and identified an independent association of elevated day 28 sVEGFR1 with NRM. Further studies are needed to elucidate the pathophysiology of alterations in VEGF ligands and receptor binding in HCT, the role of soluble receptors as an angiogenic factor ‘sink’, and methods of manipulating these pathways to reduce risks of both aGVHD and NRM.
71 Deleterious Effect of High-Expression HLA-DPB1 Allele Mismatch in Patients (pts) Undergoing 10/10 Match Unrelated Donor (MUD) Hematopoietic Cell Transplant (HCT) for Hematological Malignancies Monzr M. Al Malki 1, Ketevan Gendzekhadze 2, Andy Dagis3, Joycelynne Palmer 3, Chatchada Karanes 1, Pablo Parker 1, David Senitzer 2, Stephen J. Forman 1, Auayporn Nademanee 1. 1 Hematology/Hematopoietic Cell Transplant, City of Hope National Medical Center, Duarte, CA; 2 HLA, City of Hope National Medical Center, Duarte, CA; 3 Information Sciences, City of Hope National Medical Center, Duarte, CA
We quantified plasma levels of the VEGFR1 ligands (VEGF-A, PlGF, and VEGF-B), the soluble forms of the VEGFR1 and VEGFR2 receptors (sVEGFR1, sVEGFR2), as well as tumor necrosis factor-alpha (TNFa) at day 0 (pre-HCT), day 28, and day 100 post-HCT. Results: 247 patients had plasma samples available for analysis, with tacrolimus/methotrexate (Tac/MTX) GVHD prophylaxis in 126 (51%) and tacrolimus/sirolimus (Tac/Sir) in 121 (49%). Longitudinal changes: At day 28, sVEGFR1 levels were elevated 3-fold compared to day 0 and day 100, especially in recipients of Tac/Sir (Figure 1, p¼0.02). GVHD: Patients who developed grade II-IV aGVHD had higher levels of both VEGF-A and PlGF at day 0, as well as a lower sVEGFR1/VEGF-A ratio (p¼0.02, 0.03, and 0.04). While there was no significant correlation with day 28 levels of any factor,
Background: HLA mismatch at DP locus (mmDP) has been associated with significant increase in the incidence of acute graft versus host disease (aGvHD) and decrease in relapse rate (RR) in myeloablative HCT using 10/10 MUD. Lately, DP mismatch with high protein expression (based on SNP rs9277534G vs. A) in pts was described to be an independent predictor of increased risk of aGVHD but no impact on overall survival (OS). We evaluate the impact of DP mismatch and the expression of HLA-DPB1 allele on the outcome of 10/10 MUD in patients with hematological malignancies undergoing myeloablative (MAC) or reduced conditioning regimen (RIC). Patients and Methods: 264 pts who underwent (10/10 HLAA, B, C, DR, and DQ) MUD HCT at City of Hope from 2006 to 2012 were included. HLA DPB1 alleles were grouped based on linkage disequilibrium reported between rs9277534 and HLA-DPB1 alleles (Petersdorf et al. 2015). 23% (n¼61) of pts were 12/12 matched DP (mDP), 77% (n¼203) were mmDP (at single or double alleles), 21% (n¼57) pts had high expression mismatched allele (HmmDP), and 30% (n¼80) low expression mismatched allele (LmmDP). Median age was 54.5 years (range: 18-73). Seventy-eight percent received Tacrolimus/Sirolimus-based GVHD prophylaxis; Mini-methotrexate or ATG was added in 22% (n¼60). Conditioning regimen used was MAC (39%, n¼103) and RIC (61%, n¼161). Diseases included acute leukemia (n¼166), MDS/MPN (n¼44), NHL (n¼32), HL (n¼2), CLL (n¼7), CML (n¼10), and multiple myeloma (n¼3). Disease risk was low in 40% (n¼106), intermediate in 11% (n¼30) and high in 44% pts (n¼115). With the exception of disease risk (p¼0.04), patient/disease characteristics were similar in all groups.
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Abstracts / Biol Blood Marrow Transplant 22 (2016) S19eS481
Results: With median follow-up of 3.8 years (range: 1.4 to 8.2 years) for surviving pts 51% were alive and 31% had relapsed. In univariate analysis, mmDP had lower RR compared to mDP (HR¼0.62, [95% CI: 0.39-1.00] p¼0.05), which translates to better EFS (HR¼0.68, [95% CI: 0.47-0.98] p¼0.04). This was confirmed in a multivariable analysis after adjusting for age, disease risk, and conditioning regimen used. However, no significant effect was found on the incidence of aGvHD, NRM or OS. In multivariable analysis, pts with HmmDP had increased incidence of II-IV aGvHD (HR¼1.74, [95% CI: 1.04-2.9] p¼0.03) as well as III-IV aGVHD (HR¼2.96, [95% CI: 1.2-7.3] p¼0.02) when compared to pts with LmmDP. This was adjusted for age, disease risk and intensity of conditioning (p¼0.03). This has led to a trend in increased overall mortality (HR¼1.62, [95% CI: 0.96-2.76] p¼0.07). No significant effect was found on RR or NRM. Conclusions: In pts undergoing 10/10 MUD HCT, mmDP improved RR when compared to mDP. Among patients with mismatch, those with HmmDP had higher risk of II-IV and IIIIV aGVHD. Selecting donor with DP mismatch may result in a better outcome, however donor-patient mismatched for high-expression DPB1 allele should be avoided. *MMA and KG contributed equally
Figure 1a. Overall survival by rs3135006 genotype, cohort 1
72 Functional Single Nucleotide Polymorphisms (SNPs) in the Major Histocompatibility Complex (MHC) Class II Region Are Associated with Overall Survival (OS) after HLA Matched Unrelated Donor BMT: Results from the Discovery-BMT Study Lara Sucheston-Campbell 1, Leah Preus 1, Stephen Spellman 2, Marcelo C. Pasquini 3, Philip L. McCarthy 4, Kenan Onel 5, Xiaochun Zhu 6, Christoper Haiman 7, Daniel O. Stram 7, Loreall Pooler 7, Xie Sheng 7, Qianqian Zhu 8, Li Yan 8, Qian Liu 9, Qiang Hu 8, Song Liu 8, Alyssa Clay 1, Sebastiano Battaglia 10, Theresa E. Hahn 4. 1 Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY; 2 Center for International Blood and Marrow Transplant Research, National Marrow Donor Program, Minneapolis, MN; 3 CIBMTR, CIBMTR (Center fo, Milwaukee, WI; 4 Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY; 5 Pediatrics, University of Chicago, Chicago, IL; 6 Department of Medicine, CIBMTR (Center for International Blood and Marrow Transplant Research), Medical College of Wisconsin, Milwaukee, WI; 7 Preventive Medicine, University of Southern California, Los Angeles, CA; 8 Biostatistics & Bioinformatics, Roswell Park Cancer Institute, Buffalo, NY; 9 Biostatistics, State University of New York at Buffalo, Buffalo, NY; 10 Pharmacology & Therapeutics, Roswell Park Cancer Institute, Buffalo, NY The MHC region, 6p22.1-21.3, is the most polymorphic region of the human genome. MHC class I and II contain genes for HLA, while MHC class III genes relate to the complement cascade, cytokines and heat shock proteins. We performed a genome-wide association study, Determining the Influence of Susceptibility COnveying Variants Related to one-Year mortality after BMT (DISCOVeRY-BMT), of 1-year survival in 3,532 AML, ALL or MDS patients reported to CIBMTR from 2000-2011 and their 8/8 HLA-matched URD using the Illumina HumanOmniExpress-24 Chip. After quality control, almost 9 million typed and imputed SNPs were available on donor-recipient pairs in cohorts 1 (N1 ¼2,111) and 2 (N2¼779). Due to the small number of non-Europeans, we report results of European American donors and recipients only. Survival analyses were conducted using Cox proportional hazard models adjusting for age, disease (AML, ALL, MDS), disease status, and graft source. Combined P-values
were determined using METAL software weighted by sample-size (Pmeta). In donor-recipient pairs, 10/10 matched at HLA-A, -B, -C, -DRB1 and DQB1 (n1¼2111, n2¼632), both the recipient and donor T allele of rs3135006 associates with increased hazard of death in the first year post-BMT; rs4947344 shows similar effect size and P values (Table 1). Recipient and donor genotypes were identical at both SNPs and thus we present
Figure 1b. Overall survival by HLA-DQB1*06 allele count, cohort 1