Different Panel of Gene Variants Influence Outcome of Transplant From Sibling Donors Compared to HLA-Identical Unrelated Donors

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4182-4182 ◽  
Author(s):  
Ahmet H Elmaagacli ◽  
Michael Koldehoff ◽  
Nina Kristin Steckel ◽  
Markus Ditschkowski ◽  
Rudolf Trenschel ◽  
...  
Keyword(s):  
Acute Gvhd ◽  
Conflicts Of Interest ◽  
Favorable Effect ◽  
Gene Variants ◽  
Allogeneic Transplant ◽  
Donor Side ◽  
Gvhd Prophylaxis ◽  
Il10 Gene ◽  
Unrelated Donors

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. Disclosures: No relevant conflicts of interest to declare.

Results of Simultaneously Performed Analysis of 48 Gene Variants Reported to Have Influence on Transplant outcome

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3047-3047
Author(s):  
Ahmet Elmaagacli ◽  
Michael Koldehoff ◽  
Nina Steckel ◽  
Hellmut Ottinger ◽  
Dietrich Beelen
Keyword(s):  
T Cell ◽  
Acute Gvhd ◽  
Conflicts Of Interest ◽  
Conditioning Regimen ◽  
Gene Variants ◽  
Donor Side ◽  
Transplant Outcome ◽  
Gvhd Prophylaxis ◽  
Grade 3 ◽  
Set Up

Abstract Abstract 3047 Up to date, there are many conflicting reports existing in which different gene variants have been proposed to have influence on the outcome of allogeneic transplant. Hereby many of the published studies bare a distressing high weakness in the study set up as for example low number of study patients, large heterogeneity of donor types and/or GVHD prophlyaxis regimens and/or T cell depleting of grafts and/or type of conditioning regimens. In this study we aimed to evaluate in 285 patients and their HLA identical sibling donors the following in table 1 shown 48 different gene variants from which were reported to have influence on the outcome of transplants. Our study group consists of a homogenous group of patients who underwent all a non T cell-depleted transplantation after receiving a myeloablative conditioning regimen and a GVHD prophylaxis with MTX and CSA or CSA and MMF. Patients were transplanted from a HLA-identical sibling donor for various diseases like acute leukemia, CML, MDS, lymphoma and MM between January 2000 and June 2010 at our center We could confirm an influence of gene variants of NOD2 (80, 4% vs 61, 6%, p=0.0013), IL23R, MTHFR1298, and LCT 13910 on the occurrence of acute GVHD grade 1–4 on recipients side, whereas no influence was seen of any gene variant on the occurrence of grade 2–4 acute GVHD. But, NOD2 gene variants had a significant (p=0.041) influence on the occurrence of severe acute GVHD grade 3–4. The occurrence of acute GVHD grade 1–4 was significantly modified by the detection of following gene variants at donors side: CCL5 28 promotor (30, 8% vs 69, 2% p=0.033), GSTP 313 (74, 3% vs 62, 4%, p=0.043);IL23R (69, 9% vs 48%, p=0.049), MTHFR129 (86, 7 vs 37, 3% p=.0.06), MTHFR 677 (53, 8% vs 70%, p=0.05), NOD2 (65, 9% vs 84, 4%, p=0.01). Acute GVHD grade 2 –4 was significantly influenced only by GSTP (p<0.015) and MTHFR129 (p<0.025). Severe acute GVHD grade 3–4 was only influenced by GSTP gene variants (p<0.04). The 5-year TRM was influenced by MTHFR677 (30, 4% vs 19, 2%, p=0.05) at recipient side, and at donor side by the genes IL18 Rap (38, 5% vs 19%, p=0.046) and CYP1B1 (28, 8% vs 15, 6%, p=0.07). IL10 gene variants at recipients side influenced the 5-year OS significantly, at donor side the 5-year OS was influenced by CTLA4 (69, 4 vs 52, 2%, p=0.06) IL23R (53, 6% vs 71, 6%, p=0.044) and MBL2CD55 48, 9% vs 65, 2% p=0.02). In this study we could confirm that the above described gene variants might influence moderately the transplant outcome and may therefore be qualified for screening in patients and their respective donors prior to transplant.CCL5 28 promotor G/Crs1800825MBL2 Codon220rs7096206CCR5 2086 A/Grs1800023MBL2 Codon4rs7095891CCR5 2554 G/Trs2734648MBL2 Codon550rs11003125CP2C19*2rs4244285MBL2[G54D]rs1800450CP2C19*3rs4986893MBL2[G57E]rs1800451CTLA4 A/G pos.49rs231775MBL2[R55C]rs5030737CYP1B1 432rs1056836MCP1 1543 C/Trs13900CYP2C9*2rs1799853mdr1 C3435Trs1045642CYP2C9*3rs1057910MTHFR1298rs1801131CYP2D6*3rs4986774MTHFR677rs1801133CYP2D6*4,rs1800716NFKBIL1rs2857605CYP2D6*6rs5030655NOD2 G908Rrs2066847CYP3A4*1BNOD2 L1007F insCrs2066847CYP3A5*3NOD2 R702Wrs2066844FAS 670 G/Ars4934436TLR2 R753Qrs5743708GSTA1 A567T, 69C 52Grs3957356TLR3rs3775291GSTP1 313A/Grs1695TLR4 [D299G]rs4986790IL10 -1082rs1800896TLR4 [T399I]rs4987233IL10 592 C/Ars1800872TLR5rs764535IL23RTLR6 745C>Trs5743810IL18 137 G/Crs187238TLR9 C-1237Trs5743836IL18 RAPrs917997TLR9 T-1486Crs187084IL6 G174Crs1800795TNF alpha 238 A/Grs361525LTArs2844484VEGF 405G/Crs833061 Disclosures: No relevant conflicts of interest to declare.

TLR9 but Not NOD2/CARD15 Gene Polymorphism Influence Outcome in AML-Patients Transplanted From HLA-Identical Sibling Donors.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1191-1191
Author(s):  
Ahmet H Elmaagacli ◽  
Michael Koldehoff ◽  
Tania Gromke ◽  
Nina K Steckel ◽  
Dietrich W. Beelen
Keyword(s):  
Overall Survival ◽  
Immune System ◽  
Gene Polymorphism ◽  
Acute Gvhd ◽  
Innate Immune ◽  
Gene Variants ◽  
Gene Variant ◽  
Donor Side ◽  
Tlr9 Gene

Abstract Abstract 1191 Poster Board I-213 Background. We evaluated in a homogenous group of 101 AML-patients after non-T-cell depleted, myeloablative transplantation from HLA-identical sibling donors the role of gene polymorphism of TLR1, TLR4,TLR9, IL23R, and NOD2 on the outcome of transplant. TLR9 and NOD2 are part of the innate immune system, which are able to recognize and bind to the so-called pathogen-associated molecular patterns (PAMPs) from invading pathogens. They induce a rapid innate immune response to microbial invaders and thereby also an activation of the adoptive immune system. TLR9 is activated by DNA containing unmethylated CpG motifs and produces potent Th1-type innate and adaptive immune responses. NOD2 was reported to influence the outcome of transplant. Methods. Here we evaluated the genotype of 101 AML-patients with their donors for the occurrence of the TLR1, TLR4 (A1063G and C1363T), TLR9 (T1237C and T1486C), IL23R (G1142A) and NOD2 by real-time PCR who underwent allogeneic transplantation. Results. Gene variants of the NOD2 gene at patients and donors side were observed in 8.8% of the patients. The CC gene variant of TLR9 -1486 occurred in 19.1% of patients. In our retrospective analyzed study we found that the TLR9 gene variant was the only polymorphism that influenced the outcome of transplant. The estimate for 5-year overall survival (OS) in patients with the CC gene variant of TLR9 at (T1486C) was 74.6% ± 11.1% compared to 45.2% ± 6.0% (p<0.01) in patients with TC/TT of TLR9 gene variants. No influence on 5-year OS was seen for gene polymorphisms of NOD2 or IL23R in this study group. Patients with TLR9 CC gene variant at 1486 or NOD2 gene variants (at recipient and donor side) had a lower rate of leukemic relapse at 5-year post transplant 24.6% ±10.4% versus 44.4 ± 6.6% for TLR9 [p<0.10], and 25% ± 15.3% versus 39.7% ± 7.7% NS). 5-year TRM was lowest in patients with CC gene variant of TLR9 with 7.7% versus 23.7%. Surprisingly also patients with NOD2 gene variant at donor and recipient side hade a reduced 5-year TRM compared to patients with wild-type of NOD2. Acute GVHD grade 2-4 was higher (although not significant) in patients with NOD2 gene variants (recipient and donor side) with 57.1% versus 39.3%. In contrast to NOD2, patients with the gene variant of TLR9 had a no difference in the incidence of acute GVHD grade 2-4 with 22.8% versus 33.1% demonstrating that the lower estimate for relapse risk in patient with TLR9 gene variant was not associated with increased GVHD. Conclusions. The results presented here suggest that the CC gene variant of TLR at 1483 is a strong marker for outcome of transplant, whereas NOD2 gene variants had no influence on the overall survival. The role of NOD2 in transplant must be further evaluated. The gene variant of TLR9 might be helpful in patients planning a transplant as a prognostic positive factor. Disclosures. No relevant conflicts of interest to declare.

One Antigen HLA-Mismatched Related and 8/8 Allele Matched Unrelated Donors Are Associated with Similar Survival after Hematopoietic Cell Transplantation for Acute Leukemia.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 965-965
Author(s):  
David Valcarcel ◽  
Fangyu Kan ◽  
Tao Wang ◽  
Stephanie J. Lee ◽  
Stephen R Spellman ◽  
...  
Keyword(s):  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Disease Free Survival ◽  
Unrelated Donor ◽  
Free Survival ◽  
Gvhd Prophylaxis ◽  
Unrelated Donors ◽  
Related Donor ◽  
Disease Free

Abstract Patients in need of an allogenetic hematopoietic cell transplant but who lack an HLA genotypically identical sibling donor, are faced with the decision to consider a single HLA antigen mismatched related donor, or a search for a suitable 8/8 matched unrelated donor. We compared the outcomes of adult patients (≥18 years old) receiving a transplant for the treatment of AML or ALL in first or second remission from either a one-antigen mismatched related donor (MMRD group, N=89) reported to the CIBMTR or an 8/8 HLA-A, B, C and DRB1 allele matched unrelated donor (UD group, N=700) facilitated by the NMDP between 1995–2005. MMRD group was typed by serological or DNA-based methods for HLA-A, -B and –DR with all results verified by lab report review. The UD group was retrospectively typed for HLA-A, B, C and DRB1 by high resolution typing methods. Most received myeloablative conditioning regimens (77%), calcineurin inhibitor-based GVHD prophylaxis (100%) and T cell replete grafts (100%). 13% received ATG with the conditioning regimen. Median follow-up was 54 and 38 months in the MMRD and UD groups, respectively. The MMRD group was younger (median age 35 vs 43, p=0.002), had more ALL patients with low-risk cytogenetics (43% vs 18%, p=0.005), had older donors (median age: 38 vs 34, p=0.047), were more likely to receive methotrexate for GVHD prophylaxis (89% vs 77%, p=0.014) and were more likely to be transplanted prior to 2001 (62% vs 24%; p<0.001). There were no differences in patient or donor gender, diagnosis, disease-status, cytogenetic-risk of AML, time from diagnosis to transplant, stem cell source, conditioning regimen, use of ATG and Karnofsky index. Univariate comparisons (MMRD vs. UD) showed: 3-year OS (42% vs 44%, p=0.647), 3-year DFS (41% vs 41%, p=0.931), 3-year TRM (39% vs 31%, p=0.136), 3-year incidence of relapse (20% vs 28%, p=0.094), grade III–IV acute GVHD by 100 days (22% vs. 15%, p=0.147), chronic GVHD by 1 year (35% vs 47%, p=0.029). All multivariate analyses were adjusted for patient and transplant characteristics and are shown in the table below. In summary, transplants utilizing one-antigen mismatched related and 8/8 allele-matched unrelated donors did not significantly differ in overall survival or disease free survival, but chronic GVHD was more frequent after UD transplantation. Outcome RR (MMRD vs. UD) 95% CI p-value Survival 0.99 0.73–1.34 0.94 Disease-free survival 1.06 0.80–1.41 0.69 Treatment related mortality 1.14 0.77–1.69 0.52 Relapse 0.81 0.50–1.30 0.38 Acute GVHD III–IV 1.53 0.91–2.57 0.11 Chronic GVHD 0.58 0.39–0.85 0.006

Busulfan (Bu) Plus Cyclophosphamide (Cy) Versus TBI Plus Cy Conditioning for Allogeneic Stem Cell Transplantation (alloSCT) From Matched Unrelated Donors (MUD) In Adult Patients with AML in First Relapse: A Survey From the Acute Leukemia Working Party of EBMT

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 161-161 ◽  
Author(s):  
Arnon Nagler ◽  
Myriam Labopin ◽  
Avichai Shimoni ◽  
Jürgen Finke ◽  
Dietrich Beelen ◽  
...  
Keyword(s):  
Acute Gvhd ◽  
Conflicts Of Interest ◽  
Working Party ◽  
Risk Groups ◽  
Adult Patients ◽  
Free Survival ◽  
Unrelated Donors ◽  
Conditioning Regimens ◽  
First Relapse

Abstract Abstract 161 TBY/Cy and Bu/Cy are the standard myeloablative conditioning regimens for alloSCT in adults with AML. Whether, one is associated with better outcomes compared to the other in the setting of relapsed AML is not well described. We therefore compared TBI/Cy to Bu/Cy conditioning prior to alloSCT in 158 adult patients (pts) with AML in first relapse (Rel 1) that underwent alloSCT from HLA matched (6/6) unrelated donors. 83 patients were given TBI/Cy and 75 Bu/Cy. The median age was 38 years (range, 19–62) in the TBI/Cy vs. 42 years (19–72) in the Bu/Cy group (P<0.012). FAB classifications, cytogenetic risk, time from diagnosis to alloSCT, donor gender and CMV serostatus were not different between the 2 groups. Median year of alloSCT was 2004 vs. 2007 (P<0.0001) for the TBI/Cy vs. Bu/Cy groups, respectively. Conditioning included ATG in 31% vs. 67% in the TBI/Cy and Bu/Cy groups, respectively (P<0.001). 78% of the Bu/Cy group and 80% of the TBI/Cy group, received PBSC grafts, while 22% and 20% received BM grafts, respectively (P=0.8). Median follow-up was, 23 months (range, 1–125) in TBI/Cy and 21 months (1–119) in Bu/Cy. The engraftment rate was similar between both groups with ANC>500/μL achieved at a median of 17 (10–33) and 16 (6–31) days in the TBI/Cy and Bu/Cy groups, respectively (P=0.23). Similarly, acute GVHD (≥Gr II) incidence did not differ between the 2 groups: 33% vs. 37% for the TBI/Cy vs. Bu/Cy, respectively. Death before day 100 occurred in 38% vs. 25% with TBI/Cy vs. Bu/Cy, respectively (P=0.25). 2- year NRM was similar between the 2 groups, 31±5% vs. 21±5%, respectively (P=0.15). In addition, the 2-year relapse rate did not differ between the 2 groups: 50±4% vs. 50±6%, respectively (P=0.93). Leukemia-free survival (LFS) at 2 years, was also similar between the TBI/Cy vs. Bu/Cy groups: 18 ± 5% vs. 29 ± 6 %, respectively (P=0.10). However, overall survival (OS) was significantly higher with Bu/Cy vs. TBI/Cy 38±6% vs. 21±4%, respectively (P=0.02). The main cause of death was disease relapse: 53% and 60%, with TBI/Cy vs. Bu/Cy, respectively (p=0.49). Of note, there were no differences in death from organ toxicities including VOD between the 2 groups. The rate of infection-related deaths did not differ between the groups, as well, 19% vs. 11% (p=0.25). In multivariate analysis, age, cytogenetic risk groups, use of ATG and interval from diagnosis to alloSCT were not significant prognostic factors for survival. In all, these results suggest that in AML patients in Rel 1 undergoing myeloablative alloSCT, Bu/Cy and TBI/Cy conditioning regimens can lead to similar outcomes including GVHD, NRM, disease progression and LFS. However, in terms of OS, there is a suggestion for an advantage in favor of the Bu/Cy regimen possibly due to a lower overall toxicity and improved capacity for salvage therapy. Disclosures: No relevant conflicts of interest to declare.

Addition of More Immunosuppressive Drugs As Graft-Versus-Host Disease (GVHD) Prophylaxis Does Not Improve Gvhd Outcomes in Reduced Intensity Allogeneic Hematopoietic Cell Transplantation from Unrelated Donors

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5786-5786
Author(s):  
Mauricette Michallet ◽  
Mohamad Sobh ◽  
Fiorenza Barraco ◽  
Xavier Thomas ◽  
Marie Balsat ◽  
...  
Keyword(s):  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Immunosuppressive Drugs ◽  
Advisory Committees ◽  
Gvhd Prophylaxis ◽  
Unrelated Donors ◽  
Group 3 ◽  
Group 2 ◽  
Related Mortality ◽  
Group 1

Abstract Background: Reduced-intensity conditioning (RIC) regimens have led to a dramatic reduction of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). The concept of RIC is to deliver adequate immunosuppression with manageable graft-versus-host disease (GVHD) and the eventual development of a potent graft-versus-leukemia effect. Nevertheless, GVHD prophylaxis remains a challenging task after allo-HSCT. While the combination of cyclosporine A (CsA) and a short course of methotrexate (Mtx) after transplantation is considered as the gold standard for GVHD prophylaxis after conventional myeloablative allo-HSCT from HLA-identical siblings, there is no consensus on the optimal preventive GVHD prophylaxis after RIC allo-HSCT. On the other hand, recent and ongoing studies are evaluating a promising GVHD prophylaxis strategy using post-transplantation cyclophosphamide (PTCy). The aim of this study is to evaluate the impact of different GVHD prophylaxis used after RIC allo-HSCT in patients receiving peripheral blood stem cells (PBSC) from unrelated donors for hematological malignancies. Patients and methods: We evaluated 127 consecutive patients with hematological malignancies who received RIC allo-HSCT and were followed in our center between January 2008 and January 2016; 74 (58%) were males, median age was 58 years (range: 18-70), 52 (41%) had acute myeloid leukemia, 36 (28%) myelodysplastic syndrome, 12 (10%) myeloproliferative syndrome, 9 (7%) Non-Hodgkin lymphoma, 9 (7%) chronic lymphocytic leukemia, 6 (5%) multiple myeloma and 3 (2%) chronic myeloid leukemia. At transplantation, 65 (51%) patients were in complete response (CR) or chronic phase (CP). RIC regimen consisted on fludarabine, intermediate doses of IV busulfan and anti-thymocyte golbulins (ATG) (Thymoblobulin) in 56 (44%) patients and a sequential FLAMSA regimen in 71 (56%) patients and who also received similar doses of ATG (Thymoglobulin). PBSC donors were 10/10 HLA matched in 81 (64%) patients and 9/10 HLA mismatched in 46 (36%) patients. Patients were divided according to GVHD prophylaxis into 3 groups: group 1 consisted on CsA alone with 23 (18%) patients, group 2 include patients who received either CsA + mycophenolate mofetil (MMF), n= 64 (50%) or CsA + Mtx, n= 20 (16%) or CsA + cyclophosphamide n= 5 (4%), and group 3 included patients receiving CsA + MMF + tacrolimus n= 15 (12%) patients. Results: After transplantation, all patients in group 1 engrafted after a median of 17 (3-25) days, 81/89 (91%) engrafted in group 2 after a median of 17 (5-58) days and 14/15 (94%) engrafted in group 3 after a median of 16 (9-24) days. We did not observe any significant impact of the type of GVHD prophylaxis on the 100-day incidence of grade II to IV acute GVHD, which occurred in 6/15 (40%), 34/81 (42%) and 7/14 (50%) for the groups 1, 2 and 3 respectively (p=0.18). Grade III-IV acute GVHD occurred in 3 (20%), 24 (29%) and 5 (33%) in the three groups respectively (p=0.11). Similarly, cumulative incidence of 1 year chronic GVHD was not different between groups 1, 2 and 3 reaching 46%, 43% and 46% respectively (p=0.6) among them 3/15 (20%), 18 (22%) and 3/14 (21%) patients had an extensive form. After a median follow-up of 22 months for surviving patients, although there was no significant difference between the three groups in terms of non-relapse mortality, we observed more infection-related mortality with 45% and 83% in groups 2 and 3 respectively compared to 47% in group 1. The cumulative incidence of relapse at 2 years was 22%, 31 and 26% for the three groups respectively (p=0.23). Overall survival rates at two years were 43%, 31% and 44 % for groups 1, 2 and 3 respectively (p=0.42). The multivariate analysis taking into account the type of disease, donor HLA matching, disease status at transplantation, type of RIC and the type of prophylaxis, showed that the incidence of acute GVHD was influenced only by the use of FLAMSA regimen from mismatched donors, HR= 2.2 [1.3-3.1], p=0.05 which had also the same impact on the occurrence of chronic GVHD. Conclusion: Despite its limitations and the need for prospective randomized studies, the results of our study suggest that in the RIC allo-HSCT from unrelated donors, the different GVHD prophylaxis associations lead to similar GVHD outcomes. Patients with more immunosuppressive drugs had a higher incidence of infection-related mortality and in which PTCy could be a better option. Disclosures Nicolini: BMS: Consultancy, Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees.

scholarly journals Dual T-Cell Depletion with a Very Low Dose of ATG and Ptcy Provides an Effective Control of Acute Gvhd in PBSC RIC Allo-HSCT

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5669-5669
Author(s):  
Maria Queralt Salas ◽  
Arjun Law ◽  
Wilson Lam ◽  
David Loach ◽  
Zeyad Al-Shaibani ◽  
...  
Keyword(s):  
Low Dose ◽  
Acute Gvhd ◽  
Effective Control ◽  
Post Transplant ◽  
Transplant Outcomes ◽  
Gvhd Prophylaxis ◽  
Unrelated Donors ◽  
Grade Ii ◽  
The Impact

Introduction As has been described by Dr. Viswabandya et al, the combination of anti-thymoglobulin (ATG), post-transplant cyclophosphamide (PTCy) and cyclosporine (CsA) provides an effective control of graft-versus host disease (GVHD) in peripheral blood (PB) allo-HSCT. We aim to report our experience in reduced intensity conditioning (RIC) allo-HSCT using a novel GVHD prophylaxis composed by a very low dose of ATG, PTCy and CsA for GVHD prophylaxis. Patients and methods Between May 2018 and April 2019, 106 adult patients underwent RIC allo-HSCT with the present GVHD prophylaxis. All these recipients were included in the study. RIC regimen was composed by fludarabine, busulfan, and 200cGy of total body irradiation. For GVHD prophylaxis all recipients received a total dose of 2mg/kg of rabbit-ATG on day -3 (0.5mg/kg) and -2 (1.5mg/kg), PTCy 50mg/m2/day on day +3 and +4, and CsA since day +5. Data was collected retrospectively and updated on July 2019. The median follow-up was 7.6 months (range: 0.4-14.6) and survival percentages were calculated at 6 months. The cum.Inc of GVHD was assessed accounting relapse and death as competing events. Results The main baseline and post-transplant information is summarized in the Table 1 and 2. The cum.Inc of grade II-IV and III-IV acute GVHD at day +100 was 19% and 7.7%. The cum.Inc of grade II- IV was not significantly affected by donor type (P=0.787). However, the cum.Inc of grade III-IV was significantly higher in those recipients who received haploidentical or 9/10 matched unrelated donor (MUD) grafts (p=0.048). Rates of CMV and EBV reactivation were respectively 62.3% and 68.9%. No patients were diagnosed with CMV disease. Biopsy proven post-transplant lymphoproliferative disorder was diagnosed in only 1 recipient and successfully resolved after rituximab. Thirty-two (30.2%) recipients died and 16 (15.1%) relapsed during the follow-up. Main causes of death were relapse 13 (12.3%) and infection 6 (5.7%). The main outcome information is reported in the Table 2 and Plot 1 and 2. Those recipients who received grafts from matched related and unrelated donors had a significant better non-relapse mortality (NRM) (P=0.001), overall survival (OS) (P=0.02), relapse-free survival (RFS) (P=0.03) and GVHD-free/RFS (P=0.006). Table 3 shows the impact of risk factors in transplant outcomes. Those recipients with an HCT-CI score ≥3 had a significant worse OS (HR 2.5; P=0.024) and RFS (HR 2.5; P=0034). Those recipients who received grafts from 9/10 MUD and haploidentical donors had a significant worse RFS (HR 2.1; P=0.049). Disease risk index was not a significant risk factor for OS or RFS. Lastly, those recipients who received grafts from haploidentical donors had a significant worse GRFRS (HR 2.9; P=0.04). Conclusion The dose of ATG for GVHD prophylaxis is not well established. The combination of ATG (2mg/kg), PTCy, and CsA is safe and provides an effective acute GVHD prophylaxis in PB RIC allo-HSCT. Further investigations are required to analyze the effect of this prophylaxis in chronic GVHD to better state long-term outcome conclusions and to improve post-transplant outcomes in those recipients who received grafts from mismatched donor sources (haploidentical and 9/10 matched unrelated donors). Disclosures Michelis: CSL Behring: Other: Financial Support. Mattsson:Celgene: Honoraria; Therakos: Honoraria; Gilead: Honoraria.

Primed-G-CSF BMT for Children with Fanconi Anemia (FA) Using Mycophenolate Mofetil (MMF) and Cyclosporine-A for Gvhd Prophylaxis: Rapid Neutrophil Engraftment, Less Mucositis and Low Incidence of Chronic Gvhd

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3522-3522
Author(s):  
Fabiana Ostronoff ◽  
Mauricio Ostronoff ◽  
ANA Patricia Souto Maior ◽  
Rodolfo Calixto ◽  
Monique Martins ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cyclosporine A ◽  
Acute Gvhd ◽  
Conflicts Of Interest ◽  
Bone Marrow Failure ◽  
Chronic Gvhd ◽  
Hematological Toxicity ◽  
Gvhd Prophylaxis ◽  
Cmv Antigenemia ◽  
Neutrophil Engraftment

Abstract Abstract 3522 Given the historically poor outcomes with standard-dose cyclophosphamide (Cy), preparative regimens for FA have been modified significantly with the goal of limiting toxicity while maintaining engraftment. The most frequently used preparative regimen for patients with bone marrow failure due to FA undergoing matched related HSCT is low dose of Cy. Primed-GCSF BMT (G-BMT) has shown to result in rapid neutrophil recovery and lower incidence of chronic GVHD in comparison to PBSCT likely due to the harvest of higher number of CD34+ cells and a lower number of lymphocytes. In addition, the use of MMF instead of methotrexate (MTX) for GVHD prophylaxis can decrease both severity of mucositis and hematological toxicities. From April 2003 to December 2009, 10 children with bone marrow failure due to FA were transplanted in our center. The patients were 3 females and 7 males, with a median age of 10 years (range, 4 to 15 years). FA was diagnosed based on clinical and radiological findings as well as a positive DEB test. The median time between the diagnosis of bone marrow failure due to FA and BMT was 24 months (range, 6 to 48 months). The protocol was approved by our institutional review board and informed consent was obtained from each patient and donor and or their guardians. Half of these patients had previously been treated with steroids, cyclosporine-A, oxymetholone and ferrous sulfate prior to BMT. One patient had undergone splenectomy prior to BMT. All patients were heavily transfused prior to being referred for transplantation. They all had severe bone marrow insufficiency. Conditioning consisted of Fludarabine (Flu) 30mg/m2 (day -5 to day -2), cyclophosphamide (cy) 15mg/kg/day (day-5 to day -2) in. The first five patients. In the subsequent 5 patients we used cy only, at same dose and schedule, as our institution started participation in a multicenter clinical trial. GVHD prophylaxis consisted of CSA 5mg/kg/day orally for one year and MMF 45mg/kg/day for 6 months. The donors received G-CSF 5 μg/kg/d SC for 5 days before bone marrow harvest (day –4 to day 0). Median CD34+, CD3+ and CD8+ cell count was respectively 3.5×106 cells/ kg (3.5-7.0), 31×106 cells/kg (30-45) and 12×106 cells/kg (10-18). All patients received G-CSF 10 micrograms/kg/day SC from day +1 until neutrophil engraftment. Patients received filtered and irradiated blood product transfusions if needed. Antimicrobial prophylaxis consisted of trimethoprim- sulfamethoxazole, acyclovir, antibacterial and antifungal as indicated. CMV-antigenemia was performed twice weekly until day +120. All patients had complete chimerism by VNTR on day +30. Neutropenia (≤ 500 cells/mm3) was shortly observed in 8 out of 10 pts (80%), median 4 days (2-8 d). Thrombocytopenia (≤ 20.000 cells/mm3) also occurred in 8 pts, median 7 days (4-12 d). There were no infectious complications. Only 6 patients received IV antibiotics or antifungal during the aplasia. All CMV-antigenemia were negative. One patient had late graft rejection 2 years after the transplant and was successfully treated with a 2nd transplant using the same donor with TBI 300 rads, fludarabine 30 mg/m2 (day -4 to day -2) and Cy 20mg/kg/d (day -4 to day -2). Two out of 10 patients (20%) had grade ≥ 2 acute GVHD. One patient died of steroid-resistant acute GVHD and 1 patient developed extensive chronic GVHD which completely resolved after treatment. OS was 90% with median follow up of 53 months (range, 12 to 90 months). All patients who survived have an excellent quality of life. The use of G-BMT for patients with bone marrow failure due to FA resulted in a rapid granulocyte engraftment with low rate of chronic GVHD. In addition, replacing MTX by MMF seems to reduce the incidence of mucositis and the hematological toxicity. Disclosures: No relevant conflicts of interest to declare.

Superior Immunomodulatory Effects of Cultured Mast Cells: Potent Strategy for Treatment of Gvhd

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4684-4684
Author(s):  
Raita Araki ◽  
Hideaki Maeba ◽  
Rie Kuroda ◽  
Toshihiro Fujiki ◽  
Shintaro Mase ◽  
...  
Keyword(s):  
Mast Cells ◽  
Acute Gvhd ◽  
Mixed Lymphocyte Reaction ◽  
Conflicts Of Interest ◽  
Tumor Development ◽  
Independent Manner ◽  
Hematopoietic Stem ◽  
Effector Cells ◽  
Ige Mediated

Abstract Abstract 4684 Mast cells have long been known as effector cells in the various IgE-mediated allergic responses. However, recent studies demonstrated that mast cells play various roles in immune reactions in coordination with other immune cells. That is, mast cells exert pro-inflammatory or anti-inflammatory effects depending on the situation. In addition, mast cells have association with tumor development. In allogeneic hematopoietic stem cell transplantation (HSCT), only a few have reported that the numbers of mast cells were correlated with the severity of acute GVHD in the skin. However, exact role of mast cells in GVHD remains unclear. With the purpose of potential application of mast cells in a clinical HSCT for GVHD, mixed lymphocyte reaction (MLR) was performed to clarify whether mast cells impaired the alloreaction or not. To generate bone marrow derived cultured mast cells (BMCMCs), BM cells from mice were incubated in complete RPMI containing IL-3 for 6 weeks. As shown in the figure, we showed that MLR was strongly inhibited when BMCMCs from the stimulator strain were added to the coculture (Stimulator (S): DCs obtained from C57BL/6, Responder (R): splenocytes from Balb/c, BMCMCs from C57BL/6). Next, when BMCMCs from the responder strain were added to the coculture, MLR was also suppressed (S: DCs obtained from C57BL/6, R: splenocytes from Balb/c, BMCMCs from Balb/c). In conclusion, mast cells suppressed lymphocyte proliferation induced by allo-DCs in an MHC-independent manner. Just like mesenchymal stem cells, cell therapy utilizing cultured mast cells may reduce GVHD severity. Disclosures: No relevant conflicts of interest to declare.

A Matched Controlled Analysis of Post-Transplant Cyclophosphamide (CY) Versus Tacrolimus and Mini-Dose Methotrexate in Matched Sibling and Unrelated Donor Transplant Recipients Receiving Reduced-Intensity Conditioning: Post-Transplant CY Is Associated with Higher Rates of Acute Gvhd

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4200-4200 ◽  
Author(s):  
Amin M. Alousi ◽  
Rima M Saliba ◽  
Julianne Chen ◽  
Borje S Andersson ◽  
Issa Khouri ◽  
...  
Keyword(s):  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Disease Status ◽  
Control Group ◽  
Unrelated Donor ◽  
Post Transplant ◽  
Gvhd Prophylaxis ◽  
Unrelated Donors ◽  
Matched Sibling ◽  
And Control

Abstract Abstract 4200 Graft-vs.-Host Disease (GVHD) remains a common complication following matched sibling and unrelated donor hematopoietic cell transplantation (HCT). Standard GVHD prophylaxis calls for prolonged immune suppression, typically with a calcineurin-inhibitor. Recently, post-transplant cyclophosphamide (CY) has been studied as sole prophylaxis in matched related and unrelated bone marrow (BM) transplant recipients following an ablative conditioning regimen with busulfan (Bu) and CY and demonstrated comparable rates of acute GVHD and lower rates of chronic GVHD as traditional GVHD prophylaxis regimens. We recently conducted a phase II study of post-transplant CY following a reduced-intensity conditioning (RIC) regimen of Busulfan (Bu) and Fludaribine (Flu) in matched related and unrelated donor transplants and performed a matched-control analysis comparing their results with patients who received traditional GVHD prophylaxis with tacrolimus and mini-dose methotrexate (MTX) during the same time period. Forty-nine (49) patients were enrolled onto this study. They received Flu at a dose of 40mg/m2 over 1hour followed by intravenous Bu over 3 hours targeting a daily AUC of 4,000 microMol-min on days –6 to –3. Recipients of unrelated transplants received ATG on days –3 to –1 (total dose 4 mg/kg). CY was given as sole GVHD prophylaxis at a dose of 50 mg/kg on days +3 and +4. During the same period of time, 133 patients received a RIC regimen with intravenous Bu/Flu or Flu and melphalan (Mel) and received GVHD prophylaxis with tacrolimus plus mini-dose MTX (10mg/m2 on day +1, 5mg/m2on days +3, +6, +11). Unrelated donor transplants also received ATG. A computer generated algorithm was used to identify a comparable control group from our departmental database matching, in order of priority, on age, diagnosis, disease status, donor (matched-related versus unrelated) and graft source (PB versus BM). Matched controls (control group) were successfully identified for 37 study patients (Post-Cy group). Results: The median age for the Post- CY group and control group was 61 (range, 39–72) and 62 years (range, 37–72). Eight-one (81) % of patients in both groups had AML or MDS, 3% had ALL and 16% had NHL or CLL. Fifty-nine (59) % of patients in both groups had unrelated donors and received ATG in the conditioning. Disease status for the Post-CY and control groups respectively were CR1: 14 and 14%, CR2: 8 and 11%, >CR2: 38 and 32% and Primary Induction Failure / Untreated: 40 and 32%. Seventy (70) % of the post-CY group received BM versus 48% of the control group, whereas sex mismatching (Male donor for Female patient) occurred in 22% of the post-Cy and 8% of the control group. The cumulative incidence of grade II-IV acute GVHD and chronic GVHD in the post-CY and control groups were: 46% versus 19% (Hazard Ratio (HR): 2.8, 95% CI, 1.1–6.7; p=0.02) and 14% versus 21% (HR: 0.8, 95% CI, 0.2–2.6, p=0.7). Grades III/IV acute GVHD occurred in 14% (95% CI, 6–32) of the patients in the post-CY group whereas there were no cases of grade III/IV in the control group (p=0.02). Overall, progression-free and non-relapse mortality at 2-years are shown in the table below. Conclusion: Post-transplant CY following RIC is associated with higher rates of acute GVHD, with resultant trends for higher non-relapse mortality and lower overall survival when compared to tacrolimus and mini-dose MTX. The use of post-transplant CY as a sole GVHD prophylaxis regimen should be avoided following RIC transplant in matched-related and unrelated donors. Disclosures: Off Label Use: azacitidine: off-label use as maintenance therapy following allogeneic stem cell transplant for MDS/AML.

Thymoglobulin Does Not Impact Relapse or Survival after Matched Unrelated Transplantation for AML/MDS Compared to Matched Related Donor Transplantation without Thymoglobulin Use

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5477-5477
Author(s):  
Yasser Khaled ◽  
Rushang D. Patel ◽  
Shahram Mori ◽  
Wesam B. Ahmed ◽  
Melhem Solh
Keyword(s):  
Overall Survival ◽  
Cumulative Incidence ◽  
Acute Gvhd ◽  
Conflicts Of Interest ◽  
Chronic Gvhd ◽  
Hematopoietic Stem ◽  
Gvhd Prophylaxis ◽  
Related Donor ◽  
Full Intensity ◽  
Conditioning Intensity

Abstract Thymoglobulin does not impact relapse or survival after matched unrelated transplantation for AML/MDS compared to matched related donor transplantation without Thymoglobulin use. Background: Thymoglobulin has been used customarily after matched related (RD) and unrelated (MUD) hematopoietic stem cell transplantation (HCT) to decrease risk of GVHD and graft rejection. However, its use has been implicated in increasing the risk of relapse. As matched sibling related donors considered the best available donor source for patients with AML /MDS, we hypothesized that production of outcomes (Relapse/Survival) after MUD transplant with use of thymoglobulin similar to RD transplantation without the use of thymoglobulin, would justify the use of thymoglobulin after MUD HCT in AML/MDS. Method: We compared the outcomes of 98 (29 matched RD/ 69 matched MUD) consecutive patients with AML/MDS who underwent HCT with Fludarabine/ Busulfan based conditioning between 7/2009-12/2014. Patients Characteristics are shown in Table-1. Patients received full intensity conditioning (FIC) with Fludarabine 40 mg/m2 for 4 days and Busulfan 3.2 mg/Kg single daily dose for 4 days (AUC 4200-5000). GVHD prophylaxis for FIC was Tacrolimus/mini Methotrexate and Tacrolimus/Mycophenolate for RIC. Thymoglobulin was added at dose of 1.5 mg/Kg for 3 days for MUD patients only regardless the conditioning intensity. Results: With median follow up 696 days (RD 746 days, MUD 676 days), the overall survival at 1 year was 75% +/- 8% and 74% +/- 5% for RD and MUD respectively, P=0.66. All patient engrafted except two patients in FIC MUD group. The cumulative incidence of relapse at 1 year was 31% +/- 8% and 23% +/- 5% for RD & MUD respectively, while the treatment related mortality (TRM) was 3.5% +/- 3% and 10% +/- 3% for RD and MUD HCT recipients. Cumulative Incidence acute GVHD grade II-1V was 29% in RD and 49% in MUD. Grade III-IV acute GVHD was 14% in Both RD and MUD recipients. Higher cumulative incidence of extensive chronic GVHD was observed in MUD recipients of 28% vs 20% in RD recipients. Conclusion: The addition of thymoglobulin to MUD HCT did not increase the cumulative incidence of relapse compared to RD HCT patients who did not receive thymoglobulin. RD HCT remained associated with lower TRM than MUD HCT despite the addition of thymoglobulin. MUD HCT with thymoglobulin produced similar overall survival to RD HCT without thymoglobulin. Our data suggest continued use of low dose thymoglobulin with MUD HCT while avoiding its use with matched RD HCT.Table 1.PatientsRelated DonorUnrelated DonorNumber2969AML2261MDS78Graft Failure02Age (Range)53 (35-71)56 (25-73)Reduced Intensity825Full Intensity2144CR11747CR245Relapsed/Refractory817 Disclosures No relevant conflicts of interest to declare.

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