Amino Acid Substitution At Peptide-Binding Pockets of HLA Class I Molecules Adversely Impacts Hematopoietic Cell Transplantation Outcomes

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 467-467
Author(s):  
Joseph Pidala ◽  
Tao Wang ◽  
Michael D Haagenson ◽  
Stephen Spellman ◽  
Medhat Askar ◽  
...  
Keyword(s):  
Amino Acid ◽  
Cell Transplantation ◽  
Amino Acid Substitution ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Peptide Binding ◽  
Multivariable Analysis ◽  
Hla Class I ◽  
Class I ◽  
Increased Risk

Abstract Abstract 467 Background: While donor-recipient disparity at HLA loci is associated with greater risk for severe acute graft vs. host disease (GVHD) and inferior survival after unrelated donor allogeneic hematopoietic cell transplantation (HCT), the impact of amino acid substitution (AAS) at peptide binding pockets of the HLA molecule is incompletely understood. Methods: Adult and pediatric patients who received myeloablative or reduced intensity/non-myeloablative first unrelated bone marrow or peripheral blood stem cell transplantation for AML, ALL, CML or MDS between 1988 and 2009 were included. Donors and patients were fully high resolution matched for HLA-A, B, C, and DRB1 (8/8) or had single mismatch (7/8) at one HLA class I locus. Among 7/8 donor-recipient pairs, cases were categorized based on the presence or absence of the AAS of interest at positions 9, 77, 99, 116, or 156 of the class I molecule. In multivariable analysis accounting for patient, disease, and transplantation variables, we studied the independent impact of AAS at these residues on risk for grade III-IV acute GVHD, chronic GVHD, treatment-related mortality, primary malignancy relapse, and overall survival. We compared 7/8 donor-recipient pairs with AAS of interest to 7/8 pairs without these AAS in the primary analyses. Additionally, we performed this analysis restricted to each HLA class I locus. Results: Donor-recipient pairs were 8/8 matched (n=5282), 7/8 with AAS of interest (n=1713), or 7/8 without AAS of interest (n=318). In multivariable analysis, AAS at position 116 was associated with increased risk for grade III-IV acute GVHD (HR 1.21, 1.04–1.42, p=0.0165). No other significant association was detected between AAS studied and clinical outcomes. In multivariable analysis restricted to each class I HLA locus, we detected the following: Among 7/8 matched pairs with mismatch at HLA-C, AAS at position 116 was associated with increased risk for severe acute GVHD (HR 1.42, 1.13–1.79, p=0.0031) and inferior OS (HR 1.2, 1.01–1.41, p=0.0343). AAS at position 99 was associated with increased TRM (HR 1.37, 1.11–1.69, p=0.0037). Of 7/8 pairs with mismatch at HLA-B, AAS at position 9 was associated with increased chronic GVHD (HR 2.19, 1.31–3.66, p=0.0029). Specific amino acid substitution pairs with frequency > 30 were tested for association with HCT outcomes. None met the significance level of 0.00125, pre-specified for multiple comparisons. Conclusions: These results support the concept that AAS at key peptide-binding residues in the HLA class I molecule are associated with increased risk for severe acute GVHD and lower survival. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Pre-transplant Marital status and Hematopoietic Cell Transplantation Outcomes

2020 ◽  
Vol 27 (6) ◽  
Author(s):  
J. Tay ◽  
S. Beattie ◽  
C. Bredeson ◽  
R. Brazauskas ◽  
N. He ◽  
...  
Keyword(s):  
Social Support ◽  
Marital Status ◽  
Cell Transplantation ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Chronic Gvhd ◽  
Multivariable Analysis ◽  
Hematopoietic Cell ◽  
Increased Risk ◽  
The Impact

Background Evidence regarding the impact of pre-hematopoietic cell transplantation (HCT) marital status on post-HCT outcomes is conflicting. Methods We identified patients, ≥40-years within the Center for International Blood and Marrow Transplant Research registry who received a HCT between January 2008 and December 2015. Pre-HCT marital status was declared as either 1) Married/living with a partner, 2) Single/never married, 3) Separated/divorced, and 4) Widowed. We performed multivariable analysis to determine the association of marital stsatus with post-HCT outcomes. Results We identified 10,226 allogeneic and 5,714 autologous HCT patients with a median follow-up of 37 months (range 1-102) and 40 months (range 1-106) respectively. There was no association between marital status and OS in both allogeneic (p=0.58) and autologous (p=0.17) settings. However, marital status was associated with grade 2-4 acute GVHD (p<0.001) and chronic GVHD (p=0.04). There was an increased risk of grade 2-4 acute GVHD in separated patients compared with married patients [HR 1.13, 95%CI (1.03-1.24)], while single patients had a reduced risk of grade 2-4 acute GVHD [HR 0.87, 95%CI (0.77-0.98)]. The risk of chronic GVHD was lower in widowed patients [HR 0.82, 95%CI (0.67-0.99)] compared with married patients. Conclusions OS post-HCT is not influenced by marital status, but there are associations between marital status and grade 2-4 acute and chronic GVHD. Future research should consider measuring social support using validated scales, patient and caregiver reports of caregiver commitment, and assess health-related quality of life together with health-care utilization to better appreciate the impact of marital status and social support.

scholarly journals Amino acid substitution at peptide-binding pockets of HLA class I molecules increases risk of severe acute GVHD and mortality

Blood ◽  
2013 ◽  
Vol 122 (22) ◽  
pp. 3651-3658 ◽  
Author(s):  
Joseph Pidala ◽  
Tao Wang ◽  
Michael Haagenson ◽  
Stephen R. Spellman ◽  
Medhat Askar ◽  
...  
Keyword(s):  
Amino Acid ◽  
Amino Acid Substitution ◽  
Peptide Binding ◽  
Hla Class I ◽  
Class I ◽  
Graft Versus Host ◽  
Hla Class I Molecules ◽  
Key Points ◽  
Binding Pockets ◽  
Binding Residues

Key Points Amino acid substitution at peptide-binding residues of the HLA class I molecule is associated with graft-versus-host disease and mortality. Avoidance of donor-recipient combinations that result in amino acid substitution at peptide-binding residues may improve transplant outcomes.

Evaluation of NIH Consensus Criteria for Classification of Late Acute and Chronic Gvhd in Reduce Intensity Conditioning (RIC) Stem Cell Transplantation (SCT).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1139-1139 ◽  
Author(s):  
Jifang Zhou ◽  
Sylvain Thepot ◽  
Aurrore Perrot ◽  
Marie Robin ◽  
Regis Peffault de Latour ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Cumulative Incidence ◽  
Acute Gvhd ◽  
Late Onset ◽  
Chronic Gvhd ◽  
Time Dependent ◽  
Increased Risk ◽  
Nih Consensus Criteria

Abstract Abstract 1139 Poster Board I-161 Background Chronic graft-versus-host disease (GVHD) occurs frequently after allogeneic stem cell transplantation (SCT) and has an impact on morbidity and survival. The National Institutes of Heath (NIH) consensus criteria for the diagnosis of GVHD, emphasized clinical manifestations of GVHD rather than the classical time of onset (day 100). Incidence and impact in term of relapse and no-relapse mortality (NRM) of this new classification is not well known after RIC. Methods We retrospectively reviewed 116 consecutive patients (pts) in Saint Louis' Hospital undergoing an SCT for hematologic malignancy and surviving at least day + 100 after RIC between August 2005 and December 2008. We evaluated non-relapse mortality (NRM) and recurrent malignancy. Cumulative incidence was computed using death as a competing event. Incidence of relapse and NRM was counted from 100 days post-transplant for patients without chronic GVHD or from chronic GVHD onset. Patients with relapse/progression before chronic GVHD onset were considered as not having chronic GVHD in these analyses. The association of occurrence of chronic GVHD with the risk of relapse and non-relapse death was analyzed using time-dependent covariates in cause-specific proportional hazards models. Results Among 116 pts ( M/F: 71/45), with a median age of 53 years old (19-68 years) 28 pts (24%) were transplanted for acute leukemia in, 11 pts (9%) for chronic leukemia, 27 pts (23%) for lymphoma, 30 pts (26%) for MPD/MDS and 20 pts (17%) for plasma cell disorder. Sixty-three pts (54%) received HLA-identical sibling transplantation, 53 pts (46%) received transplantation from unrelated donors. Source of stem cells was mobilized peripheral blood stem cell for 108 pts (93%), bone marrow for 4 pts (3%) and 4 cord blood (3%). After a median follow-up of 18 months (range 5-45 months), a total of 67 pts (58%) developed chronic GVHD according to the Seattle day 100 landmark criteria and when using NIH consensus criteria, 55 pts (47%) developed chronic GVHD, including 43 pts (53%) with classic chronic GVHD and 8 pts (10%) overlap syndrome. Patients reclassified included; 3 pts with late onset acute GvHD, 19 pts had recurrent and 8 had persistent acute GVHD (numbers do not to previous sentence because some of these patients latter developed chronic GvHD). The cumulative incidence of chronic GVHD at 36 months was 64% (95%CI; 53%-73%) when using Seattle criteria compared to 56% (95%CI; 45%-67%) with NIH chronic GVHD criteria. Two-year Cumulative incidences of relapse and NRM using both classifications are summarized in Table. In Cox model with GvHD as a time dependent covariate, the NRM was significantly higher in patients with late onset, persistent and recurrent acute GVHD compared to no GVHD (hazard ratio (HR) 31, 47 and 30; p = 0.005, p <0.0001, p <0.0001, respectively), whereas the NRM was statistically increased in case of chronic GVHD using Seattle day 100 criteria (HR: 2.8; P=0.034). Conclusion The cumulative incidence of chronic GVHD “decrease” about 10% when using NIH consensus criteria compared to Seattle criteria in our cohort of RIC. Most of the NRM occurred beyond 100 days after SCT was due to the increased risk of NRM in patients with late onset, recurrent or persistent acute GVHD. Disclosures No relevant conflicts of interest to declare.

scholarly journals Non-Infectious Pulmonary Toxicity after Allogeneic Hematopoietic Cell Transplantation (HCT): A Center for International Blood and Marrow Transplant Research (CIBMTR) Study

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 7-8
Author(s):  
Sagar S. Patel ◽  
Kwang Woo Ahn ◽  
Manoj Khanal ◽  
Caitrin Fretham ◽  
Celalettin Ustun ◽  
...  
Keyword(s):  
Risk Factors ◽  
Lower Risk ◽  
Research Funding ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Multivariable Analysis ◽  
Marrow Transplant ◽  
Smoking History ◽  
Platelet Recovery ◽  
Increased Risk

Introduction Early non-infectious pulmonary toxicity (NIPT) is a significant HCT complication and comprises diffuse alveolar hemorrhage (DAH), idiopathic pneumonia syndrome (IPS), and cryptogenic organizing pneumonia (COP) with an overall incidence ranging 1-10%. Treatment options are primarily immunosuppressive therapy and supportive care with limited efficacy. Mortality in IPS, for example, approaches 60-80% (PMID: 21531955). Therefore, to better identify potentially high-risk patients (pts) we performed a registry-based analysis of the incidence, risk factors, and outcomes of early NIPT after HCT. Methods This retrospective study included adult pts undergoing allogenic HCT for hematologic malignancies and non-malignant disorders as reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) (2008-2017). Data analyses were divided into four common disease categories (AML/ALL, CML/MDS/MPN, NHL/CLL/PCD, and non-malignant diseases) to minimize statistical interactions in the multivariate model. The primary outcome was the incidence of and risk factors for individual NIPT and a composite of the three NIPT (IPS, DAH, COP); the secondary outcome was overall survival (OS). Multivariable Cox proportional hazards regression models were developed to identify the risk factors for NIPT and OS. In addition to baseline pre-transplant covariates, post-transplant neutrophil recovery (&gt;500/mcL x 3 consecutive days), platelet recovery (&gt;20k/mcL x 3 consecutive days, without transfusion in 7 previous days) and grade 2-4 acute GVHD were included as time-dependent covariates in the multivariable models. Results Characteristics of 21,587 adult pts are shown in Table 1. Median age at HCT was 54 years, 59% were male, and 39% had KPS &lt;90. Median follow-up was 49 months. Per the HCT-Comorbidity Index (HCT-CI), 15% and 24% of pts had a severe (FEV1 and/or DLCO≤65%, dyspnea at rest, requiring supplemental oxygen) and moderate (FEV1 and/or DLCO 66-80%, dyspnea on slight activity) pulmonary comorbidity, respectively. Pre-transplant, 3% of pts had a history of mechanical ventilation, 5% had a history of pulmonary fungal infection, and 40% reported a smoking history. Most pts had a matched sibling or unrelated donor (68%) and received peripheral blood graft (71%). Myeloablative conditioning was used in 49% pts, and 39% received total body irradiation (TBI). Table 2 shows the cumulative incidence of early NIPT amongst pts in the four disease categories. Multivariable analysis in the AML/ALL group identified TBI-based conditioning, grade 2-4 acute GVHD, HCT-CI score of 1-3, and prior autologous HCT were associated with increased risk of NIPT, while platelet recovery decreased the risk of NIPT. In the CML/MDS/MPN group, smoking history, grade 2-4 acute GVHD and HCT-CI scores of 2-5+ were associated with increased risk of NIPT, while non-TBI and non-myeloablative TBI conditioning and platelet recovery were associated with a lower risk. In the NHL/HD/CLL/PCD group, a higher risk of NIPT was seen with severe pulmonary comorbidity pre-HCT and chronic GVHD, while platelet recovery and non-TBI regimens were associated with a lower risk. In the non-malignant disease group, both neutrophil and platelet recovery were associated with a lower risk of NIPT. Furthermore, the multivariable analysis for OS (Table 2) showed across all disease groups, NIPT increased the risk of mortality (vs. no NIPT; HR of 4.3 in AML/ALL, 4.1 in CML/MDS/MPN, 3.5 in NHL/CLL/PCD, 6.8 in non-malignant diseases; p&lt;0.0001). Conclusions This large registry-based analysis of allogeneic HCT pts highlights several risk factors for the development of early NIPT including smoking history, severe pulmonary comorbidity, myeloablative TBI conditioning, and acute and/or chronic GVHD. Identification of these risk factors can enhance appropriate selection of pts prior to HCT. We also found that post-transplant, platelet and neutrophil recovery was associated with a reduced risk of NIPT. Furthermore, early NIPT is associated with a several-fold higher mortality risk in the current era despite significant advances in supportive care. Future studies are needed to optimize risk factors such as conditioning regimen and graft source selection to reduce the risk of early NIPT. Disclosures Ustun: Kadmon: Honoraria. Hamilton:Syndax Pharmaceuticals: Consultancy, Honoraria. Majhail:Anthem, Inc.: Consultancy; Incyte: Honoraria; Nkarta Therapeutics: Honoraria; Mallinckrodt: Honoraria. Sorror:Jazz Pharmaceutical: Other: Honorarium for Advisory role. . Stadtmauer:Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Novartis, Onyx Pharmaceuticals, an Amgen subsidiary, Takeda Oncology: Consultancy. Pasquini:Bristol Myers Squibb: Consultancy; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Other; Novartis: Research Funding; Kite: Research Funding.

scholarly journals Clinical Relevance of HLA Supertype Matching after Myeloablative Conditioning 7/8 Unrelated Donor Hematopoietic Cell Transplantation: A CIBMTR Study

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2572-2572
Author(s):  
Aleksandr Lazaryan ◽  
Tao Wang ◽  
Stephen R. Spellman ◽  
Hai-Lin Wang ◽  
Carlheinz R. Müller ◽  
...  
Keyword(s):  
Clinical Outcomes ◽  
Cell Transplantation ◽  
Hematopoietic Cell Transplantation ◽  
Hla Class I ◽  
Hematopoietic Cell ◽  
Class I ◽  
Unrelated Donor ◽  
Myeloablative Conditioning ◽  
Increased Risk ◽  
The Impact

Abstract The diversity of the HLA class I and II alleles can be simplified by consolidating them into fewer supertype clusters based on functional or predicted structural similarities in epitope binding grooves of HLA molecules. HLA class I and II supertypes have been increasingly studied in association with immune susceptibility to infection and cancer with potential implications for vaccine development. However, the significance of individual allele mismatching within and outside of HLA class I or II supertypes remains unknown in the context of hematopoietic cell transplantation (HCT). We therefore studied the impact of HLA supertype disparities on clinical outcomes of 1934 patients with AML (45%), ALL (31%), CML (14%) or MDS (9%) who underwent 7/8 unrelated donor myeloablative conditioning HCT from 1999 to 2011 and were registered with CIBMTR. Median age at transplant was 35 years (range, 1-70); 53% were males; 81% Caucasian; 56% received peripheral blood grafts; 50% were ABO-mismatched; 36% had in-vivo T-cell depletion; 62% received tacrolimus- and 36% cyclosporine A-based GVHD prophylaxis; 72% male or non-parous female donors; median follow up of survivors was 54 months (3-149). Supertype assignment methods of (1) revised main HLA anchor specificities (Sydney, 2008) and (2) bioinformatics (Doytchinova, 2004-05) were used to categorize single mismatched alleles into 6 HLA-A (A01, A01A03, A01A24, A02, A03, A24), 6 HLA-B (B07, B08, B27, B44, B58, B62), 2 HLA-C (C1, C2), and 5 DRB1 (DR1, DR3, DR4, DR5, DR9) supertypes. Overall survival (OS), disease-free survival (DFS), relapse, treatment-related mortality (TRM), acute graft vs. host disease (aGVHD) and chronic GVHD were compared across matched vs. mismatched HLA-A (265 vs. 429), -B (230 vs. 92), -C (365 vs. 349), and -DRB1 (153 vs. 51) supertypes. We used predetermined α=0.01 for statistical significance as multiple exploratory analyses were conducted by Kaplan-Meier, Gray, and Cox proportional hazard methods. In the multivariable analysis, supertype B-mismatch was associated with increased risk of grade II-IV aGVHD (HR=1.78; 95% CI, 1.23-2.59, p=0.0025), however no difference was found for grade III-IV aGVHD or other clinical outcomes compared to supertype B-matches. Supertype DRB1-mismatch was associated with shorter neutrophil recovery (HR=0.51; 95% CI, 0.36-0.71, p=0.0001), yet a trend toward inferior OS (HR=1.58; 95% CI 1.04-2.38, p=0.037) and higher TRM (HR=1.64; 95% CI, 0.99-2.74, p=0.0565) compared to DRB1 matches within supertypes. There was no increased risk of GVHD with DRB1 supertype mismatch. No associations were observed between HLA-A and -C supertypes or aggregate supertype-matched vs. -mismatched groups for any outcomes. Our analysis demonstrated differential influence of HLA supertype-based allele matching within -B and -DRB1 loci on clinical outcomes after myeloablative 7/8 URD HCT. Disclosures No relevant conflicts of interest to declare.

scholarly journals Analysis of Risk Factors Determining Incidence and Outcome of Infections in Children and Adults after Hematopoietic Cell Transplantation

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3364-3364
Author(s):  
Jan Styczynski ◽  
Krzysztof Czyzewski ◽  
Sebastian Giebel ◽  
Jowita Fraczkiewicz ◽  
Malgorzata Salamonowicz ◽  
...  
Keyword(s):  
Risk Factors ◽  
Acute Leukemia ◽  
Bacterial Infections ◽  
Acute Gvhd ◽  
Viral Infections ◽  
Chronic Gvhd ◽  
Multivariable Analysis ◽  
Risk Of Death ◽  
Increased Risk ◽  
Cmv Reactivation

Abstract BACKGROUND: Recent EBMT analysis showed that infections are responsible for 21% of deaths after allo-HCT and 11% after auto-HCT. However, the risk, types and outcome of infections vary between age groups. The aim of the study is the direct comparison of risk factors of incidence and outcome of infections in children and adults. PATIENTS AND METHODS: We analyzed risk factors for the incidence and outcome of bacterial, fungal, and viral infections in 650 children and 3200 adults who received HCT between 2012-2015. The risk factors were determined by multivariable logistic regression analysis. RESULTS: A total number of 395/650 (60.8%) children and 1122/3200 (35.0%) adults were diagnosed for microbiologically confirmed infection, including 345/499 (69.1%) and 679/1070 (63.5%), respectively after allo-HCT, and 50/151 (33.1%) and 443/2130 (20.8%) respectively, after auto-HCT. At 2 years after HCT, the incidences of microbiologically documented bacterial infection were 36.0% and 27.6%, (p<0.001) for children and adults, respectively. Incidences of proven/probable invasive fungal disease (IFD) were 8.4% and 3.7% (p<0.001), respectively; and incidences of viral infection were 38.3%, and 13.5% (p<0.001), respectively. Overall, 31/650 (4.8%) children and 206/3200 adults (6.4%) have died after these infections. The distribution of deaths was different in children (35.5% bacterial, 48.4% fungal, 16.1% viral) and adults (61.7% bacterial, 24.7% fungal, 13.6% viral). BACTERIAL INFECTIONS: In multivariable analysis, the risk of infections was higher after allo-HCT (HR=1.8; p<0.001). In allo-HCT patients, the risk was higher in children (HR=2.1; p<0.001), in patients with acute leukemia (HR=1.6; p<0.001), matched unrelated (MUD) vs matched family-donor (MFD) HCT (HR=1.6; p<0.001), mismatched unrelated (MMUD) vs MFD HCT (HR=2.0; p<0.001), myeloablative vs reduced-intensity conditioning (RIC) (HR=1.3; p<0.001), delayed (>21d) hematological recovery (HR=3.3; p<0.001), acute GVHD before infection (HR=1.7; p<0.001), and chronic GVHD before infection (HR=1.4; p=0.014). In auto-HCT patients, the risk was higher in children (HR=1.7; p<0.001), and in patients with delayed hematological recovery (HR=2.8; p<0.001). In patients with multiple myeloma (MM) the risk was decreased (HR=0.7; p=0.005). FUNGAL INFECTIONS: The risk of proven/probable IFD was higher after allo-HCT (HR=5.4; p<0.001). In allo-HCT patients, the risk was higher in children (HR=3.9; p<0.001), in patients with acute leukemia (HR=3.8; p<0.001), MUD vs MFD HCT (HR=1.5; p=0.013), MMUD vs MFD HCT (HR=2.5; p<0.001), delayed hematological recovery (HR=3.3; p<0.001), acute GVHD before infection (HR=1.5; p=0.021), and chronic GVHD before infection (HR=2.2; p<0.001). In auto-HCT patients, the risk was higher in children (HR=1.8; p=0.025). Patients with MM were at decreased risk of IFD (HR=0.6; p=0.005). VIRAL INFECTIONS: In multivariable analysis, the risk of infections was higher after allo-HCT (HR=6.1; p<0.001). In allo-HCT patients, the risk was higher in children (HR=1.3; p=0.010), in patients with acute leukemia (HR=1.7; p<0.001), MUD vs MFD HCT (HR=2.0; p<0.001), MMUD vs MFD HCT (HR=3.3; p<0.001), myeloablative vs RIC (HR=1.8; p=0.050), acute GVHD before infection (HR=1.5; p<0.001) and chronic GVHD before infection (HR=2.7; p=0.014). Among auto-HCT patients, diagnosis of MM brought decreased risk of viral infections (HR=0.5; p<0.001). DEATH FROM INFECTION: In allo-HCT patients, adults (HR=3.3; p<0.001), recipients of MMUD-HCT (HR=3.8; p<0.001), patients with acute leukemia (HR=1.5; p=0.023), chronic GVHD before infection (HR=3.6; p=0.014), CMV reactivation (HR=1.4; p=0.038) and with duration of infection treatment >21 days (HR=1.4; p=0.038) were associated with increased risk of death from infection. Among patients with bacterial infections, the risk was higher in G- infections (HR=1.6; p=0.031). Among auto-HCT patients, no child died of infection. In adults, the risk of death was higher if duration of treatment of infection was >21 days (HR=1.7; p<0.001). In patients with MM the risk was decreased (HR=0.4; p<0.001). CONCLUSIONS: The profile of infections and related deaths varies between children and adults. MMUD transplants, diagnosis of acute leukemia, chronic GVHD, CMV reactivation and prolonged infection are relative risk factors for death from infection after HCT. Disclosures Kalwak: Sanofi: Other: travel grants; medac: Other: travel grants.

scholarly journals Sirolimus Combined with Cyclosporine (CSP) and Mycophenolate Mofetil (MMF) As Graft-Vs-Host Disease (GVHD) Prophylaxis after Nonmyeloablative (NMA) Hematopoietic Cell Transplantation (HCT) Using HLA Class I or Class II Antigen Mismatched Donors: Results from a Phase II Multi-Center Trial

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 369-369
Author(s):  
Brian Kornblit ◽  
Barry Storer ◽  
Michael B. Maris ◽  
Niels Smedegaard Andersen ◽  
Thomas R. Chauncey ◽  
...  
Keyword(s):  
Cell Transplantation ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Hla Class I ◽  
Class Ii ◽  
Hematopoietic Cell ◽  
Class I ◽  
Current Trial ◽  
Gvhd Prophylaxis ◽  
Class Ii Antigen

The success of HCT is highly dependent on the availability of compatible donors. Depending on ethnicity, fully HLA-matched donors cannot be identified for 25-84% of patients. In an effort to extend the use of HLA-mismatched donors to patients only eligible for NMA HCT, we previously demonstrated that engraftment and long-term survival can be achieved using CSP and MMF immunosuppression after HLA class I antigen-mismatched HCT (Nakamae et al, 2010). Based on this trial, we designed a phase II multi-center trial to assess the efficacy of GVHD prophylaxis with triple immune suppression with CSP, MMF and sirolimus after HLA class I or class II antigen mismatched NMA HCT (fludarabine 90mg/m2 and 2-3 Gy TBI). Patients ineligible for high-dose conditioning with only HLA class I or class II antigen mismatched donors available were eligible for inclusion. The primary objective was to determine whether the incidence of grades 2-4 acute GVHD can be reduced to less than the historical rate of 70% with the triple-immunosuppression. The evaluation was planned to be carried out separately among HLA class I and class II mismatched patients. Secondary objectives included day 100 non-relapse mortality (NRM) and grades 3-4 acute GVHD. CSP was started on day -3 and continued to day +150 and then tapered off by day +180. Sirolimus was started on day -3 through day +180 and then tapered off by day +365. MMF was given thrice daily from days 0 to +30 then twice daily to day +100 and tapered off by day +150. A total of 76 patients were enrolled and received conditioning with fludarabine and TBI followed by infusion of unmodified G-CSF mobilized peripheral blood stem cell (PBSC) grafts. The median age was 63 (21-76) years, and median follow-up of surviving patients was 47 (4-94) months. 51 (67%) and 25 (33%) of patients had HLA class I or II mismatches, respectively. Transplant demographics are summarized in Table 1. Sustained engraftment was observed in all but 1 (1%) patient with myeloproliferative disease who had autologous recovery after transplant. Median number of days with neutrophils &lt; 500 cells/ml and platelets &lt;20,000 platelets/ml were 14 (0-67) and 2 (0-70), respectively. Full donor T-cell chimerism (&gt;95% donor) was achieved in 48% and 63% at days +28 and 84, respectively. Outcomes are summarized in Table 2.The cumulative incidence of grade 2-4 acute GVHD at day +100 was 34% in all patients (29% and 48% after HLA class I and class II mismatched, respectively; p=0.09) (Figure 1), with only 3% of patients experiencing grade 3 acute GVHD and no patients experienced grade 4 acute GVHD. NRM at day +100, 2 years and 4 years were 4%, 15% and 17%, respectively (HLA class I vs class II: p=0.58) (Figure 2). The 2- and 4-year cumulative incidences of chronic GVHD were 54% and 57% (HLA class I vs. class II: p=0.11). Relapse incidences at 2 and 4 years were 26% and 31% with no differences between the class I and II mismatched patients (p=0.54) (Figure 2). The cumulative incidences at 2 and 4 years of progression-free survival (PFS) were 59% and 52%, and overall survival (OS) were 68% and 62% with no differences between HLA class I and II mismatches for PFS or OS (p=0.64 and 0.90, respectively) (Figure 2). Compared to historical data from our previous trial using MMF and CSP prophylaxis alone in patients with HLA class I mismatches, the addition of sirolimus to GVHD prophylaxis with CSP/MMF improved outcomes both after HLA class I or class II mismatched HCT (Nakamae et al, 2010). In a comparison of HLA class I mismatches only, day +100 grade 2-4 acute GVHD was reduced from 69% in the historical cohort to 29% in the current trial. The relapse incidences were comparable, while 2-year NRM decreased from 47%, in historical controls, to 16%, and translated into improved OS from 26% to 67% at 2 years in the current study. No difference was observed in the incidence of chronic GVHD. Furthermore, in the current trial, similar results were seen using HLA class II mismatched donors, suggesting that the triple drug immunosuppression could be used with either type of mismatch. The current trial demonstrates that triple drug immunosuppression with CSP, MMF, and sirolimus is safe and effective in reducing both acute GVHD and NRM after NMA HCT with either HLA class I or class II antigen mismatched donors. Disclosures Maloney: Juno Therapeutics: Honoraria, Patents & Royalties: patients pending , Research Funding; Celgene,Kite Pharma: Honoraria, Research Funding; BioLine RX, Gilead,Genentech,Novartis: Honoraria; A2 Biotherapeutics: Honoraria, Other: Stock options . OffLabel Disclosure: In the current study cyclosporine, mycophenolate mofetil and sirolimus are used to prevent graft versus host disease after allogeneic hematopoietic cell transplantation. Fludarabine is used together with total body irradiation as at part of the conditioning prior to allogeneic hematopoietic cell transplantation.

Impact of antithymocyte globulin (ATG)-containing conditioning regimens on patients undergoing allogeneic stem cell transplantation (allo-CST) for poor risk cytogenetic IPSS myelodysplastic syndrome (PRC-MDS): A report from the French Society of Stem Cell Transplantation and Cell  Therapy (SFGM-TC).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 6542-6542
Author(s):  
Ibrahim Yakoub-Agha ◽  
Gandhi Laurent Damaj ◽  
Marie Robin ◽  
Stephane Vigouroux ◽  
Alice Garnier ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Cumulative Incidence ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
French Society ◽  
Poor Risk ◽  
Increased Risk

6542 Background: Due to a risk of relapse of underlying disease in patients with PRC-MDS, the use of ATG, incorporated within the conditioning regimen prior to allo-SCT, is still controversial. Methods: Inclusion criteria included patients aged over 18 (n=101) who received allo-SCT transplanted between 1999 and 2009 from either a sibling (n=68) or HLA-allele-MUD (10/10) (n=33) for PRC-MDS. HLA matching was double-checked by the national Bone Marrow Donor Registry. Results: According to the FAB/WHO classification at diagnosis, 22 pts had RA/RARS/RCMD, 40 RAEB1, 30 REAB2 and 9 RAEB-t/AML. 34 pts had progressed to a more advanced disease before allo-SCT. At diagnosis, 89 patients had an IPSS int-2 or higher. At transplant, 36 pts were responders (CR, PR, CRm) and 62 with progressive disease (relapsed/refractory, untreated or stable disease without hematological improvement). Median age at transplantation was 54 years (range, 22-69). Pts received myeloablative conditioning (n=46) and nonmyeloablative (n=55). In this series, 48 patients received ATG as part of conditioning ('ATG' group), whereas 53 did not ('no-ATG’ group). As of April 1st 2011, 44 patients died of relapse and 22 of TRM. 3-year relapse, overall and event-free survival rates were not significantly different between the two groups. In contrast, the cumulative incidence of grade 2-4 acute GVHD was 48% in the no-ATG group and 30% ATG group (P <.005). Although the cumulative incidence of chronic GVHD was similar in the no-ATG and ATG groups, a trend for a lower TRM was observed in the ATG group (p=.06). In multivariate analysis, the absence of use of ATG was associated with an increased risk of acute grade 2-4 [HR = 1.92, p=.044]. Conclusions: The addition of ATG to the conditioning regimen resulted in a decreased incidence of acute GVHD without increasing relapse rates and compromising survival of patients undergoing allo-SCT for poor risk cytogenetic MDS.

scholarly journals Genetic variations in the heparanase gene (HPSE) associate with increased risk of GVHD following allogeneic stem cell transplantation: effect of discrepancy between recipients and donors

Blood ◽  
2010 ◽  
Vol 115 (11) ◽  
pp. 2319-2328 ◽  
Author(s):  
Olga Ostrovsky ◽  
Avichai Shimoni ◽  
Avital Rand ◽  
Israel Vlodavsky ◽  
Arnon Nagler
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Human Leukocyte ◽  
Nucleotide Polymorphisms ◽  
Hematopoietic Stem ◽  
Mortality And Morbidity ◽  
Increased Risk

Abstract Graft-versus-host disease (GVHD) is the most common cause of nonrelapse mortality and morbidity after hematopoietic stem cell transplantation (HSCT). The well-documented involvement of heparanase in the process of inflammation and autoimmunity led us to investigate an association between HPSE gene single-nucleotide polymorphisms (SNPs) and the risk of GVHD. The present study indicates a highly significant correlation of HPSE gene SNPs rs4693608 and rs4364254 and their combination with the risk of developing acute GVHD. Moreover, the study revealed that discrepancy between recipient and donor in these SNPs may elevate significantly the risk of acute GVHD. This association was statistically significant when the recipients possessed genotype combinations dictating higher levels of heparanase compared with their human leukocyte antigen (HLA)–matched donors. In addition, HPSE gene SNPs disclosed a correlation with extensive chronic GVHD, nonrelapse mortality, and overall survival. Our study indicates involvement of heparanase in the development of acute and extensive chronic GVHD. Moreover, it suggests a possible mechanism for the aggressive behavior of T lymphocytes leading to GVHD when the recipients possess genotype combinations that dictate high levels of heparanase mRNA compared with their HLA-matched donors expressing low levels of heparanase.

scholarly journals Graft-Versus-Tumor Effects After Allogeneic Hematopoietic Cell Transplantation With Nonmyeloablative Conditioning

2005 ◽  
Vol 23 (9) ◽  
pp. 1993-2003 ◽  
Author(s):  
Frédéric Baron ◽  
Michael B. Maris ◽  
Brenda M. Sandmaier ◽  
Barry E. Storer ◽  
Mohamed Sorror ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Cell Transplantation ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Hematopoietic Cell ◽  
High Dose ◽  
Increased Risk ◽  
Risk Of Relapse

Purpose We have used a nonmyeloablative conditioning regimen consisting of total-body irradiation (2 Gy) with or without fludarabine (30 mg/m2/d for 3 days) for related and unrelated hematopoietic cell transplantation (HCT) in patients with hematologic malignancies who were not candidates for conventional HCT because of age, medical comorbidities, or preceding high-dose HCT. This approach relied on graft-versus-tumor (GVT) effects for control of malignancy. Patients and Methods We analyzed GVT effects in 322 patients given grafts from HLA-matched related (n = 192) or unrelated donors (n = 130). Results Of the 221 patients with measurable disease at HCT, 126 (57%) achieved complete (n = 98) or partial (n = 28) remissions. In multivariate analysis, there was a higher probability trend of achieving complete remissions in patients with chronic extensive graft-versus-host disease (GVHD; P = .07). One hundred eight patients (34%) relapsed or progressed. In multivariate analysis, achievement of full donor chimerism was associated with a decreased risk of relapse or progression (P = .002). Grade 2 to 4 acute GVHD had no significant impact on the risk of relapse or progression but was associated with increased risk of nonrelapse mortality and decreased probability of progression-free survival (PFS). Conversely, extensive chronic GVHD was associated with decreased risk of relapse or progression (P = .006) and increased probability of PFS (P = .003). Conclusion New approaches aimed at reducing the incidence of grade 2 to 4 acute GVHD might improve survival after allogeneic HCT after nonmyeloablative conditioning.

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