Disparities of Minor Histocompatibility Antigens in Unrelated Allo-HCT.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3070-3070
Author(s):  
Miroslaw Markiewicz ◽  
Urszula Siekiera ◽  
Jerzy Wojnar ◽  
Iwona Wylezol ◽  
Sebastian Giebel ◽  
...  
Keyword(s):  
Immune Responses ◽  
Tissue Distribution ◽  
Graft Failure ◽  
Medical Center ◽  
Chronic Gvhd ◽  
Unrelated Donor ◽  
Histocompatibility Antigens ◽  
Minor Histocompatibility Antigens ◽  
Leukemia Relapse ◽  
The Impact

Abstract Disparities of minor Histocompatibility antigens (mHag) have been considered as an important immunogenetic factor influencing immune responses following transplantation despite fully matched HLA of donor and recipient. The aim of our study was to answer whether mHag incompatibility may influence the outcome of allo-HCT. DNA samples from 92 unrelated donor/recipient pairs completely matched in HLA-A*,B*,C*,DRB1*,DQB1* alleles were collected in order to define minor Histocompatibility HA-1, HA-2, HA-3, HA-8, HB-1, ACC-1, ACC-2, HwA-9, HwA-10, UGT2B17, HY genotypes with use of Dynal AllSet kits by PCR-SSP method. Unrelated allo-HCTs were performed in the Department of Hematology and BMT in Katowice, Poland, with use the same standard operating procedure from January 2004 until December 2006. Host versus Graft or Graft versus Host direction of immune responses in donor/recipient pairs was analyzed with use of the minor Histocompatibility Database of Leiden University Medical Center. We observed the impact of mHAg mismatches upon chronic GVHD, incidence of leukemia relapse and graft failure. Patients transplanted from donors with mHAg’s incompatibility in GVH direction had higher probability of chronic GVHD in comparison to other pairs (54% vs 31%, p=0.07). This impact was most prominent for mismatched mHAgs with broad tissue distribution (62% vs 36%, p=0.04), especially HY (66% vs 38%, p=0.02). Opposite influence of HY mismatches in GVH direction was observed upon the probability of relapse, which was lower in the HY-mismatched than in HY-matched group (6% vs 23%, p=0.046). Two mHAgs with tissue distribution restricted to hematopoietic cells mismatched in HVG direction were associated with higher incidence of graft failure than in matched pairs: HA-1 (38% vs 12%, p=0.09) and HA-2 (50% vs 13%, p=0.09). Minor Histocompatibility typing of completely HLA matched patients helps to identify individuals who are at higher risk of cGVHD, leukemia relapse and graft failure, and thus supports precise matching of donor/recipient pairs for unrelated allo-HCT.

Unrelated Allogeneic Stem Cell Transplantation for Severe Acquired Aplastic Anemia: Has Outcome Improved?.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3105-3105 ◽  
Author(s):  
Sebastien Maury ◽  
M.-Lorraine Balere-Appert ◽  
Zina Chir ◽  
J.-Michel Boiron ◽  
Claire Galambrun ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Aplastic Anemia ◽  
Graft Failure ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Young Patients ◽  
Unrelated Donor ◽  
Hla Matching ◽  
The Impact

Abstract We aimed to determine whether outcome of HSCT from an unrelated donor has improved over time for patients with severe acquired aplastic anemia (SAA) and, if so, to determine whether improvement resulted from changes in patient selection, changes in transplantation technique, or both. We thus analyzed the outcome of 89 patients (median age 17 years, range 0–52) who received such transplantations between 1989 and 2004. We compared two cohorts of patients transplanted within two successive time-periods (1989–1998 and 1999–2004) associated with probabilities (± 95% confidence interval) of 5-year survival significantly different: 29% ± 7% and 50% ± 7%, respectively (P<.01, Figure 1). Significant differences between the two cohorts concerned transplant-related, but not patient- and disease-related variables: the use of ATG and of fludarabine within conditioning and HLA matching at the allelic level for the 10 HLA-A, -B, -C, -DRB1 and -DQB1 loci (P=.0004) were more frequent in the recent 1999–2004 period. In multivariate analysis, the only 2 factors influencing survival were HLA allelic matching (P<.01) and younger age of recipient (<17 years, P<.0001). Of note, the impact of HLA matching disappeared in multivariate analysis when it was considered at the antigenic level for HLA-A, -B and -DR antigens, which underlines the importance of considering HLA matching at the allelic rather than the generic level for these transplantations. Survival reached 78% ± 11% at 5-year for the younger patients fully HLA-matched (n=14), which can be compared with survivals obtained for HLA-identical sibling transplants in similar young patients. Cumulative incidences of graft failure, grade II–IV or grade III–IV acute GVHD, and chronic GVHD were: 14% ± 4 % at 2 years, 50% ± 5 % and 24% ± 4 % at 100 days, and 28% ± 5 % at 2 years after HSCT (limited: 17% ± 4 %, extensive: 11% ± 3 %), respectively. In a competing risk analysis, allelic HLA matching - particularly incorporating HLA-C but not -DQB1 matching - but also a high cell-dose injected (> 2,6.108/kg nucleated cells, the median value of the cohort) and the use of fludarabine and/or ATG in the conditioning regimen were found as protective against graft failure and acute GVHD, respectively. Our results suggest that survival after unrelated transplantation for SAA has improved over the past 15 years, due to a better HLA matching at the allelic level for both HLA class I and class II antigens, but also to other transplant-related factors. Figure 1 Figure 1.

scholarly journals Family Mismatched Donor Transplantation for Myelofibrosis: A Retrospective Analysis of the EBMT Chronic Leukaemia Working Party

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4655-4655 ◽  
Author(s):  
Kavita Raj ◽  
Eduardo Olavarria ◽  
Diderik-Jan Eikema ◽  
Liesbeth C de Wreede ◽  
Linda Koster ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cumulative Incidence ◽  
Graft Failure ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Unrelated Donor ◽  
Stem Cell Source ◽  
Gvhd Prophylaxis ◽  
Cell Source ◽  
Mismatched Donor

Abstract Background: Allogeneic stem cell transplantation is a treatment option for patients with advanced myelofibrosis. Problems encountered include an increased risk of delayed or poor engraftment and in the mismatched unrelated donor setting a higher rate of GVHD and particularly poor outcomes. As for other indications for allogeneic stem cell transplants, patients for whom either a matched sibling or matched unrelated donor is not available are considered for either a double umbilical cord blood, a mismatched unrelated donor or haploidentical stem cell transplant. Data on the latter option are limited and we reviewed registry data on all family mismatched donor transplants performed between 2001 and 2015 and reported to the EBMT registry. Results: Records retrieved 69 patients with myelofibrosis transplanted between November 2001 and November 2015. 44 (64%) were male. 50 (74%) had primary myelofibrosis,18 (27%) had secondary myelofibrosis (6 from ET, 5 from PRV and 7 others) and unknown 1(2%). Of 25 patients for whom the JAK2 V617F mutation status was known, 15 (22%) harboured the mutation. Patient Karnofsky performance status was > 70% in 98%. Of the mismatched family donors, 47 (68%) were male and 22 (31%) female. Donors were HLA mismatched at 1 locus in 12 (17%) and 2 or more loci in 48 (69%). Donor-recipient serology combinations were CMV -/- in 8 (12%), +/- in 4 (6%), -/+ in 15 (22%) and +/+ in 34 (49%) missing 8 (12%). Bone marrow was the stem cell source in 34 (49%) and peripheral blood in 35 (51%). The median total nucleated cell count (TNC) infused was 7.5x108/kg (range 2.3-21x108/kg) from data available in 17 patients. The median CD34+ cell dose was 6.9x106/kg (range 1.9-18.18x106/kg) from data available in 19 patients. Conditioning was myeloablative in 48 (70%) and RIC in 21 (30%) The conditioning regimes were varied but the predominant ones were Fludarabine, Busulphan, ATG (FBATG) and Thiotepa, Busulphan, Fludarabine (TBF). TBI was administered in 8 (12%) and in vivo T cell depletion in 22 (32%), ex-vivo T cell depletion in 5 (7%) patients. GVHD prophylaxis varied with post transplant Cyclophosphamide administered in 34/67 (49%) and ATG in 19/67 patients (28%). Neutrophil engraftment was established in 53 (82%) at a median of 20 days (range 11-83). Primary graft failure occurred in 8 (12%) and secondary graft failure in 4 (6%). This occurred at a median of 12 months (range 4.5-35 months). Eleven of these patients had a second allograft at a mean interval of 6.4 months. Responses to the first allograft (censoring for patients who had a second allograft) with data available in 45 patients, showed that complete remission was achieved in 35 patients (78%), 6 (13%) were never in CR and 4 (9%) were not evaluable. The cumulative incidence of grade II-IV acute GvHD at 100 days was 12% (95% CI 4-21%) and for grade III-IV acute GvHD at 100 days it was 5% (95% CI 3-11%). Data for chronic GVHD was valid in 49 patients. The cumulative incidence of chronic GvHD at 2 years was 62% (95% CI 47-76%). The cumulative incidence of limited cGvHD was 45% (95% CI 31-59%) whereas the cumulative incidence of extensive cGvHD was 10% (95% CI 2-19%). The median follow up was 24 months (95% CI 13-35 months). The 2-year OS was 51% (95% CI 37-76%) and the 5-year OS was 38% (95% CI 21-55%). The 2-year RFS was 44% (95% CI 30-59%) and the 5-year RFS was 31% (95% CI 15-48%). The 2 year cumulative incidence of relapse was 14% (95% CI 5-24%). The 2 year NRM was 41% (95% CI 28-55%), which increased to 54% (95% CI 37-72%) at 5 years. The main causes of death were infection (16, 24%), GVHD (7, 10%) organ damage or failure (3, 5%), relapse/disease progression (1, 2%) and secondary malignancy or PTLD (1, 2%). On univariate analysis there was no significant effect of recipient gender, donor gender, degree of HLA mismatch 1 vs >1 Ag MM, CMV matching between donor and recipient, primary or secondary MF, disease stage at transplant (chronic versus advanced phase), conditioning intensity, conditioning regimen, GVHD prophylaxis with ATG or post transplant cyclophosphamide or stem cell source on overall survival. Conclusion: Concerns regarding engraftment and secondary graft failure have excluded patients with myelofibrosis from clinical trials of mismatched related donor transplant. The data suggest that engraftment is feasible, and PFS and OS can be attained with limited severe chronic GVHD with family mismatched donors in this setting. Disclosures Ciceri: MolMed SpA: Consultancy.

scholarly journals Recurrence of aplastic anemia following cyclophosphamide and syngeneic bone marrow transplantation: evidence for two mechanisms of graft failure

Blood ◽  
1985 ◽  
Vol 65 (3) ◽  
pp. 553-556 ◽  
Author(s):  
FR Appelbaum ◽  
MA Cheever ◽  
A Fefer ◽  
R Storb ◽  
ED Thomas
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Aplastic Anemia ◽  
Marrow Transplantation ◽  
Graft Failure ◽  
Host Cells ◽  
High Dose ◽  
Immunological Reactivity ◽  
Histocompatibility Antigens ◽  
Minor Histocompatibility Antigens

Abstract Two patients with aplastic anemia were treated with high-dose cyclophosphamide and marrow transplantation from their normal, genetically identical twin. Both patients rapidly recovered normal marrow function, but marrow failure recurred 13 and 18 months later. Because donor and host pairs were identical twins, these cases of graft failure could not have resulted from the usual cause of graft failure, ie, immunological reactivity of host cells against unshared minor histocompatibility antigens of the donor. These results imply that there are at least two mechanisms responsible for graft failure after marrow transplantation for severe aplastic anemia.

No Improvement of Overall-Survival in Children with High-Risk Acute Myeloid Leukemia by Stem Cell Transplantation in 1st Complete Remission.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 320-320 ◽  
Author(s):  
Dirk Reinhardt ◽  
Bernhard Kremens ◽  
Martin Zimmermann ◽  
Josef Vormoor ◽  
Michael Dworzak ◽  
...  
Keyword(s):  
Overall Survival ◽  
High Risk ◽  
Complete Remission ◽  
Children And Adolescents ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Disease Free Survival ◽  
Hla Typing ◽  
Unrelated Donor ◽  
The Impact

Abstract One aim of the AML-BFM 98 study was to evaluate prospectively the impact of matched sibling donor (MSD)-SCT in 1st complete remission (CR) in children with high-risk (HR)-AML. Patients: Between 7/1998 and 3/2004 494 children and adolescents were enrolled in the studies AML-BFM 98 and the AML-BFM 98 Interim 2003. Patients with favorable cytogenetics [t(8;21), inv(16), t(15;17)], corresponding morphology (AML FAB M1/2 with Auer rods, M4eo, M3) and < 5% blasts on day 15 were defined as standard risk (SR)-group (n=177). All others were stratified to HR-group (n=317) and eligible for SCT in 1st CR. Out of 275 patients achieving 1st CR (87%) 63 patients had a MSD and 188 had no MSD (intent-to-treat group, ITT) while 24 patients had to be excluded due to missing HLA typing or initial refusal to SCT. Thirty-six patients received MSD-SCT (=as-treated group), another two children were transplanted from a matched unrelated donor (MUD) although an MSD was available. The reasons not performing SCT in 1st CR in the remaining 25 children with a donor available were early relapse (n=7), death in CR (n=2), clinical reasons (n=8), or refusal of SCT (n=8). Chemotherapy (CHT) only was given in 192 patients (n=167 without MSD, n=25 with a MSD). Another 21 children were transplanted from an unrelated donor (n=18), family donor (n=1), haploidentical donor (n=2). The reasons were slow response, very poor cytogenetics or other clinical reasons. Treatment: All patients received double induction and consolidation. MSD-SCT in 1st was scheduled after 4 blocs of treatment. Children who were not transplanted in 1st CR received intensification and a 1-year maintenance therapy. The recommended conditioning regimen consisted in busulfan and cyclophosphamide. Results ITT analysis revealed no significant differences in of 5 year disease-free survival (DFS) and overall survival (OS) between children with or without a donor (no donor vs. donor: DFS 43±4% vs. 47±7% plog rank 0.52; OS 56±4% vs. 58±9%, plog rank 0.16). The as-treated analysis gave similar results: CHT only vs. MSD-SCT: DFS 35±11% vs. 59±9% p Mantel-byar 0.13; OS 59±13% vs. 62±12%, p Mantel-byar 0.51). The major reasons of treatment failures were relapses in all groups [CHT only n=100 (52%), MSD-SCT n=13 (34%), MUD-SCT n=9 (50%)]. A 2nd CR was achieved in 71% of the CHT only group (n=74). After SCT in 2nd CR, OS was 40±6%. By contrast, only two children (9%) of 22 children after relapse following SCT in 1st CR could be salvaged. Severe late adverse events (e.g. severe chronic GvHD CTC grade IV, destruction of big joints, intracerebral bleedings) were more frequent in children transplanted in 1st CR (15%) than in those with CHT only (including SCT in 2nd CR; 5%, p×2< 0.05). Conclusion: In the population-based, prospective multi-center study AML-BFM 98 allogeneic MSD-SCT in 1st CR showed no advantage in children and adolescents with HR-AML. Considering the higher toxicity of allogeneic SCT, in the ongoing trial AML-BFM 2004, this SCT (MSD or MUD) is restricted to patients in 2nd CR and refractory AML.

Genome Wide Single Nucleotide Polymorphism Typing for Identification of Putative Minor Histocompatibility Antigens in Graft Versus Host Disease.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 447-447 ◽  
Author(s):  
Ann Mullally ◽  
Cheng Li ◽  
Haesook Kim ◽  
Mehrdad Mohseni ◽  
Edwin P. Alyea ◽  
...  
Keyword(s):  
Stem Cell ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Histocompatibility Antigens ◽  
Single Nucleotide ◽  
Hematopoietic Stem ◽  
Minor Histocompatibility Antigens ◽  
Sibling Pairs ◽  
Graft Versus Host ◽  
Genome Wide

Abstract Previous studies have demonstrated that disparity across minor histocompatibility antigens (mHA) can cause graft versus host disease (GVHD) in patients who receive hematopoietic stem cell grafts from HLA-identical donors. mHA are peptide epitopes derived from normal cellular proteins presented by self MHC. Most autosomal mHA are generated as a result of non-synonymous coding single nucleotide polymorphisms (cSNPs), which lead to differences in the amino acid sequences of homologous proteins between donor and recipient cells. Although it is estimated that several hundred mHA exist in humans, only 16 have been definitively characterized to date. Using the Affymetrix 20K cSNP array we performed SNP typing on 97, HLA-A2+ hematopoietic stem cell transplant (HSCT) recipients and their sibling donors. Genomic DNA was extracted from peripheral blood mononuclear cells (PBMC) obtained from patients and their donors. All patients were in remission at the time of sampling, all had undergone HSCT at the Dana-Farber Cancer Institute between 1998 and 2005 and all samples were drawn prior to transplantation. The transplants included myeloablative and non-myeloablative conditioning regimens, T cell depleted and non-T cell depleted grafts and sex matched and sex mis-matched donors. Using dChip software, we evaluated each of the 20,000 non-synonymous cSNPs on the array for mismatch between sibling pairs and for an association between mismatch in the GVHD direction and the development of acute or chronic GVHD. Mismatch in the GVHD direction was defined as a homozygous donor (AA or BB) and a heterozygote recipient (AB) or a homozygous donor (AA or BB) and a homozygously mismatched recipient (BB or AA). We ranked the cSNPs on the array in order of the strength of the association between mismatch in the GVHD direction and the development of either acute or chronic GVHD. There was no overlap between the 40 mismatched cSNPs most strongly associated with acute GVHD and the 40 most tightly associated with chronic GVHD. Mismatch at the SNP rs12407003 in the OMA1 gene was most highly associated with acute GVHD with mismatch in the GVHD direction occurring in 13 of 41 pairs with acute GVHD and 2 of 56 without (p=0.0003 by Fisher’s Exact Test). OMA1 encodes a mitochondrial membrane-bound metallopeptidase. 65 sibling pairs were assessable for chronic GVHD. Mismatch at the SNP rs2740349 in the GEMIN4 gene was most strongly associated with chronic GVHD with mismatch in the GVHD direction occurring in 10 of 26 pairs with chronic GVHD and 1 of 39 without (p=0.0002). GEMIN4 is part of a cytoplasmic multiprotein complex. This study demonstrates a novel, genome-wide method of identifying putative mHA using a cSNP array. It reveals that mismatch of non-synonymous cSNPs in the GVHD direction occurs at an appreciable frequency in sibling pairs consistent with the hypothesis that the number of mHA in humans is large. Interestingly, the pattern of mismatch differs between acute and chronic GVHD. The study also identifies individual non-synonymous cSNPs for which mismatch in the GVHD direction is highly associated with the development of GVHD. Further evaluation of these cSNPs in larger independent cohorts will be undertaken to validate this association and targeted immunologic analysis of peptides derived from these cSNPs will examine their role as putative mHA.

Unrelated Donor Transplants for Severe Aplastic Anemia: A Report from the EBMT SAA Working Party.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3054-3054
Author(s):  
Andrea Bacigalupo ◽  
Gerard Sociè ◽  
Franco Locatelli ◽  
Hubert Schrezenmeier ◽  
Elisabeth Korthof ◽  
...  
Keyword(s):  
Clinical Data ◽  
Graft Rejection ◽  
Graft Failure ◽  
Causes Of Death ◽  
Low Dose ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Unrelated Donor ◽  
Actuarial Survival ◽  
Median Interval

Abstract Background. SAA patients were transplanted from unrelated donors on two regimes. Regimen A, is a combination of fludarabine (FLU) 30 mg/m^2 /day ×4, cyclophopshamide (CY) 300 mg/m^2/day ×4 and anti-thymocyte globulin (ATG) (Genzyme, USA) 3.75 mg/kg ×4. Regimen B includes FLU -CY at the same dose as Regimen A, with the addition of total body irradiation (TBI) 2 Gy, on day 0,and a reduced does of ATG (7.5 mg/kg). Graft-versus-host disease (GvHD) prophylaxis was cyclosporin and short methotrexate. Patients. We are now reporting 70 consecutive patients. Clinical data and major outcome measures are detailed in the Table. The major difference is that Regimen A included mainly children, the median age being 13 years, with only 3 patients over the age of 30, whereas Regimen B was designed for adults, with the addition of low dose TBI becauses of increase rejection: the median age for Regimen B is 29 years, with only one patient under 16. All patients had failed at least 1 course of immunosuppressive treatment. Graft Rejection was seen in 20% of patients receiving Regimen A: 6/22 for patients >13 years of age (27%) and 3/23 for patients aged <=13 years (12%). Rejection was seen in 3 patients receiving Regimen B (12%). Acute GvHD grade II-IV was scored in 11% and 12% in the two regimens respectively. Chronic GvHD was scored as limited/ extensive in 14%/2% of patients in Regimen A ; these percentages were 27% and 9% for Regimen B.. Survival: The overall actuarial survival is 78% and 77% respectively. In Regimen A survival was 91% vs 67% for patients aged </=>13 years. It was 87% for patients transplanted before the median interval from diagnosis (496 days), compared with 73% for patients grafted later. In Regimen B there was no effect of age on outcome; survival was 92% vs 70% for patients grafted within or beyond the median interval diagnosis-BMT. Causes of death in Regimen A were as follows: graft failure (n= 6), EBV-related lymphoprolipherative disease (n=2) and evolution to myelodysplasia (n=1). For Regimen B causes of death were: graft failure (n=2), infections (n=2) and GvHD (n=1). Conclusion: The FLU-CY-ATG conditioning regimen seems suitable for young children with acquired SAA undergoing an UD transplant. In patients above the age of 13 years, graft rejection remains a problem. The addition of low dose TBI, reduces graft rejection and produces encouraging outcome in adults with acquired SAA. The current survival exceeding 75%, the low incidence of acute and chronic GvHD, and the negative effective of delayed transplantation, suggest the opportunity to consider UD BMT early in the treatment strategy of patients with acquired SAA. Clinical data of patients prepared for transplant with Regimen A or Regimen B Regimen A: FLU CY ATG Regimen B: FLU CY ATG + TBI 2 Gy Patients 45 25 Median age (yy) 13 (3–56) 29 (7–49) Median Interval Dx-Tx (dd) 496 572 Unrelated donor 37 20 Family mismatched donor 8 5 Stem cell source: BM 41 25 Median follow up (dd) 1160 (6–3364) 765 (151804) Graft Rejection 9 (20%) 3 (12%) Acute GvHD II-IV 6 (13%) 3 (12%) Deceased 9 (20%) 5 (20%) Actuarial survival 79% 77% Figure Figure

Impact of the Donor Recipient Sex Combination in Hematopoietic Stem Cell Transplantation: H-Y as a Model for the Interaction between Major and Minor Histocompatibility Antigens.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 481-481 ◽  
Author(s):  
Alois Gratwohl ◽  
Martin Stern ◽  
Ronald Brand ◽  
Theo de Witte ◽  
Anna Sureda ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Cord Blood ◽  
Hematopoietic Stem Cell ◽  
Disease Stage ◽  
Histocompatibility Antigens ◽  
Hematopoietic Stem ◽  
Minor Histocompatibility Antigens ◽  
The Impact

Abstract The importance of minor histocompatibility antigens (miHAg) on outcome in hematopoietic stem cell trans-plantation (HSCT) is well described. H-Y encoded miHAg’s were one of the first to be identified as clinically relevant genetic factors outside HLA. A higher risk of graft-versus-host disease (GvHD) in male recipients of female grafts, specific H-Y directed T-cell responses and antibody reactivity have been documented. As a beneficial effect, a reduced risk of relapse has been observed. Still, the role of H-Y miHAg’s has been disputed in some studies. We studied the effects of the donor recipient sex combination of 63′609 patients (59% male, 41% female, median age 33 years, range 0 to 77 years) with an allogeneic HSCT transplanted between 1980 and 2005 and reported to the EBMT. Main diagnoses were acute leukemias (32′671; 51%), chronic leukemias (15′167; 24%), lymphomas (3901; 6%), plasma cell disorders (1643; 3%), MDS/MPS (5′678; 9%) and aplastic anemia (4459; 7%). Patients were stratified by disease, disease stage (good (55%), intermediate (26%), high risk (19%)), stem cell source (bone marrow (62%), peripheral blood (36%), cord blood (2%)), age (<20 years (27%), 20–40 years (41%), >40 (32%) years), donor age (<20 (21%), >20 (79%) years), conditioning intensity (myeloablative (86%), RIC (14%) and year of transplant. Endpoints analysed were cumulative risks of transplant related mortality (TRM) or relapse (REL) and probability of survival. Results of multivariate analyses are presented. There was a 15% higher relative risk of TRM in male patients receiving a female donor (RMDF) transplant compared to all other gender combinations (RR 1.15; 1.12–1.19). Despite a 9% significant reduction in relapse (RR 0.91; 0.88–0.95), overall survival remained worse (RR 1.08; 1.05–1.11). A higher TRM for RMDF was seen over all calendar years, in all disease categories, disease stages, age classes and with all stem cell sources, with a few distinct exceptions: it was not seen in patients with donors <20 years (RR 0.98; 0.9–1.1), it was not observed in patients with lymphoma (RR 1.06; 0.93–1.20) and it was not observed in the cord blood cohort (RR 0.8; 0.62–1.04). In view of the discordant effects on TRM and REL, the relative impact on survival varied, depending on disease, disease stage and age; e.g., survival was similar in high risk patients for the RMDF and “other” group. Moreover, the higher TRM with RMDF was limited to HLA-identical sibling transplants (RR 1.22; 1.17–1.26) and matched unrelated transplants (RR 1.22; 1.13–1.32). It was neither observed in mismatched related (RR 0.97; 0.87–1.08) nor in mismatched unrelated HSCT (RR 1.03; 0.91–1.18). These data clarify the role of the donor recipient sex combination and form the basis for donor selection algorithms. In addition, they substantiate the close interaction between major and minor histocompatibility antigens: the higher the degree of matching for HLA-antigens, the higher the impact of H-Y difference. It is likely, that the same mechanisms will hold true for other miHAg’s as well.

Mismatch at 1-2 HLA Loci Does Not Reduce Survival Following Alemtuzumab-Based Reduced Intensity Unrelated Donor Allogeneic Transplantation

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3008-3008
Author(s):  
Adam J Mead ◽  
Kirsty J Thomson ◽  
Emma C Morris ◽  
Ronjon Chakraverty ◽  
David C. Linch ◽  
...  
Keyword(s):  
Stem Cell ◽  
Molecular Typing ◽  
Graft Failure ◽  
Chronic Gvhd ◽  
Significant Trend ◽  
Hla Typing ◽  
Mixed Chimerism ◽  
Unrelated Donor ◽  
Significant Difference ◽  
Reduced Intensity

Abstract Most candidates for reduced-intensity allogeneic stem cell transplantation (RIC) do not have a human leukocyte antigen (HLA)-matched sibling donor available. Improved HLA-typing techniques allow more stringent matching of unrelated donors (UD), but have reduced the likelihood of identifying a fully matched UD (MUD), defined as a 10/10 locus match by molecular typing. Whilst donors matching at 8–9/10 HLA loci (MMUD) are considered appropriate by some groups, it is unclear the degree to which HLA-mismatch increases procedural toxicity and how this is influenced by different regimens. Availability of alternative stem cell sources such as umbilical cord blood makes it important to clearly define such risks. We therefore analyzed outcomes of 99 consecutive patients who underwent RIC using an UD in our institution from October 1998 to July 2008. Donor selection was performed according to standard criteria, including molecular typing for HLA-A, -B, -C, DRB1 and DQB1. Donors were 10/10 HLA-matched (n=62) or mismatched at up to 2 HLA loci (n=37). Conditioning was 20mg/d alemtuzumab for 5 days, fludarabine 30mg/m2 for 5 days and melphalan 140mg/m2 for 1 day, with cyclosporine from day -1. Peripheral blood stem cells were used in 51 (30 MUD, 21 MMUD) and bone marrow in 48 (32 MUD, 16 MMUD). Median age was 47 years (13– 67), and underlying disease was AML (n=9), myeloma (n=13), Hodgkin (n=18) or non- Hodgkin lymphoma (n=40), and others (n=19). Patients had a median of 4 previous lines of treatment (0–9) and 49 had failed a prior autograft. There were no significant differences between the groups in terms of age, sex, prior autograft, number of treatment lines, or chemosensitivity at transplantation. There were significantly more CMV seropositive recipients in the MMUD group (P.002). Neutrophil recovery (&gt;0.5 × 109/l) occurred at a median of 12 days (9–57) and did not differ between MUD and MMUD (median 11 vs 12 days). Two patients, both MUDs, had primary graft failure and engrafted following CD34 top-up. Three patients rejected the graft, all MMUDs (P.07 for MUD vs MMUD). Secondary graft failure occurred in 3 cases, all MMUDs (P.07 for MUD vs MMUD). All 3 received CD34 top-up with subsequent improvement in counts in one, another died shortly after infusion of cells and 1 remains cytopenic 4 years following the transplant. Of 40 at risk cases, CMV reactivation requiring treatment occurred in 35 (88%; 85% MUD and 90% MMUD). Donor lymphocyte infusions (DLI) were administered in 35 cases, 23 for disease relapse and 12 for mixed chimerism alone, with no significant difference between MUD (n=25, 40%) and MMUD (n=10, 27%, P.4). There was no difference in the incidence of grade 2–4 acute graft-versus-host disease (aGvHD) between MUD (27%) and MMUD (30%, P.7). Prior to DLI, only 3 cases of grade 3 aGvHD occurred (2 MUD and 1 MMUD) and no grade 4 aGvHD. Chronic GvHD (cGvHD) at 1 year occurred in 30%, with a non-significant trend for a lower incidence in MUD versus MMUD patients (24% vs 40%, P.1). Extensive cGvHD at 1 year was 15% (MUD 13% and MMUD 18%, P.6) excluding post-DLI GvHD, and was 26% at 1 year (MUD 26% and MMUD 27%, P.4) and 40% at 3 years (MUD 34% and MMUD 46%) including post-DLI GvHD. With a median follow-up of 3.0 years, transplant related mortality (TRM) for the whole cohort was 14% at 100 days and 28% at 1 year, with no significant difference between MUD (13% and 30%) and MMUD (16% and 27%). Overall survival (OS) at 3 years was 46% for the whole cohort (45% for MUD, 48% for MMUD). The outcome of 1 (n=20) versus 2 (n=17) locus mismatched transplants was also compared. There was a non-significant trend to increased grade 2–4 aGvHD (16% versus 39%, P.2) in the 2 locus MMUD group but extensive cGvHD (including post-DLI GvHD) at 1 year was not different (30% vs 24%, P.6). Survival was not inferior in the 2 locus MMUD group relative to the single mismatches, with 100 day TRM (20% 1 locus vs 13% 2 locus, P.5), 1-year TRM (43% 1 locus vs 19% 2 locus, P.5), and 3 year OS (32% 1 locus vs 63% 2 locus, P.3). We conclude that 8–9/10 MMUD-RIC is a viable option using T-cell depletion with 100mg alemtuzumab in vivo, without a significant adverse impact on TRM or OS compared with 10/10 MUD. The long-term OS of 48% following MMUD-RIC is encouraging given the inclusion mainly of patients with multiply relapsed/refractory hematological malignancy.

Improved Outcome After Reduced Intensity Allogeneic Hematopoietic Stem Cell Transplantation (RI-HCT) for Myelodysplastic Syndrome (MDS) Using Tacrolimus/Sirolimus-Based Gvhd Prophylaxis.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2771-2771 ◽  
Author(s):  
Ryotaro Nakamura ◽  
Joycelynne Palmer ◽  
Pablo Parker ◽  
Anthony Stein ◽  
Tracey Stiller ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Chronic Gvhd ◽  
Unrelated Donor ◽  
Hematopoietic Stem ◽  
Gvhd Prophylaxis ◽  
Significant Difference ◽  
One Year ◽  
The Impact ◽  
Bone Marrow Blasts ◽  
Improved Outcome

Abstract Abstract 2771 Poster Board II-747 We previously reported an encouraging result with RI-HCT for MDS (Bone Marrow Transplant 2007; 40:843-50) using flugarabine/melphalan conditioning and cyclosporine (CSA)/mycophenolate (MMF) as GVHD prophylaxis. In order to further improve upon the outcome in the RI-HCT setting, we initiated a series of clinical trials at City of Hope National Medical Center designed to evaluate the impact of tacrolimus (FK)/sirolimus (SIRO)-based GVHD prophylaxis. Here we report the combined, updated results from a consecutive case-series of 89 patients with MDS (including AML progressed from MDS) who underwent RI-HCT from 2000 to 2008 and received either CSA/MMF (n =44) or FK/SIRO (n=45)-based GVHD prophylaxis. All patients received fludarabine 125 mg/m2 plus melphalan 140 mg/m2 followed by an allogeneic HCT (peripheral blood: n=83, bone marrow: n=6) from an HLA-identical sibling (SIB: n=35) or unrelated donor (MUD: n=54). Additional ATG was given to 12 patients. For MUD transplants a short course of methotrexate was added to CSA/MMF or FK/SIRO. The median age was 59 years (range: 20-71) and 31 (35%) patients were female, 58 (65%) were male. Diagnoses at transplant were RA (n=21), RARS (n=1), RAEB/RAEBT (n=36), and AML from prior MDS (n=31). Cytogenetic risk was low in 15 (17%), intermediate in 37 (41.5%), high in 37 (41.5%) patients. By IPSS criteria (for MDS only), 2 patients had low, 24 had int-1, 20 had int-2, and 12 had high-risk MDS. Twenty-seven patients had therapy-related MDS including 14 with prior autologous HCT. The median follow-up time for surviving patients was 39 months (range: 24-68) for the CSA/MMF group and 17 months (range: 4-39) for the FK/SIRO group. All but two patients (1 in CSA/MMF, 1 in FK/SIRO) engrafted with the median neutrophil recovery at 15 days (range: 11-55). The baseline patient, disease and transplant characteristics were similar between CSA/MMF and FK/SIRO, except for an increased percentage of therap-related MDS in the CSA/MMF group (43% vs. 18%, p<0.01). The median donor chimerism by STR at day 30 post-transplant was 100% in both groups (p=0.6). FK/SIRO was associated with a significantly reduced one-year non-relapse mortality (NRM) (11.4%) compared with CSA/MMF (36.2%, p=0.01). This improvement in NRM translated into a trend for improved overall survival (81.4% vs. 52.3%, p=0.1) and disease-free survival (72.2% vs. 52.3%, p=0.08) at one year. While we observed no significant difference in acute GVHD grade II-IV between CSA/MMF and FK/SIRO, FK/SIRO was associated with a significant reduction in grade IV GVHD (0% versus 26%, p<0.01) and a trend for III-IV GVHD (31% vs. 55%, p=0.1). There was no significant difference in chronic GVHD between FK/SIRO (60%) and CSA/MMF (56%, p=0.8). In multivariate analysis, the use of FK/SIRO was independently associated with improved NRM after adjusted for donor type, therapy-related MDS, %bone marrow blasts, and HLA match status (Table). In conclusion, FK/SIRO-based GVHD prophylaxis was associated with an improved outcome after RI-HCT for MDS attributable to the reduced risk for severe acute GVHD.Variables for NRMHazard Ratio (95% CI)p-valueDe novo (n=62) Therapy-related (n=27)baseline 0.75 (0.31–1.89)0.55Sibling donor (n=35) Unrelated donor (n=54)baseline 2.17 (0.70–6.74)0.18Bone marrow blasts < or =10% (n=67) Bone marrow blasts >10% (n=22)baseline 2.13 (0.92–4.96)0.08HLA match (sibling donor or 10/10 MUD, n=72)HLA < mismatch MUD (<10/10 match, n=17)baseline 6.26 (2.11–18.55)0.001FK/SIRO (n=45) CSA/MMF (n=44)baseline 6.58 (2.15–20.14)0.001 Disclosures: Off Label Use: cyclosporine, cellcept, tacrolimus, sirolimus, and methotrexate for GVHD prophylaxis.

OUTCOME of Unrelated DONOR BONE MARROW TRANSPLANTATION for THALASSEMIA MAJOR PATIENTS

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 149-149 ◽  
Author(s):  
Franco Locatelli ◽  
Roberto Littera ◽  
Daria Pagliara ◽  
Benedetta Contoli ◽  
Giovanna Giorgiani ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Graft Failure ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Thalassemia Major ◽  
Unrelated Donor ◽  
Class Iii ◽  
Patients At Risk ◽  
Grade Iii

Abstract Abstract 149 At present, allogeneic bone marrow transplantation (BMT) is still recognized as the only treatment potentially able to cure a large proportion of patients with thalassemia major. For many years, the only donor employed was an HLA-identical sibling. Unfortunately, at least 70% of patients who might benefit from BMT lack a compatible sibling. With the establishment of bone marrow donor registries, including now more than 15 million volunteers world-wide, many patients are able to locate a suitable unrelated donor. Aim of this study was to evaluate the outcome of patients transplanted from an unrelated volunteer, selected using stringent criteria of compatibility after high-resolution molecular typing of HLA loci, and to identify factors with a prognostic relevance. We analyzed 122 thalassemia patients (96 children and 26 adults, age range at time of BMT 1–35 years, median 10,5) given the allograft in one of 4 Italian Centers participating to this study. Seventy-one patients were males and 51 females; 13 patients had positive Hepatitis C Virus (HCV) serology. Prior to transplantation, all patients underwent a complete check-up and children were assigned to one of 3 classes of risk according to the criteria proposed the Pesaro group. In detail, 39 pediatric patients belonged to the class I, 41 to the class II (23) and 16 to the class III of the Pesaro classification. In 105 donor/recipient pairs were matched for the HLA-A, -B, -C, -DRB1 loci; 17 donor/recipient pairs had a disparity at the HLA-C locus, but both HLA-C molecules pertained to the same HLA-C ligand group. The patients were prepared for the allograft using a myeloablative conditioning regimen based on the combination of busulfan/treosulfan (BU/TREO), thiotepa (TT) and either cyclophosphamide (CY, 54 patients), or fludarabine (FLU, 68 patients). All patients received fresh, unmanipulated bone marrow cells, the median dose of nucleated cells infused being 5×108/Kg recipient b.w. (range 1.4–15). Graft-versus-host disease (GvHD) prophylaxis was homogeneous in all patients and consisted of cyclosporine-A, short-term methotrexate (15 mg/m2 on day +1 and 10 mg/m2 on days +3, +6 and + 11) and anti-thymocyte globulin (ATG, 2.5 mg/Kg from day –4 to –2). Twenty patients died and 16 patients had either primary (11 patients) or secondary (5 patients) graft failure, the 5-year probability of overall survival (OS), and thalassemia-free survival (TFS) being 84% (95% Confidence Interval, CI, 76–90) and 75% (95% CI, 66–81) respectively. Acute and chronic GvHD were the main causes of death accounting for 6 and 4 fatal events respectively. Thirty-four patients at risk (28%) developed grade II-IV acute GvHD with 16 of them (13%) experiencing grade III-IV acute GvHD. Fourteen patients at risk (13%) had chronic GvHD, which was limited in 8 cases and extensive in 6. The probability of survival was not influenced by the occurrence of graft failure which was responsible of only 2 of the 20 fatal events. The chance of being alive for children belonging to class I, II and III of the Pesaro classification was 97% (95% CI, 83–100), 85% (95% CI, 70–93) and 78% (95% CI, 51–93), respectively, while that of adults was 65% (95% CI, 44–80) (p<0.01). Occurrence of both grade III-IV acute and chronic GvHD, older patient's age, positive HCV serology and adult/class III group of risk predicted a poor survival in univariate analysis; however, in multivariate analysis, only occurrence of grade III-IV acute GvHD was associated with a poor outcome (Hazard ratio, 10.4, 95% CI 3.19 – 34.06, P=0.001). Altogether, these data indicate that, provided that selection of the donor is based on stringent criteria of HLA-compatibility, transplantation from unrelated volunteers is able to cure a large proportion of patients with patients with thalassemia major, the results being comparable to those obtained when the donor is an HLA-compatible sibling. Prevention of severe acute GvHD is able to optimize the outcome of patients with thalassemia major transplanted from an unrelated volunteer. Disclosures: No relevant conflicts of interest to declare.

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