Unrelated Donor Hematopoietic Stem Cell Research Articles

Unrelated Hematopoietic Stem Cell Donor Matching Probability and Search Algorithm

In transplantation of hematopoietic stem cells (HSCs) from unrelated donors a high HLA compatibility level decreases the risk of acute graft-versus-host disease and mortality. The diversity of the HLA system at the allelic and haplotypic level and the heterogeneity of HLA typing data of the registered donors render the search process a complex task. This paper summarizes our experience with a search algorithm that includes at the start of the search a probability estimate (high/intermediate/low) to identify a HLA-A, B, C, DRB1, DQB1-compatible donor (a 10/10 match). Based on 2002–2011 searches about 30% of patients have a high, 30% an intermediate, and 40% a low probability search. Search success rate and duration are presented and discussed in light of the experience of other centers. Overall a 9-10/10 matched HSC donor can now be identified for 60–80% of patients of European descent. For high probability searches donors can be selected on the basis of DPB1-matching with an estimated success rate of >40%. For low probability searches there is no consensus on which HLA incompatibilities are more permissive, although HLA-DQB1 mismatches are generally considered as acceptable. Models for the discrimination of more detrimental mismatches based on specific amino acid residues rather than specific HLA alleles are presented.

Both Optimal Matching and Procedure Duration Influence Survival of Patients after Unrelated Donor Hematopoietic Stem Cell Transplantation

Eighty-six patients suffering from hematological malignancies, immunodeficiencies, and aplastic anemias received alloHSCT from unrelated donors. Donors were selected from the BMDW files and further matching was performed according to the confirmatory typing procedure with the use of PCR SSP and that based on sequencing. The time from the clinical request of the donor search to the final decision of clinicians accepting the donor was from 0.3 to 17.8 months (median 1.6). Matching was analyzed at the allele level, and 50, 27, and 9 donor-recipient pairs were 10/10 matched, mismatched in one or more alleles, respectively. In an univariate analysis we found better survival if patients were transplanted: (i) from donors matched 10/10 (P = 0.025), (ii) not from female donor to male recipient (P = 0.037), (iii) in female donation from those with ≤1 pregnancy than multiparous (P = 0.075). Notably, it became apparent that duration of the confirmatory typing process affected the survival (HR = 1.138, P = 0.013). In multivariate analysis only the level of matching and the duration of the matching procedure significantly affected the survival. In conclusion, the duration of the matching procedure in addition to the level of matching should be considered as an independent risk factor of survival.

The combination of sirolimus plus tacrolimus improves outcome after reduced-intensity conditioning, unrelated donor hematopoietic stem cell transplantation compared with cyclosporine plus mycofenolate

Different types of graft-versus-host disease prophylaxis have been proposed in the setting of reduced intensity and non-myeloablative allogeneic stem cell transplantation. An alternative combination with sirolimus and tacrolimus has recently been tested although comparative studies against the classical combination of a calcineurin inhibitor and mycophenolate mofetil or methotrexate are lacking. We describe the results of a prospective, multicenter trial using sirolimus + tacrolimus as immunoprophylaxis, and compare this approach with our previous experience using cyclosporine + mycophenolate in the setting of unrelated donor transplantation setting after reduced-intensity conditioning. Forty-five patients received cyclosporine + mycophenolate between 2002 and mid-2007, while the subsequent 50 patients, who were transplanted from late 2007, were given sirolimus + tacrolimus. No significant differences were observed in terms of hematopoietic recovery or acute graft-versus-host disease overall, although gastrointestinal acute graft-versus-host disease grade ≥ 2 was more common in the cyclosporine + mycophenolate group (55% versus 21%, respectively, P=0.003). The 1-year cumulative incidence of chronic graft-versus-host disease was 50% versus 90% for the patients treated with the sirolimus- versus cyclosporine-based regimen, respectively (P<0.001), while the incidence of extensive chronic disease was 27% versus 49%, respectively (P=0.043). The 2-year non-relapse mortality rate was 18% versus 38% for patients receiving the sirolimus- versus the cyclosporine-based regimen, respectively (P=0.02). The event-free survival and overall survival at 2 years were 53% versus 29% (P=0.028) and 70% versus 45% (P=0.018) among patients receiving the sirolimus- versus the cyclosporine-based regimen, respectively. In conclusion, in the setting of reduced intensity transplantation from an unrelated donor, promising results can be achieved with the combination of sirolimus + tacrolimus, due to a lower risk of chronic graft-versus-host disease and non-relapse mortality, which translates into better event-free and overall survival rates, in comparison with those achieved with cyclosporine + mycophenolate.

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Aim A hematopoietic stem cell transplantation program in Santiago, Chile affiliated with St. Jude Children’s Research Hospital referred 190 patients and their family members for HLA typing between 2000 and 2011. Methods These individuals were studied for HLA specificities by the use of sequence-specific oligonucleotide primers (SSP), sequence-specific oligonucleotide probes (SSO) and DNA sequencing. Haplotype assignment could be made unambiguously in all cases from family studies. Results The expectation of the referring center was that this group consisted largely of those of western European origin. HLA typing of the large proportion of this referred group indicated that although 70 - 80 % was similar to populations found in western Europe, a substantial number demonstrated alleles not found in western Europeans and which were initially described in native South American populations. For example, of 35 patient samples positive for HLA-A ∗ 68, 34 (97%) were found to be HLA-A ∗ 68:01:02 by DNA sequencing, a variation described in native South American populations. HLA-A ∗ 68:23 was identified in 8 unrelated individuals in this group of 719 patients and family members. This would indicate that this unusual allele would meet the criteria for a common and well-documented allele in this population. Alleles of HLA-A ∗ 02, A ∗ 24, as well as other A ∗ 68 alleles not commonly seen in those of western European heritage were also found. Eleven HLA-B ∗ 35, six HLA-B ∗ 39 and five HLA-B ∗ 51 alleles first described in native South American populations were also found in HLA typing of this group from Chile. HLA-DRB1 ∗ 04:07 was shown in 87 and HLA-DRB1 ∗ 08:02 in 55 of these 719 individuals. Conclusions Unrelated donor registries in Argentina and Brazil have recently formed cooperative agreements with the National Marrow Donor Program and can be expected to be beneficial for those patients from South America requiring unrelated hematopoietic stem cell donors.

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In order to reduce the time required to identify a match for unrelated donor hematopoietic stem cell transplantation, a one-step DNA sequencing strategy was employed at the time of recruitment. The impact of this strategy on typing resolution and the effect of current registry requirements on resolution and coding of assignments were evaluated. Sanger-based DNA sequencing was used to obtain diploid exons 2 and 3 HLA-A,-B,-C assignments of 2,746 unrelated African American volunteers at recruitment. The results are high resolution; using IMGT/HLA database 2.28.0, ∼90% of donors carried 3 or less alternative genotypes (e.g., 89% HLA-C). Of those individuals whose HLA typing resulted in alternative genotypes, the majority (∼90%) were predicted to have only a single “common” genotype among the alternatives. Higher resolution typing confirmed these predictions. A small percentage of all assignments (3.4% A, 8.6% B, 3.9% C) included greater than two antigen groups. For HLA-B, only 4 of the 48 unique haplotypes with >2 antigens included two common genotypes, impacting only 18 of the 2746 individuals. The need for secondary assays to resolve these few combinations at the time of recruitment is questionable because of the high resolution of the screening-level typing, the focus on matching alleles not antigens, the additional cost, the increased opportunity for errors, and the less robust nature of the secondary assays. The assignment of NMDP-designated allele codes reduced the resolution substantially and introduced genotypes that were not included in the laboratory’s assignments. We suggest an alternative strategy: use the exons 2-3 diploid sequence as the assignment to avoid the limitations mentioned above, as well as to “immortalize” the assignment in time regardless of the introduction of novel alleles. To keep pace with current donor selection criteria and with the increasing number of new alleles, it is time to rethink our recruitment typing strategies.

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Aim To study the various HLA high resolution typing mismatching of donor-recipient pairs impact to success of unrelated donor hematopoietic stem cell transplantation. Methods 835 donor-recipient pairs of CMDP data were analyzed from 2005 to 2010. HLA-A, B, C, DRB1 and DQB1 typing were performed using SBT, SSOP and SSP. All the patients were undergoed transplantation for AML (n = 288), ALL (n = 227), CML (n = 187), MDS (n = 52), NHL (n = 25) and AA (n = 42). In the 835 donor-recipient pairs, 362 pairs were completely matched, 473 pairs were mismatched include of single allele and antigen, both allele and antigen, double allele and antigen, multiple allele and antigen. Results HLA-matched pairs was associated with better overall survival compared with HLA-mismatched pairs (79.83% vs 73.15%), but there were no statistically significant differences. HLA mismatches of single allele plus single antigen were a significant risk factor for OS, DFS and TRM. In the patients of difference FAB groups, OS from high to low in turn was MA, AA, CML, MDS, AML, NHL, ALL. OS of HLA locus mismatching were DRB1(94.4%), DQB1(83.3%), B(75%), A(74.4%) and C(71.4%), respectively. OS of single allele mismatch at HLA locus from high to low in turn was DRB1, C, A, B and DQB1.HLA-A, B, C locus mismatch was statistically significant differences associated with lower OS and gradeII-IVacute GVHD compared with HLA-matched pairs. The donor-recipient pairs with HLA-B ∗ 15:01/B ∗ 15:05, DRB1 ∗ 12:01/DRB1 ∗ 12:02, C ∗ 04:01/C ∗ 03:04, DQB1 ∗ 03:02/DQB1 ∗ 03:03 alleles mismatch were priority accepted. But the donor-recipient pairs with HLA-B ∗ 39:01/B ∗ 39:05,C ∗ 15:02/C ∗ 14:02, C ∗ 08:01/C ∗ 03:04,C ∗ 07:02/C ∗ 15:02 alleles mismatch, were nonpermissive. These were risk factors to impact OS and the occurrence of severe aGVHD of HSCT. Conclusions The high resolution typing for HLA-A, B, C, DRB1,DQB1 can be identified nonpermissive mismatch, that is would be beneficial for the selection of a suitable donor and can be improved higher rates of survival on unrelated donor HSCT.

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Aim Increased novel allele discovery has a huge contribution to HLA diversity, which could, however, complicate donor search. Currently, no clear guidelines of unrelated hematopoietic stem cell (HSC) donor search are available when novel alleles are involved. Novel alleles raise questions of the clinical significance of the substitution and its effect on unrelated donor search. In this study we present an approach to evaluate a novel allele for donor search. Methods HLA high resolution typing was performed by SBT. We examined the clinical significance of a novel DQB1 ∗ 06:XX allele for the difference between it and the common DQB1 ∗ 06:02, the nature of the changed amino acid, and the location of the changed amino acid on three dimensional structure (α helix or β sheet). Results DQB1 high resolution typing revealed a novel allele identical to DQB1 ∗ 06:02 with except for a mismatch at position 25 within exon 2. The Nucleotide changed from ‘G’ to ‘T’ which caused amino acid changing from Glycine to Valine at codon 13(β13) in the amino-terminal region. The mutation is located on the floor of groove accommodating anchor position pocket 4 (P4). The side group of Glycine in DQB1 ∗ 06:02 changed from –H to –C3H7 for Valine in novel DQB1 ∗ 06:XX. The replaced side group –C3H7 occupies more space and possesses more hydrogen bonds. Although the shape and affinity of the peptide binding pocket might be altered due to changing of the side chain, both Valine and Glycine still belong to hydrophobic amino acid group. High resolution HLA typing of his mother and three siblings were also performed. The novel allele was inherited from the mother. Conclusions Our findings suggest that the amino acid change of the novel allele DQB1 ∗ 06:XX might not be clinically significant based on its location and characteristics when compared to the common DQB1 ∗ 06:02. The method we used to evaluate a novel allele could be a practical approach for the unrelated donor search for a potential HSC recipient with a novel allele of any loci.

MICA*066, a novel major histocompatibility complex class I‐related chain A allele found by high‐resolution HLA‐matching tests for hematopoietic stem cell transplantation

MICA*066, a novel MICA allele identified in HLA/MICA typing of a unrelated donor hematopoietic stem cell transplantation donor-patient pair.

Discovery of the novel HLA‐DRB1*03:77 allele in a Taiwanese unrelated hematopoietic stem cell donor by a sequence‐based typing method and identification of the probable HLA haplotype in association with DRB1*03:77

Here, we report a novel human leucocyte antigen (HLA)-DRB1 allele, DRB1*03:77, discovered in a Taiwanese unrelated volunteer hematopoietic stem cell donor by a sequence-based typing (SBT) method. The DNA sequence of DRB1*03:77 is identical to the DNA sequence of DRB1*03:01:01 in exon 2 except one nucleotide at position 223 (G→C). The nucleotide substitution caused an amino acid replacement at residue 46 (E→Q). The formation of DRB1*03:77 was thought as the result of a nucleotide point mutation. The probable HLA-A, HLA-B and HLA-DRB1 haplotype in association with DRB1*03:77 may be deduced as A*33-B*58-DRB1*03:77. The donor was a Minna Taiwanese whose ancestors came from mainland China.

Peripheral Blood or Marrow: Is One Better Than the Other?

A study by Bertz et al. [1] in this issue of Biology of Blood andMarrow Transplantation shows that the results of unrelated donor hematopoietic stem cell transplant for adults with acute myelogenous leukemia or myelodysplastic syndrome are better with transplantation of peripheral blood progenitor cells (PBPCs) compared to bone marrow (BM). Overall mortality risks were lower after transplantation of PBPC compared to BM. With a median follow-up of 10 years, event-free survival rate after PBPC transplants was 55% and significantly higher compared to 28% after BM transplants. This is in contrast to the findings of a randomized multicenter trial of unrelated donor PBPC vs BM for hematologic malignancies in North America [2]. That trial randomized 273 patients to receive PBPC and 278 patients to receive BM. With a median follow-up of 3 years, event-free survival rates were not significantly different after PBPC and BM transplants, 47% and 44%, respectively [2]. However, the incidence of chronic graft-versus-host disease (cGVHD) was more after transplantation of PBPC compared to BM grafts (53% vs 40%; P 5 .02) and without significant differences in non-relapse mortality rates between the 2 treatment groups [2]. Bertz et al. [1] also report more cGVHD after PBPC compared to BM transplants, but the observed difference was not statistically significant (52% vs 33%; P 5 .11). The probability estimates reported by Bertz et al. [1] and Anasetti et al. [2] are similar. Relatively few events in the small patient population in the report by Bertz et al. [1] are the most likely explanation for their inability to detect statistically significant differences in cGVHD rates between the 2 graft sources. The reported higher event-free survival rate in the PBPC group with a median follow-up of 10 years is intriguing. Several groups have reported on the

Excellent outcome of matched unrelated donor transplantation in paediatric aplastic anaemia following failure with immunosuppressive therapy: a United Kingdom multicentre retrospective experience

We retrospectively analysed the outcome of consecutive children with idiopathic severe aplastic anaemia in the United Kingdom who received immunosuppressive therapy (IST) or matched unrelated donor (MUD) haematopoietic stem cell transplantation (HSCT). The 6-month cumulative response rate following rabbit antithymocyte globulin (ATG)/ciclosporin (IST) was 32·5% (95% CI 19·3-46·6) (n = 43). The 5-year estimated failure-free survival (FFS) following IST was 13·3% (95% confidence interval [CI] 4·0-27·8). In contrast, in 44 successive children who received a 10-antigen (HLA-A, -B, -C, -DRB1, -DQB1) MUD HSCT there was an excellent estimated 5-year FFS of 95·01% (95% CI 81·38-98·74). Forty of these children had failed IST previously. HSCT conditioning was a fludarabine, cyclophosphamide and alemtuzumab (FCC) regimen and did not include radiotherapy. There were no cases of graft failure. Median donor chimerism was 100% (range 88-100%). A conditioning regimen, such as FCC that avoids total body irradiation is ideally suited in children. Our data suggest that MUD HSCT following IST failure offers an excellent outcome and furthermore, if a suitable MUD can be found quickly, MUD HSCT may be a reasonable alternative to IST.

Comparison of Survival and Incidence of Graft Versus Host Disease in Fully Matched, Single C Mismatched and Other Mismatched Unrelated Donor Hematopoietic Stem Cell Transplants in a Pediatric Population

Comparison of Survival and Incidence of Graft Versus Host Disease in Fully Matched, Single C Mismatched and Other Mismatched Unrelated Donor Hematopoietic Stem Cell Transplants in a Pediatric Population

HLA-DPA1 Mismatch Is Associated with Decreased Overall Survival Following Unrelated Donor Hematopoietic Stem Cell Transplantation

HLA-DPA1 Mismatch Is Associated with Decreased Overall Survival Following Unrelated Donor Hematopoietic Stem Cell Transplantation

Donor and Recipient Hbv Immunity Before Transplantation Simultaneously Affects the Acquisition of Hbv Immunity After Unrelated-Donor Hematopoietic Stem Cell Transplantation

Patients undergone allogeneic hematopoietic stem cell transplantation (HSCT) are accompanied by intensive chemotherapy and immunosuppression. Such patients are in high risk of hepatitis B virus (HBV) infection. Recovery of recipient immunity on HBV post-transplantation has a potential role in HBV prevention. In the current study, we performed a retrospective analysis of recipient immunity on HBV after HSCT and attempted to find out some factors associated with the HBV immunity acquisition posttransplantation. Between June 1999 and March 2009, 135 HBsAg(-) patients undergone unrelated HSCT were enrolled. HBV serum markers including HBsAg, HBeAg, HBeAb, HBsAb and HBcAb were tested for donor screen and recipients. HBV immunity was defined as positive HBsAb within 6 months posttransplantation. Patients were divided into 4 groups (R+/D+, R+/D-, R-/D+ and R-/D-; R represents recipient and D represents donor) according to + or - HBsAb in recipients and donors. The data were analyzed using spss v17.0 software. Pretransplantation characteristics of patients and donors were summarized in Table 1. Multivariate analysis showed that primary disease type, donor and recipient's sex and age, HLA disparity and conditioning regimen containing ATG were not statistically different among the 4 groups. In total 42 of 42 (100%), 22 of 32 (68.8%), 24 of 26 (92.3%) and 0 of 35 (0%) patients acquired HBV immunity posttransplantation in D+/R+, D+/R-, D-/R+ and D-/R-group respectively (p<0.05 between D+/R+ and D+/R- group, D+/R+ and D-/R- group, D+/R- and D-/R+ group, D+/R- and D-/R- group, D-/R+ and D-/R- group) indicating HBsAb in both donors and recipients had a significant favorable effect on maintaining the HBV immunity of recipients with HBsAb before transplantation. A total of 2 recipients experienced HBV reactivation posttransplantation(1 in D-/R+ and D-/R- group each) indicating HBV immunity in donors have protective effects on HBV reactivation. The mean duration from stem cell transfusion to HBsAb appearance was 25, 28, 20 and 24 days in the correspoinding group respectively (p>0.05). Our data support that donor and recipient HBV immunity before transplantation can simultaneously affect the acquisition of HBV immunity and have a vital role in HBV reactivation after unrelated-donor HSCT. HBV vaccination should be performed in both donors and recipients who have no HBV immunity before transplantation.Table 1Pretransplantation Characteristics of Patients and donors before TransplantationD+/R+ groupD+/− groupD−/R+ groupD−/R− groupp valueMedian recipient age(years)25272827>0.05Male recipient number27201621>0.05Conditioning regimen containing ATG5343>0.05Donor mean age30282931>0.05HLA mismatched5343>0.05Positive HBcAb in recipients12879>0.05Total number42322635 Open table in a new tab

Donor-specific anti-HLA Abs and graft failure in matched unrelated donor hematopoietic stem cell transplantation

AbstractAnti-HLA donor-specific Abs (DSAs) have been reported to be associated with graft failure in mismatched hematopoietic stem cell transplantation; however, their role in the development of graft failure in matched unrelated donor (MUD) transplantation remains unclear. We hypothesize that DSAs against a mismatched HLA-DPB1 locus is associated with graft failure in this setting. The presence of anti-HLA Abs before transplantation was determined prospectively in 592 MUD transplantation recipients using mixed-screen beads in a solid-phase fluorescent assay. DSA identification was performed using single-Ag beads containing the corresponding donor's HLA-mismatched Ags. Anti-HLA Abs were detected in 116 patients (19.6%), including 20 patients (3.4%) with anti-DPB1 Abs. Overall, graft failure occurred in 19 of 592 patients (3.2%), including 16 of 584 (2.7%) patients without anti-HLA Abs compared with 3 of 8 (37.5%) patients with DSA (P = .0014). In multivariate analysis, DSAs were the only factor highly associated with graft failure (P = .0001; odds ratio = 21.3). Anti-HLA allosensitization was higher overall in women than in men (30.8% vs 12.1%; P < .0001) and higher in women with 1 (P = .008) and 2 or more pregnancies (P = .0003) than in men. We conclude that the presence of anti-DPB1 DSAs is associated with graft failure in MUD hematopoietic stem cell transplantation.

Favorable outcome of allogeneic hematopoietic cell transplantation for 8p11 myeloproliferative syndrome associated with BCR‐FGFR1 gene fusion

We report the case of a child who presented with nonspecific symptoms suggestive of a rheumatologic disorder, whose bone marrow had a complex translocation involving the FGFR1 locus. Hematopathologic findings were subtle and did not definitively indicate malignancy. Because he responded poorly to initial treatment with hydroxyurea, and in light of the progressive clinical course associated with the 8p11 myeloproliferative syndrome, he underwent an unrelated-donor hematopoietic stem cell transplant. This patient's atypical presentation highlights the importance of obtaining cytogenetic analysis at the time of bone marrow sampling and considering this uncommon entity in the differential diagnosis of hematologic disorders.

Unrelated Donor Hematopoietic Stem Cell Transplantation for the Treatment of Advanced Multiple Myeloma: The John Theurer Cancer Center Experience,

Abstract 4162Allogeneic hematopoietic stem cell transplantation has been associated with a graft-versus-myeloma effect and may be the only potentially curative option for patients with advanced multiple myeloma. Unfortunately, the majority of patients (pts) do not have an HLA-identical sibling. Unrelated donor transplantation is an alternative option for these patients. We conducted a retrospective analysis of patients with advanced multiple myeloma who received an unrelated donor (URD) hematopoietic stem cell transplant at our institution between 11/1997 and 11/2010. Analyses were done using Kaplan Meier survival and Cox regression on the SAS version 9.2 software.Between 11/1997 and 11/2010, 27 pts with multiple myeloma received an URD transplant. One patient was lost to follow-up and 26 pts are evaluable. Patient characteristics included: median age 52 years (range 37–64), male 58%, all patients had prior autologous transplant (23% of pts had 2 or more prior transplants), and 43% of pts had refractory or progressive disease at the time of transplantation. Transplant regimens were ablative (defined as melphalan dose > 140mg/m2) in 73% of pts. GVHD prophylaxis was tacrolimus-based in all. Hematopoietic cell source was peripheral blood for 92% of pts, 46% of pts received a 10/10 HLA matched URD and 54% had a least one allele mismatch. Results:With a median follow up of 3.4 years, 54% of patients are alive and 47% of patients are progression-free. The treatment-related mortality at day 100 was 15%. The incidence of acute graft-versus-host disease (GVHD) was 44% and chronic GVHD 25%. Univariate analysis of risk of progression or relapse and overall survival failed to show any significance for disease status at the time of transplantation, degree of donor match, transplant regimen, refractoriness to bortezomib or lenalidomide, acute or chronic GVHD. Conclusion:In this analysis, URD transplantation has an acceptable treatment related mortality, and leads to durable remissions even in patients with relapsed and/or refractory disease. The 3.4 year PFS is similar to the BMT CTN 0102 sibling data and compares favorably to related donor transplantation for relapsed disease. In comparison to the BMT CTN study, the preparative regimen in this current analysis was overall more intense and regimen intensity has been previously shown to be significant. Allogeneic transplantation is an effective treatment strategy in multiple myeloma. Unrelated donor transplantation should be offered to patients with advanced multiple myeloma who do not have an HLA-identical sibling. Disclosures:No relevant conflicts of interest to declare.

Anti-CD25 Monoclonal Antibody for Graft-Versus-Host Disease Prophylaxis Following Unrelated Donor Peripheral Blood Stem Cell Transplantation,

Abstract 4070 Introduction:Enhanced risk of graft-versus-host disease (GVHD) makes one of major critical barriers to successful unrelated donor hematopoietic stem cell transplantation (URD-HSCT). Antithymocyte globulin (ATG) has been combined to standard GVHD prophylaxis regimens and significantly reduced GVHD in URD-HSCT. But ATG is associated with increases of infections and post-transplant lympholiferative disease (PTLD). Thus it is valuable to find alternative immunosuppressive agent for GVHD prophylaxis in URD-HSCT. Basiliximab and daclizumab, two anti-CD25 monoclonal antibodies, prevent graft failure in renal transplantation, which also effectively treat steroid-refractory graft-versus-host disease (GVHD). However, only few researches report that anti-CD25 monoclonal antibodies prevent GVHD. Here we firstly retrospectively explored the prophylactic effects of basiliximab or daclizumab against GVHD in 93 patients with hematological malignancies following unrelated donor peripheral blood stem cell transplantation (URD-PBSCT). Patients/methods:Between April 2004 and May 2011, 93 patients with hematological malignancies received basiliximab or daclizumab additional to standard GVHD prophylaxis regimens and underwent URD-PBSCT in our department. Their clinical data were retrospectively collected and analyzed. All patients received GVHD prophylaxis regimen consisting of cyclosporine A, short-course methotrexate, mycophenolate mofetil and an anti-CD25 monoclonal antibody. Basiliximab was administrated to 71 patients at a dose of 20 mg, while daclizumab was given to 22 patients at a dose of 1 mg/kg on day 0 (2 hours before transplantation) and day +4. Eighteen patients were 8/8 identical, 41 were 7/8 identical and 34 were 6/8 identical at HLA-A,-B,-Cw and -DRB1. The median number of infused nucleated cells and CD34+ cells were 7.5×108/kg and 5.8×106/kg, respectively. Results:i) All the recipients achieved engraftment. The median time to neutrophil recovery and platelet recovery were 12 days and 15 days, respectively. The rates of grade II-IV and III-IV acute GVHD (aGVHD) were 35.5% and 18.3%, respectively. Chronic GVHD (cGVHD) developed in 43.4% of evaluable patients. The limited cGVHD rate was 27.6% and the extensive cGVHD rate was 15.8%. The transplantation-related mortality (TRM) was 19.4% while relapse rate (RR) was 10.8%. The 2-year overall survival (2-yr OS) reached 74.2% and disease free survival (2-yr DFS) accumulated to 69.6% during a median follow-up of 24 months.ii)The side effects of basiliximab and daclizumab were moderate and tolerable. The infectious rate was 66.7% including 44.1% bacterial infection, 10.8% probable or proven invasive fungal infection, and 11.8% mixed infection. The infection-related mortality was 7.5%. The CMV reactivation rate was 46.2% and only one patient suffered CMV pneumonia. Moreover there was no clinical evidence of PTLD.iii) There were no significant differences in aGVHD onset and survival between daclizumab and basiliximab group. However, basiliximab presented superior prophylactic effects on cGVHD than daclizumab (cGVHD rate, 31.1% versus 66.7 %, P=0.007).iiii) The aGVHD rate, cGVHD rate, RR, TRM, 2-yr OS and 2-yr DFS were compared among different HLA matching groups. There were significant differences in the occurrence of grade II-IV aGVHD (11.1% versus 36.6%, P=0.047) and cGVHD(18.8% versus 51.6%, P=0.03) between HLA 8/8 identical group and HLA 7/8 identical group. Comparing HLA 8/8 identical group versus HLA 6/8 identical group, there were not only significant decreases in the rate of grade II-IV aGVHD (11.1% versus 47.1%, P=0.01) and grade III-IV aGVHD (5.6% versus 32.4%, P=0.039), but also a significant increase in the RR (22.2% versus 2.9%, P=0.043). There were no significant differences between HLA 7/8 identical group and HLA 6/8 identical group. Interestingly, the survival was not significantly different among three HLA matching groups. Conclusion:Basiliximab or daclizumab prevents GVHD efficiently and feasibly following URD-PBSCT, especially in HLA identical or only one allele mismatched recipients. Furthermore, anti-CD25 monoclonal antibodies benefit the outcome, even for those recipients with two or more HLA disparities. Basiliximab has similar effects on aGVHD prophylaxis but superior effects on cGVHD prophylaxis than daclizumab. Further prospective and randomized control studies are needed. Disclosures:Off Label Use: Drug: basiliximab (Simulect, Novartis Pharmaceuticals); daclizumab (Zenapax, Roche Pharmaceuticals). Purpose: for graft-versus-host disease prophylaxis following unrelated donor peripheral blood stem cell transplantation.

Negative Correlation Between the Hematopoietic Stem Cell Transplant Comorbidity Index (HCT-CI) and Total Hospital Stay in Patients Who Underwent Unrelated Donor Hematopoietic Stem Cell Transplantation (HSCT)

Abstract 4462The hematopoietic stem cell transplant comorbidity index (HCT-CI) was developed as a risk assessment tool in patients undergoing allogeneic HCT. HCT-CI scores have been shown to be associated with non-relapse mortality (NRM) and overall survival (OS) in retrospective studies. However the correlation between HCT-CI scores and post-transplant resource utilization has not been investigated. Previously, we reported a correlation between the HCT-CI and increased hospitalization in the matched related donor setting (Szwed E, et al. Blood. 2010; 116: 4748a). In the unrelated donor population, we retrospectively analyzed 229 consecutive patients who had undergone matched unrelated donor stem cell transplant between January 2001 and December 2008. Donor stem cell sources included peripheral blood (n=90), bone marrow (n=67), and umbilical cord blood (n=72). Conditioning regimens were divided into myeloablative (MA, n = 159), reduced intensity (RIC, n = 28) and non-myeloablative (NMA, n = 42). HCT-CI scores were calculated by method of Sorror (Sorror ML, et al. Blood. 2005 106: 2912–19). Median follow-up was 6.2 years. Consistent with prior findings, HCT-CI correlated with NRM (rs = 0.16, p = 0.015) and overall survival (median survival when score ≤ 3 = 761 days vs score > 3 = 212 days [p = 0.0005]). A negative correlation was found between HCT-CI score and total hospital days as well as days spent in hospital after discharge from initial transplant hospitalization, implying that the higher the score the less time spent in the hospital after transplant (Table 1). However, this correlation disappeared when adjusted for patient survival. We also noted that the majority of readmissions and hospitalizations occurred within the first 100 days from transplant. In subgroup analysis, we found a relationship between HCT-CI score and total hospital days (rs = 0.37, p = 0.0032) and in number of hospital days after discharge for transplant (rs = 0.35, p = 0.0047) for patients who underwent a myeloablative cord blood transplant, even after adjusting for patient survival. In summary, our analysis validated the correlation between HCT-CI score and NRM/overall survival, but we were unable to find a statistically significant correlation between HCT-CI and hospitalizations, except in the myeloablative cord blood setting. We found that most readmissions and hospital days occur early in the post-transplant period (<100 days). We hope further analyses will help unravel these apparent discrepancies in this particular transplant population.Table 1:Spearman Correlation Coefficients between HCT-CI vs. Readmissions and Hospital DaysNMedian Age (yrs)Readmission*Hospital days for Transplant#Admissions after Transplant#Total#Total22935.4−0.002 (0.98)0.0068 (0.92) −0.004 (0.95)−0.26 (<0.0001)0.041 (0.54)−0.16 (0.023)0.11 (0.089)MA−NC9638.9−0.12 (0.24)−0.11 (0.32) −0.17 (0.10)−0.04 (0.68)0.093 (0.36)−0.11 (0.32)0.097 (0.34)MA−C6314.30.11 (0.39)0.093 (0.49) 0.13 (0.32)0.055 (0.67)0.35 (0.0047)0.14 (0.32)0.37 (0.0032)NMA4249.9−0.80 (0.61)−0.32 (0.045) 0.15 (0.35)0.020 (0.90)0.073 (0.65)−0.43 (0.0064)−0.14 (0.39)RIC2847.9−0.10 (0.61)0.18 (0.36)0.011 (0.95)−0.19 (0.35)0.095 (0.63)0.015 (0.94)0.31 (0.11)MA-NC=myeloablative, no cord; MA-C=myeloablative cord; NMA=non-myeloablative; RIC=reduced intensity;() p values in parentheses#Top numbers refer to unadjusted values, bottom are adjusted for patient survivalStatistically significant values are bold Disclosures:No relevant conflicts of interest to declare.

Interactions between killer immunoglobulin‐like receptors and their human leucocyte antigen Class I ligands influence the outcome of unrelated haematopoietic stem cell transplantation for thalassaemia: a novel predictive algorithm

In a study conducted on 114 patients undergoing unrelated donor haematopoietic stem cell transplantation (HSCT) for thalassaemia, we observed that the lack of activating killer immunoglobulin-like receptors (KIRs) on donor natural killer (NK) cells significantly increased the risk of graft-versus-host disease (GvHD) [hazard risk (HR) 4.2, 95% confidence interval (CI) 1.7-10.1, P = 0.002] and transplantation-related mortality (HR 4.7, 95% CI 1.6-14.2, P = 0.01). The risk of GvHD furthermore increased when recipients heterozygous for HLA-C KIR ligand groups (C1/C2) were transplanted from donors completely lacking activating KIRs (HR 6.1, 95% CI 1.9-19.2, P = 0.002). We also found that the risk of rejection was highest when the recipient was homozygous for the C2 HLA-KIR ligand group and the donor carried two or more activating KIRs (HR 6.8, 95% CI 1.9-24.4, P = 0.005). By interpolating the number of donor activating KIRs with recipient HLA-C KIR ligands, we created an algorithm capable of stratifying patients according to the immunogenetic risk of complications following unrelated HSCT. In clinical practice, this predictive tool could serve as an important supplement to clinical judgement and decision-making.