339: HLA-DRB1 allele and DRB1-DQB1 haplotype frequency as prediction criterion for the duration of an unrelated blood stem cell donor search

J. Mytilineos, K. Hirv
2007 Biology of Blood and Marrow Transplantation  
We investigated the potential correlation between the characteristics prior transplantation and the subsequent clinical outcomes in 175 consecutive patients who received HSC transplantation from HLA-mismatched/haploidentical donors. Patients eligible for study were those with a diagnosis of leukemia, all lacking an HLA matched sibling or unrelated donor. Patients ranged in age from 6 to 53 years (median 25 years) and donors from 13 to 66 years (median 40 years). Compatibility testing of family
more » ... embers included serology and intermediate resolution DNA typing for HLA-A, -B, and -C antigens, plus high resolution DNA typing for HLA-DRB1, -DQB1, and -DPB1. Donors included 72 mothers (41%), 29 fathers (16.6%), 54 siblings (31%), 16 children (9%), 4 cousins (2.3%), with various grades of HLA disparity: 28 (16%) with 1; 79 (45%) with 2; 68 (39%) with 3 antigen mismatch. Grafts (BMϩPB) was harvested from donor BM collected after four days of G-CSF, and PB collected after 5 days of G-CSF. The graft was analyzed for content of CD34 ϩ cells and subsets of lymphoid cell populations, CD3 ϩ , CD4 ϩ , CD8 ϩ , and CD14 ϩ , using standardized Multi-set kits (Becton-Dickinson, San Jose, CA, USA). All patients enrolled in this study were treated with a uniform conditioning regimen (BuCy2ϩATG), given GVHD prophylaxis (CsAϩ short term MTX), and followed from 36 to 1191days after transplantation (median 401 days). Univariate analysis for survival indicated that disease status prior transplantation and donor CD3 ϩ cell dose were the only predictors of the 2-year probability of survival: early disease (77.8%), intermediate disease (38%), and those with advanced disease (52%), [Pϭ0.018]; survival in those given a CD3 ϩ cell dose Ͻ150 ϫ10 6 /kg was 52% and CD3 ϩ cell dose Ն150ϫ10 6 /kg was 74%, respectively [Pϭ0.0215]. This was confirmed by multivariate analysis: patients transplanted with intermediate/advanced stage disease [RRϭ1.568 (95% CI, 1.128-2.17); Pϭ0.007] had a worse overall survival; Infusion of a high dose of CD3 ϩ cells (Ն150 ϫ 10 6 /kg) had improved survival [0.530 (0.300-0.95); Pϭ0.03] without increase the incidence of developing Grade 3-4 aGVHD [1.27 (0.58-2.76); Pϭ0.56]. Our data have indicated that with the current protocol, patients given a relatively high dose of CD3 ϩ cells (Ն150ϫ10 6 /kg) have a significantly better overall survival after transplantation than those given lower doses of CD3 ϩ cells (Ͻ150 ϫ10 6 /kg). Identification of at least one fully compatible unrelated blood stem cell donor requires confirmatory typing (CT) of 2-5 potentially matched donors. We developed an algorithm, based on the frequency of the HLA-DRB1 alleles and the estimated DRB1-DQB1 haplotypes of the patient, which defined the number of potentially matched donors requested for CT. This strategy aimed to result to a shorter UDS duration as well as to cost-effectiveness in the process of a Unrelated donor search (UDS). HLA-DRB1 allele frequencies were calculated based on the National Marrow Donor Program dataset of 65752 individuals. HLA-DRB1-DQB1 haplotype data were obtained from the German National Donor Registry (ZKRD). HLA-DRB1 allele frequencies within a given broad allele family (e.g. HLA-DRB1*11) were the main point of consideration, since for most donors only a low resolution typing was available. HLA-DRB1 alleles with a frequency of 80-100% within their broad allele family were considered as very frequent. Alleles with a frequency of 30-79% within their broad allele family as average, and a frequency of 0-29% as rare. In addition, if the association of a particular HLA-DRB1 allele with the corresponding HLA-DQB1 allele was more frequent than 80%, this DRB1-DQB1 haplotype was considered as very common. A haplotype corresponding to 20% to 79% of a given DRB1 allele was classified as average, whereas a haplotype frequency of lower than 20% of a particular DRB1 allele was considered as rare. Based on this algorithm, the probability to find a fully compatible donor for a patient was considered high, medium or low. For the patients with high, medium or low probability, three, 4 or 5 potentially matched unrelated donors were requested for CT at the beginning of a UDS, respectively. In a group of 794 patients, the average duration of UDS and the average number of identified donors has been calculated. Eighty percent of the searches showed a high, 7% a medium and 13% a low probability to find a fully compatible donor. The average UDS duration was 55, 105, and 135 days in the three groups, respectively. An average of 2.0, 1.6, and 1.0 donors were found in the groups with high, medium, and low probability, respectively. The algorithm used in our search unit, allows a prediction of UDS duration and the estimation of the UDS success rate. A variable number of potentially matched donors should be requested for CT, which allows economising the UDS process without prolongation of the UDS duration. Although allogeneic stem cell transplantation from a human leukocyte antigen (HLA)-identical related donor offers a potential cure for patients with acute myeloid leukemia (AML) not in remission, a suitably matched related donor is unavailable for approximately two-thirds of patients. Recently, umbilical cord blood from unrelated donors have been used as an alternative stem cell source for adult patients with AML. Here, we report our clinical results of unrelated cord blood transplantation (CBT) after myeloablative conditioning for 30 adult patients with AML not in remission. Between August 1998 and November 2005, 30 adult patients with AML not in remission were treated with unrelated CBT at The Institute of Medical Science, University of Tokyo. Diagnoses at transplantation included de novo AML (nϭ14) and MDS-related secondary AML (nϭ16). All patients received four fractionated 12 Gy total body irradiation and chemotherapy as myeloablative conditioning. 27 patients received standard cyclosporine (CyA) and methotrexate, and 3 patients received CyA only as a graft-versus-host disease (GVHD) prophylaxis. Among the patients the median age was 45.5 years (range, 19-55 years), the median weight was 55 kg (range, 36-76 kg) and the median number of cryopreserved nucleated cells was 2.43 ϫ 10 7 /kg (range, 1.16-5.29 ϫ 10 7 /kg). 28 patients had myeloid reconstitution and the median time to more than 0.5 ϫ 10 9 /L absolute neutrophil count was 21.5 days. A self-sustained platelet count more than 50 ϫ 10 9 /L was achieved in 23 patients at a median time of 42 days. Acute GVHD above grade II occurred in 15 of 28 evaluable patients and chronic GVHD occurred in 17 of 23 evaluable patients. Among 17 chronic GVHD patients, 7 patients were extensive type. 16 patients are alive and free of disease at between 280 and 2937 days after transplantation. With a median follow-up of 2013 days, the probability of disease-free survival at 5 years was 51.8%. These results suggest that adult patients with AML not in remission should be considered as candidates for CBT.
doi:10.1016/j.bbmt.2006.12.344 fatcat:gogtjrnnxvbffme2kl72pjodrq