ALBERT

Description: [Study purpose] We have reported that overall results of cord blood transplantation (CBT) were inferior to those of bone marrow transplantation (BMT) from unrelated donor in myelodysplastic syndrome (MDS) including transformed acute myelogenous leukemia (AML/MDS) (ASH 2007). Poor engraftment and higher incidence of relapse in CBT patients were serious problems. We now show here the impact of conditioning regimen and GVHD prophylaxis method on clinical outcomes of CBT, and then show the results when we looked for the appropriate graft selection in terms of human leukocyte antigen (HLA) compatibility and cell dose. [Patients and Methods] Clinical data of 333 patients with MDS including AML/MDS who received unrelated CBT without prior transplant history between 1998 and 2006 in Japan were collected by the Japan Cord Blood Bank Network (JCBBN). The median period of follow-up for survivors (n=148) after transplants was 13 (range, 1–99) months. We analyzed the hematopoietic recovery, incidences of acute and chronic graft-versus-host disease (GVHD), risks of transplant-related mortality (TRM) and relapse, and disease-free survival (DFS) using competing risk regression models. [Results] Both myeloablative conditioning regimen including 8Gy or more dose of total body irradiation (TBI) and GVHD prophylaxis as calcineurin inhibitor (cyclosporin or taclorimus) plus methotrexate (MTX) significantly (p

Description: Abstract 1206 Poster Board I-228 [Study purpose] With the increased number of cord blood transplantation (CBT) for adults, more human leukocyte antigen (HLA)-mismatched grafts are selected as alternative donor. In Japan, we have performed more than 5,500 CBT and almost two-third of them has been using 2-loci HLA-mismatched grafts. Slow engraftment and high risk of graft failure should be solved to improve the clinical results. In general, the degree of HLA disparity is known to be associated with risks of poor graft function and of graft-versus-host disease (GVHD). On the other hand, those risks of transplant-related complications are not equivalent even in the donor-recipient pairs who have same number of mismatched HLA antigens. There might be “haplotype matching effect” because novel undetected major histocompatiblility antigen (MHC) resident variation encoded on HLA haplotypes and those mismatching could be responsible for post-transplant risks. In this study, we have analyzed the impact of HLA haplotype matching in HLA-mismatched CBT using the same method in the single institute. [Patients and Methods] We studied the clinical outcomes of 149 consecutive adult patients who received unrelated CBT between August 1998 and June 2009 in the institute of medical Science, University of Tokyo. Patients received previous allogeneic tranplants were excluded from this study. All patients received myeloablative regimens including 12 Gy of total body irradiation, cyclosporine plus short term methotraxate for GVHD prophylaxis and almost the same supportive care. By low-resolution typing method for HLA-A, -B and –DR loci, 9 patients received matched grafts, 46 received 1 antigen-mismatched and 94 received 2 antigens-mismatched grafts in the host-versus-graft (HvG) direction. In the graft-versus-host (GvH) direction, 7 patients received matched grafts, 51 received 1 antigen-mismatched and 91 received 2 antigens-mismatched grafts. When we looked at the maximum number of mismatched antigens for both directions, 38 patients received 1 antigen-mismatched and 111 received 2 antigens-mismatched grafts respectively, but there was no matched pair. Common haplotypes in Japanese population were referred from the 11th International Histocompatibility Workshop and other previous reports. Median numbers of leukocytes and CD34+ progenitor cells before freezing of cord blood grafts were 2.4×107/kg and 0.9×105/kg, respectively. Median follow-up was 39 months. We evaluated the impact of haplotype matching on cumulative incidences of hematopoietic recovery, of GVHD, of relapse and of non-relapse mortality (NRM) using the Pepe and Mori's test. Estimates of overall survival were calculated using the Kaplan-Meier method and analyzed by the log-rank test. [Results] Thirty (11 of 38 one antigen-mismatched and 19 of 111 two antigens-mismatched) among all 149 pairs were defined as the haplotype-matched pairs sharing same haplotypes in both grafts and recipients. The age, sex, cytomegalovirus serological status, diagnosis, risk of the disease at the transplant, numbers of total nucleated cells and CD34+ cells at the cryopreserved were not significantly different between both groups with and without matched haplotypes. Among the 1 antigen-mismatched pairs in the HvG direction, early engraftment of neutrophil after CBT occurred in haplotype-matched group compared with control group (median: 20.5 days versus 23 days, P=0.01). The haplotype matched group had better platelet engraftment in the 1 antigen-mismatched pairs (cumulative incidence on day 120: 86% versus 62%; median: 41 days versus 53 days), but this is not significant (P=0.29). Such correlation between engraftment and haplotype matching was not observed in 2 antigens-mismatched pairs. The cumulative incidences of grades II to IV acute GVHD were not significantly different between haplotype matched and control groups, however, those of grades III and IV in patients with matched-haplotype tended to be lower among 1 antigen-mismatched pairs in GvH direction (P=0.10) and were significantly lower among 2 antigens-mismatched pairs (P=0.02). Those haplotype matching effects were not observed in survival rates, cumulative incidences of relapse and NRM among any HLA mismatched pairs. [Conclusion] Those data suggest that untyped variation carried on the HLA haplotytpe might be better to be matched and the haplotype matching might effect on better engraftment and lower risk of sever acute GVHD after HLA-mismatched CBT. Disclosures: No relevant conflicts of interest to declare.

Description: We previously reported some promising results of cord blood transplantation (CBT) compared with bone marrow transplantation (BMT) from unrelated donors in terms of graft-versus-host disease (GVHD), transplant-related mortality (TRM), and disease-free survival (DFS) in our institute (Blood104: 3813, 2004). If the patient was eligible for allogeneic transplantation without any related donors, we performed CBT immediately, rather than waiting for the results of an unrelated marrow donor search. This might be one of the reasons for our favorable CBT results in adults compared with most previously published studies. We studied the clinical outcomes of 163 adults with hematological malignancies who received unrelated CBT (n=92), or BMT or peripheral blood stem cell transplantation (PBSCT) from related donors (n=71, 55 BMT and 16 PBSCT) between January 1997 and February 2005. All patients received myeloablative regimens including 12 Gy of total body irradiation and almost the same supportive care. We analyzed the hematopoietic recovery, rates of GVHD, risks of TRM and relapse, and DFS using Cox proportional hazards models. The age, sex, cytomegalovirus serological status, time from diagnosis to transplantation, and GVHD prophylaxis regimens were not significantly different between both groups. Overall rates of high-risk patients in the CBT and in BMT/PBSCT groups were 58% and 63%, respectively. Human leukocyte antigen (HLA) was scored serologically for HLA-A and B and genetically for DRB1 alleles. There were no complete matches in CBT and 54 (76%) matched grafts in BMT/PBSCT. Median numbers of leukocytes and CD34+ progenitor cells before freezing of cord blood grafts were 2.4x107/kg and 0.9x105/kg, respectively. Median follow-up was 27 months for CBT and 50 months for BMT/PBSCT. Significant delays in neutrophil and platelet engraftment rates occurred after CBT; however, overall myeloid engraftment rates were almost the same for both grafts (94% in CBT and 98% in BMT/PBSCT). The cumulative incidences of grades II to IV acute GVHD, of grades III and IV acute GVHD, and of requiring steroids for treating acute GVHD among CBT recipients were 58%, 8%, and 18%, respectively. Those among BMT/PBSCT recipients were 58%, 19%, and 38%, respectively. Chronic GVHD affected 68 of 75 CBT and 49 of 60 BMT/PBSCT evaluable recipients. Twenty-two CBT and 30 BMT recipients developed extensive GVHD. The 1-year cumulative incidence of TRM, the 3-year cumulative incidence of relapse, and the 3-year probability of DFS in CBT recipients were 9%, 18%, and 71%, compared with 13%, 26%, and 60% in BMT/PBSCT recipients. Multivariate analysis demonstrated no apparent difference in those outcomes between both groups. Taken together, engraftment speed was slower and severe acute GVHD and extensive chronic GVHD tended to be lower in CBT recipients compared with BMT/PBSCT recipients; however TRM, relapse and DFS were comparable in both groups. These data suggest that cord blood from unrelated donors could be as safe and effective a stem cell source as bone marrow or mobilized peripheral blood from related donors for adults when it is used as a primary unrelated stem cell source.