ALBERT

Description: Abstract 1196 Poster Board I-218 Introduction: Allogeneic hematopoietic stem cell transplantation (alloSCT) from volunteer unrelated donors (URD) may be associated with a higher non-relapse mortality (NRM) and worse outcome as compared to alloSCT using HLA-identical sibling donors. However, many parameters next to donor type define NRM. The impact on outcome of allele-matching for HLA-A, -B, -C and -DRB1 between donor and recipient has clearly been demonstrated. The prognostic impact of the EBMT risk score, that takes into account age, stage of disease, time from diagnosis to transplantation, donor type and donor-recipient gender combination, has recently been validated in a variety of hematological malignancies including acute leukemia and myelodysplastic syndrome (MDS). We evaluated the relative prognostic value of high-resolution HLA matching and the EBMT risk score for patients with poor-risk acute leukemia and MDS who received an URD transplant. Patients and methods: Between 1987 and 2006, 327 patients (≥16y) with poor-risk acute leukemia and MDS underwent URD alloSCT in the Netherlands. Patients were in 1st complete remission (CR1, n=129), 2nd CR (CR2, n=91), beyond CR2 or not in remission (n=107). The leukemia-risk was considered to be poor if patients had adverse cytogenetics or were not in CR1. The majority of the grafts was T-cell depleted (94%). High-resolution typing of HLA-A, -B, -C, and -DRB1 alleles was available for analysis in 270 donor-recipient pairs and had in part been performed retrospectively. Results: We evaluated the impact of high-resolution matching for HLA-A, -B, -C and -DRB1 on progression free survival (PFS) and overall survival (OS). Patients who were fully matched (8/8) with their donors (n=170) hadsignificantly superior PFS (40+/-4% vs 26+/-5%, hazard ratio (HR)=0.68; 95%CI 0.50–0.92, p=0.01) and OS (39+/-4% vs 29+/-5%, HR=0.70; 95%CI 0.51-0.96, p=0.03), compared to patients with mismatched (≤7/8) donors (n=100). Superior OS in the 8/8 group appeared to be due to a lower NRM (24+/-4% vs 39+/-5%, HR=0.54; 95%CI 0.35-0.85, p=0.008), while the relapse mortality rate was identical in both groups (37+/-4% vs 32+/-5%). Patients with EBMT risk scores of 1-2 (n=71), 3 (n=77), 4 (n=76) and 5-7 (n=103) had a predicted 5 year OS of 52%, 41% (HR=1.57; 95%CI 0.98-2.52), 29% (HR=2.07; 95%CI 1.32-3.26) and 19% (HR=2.69; 95%CI 1.76-4.11), respectively (p4) had a dismal outcome, despite allele-matching. These results emphasize the importance of incorporating age, disease stage, donor-recipient gender combination and time interval from diagnosis to transplantation (EBMT risk score parameters) as well as high-resolution HLA-typing in the risk assessment prior to URD alloSCT. As excellent OS was noted in well matched EBMT low-risk patients, our data underscore the importance of an immediate search for an unrelated donor in poor-risk leukemia patients in CR1 below the age of 40, who should then receive their alloSCT as early consolidation therapy following induction chemotherapy. Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 3026 Background Double umbilical cord blood transplantation (UCBT) results in higher engraftment rates as compared to single UCBT in adult patients. Sustained hematopoiesis is usually derived from a single cord blood unit (CBU) after double UCBT. So far, the mechanism of predominance of a particular CBU is unresolved. In a prospective single-arm phase II study (HOVON-106) we monitored early engraftment kinetics to determine whether graft predominance after double UCBT is driven by specific leukocyte subpopulations. Methods 36 consecutive patients (pts) from 5 Dutch centers with high-risk hematological diseases received a double UCBT, preceded by a reduced-intensity conditioning regimen (Cy 60 mg/kg/ Flu 160 mg/m2/ TBI 2×2 Gy). CBUs were selected by intermediate resolution typing for HLA-A and -B loci and by high-resolution typing for HLA-DRB1. The minimal required HLA-match grade was 4/6. Chimerism analysis (STR-PCR) of unseparated peripheral blood (PB) and bone marrow (BM) cells was performed as from day +32 onwards. In addition, chimerism analysis in PB leukocyte subpopulations by flowcytometry using lineage-specific (CD45, CD3, CD4, CD8, CD19, CD16/56, CD14 and CD33) monoclonal antibodies (mAbs) in combination with human HLA-antigen specific mAbs (HLA-mAbs) was performed at day +11, +18, +25 and +32 if discriminating HLA-mismatches between recipient and CBUs were present. Day +32 flowcytometry results were compared to day +32 PB STR-PCR results. Results The median number of prefreeze total nucleated cells (TNC) per CBU was 2.3×107/kg (range: 1.5–5.5). Median numbers of post-thaw viable CD34+ cells, T-, B- and NK cells were 0.32 (range: 0–1.7), 4.4 (range: 0.4–36), 9.7 (range: 0.7–79) and 7.2 (range: 0.24–45) x105/kg, respectively. One pt was non-evaluable for engraftment due to insufficient follow up after early relapse. The cumulative incidence of neutrophil recovery (≥0.5×109/l) was 91% with a median time to neutrophil recovery of 33 days (range: 15–82). Primary graft failure occurred in 1 pt. Chimerism analysis, performed at day +32 by STR-PCR revealed single CBU predominance in all pts whereas residual non-engrafting CBU and recipient cells were detectable in only 3 and 7 pts, respectively. Simultaneous 3-donor-origin detection of leukocyte subpopulations by flowcytometry based on HLA disparities was possible in 12 pts. Flowcytometry using HLA-mAbs demonstrated single CBU predominance in various leukocyte subsets as from day +11 onwards in the majority of pts. Moreover, ultimate engraftment of a particular CBU was reliably predicted for by chimerism within the CD4+ (in 90% of pts) and NK cell (in 90% of pts) subsets at this early time point. In contrast, predominance of the engrafting CBU in monocytic en myeloid subsets was observed in only 70% and 33% of pts, respectively, at day +11. The numbers of CD8+ and B-cells were too low for analysis in the majority of pts. Predominance of the ultimate engrafting CBU was established in all subpopulations at day +18. Furthermore, the contribution of the non-engrafting CBU to the different leukocyte subsets was negligible or even absent as from day +18 onwards. Recipient hematopoiesis did not contribute to PB cell recovery either. The results of day +32 flowcytometry (CD45+ population) were similar to results of day +32 PB STR-PCR. The number of prefreeze TNC did not predict for the ultimately engrafting CBU, nor did the number of post-thaw CD34+, T, B or NK cells. Engraftment was not associated with the degree of HLA mismatches or presence of KIR ligand mismatches among recipient and CBUs. Conclusions These results show that single donor chimerism is rapidly established after double UCBT, preceded by a 4 Gy TBI-based conditioning regimen without ATG. In addition, our flowcytometry data suggest the occurrence of CBU predominance within 2 weeks post transplant, in the course of which both CD4+ and NK cell predominance at day +11 are highly predictive for ultimate single donor chimerism. That early engraftment pattern of leukocyte subsets might suggest a key role for either CD4+ T cells or NK cells in CBU predominance. Disclosures: Janssen: Novartis: Consultancy.