We report outcomes of 932 recipients (rcpts) of UD PBSC HCT facilitated by NMDP from 1999 through 2003 (median f/u 3.3 yrs). Indications were AML (419 rcpts), ALL (185 rcpts), CML (134 rcpts), and MDS (194 rcpts). Preparative regimens included myeloablative (MA, N = 611), reduced intensity (RI, N = 160), and non-myeloablative (NMA, N = 161). Distributions of HLA-match grade, CMV status, Karnofsky scores (KS), and donor characteristics were similar between the preparative regimens, however, fewer rcpts with advanced disease received NMA (p = 0.035), while more rcpts with coexisting diseases received RI and NMA regimens (p < 0.001). The age of rcpts receiving RI and NMA regimens was substantially higher than rcpts receiving MA regimens (median RI 56 yo, NMA 57 yo, MA 38 yo, p < 0.001). Optimal cell dose cutpoints for TNC, MNC and CD34+ were determined based on Martingale residuals from Cox regression analyses. For MA rcpts, CD34+ counts >3.8 × 106/kg improved day +25 neutrophil and day +60 platelet engraftment; higher infused TNC doses (>6.9 × 108/kg) predicted decreased grade III-IV aGVHD, while improved overall survival (OS) and reduced TRM (RR 0.55) were seen with MNC doses >4.4 × 108/kg. For RI and NMA rcpts, OS was higher and TRM was decreased in those receiving >3.8 × 106 CD34+cells/kg. Of note, cGVHD was not increased with higher cell doses in rcpts of any type of preparative regimen. Additional predictors of improved OS included early disease, and for MA rcpts only, HLA-matched donors, KS ≥ 90, and CsA-based GVHD prophylaxis. Three year OS and DFS of rcpts receiving MA, RI, and NMA approaches were similar (33, 35, and 32% OS; 33, 30, and 29% DFS: MA, RI, and NMA, respectively). Higher risk of relapse at 3 yrs in RI and NMA approaches (35, 37 vs. 24% RI, NMA, MA, respectively, p < 0.001) was offset by higher 3 yr TRM using MA regimens (43 vs. 34, 34% MA, RI, NMA, respectively, p = 0.008). Sub-analyses of 1) rcpts with AML-CR1, 2) rcpts with AML/MDS/CML (excluding ALL), or 3) rcpts between the ages of 40–60 with AML/MDS also showed similar survival with MA vs. RI vs. NMA approaches. In summary, rcpts of UD PBSC HCT receiving preparative regimens differing in intensity experienced similar survival. Higher cell doses resulted in more rapid engraftment, less severe aGVHD (MA rcpts), and better 3 year OS (37 vs. 18%, MA; 36 vs. 21% RI/NMA, p < 0.001), but did not increase the risk of cGVHD.

Cord blood banks (CBB) are required to monitor clinical outcomes of cord blood unit (CBU) transplants performed by transplant centers (TC). Obtaining accurate and timely follow-up data on clinical outcomes from the TC can be very difficult. The National Marrow Donor Program (NMDP), by virtue of their comprehensive activities with member network centers, collects outcomes data on recipients transplanted with either cord blood or adult donor cells. NMDP member transplant centers are required to submit data at defined intervals as part of their participation agreement. A system is in place to monitor compliance that includes a due process procedure for non-compliant centers. Recipients sign an IRB-approved consent form for data submission to the NMDP. All submitted data are verified through system checks at time of data entry. Identified errors are subject to a formal error correction process. Transplant centers are audited on a four year cycle to assure the accuracy and integrity of the data provided. At any given time, >90% of NMDP centers are compliant with forms submission requirements. The data elements include information on the results of the thaw, infusion related reactions, preparative regimens, neutrophil and platelet engraftment, GVHD, relapse, survival and death. Member cord blood banks receive a quarterly report from the NMDP which includes comprehensive data on the individual recipients for which their CBUs were used. The data include recipient demographics, infused cell dose, degree of HLA match, engraftment, GVHD, relapse, survival, and cause of death. While outcomes data are reported quarterly to member banks, thaw data are reported and reviewed on a continuous basis. TNC recoveries that are low (<60%) or high (>100%) are reviewed by NMDP staff to detect problems with CBU potency that might be linked to a certain bank, shipping procedure or thawing protocol at a TC. Future directions include trending analysis reports and review with the NMDP Quality Standards subcommittee. The NMDP's process for reporting quality assurance data to member banks is a valuable service that is unlikely to be feasible in a single bank.

The outcome of patients with multiple myeloma treated with standard therapy is disappointing, with a historical median survival of 3 years. Although high-dose therapy with autologous stem cell transplant has improved treatment outcomes, cure is unlikely. Allogeneic transplant provides a tumor-free graft and a graft-versus-myeloma effect. However, only a minority of patients has a compatible sibling donor. Unrelated hematopoietic stem cell transplant is another option. We analyzed the outcome of patients who received an unrelated bone marrow transplant facilitated by the National Marrow Donor Program (NMDP). Between 1989 and 2000, 71 patients received a myeloablative unrelated transplant for multiple myeloma; 70 patients consented for this analysis. The median recipient age was 44 years. A total of 31% of patients had received a prior autologous transplant. In all, 91% of patients engrafted. The 3-year cumulative incidence estimate of relapse was 34+/-10%. The incidence of Grade II-IV GVHD was 47%. The Kaplan-Meier estimate for overall survival at 5 years was 9+/-7%. The 100-day treatment-related mortality was 42%. In multivariate analysis, only a male donor was a significant predictor for survival. Better strategies are needed to treat patients with multiple myeloma, perhaps by using less-toxic, nonmyeloablative conditioning regimens.

Poster Presentations -Session I ent of pretransplant disease status.The overali survival was better in CML patients transplanted in chronic phase (45-55%) or ALL patients transplanted in CR1 (33%7 whether from RD or URD (P < 0.057.There was no statistically significant difference in the relapse rate between RD & URD transplants for both ALL & CML patients with relapse mortality being 30% vs. 20% (p -0.4) for ALL and 8% vs. 4% for CML (p=0.08).Acute GvHD of grade III or IV severity was observed in i5 % of the RD patients as compared to 27% of the URD patients.In conclusion, allogeneic transplantation from an URD at our institution appears to have equivalent outcome to transplant from RD for patients with CML or ALL.Transplantation of marrow from URD is reasonable and effective therapy for patients with CML or ALL who are candidates for allogeneic transplant, but has no RD. 41

Between 1988 and 1999, 127 patients with poor-risk acute lymphoblastic leukemia (ALL) received a matched unrelated donor transplant using marrow procured by National Marrow Donor Program (NMDP) collection centers and sent out to 46 transplant centers worldwide. Poor risk was defined by the presence of the translocations t(9;22) (n = 97), or t(4;11) (n = 25), or t(1;19) (n = 5). Sixty-four patients underwent transplantation in first remission (CR1), 16 in CR2 or CR3, and 47 patients had relapsed ALL or primary induction failure (PIF). Overall survival at 2 years from transplant was 40% for patients in CR1, 17% in CR2/3, and 5% in PIF or relapse. Treatment-related mortality (TRM) and relapse mortality, estimated as competing risk factors, were 54% and 6%, respectively, in CR1, 75% and 8% in CR2/3, and 64% and 31% in PIF or relapse. Currently 23 CR1 patients are alive and free of disease with a median follow-up of 24 months (range, 3-97). Multivariable analysis showed that CR1, shorter interval from diagnosis to transplantation, DRB1 match, negative cytomegalovirus (CMV) serology (patient and donor), and presence of the Philadelphia chromosome, t(9;22), were independently associated with better disease-free survival (DFS). Transplantation in CR and presence of t(9;22) were associated with lower risk of relapse. Shorter interval from diagnosis to transplantation, DRB1-match, negative CMV, higher marrow cell dose, and Karnofsky score of 90 or higher were associated with less TRM. These results indicate that, despite a relatively high TRM, the low relapse rate resulted in a 37% +/- 13% DFS for CR1 patients, comparing favorably to results obtained with chemotherapy alone and matching results following HLA-identical sibling transplantation.

The National Marrow Donor Program (NMDP) maintains a registry of approximately 4 million volunteer unrelated donors for patients in need of a stem cell transplant. When several comparably HLA-matched volunteers are identified for a patient, various criteria are used to select a donor. A retrospective analysis of 6978 bone marrow transplantations facilitated by the NMDP from 1987 to 1999 was conducted to study the effects of various donor characteristics on recipient outcome. The evaluation addressed possible effects of donor age, cytomegalovirus serologic status, ABO compatibility, race, sex, and parity on overall and disease-free survival, acute and chronic graft-versus-host disease (GVHD), engraftment, and relapse. Age was the only donor trait significantly associated with overall and disease-free survival. Five-year overall survival rates for recipients were 33%, 29%, and 25%, respectively, with donors aged 18 to 30 years, 31 to 45 years, and more than 45 years (P =.0002). A similar effect was observed among HLA-mismatched cases (28%, 22%, and 19%, respectively). A race mismatch between recipient and donor did not affect outcome. The cumulative incidences of grade III or IV acute GVHD were 30%, 34%, and 34%, respectively, with donors aged 18 to 30 years, 31 to 45 years, and more than 45 years (P =.005). The corresponding incidences of chronic GVHD at 2 years were 44%, 48%, and 49% (P = 0.02). Recipients with female donors who had undergone multiple pregnancies had a higher rate of chronic GVHD than recipients with male donors (54% versus 44%; P <.0001). The use of younger donors may lower the incidence of GVHD and improve survival after bone marrow transplantation. Age should be considered when selecting among comparably HLA-matched volunteer donors.

Allogeneic bone marrow transplantation (BMT) may be curative for more patients than chemotherapy for the child with relapsed acute lymphoblastic leukemia. This study reviewed the outcomes of 363 children with acute lymphoblastic leukemia in second remission who received unrelated donor BMT from 1988 to 2000 in order to define prognostic factors that affect leukemia-free survival (LFS). Median patient age was 9 years (range, 0-19 years), and median follow-up 29 was months (range, 0-125 months). The median duration of first remission was 24 months (range, 0-109 months). Prognostic factors, including age, duration of first remission, HLA matching, and graft-versus-host (GVH) disease, were analyzed using both univariate and multivariate analyses. Overall survival was 38%, and LFS was 36% at 5 years. LFS was significantly worse for patients 15 years or older (log-rank, P =.009). HLA matching was associated with improved LFS. Acute GVH disease developed in 71%, with 29% having grades III-IV. The incidence of chronic GVH disease was 39% for patients who survived more than 80 days and was significantly higher for female patients receiving marrow from female donors (P =.0009). Transplantation-related mortality was 42% and was associated with HLA mismatches, age 15 years and older, and first remission less than 12 months. The 5-year estimate for relapse was 22%, with first remission at least 6 months associated with a lower risk. Results of unrelated donor BMT appear similar to multi-institutional studies of matched related donor BMT, and this approach appears to be curative for many patients. However, innovative approaches are needed for patients with initial remissions of less than 6 months and for older teenagers.

Over a period of 8.5 years (February 1988 to October 1996), 1423 patients with chronic myelogenous leukemia (CML) underwent unrelated donor (URD) bone marrow transplants (BMTs) facilitated by the National Marrow Donor Program (NMDP) at 85 transplant centers. One hundred thirty-seven evaluable (9.9%) patients failed to engraft, and an additional 83 (6.6%) evaluable patients experienced late graft failure. Grade III/IV acute graft-versus-host disease (GVHD) developed in 33% of patients (95% confidence interval [CI], 30%-36%). The incidence of extensive chronic GVHD was 60% (95% CI, 56%-63%) at 2 years. Only 5.7% of patients (95% CI, 3.6%-7.8%) transplanted in chronic phase developed hematologic relapse at 3 years. Several factors were independently associated with improved disease-free survival (DFS), including transplant in chronic phase, transplant within 1 year of diagnosis, younger recipient age, a cytomegalovirus seronegative recipient, and development of no or mild acute GVHD. The combined effect of these factors on outcome is manifest in a subset (n = 157) of young (less than 35 years), chronic phase patients transplanted within 1 year of diagnosis using HLA-matched donors who had 63% (95% CI, 53%-73%) DFS at 3 years. URD BMT therapy for CML is both feasible and effective with more frequent and more rapid identification of suitable donors. Early URD transplant during chronic phase yields good results and should be considered in CML patients otherwise eligible for transplant but without a suitable related donor.

We analyzed engraftment of unrelated-donor (URD) bone marrow in 5246 patients who received transplants facilitated by the National Marrow Donor Program between August 1991 and June 1999. Among patients surviving at least 28 days, 4% had primary graft failure (failure to achieve an absolute neutrophil count > 5 × 108/L before death or second stem-cell infusion). Multivariate logistic regression analysis showed that engraftment was associated with marrow matched at HLA-A, HLA-B, and DRB1; higher cell dose; younger recipient; male recipient; and recipient from a non–African American ethnic group. More rapid myeloid engraftment was associated with marrow serologically matched at HLA-A and HLA-B, DRB1 match, higher cell dose (in non-T-cell–depleted cases), younger recipient, recipient seronegativity for cytomegalovirus (CMV), male donor, no methotrexate for graft-versus-host disease prophylaxis, and transplantation done in more recent years. A platelet count higher than 50 × 109/L was achieved by 47% of patients by day 100. Conditional on survival to day 100, survival at 3 years was 61% in those with platelet engraftment at day 30, 58% in those with engraftment between day 30 and day 100, and 33% in those without engraftment at day 100 (P < .0001). Factors favoring platelet engraftment were higher cell dose, DRB1 allele match, recipient seronegativity for CMV, HLA-A and HLA-B serologically matched donor, and male donor. Secondary graft failure occurred in 10% of patients achieving initial engraftment, and 18% of those patients are alive. These data demonstrate that quality of engraftment is an important predictor of survival after URD bone marrow transplantation.

Long-term survival and improved neuropsychological function have occurred in selected children with Hurler syndrome (MPS I H) after successful engraftment with genotypically matched sibling bone marrow transplantation (BMT). However, because few children have HLA-identical siblings, the feasibility of unrelated donor (URD) BMT as a vehicle for adoptive enzyme therapy was evaluated in this retrospective study. Forty consecutive children (median, 1.7 years; range, 0.9 to 3.2 years) with MPS I H received high-dose chemotherapy with or without radiation followed by BMT between January 27, 1989 and May 13, 1994. Twenty-five of the 40 patients initially engrafted. An estimated 49% of patients are alive at 2 years, 63% alloengrafted and 37% autoengrafted. The probability of grade II to IV acute graft-versus-host disease (GVHD) was 30%, and the probability of extensive chronic GVHD was 18%. Eleven patients received a second URD BMT because of graft rejection or failure. Of the 20 survivors, 13 children have complete donor engraftment, two children have mixed chimeric grafts, and five children have autologous marrow recovery. The BM cell dose was correlated with both donor engraftment and survival. Thirteen of 27 evaluable patients were engrafted at 1 year following URD BMT. Neither T-lymphocyte depletion (TLD) of the bone marrow nor irradiation appeared to influence the likelihood of engraftment. Ten of 16 patients alive at 1 year who received a BM cell dose greater than or equal to 3.5 x 10(8) cells/kg engrafted, and 62% are estimated to be alive at 3 years. In contrast, only 3 of 11 patients receiving less than 3.5 x 10(8) cells/kg engrafted, and 24% are estimated to be alive at 3 years (P = .05). The mental developmental index (MDI) was assessed before BMT. Both baseline and post-BMT neuropsychological data were available for 11 engrafted survivors. Eight children with a baseline MDI greater than 70 have undergone URD BMT (median age, 1.5 years; range, 1.0 to 2.4 years). Of these, two children have had BMT too recently for developmental follow-up. Of the remaining six, none has shown any decline in age equivalent scores. Four children are acquiring skills at a pace equal to or slightly below their same age peers; two children have shown a plateau in learning or extreme slowing in their learning process. For children with a baseline MDI less than 70 (median age, 2.5 years; range, 0.9 to 2.9 years), post-BMT follow-up indicated that two children have shown deterioration in their developmental skills. The remaining three children are maintaining their skills and are adding to them at a highly variable rate. We conclude that MPS I H patients with a baseline MDI greater than 70 who are engrafted survivors following URD BMT can achieve a favorable long-term outcome and improved cognitive function. Future protocols must address the high risk of graft rejection or failure and the impact of GVHD in this patient population.