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1.  Use of Matched Unrelated Donors Compared with Matched Related Donors is Associated with Lower Relapse and Superior Progression Free Survival after Reduced Intensity Conditioning Hematopoietic Stem Cell Transplantation 
As success of reduced intensity conditioning (RIC) hematopoietic stem cell transplantation (HSCT) relies primarily on graft-versus-leukemia (GVL) activity, increased minor HLA disparity in unrelated compared to related donors could have a significant impact on transplant outcomes. To assess whether use of unrelated donors (URD) engenders more potent GVL in RIC HSCT compared to matched related donors (MRD), we retrospectively studied 433 consecutive T-replete 6/6 HLA matched URD (n= 246) and MRD (n=187) RIC HSCT for hematologic malignancies at our institution. Diseases included: AML(127), NHL(71), CLL (68), MDS (64), HD(40), CML (25), MM(23), MPD (12), ALL(7), other leukemia (1). All received uniform fludarabine and intravenous busulfan conditioning, and GVHD prophylaxis with tacrolimus/mini-MTX or tacrolimus/sirolimus +/− mini-MTX. Unrelated donors were younger compared to MRD (median age: 33 yrs vs. 52 yrs, p<0.0001), and provided larger CD34+ products (median CD34+ cells infused: 8.7 × 106/kg vs. 7.5 × 106/kg, p=0.002). Distribution of diseases, disease risk, prior transplant, and CMV status was similar in both cohorts. Cumulative incidence of grade II–IV acute GVHD (at day+180), 2 year-chronic GVHD, and 2-year non-relapse mortality (NRM) were 20% vs. 16%, 55% vs. 50%, and 8% vs. 6% in URD and MRD, respectively (p=NS). Cumulative incidence of relapse at 2 years was lower in URD, 52% vs. 65% (p=0.005). With median follow-up of 26.5 and 35.8 months, 2-yr progression free survival (PFS) was significantly better in unrelated donor transplants, 39.5% for URD and 29% for MRD (p= 0.01). Overall survival at 2 years were 56% for URD vs. 50% for MRD (p=0.53). In multivariable analysis, URD was associated with a lower risk of relapse (HR 0.67, p =0.002) and superior PFS (HR 0.69, p=0.002). These results suggest that URD is associated with greater GVL activity than MRD, and could have practice changing impact on future donor selection in RIC HSCT.
PMCID: PMC3080446  PMID: 21193054
2.  Reduced Intensity Allogeneic Transplant In Patients Older Than 55 Years: Unrelated Umbilical Cord Blood Is Safe And Effective For Patients Without A Matched Related Donor 
The lower morbidity and mortality of reduced-intensity conditioning (RIC) regimens have allowed allogeneic hematopoietic cell transplantation (HCT) in older patients. Unrelated umbilical cord blood (UCB) has been investigated as an alternative stem cell source to suitably HLA matched related (MRD) and adult volunteer unrelated donors. We hypothesized that RIC HCT using UCB would be safe and efficacious in older patients and compared the transplant related mortality (TRM) and overall survival of RIC HCT in patients older than 55 years using either MRD (n=47) or, in patients with no 5/6 or 6/6 HLA compatible related donors, UCB (n=43). RIC regimen consisted of total-body irradiation (200 cGy) and either cyclophosphamide and fludarabine (n=69), or busulfan and fludarabine (n=16) or busulfan and cladribine (n=5). The median age of MRD and UCB cohorts was 58 (range, 55-70) and 59 (range, 55-69) years, respectively. AML/MDS (50%) was the most common diagnosis. All MRD grafts were 6 of 6 HLA matched to the recipient. Among patients undergoing UCB HCT, 88% received two UCB units to optimize cell dose and 93% received 1-2 HLA mismatched grafts. The median followup for survivors was 27 (range, 12-61) months. The 3-year probabilities of progression-free survival (30% vs. 34%, p=0.98) and overall survival (43% vs. 34%, p=0.57) were similar for recipients of MRD and UCB. The cumulative incidence of grade 2-4 acute graft-versus-host disease (42% vs. 49%, p=0.20) and TRM at 180-days (23% vs. 28%, p=0.36) were comparable. However, UCB recipients had a lower incidence of chronic graft-versus-host disease at 1-year (40% vs. 17%, p=0.02). On multivariate analysis, graft type had no impact on TRM or survival and HCT comorbidity index score was the only factor independently predictive for these endpoints. Our study supports the use of HLA mismatched UCB as an alternative graft source for older patients who need a transplant but do not have a MRD. The use of RIC and UCB extends the availability of transplant therapy to older patients previously excluded on the basis of age and lack of a suitable MRD. A careful review of existing comorbidities is necessary when considering older patients for HCT.
PMCID: PMC2674378  PMID: 18275894
Allogeneic Stem Cell Transplantation; Umbilical Cord Blood Transplantation; Non-myeloablative Conditioning Regimen; Reduced Intensity Conditioning Regimen
3.  Alternative Donor Transplantation for Older Patients with Acute Myeloid Leukemia in First Complete Remission: a CIBMTR-Eurocord Analysis 
We studied AML patients over age 50 in CR1 after adult unrelated donor (URD; n = 441, 8/8 and n = 94 7/8 HLA-matched) or umbilical cord blood (UCB; n = 205) transplantations. UCB recipients less often achieved CR1 within 8 weeks, more often received reduced-intensity conditioning, and cyclosporin-based graft-versus-host disease (GVHD) prophylaxis. Neutrophil recovery was slower in UCB (69% by day 28) vs. 8/8 URD (97%); 7/8 (91%) (p<0.001). Three-year transplant-related mortality (TRM) was higher and leukemia-free survival (LFS) lower with UCB (35% and 28%, respectively) vs. 8/8 URD (27% and 39%). TRM was higher in 7/8 URD (41%, p=0.01), but LFS similar 34% (p=0.39). Three-year chronic GVHD was least in UCB (28%) vs. 53% and 59% in 8/8 and 7/8 URD recipients. Three-year survival was 8/8 URD 43% (95% CI 38-48), UCB 30% (95% CI 23-37) (p=0.002) and 7/8 URD 37% (95% CI 27-46). Allotransplantation for AML in CR1 with any of these grafts extends LFS for over a third of older patients. In the absence of an 8/8 HLA-matched URD or when transplantation is needed urgently, UCB can provide extended survival. Less frequent chronic GVHD with UCB transplantation may be of particular value for older patients.
PMCID: PMC4085692  PMID: 24582782
Allogeneic transplantation; AML; umbilical cord blood; unrelated donors
4.  Comparable Survival for Pediatric Acute Myeloid Leukemia With Poor-Risk Cytogenetics Following Chemotherapy, Matched Related Donor, or Unrelated Donor Transplantation 
Pediatric blood & cancer  2013;61(2):269-275.
We sought to better define the role of hematopoietic cell transplantation (HCT) in first remission (CR1) for high-risk pediatric acute myeloid leukemia (AML).
Outcomes were compared among patients aged less than 21 years with cytogenetically defined poor-risk AML treated with chemotherapy, matched related (MRD), or unrelated donor (URD) transplantation in CR1. Poor-risk cytogenetics was defined as monosomy 7/del7q, monosomy 5/del 5q, abnormalities of 3q, t(6;9)(p23;q34), or complex karyotype. Included are patients treated on Children’s Oncology Group trials or reported to the Center for International Blood and Marrow Transplant Research from 1989 to 2006.
Of the 233 patients, 123 received chemotherapy, 55 received MRD HCT, and 55 received URD HCT. The 5-year overall survival from the time of consolidation chemotherapy or transplant conditioning was similar: chemotherapy (43% ± 9%), MRD (46% ± 14%), or URD (50% ± 14%), P = 0.99. Similarly, multivariate analysis demonstrated no significant differences in survival [(reference group = chemotherapy); MRD HR 1.08, P = 0.76; URD HR 1.13, P = 0.67] despite lower relapse risk with URD HCT (HR = 0.43, P = 0.01).
Our findings do not provide support for the preferential use of HCT over chemotherapy alone for children with cytogenetically defined poor-risk AML in CR1.
PMCID: PMC3919967  PMID: 23955900
acute myeloid leukemia; chemotherapy; hematopoietic cell transplantation; pediatrics
5.  Myeloablative Hematopoietic Cell Transplantation for Acute Lymphoblastic Leukemia: Analysis of Graft Sources and Long-Term Outcome 
Journal of Clinical Oncology  2009;27(22):3634-3641.
Analysis of hematopoietic cell transplantation (HCT) for high-risk or recurrent acute lymphoblastic leukemia (ALL) using different donor sources is confounded by variable conditioning and supportive care.
Patients and Methods
We studied 623 consecutive ALL myeloablative HCT (1980 to 2005). Donors were autologous (n = 209), related (RD; n = 245), unrelated (URD; n = 100), and umbilical cord blood (UCB; n = 69).
After median of 8.3 years of follow-up, 5-year overall survival (OS), leukemia-free survival (LFS), and relapse were 29% (95% CI, 26% to 32%), 26% (95% CI, 23% to 29%), and 43% (95% CI, 39% to 47%), respectively. Treatment-related mortality (TRM) at 2 years was 28% (95% CI, 25% to 31%). Mismatched URD sources yielded higher TRM (relative risk [RR], 2.2; P < .01) and lower OS (RR, 1.5; P = .05) than RD or UCB HCT. Autografting yielded significantly more relapse (68%; 95% CI, 59% to 77%; P < .01) and poorer LFS (14%; 95% CI, 10% to 18%; P = .01). HCT in first complete remission (CR1) yielded significantly better outcomes than later HCT. In a 1990 to 2005 allogeneic CR1/second complete response cohort, 5-year OS, LFS, and relapse rates were 41% (95% CI, 35% to 47%), 38% (95% CI, 32% to 44%), and 25% (95% CI, 19% to 31%), respectively; 2-year TRM was 34% (95% CI, 28% to 40%). With RD, well-matched URD and UCB sources, 5-year LFS was 40% (95% CI, 31% to 49%), 42% (95% CI, 14% to 70%), and 49% (95% CI, 34% to 64%), respectively, while relapse was 31% (95% CI, 22% to 40%), 17% (95% CI, 0% to 37%), and 27% (95% CI, 13% to 41%). Acute graft-versus-host disease was associated with fewer relapses. Since 1995, we noted progressive improvements in OS, LFS, and TRM.
Allogeneic, but not autologous, HCT for ALL results in durable LFS. Importantly, HCT using UCB led to similar outcomes as either RD or well-matched URD. HCT in early remission can best exploit the potent antileukemic efficacy of allografting from UCB, RD, or URD sources.
PMCID: PMC2720079  PMID: 19581540
6.  Transplant Outcomes in Acute Leukemia (I) 
Seminars in hematology  2010;47(1):46.
Umbilical cord blood (UCB) has gradually emerged over the last decade as an alternative source of hematopoietic cells for transplantation in children and adults with high-risk or advanced hematological malignancies who do not have a suitably matched related or unrelated adult donor. This increase in use of UCB is due to favorable results in children, growing availability of UCB units with large cell doses, less stringent donor-recipient HLA matching and rapid identification and acquisition of the unit. In children with acute leukemia, the data support similar leukemia-free survival after transplantation of HLA-matched and 1 or 2 HLA-mismatched UCB and HLA-matched unrelated donor bone marrow. In adults with acute leukemia, some reports suggest a survival advantage after transplantation of matched unrelated bone marrow compared to UCB and others, similar leukemia-free survival. Work is in progress to improve hematopoietic recovery and lower early transplant-related deaths, the two major limitations to a successful outcome after UCB transplant. The importance of HLA-matching and cell dose on outcomes after UCB transplantation support the need for an even greater investment in public cord blood banks. Simultaneously searching of accredited cord blood banks and bone marrow donor registries for patients without an HLA-matched sibling thought to benefit from hematopoietic stem cell transplantation is encouraged.
PMCID: PMC2814074  PMID: 20109611
7.  Umbilical Cord Blood Transplantation: Basic Biology and Clinical Challenges to Immune Reconstitution 
Clinical immunology (Orlando, Fla.)  2008;127(3):286-297.
Allogeneic stem cell transplantation has continued to evolve as a common procedure for the treatment of hematological malignancies and bone marrow failure. Donor bone marrow and mobilized peripheral stem cells are routinely employed for the reconstitution of immune function in leukemia and lymphoma patients following radiation and/or chemotherapy. Unfortunately, only 30% of patients have an HLA identical sibling donor and the identification of matched unrelated donors, particularly for minorities, can present an exceptional challenge. The transplantation of umbilical cord blood (UCB) represents the most recent strategy to expand the potential donor pool while maintaining an acceptable level of treatment related complications. First utilized in children, UCB transplantation permits a higher degree of HLA disparity while demonstrating a reduction in the incidence and severity of graft versus host disease (GvHD) compared to previous transplantation modalities. Despite the apparent decrease in GvHD, relapse rates remain comparable to transplantation with bone marrow or mobilized peripheral blood suggesting a strong graft versus leukemia/lymphoma (GvL) effect. However, several issues complicate the use of UCB transplantation and its extension to the treatment of adults. Many infections that afflict transplant patients are particularly frequent and more severe in the context of UCB transplantation. UCB T cells are naïve and therefore display less proliferation and IFN-γ production in response to cognate antigen and also appear to demonstrate defects in signal transduction mechanisms. In addition, UCB contain T regulatory cells (Treg) with more potent suppressor function than adult Treg. Furthermore, adult patients often require more total cells and CD34+ progenitors for transplantation than a single UCB unit can provide. Thus, strategies to expand selected subpopulations from UCB and the use of multi-unit transplantation are areas of active research. This review will provide a condensed summary of the clinical history of UCB transplantation and emphasize the advantages and disadvantages of this approach to hematological malignancies in comparison to other methods of hematopoietic stem cell transplantation. Subsequently, it will mainly focus on the current challenges to immune reconstitution presented by UCB transplantation, recent research into their cellular and molecular mechanisms, and experimental approaches to overcome them.
PMCID: PMC2468219  PMID: 18395491
Cord Blood transplantation; tolerance; immune reconstitution; post-transplant infections
8.  Costs of pediatric allogeneic hematopoietic-cell transplantation 
Pediatric blood & cancer  2010;54(1):138-143.
Allogeneic hematopoietic-cell transplantation (HCT), although curative for some high-risk diseases, is a complex and costly procedure. The costs of transplantation among children have not been described previously.
We compared the costs of HCT within the first 100-days among children who received myeloablative HCT from either a matched related donor (MRD, N=27), matched unrelated donor (MUD, N=28) or unrelated umbilical cord blood (UCB, N=91). We also conducted analyses to describe predictors of higher costs of transplantation.
The 100-day probabilities of overall survival were 96%, 96% and 87% for MRD, MUD and UCB, respectively. The median cost per day survived (excluding costs of graft acquisition) was $3,403 (interquartile-range [IQR], 2,838-3,819) for MRD, $3,833 (IQR, 3,402-4,134) for MUD and $3,964 (IQR, 3,351-4,952) for UCB recipients. The costs of MUD and UCB HCT remained similar when costs of graft acquisition were considered within total costs of transplantation. In multivariate analysis adjusting for important patient, disease and transplant related characteristics, factors associated with higher costs within the first 100-days were HCT using MUD (relative-risk [RR] 1.2 [95% confidence-intervals, 1.0-1.3]) or UCB (RR 1.2 [1.1-1.3]), Lansky score <90 at transplant (RR 1.3 [1.2-1.4]), graft failure (RR 1.6 [1.5-1.7]), need for dialysis (RR 1.7 [1.6-1.8]), need for mechanical ventilation (RR 1.4 [1.3-1.5]) and occurrence of hepatic veno-occlusive disease (RR 1.3 [1.1-1.6]).
Within the first 100-days, the absolute costs of MUD and UCB HCT are similar, while MRD HCT is less costly. These costs are primarily driven by severe post-transplant complications and graft failure.
PMCID: PMC4111794  PMID: 19693941
Hematopoietic-cell transplantation; Pediatric; Allogeneic; Costs; Complications
9.  Hematopoietic Stem Cell Transplantation in Children with Leukemia: A Single Institution Experience with Respect to Donors 
Journal of Korean Medical Science  2011;26(12):1548-1555.
Aim of this study was to compare the outcomes of transplantation by donor source and to help select the best alternative donor in children with leukemia. Donor sources included matched related donor (MRD, n = 35), allele-matched unrelated donor (M-UD, n = 10) or -mismatched (MM)-UD (n = 13) or unrelated umbilical cord blood (UCB, n = 11). UCB group had a significantly higher incidence of grade II-IV acute graft versus host disease (MRD, 11.8%; M-UD, 30.0%; MM-UD, 15.4%, UCB, 54.4%, P = 0.004) but there was no difference in incidence of chronic graft versus host disease between 4 groups. The 5-yr leukemia-free survival (LFS) was 76.7%, 60.0%, 69.2%, and 45.5%, respectively (P = 0.128). MRD group showed higher LFS rate than UCB group (P = 0.022). However, LFS of M-UD and MM-UD together (65.2%) was not different from that of MRD group (76.7%, P = 0.325), or from that of UCB (45.5%, P = 0.190). The relapse incidence at 5 yr was 17.1%, 20.0%, 15.4%, and 0%, respectively (P = 0.460). The 100-day treatment-related mortality was 2.9%, 20.0%, 7.7%, and 36.4%, respectively (P = 0.011). Despite the limitations of small number of patients, unrelated donor transplants including even allele-mismatched ones, seem to be as effective in children with leukemia lacking suitable relative donors. Also, UCB transplant may serve as another possible option in urgent transplants.
PMCID: PMC3230013  PMID: 22147990
Allogeneic Hematopoietic Stem Cell Transplantation; Leukemia; Unrelated Donor; Umbilical Cord Blood
10.  Sirolimus, tacrolimus and low-dose methotrexate as graft versus host disease prophylaxis in related and unrelated donor reduced intensity conditioning allogeneic peripheral blood stem cell transplantation 
We assessed the combination of sirolimus, tacrolimus and low-dose methotrexate as acute graft versus host disease prophylaxis after reduced intensity conditioning allogeneic peripheral blood stem cell transplantation from matched related (MRD, n=46) and unrelated (URD, n=45) donors. All patients received fludarabine and intravenous busulfan conditioning followed by transplantation of mobilized peripheral blood stem cells. The median time to neutrophil engraftment was 13 days. The cumulative incidence of grade II–IV and III–IV acute GVHD were 16% and 7%, respectively. There was no difference in the incidence of acute GVHD between MRD and URD cohorts. Two year cumulative incidence of extensive chronic GVHD was 40%. Relapse-free survival at two years was 34%: 21% in MRD and 45% in URD. Overall survival at two years was 59%: 47% in MRD and 67% in URD. High levels (>90%) of donor derived hematopoiesis were achieved in 59% of patients early after transplantation. The addition of sirolimus to tacrolimus and low-dose methotrexate as GVHD prophylaxis following reduced intensity conditioning with fludarabine and low dose intravenous busulfan is associated with rapid engraftment, low rates of acute GVHD, and achievement of high levels of donor chimerism.
PMCID: PMC3805273  PMID: 18640576
11.  Myeloablative Transplantation using either Cord Blood or Bone Marrow leads to Immune Recovery, High Long-Term Donor Chimerism and Excellent Survival in Chronic Granulomatous Disease 
The curative potential of hematopoietic stem cell transplantation (HSCT) in patients with chronic granulomatous disease (CGD) depends upon availability of a suitable donor, successful donor engraftment and maintenance of long-term donor chimerism. Twelve consecutive children (median age 59.5 months; range, 8–140) with severe CGD (serious bacterial/fungal infections pre-transplant, median 3; range, 2–9) received myeloablative HSCT using sibling bone marrow (SibBM; n=5), unrelated cord blood (UCB; n=6), and sibling cord blood (SibCB; n=1) at our center between 1997–2010. SibBM and SibCB were HLA matched at 6/6 while UCB were 5/6 (n=5) or 6/6 (n=1). Recipients of SibBM were conditioned with Busulfan and Cyclophosphamide (Bu/Cy) + ATG while 6 of 7 CB recipients received Fludarabine/Bu/Cy/ATG. Seven patients received G-CSF-mobilized granulocyte transfusions from directed donors. The first 2 UCB recipients had primary graft failure but were successfully re-transplanted with UCB. Highest acute GvHD was grade III (n=1). Extensive chronic GvHD developed in 3 patients. All patients are alive with median follow-up of 70.5 (range 12–167) months with high donor chimerism (>98%, n=10; 94%, n=1; and 92%, n=1). Myeloablative HSCT led to correction of neutrophil dysfunction, durable donor chimerism, excellent survival, good quality of life, and low incidence of GvHD regardless of graft source.
PMCID: PMC3540103  PMID: 22326631
12.  Effect of Graft Source on Unrelated Donor Haemopoietic Stem-Cell Transplantation in Adults with Acute Leukemia: A Retrospective Analysis 
The lancet oncology  2010;11(7):653-660.
Umbilical cord blood (UCB) is increasingly considered as an alternative to peripheral blood progenitor cells (PBPC) or bone marrow (BM), especially when a HLA-matched adult unrelated donor is not available.
In order to establish the appropriateness of current graft selection practices, we retrospectively compared leukemia-free survival and other outcomes for each graft source in patients aged >16 years transplanted for acute leukemia using Cox regression. Data were available on 1525 patients transplanted between 2002 and 2006 using UCB (n=165), PBPC (n=888) and BM (n=472). UCB units were matched at HLA-A and B at antigen level and DRB1 at allele level (n=10) or mismatched at one (n=40) or two antigens (n=115). PBPC and BM grafts from unrelated adult donors were matched for allele-level HLA-A, B, C and DRB1 (n=632; n=332) or mismatched at one locus (n=256; n=140).
Leukemia-free survival after UCB transplantation was comparable to that observed after 8/8 and 7/8 allele-matched PBPC or BM transplantation. Transplant-related mortality, however, was higher after UCB transplantation compared to 8/8 allele-matched PBPC (HR 1.62, p<0.01) or BM (HR 1.69, p<0.01). Grades 2–4 acute and chronic graft-versus-host disease were lower in UCB recipients compared to allele-matched PBPC (HR 0.57, p<0.01 and HR 0.38, p<0.01, respectively), while chronic and not acute graft-versus-host disease was lower after UCB compared to allele-matched BM transplantation (HR 0.63, p=0.01).
Together, these data support the use of UCB for adults with acute leukemia when an HLA-matched unrelated adult donor is lacking and when transplant is urgently needed.
PMCID: PMC3163510  PMID: 20558104
13.  HLA-Identical Sibling Compared With 8/8 Matched and Mismatched Unrelated Donor Bone Marrow Transplant for Chronic Phase Chronic Myeloid Leukemia 
Journal of Clinical Oncology  2009;27(10):1644-1652.
Transplantation of hematopoietic stem cells from an unrelated donor (URD) is an option for many patients who do not have an HLA-identical sibling donor (MSD). Current criteria for the selection of URDs include consideration for HLA alleles determined by high resolution typing methods, with preference for allele-matched donors. However, the utility and outcome associated with transplants from URDs compared with those from MSDs remains undefined.
Patients and Methods
We examined clinical outcome after patients received bone marrow transplants (BMTs) from MSDs; HLA-A, -B, -C, and DRB1 allele-matched URDs (8/8); and HLA-mismatched URDs in a homogeneous population of patients with chronic myeloid leukemia (CML) in first chronic phase (CP1) where a strong allogeneic effect and hence a lower risk of relapse is anticipated. Transplantation outcomes were compared between 1,052 URD and 3,514 MSD BMT recipients with CML in CP1.
Five-year overall survival and leukemia-free survival (LFS) after receipt of BMTs from 8/8 matched URDs were worse than those after receipt of BMTs from MSDs (5-year survival, 55% v 63%; RR, 1.35; 95% CI, 1.17 to 1.56; P < .001; LFS, 50% v 55%; RR, 1.21; 95% CI, 1.06 to 1.40; P = .006). Survival was progressively worse with greater degrees of mismatch. Similar and low risk of relapse were observed after receipt of transplant from either MSD or URD.
In this homogeneous cohort of good risk patients with CML in CP1, 5-year overall survival and LFS after receipt of transplant from 8/8 allele-matched donors were modestly though significantly worse than those after receipt of transplant from MSDs. Additive adverse effects of multilocus mismatching are not well tolerated and should be avoided if possible.
PMCID: PMC2668970  PMID: 19224849
14.  Sibling versus Unrelated Donor Allogeneic Hematopoietic Cell Transplantation for CML: Refined HLA-matching shows more GVHD but not less relapse 
Unrelated donor (URD) hematopoietic cell transplantation (HCT) can eradicate chronic myelogenous leukemia (CML). It has been postulated that greater donor:recipient-histoincompatibility can augment the graft vs. leukemia (GvL) effect. We previously reported similar, but not equivalent outcomes of URD vs. sibling donor HCT for CML using an older, less precise classification of HLA-matching.
Our recently refined HLA-matching classification, suitable for interpretation when complete allele-level typing is unavailable was used to reanalyze outcomes of previous HCT for CML.
We observed that new matching criteria identifies substantially more frequent mismatch than older, less precise “6 of 6 antigen” matched URD-HCT. Only 37% of those previously called “HLA-matched” were HLA-well-matched in new classification and 44% were partially-matched. The refined matching classification confirmed that partially matched or mismatched URD:recipient pairs have significantly greater risks of graft failure compared to either sibling or well-matched URD-HCT. Acute and chronic GVHD are significantly more frequent with all levels of recategorized URD HLA-matching. Importantly, survival and leukemia-free survival remain significantly worse following URD-HCT at any matching level. No augmented GvL effect accompanied URD HLA-mismatch. Compared to sibling donor transplants, we observed marginally increased, but not significantly different risks of relapse in either well-matched, partially-matched or mismatched URD-HCT.
These data confirm the utility of our revised HLA-matching schema as applicable for analysis of retrospective data sets when fully informative, allele level-typing is unavailable. In this analysis, greater histoincompatibility can augment GVHD but does not improve protection against relapse thus the best donor is still the most closely matched.
PMCID: PMC2929002  PMID: 19822308
CML; HLA matching; Unrelated donor allotransplantation; Graft vs. Leukemia; Graft vs. Host disease
15.  Comparison of Matched Unrelated and Matched Related Donor Myeloablative Hematopoietic Cell Transplantation for Adults with Acute Myeloid Leukemia in First Remission 
Hematopoietic cell transplantation (HCT) from a matched related donor (MRD) benefits many adults with acute myeloid leukemia (AML) in first complete remission (CR1). The majority of patients do not have such a donor, however, requiring use of an alternative donor if HCT is undertaken. We retrospectively analyzed 226 adult AML CR1 patients undergoing myeloablative unrelated donor (URD) (10/10 match, n=62; ≤9/10, n=29) or MRD (n=135) HCT from 1996–2007. Five-year estimates of overall survival (OS), relapse, and non-relapse mortality (NRM) were 57.9%, 29.7%, and 16.0%, respectively. Failure for each of these outcomes was slightly higher for 10/10 URD than MRD HCT, although statistical significance was not reached for any endpoint. The adjusted hazard ratios (HR) were 1.43 (0.89–2.30, p=0.14) for overall mortality, 1.17 (0.66–2.08, p=0.60) for relapse, and 1.79 (0.86–3.74, p=0.12) for NRM, respectively, and the adjusted odds ratio (OR) for grades 2–4 acute graft-versus-host disease was 1.50 (0.70–3.24, p=0.30). Overall mortality among 9/10 and 10/10 URD recipients was similar (adjusted HR=1.16 [0.52–2.61], p=0.71). These data indicate that URD HCT can provide long-term survival for CR1 AML; outcomes for 10/10 URD HCT, and possibly 9/10 URD HCT, suggest that this modality should be considered in the absence of a suitable MRD.
PMCID: PMC3001162  PMID: 20485378
acute myeloid leukemia (AML); first complete remission; hematopoietic stem cell transplantation; unrelated donor; matched related donor
Bone marrow transplantation  2014;50(2):197-203.
Alternative donor transplantation is increasingly used for high risk lymphoma patients. We analyzed 1593 transplant recipients (2000 to 2010) and compared transplant outcomes in recipients of 8/8 allele human leukocyte antigen (HLA)-A, -B, -C, and DRB1 matched unrelated donors (MUD; n=1176), 7/8 allele HLA-matched unrelated donors (MMUD; n=275) and umbilical cord blood donors (1 or 2 units UCB; n=142). Adjusted 3-year non-relapse mortality of MMUD (44%) was higher as compared to MUD (35%; p=0.004), but similar to UCB recipients (37%; p=0.19), although UCB had lower rates of neutrophil and platelet recovery compared to unrelated donor groups. With a median follow-up of 55 months, 3-year adjusted cumulative incidence of relapse was lower after MMUD compared with MUD (25% vs 33%, p=0.003) but similar between UCB and MUD (30% vs 33%; p=0.48). In multivariate analysis UCB recipients had lower risks of acute and chronic graft versus host disease compared with adult donor groups (UCB vs MUD: HR=0.68, p=0.05; HR=0.35; p<0.001). Adjusted 3-year overall survival was comparable (43% MUD, 37% MMUD and 41% UCB). Data highlight that patients with lymphoma have acceptable survival after alternative donor transplantation. MMUD and UCB can expand the curative potential of allotransplant to patients who lack suitable HLA-matched sibling or MUD.
PMCID: PMC4336786  PMID: 25402415
Umbilical Cord Blood; Lymphoma; Alternative Donor Transplantation
Current opinion in pediatrics  2009;21(1):22-29.
Purpose of Review
2008 marks the 20th anniversary of the first use of umbilical cord blood (UCB) as a source of donor cells for hematopoietic stem cell transplantation. In those early days, there was great doubt and skepticism about the utility of UCB as a source of hematopoietic stem cells. Doubts about whether UCB, containing 10-20x fewer cells than bone marrow, had sufficient cells to durably engraft a myeloablated patient and, after demonstration that engraftment occurred with less graft-versus-host disease (GvHD), whether it would confer graft versus leukemia (GvL) activity were raised.
Recent Findings
Transplantation with UCB is effective in the treatment of children with hematological malignancies, marrow failure, immunodeficiencies, hemoglobinopathies and inherited metabolic diseases. Transplantation without full HLA matching is possible and despite a lower incidence of GvHD, GvL is preserved. The number of cells in a single UCB can be limiting, but the use of 2 UCBs for a single transplant shows promise to overcome this obstacle.
Cord blood transplantation is now an established field with enormous potential. UCB increases access to transplantation therapy for many patients unable to indentify a fully matched adult donor. In the future, it may emerge as a source of cells for cellular therapies focused on tissue repair and regeneration.
PMCID: PMC3682484  PMID: 19253461
Umbilical Cord Blood; Unrelated Donors; Hematopoietic Stem Cell Transplantation; Inborn Errors of Metabolism
18.  Long-term Outcomes of Adults with Acute Lymphoblastic Leukemia after Autologous or Unrelated Donor Bone Marrow Transplantation 
Bone marrow transplantation  2007;41(7):635-642.
For adults with high-risk or recurrent acute lymphoblastic leukemia (ALL) who lack a suitable sibling donor, the decision between autologous (Auto) and unrelated donor (URD) hematopoietic stem cell transplantation (HSCT) is difficult due to variable risks of relapse and treatment-related mortality (TRM). We analyzed data from two transplant registries to determine outcomes between Auto and URD HSCT for 260 adult ALL patients in first (CR1) or second (CR2) complete remission. All patients received a myeloablative conditioning regimen. The median follow-up was 77 (range 12-170) months. TRM at 1 year post-transplant was significantly higher with URD HSCT; however, there were minimal differences in TRM according to disease status. Relapse was higher with Auto HSCT and was increased in patients transplanted in CR2. Five year leukemia-free (37% vs. 39%) and overall (38% vs. 39%) survival rates were similar for Auto HSCT vs. URD HSCT in CR1. There were trends favoring URD HSCT in CR2. The long follow-up in this analysis demonstrated that either Auto or URD HSCT can result in long-term leukemia free and overall survival for adult ALL patients. The optimal time (CR1 vs. CR2) and technique to perform HSCT remains an important clinical question for adult ALL patients.
PMCID: PMC2587442  PMID: 18084335
acute lymphoblastic leukemia (ALL); adult; autologous HSCT; unrelated donor HSCT
19.  The impact of HLA matching on unrelated donor hematopoietic stem cell transplantation in Korean children 
The impact of HLA matching on outcomes of unrelated donor (URD) hematopoietic stem cell transplantation (HSCT) varies in different racial or ethnic groups. Since little is known about the impact of such matching on URD HSCT in Korean children, we analyzed this issue.
We analyzed the outcomes of 142 patients who underwent URD HSCT at 4 Korean medical centers. All patient donor pairs were fully typed for HLA-A, -B, -C, and -DR alleles.
At a median follow-up of 22 months, 3-year survival rates for patients with 8, 7, and ≤6 matched alleles were 88.4%, 70.7%, and 53.6%, respectively. A single mismatch (Mm) at HLA-B or -C was associated with lower survival compared with that associated with 8 matched alleles. No significant differences were observed between single-allele and single-antigen Mms with respect to survival rate or acute graft-versus-host disease (aGVHD) incidence rates. HLA disparity had a greater impact on the survival of patients with high-risk malignancy than of those with low-risk malignancy. Among pairs with a single Mm, only locus A showed a significant association and higher risk of grade III-IV aGVHD compared to those in patients with 8 matched alleles.
Disparity in HLA class I, regardless of antigen or allele Mm, adversely affected both survival and grade III-IV aGVHD development. An increased number of HLA Mms was associated with a higher risk of post-transplantation complications. Further investigations using larger cohorts are required to confirm the effects of HLA mismatching on URD HSCT patient outcomes.
PMCID: PMC3065620  PMID: 21461298
URD HSCT; HLA; Korean children
20.  Cytotoxic T-Lymphocyte Antigen-4 (CTLA-4) Single Nucleotide Polymorphisms Are Not Associated with Outcomes after Unrelated Donor Transplant: A Center for International Blood and Marrow Transplant Research Analysis 
Cytotoxic T-Lymphocyte Antigen-4 (CTLA-4) plays an essential role in T cell homeostasis by restraining immune responses. AG and GG genotypes of donor CTLA-4 SNP rs4553808 in patients after unrelated donor (URD) hematopoietic stem cell transplants (HSCT) have been shown to be an independent predictor of inferior relapse free survival (RFS) and overall survival (OS) compared to the AA genotype in single center studies. We tested the hypothesis that SNP rs4553808 is associated with RFS, OS, non-relapse mortality (NRM) and the cumulative incidence of acute graft-versus-host disease (aGVHD) and chronic graft-versus-host disease (cGVHD) in adults with acute myeloid leukemia (AML) and advanced myelodysplastic syndrome (MDS) undergoing a first 8/8 or 7/8 HLA matched URD HSCT. Multivariable analysis adjusting for relevant donor and recipient characteristics showed no significant association between SNP rs4553808 and OS, RFS, NRM, and incidence of aGVHD and cGVHD. An exploratory analysis of other CTLA-4 SNPs as well as studying the interaction with ATG also demonstrated no significant associations. Our results indicate that CTLA-4 SNPs are not associated with HSCT outcomes.
PMCID: PMC4034271  PMID: 24631737
CTLA-4; SNPs; hematopoietic stem cell transplantation
21.  Impact of ABO-Mismatch on Risk of Graft-versus-Host Disease after Umbilical Cord Blood Transplantation 
Bone marrow transplantation  2013;48(8):1046-1049.
Recent advances in allogeneic hematopoietic cell transplant (HCT) have led to an increasing use of alternative donors, including banked umbilical cord blood (UCB). Despite these advances, acute graft-versus-host disease (aGvHD) and chronic GvHD (cGvHD) continue to be the leading causes of early and late transplant related mortality. ABO-mismatch has been frequently reported as a risk factor for GvHD, however data in the UCB recipients is limited. We hypothesized that since the lymphocytes in the cord blood are thought to be naive, they will therefore be less likely to mediate GvHD. Therefore, we analyzed the impact of ABO-mismatch on aGvHD and cGvHD in recipients of single and double UCB-HCT. In both univariate and multivariate analysis presence of ABO-mismatch did not impact aGvHD or cGvHD. While ABO compatible donors are preferred in recipients of URD-HCT, ABO compatibility generally need not be considered in recipients of UCB-HCT.
PMCID: PMC3740145  PMID: 23419434
ABO-mismatch; GvHD; allogeneic hematopoietic cell transplantation; cord blood transplantation
22.  Improving Engraftment and Immune Reconstitution in Umbilical Cord Blood Transplantation 
Umbilical cord blood (UCB) is an important source of hematopoietic stem cells (HSC) for allogeneic transplantation when HLA-matched sibling and unrelated donors (MUD) are unavailable. Although the overall survival results for UCB transplantation are comparable to the results with MUD, UCB transplants are associated with slow engraftment, delayed immune reconstitution, and increased opportunistic infections. While this may be a consequence of the lower cell dose in UCB grafts, it also reflects the relative immaturity of cord blood. Furthermore, limited cell numbers and the non-availability of donor lymphocyte infusions currently prevent the use of post-transplant cellular immunotherapy to boost donor-derived immunity to treat infections, mixed chimerism, and disease relapse. To further develop UCB transplantation, many strategies to enhance engraftment and immune reconstitution are currently under investigation. This review summarizes our current understanding of engraftment and immune recovery following UCB transplantation and why this differs from allogeneic transplants using other sources of HSC. It also provides a comprehensive overview of promising techniques being used to improve myeloid and lymphoid recovery, including expansion, homing, and delivery of UCB HSC; combined use of UCB with third-party donors; isolation and expansion of natural killer cells, pathogen-specific T cells, and regulatory T cells; methods to protect and/or improve thymopoiesis. As many of these strategies are now in clinical trials, it is anticipated that UCB transplantation will continue to advance, further expanding our understanding of UCB biology and HSC transplantation.
PMCID: PMC3932655  PMID: 24605111
umbilical cord blood; transplantation; hematopoietic stem cells; engraftment; immune reconstitution
23.  Trends of Hematopoietic stem cell transplantation in the Eastern Mediterranean region, 1984–2007 
Hematopoietic stem cell transplantation (HSCT) activity was surveyed in the 9 countries in the WHO Eastern Mediterranean (EM) region that are reported to carry out transplants. Between the years of 1984 and 2007, 7933 transplants were reported. The total number of HSCT per year has continued to increase, with a plateau in allogeneic HSCT (allo-HSCT) between 2005 and 2007. Overall, a greater proportion of transplants were allogeneic HSCT (allo-HSCT) (n=5761, 77%) compared to autologous HSCT (ASCT) (n=2172, 23% ASCT). Of 5761 allo-HSCT, acute leukemia constituted the main indication (n=2124, 37%). There was a relatively high proportion of allo-HSCT for bone marrow failure (n=1001, 17%) and hemoglobinopathies (n=885, 15%). The rate of unrelated donor transplants remained low, with only 2 non-umbilical cord matched unrelated donor (MUD) allo-HSCT reported. One hundred umbilical cord (UCB) transplants were reported (0.017% of allo- HSCT). Peripheral blood stem cells (PBSC) were the main source of graft in allo-HSCT, and PBSCT increasingly constitutes the main source of stem cells. Reduced intensity conditioning was utilized in 5.7% of allografts over the surveyed period. ASCT numbers continue to increase. There has been a shift in the indication for ASCT from acute leukemia to lymphoproliferative disorders (45%) followed by myeloma (26%). The survey reflects transplantation activity according to the unique health settings of this region. Notable differences in transplant practices as reported to the European Group for Blood and Marrow Transplantation (EBMT) over recent years are addressed.
PMCID: PMC3371191  PMID: 21440654
Hematopoietic stem cell transplantation; EMRO; stem cell source; conditioning
24.  Reduced Late Mortality Risk Contributes to Similar Survival after Double Unit Cord Blood Transplantation as Compared with Related and Unrelated Donor Hematopoietic Stem Cell Transplantation 
Cord blood transplantation (CB-T) is increasingly used as a treatment alternative for hematologic malignancies. However, how CB-T compares to related (RD-T) and unrelated donor transplantation (URD-T) is not established. We compared survival of 75 double unit CB-T, 108 RD-T, and 184 URD-T recipients transplanted over the same period for the treatment of hematologic malignancies. Patients had similar ages and disease-risk, and a similar percentage had acute leukemia. The incidence of day 180 transplant-related mortality (TRM) of 21% (95%CI:12-31) after CB-T was higher than that of RD-T recipients. However, this was compensated for by a low risk of TRM after day 180, and a relatively low incidence of relapse. Hence, the 2 year progression-free survival (PFS) of 55% (95%CI:45-68) after CB-T was similar to that after RD-T or URD-T (p = 0.573). In multivariate analysis, donor source had no influence on PFS, with the only significant factors being recipient age and disease-risk. In a sub-analysis of 201 patients with acute leukemia, CB-T, RD-T and URD-T recipients also had similar 2 year disease-free survival (p = 0.482). These data provide strong support for the further investigation of double unit CB grafts as an alternative hematopoietic stem cell source.
PMCID: PMC3156939  PMID: 21232625
25.  Platelet and Red Blood Cell Utilization and Transfusion Independence in Umbilical Cord Blood and Allogeneic Peripheral Blood Hematopoietic Cell Transplants 
Allogeneic hematopoietic cell transplantation (HCT) recipients have substantial transfusion requirements. Factors associated with increased transfusions and the extent of blood product use in umbilical cord blood (UCB) recipients are uncertain. We reviewed blood product use in 229 consecutive adult recipients of allogeneic HCT at the University of Minnesota: 147 with leukemia, 82 lymphoma or myeloma; 58% received unrelated UCB and 43% sibling donor peripheral blood stem cell (PBSC) grafts. Although neutrophil recovery was prompt (UCB median 17, range 2–45 days, and PBSC 14, range 3–34 days), only 135 of 229 (59% cumulative incidence, CI) achieved RBC independence and 157 (69%) achieved platelet independence by 6 months. Time to platelet independence was prolonged in UCB recipients (median UCB 41 vs. PBSC 14 days) and in patients who had received a prior transplant (median 48 vs. 32 days). Patients who received UCB grafts required more RBC through day 60 post HCT (mean UCB 7.8 (95% CI 6.7–8.9) vs. PBSC 5.2 (3.7–6.7) transfusions, p=0.04), and more platelet transfusions (mean 25.2 (95% CI 22.1–28.2) vs. 12.9 (9.4–16.4), p<0.01) compared to PBSC recipients. Patient receiving myeloablative (MA) conditioning required more RBC and platelet transfusions during the first 2 months post HCT compared to reduced intensity conditioning (RIC) (7.4 vs. 6.2, p=0.3 for RBC; 23.2 vs 17.5, p=0.07 for platelets). Despite prompt neutrophil engraftment, UCB recipients had delayed platelet recovery as well as more prolonged and costly blood product requirements. Enhanced approaches to accelerate multilineage engraftment could limit the transfusion-associated morbidity and costs accompanying UCB allotransplantation.
PMCID: PMC3010271  PMID: 20813199

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