HLA-matched Family Donor Research Articles

The Graft-vs-Host Hematopoietic Effect Generated after Nonmyeloablative Allogeneic Stem Cell Transplantation (NST) Cures Patients with Severe PNH.

Paroxysmal nocturnal hemoglobinuria (PNH) is a clonal disorder of hematopoietic stem cells characterized by RBC susceptibility to complement-mediated lysis. Infections related to neutropenia, bleeding associated with thrombocytopenia, and thrombosis all contribute to morbidity and mortality. Although allogeneic hematopoietic cell transplantation (HCT) can be curative, the high-risk of treatment-related mortality with myeloablative HCT precludes this approach for most patients with severe disease. We previously reported in vitro and in vivo data showing PNH cells could be killed by allo-reactive donor T-cells recognizing minor histocompatibility antigens expressed on both normal and GPI negative cells. Here we present updated data on a cohort of 11 patients with severe PNH who received a NST at the NHLBI from 5/99 through 6/2004. Eligibility included a diagnosis of PNH associated with one or more of the following :1) Transfusion dependence (n=9) 2) Prior thrombotic episodes (n=4) 3) Recurrent debilitating hemolytic crisis (n=7). Patients received a T-cell replete G-CSF mobilized blood stem cell transplant from an HLA-matched family donor following nonmyeloablative conditioning with cyclophosphamide (120mg/kg) and fludarabine (125mg/m2). Patients with a significant transfusion history had horse ATG (40mg/kg/day x 4) added to the conditioning regimen (n=9). CSA either alone (n=1) or combined with either MMF (n=4) or mini-dose methotrexate (n=6) was used as GVHD prophylaxis. The median % of GPI anchored protein negative neutrophils pre-transplant was 83% (range 13%–99%). Blood samples obtained post-transplant were analyzed by FACS to determine the percentage of persisting GPI negative neutrophils (CD15+/CD66b−/CD16−). Chimerism was also assessed post-transplant in T-cell and myeloid fractions by PCR assay of polymorphic short tandem repeats (STR).Neutrophil recovery occurred at a median 15 days (range 10–19). STR analysis revealed donor engraftment occurred in both myeloid and T-cell lineages in all patients. Self-limiting febrile hemolytic reactions associated with ATG administration (6/9 patients) and grade II-IV acute GVHD (n=5) were the most common complications associated with transplantation. With a median follow-up of 458 days (range 31–1917), all patients survive either in remission (n=8) or with declining GPI negative populations (n=3); GPI negative neutrophils were detected in all patients at engraftment but gradually declined until no longer detectable (<0.1%) in all 8 patients evaluable more than 100 days after transplantation, while 3 with shorter follow-up (days + 37, +51, +78) have persistent albeit rapidly declining PNH populations. The observation that GPI negative neutrophils populations decrease and ultimately disappear when myeloid chimerism transitions from mixed to full donor chimerism is consistent with PNH cells being eradicated through a graft-vs-host hematopoietic effect. None of the 7 patients with more than 1 year follow-up have had reoccurrence of their PNH clone. Conclusion: Alloreactive donor T-cells mediating graft-vs-host hematopoietic effects can immunologically eradicate PNH following NST. NST should be considered a viable and potentially curative option for patients with severe PNH.

Preliminary Results of Reduced Intensity Allogeneic Stem Cell Transplantation (RI ALLOSCT) followed by a Dose Escalation of Targeted Consolidative Immunotherapy with Gemtuzumab Ozogamicin (GO) in Pediatric Recipients with CD33+ AML.

Myeloablative (MA) AlloSCT has been successfully used to treat childhood AML but may be associated with significant toxicity and recurrent disease (Woods et al, Blood 2001). Reduced intensity (RI) AlloSCT may offer a less toxic approach to patients with AML/MDS (Taussig et al, J Clin Oncol 2003); however, RI may be associated with an increased risk of relapse. CD33, a sialic acid cell surface receptor, is expressed in 80% of AML, especially FAB subtypes M1-M6 (Sievers et al, Blood 1999). GO, a recombinant humanized CD33 antibody conjugated to calicheamicin, is internalized after binding to CD33, releasing calicheamicin and causing cell death. GO has induced responses in over 30% of adult patients with recurrent CD33+ AML but may be associated with liver sinusoidal obstructive syndrome (SOS), especially when used in combination with MA AlloSCT (Sievers et al, J Clin Oncol 2001). We therefore hypothesized that RI AlloSCT followed by GO might reduce overall toxicity compared to MA AlloSCT and reduce the relapse rate in pediatric patients with CD33+ AML. We are currently studying the feasibility and toxicity of RI AlloSCT followed by a dose escalation of GO (4.5, 6.0, 7.5 mg/m2 x 2 doses starting 8–10 weeks after AlloSCT), in pediatric patients with average risk AML. Four patients with CD33+ AML (M4/M5, M5, M4, and M0) in CR1 (3) and CR2 (1) were transplanted using a RI conditioning regimen of fludarabine 30 mg/m2 for 6 days, and busulfan 3.2 mg/kg (< 4 yrs, 4 mg/kg/day) for 2 days. GVHD prophylaxis consisted of tacrolimus and mycophenolate mofetil (Osunkwo/Cairo et al, BBMT 2004). The donor sources were: 2 6/6 HLA matched peripheral blood stem cell family donors, 1 6/6 sibling cord blood, and 1 4/6 unrelated cord blood. Day 30 and Day 60 donor chimerism for these patients were 98%, 98%, 98%, 14% and 95%, 85%, 92%, 0% respectively. All 4 patients had CR bone marrows on Day 60. Median time to ANC≥500/ml3 x 2 days and platelet count≥500/ml3 x 7 days, untransfused, was 15 days (7–17) and 11 days (1–42), respectively. The first 3 patients went on to receive consolidation therapy post AlloSCT with 1 (n=1) and 2 (n=2) doses of GO at dose level one, 4.5 mg/m2 followed by GM-CSF (250 mcg/m2/d until ANC≥2500); all patients tolerated RIAlloSCT without grade 3–4 toxicity. All patients experienced grade IV neutropenia following each dose of GO. ANC recovery after first GO was achieved on day 18, 14, and 18, and day 14 and 13, after the second dose. Grade IV thrombocytopenia was only observed with dose 1 in 1 patient. No patients have developed SOS and all have maintained >80% donor chimerism. In summary, the administration of GO post RI Allo in pediatric recipients with average risk AML is feasible and well tolerated with minimal toxicity. The MTD has yet to be determined for GO post RI AlloSCT for CD33+ AML. Studies are underway to determine the change, if any, in minimal residual disease (MRD) by WT1 gene expression before and after GO consolidation therapy post RI AlloSCT.

Unrelated-donor cord blood transplantation in patients with chronic myeloid leukemia

Despite the promising results with imatinib, allogeneic stem cell transplantation remains the only proven curative approach for patients with chronic myeloid leukemia (CML). This study reports the results of unrelated-donor cord blood transplantation (UD-CBT) in a series of 20 patients with CML treated in a single institution. Fourteen were in chronic phase (CP; 8 in CP1 and 6 in CP2), 2 in accelerated phase and 4 in blast crisis. Median age was 32 years (range, 16–46). Conditioning consisted of thiotepa, busulfan, cyclophosphamide and antithymocyte globulin, and GVHD prophylaxis of cyclosporine and prednisone. HLA match was 5/6 in 7 cases and 4/6 in 13. The median number of nucleated and CD34+ cells infused was 1.8 × 107/kg (range, 1.2–4.9) and 0.8 × 105/kg (range, 0.3–2.2), respectively. Median time to PMN above 0.5 × 109/L and to platelets above 20 × 109/L was 22 days (range, 10–52) and 69 days (range, 43–188), and the cumulative incidence of myeloid and platelet engraftment was 85% and 45%, respectively. Time to myeloid engraftment showed a direct relationship with the number of CFU-GM (P = .009) and CD34 cells (P = .02) infused. Platelet engraftment was faster in patients receiving a higher number of CFU-GM (P = .05), in those transplanted in CP (P = .04) and in those not developing acute GVHD above grade I (P = .001). Eight patients developed acute GVHD above grade II, and 7 of 11 patients at risk had extensive chronic GVHD. With a median follow-up of 49 months (range, 28–82), the probability of disease-free survival (DFS) at 3 years was 40% and was related to age (P = .01) and phase of the disease at transplant (P = .04). The probability of DFS at 3 years was 60% for patients younger than 31 years and 57% for those transplanted in CP. Six of 8 patients aged 30 years or younger and transplanted in CP remain alive and disease-free. These data suggest that UD-CBT is an acceptable alternative for younger patients with CML in CP requiring transplantation and lacking a HLA-matched family or unrelated bone marrow donor. Despite the promising results with imatinib, allogeneic stem cell transplantation remains the only proven curative approach for patients with chronic myeloid leukemia (CML). This study reports the results of unrelated-donor cord blood transplantation (UD-CBT) in a series of 20 patients with CML treated in a single institution. Fourteen were in chronic phase (CP; 8 in CP1 and 6 in CP2), 2 in accelerated phase and 4 in blast crisis. Median age was 32 years (range, 16–46). Conditioning consisted of thiotepa, busulfan, cyclophosphamide and antithymocyte globulin, and GVHD prophylaxis of cyclosporine and prednisone. HLA match was 5/6 in 7 cases and 4/6 in 13. The median number of nucleated and CD34+ cells infused was 1.8 × 107/kg (range, 1.2–4.9) and 0.8 × 105/kg (range, 0.3–2.2), respectively. Median time to PMN above 0.5 × 109/L and to platelets above 20 × 109/L was 22 days (range, 10–52) and 69 days (range, 43–188), and the cumulative incidence of myeloid and platelet engraftment was 85% and 45%, respectively. Time to myeloid engraftment showed a direct relationship with the number of CFU-GM (P = .009) and CD34 cells (P = .02) infused. Platelet engraftment was faster in patients receiving a higher number of CFU-GM (P = .05), in those transplanted in CP (P = .04) and in those not developing acute GVHD above grade I (P = .001). Eight patients developed acute GVHD above grade II, and 7 of 11 patients at risk had extensive chronic GVHD. With a median follow-up of 49 months (range, 28–82), the probability of disease-free survival (DFS) at 3 years was 40% and was related to age (P = .01) and phase of the disease at transplant (P = .04). The probability of DFS at 3 years was 60% for patients younger than 31 years and 57% for those transplanted in CP. Six of 8 patients aged 30 years or younger and transplanted in CP remain alive and disease-free. These data suggest that UD-CBT is an acceptable alternative for younger patients with CML in CP requiring transplantation and lacking a HLA-matched family or unrelated bone marrow donor.

Increase of interleukin-18 serum levels after engraftment correlates with acute graft-versus-host disease in allogeneic peripheral blood stem cell transplantation.

Acute graft-versus-host disease (GvHD) is a constant and severe complication after allogeneic stem cell transplantation regularly involving skin, liver, gut, and lungs. The cytokine interleukin-18 (IL-18) has been shown to increase in patients who develop acute GvHD after bone marrow tranplantation (BMT). Here, we measured IL-18 serum levels after peripheral blood stem cell transplantation (PBSCT) at several characteristic time points in 24 patients (median age 46 years). Patients received a median of 7.3 x 10(6)/kg bodyweight CD34-positive blood stem cells from HLA-matched family donors (n = 5), matched unrelated donors (n = 18), and one mismatched unrelated donor. GvHD prophylaxis consisted of cyclosporin A alone or combined with methotrexate and/or mycophenolate mofetil. In 14 patients we observed no GvHD or only GvHD grade I whereas ten patients developed GvHD grade II-IV post transplant. Low, intermediate, and high levels of serum IL-18 were found in patients after allogeneic PBSCT independently of GvHD after transplantation. In contrast to GvHD arising after BMT, there was no clear correlation between absolute IL-18 serum levels and GvHD grade after PBSCT. However, the individual time course of IL-18 serum level after engraftment correlates with acute GvHD after PBSCT. In detail, an increase of serum IL-18 of at least 1.6-fold after engraftment is associated with acute GvHD II or higher with a sensitivity of three out of four. Using the 1.6 "cut-off" for IL-18 increase after engraftment, a specificity of up to 100% can be achieved. The time course of IL-18 serum levels might be used for GvHD prediction after PBSCT comparable to absolute serum levels after BMT.

Unrelated donor marrow transplantation for congenital immunodeficiency and metabolic disease: an update of the experience of the Japan Marrow Donor Program.

We retrospectively analyzed the clinical results of 81 patients with congenital genetic diseases who were treated with bone marrow transplantation (BMT) from unrelated donors identified through the Japan Marrow Donor Program. The patients were aged between 1 and 38 years (median, 4 years). Thirty-five patients underwent transplantation for metabolic disease (MD), ie, mucopolysaccharidosis (n = 25), adrenoleukodystrophy (n = 7), and others (n = 3). The remaining 46 patients had Wiskott-Aldrich syndrome (n = 16), hemophagocytic syndrome including the inherited type (n = 9), severe combined immunodeficiency (n = 6), hyper-IgM syndrome (n = 4), Chédiak-Higashi syndrome (n = 3), Kostmann syndrome (n = 3), and others (n = 5). Fifty-two donor-patient pairs were fully matched at HLA-A, HLA-B, and HLA-DRB1 alleles. The remaining 24 patients received allele-mismatched grafts (20 matched at 5 of 6 loci and 4 matched at 4 of 6 loci). Engraftment occurred in 82.4% of the MD group and 90.7% of the other genetic disease (OGD) group; however, 14 patients (18.2%) experienced either early or late graft failure. The cumulative incidence of grade II to IV acute graft-versus-host disease (GVHD) was 35.5% - 9.8% in the MD group and 47.3% - 9.5% in the OGD group, and the rate of chronic GVHD was 20% in both groups. Forty-nine patients have survived for 3 to 96 months (median, 20 months). The probabilities of 5-year overall survival and event-free survival were 72.6% - 11.5% and 65.3% - 8.6%, respectively, for MD (n = 35) and 72.5% - 7.3% and 63.6% - 7.3% for OGD (n = 46). Although patient status before BMT and the occurrence of grade III to IV acute GVHD significantly affected outcome, unrelated BMT is a curative therapeutic option for children with congenital genetic diseases who have no HLA-matched family donors.

Dose-escalated donor lymphocyte infusions following reduced intensity transplantation: toxicity, chimerism, and disease responses

AbstractData on the application of donor lymphocyte infusions (DLIs) following reduced-intensity transplantation (RIT) remain limited. Persistence of host antigen-presenting cells might increase the efficacy or toxicity of cellular immunotherapies. We report the results of dose-escalating DLIs in 46 patients undergoing RIT, who received a total of 109 infusions to treat mixed chimerism or residual or progressive disease. Diagnoses were myeloma (n = 19), Hodgkin lymphoma (n = 13), non-Hodgkin lymphoma (n = 10), and other (n = 4). Thirty-two had an HLA-matched family donor and 14 an unrelated donor. Grades II to IV graft-versus-host disease (GVHD) occurred in 5 sibling and 7 unrelated donor recipients. GVHD was more common (P = .002), occurred at lower T-cell doses, and was more severe in the unrelated donor cohort. Conversion from mixed to multilineage full donor chimerism occurred in 30 of 35 evaluable patients. Presence of mixed chimerism in the granulocyte lineage at the time of DLI did not predict for chimerism response or GVHD. Disease responses occurred in 63% of patients with myeloma and 70% of those with Hodgkin lymphoma and were not predicted by changes in chimerism. These data support the presence of clinically relevant graft-versus-Hodgkin activity and indicate that DLI may be associated with a significantly increased toxicity in unrelated compared to sibling donor transplant recipients receiving identical treatment protocols.

In vitro and in vivo evidence of PNH cell sensitivity to immune attack after nonmyeloablative allogeneic hematopoietic cell transplantation

AbstractIt has been proposed that paroxysmal nocturnal hemoglobinuria (PNH) cells may proliferate through their intrinsic resistance to immune attack. To evaluate this hypothesis, we examined the impact of alloimmune pressure on PNH and normal cells in the clinical setting of nonmyeloablative allogeneic hematopoietic cell transplantation (HCT). Five patients with severe PNH underwent HCT from an HLA-matched family donor after conditioning with cyclophosphamide and fludarabine. PNH neutrophils (CD15+/CD66b–/CD16–) were detected in all patients at engraftment, but they subsequently declined to undetectable levels in all cases by 4 months after transplantation. To test for differences in susceptibility to immune pressure, minor histocompatibility antigen (mHa)–specific T-cell lines or clones were targeted against glycosylphosphatidylinositol (GPI)–negative and GPI-positive monocyte and B-cell fractions purified by flow cytometry sorting. Equivalent amounts of interferon-γ (IFN-γ) were secreted following coculture with GPI-negative and GPI-positive targets. Furthermore, mHa-specific T-cell lines and CD8+ T-cell clones showed similar cytotoxicity against both GPI-positive and GPI-negative B cells. Presently, all 5 patients survive without evidence of PNH 5 to 39 months after transplantation. These in vitro and in vivo studies show PNH cells can be immunologically eradicated following nonmyeloablative HCT. Relative to normal cells, no evidence for a decreased sensitivity of PNH cells to T-cell–mediated immunity was observed.

A pilot study of reduced intensity conditioning and allogeneic stem cell transplantation from unrelated cord blood and matched family donors in children and adolescent recipients.

Reduced intensity (RI) allogeneic stem cell transplantation (AlloSCT) was initially demonstrated in adults following HLA-matched family and unrelated adult donor AlloSCT. There is little information about RI AlloSCT in children. We report results of a pilot study of RI AlloSCT in 21 recipients (< or =21 years). Age: median 13 (0.5-21) years, 8F:13M, 14 unrelated cord blood units (UCB) (10 4/6, 4 5/6), two related BM (6/6, 5/6), four related PBSC (2 6/6, 2 5/6), and one related BM+PBSC (6/6). RI: fludarabine, busulfan (n=14); fludarabine, cyclophosphamide (n=4); fludarabine, melphalan (n=1); total body irradiation, fludarabine, cyclophosphamide (n=1); or fludarabine, cyclophosphamide, and etoposide (n=1). Graft-versus-host disease prophylaxis: FK506 0.03 mg/kg/day and mycophenolate mofetil 15 mg/kg/q 12 h. UCB median nuc/kg and CD34/kg was 4.3 x 10(7)/kg (0.9-10.8) and 1.9 x 10(5)/kg (0.3-6.9), and related BM/PBSC median nuc/kg and CD34/kg was 8.3 x 10(8) (4.7-18.9) and 5.0 x 10(6)/kg (4.6-6.4). Maximal chimerism following unrelated cord blood transplantation, 100% x 7, 98% x 1, 95% x 2, 55% x 1, and 0% x 3; related PBSC/BM, 100% x 5, 65% x 1, and 55% x 1. Graft failure occurred in 5/21 (24%). In summary, RI AlloSCT in children is feasible and tolerable (< or =25% GF) and results in > or =85% of recipients initially achieving > or =50% donor chimerism.

Juvenile myelomonocytic leukemia.

Juvenile myelomonocytic leukemia is an aggressive neoplasia of early childhood. Only allogeneic stem cell transplantation (SCT) offers long-term cure. In the absence of an HLA-matched family donor, early SCT from an unrelated donor is the treatment of choice for most children. With clear evidence of a graft-versus-leukemia effect and a high post-transplant relapse rate, the outcome of SCT depends, in part, on the management of immunosuppression during the procedure. The impact of pretransplant cytoreductive treatment, such as intensive chemotherapy, splenectomy, or 13-cis retinoic acid, is unclear. Hypersensitivity for granulocyte-macrophage colony-stimulating factor and pathologic activation of the Ras/MAPK pathway play an important role in the pathophysiology of juvenile myelomonocytic leukemia and provide the opportunity for several novel therapeutic approaches.

Hematopoietic stem cell transplantation: contrasting the outcome of transplantations from HLA-identical siblings, partially HLA-mismatched related donors, and HLA-matched unrelated donors

AbstractAllogeneic hematopoietic stem cell transplantation (HSCT) is a proven curative therapy for many hematologic malignancies. HSCT from HLA-identical sibling donors (ISDs) is still the golden standard. For the remaining 70% of the patients lacking an ISD, alternative (partially) HLA-matched family donors (MFDs) and HLA-matched unrelated donors (MUDs) are now widely accepted. However, it is presently unclear whether outcome after HSCT from an MFD or an MUD is superior. Thus, the classical clinical end points after HSCT from an ISD (n = 138), MFD (n = 86), and MUD (n = 101) were compared by means of univariate and multivariate statistical analyses. MFD transplantations with HLA class II (DRB1 ± DQB1) mismatches in graft-versus-host (GVH) direction showed an increased risk of grades II to IV graft-versus-host disease, and MFD transplantations with more than a single HLA class I (A ± B ± C) mismatch in host-versus-graft (HVG) direction were associated with a higher risk of graft failure. However, no significant difference in overall survival was detectable among the 3 study groups after adjustment for the main predictors of transplantation outcome. Thus, for patients lacking an ISD, an already identified MFD with an HLA-DRB1 ± DQB1 mismatch in GVH or a combined HLA-A ± B ± C mismatch in HVG direction should be accepted only in clinically urgent settings that leave no time to identify an MUD.

A prospective analysis of immune recovery in children following allogeneic transplantation of t-cell-depleted or non-T-cell-depleted hematopoietic cells from HLA-disparate family donors

Transplantation of HLA-disparate hematopoietic stem cells from related donors is an alternative for the treatment of patients lacking an HLA-matched family or unrelated donor. In the cases of a single HLA antigen disparity, extensive T-cell depletion (TCD) is not required, yet antithymocyte globulin (ATG) must be administered to prevent GvHD or graft rejection. The major concern after HLA-mismatched transplants remains immune reconstitution. Therefore, we prospectively studied the recovery of lymphocyte subsets among 22 children transplanted from partially HLA-matched family donors. We compared two groups of patients: (1) the TCD group included children (n = 1.3) who received grafts after TCD (MACS) due to an HLA disparity for more than one antigen; (2) The non-TCD group included children with either one HLA-mismatched antigen, n = 7; or more than one disparate antigen (n = 2) who received T-cell-repleted grafts and ATG. The study demonstrated rapid NK cell reconstitution among the TCD group. TCD compromised T-cell reconstitution, thus preventing GvHD, but resulting in a higher incidence of severe infectious complications, graft rejection, and disease relapse. Increasing mixed chimerism required the application of donor T-cell addbacks, thus potentiating the risk of GvHD. Primary graft rejection occurred in eight children, who required further transplants. In the non-TCD group faster T-cell reconstitution (predominantly CD3+CD8+ cells) resulted in a lower rate of relapse and infection, yet a higher rate of GvHD, including two fatal cases. Due to improved immune reconstitution, in spite of an increased risk of GvHD, non-TCD transplants from single HLA-mismatched family donors remain a valuable option for children without matched donors.

Juvenile myelomonocytic leukemia.

Juvenile myelomonocytic leukemia is an aggressive neoplasia of early childhood. Only allogeneic stem cell transplantation (SCT) offers a long-term cure. In the absence of an HLA-matched family donor, early SCT from an unrelated donor will be the treatment of choice for most children. With clear evidence of a graft-versus-leukemia effect and a high post-transplant relapse rate, outcome of SCT will depend, in part, on the management of immunosuppression during the procedure. The impact of pretransplant cytoreductive treatment, such as intensive chemotherapy, splenectomy, or 13-cis retinoic acid, is unclear. Hypersensitivity for granulocyte-macrophage colony-stimulating factor and pathologic activation of the Ras/MAPK pathway play an important role in the pathophysiology of juvenile myelomonocytic leukemia and will provide the opportunity for several novel therapy approaches.

Place of hematopoietic stem cell transplantation in the treatment of myelodysplastic syndromes

Allogeneic hematopoietic stem cell transplantation from HLA-matched family or unrelated donors is currently the only potentially curative therapy. Outcome is determined by disease-, patient- and treatment-related features, which will be discussed in this review. Autologous transplantation is an alternative approach for patients which lack a suitable allogeneic stem cell donor. Autografts should be harvested in complete remission after intensive chemotherapy. Reduced treatment-related mortality is accompanied by increased risk of relapse. Clinical trials are currently evaluating dose-modified preparative regimens with decreased toxicity, which offer transplantation options also to older patients or patients with comorbidities.

Bone marrow transplantation for beta-thalassemia: the University of California San Francisco experience.

We report the results of allogeneic HLA-matched family donor stem cell transplantation in 17 North American children with beta-thalassemia major or hemoglobin E/beta-thalassemia who received transplants at the University of California San Francisco. Pretransplantation conditioning was with busulfan, cyclophosphamide, and antithymocyte globulin and graft-versus-host prophylaxis used cyclosporine, usually with added methotrexate. Twelve children are alive, well, and free of the clinical manifestations of thalassemia. Four experienced graft rejection and autologous recovery, and one died from complications shortly after transplantation. Overall survival was 94% and event-free survival 71%, results similar to those obtained by other transplantation centers. Improved conditioning regimes and enlargement of the donor pool will be needed to improve the outcome of transplantation and to make this treatment available to more children with thalassemia.

Placental/umbilical cord blood (PCB) stem cells for transplantation: early clinical outcomes and the status of ex vivo expansion strategies.

Placental/umbilical cord blood (PCB) stem cells for transplantation provide a potentially useful alternative for patients who do not have an HLA-matched family or unrelated bone marrow donor. Concerns regarding this source of stem cells include the limited number of stem cells in a PCB unit and the delayed time to platelet engraftment. Because of the limited number of stem cells, there is a very clear cell dose effect for both success of engraftment and time to engraftment. As a result, many transplant centers will only consider PCB stem cells as a second choice for transplanting adults, despite the very favorable profile of post-transplant graft-versus-host disease (GvHD). This has resulted in considerable interest in the development of ex vivo stem cell expansion strategies. This review outlines the current status of PCB transplant outcomes as well as the status of our understanding of stem cell expansion with the currently available technologies. A stem cell dose-limiting effect on outcome will result in a narrower window of clinical indications for the use of this stem cell source, despite the acknowledged reduction in GvHD. The trade-offs between poor engraftment and reduction in fatal or severe chronic GvHD remain to be quantitated.