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Also see RELATED-DONOR CORD BLOOD TRANSPLANTS and REVIEWS
i. MALIGNANT DISORDERS
1. Outcomes of transplantation of unrelated donor umbilical cord blood and bone marrow in children with acute leukemia: a comparison study. Eapen M, Rubinstein P, Zhang MJ, Stevens C, Kurtzberg J, Scaradavou A, Loberiza FR, Champlin RE, Klein JP, Horowitz MM, Wagner JE. Lancet. 2007;9;369(9577): 1947-54. 
Allele-matched bone marrow is generally regarded as the preferred graft source. The aim of this study was to compare the leukemia-free survival after hematopoietic cell transplantation using allele-matched BMT and unrelated donor umbilical cord blood. These alternatives were compared utilizing present HLA-matching practices. The authors also assessed the relative effect of cell dose and HLA match, and their potential interaction on leukemia-free survival after cord-blood transplantation.
Outcomes of 503 children (<16 years) with acute leukemia and transplanted with umbilical cord blood were compared with outcomes of 282 bone-marrow recipients. All transplantation took place in the USA. Recipients of umbilical cord blood were transplanted with grafts that were HLA-matched (n=35) or HLA-mismatched for one (n=201) or two antigens (n=267) (typing at antigen level for HLA-A and HLA-B, and allele level for HLA-DRB1). Bone-marrow recipients were transplanted with grafts that were matched at the allele level for HLA-A, HLA-B, HLA-C, and HLA-DRB (n=116), or mismatched (n=166). The primary endpoint was 5-year leukemia-free survival.
In comparison with allele-matched bone-marrow transplants, 5-year leukemia-free survival was similar to that after transplants of umbilical cord blood mismatched for either one or two antigens and possibly higher after transplants of HLA-matched umbilical cord blood. Transplant-related mortality rates were higher after transplants of two-antigen HLA-mismatched umbilical cord blood (relative risk 2.31, p=0.0003) and possibly after one-antigen HLA-mismatched low-cell-dose umbilical-cord-blood transplants (1.88, p=0.0455). Relapse rates were lower after two-antigen HLA-mismatched umbilical-cord-blood transplants (0.54, p=0.0045). Treatment failure rates after transplantation of matched cord blood, one- or two-antigen mismatched cord blood and allele-mismatched bone marrow were similar to those of allele-matched bone marrow.
Interstitial pneumonitis and infections were frequent causes of early mortality after mismatched cord-blood transplants, but death from organ failure was more common after bone-marrow transplants than after cord-blood transplants. The proportions of early deaths due to recurrent leukemia and GVHD were similar in both groups.
The authors interpreted these data to support the use of HLA-matched and one- or two-antigen HLA-mismatched umbilical cord blood in children with acute leukemia who need transplantation. Because better HLA matching and higher cell doses significantly decrease the risk of transplant-related mortality after umbilical-cord-blood transplantation, greater investment in large-scale banking is needed to increase HLA diversity.
2. Outcomes of transplantation in children with acute leukaemia. Rocha V, Gluckman E. Lancet. 2007;369(9577):1906-1908.
This article is a commentary on an article by Eapen et al. (Outcomes of transplantation of unrelated donor umbilical cord blood and bone marrow in children with acute leukemia: a comparison study. Lancet. 2007;9;369(9577): 1947-1954) The Eapen article is posted above, citation #1.)
Umbilical cord blood (UCB) has made allogeneic hematopoietic stem-cell transplantation available to patients who do not have an HLA-identical sibling or an unrelated donor. [Comment: UCB transplants are also increasingly used even if a matched, unrelated donor is available, especially in children.] More than 10,000 cord blood transplants in children and adults have been performed for various genetic, hematological, or immunological disorders.
The authors point out that even in children given an HLA allele-matched bone marrow unrelated graft (eight of eight), leukemia-free survival was not statistically significantly different from one or two HLA-mismatched umbilical cord blood transplantations compared with a HLA-allele-matched bone marrow, and that probably an HLA-matched recipient of umbilical cord blood had better outcomes than did an HLA-matched bone-marrow recipient. However, transplant-related mortality was increased in children transplanted with a low cord blood cell dose (<3 x 107/kg) and one HLA-mismatched cord blood graft, or in children given two HLA-mismatched cord blood transplants, independently of cell dose.
Therefore the recommended dose for choosing a cord blood unit should be more than 3 x 107 nucleated cells per kg or more than 2 x 105 CD34+ cells per kg. Additionally, the cell dose should be increased with the number of HLA mismatches. Cell dose should not be regarded as a limiting factor for cord blood graft acquisition, because of encouraging results of double cord blood transplantations and other efforts to improve engraftment. However, better HLA matching will only be possible by increasing the cord blood inventory and the quality of cord blood banked units.
3. Is it time to expand the use of cord blood donor transplantation in relapsed ALL? Kurtzberg J. Pediatr Blood Cancer. 2005;45:874-5.
This commentary is inspired by the publication of Sawczyn et al (see citation # 4, below). Although the majority of newly diagnosed children with ALL can be cured with standard chemotherapy, the treatment of patients with very high-risk disease or those who relapse remains both controversial and generally disappointing. Allogeneic transplantation is indicated for children with very high-risk disease and for those who relapse on therapy and achieve a second remission. However, for the patients lacking a matched-related donor, there is reluctance to refer for unrelated transplantation until it is obvious that the patient cannot be cured with standard therapy alone.
Another obstacle to early transplantation is the belief that a matched unrelated adult donor is superior to a partially mismatched unrelated cord blood transplant. Often the search for a perfectly matched unrelated adult donor goes on for months and months during which time the child relapses and either is no longer a candidate for transplant or goes to transplant with a poorer prognosis.
The report by Sawczyn et al provides data on 26 consecutive children with high risk or relapsed ALL in 1st, 2nd or 3rd CR who were transplanted with partially mismatched unrelated donor umbilical cord blood (except one related transplant. After a median of 528 days, 62% of the children are surviving event-free. In multivariate analysis, cell dose was the strongest predictor of survival. Patients receiving a low dose of UCB cells (<3 x 107 cells/kg) had dramatically lower EFS rates (15-20%) as compared to those receiving >3 x 107 cells/kg (>90% EFS [P = 0.007].
These results are excellent for children with ALL undergoing allogeneic, unrelated transplantation. The fact that only 4 of 20 evaluable children relapsed (20%) suggests that cord blood can confer a graft-versus-leukemia effect without intolerable GVHD.
Since 1993, over 5,000 unrelated donor cord blood transplants have been performed world wide. Knowledge about donor selection, preparative regimens, GVHD prophylaxis, and supportive care is expanding. Given current results, pediatric oncologists treating children with high risk or relapsed ALL must think of referring their patients for unrelated donor cord blood transplantation earlier in the course of their disease when their chances for success are best. Cord blood donors are readily available and easily procured. A donor unit can be made available within 1-2 weeks. Waiting for a closer HLA match or choosing a low cell dose donor to achieve a closer HLA match does not appear to be the best strategy.
4. Cord blood transplant in childhood ALL. Sawczyn KK, Quinones R, Malcolm J, Foreman N, Garrington T, Gore L, Gao D, Giller R. Pediatr Blood Cancer. 2005;45:964-70.
Allogeneic hematopoietic stem cell transplant (HSCT) has been used as a strategy to augment therapy for patients in initial remission (CR1) who are predicted to be at high risk of treatment failure if managed by chemotherapy alone, or for patients who have suffered relapses of their disease. A recent review of survival of patients with bone marrow relapses occurring within 3 years of initial diagnosis has suggested poor outcomes regardless of treatment strategy. Chemotherapy and matched unrelated donor (MUD) HSCT have had limited success in salvaging such patients. The former is limited by higher rates of relapse, whereas transplant-related mortality (TRM) compromises MUD HSCT outcomes. In addition, there are limitations in donor availability with MUD HSCT due to the stringency of HLA-matching required between donor and recipient. Therefore, cord blood transplant (CBT) is being explored as a now widely available, alternative stem cell source. In comparison to obtaining unrelated cord blood for HSCT, the donor identification process for MUD HSCT may be quite lengthy, extending time to transplant as a consequence. Increased interest in the use of CBT has prompted umbilical cord blood banks to be established worldwide and now there is a wide availability of donor products. Since 1998, all cord blood donor searches for patients with ALL at the authors' institution have resulted in HSCT when clinically indicated.
In this study, the authors evaluated 26 consecutive cord blood transplants (CBT) for ALL performed using consistent conditioning therapy and graft-versus-host disease (GVHD) prophylaxis. Median patient age was 8.5 years (range, 0.5-24 year). Cord blood (CB) was from unrelated donors in 25/26 cases. Median CB nucleated cell dose was 3.26 x 107/kg (range, 0.8-12.9). With median follow-up of 548 days, 16/26 patients (62%) are event-free survivors. Acute GVHD developed in 14/24 evaluable patients, reaching grade III-IV in 7 patients. Chronic GVHD occurred in 10/22 evaluable patients. Multivariate analysis showed higher total nucleated cell dose per kilogram to be the strongest predictor of event-free survival.
The conclusion reached by the authors was that their results suggest that CBT is an effective therapy for patients with high risk or recurrent ALL. The findings are more optimistic than much of the historically reported data, which are quite pessimistic regarding the potential for cure of high risk or refractory ALL by chemotherapy retreatment alone.
When an HLA-matched sibling donor is unavailable, CBT may offer advantages over MUD HSCT as the preferred method of HSCT because of the ability to accept lesser degrees of HLA-matching, consequent increase in available donors, and shorter time to HSCT. These encouraging results with respect to EFS using cord blood donors may derive from limited TRM while maintaining a low relapse rate.
5. Total body irradiation, fludarabine, melphalan, and allogeneic hematopoietic stem cell transplantation for advanced pediatric hematologic malignancies. Petropoulos D, Worth LL, Mullen CA, Madden R, Mahajan A, Choroszy M, Ha CS, Champlin RC, Chan KW. Bone Marrow Transplant. 2006; 37:463-7.
The authors evaluated the efficacy and toxicity of adding 9 Gy of total body irradiation (TBI), in three single daily fractions of 3 Gy, to the reduced intensity regimen of fludarabine 30 mg/m2 i. v. x 4 days and melphalan 140 mg/m2 i. v. x 1 day in advanced pediatric hematologic malignancies. Twenty-two acute lymphoblastic leukemia (ALL), six acute myeloid leukemia (AML), and one non-Hodgkin lymphoma patients were transplanted. Of these, 13 were beyond second remission, and five had prior hematopoietic stem cell transplant (HSCT). Twenty-one donors were unrelated, of which 19 were from cord blood (CB) units. Three of the eight related donors were genotypically disparate. Oral mucositis and diarrhea were the most common toxicities.
Twenty-seven patients achieved neutrophil engraftment (median 16 days), and 23 had platelet engraftment (median 42 days). One patient had primary graft failure. Seven patients died of non-relapse causes in the first 100 days. With a median follow-up of 52 months, seven of 22 ALL, five of six AML, and one of one lymphoma patients are alive and in remission.
The authors concluded that the regimen of TBI, fludarabine, and melphalan allows the engraftment of allogeneic hematopoietic stem cells (including mismatched CB). It was fairly well tolerated in pediatric patients, even for second transplants. Its efficacy requires further evaluation.
6. Busulfan/Melphalan/Antithymocyte Globulin Followed by Unrelated Donor Cord Blood Transplantation for Treatment of Infant Leukemia and Leukemia in Young Children: The Cord Blood Transplantation Study (COBLT) Experience. Wall DA, Carter SL, Kernan NA, Kapoor N, Kamani NR, Brochstein JA, Frangoul H, Goyal RK, Horan JT, Pietryga D, Wagner JE, Kurtzberg J. Biol Blood Marrow Transplant. 2005;11:637-46.
Although allogeneic transplantation offers potentially curative therapy to children and adults with otherwise untreatable malignancies, only a fraction of patients will have an HLA-matched donor in their family. Networks of unrelated volunteer donors have been established to provide an alternative donor source for those without family donors. However, with current HLA matching requirements, there remain a large proportion of patients for whom an unrelated volunteer donor is not identified in a timely fashion. Allogeneic transplantation from unrelated marrow donors is more frequently complicated by severe graft-versus-host disease (GVHD) or graft rejection.
Most prior studies with CBT have focused on total body irradiation (TBI)-based preparative regimens. There was interest in evaluating a non-TBI regimen for patients unable to tolerate TBI because of pretransplantation toxicity and leukemia patients <4 years of age. One stratum of the COBLT trial was to investigate the safety and efficacy of busulfan, melphalan, and antithymocyte globulin (ATG) as an alternative conditioning regimen to TBI.
Thirty-eight patients with leukemia or myelodysplastic syndrome (MDS) were enrolled in the study. The article presents the outcome of transplantations in the 32 children <4 years old who were enrolled on the trial. Within that subset, infant leukemia was defined as all cases diagnosed as leukemia before 6 months of age or diagnosed before 12 months of age with cytogenetic rearrangements carrying the mixed lineage leukemia gene.
The cumulative incidence (CINC) of neutrophil recovery (absolute neutrophil count >500/µL) at day 42 was 0.59 (95% confidence interval [CI], 0.44-0.78) at a median of 31 days (range, 23-55 days). The CINC and Kaplan-Meier estimates of platelet engraftment at day 180 were 0.53 (95% CI, 0.34-0.69) and 0.82 (95% CI, 0.61-1.00), respectively. CINC estimates of grade III/IV acute GVHD at day 100 and chronic GVHD at 1 year were 0.25 (95% CI, 0.09-0.41) and 0.26 (95% CI, 0.09-0.44), respectively. The CINC estimate of relapse was 0.31 (95% CI, 0.16-0.47) at 2 years. With a median follow-up of 27.8 months (range, 23.4-46.7 months), the probability of survival at 1 year was 0.47 (95% CI, 0.30-0.64).
The authors state that, in this small cohort, relapse and relapse-free survival were similar between patients in CR1 and those in CR2 and beyond. On the basis of current results with improved outcome in front-line chemotherapy and the reasonable salvage with CBT in CR2, it is reasonable to consider CBT for infant acute leukemia in CR1 for those who are at high risk for relapse and who would be unlikely to enter a second remission should relapse occur. The benefit of CBT over a volunteer unrelated stem cell donor is that the time to donor identification is short, thus allowing transplantation immediately after reinduction/consolidation.
[Note: As an incidental finding, these authors found that high-resolution molecular HLA typing for HLA-A, -B, and -DRB1, performed in retrospect, correlated with improved survival. Such a finding is in apparent disagreement with the data presented by Kogler et al (See Annotated Bibliography IX, HLA matching, citation #5) who reported that high-resolution HLA typing by sequencing for HLA-A, -B, -C, -DR, -DQ in 122 unrelated cord blood/patient pair transplants hardly improves long-term clinical outcome.]
7. Outcomes of unrelated cord blood transplants and allogeneic-related hematopoietic stem cell transplants in children with high-risk acute lymphocytic leukemia. Jacobsohn DA, Hewlett B, Ranalli M, Seshadri R, Duerst R, Kletzel M. Bone Marrow Transplant. 2004;34:901-7.
The authors pointed out that, in publications describing outcomes of children with leukemia who underwent unrelated cord blood (UCB) transplants compared to results using unrelated donor marrow transplants, the results are similar. In this study, the authors compared outcomes using UCB vs. allogeneic-related hematopoietic stem cells in pediatric ALL patients since 1992. A total of 49 patients were analyzed. All patients were either in CR1 with high-risk features (n=21) or in CR2 (n-28). In all, 23 patients underwent allogeneic-related bone marrow transplants and 26 underwent UCB transplantation. Other than increased time to engraftment for the UCB recipients, results are equivalent. The 3-year overall survival is 64% and 3-year event-free survival is 60% for both groups. Rates of GVHD and transplant-related mortality are also equivalent. The delayed hematopoietic reconstitution did not appear to adversely affect these patients, as the TRM was not statistically different when compared to the allogeneic-related transplants.
Notably, most UCB grafts were mismatched at one or two HLA alleles, with almost half of them being two allele mismatches. The median nucleated cell dose or UCB transplants was 0.58 x 108/kg and the median neutrophil and platelet engraftment was 29 and 51 days, respectively. The authors suggest that their favorable results may be due to the strategy (since 1988) of selecting UCB units with a high cell count.
The authors concluded that for children with high-risk ALL in CR1 or children with ALL with initial remission less than 36 months in CR2, an unrelated cord blood transplant provides equivalent long-term results when compared to the gold standard – a matched-sibling transplant.
The policy at the authors' institution for patients without an HLA-identical sibling is that if there is a UCB unit that has 2 or fewer HLA mismatches and a cell count greater than 4.0 x 107 TNC/kg, the patient will receive a UCB transplant instead of an unrelated donor marrow transplant.
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