5. Comparative single-institute analysis of cord blood transplantation from unrelated donors with bone marrow or peripheral blood stem cell transplantation from related donors in adult patients with hematological malignancies after myeloablative conditioning regimen. Takahashi S, Ooi J, Tomonari A, Konuma T, Tsukada N, Oiwa-Monna M, Fukuno K, Uchiyama M, Takasugi K, Iseki T, Tojo A, Yamaguchi T, Asano S. Blood 2007; 109:1322-1330.

The authors studied the outcomes of 171 adults with hematological malignancies who received unrelated cord blood transplantation (CBT) as a primary unrelated stem cell source (n=100), or bone marrow transplantation (BMY) or peripheral blood stem cell transplantation (PBSCT) from unrelated donors (n=71, 55 BMT and 16 PBSCT). All patients received myeloablative regimens including 12 Gy TBI. The authors analyzed the hematological recovery, risks of GVHD, transplant-related mortality (TRM) and relapse, and disease-free survival (DFS).

Significant delays in engraftment occurred after CBT; however, overall engraftment rates were almost the same for both grafts. The cumulative incidences of grades III to IV aGVHD and extensive cGVHD among CBT recipients were significantly lower than those among BMT/PBSCT recipients. Multivariate analysis demonstrated no apparent differences in TRM (9% in CBT and 13% in BMT/PBSCT), relapse (17% in CBT and 26% in BMT/PLBSCT) and DFS (70% in CBT and 60% in BMT/PBSCT) between both groups.

The authors concluded that the data suggest that unrelated cord blood could be as safe and effective a stem cell source as related bone marrow or mobilized peripheral blood for adult patients when it is used as a primary unrelated stem cell source.

The authors speculated on the possible reasons for their favorable results in CBT. (1) One reason might be the availability of grafts containing sufficient numbers of cells --- only 7 patients received cord blood grafts containing <2 x 10⁷ NC/kg among the 100 CBT recipients. (2) Secondly, Japanese patients might have some advantages in the setting of HLA-mismatched transplantation due to HLA or non-HLA immune genetics. Indeed, there is mounting evidence indicating that polymorphisms in non-HLA immune mediators and host defense genes, such as tumor necrosis factor, interleukin-10, or their receptor genes, could affect the severity of GVHD. (3) The preparative conditioning and GVHD prophylaxis regimens used in this study might also have been favorable factors. (4) The quick availability of cord blood as a stem cell source is thought to be one of the most important advantages compared with unrelated bone marrow grafts. If the patient was eligible for allogeneic transplantation but had no related donor, the authors generally selected a cord blood graft first, rather than waiting for the results of an unrelated marrow donor search. In fact, CBTs were performed at the same timing as BMT/PBSCT from a related donor.

6. Umbilical cord blood transplantation and banking. Brunstein CG, Wagner JE. Annu Rev Med. 2006;57:403-17.

This is a thorough yet concise review from a leading center of umbilical cord blood transplantation.

Although there are currently seven million adult volunteers registered worldwide, one third of patients still will not find a suitably HLA-matched unrelated donor and thus cannot access this potentially curative therapy. If the patient belongs to an ethnic minority, the probability of not finding an HLA-matched donor is even greater. Moreover, because the search process often takes weeks to months, a significant proportion of patients will die, become higher-risk, or become ineligible for transplantation altogether while they wait for the completion of the donor search. As umbilical cord blood (UCB) units are HLA-typed, tested for infectious agents, and stored, they are immediately available upon request and can be shipped to any transplant center in the world with relative ease. UCBT is associated with a low incidence of acute GVHD, and partial HLA match between the donor and recipient is tolerable.

UCB, however, has limitations. First, multiple registry and single-center analyses have shown that the number of progenitor cells is important in engraftment and survival. The lower the cell dose, the poorer the outcome. Because the cell dose in a single unmanipulated UCB unit is fixed, most adults are denied routine access to UCB. A second obstacle is the inability to go back to the donor to collect lymphocytes or additional HSC, in case of disease progression or relapse, or graft failure. Third, there is substantially less experience with UCBT than with bone marrow transplant (BMT), particularly in adult patients.

UCB transplantation in children: At pediatric centers, the frequency of transplantation of UCB is rapidly approaching that of bone marrow and has surpassed that of PBSC. Clinical studies demonstrate slower but complete hematopoietic reconstitution in the majority of patients. Although factors associated with the speed of neutrophil recovery have varied between reports, most include nucleated cell dose, and some also identify CD34⁺ or CFU-GM dose. In most reports, the incidence of acute GVHD after UCBT is lower than that expected for BMT. In contrast to acute GVHD, most comparative studies fail to demonstrate a statistical difference between UCB and bone marrow with regard to chronic GVHD in the unrelated setting. The treatment-related mortality (TRM) rate after UCBT is not consistent between reports. The incidence of relapse after UCBT is similar to that in recipients of unmanipulated marrow, suggesting that the graft-versus-leukemia (GVL) effect is intact.

In summary, current evidence demonstrates the safety and efficacy UCBT for children. The speed of the donor search, high likelihood of finding a suitably HLA-matched UCB unit (particularly for patients of ethnic and racial minorities) with an adequate cell dose, and lower rate of acute GVHD despite HLA mismatch lead many centers to choose unrelated donor UCB over unrelated adult marrow or peripheral blood. Major endpoints such as TRM, relapse rate, and overall survival are at least comparable, making UCB frequently the preferred alternative HSC source for children who lack a HLA-matched sibling donor.

UCB transplantation in adults: As expected based on the early results in children, the rate and incidence of neutrophil and platelet engraftment were lower after UCBT than after PBSCT or BMT, with a median time to neutrophil recovery after UCBT ranging between 22 and 32 days. In adults, both cryopreserved and infused nucleated cell dose are associated with speed of hematopoietic recovery. Furthermore, the incidence of graft failure in adult recipients of UCB was as high as 35%. The relatively low nucleated cell dose and greater likelihood of use of a HLA 2-antigen-mismatched graft probably accounts for this slow recovery and high graft failure rate.

Despite a higher degree of HLA mismatch, adult recipients of UCB had a comparable or lower incidence of acute GVHD compared to adult recipients of HLA-matched, T cell–replete bone marrow. Adults who received UCB had a lower incidence of acute GVHD than did those who received HLA-mismatched unrelated marrow. The incidence of chronic GVHD after UCBT has been reported to be as high as 80%, and extensive chronic GVHD is as high as 46%. Comparative studies with unrelated BMT recipients show conflicting results.

TRM in adult recipients of UCB after a myeloablative regimen has been reported to be as high as 60%. Studies comparing recipients of UCB and bone marrow yield conflicting results; some studies demonstrate lower TRM, some higher TRM, and some similar TRM. For example, Rocha et al reported similar TRM in recipients of HLA-mismatched UCB and HLA-matched unrelated marrow, whereas Laughlin et al found that TRM after UCBT was higher than that observed with HLA-matched unrelated-donor BMT, but similar to that observed with HLA-mismatched BMT.

As reported for children with malignant disease, the incidence of disease relapse was not increased among adult UCBT recipients. It remains to be proven whether survival after UCBT is comparable to that in recipients of HLA-matched unrelated bone marrow.

In summary, the above data suggest that UCBT is a reasonable alternative for adult patients who lack an HLA-matched sibling or unrelated marrow donor. Various strategies to overcome the principal limitation of cell dose in the adult population are being tried.

Multiple Umbilical Cord Blood Units: Barker et al were the first to report the successful use of two UCB units to overcome the cell-dose limitation. Others have subsequently utilized two or more UCB units with variable results.

In the Minnesota experience in adult and adolescent recipients of "double" UCBT for hematologic malignancies the graft consisted of two units that were matched at a minimum of 4 out of 6 HLA A, HLA B, and DRB1 antigens with the recipient and each other (not necessarily at the same HLA loci). In the original cohort, the total graft nucleated cell dose had to exceed 1.5 x 10⁷/kg, with the one unit containing a minimum cell dose of 1.0 x 10⁷/kg. Median time to neutrophil engraftment was 23 days, and all evaluable patients developed complete chimerism with no secondary graft failure. Notably, double chimerism (i.e., contributions from both UCB units) was detectable in the bone marrow in only ~25% between days 21 and 28. By day 100, hematopoiesis was derived from a single unit in all patients. Importantly, no factor (i.e., total nucleated cell dose, CD34 dose, CD3 dose, HLA match, ABO match, sex match, order of infusion) predicts the long-term engrafting unit; the clinical experience to date suggests that engraftment is random. TRM and survival after double UCB transplantation appear superior to those reported in recently published series. Kai et al reported similar results on a smaller number of patients with hematological malignancies who received double UCB grafts, utilizing the same HLA-matching criteria.

In summary, the above data suggest that the utilization of two UCB units in combination with fludarabine in the preparative regimen has overcome, at least in part, the cell-dose limitation for UCBT, with improved engraftment and survival. The relative contributions of double UCBT and the benefit of fludarabine to the overall success of the transplant procedure remains to be determined; it is possible that cell dose has a markedly diminished effect in recipients of fludarabine in combination with cyclophosphamide and TBI. Multi-institutional randomized trials have been proposed to address this issue in both children and adults.

Nonmyeloablative UCB transplantation: The Minnesota group evaluated the potential benefit of UCBT in the setting of a reduced-intensity preparative regimen. However, it was recognized that, in contrast to sibling or unrelated adult donor HSCT, donor lymphocyte infusions to enhance engraftment or promote GVL would not be possible. In order to meet the cell-dose criteria, approximately three quarters of the patients received two partially HLA-matched UCB units. The regimen consisted of cyclophosphamide 50 mg/kg on day -6, fludarabine 40 mg/m² on days -6 to -2, and TBI 200 cGy on day -1 with cyclosporine and mycophenolate mofetil immunoprophylaxis.

The results in the first 59 adult recipients of NST and UCBT have been analyzed. Neutrophil recovery was rapid (median of 8 days). The cumulative incidence of sustained donor-derived engraftment was 89%. As observed in recipients of a myeloablative preparative regimen, one unit ultimately predominates with no factor predictive of the long-term engrafting UCB unit. Importantly, the cumulative incidence of acute GVHD may be higher than that previously reported in children or adults after a myeloablative regimen, with 65% of the patients developing grades II–IV acute GVHD and 25% developing grades III–IV acute GVHD. However, despite the higher incidence of acute GVHD, TRM is low (19%). Thus far, only fitness status at the time of transplant is associated with TRM; age by itself is not a limiting factor. The probability of overall and progression-free survival is 44% and 35% at two years. Insufficient numbers for any one disease group prevent disease-specific evaluations, which are the goal of ongoing multi-institutional trials.

Future directions: Brief comments are made about T regulatory cells, ex-vivo expansion of progenitor cells, intra-bone marrow injection, mesenchymal stem cells and cord blood banking.

Conclusions: The increasing experience with UCBT is changing the standard of care in many institutions. Initial concerns regarding the potency of the GVL effect of UCB have been dismissed by publications from several experienced groups showing relapse rates similar to those associated with other HSC sources. In the pediatric setting, UCBT is now established practice and will soon surpass the number of unrelated adult volunteer donor transplants. Favorable results compared with historical controls have contributed to changes in clinical practice.

In the adult setting, progress has been slower owing to the cell-dose limitation. Engraftment and survival of adult patients who received single UCB unit grafts have been suboptimal. Strategies focused on overcoming this limitation are under intense investigation. Thus far, ex vivo expansion of UCB has not yet been shown to influence engraftment. Recent registry-based studies suggest that the results of adult UCBT are comparable to those of HLA-matched and -mismatched unrelated-donor BMT. Notably, the utilization of double UCB unit grafts has shown promising results. Engraftment rates and survival seem to be superior to historical data. However, this strategy still requires validation with larger patient numbers and longer follow-up at multiple institutions.

The utilization of nonmyeloablative preparative regimens broadens the range of patients who might benefit from UCBT. The fludarabine, cyclophosphamide, TBI regimen proposed at the University of Minnesota has shown encouraging results with high engraftment rates and low TRM for a high-risk group of patients.

7. A meta-analysis of unrelated donor umbilical cord blood transplantation versus unrelated donor bone marrow transplantation in adult and pediatric patients. Hwang WY, Samuel M, Tan D, Koh LP, Lim W, Linn YC. Biol Blood Marrow Transplant. 2007;13:444-53.

This article presents the results of a systematic review and meta-analysis of pooled data on comparative studies of UCBT and UBMT in patients requiring hematopoietic stem cell transplantation.

Combining the studies, 161 children and 316 adults undergoing UCBT (mostly 1 or 2 antigen-mismatched), along with 316 children and 996 adults undergoing UBMT (almost entirely fully matched with the recipient), were analyzed. T-cell-depleted UBMT was excluded; where data were available, only fully matched UBMT was used in the analysis.

Pooled comparisons of studies of UCBT and UBMT in children found that the incidence of chronic graft-versus-host disease (GVHD) was lower with UCBT (relative risk [RR] = 0.26; 95% confidence interval [CI] = 0.12-0.57; P = .16), but the incidence of grade III-IV acute GVHD did not differ (RR = 1.46; 95% CI = 0.42-5.03; P = .55). There was no difference in 2-year OS in children when studies were pooled (RR = 0.76; 95% CI = 0.31-1.87; P = .55). For adults, transplantation-related mortality (pooled estimate, 1.04; 95% CI = 0.52-2.08; P = .91) and disease-free survival (DFS) (pooled estimate, 0.59; 95% CI = 0.18-1.96; P = .39) were not statistically different.

Because of the unavailability of randomized controlled trials, pooled analysis of nonrandomized comparative studies was performed. Thus, this meta-analysis confirmed that UCBT in children and adults had consistently equivalent survival outcomes compared with UBMT despite greater donor-recipient HLA disparity with UCBT.

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