CBF

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.

  1. 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.

  1. Strategies of the donor search for children with second CR ALL lacking a matched sibling donor. Lanino E, Sacchi N, Peters C, Giardino S, Rocha V, Dini G; EBMT Paediatric, Acute Leukemia Working Parties; Eurocord. Bone Marrow Transplant. 2008 Jun;41 Suppl 2:S75-9.

During the last 10 years, the number of alternative haematopoietic stem cell transplantations (HSCTs) performed on children in Europe has increased significantly and has reached 61% of the allografts. The authors provide practical guidelines to help define an algorithm for the treatment of children relapsing during or after first-line chemotherapy for ALL and lacking a matched sibling donor. The study focuses mainly on the effects of some factors, such as HLA matching, on survival in an effort to highlight the influence that these factors have on our choices.

A simultaneous search for an unrelated donor and for a cord blood unit should be started. Although the availability of a well-matched donor is associated with improved overall survival, the major limiting factor for successful unrelated donor HSCT occurs when patients with rare phenotypes relapse while the search is still ongoing (Also see Category VI. Availability and time required to obtain cord blood versus bone marrow, citations 1, 2, 4, 5) A less than two antigen mismatched cord blood unit containing more than 3 x 107 nuclear cells should be considered equivalent to an 8/8 allele-matched unrelated donor. The decision should be made based on the urgency of the HSCT. Haploidentical HSCT should be offered if no donors and no cord blood units with acceptable characteristics are available.

  1. Searching for alternative hematopoietic stem cell donors for pediatric patients. Rocha V, Locatelli F. Bone Marrow Transplant. 2008;41:207-14.

The survival rates of unrelated donor HSCT refer only to patients who undergo transplantation and do not take into account those who did not find a donor. The time needed to identify the right donor from a potential panel, to establish eligibility and to harvest the cells may, in patients who urgently need a transplant, favor the occurrence of leukemia relapse/progression, thus precluding the transplant feasibility, consequently, for patients who do not have a matched donor or who urgently need HSCT, attention has focused on umbilical cord blood transplantation and full haplotype-mismatched family members.

Retrospective comparative studies.

UCBT compared to BMT from unrelated donors: (1) Three published reports and a Eurocord registry analysis have concluded that the overall survival probability was not significantly different in UCBT or UBMT pediatric recipients, (2) A meta-analysis combining these comparative studies confirmed that there was no difference in 2-year overall survival between children given an unrelated UCBT or UBMT, (3) a more recent analysis compared results observed in 503 UCBT recipients with those of 282 UBMT recipients. In comparison with children given an allele-matched UBMT, patients transplanted with one or two HLA-disparate UCB unit had a similar 5-year disease free survival, while an even possible better outcome was evident for the 35 children given HLA-matched UCBT. (See category VII Cord blood transplantation in Children, i Malignant disorders, Citation #1)

Comparison of UCBT with full haplotype disparate donor HSCT in children with ALL. The Eurocord group in collaboration with the EBMT compared the outcome of patients given either UCBT or haplo-HSCT by performing a retrospective comparison of pediatric patients with high-risk ALL. There was no difference in terms of TRM and DFS.

  1. Indications and donor selections for allogeneic stem cell transplantation in children with hematologic malignancies. Handgretinger R, Kurtzberg J, Egeler RM. Pediatr Clin North Am. 2008;55:71-96.

This article provides a detailed review of the indications for stem cell transplantation in children with various hematologic malignancies. The authors provide a well organized and detailed review including 148 references, and the present article should be read in its entirety. Data regarding indications for transplantation are provided for patients (1) with high-risk features of ALL in first CR, (2) with relapsed ALL in second complete remission and beyond, (3) AML in first complete remission, (4) AML in second complete remission and beyond, (5) myelodysplastic syndromes, (6) juvenile myelomonocytic leukemia, (7) therapy-related myelodysplastic syndrome and AML and (8) CML.

Also, preparative regimens and donor selection for stem cell transplantation are reviewed. Regarding alternative-donor transplantations, the authors point out that a distinct advantage of unrelated donor UCB or haploidentical related donors is their rapid availability. A recent review of outcomes data reported to the CIBMTR showed that outcomes using 5 of 6 matched UCB donors were equivalent to those with matched bone marrow. (See category VII Cord blood transplantation in Children, i Malignant disorders, Citation #1)

  1. Indications and results of cord blood transplant in children with leukemia. Gluckman E, Rocha V; EBMT Paediatric, Acute Leukemia Working Parties; Eurocord. Bone Marrow Transplant. 2008 Jun;41 Suppl 2:S80-82.

The Eurocord registry has collected and analyzed data on unrelated cord blood transplants (UCBTs) performed in European Blood and Marrow Transplant Group (EBMT) and non-EBMT centers. The literature shows that after UCBT relapse rate (RR), disease-free survival and overall survival of children with acute leukemia are similar to other hematopoietic stem cell sources (matched unrelated BM). Disease status at the time of transplantation is found in several studies to be a very important determinant of long-term outcome.

The authors pointed out the following important facts about cord blood transplantation in children with leukemia:

The advantages of using cord blood are:

  1. The immediate availability of the donor. This allows the transplant to be scheduled at the time of remission before the patient relapses. This is a considerable advantage in children with high-risk leukemia who need a transplant as early as possible after reaching remission.
  2. The current consensus is to use any cord blood donor with 0-2 HLA differences and a number of nucleated cells ≥3 x 107/kg. Therefore, it is now very rare to deny a transplant to a patient in need because of the lack of a donor. (Note: This is particularly true for Caucasians, but is less true for members of certain minority groups.) In contrast, recommendations for an adult unrelated BMT where high-resolution typing must be performed for HLA-A, -C, DRB1, and –DQB1, the probability of finding a donor is approximately 50% and is strongly dependent on the ethnic origin of patients
  3. The use of double cord blood transplants has overcome the problem of a low cell dose (in particular, for adults).
  4. There is a decrease of GVHD while it seems that the GVL effect is observed.

The authors concluded that umbilical cord blood is a valuable alternative source of hematopoietic stem cell transplantation in children with acute leukemia who need an allogeneic transplant, but lack a suitable sibling donor.

  1. 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 # 8, 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.

  1. 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.

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