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This is a succinct review (3½ pages) which provides a great deal of information in summary form along with the pertinent reference citations. A major part of the review provides comparisons between the outcomes of CBT and BMT or PBSCT.
In children with malignant diseases, two studies compared the outcome of unrelated UCBT and BMT. Eurocord published a study comparing the outcome of matched unrelated BMT (HLA 6 out of 6) either unmanipulated or T depleted to mismatched UCBT. Results showed that after UCBT, engraftment was delayed, GVHD was reduced similarly to T-cell depleted BMT; relapse was the same as was leukemia free survival. Eapen M et al. compared outcomes of 503 children with acute leukemia given an unrelated mismatched UCBT with 282 unrelated BM transplant recipients (116 HLA allele matched 8 out of 8). HLA allele mismatched BM recipients had more acute and chronic GVHD without decreasing leukemia free survival (LFS). Importantly, they found that even using an allele matched BM donor, LFS was not statistically different from one or 2 HLA disparate UCBT and that an HLA matched UCBT recipient had better outcomes compared to HLA allele matched BM recipients. However, an increased transplant related mortality was observed in children transplanted with a low CB cell dose (<3x 107/kg) and 1 HLA disparate CB graft or in children given a 2 HLA disparate UCBT independently of the cell dose infused. Interestingly, use of 2 HLA mismatched UCBT was associated with lower incidence of relapse.
The same studies were performed in adults with malignancies. The Eurocord study compared adults with acute leukemia receiving either a matched unrelated bone marrow transplant (HLA 6 out of 6) or a mismatched cord blood transplant. Results showed that, despite a delay of engraftment, CBT gave a similar leukemia survival to BMT. The NYCBB showed that, in adults with malignancies, CBT gave the same LFS survival to 1 antigen mismatched UBMT. Also, a Japanese study showed that CBT gave better results than MUD.
In a meta analysis combining the published 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 GVHD was lower with UCBT, but the incidence of grade III–IV acute GVHD did not differ. There was no difference in 2-year overall survival in children when studies were pooled.
For adults, there was no statistical difference between transplantation-related mortality (TRM) and LFS. Recently, Eurocord and CIBMTR performed a study comparing the outcome of unrelated HLA matched or 1–2 antigens mismatched bone marrow (n=364) or G-CSF mobilized peripheral blood (n=728) to mismatched cord blood transplant (n=148) in adults with acute leukemia. In multivariate analysis, in UCBT, TRM was higher but relapse rate and GVHD were lower resulting in the same LFS compared to the other sources of stem cells.
The results of these comparative studies and the meta-analysis considered together showed that (i) UCBT is feasible in adults when a cord blood unit contains a higher number of cells and should be considered an option as an allogeneic stem cell source for patients lacking an HLA matched bone marrow donor; (ii) despite increased HLA disparity, UCB from unrelated donors offers sufficiently promising results to matched UBM in adults with hematologic malignancies leading to the conclusion, as in children, that the donor search process for BM and UCB from unrelated donors should be started simultaneously, especially in patients with acute leukemia, where the time factor is crucial.
Additional points of interest are that more than 20,000 UCBTs have been performed in children and adults. In comparison with other sources of allogeneic HSCT, UCB offers substantial logistic and clinical advantages such as (1) significantly faster availability of banked cryopreserved UCT units, (2) extension of the donor pool due to tolerance of 1-2 HLA mismatches out of 6, (3) lower incidence and severity of GVHD, (4) lower risk of transmitting infections by latent viruses, (5) lack of donor attrition, (6) lack of risk to the donor, and (7) greater effectiveness to target ethnic minorities.
- Allogeneic hematopietic cell transplantation for AML when a matched related donor is not available. Appelbaum F. American Society of Hematology Education Program Book, 2008, pp.412--417
There is reluctance on the part of some transplant physicians to perform an allogeneic hematopoietic cell transplant (HCT) if a matched related donor is not available. This article reviews the effectiveness of alternative donor sources. With the use of high-resolution typing, HCT outcomes using unrelated donors matched at HLA-A, -B, -C and –DRB1 give results very similar to those expected with matched related donors. Published data indicate that it is reasonable to accept similar indications for HCT in AML using matched related or 10 of 10 matched unrelated donors.
The use of umbilical cord blood for HCT has the advantages of quicker availability and an apparent tolerance for greater HLA disparity than use of T-replete marrow or peripheral blood from related or unrelated donors. Two retrospective reports (from the IBMTR and Eurocord) comparing outcomes of unrelated (adult) donor transplants and cord blood transplants for adults with acute leukemia have indicated that the differences in long-term survival were sufficiently small to make cord blood transplant a potential option for appropriate adults. Although inadequate cell dose was a limiting factor in early cord blood transplants, double cord blood transplants have been used to overcome this limitation. Double cord blood transplants appear to lessen the risk of graft rejection and to improve early survival thus making cord blood transplantation an option for adults without a single large cord available.
Haploidentical HCT involving the use of a conditioning regimen of TBI, fludarabine, thiotepa and ATG followed by transplantation of CD34 -selected cells from the peripheral blood has produced EFS at 1 year of 48% and 46% for 42 AML and 24 ALL patients transplanted in remission, respectively, and only 4% for the 38 patients transplanted in relapse
The author concludes: “The option of allogeneic HCT for adults with AML is no longer limited to those patients with matched siblings.”
An important final point is that ~13,000 cases of AML were diagnosed last year but only ~2,000 allogeneic transplants were performed, “a figure that seems quite a bit below what would be appropriate if we took advantage of current knowledge of the use of alternative donors.”
- Matched unrelated or matched sibling donors result in comparable
survival after allogeneic stem-cell transplantation in elderly patients
with acute myeloid leukemia: a report from the cooperative German Transplant
Study Group. Schetelig J, Bornhäuser M, Schmid C, et al. J
Clin Oncol. 2008;26:5183-5191.
[Comment: Patients in need of a hematopoietic cell transplant (HCT) may be denied the procedure if a matched sibling donor is not available. Evidence is accumulating that this policy is inappropriate since the outcomes following matched unrelated donor transplantation are similar to those using sibling donors.]
The authors of this report sought to determine whether transplant outcomes differed when the source of the stem cell product is an unrelated donor as compared to a matched sibling donor in this era of high-resolution DNA-based HLA typing. They performed univariate and multivariate analyses of event-free survival (EFS) and overall survival (OS) in patients older than 50 years with standard- or high-risk AML who had received an allogeneic HCT between 1995 and 2005. Available DNA from donors and recipients of unrelated HCT was retyped so that the HLA-A, -B, -C, and -DRB1 alleles could be characterized in detail. Unrelated donors (UDs) were classified as matched (8/8), possibly matched (matched, but incomplete information), partially matched (one mismatch), or poorly matched (two or more mismatches) according to the final typing results. Data from 368 patients with a median age of 57 years (range, 50 to 73 years) were included. Multivariate Cox regression analysis revealed that patients' disease status at HCT (P < .001) and the cytogenetic risk (P < .001) highly significantly predicted EFS and OS.
OS and EFS after allogeneic HCT in AML patients older than 50 years was not different in patients with matched unrelated donors compared with matched siblings. Compared with patients with matched sibling donors, the adjusted relative risk of EFS was 0.7 (95% CI, 0.4 to 1.1) for patients with matched UDs and 1.0 (95% CI, 0.7 to 1.6) for patients with partially matched UDs.
The authors concluded that donor type is not a major prognostic factor for HCT in elderly patients with standard- or high-risk AML. It is debatable whether different therapeutic guidelines for matched sibling or matched unrelated HCT are still justified in high-risk diseases like AML.
- Equivalent survival for sibling and unrelated donor allogeneic
stem cell transplantation for acute myelogenous leukemia.
Moore J, Nivison-Smith I, Goh K, Ma D, et al. Biol Blood Marrow Transplant.
2007;13:601-607.
The authors compared outcomes for 105 patients aged 16 to 59 years undergoing unrelated donor transplants for AML who were reported to the Australasian Bone Marrow Transplant Recipient Registry between 1992 and 2002, and a strictly selected matching set of 105 HLA-matched sibling donor transplants.
Both neutrophil and platelet engraftment were significantly more rapid in the sibling group, but transplant-related mortality at 100 days was not significantly different. There was no difference in the cumulative incidence of acute GVHD grade II or above at 100 days. Relapse occurred in 28% of good risk unrelated donor subjects and 16% of siblings (P = .3), and in poor risk subjects 39% and 29%, respectively (P = .2). Based on these data, unrelated donor allografts should be considered in AML patients without a matched sibling donor.
- 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.
- Unrelated cord blood and mismatched unrelated volunteer donor
transplants, two alternatives in patients who lack an HLA-identical
donor. Ringdén
O, Okas M, Uhlin M, Uzunel M, Remberger M, Mattsson J. Bone Marrow Transplant.
2008;42:643-8.
The aim was to evaluate two transplant strategies for patients who lack HLA-identical donors, namely HLA-A, HLA-B or -DR beta 1 mismatched unrelated donor (MM URD) transplants (n=14) and umbilical cord blood transplants (UCB, n=27). Diagnosis, disease stage and age were similar in the two groups. Cell dose was lower in the UCB group (P<0.001). Median time to ANC of >0.5 x 10(9)/l was 30 days in the UCB group and 17 days in the MM URD group (P=0.002). Engraftment of platelets was delayed in the UCB group (P=0.03). The UCB patients required fewer erythrocyte transfusions (P=0.001). At 100 days, complete donor chimerism for CD3 was 63 and 44% in the UCB and MM URD groups, respectively. Acute GVHD of grades II-IV were 30% in the UCB group and 21% in the MM URD group. The corresponding figures for chronic GVHD were 9 and 20%, respectively. TRM was 30% in the UCB patients and 50% in the MM URD patients.
Three-year survival was 66% in the UCB group and 14% in the MM URD group (P=0.006). Although the material is small and heterogeneous, engraftment was delayed, leukocyte chimerism was not significantly different and survival was superior using UCB rather than MM URD transplants.
- Allogeneic hematopoietic stem cell transplantation in adult
acute lymphocytic leukemia: impact of donor source on survival. Kumar P, Defor TE, Brunstein
C, Barker JN, Wagner JE, Weisdorf DJ, Burns LJ. Biol Blood Marrow Transplant.
2008;14:1394-1400.
The authors studied the relative impact of donor source on outcomes following myeloablative hematopoietic stem cell transplantation (HSCT) for adult patients with acute lymphocytic leukemia (ALL).
In this single center study, 138 patients aged 18-61 (median 31) years underwent myeloablative conditioning followed by allogeneic HSCT. Stem cell source was an HLA matched related donor (MRD) in 90, HLA matched unrelated donor (URD:M) in 15, HLA mismatched unrelated donor (URD:MM) in 14, and HLA 0-2 (A, B, DRB1) mismatched umbilical cord blood (UCB) in 19 patients. Demographics and disease characteristics were similar in all 4 groups except all UCB recipients were treated since 1996 and received growth factors.
Overall survival (OS) at 3 years for the UCB group was 66% compared to 27% in the MRD group, and only 13% and 14% in the URD:M and URD:MM groups, respectively. Similarly, leukemia free survival (LFS) at 3 years was better in the UCB group at 61% compared to 27% in the MRD and only 13% in the URD:M group and 14% in URD:MM group. Transplant-related mortality (TRM) at 3 years was the lowest in the UCB group at 34% and higher in the other donor groups: MRD 47%, URD:M 67%, and URD:MM 86%.
The authors concluded that, when compared with matched unrelated donors, OS with UCB was better (RR 0.3, 95% CI, 0.1-0.7, P = .01), supporting the use of UCB as an alternative stem cell source for adults with ALL.
Additional comments by the authors include (1) Umbilical cord blood has emerged as an attractive alternative when a matched related donor is not available because of the rapidity of procurement and the ability to use HLA mismatched units with a low incidence of GVHD. (2) The median time to obtain an UCB graft was 13.5 days compared to 50 days for an unrelated donor graft. (3) Improvement in induction regimens, supportive care, management of CMV infections, use of growth factor, and better HLA match are factors that could account for the improved results seen in more recent studies of outcomes of HSCTs.
- Unrelated cord blood transplantation after myeloablative conditioning
in adults with acute myelogenous leukemia. Ooi J, Takahashi S, Tomonari
A, Tsukada N, Konuma T, Kato S, Kasahara S, Sato A, Monma F, Nagamura
F, Iseki T, Tojo A, Asano S. Biol Blood Marrow Transplant. 2008;14:1341-1347.
The authors analyzed the disease-specific outcomes of adult acute myelogenous leukemia (AML) patients treated with unrelated cord blood transplantation (CBT) after myeloablative conditioning. Between August 1998 and February 2008, 77 adult patients with AML were treated with unrelated CBT. All patients received 4 fractionated 12 Gy total body irradiation (TBI) and chemotherapy as myeloablative conditioning. The median age was 45 years, the median weight was 55 kg, the median number of nucleated cells was 2.44 x 107/kg, and the median number of CD34-positive cells was 1.00 x 105/kg. All patients received a single and HLA mismatched cord blood unit. The cumulative incidence of neutrophil recovery at day 50 and platelet recovery at day 200 was 94.8% and 91.7%, respectively. A higher CD34-positive cell dose was associated with faster hematopoietic recovery. The cumulative incidence of grade III to IV acute graft-versus-host disease (aGVHD) and extensive-type chronic GVHD (cGVHD) was 25.1% and 28.6%, respectively. With a median follow-up of 78 months, the probability of event-free survival (EFS) at 5 years was 62.8%. The 5-year cumulative incidence of treatment related-mortality (TRM) and relapse was 9.7%, 25.8%, respectively. In multivariate analyses, the risk factor identified for event free survival (EFS) was disease status and cytogenetics. These results suggest that unrelated CBT after myeloablative conditioning could be safely and effectively used for adult patients with AML.
- Disease-specific analyses of unrelated cord blood transplantation
compared with unrelated bone marrow transplantation in adult patients
with acute leukemia. Atsuta Y, Suzuki R, Nagamura-Inoue T,
Taniguchi S, Takahashi S, Kai S, Sakamaki H, Kouzai Y, Kasai M, Fukuda
T, Azuma H, Takanashi M, Okamoto S, Tsuchida M, Kawa K, Morishima Y,
Kodera Y, Kato S; Japan Cord Blood Bank Network. Blood. 2009;113:1631-1638.
Allogeneic hematopoietic stem cell transplantation (HSCT) with bone marrow (BM) or peripheral blood, the curative treatment of choice for acute leukemia, is limited by the inadequate supply of human leukocyte antigen (HLA)–identical related donors. Bone marrow from HLA-matched unrelated donors has been a major alternative graft source. Umbilical cord blood (CB), an alternative stem cell source to BM or peripheral blood stem cells, has been used primarily in children but its use in adults is increasing.
The authors made a disease-specific comparison of unrelated cord blood (CB) recipients and HLA allele-matched unrelated bone marrow (BM) recipients among 484 patients with acute myeloid leukemia (AML; 173 CB and 311 BM) and 336 patients with acute lymphoblastic leukemia (ALL; 114 CB and 222 BM) who received myeloablative transplantations. In multivariate analyses, among AML cases, lower overall survival (hazard ratio [HR]=1.5; 95% confidence interval [CI], 1.0-2.0, P= .028) and leukemia-free survival (HR=1.5; 95% CI, 1.1-2.0, P= .012) were observed in CB recipients.
The relapse rate did not differ between the 2 groups of AML (HR=1.2; 95% CI, 0.8-1.9, P= .38); however, the treatment-related mortality rate showed higher trend in CB recipients (HR=1.5; 95% CI, 1.0-2.3, P= .085).
In ALL, there was no significant difference between the groups for relapse (HR=1.4, 95% CI, 0.8-2.4, P= .19) and treatment-related mortality (HR=1.0; 95% CI, 0.6-1.7, P= .98), which contributed to similar overall survival (HR=1.1; 95% CI, 0.7-1.6, P= .78) and leukemia-free survival (HR=1.2; 95% CI, 0.9-1.8, P= .28).
The authors concluded that matched or mismatched single-unit CB is a favorable alternative stem cell source for patients without a human leukocyte antigen-matched related or unrelated donor. For patients with AML, decreasing mortality, especially in the early phase of transplantation, is required to improve the outcome for CB recipients.
- Umbilical Cord Blood (UCB) Transplantation:
An Alternative to the Use of Unrelated Volunteer Donors? Barker
JN Hematology Am Soc Hematol Educ Program. 2007;2007:55-61.
This is a succinct and authoritative review of the present state of the art of umbilical cord blood (UCB) transplantation as presented by Dr. Barker as part of the Educational Program at the American Society of Hematology Meeting, December 8-11, 2007.
The article summarizes the current status of unrelated donor UCBT and describes both the challenges and current areas of research associated with this HSC source. The author points out that the success of UCB transplants has resulted in dramatic increases in the number of such transplants being performed. UCB has clear benefits of rapid availability and a reduced stringency of requirement for HLA match. The latter attribute has the potential to extend the donor pool, which is of great importance for racial and ethnic minorities. Furthermore, new preparative regimens combined with double-unit grafts have been associated with improved engraftment and survival in larger children and adults, making UCBT a viable potential alternative to unrelated volunteer donor transplantation, especially in preference to transplantation using mismatched volunteers.
Topics reviewed include: Cell Dose and HLA Match; Impact on UCBT Outcome; Strategies to Improve UCBT in Adults; UCBT for Nonmalignant Diseases; Comparisons of Unrelated Donor UCB and Bone Marrow; and Current Areas of Research and Development.
The author concludes by pointing out that the US General Accounting Office has documented that more than 10,000 patients per year in the US need an unrelated donor HSC transplantation and do not receive one. UCB has the potential to nearly resolve the limitations of search time, donor availability, and the lack of suitably matched donors for many patients. UCBT is currently considered by many as a valid potential alternative for any patient who requires an unrelated donor allograft and who is without a suitably matched and readily available volunteer. Some transplantation centers now give UCB the priority as the unrelated HSC source of choice in children and, albeit less frequently, also in adults. Others conduct a simultaneous search for both unrelated volunteers and UCB, thus offering UCB as an immediate potential alternative to unrelated volunteers. It is possible that UCB (particularly 5-6/6 HLA-matched) may become the preferred HSC source even for those patients with fully matched unrelated volunteer donors. Finally, assuming we can increase the global UCB inventory, UCB is likely the best way to extend transplantation access to minorities; thus, in the future we may be able to offer an HSC source to all.
