Introduction

Perhaps the most critical issue in cord blood transplantation is the effectiveness of cord blood units for transplantation of adults because at least 75% of patients in need of a hematopoietic cell transplant are adults.

Can cord blood units, which require less stringent HLA matching of donor and recipient, satisfy the unmet need for donors for adult patients in need of hematopoietic cell transplants? Guidelines for an adequate cell dose in cord blood transplantation have steadily evolved and the critical importance of cell dose is now firmly established. Selection of a single cord blood unit with adequate cell dose, or the use of more than one cord blood unit are being utilized successfully in a number of transplant centers. In addition, reduced-intensity (nonmyeloablative) conditioning regimens have contributed to successful outcome.

Also, in Annotated Bibliography, see under headings: III. Multi-cord Transplants; IV. Reduced Intensity and Non-Myeloablative Transplants; V. Donor Selection for Unrelated Cord Blood Transplantation; VI. Availability and Time Required to Obtain Cord Blood versus Bone Marrow

(For a commentary regarding the unrealized potential of umbilical cord blood (UCB) units for unrelated donor hematopoietic cell transplantation, go to: Interactive Forum for Medical Professionals on the left hand column of the Home Page of this website.)

1. Cord blood transplantation for adults. Brunstein CG, Wagner JE. Vox Sang. 2006; 91:195-205.

Advantages and disadvantages of umbilical cord blood (UCB) over donations from unrelated adults: Advantages are (1) that UCB units are immediately available for transplantation, (2) there is no risk to the donor, (3) there is a low risk of viral transmission of CMV, hepatitis and HIV, and (4) a higher degree of HLA mismatch appears to be acceptable with a comparatively lower risk of acute and chronic GVHD. Disadvantages are (1) there are a limited number of hematopoietic progenitor cells in a single UCB unit and cell dose has been shown to be a major determinant of engraftment and survival. (2) there is no access to donor lymphocytes in the event of relapse after UCB transplantation, and (3) there is significantly less experience with UCB than with unrelated donors, especially in adults.

COMPARISONS OF UCB AND OTHER HSC SOURCES:

The results of two reported studies that compared related donor HSC vs. unrelated UCB transplantation are summarized in the text and in a detailed table. The first study compared unrelated UCB to HLA- and partially HLA-matched related donors after a myeloablative preparative regimen. Time to neutrophil and platelet recovery were longer in the UCB cohort, but overall donor-derived engraftment was comparable by day 42. The rate of aGVHD grades II-IV was the same but grade III-IV aGVHD was significantly more frequent among recipients of a related donor graft (8% vs. 19%, p=0.04). The incidences of cGVHD and TRM, and the 3-year relapse rate, as well as probability of 3-year survival were comparable between the two groups. The second study compared outcomes in patients transplanted with unrelated UCB and haploidentical T-cell depleted marrow grafts for the treatment of AML and ALL. Once again, median time to neutrophil recovery was longer in the UCB cohort. The incidence of grades II-IV aGVHD was higher for the UCB group. Other than GVHD, patients with AML had similar outcomes, regardless of graft source. However, patients with ALL had a higher probability of 2-year-leukemia-free survival if the received a UCB graft.

At least three retrospective studies have been reported that compared UCB with unrelated donor transplantation in adults after a myeloablative preparative regimen. Again the tie to neutrophil and platelet recovery was significantly delayed, and graft failure was higher after UCB transplantation. The incidence of grades II-IV aGVHD after UCB transplantation was similar or lower. Relapse rates were similar between UCB and unrelated donor grafts in all studies. The impact of graft source on TRM and survival has been more controversial. One study showed TRM after UCB transplantation to be significantly higher than after HLA-matched unrelated marrow (although similar to HLA-mismatched unrelated marrow), another study showed similar TRM rates for UCB and unrelated marrow grafts, while the third study observed lower TRREM for the UCB group compared with unrelated marrow. Overall, these studies suggest that UCB transplantation is an acceptable alternative for all patients who do not have a suitable related and unrelated donor. The question, at present, is the relative place of UCB – first-line or second-line therapy.

MULTIPLE UCB UNITS

It is unequivocally clear that cell dose and HLA match are central factors in predicting the risk of TRM. Furthermore it is clear that low cell dose amplifies the deleterious effect of HLA mismatch. The use of "double" UCB transplantation is based on the rationale that if a single unit does not provide an adequate cell dose for an adult patient, perhaps the combined cell dose of two partially HLA-matched units could improve the outcome.

Double UCB transplantation after a myeloablative preparative regimen: In a study comparing outcomes after single or double UCB transplantation for acute leukemia patients, sustained neutrophil engraftment and TRM were virtually the same indicating that patients can receive single UCB unit grafts if the cell dose is high enough. There was a threefold higher incidence of grade II-IV aGVHD among recipients of double cords, but no difference in the incidence of grades III-IV aGVHD or cGVHD. An unexpected finding was a lower leukemia relapse rate among recipients of double UCB graft when transplanted in first and second complete remission. The results of the multivariate analysis indicated that transplantation with two units is associated with a 10-fold lower risk of relapse. This may be explained by the fact that recipients of a double UCB graft most often receive a 4/6 HLA-matched graft, which may lead to more GVL effect.

Double UCB transplantation after non-myeloablative transplantation: Non-myeloablative (NMA) preparative regimens have allowed patients who are older, and heavily pretreated, and with significant comorbidities to undergo allogeneic transplantation. Most groups have used fludarabine combined with an alkylating agent preparative regimen with our without low-dose TBI. In two studies, patients who received double UCB unit grafts, with a higher median infused NCD and CD34 cell dose, were more likely to have sustained donor engraftment, at a median of approximately 2 weeks. The incidence of acute and chronic GVHD varied widely but TRM was consistently lower than 30%. In the largest single-center experience, progression-free survival was 38% and overall survival was 44%. However, patients who receive an NMA preparative regimen because of poor organ function, recent fungal infection, or low performance status still have a significantly higher risk of TRM and poor survival. Patients who were not exposed to multiagent chemotherapy in the 3 months before NMA UCB were at high risk of graft failure, and patients who receive ATG have an increased risk of EBV viremia and post-transplant lymphoproliferative disorder. In summary, the data clearly support the utilization of UCB as an HSC source for NMA transplantation.

NOVEL STRATEGIES TO IMPROVE ENGRAFTMENT, REDUCE GVHD, REDUCE TRM AND ENHANCE GFL:

1. Use of drugs or cell populations to reduce host resistance.
2. Ex- vivo expansion to augment the HSC and progenitor cell numbers.
3. Use of novel therapies that limit the use of myelotoxic drugs in the peritransplant period.
4. Ways to minimize the non-specific loss of circulating HSCs and potentially homing to the marrow microenvironment.

2. Umbilical cord blood transplantation after nonmyeloablative conditioning: impact on transplant outcomes in 110 adults with hematological disease. Brunstein CG, Barker JN, Weisdorf DJ, Defor TE, Miller JS, Blazar BR, McGlave PB, Wagner JE. Blood 2007;110:3064-70.

This report establishes the safety profile of a nonmyeloablative treatment regimen consisting of fludarabine (FLU), cyclophosphamide (CY) and single fraction total body irradiation (TBI) in recipients of UCB in 110 consecutive adult patients with hematological disease. Ninety-three of the 110 patients received a double cord transplant.

Inclusion Criteria. Patients with advanced or high-risk hematologic disease were eligible for UCB transplantation if they had no related donor matched at 5-6/6 HLA loci (A, B, and DRB1). Patients were eligible for nonmyeloablative therapy if they met any of the following criteria: age >45 years, pre-existing high risk clinical features for TRM (serious organ dysfunction; invasive mold infection within 4 months prior to transplantation; Karnofsky Performance score 50-60 or history of extensive prior therapy [defined as: >12 months alkylator-based chemotherapy; >6 months alkylator-based chemotherapy plus extensive radiation; or history of autologous transplantation]).

UCB unit selection algorithm. UCB units were required to be matched at >4 of 6 HLA antigens based on antigen-level HLA-A and B typing and allele-level HLA-DRB1 typing. UCB units were required to have a minimum cryopreserved total nucleated cell (TNC) dose of 2.0 x 10⁷/kg. However, the target cell dose was ≥3.0 x 10⁷ TNC/kg resulting in the selection of a second partially HLA matched UCB unit if available. In those for whom a second UCB unit could be identified, the second unit also had to be 4 of 6 antigen matched with the first unit.

Treatment. 110 patients received a single dose of CY 50 mg/kg on day -6, FLU 40 mg/m² daily on days -6 to -2, and a single fraction of TBI 200 cGy without shielding on day -1. ATG was given at 15 mg/kg every 12 hours on days -3 to -1 in a subpopulation of patients who had received less than two cycles of multiagent chemotherapy within the 3 months prior to enrollment (and no history of autologous transplantation.). All patients received CsA twice daily from day -3 for at least 3 months with target trough levels of 200-400 ng/ml and MMF at 1 g intravenously or orally twice daily from day -3 to +30.

Results. Most patients received two UCB units (n=93) to achieve the required cryopreserved cell dose. Neutrophil recovery was achieved in 92% at median of 12 days. Incidences of grades III-IV acute and chronic GVHD were 22% and 23%, respectively. Transplant-related mortality was 26% at 3 years. Survival and event-frees survival at 3 years were 45% and 38%, respectively.

Favorable risk factors were absence of high risk clinical features and absence of severe GVHD (p=0.04) for survival, and absence of high risk clinical features (p<0.01) and use of two UCB units (p=0.07) for event-free survival.

Discussion. The study supports the use of UCB transplantation after a non-myeloablative therapy in adults with hematologic disease. It is clear that the use of the double UCB platform in the setting of a nonmyeloablative therapy extends the availability of transplantation to those who cannot find a suitably HLA matched adult volunteer marrow or peripheral blood donor and who are at increased risk of regimen-related toxicity and transplant related mortality, such as older or heavily treated patients.

3. Adult umbilical cord blood transplantation: a comprehensive review. Schoemans H, Theunissen K, Maertens J, Boogaerts M, Verfaillie C, Wagner J. Bone Marrow Transplant. 2006; 38: 83-93.

This article summarizes the evidence available to date supporting the efficacy of umbilical cord blood transplantation (UCBT) in adults based on published clinical trials, and puts into perspective the various approaches currently under investigation to improve these results.

In addition to a comprehensive text, the article contains detailed tables including (1) a comparison of the main features of UCBT and BMT, (2) summaries of studies comparing single unit unrelated UCBT and matched unrelated BMT, (3) studies of UCBT in adults, (4) studies using reduced intensity conditioning in adult UCBT, (5) studies of multiple unit UCBT, and (6) studies of newer approaches in adult UCBT.

Comparing UCBT to BMT. The three most distinctive features distinguishing unrelated donor UCB transplantation from PBSC or BMT are: (1) the number of stem cells available for transplantation, (2) the speed of their availability and (3) the HLA matching requirements.

   Cell Dose: It is clear that transplantation outcome after UCBT is correlated with the cell dose infused: a threshold must be reached to get consistent engraftment and lower incidence of transplant-related events. Cell dose also directly correlates with rate of neutrophil and platelet recovery such that recipients of higher cell doses have significantly more rapid recovery as compared to those with lower cell doses. The current empirically accepted threshold limits are 1. 7 x 10⁵ infused CD34⁺ cells/kg or 2. 5 x 10⁷ cryopreserved nucleated cells/kg.

   Graft availability: UCB units are almost immediately available for transplant as they are fully HLA-typed before storage without risk of donor morbidity or attrition. With the expansion of the UCB banks, the search of a unit now takes about 1 day for University of Minnesota searches, whereas an unrelated PBSC/BMT donor search will take an average of 3-4 months. Such rapid availability can be particularly useful for patients with high-risk malignancy or rapidly progressive non-malignant diseases, although the clinical significance of this potential advantage has not yet been defined.

   HLA matching: UCB is less restricted with regards to HLA matching requirements relative to bone marrow stem cells from adult donors. It is customary to accept HLA matching at the serological level for HLA-A and HLA-B, and high resolution allelic typing for HLA-DRB1. Attempts to better define compatibility through high resolution typing failed to correlate with survival, in sharp contrast to unrelated BMT where any single serological mismatch or multiple high resolution mismatches are considered as risk factors.

This permissive HLA mismatching increases the number of potential units available per patient. One cord blood bank recently reported that patients had a 99% chance of finding a 4/6 HLA matched unit, and a 70% chance of finding a 5/6 or 6/6 HLA match, without mismatch in the GVHD direction. Further limitations are linked to the cell content of the unit.

Choosing the “best”unit. While higher cell dose may partially overcome the negative impact of HLA disparity, the best matched unit with a cell dose of >2. 5 x 10⁷ cryo-preserved nucleated cells per kilogram should be used.

Comparing unrelated UCBT and unrelated BMT. Several reports reached somewhat discrepant conclusions. A report from the IBMTR/NYBC concluded that results of UCBT were comparable to those observed in recipients of one-HLA-mismatched unrelated BMT, but inferior to a fully HLA-matched unrelated BMT. A report from the EBMT considered both transplantation modalities (HLA-mismatched UCBT vs. HLA-matched unrelated BMT) to be equivalent. A study from Japan concluded that UCBT was superior to unrelated BMT in the light of their survival results.

Possible reasons for the differing results included the fact that the IBMTR/NYBC study included data from the pioneering period of UCBT and greater disparity in HLA matches between donor and recipient. The excellent data from Japan may be due their extensive experience with UCBT in more that 555 adults, lower median weight of Japanese patients, more homologous HLA genotype on the island, prolonged hospitalization of patients after transplant, the high proportion of limited cGVHD and possibly differences in conditioning therapy.

Reduced intensity conditioning in the setting or UCBT. From 2001 to 2005, results of about 330 reduced intensity conditioning (RIC) UCBT have been published. Interpretation of the data is difficult as some of these studies were carried out with multiple UCB units and conditioning regimens varied between centers.

Multiple unit UCB transplantation. Results of double unit UCBT in 142 patients have been reported and are summarized in a table. There is a wide range of neutrophil engraftment (12-26 days), partially explained by the different conditioning used, but impressively low frequencies of graft failure (0-22%). Only one of the two units infused predominated over time, generally by day 100. Incidence of grade II-IV aGVHD appeared to be slightly higher and cGVHD in the same range as previously described (44-65% for aGVHD and 21-25% for cGVHD). TRM rates remained low (14-48%) and 1-year survival ranged from 31 to 79%. UCB transplantation with 2 units appears therefore safe and feasible both in the myeloablative and non-myeloablative setting. Double transplants make UCBT feasible for almost all adults for whom a single cord blood unit would have been insufficient.

Some recent studies compare single unit to double unit UCBT. A retrospective comparative analysis of the University of Minnesota data demonstrated high engraftment and less relapse, but increased grade II-IV aGVHD, with possibly improved survival with double unit UCBT. However, as double unit transplants were initiated, the standard conditioning regimen also shifted from ATG to fludarabine, and GVHD prophylaxis was change from methylprednisone/cyclosporine to mycophenolate mofetyl/cyclosporine; this may explain the shorter time to engraftment and better over all survival. Creer et al also showed better time to engraftment and better survival in double unit UCBT essentially because of the absence of deaths due to opportunistic infections in the double UCBT cohort.

Ex vivo expansion. Clinical studies have confirmed the feasibility and safety of ex vivo expansion procedures in terms of infusional toxicity, but have failed to show better recovery kinetics than historical controls. Of note, however, pre-clinical data suggest superior engraftment capacity of UCB progenitor cells compared to BM and peripheral blood stem cells, thus perhaps signifying that these cells represent optimal targets for ex vivo expansion.

Co-infusion of PBSC in UCBT. Fernandez et al studied the effect of co-infusion of highly purified, T-cell depleted PBSC from a haploidentical donor, in an attempt to make use of the typically rapid neutrophil recovery observed with PBSC as a “cover” while waiting for UCB recovery. The impressive overall survival statistics (67% at 4 years, or 20/28 patients) of this small patient cohort warrant further study of this novel approach.

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