sibling donor cord blood transplantation for …...identical and 14 have received cord blood...

206

Ann. N.Y. Acad. Sci. 1054: 206–213 (2005). © 2005 New York Academy of Sciences.doi: 10.1196/annals.1345.025

Sibling Donor Cord Blood Transplantation for Thalassemia Major: Experience of the Sibling Donor Cord Blood Program

MARK C. WALTERS, LYNN QUIROLO, ELIZABETH T. TRACHTENBERG,SANDIE EDWARDS, LISA HALE, JOANNA LEE, JOI MORTON-WILEY,KEITH QUIROLO, SHANDA ROBERTSON, JULIE SABA, AND BERT LUBIN

Children’s Hospital & Research Center at Oakland, Oakland, California 94609, USA

ABSTRACT: The Sibling Donor Cord Blood (SDCB) Program was initiated in1998 as a resource to collect, characterize, and release cord blood units (CBUs)from families affected by malignant and nonmalignant disorders for trans-plantation. Families in the United States were recruited by telephone after re-ferrals by community and academic physicians. Collection kits were mailed toprospective participants and family members were instructed about CBU pro-curement from community hospitals and shipping to a central laboratory. Dataabout the infant’s delivery and CBU harvest, CBU processing, prethaw char-acteristics, sterility, and human leukocyte antigen (HLA) typing were collected.Standard outcome data were collected after CBU release for transplantation.Descriptive analyses of CBU collections, processing, release, and transplanta-tion outcomes were performed. Currently, 1617 CBU collections have been pro-cessed from families with thalassemia (6%), sickle cell disease (28%),malignant disorders (49%), and other rare hematological disorders (17%).Thirty-two of 96 donor–recipient pairs with thalassemia major were HLAidentical and 14 have received cord blood transplantation, either alone or incombination with bone marrow or peripheral blood progenitor cells (N = 4)from the same donor. Eleven of the 14 survive free of thalassemia after trans-plantation. These preliminary results confirm the feasibility and utility ofremote-site sibling donor cord blood collection and subsequent transplantationfor hematological disorders, with a very high rate of usage from a cord bloodbank dedicated to performing these unique collections. It was concluded thatcord blood transplantation from sibling donors represents a suitable alterna-tive to bone marrow transplantation.

KEYWORDS: transplantation; thalassemia; human leukocyte antigen; cordblood

INTRODUCTION

Since the first successful report of transplantation for thalassemia major two de-cades ago, significant advances in the optimal selection of individuals who might

Address for correspondence: Mark C. Walters, Children’s Hospital & Research Center atOakland, 747 52nd St., Oakland, CA 94609. Voice: 510-428-3374; fax: 510-601-3916.

[email protected]

207WALTERS et al.: SIBLING DONOR CORD BLOOD TRANSPLANTATION

benefit from this intervention, coupled with advances in supportive care, have gen-erated better outcomes after hematopoietic cell transplantation.1–4 Currently, a focusof research is to broaden the availability of transplantation by using hematopoieticstem cell sources other than bone marrow from human leukocyte antigen (HLA)–identical sibling donors.5,6 To this end, we have established and expanded a SiblingDonor Cord Blood (SCDB) Bank that was created to benefit families with thalas-semia major and other disorders treatable by transplantation.7,8 As a public resourcefor families expecting a full sibling of a child with a hematological, immunological,or oncological disorder, more than 1600 cord blood units (CBUs) have been collect-ed, characterized, and cryopreserved by the Sibling Donor Cord Blood Program inOakland, California. In this report, we describe the program, summarize its activityto date, and report the preliminary outcome of transplantation for thalassemia whenCBUs released by our cord blood bank were used.

Cord blood transplantation offers potential benefits in its immediate availability,in a reduced risk of graft-versus-host disease (GVHD) compared with other stem cellsources, particularly among those with genetic disorders for whom the graft-versus-host reaction has no benefit, and in the elimination of risk and discomfort to do-nors.9,10 Its chief disadvantages are a limiting number of hematopoietic progenitorcells and delayed time to engraftment, which together are associated with a risk ofnonengraftment and accompanying opportunistic infections. However, the tempo ofimmune reconstitution is similar to and even more rapid than after transplantationfrom other hematopoietic cell sources.11 Preliminary results of sibling CB transplan-tation for children with severe hemoglobinopathies are particularly encouraging andindicate that this treatment option may prove important in the future.12 To create apublic resource for families and to support future investigations of CB transplanta-tion, we established a CB banking resource in 1998. Although initial CB transplan-tation experience involved directed sibling donations, no standardized resource forsibling CB banking had been developed before this effort, and most reports of um-bilical cord blood (UCB) banking focused on unrelated donors.13,14 In particular,CBUs were rarely available when procurement and processing from remote, com-munity-based hospitals was a requirement for banking. Here, we report the updatedexperience of the SDCB Program and also speculate about when a CBU might bechosen for transplantation in lieu of marrow- or granulocyte-colony stimulating fac-tor (G-CSF)–mobilized peripheral blood stem cells from a sibling donor.

RESULTS

The collection, characterization, and storage of CBUs was performed initially at nocost to participating families, but currently, in response to the growth of the programand its service population, it is performed for a nominal fee to families affected by on-cological disorders, and free of charge to families with hemoglobinopathies. The valueof the program has been validated in part by the sustained referral patterns and by theincreased use of CBUs banked by this program for use in transplantation therapy. Thegrowth of the program stemmed primarily from outreach efforts to inform the profes-sional and lay public about this unique resource. These included the publication of aperiodical newsletter, updated Web site, and dissemination of information about theprogram and transplant outcomes at professional and scientific meetings.

208 ANNALS NEW YORK ACADEMY OF SCIENCES

Since the program’s inception in 1998, the program has enrolled 1751 familiesand banked 1617 CBU collections. The enrollments categorized by disease areshown in FIGURE 1. While 48% of the collections occurred in families affected byhematological malignancies, 28% of collections were performed for sickle cell dis-ease families and 6% for thalassemia families. Families affected by metabolic stor-age disease, immunodeficiency diseases, and other hematological disordersaccounted for 15% of the total. Thus, our outreach efforts to promote enrollment infamilies with hemoglobinopathies have been very successful, and compared with thenational transplantation rates for these disorders, there is a significant overrepresen-tation of hemoglobinopathy families in the SDCB Program Bank. The annual casecollection enrollment is depicted in FIGURE 2 and includes 1751 families enrolledsince the inception of the program. As shown, the distribution of cases enrolled hasnot varied significantly from year to year. The plateau observed in case enrollmentis the consequence of new policies that were instituted to optimize the use of CBUsand to focus on collections in families with hereditary hematological disorders.

The characteristics of the CB units are summarized in TABLE 1. After processing,the median total nucleated cell count was 9.4 ± 6 × 108 and the median CD 34+ cellcontent was 3.7 ± 4.5 × 106. The rate of bacterial contamination as measured by aer-obic and anaerobic culture was 3.3%. Collections with volumes less than 20 mLwere not processed, and these low-volume collections accounted for 4.4% of theCBUs received for processing. Thus, most CBUs underwent processing and cryo-preservation, were free of bacterial contamination, and had a cellular content thatwas projected to be adequate for engraftment, based on the weight of the prospectiverecipient reported to the SDCB Program at collection.

To screen sibling CB collections for transplantation suitability, Class I HLA-A,HLA-B, and class II HLA-DRB1 DNA typing were performed at an intermediatelevel of resolution. Since having a full sibling was a requirement for enrollment,

FIGURE 1. Sibling donor CB collections by disease category. The SDCB Program hasbanked a total of 1617 CB collections since its inception. The demographics by disease cat-egory are depicted in this pie chart, with each category designated by filled segments. Mostcollections occurred for the indication of malignant disorders; however, collections in fam-ilies affected by hemoglobinopathies accounted for many of the cases.


high-resolution (allelic) analysis was used rarely, and only to resolve ambiguitieswhen they occurred in the donor screening. If there was one or fewer antigen mis-match at HLA-A and B, the DRB1 locus was analyzed. Using this strategy, we ob-served that only 33% of cases required class II analysis, as the objective of the CBUbanking program is to identify HLA-identical donor–host pairs.

To date, 1114 of the 1617 CBUs banked have been analyzed by HLA typing.Overall, 259 of the CBUs were HLA identical to the prospective recipient (23%),

TABLE 1. Characteristics of cord blood units processed by the SDCB Program

Mean SD Range

Volume (w/35 mL anticoagulant) 102.1 32.9 31–257

Total nucleated cells (TNC) × 108 9.4 6.0 0.6–53.6

Total mononuclear cells (MNC) × 108 5.1 3.7 0.3–34.8

CD34+/collection × 106 3.7 4.5 0.1–88.1

CFU/collection × 106, n = 1195 1.1 1.3 0.01–13.5.0

Recovery (%), n = 1121 94.3 8.7 41.7–100

NOTE: Failed sterility test: 54 out of 1635 units. Number of CB released: total of 52 units.TNC, MNC, CD34+, and CFU values are postprocessing data.

FIGURE 2. Annual enrollment in the SDCB Program. The number of new cases en-rolled annually in the SDCB Program is presented from 1998 to 2004. The annual enroll-ment is also characterized by disease category, as indicated by hatched segments in thecolumns representing cases. The cumulative enrollment over this period was 1751 cases.


and 16 and 87 CBUs were mismatched for one and two HLA antigens, respectively.Ninety-four collections for thalassemia major were analyzed (α-thalassemia, N = 6and β-thalassemia, N = 88) by HLA typing. Of these, 32 (34%) donor–recipient pairswere HLA identical. Three hundred eighty-nine CBUs were collected from familiesaffected by sickle cell disease. The observed frequency of having an HLA-identicalCBU was 23% (120 of 389) among the sickle cell disease families, and the lower fre-quency compared to thalassemia might reflect a higher degree of HLA heterogeneityamong African-Americans compared with non-African thalassemia populations.

There was a high rate of CBU use for transplantation by families affected bythalassemia major. Of 102 thalassemia collections performed, 15 have been released,and 14 CBUs were used for transplantation (14% of CBUs collected). The rate ofCBU use for transplantation among thalassemia families with HLA-identical sib-lings was 44% (14 of 32). This compares with a usage rate of 9% in sickle cell dis-ease (8 of 89 HLA-identical pairs), 8.5% in acute myelogenous leukemia (7 of 82collections), and 1.4% in acute lymphoblastic leukemia (9 of 636 collections). Thus,it appears that thalassemia families that participate in the SDCB Program are verymotivated to proceed to transplantation if a suitable CBU is identified. Overall, therate of CBU use in related donors is somewhat higher than the rate observed by un-related donor banks, as expected.15,16

To date, 47 patients have proceeded to transplantation, supported by the siblingdonor CBU either alone (N = 37) or in combination with marrow or peripheral bloodstem cells (N = 10) from the same sibling donor as the source of allogeneic hemato-poietic cells. The median follow-up is 12.4 months with a range of 0.5–77 months.These patients had thalassemia (N = 14), sickle cell disease (N = 8), acute leukemia(N = 16), myelodysplastic syndrome (N = 1), or other nonmalignant hematologicaldisorders (N = 8). All but five received HLA-identical sibling allografts, and four pa-tients received haploidentical allografts mismatched at two HLA loci. Thirty-eightof 47 patients survive after transplantation, 36 free of the underlying disease. Themedian time to absolute neutrophil count (ANC) of more than 500 and platelet countof more than 20,000/mm3 was 23 and 45 days, respectively. Graft failure associatedwith disease relapse was observed in two patients with acute leukemia and in one pa-tient with thalassemia, and one additional patient received a CB boost to treat graftrejection after a nonmyeloablative marrow transplantation, and the CB infusion wasunsuccessful in reversing the rejection. Six patients died of relapsed leukemia, onepatient with sickle cell anemia died of intractable seizures approximately 100 daysafter transplantation, and two more patients with hemoglobinopathies died of pul-monary toxicity after CB transplantation. In total, 18 of 22 patients with sickle celldisease or thalassemia survive event-free after transplantation, which includes 12 of14 patients with thalassemia major. One patient with thalassemia had disease recur-rence after transplantation.

The Kaplan–Meier probability of survival after sibling donor CB transplantationis 75% among 44 patients for whom there is at least 6 months of follow-up (FIG. 3).The indications for transplantation are shown in the figure, and include five patientswho received HLA-mismatched CB grafts for advanced disease. The transplantswere performed in 31 U.S. transplantation centers, and patients were prepared witha variety of conditioning regimens that were tailored to the underlying disease. Sim-ilarly, therapy to prevent GVHD varied from center to center. There were no deathsrelated to GVHD.


FIG

UR

E3.

Sur

viva

l an

d ev

ent-

free

sur

viva

l af

ter

sibl

ing

dono

r C

B t

rans

plan

tati

on.

The

Kap

lan–

Mei

er p

roba

bili

ties

of

surv

ival

and

eve

nt-f

ree

surv

ival

aft

er s

ibli

ng d

onor

CB

tran

spla

ntat

ion

is s

how

n. T

ime

afte

r tr

ansp

lant

atio

n in

mon

ths

is in

dica

ted

in th

e x

axis

. Eve

nts

wer

e de

fine

d as

dea

th,

graf

t re

ject

ion,

or

rela

pse,

and

pat

ient

s w

ere

cens

ored

at

the

tim

e of

an

even

t. T

he i

ndic

atio

ns f

or t

rans

plan

tati

on a

re s

how

n.


DISCUSSION

Despite the challenge of remote-site CB collections caused by the unpredictabletiming of birth and linguistic and cultural barriers, this experience demonstrates thatsibling CBU collection in the United States can be accomplished in a closed collec-tion system, with uniform standardized procedures and rigorous quality systems.Approximately 90% of units processed by the program had characteristics that madethem acceptable for allogeneic CB transplantation. The transplantation outcomes re-ported here strongly suggest that sibling CBUs will continue to be used, especiallyin children with thalassemia major and other hereditary disorders. It is notable thatwe have observed this usage pattern even though, in most instances, bone marrowharvesting from the same sibling donor was also available. Use of CBUs by childrenwith malignant diseases was lower, but this reflects the fact that more than 95% ofthese children were receiving either primary induction therapy or were in a first re-mission at the time of sibling CB banking. While a longer period of follow-up willbe necessary to determine the true rate of sibling CB use for malignant disorders, ourpreliminary experience suggests that more families with hereditary hematologicaldisorders are motivated to proceed immediately to sibling CB transplantation.

This preliminary experience also indicates that, like marrow, CB might also beconsidered as an acceptable source of allogeneic cells for HLA-identical sibling he-matopoietic cell transplantation. The principal advantage in the setting of hereditarydisorders such as thalassemia major has to do with a lowered risk of GVHD aftertransplantation, a complication that has no apparent beneficial effect for these disor-ders, but rather is a leading cause of morbidity and mortality after transplantation.1

This benefit, however, must be weighed carefully against the potential for delayedengraftment and graft rejection, which also can contribute to the toxicity of trans-plantation.12 This risk has been countered successfully by the administration of im-munosuppressive therapy before transplantation and by the supplementation withsibling donor marrow when the cellular content of the CBU is judged insufficient toguarantee engraftment. This strategy has proved quite successful as demonstrated bythe excellent outcomes after SDCB transplantation reported here. Together with avery high rate of use and enthusiastic participation by families who could benefitfrom this program, we believe that banking sibling CBUs represents an importantpublic resource, which warrants ongoing support to expand and maintain this ser-vice. In addition, it is possible and even likely that this bank will act as a core re-source to support ongoing and future research aimed at studying the capacity of UCBstem cells to repair preexisting organ damage after transplantation and to study novelgene transfer vectors whose transduction rates might be optimized in UCB stemcells.

REFERENCES

1. GAZIEV, J. & G. LUCARELLI. 2005. Stem cell transplantation for thalassaemia. Reprod.Biomed. Online 10: 111–115.

2. LUCARELLI, G., M. GALIMBERTI, P. POLCHI, et al. 1990. Bone marrow transplantation inpatients with thalassemia. N. Engl. J. Med. 322: 417–421.

3. SODANI, P., D. GAZIEV, P. POLCHI, et al. 2004. New approach for bone marrow trans-plantation in patients with class 3 thalassemia aged younger than 17 years. Blood104: 1201–1203.


4. THOMAS, E.D., C.D. BUCKNER, J.E. SANDERS, et al. 1982. Marrow transplantation forthalassaemia. Lancet 2: 227–229.

5. GAZIEV, D., M. GALIMBERTI, G. LUCARELLI, et al. 2000. Bone marrow transplantationfrom alternative donors for thalassemia: HLA-phenotypically identical relative andHLA-nonidentical sibling or parent transplants. Bone Marrow Transplant. 25: 815–821.

6. LA NASA, G., C. GIARDINI, F. ARGIOLU, et al. 2002. Unrelated donor bone marrow trans-plantation for thalassemia: the effect of extended haplotypes. Blood 99: 4350–4356.

7. REED, W., R. SMITH, F. DEKOVIC, et al. 2003. Comprehensive banking of sibling donorcord blood for children with malignant and nonmalignant disease. Blood 101: 351–357.

8. REED, W., M. WALTERS & B.H. LUBIN. 2000. Collection of sibling donor cord blood forchildren with thalassemia. J. Pediatr. Hematol. Oncol. 22: 602–604.

9. ROCHA, V, J.E. WAGNER, JR., K.A. SOBOCINSKI, et al. 2000. Graft-versus-host disease inchildren who have received a cord-blood or bone marrow transplant from an HLA-identical sibling. Eurocord and International Bone Marrow Transplant RegistryWorking Committee on Alternative Donor and Stem Cell Sources. N. Engl. J. Med.342: 1846–1854.

10. BARKER, J.N. & J.E. WAGNER. 2003. Umbilical cord blood transplantation: currentpractice and future innovations. Crit. Rev. Oncol. Hematol. 48: 35–43.

11. TALVENSAARI, K., E. CLAVE, C. DOUAY, et al. 2002. A broad T-cell repertoire diversityand an efficient thymic function indicate a favorable long-term immune reconstitu-tion after cord blood stem cell transplantation. Blood 99: 1458–1464.

12. LOCATELLI, F., V. ROCHA, R.W. REED, et al. 2003. Related umbilical cord blood trans-plantation in patients with thalassemia and sickle cell disease. Blood 101: 2137–2143.

13. COHEN, Y., D. KREISER, M. MAYOROV & A. NAGLER. 2003. Unrelated and related cordblood banking and hematopoietic graft engineering. Cell Tissue Bank 4: 29–35.

14. RUBINSTEIN, P., C. CARRIER, A. SCARADAVOU, et al. 1998. Outcomes among 562 recipi-ents of placental-blood transplants from unrelated donors. N. Engl. J. Med. 339:1565–1577.

15. KOGLER, G., T. SOMVILLE, G.U. GOBEL, et al. 1999. Haematopoietic transplant poten-tial of unrelated and related cord blood: the first six years of the EUROCORD/NET-CORD Bank Germany. Klin. Padiatr. 211: 224–232.

16. RUBINSTEIN, P., J.W. ADAMSON & C. STEVENS. 1999. The Placental/Umbilical CordBlood Program of the New York Blood Center. A progress report. Ann. N.Y. Acad.Sci. 872: 328–334; discussion 334–335.

sibling donor cord blood transplantation for …...identical and 14 have received cord blood...

Documents