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222 Cancer Control October 2011, Vol. 18, No. 4

tation. UCB is now used in a growing number of trans-plant centers worldwide for the treatment of metabolic and deposit diseases, bone marrow failure syndromes, hemoglobinopathies, and malignancies. As the number of UCB transplant procedures has increased, a growing body of evidence has demonstrated that this alternative source of HSCs could, at least in part, close the gap in fi nding a donor for patients who require a potentially curative allo-geneic transplant but lack a suitable related or unrelated adult donor. The use of UCB is standard practice in pe-diatrics and has become an expanding practice in adults for the treatment of malignant diseases. The advantages of UCB transplantation include rapid availability, low risk of infection transmission, absence of donor risk, and the relatively lower risk of graft-vs-host disease (GVHD) with

From the Blood and Marrow Transplant Program and Division of Hematology, Oncology and Transplantation at the University of Minnesota, Minneapolis, Minnesota.

Submitted February 8, 2011; accepted May 3, 2011.

Address correspondence to Claudio G. Brunstein, MD, PhD, De-partment of Medicine, University of Minnesota, Mayo Mail Code 480, 420 Delaware Street, SE, Minneapolis, MN 55455. E-mail: [email protected]

No signifi cant relationship exists between the author and the com-panies/organizations whose products or services may be refer-enced in this article.

Gene Elling. St. Lucia. Photograph.

Umbilical cord blood transplantation

is a useful treatment in several types

of hematologic malignancies.

Umbilical Cord Blood Transplantation for the Treatment of Hematologic Malignancies

Claudio G. Brunstein, MD, PhD

Background: The use of unrelated umbilical cord blood (UCB) has grown as an allogeneic source of hematopoietic cells for transplantation of patients with hematologic malignancies. As the number of UCB transplantation procedures has grown, an increasing number of publications have focused on disease-specifi c outcomes.Methods: This review focuses on the outcome data following UCB transplantation in subsets of hematologic malignancies in which experience with this graft source is greater.Results: Registry and single-institution reports regarding the outcomes of children and adults with acute leukemias after UCB transplantation include many patients, while data on the clinical outcomes of other leukemias are limited due in part to the small number of patients with these diseases. UCB is now routinely used as a source of hematopoietic stem cells (HSCs) in pediatric allogeneic transplantation when a suitable sibling donor is not available. Data also support the use of UCB as an alternative source of HSC for transplantation of patients with hematologic malignancies who lack a more conventional donor. Current data also support UCB for patients who require an allograft in the setting of prospective clinical trials.Conclusions: Along with safety and feasibility in UCB transplantation, continued study is needed that focuses on issues such as accelerating engraftment, extending access, ensuring quality, and examining outcomes in specifi c subgroups of patients.

IntroductionOver the last decade we have seen a signifi cant increase in the use of umbilical cord blood (UCB) as a source of hematopoietic stem cells (HSCs) for allogeneic transplan-

October 2011, Vol. 18, No. 4 Cancer Control 223

preserved graft-vs-malignancy effects. The disadvantages of UCB transplantation are the limited cell dose, delayed engraftment, and lack of additional immune cells if donor lymphocytes are needed. Controversial issues include, but are not limited to, immune reconstitution and risk of infections. While advances have improved results with UCB transplantation, outcomes with matched unrelated transplants have also improved. Determining the optimal source requires further study and is beyond the scope of this manuscript.

The fi eld of UCB transplantation has advanced from investigating its safety and feasibility to addressing more specifi c issues such as accelerating engraftment, extend-ing access, ensuring quality and, importantly, examining outcomes in specifi c subgroups of patients. This review focuses on our current knowledge about disease-specifi c outcomes with UCB transplantation.

LeukemiaLeukemia is currently the disease subset in which the largest amount of data is available regarding UCB trans-plantation, in particular acute leukemia. Registry and single-institution reports on the outcomes of both chil-dren and adults with acute leukemias after UCB trans-plantation include hundreds of patients. However, data on the clinical outcomes of other leukemias are limited due in part to the small number of patients with these diseases. Although most series on the outcomes of hema-tologic malignancies after UCB transplantation include a small number of patients with chronic myeloid leukemia (CML), myelodysplastic syndrome (MDS), and other my-eloproliferative disease, only a few reports address the specifi c outcomes associated with these diseases.

Acute Leukemia in ChildrenEarly reports of UCB transplantation tended to refl ect the outcomes of pediatric patients, with acute leukemia representing 30% to 50% of patients in most series.1-9 These initial series consisted mostly of pediatric patients, mainly because the cell dose available from a single UCB unit was not suffi cient for use with larger adolescent and adult patients.

Data on outcomes of children with acute leukemia fi rst became available in the late 1990s. Table 1 summa-rizes these outcomes from selected publications of the treatment of children with acute leukemia.7,10-18 These are mostly manuscripts that describe comparisons to other HSC sources. Acute leukemia patients were re-ported to have engraftment rates of about 80%, with treatment-related mortality (TRM) rates of 44%, relapse rates of approximately 40%, and event-free survival rates at 2 years of 30% to 40%.10,13 More recently, data on the treatment of acute leukemia from the Cord Blood Trans-plantation Study (COBLT) were reported.16,18 The data on infants and young children with acute leukemia showed rates of neutrophil engraftment of only 60%, relapse of

31%, and a probability of survival at 1 year of 47%.16 In a more recent report from COBLT on children with hema-tologic malignancies, 84% of whom had acute leukemia, the cumulative incidence of neutrophil engraftment was 80%, the relapse rate at 2 years was 20%, and the 2-year survival rate was 50%.18 In this later study, children who received better HLA-matched grafts achieved better sur-vival. These studies, however, included mostly patients treated in the 1990s, a time period in which the standard cell dose was lower and UCB grafts with up to 3 HLA mismatches were used more frequently. Moreover, the methodology of HLA typing changed, making it diffi cult to compare older reports with more recent series. The fi rst studies comparing UCB to unrelated adult donor (URD) bone marrow showed promising results with similar to slightly inferior outcomes after UCB transplan-tation.11,12,14 A registry-based landmark analysis by the Center for International Blood and Marrow Transplant Research (CIBMTR) compared UCB to the gold standard of 7–8/8 allele-matched URD bone marrow grafts.17 This study of recently treated patients again showed delayed neutrophil engraftment even though patients received UCB grafts that were selected based on modern standards of cell dosage for UCB graft selection. Interestingly, 4 of 6 HLA-matched UCB grafts had a higher TRM but a lower relapse risk, while 5–6/6 HLA-matched UCB grafts had a lower TRM and higher relapse risk. In contrast to prior studies comparing UCB to URD, this study showed that 6 of 6 HLA-matched UCB grafts had superior leukemia-free survival, compared to less well-matched UCB grafts and to URD grafts (Fig 1).17

Thus, considering the substantial body of evidence and experience of UCB transplantation for the treatment of acute leukemia in children, UCB is now routinely used as a source of HSC in pediatric allogeneic transplantation when a suitable sibling donor is not available.

Acute Leukemia in AdultsThe feasibility of UCB transplant in adults with acute leu-kemia was initially established by a large registry-based study of 68 patients (34 adults with acute leukemia)6 and by the adult cohort of COBLT, which included mostly acute leukemia patients.19 These early studies demon-strated that engraftment was poor in the small number of long-term survivors due in part to the nature of the study population, which consisted of many heavily pretreated patients with high-risk disease.

More recently, studies comparing the outcomes of adults with leukemia who received either UCB or adult donor HSC sources have become available (Table 2).20-28 Two landmark papers in particular advanced the fi eld of UCB transplantation in adults.20,21 These studies com-pared the outcomes of adults with leukemia undergoing transplantation with UCB or unrelated donor bone mar-row after myeloablative conditioning. In these studies, analysis of HLA-A and -B typing at the antigen level and


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4.7

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Cont

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5


Tabl

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— U

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Tran

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Chro

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DRB1 at the allele level was performed, and leukemia-free survival was similar for recipients of UCB and unrelated donor bone marrow. Despite some methodological dif-ferences, these studies reported that leukemia-free sur-vival for UCB was similar to mismatched URD and similar to slightly inferior to matched URD. These studies set the stage for an increase in the utilization of UCB as a source of HSC for adult transplantation worldwide. More recently, two additional registry-based studies revisited the issue of the effi cacy of UCB relative to URD grafts.26,27 A study from the Japan Cord Blood Bank Network and the Japan Marrow Donor Program examined the out-comes of patients with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) who received 4–6/6 HLA-matched UCB grafts to 8/8 allele-matched URD bone marrow.26 Both ALL and AML patients were found to have signifi cantly lower rates of neutrophil engraftment. Relapse rates were similar for both graft sources. Notably, while outcomes for ALL patients were similar for both graft sources, UCB recipients with AML had a higher rate of TRM and a lower rate of leukemia-free survival compared to bone marrow transplantation (Table 2). The authors attributed these fi ndings not only to delayed engraftment after UCB transplantation but also to the relative risk of acute and chronic GVHD among bone marrow recipients. A collaboration between the CIBMTR and Eurocord registries led to an updated study in adult patients with leukemia comparing UCB to URD grafts.27 In contrast to prior registry studies, this analysis compared the outcomes of 4–6/6 HLA-matched UCB grafts with a cryopreserved nucleated cell dose of ≥ 2.5

× 107/kg to 7–8/8 allele-matched URD grafts from bone marrow and/or peripheral blood. While TRM was higher among recipients of UCB, the leukemia-free survival was similar for all graft types, thus further supporting the utilization of UCB as an alternative source of HSC for patients with low-risk and high-risk leukemia (Fig 2) with no HLA-matched unrelated donor. Single institutions have also compared UCB with adult donor stem cell sources in cohorts that largely consisted of patients with leukemia.22-26 Takahashi et al22 studied 113 patients with hematologic malignancies (70% with acute leukemia) who received either 3–6/6 HLA-matched UCB or 5–6/6 HLA-matched URD grafts. In contrast to registry-based studies, they observed a lower risk of TRM and better disease-free survival after UCB transplantation. Another report by Takahashi et al23 compared 171 patients with hematologic malignancies (70% with acute leukemia) who received either UCB or related donor grafts (pe-ripheral blood and bone marrow). While the incidence of severe acute and extensive chronic GVHD was lower in recipients of UCB grafts, the incidences of grade II–IV GVHD, TRM, relapse, and disease-free survival were simi-lar for both HSC sources.

As the number of adults receiving UCB transplanta-tion is still relatively small, most series have not provided outcomes for specifi c leukemia subtypes. Reports on the outcomes of patients with AML are promising, with fac-tors that infl uence these outcomes ranging from graft selection to disease stage at transplantation.29-31 Ooi et al29 reported on 18 patients with de novo AML who received single UCB grafts after myeloablative condition-

Time After Transplantation (Years)

Ad

just

ed P

rob

abili

ty (

%)

0

20

40

60

80

100

HLA-matched cord blood 35 20 13 81117

0 1 3 42 5

HLA-matched bone marrow 116 62 35 2945 24One-mismatched cord blood (high cell dose) 157 72 44 3255 25

HLA-mismatched bone marrow 166 77 53 4460 30One-mismatched cord blood (low cell dose) 44 19 12 1013 6

Two-mismatched cord blood 267 100 49 3467 21

Number at Risk

Fig 1. — Leukemia-free survival of children with acute leukemia after myeloablative single umbilical cord blood or unrelated donor bone marrow transplantation. From Eapen M, Rubinstein P, Zhang MJ, et al. Outcomes of transplantation of unrelated donor umbilical cord blood and bone marrow in children with acute leukaemia: a comparison study. Lancet. 2007;369(9577):1947-1954. Reproduced with permission from Elsevier.


Tabl

e 2.

— S

tudi

es C

ompa

ring

Umbi

lical

Cor

d Bl

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to O

ther

Typ

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f Don

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plan

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n of

Adu

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mia

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ias

Incl

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Sour

ceNo

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nts

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ian

Age

(Ran

ge)

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Tim

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≥

500/

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× 1

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e GV

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(% o

r RR

and

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nic

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(% o

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Su

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al(%

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Laug

hlin

et a

l20

2004

AML

ALL

MDS

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150

(16–

60)d

2760

0.81

a

(0.5

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10)

0.66

b

(0.4

4–0.

99

1.62

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42)

1.12

(0.6

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02)

0.73

(0.4

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0.85

(0.4

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70)

1.89

(1

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99

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1.48

(1

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94

(0.6

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28)

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row

367

(16–

60)d

2029

1.0a

1.0a

1.0a

1.0a

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row

83(1

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Roch

a et

al21

2004

AML

ALL

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9825

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26NA

0.57

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0.64

(0.3

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02(0

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13(0

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0

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1.9

3.5

0.7

0

Taka

hash

i et a

l22

2004

AML

ALL

MDS

CML

UCB

6836

(16–

53)

2240

0.61

(0.3

7–1.

01)

0.60

(0.2

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28)

0.75

(0.1

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56)

0.32

(0.1

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86)

0.27

(0.1

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51)

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mar

row

4526

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50)

1825

1.0

1.0

1.0

1.0

1.0

P Va

lue

.01

.01

.05

.18

.73

.02

< .0

1

Taka

hash

i et a

l23

2007

AML

ALL

MDS

CML

UCB

9238

2240

1.09

(0.7

1–1.

68)

0.49

(0.2

9–0.

85)

0.72

(0.4

4–1.

25)

0.49

(0.1

9–1.

24)

0.74

(0.4

4–1.

25)

REL

7140

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01.

01.

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0

P Va

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< .0

1<

.01

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.01

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.13

.26

Cont

inue

s on

pag

e 22

8


Tabl

e 2.

— S

tudi

es C

ompa

ring

Umbi

lical

Cor

d Bl

ood

to O

ther

Typ

es o

f Don

ors

for T

rans

plan

tatio

n of

Adu

lts W

ith L

euke

mia

Refe

renc

eLe

ukem

ias

Incl

uded

HSC

Sour

ceNo

. of

Patie

nts

Med

ian

Age

(Ran

ge)

Med

ian

Tim

e to

ANC

≥

500/

µL(d

ays)

Med

ian

Tim

e to

Pla

tele

t Co

unt

> 20

× 1

09 /L(d

ays)

Acut

e GV

HD

II–IV

(% o

r RR

and

95%

CI)

Chro

nic

GVHD

(% o

r RR

and

95%

CI)

Rela

pse

(% o

r RR

and

95%

CI)

Trea

tmen

t-Re

late

d M

orta

lity

(% o

r RR

and

95%

CI)

Dise

ase-

Free

Su

rviv

al(%

or R

R an

d 95

% C

I)

Kum

ar e

t al24

2008

ALL

UCB

1930

NANA

32e

165

3461

MRD

9030

NANA

20e

2226

4427

URD

1532

NANA

10e

4720

5313

URD

MM

1431

NANA

7e21

086

14P

Valu

e1.

0.6

4e.0

1.0

8<

.01

< .0

1

Tom

blyn

et a

l25

2009

ALL

UCB

6913

NANA

NANA

0.6

(0.3

–1.1

)1.

5(0

.8–3

.1)

0.9

(0.5

–1.4

)UR

D M

M58

NANA

NANA

0.4

(0.2

–1.0

)2.

2b

(1.4

–3.5

)1.

4(1

.0–2

.0)

pmUR

D23

NANA

NANA

1.0

(0.4

–2.5

)1.

4(0

.6–3

.0)

1.1

(0.6

–2.0

)w

mUR

D19

NANA

NANA

0.5

(0.2

–1.5

)0.

9(0

.4–2

.2)

0.8

(0.4

–1.5

)AU

TO20

9NA

NANA

NA2.

2a

(1.6

–3.1

)0.

6c

(0.4

–1.0

)1.

4(1

.1–1

.8)

REL

245

NANA

NANA

1.0

1.0

1.0

P V

alue

< .0

1a<

.01b

.05c

NS

Atsu

ta e

t al26

2009

AML

UCB

173

38NA

NA32

2831

3036

URD

311

38NA

NA35

3224

1954

P Va

lue

.39

.46

.067

.004

< .0

01AL

LUC

B AL

L11

434

NANA

2827

3133

45UR

D AL

L22

232

NANA

4230

2422

51P

Valu

e.0

08.5

0.0

85.8

3.0

6

Cont

inue

s on

pag

e 22

9


Tabl

e 2.

— S

tudi

es C

ompa

ring

Umbi

lical

Cor

d Bl

ood

to O

ther

Typ

es o

f Don

ors

for T

rans

plan

tatio

n of

Adu

lts W

ith L

euke

mia

Refe

renc

eLe

ukem

ias

Incl

uded

HSC

Sour

ceNo

. of

Patie

nts

Med

ian

Age

(Ran

ge)

Med

ian

Tim

e to

ANC

≥

500/

µL(d

ays)

Med

ian

Tim

e to

Pla

tele

t Co

unt

> 20

× 1

09 /L(d

ays)

Acut

e GV

HD

II–IV

(% o

r RR

and

95%

CI)

Chro

nic

GVHD

(% o

r RR

and

95%

CI)

Rela

pse

(% o

r RR

and

95%

CI)

Trea

tmen

t-Re

late

d M

orta

lity

(% o

r RR

and

95%

CI)

Dise

ase-

Free

Su

rviv

al(%

or R

R an

d 95

% C

I)

Eape

n et

al27

2010

AML

ALL

UCB

165

2824

52NA

NANA

NANA

URD

mar

row

332

3919

280.

78

(0.5

6–1.

08)

0.63

(0.4

4–0.

90)

0.85

(0.5

9–1.

20)

1.69

(1.1

9–2.

39)

1.15

(0.9

0–1.

47)

URD

mar

row

MM

140

0.59

(0.4

1–0.

86)

0.59

(0.3

9–0.

90)

0.84

(0.5

5–1.

28)

1.06

(0.7

2–1.

58)

0.93

(0.6

9–1.

24)

URD

PB63

233

1419

0.57

(0.4

2–0.

77)

0.38

(0.2

7–0.

53)

0.85

(0.6

1–1.

17)

1.62

(1.1

8–2.

23)

1.12

(0.8

9–1.

39)

URD

PB

MM

256

0.49

(0.3

5–0.

68)

0.46

(0.3

2–0.

67)

0.91

(0.6

7–1.

32)

0.95

(0.6

8–1.

34)

0.91

(0.7

1–1.

17)

P Va

lue

< .0

001

< .0

001

NA.0

01<

.000

1.8

6<

.000

1.0

9

Brun

stei

n et

al28

2010

AML

ALL

MDS

CML

dUCB

128

2526

531.

01.

01.

01.

01.

0M

RD20

440

1620

1.08

(0.8

2–1.

43)

1.58

a

(1.0

3–2.

43)

3.67

a

(2.1

4–6.

27)

0.31

a (0

.18–

0.53

)1.

09(0

.80–

1.49

)UR

D15

231

1921

1.83

a

(1.3

6–2.

47)

1.71

b

(1.1

2–2.

63)

3.05

a

(2.1

4–6.

27)

0.61

(0.3

3–1.

15)

0.85

(0.6

1–1.

20)

URD

MM

5231

18.5

212.

35a

(1.5

2–3.

63)

2.07

b

(1.1

9–3.

60)

2.50

a

(1.2

3–5.

07)

0.38

a

(0.2

4–0.

59)

1.12

(0.7

3–1.

73)

P Va

lue

< .0

1<

.01

< .0

1<

.01

.03a

.01b

< .0

1<

.01

NS

a Ind

icat

es re

latio

n be

twee

n pe

rcen

tage

or R

R re

sults

in th

e sp

ecifi

c ta

ble

colu

mn

and

the

P va

lues

for t

hat c

olum

n w

ithin

the

sam

e st

udy.

b RR

appl

ies

to c

ompa

rison

bet

wee

n UC

B co

mpa

red

to m

atch

ed U

RD.

c RR

appl

ies

to c

ompa

rison

bet

wee

n UC

B co

mpa

red

to m

ism

atch

ed U

RD.

d Age

repo

rted

by in

terv

als

of 1

6–20

, 21–

30, 3

1–40

, 41–

50, a

nd 5

1–60

. No

med

ian

avai

labl

e.e R

efer

s to

gra

de II

I–IV

acu

te G

VHD.

Dat

a on

gra

de II

–IV

wer

e no

t ava

ilabl

e.HS

C =

hem

atop

oiet

ic s

tem

cel

l, AN

C =

abso

lute

neu

troph

il co

unt,

GVHD

= g

raft-

vs-h

ost d

isea

se, A

ML

= ac

ute

mye

loid

leuk

emia

, ALL

= a

cute

lym

phob

last

ic le

ukem

ia, M

DS =

mye

lody

spla

stic

syn

drom

e,

UCB

= um

bilic

al c

ord

bloo

d, U

RD =

unr

elat

ed d

onor

, URD

MM

= H

LA-m

ism

atch

ed u

nrel

ated

don

or, C

ML

= ch

roni

c m

yelo

id le

ukem

ia, R

EL =

rela

ted

dono

r with

no

refe

renc

e to

HLA

-mat

chin

g, M

RD =

mat

ched

un

rela

ted

dono

rs, p

mUR

D =

parti

ally

HLA

-mat

ched

unr

elat

ed d

onor

, wm

URD

= w

ell H

LA-m

atch

ed u

nrel

ated

don

or, A

UTO

= au

tolo

gous

don

or, d

UCB

= do

uble

um

bilic

al c

ord

bloo

d, C

I = c

onfi d

ence

inte

rval

, NS

= n

ot s

igni

fi can

t.


ing. Seventeen of the 18 patients achieved neutrophil recovery, and 16 achieved sustained platelet recovery. Half of the 6 patients died of AML relapse. One patient died of treatment-related causes. At the time of the re-port, 14 patients were alive and disease-free, resulting in a disease-free survival rate of 77% at 2 years. In a more recent report, Sanz et al30 evaluated 49 adults with AML treated with myeloablative UCB transplantation. In this study, UCB selection took into consideration both the nucleated and CD34+ cell doses. The cumulative inci-dence rates of neutrophil and platelet engraftment were 96% and 73%, respectively. The incidence of TRM was 39%, with a relapse rate of 19% at 2 years. The overall leukemia-free survival rate in this cohort was 37% at 4

years, which was infl uenced by the infused nucleated cell dose. A preliminary study describing the outcomes of AML after reduced-intensity conditioning was presented at the 2006 American Society of Hematology meeting.31 This study included patients with high-risk AML who received either a 4–6/6 HLA-matched UCB graft (n = 43) or an HLA-matched sibling peripheral blood stem cell (PBSC) graft (n = 21). Most of the UCB grafts (n = 28) consisted of two UCB units. In this limited number of patients, the proportion of engraftment was not signifi -cantly lower after UCB (88% vs 100%, P = .10). When comparing UCB and PBSC recipients, there were similar incidence rates of TRM at 1 year (28% vs 38%, P = .43) and relapse rates at 2 years (35% vs 35%, P = .72), resulting

Fig 2. — Leukemia-free survival of adults with acute leukemia after myeloablative transplantation comparing single umbilical cord blood to unrelated donor 7–8/8 allele level HLA-matched bone marrow and peripheral blood with low- (A) and high-risk disease (B). PBPC = peripheral blood progenitor cells, UCB = umbilical cord blood. From Eapen M, Rocha V, Sanz G, et al. Effect of graft source on unrelated donor haemopoietic stem-cell transplantation in adults with acute leukaemia: a retrospective analysis. Lancet Oncol. 2010;11(7):653-660. Reproduced with permission from Elsevier.

A

B

8/8 matched bone marrowNumber at Risk

7/8 matched bone marrow8/8 matched PBPC7/8 matched PBPC

4/6–6/6 matched UCB

246106452166123

17769

3168977

13946

2206647

9935

1434530

82

Months

Leu

kem

ia-F

ree

Su

rviv

al (

%)

100

80

50

40

20

0

90

70

60

30

10

Bone marrow matchedBone marrow mismatchedPBPC matchedPBPC mismatchedUCB

Bone marrow matchedBone marrow mismatchedPBPC matchedPBPC mismatchedUCB

0 6 12 18 24

311123624

8/8 matched bone marrowNumber at Risk

7/8 matched bone marrow8/8 matched PBPC7/8 matched PBPC

4/6–6/6 matched UCB

8634

1809042

3112633417

175

391910

133

1912

9

10

Leu

kem

ia-F

ree

Su

rviv

al (

%)

100

80

50

40

20

0

90

70

60

30

10

Months0 6 12 18 24

314

86


in similar survival rates at 2 years (31% vs 32%, P = .62). In multivariate analysis, only the disease-risk group was associated with an increased relative risk (RR) of relapse (RR = 2.9, 95% confi dence interval [CI], 1.3–6.2, P < .01) and death (RR = 2.6, 95% CI, 1.1–5.5, P = .02). Inves-tigators at the University of Minnesota compared the outcomes of UCB to other graft sources after myeloabla-tive conditioning for the treatment of ALL.24,25 Signifi cant differences were reported among the stem cell sources regarding year of transplantation, time from diagnosis to transplantation and, as expected, cell doses infused. The worst outcomes were observed after autologous transplantation25 and mismatched URD graft.24,25 While other graft sources including UCB had similar leukemia-free survival, other factors that were predictors of poorer outcome were advanced disease (≥ CR3), white blood cell count ≥ 30 × 109/L at diagnosis, a cytomegalovirus seropositive recipient or donor, and ≥ 2 induction cycles to achieve a complete response. In patients transplanted in CR1–2, independent predictors of poorer outcomes were older age, white blood cell count ≥ 30 × 109/L at diagnosis, and mismatched URD graft.

Cell dose is well recognized as a factor that infl u-ences outcomes following UCB transplantation. This is a particular problem for adults for whom fi nding a single unit with an adequate cell dose to proceed to transplanta-tion can be diffi cult. A recent collaboration between the University of Minnesota and the Fred Hutchinson Cancer Research Center compared the outcomes of leukemia patients after double UCB transplantation to adult-related and URD adult donor grafts after cyclophosphamide/total body irradiation (TBI)-based myeloablative conditioning28 (Table 2). Double UCB transplantation has been shown to overcome, at least in part, the cell dose limitation imposed by single UCB grafts. While the combination of 2 UCB units provides a graft suitable to proceed to transplantation, neutrophil engraftment was still delayed following double UCB compared to adult donor grafts

as previously observed in single UCB transplants. The TRM rate was signifi cantly higher after double UCB and was largely infl uenced by delayed engraftment. For patients who recovered neutrophil counts before 26 days, which was the median time to neutrophil recovery among double UCB recipients, TRM was similar to other donor types. In contrast, patients recovering neutrophil counts after 26 days had substantially higher TRM. The higher TRM among double UCB recipients was offset by a signifi cantly lower relapse risk in this group. While the mechanism behind the lower relapse rate is poorly understood and requires confi rmation in prospective trials, the net result was that leukemia-free survival was equivalent for all donor types (Fig 3).28

A large proportion of patients with acute leukemia are older and not candidates for treatment with con-ventional myeloablative conditioning regimens. Similar to the myeloablative setting, early studies in the non-myeloablative setting included a signifi cant proportion of patients with acute leukemia.32,33 While preliminary reports suggest similar outcomes for AML patients when comparing UCB and related donor grafts in the nonmy-eloablative setting,31 additional study is needed. An on-going analysis by CIBMTR is comparing acute leukemia outcomes after reduced-intensity conditioning between UCB and URD peripheral blood grafts, and initial results are expected soon.

Taken together, these data support the utilization of UCB as an alternative source of HSC for transplanta-tion of patients with acute leukemia who lack a suitable related donor.

Chronic Myeloid LeukemiaSince tyrosine kinase inhibitors became the fi rst line of therapy for CML,34-37 this type of leukemia went from being the most common indication of allogeneic trans-plantation38 to one of the least frequent ones. The in-troduction of tyrosine kinase inhibitors also coincided with the increased interest in UCB as a source of HSCs. Considering the effi cacy of donor lymphocyte infusion for the treatment of relapsed hematologic malignancies, CML is by far the leukemia with the highest response rates.39-41 As there are no donor lymphocytes available from UCB, URD grafts are a more desirable HSC source for patients with CML. Still, a substantial number of patients with CML may not be able to fi nd a suitable adult donor and would require an alternative HSC graft source. Limited data on the outcomes of CML patients after UCB transplantation have been described in case reports42,43 and small case se-ries.44-47 Initial reports suggested that engraftment was re-duced in patients with CML compared to those with other leukemias. However, this effect was likely due to small cell dose since most CML patients were adults receiving what would now be considered a suboptimal cell dose for UCB grafts.5 Sanz et al46 initially reported on 9 adults who received a UCB transplant in chronic phase (CP1, n

Years Post-Transplantation

Cu

mu

lati

ve P

rop

ort

ion

1.0

0.0

0.2

0.6

0.8

0.4

0 1 2 3 4 5

Double umbilical cord blood

Mismatched unrelated donorMatched unrelated donorMatched related donor

Fig 3. — Leukemia-free survival of adults with leukemia after myeloablative transplantation comparing double umbilical cord blood to matched related donor and 7-8/8 allele level HLA-matched unrelated donors. From Brunstein CG, Gutman JA, Weisdorf DJ, et al. Allogeneic hematopoietic cell trans-plantation for hematologic malignancy: relative risks and benefi ts of double umbilical cord blood. Blood. 2010;116(22):4693-4699. Reproduced with permission from American Society of Hematology (ASH).


= 5; CP2, n = 1), accelerated phase (n = 1) or blast crisis (n = 2). All had failed more conventional treatments and autologous transplantation (n = 3) and lacked a suitable unrelated or related donor. Patients were conditioned with a myeloablative regimen using a combination of thiotepa, busulfan, cyclophosphamide or fl udarabine, and antithymocyte globulin (ATG). Four of the 9 patients, all transplanted in chronic phase, had prolonged remissions. This group recently updated their experience, reporting outcomes for 26 patients who received the same condi-tioning regimen.47 Most patients were in chronic phase (CP1, n = 7; CP2, n = 11). All patients in accelerated phase or blast crisis died of transplant-related causes. For the whole cohort, the disease-free survival rate at 8 years was 41% for all patients and 59% for only chronic phase patients. In another report, 20 patients with CML (CP1, n = 6; accelerated phase, n = 14) received UCB transplants after myeloablative (n = 12) or nonmyeloablative (n = 8) conditioning.45 With the exception of time to neutrophil engraftment, which was longer for myeloablation (21 vs 13 days), both conditioning regimens resulted in similar rates of acute GVHD, TRM, relapse, and survival. Notably, the relapse rate was approximately 10% and the overall survival rate was 50%. Although a large proportion of patients were transplanted with advanced disease, relapse rates were low, suggesting a potent graft-vs-leukemia ef-fect of UCB in CML.5,44-47

Myelodysplastic SyndromeMDS is a relatively uncommon hematologic malignancy, and the only potentially curative therapy for MDS is allo-geneic HSC transplantation. Ooi et al48 initially reported on 13 adults with MDS and AML secondary to MDS who received single UCB grafts after myeloablative condition-ing. Notably, neutrophil recovery occurred in 12 of 13 patients, with 10 patients being alive and disease-free at the time of their report. In an update of this cohort that included 33 patients, they continue to observe a high incidence of neutrophil engraftment (90%), low TRM (14%), low relapse risk (16%), and an encouraging event-free survival rate at 5 years of 70%.49 A Eurocord study of 171 adult recipients of UCB transplants, includ-ing 16 patients (9%) with MDS, reported a 30% relapse rate.44 An analysis of a larger number of MDS patients should be available soon. A report from the University of Minnesota50 described the outcomes of 84 adults with MDS undergoing myeloablative (62%) and nonmyeloabla-tive (38%) transplantation, of whom 26 patients (31%) received UCB grafts. Although engraftment was delayed after UCB transplant, the cumulative incidence of engraft-ment did not signifi cantly differ from other donor types. Relapse and disease-free survival rates were similar across donor types. The main determinant of outcome seemed to be the percentage of blasts at the time of transplanta-tion, in which patients with < 5% blasts had a lower risk of relapse (16% vs 35%, P = .06) and a better disease-free

survival at 5 years (42% vs 19%, P = .12). Investigators at Duke University recently published a pediatric series involving 23 patients with MDS who received 4–6/6 HLA-matched UCB grafts and TBI-based myeloablative conditioning. Outcomes for this cohort were comparable to previous studies, with a neutrophil engraftment rate of 80%, a relapse risk of 13%, a TRM rate of 27%, and an event-free survival rate at 3 years of 61%. Taken together, these limited data suggest that MDS patients who lack a suitable, more conventional donor can be considered for UCB transplantation, preferably in prospective studies.

Lymphoid MalignanciesUCB has recently been evaluated for the treatment of lymphomas and multiple myeloma. Although data on multiple myeloma are limited to a few cases in larger series or case reports,51-55 several studies on patients with lymphomas treated with UCB transplantation sug-gest that UCB may be a valuable alternative for patients with this diagnosis who require an allogeneic transplant (Table 3).56-61 Yuji et al56 reported the outcomes of 20 patients with Hodgkin and non-Hodgkin lymphomas after reduced-intensity conditioning and UCB transplanta-tion. The conditioning regimen consisted of fl udarabine, melphalan, and 4 Gy of TBI. Although 8 patients died of transplant-related causes, 15 achieved primary neutro-phil recovery and 10 were alive and progression-free at the time of the report. An updated analysis by this same group on 110 patients with low-, intermediate-, and high-grade lymphoma/leukemia was presented at a meeting of the American Society of Hematology.58 The conditioning regimen was the same except that the TBI dose was 0–8 Gy. The higher dose of TBI was given to patients with high-grade disease. Notably, one-third of patients had an Eastern Cooperative Oncology Group (ECOG) performance score ≥ 3. This ECOG score was a primary infl uence on outcomes, as seen in a PFS rate of 23% at 3 years, a TRM rate of 42%, and a relapse rate of 29%. Patients with high-grade lymphoma/leukemia who received higher TBI doses had a better PFS. In-terestingly, in the subgroup of patients with mature lymphoid malignancies (n = 84), low levels of lactate dehydrogenase (LDH) was the only independent predic-tor of a better PFS. Eurocord reported the results of a study that included patients with lymphoid malignancies who received UCB transplant after reduced-intensity conditioning (n = 64) or myeloablative conditioning (n = 36).60 Neutrophil recovery was achieved in 84% of patients, with a slightly shorter interval to recovery for recipients of reduced-intensity conditioning (17 days vs 22 days) and a higher engraftment rate for patients who received a conditioning regimen that included TBI and a higher CD34+ cell dose but did not receive antilympho-cyte globulin/ATG (ALG/ATG). The TRM rate was 28% at 1 year and the relapse/progression rate was 35% at 2 years. The PFS rate was 36% at 2 years and was better


Tabl

e 3.

— U

mbi

lical

Cor

d Bl

ood

Tran

spla

ntat

ion

for A

dults

With

Lym

phoi

d M

alig

nanc

ies

Refe

renc

eLy

mph

oid

Mal

igna

ncie

sIn

clud

ed

HSC

Sour

ceNo

. of

Patie

nts

Med

ian

Age

(yrs

)

Med

ian

Tim

e to

AN

C >

500/

µL(d

ays)

Med

ian

Tim

e to

Pl

atel

et C

ount

>

20 ×

109 /L

(day

s)

Acut

e GV

HDII–

IV(%

)

Chro

nic

GVHD

(%)

Rela

pse/

Prog

ress

ion

(%)

Trea

tmen

t-Re

late

d M

orta

lity

(%)

PFS

(%)

Yuji

et a

l56

2005

NHL

HLUC

B20

4720

308

of 1

52

of 1

1NA

4150

Maj

hail

et a

l57

2006

HLUC

BRE

L9 12

28 4210 7

NA NA67 58

11 33NA NA

22 2525 20

P Va

lue

.02

.70

.24

.88

.67

Wak

e et

al58

2008

NHL

HL MM

ATL

LBL

UCB

2653

19NA

4238

2942

23 a

t 3 y

rs

Brun

stei

n et

al59

2009

NHL

HL CLL

UCB

6546

846

5719

4215

34 a

t 3 y

rsCu

rren

t PFS

:49

at 3

yrs

Rodr

igue

s et

al60

2009

NHL

HL CLL

UCB

104

4117

NA24

1935

2836

at 2

yrs

Rodr

igue

s et

al61

2009

NHL

HL CLL

UCB

URD

75 284

44 48NA NA

NA NA33 31

37 4838 35

28 3034

at 2

yrs

34 a

t 2 y

rs

P Va

lue

NS.0

5NS

NSNS

HSC

= he

mat

opoi

etic

ste

m c

ell,

ANC

= ab

solu

te n

eutro

phil

coun

t, GV

HD =

gra

ft-vs

-hos

t dis

ease

, PFS

= p

rogr

essi

on-fr

ee s

urvi

val,

NHL

= no

n-Ho

dgki

n ly

mph

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= u

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for patients with chemotherapy-sensitive disease who received a higher nucleated cell dose and a conditioning regimen that included low-dose TBI.

Intermediate- and low-grade lymphoid malignancies are more frequently diagnosed in older patients, and often patients have received an autologous transplant by the time they are referred for allogeneic transplantation. Thus, the number of reduced-intensity conditioning UCB trans-plantations for lymphomas is likely to be greater than that of myeloablative conditioning transplantation as many institutions would consider recipients of prior autologous transplantation heavily pretreated to withstand a second myeloablation. A study of 65 adults with high-, intermedi-ate-, and low-grade lymphoid malignancies with a median of 4 previous treatments was reported by the University of Minnesota (Table 3).59 All patients received a condition-ing regimen consisting of cyclophosphamide, fl udarabine, and 2 Gy of TBI. Median time to neutrophil recovery was only 8 days. A large proportion (86%) received double UCB grafts, resulting in 57% of patients developing grade II–IV acute GVHD. TRM was relatively low (15%), the relapse/progression rate was 42%, and the PFS rate was 34%. However, of 26 patients who had disease relapse/progression, 15 patients, of whom 9 achieved a complete response, had immunosuppression removed or received some form of additional antilymphoma therapy, which generally included rituximab. Thus, the current PFS rate was 49% and the overall survival rate was 55%. Patients with low-grade disease had a particularly improved cur-rent PFS rate of 68% (Fig 4).59 Preliminary data from the same institution suggested that outcomes of Hodgkin lymphoma patients are similar, regardless of whether they receive a UCB or related-donor graft (Table 3).56 More recently, the Eurocord presented a study comparing the outcomes of lymphoid malignancy patients after 4–6/6 HLA-matched UCB transplantation (n = 75) or 6/6 or 8/8

HLA-matched peripheral blood URD (n = 284) transplan-tation in the setting of reduced-intensity conditioning.61 As part of the conditioning regimen, it was more common for UCB patients to receive TBI and for URD patients to receive ATG/ALG or alemtuzumab. Neutrophil engraft-ment was higher after URD transplantation (98% vs 85%, P < .0001). Acute GVHD, TRM, and relapse risks were similar between the two groups, but there was slightly less chronic GVHD after UCB transplantation (37% vs 48%, P = .05). The PFS at 2 years was 34%, the same for both UCB and URD. A fi nal analysis based on this presentation should be available soon.

While the outcomes of UCB transplantation need to be evaluated in larger numbers of patients with specifi c subtypes of lymphoid malignancy, current data support the utilization of UCB for patients who require an al-lograft in the setting of prospective clinical trials.

ConclusionsSupported by a rapidly growing body of evidence dem-onstrating the safety and effi cacy of UCB transplantation, this HSC source has been used more frequently for the treatment of patients with hematologic malignancies. After an initially limited utilization among adults in con-trast to routine utilization in children who lack a suitable sibling donor, UCB transplantation for older and larger patients is also increasing. Factors that specifi cally con-tributed to the expanded use of UCB in adults include, but are not limited to, results of outcomes utilizing a higher minimum nucleated cell dose to select grafts that yielded results similar to other donor types, the utilization of double UCB grafts for adult patients who do not have a single unit large enough to proceed to transplantation, and the use of reduced-intensity conditioning regimens in UCB transplantation.

The fi eld of UCB transplantation is still relatively young, and several areas of this fi eld require additional research to further improve outcomes. One example is the reduced rate and cumulative incidence of engraft-ment in UCB recipients that could potentially impact the risk of TRM. Efforts in improving engraftment are ongoing and include expanding the inventory of high-quality UCB units, utilizing double UCB grafts,28 coadmin-istering third-party CD34+ progenitors,62 improving ex vivo expansion,63 activating homing receptors (such as CXCR4),64 and utilizing intra-bone marrow injection.65,66 Others have been investigating how to reduce the risk of GVHD and potentially improve immune reconstitu-tion and reduce the risk of infections.67 As with unre-lated donor transplantation, outcomes in specifi c patient subgroups could also be improved by refi ning donor selection such as considering killer immunoglobulin-like receptor (KIR) ligand matching.68,69 The results of ongoing multicenter prospective clinical trials in both Europe and the United States will improve understanding of the indications and applicability of double UCB grafts

Months Post-UCBT

Cu

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ort

ion

0.0

0 12 24 36

0.2

0.4

0.6

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1.0follicular lymphoma/CLL

large-cell/mantle-cell lymphoma

Hodgkin lymphoma

Fig 4. — Current progression-free survival of patients with lymphoid malignancies after reduced-intensity umbilical cord blood transplantation. Brunstein CG, Cantero S, Cao Q, et al. Promising progression-free survival for patients low and intermediate grade lymphoid malignancies after nonmye-loablative umbilical cord blood transplantation. Biol Blood Marrow Transplant. 2009;15(2):214-222. Reproduced with permission from Elsevier.


(eg, CTN-0501) and reduced-intensity conditioning (eg, CTN-0604) UCB transplantation.

Appreciation is expressed to Michael J. Franklin, MS, of the University of Minnesota for assistance in editing and to Carol Taubert for assistance in preparing this manuscript.

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69. Willemze R, Rodrigues CA, Labopin M, et al. KIR-ligand incompatibil-ity in the graft-versus-host direction improves outcomes after umbilical cord blood transplantation for acute leukemia. Leukemia. 2009;23(3):492-500.

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