Cord blood selection, release, and transplantation

6th World Congress Tissue Banking

Barcelona, Spain, 10 November 2011

Guillermo Sanz

Hospital Universitari i Politecnic La Fe Valencia, Spain

Main conclusions of studies comparing Main conclusions of studies comparing UCB and BM from MUD as graft sources UCB and BM from MUD as graft sources

for hematologic malignanciesfor hematologic malignancies

An adequate UCB unit selection is critical for success

Pro

bab

ilit

y,

%

Months

100

0

20

40

60

80

90

10

30

50

70

0

100

20

40

60

80

90

10

30

50

70

CB, 37%

0 12 248 16 20

PBPC matched, 43%PBPC mismatched,

35%

BM matched, 47%

4

BM mismatched, 38%

Eapen M at al. Lancet Oncol 2010

Unrelated UCB (NC dose >2.5 x 107/kg), BM or MPB transplants in adults with acute leukemia

Overall survival

Should we use in children and adults the same criteria for UCB unit choice?

Not at all

Main prognostic factors after UCBT in Main prognostic factors after UCBT in childrenchildren with hematologic malignancies with hematologic malignancies

• Cell dose

• HLA match

Interaction cell dose – HLA match presentA higher cell dose can overcome the negative

impact of a lower degree of HLA matching

Cumulative incidence (CI) of PMN engraftment according to TNC (×107/kg) and HLA match

Barker J N et al. Blood 2010;115:1843-1849

Main prognostic factors after UCBT in Main prognostic factors after UCBT in adultsadults with hematologic malignancies with hematologic malignancies

• Cell dose

• Status of disease at transplant

HLA match does not impact outcomesCell dose is the major obstacle and criteria

0

0.1

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0.6

0.7

0.8

0.9

1

0 12 24 36 48

Months after transplant

Cum

ulat

ive

prob

abili

tyHigh-risk AML in CR1 (n = 30)

LFS by nucleated cells infused

> 2 107/kg (n = 18): 75% at 4 y

≤ 2 107/kg (n = 12): 25% at 4 y

P = 0.03

Sanz J et al. Biol Blood Marrow Transplant 2010; 16: 86-94.

Policy on cell dose for UCB unit choicePolicy on cell dose for UCB unit choice

• Most transplant centers use the number of collected TNC as the only cell dose criteria for unit choice

– Greater TNC dose threshold for higher degree of HLA mismatch

• 2.5 – 3.5 × 107/kg if 0 or 1 HLA mismatches

• 3.5 – 5 × 107/kg if 2 HLA mismatches

Is this policy reasonable?No, use both collected TNC and CD34+ cells

CD34+ measurement is now CD34+ measurement is now almostalmost standardizedstandardized

• CD34+ quantification performed at NetCord CB banks according to a uniform protocol (ISHAGE)

• Quality control available and likely required for accreditation in near future

– i.e. Proficiency testing UKNEQAS

Prognostic value of infused CD34+ cellsPrognostic value of infused CD34+ cells((× 10× 1055/kg) /kg) after myeloablative UCBT in adults after myeloablative UCBT in adults

with hematologic malignancieswith hematologic malignancies

1 N Engl J Med 2001;344:1815-22.2 Br J Haematol 2007;139:464-74.

3 Biol Blood Marrow Transplant 2008;14:1341-7.4 Biol Blood Marrow Transplant 2010;16:86-94.

5 Biol Blood Marrow Transplant 2010;16:1589-95.

Reference

PMN engraftment DFS

Cut-off point

Pvalue

Cut-off point

Pvalue

Laughlin, 20011 1.2 0.05NS

Van Heekeren, 20072 NSHigher 0.015

Ooi, 20083 NS1.0 < 0.0001

Sanz, 20104 NS1.5 0.009

Sanz, 20105 NS0.6 0.02

0

0,1

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0,5

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1

0 10 20 30 40 50 60

Days after transplant

Cum

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ive

inci

denc

e

CD34+ > 1.5 x 105/kg(n = 92)CI: 96%

Median: 20 days

CD34+ ≤ 1.5 x 105/kg(n = 73)CI: 90%

Median: 23 days

P = 0.007

Myeloid engraftment after myeloablative single UCBT in adults with malignant

disorders (n = 165) by collected CD34+ cells

Correlation between collected and infused CD34+ cells after myeloablative single UCBT in adults with

malignant disorders (n = 164)

R = 0.67P < .0001

CD34+ cells infused (× 105/kg)

CD

34+

ce

lls c

olle

cted

(×

105 /

kg)

0

1

2

3

4

5

6

7

8

0 1 2 3 4 5 6 7 8

Guidelines for UCB unit choiceGuidelines for UCB unit choice Eurocord 2009 criteria for malignant disorders

• UCB unit with 5/6 or 6/6 HLA match

– Collected TNC > 2.5 × 107/kg

– Collected/infused CD34+ cells > 1.2 × 105/kg

• UCB unit with 4/6 HLA match

– Collected TNC > 3.5 × 107/kg

– Collected/infused CD34+ cells > 1.7 × 105/kg

Rocha V & Gluckman E on behalf of Eurocord/EBMT. Br J Haematol 2009; 147:262-274.

These thresholds are difficult to achieve for many adults

Capacity of Eurocord 2009 criteria of reaching a Capacity of Eurocord 2009 criteria of reaching a target number of infused CD34+ cells (1 × 10target number of infused CD34+ cells (1 × 1055/kg)/kg)

Experience in 164 UCB transplantsExperience in 164 UCB transplants

Eurocord 2009 criteria

No. ofpatients

(%)

No. of patients (%) with infused CD34+ cells > 1 × 105/kg

Fulfilled 65 (40) 52 (80)

Absent 99 (60) 53 (54)

Thresholds may be excessive/inappropriate

Capacity of current Hospital La Fe criteria* for Capacity of current Hospital La Fe criteria* for CB unit choice of reaching a target number of CB unit choice of reaching a target number of

infused CD34+ cells (1 × 10infused CD34+ cells (1 × 1055/kg)/kg)Experience in 164 UCB transplantsExperience in 164 UCB transplants

Hospital La Fe criteria*

No. ofpatients

(%)

No. of patients (%) with infused CD34+ cells > 1 × 105/kg

Fulfilled 129 (79) 52 (74)

Absent 35 (21) 10 (29)

* Collected TNC > 2 × 107/kg and collected CD34+ cells > 1 × 105/kg

Criteria as efficient as Eurocord 2009 criteria (74% vs 80%) and accessible to a higher number of patients (79% vs 40%)

Protocol UCBT GETH 2005 (n = 89) Myeloid engraftment (PMN > 0.5 109/L)

GETH cooperative group. Unpublished data

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Days

Cu

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Cumulative incidence: 94%Median: 19 d

Range: 11 – 52 d

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Days

Cu

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Cumulative incidence: 94%Median: 19 d

Range: 11 – 52 d

Cumulative incidence: 94%Median: 19 days

Protocol UCBT GETH 2005 (n = 89) Early non-relapse mortality (NRM)

GETH cooperative group. Unpublished data

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NRM100: 13%

NRM180: 22%

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NRM100: 13%

NRM180: 22%

• NRM100: 15%

• NRM180: 22%

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0 6 12 18 24 30 36 42 48

Months

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Protocol UCBT GETH 2005 (n = 89) DFS at 2 yr by status of disease at transplant

P = 0.003

Early (n = 46): 52%

Intermediate (n = 23): 38%

Advanced (n = 20): 18 %

GETH cooperative group. Unpublished dataMedian follow-up (range): 33 (8 – 49) mo

TNC > 2 × 107/kg and > 150 × 107

CD34+ cells > 1 × 105/kg and > 70 × 106

Current cell dose criteria (at freezing) Current cell dose criteria (at freezing) for UCB unit choice at Hospital La Fefor UCB unit choice at Hospital La Fe

Both cell dose criteria required

Only functional test available

Not standardized

No threshold available

Other criteria for UCB unit choiceOther criteria for UCB unit choiceCFU assayCFU assay

Always perform CFU assayDo not use units with no or very small growth

Poorer engraftment rate and shorter overall survival when major ABO incompatibility present (Eurocord registry)

Other criteria for UCB unit choiceOther criteria for UCB unit choiceABO matchABO match

Avoid units with major ABO mismatch if possibleFor units with similar cell dose select those units ABO

compatible or with minor ABO incompatibility

No data on impact of CBB in outcomes available

Not all CBB standards are equal; nor speed of response

Other criteria for UCB unit choiceOther criteria for UCB unit choiceCB bankCB bank

NetCord-accredited banks preferredGeographical proximity preferred

No superiority of units frozen in more recent years demonstrated

Units stored in more recent years have followed higher quality standards

Other criteria for UCB unit choiceOther criteria for UCB unit choiceYear of storageYear of storage

More recent units preferred

Potential relationship with CFU assay and 7-AAD CD34+ cell viability (preliminary data)

Other criteria for UCB unit choiceOther criteria for UCB unit choiceTime from UCB collection to freezingTime from UCB collection to freezing

Lower than 48 h required(lower than 24 h preferred)

High-resolution HLA match

HLA-C match

NIMA match

KIR mismatch

GVH direction match

Other criteria for UCB unit choiceOther criteria for UCB unit choice

Currently not used(pending confirmatory data)

Concluding remarksConcluding remarks

• Selection of an adequate UCB unit is essential for success of UCB transplants

• The number of collected CD34+ cells must be included among the cell dose criteria

• Currently accepted thresholds for collected TNC and CD34+ cells need to be properly reviewed

• Additional criteria for UCB choice may be valuable but always remember that the major advantage of UCB is fast availability: do not delay transplant by adding more and more criteria