Should the number of collected CD34+ cells be considered major

criteria for UCB unit choice in adults?

Reunión anual GETH 2011

Madrid, 11 marzo 2011

Guillermo Sanz

Hospital Universitario La Fe, Valencia, Spain

Main prognostic factors after UCBTMain prognostic factors after UCBT

• Number of TNC infused

• Degree of HLA match

Gluckman E et al. Exp Haematol 2004; 32:397-407.

Guidelines for UCB unit choiceGuidelines for UCB unit choice Eurocord 2004 criteria

• At least 4/6 HLA match

• Collected TNC above 2.5 – 3.0 × 107/kg

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 × 107/kg if 0 or 1 HLA mismatches

• 3.5 × 107/kg if 2 HLA mismatches

Is this cell dose criteria enough?

Should the number Should the number of collected CD34+ cells be considered an

additional major cell dose criteria in adults for guiding UCB unit choice? for guiding UCB unit choice?

Reasons for not including the number Reasons for not including the number of collected CD34+ cells among criteria of collected CD34+ cells among criteria

for guiding UCB unit choicefor guiding UCB unit choice

• Not enough data on impact of CD34+ cells (infused or collected)

• Measurement of CD34+ cells not well standardized– Great differences among CB banks could emerge

• TNC dose could be a good surrogate of CD34+ cells

• No available data on correlation between number of CD34+ cells collected and infused

• Number of collected CD34+ cells not available for 25 – 50% UCB units worldwide

Number of infused CD34+ cells is Number of infused CD34+ cells is relevant after UCB transplants relevant after UCB transplants

• Impact on engraftment (children and adults)

• Impact on survival (children and adults – some series)

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

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

0,2

0,3

0,4

0,5

0,6

0,7

0,8

0,9

1

0 10 20 30 40 50 60

Days after transplant

Cum

ulat

ive

inci

denc

e

CD34+ > 1 x 105/kg(n = 111)CI: 94%

Median: 20 days

CD34+ ≤ 1 x 105/kg(n = 66 )CI: 89%

Median: 25 days

P = 0.0002

Myeloid engraftment after myeloablative single UCBT in adults with malignant

disorders (n = 177) by infused CD34+ cells

0

0,1

0,2

0,3

0,4

0,5

0,6

0,7

0,8

0,9

1

0 10 20 30 40 50 60

Days after transplant

Cum

ulat

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

0

0,1

0,2

0,3

0,4

0,5

0,6

0,7

0,8

0,9

1

0 10 20 30 40 50 60

Days after transplant

Cum

ulat

ive

inci

denc

e

TNC ≤ 2.5 × 107/kg(n = 58)CI: 93%

Median: 22 days

TNC > 2.5 × 107/kg(n = 120)CI: 92%

Median: 22 days

P = 0.6

Myeloid engraftment after myeloablative single UCBT in adults with malignant disorders (n = 178) by collected TNC

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

adults with malignant disorders (n = 164)

0

1

2

3

4

5

6

7

8

0 1 2 3 4 5 6 7 8

R = 0.52P < .0001

CD34+ cells infused (× 105/kg)

TN

C c

olle

cted

(×

107 /

kg)

0

1

2

3

4

5

6

7

8

0 1 2 3 4 5 6 7 8

R = 0.52P < .0001

CD34+ cells infused (× 105/kg)

TN

C c

olle

cted

(×

107 /

kg)

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

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

Capacity of collected TNC and CD34+ cells of Capacity of collected TNC and CD34+ cells of reaching a target number of infused CD34+ cells reaching a target number of infused CD34+ cells

(1 (1 × 10× 1055/kg)/kg) Experience in 164 UCB transplantsExperience in 164 UCB transplants

Number of cells collected

No. ofpatients

(%)

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

> 2.5 × 107 TNC/kg 112 (68) 82 (73)

≤ 2.5 × 107 TNC/kg 52 (32) 23 (44)

> 1 × 105 CD34+ cells/kg 131 (80) 97 (74)

≤ 1 × 105 CD34+ cells/kg 33 (20) 8 (24)

Collected CD34+ cells perform better that TNC

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.

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

Should it be possible to use a lower CN Should it be possible to use a lower CN and CD34+ threshold for UCB transplants and CD34+ threshold for UCB transplants

in adults with a single unit if BOTH cell in adults with a single unit if BOTH cell dose criteria are included in UCB unit dose criteria are included in UCB unit

choice?choice?

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

GETH/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 almost as efficient as Eurocord 2009 criteria and accessible in a higher number of patients

Concluding remarksConcluding remarks

• The number of collected CD34+ cells must be included among the criteria for UCB unit choice

• Currently accepted thresholds for collected TNC and CD34+ cells in adults with hematologic malignancies need to be properly reviewed

• Additional criteria for accurately predicting the potency of the UCB graft are required