Double Unit Cord Blood Transplantation for Acute Leukemia

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Juliet N. Barker, MBBS (Hons), FRACP Associate Attending

Director, Cord Blood Transplant Program Memorial Sloan-Kettering Cancer Center

CSA/ MMF -3 -2 -1 -4 -6 -5 30 100 0

Acknowledgements

U of Minnesota John E. Wagner

Pablo Rubinstein Cladd Stevens

Machi Scaradavou

MSKCC Staff of Adult & Pediatric

Transplant Search: Courtney Byam, Rosanna Ferrante Debbie Wells, Melissa Sideroff, Sinda Lee

Cell Therapy Lab CB Research Staff: Marissa Lubin Anne Marie Gonzales , Katie Evans

Cellular Immunology Lab: Kathy Smith Pediatrics: Machi Scaradavou

Nancy Kernan & Richard O’Reilly Adult BMT Service: Doris Ponce

Marcel van den Brink & Sergio Giralt

Funding Gabrielle’s Angel Foundation for Cancer Research, the MSKCC Society,

MSKCC Translational and Integrative Medicine Research Grant, P01 CA23766 NCI, NIH.

Original Reasons for Double Unit CB Grafts

• Platform for investigation of expansion or other graft manipulation. • Augment graft cell dose = improve engraftment, reduce TRM, improve survival.

Reasons for Double Unit CB Grafts: Successful?

• Platform for investigation of expansion or other graft manipulation?: YES • Augment graft cell dose = improve engraftment, reduce TRM, improve survival?: YES in adults, children?

Sibling typing → simultaneous URD & CB search

Suitable Sibling or URD: Suitable CB Graft: 4-6/6 A,B antigen, DRB1 allele 2 units: each > 2 x 107 NC/kg

Hi Dose Prep RIC or Mini Children (Young adults)

RIC/ Mini + 10/10 donor

Hi Dose + TCD 9-10/10 donor

MSKCC Donor Algorithm: DCBT Extends Access

Donors identified for > 95% patients.

URD (n=465) CB (n=156) No Graft (n=36)

NW Europe Asian

Eastern Europe African

Southern Europe White Hispanic

Europe Mix Middle Eastern

Non-Europe Mix

Transplant Type by Patient Ancestry (n = 657)

> 50% CBTs non-European

ancestry: DCB extends

access.

2012 update from Barker et al 2010, BBMT

P = NS

Comparable 5-Yr LFS: DCBT, MRD, & URD (U of Minnesota & Fred Hutchinson CRC, n = 536)

Brunstein & Delaney, Blood 2010

DCBT: Lower risk of relapse compensated for higher TRM = comparable LFS to sib & URD.

(Similar results: Ponce et al, BBMT 2011; Dana Farber).

MSKCC DCBT for Acute Leukemia in Adults & Children

• 10/2005 - 5/2012. • High risk acute leukemia in morphologic CR1-4 or aplasia or MDS/ MPD < 5% blasts. • High dose or RIC (both ablative). • Follow-up: median 3.2 years.

Barker et al, ASBMT 2013

High*: Cy 120 Flu 75 TBI 1375

“Midi” is new prep alternative

Mini: Cy 50 Flu 150 TBI 200

Midi**: Cy 50 Thio 10 Flu 150 TBI 400

MSKCC Conditioning for Acute Leukemia/ MDS

* If no TBI: Clo/ Mel/ Thio ** Ponce et al, BBMT 2013

2-Yr DFS in 92 DCBT if Acute Leuk, MDS/MPD

Adults (n = 65, median 47 yrs, 2.7 + 2.0): 65% (95%CI: 55-78)

Months Post-Transplant

0 6 12 18 24

Children (n = 27, median 7 yrs, 4.4 + 2.9): 73% (95%CI: 56-93)

High rates of 2-year DFS after DCBT- esp. given median 2.1 TNC dose of winner in adults.

Median TNC winner: Peds 4.3, Adults 2.1

Early analyses: • No relationship: TNC or CD34+ dose. Association with higher CD3+ dose. • No relationship: HLA-match to patient.

Why Does One Unit Win?*

Barker et al, Blood 2005

% of Viable CD34+ Cells

Winner (n = 44)

Loser (n = 44)

< 75% (n = 16) 1 15

≥ 75% (n = 72) 43 29

Engraftment in 44 Double Unit CBT Recipients By Post-Thaw CD34+ Cell Viability (n = 88 Units)

Using threshold of 75% viable CD34+s (mean-2SD), all but one (43/44) engrafting units had

CD34+ viability > 75% (p = 0.0006). ie Only 1/16 poor viability units engrafted.

Poor CD34+ viability correlated with lower CFUs (p = 0.02).

Scaradavou, BBMT 2010

NYBC (n=149)

Other US (n=123)

International (n=94)

% Viable CD34+s Post-Thaw by Bank (n = 366 units) Median

94% (68-99)

Median 89%

(34-98)

Median 92%

(34-98)

Variability in viability by unit & bank: potential problem for single unit transplants. Emphasizes importance of post-thaw

potency as critical unit release criteria.

DCB with CD34pos

DCB with MNC

MNC #1

MNC #2

CD34pos Selection

Sacrifice mice weeks 4-8 Correlate murine & patient engraftment.

Double Unit CBT in NSG Mice Using Samples from Patient Grafts

Eldjerou et al, Blood, 2010

DCB with CD34pos

DCB with MNC

MNC #1

MNC #2

CD34pos Selection

Unit dominance. Clinical correlation.

No unit dominance. No clinical correlation.

DCB with CD34pos

CD34neg #2

+Add-back CD34neg #2

#1 #2MNC #1

MNC #2

CD34neg #1

+Add-back CD34neg #1

CD34pos Selection

Added CD34 negs - clinically engrafting unit: 100% murine engraftment with that unit.

Added CD34 negs - clinically NON-engrafting unit: 100% murine engraftment with that unit.

Double Unit CBT: NSG Murine Model

Eldjerou et al 2010, Blood

• Murine-patient correlation suggests host factors not relevant. • Unit dominance mediated by CD34- fraction.

If either unit has engraftment potential (majority but not all),

unit dominance is immune mediated.

In 9/10 DCBT Recipients: Development of IFN-γ–Secreting CD8+ T-cells Recognizing Allo-antigens

Expressed by Non-engrafting Unit

Gutman et al, Blood 2010

Unit dominance is mediated by effector

CD8+ T-cells

developed from naïve precursors in winner

In 9/10 DCBT Recipients: Development of IFN-γ–Secreting CD8+ T-cells Recognizing Allo-antigens

Expressed by Non-engrafting Unit

Gutman et al, Blood 2010

Unit dominance correlated

with higher naïve CD8+

T-cell dose:

Milano et al, BBMT 2012

Day post-CBT

N (%) with loser detected

Unit-unit match: 1-6/10

Unit-unit match: 7-10/10

+21 (n = 83) 2/ 56 (4%) 14/ 27 (52%) < 0.0001

+28 (n = 79) 0/ 54 (0%) 14/ 25 (56%) < 0.0001

+60 (n = 72) 0/ 47 (0%) 8/ 25 (32%) < 0.0001

+100 (n = 68) 0/ 45 (0%) 3/ 23 (13%) 0.04

+365 (n = 43) 0/ 30 (0%) 1/ 13 (8%) 0.30

Serial Detection of Losing Unit After DCBT by Unit-Unit HLA-match (n = 83)

Higher level of unit-unit HLA-match associated with co-engraftment of both units.

Avery et al, Blood 2011

Why does one unit win?*: Hematopoietic potential of each unit.

Unit vs unit immune interactions (T-cell mediated).

As important:

What attributes of graft determine engraftment success,

GVHD & survival after DCBT?

Infused Doses of Winner & Neutrophil Engraftment

Avery S et al, Blood 2011 Infused viable CD34+ cell dose of winner determines engraftment

Inf. Total Doses (Both Units Combined) & Engraftment

Total TNC & CD3+ cell dose also have dose dependent effects.

Avery S et al, Blood 2011

Neutrophil Engraftment after 92 DCBT by Infused Viable CD34+ Cell Dose x 105/kg of Winner*

Days Post-Transplant

0 10 20 30 40

< 0.50 (n = 23)

0.51-1.00 (n = 27)

1.01-1.50 (n = 19)

> 1.51 (n = 23)

100% engraftment

success if winning unit had viable CD34+ cell dose > 1.0.

* Unit predominating in assessment of hematopoiesis in 1st month post DCBT

P < 0.001 Barker et al, ASBMT 2013

Day 180 Platelet Engraftment to 20,000 (n = 92)

Days Post-Transplant

0 45 90 135 180

Children: 85% (95%CI: 63-95) Median 50 days (range 29-118)

Adults: 83% (95%CI: 71-90) Median 48 days (range 29-162)

High rates of platelet engraftment by CBT standards.

93% if winning unit infused CD34+ cell dose > 1.0 x 105/kg

(vs 78% if lower, p = 0.01)

4-6/6 Allele 1-3/6 Allele

Months Post-Transplant 0

1-7/10 Allele

8-9/10 Allele

1 2 3 4 5 6 0 1 2 3 4 5 6

Ponce, D., BBMT 2013

Gr. III-IV Acute GVHD after DCBT by Winning Unit HLA-Allele Match to Patient (n = 115)

HLA-allele match of winning unit to patient is important.

Comparison 2-Yr DFS P Value Age 0-15 years (n = 27)

> 16 years (n = 65) 73% 65%

Ancestry Europeans (n = 40) Non-Europeans (n = 52)

69% 66%

Remission Status

CR1 (n = 49) All others (n = 43)

66% 69%

Conditioning Intensity

High-dose (n = 54) RIC (n = 38)

70% 64%

Recipient CMV Sero-status

CMV+ (n = 51) CMV- (n = 41)

54% 85%

2-Yr DFS after DCBT for Acute Leukemia By Recipient Characteristics (n = 92)

• Comparable DFS in Europeans & non-Europeans. • RIC (“midi”) promising alternative to high dose prep. • Recipient CMV+ remains challenging.

Comparison 2-Yr DFS P Value HLA-match

Dominant Unit 2-5/10 (n = 34) 6-7/10 (n = 39) 8-9/10 (n = 19)

69% 65% 68%

Inf. CD34+ Dose Dominant Unit

< 1.0 (n = 50) > 1.0 (n = 52)

64% 72%

Inf. TNC Dominant Unit

< 2.0 (n = 34) 2.0-2.85 (n = 27) > 2.85 (n = 31)

62% 74% 68%

• Mismatch had no impact on DFS. • Suggestion of improved DFS if winner had higher CD34+

2-Yr DFS after DCBT for Acute Leukemia By Winning Unit Characteristics (n = 92)

Due to unit vs unit

interactions? Verneris et al, Blood 2009

Double CBT: Reduced Relapse? Myeloablative DCBT for Acute Leukemia, U of MN

Supported by multiple other analyses: Brunstein, Blood 2007; Rodrigues, JCO 2009; Brunstein, Blood 2010;

Kindwall-Keller BMT 2012; Rocha, ASH abs 2012.

2-year DFS after RIC CBT in Adult Acute Leukemia - CR1

P = 0.03

In multivariate analysis,

double CBT associated

with improved DFS (p = 0.04).

Advantage attributed to reduced relapse risk.

Double CBT (n = 136): 51 ± 5%

Single CBT (n = 76): 32 ± 3%

Slide courtesy of V. Rocha, 2013

Overall Survival after Doubles (n = 303) & Adequately Dosed Singles (n = 106, TNC > 2.5)

Scaradavou A et al. Blood 2013

• Myeloablative & RIC. • Median inf. TNC: singles 2.8, doubles 3.7.

DCBT extends access to those without an adequate single.

Months 0 3 6 9 12

Double CBT: 64% (54 – 72)

Single CBT: 68% (58 – 76)

BMT CTN 0501 Pediatric Ablative Randomized Trial: 1-Yr Disease-free Survival

P = 0.22

Slide Courtesy of Dr J. Wagner, ASH 2012

No DFS advantage after myeloablative DCBT in children

Median cryo. TNC: singles 4.8, doubles 8.9.

-7 0 +100

U of MN Changes to Prep & IS for DCBT

Cy 120/ Flu 75/ TBI 1320

CSA/ MP

-8 0 +100

Cy 120/ ATG/ TBI 1320

CSA/ MMF Prep & IS changes contributed to DCBT benefit

Barker et al, Blood 2005

Unit Type N Units Transplanted (N = 26)

Median (Range) Cost Per Unit

NMDP-International 4 (15%) $41,338 (38,233 – 46,418) NMDP-Domestic (excl. NYBC)

14 (54%) $38,570 (33,150 - 40,230)

NYBC-Direct 7 (27%) $42,500 NCBI NYBC via NMDP 1 (4%)* $48,725

Charges to MSKCC for CB Units Jan-April 2013

Approximate cost of double unit graft with 6 units typed: $90,000.

* NCBI unit = must be purchased via NMDP.

• 13 DCBT (n = 26 units). • Median 6 units typed per patient (range 4-13).

DFS After DCBT in Engrafting Adults by Speed of Neutrophil Recovery: Day 45 Landmark (n = 61)

P = 0.02

Time Post-Transplant

45 days 6mo 12mo 18mo 24mo

Neut. recovery < 25 days (n = 32): 84% (95%CI: 72-98)

Neut. recovery > 25 days (n = 29): 54% (95%CI: 39-76)

Marked survival advantage if rapid engraftment: need to speed engraftment for all.

-8 0 +1 +28 +100

Compare engraftment (speed, success, chimerism) to DCB controls

Hi dose or midi myeloablative

MSK Approach to Speed Neutrophil Recovery: DCBT + Haplo

Graft > 100k-but earlier neutrophil recovery = less resources + earlier discharge compensates.

34+ selected PBSC

(Miltenyi)

Haplo-identical family member

Double Unit CBT: Conclusions • Extends access.

• Insurance policy against poor viability unit.

• Facilitates engraftment in low dose setting: oImplies loser has biologic activity. oWinner determines engraftment & GVHD. oAs compared with singles, need to analyze doubles based on characteristics of winner: is loser doing anything?

(or if better unit had been given alone??). • High rates of DFS in acute leukemics. • Preliminary data: Europeans & non-Europeans comparable DFS. • Multiple series: DCBTs comparable DFS with URDs.

• Problems: o2 un-manipulated units not enough. oEscalating cost is a major problem.

Double Unit Cord Blood Transplantation for Acute Leukemia

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