Double Unit Cord Blood Transplantation for Acute Leukemia
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Transcript of 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
Double Unit Cord Blood Transplantation for Acute Leukemia
CSA/ MMF -3 -2 -1 -4 -6 -5 30 100 0
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Acknowledgements
U of Minnesota John E. Wagner
NYBC
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.
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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.
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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?
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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.
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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
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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).
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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
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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
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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)
0.0
0.2
0.4
0.6
0.8
1.0
Months Post-Transplant
Dis
ease
-Fre
e Su
rviv
al
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
Barker et al, ASBMT 2013
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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
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% 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
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0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
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)
% V
iabi
lity
CD
34+s
(7-
AA
D)
Variability in viability by unit & bank: potential problem for single unit transplants. Emphasizes importance of post-thaw
potency as critical unit release criteria.
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DCB with CD34pos
#1 #2
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
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DCB with CD34pos
#1 #2
DCB with MNC
MNC #1
MNC #2
CD34pos Selection
Unit dominance. Clinical correlation.
Double Unit CBT in NSG Mice Using Samples from Patient Grafts
Eldjerou et al, Blood, 2010
No unit dominance. No clinical correlation.
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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 in NSG Mice Using Samples from Patient Grafts
Eldjerou et al, Blood, 2010
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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.
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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
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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
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Day post-CBT
N (%) with loser detected
Unit-unit match: 1-6/10
Unit-unit match: 7-10/10
P
+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
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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?
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Infused Doses of Winner & Neutrophil Engraftment
Avery S et al, Blood 2011 Infused viable CD34+ cell dose of winner determines engraftment
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Inf. Total Doses (Both Units Combined) & Engraftment
Total TNC & CD3+ cell dose also have dose dependent effects.
Avery S et al, Blood 2011
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Neutrophil Engraftment after 92 DCBT by Infused Viable CD34+ Cell Dose x 105/kg of Winner*
0.0
0.2
0.4
0.6
0.8
1.0
Days Post-Transplant
Cum
ulat
ive
Inci
denc
e
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
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Day 180 Platelet Engraftment to 20,000 (n = 92)
0.0
0.2
0.4
0.6
0.8
1.0
Days Post-Transplant
Cum
ulat
ive
Inci
denc
e
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)
Barker et al, ASBMT 2013
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20
40
60
80
100
0
4-6/6 Allele 1-3/6 Allele
Months Post-Transplant 0
100
80
60
40
20
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.
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Comparison 2-Yr DFS P Value Age 0-15 years (n = 27)
> 16 years (n = 65) 73% 65%
0.32
Ancestry Europeans (n = 40) Non-Europeans (n = 52)
69% 66%
0.86
Remission Status
CR1 (n = 49) All others (n = 43)
66% 69%
0.98
Conditioning Intensity
High-dose (n = 54) RIC (n = 38)
70% 64%
0.60
Recipient CMV Sero-status
CMV+ (n = 51) CMV- (n = 41)
54% 85%
0.01
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.
Barker et al, ASBMT 2013
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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%
0.84
Inf. CD34+ Dose Dominant Unit
< 1.0 (n = 50) > 1.0 (n = 52)
64% 72%
0.13
Inf. TNC Dominant Unit
< 2.0 (n = 34) 2.0-2.85 (n = 27) > 2.85 (n = 31)
62% 74% 68%
0.29
• Mismatch had no impact on DFS. • Suggestion of improved DFS if winner had higher CD34+
dose.
2-Yr DFS after DCBT for Acute Leukemia By Winning Unit Characteristics (n = 92)
Barker et al, ASBMT 2013
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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.
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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
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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.
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100
0
20
40
60
80
0
100
20
40
60
80
Prob
abili
ty, %
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.
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-7 0 +100
U of MN Changes to Prep & IS for DCBT
Cy 120/ Flu 75/ TBI 1320
CSA/ MP
CB #2
CB #1
-8 0 +100
Cy 120/ ATG/ TBI 1320
CB #2
CB #1
CSA/ MMF Prep & IS changes contributed to DCBT benefit
Barker et al, Blood 2005
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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).
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DFS After DCBT in Engrafting Adults by Speed of Neutrophil Recovery: Day 45 Landmark (n = 61)
P = 0.02
0.0
0.2
0.4
0.6
0.8
1.0
Time Post-Transplant
DFS
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.
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-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
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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.