Juliet N. Barker, MBBS (Hons), FRACPAssociate Attending
Director Cord Blood Transplant ProgramMemorial Sloan-Kettering Cancer Center
Optimising Cord BloodUnit Selection
CSA/ MMF -3 -2 -1-4-7 -6 -5 30 1000
Acknowledgements
U of Minnesota John E. Wagner
NYBCPablo Rubinstein
Cladd StevensMachi Scaradavou
MSKCC
Staff of Adult and Pediatric Transplant
Search: Courtney Byam, Rosanna FerranteDebbie Wells, Kathleen Doshi, Sinda LeeCytotherapy Lab: esp Allison Schaible
CB Research Staff: Marissa LubinAnne Marie Gonzales , Katie Evans
Cellular Immunology Lab: Kathy SmithMalcolm Moore
Machi ScaradavouNancy Kernan & Richard O’Reilly
Doris PonceMarcel van den Brink & Sergio Giralt
What have we achieved?
One Strategy to Improve Outcome By Augmenting Cell Dose: Use 2.
Barker et al, NEJM 2001, Blood 2003, Blood 2005
Retrospective studies suggest improved engraftment & GVL.
Sibling typing →simultaneous URD & CB search
Suitable Sibling(match/ donor health)
Suitable URD (match/ availability):
Suitable CB Graft (match/ dose):
4-6/6 A,B antigen, DRB1 allele2 units: each > 2 x 107 NC/kg
Hi Dose Prep Midi or Mini (Unmodified)Children(Young adults)
Midi/ Mini + 10/10 donor
Hi Dose +TCD 9-10/10 donor
MSKCC Donor Algorithm
Donors identified for > 95% patients.
-7 0 +100
High (< 50): Acute leuk/ MDS/ hi grade NHLMidi (< 70): AML/ ALL/ MDS/ CML/ NHL/ CLL (or Mel/ Flu for Hodgkins not in CR)Mini (< 70): Hodgkins in CR/ Indolent NHLs/ CLL
CB #2
CB #1
CBT Preps & Immune SuppressionHigh: Cy 120/ Flu 75/ TBI 1375 (or Clo/ Mel/ Thio if no TBI)Midi: Cy 50/ Flu 150/ Thio 10/ TBI 400 (or Mel 140/ Flu 150)Mini: Cy 50/ Flu 150/ TBI 200
GVHD prophy: CSA/ MMF
3 intensities, mainly Cy-Flu-TBI based, no ATG, no steroids.
0 10 20 30 40
0.0
0.2
0.4
0.6
0.8
1.0
Days Post-Transplant
Cum
ulat
ive
Inci
denc
eAblative: 94%@ 25 days
NMA*: 96% @ 10 days
Neutrophil Engraftment after DCBT (n = 108) Median 41 yrs (range 6-69), high risk heme malignancies
* Early auto recovery –switched to sustained donor engraftment
Dahi, P., ASBMT 2012
High rates of sustained donor engraftment.
Months Post-Transplant
Pro
gres
sion
-Fre
e Su
rviv
al
0 12 24 36 48 60
0.0
0.2
0.4
0.6
0.8
1.0
P = 0.573
MSK Allo Tx for Heme Malignancies 2005-2009: 2 Year PFS After Double-Unit CB vs RD vs URD Transplant
Ponce, BBMT 2011
2 Yr PFS after CBT: comparable to RD or URD transplant.
CB (n = 75)RD (n = 108)URD (n = 184)
Up-front TRM compensated by reduced late mortality
Comparison of Donor-Recipient HLA-Match:CB (n = 75, 150 units) vs URD (n = 184)
CB grafts: marked HLA-disparity.
CD34+ cell dose also much lower: RD 7.9, URD 6.0, CB 0.09 ( p < 0.001).
0%
10%
20%
30%
40%
50%
60%
70%
10 Allele HLA Match
Perc
ent o
f Don
orsHLA-Match for CB units
. 6/6 (n=5): 4/10 - 9/10
. 5/6 (n=82): 4/10 - 9/10
. 4/6 (n=63): 2/10 - 7/10
2 3 4 5 6 7 8 9 10
CB URD P < 0.001
Ponce, BBMT 2011
Time Post-Transplant (Months)
Dis
ease
-Fre
e Su
rviv
alAdults** (n = 52, median 41 yrs, range 16-69): 64%
Children* (n = 23, median 9 yrs, range 0.9-15): 78%
DCBT if Acute Leukemia & MDS/MPD: 2-yr DFS
Barker et al, ASH 2011
Low incidenceof relapse
(9% children, 6% adults) translates
to relatively high survival
rates.
Inf. TNC: * 3.3 + 2.6 ** 2.7 + 1.9
Time Post-Transplant (Months)
Dis
ease
-Fre
e Su
rviv
al
Adults 16-69 yrs (n = 52): 64% (Europeans 62%, Non-Europeans 66% )
Children 0-15 yrs (n = 23): 78% (Europeans 86%, Non-Europeans 75%)
DCBT if Acute Leukemia & MDS/MPD: 2-yr DFS
No differencebetweenEuropean &non-Europeanpatients.
In multivariateanalysis onlyCMV serostatuswas significant.
Barker et al, ASH 2011
Why are these results important?
Best Matched URD & Best CB if Combined Search by Patient Ancestry (n = 525)
Best Donors Europeans(n = 341)
Non-Europeans(n = 184)
p
Best URD10/10 (n = 218) 180 (53%) 38 (21%) <0.0019/10 (n = 148) 99 (29%) 49 (27%)<8/10 (n = 159) 62 (18%) 97 (53%)Best CB5-6/6 (n = 401) 270 (79%) 131 (71%)4/6 (n = 90) 56 (16%) 34 (18%)No CB (n = 34) 15 (4%) 19 (10%)
Volunteer unrelated donors: poor HSC source for non-Europeans.
Barker et al 2010, BBMT
NW E
urope
Eastern
Euro
pe
SouthEuro
pe
Mix:
Euro
peAsia
n
Africa
n
White
Hisp
anic
Middle
Eastern
Mix:
Non
Euro
pe0
10
20
30
40
50
60
70
80
No graft (n=26) CB (n=90)
URD (n=269)
Num
ber
of P
atie
nts
Barker et al 2010, BBMT
CB Extends Transplant Access to “Minorities”:URD vs CB vs No Graft by Ancestry (n = 385)
URD (n=426) CB (n=137) No Graft (n=34)
NW Europe Asian
Eastern Europe African
Southern Europe White Hispanic
Europe Mix Middle Eastern
Non-Europe Mix
Updated Data, MSKCC 2012 (n = 597)
Greater than 50% of CBTs had non-European ancestry
25% 53% 76%
• Immunosuppression: rejection/ GVHD• Supportive care: infection, bleeding, nutrition
-7 +28 +100 +180 +1 year0
• Conditioning: High, Midi , Mini
Patient Related Factors• Biology of Malignancy: determines need for hi dose prep vs
reliance on GVL• Patient Characteristics: age, extent of prior Rx, co-morbidities.
CB: Dose, match, qualityTransplant Related Factors
Variables that Determine Outcome
How to Select Units?
10957303650
CI o
f Tra
nspl
ant-
Rel
ated
Mor
talit
y
Years Post-Transplant
4/6 & TNC <2.5
4/6 & TNC ≥5.0
4/6 & TNC 2.5-4.9
5/6 & TNC 2.5-4.9
5/6 & TNC <2.5
5/6 & TNC ≥5.0
80
100
20
40
60
0 1 2 3
6/6 & all doses (mean TNC 4.4)
TRM by Combined TNC Dose & A,B Antigen, DRB1 Allele-Match1061 NYBC Single Unit Myeloablative CBT 1993-2006
Very high TRM if mismatch & low TNC
Barker et al, Blood 2010Lowest TRM: best HLA-match, not highest dose.
Lowest TRM: 6/6 match
Implications for Unit Selection(applies to single unit CBT, may also apply to double)
• Biggest cell dose not necessarily the best. 6/6 units highly attractive (?cell dose threshold).• Sliding scale: more mismatch, greater required cell dose. Converse also true: match can compensate for low dose.
Implies:• Above a cell dose threshold best matched unit the best.• New measures needed if best unit is mismatched.
Barker, Blood 2010
Additional factors to consider in unit selection -
revealed in investigation of double unit biology
% CD34+ Cell
Viability
EngraftingUnit
(N=44)
Non-Engrafting
Unit (N=44)
<75%(N=16) 1 15
≥75%(N=72) 43 29
Engraftment in 44 Double Unit CBTs Engrafting with a Single Unit.
Using CD34+ viability threshold of 75% (mean-2SD), all but one (43/44) engrafting units had CD34+ viability >75% (p=0.0006)
OR Only 1/16 poor viability units engrafted.Poor CD34+ viability correlated with lower CFUs (p=0.02).
Scaradavou, BBMT 2010
BAD UNIT GOOD
GOOD UNIT
90% viable
50%viable
Unit Quality: Schema of CD34+s of 2 CB Units
Units similar infused viable CD34+ doses-but very different.
In part, double unit CBT effective as increases chance of transplanting at least one good quality unit.
Total CD34+ Cells in 2 Units
Unit #1 Unit #2
Scaradavou, BBMT 2010
Implications• Unit quality varies from unit to unit, & bank to bank. Not all banks are the same.
• Factors that dictate unit quality need to be determined eg collection standards, processing methodology, red cell content, cryo volume, age.
• Methods to test unit quality prior to thaw should be priority eg testing the segment.
Do the principles of single unit CBTalso apply to double unit CBT?
Sustained Neutrophil Engraftment After Myeloablative DCBT by CD34+ Cell Dose of Engrafting Unit (n = 61)
>2.0 (n=10): 100%
@ 16.5 days
1.0-2.0 (n=13): 100%@ 20 days
<1.0 (n=38): 89%
@ 27.5 days
P < 0.001
High rate sustained engraftment directly dependent on infused CD34+ of winner; if low can be very slow.
Avery, Blood 2011
Sust
aine
d N
eutr
ophi
l Eng
raft
men
t
Avery, Blood 2011
Total Graft Cell Dose & DCB Engraftment (n = 61)
Time Post Transplant (Days)
0.0
0.2
0.4
0.6
0.8
1.0
p = 0.10
0.0
0.2
0.4
0.6
0.8
1.0
p = 0.001p = 0.020.0
0.2
0.4
0.6
0.8
1.0
0.0
0.2
0.4
0.6
0.8
1.0
p = 0.00070 10 20 30 40 50 0 10 20 30 40 50
0 10 20 30 40 50 0 10 20 30 40 50
>4.3 x107/kg:100%
<4.3 x107/kg:87%
>1.8 x105/kg:97%
<1.8 x105/kg:90%
>6.2 x104/kg:97% <6.2 x104/kg:
90%
>7.8 x106/kg:97%
<7.8 x106/kg:90%
TNC CD34+
CFU CD3+
Total TNC & CD3+ dose of graft also have an effect.
Months Post-Transplant
C.I.
Gra
de II
I-IV
aG
VH
D
0 1 2 3 4 5 6
20
40
60
80
100
0
2-7/10 HLA Match
8-9/10 HLA Match
Grade III-IV aGVHD by Engrafting Unit-Recipient 10 Allele HLA-Match (n = 115)
Recipient-Unit Match HR P2-7/10 (n = 88) Reference8-9/10 (n = 27) 0.37 0.105
P = 0.07 on multivariate: HLA-match likely critically important
Ponce, D., ASBMT 2012
Evaluate search for units 4-6/6 & > 2.0 x 107/kg.
Review info & bank for each unit.Obtain missing info, CT units of interest.
Prepare CB Search Summary Report.
Rank units by A,-B antigen, -DRB1 allele match*Hi to low TNC within each match grade (correct for RBC).
6/6 units:Choose largest.
5/6 units: Choose largest.
4/6 units: Choose largest.
Make final selection of unit(s) (1a & 1b if double).
1st 2nd 3rd
Plan shipment(s)
Review CTs, update Search Summary
Prepare domestic back-up unit(s).
* Ignore unit-unit match in double unit CBT
Require att. segment for identity testing & complete IDMs. Select on bank, dose, match, other (RBC content).
What about higher resolution match?
Kurtzberg, J. et al,Blood 2008
COBLT Single CBT: OS in Pediatric Malignancies
A, B, DRB1allele match:< 5/6 allele matchassociated with higher severe aGVHD.Trend towardimproved OSwith better match.
Eapen, M. et al, Lancet, 2011
Effect of C: A,B,C Antigen, DRB1 Allele N = 803, median 10 yrs (<1 – 62), leukemia/ MDS
• Inferior neut engraftment with hi degree MM (< 5/8).• Worse GVHD if < 5/8 including HLA-A MM.• Relapse lower if any MM vs match (but no advantage to multiple mismatches.• TRM significantly worse if < 6/8 (trend for 7/8).• 3 year TRM: 8/8 9%; 7/8 (non-C) 19%; 7/8 (C) 26%; 6/8 (C + other) 31%.• Significance lost in overall mortality except for 6/8 (C + other). Contributed to by rel. high TNC of group?
C is important-but how to trade off against cell dose?What is new lower limit of acceptable match?
New…… & Easy to Implement
CI of Neutrophil Engraftment
Stevens C E et al. Blood 2011
Incorporating Vector of HLA-Match: 1202 Single Unit CBT, NYBC
Significant advantage to both 0 & GVHD vector only mismatches
Stevens C E et al. Blood 2011;118:3969
CI of 3 Year TRM
HLA-Match Vector: 1202 Single Unit CBT
In heme maligs: GVH only mismatch equal to 0 mismatch.
New……… But More Difficult to Implement
NIMA-Match: 1121 Single Unit CBT, NYBC
van Rood J et al. PNAS 2009
3 Year TRM in Patients > 10 Years Old
If 1 MM,advantage ifthis is a NIMAmatch (predom. due tobetter neutrophilengraftment).
0 HLA Mismatch (n=45) Shared IPA (n=751)
No Shared IPA (n=49)
C
.I. o
f Rel
a pse
0.2
0.4
0.8
1.0
0.6
0.0
Cox Regression: Multivariate
1-3 HLA MM, No Shared IPA Reference1-3 HLA MM, Shared IPA 0.4 <0.001 0 HLA MM 0.3 0.012
0 1 2 3 Years Post-Transplant
Relapse by Shared IPA: 845 Singles (AML/ALL)
Patient shares IPA = reduced relapse. ??Indirect evidence that maternal T-cells mediate GVL?
• CB banks should report maternal HLA type.
• Should:o Select for NIMA match – expands no. of “well
matched” units. o Avoid “No Shared IPA” grafts in leukemics.
Implications for Unit Selection
1) TNC/ HLA-match: Above 2.0 x 107/kg prioritize match Within match grade choose largest. Consider vector & C.
2) Also consider bank of origin (speed, reliability, quality).3) For malignancy use 2: Increase chance of transplanting at
least one unit of good quality PLUS unit vs unit effects may augment engraftment & reduce relapse.
4) For doubles same rules apply to selecting units 1 & 2. Ignore unit-unit HLA-match.
5) Consider hi res match if possible-esp in children.6) Unresolved issues: selecting based on CD34+ dose, red cell
content, testing of segment, high res match vs dose, incorporation of NIMA & IPA.
MSKCC Strategy for Unit Selection
Barker, Blood 2011 -How I Treat
