Juliet N. Barker, MBBS (Hons), FRACP Associate Attending Director Cord Blood Transplant Program

transcript

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

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

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

Days Post-Transplant

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

0 12 24 36 48 60

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).

10 Allele HLA Match

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)

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)

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)

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

Eastern

SouthEuro

peAsia

Africa

Middle

Eastern

No graft (n=26) CB (n=90)

URD (n=269)

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

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

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

Total Graft Cell Dose & DCB Engraftment (n = 61)

Time Post Transplant (Days)

p = 0.10

p = 0.001p = 0.020.0

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:

>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

0 1 2 3 4 5 6

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)

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

Juliet N. Barker, MBBS (Hons), FRACP Associate Attending Director Cord Blood Transplant Program

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