Haplo vs Cord1949-2012:

The Search for the Perfect Donor.

1960’s: Importance of HLA type in Animal Models

Thomas: A History of Haemopoietic Cell Transplantation, Brit J Haematol, 1999, 105, 330-339

Survival of Dogs Given 1000 RAD TBI and a Marrow Infusion from a Littermate Matched or Mismatched for Dog Leucocyte Antigens (Epstein 1968, Storb 1971)

4

DNA Issues: Explosion of Alleles

Known AllelesOctober 2009A = 893

B = 1431

C = 569

DRB1 = 814

NATIONAL MARROW DONOR PROGRAM®

Entrusted to operate the C.W. Bill Young Cell Transplantation Program, including the Be The Match Registry®

8/8 Allele, Available-Match Rates in the Adult Donor Registry

5

MHC is the major determinant of GVHD:The MHC complex is located on Chromosome 6

MHC is the major determinant of GVHD:The MHC complex is located on Chromosome 6

A B C DR DP DQ

Haplo-identical SCT: The Mega-dose Stem Cell

Concept

Aversa et al, NEJM, 1998, 339, 1886

CI Relapse after Mega-Dose Stem Cell Transplant

Aversa

NRM after Mega-dose Stem Cell Tx

Elimination of allo-reactive effector cells by post tx

Cyclophosphamide

Luznik, Immunology Research, 47, 65-77, 2010

Elimination of allo-reactive effector cells by post tx

Cyclophosphamide

Haplo Tx OutcomeLee et al, Korea, Blood 2011 Lu et al, Bejing, Blood 2008

Aversa et al, Italy, Blood cells 2008 Luznik et al, USA BBMT2008

Haplo Transplant – a variety of approaches

N Age High Risk

Cond GVHD prophylaxis

DFS 2yrs

Sodani1 22 8 RIC ATG CD34+ 60%

Mehta8 201 23 67 Abl T-depl+ATGCSA MPD

20%

Lu4 159 24 24 Abl ATG 64%

Lacerda2 14 25 20 RIC CD34+ 41%

Aversa10 255 29 46 Abl T-depl 25-50%

Ichinohe3 35 28 63 various

tacrolimus 50%

Lee5 83 40 40 BuFlu ATG 45%

Luznik9 68 48 ? RIC Cyclo 35%

Rizzieri6 49 48 66 FluCy Campath 25%

Grosso7 27 52 30 TBI CY Cyclo T depl DLI

48%

1 Blood 2010, 2 BBMT 2003, 3 Blood 2004, 4 Blood 2006, 5 Blood 2011, 6 JCO 2007, 7 Blood 2011, 8 BMT 2004, 9 BBMT 2008, 10 Blood, Cells, Molec 2009

Donor Determinants and Tx Outcome

Maternal DonorStern et al Blood 2009

KIR AlloReactivityRuggeri et al Blood 2007

Lessons

Haplo can be curative. Cure rates may be superior in

younger pts Cure rates depend on disease status

at transplant Maternal Donor is superior. Some studies show increased

recurrence rate, particularly in AML NK-KIR mismatching may matter,

particularly in T-cell depleted Tx

Alternative Donor Transplant

Cord: – Delayed Engraftment– Decreased GVHD– Decreased Relapse?

Brunstein C G et al. Blood 2010;116:4693-4699©2010 by American Society of Hematology

D-UCB vs Adult Donor SCTCauses of Death

Parallel CTN trials

Haplo: Low TRM-High Relapse UCB: Higher TRM-Low Relapse

Brunstein, Blood 2011

Parallel CTN Trials

Haplo UCB

Time

% D

on

or

Ch

imer

ism

Cord Blood

Haplo- identical transplant

100 40

Haplo- identical transplant

Melphalan (70 mg/m2)

Tacrolimus

Fludarabine* (30 mg/m2/day)

Flu-Mel

-7 -6 -5 -4 -3 -2 -1 0 Day

d –2-d 180

Thymo 1.5 mg/kg

Fludarabine Melphalan ATGFludarabine Melphalan ATG

d 0-d 60Mycophenolate

Patient and Donor Eligibility

Patient:• Advanced Hematologic Malignancy or SAA• PS>2• No Age or Weight Limit

Haplo Donor• HLA mismatched Relative • G-CSF mobilized• CD34 selected Isolex/Miltenyi Clinimax

UCB Donor: • Matching > Cell doseMore recently we avoided donors targeted by recipient

DSA

Age median (range) 50 (20-69)

Weight kg (range) 80 (41-125)

Gender (M/F) 30/15

Ethnic/racial Minority 13 (29%)

Diagnosis

AML/MDS 29 (70%)

ALL 7 (16%)

Lymphoma 5 (11%)

CLL/MPD 4 (8%)

Disease Stage

Active disease at Tx 26 (58%)

Prior Transplant 7 (16%)

KPS 0/1 30/15

HCT CI 0-2/3 or more 34/11

Patient Characteristics (n=45)

06/30/11

Cord match 6/6 3 (7%)

5/6 33 (73%)

4/6 9 (20%)

Cord cell dose TNC ( x10^7/kg) 1.5 (1.2-2.1 IQR)

CD34 (10^5/kg) 0.63 (0.4-0.8 IQR)

Haplo Source Sibling 20 (45%)

Mother 1 (2%)

Father 4 (9%)

Child 20(45%)

Haplo cell dose CD3+ (10^4/kg) 0.7 (0.2-1.2 IQR)

CD34 (10^6/kg) 3.5 (2.4-4.6 IQR)

Graft Characteristics

N=45, 06/30/11*26 Isolex, 19 Miltenyi

Cumulative Incidence of Platelet and Neutrophil Recovery

03/02/11

Chimerism

Outcomes100 Days 1 Year

Relapse (Cum Inc) 11% (3-19) 30% (14-44)

TRM (Cum Inc) 9% (1-17) 28% (13-43)

PFS (KM) 42% (25-79)

OS (KM) 55% (39-71)

Median FU for survivors 11 mo (2-42 mo)

N=43, 03/02/11

Cell dose, Pt or disease characteristics do not predict for outucome

Haplo Cord vs Sib/MUD: AML/MDS:Recurrence

Haplo Cord vs Sib/MUD: Survival

All Patients High Risk Patients

Immunity And the Feto-maternal Axis

IPA-targeting

Van Rood, PNAS 2012

Conclusions RIC Haplo Cord Transplantation results in

predictable and rapid engraftment of neutrophils (d11) and platelets (d19)

UCB cell dose no longer determines engraftment, increasing potential UCB pool.

A suitable donor combination is available for >90% of all patients.

Recurrence rates may be decreased. Possibly via IPA mediated mechanisms

Conclusions cont’d Cure is possible with haplo-haplo-cord or DUCB Technology is rapidly evolving

– NK-Kir– NIPA– HLA-antibodies– Adoptive Immunotherapy

Everybody has a donor!!!

Thanks to: Collaborators

– Hong Tao Liu– Andy Artz– John Cunningham– Lucy Godley– Elizabeth Rich– Justin Kline– Richard Larson– Vu Nguyen– Toyosi Odenike– Wendy Stock– Amittha Wickrema

Res RN & NP– Paula Del Cerro– Linda Pape– Lisa Schroeder– Ima Garcia– Beth Hurter

Pharm D– Sandeep Parsad

Transplant Unit Staff Biostatistics

Ted Karrison Chimerism

Loren Joseph HLA

Susana Marino

Thanks to: Collaborators

– Hong Tao Liu– Andy Artz– John Cunningham– Lucy Godley– Elizabeth Rich– Justin Kline– Richard Larson– Vu Nguyen– Toyosi Odenike– Wendy Stock– Amittha Wickrema

Res RN & NP– Paula Del Cerro– Linda Pape– Lisa Schroeder– Ima Garcia– Beth Hurter

Pharm D– Sandeep Parsad

Transplant Unit Staff Biostatistics

Ted Karrison Chimerism

Loren Joseph HLA

Susana Marino