Haplo-cord transplantation offers similar results compared to MUD transplantation

in High-Risk Adult Patients with Hematologic Disorders

Mi Kwon Gregorio Marañon Institute for Health Research;

Department of Hematology, Hospital General Universitario Gregorio Marañon, Madrid, Spain

Gregorio Marañon Institute for Health Research

No conflicts of interest to declare

Disclosures

Unrelated umbilical cord blood has been increasingly used as an alternative stem cell source for adult patients eligible for allogeneic SCT lacking HLA-matched adult donors

Unrelated Donor Stem Cell Sources by Recipient Age

2001-2010

Unrelated Cord Blood Transplants, by Age Registered with the CIBMTR

2001-2010

Source for allogeneic SCT

Age ≤ 20 yrs Age > 20 yrs

0

20

40

60

80

100

2001-2005 2006-2010 2001-2005 2006-2010

Bone Marrow (BM)Peripheral Blood (PB)Cord Blood (CB)

0

100

200

300

400

500

600

700

800

900

1,000

2001 2002 2003 2004 2005 2006 2007 2008 2009 2010

>= 16 years< 16 years

Outcomes after Transplantation of Cord Blood or Bone Marrow from Unrelated Donors in Adults with Leukemia

Mary J. Laughlin, M.D., Mary Eapen, M.B., B.S., Pablo Rubinstein, M.D.,

et al.

2004; 351:2265-2275, Nov 25, 2004.

“The slow rate of hematopoietic recovery remains a major deterrent to the use and success of cord-blood transplantation in adults, and novel strategies to overcome this obstacle are needed”

Single CB compared to MUD

NRM

Months

Eapen et al., Lancet Oncol 2010

Neutrophil Recovery

Dual Transplantation: Haplo-Cord

Days after SCT

Neutrophils

CBU TPD* 3x106 /kg CD34+ <1x104 /kg CD3+

Conditioning

(*) Third party donor: G-CSF mobilization and CD34+ Immunomagnetic positive selection (Miltenyi’s CliniMACS®)

Haplo-Cord SCT experience

Reference N Age Disease Conditioning ANC>500/uL F-up months NRM DFS OS

Fernandez et al Br J Haem 2010 55 34 High-risk

MA CY-Flu-TBI/Bu ATG aaaaaaaaa CsA+Pred

10 days 13 15% 51% 54%

Liu et al Blood 2011 45 50 High-risk

(58% active) RIC__________ Flu-Mel-ATG 11 days 12 28% 42% 55%

Lindemans et al BBMT 2012 Tandem Meeting 2011

9 12 Non-malignant (n=7)

MA Bu-CY or Flu ATG or Campath CsA + Pred

12 days (N=8) 8 2/9 33% NR

Gormley et al ASH 2011 8 18 SAA MA

CY-Flu-TBI-ATG 10 days 9 1/8 7/8 7/8

The objective of this study was to analyze toxicity and survival rates

of adults who underwent haplo-cord SCT and to compare these

rates with those in a cohort of patients who underwent myeloablative

MUD SCT in our center in the same time period (2004-2012).

Haplo-cord vs MUD: Patients Characteristics of patients Haplo-Cord (N=29) MUD (N=31) p Age, years

Median (p25-p75) 40 (31-47) 38 (31-45) 0.6

Sex, no (%) Male 15 (52) 18 (58) 0.6 Female 14 (48) 13 (42)

Weight kg, median (range) 70 (42-103) 68 (45-98) 0.6

Disease status at transplant, no. (%) AML/MDS 15 (52) 22 (71)

0.4 CR1 9 (60) 10 (45) Other 6 (40) 12 (55)

ALL 8 (28) 4 (13) 0.6 CR1 5 (63) 3 (75)

Other 3 (37) 1 (25) Lymphoproliferative disease 4 (14) 2 (6) 0.77 Other 2 (7) 3 (10) 0.57

Active disease, (%) 33 (9/27) 45 (13/29) 0.42

Previous transplant, no. (%) 3 (10) 4 (13) 0.68

Months to transplantation (patients in 1st CR) Median (p25-p75) 8 (6-9) 9 (6-14) 0.11

HCT-CI 0-2 25 (86) 24 (83)

1 >2 4 (14) 5 (17)

Conditioning: Haplo-cord vs MUD Haplo-Cord Fludarabine 30 mg/m2/day

Busulfan 3.2 mg/kg/day (*)

Cyclophosphamide 60 mg/kg/day

rATG 2 mg/m2/day

Metilprednisolone 1 mg/m2/day

CsA from day -5

0 -1 -2 -3 -4 -5 -6 -7 -8 +10 +50 … …

* TBI (fr) 10 Gy

MUD 0 -1 -2 -3 -4 -5 -6 +3 +11 +1 +6 Fludarabine 40 mg/m2/day

Busulfan 3.2 mg/kg/day (*)

rATG 2.5 mg/m2/day

CsA from day -7

MTX * CTX or Mel

+50

Transplant and Graft characteristics Characteristics of transplants Haplo-Cord (N=31) MUD (N=31) ABO blood group mismatch, no. (%)

Major / Minior 11 (35) / 5 (16) 12 (39) / 2 (6) None 15 (48) 17 (55)

Conditioning, no. (%) BU - FDR - 19 (63) TBI containing regimen 2 (6) 6 (19) BU - FDR - CTX 27 (87) - ATG 31 (100) 29 (93)

GVHD prophylaxis, no. (%) CsA + MTX - 30 (97) CsA + steroids 29 (94) 0 CsA +/- MMF 2 (6) 0

CB cells, median (range) * TNC (x 10⌃7/kg) 2.9 (1.48-4.74) - CD34+ (x 10⌃5/kg) 1.9 (0.73-3.2) -

Third party donor cells, median (range) ** CD34+ (x 10⌃6/kg) 2.9 (1.5-3.46) - CD3+ (x 10⌃4/kg) 0.25 (0.05-1.5) -

MUD cells, median (range) ** TNC (x 10⌃8/kg) - 6 (0.8-18) CD34+ (x 10/⌃6/kg) - 4 (0.8-19)

HLA match, no. (%) 8/8 - 31 (100) 6/6 0 - 5/6 8 (26) - 4/6 23 (74) -

*After procesing, before cryopreservation ** Infused cells

Engraftment

Haplo-cord MUD ANC > 500/uL 15 (9-28) 16 (12-28) Platelets >20,000/uL 29 (9-84) 12 (9-41)

ANC >500/μL at 30 days Platelets >20,000/μL at 60 days

Days after SCT Days after SCT

Haplo-cord 90%

Haplo-cord 77.5%

MUD 97%

MUD 85%

p=0.5 p=0.001

Haplo-cord SCT: Chimerism

The CI of PB complete CB chimerism was 75% at 60 days and 87% at 90 days, achieved in a median of 29 days (range 14-71) All showed sustained CC in the last FU

Kwon et al, BBMT 2013, under review

Haplo-cord SCT: Graft failure

• In 2/28 patients, failure of both CB and TPD grafts was documented • Poor viability (1): second haplo-cord, alive in CR • HLA antibodies against CB antigens (1): haploidentical SCT, alive in CR

• In 3/28 patients, engraftment occurred at the expense of TPD only • Unknown (1): early relapse after Haploidentical rescue • Poor viability (2): relapse / infection after second haplo-cord

• Overall, CB graft failure was documented in 5 cases (17%) Kwon et al, BBMT 2013, under review

Survival

Median follow-up 33 months MUD 34 months (IQR 24-75) Haplo-cord 21 months (IQR 11-78)

DFS OS

45%

p = 0.7

51%

p = 0.7

Months Months

a

Relapse

MUD 32%

p=0.57 1.0

0.8

0.6

0.4

0.2

20 40 60 80 100 0 0.0

Cum

ulat

ive

inci

denc

e

Months

Haplo-cord 26%

at 36 months

No patient in either group experienced relapse beyond 2 years after transplantation

GvHD

MUD 32%

aGVHD II-IV 1.0

0.8

0.6

0.4

0.2

20 40 60 80 100 0 0.0

Cum

ulat

ive

inci

denc

e

Days

Haplo-cord 10%

p=0.06

cGVHD mod-severe 1.0

0.8

0.6

0.4

0.2

20 40 60 80 100 0 0.0

Months

p=0.03

MUD 27%

Haplo-cord 5%

In addition, 3 patients from the MUD group developed severe GVHD after rapid withdrawal of IS in 2 patients and DLI 1 patient (relapse and increasing MC)

Non Relapse Mortality

p=0.46 1.0

0.8

0.6

0.4

0.2

20 40 60 80 100 0 0.0

Cum

ulat

ive

inci

dene

Months

MUD 23%

Haplo-cord 29%

at 36 months

Most of the transplantation-related deaths occurred within the first year after SCT Haplo-cord: • Infection 4 • GvHD 1 • Toxicity/MOF 3

MUD: • Infection 1 • GvHD 5 • Toxicity/MOF 1

Infections MUD Haplo-cord

Bacteria 13 (1*) 19 (2*)

CMV (PCR, preemptive)

19

18

Hemorrhagic cystitis Grade 2-4

5 (BK)

8 (2 CMV

5 BK 1 Adenovirus*)

VEB 2 (1*) 2 HHV-6 - 1 Other 1 1

TB - 1

IFI possible 5 7

IFI proven 1 2*

Other 1* - * Death

Haplo-cord vs MUD: Conclusions • Haplo-cord SCT in high-risk patients offers time to

engraftment and survival rates comparable to those seen with myeloablative 8/8 HLA-matched unrelated donor transplantation, with significantly lower GVHD rates

• In contrast to previous comparative studies including

single CB transplantations, the Haplo-cord approach offers similar NRM rates as MUD transplantation

• Haplo-cord SCT provides a valuable option for high-risk

patients who lack a matched adult donor or who require urgent transplantation

• Thus, this CB transplantation approach merits broader

evaluation

Haplo-cord SCT Spanish Experience

140 transplants in 132 patients between 1999 and June 2012

Hospital Universitario Puerta de Hierro (Madrid) N=95

Hospital Universitario Gregorio Marañón (Madrid) N=30

Hospital Duran i Reynals (ICO, Barcelona) N=15

Preliminary Analysis of 125 transplants

Haplo-cord SCT. 1999-2012.

AML 47 40% ALL 40 34% MDS 11 10% CML 5 4% NHL 8 7% Other 6 5% Active disease 39% Previous transplant 25 (21%)

TNC x 107/kg 2.4 (1.1-6) CD34+ x 105/kg 1.28 (0.35-5.86) HLA matching 6/6 16 14% 5/6 45 38% 4/6 52 44.5% 3/6 4 3.5% TPD 82% related, 18% unrelated 69% haplo, 31% <haplo CD34+ x 106/kg 2.5 (0.8-4.0) CD3+ x 104/kg 0.24 (0.05-1.5)

Median follow-up 5 years (1.4 m – 13.5 years)

125 SCT, 117 patients Age 35 (16-60) M/F 45 (39%) / 72 (61%) Weight 70 kg (42-111)

a

Engraftment ANC >500/uL Plt >20.000/uL

ANC > 500/uL Platelets > 20.000/uL Median, days 12 (9-36) 31 (9-98)

97% at 40 days 93% at 100 days

Days after SCT Days after SCT

a

CB engraftment: full CB chimerism

75% at 180 days

Median 60 days (11-180)

Early death 11 Graft failure/Rejection 8 Relapse 7 Early course 2

FULL CB CHIMERISM

Influence of CB TNC & CD34+ cells

0,00

0,25

0,50

0,75

1,00

0 20 40 60 80 100 120Days

<=2,54>2,54

CB-TNC Median 2.5 x 107/Kg

0,00

0,25

0,50

0,75

1,00

0 20 40 60 80 100 120Days

<0,17>=0,17

0,00

0,25

0,50

0,75

1,00

0 20 40 60 80 100 120

Cumulative Incidence Plot

Days

<=0,141>0,141

CD34+ cells < vs ≥ 0.14 x106/Kg

CD34+ cells < vs ≥ 0.17 x106/Kg

MN Fernandez. CB symposium 2012

62 58 45 75

a

Relapse

21% at 1 year 25% at 5 years

a

aGvHD

23%

Days

aGvHD II-IV cGvHD

Cum

ulat

ive

inci

denc

e

Days

24%

63% limited 37% extensive

a

Non Relapse Mortality

42 deaths: • 18 infections (8 virus, 4 fungus, 2 Toxoplasmosis, 1 Chagas, 2 bacteria, 1 other) • 4 VOD, 8 MOF • 9 GVHD • 1 graft rejection • 2 Toxicity/infection

36% at 2 years

17% at 100 days

a

Survival

40% at 5 years 44% at 5 years

Months Months

DFS OS

a

Survival in AML/ALL N=87 (74%)

43% at 5 years

p = 0.01

Active disease 25%

Months Months

CR 51%

OS OS

Conclusions: Haplo-cord SCT • Provides a prompt myeloid reconstitution even using CB

units with relatively low cell content • CB should be considered as a front line option for patients

in need of an allogeneic SCT, especially for patients with acute leukemia

• May allow the reduction of cell dose requirements, expanding CB availability and facilitating selection on the basis of HLA match (especially relevant for uncommon haplotypes, CCR5 mutation in HIV+ patients)

• Efforts to improve immune reconstitution should continue since post-engraftment infections remain an issue

Haplo-cord Trasplant Project Spain

Hospital Duran y Reinals ICO I S. Ortega-Sánchez R. Duarte

Hospital Univ. Gregorio Marañón M. Kwon J. Gayoso D. Serrano I. Buño J. Anguita P. Balsalobre J.L. Díez Martín

Hospital Univ. Puerta de Hierro G. Bautista A. de Laiglesia R. Forés I. Millán C. Regidor J.R. Cabrera

M.N. Fernández