Updates for Haploidentical Donor Transplant

Updates for Haploidentical
Hematopoietic Transplantation
Outcomes
Piyanuch Kongtim, MD
Division of Hematology
Department of Internal Medicine
Faculty of Medicine
Thammasat University

Disclosure Information
Piyanuch Kongtim, MD
• I have no financial relationship to disclose.
• I will not include discussion of investigational
or off-label use of a product in my
presentation.

Outline
• T cell depleted HaploSCT: from complete to partial ex
vivo T cell depletion
• T cell replete Haploidentical transplantation with
post transplantation cyclophosphamide
• Update haploidentical transplant outcomes
• Comparative outcomes with matched transplants

Inheritance of HLA-Haplotypes
Parents
Progeny
A B C D
A C B R B C B DA D

Historical Perspective
• Haploidentical cell transplantation (Haplo SCT) -
established treatment for patients without a
matched donor
• Historically limited by higher bidirectional
alloreactivity - high rate of graft failure and GVHD

T-cell Replete BMT with Conventional GVHD
Prophylaxis
• Powles et al. reported the outcomes of 35 patients with AML and
ALL received 1-3 HLA-mismatched related BMT
• Conditioning: Cy/TBI or Cy/Mel
• GVHD prophylaxis: Cyclosporin + MTX
• 10/35 had primary graft failure
• 12/35 patients died from a syndrome consisting of pulmonary
edema, seizures, intravascular hemolysis and renal failure
___________________________________________________________________
Powles RL, et al. Lancet 1983; 1: 612

From complete to partial ex vivo
T cell depleted HaploSCT

T-cell Depleted Haploidentical SCT
• T cell depletion of the graft was developed which aimed to
minimize T cell alloreactivity reaction across the HLA barrier
• The EBMT study - Largest experience with TCD HaploSCT
• Retrospective study on 266 patients (173 AML 93 ALL)
• Myeloablative TBI-based conditioning (TBI/Flu/TT/ATG)
• 91% engrafted
• Grade II-IV aGVHD: 5% AML and 18% ALL patients
• TRM: 36-66% based on disease status at transplant
• LFS: 48% for AML, and 30% for ALL
_______________________________________________________________________
Ciceri F, et al. Blood. 2008; 112:3574-81.

Current selective approaches to TCD haploSCT
Approach Rationale and advantages
Tregs and Tcons co-
infusion
- Prevent GVHD by Tregs while promoting immune
reconstitution by addition of Tcons
Selective αβ T cell
depletion
- Removing αβ T cells that are most responsive for
aGVHD
- Remaining γδ T cells are thought to have an innate
immune like response capability without inducing
GVHD.
Photodepletion of
alloreactive T cells
- ex vivo depletion of alloreactive T cells with TH9402
that accumulates in activated T cells
Selective CD45RA+ T cell
depletion
- Elimination of CD45RA+ naïve T cells thought to
play a major role in GVHD.
- Preserves memory T cells that are active against
infections
Kongtim et al BBMT 2015

TCR Haploidentical SCT with High-
dose Post-Transplant
Cyclophosphamide

TCR Haploidentical SCT with High-dose Post-
Transplant Cyclophosphamide
• Recent approach using a T-cell replete (TCR) haploidentical
graft and HDPTCy for GVHD prophylaxis
• Barenbaum - Cy can prevent skin graft rejection in murine
models
• Luznik et al. - HDPTCy may induce donor-host tolerance and
eliminate alloreactive T-cells responsible for GVHD
• HDPTCy attenuated lethal and non-lethal GVHD in mice and
prolonged their survival
______________________________________________________________________________
Berenbaum MC, Brown IN. Nature. 1963;200:84.
Santos GW, Owens AH. Bull Johns Hopkins Hosp. 1965;116:327-340.
Luznik L, et al. Blood. 2001;98:3456-3464.

Mechanism Post-transplant Cyclophosphamide
Luznik L, et al. Blood. 2001;98:3456-3464.

TCR Haploidentical SCT with High-dose Post-
Transplant Cyclophosphamide
• Kastan et al. - human hematopoietic progenitor cells
express high levels of cytoplasmic aldehyde
dehydrogenase (ALDH) which makes them resistant
to the cytotoxic effect of CY.
• A recent study from the same group has
demonstrated the resistances of Tregs to CY through
expression of ALDH, which may contribute to GVHD
prevention in this setting.

Conditioning Chemotherapy for Haplo SCT
with Post-Transplantation Cy
• Phase I study by John Hopkin group
• Conditioning: fludarabine, 30 mg/m2 per day from Day -6 to -2, CY
14.5 mg/m2 on Day -6, -5 and TBI 2 Gy on Day -1.
• This protocol used only on day of CY 50 mg/kg on day+3.
• The modified regimen: CY on Day+3 and +4.
• Graft failure: 13%,
• aGVHD grade III-IV: 6%
• extensive cGVHD: 5%
• 1-year NRM of only 15%.
• However, more than a half of the patients relapsed after 1 year
post-transplant
O’Donnell P, et al. BBMT. 2002;8:377 Luznik L, et al. BBMT. 2008;14:641
________________________________________________________________________

MAC and PTCy
• 20 patients with relapse/refractory hematologic
malignancies
• Busulfan-based myeloablative conditioning
followed by PTCY.
• 100% Donor engraftment
• Grade II-IV aGVHD 30%, grade III-IV 10%
• NRM was only 10%.
• With a median follow-up of 20 months, disease
free survival was 50%
Solomon SR, Biol Blood Marrow Transplant. 2012;18(12)1859-66
________________________________________________________________________

T cell depleted vs T cell replete
HaploSCT

TCR vs TCD
• Ciurea et al: 33 TCD, 32 TCR haploSCT at
MDACC
• Conditioning: Flu/Mel/Thio
• GVHD prophylaxis
– TCD: rabbit ATG at 1.5 mg/kg/ day on days −6, −5,
−4, and −3, followed by infusion of CD34+ selected
cells
– TCR: PTCy, Tacro, MMF
Ciurea SO, et al. Biol Blood Marrow Transplant. 2012;18:1835

Conditioning Regimens
D-8 Admit/hydration
D-7 Melphalan 100-140mg/m2
D-6 Fludarabine 40 mg/m2
D-2 TBI 2Gy
D-1 Rest
D 0 Unmanipulated bone marrow stem
cell infusion
D+3 Cyclophosphamide 50mg/ kg/day
D+5 Tacrolimus for 6 months and MMF
until day 100 then taper
D+7 G-CSF 5mcg/kg/day
D-8 Admit/hydration
D-7 Melphalan 100-140mg/m2
D-6 Thiotepa 5mg/kg
D-1 Rest
D 0 Unmanipulated bone marrow stem
cell infusion
D+5 Tacrolimus for 6 months and MMF
until day 100 then taper
D+7 G-CSF 5mcg/kg/day

PFS all and Patients in Remission
(N=32 TCD and N=33 TCR)
0 2 4 6 8 10 12 14 16 18 20 22 24
Months Post Transplant
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
CumulativeProportionSurvivingProgressionFree
TCR Overall
TCD Overall
0 2 4 6 8 10 12 14 16 18 20 22 24
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
CumulativeProportionSurvivingProgressionFree
TCR Remission
TCD Remission
_______________________________________________________________________________________
50%
21%
P=0.02

NRM (left) and Mortality from Infectious
Complications (right)
0 10 20 30 40 50 60 70 80
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
CumulativeIncidenceofInfectionRelatedDeath TCR, 9%
TCD, 24%
P at 2 yrs 0.01
0 10 20 30 40 50 60 70 80 90
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
CumulativeIncidenceofNRM
TCD, N=33, 42%
TCR, N=32, 16%
P at 1yr 0.03
_______________________________________________________________________________________

Gr. II-IV aGVHD and cGVHD
_______________________________________________________________________________________

Haploidentical Transplantation for
Myeloid and Lymphoid
Malignancies

Reference Conditioning regimen Diseases No.
pts
Graft aGVHD
(II-IV)
NRM Relapse
rate
PFS
MYELOID
MALIGNANCIES*
Bashey A, et al.
JCO.
2013;31:1310
Bu/Flu/Cy regimen
Fludarabine 25mg/m2 on days -6 to -2 (total 125
mg/m2)
Busulfan 110-130mg/m2/day IV on days -7 to -4
Cyclophosphamide 14.5 mg/kg days -3 and -2
(total 29mg/kg)
AML 32%
MDS/MP
D 15%
ALL 19%
53 BM
60%
30% 7% at
1yr
33% at
2yrs
60% at
2yrs
Raiola A, et al.
BBMT.2013:19:1
17.
Thio/Bu/Flu regimen
Thiotepa 5mg/kg on days -6 and -5 (total
10mg/kg)
Busulfan 3.2 mg/kg IV on days -4 to -2 (total
9.6mg/kg)
Fludarabine 50mg/2 on days -4 to -2
Flu/TBI regimen
TBI 3.3 Gy on days -8 to -6 (total 9.9 Gy);
Fludarabine 30mg/m2 on days -5 to -2 (total
120mg/m2)
AML 50%
ALL 25%
MPD 16%
35
15
BM 12% 18% at
18 mo
26% at 18
mo
51% at
18 mo
Di Stasi A, et al .
BBMT.2014
Flu/Mel140 regimen
Fludarabine 40 mg /m2 on days -5 to -2
Mephalan 140mg/m2 on day -6
+/- Thiotepa 5-10mg/kg on day -7
AML/MD
S
100%
32 BM 29% 24% at
1yr
33% at
3yrs
56.5% at
3yrs*
Solomon S, et al. Flu/TBI regimen
Fludarabine 25mg/m2 on days -7 to -5
TBI 150 cGy BID on days -4 to -1 (total dose 12Gy)
AML 70%
ALL 10%
CML 15%
30 PB 44% 5% at
2yrs
19% at
2yrs
76% at
2yrs

Reference Conditioning regimen Diseases No.
pts
Graft aGVHD
(II-IV)
NRM Relapse
rate
PFS
LYMPHOID
MALIGNANCIES
Burroughs et al.
BBMT.
2008;14:1279
Flu/Cy/TBI 200
Fludarabine 30 mg/m2/day on days −6
to −2
Cyclophosphamide 14.5 mg/kg/day
on days −6 and −5
2 Gy TBI on day −1.
HD 100% 28 BM 43% 9% at
2yrs
40% at
2yrs
51% at
2yrs
Castagna et al.
BMT.2014
Flu/Cy/TBI 200
Fludarabine 30 mg/m2/d IV daily on
days −6 to −2
Cyclophosphamide 14.5 mg/kg IV on
days −6 and −5 and
2 Gy TBI on day −1
HD 55%
NHL 39%
49 BM 26% 16%
at
2yrs
19% at
2yrs
65% at
2yrs
Kanakry JA, et al.
BBMT.
2013;19:602
Flu/Cy/TBI, Flu/TBI PTCL 100% 22 BM 16% 11%
at 1 yr
34% at 1
yr
40% at 2
yrs**
Kasamon Y, et al. Flu/Cy or Flu/Cy/TBI
Fludarabine 30 mg/m2 on days -6 to
-2
2 Gy TBI on day -1
NHL 75%
HD 25%
151 BM 32% 16%
at 1yr
31% at
1yr
40% at
3yrs
Brammer J, et al. Flu/Mel100/TBI 200
Fludarabine 40 mg /m2 day on days -
5 to -2
Mephalan 100mg/m2 on day -6
2 Gy TBI on day -1
HD 37%
NHL 37%
CLL/PLL
26%
19 BM 44% 11%
at 2
yrs
26% at
2yrs
52% at
22 mo

Haploidentical Transplantation with Post-transplant
Cyclophosphamide and Melphalan-based Conditioning–
A retrospective Analysis of the First 100 Patients
Treated at MD Anderson Cancer Center
Piyanuch Kongtim, Ravi Pingali, Antonio M. Jimenez, Roberto Ferro, Gabriela Rondon, Julianne Chen,
Oran Betul, Aimee Hammerstrom, Lindsey Lombardi, Partow Kebriaei, Martin Korbling, Uday R. Popat,
Simrit Parmar, Dean A Lee, Laurence Cooper, Katayoun Rezvani, Issa Khouri, Elizabeth J. Shpall, Richard
E. Champlin, Stefan O. Ciurea
Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center,
Houston, TX

Patients and Methods
• We retrospectively analyzed the outcomes of 100 patients
who underwent haploSCT for various hematologic
malignancies between September 2009 to July 2012 at the
university of Texas MD Anderson Cancer Center.
• Diseases were: AML/MDS 54 (33 had high-risk
cytogenetics), lymphoma/CLL 17 (12 not in remission at
transplant), ALL 12 (11 beyond first remission), CML 12
(all progressed to accelerated/blast phase), other 5 pts.
Kongtim P, et al. Abstract ASCO 2014

Patients and Methods
• The conditioning regimen included melphalan
(100-140 mg/m2), fludarabine (160 mg/m2) +/-
thiotepa (5-10 mg/kg).
• GVHD prophylaxis consisted of cyclophosphamide
50 mg/kg on day +3 and +4, tacrolimus and
mycophenolate.

Patient and transplant characteristics
Characteristics Number
Median age (year) 45 (IQR 19-67)
Gender female/male 46/54
Diagnosis
AML/MDS
Lymphoma/CLL
ALL
CML
MPN
Aplastic anemia
Myeloma
54
17
12
12
2
2
1
Disease status at transplant
CR
Not in CR
58
42
Cytogenetic risk (N=66)
Good
Intermediate
High
4
29
33
Prior AlloSCT 11
Prior ASCT 12
RIC 33
SC sources
Marrow
Peripheral blood
96
4

Results
• The median follow-up of 55 survivors was 18
months (range 2-48 months).
• Ninety-six patients engrafted with time to ANC
engraftment of 18 days (range 11-43 days).
• Delayed engraftment was seen in 2 patients.
• Of 96, 89 patients achieved full donor chimerism.
• At day +30 post SCT, 90 and 4 patients achieved CR
and PR respectively.

Transplant outcomes according to diseases
Outcomes (%) All patients
(N=100)
Myeloid
malignancies
in CR (N=40)
Lymphoid
malignancies
(N=17)
ALL
(N=12)
3-year PFS 43.3 56.5 62.3 44.4
1-year TRM 24.1 11.8 25.9 33.3
1-year CI of
relapse
23.3 30.1 24.4 33.3
aGVHD grade
2-4
30 25 35.3 50
aGVHD grade
3-4
10 0 11.8 41.7
cGVHD 15 12.5 11.8 44.4
cGVHD
(extensive)
8 10 5.9 8.3

Transplant outcomes according to first and
second SCT
Outcomes
(%)
1ST SCT (N=89) Second SCT
(N=11)1st CR Others P value
3-year PFS 62.3 36.4 0.131 32.7
1-year TRM 19.9 28 0.402 10
1-year CI of
relapse
21 34.2 0.236 61.8
aGVHD grade 2-
4
25 32.8 0.620 27.3
aGVHD grade 3-
4
14.3 8.2 0.454 9.1
cGVHD 12 22.9 0.354 9.1
cGVHD
(extensive)
3.6 9.8 0.426 9.1

Comparative Outcomes with
Matched Donor Transplants

Haploidentical vs. Matched Transplants -
MDACC
• 227 AML/MDS patients
• 87 MRD, 108 MUD, 32 haploSCT
• Conditioning:
– Fludarabine (120 to 160 mg/m2 in 4 daily doses)
– Melphalan 140 mg/m2 (n . 190, 84%) or 100 mg/m2 (n .
37, 16%) as a single dose.
– Thiotepa 5 to 10 mg/kg was added for haploidentical
transplantation
• GVHD prophylaxis
– Matched transplantations: tacrolimus and mini-
methotrexate +/- ATG (for MUD)
– Haplo: PTCy 50 mg/kg on days 3,4, tacrolimus, MMF
Di Stasi A, et al. BBMT.2014

Transplant Outcomes for Patients in CR
MSD (N=25) MUD (N=26) HAPLO (N=19) P
Engraftment (CR) 100% 100% 100%
TRM
Day100
1 year
0%
8%
4%
8%
5%
18% 0.8
aGVHD
gr II-IV
gr III-IV
24%
4%
19%
4%
26%
0%
0.9
0.6
cGVHD
Lim+ext
Ext
46%
29%
42%
23%
27%
17%
0.5
Relapse 12% 16% 18% 0.8
PFS (at 3 years) 57% 45% 41% 0.4
Di Stasi A, et al. BBMT.2014

Retrospective Single Institution Studies
Haplo vs. MUD
Diseases Conditioni
ng
SC
source
Gr 2-4
aGVHD
cGVHD NRM RR DFS Reference
Hodgkin
’s
100%
NMA
N/A 43% v.
50%
35% v.
63%
9% v. 8% 40% v.
63%
at 2 yrs
51% vs.
29% at 2
yrs
Burroughs
LM. BBMT.
2008
Various
HM
66% v.
54%
RIC/NMA
60% v.
6% BM
30% v.
39%
38% v.
54%
7%
v.16%
at 2 yrs
33% v.
34% at 2
yrs
60% v.
52% at 2
yrs
Bashey A.
JCO. 2013
Various
HM
77% vs.
72%
MA
100% v.
60%
BM
14% v.
21%
15% v.
22%
17% v.
26% at 4
yrs
18% v.
20%
at 4 yrs
60%
v.35% at
4 yrs
Raiola A.
BBMT.
2014
AML/M
DS
100%
MA/RIC
97% v.
46% BM
29% v.
29%
19% v.
42%
18% v.
8%
at 1 yr
18% v.
16% at 1
yr
41% v.
45%
at 3 yrs
Di Stasi.
BBMT.2014

Haplo vs. MUD CIBMTR Analysis
• Selection criteria:
– Acute myeloid leukemia (AML), age 21-70 pts reported to CIBMTR transplanted
– First allogeneic transplant performed in US between 2008-2012; a single Italian
center contributed with their pts (N= 37)
– Haploidentical transplants – unmanipulated with PTCy; majority received a CNI and
MMF (19 centers)
– MUD transplants – with and without T cell depletion
• 2174 pts with AML:
– 1982 pts 8/8 MUD
– 192 pts haploidentical
• Myeloablative (MAC): 1245 had MUD, 104 haplo
• Reduced-intensity conditioning (RIC): 737 had MUD, 88 haplo
• Primary objective – 2 year OS for pts treated with a haploidentical vs. 8/8
matched unrelated donor
________________________________________________________________________

Patients’ Characteristics
• MAC:
– Similar characteristics with regards to age at transplant, disease status,
secondary AML, time diagnosis to transplant
– Source of stem cells - BM for haploidentical transplants (82%) and PB
for MUDs (81%)
• RIC:
– MUD transplants older (median 62 vs. 57 yrs, p<0.001), more likely to
have a PS< 90% (41% vs. 26%, p=0.03)
– MUD transplants: more in CR1 (61% vs. 49%, p<0.001) an shorted
interval diagnosis to transplant (≤ 12 mo, 77% vs. 65%, p=0.01)
________________________________________________________________________
____________________________________________________________________

0
Probability,%
Leukemia Free Survival
Adjusted for DRI, performance score, secondary AML
Years
Myeloablative100
0
20
40
60
80
0 1 32
HR 0.98 (95% CI 0.75-1.27), p=0.87
MUD 42% (40-45)
HAPLO 41% (32-51)
0
100
20
40
60
80
Years
1 32
Reduced Intensity
HR 0.98 (95% CI 0.74-1.30), p=0.89
MUD 37% (33-40)
HAPLO 35% (25-45)
Ciurea SO, et al. Blood 2015

0
CumulativeIncidence,%
Relapse
Adjusted for DRI, performance score, secondary AML
Myeloablative100
0
20
40
60
80
Years
0 1 32
HR 0.89 (95% CI 0.66-1.21), p=0.46
HAPLO 44% (34-53)
MUD 39% (37-42)
0
100
20
40
60
80
Years
1 32
Reduced Intensity
HR 0.73 (95% CI 0.54-1.00), p=0.05
HAPLO 58% (46-68)
MUD 42% (38-45)

0
Non Relapse Mortality
Adjusted for performance score, DRI
Years
0 1 32
Reduced Intensity
Myeloablative100
0
20
40
60
80
HR 1.32 (95% CI 0.78-2.23), p=0.31
MUD 20% (18-22)
HAPLO 14% (8-22)
0
100
20
40
60
80
Years
1 32
HR 2.46 (95% CI 1.21 – 4.99), p=0.01
HAPLO 9% (4-16)
MUD 23% (19-26)

12
Grade II-IV Acute Graft vs. Host Disease
Months
0
100
0
20
40
60
80
0 6 9
Myeloablative
3
HR 2.50 (95% CI 1.62-3.87) p<0.0001
MUD 42% (39-45)
HAPLO 21% (14-30)
0
100
20
40
60
80
Months
6 123 9
Reduced Intensity
HR 1.47 (95% CI 0.99 – 2.18) p=0.05
MUD 35% (31-38)
HAPLO 25% (17-34)

0
Chronic Graft vs. Host Disease
Years
100
0
20
40
60
80
0 1 32
Myeloablative
HR 2.16 (95% CI 1.49-3.13) p<0.0001
MUD 53% (50-56
HAPLO 30% (21-39
0
100
20
40
60
80
Years
1 32
Reduced Intensity
HR 1.95 (95% CI 1.33-2.84), p=0.0006
MUD 52% (48-55)
HAPLO 34% (24-44)

Haploidentical vs identical-sibling transplant for AML
in remission: a multicenter, prospective study (China)
• Wang et al. compare the outcomes of AML patients
in CR1 undergoing TCR haploSCT vs MSD performed
at 3 centers in China.
• 450 patients (231 haplo, 219 MSD)
• 3-yr PFS 74% and 78% (P = .34)
• 3-yr OS 79% and 82% (P = .36)
• CI of relapse were 15% and 15% (P = .98)
• NRM 13% and 8% (P = .13)
Wang et al., Blood. 2015;125(25):3956-62.

Conclusions
• Haploidentical transplantation extends allogeneic
transplantation to almost all patients in need
• Biggest advantages of related donor transplantation – low
cost and rapid donor availability
• Post-Cy will likely extend haplo transplantation world wide
• Outcomes with haploidentical transplants are now similar
with MUD transplants
• Next step in improving outcomes - preventing disease relapse
by using cellular therapy post-transplant
• Related donor transplantation is the best platform for that

Acknowledgments
• Stefan O Ciurea, MD
• Richard E. Champlin, MD
• Kai Cao, PhD (HLA lab)
• Milton Denai (Biostatistics)
• Peter Thall, PhD (Biostatistics)
• Dean Lee, MD, PhD (NK cells)
• Laurence Cooper, MD and Partow Kebriaei, MD (CAR T cells)
• Antonio Di Stasi, MD, PhD (Fellow)

Updates for Haploidentical Donor Transplant

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