Updates For Haploidentical Hematopoietic Transplantation Outcomes

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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

A B C D

Progeny

A C A D B R B C B 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- - Prevent GVHD by Tregs while promoting immune
infusion reconstitution by addition of Tcons
Selective T cell - Removing T cells that are most responsive for
depletion aGVHD
- Remaining T cells are thought to have an innate
immune like response capability without inducing
GVHD.
Photodepletion of - ex vivo depletion of alloreactive T cells with TH9402
alloreactive T cells that accumulates in activated T cells
Selective CD45RA+ T cell - Elimination of CD45RA+ nave T cells thought to
depletion 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
________________________________________________________________________
ODonnell 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-8 Admit/hydration


D-7 Melphalan 100-140mg/m2 D-7 Melphalan 100-140mg/m2
D-6 Fludarabine 40 mg/m2 D-6 Thiotepa 5mg/kg
D-5 Fludarabine 40 mg/m2 D-5 Fludarabine 40 mg/m2
D-4 Fludarabine 40 mg/m2 D-4 Fludarabine 40 mg/m2
D-3 Fludarabine 40 mg/m2 D-3 Fludarabine 40 mg/m2
D-2 TBI 2Gy D-2 Fludarabine 40 mg/m2
D-1 Rest D-1 Rest
D 0 Unmanipulated bone marrow stem D 0 Unmanipulated bone marrow stem
cell infusion cell infusion
D+3 Cyclophosphamide 50mg/ kg/day D+3 Cyclophosphamide 50mg/ kg/day
D+4 Cyclophosphamide 50mg/ kg/day D+4 Cyclophosphamide 50mg/ kg/day
D+5 Tacrolimus for 6 months and MMF D+5 Tacrolimus for 6 months and MMF
until day 100 then taper until day 100 then taper
D+7 G-CSF 5mcg/kg/day D+7 G-CSF 5mcg/kg/day
PFS all and Patients in Remission
(N=32 TCD and N=33 TCR)

1.0 1.0

0.9 0.9 TCR Remission


P=0.02

Cumulative Proportion Surviving Progression Free


Cumulative Proportion Surviving Progression Free

0.8 0.8

0.7
50% 0.7

0.6 0.6
TCR Overall
0.5 0.5

0.4
0.4

0.3
0.3
21% TCD Remission
0.2
0.2
TCD Overall
0.1
0.1

0.0
0.0 0 2 4 6 8 10 12 14 16 18 20 22 24
0 2 4 6 8 10 12 14 16 18 20 22 24
Months Post Transplant
Months Post Transplant

_______________________________________________________________________________________
Ciurea SO, et al. Biol Blood Marrow Transplant. 2012;18:1835
NRM (left) and Mortality from Infectious
Complications (right)

1.0
1.0 P at 1yr 0.03 P at 2 yrs 0.01

0.9

Cumulative Incidence of Infection Related Death


0.9
0.8
0.8
0.7
Cumulative Incidence of NRM

0.7
0.6
0.6
0.5
0.5
TCD, N=33, 42% 0.4
0.4
0.3
TCD, 24%
0.3
0.2
0.2
TCR, N=32, 16% 0.1 TCR, 9%
0.1
0.0
0 10 20 30 40 50 60 70 80
0.0
0 10 20 30 40 50 60 70 80 90 Months Post Transplant
Months Post Transplant

_______________________________________________________________________________________
Ciurea SO, et al. Biol Blood Marrow Transplant. 2012;18:1835
Gr. II-IV aGVHD and cGVHD

_______________________________________________________________________________________
Ciurea SO, et al. Biol Blood Marrow Transplant. 2012;18:1835
Haploidentical Transplantation for
Myeloid and Lymphoid
Malignancies
Reference Conditioning regimen Diseases No. Graft aGVHD NRM Relapse PFS
pts (II-IV) rate

MYELOID
MALIGNANCIES*
Bashey A, et al. Bu/Flu/Cy regimen AML 32% 53 BM 30% 7% at 33% at 60% at
Fludarabine 25mg/m2 on days -6 to -2 (total 125 MDS/MP 60% 1yr 2yrs 2yrs
JCO. mg/m2) D 15%
2013;31:1310 Busulfan 110-130mg/m2/day IV on days -7 to -4 ALL 19%
Cyclophosphamide 14.5 mg/kg days -3 and -2
(total 29mg/kg)

Raiola A, et al. Thio/Bu/Flu regimen AML 50% 35 BM 12% 18% at 26% at 18 51% at
Thiotepa 5mg/kg on days -6 and -5 (total ALL 25% 18 mo mo 18 mo
BBMT.2013:19:1 10mg/kg) MPD 16%
17. 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 15
TBI 3.3 Gy on days -8 to -6 (total 9.9 Gy);
Fludarabine 30mg/m2 on days -5 to -2 (total
120mg/m2)

Di Stasi A, et al . Flu/Mel140 regimen AML/MD 32 BM 29% 24% at 33% at 56.5% at


Fludarabine 40 mg /m2 on days -5 to -2 S 1yr 3yrs 3yrs*
BBMT.2014 Mephalan 140mg/m2 on day -6 100%
+/- Thiotepa 5-10mg/kg on day -7

Solomon S, et al. Flu/TBI regimen AML 70% 30 PB 44% 5% at 19% at 76% at


Fludarabine 25mg/m2 on days -7 to -5 ALL 10% 2yrs 2yrs 2yrs
TBI 150 cGy BID on days -4 to -1 (total dose 12Gy) CML 15%
Reference Conditioning regimen Diseases No. Graft aGVHD NRM Relapse PFS
pts (II-IV) rate

LYMPHOID
MALIGNANCIES
Burroughs et al. Flu/Cy/TBI 200 HD 100% 28 BM 43% 9% at 40% at 51% at
BBMT. Fludarabine 30 mg/m2/day on days 6 2yrs 2yrs 2yrs
to 2
2008;14:1279
Cyclophosphamide 14.5 mg/kg/day
on days 6 and 5
2 Gy TBI on day 1.
Castagna et al. Flu/Cy/TBI 200 HD 55% 49 BM 26% 16% 19% at 65% at
BMT.2014 Fludarabine 30 mg/m2/d IV daily on NHL 39% at 2yrs 2yrs
days 6 to 2 2yrs
Cyclophosphamide 14.5 mg/kg IV on
days 6 and 5 and
2 Gy TBI on day 1
Kanakry JA, et al. Flu/Cy/TBI, Flu/TBI PTCL 100% 22 BM 16% 11% 34% at 1 40% at 2
BBMT. at 1 yr yr yrs**

2013;19:602
Kasamon Y, et al. Flu/Cy or Flu/Cy/TBI NHL 75% 151 BM 32% 16% 31% at 40% at
Fludarabine 30 mg/m2 on days -6 to HD 25% at 1yr 1yr 3yrs
-2
2 Gy TBI on day -1

Brammer J, et al. Flu/Mel100/TBI 200 HD 37% 19 BM 44% 11% 26% at 52% at


Fludarabine 40 mg /m2 day on days - NHL 37% at 2 2yrs 22 mo
5 to -2 CLL/PLL yrs
Mephalan 100mg/m2 on day -6 26%
2 Gy TBI on day -1
MDACC experience
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.

Kongtim P, et al. Abstract ASCO 2014


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

Kongtim P, et al. Abstract ASCO 2014


Transplant outcomes according to diseases

Outcomes (%) All patients Myeloid Lymphoid ALL


(N=100) malignancies malignancies (N=12)
in CR (N=40) (N=17)
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 23.3 30.1 24.4 33.3
relapse
aGVHD grade 30 25 35.3 50
2-4
aGVHD grade 10 0 11.8 41.7
3-4
cGVHD 15 12.5 11.8 44.4
cGVHD 8 10 5.9 8.3
(extensive)
Kongtim P, et al. Abstract ASCO 2014
Transplant outcomes according to first and
second SCT

Outcomes 1ST SCT (N=89) Second SCT


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

Kongtim P, et al. Abstract ASCO 2014


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 0% 4% 5%
1 year 8% 8% 18% 0.8
aGVHD
gr II-IV 24% 19% 26% 0.9
gr III-IV 4% 4% 0% 0.6
cGVHD
Lim+ext 46% 42% 27% 0.5
Ext 29% 23% 17%
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 SC Gr 2-4 cGVHD NRM RR DFS Reference
ng source aGVHD

Hodgkin 100% N/A 43% v. 35% v. 9% v. 8% 40% v. 51% vs. Burroughs


s NMA 50% 63% 63% 29% at 2 LM. BBMT.
at 2 yrs yrs 2008

Various 66% v. 60% v. 30% v. 38% v. 7% 33% v. 60% v. Bashey A.


HM 54% 6% BM 39% 54% v.16% 34% at 2 52% at 2 JCO. 2013
RIC/NMA at 2 yrs yrs yrs

Various 77% vs. 100% v. 14% v. 15% v. 17% v. 18% v. 60% Raiola A.
HM 72% 60% 21% 22% 26% at 4 20% v.35% at BBMT.
MA BM yrs at 4 yrs 4 yrs 2014

AML/M 100% 97% v. 29% v. 19% v. 18% v. 18% v. 41% v. Di Stasi.


DS MA/RIC 46% BM 29% 42% 8% 16% at 1 45% BBMT.2014
at 1 yr yr at 3 yrs
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)
____________________________________________________________________
Leukemia Free Survival
Adjusted for DRI, performance score, secondary AML
100
Myeloablative Reduced Intensity 100

80 80
Probability, %

60 MUD 42% (40-45) MUD 37% (33-40) 60

40 40
HAPLO 41% (32-51)
HAPLO 35% (25-45)

20 20
HR 0.98 (95% CI 0.75-1.27), p=0.87 HR 0.98 (95% CI 0.74-1.30), p=0.89

0 0
0 1 2 3 0 1 2 3
Years Years
Ciurea SO, et al. Blood 2015
Relapse
Adjusted for DRI, performance score, secondary AML

100
Myeloablative Reduced Intensity 100

80 HR 0.89 (95% CI 0.66-1.21), p=0.46 HR 0.73 (95% CI 0.54-1.00), p=0.05 80


Cumulative Incidence, %

60 HAPLO 58% (46-68) 60


HAPLO 44% (34-53)

40 40
MUD 42% (38-45)
MUD 39% (37-42)
20 20

0 0
0 1 2 3 0 1 2 3
Years Years
Ciurea SO, et al. Blood 2015
Non Relapse Mortality
Adjusted for performance score, DRI

100
Myeloablative Reduced Intensity 100

80 80
Cumulative Incidence, %

HR 1.32 (95% CI 0.78-2.23), p=0.31 HR 2.46 (95% CI 1.21 4.99), p=0.01

60 60

40 40

MUD 20% (18-22) MUD 23% (19-26)


20 20
HAPLO 9% (4-16)
HAPLO 14% (8-22)
0 0
0 1 2 3 0 1 2 3
Years Years
Ciurea SO, et al. Blood 2015
Grade II-IV Acute Graft vs. Host Disease
Myeloablative Reduced Intensity
100 100

80 80
Cumulative Incidence, %

HR 2.50 (95% CI 1.62-3.87) p<0.0001 HR 1.47 (95% CI 0.99 2.18) p=0.05


60 60
MUD 42% (39-45)
MUD 35% (31-38)
40 40

20 20
HAPLO 21% (14-30) HAPLO 25% (17-34)

0 0
0 3 6 9 12 0 3 6 9 12
Months Months
Ciurea SO, et al. Blood 2015
Chronic Graft vs. Host Disease
Myeloablative Reduced Intensity
100 100

80 HR 2.16 (95% CI 1.49-3.13) p<0.0001 HR 1.95 (95% CI 1.33-2.84), p=0.0006 80


Cumulative Incidence, %

60 MUD 53% (50-56 60


MUD 52% (48-55)

40 40

HAPLO 30% (21-39 HAPLO 34% (24-44)


20 20

0 0
0 1 2 3 0 1 2 3
Years Years
Ciurea SO, et al. Blood 2015
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)

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