Updates for Haploidentical Donor Transplant

Updates for Haploidentical Hematopoietic Transplantation Outcomes

Piyanuch Kongtim, MDDivision of Hematology

Department of Internal MedicineFaculty of Medicine

Thammasat University

Disclosure InformationPiyanuch 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

Kongtim et al BBMT 2015

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.


• 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/hydrationD-7 Melphalan 100-140mg/m2D-6 Fludarabine 40 mg/m2 D-5 Fludarabine 40 mg/m2D-4 Fludarabine 40 mg/m2D-3 Fludarabine 40 mg/m2D-2 TBI 2GyD-1 RestD 0 Unmanipulated bone marrow stem cell infusionD+3 Cyclophosphamide 50mg/ kg/dayD+4 Cyclophosphamide 50mg/ kg/dayD+5 Tacrolimus for 6 months and MMF until day 100 then taperD+7 G-CSF 5mcg/kg/day

D-8 Admit/hydrationD-7 Melphalan 100-140mg/m2D-6 Thiotepa 5mg/kgD-5 Fludarabine 40 mg/m2D-4 Fludarabine 40 mg/m2D-3 Fludarabine 40 mg/m2D-2 Fludarabine 40 mg/m2 D-1 RestD 0 Unmanipulated bone marrow stem cell infusionD+3 Cyclophosphamide 50mg/ kg/dayD+4 Cyclophosphamide 50mg/ kg/dayD+5 Tacrolimus for 6 months and MMF until day 100 then taperD+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

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TCD Remission


_______________________________________________________________________________________

50%

21%

P=0.02

NRM (left) and Mortality from Infectious Complications (right)

0 10 20 30 40 50 60 70 80


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TCD, 24%

P at 2 yrs 0.01

0 10 20 30 40 50 60 70 80 90


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TCD, N=33, 42%

TCR, N=32, 16%

P at 1yr 0.03


_______________________________________________________________________________________

Gr. II-IV aGVHD and cGVHD


_______________________________________________________________________________________

Haploidentical Transplantation forMyeloid 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 regimenFludarabine 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/MPD 15%ALL 19%

53 BM 60%

30% 7% at 1yr

33% at 2yrs

60% at 2yrs

Raiola A, et al.BBMT.2013:19:117.

Thio/Bu/Flu regimenThiotepa 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 regimenTBI 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 -2Mephalan 140mg/m2 on day -6+/- Thiotepa 5-10mg/kg on day -7

AML/MDS100%

32 BM 29% 24% at 1yr

33% at 3yrs

56.5% at 3yrs*

Solomon S, et al. Flu/TBI regimenFludarabine 25mg/m2 on days -7 to -5TBI 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 200Fludarabine 30 mg/m2/day on days −6 to −2Cyclophosphamide 14.5 mg/kg/day on days −6 and −52 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 200Fludarabine 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/TBIFludarabine 30 mg/m2 on days -6 to -22 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 200Fludarabine 40 mg /m2 day on days -5 to -2Mephalan 100mg/m2 on day -62 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

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. CiureaDepartment 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 NumberMedian age (year) 45 (IQR 19-67)Gender female/male 46/54DiagnosisAML/MDSLymphoma/CLLALLCMLMPN Aplastic anemiaMyeloma

54171212221

Disease status at transplantCRNot in CR

5842

Cytogenetic risk (N=66)GoodIntermediateHigh

4

2933

Prior AlloSCT 11Prior ASCT 12RIC 33SC sourcesMarrow Peripheral blood

964

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 9.1cGVHD (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%

TRMDay1001 year

0%8%

4%8%

5%18% 0.8

aGVHDgr II-IVgr III-IV

24%4%

19%4%

26%0%

0.90.6

cGVHDLim+extExt

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 Conditioning

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/MDS

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

Prob

abili

ty, %

Leukemia Free SurvivalAdjusted 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

Years1 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

Cum

ulati

ve In

cide

nce,

%

RelapseAdjusted for DRI, performance score, secondary AML

Myeloablative100

0

20

40

60

80

Years0 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

Years1 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 MortalityAdjusted for performance score, DRI

Years0 1 32

Reduced Intensity

Cum

ulati

ve In

cide

nce,

%

Myeloablative100

0

20

40

60

80HR 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

Years1 32

HR 2.46 (95% CI 1.21 – 4.99), p=0.01

HAPLO 9% (4-16)

MUD 23% (19-26)


12

Cum

ulati

ve In

cide

nce,

%

Grade II-IV Acute Graft vs. Host Disease

Months0

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

Months6 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

Cum

ulati

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cide

nce,

%

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

Years1 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)

Education

Updates for Haploidentical Donor Transplant