Download - 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
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/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
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Cum
ulat
ive
Pro
porti
on S
urvi
ving
Pro
gres
sion
Fre
e
TCR Overall
TCD Overall
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
Cum
ulat
ive
Pro
porti
on S
urvi
ving
Pro
gres
sion
Fre
e TCR Remission
TCD Remission
Ciurea SO, et al. Biol Blood Marrow Transplant. 2012;18:1835
_______________________________________________________________________________________
50%
21%
P=0.02
NRM (left) and Mortality from Infectious Complications (right)
0 10 20 30 40 50 60 70 80
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
Cum
ulat
ive
Inci
denc
e of
Infe
ctio
n R
elat
ed D
eath
TCR, 9%
TCD, 24%
P at 2 yrs 0.01
0 10 20 30 40 50 60 70 80 90
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
Cum
ulat
ive
Inci
denc
e of
NR
M
TCD, N=33, 42%
TCR, N=32, 16%
P at 1yr 0.03
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 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.
Kongtim P, et al. Abstract ASCO 2014
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.
Kongtim P, et al. Abstract ASCO 2014
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
Kongtim P, et al. Abstract ASCO 2014
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
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%
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)
Ciurea SO, et al. Blood 2015
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)
Ciurea SO, et al. Blood 2015
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)
Ciurea SO, et al. Blood 2015
0
Cum
ulati
ve In
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)
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)