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Lessons from the Myeloproliferative
Disorders in Allogeneic Stem Cell Transplantation
H. Jean Khoury, MD, FACPR. Randall Rollins Chair in Oncology
Professor of Hematology and Medical OncologyDirector Division of Hematology
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The Previous Millennium
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Blood 1999; 94(11): 3668‐3677
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O Ringden et al. J Clin Oncol 2004 22:416‐423.
aGVHD
cGVHD
TRM
OS
N=1888Ringden O. et al. British J of Haem, 2012, 157, 220–229
Khoury HJ et al. Blood. 2006;107:1712‐1716
N=2719
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Horowitz MM, et al. Blood, 1990; 75(3): 555‐562Clift et al. Blood 1991; 77(8):1660‐1665
Kerbauy FR et al. Leukemia 2005; 19, 990–997
n=186
Crawley C. Blood 2005; 106:2969‐2976
n=24
Khoury H. Biol Blood Marrow Transpl. 2001;7:352.
n=30
Busulfan/Fludarabine/ATG in 85%
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Lessons from the Current Millennium:
Chronic Phase CML
Survival without AP/BC
Event-free Survival% w
ithou
t eve
nt
0
10
20
30
40
50
60
70
80
90
100
Months since randomization0 6 12 18 24 30 36 42 48 54 60 66
93%
83%
42%
28%
Transplants 2,000
3,000
1,000
500
0
1,500
2,500
SUM1
Slide
1999 2000 2001 2002 2003 2004 2005 2007 20082006 * *
* Data incomplete
AMLALLCMLAALYM / MM / CLL
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Population Based Studies
J Clin Oncol 29:2514‐2520. © 2011
Reliable Blood Monitoring
Lima et al. Cancer 2011;117:1245–52; 2010
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Early Progression Blast PhaseSustained
Response with Imatinib
Resistant to Imatinib but
sustained response with 2nd line TKI
Resistant to Imatinib and
transient response to 2nd line TKI
CML in Chronic Phase
Imatinib
Individualized Medicine
EarlyBlast Phase
Study (n) Early Progression, n(%)
Early BP
Hammersmith (204) 8 (4%) 3 My; 2 Ly, 2 missing
German Study IV (1151)
25 (2%) 13 My, 10 Ly, 2 missing
SPIRIT (319) 9 (3%) 5 My, 1 Ly, 1 biphenotypic
Personal Communications: Susanne Saussele, Francois Guilhot, David Marin
N=11077 No aberrant cells – 2 BP post self ‐discontinuation TKI
33 aberrant cells
2/2 Ly – Ly BP < 1 year
3/31 My – Ly BP > 1 year
El‐Rassi et al. Cancer 2014 In Press
(1%)
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Early Progression Blast Phase
Myeloid BP-CMLN=52
Lymphoid BP-CML
N=10MaHR 29% 40%Any CyRa 37% 50%
MCyR 19% 40%CCyR 15% 30%
PonatinibMyeloid BP-CML
N=52
MaHR 28%CHR 15%
MCyR 37%CCyR 28%
Bosutinib
Early Progression Blast PhaseSustained
Response with Imatinib
Resistant to Imatinib but
sustained response with 2nd line TKI
Resistant to Imatinib and
transient response to 2nd line TKI
CML in Chronic Phase
Imatinib
Individualized Medicine
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J Natl Cancer Inst 2011;103:553–561
Long-Term Imatinib
Discontinuation from AEs 2% - SAE related to IM 3%
Lancet Oncol 2010; 11: 1029–35
N=100
Blood.2013;122(4):515‐522
Haematologica 2012; 97 (6)
N=43
Sustained Response off
Imatinib
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0
0.2
0.4
0.6
0.8
1
1.2
0 10 20 30 40 50 60
Months
Loss of MMR
Median follow-up = 30 months (range 18-48)
Imatinib Discontinuation n=12 (11/2010-11/2014)
Early Progression Blast PhaseSustained
Response with Imatinib
Resistant to Imatinib but
sustained response with 2nd line TKI
Resistant to Imatinib and
transient response to 2nd line TKI
CML in Chronic Phase
Imatinib
Individualized Medicine
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Resistant to Imatinib but sustained response
with 2nd line TKI Dasatinib
Leukemia (2012) 1 – 6
Nilotinib
Blood. 2011;118(17): 4567‐4576
Bosutinib
CTG response, SokalIM-associated neutropenia
Haematologica. 2010; 95:224‐231
Blood. 2011;117(6):1822‐1827
CTG response at 12 months ECOG PS
SJ Lee et al. Blood. 2008;112:3500-3507
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Early Progression Blast PhaseSustained
Response with Imatinib
Resistant to Imatinib but
sustained response with 2nd line TKI
Resistant to Imatinib and
transient response to 2nd line TKI
CML in Chronic Phase
Imatinib
Individualized Medicine
Khoury HJ et al. Blood. 2012;119(15):3403‐412
Cortes et al. N Engl J Med 2013;369:1783‐96
Third-line TKI Ponatinib Bosutinib
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Chronic Phase CML
First‐line TKI
2nd line TKIABL domain mutation
directed
Trial TKI discontinuation
Molecular Monitoring
Resistant/relapseIntolerant
Sustained Response
ResistantIntolerant
AlloHSCT
Maintenance Dose‐adjusted 2nd line TKI
3d/4th line TKI
SustainedResponse
Allo if Ly blasts by FC Trial TKI
discontinuation PCR (‐) x2 years
The Life After Stopping Tyrosine Kinase Inhibitors Study(The LAST study)
The Life After Stopping Tyrosine Kinase Inhibitors Study(The LAST study)
Lessons from the Current Millennium:
Advanced Phase CML/Ph+ ALL
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HyperCVAD-TKI in Ph+ ALL
Thomas et al, Blood 2004, 103:4396-4467
Prob
abili
ty o
f O
S, %
100
0
20
40
60
80
90
10
30
50
70
100
0
20
40
60
80
90
10
30
50
70
0
100
20
40
60
80
90
10
30
50
70
0
100
20
40
60
80
90
10
30
50
70
IM+ (n=96)
0 1 32
IM- (n=88)
Prob
abili
ty o
f O
S,
%
100
0
20
40
60
80
90
10
30
50
70
100
0
20
40
60
80
90
10
30
50
70
0
100
20
40
60
80
90
10
30
50
70
0
100
20
40
60
80
90
10
30
50
70
IM+ (n=91)
0 1 32
IM- (n=94)
Prob
abili
ty o
f O
S,
%
100
0
20
40
60
80
90
10
30
50
70
100
0
20
40
60
80
90
10
30
50
70
IM+ (n=37)
0 1 32
IM- (n=43)
AP
BP
CP2
Khoury HJ et al. Bone Marrow transplant. 2012; 47(6):810-6
Kebrei P. Biol Blood Marrow Transplant 2012;18: 584‐592
Ph+ ALL
Allo HSCT in AP/BP and Ph+ALL
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Advanced Phases CML/Ph+ALL
TKI+/‐ ChemoDonor Identified
2nd/3d line TKIABL domain mutation
directed
Maintenance TKI
Molecular Monitoring
Molecular Progression
ResponseTolerance
Resistant
AlloHSCTCR2
Maintenance Dose‐adjusted
TKI
AlloHSCT CR1
0
0.2
0.4
0.6
0.8
1
1.2
3 6 9 1215182124273033363942454851545760
N=23
November‐03
May‐04
November‐04
May‐05
November‐05
May‐06
November‐06
May‐07
November‐07
May‐08
November‐08
May‐09
November‐09
May‐10
November‐10
May‐11
November‐11
May‐12
November‐12
May‐13
November‐13
May‐14
November‐14
Blasts
FISH
PCR
IM Dasatinib Bosutinib (53 months) ObservationHCVAD
**
** Resistant to salvage chemo
Cure with TKI in a resistant Ly BP CML ?
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T‐cell activation
Choi J et al. Blood. 2012;120(19):4093‐4103
Choi J et al. PLOS 2014; 9 (10):e109799
Donor BM: H-2 b , Ly5.1 +
C57BL/6 BALB/c (H‐2Kd)
H‐2Kb
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Ruxolitinib reduces GVHD severity
Donor BM:H-2b, Ly5.1+
C57BL/6
Ruxolitinib blocks proinflammatorycytokine production
Ruxolitinib impairs alloreactive T‐cell expansion
Blood. 2014;123(24):3832‐3842
BALB/c (H‐2Kd)
H‐2Kb
Ruxolitinib treatment affectsthe T‐cell phenotype
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6/2012
CR
7/2013
Hypomethylating agent FluMel
72 yo man
URD BM
8/2013
SteroidsCSA/MMF
GVHD
Femoral head
fracture
Myopathy
RSV
Pancytopenia
CD34 selected stem cell boost
12/20132/2014 4/2014
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6/2014 7/2014
SteroidsCSA/MMF
Ruxolitinib
9/2014 11/2014
Prednisone
CSA
MMF
Duration of Ruxolitinib?
MDT?
Conclusions• Clinical observations and molecular
pathogenesis impacted allogeneic HSCT
• Tailored pre-emptive (? therapeutic) post-transplant TKI for advanced phases CML and Ph+ ALL
• Tailored approach possible-simple/reliable monitoring and effective TKI
• Will inhibition of JAK1/2 be a home run in GVHD?
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Acknowledgments
Zachariah DeFilipp, MD
Fuad El Rassi , MD
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