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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