1. Whom should you refer for allogeneic stem cell transplantation?
Myelofibrosis:
Whom should you refer for
allogeneic stem cell transplantation?
Those with the greatest disease risk
will gain the greatest benefit
Ronald Hoffman, MD
Albert A. and Vera G. List Professor of Medicine
Mount Sinai School of Medicine
New York, NY

2. Disclosures
Research Funding
Roche/Genentech
Novartis
Geron
Incyte

3. I.W.G. Prognostic Scoring System
Risk factors at presentation of PMF
selected at the stepwise Cox regression model
for their significant association with shorter survival *
______________________________________________________________________________________
Risk factor Frequency in the series Hazard ratio (95% CI) z-test p value
Age > 65 years % (1.61 – 2.36) <
Constitutional symptoms % (1.62 – 2.40) <
Hb < 10 g/dL % (2.46 – 3.61) <
WBC count > 25 x 109/L % (1.83 – 3.14) <
Blood blasts ≥ 1% % (1.50 – 2.17) <
* In 1,001 patients with the five variables available
Cervantes et al. Blood 2009: 113,

4. Cervantes et al. Blood 2009: 113, 2895-2901
I.W.G. Prognostic Scoring System
Definition, frequency and survival of the risk groups of the prognostic scoring system of PMF
Risk group No. of factors Proportion of patients Median survival Proportion of deaths
(95% CI) *
Low % (117 – 181) %
Intermediate % (79 – 114) %
Intermediate % (43 – 59) %
High ≥ % (23 – 31) %
* In month
Cervantes et al. Blood 2009: 113,

5. COMFORT-1 Percent Change From Baseline in Spleen Volume in Individual Patients at Week 24
Ruxolitinib (n = 139)
Placebo (n = 106)
35% decrease
At week 24, ruxolitinib-treated patients
had a median 33.0% decrease in spleen volume
and placebo-treated patients had a median 8.5% increase (P < )
Verstovsek S et al. NEJM 2012: 366,

6. Proportion of Patients with ≥50% Reduction
in Total Symptom Score Over Time
Ruxolitinib
Placebo
% of Patients
Weeks From Day 1 24 60 50 40 30 20 10 2 4 6 8 12 14 16 18 22
Patients who discontinued or had missing data
were considered non-responders
Verstovsek S et al. NEJM 2012: 366,

7. Overall Survival Update: ITT
HR=0.50 (0.25–0.98) P=0.04
Number of Patients at Risk—Ruxolitinib
155
155
155
154
153
152
148
144
143
143
140
134
102 68 52 37 18 8 3
Number of Patients at Risk—Placebo
154
152
151
148
147
147
142
139
132
131
123
115 83 58 45 35 20 9 3
No effect on marrow histopathololgy, JAK2V617F allele burden
and marker cytogenetic abnormalities
Verstovsek S et al. NEJM 2012: 366, 7

8. AZD1480 (JAK 1/2 Inhibitor) Treatment
Resulted in Reductions in Both Splenic and PB MF
Hematopoietic Progenitor Cells (HPCs) A B
(% of Cytokines Alone)
Splenic MF Colonies
(% of Cytokines Alone)
PB MF Colonies **
***
***
***
**P<0.01;***P< n=10
Wang X, et al. ASH 2013

9. Effects of Treatment with AZD1480 on MF SCID Repopulating Cells (SRC)
Wang X, et al. ASH 2013

10. Ruxolitinib is an Effective Agent for Symptomatic Improvement
But Does Not Prevent Clonal Evolution of MF
Kremyanskaya M, et al. unpublished

11. Development of Acute Leukemia in
Myelofibrosis Patients on Ruxolitinib at Mt. Sinai
Patient 1 2 3 4 5
Age 56 70 62 58 83
Sex F M
Type of MPN
Post-PV MF
PMF
Post-ET MF
Molecular Marker
JAK2V617F
36.6%
negative
MPL W515L
70.16%
22.6%
Extramedullary Disease
Yes No
Site of Extramedullary Disease
Skin
N/A
Bone (granulocytic sarcoma)
Karyotype at Transformation
Complex
Del 13q
Normal
Bone Marrow Involvement
Peripheral Blood Blasts 6% 2% 1%
20%
Type of Leukemia
AML
CMML
Length of Ruxolitinib tx
3 months
12 months
18 months
14 months

12. Allogeneic Hematopoietic
At Present,
Allogeneic Hematopoietic
Stem Cell Transplantation (HSCT) Is The Only Treatment Modality
That Has The Potential To Cure Myelofibrosis

13. Background Number of Patients Age Poor Risk Regimen TRM (at 1 year) CROS
Guardiola, et al.
(Blood 1999/NEJM 2000) 55 42
50%
Myeloabl
27%
40%
14% (>45 yrs.)
at 5 yrs.
62% (<45 yrs.)
Daly, et al.
(BMT 2003) 25 48
28%
48%
33%
41% 2 yrs.
Deeg, et al.
(Blood 2003) 56 43
23%
32%
53%
58% 3 yrs.
Devine, et al.
(Blood 2002)
(Updated FU) 4
100%
Flu-Mel 0%
4/4
100% 3.5 yrs.

14. Overall Survival Following Allogeneic Transplantation for Intermediate/High Risk MF Patients with Reduced Intensity Conditioning
Median follow-up (months)
22.6% ( )
Overall Survival
85% (18/21)
Event-free Survival
80% (17-21)
Relapse
10% (2/19)
TRM d100 & 1 yr.
Rondelli D, Blood :

15. Reduction of Spleen Size and Marrow Fibrosis After Allogeneic RIC HSCT
Ciurea et al. Br J Haemat. 2008

16. Patient Characteristics of EBMT MF Transplant Trial
Donor Unrelated n = 69 Related n = 33
JAK2 Positive n = 51
Negative n = 29
HLA-typing matched (8/8 allele) n = 86
Mismatched n = 12
DRB1 n = 2
DQB1 n = 5
A n = 4
B n = 1
Kroger, et al. Blood 2009; 114:

17. Disease-free survival after
Allogeneic Stem Cell Transplantation for PMF
DFS
500
1000
1500
2000
1,0
0,8
0,6
0,4
0,2
58%
Kroger, et al. Blood 2009; 114: 17

18. Survival of MF Patients in Seattle With Transplantation by DIPSS
MF Patients: Age: (51.5)
86 Related Donors, 84 Unrelated Donors
DIPPS Risk
Survival (median; years)
No Transplant
(at reporting)
Transplant
(med F/U 5.9 years)
Low
Not Reached
Intermediate 1
14.2
Intermediate 2 4 7
High
1.5
2.5
Provided by J. Deeg, Seattle
Scott et al. Blood 2012; 119:

19. Who Should go for Transplant?
Benefit
Risk

20. Candidates for Allogeneic Stem Cell Transplantation
Intermediate and High Risk MF Patients
with Available Stem Cell Donor
Patients w/ Primary Myelofibrosis and MDS
following ET or PV
All young patients ≤ 55
Ages between 55 and 70 with good performance status
MPN patients who have evolved to AML
following successful induction therapy
Individuals for Whom Allogeneic Stem Cell Transplantation
Should Not be Considered:
Pre-fibrotic form of myelofibrosis
Low risk MF ET PV
Age≥70 years
No stem cell donor available- results with CB donors and haplo-indentical donors are unknown
Poor performance status