1. Whom should you refer for allogeneic transplantation?
- Those with the best performance status will gain the greatest benefit -
Srdan (Serge) Verstovsek
M.D., Ph.D.
Professor of Medicine
Department of Leukemia
University of Texas
MD Anderson Cancer Center
Houston, Texas, USA 1

2. Allogeneic HCT in Myelofibrosis
Consider in younger, higher risk patients whose survival is expected to be <5 years
Traditionally limited to patients aged <60 years and those with HLA-identical sibling match, although increasing use of MUDs and MMRDs1
High transplant related mortality due to acute and chronic GVHD
Estimated 1-year treatment-related mortality: approximately 30%2-5
OS with alloSCT: approximately 50%2-4
BOTTOM LINE: less than 10% of patients undergo SCT
IPSS high risk
Median survival: ~27 mo
IPSS intermediate-2 risk
Median survival: ~48 mo
alloSCT: allogeneic stem cell transplant; GVHD: graft-versus-host disease; HLA: human leucocyte antigen; IPSS: International Prognostic Scoring System; MMRD: mismatched related donors; MUD: matched unrelated donor.
1. Samuelson S et al. Br J Haematol. 2011;153: Ballen KK et al. Biol Blood Marrow Transplant. 2010;16: Kroger N et al. Blood. 2009;114: Patriarca F et al. Haematologica. 2008;93: Bacigalupo A et al. Bone Marrow Transplant. 2010;45:

3. Performance Status is a negative risk factor for survival after HCT

4. Splenomegaly is a negative risk factor for survival after HCT
Risk variables
Spleen >22 cm
Transfusions >20
Donor other than
HLA-id sibling
Low risk= 0-1 variables
High risk= >2 variables
1 Bacigalupo A, BMT 2010; 45:458-63

5. Potential Impact of JAK2 Inhibitors on HCT Therapeutic Decisions 
McLornan DP, BJH 2012; 157:413-25

6. Spleen Volume Response: Ruxolitinib vs. BAT
132 (97%)
35 (56%)
↑ Spleen volume
4 (3%)
28 (44%)

7. Improvement in Symptoms
Worsening
Improvement *
Fatigue *
Dyspnea *
Appetite loss *
Insomnia *
Pain *
Diarrhea
Nausea/vomiting
Constipation
Financial impact
Overall Adjusted Mean Change From Baseline Score
Ruxolitinib
BAT

8. Improved Exercise Capacity and Body Weight
6-minute walk test (6MWT) is well established measure of exercise capacity
MF patients walk meters less than age-matched healthy volunteers 28 56 84
112
140
168
-9.5
-7.5
-5.5
-3.5
-1.5
0.5
2.5
4.5
6.5
8.5
10.5
12.5
Mean Lowest Quartile
Days on Study
Change in Body Weight, kg
Ruxolitinib phase I/II

9. Efficacy of ruxolitinib in patients with MF without clinically significant splenomegaly
Fatigue improved 6
Resolution of night sweats 2
Itching
Weight gain
(up to 17%) 5
Improved performance status
Reduction of liver size 50-68%
3 of 3
All pts were symptomatic
Ruxolitinib was administered at the dose of 25mg BID
Benjamini et. al., Blood 2012; 120:

10. Overall Survival: ruxolitinib vs. BAT (int-2/high risk MF)
52% reduction in risk of death in the ruxolitinib arm compared to BAT arm (HR = 0.48; 95% CI, ; log-rank P = .009)

11. What happens if therapy with ruxolitinib is interrupted?
Number of patients: 34 33 33 34 34 33 33 33 36 37 39 40 40 40 34 29 26 23 24 24 22 22 22 20 21 20 18 17 15
Days Around Dose Change
Return of the symptoms within 7 days

12. Ruxolitinib as Pretreatment Before Allogeneic Stem Cell Transplantation For Myelofibrosis
N=22; Median age 59 years (r: 42 – 76)
21 patients (96%) had constitutional symptoms and all patients had splenomegaly
Median time from start of ruxolitinib to allogeneic SCT was 133 days and the median treatment duration was 97 days
It was planned to give ruxolitinib until first day of conditioning treatment
Busulfan 10 mg/kg / fludarabine most commonly used (n=16) conditioning
Nicolaus Kröger at al. Abstract 392

13. Results overall at transplant
Med. duration of ruxolitinib prior to SCT
97 days (r: 30 – 316)
Response to ruxolitinib:
Spleen size reduction > 50%
Spleen size reduction < 50%
No response/loss of response at SCT
Constitutional symptoms
45% %
23% %
31% %
86%
Graft failure
n = 0
Leukocytes > 1.0 x 109/l
med. 15 days (10 – 66)
Platelets > 20 x 109/l
med. 17 days (8 – 122)
Acute GvHD II-IV III/IV
38% 27%
overall
at transplant
Immunoreconstitution on day 100 not affected

14. Survival according to response at time of SCT
response yes n=12
no / lost response n=10
p=0.02

15. Conclusions
Ruxolitinib improves performance status and spleen size in the majority of myelofibrosis patients prior to allogeneic stem cell transplantation
Ruxolitinib does not appear to adversely affect early outcome after reduced allo HCT
Preliminary data suggest that patients responding to Ruxolitinib have a more favorable outcome to those who received the transplant after loosing response or being refractory to Ruxolitinib

16. Ruxolitinib Before HCT: The JAK-ALLO Study Design
Lille Or IPSS
Primary or secondary MF
High- or intermediate-risk patients
HLA-matched sibling: 9/10 or 10/10 UR
Donor search
15 mg BID
Progressive ↕ day -1
Ruxolitinib 4 months
No donor
Fludarabine 90 mg/m2
Melphalan 140 mg/m2
Donor
Ruxolitinib
Splenectomy?
Allo SCT
Robin M. ASH Abstract 306.

17. 17 patients with a donor on ruxolitinib 16 patients eligible for HSCT
JAK-ALLO: Results
17 patients with a donor on ruxolitinib
16 patients eligible for HSCT
2 TLS after conditioning regimen
5 deaths after transplantation (incl. acute GVHD)
1 graft rejection
1 cardiogenic shock 11 days after HSCT
3 splenectomies
14 HSCT
Robin M. ASH Abstract 306.

18. “Allogeneic hematopoietic cell transplantation for myelofibrosis in patients pretreated with ruxolitinib”
14 patients (median age 58 years)
Before ruxolitinib, allogeneic HCT was not considered to be the appropriate
median exposure of 6.5 months to ruxolitinib
MF-related symptoms were ameliorated in 10 (71.4%) patients and palpable spleen reduced by a median of 41% in 7 (64%) of 11 patients with splenomegaly.
ruxolitinib was continued up to the day preceding the start of the conditioning regimen
related (3) and unrelated (11) donors
Median follow-up was 9 months
Jaekel N, Behre G, Behning A, Wickenhauser C, Lange T, Niederwieser D, Al-Ali HK. Bone Marrow Transplant Feb;49(2):

19. Conditioning: fludarabine-based RIC in 11 (78.6%) (with busulphan p.o. in 7 and TBI in 4), and myeloablative conditioning in 3 (21.4%) patients.
engraftment in 13 (93%) patients, acute GvHD grade-III occurred in 2 (14%) patients
Survival, EFS and treatment-related mortality were 78.6, 64 and 7%, respectively
overall probability of survival at 1 year was 50%

20. Why the Difference in Results?
Small trials with limited numbers of patients
Different conditioning regimens
Contradictory results suggest that combination of ruxolitinib in transplant protocols should be used with caution
Appropriate drug regimen and timing of stoppage of therapy must still be determined
The use of ruxolitinib prior to transplant should be preferentially used as part of prospective clinical trials or at experienced centers

21. Potential Impact of JAK2 Inhibitors on HCT Therapeutic Decisions 
McLornan DP, BJH 2012; 157:413-25

22. THANK YOU