1. Role of JAK inhibitors and JAK2 V617F mutation monitoring in timing and conduct of transplant in MF
Radovan Vrhovac, MD, PhD
University Hospital Centre Zagreb, University of Zagreb School of Medicine

2. Presentation outline Background
Timing and choice of candidates for HSCT
JAK inhibitors and JAK2 V617F monitoring in the context of HSCT
Conclusions

3. Background
Timing and choice of candidates for HSCT
JAK inhibitors and JAK2 V617F monitoring in the context of HSCT
Conclusions

4. Background (1/2) Median age of patients with MF is 62-66 yrs
Clinical course is very heterogeneous
Survival varies (months vs. more than a decade)
JAK inhibitors revolutionized treatment of MF, but..

5. Background (2/2)
Allogeneic HSCT remains the only curative treatment. Controversies about:
Optimal choice of patients, conditioning and timing of HSCT
Place of JAK inhibitors in the pre-HSCT setting
Role of JAK2 V617F monitoring in the post-HSCT setting

6. Background
Timing and choice of candidates for HSCT
JAK inhibitors and JAK2 V617F monitoring in the context of HSCT
Conclusions

7. Allogeneic HSCT in Myelofibrosis
Was traditionally limited to patients aged <60 yrs and those with HLA-identical siblings
Historically, high transplant-related mortality due to acute and chronic GVHD
Today, increasing use of MUDs and MMRDs1
RIC >>> MAC2
1. Samuelson S et al. Br J Haematol. 2011;153: Passweg JR et al. Bone Marrow Transplant. 2014;1-7.

8. Disease indications for an allo-HSCT in Europe in 2012
sdsAD
... number of transplanted patients with MF is expected to increase over time, but HSCT will remain an option only for a minority of MF patients
Passweg JR et al. Bone Marrow Transplant. 2014; 1-7

9.
HSCT performed only in a minority of patients (3.4%)

10. Summary of outcomes of HSCT in MF
1-year NRM ≈ 15-40%
5-year OS ≈ 30-70%
Babushok D, Hexner E. Curr Opin Hematol 2014, 21:

11. ..the risk of allogeneic stem cell-related-complications is justified in transplant-eligible patients whose median survival time is expected to be less than 5 years.

12. Evolving prognostic scores in MF
Lille
IPSS
DIPSS
DIPSS+
Anemia (Hb<10) x
Leukocytes ˃25
Blasts ≥1%
Constitutional symptoms
Age >65
Karyotype (-8, -7, -5, i17q, 12p-, inv 3, 11q23 or complex)
Plt <100
RBC transfusion dependent
Dupriez 1996
Cervantes 2009
Passamonti 2010
Gangat
2011

13. DIPSS+ Points DIPSS-low DIPSS-int-1 1 DIPSS-int-2 2 DIPSS-high 3
DIPSS-int-1 1
DIPSS-int-2 2
DIPSS-high 3
Unfavourable karyotype
Transfusion dependence
Plt<100
Prognostic category
Points
Median survival (mo)
Low
185
Intermediate-1 1 78
Intermediate-2
2-3 35
High
4-6 16
Gangat N. et al. J Clin Oncol 2011; 29: 392

14. Clonal molecular changes of adverse prognostic significance in MF
Gene
Overall frequency
ASXL1
21.7%
EZH2
5.1%
SRSF2
8.5%
IDH1/2
2.6%
Vannucchi AM. et al. Leukemia 2013; 27: 1861

15. Prognostic effect of calreticulin mutations in MF

16. Allogeneic HSCT in Myelofibrosis
Should be considered in younger, higher risk patients whose survival is expected to be <5 yrs
Transplant-related decisions directed by:
Prognostic scores
Novel prognostic markers
Individual perception of benefit/risk of HSCT in a given patient

17. HSCT outcome according to DIPSS
High and intermediate-2 pts have worse outcomes compared to low DIPSS pts
Most of the difference attributable to NRM
high DIPSS: NRM 3.41 times higher than low DIPSS
intermediate-2 DIPSS: NRM 3.19 times higher than low DIPSS
Possible reasons:
High catabolic rate?
Cachexia?
Increased cytokine levels?
Poor PS?
Massive splenomegaly? …
Scott BL. et al. Blood 2012; 119:2657

18. Background
Timing and choice of candidates for HSCT
JAK inhibitors and JAK2 V617F monitoring in the context of HSCT
Conclusions

19. JAK inhibitor (Company)
JAK2 inhibitors
Not selective for mutated JAK2 V617F enzyme
May benefit patients with and without JAK2 V617F mutation
JAK inhibitor (Company)
Diseases and studies
CEP701 (Cephalon)
MF, ET/PV: phase II finished
AZD1480 (AstraZeneca)
MF: phase I/II finished, development stopped
XL019 (Exelixis)
SAR302503/TG101348, fedratinib (Sanofi/Targegen)
MF: phase I/II/III completed; development stopped
BMS (BMS)
MF: phase I/II completed
LY (Lilly)
ET/PV/MF: phase I/II completed; MF: phase II ongoing
NS-018 (NS Pharma)
MF: phase I/II ongoing
SB1518, pacritinib (CTI/S*Bio)
MF: phase I/IIx2 completed, phase III ongoing
CYT387, momelotinib (Gilead/YM/Cytopia)
MF: phase I/II QD completed; phase I/II BID completed; phase III ongoing
INCB018424/ruxolitinib (Incyte/Novartis)
MF: US-approved for intermediate or high-risk MF; EU- approved for disease related splenomegaly or symptoms
ET/PV: phase II completed; PV: phase III completed

20. JAK inhibition before allogeneic HSCT
Author N
Conditioning
Graft failure
GVHD
II-IV
TRM
Med. Duration of ruxo. (mos)
Spleen response
Stop of ruxo.
Withdrawal syndrome
Stübig et al. Leukemia 2014 22
RIC
None
36%
14% 3
45% (>50%)
24% (<50%)
At conditioning
Jaekel et al. BMT 2014 14
MAC/RIC/
NMA 7%
6.5
64%
Tapering off at conditioning
Lebon et al.
ASH 2013 11
45%
N.R.
72%
Different
Robin et al. 23
(16 eval. for response, 8 HSCT)
RIC (Flu/Mel)
2 deaths due to GVHD
50%
Severe AE after discontinuation in 10 pts

21. N=22; Median age 59 years (range: 42-76)
21 patients (96%) had constitutional symptoms and all patients had splenomegaly
Median time from start of ruxolitinib to allogeneic HSCT was 133 days and the median treatment duration was 97 days
It was planned to give ruxolitinib until first day of conditioning treatment
Stübig T et al., Leukemia 2014; Feb 26

22. Patients characteristics (n=22)
JAK2 V617F
positive
Negative
n = 15
n =  7
IPSS at transplant
Low
Intermediate-1
Intermediate-2
High
n = 0
n = 3
n = 14
n = 5
RIC conditioning
Busulfan 10 mg/kg / fludarabine
Treosulfan 36 g/m2 / fludarabine
Melphalan 140 mg/m2 / fludarabine
n = 16
n =  3
Donor HLA-identical sibling
matched unrelated
mismatched unrelated
n =  2
n = 14
n =  6
Stem cell source
PBSC BM
n = 21
n =  1
Stübig T et al., Leukemia 2014; Feb 26

23. Results Med. duration of ruxolitinib prior to HSCT
97 days (range: 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%
Stübig T et al., Leukemia 2014; Feb 26

24. Survival according to spleen response
Overall survival
Survival according to spleen response
at time of HSCT
n=12
n=10
p=0.02
Stübig T et al., Leukemia 2014; Feb 26

25. Immune reconstitution on day 100 (mean)
Ruxo (n = 10)
RIC without Ruxo
(n = 11)
CD3+
1174 / µl
978 / µl
CD4+
159 / µl
139 / µl
CD8+
566 / µl
620 / µl
CD4/CD45RA
12 / µl
23 / µl
Stübig T et al., Leukemia 2014; Feb 26

26. JAK inhibition before allogeneic HSCT
Author N
Conditioning
Graft failure
GVHD
II-IV
TRM
Med. Duration of ruxo. (mos)
Spleen response
Stop of ruxo.
Withdrawal syndrome
Stübig et al. Leukemia 2014 22
RIC
None
36%
14% 3
45% (>50%)
24% (<50%)
At conditioning
Jaekel et al. BMT 2014 14
MAC/RIC/
NMA 7%
6.5
64%
Tapering off at conditioning
Lebon et al.
ASH 2013 11
45%
N.R.
72%
Different
Robin et al. 23
(16 eval. for response, 8 HSCT)
RIC (Flu/Mel)
2 deaths due to GVHD
50%
Severe AE after discontinuation in 10 pts

27. JAK2 V617F monitoring post HSCT
Rapid clearance of JAK2 V617F mutation is associated with a reduced risk of relapse
Lange T et al., Haematologica 2013; 98:772

28. JAK2 V617F monitoring post HSCT
In cases of residual disease persistence, pre-emptive donor lymphocyte infusion can induce molecular remissions
All 8 patients with MRD achieved mCR following DLI
Kroger N et al. Blood 2009; 113: 1866

29. Background
Timing and choice of candidates for HSCT
JAK inhibitors and JAK2 V617F monitoring in the context of HSCT
Conclusions

30. Role of JAK inhibitors and JAK2 V617F mutation monitoring in timing and conduct of transplant in MF Conclusions (1/3)
Treatment of MF patients with JAK inhibitors and HSCT not mutually exclusive
Ruxolitinib improves performance status and spleen size in the majority of MF patients prior to HSCT
Ruxolitinib does not appear to adversely affect early outcome after RIC allo HSCT
Preliminary data suggest that patients responding to ruxolitinib prior to HSCT have a more favorable outcome

31. Role of JAK inhibitors and JAK2 V617F mutation monitoring in timing and conduct of transplant in MF Conclusions (2/3)
Only a few studies, limited number of patients, various conditioning regimens
Studies have somewhat different results
Use of ruxolitinib before transplantation needs further investigation:
Timing of drug stoppage?
Interaction with other drugs / conditioning regimen?
Prospective clinical trials!

32. Role of JAK inhibitors and JAK2 V617F mutation monitoring in timing and conduct of transplant in MF Conclusions (3/3)
Rapid clearance of JAK2 V617F mutation post-transplant is associated with a reduced risk of relapse
Monitoring JAK2 mutant allele burden post-transplant can guide prophylactic immunotherapy to prevent or treat relapse

33. Thank you !