1. Perspectives on defining ruxolitinib resistance/suboptimal response and therapeutic decision-making in this setting Claire Harrison, MD

2. Burden of Myelofibrosis
MF Associated
Symptoms
Splenomegaly
Premature death
Anemia/
Cytopenias

3. Assessing Ruxolitinib in MF Patients
Anemia
PLTS
Therapy
Symptoms
Anemia
PLTS
Spleen
Symptoms
NET
Spleen

4. Ruxolitinib Therapy Scenarios
Clear benefit spleen, symptoms, no heme toxicity
Clear benefit spleen/ symptoms, heme tox
Clear benefit symptoms, suboptimal spleen, no heme tox
Clear benefit symptoms, suboptimal spleen, heme tox
Suboptimal symptoms/ Spleen, no heme tox
Suboptimal symptoms/Spleen, heme tox
Minimal symptoms +/- Spleen, no heme tox
Minimal symptoms +/- Spleen, heme tox
No response, no heme tox
No response, heme tox
? Change
Change

5. Definitions…………………
Primary resistance an inability to achieve landmark response, eg fail to achieve major or complete cytogenetic response in CML ie optimal vs suboptimal response
Secondary resistance those who achieve but subsequently lose relevant response
Relapse ? more appropriate here progression
Intolerance usually heme toxicity for ruxolitinib

6. In addition Requires a facet – eg measure of symptoms or spleen size
Requires definition of appropriate response
AND
Definition of sufficient “lack of” or “loss of” response or progression

7. Spleen Definition of “optimal response” Definition of progression?
Comfort I – 25% beyond baseline
Comfort II – 25% above nadir
eg, patient with a starting spleen volume of 2000cm3 and study nadir of 500cm3 would have progressed with a spleen volume of 625cm3 on Comfort –II, but 2500cm3 on Comfort-I.

8. Symptoms Optimal response ……..?
Progression could be loss of that response but by how much? and what about durability?

9. Molecular resistance We do not understand this aspect well!
At present patients are poorly characterised
Potential mechanisms eg specific mutations or overexpression of JAK1 have been described in vitro but not in vivo

10. Other aspects of resistance/progression
Other disease progression?
Anemia or thrombocytopenia
Blasts
Leucocytosis
Event eg thrombosis?

11. CASE
63 year ♂, MF diagnosed 2008, presented with pancytopenia and splenomegaly, JAK2 V617F neg
HC but dose limited by cytopenias
Enrolled COMFORT II trial Oct 2009 commenced 15mg bd
Dose reduction Jan 2010 for thrombocytopenia, 10 mg and then further to 5 mg
Ongoing bone pain
Stopped trial at week 72 due to lack of effect on symptoms and splenomegaly and thrombocytopenia.

12. Thrombocytopenia
Start of study
Dose reduction
Dose reduction
Stop

13. Week Week 60

14. Primary refractory disease +/- intolerance
Stopped ruxolitnib
Managed with small doses of HC
Enrolled in ARD12181 with JAK inhibitor SAR302503
Currently cycle 12 on study
Reduction in spleen and symptom improvement

15. SAR302503 Phase II Study Design: ARD12181 JAKARTA 2
Phase 2, single arm, multicenter, open-label study
Subjects who previously received Ruxolitinib treatment for PMF or Post-PV MF or Post-ET MF or PV or ET for at least 14 days and discontinued the treatment for at least 14 days prior to study entry
Intermediate or High risk Primary MF
Post-Polycythemia Vera Myelofibrosis
Post-Essential Thrombocythemia Myelofibrosis according to the 2008 World Health
Organization (WHO) criteria
Recent amendment changing discontinuation period from 30 days to 14 days
70 pts
Dose regimen
SAR once daily,
Starting dose: 400mg/day
Continuously in 28-day cycles
Titration allowed: 200mg, 300mg, 400mg, 500mg or 600mg
Primary endpoint:
% of patients who achieve ≥35% reduction in spleen volume from baseline at C6 EOC by MRI/CT.
Secondary endpoint:
- % of subjects with a ≥50% reduction from baseline to the end of Cycle 6 in the total symptom score using the modified MFSAF
Safety, PK/PD, JAK2V617F allele burden, JAK-STAT and other signaling pathways, OS 15

16. Study population Key inclusion criteria
Diagnosis of PMF or Post-PV MF or Post-ET MF, according to the 2008 World Health Organization (Appendix B) and IWG-MRT criteria
Subjects who previously received Ruxolitinib treatment for PMF or Post-PV MF or Post-ET MF or PV or ET for at least 14 days and discontinued the treatment for at least 14 days prior to study entry.
Myelofibrosis classified as high-risk or intermediate-risk (IWG-MRT response criteria DIPSS assess MF score (Passamonti).
Spleen ≥5 cm below costal margin as measured by palpation.
Key exclusion criteria
Absolute Neutrophil Count (ANC) <1.0 x 109/L
Platelet count <50 x 109/L

17. Platelet count while on ARD12181

18. Haemoglobin on ARD12181

19. Leucocyte count on ARD12181

20. Current status
Spleen
MRI 20/11/2012

21. Current status
Bone marrow

22. Why do patients respond differently to different agents?
Heterogeneity of disease
Molecular
Cytokine
Stage
Hemopoietic reserve
Individual target of patient/physician
Ability to withstand different toxicities

23. Binding Specificity of JAK2 Inhibitors In Clinical Development
Fold-increase in concentration in comparison to that needed to inhibit JAK2
JAK2 (nM)
JAK1
JAK3
TYK2
FLT3
JAK2 V617F
Other†
Ruxolitinib1
2.8 1X
153X 7X -
SAR 3
35X
334X
135X 5x
CYT3873 18 9X
JNK1, CDK2
AZD14804
<3
16X
TrkA, Aurora A, FGFR
SB15185 23
56X
23X 2X
Yes LY
2260
0.024X
(55)
Lestaurtinib8 1 NA 3X
JAK2 inhibitors have different binding specificities and several of the JAK2 inhibitors have additional kinase targets
SAR302503, SB1518 and AZD1480 exhibit selective binding specificity for JAK2.
Ruxolitinib and CYT387 are dual JAK1 and JAK2 inhibitors, which may potentially cause more off-target effects.
LY is unique amongst the JAK2 inhibitors, as it is highly specific for the JAK2V617F mutant allele.
References
1. Quintás-Cardama A, et al. Blood 2010; 115:3109–3117.
2. Wernig G, et al. Cancer Cell 2008; 13:311–320.
3. Tyner JW, et al. Blood 2010; 115:5232–5240.
4. Ioannidis S, et al. J Med Chem 2011; 54:262–276.
5. Hart S, et al. Leukemia 2011;25:1751–1759.
6. Paquette R, et al. Blood 2008; 112: Abstr 2810.
7. Ma L, et al. ASH Annual Meeting 2010; Poster
8. Hexner EO, et al. Blood 2008; 111:5663–5671.
Data are taken from separate studies and are not comparative. †Includes other kinases of note. Extensive lists of kinases tested and IC50 values are available in the literature.CDK2, cyclin-dependent kinase 2; FGFR, fibroblast growth factor-receptor; FLT3, Fms-like tyrosine kinase 3; JNK1, Mitogen-activated protein kinase 8; TrkA, neurotrophic tyrosine kinase receptor type 1.
A full list of references is provided in the slide notes.

24. SUMMARY
JAK inhibitors deliver meaningful effects upon splenomegaly, symptoms and survival BUT optimal response is not yet defined
Resistance, progression and intolerance need to be defined but are being identified in some patients
Switching to alternative JAK inhibitors may be a successful strategy for these patients