Perspectives on defining ruxolitinib
resistance/suboptimal response
and therapeutic decision-making in this
setting
Claire Harrison, MD
Burden of Myelofibrosis
Splenomegaly
Premature
death
MF Associated
Symptoms
Anemia/
Cytopenias
Assessing Ruxolitinib in MF Patients
Anemia
PLTS
Therapy
Symptoms
Anemia
PLTS
Spleen
Symptoms
Spleen
NET
Ruxolitinib Therapy Scenarios
1. Clear benefit spleen, symptoms, no heme toxicity
2. Clear benefit spleen/ symptoms, heme tox
3. Clear benefit symptoms, suboptimal spleen, no heme tox
4. Clear benefit symptoms, suboptimal spleen, heme tox
? Change
5. Suboptimal symptoms/ Spleen, no heme tox
6. Suboptimal symptoms/Spleen, heme tox
Change
7. Minimal symptoms +/- Spleen, no heme tox
8. Minimal symptoms +/- Spleen, heme tox
9. No response, no heme tox
10. No response, heme tox
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
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
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.
Symptoms
• Optimal response ……..?
• Progression could be loss of that response
but by how much?.......and what about
durability?
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
Other aspects of resistance/progression
• Other disease progression?
– Anemia or thrombocytopenia
– Blasts
– Leucocytosis
• Event eg thrombosis?
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.
Thrombocytopenia
Start of study
Dose reduction
Dose reduction
Stop
Week 12
Week 60
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
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 PostPV 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
Recent amendment changing discontinuation period from 30
days to 14 days
70 pts
- Intermediate or High risk
Primary MF
-Post-Polycythemia Vera
Myelofibrosis
Post-Essential
Thrombocythemia
Myelofibrosis according to the
2008 World Health
Organization (WHO) criteria
Dose regimen
• SAR302503 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
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
16
Platelet count while on ARD12181
Haemoglobin on ARD12181
Leucocyte count on ARD12181
Current status
• Spleen
MRI 20/11/2012
Current status
• Bone marrow
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
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
Ruxolitinib1
2.8
1X
153X
7X
SAR3025032
3
35X
334X
135X
CYT3873
18
1X
9X
1X
-
JNK1, CDK2
AZD14804
<3
-
16X
-
-
TrkA,
Aurora A,
FGFR
SB15185
23
56X
23X
2X
LY27845447
2260
-
-
-
Lestaurtinib8
1
NA
3X
NA
5x
Yes
JAK2 V617F
Other†
-
-
1X
1X
0.024X
(55)
Yes
-
1X
● JAK2 inhibitors have different binding specificities and several of the JAK2
inhibitors have additional kinase targets
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.
23
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