Transcript Case from CH
Perspectives on defining ruxolitinib resistance/suboptimal response and therapeutic decision-making in this setting
Claire Harrison, MD
Burden of Myelofibrosis
Splenomegaly MF Associated Symptoms Premature death Anemia/ Cytopenias
Assessing Ruxolitinib in MF Patients
Anemia PLTS Symptoms
Spleen
Therapy
Anemia PLTS 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 5. Suboptimal symptoms/ Spleen, no heme tox
? Change
6. Suboptimal symptoms/Spleen, heme tox 7. Minimal symptoms +/- Spleen, no heme tox 8. Minimal symptoms +/- Spleen, heme tox 9. No response, no heme tox 10. No response, heme tox
Change
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
• • S
econdary 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 2000cm 3 and study nadir of 500cm 3 would have progressed with a spleen volume of 625cm 3 on Comfort –II, but 2500cm 3 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
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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
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Intermediate or High risk Primary MF
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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 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
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Study population
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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 10 9 /L Platelet count <50 x 10 9 /L
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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
Ruxolitinib 1
SAR302503 2
CYT387 3 AZD1480 4 SB1518 5 LY2784544 7 Lestaurtinib 8
JAK2 (nM)
2.8
3
18 <3 23 2260 1
Fold-increase in concentration in comparison to that needed to inhibit JAK2 JAK1 JAK3 TYK2 FLT3 JAK2 V617F Other †
1X 153X 7X -
35X
1X -
334X
9X 16X
135X
1X -
5x 1X
JNK1, CDK2 TrkA, Aurora A, FGFR 56X NA 23X 3X 2X NA Yes Yes 1X 0.024X
(55) 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 IC 50 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.
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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