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Burden of Myelofibrosis

Perspectives on defining ruxolitinib resistance/suboptimal response and therapeutic decision-making in this setting Claire Harrison, MD. Burden of Myelofibrosis. MF Associated Symptoms. Splenomegaly. Premature death. Anemia/ Cytopenias. NET. Assessing Ruxolitinib in MF Patients. Anemia

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Burden of Myelofibrosis

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

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

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

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

  5. Definitions………………… • Primary resistancean inability to achieve landmark response, eg fail to achieve major or complete cytogenetic response in CML ieoptimal vs suboptimal response • Secondary resistancethose who achieve but subsequently lose relevant response • Relapse ? more appropriate here progression • Intolerance usually hemetoxicity 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 Stop Dose reduction Dose reduction

  13. Week 12 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: ARD12181JAKARTA 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 • 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

  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 • 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.

  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

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