burden of myelofibrosis
DESCRIPTION
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 - PowerPoint PPT PresentationTRANSCRIPT
Perspectives on defining ruxolitinib resistance/suboptimal response and therapeutic decision-making in this setting
Claire Harrison, MD
Burden of Myelofibrosis
Anemia/Cytopenias
Splenomegaly MF AssociatedSymptoms
Premature death
Assessing Ruxolitinib in MF Patients
NET
Spleen
Symptoms
AnemiaPLTS
Spleen
Symptoms
AnemiaPLTS
Therapy
Ruxolitinib Therapy Scenarios1. Clear benefit spleen, symptoms, no heme toxicity2. Clear benefit spleen/ symptoms, heme tox3. Clear benefit symptoms, suboptimal spleen, no heme tox4. Clear benefit symptoms, suboptimal spleen, heme tox5. Suboptimal symptoms/ Spleen, no heme tox6. Suboptimal symptoms/Spleen, heme tox7. Minimal symptoms +/- Spleen, no heme tox8. Minimal symptoms +/- Spleen, heme tox9. No response, no heme tox10. No response, heme tox
? Change
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
• 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 responseAND• 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: ARD12181JAKARTA 2
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Phase 2, single arm, multicenter, open-label study
Dose regimen • SAR302503 once daily, • Starting dose: 400mg/day • Continuously in 28-day cycles• Titration allowed: 200mg, 300mg, 400mg, 500mg or 600mg
- 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
70 pts
• 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
Recent amendment changing discontinuation period from 30 days to 14 days
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
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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
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●JAK2 inhibitors have different binding specificities and several of the JAK2 inhibitors have additional kinase targets
A full list of references is provided in the slide notes.
Fold-increase in concentration in comparison to that needed to inhibit JAK2
JAK2 (nM) JAK1 JAK3 TYK2 FLT3JAK2
V617F Other†
Ruxolitinib1 2.8 1X 153X 7X - -
SAR3025032 3 35X 334X 135X 5x 1X
CYT3873 18 1X 9X 1X - JNK1, CDK2
AZD14804 <3 - 16X - -TrkA,
Aurora A, FGFR
SB15185 23 56X 23X 2X Yes 1X
LY27845447 2260 - - - 0.024X(55) -
Lestaurtinib8 1 NA 3X NA Yes 1X
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.
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