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 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 Stop
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 15 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 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 -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 10 9 /L ● Platelet count <50 x 10 9 /L 16
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 23 ● 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)JAK1JAK3TYK2FLT3JAK2 V617FOther † Ruxolitinib 1 2.81X153X7X-- SAR302503 2 335X334X135X 5x 1X CYT387 3 181X9X1X-JNK1, CDK2 AZD1480 4 <3-16X-- TrkA, Aurora A, FGFR SB1518 5 2356X23X2X Yes 1X LY2784544 7 2260--- 0.024X (55) - Lestaurtinib 8 1NA3XNA Yes 1X 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.
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