5Definitions…………………Primary resistance an inability to achieve landmark response, eg fail to achieve major or complete cytogenetic response in CML ie optimal vs suboptimal responseSecondary resistance those who achieve but subsequently lose relevant responseRelapse ? more appropriate here progressionIntolerance usually heme toxicity for ruxolitinib
6In addition Requires a facet – eg measure of symptoms or spleen size Requires definition of appropriate responseANDDefinition of sufficient “lack of” or “loss of” response or progression
7Spleen Definition of “optimal response” Definition of progression? Comfort I – 25% beyond baselineComfort II – 25% above nadireg, 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.
8Symptoms Optimal response ……..? Progression could be loss of that response but by how much? and what about durability?
9Molecular resistance We do not understand this aspect well! At present patients are poorly characterisedPotential mechanisms eg specific mutations or overexpression of JAK1 have been described in vitro but not in vivo
10Other aspects of resistance/progression Other disease progression?Anemia or thrombocytopeniaBlastsLeucocytosisEvent eg thrombosis?
11CASE63 year ♂, MF diagnosed 2008, presented with pancytopenia and splenomegaly, JAK2 V617F negHC but dose limited by cytopeniasEnrolled COMFORT II trial Oct 2009 commenced 15mg bdDose reduction Jan 2010 for thrombocytopenia, 10 mg and then further to 5 mgOngoing bone painStopped trial at week 72 due to lack of effect on symptoms and splenomegaly and thrombocytopenia.
12ThrombocytopeniaStart of studyDose reductionDose reductionStop
14Primary refractory disease +/- intolerance Stopped ruxolitnibManaged with small doses of HCEnrolled in ARD12181 with JAK inhibitor SAR302503Currently cycle 12 on studyReduction in spleen and symptom improvement
15SAR302503 Phase II Study Design: ARD12181 JAKARTA 2 Phase 2, single arm, multicenter, open-label studySubjects 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 entryIntermediate or High risk Primary MFPost-Polycythemia Vera MyelofibrosisPost-Essential Thrombocythemia Myelofibrosis according to the 2008 World HealthOrganization (WHO) criteriaRecent amendment changing discontinuation period from 30 days to 14 days70 ptsDose regimenSAR once daily,Starting dose: 400mg/dayContinuously in 28-day cyclesTitration allowed: 200mg, 300mg, 400mg, 500mg or 600mgPrimary 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 MFSAFSafety, PK/PD, JAK2V617F allele burden, JAK-STAT and other signaling pathways, OS15
16Study 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 criteriaSubjects 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 criteriaAbsolute Neutrophil Count (ANC) <1.0 x 109/LPlatelet count <50 x 109/L
22Why do patients respond differently to different agents? Heterogeneity of diseaseMolecularCytokineStageHemopoietic reserveIndividual target of patient/physicianAbility to withstand different toxicities
23Binding Specificity of JAK2 Inhibitors In Clinical Development Fold-increase in concentration in comparison to that needed to inhibit JAK2JAK2 (nM)JAK1JAK3TYK2FLT3JAK2 V617FOther†Ruxolitinib12.81X153X7X-SAR335X334X135X5xCYT3873189XJNK1, CDK2AZD14804<316XTrkA, Aurora A, FGFRSB151852356X23X2XYesLY22600.024X(55)Lestaurtinib81NA3XJAK2 inhibitors have different binding specificities and several of the JAK2 inhibitors have additional kinase targetsSAR302503, SB1518 and AZD1480 exhibit selective binding specificity for JAK2.Ruxolitinib and CYT387 are dual JAK1 and JAK2 inhibitors, which may potentially cause more off-target effects.LY is unique amongst the JAK2 inhibitors, as it is highly specific for the JAK2V617F mutant allele.References1. Quintás-Cardama A, et al. Blood 2010; 115:3109–3117.2. Wernig G, et al. Cancer Cell 2008; 13:311–320.3. Tyner JW, et al. Blood 2010; 115:5232–5240.4. Ioannidis S, et al. J Med Chem 2011; 54:262–276.5. Hart S, et al. Leukemia 2011;25:1751–1759.6. Paquette R, et al. Blood 2008; 112: Abstr 2810.7. Ma L, et al. ASH Annual Meeting 2010; Poster8. Hexner EO, et al. Blood 2008; 111:5663–5671.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.
24SUMMARYJAK inhibitors deliver meaningful effects upon splenomegaly, symptoms and survival BUT optimal response is not yet definedResistance, progression and intolerance need to be defined but are being identified in some patientsSwitching to alternative JAK inhibitors may be a successful strategy for these patients