New treatments in the pipeline for MPN. Claire Harrison Guy s and St Thomas Hospital NHS Foundation Trust, London, UK

Transcription

1 New treatments in the pipeline for MPN Claire Harrison Guy s and St Thomas Hospital NHS Foundation Trust, London, UK

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3 Beyond JAK2 V617F Mutation: Molecular Complexity of MPNs Mutations affecting the JAK-STAT Signaling JAK2 MPL LNK c-cbl SOCS1-3 CALR Mutations affecting the epigenetic regulation TET2 EZH2 ASXL1 IDH1/2 DNMT3A JAK2V617F Mutations associated with Leukemic transformation IDH1/2 IKZF1 TP53 NF1 RUNX1 NRAS KRAS DNMT3A 3

4 William Dameshek uses the term myeloproliferative Approval of ruxolitinib for PV Description of JAK2V617K Bergamo trial of hydroxycarbamide in ET Heuck describes PMF and Vaquez PV PVSG trials report CALR PVSG studies with hydroxycarbamide, busulfan, pipobroman venesection, chlorambucil, 32P are reported s Description of CALR mutations RIC allosct for Myelofibrosis reported 1990s Blood volume suggest PCV target 0.45 Hemorrhagic thrombocythemia or ET, Epstein & Goedel ECLAP study aspirin in PV PT-1 study hydroxycarbamide vs anagrelide in ET ET PVSG starts PVSG studies initiated and first diagnostic criteria First use of Interferon (Linkesch) and anagrelide (Silverstein) Trials with JAK inhibitors begin CYTOPV study confirms target PCV Approval of ruxolitinib for MF

5 PHYSICIANS PATIENTS ET Prevent vascular events Slow or delay condition ET Prevent vascular events Slow or delay condition Healthy blood counts Healthy blood counts Better QoL Symptom improvement Better QoL Reduction in spleen size Symptom improvement Reduce frequency of phlebotomy Prevent vascular events Prevent vascular events PV Slow or delay condition Healthy blood counts PV Slow or delay condition Healthy blood counts Better QoL Better QoL Symptom improvement Symptom improvement Hematocrit <45% Hematocrit <45% Reduce phlebotomies Reduce phlebotomies Reduce spleen size Reduce spleen size MF Prevent vascular events Slow or delay condition MF Prevent vascular events Slow or delay condition Healthy blood counts Healthy blood counts Better QoL Better QoL Symptom improvement Symptom improvement Anemia treatment Anemia treatment Reduce blood transfusion Reduce phlebotomies Reduce spleen size Reduce spleen size

6 Prevent vascular events TARGETS for MF Slow or delay condition Healthy blood counts Better QoL Symptom improvement Anemia treatment Reduce blood transfusion Reduce spleen size Physicians Prevent vascular events Slow or delay condition Healthy blood counts Better QoL Symptom improvement Anemia treatment Reduce phlebotomies Patients Reduce spleen size

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8 Its not all about drugs.. Sometimes research is asking a simple question how are your symptoms? or even just for a small amount of blood this study led to our discoveries of JAK2 and CALR mutations Bloodletting 18th Century Persian manuscript illustration

9 WHY DO MPNs DEVELOP?? CIs: Mary Frances McMullin, Andrew Duncombe, Lesley Ashton

10 ET and PV FOCUS on SECOND LINE Still???s about RUXOLITINIB

11 Primary data for ET presented at EHA and ASH 2016 MAJ C Only on-going study in PV ( & ET) likely to answer questions about transformation and thrombosis A RandoMised study of best Available therapy versus JAK Inhibition in patients with high risk Polycythaemia Vera or Essential Thrombocythaemia who are resistant or intolerant to HydroxyCarbamide TAP Fully recruited

12 Effects of Tamoxifen on Patients with Myeloproliferative Neoplasms New study funded by Bloodwise opened in August A total of 42 patients to be recruited over 12 months including a minimum of 15 Polycythaemia vera (PV) patients, 10 Essential Thrombocythaemia (ET) patients and 5 Myelofibrosis (MF) patients

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14 Myelofibrosis: therapeutic landscape in 2016 Primary, post-et or post-pv myelofibrosis Calculate DIPSS MF score & assess MF symptoms (MPN-SAF) Low risk Asymptomatic Low risk Symptomatic Int-1 Symptomatic Int-2 & High risk Observation vs.? interferon??? JAK inhib? JAK inhib vs. allo SCT** vs. anemia Rx JAK inhibitor failure? Switch to another agent or switch to combination Reconsider Allo SCT JAK inhib Or clinical trial Allo SCT?? Clinical trial first if high-risk allo

15 Trial design: RETHINK ruxolitinib vs placebo (MF DIPSS LR/HMR+) Survival Follow up Screening Treatment Phase Ruxolitinib 10 mg bid Ruxolitinib 5/15/20 mg bid IF WE USE RUXOLITINIB MF Patients Spleen 5 cm below LCM PFS1* PFS2 1:1 EARLIER IN THE COURSE OF HMR+ (ASXL1, EZH2, SRSF2 or IDHI1/2) N = 320 Ruxolitinib DISEASE CAN Placebo WE ACHIEVE 5/15/20 mg bid MORE? Inclusion Population: Hb > 10 g/dl; transfusion independent ANC > 1, WBC < Blast < 1% Platelets > MPN10 15 (individual items 3) Primary Endpoint: PFS-1 (90 events) Secondary Endpoints PFS-2, safety & tolerability, QOL, OS *If progression is achieved by spleen or symptoms HMR, high molecular risk

16 Myelofibrosis: therapeutic landscape in 2016 Primary, post-et or post-pv myelofibrosis Calculate DIPSS MF score & assess MF symptoms (MPN-SAF) Low risk Asymptomatic Low risk Symptomatic Int-1 Symptomatic Int-2 & High risk Observation vs.? interferon??? JAK inhib? JAK inhib vs. allo SCT** vs. anemia Rx JAK inhibitor failure? Switch to another agent or switch to combination Reconsider Allo SCT JAK inhib Or clinical trial Allo SCT?? Clinical trial first if high-risk allo

17 Definitions of inadequate response/resistance Primary resistance an inability to achieve landmark response, eg fail to achieve major or complete cytogenetic response in CML ie optimal vs suboptimal response

18 JAK Inhibitors and Status of Development Myelofibrosis as lead indications * * Pacritinib on clinical hold Feb 2016 * * Now Testing in PV No Longer in Development For MPNs

19 SIMPLIFY-2 Randomize SIMPLIFY-1 Randomize JAK Inhibitor Monotherapy (Phase 3 Programs - MF) Momelotinib (Gilead, USA) JAK1/ JAK2 Inhibitor: Phase II Program Spleen, MPN Sx, Hemoglobin MF Int 1& 2/ High Risk PLT 50 x 10(9)/L Momelotinib 200 QD Ruxolitinib (PI Dose) Response 35% SV MPN-SAF Anemia Fully recruited results 2017 MF Int 1& 2/ High Risk BL Anemia/ TPN No JAK excl Momelotinib 200 QD BAT (include Rux) Response 35% SV MPN-SAF Anemia

20 Ruxolitinib combinations INFa 2a BKM-120 Buparlisib (PI3 K) Danazol (Androgen) Ruxolitinib + LDE-225 Sonidegib (HH) Pomalidomide (IMID) 5 AZA (HMA) Panobinostat (HDAC) WHY??? Reduce toxicity Enable effective dose eg. anemia Improve benefits

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22 Newer Drugs for MPN (Excluding JAKi) Class Agent* Target PI3K pathway inhibitors BKM120/Buparlisib RAD001/Everolimus PI3K/Akt/ mtor Histone deacetylase (HDAC) inhibitors Panobinostat Vorinostat Givinostat Pacrinostat HDACs (different classes) HSP90 DNA methyltransferase inhibitors Azacitidine Decitabine DNA methyltransferase Hedgehog inhibitors LDE225 Smo Telomerase inhibitors Imetelstat Telomerase Bone marrow fibrosis inhibitors Pentraxin DAMPs and monocytes / macrophages * list not exhaustive

23 Imetelstat Tefferi et al. NEJM - September 3, 2015

24 Dysregulated Telomerase Activity in MPN Upregulated telomerase activity may be involved in proliferation and replication immortality of neoplastic progenitor cells, and has been shown to occur also in MPN cells IMETELSTAT is the first telomerase inhibitor in clinical development Competitively binds to RNA template of telomerase and inhibits is activity IMETELSTAT inhibited growth of spontaneous CFU-MK from ET pts Did not inhibit cytokine-induced CFU-MK growth from healthy controls Ruella M et al, Exp Hematol Jul;41(7):627-34; Baerlocher GM, et al. Blood Nov 2012; 120: 179

25 Data potentially very interesting IMBARK study on-going

26 PRM-151: Recombinant Human Pentraxin- 2 (PTX-2) PTX-2 ( ) is an endogenous regulator of tissue repair PTX-2 binds to damaged tissue ( ) and monocytes/macrophages PTX-2 prevents and reverses fibrosis in pre-clinical models PTX-2 levels are low in MF patients Also low in patients with renal, pulmonary and liver fibrosis X Hypothesis: Reduction of bone marrow fibrosis will restore hematopoiesis and improve cytopenias X Pro-inflammatory macrophages X Pro-fibrotic macrophages Pro-resolutive macrophages Verstovsek et. al. ASH 2015

27 Hemoglobin (g/l) and % of patients with transfusions Hemoglobin and RBC Transfusions Patients with baseline Hgb < 100 g/l who completed 72 weeks (n=5)

28 Platelets x 10 9 /L and % of patients with PLT transfusions Platelets and Platelet Transfusions Patients with Baseline Platelets < 100 x 10 9 /L who completed 72 weeks (n=9) PROMOTE study on-going Verstovsek et. al. ASH 2015

29 The landscape is changing Guy s a hospital for the incurables and criminally insane Guy s, London Thanks to many patients, teams & colleagues for dedication & sharing data