7/28/2014 Winship Cancer Institute of Emory University New Determinants and Approaches for MPN Elliott F. Winton, MD Professor of Hematology & Medical Oncology Disclosures, Elliott Winton External Company Name Role Industry Relationships Industry funds to Incyte Corporation Phase 1,2&3 Trials Emory for my Sanofi-Adventis Phase 2 Trial research Gilead Sciences Phase 3 Trial Advisory Board Incyte Corporation Consultant 1
7/28/2014 Outline: MPN Determinants, Approaches • Diagnosis • Prognosis • Treatment Outline: MPN Determinants, Approaches • Diagnosis – New mutations – New WHO – Which test, when 2
7/28/2014 MPN’s: History of Diagnostic Criteria PVSG-1978 Berlin PVSG-1996 Modified, Pearson WHO-2001 WHO-2008 Proposal, WHO-2014 WHO Myeloid Malignancies: 2008 MPN AML MDS Non ‐ Classical Classical MDS/ MPN CML CNL PRV CEL ‐ NOS MPN ‐ SM ET MPM ‐ U eos PMF 3
7/28/2014 WHO Myeloid Malignancies: 2008 MPN AML MDS MDS/ CMML JMML MPN aCML MPN/ MPN ‐ MDS ‐ U eos RARS ‐ T WHO Myeloid Malignancies: 2008 MPN AML MDS MDS/ PDGFR Imatinib MPN sensitive PDGFR MPN ‐ FGFR eos 4
7/28/2014 Calreticulin Fills a Gap • ET, PMF “molecular diagnostic gap” 35 ‐ 40% patients, until ‐ ‐ ‐ • December 2013 – 2 groups report CALR mutations seen in JAK2/MPL unmutated – ET: 67 ‐ 71% – PMF: 56 ‐ 88% – Post ‐ ET MF: 85% • Mutual exclusivity: did not observe a patient with both a JAK2 V617F and MPL 515 , or CALR and JAK2 V617F or MPL 515 Naglia J, et al, NEJM 2013; 369:2391 ‐ 405. Klampfl T, et al, NEJM 2013;369: 2379 ‐ 90 CALR: What Does It Do in Cell • Chromosomal location: 19p13.2 • Normal CALR functions: – In ER: protein folding; Ca+ homeostasis – On cell surface: pro ‐ phagocytotic signaling • The mutations (del or ins in exon 9) result in 1+ BP frame shift resulting in novel C ‐ terminus, basic instead of acidic amino acids • CALR mutant cells have increased STAT5 phosphorylation, can be blocked by JAK2 inhibitors; correlates with clinical observations 5
7/28/2014 CALR vs JAK2 V617F ET and PRV Rumi E, et al, Blood 2014, 123: 1544 ‐ 1551 Mutations in PRV 2% 1% JAK2V617F JAK2 exon 12 Other 97% 6
7/28/2014 Mutations in ET 10% 4% JAK2V617F CALR 24% MPL515 Triple negative 62% Mutations in PMF 9% 8% JAK2V617F CALR MPL515 25% 58% Triple negative 7
7/28/2014 Molecular Genetic Tests, MPN Diagnosis PRV ET or PMF + + JAK2 V617F JAK2 V617F stop stop ‐ ‐ + JAK2 + CALR stop stop exon 12 ‐ + PRV: 1% double negative MPL 515 stop ET PMP: 10% triple negative WHO 2014 Proposed PRV Criteria MINOR CRITERIA MAJOR CRITERIA Hgb, g per dL/HCT,% Subnormal Men: >16.5/49 erythropoietin level Women: >16/48 BM trilineage myeloproliferation, Diagnosis: pleomorphic megakaryocytes ‐ All 3 majors, or ‐ 1 st two majors JAK2 V617F or and the minor JAK2 exon 12+ Tefferi A, Thiele J, Barbui T, Leukemia, 2014: 1 ‐ 7 8
7/28/2014 WHO 2014 Proposed ET Criteria MINOR CRITERIA MAJOR CRITERIA Platelet count > Presence of a clonal 450,00/mcL marker or absence of evidence for reactive Megakaryocyte thrombocytosis proliferation with large mature morphology Not meeting WHO criteria Diagnosis: CML, PRV, PMF, MDS ‐ All 4 majors, or ‐ 1 st 3 majors Presence JAK2, CALRCALR or and the minor MPL 515 Tefferi A, Pardanani A, Nat Rev Clin Onc 2014, 11:125 ‐ 6 WHO 2014 Proposed MF Criteria MINOR CRITERIA MAJOR CRITERIA Presence of a clonal marker Megakaryocyte or absence of evidence for proliferation with atypia reactive marrow fibrosis plus reticulin and/or collagen fibrosis Anemia or palpable spleen Not meeting WHO criteria Leukoerythroblastic blood CML, PRV, PMF, MDS picture or elevated LDH Diagnosis: Presence JAK2 V617F , ‐ All 3 majors, or CALR or MPL 515 ‐ 1 st 2 majors and all 3 minor Tefferi A, Pardanani A, Nat Rev Clin Onc 2014, 11:125 ‐ 6 9
7/28/2014 Outline: MPN Determinants, Approaches • Diagnosis • Prognosis • Treatment Outline: MPN Determinants, Approaches • Diagnosis • Prognosis – Genotype ‐ clinical phenotype – Clonal evolution – Prognostic scores 10
7/28/2014 CALR Effect on Thrombosis: ET Klampfl T, et al, NEJM 2013;369: 2379 ‐ 90 CALR vs JAK2 V617F and Thrombosis Rumi E, et al, Blood 2014, 123: 1544 ‐ 1551 11
7/28/2014 CALR Effect on Survival: ET Klampfl T, et al, NEJM 2013;369: 2379 ‐ 90 CALR Effect on Survival: MF Klampfl T, et al, NEJM 2013;369: 2379 ‐ 90 12
7/28/2014 Creation of Sub ‐ Clones in Clones Disease initiating mutation 25 Creation of Sub ‐ Clones in Clones Disease modifying mutation 26 13
7/28/2014 Creation of Sub ‐ Clones in Clones Disease transforming mutation 27 ET to PRV Transformation Rumi E, et al, Blood 2014, 123: 1544 ‐ 1551 14
7/28/2014 JAK2 V617F MPN: Copy Neutral LOH Cazzola M, Kralovics R, Blood 2014; 123:3714 ‐ 3719 Allele Burden and Clinical Phenotype Rumi E, et al, Blood 2014, 123: 1544 ‐ 1551 15
7/28/2014 Regulation in JAK ‐ STAT Pathway 31 Oh ST and Gotlib J. Expert Reviews, 2010;3:323-337 MPN Associated Mutations • Drivers of proliferation – JAK2, MPL, CALR: all activate JAK ‐ STAT • Negative regulators of JAK ‐ STAT – LNK, c ‐ CBL, SOCs • Altered epigenetic regulation – TET2, ASXL1, DNMT3A, EZH2, IDH1 • Transformation associated – IZF1, TP53, RUNX1, IZH1/2 32 Vainchenker W et al, Blood 2011; 118:1723-1735 16
7/28/2014 Mutations in Clonal Evolution MPN • Next Gen Sequencing, 197 MPN pts, 104 genes • 427 mutations – 334 germline (e.g. in non ‐ heme cells) – 103 somatic mutations in 28 genes (heme cells) • Frequency of # of mutations: – 10%, 0 mut’s; 54%, 1 mut; 36% > 1 mut – JAK2 V617F >CALR>epigenetic regulators – More mutations, poorer survival • Majority of mutations present at diagnosis, very slow rate of acquisition (1/45 pt yrs) Lundberg P et al, Blood 2014;123:2220 ‐ 2228 MPN: Mutation Associations Lundberg P et al, Blood 2014;123:2220 ‐ 2228 17
7/28/2014 Clonal Evolution in MPN Lundberg P et al, Blood 2014;123:2220 ‐ 2228 Adverse Effects of P53, TET2 Mutations Lundberg P et al, Blood 2014;123:2220 ‐ 2228 18
7/28/2014 Outline: MPN Determinants, Approaches • Diagnosis • Prognosis – Genotype ‐ clinical phenotype – Clonal evolution – Prognostic scores DIPPS to Predict Survival, MF 38 Passamonti F et al., Blood 2010; 155:1703-1708 19
7/28/2014 DIPPS to Predict Survival, MF 0 points 1 ‐ 2 points 5 ‐ 6 points 3 ‐ 4 points 39 Passamonti F et al., Blood 2010; 155:1703-1708 IPSET for ET Thrombosis Risk • 891 WHO defined ET, 7 centers • Multivariable analysis derived HR’s – Age > 60, HR=1.5, 1 point – Thrombosis hx, HR=1.9, 2 point – CV risk factors, HR=1.6, 1 point – JAK2 V617F, HR=2.0, 2 point • Scoring: – Low risk: < 2 points – Intermed risk: = 2 points – High risk: > 2 points Barbui T et al Blood 2012, 120:5128-5133 20
7/28/2014 ET, Thrombosis Free Survival Barbui T et al Blood 2012, 120:5128-5133 Overall Survival PRV Tefferi A et al Leukemia 2013: 1 ‐ 8 21
7/28/2014 Defining High Risk PRV Age: > 67 – 5 pts 57-66 – 2 pts WBC>15X10 3 /uL – 1 pt Venous thrombosis – 1 pt Score>3 Score=0 Score=1 ‐ 2 Tefferi A et al Leukemia 2013: 1 ‐ 8 PRV, Risk of Leukemia Tefferi A et al Leukemia 2013: 1 ‐ 8 22
7/28/2014 Outline: MPN Determinants, Approaches • Diagnosis • Prognosis • Treatment Outline: MPN Determinants, Approaches • Diagnosis • Prognosis • Treatment – Ruxolitinib – long term, PRV – Other developments 23
7/28/2014 Long ‐ Term Outcomes of Ruxolitinib Therapy in Patients with Myelofibrosis: 3 ‐ Year Update From COMFORT ‐ I Srdan Verstovsek, 1 Ruben A. Mesa, 2 Jason Gotlib, 3 Richard S. Levy, 4 • Vikas Gupta, 5 John F. DiPersio, 6 John V. Catalano, 7 Michael W.N. Deininger, 8* Carole B. Miller, 9 Richard T. Silver, 10 Moshe Talpaz, 11 Elliott F. Winton, 12 Jimmie H. Harvey, Jr., 13 Murat O. Arcasoy, 14 Elizabeth O. Hexner, 15 Roger M. Lyons, 16 Azra Raza, 17 Kris Vaddi, 4 William Sun, 4 Wei Peng, 4 Victor Sandor, 4 and Hagop Kantarjian, 1 for the COMFORT ‐ I investigators Verstovsek S, ASH 2013 Discontinuation Over Time • Approximately 50% of patients originally randomized to ruxolitinib remain on therapy 1.0 0.8 Discontinuation rates: – At year 1: 21% – At year 2: 35% Probability 0.6 – At year 3: 51% 0.4 0.2 0 0 24 48 72 96 120 144 168 Weeks No. of patients at risk Ruxolitinib 155 139 122 107 101 87 27 0 Verstovsek S, ASH 2013 48 24
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