Winship Cancer Institute of Emory University New Determinants and Approaches for MPN

Transcription

1 Winship Cancer Institute of Emory University New Determinants and Approaches for MPN Elliott F. Winton August 8, 2014 Sea Island, Georgia

2 Outline: MPN Determinants, Approaches Diagnosis Prognosis Treatment

3 Outline: MPN Determinants, Approaches Diagnosis New mutation Which test, when

4 MPN s: History of Diagnostic Criteria PVSG-1978 Berlin PVSG-1996 Modified, Pearson WHO-2001 WHO-2008 Proposal, WHO-2014

5 WHO Myeloid Malignancies: 2008 MPN AML MDS MDS/ MPN MPNeos

6 WHO Myeloid Malignancies: 2008 MPN AML MDS MDS/ MPN MPNeos Classical CML PRV ET PMF Non-Classical CNL CEL-NOS SM MPM-U

7 WHO Myeloid Malignancies: 2008 MPN AML MDS MDS/ MPN MPNeos Classical CML PRV ET PMF Non-Classical CNL CEL-NOS SM MPM-U

8 WHO Myeloid Malignancies: 2008 MPN AML MDS MDS/ MPN MPNeos CMML JMML acml MPN/ MDS-U RARS-T

9 WHO Myeloid Malignancies: 2008 MPN AML MDS MDS/ MPN MPNeos PDGFRα PDGFRβ FGFR Imatinib sensitive

10 Calreticulin Fills a Gap ET, PMF molecular diagnostic gap 35-40% patients, until December 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: Klampfl T, et al, NEJM 2013;369:

11 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, e.g ET at dx

12 CALR vs JAK2 V617F ET and PRV Rumi E, et al, Blood 2104, 123:

13 Mutations in CML BCR/ABL 100%

14 Mutations in PRV 2% 1% JAK2V617F JAK2 exon 12 Other 97%

15 Mutations in ET 10% 4% 24% 62% JAK2V617F CALR MPL515 Triple negative

16 Mutations in PMF 9% 8% 25% 58% JAK2V617F CALR MPL515 Triple negative

17 Molecular Genetic Tests, MPN Diagnosis PRV ET or PMF JAK2 V617F - JAK2 exon 12 + stop + stop PRV: 1% double negative ET, PMF: 10% triple negative JAK2 V617F - CALR - MPL stop + stop + stop

18 Outline: MPN Determinants, Approaches Diagnosis Prognosis Genotype-clinical phenotype Clonal evolution

19 CALR Effect on Thrombosis: ET P=0.003 Klampfl T, et al, NEJM 2013;369:

20 CALR vs JAK2 V617F and Thrombosis Rumi E, et al, Blood 2104, 123:

21 CALR Effect on Survival: ET P=0.04 Klampfl T, et al, NEJM 2013;369:

22 CALR Effect on Survival: MF P<0.001 Klampfl T, et al, NEJM 2013;369:

23 Exponential Clonal Expansion 23

24 Exponential Clonal Expansion 24

25 Exponential Clonal Expansion 25

26 Exponential Clonal Expansion Div # cells 10 thousand 20 million 30 billion 40 trillion 26

27 Creation of Sub-Clones in Clones Div # cells 10 thousand 20 million 30 billion 40 trillion 27

28 Creation of Sub-Clones in Clones Div # cells 10 thousand 20 million 30 billion 40 trillion 28

29 Creation of Sub-Clones in Clones Disease initiating mutation 29

30 Creation of Sub-Clones in Clones Disease modifying mutation 30

31 Creation of Sub-Clones in Clones Disease transforming mutation 31

32 ET to PRV Progression Rumi E, et al, Blood 2104, 123:

33 JAK2 V617F MPN: Copy Neutral LOH Cazzola M, Kralovics R, Blood 2014; 123:

34 Allele Burden and Clinical Phenotype Rumi E, et al, Blood 2104, 123:

35 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 Others IZF1, TP53, RUNX1, IZH1/2, SRSF2 Vainchenker W et al, Blood 2011; 118: Zang S-J et al Bood 2012; 119:

36 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, IDH1/2 Others IZF1, TP53, RUNX1, IZH1/2, SRSF2 Vainchenker W et al, Blood 2011; 118: Zang S-J et al Bood 2012; 119:

37 Mutations in Clonal Evolution MPN Next Gen Sequencing, 197 MPN pts, 104 genes 437 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:

38 MPN: Mutation Associations Lundberg P et al, Blood 2014;123:

39 Clonal Evolution in MPN Lundberg P et al, Blood 2014;123:

40 Adverse Effects of Specific Mutations Lundberg P et al, Blood 2014;123:

41 Outline: MPN Determinants, Approaches Diagnosis Prognosis Treatment Ruxolitinib 3 year COMFORT1 Therapies being investigated

42 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

43 Discontinuation Over Time Approximately 50% of patients originally randomized to ruxolitinib remain on therapy 1.0 Probability Discontinuation rates: At year 1: 21% At year 2: 35% At year 3: 51% No. of patients at risk Weeks Ruxolitinib Verstovsek S, ASH

44 Mean Daily Dose of Ruxolitinib Over Time Mean Daily Dose (mg, BID) ± SEM Number of patients 20 mg BID mg BID mg BID starting dose 15 mg BID starting dose Weeks Approximately 70% of patients had dose adjustments during the first 12 weeks of therapy By week 24, patients originally randomized to RUX 15 mg BID and 20 mg BID were titrated to a mean dose of ~10 mg BID and mg BID, respectively Verstovsek S, ASH

45 Percentage Change in Spleen Volume Mean reduction in SV with ruxolitinib was stable over time Mean Percentage Change from Baseline n = Ruxolitinib Placebo Weeks 45 Verstovsek S, ASH 2013

46 Improvements in EORTC QLQ-C30 Over Time Mean Change From Baseline Mean Change From Baseline Global Health Status/QoL Weeks Role Functioning Weeks Mean Change From Baseline 10 RUX PBO Arrows indicate improvement Mean Change From Baseline Fatigue Weeks Physical Functioning Weeks Verstovsek S, ASH 2013

47 Overall Survival Overall survival favored patients originally randomized to ruxolitinib compared with patients originally randomized to placebo Original Ruxolitinib Probability HR=0.69 (95% CI: 0.46, 1.03); P=0.067 Original Placebo 0.2 No. of deaths: Ruxolitinib=42; Placebo=54 Median follow up: 149 weeks Number of patients at risk Weeks Ruxolitinib Placebo Verstovsek S, ASH 2013

48 Mean Platelets & Hemoglobin Over Time Platelet Count Hemoglobin Mean Platelets (x10 9 /L) Ruxolitinib Placebo Ruxolitinib Placebo Mean Hemoglobin (g/l) Weeks Number of patients RUX PBO Weeks Number of patients Verstovsek S, ASH

49 MPN Therapies Being Investigated JAK1/2 inhibitors Ruxolitinib RESPONSE and RELIEF trials, PRV Ruxolitinib Phase II, CNL Ruxolitinib - MPD-RC 114: 3+ months prior to RI allo transplant, MF, intermed 2+ Momelotinib MF intermed 2+, as effective as ruxo?, less anemia? Phase III SIMPLIFY1 no prior JAK inh, head to head, ruxolitinib Phase III SIMPLIFY2 prior ruxolitinib with RBC transfusion need or grade 3 hgb or platelet toxicity, vs BAT (2:1 randomization)

50 MPN Therapies Being Investigated Hedgehog inhibitors Pfizer PF , MF intermed 2+, prior ruxolitinib, double blind randomized Pegylated α interferon MPD-RC 111 phase II, high risk ET, PRV HU intolerant, resistant; or prior major clot MPD-RC 112 phase III, rand with HU, high risk ET, PRV Early MF, Phase III, peg inf vs HU, 2:1 rand

51 Thank You!? s ewinton@emory.edu