New Determinants and Approaches for MPN Elliott F. Winton, MD - - PDF document

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New Determinants and Approaches for MPN Elliott F. Winton, MD - - PDF document

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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

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7/28/2014 1 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 Industry Relationships Company Name Role Industry funds to Emory for my research Incyte Corporation Sanofi-Adventis Gilead Sciences Phase 1,2&3 Trials Phase 2 Trial Phase 3 Trial Advisory Board Incyte Corporation Consultant

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Outline: MPN Determinants, Approaches

  • Diagnosis
  • Prognosis
  • Treatment

Outline: MPN Determinants, Approaches

  • Diagnosis

–New mutations –New WHO –Which test, when

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MPN’s: History of Diagnostic Criteria

PVSG-1978 Berlin PVSG-1996 Modified, Pearson WHO-2001 WHO-2008 Proposal, WHO-2014

WHO Myeloid Malignancies: 2008

AML MPN MDS/ MPN MDS MPN‐ eos

CML PRV ET PMF CNL

CEL‐NOS

SM MPM‐U

Classical Non‐Classical

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WHO Myeloid Malignancies: 2008

AML MPN MDS/ MPN MDS MPN‐ eos

CMML JMML aCML

MPN/ MDS‐U

RARS‐T

WHO Myeloid Malignancies: 2008

AML MPN MDS/ MPN MDS MPN‐ eos

PDGFR PDGFR FGFR

Imatinib sensitive

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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 JAK2V617F and MPL515 , or CALR and JAK2V617F or MPL515

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

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CALR vs JAK2V617F ET and PRV

Rumi E, et al, Blood 2014, 123: 1544‐1551

Mutations in PRV

97% 2% 1% JAK2V617F JAK2 exon 12 Other

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Mutations in ET

62% 24% 4% 10% JAK2V617F CALR MPL515 Triple negative

Mutations in PMF

58% 25% 8% 9% JAK2V617F CALR MPL515 Triple negative

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Molecular Genetic Tests, MPN Diagnosis

PRV ET or PMF

JAK2V617F JAK2 exon 12 MPL515 CALR JAK2V617F

‐ +

stop

+

stop

+

stop

+

stop

+

stop

‐ ‐

PRV: 1% double negative ET PMP: 10% triple negative

WHO 2014 Proposed PRV Criteria

Tefferi A, Thiele J, Barbui T, Leukemia, 2014: 1‐7

Hgb, g per dL/HCT,% Men: >16.5/49 Women: >16/48 JAK2V617F or JAK2 exon 12+ Subnormal erythropoietin level BM trilineage myeloproliferation, pleomorphic megakaryocytes

MAJOR CRITERIA

Diagnosis: ‐ All 3 majors, or ‐ 1st two majors and the minor

MINOR CRITERIA

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WHO 2014 Proposed ET Criteria

Tefferi A, Pardanani A, Nat Rev Clin Onc 2014, 11:125‐6

Platelet count > 450,00/mcL Megakaryocyte proliferation with large mature morphology Presence JAK2, CALRCALR or MPL515 Presence of a clonal marker or absence of evidence for reactive thrombocytosis Not meeting WHO criteria CML, PRV, PMF, MDS

MAJOR CRITERIA

Diagnosis: ‐ All 4 majors, or ‐ 1st 3 majors and the minor

MINOR CRITERIA

WHO 2014 Proposed MF Criteria

Tefferi A, Pardanani A, Nat Rev Clin Onc 2014, 11:125‐6

Anemia or palpable spleen Megakaryocyte proliferation with atypia plus reticulin and/or collagen fibrosis Presence JAK2V617F, CALR or MPL515 Presence of a clonal marker

  • r absence of evidence for

reactive marrow fibrosis Not meeting WHO criteria CML, PRV, PMF, MDS

MAJOR CRITERIA MINOR CRITERIA

Diagnosis: ‐ All 3 majors, or ‐ 1st 2 majors and all 3 minor

Leukoerythroblastic blood picture or elevated LDH

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Outline: MPN Determinants, Approaches

  • Diagnosis
  • Prognosis
  • Treatment

Outline: MPN Determinants, Approaches

  • Diagnosis
  • Prognosis

–Genotype‐clinical phenotype –Clonal evolution –Prognostic scores

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CALR Effect on Thrombosis: ET

Klampfl T, et al, NEJM 2013;369: 2379‐90

CALR vs JAK2V617F and Thrombosis

Rumi E, et al, Blood 2014, 123: 1544‐1551

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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

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Creation of Sub‐Clones in Clones

25

Disease initiating mutation

Creation of Sub‐Clones in Clones

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Disease modifying mutation

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Creation of Sub‐Clones in Clones

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Disease transforming mutation

ET to PRV Transformation

Rumi E, et al, Blood 2014, 123: 1544‐1551

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JAK2V617F 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

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Regulation in JAK‐STAT Pathway

Oh ST and Gotlib J. Expert Reviews, 2010;3:323-337

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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

Vainchenker W et al, Blood 2011; 118:1723-1735

32

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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 – JAK2V617F>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

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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

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Outline: MPN Determinants, Approaches

  • Diagnosis
  • Prognosis

–Genotype‐clinical phenotype –Clonal evolution –Prognostic scores

Passamonti F et al., Blood 2010; 155:1703-1708

38

DIPPS to Predict Survival, MF

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0 points 1‐2 points 3‐4 points 5‐6 points 39

Passamonti F et al., Blood 2010; 155:1703-1708

DIPPS to Predict Survival, MF

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

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ET, Thrombosis Free Survival

Barbui T et al Blood 2012, 120:5128-5133

Overall Survival PRV

Tefferi A et al Leukemia 2013: 1‐8

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Defining High Risk PRV

Tefferi A et al Leukemia 2013: 1‐8

Age: > 67 – 5 pts 57-66 – 2 pts WBC>15X103/uL – 1 pt Venous thrombosis – 1 pt

Score=0 Score=1‐2 Score>3

PRV, Risk of Leukemia

Tefferi A et al Leukemia 2013: 1‐8

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Outline: MPN Determinants, Approaches

  • Diagnosis
  • Prognosis
  • Treatment

Outline: MPN Determinants, Approaches

  • Diagnosis
  • Prognosis
  • Treatment

–Ruxolitinib – long term, PRV –Other developments

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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

48

Discontinuation rates: – At year 1: 21% – At year 2: 35% – At year 3: 51%

139 107 87 Ruxolitinib

  • No. of patients at risk

155 122 101 27 1.0 0.8 0.6 0.4 0.2 24 72 120 168

Probability Weeks

48 96 144

Verstovsek S, ASH 2013

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Mean Daily Dose of Ruxolitinib Over Time

49

  • Approximately 70% of patients had dose adjustments during the first 12 weeks
  • f 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 15-20 mg BID, respectively

25 20 15 10 5

Mean Daily Dose (mg, BID) ± SEM

8 16 24 32 72 104 136 144 48 88 120 64 56 96 128 40 80 112

Weeks

20 mg BID starting dose 15 mg BID starting dose

98 62 20 mg BID 49 20 15 mg BID Number of patients 100 55 77 69 33 26 73 30 93 35

Verstovsek S, ASH 2013

Percentage Change in Spleen Volume

  • 40
  • 35
  • 30
  • 25
  • 20
  • 15
  • 10
  • 5

5 10 15

50

Ruxolitinib Placebo

Weeks Mean Percentage Change from Baseline 12 24 48 72 96 120 144 12 24 48

148 139 120 107 100 84 132 107 35 73

  • Mean reduction in SV with ruxolitinib was stable over time

n =

Verstovsek S, ASH 2013

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Improvements in EORTC QLQ‐C30 Over Time

51 51

Arrows indicate improvement RUX PBO

Global Health Status/QoL

Mean Change From Baseline

12 24 36 48 72 96 120 144

Weeks

20 10

  • 5
  • 15

15 5

  • 10

60 84 108 132

Fatigue

Mean Change From Baseline

12 24 36 48 72 96

Weeks

10

  • 10
  • 15
  • 25
  • 35

5

  • 5
  • 20
  • 30

60 84 120 144 108 132

Physical Functioning

Mean Change From Baseline Weeks

15 5

  • 5
  • 10

10 12 24 36 48 72 96 60 84 120 144 108 132

Role Functioning

Mean Change From Baseline

Weeks

25 10

  • 5
  • 15
  • 25

15 5

  • 10
  • 20

20 12 24 36 48 72 96 60 84 120 144 108 132

Verstovsek S, ASH 2013

Overall Survival

  • Overall survival favored patients originally randomized to ruxolitinib compared

with patients originally randomized to placebo

52 153 144 129 114 105 100 92 85 8 Placebo 155 148 143 131 124 115 111 108 1 Ruxolitinib Number of patients at risk 154 155 149 134 119 107 100 95 88 79 153 145 137 125 122 112 111 101 38 45 82 106 68 28 84 19 Original Placebo Original Ruxolitinib 1.0 0.8 0.6 0.4 0.2 8 24 40 56 72 88 104 120 136 168 176

Probability Weeks

16 32 48 64 80 96 112 128 152 144 160

HR=0.69 (95% CI: 0.46, 1.03); P=0.067

  • No. of deaths: Ruxolitinib=42; Placebo=54

Median follow up: 149 weeks

Verstovsek S, ASH 2013

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Mean Platelets & Hemoglobin Over Time

Platelet Count Hemoglobin

Ruxolitinib Placebo Ruxolitinib Placebo 53 85 90 95 100 105 110 115 12 24 36 48 60 72 84 96 108 120 132 144 Weeks Mean Hemoglobin (g/L) 120 170 220 270 320 12 24 36 48 60 72 84 96 108 120 132 144 Weeks Mean Platelets (x109/L)

128 82 PBO 144 136 112 107 100 88 RUX Number of patients 151 155 112 37 143 124 110 104 94 79 132 83 145 136 113 107 100 88 151 155 113 37 143 124 110 104 94 79 Number of patients

Verstovsek S, ASH 2013

Winship Cancer Institute of Emory University

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Ongoing Trial, WCI

  • Phase 3 double dummy, momelotinib vs

ruxolitinib, int2+ MF (Gilead Sciences)

  • Phase 3 comparison hydroxyurea vs pegylated

interferon‐2a, high risk ET, PRV (MPD‐RC)

  • Phase 2 ruxolitinib prior to RI allo BMT, MF
  • Phase 3 trial hedgehog inhibitor (PF04449913),

high risk MF prior JAK1/2 inhibitor (Pfizer)

  • Phase 2 trial, ruxolitinib in chronic neutrophilic

leukemia (Oregon Health Sciences Univ)