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Disclosures for Ayalew Tefferi Presentation includes discussion of the following off-label use of a drug or medical device: Hydroxyurea, Interferon-alpha, Busulfan, Thalidomide, Lenalidomide, Pomalidomide, Ruxolitinib, Androgen preparations, Erythropoiesis stimulating agents Principal investigator role Janssen, Geron, Celgene, Sanofi-Aventis, Gilead Sciences, Incyte Employee None Consultant None Major Stockholder None Speakers’ Bureau None Scientific Advisory Board None
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Disclosures for Ayalew Tefferi - Indy Hematology … for Ayalew Tefferi Presentation includes discussion of the following off-label use of a drug or medical device: Hydroxyurea, …

May 23, 2018

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  • Disclosures for

    Ayalew Tefferi

    Presentation includes discussion of the following off-label use of a drug or

    medical device: Hydroxyurea, Interferon-alpha, Busulfan, Thalidomide,

    Lenalidomide, Pomalidomide, Ruxolitinib, Androgen preparations,

    Erythropoiesis stimulating agents

    Principal investigator role Janssen, Geron, Celgene, Sanofi-Aventis,

    Gilead Sciences, Incyte

    Employee None

    Consultant None

    Major Stockholder None

    Speakers Bureau None

    Scientific Advisory Board None

  • Myeloproliferative Neoplasms

    2017

    Ayalew Tefferi, MD

    Mayo Clinic, Rochester, MN

  • Objectives

    1. 2016 WHO revision of classification and diagnostic criteria

    2. Practical diagnostic algorithm

    3. Survival and prognosis

    4. Treatment

    5. Eosinophilic disorders

    6. Systemic mastocytosis

  • Chronic Myeloid Neoplasms

    Monocytosis

    Dyserythropoiesis

    Dysgranulopoiesis

    CML

    -BCR-ABL1 100%

    PV

    -JAK2 99%

    ET

    -JAK2/CALR/MPL 85%

    JAK2 60%

    CALR 20%

    MPL 5%

    Triple-negative 15%

    PMF

    Same as ET

    CNL

    -CSF3R 80-100%

    CEL

    MPN-U

    Chronic myelomonocytic leukemia (CMML)

    -TET2 40-60%

    -SRSF2 30-50%

    -ASXL1 40%

    Juvenile myelomonocytic leukemia (JMML)

    -genetic abnormality 90%

    - RAS/MAPK pathway mutation 60%

    (PTPN11, KRAS, and NRAS)

    -CBL mutation 15%

    -Germline NF1 mutations 15%

    MDS/MPN-RS with thrombocytosis

    -SF3B1 80-90%

    -JAK2V617F 50%

    Atypical chronic myeloid leukemia (aCML)

    -SETBP1 30%

    MDS/MPN-U

    Monocytosis Erythrocytosis

    Granulocytosis

    Thrombocytosis Dyserythropoiesis

    Dysgranulopoiesis

    Absence of

    cytosis

    Myelodysplastic

    Syndromes

    (MDS)

    Myelodysplastic/

    Myeloproliferative

    Overlap (MDS/MPN)

    Myeloproliferative

    Neoplasms

    (MPN)

    Eosinophilia

    Mastocytosis

    Myeloid/Lymphoid neoplasm

    with eosinophilia and

    PDGFR/FGFR1 mutation

    Presence of

    PDGFRA/B

    or FGFR1 or

    PCM1-JAK2

    mutation

    Tefferi and Pardanani. JAMA Oncology 2015 (modified)

    PDGFRA rearranged

    -FIP1L1-PDGFRA 100%

    PDGFRB rearrange

    -PDGFRB mutation 100%

    FGFR1 rearranged

    -FGFR1 mutation 100%

    PCM1-JAK2 rearranged

    -PCM1-JAK2 100%

    MORPHOLOGY

    MUTATIONS

    MDS with single lineage dysplasia

    MDS with multilineage dysplasia

    MDS with ring sideroblasts (MDS-RS)

    MDS-RS with single lineage dysplasia

    MDS-RS with multilineage dysplasia

    MDS with excess blasts

    MDS with isolated del(5q)

    MDS unclassifiable

    Provisional: Refractory cytopenia of childhood

  • Polycythemia

    Vera

    Essential

    Thrombocythemia

    Primary

    Myelofibrosis

    Prefibrotic

    Primary

    Myelofibrosis

    Major

    criteria

    1 Hemoglobin (Hgb)

    >16.5 g/dL (men)

    >16 g/dL (women)

    or

    Hematocrit

    >49% (men)

    >48% (women)

    1 Platelet count 450 x 109/L 1 Megakaryocyte proliferation and atypia***

    and grade 2 reticulin/collagen fibrosis

    ***megakaryocytes with aberrant nuclear/cytoplasmic ratio and hyperchromatic and irregularly folded nuclei and dense clustering

    Megakaryocyte proliferation and atypia***

    and grade 1 reticulin/collagen fibrosis,

    Increased cellularity, granulocytic

    Proliferation and decreased erythropoiesis

    2 BM trilineage myeloproliferation

    with pleomorphic megakaryocytes

    2 BM megakaryocyte proliferation

    with large and mature morphology

    2 Not meeting WHO criteria for

    other myeloid neoplasm

    Not meeting WHO criteria for

    other myeloid neoplasm

    3 Not meeting WHO criteria for

    other myeloid neoplasms

    3 Presence of JAK2, CALR or MPL mutation

    or

    presence of another clonal marker

    or

    absence of evidence for reactive

    bone marrow fibrosis

    Presence of JAK2, CALR or MPL mutation

    or

    presence of another clonal marker

    or

    absence of evidence for reactive

    bone marrow fibrosis

    3 Presence of JAK2 mutation

    4 Presence of JAK2, CALR or MPL

    mutation

    Minor

    criteria

    1. Subnormal serum Epo level

    1. Presence of a clonal marker

    or absence of evidence for reactive

    thrombocytosis

    1 1. Anemia

    2. Leukocytosis

    3. Palpable splenomegaly

    4. Increased LDH

    1. Anemia

    2. Leukocytosis

    3. Palpable splenomegaly

    4. Increased LDH

    5. Leukoerythroblastosis

    2016 Proposed Revised WHO Diagnostic Criteria (Barbui et al. Blood Cancer Journal (2015) 5, e337; doi:10.1038/bcj.2015.64 Published online 14 August 2015)

    diagnosis requires meeting all 4 major criteria or

    first three major criteria and one minor criterion

    diagnosis requires meeting all 3 major criteria and

    at least one minor criterion (diagnosis requires meeting all three major criteria or

    the first two major criteria and one minor criterion

    diagnosis requires meeting all 3 major criteria and

    at least one minor criterion

  • Diagnostic approach in routine clinical practice

  • Practical algorithm for diagnosis of myeloproliferative neoplasm Tefferi and Pardanani; JAMA Oncology 2015

    Polycythemia vera

    suspected

    Blood mutation screening

    JAK2V617F+

    Essential

    thrombocythemia

    suspected

    Primary

    myelofibrosis

    suspected

    Blood mutation screening

    JAK2 exon 12+

    If negative

    If negative

    Subnormal

    serum erythropoietin

    level

    Diagnosis unlikely

    If JAK2 unmutated and

    serum erythropoietin level

    normal or increased

    JAK2V617F+

    CALR+

    MPL+

    Triple-negative

    Bone marrow biopsy

    with mutation screening

    and cytogenetics

    If negative

    If negative

    If negative

    Diagnosis

    likely

    Bone marrow examination advised to

    confirm diagnosis

    Bone marrow examination required to

    confirm diagnosis and distinguish

    ET from prefibrotic PMF

    Diagnosis considered If bone marrow

    morphology is consistent with PMF and

    1. JAK2, CALR or MPL mutated or

    2. trisomy 9 or del(13q) present or

    3. Other myeloid malignancies are excluded

  • Survival and prognosis

  • Comparison of survival in 826 Mayo Clinic patients with

    essential thrombocythemia vs polycythemia vera vs primary myelofibrosis.

    Tefferi et al. Blood 2014

  • Tefferi et al. Blood 2015

    Comparison of survival in 389 young patients with

    essential thrombocythemia vs polycythemia vera vs primary myelofibrosis.

  • Essential thrombocythemia

    1. Karyotype (i.e. cytogenetics) 7% abnormal at diagnosis (Trisomy 9 most frequent)

    Limited prognostic value

    2. Driver mutational status JAK2 60%

    CALR 22%

    MPL 3%

    Triple negative 15%

    3. Presence or absence of other mutations Prevalence of mutations/variants other than JAK2/CALR/MPL = 53% Driver mutational status did not affect prevalence Most frequent were ASXL1 andTET2 41%, 8% and 4% harbored 1, 2 or 3 such mutations 6 genes were identified as being affected by adverse mutations/variants

    SF3B1, SH2B3, EZH2, TP53, U2AF1, IDH2 (15% affected)

    Eur J Haematol. 2009;83:17

    Blood 2014 124:2507

    Blood Advances 2016;1:21

  • Overall survival in 495 patients with essential thrombocythemia

    stratified by driver mutational status

    Am J Hematol. 2016;91:503

  • Myelofibrosis-free survival in 495 patients with essential thrombocythemia

    stratified by driver mutational status

    Am J Hematol. 2016;91:503

  • Thrombosis-free survival in 495 patients with essential thrombocythemia

    stratified by driver mutational status

    Am J Hematol. 2016;91:503

  • ET

    Blood Advances 2016;1:21

    Prevalence = 53% Driver mutational status did not affect prevalence Most frequent were ASXL1 andTET2 41%, 8% and 4% harbored 1, 2 or 3 mutations 6 genes were identified as being affected by adverse mutations/variants

    SF3B1, SH2B3, EZH2, TP53, U2AF1, IDH2 (15% affected)

    Prognostic relevance of ET mutations/variants other than JAK2/CALR/MPL

    Mayo patients Italian patients

  • Polycythemia Vera

    1. Karyotype (i.e. cytogenetics) 19% abnormal at diagnosis (20% of abnormal karyotype were unfavorable)

    Most frequent were +9, 20q-, -Y and +8

    Prognostically relevant for overall, leukemia-free and myelofibrosis-free survival

    2. Driver mutational status JAK2 99%

    3. Presence or absence of other mutations Prevalence of mutations/variants other than JAK2/CALR/MPL = 53% Most frequent were ASXL1 andTET2 30%, 20% and 3% harbored 1, 2 or 3 such mutations 3 genes were identified as being affected by adverse mutations/variants

    ASXL1, SRSF2, IDH2

    ASH 2016

    Blood 2014 124:2507

    Blood Advances 2016;1:21

  • PV

    Blood Advances 2016;1:21

    Prognostic relevance of PV mutations/variants other than JAK2/CALR/MPL

    Prevalence = 53% Most frequent were ASXL1 andTET2 30%, 20% and 3% harbored 1, 2 or 3 such mutations 3 genes were identified as being affected by adverse mutations/variants

    ASXL1, SRSF2, IDH2

  • Primary myelofibrosis

    1. Karyotype (i.e. cytogenetics) 43% abnormal at diagnosis (unfavorable 15%)

    Most frequent were 20q-, 13q-, +8. +9 and 1q+

    Prognostically very relevant

    2. Driver mutational status JAK2 60%

    CALR 24%

    MPL 6%

    Triple negative 10%

    3. Presence or absence of other mutations Prevalence of mutations/variants other than JAK2/CALR/MPL = 81% Driver mutational status did not affect prevalence Most frequent were ASXL1 36%, TET2 18%, SRSF2 18%, U2AF1 16% 35%, 26%, 10% and 9% harbored 1, 2, 3 or 4 such mutations 7 genes were identified as being affected by adverse mutations/variants

    ASXL1, SRSF2, CBL, KIT, RUNX1, SH2B3 and CEBPA (56% affected)

    Br J Haematol. 2015;169:71

    Blood. 2011;118:4595

    Blood 2014 124:2507

    Blood Advances 2016;1:105

  • 0

    .2

    .4

    .6

    .8

    1

    0 5 10 15 20 25 30

    Survival data in 903 patients with primary myelofibrosis stratified by karyotype

    Years

    Survival

    High risk Monosomal

    Inv(3)/i(17q)

    -7/7q-

    11q-

    12p-

    N=67

    Int-2 risk Non-monosomal complex

    Two or more non-high risk abnormalities

    Sole +8 or other autosomal trisomies

    Sole 5q-

    Other sole abnormalities not included in low or int-1 risk categories

    N=65

    Low risk Normal

    Sole 13q-

    Sole +9

    Sole loss of Y chromosome

    N=548

    Int-1 risk Sole 20q-

    Sole 1q duplications

    Sole translocation

    Sole extra sex chromosome

    N=124

    4.355 3.311 5.727

    1.932 1.578 2.366

    1.297 1.031 1.630

    Exp(Coef) 95% Low er 95% Upper

    BLOOD Cyto risk categories: High

    BLOOD Cyto risk categories: Intermediat...

    BLOOD Cyto risk categories: Intermediat...

    Confidence Intervals for DX-last f/u new

    Censor Variable: Censor survival two

    Model: Proportional Hazards

    3.348 2.406 4.659

    1.503 1.149 1.968

    Exp(Coef) 95% Low er 95% Upper

    BLOOD Cyto risk categories: High

    BLOOD Cyto risk categories: Intermediat...

    Confidence Intervals for DX-last f/u new

    Censor Variable: Censor survival two

    Model: Proportional Hazards

    Row exclusion: 2015 PMF master database.svd

    vs. low risk

    vs. intermediate-1 risk

    vs. intermediate-2 risk

    2.146 1.581 2.914

    Exp(Coef) 95% Low er 95% Upper

    BLOOD Cyto risk categories: High

    Tefferi et al. ASH 2014

  • 0

    .2

    .4

    .6

    .8

    1

    0 5 10 15 20 25 30

    Survival in 722 Mayo Clinic patients with primary myelofibrosis

    stratified by driver mutational status S

    urv

    ival

    Years

    CALR type 1/type 1-like

    N=115

    Median 10.3 years

    JAK2-mutated

    N=477

    Median 3.8 years

    Triple-negative

    N=65

    Median 3.1 years

    MPL-mutated

    N=41

    Median 6 years

    P

  • 0

    .2

    .4

    .6

    .8

    1

    0 2.5 5 7.5 10 12.5 15 17.5 20 22.5

    Su

    rviv

    al

    Years

    P

  • Treatment in essential thrombocythemia and polycythemia vera

  • Practice-relevant revision of IPSET-thrombosis based on 1019 patients

    with WHO-defined essential thrombocythemia

    Barbui et al. Blood Cancer Journal (2015) 5, e369; doi:10.1038/bcj.2015.94

  • Contemporary treatment algorithm in essential thrombocythemia (ET) and

    polycythemia vera (PV)

    (all patients with polycythemia vera require phlebotomy to a hematocrit target of 60 years with JAK2 mutation

    Arterial

    thrombosis

    history

    at any age

    Venous

    thrombosis

    history

    at any age

    Hydroxyurea

    +

    once-daily

    aspirin

    age >60 years or

    JAK2-mutated or

    CV risk factors With

    CV risk factors

    Modified from Tefferi and Barbui AJH 2017

    Consider

    twice-daily

    aspirin

    JAK2-mutated or

    CV risk factors

    Without

    CV risk factors

    Once-daily

    aspirin

    With

    CV risk factors

    Intermediate-risk

    disease

    Age >60 years

    No history of thrombosis

    JAK2 unmutated

    Cytoreductive therapy

    might not be essential

    Avoid aspirin in the presence

    of extreme thrombocytosis

    and acquired von Willebrand

    syndrome

  • Additional management issues in PV and ET

    1. What if you cant use hydroxyurea i. Interferon alpha (Qunitas-Cardama et al. Blood 2013; CHR 76% in PV, 77% in ET; CMR 18% in PV and 17% in ET)

    i. Busulfan (Alvarez-Larran et al. Ann Hematol 2014; CHR in HU-refractory PV or ET was 83%; Kuriakose et al. Haematologica 2013; CMR in 2 (33%) of 6 PV

    patients)

    i. Anagrelide (Not recommended because of its association with disease progression into myelofibrosis and

    increased thrombosis risk in ET phase-3 study; Harrison et al, NEJM 2005)

    i. Ruxolitinib (Vannucchi et al. NEJM 2015; randomized study in HU-refractory PV with ruxo vs standard therapy;

    59% of patients on standard therapy received HU??? 21% of ruxo treated patients achieved both

    hematocrit control and 35% reduction in spleen volume; 60% hematocrit control; 49% symptoms control;

    CHR 24%; No CMR reported)

    2. What about treatment during pregnancy? i. Low-riskASA only

    ii. High-riskIFN alpha

    3. What about treatment of pruritus?....paroxetine, IFN-alpha, UVB, ruxolitinib

  • Treatment in myelofibrosis

  • Survival data of 793 patients with primary myelofibrosis evaluated at time of their first Mayo

    Clinic referral and stratified by their Dynamic International Prognostic Scoring System

    (DIPSS-plus) that employs eight variables: Age >65 yrs; Hgb

  • Myelofibrosis

    Rx

    Algorithm

    Tefferi A. AJH 2014

    Type 1 Type 1 Type 1

    Type 1

  • Leukemia 2014

  • COMFORT-2 Ruxolitinib vs best available therapy (BAT) long-term follow-up Median f/u 4.3 years

    27% ruxo-randomized patients completed 5-year treatment

    Harrison et al. Leukemia (2016) 30, 1701

    P=0.06

    AML

    5.5% with ruxo and 6.8% with BAT

    Skin cancer

    17% with ruxo and 3% with BAT

  • 0

    .2

    .4

    .6

    .8

    1

    0 20 40 60 80 100 120 140

    Months

    Surv

    ival P=0.43

    Ruxolitinib-treated, n=51

    No ruxolitinib, n=410

    Figure 1a

    Tefferi et al. NEJM 2011:365;15

  • 0

    .2

    .4

    .6

    .8

    1

    0 2 4 6 8 10 12 14 16 18

    Survival in 542 Mayo Clinic patients with high or intermediate-2 risk myelofibrosis

    stratified by treatment with momelotinib

    Su

    rviv

    al

    Years

    Momelotinib-naive

    N=442

    Median 3.8 years

    P=0.99

    Figure 1

    Momelotinib treated

    N=100

    Median 3.2 years

    Tefferi et al. ASH 2015

  • Pardanani et al. Leukemia (2015) 29, 741744

  • Diagnostic Algorithm for Primary Eosinophilia

    1st step

    2nd step

    3rd step

    Peripheral blood screening

    for FIP1L1-PDGFRA

    using FISH or RT-PCR

    Bone marrow biopsy

    with cytogenetics

    Peripheral blood lymphocyte

    phenotyping and TCR

    gene rearrangement studies

    Mutation

    present

    FIP1L1-PDGFRA

    associated

    clonal eosinophilia

    PDGFRB

    rearranged

    clonal eosinophilia

    8p11 translocation

    present

    FGFR1

    rearranged

    clonal eosinophilia

    CEL-NOS

    Abnormal or clonal

    lymphocytes present

    lymphocytic

    variant hypereosinophilia

    All the above negative

    Idiopathic eosinophilia

    including HES Tefferi et al. Mayo Clin Proc 85:158, 2010

  • Males (%) 54 (55%) Age (years), median (range) 53 (1983) AEC (x109/l), median (range) 3 (159) AEC 3 109/l (%) 52 (53%) AEC 5 109/l (%) 35 (36%) No. (%) of organs involved (including skin) None 15 (16%) One 58 (59%) Two 20 (20%) Three or more 5 (5%) No. (%) of organs involved (excluding skin) None 45 (46%) One 40 (41%) Two 10 (10%) Three or more 3 (3%) Cardiac involvement (%) 8 (8%)

    Palpable hepatosplenomegaly (%) 4 (4%)

    Pulmonary involvement (%) 27 (28%)

    Gastrointestinal involvement (%) 16 (16%)

    Hemoglobin (g/dl), median (range) 13.3 (7.916.3)

    Hemoglobin UNL (%) 4 (7%) (n=58) LDH >UNL (%) 22 (36%) (n=61) Tryptase >UNL (%) 14 (24%) (n=59) IL-5 >UNL (%) 15 (31%) (n=49)

    98 Mayo Clinic patients with WHO-defined HES/IH (Pardanani et al. Leukemia 2016;30:1924)

    NGS revealed 11% harbored pathogenic mutation;

    TET2=3, ASXL1 =2, KIT=2, and IDH2, JAK2, SF3B1 and TP53=1 each.

    15% harbored a variant of unknown significance;

    TET2=8, ASXL1=2, SETBP1=2, and CALR, CEBPA and CSF3R=1 each.

    NO DIFFERENCE IN MUTATED VS NON-MUTATED IN PHENOTYPE

    MUTATED PATIENTS HAD INFERIOR SURVIVAL IN UNIVARIATE ANALYSIS

    Risk factors for survival:

    Advanced age (2 points)

    Hgb

  • Approach to HES or HES-like clonal eosinophilia

    Peripheral blood mutation screen for PDGFRA and PDGFRB mutations

    Positive

    Imatinib 100 mg/day

    Negative

    CEL or other

    myeloid

    malignancy

    HES

    Asymptomatic may not need therapy

    If treatment necessary

    Prednisone for acute therapy

    Chronic therapy

    Low-dose prednisone

    Hydroxyurea

    Interferon alpha

    Imatinib

    Mepolizumab

    Alemtuzumab

    PDGFRA-rearranged MPN

    PDGFRB-rearranged MPN

    T clone

    present

    CSA

    MTX

    Cytoxan

  • When should you suspect mastocytosis?

    Urticaria pigmentosa-like lesions

    Mast cell mediator symptoms

    Anaphylactoid symptoms/dizziness/headache

    Diarrhea

    Flushing/urticaria

    Osteopenia/unexplained fractures

  • Practical classification of mast cell disease

    Cutaneous mastocytosis

    (skin-only disease)

    Systemic mastocytosis (SM)

    Aggressive SM (cytopenia, bone disease, organomegaly, etc.)

    1. SM without associated 2nd myeloid neoplasm

    2. SM with associated 2nd myeloid neoplasm

    3. Mast cell leukemia

    Indolent SM

    Hartmann. & Henz, Br J Derm 2001;144:682

    Travis et al. Medicine 1988;67:345

    Valent et al. Leukemia Research 2001;25:603

    Both can manifest

    mast cell mediator

    release symptoms

    1

    2

    i

    ii

  • Years from Dx

    Surv

    ival

    0 10 20 30

    020

    40

    60

    80

    100

    Expected US Survival compared to WHO classification

    01Oct08

    ISM, (n=159)

    ASM, (n=41)

    AHD, (n=138)

    MCL, (n=4)

    Expected US Survival

    Survival for 342 systemic mastocytosis patients classified by disease type

    compared with the expected age and gender matched US Populations survival

    Lim et al. Blood 2009;113:5727.

  • Mutation-augmented prognostic scoring system (MAPSS) in 94 patients

    with advanced mastocytosis

    Pardanani et al. AJH 2016;91:888

    Pardanani et al. BJH 2016;175:531

    Risk factors:

    Platelet count

  • Treatment for

    Systemic Mastocytosis

    Indolent Associated with

    MDS or CMML Aggressive

    Mast cell

    leukemia

    Treat as MDS

    or CMML

    Cladribine

    or

    AML-like therapy

    or

    Experimental

    therapy

    followed by

    Transplant?

    Cladribine

    or

    IFN-

    or

    Experimental

    therapy

    If this fails, OK

    to try IFN- or

    cladribine

    H1 and H2 blockers

    Cromolyn

    Phototherapy

    Topical steroids

    J Clin Oncol. 2014 ;32:3264

  • Gotlib J et al. N Engl J Med 2016;374:2530

    Response and progression-free survival in 116 patients with advanced mastocytosis treated with oral midostaurin (PKC-412) 100 mg twice-daily

  • Allogeneic hematopoietic stem-cell transplantation (alloHCT or HCT) outcomes in 57 patients with advanced systemic mastocytosis (SM): 38 SM-AHNMD; 12 MCL and 7 aggressive SM.

    Celalettin Ustun et al. JCO 2014;32:3264