Myeloid Malignancies Myeloproliferative Neoplasms (MPN) DNA Symposiu… · MDS MDS/MPN MPN Tefferi 2012 Myeloproliferative Neoplasms (MPN) 1. ... Leukocytosis Thrombocytosis Abnormal

CIRN_23506_5_Myelodysplastic Syndrome_DT10 7/18/2005 2:18 PM

Disclosures for Ayalew Tefferi

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

Hydroxyurea, Interferon-alpha, Busulfan, Ruxolitinib, Cladribine, ESAs, Prednisone, Danazol, Androgens, Thalidomide, Lenalidomide, Imatinib, Alemtuzumab

PI/co-PICelgene, Novartis, BMS, YM Biosciences, Sanofi-Aventis, Incyte, PharmaMar

Research support None

Employee/Consultant None

Major Stockholder None

Speakers’ Bureau None

Scientific Advisory Board None

Myeloproliferative Neoplasms 2012-2013: Science and Practice

Ayalew TefferiMayo Clinic, Rochester, MN

Myeloid Malignancies

Chronic myeloidmalignancies

Acute myeloid

leukemia

Acquired mutation *

CytopeniaGranulocytosisErythrocytosis

ThrombocytosisMonocytosisEosinophiliaMastocytosis

≥20% BM or PBblasts

Or

t(15;17)t(8;21)Inv(16)

Or

Myeloid sarcoma

Redcells

Platelets Mono-cytes

Neutro-phils

Eosino-phils

Baso-phils

Pluripotentstem cellCFUGEMM

BFUE

CFU-G

CFUEOCFUE

CFUGMCFUMegr

CFU-M

MDS MPNMDS/MPN

Tefferi 2012

Myeloproliferative Neoplasms (MPN)

1. Chronic myelogenous leukemia

2. Polycythemia vera

3. Essential thrombocythemia

4. Primary myelofibrosis

5. Mastocytosis

6. Primary eosinophilia

7. Chronic neutrophilic leukemia

8. MPN-U

Myeloproliferative Neoplasms (MPN)

1. Chronic myelogenous leukemia

2. Polycythemia vera

3. Essential thrombocythemia

4. Primary myelofibrosis

5. Mastocytosis

6. Primary eosinophilia

7. Chronic neutrophilic leukemia

8. MPN-U

BCR-ABL1-negative MPN

*

*

CMML*

Objectives

1. Pathogenetic mechanisms

2. Contemporary diagnosis

3. Prognostication

4. Management


Tefferi A. Leukemia 24:1128-38, 2010

BCR-ABL1negative

MPN

** * ** *

**

*JAK2(+)

AML

JAK2(-)AML

Blast phaseCML

Disease-initiatingmutations

BCR-ABL1

?

Polyclonal stem cellsharboring

disease-susceptibilityalleles such as

JAK2 46/1 haplotype

JAK2, MPL, TET2, ASXL1, CBL, IDH1/2, IKZF4, LNK, EZH2, DNMT3A, SF3B1, TP53

?

?

?

Disease-transformingmutations

?

Phenotype-modifyingmutations

PVET

PMF

**

****

**

**

** *

**

*

CML

?

JAK2, MPL, TET2, ASXL1, CBL, IDH1/2, IKZF4, LNK, EZH2, DNMT3A, SF3B1, SRSF2, TP53The two pathogenetic faces of myelofibrosis

Bone marrowstromal reaction

Ineffective hematopoiesis (anemia)Extramedullary hematopoiesis (splenomegaly)

Hypercatabolic symptoms, pruritus and cachexia

AMLSurvival

LeukocytosisThrombocytosisAbnormal

cytokine milieu

Secondaryinflammatory

state

Mutation-drivenclonal

myeloproliferation

Tefferi et al. JCO 2011Tefferi NEJM 2012

IL-1b

IL-1RA

IL-2R

IL-6

IL-8

IL-10

IL-12

IL-13

IL-15

TNF-α

G-CSF

INF-α

INF-γ

MIP-1a

MIP-1b

HGF

IP-10

MIG

MCP-1

VEGF

Diagnosis

PV 97% V617F and 3% JAK2 exon 12 mutationsET 60% V617F and 4% MPL515 mutationsPMF 60% V617F and 8% MPL 515 mutations

NOT FOUND IN SECONDARY POLYCYTHEMIANOT FOUND IN REACTIVE THROMBOCYTOSISNOT FOUND IN LYMPHOMA OR METASTATIC CANCER

JAK2 mutations

Levine et al. Nat Rev Cancer. 2007;7:673

RasPI3K

P PPStatStat RafAKT

Activation of genes importantin proliferation and survival

PPPStatStat Erk

Src

C

StatStat

A BLigand Binding

JAK2V617For JAK2 Exon 12

MPLW515L/K

JAK2JAK2PP

StatStat

JAK2JAK2PP

StatStat

JAK2JAK2PP

P

PMekFoxOmTOR

ErkX

?

X

SOCS1 SOCS3

BloodJAK2V617F and

Epo screen

(+) V617F

Polycythemia vera

BloodJAK2V617F

screen

Diagnostic algorithm

PV

Not PV

Screen forJAK2 exon 12

mutation

(-) V617F

Eposubnormal

Eponormal orelevated

(+) V617F

BM biopsy

(-) V617F

MPNpresent

MPNpossible

Essential thrombocythemia

Myelofibrosis V617F, +9 or 13q- = PMF

Tefferi AJH 2012

CML

PrefibroticPMF

MDS(e.g. RARS-T)

ET

VS.VS.

VS.


ET and pre-fibrotic MF vs Europe*Age- and sex-adjusted actuarial survival curves

0

0,1

0,2

0,3

0,4

0,5

0,6

0,7

0,8

0,9

1

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

Years

Su

rviv

al

Europe

ET

Pre-fibrotic MF

Survival and risk of leukemic transformation in ET are significantly influenced by accurate morphologic diagnosis:

An international study of 1,104 patients. Barbui et al. JCO 2011;29:3179

10-year AML risk <1%10-year MF risk <1%

10-year AML risk 6%10-year MF risk 12%

Prognosis

IPSET model for ET

Passamonti et al. Blood 2012

Age <60No leukocytosisNo thrombosis

Age ≥60

or

Age <60 withleukocytosisor thrombosis

Age ≥60

and

leukocytosisor thrombosis

Risk‐stratifiedsurvivalin1,545patientswithWHO‐definedpolycythemiaveraBasedon3riskfactors:age;venousthrombosis;leukocytosis

Su

rviv

al

N=568; Median survival 10.9 yearsHR 10.7; 95% CI 7.7-15.0

N=474; Median survival 18.9 years HR 3.7; 95% CI 2.6-5.2

N=503; Median survival 27.8 years

Age <57 without leukocytosis or venous thrombosis

Age 57-66 or one or both of: 1. Leukocytosis2. Venous thrombosis

Age ≥67 orAge 57-66 with one or both of: 1. Leukocytosis2. Venous thrombosis

Tefferi et al. ASH 2011

Survival and prognosis in primary myelofibrosis: A Mayo Clinic study of 884 patients

Based on 8 risk factors: Karyotype, Transfusion-dependency, Hgb <10, Plt <100, WBC >25, Circulating blasts 1%, constitutional symptoms, Age >65

DIPSS-plus intermediate-1 risk; n=128median survival ~ 94 months; 2-year mortality 11%

DIPSS-plus low risk; n=84median survival ~ 200 months; 2-year mortality 3%

DIPSS-plus high risk; n=298median survival ~ 23 months; 2-year mortality 53%


Sur

viva

l

Months

1

.8

.6

.4

.2

0

0 50 100 150 200 250 300 350 400

P<0.0001

Tefferi et al. Blood 2012

Very high risk category;* n=52median survival ~ 9 months; 2-year mortality 82%

Inv(3)/i(17q)Monosomal karyotypeTwo of the following: WBC>40k, circulating blasts >9%, unfavorable karyotype

Survival and prognosis in primary myelofibrosis: A Mayo Clinic study of 884 patients

Based on 8 risk factors: Karyotype, Transfusion-dependency, Hgb <10, Plt <100, WBC >25, Circulating blasts 1%, constitutional symptoms, Age >65


DIPSS-plus low risk; n=84median survival ~ 200 months; 2-year mortality 3%

DIPSS-plus high risk; n=298median survival ~ 23 months; 2-year mortality 53%


Sur

viva

l

Months

1

.8

.6

.4

.2

0

0 50 100 150 200 250 300 350 400

P<0.0001

Tefferi et al. Blood 2012

Very high risk category;* n=52median survival ~ 9 months; 2-year mortality 82%

Inv(3)/i(17q)Monosomal karyotypeTwo of the following: WBC>40k, circulating blasts >9%, unfavorable karyotype

ASXL1SRSF2EZH2IDH


ManagementIssues of relevance in

myeloproliferative neoplasms1. Shortened survival

2. Poor quality of life

Thrombosis

CachexiaConstitutional symptoms

Pruritus

Anemia

Splenomegaly

Leukemictransformation

Fibrotictransformation

*New data suggests a lower risk of thrombosis associated with extreme thrombocytosis, which however is associated with a bleeding diathesis in the presence of AvWS and aspirin therapyBarbui et al. JCO 2011;29:3179

My current treatment algorithm in ET and PV

Low-riskwithoutextreme

thrombocytosis

Low-riskwith

extremethrombocytosis

High-riskhydroxyurea

sensitive

ASA

VWF-RCo >30%

VWF-RCo <30%

Observation

Hydroxyurea (Plt <400k)+

ASA

Phlebotomy if PV+


Additional management issues in PV and ET

1. What about interferon alpha or JAK inhibitors as first-line therapy?

i. Both have been shown to induce remissions

ii. Interferon reduces JAK2V617F allele burden in a subset of patients

iii. The question is, will they be as safe and as effective as hydroxyurea/ASA

2. What about treatment during pregnancy?i. Low-risk…ASA only

ii. High-risk…IFN alpha

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

4. What if you can’t use hydroxyurea (i.e. second-line therapy)i. Interferon alpha

ii. Busulfan

iii. JAK inhibitors?

My current treatment algorithm in ET and PV

Low-riskwithoutextreme

thrombocytosis

Low-riskwith

extremethrombocytosis


sensitive


refractory

ASA

VWF-RCo >30%

VWF-RCo <30%

Observation

Hydroxyurea (Plt <400k)+

ASA

Busulfan

Age >65

Age <65

IFN-α

+Phlebotomy

if PV

Observation

Transplant

Conventional drugsSplenectomy

Radiotherapy Experimental drugs

Treatment optionsin myelofibrosis

Tefferi. Blood 2011 117:3494

DIPSS-plus prognostic category

Myelofibrosis treatment algorithm

High risk or Int-2 risk Low risk or Int-1 riskVery

high risk

< 45 yr. > 65 yr.

Symptomatic

45-65 yr.

Asymptomatic

Investigational drug therapy

or Refractory

Observation

CICallo-SCT

conventional drug therapyRIC

allo-SCT

Management of Myelofibrosis

Experimental drug therapy

1. Pomalidomide2. JAK inhibitors3. Others

a. mTOR inhibitorsb. Hypomethylating agentsc. HIDAC inhibitorsd. HSP90 inhibitorse. Telomerase inhibitorsf. Etc.

Conventional therapy

－Treatment for anemia

• Erythropoietin• Corticosteroids• Androgen + Prednisone• Danazol• Thalidomide + Prednisone• Lenalidomide

－Treatment for splenomegaly

• Hydroxyurea• Splenectomy

－Treatment for extramedullary hematopoiesis

• Low-dose irradiation－Supportive care

Anemia 25%Splenomegaly 0%

Works best in the presence of 5q-

Tefferi et al. Blood 2006; 108: 1158

Anemia-22%Splenomegaly-33%

Elliott et al. BJH 2002; 117: 288

Anemia-20%Splenomegaly-8%

Lenalidomide

Pomalidomide

Tefferi et al. J Clin Oncol 2009; 27: 4563

2 mg/dayor

0.5 mg/day plus prednisone

0.5 mg/day

Less neuropathyNo myelosuppression

MyelosuppressionNeuropathy

NH2O

N

O O HN

O

NH2

N

O O HN

O

O

N

O O HN

O

Thalidomide


Pomalidomide 0.5 mg/dayMayo Clinic study of 58 patients with myelofibrosis and anemia

Begna et al. Leukemia. 2011;25:301

Additional observations:1. Well tolerated with little or no myelosuppression, neuropathy or thrombosis2. Early basophilia predicted anemia response3. 58% platelet response in patients with < 100k platelets4. No spleen responses5. Increasing dose to 2 mg/day did not increase anemia response

JAK2V617F

Positive Negative

42 patientsAnemia response = 24%

16 patientsAnemia response = 0%

Response38%

Response11%

Spleen>10 cms

Spleen<10 cms

JAK inhibitors

JAK2IC50(nM)

JAK1IC50(nM)

JAK3IC50(nM)

TYK2IC50(nM)

Other targets

Currentstage

SympResp

Spleen Resp

AnemResp

Side effects

Ruxolitinib 2.8 3.3 428 19 None reported

FDAapproved

>50% 29%(MRI)

14% Anemia Thrombocytopenia

“ruxolitinib withdrawal syndrome”*

SAR302503 3 105 1040 405 FLT3,RET

Phase-3 >50% 39% 0% Nausea/DiarrheaAnemia

ThrombocytopeniaTransaminasemia

Hyper-lipase/amylasemia

Lestaurtinib <1 – 3 – FLT3, TRKAVEGFR2,

RET

Phase-2 NR >18% 25%† Nausea/DiarrheaAnemia

Thrombocytopenia

CYT387 18 11 155 17 PKD3, PKCμCDK2, ROCK2

JNK1, TBK1

Phase-2 >50% 45% 50% ThrombocytopeniaHeadaches

1st dose effect**Peripheral neuropathy

TransaminasemiaHyper-lipase/amylasemia

SB1518 23 1280 520 50 FLT3 Phase-2 >50% 32%(MRI)

†† Nausea/Diarrhea

LY2784544 – – – – – Phase-1/2 NR >22% NR Nausea/DiarrheaAnemia

Electrolyte abnormalities/TLS?Increases in serum creatinine

XL019 2 134 195 344 – Halted >50% 33% NR Peripheral neuropathy

AZD1480 <0.5 1.3 3.9 – Aurora-A, TRKAFGFR1, FLT4

Phase-1/2

BMS911543 1.1 356 73 66 None reported Phase-1/2

NS-018 <1 33 39 22 SRC, FYNABL, FLT3

Phase-1/2

Tefferi. NEJM 2012

Long-term outcome of treatment with ruxolitinibComparison of survival between 51 patients with myelofibrosis treated with ruxolitinib versus other 410 patients

with primary myelofibrosis seen at the Mayo Clinic in the last 10 years (adjusted for DIPSS-plus)S

urvi

val

Months

1

.8

.6

.4

.2

0

1000 20 40 60 80 120

P=0.58

Tefferi et al. NEJM 2011; 365:1455

Intermediate-2 riskNo ruxolitinib

140

High riskRuxolitinib-treated

High riskNo ruxolitinib

Intermediate-2 riskRuxolitinib-treated

Intermediate-1 riskNo ruxolitinib

Low riskNo ruxolitinib

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 lymphocytephenotyping and TCR

gene rearrangement studies

Mutation present

FIP1L1-PDGFRAassociated

clonal eosinophiliaTreat with imatinib

PDGFRBrearranged

clonal eosinophiliaTreat with imatinib

8p11 translocation present

FGFR1rearranged

clonal eosinophiliaHyper-CVAD & transplant

CEL-NOSTransplant or investigational

Abnormal or clonal lymphocytes present

“lymphocytic”variant hypereosinophilia

Try CSA/MTX/CTX

All the above negative

Idiopathic eosinophiliaincluding HESTefferi et al. Mayo Clin Proc 85:158, 2010

Treatment algorithm in “HES”

Any symptoms?

Prednisone for acute therapy

Chronic therapy

Low-dose prednisoneHydroxyurea

Interferon alphaImatinib

MepolizumabAlemtuzumab

YesNo

Monitor serum troponin every 3 monthsEcho once a year


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 neoplasm2. SM with associated 2nd myeloid neoplasm3. 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 manifestmast cell mediatorrelease symptoms

1

2i

ii

Years from Dx

Sur

viva

l

0 10 20 30

020

4060

8010

0

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 Population’s survival

Lim et al. Blood 2009;113:5727.

Treatment forSystemic Mastocytosis

Indolent Associated with MDS or CMML

AggressiveMast cellleukemia

Treat as MDSor CMML

Cladribine or

AML-like therapyor

Experimentaltherapy

followed by

Transplant?

Cladribineor

IFN-αor

Experimentaltherapy

If this fails, OKto try IFN-α or

cladribine

H1 and H2 blockersCromolyn

PhototherapyTopical steroids

CMMLParikh and Tefferi, Am J Hematol 2012 Jun;87(6):610-9

Diagnosis

1. Monocytosis of >1 × 10(9)/ L2. No BCR-ABL13. No PDGFR mutation4. <20% blasts or promonocytes5. Dysplasia or abnormal karyotype present

Prognosis (Mayo model ASH 2012)

1. Absolute monocyte count >10 x 10(9)/L2. Presence of circulating immature myeloid cells3. Hemoglobin < 10 g/dL 4. Platelet count < 100 × 10(9)/L

Low-risk 32 months, intermediate-risk 19 months and high-risk 10 months

Treatment

1. Observation (preferred)2. Transplant; 5-year OS 20-40%3. Investigational drug therapy4. Decitabine; OR ~30%5. Hydroxyurea

Mutations

1. ASXL1 (30-50%)2. SRSF2 (30-50%)3. TET2 (20-40%)4. RAS (20-40%)5. RUNX1 (20-30%)6. CBL (10-20%)7. JAK2, EZH2, IDH, etc. (~10%)

Documents

Myeloid Malignancies Myeloproliferative Neoplasms (MPN) DNA Symposiu… · MDS MDS/MPN MPN Tefferi 2012 Myeloproliferative Neoplasms (MPN) 1. ... Leukocytosis Thrombocytosis Abnormal