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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
45

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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Page 1: 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, …

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

Page 2: 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, …

Myeloproliferative Neoplasms

2017

Ayalew Tefferi, MD

Mayo Clinic, Rochester, MN

Page 3: 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, …

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

Page 4: 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, …

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

Page 5: 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, …

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

Page 6: 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, …

Diagnostic approach in routine clinical practice

Page 7: 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, …

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

Page 8: 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, …

Survival and prognosis

Page 9: 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, …

Comparison of survival in 826 Mayo Clinic patients with

essential thrombocythemia vs polycythemia vera vs primary myelofibrosis.

Tefferi et al. Blood 2014

Page 10: 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, …

Tefferi et al. Blood 2015

Comparison of survival in 389 young patients with

essential thrombocythemia vs polycythemia vera vs primary myelofibrosis.

Page 11: 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, …

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

Page 12: 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, …

Overall survival in 495 patients with essential thrombocythemia

stratified by driver mutational status

Am J Hematol. 2016;91:503

Page 13: 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, …

Myelofibrosis-free survival in 495 patients with essential thrombocythemia

stratified by driver mutational status

Am J Hematol. 2016;91:503

Page 14: 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, …

Thrombosis-free survival in 495 patients with essential thrombocythemia

stratified by driver mutational status

Am J Hematol. 2016;91:503

Page 15: 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, …

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

Page 16: 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, …

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

Page 17: 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, …

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

Page 18: 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, …

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

Page 19: 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, …

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

Page 20: 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, …

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<0.0001

CALR type 2/type 2-like

N=24

Median 3.5 years

Tefferi et al. ASH 2015

Page 21: 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, …

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<0.0001

No sequence variants/mutations

N=35

Median survival not reached

“Non-adverse” variants/mutations

N=45

Median survival = 6.8 years

HR 2.5 (95% CI 1.1-5.4)

Adverse variants/mutations

N=102

Median survival = 3.6 years

HR 5.1 (95% CI 2.6-10.2)

Survival in 182 patients with primary myelofibrosis stratified by

the presence or absence of adverse or non-adverse sequence variants/mutation

Adverse sequence variants/mutations: “7” genes were identified as being involved with adverse mutations/variants ASXL1, SRSF2, CBL, KIT, RUNX1, SH2B3 and CEBPA (56% affected)

Blood Advances 2016;1:105

Page 22: 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, …

Treatment in essential thrombocythemia and polycythemia vera

Page 23: 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, …

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

Page 24: 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, …

Contemporary treatment algorithm in essential thrombocythemia (ET) and

polycythemia vera (PV)

(all patients with polycythemia vera require phlebotomy to a hematocrit target of <45%)

Very low-risk

disease

•No history of thrombosis

•Age ≤60 years

•JAK2-unmutated

Hydroxyurea

+

systemic

anticoagulation

Hydroxyurea

+

once-daily

aspirin

Consider

once-daily

aspirin

Once-daily

aspirin

Consider

twice-daily

aspirin

Without

CV risk factors

Observation

alone

Low-risk

disease

•No history of thrombosis

•Age ≤60 years

•JAK2 mutated

With

CV risk factors

High-risk disease

•History of thrombosis

•or

•Age >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

Page 25: 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, …

Additional management issues in PV and ET

1. What if you can’t 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-risk…ASA only

ii. High-risk…IFN alpha

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

Page 26: 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, …

Treatment in myelofibrosis

Page 27: 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, …

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 <10 g/dL; RBC transfusion-dependent; platelets <100 x 10(9)/L; WBC > 25 x 10(9)/L; ≥1% circulating blasts; Constitutional symptoms; karyotype

prognostic scores (DIPSS-plus).

Gangat N et al. JCO 2011;29:392-397

©2011 by American Society of Clinical Oncology

Median

15.4 years

6.5 years

2.9 years

1.3 years

0 risk factors

1 risk factor

2 or 3 risk factors

4 or more risk factors

Page 28: 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, …

Myelofibrosis

Rx

Algorithm

Tefferi A. AJH 2014

Type 1 Type 1 Type 1

Type 1

Page 29: 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, …

Leukemia 2014

Page 30: 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, …

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

Page 31: 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, …

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

Page 32: 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, …

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

Page 33: 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, …

Pardanani et al. Leukemia (2015) 29, 741–744

Page 34: 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, …

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

Page 35: 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, …

Males (%) 54 (55%) Age (years), median (range) 53 (19–83) AEC (x109 /l), median (range) 3 (1–59) 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 (7.9–16.3)

Hemoglobin <LNL (%) 39 (40%) Hemoglobin <10 g/ dl (%) 11 (11%)

Leukocyte count × 109/ l, median (range) 9.4 (3.6–87)

Leukocyte count >15 × 109/ l (%) 18 (18%)

Platelet count × 109 /l, median (range) 276 (79–631)

Platelet count <150 × 109 /l (%) 4 (4%)

AST >UNL (%) 5 (6%) (n=87) Total bilirubin >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 <10 g/Dl (one point)

Cardiac involvement (one point)

Hepatosplenomegaly (3 points)

Low risk 0-1 points

High risk 2 or more points

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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

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When should you suspect mastocytosis?

• Urticaria pigmentosa-like lesions

• Mast cell mediator symptoms

– Anaphylactoid symptoms/dizziness/headache

– Diarrhea

– Flushing/urticaria

• Osteopenia/unexplained fractures

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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

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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 Population’s survival

Lim et al. Blood 2009;113:5727.

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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 <150;

albumin <3.5;

age >60;

ASXL1/CBL mutated;

Hgb <10

One risk factor other than

platelet count

Two or three

risk factors or low

platelet count

Four or more risk factors

ISM (n=44) KIT 73%

TET2 7%

No other mutations

ASM (n=25) KIT 84%

TET2 20%

ASXL1 16%

AHN (n=80) KIT 75%

TET2 45%

ASXL1 26%

CBL 19%

JAK2

DNMT3A

U2AF1

RUNX1

SF3B1

Others

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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-α

or

Experimental

therapy

If this fails, OK

to try IFN-α or

cladribine

H1 and H2 blockers

Cromolyn

Phototherapy

Topical steroids

J Clin Oncol. 2014 ;32:3264

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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

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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