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
Presentation includes discussion of the following off-label use of a drug or
medical device: Hydroxyurea, Interferon-alpha, Busulfan, Thalidomide,
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
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
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
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<0.0001
CALR type 2/type 2-like
N=24
Median 3.5 years
Tefferi et al. ASH 2015
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
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 <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
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
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 <10 g/dL; RBC transfusion-dependent; platelets <100 x 10(9)/L; WBC > 25 x 10(9)/L; ≥1% circulating blasts; Constitutional symptoms; karyotype
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
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 Population’s 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 <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
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
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.