Juliana Schwaab Hematology and Oncology

University Hospital Mannheim Heidelberg University

Germany

Molecular and clinical diversity in systemic

mastocytosis

MDS MDS

CML

aCML

MDS/MPN

PMF

ET

PV

PDGFRA

CEL-NOS

CNL

Systemic Mastocytosis

Blastic plasmacytoid dendritic cell

neoplasm

AML

PDGFRB

MPN-u FGFR1

MDS/ MPN-u

CMML

MPN

Myeloid neoplasms

MLN-eo

MPN-u FGFR1

MDS/MPN -RS-T

JMML

WHO classification 2016: myeloid neoplasms

FGFR1 PCM1-JAK2

B/T-lympho- blastic leukemia

BONE MARROW (BM) BIOPSY Aspirate, histology, immunohistochemistry,

cytogenetics, FACS analysis • Quantification of mast cell (MC) infiltration • Presence and quantification of KIT D816V 2

• Mast cell leukemia (MCL)? 3 • Associated hematologic neoplasm (AHN)? • Multilineage involvement? • CD34+ blasts?

Diagnosis of SM (according to WHO 2016): 1 major + 1 minor criterion

or > 3 minor criteria

Major criterion • Multifocal dense infiltrates of MCs,

≥15 MCs in aggregates in BM biopsies

Minor criteria (modified) • 25% of all MCs are atypical cells (type I or

type II) on BM smears or are spindle-shaped in MC infiltrates detected on sections of visceral organs

• KIT D816 mutation or other activating KIT mutation

• MCs exhibit CD25 (and/or CD2) • Baseline serum tryptase level >20 µg/L

Suspected systemic mastocytosis (SM)

CLINICAL FINDINGS • Symptoms: flushing, anaphylaxis, diarrhea,

fatigue, bone pain, pruritus, constitutional symptoms

• Skin lesions (urticaria pigmentosa) • Splenomegaly, hepatomegaly, ascites • Abdominal lymphadenopathy • Osteoporosis/osteolyses

LAB ABNORMALITIES

• Serum tryptase ↑ 1

• Cytopenia(s) • Monocytosis, eosinophilia • Albumin ↓ • Alkaline phosphatase ↑ • Vitamin B12 ↑

MOLECULAR ABERRATIONS • KIT D816 mutation in peripheral blood 2 • Additional myeloid mutations, e.g. SRSF2,

ASXL1, RUNX1, JAK2 V617F, EZH2, RAS.

BONE MARROW (BM) BIOPSY Aspirate, histology, immunohistochemistry,

cytogenetics, FACS analysis • Quantification of mast cell (MC) infiltration • Presence and quantification of KIT D816V 2

• Mast cell leukemia (MCL)? 3 • Associated hematologic neoplasm (AHN)? • Multilineage involvement? • CD34+ blasts?

Diagnosis of SM (according to WHO 2016): 1 major + 1 minor criterion

or > 3 minor criteria

Major criterion • Multifocal dense infiltrates of MCs,

≥15 MCs in aggregates in BM biopsies

Minor criteria (modified) • 25% of all MCs are atypical cells (type I or

type II) on BM smears or are spindle-shaped in MC infiltrates detected on sections of visceral organs

• KIT D816 mutation or other activating KIT mutation

• MCs exhibit CD25 (and/or CD2) • Baseline serum tryptase level >20 µg/L

Suspected systemic mastocytosis (SM)

CLINICAL FINDINGS • Symptoms: flushing, anaphylaxis, diarrhea,

fatigue, bone pain, pruritus, constitutional symptoms

• Skin lesions (urticaria pigmentosa) • Splenomegaly, hepatomegaly, ascites • Abdominal lymphadenopathy • Osteoporosis/osteolyses

LAB ABNORMALITIES

• Serum tryptase ↑ 1

• Cytopenia(s) • Monocytosis, eosinophilia • Albumin ↓ • Alkaline phosphatase ↑ • Vitamin B12 ↑

MOLECULAR ABERRATIONS • KIT D816 mutation in peripheral blood 2 • Additional myeloid mutations, e.g. SRSF2,

ASXL1, RUNX1, JAK2 V617F, EZH2, RAS.

BONE MARROW (BM) BIOPSY Aspirate, histology, immunohistochemistry,

cytogenetics, FACS analysis • Quantification of mast cell (MC) infiltration • Presence and quantification of KIT D816V 2

• Mast cell leukemia (MCL)? 3 • Associated hematologic neoplasm (AHN)? • Multilineage involvement? • CD34+ blasts?

Diagnosis of SM (according to WHO 2016): 1 major + 1 minor criterion

or > 3 minor criteria

Major criterion • Multifocal dense infiltrates of MCs,

≥15 MCs in aggregates in BM biopsies

Minor criteria (modified) • 25% of all MCs are atypical cells (type I or

type II) on BM smears or are spindle-shaped in MC infiltrates detected on sections of visceral organs

• KIT D816 mutation or other activating KIT mutation

• MCs exhibit CD25 (and/or CD2) • Baseline serum tryptase level >20 µg/L

Suspected systemic mastocytosis (SM)

B- or C-findings? B-findings

• BM MC infiltration >30% and serum tryptase >200µg/L

• Organomegaly • BM with proliferation or dysplasia

C-findings • Cytopenia(s): Neutrophils <1x109/μL,

Hb<10 g/dL and/or platelets <100x109/μL • Hepatomegaly with impaired liver function

and ascites • Palpable splenomegaly + associated

hypersplenism • Malabsorption with hypoalbuminemia and

significant weight loss • Skeletal lesions: large-sized osteolyses with

pathologic fractures • Life-threatening organ damage in other

organ systems that is caused by local MC infiltration

CLINICAL FINDINGS • Symptoms: flushing, anaphylaxis, diarrhea,

fatigue, bone pain, pruritus, constitutional symptoms

• Skin lesions (urticaria pigmentosa) • Splenomegaly, hepatomegaly, ascites • Abdominal lymphadenopathy • Osteoporosis/osteolyses

LAB ABNORMALITIES

• Serum tryptase ↑ 1

• Cytopenia(s) • Monocytosis, eosinophilia • Albumin ↓ • Alkaline phosphatase ↑ • Vitamin B12 ↑

MOLECULAR ABERRATIONS • KIT D816 mutation in peripheral blood 2 • Additional myeloid mutations, e.g. SRSF2,

ASXL1, RUNX1, JAK2 V617F, EZH2, RAS.

BONE MARROW (BM) BIOPSY Aspirate, histology, immunohistochemistry,

cytogenetics, FACS analysis • Quantification of mast cell (MC) infiltration • Presence and quantification of KIT D816V 2

• Mast cell leukemia (MCL)? 3 • Associated hematologic neoplasm (AHN)? • Multilineage involvement? • CD34+ blasts?

Diagnosis of SM (according to WHO 2016): 1 major + 1 minor criterion

or > 3 minor criteria

Major criterion • Multifocal dense infiltrates of MCs,

≥15 MCs in aggregates in BM biopsies

Minor criteria (modified) • 25% of all MCs are atypical cells (type I or

type II) on BM smears or are spindle-shaped in MC infiltrates detected on sections of visceral organs

• KIT D816 mutation or other activating KIT mutation

• MCs exhibit CD25 (and/or CD2) • Baseline serum tryptase level >20 µg/L

Suspected systemic mastocytosis (SM)

B- or C-findings? B-findings

• BM MC infiltration >30% and serum tryptase >200µg/L

• Organomegaly • BM with proliferation or dysplasia

C-findings • Cytopenia(s): Neutrophils <1x109/μL,

Hb<10 g/dL and/or platelets <100x109/μL • Hepatomegaly with impaired liver function

and ascites • Palpable splenomegaly + associated

hypersplenism • Malabsorption with hypoalbuminemia and

significant weight loss • Skeletal lesions: large-sized osteolyses with

pathologic fractures • Life-threatening organ damage in other

organ systems that is caused by local MC infiltration

CLINICAL FINDINGS • Symptoms: flushing, anaphylaxis, diarrhea,

fatigue, bone pain, pruritus, constitutional symptoms

• Skin lesions (urticaria pigmentosa) • Splenomegaly, hepatomegaly, ascites • Abdominal lymphadenopathy • Osteoporosis/osteolyses

LAB ABNORMALITIES

• Serum tryptase ↑ 1

• Cytopenia(s) • Monocytosis, eosinophilia • Albumin ↓ • Alkaline phosphatase ↑ • Vitamin B12 ↑

MOLECULAR ABERRATIONS • KIT D816 mutation in peripheral blood 2 • Additional myeloid mutations, e.g. SRSF2,

ASXL1, RUNX1, JAK2 V617F, EZH2, RAS

BONE MARROW (BM) BIOPSY Aspirate, histology, immunohistochemistry,

cytogenetics, FACS analysis • Quantification of mast cell (MC) infiltration • Presence and quantification of KIT D816V 2

• Mast cell leukemia (MCL)? 3 • Associated hematologic neoplasm (AHN)? • Multilineage involvement? • CD34+ blasts?

Diagnosis of SM (according to WHO 2016): 1 major + 1 minor criterion

or > 3 minor criteria

Major criterion • Multifocal dense infiltrates of MCs,

≥15 MCs in aggregates in BM biopsies

Minor criteria (modified) • 25% of all MCs are atypical cells (type I or

type II) on BM smears or are spindle-shaped in MC infiltrates detected on sections of visceral organs

• KIT D816 mutation or other activating KIT mutation

• MCs exhibit CD25 (and/or CD2) • Baseline serum tryptase level >20 µg/L

Suspected systemic mastocytosis (SM)

B- or C-findings? B-findings

• BM MC infiltration >30% and serum tryptase >200µg/L

• Organomegaly • BM with proliferation or dysplasia

C-findings • Cytopenia(s): Neutrophils <1x109/μL,

Hb<10 g/dL and/or platelets <100x109/μL • Hepatomegaly with impaired liver function

and ascites • Palpable splenomegaly + associated

hypersplenism • Malabsorption with hypoalbuminemia and

significant weight loss • Skeletal lesions: large-sized osteolyses with

pathologic fractures • Life-threatening organ damage in other

organ systems that is caused by local MC infiltration

ISM 0 or 1 B-finding,

No C-finding

SSM At least 2 of 3 B-

findings

MCL ASM C-findings

SM-AHN 4

1,2 An elevated serum tryptase (normal value <11.4µg/L) AND presence of a KIT D816 mutation (KIT D816V in >90% of cases) make diagnosis of SM very likely. 3 MCL is defined by >20% mast cells in BM cytology (not histology!). 4 In the majority of SM-AHN cases , the AHN is also KIT D816V positive and treatment is according to SM. In few cases, SM and AHN may represent two independent diseases and treatment of SM and AHN may differ.

KIT Mutation (Burden) in Patients with Systemic Mastocytosis

The majority (>90%) of patients with systemic mast cell disease express the imatinib resistant Asp816Val (D816V) mutation in the KIT receptor tyrosine kinase.

Erben et al., Ann Hematol. 2014; 93(1):81-8

Lim et al., Blood 2009; 113: 5727–36

ISM: indolent SM ASM: aggressive SM MCL: mast cell leukemia AHD: associated hematologic (non-mast cell lineage) disorder

Survival with SM

CLINICAL FINDINGS • Symptoms: flushing, anaphylaxis, diarrhea,

fatigue, bone pain, pruritus, constitutional symptoms

• Skin lesions (urticaria pigmentosa) • Splenomegaly, hepatomegaly, ascites • Abdominal lymphadenopathy • Osteoporosis/osteolyses

LAB ABNORMALITIES

• Serum tryptase ↑ 1

• Cytopenia(s) • Monocytosis, eosinophilia • Albumin ↓ • Alkaline phosphatase ↑ • Vitamin B12 ↑

MOLECULAR ABERRATIONS • KIT D816 mutation in peripheral blood 2 • Additional myeloid mutations, e.g. SRSF2, ASXL1, RUNX1, JAK2 V617F, EZH2, RAS

BONE MARROW (BM) BIOPSY Aspirate, histology, immunohistochemistry,

cytogenetics, FACS analysis • Quantification of mast cell (MC) infiltration • Presence and quantification of KIT D816V 2

• Mast cell leukemia (MCL)? 3 • Associated hematologic neoplasm (AHN)? • Multilineage involvement? • CD34+ blasts?

Diagnosis of SM (according to WHO 2016): 1 major + 1 minor criterion

or > 3 minor criteria

Major criterion • Multifocal dense infiltrates of MCs,

≥15 MCs in aggregates in BM biopsies

Minor criteria (modified) • 25% of all MCs are atypical cells (type I or

type II) on BM smears or are spindle-shaped in MC infiltrates detected on sections of visceral organs

• KIT D816 mutation or other activating KIT mutation

• MCs exhibit CD25 (and/or CD2) • Baseline serum tryptase level >20 µg/L

Suspected systemic mastocytosis (SM)

B- or C-findings? B-findings

• BM MC infiltration >30% and serum tryptase >200µg/L

• Organomegaly • BM with proliferation or dysplasia

C-findings • Cytopenia(s): Neutrophils <1x109/μL,

Hb<10 g/dL and/or platelets <100x109/μL • Hepatomegaly with impaired liver function

and ascites • Palpable splenomegaly + associated

hypersplenism • Malabsorption with hypoalbuminemia and

significant weight loss • Skeletal lesions: large-sized osteolyses with

pathologic fractures • Life-threatening organ damage in other

organ systems that is caused by local MC infiltration

ISM 0 or 1 B-finding,

No C-finding

SSM At least 2 of 3 B-

findings

MCL ASM C-findings

SM-AHN 4

• H1-/H2-antagonists • MC stabilizers • Leukotriene antagonists • Steroids (topic and/or systemic) • Interferon-alpha (inadequately

controlled symptoms, off-label)

• Midostaurin (SM-AHN, ASM, MCL) • Imatinib (for sensitive KIT mutations only, <1%) • Cladribine (off-label) • Interferon-alpha (off-label) • Hydroxyurea (for the AHN component)

• Allogeneic stem cell transplantation (in eligible patients in best achievable remission)

1,2 An elevated serum tryptase (normal value <11.4µg/L) AND presence of a KIT D816 mutation (KIT D816V in >90% of cases) make diagnosis of SM very likely. 3 MCL is defined by >20% mast cells in BM cytology (not histology!). 4 In the majority of SM-AHN cases , the AHN is also KIT D816V positive and treatment is according to SM. In few cases, SM and AHN may represent two independent diseases and treatment of SM and AHN may differ.

Midostaurin (PKC412, Rydapt®) in advSM

Improvement of:

• Symptoms

• Serum tryptase

• Bone marrow mast cell infiltration

• C-findings (organ dysfunction)

• BUT: no complete remission

Adverse events:

• Nausea

• Vomiting

Gotlib et al., NEJM 374, 2530-41, 2016

-100

-50

0

50

100

No (n=57)

Yes (n=32)

Decrease ≥ 50%

confirmed during 2 cycles

(56 days):

Be

st

Va

lue

, C

ha

ng

e in

Try

pta

se

Le

ve

l F

rom

Ba

se

lin

e (

%)

-100

-50

0

50

100

No (n=48)

Yes (n=24)

Be

st

Va

lue

, C

ha

ng

e in

Bo

ne

Ma

rro

w M

as

t

Cell

In

filt

rati

on

Fro

m B

aseli

ne (

%)

Decrease ≥ 50% confirmed

during 2 consecutive bone

marrow biopsies:

†† *

* Best value: 160% increase in bone marrow mast cells versus baseline. † Best value: 118% and 185% increase in serum tryptase level versus baseline.

Changes in BM Mast Cell Burden and Serum Tryptase Level

Gotlib et al., NEJM 374, 2530-41, 2016

-70

-60

-50

-40

-30

-20

-10

0

10

20

30

40 Responders (n=30)

Nonresponders (n=9)

Be

st

Va

lue

, C

ha

ng

e in

Sp

lee

n V

olu

me

Fro

m B

as

eli

ne

(%

)

-35%

8/39

increased

volume

10/39

decreased

volume ≥35%

30/39 decreased volume

Best change in spleen volume from baseline

Gotlib et al., NEJM 374, 2530-41, 2016

26

41

50 49 53 56 56 56 59

63 55

59

31

21

19 16

15 11 10 5

8

10

15 13 16

13

8 11

9 11 12

13

10

10 9 4

8 12

4 9 3

8 3 13 10

8

6 13

19 13

19 16

20 13

19 13 12

8 15

11

0

20

40

60

80

100

1 2 3 4 5 6 7 8 9 10 11 12

Pati

en

ts (

%)

Months

Major Response Partial Response Stable Disease Progresive Disease Not Evaluable

n = 89 85 74 70 66 61 59 55 49 48 47 46

Response over time

Gotlib et al., NEJM 374, 2530-41, 2016

SM Subgroup

Median OS

(95% CI), months 1-Year OS 2-Year OS 3-Year OS

ASM (n=16) NR (28.7-NE) 93 (61-99) 86 (55-96) 65 (18-90)

SM-AHN (n=57) 20.7 (16.0-44.4) 72 (58-82) 49 (34-63) 44 (27-59)

MCL (n=16) 9.4 (7.5-NE) 47 (22-69) 26 (6-54) 26 (6-54)

0

20

40

60

80

100

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52

Pati

en

ts S

urv

ivin

g,

%

Months

Kaplan-Meier Estimates (95% CI), %

Gotlib et al., NEJM 374, 2530-41, 2016

Overall survival according to subgroups

Schwaab et al., Blood 2013; 122:2460–2466; Jawhar et al., Leukemia 2016; 30:136-143

Overall frequency and prognostic impact of mutated genes in 70 advanced KIT D816V+ SM patients

0%

20%

40%

60%

80%

100%

60% of patients had ≥2 mutated genes in addition to KIT D816V

Overall survival in advanced SM depending on mutations in the SRSF2/ASXL1/RUNX1 (S/A/R) panel

S/A/Rneg

S/A/Rpos

Impact of baseline parameters on overall survival

a MCL patients with and without AHN b KIT D816V in peripheral blood

Jawhar et al., Blood 2017, in press

Impact of S/A/R Gene Panel on Overall Survival in Patients on Midostaurin

Jawhar et al., Blood 2017

Univariate and multivariate analyses of on-treatment variables regarding overall survival

b KIT D816V in peripheral blood c AP reduction ≥50% or normalization D Cheson criteria for transfusions e response criteria according to Valent f response criteria according to IWG-MRT & ECNM consensus criteria

Jawhar et al., Blood 2017, in press

Overall survival in advanced SM

Jawhar et al., Haematologica 2017

Mast cell leukemia: characteristics and impact of S/A/Rmut on overall survival

• Cytoreductive therapy: 25/28 (89%)

• Midostaurin (n=23) and/or cladribine (n=12)

• Median overall survival: 17 months (95% CI, 10-24)

• Age: median 67 years (45–82)

• BM MC infiltration: median 65% (20–95)

• Serum tryptase: median 520 µg/L (157-1854)

• KIT D816V in 68%, D816H/Y in 21%

• KIT D816V AB in PB: median 43% (20–98)

• Additional mutations in 68%, S/A/Rpos in 52%

• Hb <10g/dL and/or platelets <100x109/L in 93%

• MCL-AHN: 20/28 (71%)

• Secondary MCL: 12/28 (43%)

Systemic mastocytosis is not adequately diagnosed and subtyped

Jawhar et al., European Journal of Clinical Investigation, 2016

Initial diagnosis n=65

Diagnosis of SM by bone marrow histology, KIT D816V and tryptase

n=65

Correct subclassification

41/50, 82%

Incorrect sublassification (missed AHN)

9/50, 18%

Systemic mastocytosis 50/65, 77%

Inconsistent diagnosis

15/65, 23%

• MDS/MPNu • PMF • HES • B-cell lymphoma • ITP • Reactive

Median interval between bone marrow biopsies 6 months (range 1-48)

KIT mutation analysis in 26% of patients

performed or recommended

Quantification of mast cell infiltration in 66% of patients

Diagnosis in SM- Summary

• Underdiagnosed!!! – by clinicians AND pathologists

• Watch out for advSM:

MDS/MPN, MDS, MPN

± monocytosis ± eosinophilia

Splenomegaly ± elevated AP ± ascites ± diarrhea

LDH frequently normal

´AML´: eosinophilia, elevated serum tryptase, lack of response to chemotherapy

• Serum tryptase

• KIT D816V

• Bone marrow histology (tryptase, CD117, CD25)

Treatment in SM- Summary

• Symptomatic treatment in indolent phase disease

• Cytoreductive treatment in advanced phase disease

• Midostaurin (Rydapt®)

• Other KIT Inhibitors (Blu 285, DCC 2618)

• Cladribine

• Allogeneic stem cell transplantation in best achievable remission

Diagnosis and treatment of systemic mastocytosis

Mast cell burden

Tryptase KIT allele burden

SM

Diagnosis and treatment of SM with monocytosis

Mast cell burden

Tryptase Monocytes KIT allele burden

CMML + ISM

Mast cell burden

Tryptase Monocytes KIT allele burden

SM-CMML

Mast cell burden

Tryptase Monocytes KIT allele burden

SM-CMML

KIT inhibitor Cladribine

Hydroxyurea Azacytidine

Clinical case

Triple-negative primary myelofibrosis

Leukocytes 32 x 109/l

Monocytes 2.4 x 109/l

Eosinophils 1.3 x 109/l

Hemoglobin 11g/dl

Platelets 210 x 109/l

Spleen 2180 ccm3

Bone marrow Hypercellular

fibrosis grade 2

LDH 280U/l

AP 580U/l

Tryptase 350µg/l

Mutations Negative for JAK2 V617F, CALR,

MPL

Treatment No response on ruxolitinib

2x20mg/day

Clinical case

Triple-negative primary myelofibrosis

Leukocytes 32 x 109/l

Monocytes 2.4 x 109/l

Eosinophils 1.3 x 109/l

Hemoglobin 11g/dl

Platelets 210 x 109/l

Spleen 2180 ccm3

Bone marrow Hypercellular

fibrosis grade 2

LDH 280U/l

AP 580U/l

Tryptase 350µg/l

Mutations Negative for JAK2 V617F, CALR,

MPL

Treatment No response on ruxolitinib

2x20mg/day

Clinical case

Triple-negative primary myelofibrosis

Leukocytes 32 x 109/l

Monocytes 2.4 x 109/l

Eosinophils 1.3 x 109/l

Hemoglobin 11g/dl

Platelets 210 x 109/l

Spleen 2180 ccm3

Bone marrow Hypercellular

fibrosis grade 2

LDH 280U/l

AP 580U/l

Tryptase 350µg/l

Mutations Negative for JAK2 V617F, CALR,

MPL

Treatment No response on ruxolitinib

2x20mg/day

Clinical case

Leukocytes 32 x 109/l

Monocytes 2.4 x 109/l

Eosinophils 1.3 x 109/l

Hemoglobin 11g/dl

Platelets 210 x 109/l

Spleen 2180 ccm3

Bone marrow Hypercellular

fibrosis grade 2

LDH 280U/l

AP 580U/l

Tryptase 350µg/l

Mutations Negative for JAK2 V617F, CALR,

MPL

Treatment No response on ruxolitinib

2x20mg/day

Clinical case

Multimutated aggressive systemic mastocytosis

Leukocytes 32 x 109/l

Monocytes 2.4 x 109/l

Eosinophils 1.3 x 109/l

Hemoglobin 11g/dl

Platelets 210 x 109/l

Spleen 2180 ccm3

Bone marrow 40% mast cell infiltration

fibrosis grade 2

LDH 280U/l

AP 580U/l

Tryptase 350µg/l

Mutations Positive for KIT D816V, SRSF2,

ASXL1, RUNX1, TET2

Treatment Midostaurin, cladribine,

allogeneic SCT

In advanced SM

and myelofibrosis,

midostaurin and

ruxolitinib,

respectively, must

navigate complex

mutational

landscapes while

trying to impact

similar disease-

related burdens.

Gotlib J., Blood 130, 98-100, 2017

Thank you

Mannheim Mohamad Jawhar Georgia Metzgeroth Nicole Naumann Alice Fabarius Wolf-Karsten Hofmann Andreas Reiter

München (MLL) Claudia Haferlach Manja Meggendorfer Torsten Haferlach

Salisbury, UK Nicholas C.P. Cross

Freiburg Annette Schmitt-Gräff

München, LMU Hans-Peter Horny

Wien Peter Valent

Jena Thomas Ernst Andreas Hochhaus

Deutsche MPN-Studiengruppe

Salzburg Karl Sotlar

• SM vs. SM-AHN?

SM-AHN underdiagnosed

Survival: normal vs. median survival <5 years

• What is AHN?

Multilineage KITmut involvement

Two independent clones, e.g. CMML, JAK2 V617F, del(5q), etc.

• How important is subtyping of AHN?

e.g. MDS/MPN, CMML, MPN, CEL etc.

Mutation profile is more important than phenotype

• MCL vs. MCL-AHN

KITmut mast cells vs. multimutated multilineage stem cell disease

• SM-AML

Blasts may be KITmut negative

SM-AHN

Jawhar et al., Leukemia 2015; 29:1115-1122

TET2

KIT

ASXL1 TET2

ASXL1 TET2

KIT

• KIT D816V alone was not identified in a single colony.

• In contrast, colonies with additional mutations were frequent.

• Mutations in TET2, SRSF2 or ASXL1 precede KIT D816V.

• KIT D816V is a strong phenotype modifier.

Molecular profiling of myeloid progenitor cells in multi-mutated advanced SM patients