Fortgeschrittene systemische Mastozytose Hintergrundinformationen zu einer seltenen Erkrankung und zur ersten zugelassenen Therapie

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Joy Pierce
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zur ersten zugelassenen Therapie Georgia Metzgeroth

1 Fortgeschrittene systemische Mastozytose Hintergrundinformationen zu einer seltenen Erkrankung und zur ersten zugelassenen Therapie Georgia Metzgeroth Hämatologie und Onkologie III. Medizinische Klinik Universitätsklinikum Mannheim

2 Common features in systemic mastocytosis: KIT D816V, dense mast cell infiltrates and serum tryptase KIT D816V Tryptase BM and PB Serum BM: Bone Marrow; PB: Peripheral Blood Mast cell infiltrate

3 Systemic mastocytosis Organ infiltration Bone marrow Liver Advanced SM * SM-AHN, ASM, MCL BM MC infiltration Serum tryptase Spleen Lymph nodes GI tract Skin Indolent SM 80-90% KIT D816V 60-70% KIT D816V Allele burden allele burden Organ damage = C-findings Cytopenia(s) associated hematologic neoplasm (AHN) MDS/MPN MDS MPN saml Monocytosis Eosinophilia Dysplasia Blasts Elevated liver enzymes (AP!) Portal hypertension Splenomegaly Ascites Hypoalbuminemia Malabsorption Osteolyses * Advanced SM: SM with associated hematologic neoplasm (SM-AHN), aggressive SM (ASM), mast cell leukemia (MCL) MDS: Myelodysplastic Syndrome, MPN: Myeloproliferative Neoplasm, saml: secondary Acute Myeloid Leukemia; AP: Alkaline Phosphatase; BM: Bone Marrow

4 WHO diagnostic criteria of systemic mastocytosis (SM) Major Multifocal compact mast cell infiltrates (>15 MC) in bone marrow or other extracutaneous organs Minor Mast cell with atypical morphology (>25% MC) KIT D816V mutation Aberrant expression of CD2 and/or CD25 Serum tryptase >20 ng/ml (normal <11.4) SM: major + 1 minor or 3 minor criteria

5 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 etc.

6 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 etc.

7 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. Suspected systemic mastocytosis (SM) 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 spindleshaped 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

8 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. Suspected systemic mastocytosis (SM) 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 B- or C-findings? 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 spindleshaped 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 B-findings BM MC infiltration >30% and serum tryptase >200µg/L Organomegaly BM with proliferation or dysplasia C-findings Cytopenia(s): Neutrophils <1x10 9 /μl, Hb<10 g/dl and/or platelets <100x10 9 /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

9 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. Suspected systemic mastocytosis (SM) 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 B- or C-findings? 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 spindleshaped 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 B-findings BM MC infiltration >30% and serum tryptase >200µg/L Organomegaly BM with proliferation or dysplasia C-findings Cytopenia(s): Neutrophils <1x10 9 /μl, Hb<10 g/dl and/or platelets <100x10 9 /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

10 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 ISM 0 or 1 B-finding, No C-finding SSM At least 2 of 3 B- findings SM-AHN 4 Suspected systemic mastocytosis (SM) 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 B- or C-findings? ASM C-findings 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. MC: Mast Cell, ISM: Indolent Systemic Mastocytosis, SM-AHN: Systemic Mastocytosis with associated hematologic neoplasm, ASM: Aggressive Systemic Mastocytosis, MCL: Mast Cell Leukemia, BM: Bone Marrow, SSM: Smoldering Systemic Mastocytosis MCL 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 spindleshaped 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 B-findings BM MC infiltration >30% and serum tryptase >200µg/L Organomegaly BM with proliferation or dysplasia C-findings Cytopenia(s): Neutrophils <1x10 9 /μl, Hb<10 g/dl and/or platelets <100x10 9 /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

11 SM subtypes and clinical course SM-AHN ASM ± AHN Indolent SM MCL ± AHN (A)SM-/MCLsAML Advanced SM SM-AHN: ASM: MCL: (A)SM/MCL-sAML: Systemic Mastocytosis with Associated Hematologic Neoplasm dysplastic and/or myeloproliferative features MDS, MDS/MPN, MPN Aggressive Systemic Mastocytosis Hb <10 g/dl, platelets <100 g/l, albumin <25 g/l, splenomegaly, ascites, malabsorption, weight loss >10% (C-findings) Mast Cell Leukemia >20% mast cells in bone marrow smear with associated secondary Acute Myeloid Leukemia >30% blasts

12 Survival Survival with SM ISM: indolent SM ASM: aggressive SM MCL: mast cell leukemia AHD: associated hematologic (non-mast cell lineage) disorder Lim KH et al. SM in 342 consecutive adults: survival studies and prognostic factors. Blood 2009; 113:

13 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 ISM 0 or 1 B-finding, No C-finding SSM At least 2 of 3 B- findings H1-/H2-antagonists MC stabilizers Leukotriene antagonists Steroids (topic and/or systemic) Interferon-alpha (inadequately controlled symptoms, off-label) SM-AHN 4 Suspected systemic mastocytosis (SM) 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 B- or C-findings? ASM C-findings MCL Midostaurin (SM-AHN, ASM, MCL) Imatinib (for sensitive KIT mutations only, <1%) Cladribine (off-label) Interferon-alpha (off-label) Hydroxyurea (for the AHN component) 1,2 An elevated serum tryptase (normal value <11.4µg/L) AND presence of a KIT Allogeneic stem cell transplantation (in eligible D816 mutation (KIT D816V in >90% of cases) patients in best achievable remission) make diagnosis of SM very likely. 3 MCL is defined by >20% mast cells in BM cytology (not histology!). 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 spindleshaped 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 B-findings BM MC infiltration >30% and serum tryptase >200µg/L Organomegaly BM with proliferation or dysplasia C-findings Cytopenia(s): Neutrophils <1x10 9 /μl, Hb<10 g/dl and/or platelets <100x10 9 /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 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. MC: Mast Cell, ISM: Indolent Systemic Mastocytosis, SM-AHN: Systemic Mastocytosis with associated hematologic neoplasm, ASM: Aggressive Systemic Mastocytosis, MCL: Mast Cell Leukemia, BM: Bone Marrow, SSM: Smoldering Systemic Mastocytosis

14 Best Value, Change in Bone Marrow Mast Cell Infiltration From Baseline (%) Best Value, Change in Tryptase Level From Baseline (%) Changes in Bone Marrow Mast Cell Burden and Serum Tryptase Level 100 Decrease 50% confirmed during 2 consecutive bone marrow biopsies: * 100 Decrease 50% confirmed during 2 cycles (56 days): 50 No (n=48) Yes (n=24) 50 No (n=57) Yes (n=32) *Best value: 160% increase in bone marrow mast cells versus baseline. Best value: 118% and 185% increase in serum tryptase level versus baseline. Gotlib J et al. Efficacy and Safety of Midostaurin in Advanced Systemic Mastocytosis. NEJM 2016; 374;

15 Best change in spleen volume from baseline Best Value, Change in Spleen Volume From Baseline (%) 40 Responders (n=30) Nonresponders (n=9) /39 decreased volume 35% /39 increased volume -35% /39 decreased volume Gotlib J et al. Efficacy and Safety of Midostaurin in Advanced Systemic Mastocytosis. NEJM 2016; 374;

16 Patients (%) Response over time Major Response Partial Response Stable Disease Progresive Disease Not Evaluable n = Months Major response: 1C-finding resolved, - incomplete: MC and/or tryptase >50% and/or organomegaly >50%; - pure clinical: tryptase 50%-0% Good partial response: 1 C-finding resolved by >50% Gotlib J et al. Efficacy and Safety of Midostaurin in Advanced Systemic Mastocytosis. NEJM 2016; 374;

17 Forrest plot for subgroup analysis of response Category Response (95% CI), % Overall (n=89) 60 (49-70) ASM (n=16) 75 (48-93) SM-AHN (n=57) 58 (44-71) MCL (n=16) 50 (25-75) MCL (n=16) 50 (25-75) Non-MCL (n=73)* 62 (50-73) With AHN (n=63) 57 (44-70) Without AHN (n=26) 73 (45-92) KIT D816V+ (n=73) 63 (51-74) KIT D816V /unknown (n=16) 44 (20-70) Prior therapies (n=37) 62 (45-78) No prior therapies (n=52) 58 (43-71) AHN: Associated Hematologic Neoplasm, ASM: Aggressive Systemic Mastocytosis, SM-AHN: Systemic Mastocytosis with associated hematologic neoplasm, MCL: Mast Cell Leukemia; Non-MCL: Non-Mast Cell Leukemia Patients (%) Gotlib J et al. Efficacy and Safety of Midostaurin in Advanced Systemic Mastocytosis. NEJM 2016; 374;

MSAS Symptom Burden Hair loss Mouth sores Difficulty swallowing Constipation Vomiting Lack of energy Feeling drowsy 100 Difficulty sleeping 80 60 Pain Weight loss Feeling bloated Don t

Shortness of breath Cough Feeling sad Dizziness Swelling of arms/legs Itching Nausea MSAS: Memorial Symptom Assessment Scale, TMSAS: Total Memorial Symptom Assessment Scale Subscore

18 MSAS Symptom Burden Hair loss Mouth sores Difficulty swallowing Constipation Vomiting Lack of energy Feeling drowsy 100 Difficulty sleeping Pain Weight loss Feeling bloated Don t look like myself Urinary problems Numbness in hands/feet Problems with sex Difficulty concentrating Dry mouth Worrying Feeling nervous Skin changes Change in way food tastes Shortness of breath Cough Feeling sad Dizziness Swelling of arms/legs Itching Nausea MSAS: Memorial Symptom Assessment Scale, TMSAS: Total Memorial Symptom Assessment Scale Subscore Diarrhea Sweats Feeling irritable Lack of appetite Baseline TMSAS Best TMSAS value on treatment Gotlib J et al. Efficacy and Safety of Midostaurin in Advanced Systemic Mastocytosis. NEJM 2016; 374;

19 Patients Surviving (%) Overall survival according to subgroups Kaplan-Meier Estimates (95% CI), % 100 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 ( ) 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) Months ASM: Aggressive Systemic Mastocytosis, SM: Systemic Mastocytosis, SM-AHN: Systemic Mastocytosis with associated hematologic neoplasm, MCL: Mast Cell Leukemia; OS: Overall survival Gotlib J et al. Efficacy and Safety of Midostaurin in Advanced Systemic Mastocytosis. NEJM 2016; 374;

Univariate and multivariate analyses of on-treatment variables regarding overall survival b c d e f KIT D816V in peripheral blood AP reduction 50% or normalization Cheson criteria for transfusions

20 Univariate and multivariate analyses of on-treatment variables regarding overall survival b c d e f KIT D816V in peripheral blood AP reduction 50% or normalization Cheson criteria for transfusions response criteria according to Valent response criteria according to IWG-MRT & ECNM consensus criteria MC: Mast Cell, BM: Bone Marrow, AP: Alkaline Phosphatase, Hb: Hemoglobin, PLT: Platelet Count, IWG-MRT: International Working Group-Myeloproliferative Neoplasms Research and Treatment, EAB: Expressed Allel Burden Jawhar M et al. Response and Progression on midostaurin in advanced systemic mastocytosis: KIT D816V and other molecular markers Blood 2017; 130(2):

21 Patients Included in Analyses Reiter A et al. Pooled Analysis of Midostaurin Clinical Study Data in Patients with advsm compared with historic controls. EHA 2017; Abstract S788.

22 Comparable Baseline Characteristics, Except Age Reiter A et al. Pooled Analysis of Midostaurin Clinical Study Data in Patients with advsm compared with historic controls. EHA 2017; Abstract S788. SM: Systemic Mastocytosis

23 Overall Survival Comparisons Reiter A et al. Pooled Analysis of Midostaurin Clinical Study Data in Patients with advsm compared with historic controls. EHA 2017; Abstract S788. SM: Systemic Mastocytosis

24 Overall Survival Reiter A et al. Pooled Analysis of Midostaurin Clinical Study Data in Patients with advsm compared with historic controls. EHA 2017; Abstract S788. OS: Overall Survival, HR: Hazard Ratio, CI: Confidence Interval.

25 Overall Survival From Data of Diagnosis Based on Matched Pairs Using the Propensity Score a Reiter A et al. Pooled Analysis of Midostaurin Clinical Study Data in Patients with advsm compared with historic controls. EHA 2017; Abstract S788. OS: Overall Survival, HR: Hazard Ratio, CI: Confidence Interval.

26 Subgroup Analysis of Overall Survival Reiter A et al. Pooled Analysis of Midostaurin Clinical Study Data in Patients with advsm compared with historic controls. EHA 2017; Abstract S788. SM: Systemic Mastocytosis, AHN: Associated Hematologic Neoplasm, MCL: Mast Cell Leukemia

27 Multivariate Analysis of Overall Survival Reiter A et al. Pooled Analysis of Midostaurin Clinical Study Data in Patients with advsm compared with historic controls. EHA 2017; Abstract S788. ASM: Aggressive Systemic Mastocytosis, MCL: Mast Cell Leukemia, AHN: Associated Hematologic Neoplasm.

28 Overall Survival From Date of Last Treatment Received for Advanced SM Reiter A et al. Pooled Analysis of Midostaurin Clinical Study Data in Patients with advsm compared with historic controls. EHA 2017; Abstract S788. OS: Overall Survival, HR: Hazard Ratio, CI: Confidence Interval.

29 Conclusions Reiter A et al. Pooled Analysis of Midostaurin Clinical Study Data in Patients with advsm compared with historic controls. EHA 2017; Abstract S788. SM: Systemic Mastocytosis

30 Midostaurin in advanced SM Overall response rate: 60% Improvement of: Symptoms (30/32 MSAS, splenomegaly 70%) Serum tryptase KIT-allele burden Bone marrow mast cell infiltration C-findings (organ dysfunction) BUT: no complete remission Lower risk of death than historical controls Adverse events: Nausea Vomiting SM: Systemic Mastocytosis, MSAS: Memorial Symptom Assessment Scale

Welcome to Master Class for Oncologists. Session 3: 9:15 AM - 10:00 AM

Welcome to Master Class for Oncologists Session 3: 9:15 AM - 10:00 AM Miami, FL December 18, 2009 Myeloproliferative Neoplasms: Bringing Order to Complexity and Achieving Optimal Outcomes Speaker: Andrew