Systemic Mastocytosis: Seldomly Seen, Multiple Manifestations

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1 Systemic Mastocytosis: Seldomly Seen, Multiple Manifestations Ryan Cassaday, MD HematologyFellows Conference June 3, 2011

2 Outline Why this topic, and case discussion Brief background Classification i of systemic mastocytosis (SM) Treatment of SM (Pictures esfo from Oy Olympic pcnational a Park; May 2011)

3 If speaker floods you with useless information, seek high ground at the rear of lecture hall.

4 Why This Topic? Uncommon disease opportunity to learn Interesting disease Unique nomenclature Illustrative case

5 Case Discussion 61 yom with a h/o paroxysmal SVT and tobacco abuse March 2010: splenomegaly and weight loss Marrow: Jak 2 positive MF June 2010: splenectomy Spleen path: mast cell infiltration Retrospective review of marrow: increased mast cells Fall 2010: hepatomegaly, pruritus

6 Case Discussion (2) January 2011: admitted with increased dyspnea yp and hypoxemia WBC up from 20s to 40s Serum tryptase t = 311 ng/ml (normal l ng/ml) Pulmonary: ILD from flecainide Repeat marrow aspirate ate and dbiopsy: Markedly hypercellular (>95%) Granulocytic and megakaryocytic hyperplasia; no increased blasts Mild interstitial and moderate reticulin fibrosis Multiple mast cell aggregates seen on biopsy KIT D816V mutation detected Diagnosis: SM with persistent Jak 2 positive MF

7 Hoh Rain Forest

8 Me 700-year old metaphor for systemic mastocytosis

9 Review of Mast Cell Biology

10 WHO Diagnosis of SM Major Criterion Multifocal dense aggregates of > 15 mast cells in bone marrow or other extracutaneous tissues Minor Criteria Atypical morphology in >25% of mast cells in bone marrow or other extracutaneoustissues KIT D816V positive Mast cell expression of CD2, CD25, or both Serum tryptase level > 20 ng/ml SM = 1 major + 1 minor OR 3 minor Valent et al. WHO Classification of Tumors

11 Marrow Infiltration of Mast Cells From Path Consult DDX Fundamentals:

12 Classification of SM ISM = indolent SM SSM = smoldering SM ASM = aggressive SM SM AHNMD = SM with an associated hematologic non mast cell lineage disease Usually myeloid (CMML, HES/CEL, MDS, MPN, AML, etc.) MCL = mast cell leukemia Valent, et al. Eur J Clin Invest

13 Additional Diagnostic Features B Findings Bone marrow involvement > 30% and serum tryptase > 200 ng/ml Signs of marrow hypercellularity or dysplasia (but not sufficient to diagnose MPN or MDS) Organomegaly withoutorgan organ dysfunction C Findings Organ dysfunction caused by mast cell infiltration B = Borderline Benign, C = Consider Cytoreductiony Valent, et al. Eur J Clin Invest

14 Diagnostic Algorithm for SM Valent, et al. Eur J Clin Invest

15 Outcomes from SM Case series of 342 consecutive adults followed at Mayo Clinic from Lim, et al. Blood

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18 Supportive Care for SM Atopic/hypersensitivity symptoms Histamine receptor antagonists Glucocorticoids Epinephrine Gastrointestinal symptoms Histamine receptor antagonists Proton pump pinhibitors Osteopenia/osteoporosis Bisphosphonates Valent, et al. Blood

19 Management of Advanced SM Control of slowly progressing disease Interferon alpha +/ steroids (ORR = 53%; median duration = 12 mo) Cladribine (ORR = 55%; median duration = 11 mo) More aggressive disease High dose cytarabine Fludarabine AHNMD Treat each accordingly Allogeneic hematopoietic stem cell transplant Palliation Hydroxyurea Lim, et al. Am J Hematol Valent, et al. Blood

20 Role of KIT > 80% of adults with SM harbor mutations in exon 816 of KIT Majority of these are D816V If so common, potential therapeutic target Have I heard D816V before? Associated with worse prognosis in patients with CBF AML Not a common mutation in GIST

21 Targeted Therapy for SM: Imatinib Phase II single institution study 1 N = 20, treated from 2003 to 2005 One CR: negative for KIT D816V Trial in patients with wild type c kit codon Screened 24 subjects 5 were wild type 4 consented After 6 months, all 4 had partial response FDA approved for SM with wild type or unknown KIT status 1. Vega-Ruiz, et al. Leuk Res Hsieh, et al. Blood (ASH Annual Meeting Abstracts)

22 Targeted Therapy for SM: d 2 nd Generation Agents Phase II study of nilotinib 1 Data presented on 60 patients Response seen in 12 patients (20%) Phase II study of dasatinib 2 67 subjects with acute or chronic myeloid diseases, 33 with SM (28 were D816V positive) Response seen in 11 patients (33%) Complete response in 2 patients (6%) lasting 5 and 16 months, both were D816V negative Case reports of dasatinib + chemotherapy 1. Hochhaus, et al. Blood (ASH Annual Meeting Abstracts) Verstovsek, et al. Clin Cancer Res

23 Targeted Therapy for SM: Other Strategies Phase II study of midostaurin (PKC412) 1 Oral multi targeted kinase inhibitor, including KIT D816V 26 patients enrolled Responses observed in 18 patients (69%) Major responses lasted median of 1.5 years Toxicity: hyperlipasemia, cytopenias, N/V, fatigue Additional international trial to be reported at ASCO 2011 Other mutations with prognostic significance and thus possible targets 2 1. Gotlib, et al. Blood (ASH Annual Meeting Abstracts) Traina, et al. Blood (ASH Annual Meeting Abstracts)

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25 Group of Grazing Roosevelt Elk

26 Conclusions SM is a rare condition with a variety of clinical presentations Diagnosis based on results of peripheral blood and histopathologic evaluation Treatment based on disease classification: Symptom management and disease control Allogeneic stem cell transplant only possible option for long term remission Future directions: i Combining cytotoxic and targeted agents Identifying new targets

27 References Abraham SN, St John AL. Mast cell orchestrated immunity to pathogens. Nat Rev Immunol Jun;10(6): Gotlib JR, DeAngelo DJ, George TI, et al. KIT inhibitor midostaurin exhibits a high rate of clinically meaningful and durable responses in advanced systemic mastocytosis: report of a fully accrued phase II study. Blood (ASH Annual Meeting Abstracts). 2010;116:Abstract 316. Hochhaus A, Ottmann OG, Lauber S, et al. A phase II study of nilotinib, a novel inhibitor of c kit, PDGFR, and Bcr Abl, administered to patients with systemic mastocytosis. Blood (ASH Annual Meeting Abstracts). 2006;108:Abstract Hsieh FH, Lichtin AE, Katz HT, et al. Imatinib mesylate in the treatment of systemic mastocytosis with wild type c kit codon 816. Blood (ASH Annual Meeting Abstracts). t 2006;108:Abstract t Lim KH, Tefferi A, Lasho TL, et al. Systemic mastocytosis in 342 consecutive adults: survival studies and prognostic factors. Blood Jun 4;113(23):

28 References (2) Traina F, Jankowska A, Makishima H, et al. New TET2, ASXL1, and CBL mutations have poor prognostic impact on systemic mastocytosis and related disorders. Blood (ASH Annual Meeting Abstracts). 2010;116:Abstract Valent P, Akin C, Escribano L, et al. Standards and standardization in mastocytosis: consensus statements on diagnostics, treatment recommendations and response criteria. Eur J Clin Invest Jun;37(6): Valent P, Horny H P, Li C Y, et al. Mastocytosis. In: World Health Organization classification of tumours. Pathology and genetics of tumours of the haematopoietic and lymphoid tissues, Jaffe, ES, Harris, NL, Stein, H, Vardiman, JWV (Eds), Lyon IARC Press, Valent P, Sperr WR, Akin C. How I treat patients with advanced systemic mastocytosis. Blood Dec 23;116(26): Vega Ruiz A, Cortes J, Sever M, et al. Phase II study of imatinib mesylate as therapy for patients with systemic mastocytosis. Leuk Res. 2008Feb; 33(11): Verstovsek S, Tefferi A, Cortes J, et al. Phase II study of dasatinib in Philadelphia chromosome negative acute and chronic myeloid diseases, including systemic mastocytosis. Clin Cancer Res Jun 15;14(12):

29 Sunset at Lake Quinalt Questions?