Session II: Summary. Robert P Hasserjian, MD Professor of Pathology Massachusetts General Hospital and Harvard Medical School

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1 Session II: Summary Robert P Hasserjian, MD Professor of Pathology Massachusetts General Hospital and Harvard Medical School

2 Disclosure of speaker s interests (Prefix and Last Name) (Potential) conflict of interest Celgene Potentially relevant company relationships in connection with event

3 SH/EAHP 2017 Workshop REGISTRATION OPEN! September 7-9, 2017 Hyatt Regency, Chicago, Illinois Molecular Genetics of Hematolymphoid Neoplasms 350 cases (myeloid & lymphoid), keynote lectures and more! Organizers Robert Hasserjian, Frank Kuo, Olga Weinberg

4 Session II Cases Case# Author Panel diagnosis Mutations 205 Fend Clonal cytopenia of undetermined significance (differential diagnosis of MDS-SLD) 204 Kluk Clonal cytopenia of undetermined significance progressed to overt MDS-SLD 106 Caponetti Hypocellular bone marrow with paroxysmal nocturnal hemoglobinuria clone and clonal cytopenia of undetermined significance, suggestive of evolving aplastic anemia 311 Ballesteros Hypercellular bone marrow on active therapy, suspicious but not diagnostic of MDS or MDS/MPN 206 Tam Clonal hematopoieisis of indeterminate potential JAK2 201 Tsankov MPN, unclassifiable ZRSR2 ASXL1, EZH2, SETBP1, TET2 DNMT3A SRSF2, IDH2 301 Reichard Germline GATA2 mutation predisposition syndrome (?progression to MDS-SLD) 109 (I) Klimkowska Germline USB1 mutation predisposition syndrome USB1 GATA2, ASXL1

5 Mutation testing in the CHIP era Non-MDS cytopenia? Risk stratify Treat as appropriate Kwok B et al. Blood 2015;126:2355 Seek other causes of cytopenias

6 Spectrum of clonal hematopoietic proliferations with <10% dysplasia CHIP with no observed 206 Tam hematopoietic abnormalities ( incidental CHIP ) 201 JAK2 mutated MPN-U Tsankov CHIP with cytopenias ( CCUS ) Cytopenia probably related to the mutation(s) Cytopenia possibly related to another factor with incidental CHIP 205 Fend 311 Ballesteros 204 Kluk 106 Caponetti

7 Case 206 Tam Case 201 Tsankov Normal blood counts (borderline/intermittent erythrocytosis); normal EPO Asymptomatic Normal blood counts with decreased EPO level Bone pain associated with vertebral bone lesion

8 Case 206 Tam Case 201 Tsankov

9 Case 206 Tam Case 201 Tsankov Normal blood counts (borderline/intermittent erythrocytosis); normal EPO Asymptomatic JAK2 V617F (3.3%) Normal blood counts with decreased EPO level Bone pain associated with vertebral bone lesion JAK2 V617F (12% in blood) No histologic features of PV or other MPN JAK2 CHIP Histologic features of MPN Hypercellularity, abnormal megakaryocyte morphology MPN, unclassifiable Likelihood of eventual progression to PV unknown

10 MDS, unclassifiable MPN, unclassifiable 1. Single lineage dysplasia or isolated del(5q) with pancytopenia 2. Single/multilineage dysplasia or isolated del(5q) with 1% blood blasts 3. MDS-defining cytogenetic abnormality but lacking dysplasia The designation myeloproliferative neoplasm, unclassifiable (MPN-U) should be applied only to cases that have definite clinical, laboratory, molecular and morphological features of a myeloproliferative neoplasm (MPN) but that fail to meet the diagnostic criteria for any of the specific MPN entities, or that present with features that overlap two or more of the MPN categories

11 Take home points-1 JAK2 mutations can occur as a CHIP Usually not associated with cytopenia Diagnosis of PV/ET/PMF requires diagnostic morphologic features in bone marrow MPN-U includes cases which cannot be classifiable in any other MPN entity Morphology of MPN but not fully developed clinical picture JAK2+ disease presenting with portal/splanchnic vein thrombosis

12 Case 205 Fend Case 204 Kluk Neutropenia and thrombocytopenia x 15 years No anemia Anemia (macrocytic) and mild thrombocytopenia

13 Case 205 Fend Case 204 Kluk May 2016 November 2016

14 Case 205 Fend Case 204 Kluk Neutropenia and thrombocytopenia x 15 years No anemia Anemia (macrocytic) and mild thrombocytopenia 47,XY,+8[4],45,X,-Y[6],46,XY [15] ZRSR2 p.met7ile, c.21g>a (77%) Prolonged nature of cytopenias unusual for MDS CCUS 46, XY [20] ASXL1, EZH2, SETBP1, TET2 mutations at high VAF Confounding factor of concurrent plasma cell neoplasm CCUS, progressed to over MDS-SLD

15 Case 106 Caponetti Case 311 Ballesteros Pancytopenia Anemia (normocytic), thrombocytopenia, and neutrophilia

16 Case 106 Caponetti Case 311 Ballesteros

17 Case 106 Caponetti Case 311 Ballesteros Pancytopenia 46,XX DNMT3A c.1784t>c, p.l595p(22%). Confounding factor of PNH clone (2% RBC, 11% granulocytes) and hypocellularity Hypocellular marrow, PNH clone and CCUS,?evolving aplastic anemia Anemia (normocytic), thrombocytopenia, and neutrophilia 47,XY,+8[14], 46,XY [6] SRSF2 c.284c>a, p.pro95his IDH2 c.419g>a, p.arg140gln Confounding factor of ongoing steroid and methotrexate therapy Hypercellular marrow on active therapy?mds or MDS/MPN

18 Hasserjian R, Head D. Myelodysplastic Sydnromes, in. Hematopathology Jaffe et al. ed MDS-type mutations frequently occur in aplastic anemia

19 Aplastic anemia, MDS, and PNH Mutant stem cell waxes and wanes under selective pressure Peripheral Hemolysis contributes to the anemia Shrunken stem cell pool due to T-cell mediated destruction Sparse hemopoiesis Case 106 PNH AA MDS Mutant stem cell overtakes the marrow Progressive mutations Ineffective hematopoiesis

20 Navigating the CCUS versus MDS minefield All 4 cases presented with cytopenia and one or more pathogenic MDS-type mutations All 4 cases lacked or had borderline dysplasia All 4 cases had mitigating factors that tend to discourage an MDS diagnosis Very long history of cytopenias (15 years) Drugs known to cause cytopenia/dysplasia or neutrophilia Aplastic anemia with PNH clone Concurrent plasma cell neoplasm

21 MDS, CHIP, and general anemia incidence Incidence of MDS per 100,000 <1% incidence < Age at MDS diagnosis (years) Incidence of Anemia 10-20% incidence Incidence of CHIP 10-15% incidence Most common causes of anemia Chronic disease/inflammation Thalassemia trait Renal failure Rollison DE et al. Blood 2008;112:45-52, Jaiswal S et al. NEJM 2014; 371:2488, Steensma D et al. Blood 2015; 126:9, Tettamanti M et al. Haematologica 2010;96:1849

22 Potentially dangerous collision Incidental CHIP Non-clonal cytopenia Misdiagnosis of nonneoplastic cytopenia as MDS Bone marrow transplant for SLE-associated anemia Azacitidine therapy for alpha thalassemia Some non-mds conditions are associated with mutations Aplastic anemia?pnh Lymphomas

23 Kwok B et al. Blood 2015;126:2355; Cargo CA et al. Blood 2015;126:2362. Clues in CCUS that may indicate a true pre-mds condition (ca. 2015) Flow cytometry abnormalities 2 or more mutations Mutations with high variant allele fraction Mutation profile: specific mutations or combinations DNMT3A mutation is the most common CHIP mutation and may require particular caution

24 Malcovati Blood 2017 (Epub) Prospective evaluation of mutations in 873 patients referred for cytopenia Myeloid neoplasm ICUS Known cytopeni a CCUS Non-clonal ICUS

25 Mutation number and risk of ICUS Malcovati Blood 2017 (Epub) evolution to myeloid neoplasms Non-clonal cytopenia CCUS

26 Malcovati Blood 2017 (Epub) High-risk myeloid gene mutation pattern in CCUS Any SF3B1 mutation DNMT3A, TET2, ASXL1 mutation in combination with any other mutation All mutations should be at >10% variant allele fraction

27 Malcovati Blood 2017 (Epub) Mutation pattern and risk of evolution to myeloid neoplasms CCUS with highrisk myeloid gene mutation pattern CCUS with low-risk myeloid gene mutation pattern Non-clonal ICUS

28 Applying Malcovati rule to our cases... Case# Author Panel diagnosis Mutations High-risk mutation pattern? Followup 205 Fend CCUS?MDS-SLD ZRSR2 No No MDS yet Kluk CCUS ASXL1, EZH2, SETBP1, TET2 Yes MDS-SLD after 6 months 106 Caponetti CCUS, PNH clone,?aplastic anemia DNMT3A No No MDS yet Ballesteros Suspicious for MDS or MDS/MPN SRSF2, IDH2 No No MDS yet...

29 10,000 stem cells Clonal hematopoiesis Clonal abnormal hematopoiesis? Altered appearance of marrow cells Functionally abnormal hematopoiesis

30 Evolving concepts in clonal hematopoietic proliferations Low-count MBL (<500/µL) MGUS Low-level CHIP(<10%) High-count MBL ( /µL) Smoldering myeloma Low-risk CCUS CLL Progressive/ symptomatic CLL Overt plasma cell myeloma When to treat? What are the treatment goals? Bone marrow failure High-risk CCUS MDS AML

31 Take home points-2 MDS-type mutations in a cytopenic patient must be interpreted with caution Can be co-occurrence of CHIP and non-mds cytopenia; beware of lunging to an MDS diagnosis! Some cases are pre-mds or pre-aml: qualities of mutations (number, VAF, pattern) could help predict which cases represent true MDS Significant (>10%) dysplasia may occur in non-mds conditions Even if mutations and dysplasia are present, must exclude other possible causes of cytopenia

32 Myeloid neoplasms with germline predisposition: new WHO category Without a pre-existing platelet disorder or organ dysfunction Germline CEBPA and DDX41 mutation With pre-existing platelet disorders Germline RUNX1, ANKRD26, and ETV6 mutation Associated with organ dysfunction Germline GATA2 mutation Bone marrow failure syndromes, telomere biology disorders, neurofibromatosis, Noonan syndrome Czuchlewski DR et al. Surg Pathol Clin 2016:9:165, West AH et al. Ann NY Acad Sci 2014;1310:111.

33 Challenges in genetic predisposition myeloid neoplasms Identifying the germline mutation May need to sequence non-hematopoietic tissue to know for certain that the mutation is germline Need to be alert to clues: detailed personal and family history and use of experienced genetic counselors Often newly arising mutations where family history is unhelpful Some entities present in adulthood MDS/AML with DDX41 mutation Distinguishing platelet disorders and bone marrow failure conditions from MDS Implications for family members (including potential bone marrow donors) Czuchlewski DR et al. Surg Pathol Clin 2016:9:165, West AH et al. Ann NY Acad Sci 2014;1310:111, Wlodarski MW et al. Blood 2016;127:1387, Lewinsohn M et al. Blood 2016:127:1017.

34 Beware of diagnosing MDS based only on megakaryocyte dysplasia in germline mutation syndromes! Thrombocytopenia with germline ANKRD26 mutation Courtesy of Loann Peterson Case 301 Reichard: Germline GATA2 mutation

35 Refractory cytopenia of childhood Comprises ~50% of MDS cases in childhood Usually hypocellular; often difficult differential diagnosis with aplastic anemia Morphologic clues (erythroid islands, micromegakaryocytes) Monosomy 7 in 30-40% Somatic mutations in ~20%, also germline predisposition mutations Case 303 Yabe: RCC

36 Take home messages-3 Germline predisposition mutations are underrecognized in both children and adults presenting with cytopenias and/or MDS/AML Challenges of diagnosing true MDS in the setting of an underlying genetic predisposition Development of anemia/neutropenia Dysplasia in erythroids/granulocytes Evidence of somatic mutations or cytogenetic abnormalities

37 Thank you!

38 Malcovati Blood 2017 (Epub)