Session 4: Summary and Conclusions
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1 Session 4: Summary and Conclusions
2 Total cases in Session 4 Myeloproliferative neoplasms 16 cases Oral #300 (CEL, NOS) Mastocytosis 2 cases Oral #156 (SM-AHN) Myeloid/lymphoid neoplasms with eosinophilia and gene rearrangement (PDGFRA, PDGFRB, FGFR1 or PCM1-JAK2) Myelodysplastic/myeloproliferative neoplasms Myelodysplastic syndromes (MDS) Blastic plasmacytoid dendritic cell neoplasm 10 cases Oral #376 (PCM-JAK2 neoplasm) 17 cases Oral #124 (acml), #171 (JMML), #351 (CMML) 12 cases 2 cases Oral #314
3 Myelodysplastic syndromes Case # Submitter Panel Diagnosis Genetic features 60 Tianyu Yang MDS, unclassifiable 46,XX,del(11)(q13q23)[17]/46,XX[3]; CSF3R 88 Elizabeth Margolskee MDS, unclassifiable 45,XY,der(1)t(1;2)(q32;p11.2),der(2;11)(11pter >11q13::2 p11 >2q3?1::11q23 >11qter)[7]/46,XY[13] 289 Ming Xie MDS, unclassifiable 45,XY,inv(3)(q21q26.3),-7[2]/46,XY[19] 305 David Kim Therapy-related MDS 46,XX,t(16;21)(q24;q22)[17]/46,XX[3]; RUNX1-CBFA2T3 218 Kwun Wah MDS-RS with single lineage dysplasia DNMT3A, SF3B1, TET2 280 Catherine Leith MDS-RS with single lineage dysplasia SF3B1 363 Shanxing Zhang MDS with multilineage dysplasia U2AF1 178 Alexandra Kovach MDS with multilineage dysplasia IDH2, SRSF2, JAK2 51 Tianyu Yan MDS with multilineage dysplasia SRSF2, TET2 247 Habibe Kurt MDS with excess blasts-1 (with fibrosis) TP Jay Patel MDS with excess blasts-2 WT1, SMC3, STAG2 296 Payal Sojitra MDS with excess blasts-2 NRAS, WT1
4 What genetic studies should be done to diagnose and classify MDS? Conventional karyotype Evaluate for isolated del(5q)(+/- one other aberration) Evaluate for MDS-defining cytogenetic aberration FISH is usually not indicated if 20 metaphases are obtained SF3B1 mutation Can substitute iron stain if not available, but less sensitive (cases with 5-15% ring sideroblasts may have SF3B1 mutation and appear similar to MDS-RS with >15% ring sideroblasts) TP53 mutation in MDS with isolated del(5q)
5 Cytogenetic findings defining MDS irrespective of morphologic dysplasia Certain mutation patterns in cytopenic patients appear to predict progression to MDS/AML and poor outcome SF3B1/U2AF1/SRSF2/ZRSR2 or TET2/DNMT3A/ASXL1 + one other mutation Real MDS MDS Mutation-defined MDS Malcovati L et al. Blood 2017
6 MDS with isolated del(5q): one other cytogenetic abnormality is OK, but TP53 mutation is bad Mallo M Leukemia 2011;25:110, Jadersten M JCO 2011;29:1971, Germing U Leukemia 2012;26:1286
7 Navigating ring sideroblasts and SF3B1 data in MDS cases with <1% PB and <5% BM blasts Ring sideroblasts SF3B1 mutation Dysplastic lineages 2016 WHO <5% No or unknown One MDS with single lineage dysplasia* <5% Yes One MDS with single lineage dysplasia* <5% No or unknown Two or three MDS with multilineage dysplasia <5% Yes Two or three MDS with multilineage dysplasia 5-14% No or unknown One MDS with single lineage dysplasia* 5-14% Yes One MDS-RS with single lineage dysplasia* 5-14% No or unknown Two or three MDS with multilineage dysplasia 5-14% Yes Two or three MDS-RS with multilineage dysplasia 15% No or unknown One MDS-RS with single lineage dysplasia* 15% Yes One MDS-RS with single lineage dysplasia* 15% No or unknown Two or three MDS-RS with multilineage dysplasia 15% Yes Two or three MDS-RS with multilineage dysplasia *Classified as MDS-U if there is pancytopenia
8 Chronic myeloid leukemia, BCR-ABL1+ Case # Submitter Panel Diagnosis Blood counts Genetic features Birgitta Sander Cameron Yin CML, BCR-ABL1+, in chronic phase ( aleukemic ) CML, BCR-ABL1+, in chronic phase ( aleukemic ) HGB 11.3, WBC 7.0 (no basophilia), PLT 273 HGB 10.5, WBC 6.2 (4% metas, 5% basophils), PLT 197 t(9;22) in 3/8 metaphases, confirmed by FISH 45,X, Y,t(9;22)(q34;q11.2)[20] p210 BCR-ABL1
9 Aleukemic CML #17 5 Yin #77 Sander
10 Myeloproliferative neoplasms Case # Submitter Panel Diagnosis Genetic features 147 Madhu Ouseph Chronic neutrophilic leukemia CSF3R 222 Carmen Winters Chronic neutrophilic leukemia CSF3R, SRSF2, ASXL1 274 Shafinaz Hussein Chronic neutrophilic leukemia SRSF2, GATA2 104 Kristin Karner Essential thrombocythemia MPL 304 David Yang Favor post-et myelofibrosis with dysplastic progression (versus atypical CML, BCR-ABL1-) CALR, SF3B1, KRAS 130 April Chiu 237 Xin Liu 310 Zhihong Hu Myeloproliferative neoplasm, unclassifiable Myeloproliferative neoplasm, unclassifiable (ET versus PV with iron deficiency) Favor overt primary myelofibrosis (with monocytosis) ASXL1, SRSF2, TET2, FLT3-ITD JAK2 MPL, IDH2 361 Xueyan Chen Favor post-pv myelofibrosis JAK2, SF3B1
11 #147 Ouseph WBC 26.4, 84% polys CSF3R p.n713k
12 13 year-old with platelets 753K & Budd- Chiari. JAK2 V617F #237 Liu
13 Monocytosis in MPN versus CMML #310 Hu: 71 year old man with anemia and leukoerythroblastosis, WBC 12.5 with 24% monocytes. Bone marrow with megakaryocyte proliferation typical of PMF, grade 2 of 3 retic and positive trichrome. MPL, IDH2 mutations SSC-A Granulocyte: 57% MFI= Monocytes: 17% -400 Lymphocytes: 21% Myeloblasts: 4% CD45 V500-A B
14 What genetic studies should be done to diagnose and classify MPN (excluding eosinophilias)? Conventional karyotype Confirm clonality, evaluate for t(9;22), evaluate for secondary changes defining accelerated phase in CML BCR-ABL1 by FISH and/or qualitative RT-PCR if CML is suspected; ABL1 mutations if resistant to TKI therapy JAK2 V617F; MPL and CALR if JAK2 negative JAK2 exon12 assessment if suspected PV and JAK2 V617F negative Broader myeloid-mutation NGS panel to confirm clonality in triple negative cases CSF3R in suspected CNL
15 New genetic criteria defining AP in CML Swerdlow SH ed. Revised 4 th edition WHO Classification
16 Case # Submitter Panel Diagnosis Mutations 79 Katherine Devitt Atypical CML, BCR-ABL1 negative DNMT3A, TET2, U2AF1, KMT2A-PTD 124 John Goodlad Atypical CML, BCR-ABL1 negative SRSF2, SETBP1, CSF3R 168 Jim Cook Atypical CML, BCR-ABL1 negative SRSF2, TET2, CSF3R 212 Julia Geyer Atypical CML, BCR-ABL1 negative ASXL1, SETBP1 216 Gerald Penn Atypical CML, BCR-ABL1 negative SRSF2, ASXL1, RUNX1 315 Ashley Cunningham Atypical CML, BCR-ABL1 negative SRSF2, SETBP1, ASXL1, TET2, CSF3R 220 Kedar Inamdar CMML Adam Wood CMML-1 NPM1 351 Madhu Menon CMML-0 SRSF2, TET2, ASXL1 360 David Cantu CMML-1 SRSF2, TET2, ASXL1, JAK2 374 Scott Wendroth CMML-1 SETBP1, EZH2, NRAS, RUNX1 67 Theodore Schultheiss CMML-0 and MGUS CSF3R 122 Omar Khan JMML/Ras-associated autoimmune leukoproliferative disorder KRAS 152 Jie Li JMML PTPN Shunyou Gong JMML PTPN11, KRAS 126 John Goodlad MDS/MPN-RS-T JAK2, SF3B1, TET2 263 Christopher Cogbill MDS/MPN, unclassifiable ASXL1, SRSF2, CBL, GATA2
17 Myelodysplastic/myeloproliferative neoplasms CMML Atypical CML MDS/MPN-U MDS/MPN-RS-T Dysplasia Myeloids Myeloids (severe) Variable Erythroids (RS) Cytopenia Any Any or none Any or none Anemia Proliferation Monos 1 x 10 9 /L WBC 13 x 10 9 /L PLT 450 x 10 9 /L or WBC 13 x 10 9 /L Genetics TET2 50% ASXL1 45% SRSF2 40% RUNX1 15% CBL 15% SETBP1 10% ETNK1 2% TET2 30% SETBP1 25% ASXL1 25% NRAS 20% EZH2 15% ETNK1 9% CBL 8% TET2 30% RUNX1 15% SETBP1 10% NRAS 10% CBL 10% EZH2 10% JAK2 20% PLT 450 x 10 9 /L SF3B1 85% JAK2 60% TET2 25% DNMT3A 15% MPL 10% ASXL1 10% Median OS 31 months 12 months 22 months months Such E et al. Blood 2013;121:3005, Wang SA et al. Blood 2014;123:2645, Zoi K et al. Int J Hematol 2015;101:229, Meggendorfer M et al. Leukemia 2013;27:1852, Broseus J et al. Leukemia 2013;27:1826, Gambacorti-Passerini CB et al. Blood 2015;125:499.
18 What genetic studies should be done to diagnose and classify MDS/MPN? Conventional karyotype Confirm clonality, evaluate for t(9;22) BCR-ABL1 by FISH and/or qualitative RT-PCR to exclude CML Consider a myeloid-mutation NGS panel JAK2, MPL and CALR may suggest progression from a prior MPN JAK2 + SF3B1 common pattern in MDS/MPN-RS-T Mutation pattern can suggest CMML in borderline cases Can help confirm clonality (provided CHIP is excluded)
19 What genetic studies should be done in suspected JMML? Conventional karyotype Confirm clonality (monosomy 7), evaluate for t(9;22) BCR-ABL1 by FISH and/or qualitative RT-PCR PTPN11, KRAS, NRAS (must be somatic, not germline) CBL, NF1 (germline)
20 Blastic plasmacytoid dendritic cell neoplasm (BPDCN) Case # Submitter Panel Diagnosis Genetic findings 314 Habibe Kurt BPDCN DNMT3A, TET2 mutations 186 Anna Porwit BPDCN ZRSR2, IDH2, ETV6, PTPRT mutations
21 What genetic studies should be done in suspected blastic plasmacytoid dendritic cell neoplasm? No current genetic tests available for diagnostic purposes
22 Systemic mastocytosis (SM) Case # Submitter Panel Diagnosis Genetic findings 156 Jeffrey Craig 74 Cyrus Oster SM with associated hematologic neoplasm (CMML-0) SM with associated hematologic neoplasm (MDS-RS-SLD) KIT, ASXL1, TET2 mutations SF3B1 mutation (no KIT mutation)
23 What genetic studies should be done in (un)suspected mastocytosis? KIT Should be evaluated on lesional tissue may be absent from blood unless an associated hematologic neoplasm is present Presence of KIT mutation in bone marrow (even if involved by an overt non-mast-cell neoplasm) should stimulate a careful search for occult mast cell disease
24 Myeloid/lymphoid neoplasms (MLN) with eosinophilia and gene rearrangements Case # Submitter Panel Diagnosis Presentation 44 Nadine Aguilera MLN with PDGFRA rearrangement Atypical CML-like 312 Jo-Anne Vergilio MLN with PDGFRA rearrangement Chronic eosinophilic leukemia 349 Kyle Bradley MLN with PDGFRA rearrangement Chronic eosinophilic leukemia 324 Lawrence Low MLN with PDGFRB rearrangement Concurrent AML and T-LBL 75 Koping Chang MLN with FGFR1 rearrangement Concurrent MPN/mast cell proliferation and T-LBL 121 Omar Khan MLN with FGFR1 rearrangement MPN progressed to MPAL 286 Lynh Nguyen MLN with FGFR1 rearrangement MPN progressed to AML 379 Robert Lorsbach MLN with FGFR1 rearrangement B-ALL 32 John Astle MLN with PCM1-JAK2; small clone with PML-RARA, of uncertain significance Chronic eosinophilic leukemia 376 Magdalena Czader MLN with PCM1-JAK2 Chronic eosinophilic leukemia
25 #75: Myeloid/lymphoid neoplasm with FGFR1 rearrangement t(8;13)(p11;q12); ZMYM2 FGFR1 TdT Neck lymph node CD3
26 Bone marrow: Eosinophilia and atypical mast cell proliferation, no KIT mutation
27 Chronic eosinophilic leukemia, NOS Case # Submitter Panel Diagnosis Genetic Lesion 31 Ruijun Su CEL, NOS ETV6-ACSL6, U2AF1 and BRIP1 mutations 146 Madhu Ouseph CEL, NOS TET2 mutation 211 Daniel Socha CEL, NOS SETBP1, EZH2, JAK2, TP53 mutations 300 Geetha Jagannathan CEL, NOS ASXL1 mutation 308 Xiaohui Zhang CEL, NOS DNMT3A mutation
28 What genetic studies should be done to classify eosinophilias? Conventional karyotype Abnormality establishes CEL, NOS diagnosis or a geneticallydefined eosinophilia, also evaluate for t(9;22) to exclude CML BCR-ABL1 by FISH and/or qualitative RT-PCR FIP1L1-PDGFRA by FISH and/or RT-PCR Consider a broad myeloid-mutation NGS panel Can help establish CEL, NOS diagnosis even if karyotype is normal Should include KIT mutation assessment to evaluate for mastocytosis
29 2016 WHO Criteria for CEL, NOS
30 Mutations in idiopathic hypereosinophilias are associated with poor outcome Mutations detected in 21 patients with a diagnosis of CEL, NOS/idiopathic HES Patients ASXL1 TET2 EZH2 DNMT3A NOTCH1 SETBP1 CBL U2AF1 TP53 JAK2 NRAS BCOR GATA2 CSF3R ETV Wang SA et al. Haematologica 2017;102:1352, Wang SA et al. Mod Pathol 2016;29:854
31 Ineffective hematopoiesis Intact maturation BPDCN MDS SF3B1 RAS pathway JMML MDS/MPN ASXL1, SRSF2, SETBP1 MLN-Eo PDGFRA-v FGFR1-v PCM1-JAK2 PDGFRB-v CSF3R JAK2 MPN Effective hematopoiesis Intact maturation BCR-ABL1 MPL CALR KIT Mastocytosis B-ALL AML MPAL T-ALL Arrested maturation Myeloid lineage MLN-Eo MLN-Eo Arrested maturation Lymphoid lineage
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