Dysfunctional Families Annette S. Kim, MD, PhD Associate Professor, Harvard Medical School Brigham and Women s Hospital

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in a position to influence or control the content of CME disclose an relevant financial relationship WITH COMMERCIAL INTERESTS which the or their spouse/partner have, or have had, within

Kim declares no conflict(s) of interest to disclose Initial Presentation 55 o M diagnosed with AML after 5 ears of thromboctopenia CBC at ation: 59.68 > 9.0 (102.

$MiSeq Identification of SNVs and CNVs TAT <7d (2-3runs/week, 30 patients/run) Tpical run Average coverage: 1500-2000X >200 coverage: >90% <50 coverage: <5% Variant allele fraction Gene$

1 Dsfunctional Families Annette S. Kim, MD, PhD Associate Professor, Harvard Medical School Brigham and Women s Hospital Disclosure of Relevant Financial Relationships USCAP requires that all planners (Education Committee) in a position to influence or control the content of CME disclose an relevant financial relationship WITH COMMERCIAL INTERESTS which the or their spouse/partner have, or have had, within the past 12 months, which relates to the content of this educational activit and creates a conflict of interest. Dr. Annette S. Kim declares no conflict(s) of interest to disclose Initial Presentation 55 o M diagnosed with AML after 5 ears of thromboctopenia CBC at ation: > 9.0 (102.4) < 86 Diff: N 30 L 14 Mo 14 Ba 7 Meta 2 Melo 2 Pro 6 Blast 25 BMB: >95% cellularit, 80% blasts, micromegakaroctes Normal karotpe Flow ctometr: Positive: CD45(dim), CD13, CD33, CD34, CD117, HLA-DR Negative: CD3, CD5, CD7, CD11b, CD14, CD15, CD19, CD20, CD64 Initial Molecular Results Brigham and Women s Hospital Rapid Heme Panel 95 gene amplicon-based assa Illumina MiSeq Identification of SNVs and CNVs TAT <7d (2-3runs/week, 30 patients/run) Tpical run Average coverage: X >200 coverage: >90% <50 coverage: <5% Variant allele fraction Gene Variant (c.) Variant (p.) Diagnosis (BM) ASXL1 c.2070_2071deltc p.d690fs* 49.6% IDH1 c.394c>t p.r132c 14.0% KRAS c.34g>c p.g12r 4.0% NRAS c.37g>t p.g13c 41.7% SRSF2 c.284c>t p.p95l 33.3% Assa described in Kluk MJ et al. J Mol Diagn. 2016;18:

Interval Histor Post re-induction Subsequent Biops Induction (7+3)

re-induction, less than 5% blasts In the following 9 months, CBCs

with a monoctosis (up to 32%), thromboctopenia (12-36 K/uL), and

9 g/dl) Subsequent bone marrow biopsies showed 5-10% blasts

monoctes) D: Chronic melomonoctic leukemia (CMML-1) R: Decitabine

) Diagnosis (BM) 3 months (BM) 7 month (BM) ASXL1 c.2070_2071deltc p.

1% IDH1 c.394c>t p.r132c 14.0% NRAS c.35g>a p.g12d 22.1% 21.6% NRAS c.

3% SRSF2 c.284c>t p.p95l 33.3% 26.2% 22.

progressive pink-ellowish papules on the trunk and etremities while

Skin biopsies were performed. CBC: 5.42 > 8.3 (91.

CD1a Lsozme Positive for: S100 (subset), CD33 (uniform), Ki67

Molecular Results Gene Variant (c.) Variant (p.

2070_2071deltc p.d690fs* 49.6% 51.2% 41.0% 46.0% ETV6 c.459_460insg p.

2 Interval Histor Post re-induction Subsequent Biops Induction (7+3) and re-induction due to residual blasts on das 15 and 27 At end of re-induction, less than 5% blasts In the following 9 months, CBCs during these 9 months were notable for a leukoctosis (up to 55 K/uL) with a monoctosis (up to 32%), thromboctopenia (12-36 K/uL), and anemia ( g/dl) Subsequent bone marrow biopsies showed 5-10% blasts Hpercellular marrow Dsplasia (small hpolobated megakaroctes, atpical monoctes) D: Chronic melomonoctic leukemia (CMML-1) R: Decitabine CD34 CD34 Interval Molecular Results Gene Variant (c.) Variant (p.) Diagnosis (BM) 3 months (BM) 7 month (BM) ASXL1 c.2070_2071deltc p.d690fs* 49.6% 51.2% 41.0% ETV6 c.459_460insg p.e153fs* 21.0% 15.1% IDH1 c.394c>t p.r132c 14.0% NRAS c.35g>a p.g12d 22.1% 21.6% NRAS c.37g>t p.g13c 41.7% 24.3% 26.5% RUNX1 c.736_737insc p.p245fs* 37.2% 25.3% SRSF2 c.284c>t p.p95l 33.3% 26.2% 22.9% Bad Skin Over a 5 month period, the patient noted slowl progressive pink-ellowish papules on the trunk and etremities while on decitabine. Some became necrotic, other became coalescent. Skin biopsies were performed. CBC: 5.42 > 8.3 (91.3) < 39 (N 52 L 15 Mo 20 Eo 2 Ba 4 Meta 3 ) CD34 CD163 CD56 Langerin CD1a Lsozme Positive for: S100 (subset), CD33 (uniform), Ki67 (20-30%) Negative for: BRAF V600E, TCL1, CD123, GranzmeB, MPO Skin Molecular Results Gene Variant (c.) Variant (p.) Diagnosis (BM) 3 months (BM) 7 month (BM) 10 month (skin) ASXL1 c.2070_2071deltc p.d690fs* 49.6% 51.2% 41.0% 46.0% ETV6 c.459_460insg p.e153fs* 21.0% 15.1% IDH1 c.394c>t p.r132c 14.0% 31.2% KRAS c.182a>g p.q61r 24.5% NRAS c.35g>a p.g12d 22.1% 21.6% 2.2% NRAS c.37g>t p.g13c 41.7% 24.3% 26.5% 7.8% RUNX1 c.736_737insc p.p245fs* 37.2% 25.3% 11.9% SRSF2 c.284c>t p.p95l 33.3% 26.2% 22.9% 16.1% 2

But wait, there is more Diagnosis- What is in a name? Gene Variant (c.) Variant (p.) Diagnosis (BM) 3 months (BM) 7 month (BM) 10 month (skin) 13 month (skin) 13 month (BM) ASXL1 c.2070_2071deltc p.

1% 21.6% 2.2% 3.4% 32.2% NRAS c.37g>t p.g13c 41.7% 24.3% 26.5% 7.8% 1.8% 13.3% RUNX1 c.736_737insc p.p245fs* 37.2% 25.3% 11.9% 17.4% 28.5% SRSF2 c.284c>t p.p95l 33.3% 26.2% 22.9% 16.1% 34.5% 33.

Differential diagnosis of skin lesions in a patient with leukemia Leukemias with cutaneous histioctic lesions Clonal relatedness- stage of maturation matters Differential Diagnosis of Skin Lesions in

3 But wait, there is more Diagnosis- What is in a name? Gene Variant (c.) Variant (p.) Diagnosis (BM) 3 months (BM) 7 month (BM) 10 month (skin) 13 month (skin) 13 month (BM) ASXL1 c.2070_2071deltc p.d690fs* 49.6% 51.2% 41.0% 46.0% 33.1% 43.2% ETV6 c.459_460insg p.e153fs* 21.0% 15.1% 6.9% 8.7% IDH1 c.394c>t p.r132c 14.0% 31.2% 41.4% 4.3% KRAS c.182a>g p.q61r 24.5% 33.4% NRAS c.35g>a p.g12d 22.1% 21.6% 2.2% 3.4% 32.2% NRAS c.37g>t p.g13c 41.7% 24.3% 26.5% 7.8% 1.8% 13.3% RUNX1 c.736_737insc p.p245fs* 37.2% 25.3% 11.9% 17.4% 28.5% SRSF2 c.284c>t p.p95l 33.3% 26.2% 22.9% 16.1% 34.5% 33.0% BRAF c.1786g>c p.g596r 28.9% Cutaneous involvement b the patient s known meloid neoplasm (leukemia cutis) (with partial Langerhans cell differentiation) Wh is this an Evening Smposium Case? Differential diagnosis of skin lesions in a patient with leukemia Leukemias with cutaneous histioctic lesions Clonal relatedness- stage of maturation matters Differential Diagnosis of Skin Lesions in Patients with Leukemia Unrelated to Leukemia Secondar to Treatment Associated with Leukemia Unrelated SCC Unrelated BCC Other unrelated neoplasm or proliferation Graft-versus-host disease Infection Drug eruption Sweet's sndrome (neutrophilic) Sweet s sndrome (histioctoid) Langerhans cell histioctosis Other accumulations of histioctes/dendritic cells Histioctoid slightl more prevalent in HMs Bush and Wick. J Cutan Pathol. 2016;43: Sweet s Sndrome CD68 MPO Ghoufi et al.. Medicine. 2016;95:e3033. Histioctoid Processes Associated with Hematopoietic Neoplasms Histioctoid Process Immunophenotpe Associated Hematologic Neoplasms Generalized Eruptive Histioctosis CD68+, CD163+, CD14+, CD56-, CD123-, AML, FIP1L1-PDGFRA, CMML* CD1a-, S100-, Langerin-, FXIIIa- Langerhans Cell Histioctosis Langerhans Cell Sarcoma Meloid Dendritic Cell Dscrasia Plasmactoid Dendritic Cells Blastic Plasmactoid Dendritic Cell Neoplasms, Blastic Indeterminate Dendritic Cell Tumors, Melomonoctic Cell Tumors CD1a+, S100+, CD4, Langerin+/-, CD68+/-, CD56-/+ (high mitotitc rate and atpia) S100+, CD1a+, Langerin+, CD68+/-, usuall MPO-, CD33-, CD56-, lsozme+/- Lsozme+, GranzmeB+, BDCA-3+, MPO-, CD163/CD68+/- CD4+, CD56-, CD123+, CD68+, GranzmeB+, BDCA2+, TCL1+, MA+ BPDCN: CD123+, CD4+, CD56+/-, TCL1+; BiDCT: CD68+, CD1a+, CD33+,, CD56+/-, Langerin-, CD123- MMCT: CD68+, CD33+, MPO+ AML, MDS, JMML, CMML, T-ALL*, DLBCL, PTCL, histioctic sarcoma, ABL, ALL AML MDS, PMF, AML *Proven to be clonall related b ctogenetics or molecular CMML*, AML*, MPN*, MDS/MPN* CMML (all terms from 1 paper) Associated with Leukemia Unrelated to Leukemia Secondar to Treatment Associated with Leukemia Reactive to the leukemia Sweet s Sndrome Sweet s Sndrome Meloid Neoplasm Leukemia cutis (all neoplastic leukoctic infiltrates in the skin) Other Histioctic Proliferations Reactive to the leukemia Other Histioctic Proliferations 3

Passengers, Drivers, Backseat Drivers, and Boston Drivers = variable number of passenger mutations = founder mutation(s) z = secondar mutation(s) n = progression mutation(s) z z +n Mastoctosis HSC

Leukemia. 2015;29:1115-1122. Acquisition of KIT variant is a late event and, ecept in ASM-AHN, occurs onl in more differentiated mast cells.

Rad - Image:Hematopoiesis (human) diagram.png b A. Rad. ETV6, RUNX1, NRAS KRAS BRAF? IDH1 Where in the famil tree did things go wrong? Gene Variant (p.) AML CMML Skin ASXL1 p.d690fs* 49.6% 41.0% 46.

4 Passengers, Drivers, Backseat Drivers, and Boston Drivers = variable number of passenger mutations = founder mutation(s) z = secondar mutation(s) n = progression mutation(s) z z +n Mastoctosis HSC Initiation Evolution Defining MDS/MPNs MPNs SM RAS pathwa JAK2/CALR KIT Signaling Transcription All Epigenetic TET2, ASXL1 CNL CSF3R All RNA Splicing SRSF2, (SF3B1*, U2AF1, ZRSR2) z z +n Jawhar et al. Leukemia. 2015;29: Acquisition of KIT variant is a late event and, ecept in ASM-AHN, occurs onl in more differentiated mast cells. PRESENTATION Dsfunctional TITLE Families ASXL1 Major TET2 Subclone(s): and/or SRSF2SRSF2, NRAS, IDH1, KRAS KIT Adapted from: Mikael Häggström, from original b A. Rad - Image:Hematopoiesis (human) diagram.png b A. Rad. ETV6, RUNX1, NRAS KRAS BRAF? IDH1 Where in the famil tree did things go wrong? Gene Variant (p.) AML CMML Skin ASXL1 p.d690fs* 49.6% 41.0% 46.0% ETV6 p.e153fs* 15.1% IDH1 p.r132c 14.0% 31.2% KRAS p.g12r 4.0% KRAS p.q61r 24.5% NRAS p.g12d 21.6% 2.2% NRAS p.g13c 41.7% 26.5% 7.8% RUNX1 p.p245fs* 25.3% 11.9% SRSF2 p.p95l 33.3% 22.9% 16.1% BRAF p.g596r p.g596r found in colon, lung, bladder, and skin (cell line) INACTIVATING variant in vitro BRAF Moretti et al. Biochim Biophs Acta. 2009;1793: Take Home Messages Leukemia cutis is a ver broad term and does NOT mean cutaneous involvement b an acute leukemia Processes ma demonstrate a spectrum of maturation, and man cases just don t fit into a bo Clonal evolution can be implied b sampling multiple samples over time and comparing mutations and variant allele fractions (VAFs) This case involves at least three different clinical, morphologic, immunophenotpic, and molecular stages of differentiation of the same meloid neoplasm Mabe pathologists should be lumpers and not splitters (or lumpers and splitters ) Case 3 Panelists Diagnoses Langerhans cell sarcoma (DD: histioctic sarcoma, CMML) possibl related to AML Residual AML (5-10% blasts, dsmegakaropoiesis) on decitabine showing monoctosis in peripheral blood and differentiation to Langerhans cells in skin Underling CMML with cutaneous involvement PRESENTATION TITLE 4

References Ziegler et al. JAMA Dermatol. 2015;151:766-769. (GEH with PDGFRA) *Shon et al. J Cutan Pathol. 2013;40:725-729. (*GEH with CMML, loss of Y) Klemke et al. J Am Acad Dermatol.

5 References Ziegler et al. JAMA Dermatol. 2015;151: (GEH with PDGFRA) *Shon et al. J Cutan Pathol. 2013;40: (*GEH with CMML, loss of Y) Klemke et al. J Am Acad Dermatol. 2003;49: (GEH with AMML) Montero et al. Actas Dermosifiliogr. 2012;103: (GEH with CMML) Magro et al. Ann Diagn Pathol. 2016;25: (MDC with HMs) Sagransk et al. Am J Dermatopathol. 2013;35: (LCS with AML) Ozono et al. Int J Hematol. 2011;93: (LCH-like with JMML) Xu et al. Int J Clin Ep Med. 2015;8: (LCH and AML) Iwasaki et al. J Dermatol. 2013;41: , (LCH and CMML with review of other HMs) Edelbroek et al. Br J Dermatol. 2012;167: (LCH with HM) Pina-Oviedo et al. Am J Dermatopathol. 2016; epub (PMID ) (LCH with LC AML) *Rodig et al. Am J Hematol. 2008;83: (*LCH and T-ALL, NOTCH1 mutated) *Dargent et al. J Cutan Pathol. 2016;43: (*PDC and CMML, +13) *Vermi et al. Am J Surg Pathol. 2004;28: (*PDCs and meloid neoplasms, -7) Vitte et al. Am J Surg Pathol. 2012;36: (MMCT, MPDCP, BPDCN, BIDCT and CMML) Jawhar et al. Leukemia. 2015;29: (Mast cell neoplasm) Bush and Wick. J Cutan Pathol. 2016;43: (Sweet s sndrome) Ghoufi et al.. Medicine. 2016;95:e3033. (Sweet s sndrome) Moretti et al. Biochim Biophs Acta. 2009;1793: (BRAF variants) Mossner et al. Blood. 2016;128: (clonal evolution in MDS) Acknowledgments A special thanks to members of the AMP Chronic Meloid Neoplasm working group: Rebecca McClure Mark Ewalt Jennifer Crow Rachel Sargent Also, thanks to all m colleagues at BWH/DFCI for man informative conversations! Gabriel Griffin Jon Aster Vignesh Shanmugam Coleman Lindsle Elizabeth Morgan Frank Kuo Scott Granter Neal Lindeman Jason Hornick Important Information Regarding CME/SAMs The Online CME/Evaluations/SAMs claim process will onl be available on the USCAP website until September 30, No claims can be processed after that date! After September 30, 2017 ou will NOT be able to obtain an CME or SAMs credits for attending this meeting. 5

Please Silence Your Cell Phones. Thank You

Please Silence Your Cell Phones Thank You Utility of NGS and Comprehensive Genomic Profiling in Hematopathology Practice Maria E. Arcila M.D. Memorial Sloan Kettering Cancer Center New York, NY Disclosure