Society for Hematopathology/ European Association for Haematopathology 2013 Workshop Case 145 Nidhi Aggarwal, M.D.; Robert L. Redner, MD; Fiona E. Craig, M.D. University of Pittsburgh Medical Center

Clinical History 73 year-old male with history of a high-grade sarcoma of the thigh diagnosed January 2012, status post chemotherapy [Adjuvant Adriamycin (Doxorubicin) and Ifosfamide). Acute myeloid leukemia diagnosed November Enrolled in phase 1 trial ATRA plus Dasatinib (UPCI ). Bone marrow obtained day 28 status post chemotherapy.

Peripheral smear Patient valueReference range WBC0.5X10^9/l Hemoglobin9.7g/dl Platelet9X10^9/l Polys16% (0.08X10^9/l) Lymphocytes82% (0.41X10^9/l) Monocytes2% (0.01X10^9/l)

Bone marrow aspirate: 84% blasts

CD14 - CD36,CD64 + CD15,CD33 + HLA-DR + CD117 - CD34 - SSC CD4 + MPO +

Butyrate esteraseButyrate esterase with fluoride

t(8;16)(p11;p13)

Bone marrow biopsy day 28 status post therapy Bone marrow biopsy at the start of therapy

SH/ EAHP Case 145: Persistent therapy-related AML with t(8;16) (p11;p13). Receiving novel therapy (protocol UPCI ) with ATRA and escalating doses of Dasatinib Started on Decitabine therapy on 01/28/2013 The patient died on 03/11/2013. Follow-up:

AML with t(8;16) (p11;p13) Rare distinct subtype of AML (<1% of all AML). Atlas of Genetic and Cytogenetics in Oncology and Haematology Translocation inhibits RUNX1 regulated transcription, leading to differentiation block. Chr 8: MYST3/ MOZ Chr 16: CERBBP/ CBP

Younger patients including infants More common in women (?) More frequent in therapy related AML than de novo AML – Short latency (6-23months) – Absence of preceding MDS Extramedullary disease especially skin – may precede bone marrow involvement. Relatively high rate of DIC Extremely poor prognosis – Disease free survival very short ~3-4 months & overall survival 8-9 months – Rare spontaneous remission in infants AML with t(8;16) - Clinical features

AML with t(8;16) - Pathologic features Monocytoid/ myelomonocytoid differentiation Morphologic features can overlap with Acute promyelocytic leukemia Erythrophagocytosis Immunophenotype shows myeloid and monocytic markers, and usually CD34 negative and CD117 negative A few known collaborating somatic genetic alterations. J Clin Oncol (1993)11: ; Leukemia Research (2013) 37:32-36; Leukemia (2009) 23:934–943

ATRA classically used to induce differentiation in APL EGFR inhibitors (Erlotinib/ Gefitinib) combined with naturally occurring pro-differentiation agents (ATRA or Vitamin D) helps differentiation of AML [Cell Cycle. 2013;(12):18]. Epigenetic modification [Clin Epigenetics. 2013;5(1):12] – Histone deacetylase inhibitor: Valproic acid – DNA methylation inhibitors Furazolidone has been investigated as a differentiation agent for AML [PLoS One. 2013;8(8):e doi: / journal.pone eCollection 2013]. Therapeutic induction of differentiation.

Patient with AML-M5CD11b: Marker for differentiation Induction of differentiation with ATRA & Dasatinib Src family kinase (SFK), overexpressed in AML, is a negative regulator of ATRA-induced differentiation Dasatinib inhibits ABL and Src family kinase (SFK)

UPCI protocol: Dasatinib and All-Trans Retinoic Acid for Relapsed/Refractory and/or Elderly Patients with Acute Myeloid Leukemia (AML) Non induction candidate elderly male (>65yrs). Relapsed/Refractory AML: – Failed 2 inductions, or relapsed within 6months. If relapse after >6 months - failed 2 inductions. – AML after MDS/MPN and after chemotherapy also considered). Fixed dose ATRA with escalating doses of Dasatinib.

Diagnosis Proposed Diagnosis – Persistent acute myeloid leukemia with monocytic differentiation and t(8;16), likely therapy related. Consensus Diagnosis – Therapy-related myeloid leukemia, acute myeloid leukemia (monocytic) with t(8;16)(p11;p13)