Hemophagocytic Lymphohistiocytosis Associated with Acute Myeloid Leukemia with

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Hemophagocytic Lymphohistiocytosis Associated with Acute Myeloid Leukemia with RUNX 1 -RUNX 1 T 1

Hemophagocytic Lymphohistiocytosis Associated with Acute Myeloid Leukemia with RUNX 1 -RUNX 1 T 1 Fusion Adam J. Wood, D. O. Rhett P. Ketterling, M. D. April E. Chiu, M. D. Kaaren K. Reichard, M. D. Mayo Clinic, Rochester, MN © 2015 MFMER | slide-

Clinical History • 26 -year-old male in good health prior to 2/2015 when he

Clinical History • 26 -year-old male in good health prior to 2/2015 when he presented with constitutional symptoms: • Fevers • Nausea • Vomiting • Weakness with ↓ energy • Night sweats • 50 lb. weight loss © 2015 MFMER | slide-2

Clinical History Con’t 2/2015 4/2015 9/2015 AST (8 -48) U/L 1017 3158 1176 ALT

Clinical History Con’t 2/2015 4/2015 9/2015 AST (8 -48) U/L 1017 3158 1176 ALT (7 -55) U/L 909 1039 579 Alk phos (45 -115) U/L 182 508 338 Tbili (≤ 1. 2) md/d. L 0. 5 6. 7 1. 8 Hgb (13. 5 -17. 5) mg/d. L 14. 2 WBC (3. 5 -10. 5) x 109/L 1. 1 1. 3 ANC (1. 7 -7. 0) x 109/L 0. 55 0. 37 82 197 130 Blood Chemistries (normal values) CBC (normal values) PLTS (150 -450) x 109/L • ↑ LFTs • Cytopenias • ↑ ferritin (7614 μg/L) © 2015 MFMER | slide-3

Clinical History Con’t • Gastrointestinal work-up: • Biochemical abnormalities suggestive of Wilson’s disease •

Clinical History Con’t • Gastrointestinal work-up: • Biochemical abnormalities suggestive of Wilson’s disease • No Kayser-Fleischer rings • Liver biopsies did not reveal copper accumulation • Negative infectious disease work-up • Negative CT imaging with no significant lymphadenopathy © 2015 MFMER | slide-4

Clinical History Con’t • 10/2015: Hematology suggested bone marrow (BM) biopsy due to 8

Clinical History Con’t • 10/2015: Hematology suggested bone marrow (BM) biopsy due to 8 months of persistent unexplained constitutional symptoms & cytopenias © 2015 MFMER | slide-5

Morphologic Findings-Peripheral Blood • CBC: pancytopenia • Hgb 12. 7 g/d. L • RBC

Morphologic Findings-Peripheral Blood • CBC: pancytopenia • Hgb 12. 7 g/d. L • RBC 4. 21 x 1012/L • MCV 88. 1 f. L • RDW 17. 7% • WBC 0. 6 x 109/L • PLT 98 x 109/L • Smear: rare circulating tumor cell (inset) © 2015 MFMER | slide-6

Morphologic Findings-BM Aspirate Markedly ↑ BM histiocytes © 2015 MFMER | slide-7

Morphologic Findings-BM Aspirate Markedly ↑ BM histiocytes © 2015 MFMER | slide-7

Morphologic Findings-BM Aspirate Con’t Marked hemophagocytosis © 2015 MFMER | slide-8

Morphologic Findings-BM Aspirate Con’t Marked hemophagocytosis © 2015 MFMER | slide-8

Morphologic Findings-BM Aspirate Con’t Scattered atypical tumor cells © 2015 MFMER | slide-9

Morphologic Findings-BM Aspirate Con’t Scattered atypical tumor cells © 2015 MFMER | slide-9

Morphologic Findings-BM Aspirate Con’t Very rare single, thin, Auer rod identified © 2015 MFMER

Morphologic Findings-BM Aspirate Con’t Very rare single, thin, Auer rod identified © 2015 MFMER | slide-10

Morphologic Findings-BM Aspirate Con’t A B C D Morphologic spectrum of tumor cells, with

Morphologic Findings-BM Aspirate Con’t A B C D Morphologic spectrum of tumor cells, with (A, B) & without (C, D) Auer rods © 2015 MFMER | slide-11

Morphologic Findings-BM Aspirate Con’t A B C D Normal (A) & atypical (B-D) megakaryocytes

Morphologic Findings-BM Aspirate Con’t A B C D Normal (A) & atypical (B-D) megakaryocytes © 2015 MFMER | slide-12

Morphologic Findings-BM Biopsy CD 34 Hypocellular with panhypoplasia ↑ CD 34+ blasts (20 -30%)

Morphologic Findings-BM Biopsy CD 34 Hypocellular with panhypoplasia ↑ CD 34+ blasts (20 -30%) differentially distributed in the interstitium © 2015 MFMER | slide-13

Morphologic Findings-BM Biopsy Con’t Blasts with notched nuclei, stippled chromatin & mitosis © 2015

Morphologic Findings-BM Biopsy Con’t Blasts with notched nuclei, stippled chromatin & mitosis © 2015 MFMER | slide-14

Morphologic Findings-BM Biopsy Con’t CD 68 Markedly ↑ hemophagocytic histiocytes © 2015 MFMER |

Morphologic Findings-BM Biopsy Con’t CD 68 Markedly ↑ hemophagocytic histiocytes © 2015 MFMER | slide-15

Morphologic Findings-BM Biopsy Con’t CD 61 No significant population of small, atypical megakaryocytes ©

Morphologic Findings-BM Biopsy Con’t CD 61 No significant population of small, atypical megakaryocytes © 2015 MFMER | slide-16

Immunophenotype ↑ population of CD 34+ blasts © 2015 MFMER | slide-17

Immunophenotype ↑ population of CD 34+ blasts © 2015 MFMER | slide-17

Immunophenotype Con’t Blasts express: CD 34, CD 45 (dim), CD 13 (dim), CD 33,

Immunophenotype Con’t Blasts express: CD 34, CD 45 (dim), CD 13 (dim), CD 33, CD 117, HLA-DR, CD 7 (partial), CD 56 & CD 38 © 2015 MFMER | slide-18

Cytogenetics-Conventional Chromosome Study Normal © 2015 MFMER | slide-19

Cytogenetics-Conventional Chromosome Study Normal © 2015 MFMER | slide-19

Cytogenetics-FISH Within normal limits for KAT 6 A (MYST 3) & CREBBP gene regions

Cytogenetics-FISH Within normal limits for KAT 6 A (MYST 3) & CREBBP gene regions Within normal limits for PML & RARA gene regions © 2015 MFMER | slide-20

Cytogenetics-FISH Con’t RUNX 1 T 1 -RUNX 1 fusion in 47% of interphase nuclei

Cytogenetics-FISH Con’t RUNX 1 T 1 -RUNX 1 fusion in 47% of interphase nuclei Normal FISH result on multiple normal metaphases © 2015 MFMER | slide-21

Molecular Studies • PML-RARA m. RNA analysis, peripheral blood: Negative • Next generation sequencing

Molecular Studies • PML-RARA m. RNA analysis, peripheral blood: Negative • Next generation sequencing results, bone marrow: WT 1: c. 938 dup; p. Ala 314 Glyfs*3 (10%) © 2015 MFMER | slide-22

Proposed Diagnosis • Hemophagocytic lymphohistiocytosis with acute myeloid leukemia with RUNX 1 -RUNX 1

Proposed Diagnosis • Hemophagocytic lymphohistiocytosis with acute myeloid leukemia with RUNX 1 -RUNX 1 T 1 fusion & normal karyotype © 2015 MFMER | slide-23

Follow Up • Further investigation into the patients PMHx revealed a BM biopsy was

Follow Up • Further investigation into the patients PMHx revealed a BM biopsy was performed 4/7/15: • Low normal cellular marrow with variable dyspoiesis primarily involving the myeloid & megakaryocytic lineages, mild to moderate reticulin fibrosis, & mildly increased myeloblasts • Flow cytometric analysis: • ↑ in CD 34/CD 117 positive hematopoietic progenitor cells (5 -6%) with expression of HLA-DR, CD 13, CD 33 & aberrant CD 56 • Of uncertain significance • Special stains for AFB & fungal organisms were negative © 2015 MFMER | slide-24

Follow Up Con’t • Treatment: • Solu-Medrol for hemophagocytic lymphohistiocytosis • Induction chemotherapy with

Follow Up Con’t • Treatment: • Solu-Medrol for hemophagocytic lymphohistiocytosis • Induction chemotherapy with MEC • Occasional fevers, but liver function tests normalized & has had continued improvement in weakness & fatigue • Bone marrow biopsies (10/29/15 & 11/13/15): • No increase in blasts • No features of hemophagocytosis © 2015 MFMER | slide-25

Interesting Features 1. It is unusual to see a case of AML associated with

Interesting Features 1. It is unusual to see a case of AML associated with frank hemophagocytic lymphohistiocytosis • This phenomenon is different from that seen in AML with t(8; 16)(p 11. 2; p 13. 3), KAT 6 A(MYST 3)-CREBBP fusion, in which the blasts themselves demonstrate erythrophagocytosis 1 • In this case, the hemophagocytosis was an entirely different process © 2015 MFMER | slide-26

Interesting Features Con’t 2. Blasts versus lymphoma • Initially there was a cytologic diagnostic

Interesting Features Con’t 2. Blasts versus lymphoma • Initially there was a cytologic diagnostic dilemma • Particularly in light of the presence of hemophagocytosis & only exceedingly rare apparent Auer rods • Flow cytometric findings confirmed blasts & excluded lymphoma © 2015 MFMER | slide-27

Interesting Features Con’t 3. Normal karyotype but FISH positive for RUNX 1 -RUNX 1

Interesting Features Con’t 3. Normal karyotype but FISH positive for RUNX 1 -RUNX 1 T 1 fusion with a FISH signal pattern consistent with a balanced t(8; 21)(q 22; q 22) • The expected balanced FISH signal pattern in the interphase nuclei strongly suggests this is not a cryptic translocation which indicates the normal chromosome result is distinctly unusual • In our practice we do not routinely perform FISH for abnormalities that are not known to be cytogenetically cryptic • In this case, it was only an afterthought to order FISH for t(8; 21) after we discovered that the tumor cells were in fact blasts (& not lymphoma), were negative for the t(8; 16), had single, thin Auer rods & expressed CD 562, 3 • The lack of a t(8; 21) AML clone to divide in a BM chromosome study is extremely unusual & suggests that the BM milieu was such that the blasts were inhibited from dividing © 2015 MFMER | slide-28

References 1. Haferlach et al. Leukemia 2009; 23: 934 -43. 2. Hurwitz et al.

References 1. Haferlach et al. Leukemia 2009; 23: 934 -43. 2. Hurwitz et al. Blood 1992; 80: 3182 -8. 3. Swerdlow et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4 th edition. © 2015 MFMER | slide-29