Pei Lin Professor of Pathology Department of Hematopathology MD Anderson Cancer Center peilin@mdanderson.org

Clinical History 80-year-old man with a history of HTN, neuropathy and chronic anemia Came to MDACC to see Dr. Garcia-Manero on 8/2/2007 for an outside diagnosis of Refractory anemia or CMML one year ago Transfusion independent and untreated. Chronic fatigue, dizziness PE: o hepatosplenomegaly or peripheral adenopathy

Outside BM biopsy (3/7/2007) WBC 4.7, Hgb 11.1, MCV 93, Platelet 341, Neutrophils 41.3, Lymphs 32.3, Monos 25.3 (abs: 1189), Eos 0.9, Basos 0.2, Hypercellular bone marrow (70-90%) with left-shifted granulopoiesis, megakaryocytic hyperplasia, dyserythropoiesis and 3% blasts (see comment)

Outside BM (comment): Flow cytometry immunophenotypic analysis of a sample from the bone marrow aspirate at Dianon Systems, Stratford, Connecticut demonstrated non-specific findings including left-shifted granulopoiesis with decreased expression of CD16.

Lab (8/2007 MDACC) WBC: 5.7, hemoglobin 12, and platelet 219 Neutrophils 67%, lymphocytes 17%, monocytes 16% (abs: 912) Ferritin level is 915, Epo: 45.8.

RAS mutation negative

5/11/2010 WBC: 7.6, HGB: 9.0, MCV: 94, Platelet: 273, Neutrophils: 68.0, Lymphs: 11.0, Monos: 16.0, Eos: 2.0, Metas: 3.0

JAK2 V617F PCR: 41% RAS mutation: neg

Pomalidomide 5/21/2010 Danazol 1/7/2011 JAK2 inhibitor 4/2011

Risk Stratification IPSS, International Prognostic Score System DIPSS, dynamic IPSS DIPSS, DIPSS plus MIPSS, Molecular IPS GPSS, Genetics-Based PSS 1WBC 4 109/L or 30 109/L in Lille; WBC 25 109/L in IPSS, DIPSS, DIPSS. 2Platelets 100 109/L in DIPSS and 200 109/L in MIPSS. 3DIPSS unfavorable karyotype: complex karyotype or 1 or 2 abnormalities including 8, 7/7q, i(17q), 5/5q, 12p, inv(3) or 11q23 rearrangement; GPSS high-risk: complex without MK, 2 abnormalities not included in very high-risk category, 5q, 8, other autosomal trisomies except 9, and other sole abnormalities not included in other risk categories; very high-risk: MK, inv(3), i(17q), 7/7q, 11q or 12p. 4Includes driver mutation status (JAK2/MPL/CALR), as well as ASXL1 and SRSF2. Mascarenhas J Looking forward: novel therapeutic approaches in chronic and advanced phases of myelofibrosis in ASH education book: 2015

Monocytosis is an adverse prognostic factor for survival in younger patients with primary myelofibrosis 129 patients PMF ≤ 60 yrs. Range: 18–60, median 52) WBC: 30 k/uL Hb: 10 g/dL PLT 100 k/uL W, H, P, M W, H, P Leukocyte count (30k/uL) Hemoglobin level (<10 g/dL) Platelet count (< 100/uL) Absolute monocyte count of ≥1 × 109 L1 x 10(9)L(-1) WH M.A. Elliott, S. Verstovsek, D. Dingli, S.M. Schwager, R.A. Mesa, C.Y. Li, A. Tefferi Leuk Res 2007;31:1503-9.

Proposed Diagnosis and Take home points Dx: Primary myelofibrosis presenting with persistent monocytosis, JAK2 V617F + Monocytosis may occur as initial presentation of PMF or during the disease course Persistent monocytosis is associated with an adverse prognosis May not be associated with RAS mutations or cytogenetic aberrations Megakaryocytic dysplasia may be diagnostic clue