Primary Myelofibrosis (PMF) 2023 Update - PDF

Primary myelofibrosis (PMF) 2023 update on diagnosis ,risk stratification, and management according to (ICC) classification. Supervised by: Dr.Yassmin Ali Alaamiri Consultant hematopathologist Presented by : Samah Hasan 3rd year Iraqi board of hematopathology  Intro...

Primary myelofibrosis (PMF) 2023 update on diagnosis ,risk stratification, and management according to (ICC) classification. Supervised by: Dr.Yassmin Ali Alaamiri Consultant hematopathologist Presented by : Samah Hasan 3rd year Iraqi board of hematopathology  Introduction Primary myelofibrosis (PMF) is a myeloproliferative neoplasm (MPN) characterized by stem cell-derived clonal myeloproliferation that is often but not always accompanied by JAK2, CALR, or MPL mutations; additional features include bone marrow reticulin/collagen fibrosis,osteosclerosis, aberrant inflammatory cytokine expression, anemia, hepatosplenomegaly, extramedullary hematopoiesis (EMH), constitutional symptoms, risk of leukemic progression. The incidence of PMF is 0.44-1.5 / 100,000 person-year and occurs predominantly in the 60-70 years age.  Pathophysiology of PMF PMF results from neoplastic transformation of a pluripotent hematopoietic stem cell. Somatic Mutation of the signaling pathway (JAK2/STAT 5 ) Janus kinase/signal transducer and activator of transcription which is involved in signal transduction for erythropoietin, thrombopoietin, and granulocyte colony-stimulating factor (G-CSF) Approximately 50-60% of patients with PMF have a gain mutation in JAK2 which leads to increase cytokine responsiveness of myeloid cells.  Mutations of the thrombopoietin receptor gene (MPL) or the calreticulin (CALR ) gene also may be involved. However, there are rare cases of PMF in which none of these three mutations are present (triple-negative primary myelofibrosis). Platelets, megakaryocyte and monocyte are thought to secrete several cytokines such as platelet derived growth factor PDGF , IL-1 , transforming growth factor beta (TGF beta) , and basic fibroblast growth factor BFGF which result in fibroblast formation and excessive collagen deposition.  Clinical features of PMF in many patients, myelofibrosis is asymptomatic (30%), About one-third of people don’t show symptoms during the disorder’s early stages. When they are symtomatic (70%), the most common clinical features of myelofibrosis: Spleenomegaly (90%) Hepatomegaly (50%) Constitutional symptoms such as: Fatigue (the most common presenting symptom) Fever, Night sweats , Weight loss.  Anemia Leukocytosis or thrombocytosis is common; leukopenia or thrombocytopenia is less common Gouty arthritis and renal stones Marked thrombocytosis may lead to thrombosis or hemorrhagic episodes Uncommon symptoms include pruritus and pulmonary hypertension Other disease complications include symptomatic portal hypertension that might lead to variceal bleeding or ascites and non-hepatosplenic EMH that might lead to cord compression, pleural effusion, pulmonary hypertension, or diffuse extremity pain. Diagnosis of Primary Myelofibrosis Current diagnosis of PMF is based on the 2022 ICC criteria and involves a composite assessment of clinical and laboratory features. Complete blood count (CBC) and peripheral blood smear Bone marrow aspirate and biopsy Testing for JAK2, CALR, and MPL mutations  Classification of PMF Primary myelofibrosis (PMF) is one of four JAK2 mutation-prevalent myeloproliferative neoplasms (MPN), which also include polycythemia vera (PV), essential thrombocythemia (ET), and MPN unclassifiable (MPN-U). MPNs are included in the 2022 International Consensus Classification (ICC) category of myeloid neoplasms (which also includes acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). The ICC subclassifies PMF into “prefibrotic” and “overtly fibrotic” stages (Table 1). TABLE 1. International consensus classification (ICC) diagnostic criteria for primary myelofibrosis, overt and pre-fibrotic. Primary myelofibrosis (Overtly fibrotic stage) Primary myelofibrosis (Pre-fibrotic/early stage) (Diagnosis requires meeting all 3 major criteria and (Diagnosis requires meeting all 3 major criteria and one minor criterion) one minor criterion) 1.Major criteria: Megakaryocyte proliferation and 1.Major criteria : Megakaryocyte proliferation and atypia, accompanied by ≥grade 2 reticulin/collagen atypia, accompanied by ≤grade 1 reticulin/collagen fibrosis fibrosis, granulocyte proliferation/decreased 2.Presence of JAK2, CALR or MPL mutations, or erythropoiesis presence of other clonal markers, or absence of 2.Presence of JAK2, CALR or MPL mutations, or evidence for reactive bone marrow fibrosis presence of other clonal markers, or absence of 3.Not meeting ICC criteria for other myeloid evidence for reactive bone marrow fibrosis neoplasms 3.Not meeting ICC criteria for other myeloid neoplasms Minor criteria: Minor criteria: Anemia not otherwise explained Anemia not otherwise explained 9 9 Leukocytosis ≥11 × 10 /L Leukocytosis ≥11 × 10 /L Palpable splenomegaly Palpable splenomegaly Increased serum lactate dehydrogenase Increased serum lactate dehydrogenase A leukoerythroblastic blood smear Furthermore, about 15% of patients with ET or PV develop a PMF-like phenotype over time, referred to as post-ET or post-PV myelofibrosis (MF), with similar treatment and outcome  Complet blood count/peripheral blood smear Prefibrotic Initially normal or increased blood counts Mild neutrophilia with a left shift Thrombocytosis (mild / moderate) No OR / borderline anemia No OR/myeloblasts No OR/ leukoerythroblastosis Overt Thrombocytopenia with bizarre abnormal large platelets with altered granulation; in addition, fragmented megakaryocytes can be seen on the peripheral smear Leukoerythroblastosis and anemia Myeloblasts (usually > 5%)  Red blood cells (RBCs) are poikilocytic. Reticulocytosis and polychromatophilia may be present; teardrop-shaped RBCs (dacrocytes) are characteristic morphologic features. Nucleated RBCs and neutrophil precursors are typically present in peripheral blood Additional investigations: Lactate dehydrogenase (LDH) Prefibrotic: normal or borderline increased lactate dehydrogenase Overt: increased lactate dehydrogenase Alkaline phosphatase, uric acid, leukocyte alkaline phosphatase and vitamin B12 are increased Bone marrow examination Prefibrotic Hypercellular bone marrow with atypical megakaryocytic proliferations(clustered (loose or tight) megakaryocyte, aberrant N:C ratios hyperchromatic, bulbous or irregularly folded nuclei Often bare megakaryocytic nuclei Erythropoiesis may be reduced with excess granulocyte Absent or only slight reticulin fibrosis  Overt fibrotic stage Hypocellular bone marrow with usually alternating cellular and hypocellular regions Atypical megakaryocytes can form tight clusters or sheets Bone marrow aspirate is often difficult (dry tap) in about 50% of patients. Marrow osteosclerosis with irregular, broad bony trabeculae Markedly dilated sinuses Performing a bone marrow biopsy is essential for confirming the diagnosis.  In bone marrow biopsies, stromal structural fibres are detected by reticulin and trichrome stains, routine stains performed on bone marrow biopsy specimens in diagnostic laboratories. Increased reticulin staining (reticulin fibrosis) is associated with many benign and malignant conditions while increased trichrome staining (collagen fibrosis) is particularly prominent in late stages of severe myeloproliferative diseases or following tumour metastasis to the bone marrow Reticulin stain Bone marrow biopsy sections for each grade from grade 0 to grade 3 and each section is stained with Masson's trichrome stain and imaged at 10x magnification. Grade 0 is normal bone marrow with only perivascular type I collagen (blue). Grade 1 shows minimal presence of type I collagen in the central of bone marrow. Grade 2 shows paratrabecular and prominent central deposition with interconnecting collagen fibers. Grade 3 shows extensive interconnected type I collagen fibers.  Cytogenetic/Molecular Approximately one-third of patients with primary MF (PMF) present with cytogenetic abnormalities; the most frequent are del(20q), del(13q), trisomy 8 and 9, and abnormalities of chromosome 1 including duplication 1q. Other less frequent lesions include -7/del(7q), del(5q), del(12p), +21 and der(6)t(1;6)(q21;p21.3) Based on prognostic effect, cytogenetic findings in MF are classified as either 'favorable' or 'unfavorable  The former include normal karyotype or isolated del(20q) or del(13q) and the latter all other abnormalities. Unfavorable cytogenetic profile in both PMF and post-PV/ET MF confers an independent adverse effect on survival; it is also associated with higher JAK2V617F mutational frequency. In addition to their prognostic value, cytogenetic studies in MF ensure diagnostic exclusion of other myeloid neoplasms that are sometimes associated with bone marrow fibrosis (e.g. BCR-ABL1-positive or PDGFRB-rearranged) and also assist in specific treatment selection (e.g. lenalidomide therapy is active in MF associated with del(5q).  Somatic mutations in MPN, including PMF, are operationally classified into “driver” and “other” mutations; the former include JAK2, CALR and MPL, and the latter ASXL1, SRSF2, U2AF1, among others. It is generally believed that driver mutations are essential for the MPN phenotype whereas “other” mutations might contribute to disease progression and leukemic transformation potentially preceding the 3 primary genetic drivers of myeloproliferative neoplasm development. Research have identified other potential MF causative mutations in NRAS, KRAS, PTPN11, GATA2, TP53, and RUNX1 in less than 5% of patients.  PMF should be distinguished from other closely related myeloid neoplasms including chronic myeloid leukemia (CML), PV, ET, MDS, chronic myelomonocytic leukemia (CMML) and “acute myelofibrosis) The presence of dwarf megakaryocytes raises the possibility of CML and should be pursued with BCR-ABL1 cytogenetic or molecular testing. Patients who otherwise fulfill the diagnostic criteria for PV should be labeled as “PV” even if they display substantial bone marrow fibrosis  Prefibrotic PMF with thrombocytosis can mimic ET in its presentation and mutation profile (both can express JAK2, CALR or MPL mutations); therefore, careful morphologic examination is necessary to distinguish the two ( megakaryocytes in ET are distributed in loose clusters and are large and mature-appearing whereas those in prefibrotic PMF display tight clusters, abnormal maturation with hyperchromatic and irregularly folded nuclei) the distinction between ET and pre-fibrotic PMF is prognostically relevant.  MDS or MDS/MPN should be suspected in the presence of dyserythropoiesis or dysgranulopoiesis. CMML is a possibility in the presence of peripheral blood monocyte count ≥0.5 × 109/L and monocyte percentage ≥10%. Patients with acute MF (either acute panmyelosis with MF or acute megakaryoblastic leukemia) usually present with severe constitutional symptoms, pancytopenia, mild or no splenomegaly, and increased circulating blasts.  Risk stratification of PMF The median survival in primary myelofibrosis is 5 years from onset, but variation is wide; some patients have a rapidly progressing disorder, including development of acute myeloid leukemia, with short survival, but most have a more indolent course. Contemporary prognostic modeling in PMF started with the development of the International Prognostic Scoring System (IPSS) in 2009. The IPSS for PMF was designed for use at time of initial diagnosis and applies five independent predictors of inferior survival: age > 65 years, hemoglobin 25 × 109/L, circulating blasts ≥1% and presence of constitutional symptoms.  The IWG-MRT subsequently developed a dynamic prognostic model (DIPSS) that utilizes the same prognostic variables used in IPSS but can be applied at any time during the disease course The incorporation of three additional DIPSS-independent risk factors (platelet count