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Diagnosis and Classification of Myeloproliferative Disorders

Chapter 10 - Management of Chronic Myeloproliferative Neoplasia (MPN) in Elderly Patients

Myeloproliferative neoplasia (MPN) are relatively rare chronic haematologic malignancies that include the classic myeloproliferative disorders, such as the Philadelphia chromosome-negative essential thrombocythemia (ET), polycythaemia vera (PV), primary myelofibrosis (PMF) and Philadelphia chromosome-positive chronic myelogenous leukaemia (CML). Typical myeloproliferative disorders include molecularly defined Platelet-derived growth factor (PDGFR) A-rearranged eosinophilic/mast cell disorders; PDGFR B-rearranged eosinophilic disorders; systemic mastocytosis associated with c-kit mutation; 8p11 myeloproliferative syndrome; and juvenile myelomonocytic leukaemia with recurrent Mutations of Ras.

Ph-negative MPD are usually diagnosed later in life, at a median age of 60 years of age, which is also the median age of CML diagnosis. A considerable proportion of this patient group is above 60 years of age at diagnosis, including a relevant proportion over 70 years of age. The median survival of patients with MPN is relatively long, resulting in a comparatively high prevalence of elderly patients with MPN. Despite this clinical reality, specific treatment considerations in the era of targeted therapies, within this patient population, have not been sufficiently addressed in clinical trials.

Independent of patient age, since 2008 MPNs have been classified according to the revised World Health Organization (WHO) classification (for diagnostic criteria see Table 1). The required diagnostic procedures are outlined as follows: physical examination, examination of a blood sample, a bone marrow biopsy including molecular biology (analysis of classical cytogenetics, fluorescence in situ hybridisation [FISH] for detection of the Philadelphia chromosome and mutation analysis for diagnosis of JAK-2, and if needed mutations in the Calreticulin Exon 9 or the MPL gene). An enlarged spleen is often detected by physical examination, but ultrasound or computed tomography (CT) scans may occasionally be necessary to define spleen size in more detail. These are particularly helpful to follow spleen size reduction during therapy with novel drugs, such as JAK-inhibitors.

Diagnostic Criteria for Myeloproliferative Disorders According to the Revised World Health Organization (WHO)

CriteriaChronic myelogenous leukaemia (CML)Essential thrombocythemia (ET)Polycythaemia vera (PV)Primary myelofibrosis (PMF)
  1. BM biopsy showing hyperplasia of myelopoiesis and megakaryopoiesis
  2. Detection of Philadelphia chromosome by conventional cytogenetics and by FISH
  3. Detection of the BCR-ABL fusion transcript by PCR
  1. Sustained platelet count ≥ 450 x 109/L during work-up period
  2. BM biopsy showing proliferation mainly of the megakaryocytic lineage with increased numbers of enlarged, mature megakaryocytes; no significant increase or left-shift of neutrophil granulopoiesis or erythropoiesis
  3. Not meeting WHO criteria for PV, PMF, CML, MDS, or other myeloid neoplasm
  4. Demonstration of JAK2617V>F or other clonal marker, or in the absence of a clonal marker, no evidence for reactive thrombocytosis
  1. Haemoglobin > 18.5 g/dL in men, 16.5 g/dL in women or other evidence of increased red cell volume
  2. Presence of JAK2617V>F or other functionally similar mutation such as JAK2 exon 12 mutation
  1. Presence of megakaryocyte proliferation and atypia, usually accompanied by either reticulin and/or collagen fibrosis, or, in the absence of significant reticulin fibrosis, the megakaryocyte changes must be accompanied by an increased bone marrow cellularity characterised by granulocytic proliferation and often decreased erythropoiesis (ie, prefibrotic cellular-phase disease)
  2. Not meeting WHO criteria for PV, PMF, CML, MDS, or other myeloid neoplasm
  3. Demonstration of JAK2617V>F or other clonal marker (eg, MPL515W>L/K), or in the absence of a clonal marker, no evidence of BM fibrosis due to underlying inflammatory or other neoplastic diseases
  1. Bone marrow biopsy showing hypercellularity for age with trilineage growth (panmyelosis) with prominent erythroid, granulocytic, and megakaryocytic proliferation
  2. Serum erythropoietin level below the reference range for normal
  3. Endogenous erythroid colony formation in vitro
  1. Leukoerythroblastosis
  2. Increase in serum lactate dehydrogenase level
  3. Anaemia
  4. Palpable splenomegaly

For Diagnosis of PV

The presence of both major and 1 minor criterion or the presence of the first major criterion together with 2 minor criteria is required.

For Diagnosis of ET

All 4 major criteria are required.

For Diagnosis of MF

Diagnosis requires meeting all 3 major criteria and 2 minor criteria.

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