Table Of Contents
Overview
Myeloproliferative neoplasms are abnormal proliferations of one or more terminal myeloid cell lines in the peripheral blood (RBCs, WBCs, platelets). Myeloproliferative neoplasms are poorly characterized and poorly undersood. They all cause a predilection to extramedullary hematopoiesis, myelofibrosis, and transformation to acute leukemia.
MPNs
| CML | PV | ET | PMF | |
|---|---|---|---|---|
| WBC | Marked elevation | Normal/Increased | Normal/Increased | Variable |
| Hct | Normal/decreased | Marked elevation | Normal | Decreased |
| PLT | Varibale | Normal or increased | Marked increase | Variable |
| Mutation | bcr-abl | JAK2 | JAK2, CALR, MPL | JAK2, CALR, MPL |
| Sx | – | Erythromelalgia, Aquagenic pruritus, Low EPO | Erythromelalgia, Large platelets | Hepatosplenomegaly, Dry tap, Tear drop cells |
| Tx | Imatinib | Phelbotomy, Hydroxyurea, Aspirin, Ruxolitinib | Hydroxyurea, Aspirin, Anagrelide | Bone marrow transplant, Splenectomy, Ruxolitinib |
Characteristic mutations
| Neoplasm | Mutation |
|---|---|
| CML | bcr-abl |
| Polycythemia vera | JAK2 |
| ET and PMF | JAK2, CALR, MPL |
- WHO classification of myeloproliferative neoplasms (MPN)
- Chronic Myeloid Leukemia (CML), BCR-ABL1+
- Chronic neutrophilic leukemia (CNL)
- Polycythemia Vera (PV)
- Primary Myelofibrosis (PMF)
- PMF, pre-fibrotic/early stage
- PMF, overt fibrotic stage
- Essential thrombocythemia (ET)
- Chronic eosinophilic leukemia, not otherwise specified (NOS)
- MPN, unclassifiable
- Mastocytosis
Leukemoid Reactions
A leukemoid reaction is the presence of increased leucocyte count as >50 x 10^9/L in a reactive condition outside the bone marrow.
- Causes of leukemoid reactions
- Infections: Septicemia, Brucellosis, Shigellosis, Salmonellosis, Clostridium difficile colitis, Cryptogenic abscess, Miliary or acute necrotizing TB, Disseminated candidiasis, cryptococcosis)
- Malignancies (Carcinomas of the lung, oropharynx, GIT, gut), Hodgkin’s lymphoma, melanoma, sarcoma)
- Drugs (Corticosteroids, minocycline, recombinant hematopoietic growth factors)
Leukemoid reaction vs CML
| Leukemoid reaction | CML | |
|---|---|---|
| PBF leukocytes | Left shift: mature neutrophils, myelocytes and metamyelocytes | Left shift: mature neutrophils and myelocytes with more immature cells |
| Dysplasia | Absent | Present |
| Dohle bodies | Present | Absent |
| Toxic granulations | Present | Absent |
| Cytoplasmic granules | Present | Absent |
| Basophils | Absent | Basophilia |
| LAP score | Increased | Decreased |
| Blast crisis | Absent | May occur |
| Philadelphia chromosome | Negative | Positive |
| Eosinophils | Reduced | Present |
| Platelets | Normal or increased | Increased |
| Anaemia | Mild or absent | Present and progressive. Usually normocytic normochromic |
- How is a LAP score used to differentiate CML from leukemoid reaction?
- Leukocyte Alkaline Phosphatase is an enzyme on the membrane of secondary granules.
- Cytochemical stains (naphthol-phosphate substrate and diazo dye) are used to detect LAP activity in neutrophils and bands.
- LAP hydrolyzes and liberates naphthol. *** LAP score is derived by counting one hundred neutrophils (and or bands) and assessing the amount of stain retained in each of these neutrophilic cells. Each cell is assigned a score between 0 (no stain retained) to 4 (very dark staining). CML = low LAP score, Leukemoid reaction = increased lap score
- Patients with leukemoid leukocytosis show high LAP score
- CML neutrophils show a low LAP score
Chronic Myeloid Leukemia (CML)
CML arises from a single genetic translocation (bcr-abl) in a pluripotent stem cell. It is characterized by an increased proliferation of differentiating granulocytic cells (usually neutrophils, never lymphocytes). The peripheral blood shows an increased number of granulocytes (look for basophils) and their immature precursors (including occasional blasts). 90-95% of cases present with the Philadelphia chromosome – a shorter chromosome 22 formed by a reciprocal translocation between 9q and 22q; t9;22. 85% of cases are diagnosed in the chronic phase. Progress to the accelerated and blast phase occurs after 3-5 years.
CML accounts for 20% of cases of leukemia. It affects middle-aged individuals, 45-53 years. Average age of diagnosis is 65 years. Affects Males > Females. Although uncommon, CML can present in a more aggressive form in younger individuals.
Stages of CML
| Chronic | Stable and asymptomatic. Infection and bleeding complications are rare |
|---|---|
| Accelerated | 10-19% blasts. Suspect when CBC shows Basophilia (>20%) and Thrombocytopenia |
| Blast crisis | > 20% blasts. Resembles AML. |
- Risk factors for CML These factors precipitate the translocation bcr-abl
- Ionizing radiation e.g. Hiroshima and Nagasaki
- Chemicals e.g Benzene
- Pathogenesis of CML
- The ABL oncogene encodes a tyrosine-protein kinase
- The ABL oncogene is relocated from 9q to a specific breakpoint cluster region (BCR) in 22q.
- The fusion oncogene BCR-ABL1 encodes for a strong tyrosine kinase in hematopoietic progenitor cells
- The tyrosine kinase is constitutionally activated and confers proliferative and anti-apoptotic effects
- Signs and symptoms
- Weight loss, fever, night sweats
- Fatigue, pallor, breathlessness (due to anemia)
- Easy bruising, ecchymosis, petechiae and bleeding (due to thrombocytopenia, especially in the accelerated and acute phase)
- Hepatosplenomegaly (due to extramedullary hematopoiesis)
- LUQ pain (due to splenign infarction)
- Loss of appetite and early satiety (due to splenomegaly)
- Bone pain (due to marrow expansion)
- Investigations
- Complete blood count
- Leukocytosis (25-1000K): Basophilia, Eosinophilia, Normal lymphocyte counts
- Peripheral blood film
- Leukocytes: Leukocytosis, granulocytes in various stages of maturation with bimodal distribution IE. a higher proportion of PMNs and Myelocytes, Basophilia, Eosinophilia, Monocytosis (less than 3% relative)
- Dysplasia: Significant dysplasia affecting >10% granulocytes is absent
- Blasts: <2% of cells
- Platelets: Normal or increased, Thrombocytopenia is unusual
- Bone Marrow Aspirate or Trephine biopsy: important for staging
- Cellularity: Hypercellular with expansion of the myeloid line
- Myeloid: Increased Myelocytes, Increased Myeloid: Erythroid ratio
- Blasts: <5%
- Dysplasia: Significant dysplasia is absent
- Megakaryocytes: Small, hypo-lobate “dwarf: morphology”
- Cytogenetics
- Karyotype: t(9;22)(q34:q11.2)
- FISH: BCR-ABL fusion gene
- PCR for BCR-ABL1 fusion protein
- LAP score: low
- Complete blood count
- Investigations to follow for remission
- Complete Blood Count: Hematological remission, normal cell counts and physical exam
- FISH: Cytogenetic remission, no Ph+ cells
- PCR: Molecular remission, No BCR/ABL fusion mRNA
- Differentials for CML
- Leukamoid reaction
- Chronic neutrophilic Leukemia
- Juvenile and Chronic myelomonocytic leukemia (Both myeloid and monocyte series)
- Treatment
- Imatinib: best initial treatment. Very effective and has relatively fewer adverse effects compared to cytotoxics. Goal of therapy is 100% normal cells in 1-2 years
- Other TKIs: Dasatinib, Nilotinib, Bosutinib
- Bone marrow transplant: definitive treatment
- No response to imatinib
- The patient has to be healthy (before immunosuppression)
- Imatinib: best initial treatment. Very effective and has relatively fewer adverse effects compared to cytotoxics. Goal of therapy is 100% normal cells in 1-2 years
- Complications
- Leukostasis: WBC > 300,000/uL. Treat with Leukapheresis
- Blurred vision
- Priapism
- Decreased cognition
- Respiratory distress
- Blast crisis: Treat with Bone marrow transplant and chemotherapy
- Sudden anemia, thrombocytopenia, and suceptibility to infection. Bone marrow biopsy shows >20% blasts
- Leukostasis: WBC > 300,000/uL. Treat with Leukapheresis
Atypical Chronic Myeloid Leukemia (aCML) BRC-ABL-
Atypical CML manifests with myelodysplasia and myeloproliferation at the outset. However, it does not meet the criteria for bcr-abl+ CML or other MPNs. It affects males > females. The median age of diagnosis is 70 years.
- Causes of aCML
- Genetic mutations (no specific pattern)
- SETBP1, ETNK1, ASXL1, TET2, RAS and RUNX1 mutations
- Genetic mutations (no specific pattern)
Chronic Neutrophilic Leukemia (CNL)
CNL is a rare aggressive MPN that is characterized by persistent mature neutrophils, granulocyte hyperplasia and hepatosplenomegaly. It is associated with mutations in Colony Stimulating Factor-3 (CSF-3) receptors.
- Investigations
- Bone Marrow Aspirate
- Hypercellular with granulocyte hyperplasia, predominantly segmented and band neutrophils
- Variable erythroid and megakaryocyte hyperplasia; no/minimal dysplastic changes
- No increased myeloblasts
- Bone Marrow Aspirate
Chronic Eosinophilic Leukemia (CEL)
CEL is characterized by a persistent increase in eosinophils in peripheral blood (≥ 1.5 x 10 ^ 9/L), bone marrow and tissue. It may be accompanied by increased blasts (<20%) or clonal cytogenetic or molecular genetic abnormalities. Organ damage may occur as a result of infiltration and release of eosinophilic granules containing cytokines and humoral factors.
Mastocytosis
Mastocytosis is characterized by mast cell proliferation and accumulation within various organs, most commonly the skin. It is associated with mutations in KIT (a transmembrane tyrosine kinase receptor for SCF)
- Classification of mastocytosis
- Cutaneous mastocytosis (CM)
- Systemic mastocytosis
- Indolent systemic mastocytosis (ISM)
- Smoldering systemic mastocytosis (SSM)
- Systemic mastocytosis with an associated hematological neoplasm (SM-AHN)+
- Aggressive systemic mastocytosis (ASM)
- Mast cell leukemia (MCL)
- Mast cell sarcoma (MCS)
Essential Thrombocythemia (ET)
ET is characterized by an increase in the number of circulating platelets. It is due to the mutations JAK2, CARL, or MPL (90%) which cause sustained proliferation of megakaryocytes. Patients have a persistently elevated platelet count (>450,000/uL), and splenomegaly, and are frequently complicated by thrombotic and hemorrhagic episodes. Even so, patients are usually asymptomatic and diagnosis is incidental. Keep in mind that thrombocytosis is usually a reaction to inflammation or iron deficiency, so be sure to rule this out. The typical presentation for ET is a patient with erythromelalgia but normal hemoglobin (unlike polycythemia vera)
- Pathophysiology of ET
- Mutation in any of these 3 genes: Janus Kinase 2 (JAK2), Calreticulin (CALR), or Myeloproliferative Leukemia Virus Oncogene (MPL or TPO receptor gene) → Sustained increased production of platelets by megakaryocytes
- Thrombopoietin gene (THPO) mutation is associated with autosomal dominant hereditary thrombocytosis
- Signs and symptoms
- Bleeding (due to dyfunctional platelets)
- Deep Venous Thrombosis and Venous thromboemboli (due to platelet overproduction)
- Splenomegaly (due to extramedullary hematopoiesis)
- Hyperviscosity syndromes
- Dizziness, tinnitus, vertigo, blurred vision, headache
- Numbness in the extremities
- Fatigue, pallor, breathlessness (due to anemia)
- Investigations
- Complete Blood Count:
- Platelets: marked elevation
- WBC: modest leukocytosis
- Hb: mild anemia
- CBC: mild erythrocytosis
- Peripheral Blood Film: large platelets, immature precursor cells (myelocytes and metamyelocytes, eosinophilia and basophilia)
- Coagulation profile: Normal PT and aPTT, Prolonged BT
- Platelet function test: Impaired platelet aggregation
- Bone marrow studies: if diagnosis is unclear
- Hypercellular, megakaryocyte hyperplasia, giant megakaryocytes, granulocyte hyperplasia and reticulocyte precursor
- Molecular studies: identify JAK2, MPL and CALR mutations
- Serum ferritin: Normal
- Complete Blood Count:
- Treatment
- Hydroxyurea and Low-dose aspirin
- Anagrelide: 2nd line drug that prevents platelet maturation
Primary myelofibrosis (PMF)
PFM is characterized by the replacement of bone marrow by fibrous tissue. There are abnormal proliferating megakaryocytes and granulocytes which produce cytokines that stimulate fibrosis. Suspect PMF if a patient has anemia, teardrop RBCs, leukoerythroblastosis, and hepatosplenomegaly. No specific treatment exists.
PMF is the least common MPN. It occurs in patients > 60 years. Affects males > females and whites > other races.
Pre-fibrotic primary myelofibrosis: there is sustained proliferation of megakaryocytes without significant fibrosis (reticulin fibrosis < grade 1)
Overt fibrosis: there is sustained proliferation of megakaryocytes with significant fibrosis (reticulin fibrosis > grade 1)
Grading of myelofibrosis
| MF-0 | Scattered linear reticulin with no intersections (normal bone marrow) |
|---|---|
| MF-1 | Loose network of reticulin with many intersections |
| MF-2 | Diffuse and dense reticulin with extensive intersection. Focal bundles of collagen and focal osteosclerosis |
| MF-3 | Diffuse and dense reticulin with extensive intersections. Coarse bundles of collagen and osteosclerosis. |
- Pathophysiology
- Mutations in JAK2, CALR, or MPL → neoplastic proliferation of megakaryocytes
- Neoplastic megakaryocytes release TGF-B, PDGF, IL-1, EGF and FGF → fibroblast proliferation, matrix deposition, and endothelial proliferation
- Signs and symptoms 30% of patients are asymptomatic
- Fever, weight loss, night sweats
- Fatigue, pallor, breathlessness (due to anemia)
- Splenomegaly (90%, often considered a hallmark)
- Hepatomegaly (50%, portal hypertension develops as a complication and may precede the onset of disease)
- Leukocytosis and thrombocytopenia
- Leukopenia and thrombocytopenia (less common)
- Gouty arthritis
- Renal stones
- Thrombosis
- Hemorrhagic episodes (due to marked thrombocytosis), pruritus and pulmonary hypertension
- Investigations
- Peripheral blood evaluation
- Complete Blood Count: anemia (Hb <10g/dL), Leukopenia, Leukocytosis, Thrombocytosis
- Peripheral Blood Film: Leukoerythroblastosis with teardrop RBCs, large platelets, blasts, pegler-huet cells
- Bone Marrow examination ***BMAs are dry taps half the time
- Trephine biopsy: patchy hematopoietic cellularity, reticulin fibrosis, megakaryocytes present in clusters (may be dysplastic), distended marrow sinusoid (frequently containing intravascular hematopoiesis)
- Molecular studies ***detects JAK2, CALR, MPL, BCR-ABL
- BCR-ABL: negative
- JAK2 V617F mutations: positive (50-60%)
- CALR mutations: positive (25-20%) – better prognosis
- MPL mutation: positive (5-10%)
- Triple-negative mutation for JAK2, CALR, AND MPL: positive (8-12%)
- Other mutations in ASXL1, EZH2, TET2, IDH1/IDH2, SRSF2 or SR3B1: positive
- Karyotype: del(20q), del(13q) in 50% of cases
- Peripheral blood evaluation
- Treatment
- Splenectomy to reduce symptoms
- Ruxolitinib: some efficacy in treating constitutional symptoms
- Bone marrow transplant: the only definitive cure
Polycythemia
Polycythemia is a laboratory finding in which there is an increased number of RBCs, and accompanying elevated Hct and Hb concentration in the peripheral blood (commonly an incidental finding)
Relative polycythemia: isolated decrease in plasma volume that elevates Hb, HCT and RBC without increasing red cell mass.
Absolute polycythemia: a true increase in red cell mass.
Primary absolute polycythemia: due to acquired or inherited mutations e.g. Polycythemia Vera
Secondary absolute polycythemia: due to circulating factors e.g. EPO, hypoxia, EPO secreting tumor
Combine polycythemia: a combined increased red cell mass and reduced plasma volume. Seen in smokers
Inapparent absolute polycythemia: equally increased red cell mass and plasma volume, causing a normal Hb, Hct and RBC count.
- Factors that stimulate the relase of EPO
- Anemia
- Hypoxemia
- Decreased O2 release from Hb
- Reduced oxygen delivery to Kidneys (Vaso-occlusion)
- What is the difference between EPO-independent and EPO-drive erythrocytosis
- EPO-independent erythrocytosis ****e.g. Polycythemia Vera, suppresses renal EPO production, resulting in low serum EPO concentrations
- EPO-driven erythrocytosis e.g. Hypoxia or EPO-secreting tumors is associated with high or normal serum EPO
- Causes of polycythemia
- Germline and somatic mutational causes of polycythemia (Primary Polycythemia)
- JAK2 (PV), EPOR mutation, VHL gene mutation (Chuvash polycythemia), congenital methemoglobinemia, idiopathic familial polycythemia, high oxygen affinity hemoglobins, 2,3-BPG mutase deficiency, PHD2, HIF2-alpha
- Autonomous (Inappropriate) increase of EPO
- EPO-producing neoplasms (RCC, HCC, Cerebellar hemangioblastoma, Phaeochromocytoma, Uterine fibroids)
- EPO-producing renal lesions (cysts, hydronephrosis, renal artery stenosis and rarely distal tubular necrosis)
- Appropriate increase in EPO
- Hypoxemia: secondary to chronic pulmonary disease, R→L cardiac shunts, sleep apnea, Massive obesity aka Pickwickian syndrome, High altitude)
- Red cell defects: some cases of congenital methemoglobinemia, chronic CO poisoning including Heavy smoking, Cobalt)
- Miscellaneous causes
- Use of androgens and anabolic steroids, diuretics (relative polycythemia), Blood doping in athletes (autologous blood transfusion), Self-injection of EP, POEMS syndrome (autoimmune disease with polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin lesions)
- Germline and somatic mutational causes of polycythemia (Primary Polycythemia)
- Differentials for polycythemia **** Make sure to apply the sex and age-adjusted “normal” reference values for Hb, Hct and RBCs*
- Thalassemia minor: High RBC, Low Hb, Low MCV
- Polycythemia Vera: Low MCV, High WBC, High PPLT
- Renal Cell Carcinoma: Microscopic hematuria
- Functional endocrine tumors: Hyperglycemia and electrolyte disturbances
- Hepatocellular carcinoma: Abnormal liver function test
- Carbon monoxide poisoning: Direct blood testing > pulse oximetry alone
Polycythemia Vera
Polycythemia vera is characterised by peripheral erythrocytosis. It is commonly due to a point mutation in JAK2. Historicaly known as Polycythemia rubra vera. Thrombocytosis and leukocytosis can occur in addition to erythrocytosis. The classic presentation is an unexplained high hemoglobin with low MCV and/or low ferritin.
Phases of polycythemia vera
| Prodrome | Borderline mild erythrocytosis |
|---|---|
| Overt polycythemia | Significantly increased red cell mass |
| Spent-phase | Bone marrow fibrosis causing cytopenias and hepatosplenomegaly.<10% progress to myelofibrosis. |
- Risk factors
- Genetic predisposition
- Ionizing radiation
- Occupational toxins
- Sites involved in polycythemia vers
- Peripheral blood
- Bone marrow;
- Spleen and Liver: common sites of extramedullary hematopoiesis
- Pathophysiolgy
- Point mutation in JAK2 gene at 9p24 → constitutional activation of STAT transcription factors → growth factor-independent proliferation and survival or RBCs (and platelets)
- Signs and symptoms
- Hyperviscosity syndromes:
- Headache, blurred vision, vertigo, tinnitus, dizziness
- Chest and abdominal pain (abdominal pain is due to ischemic bowel caused by thrombosis)
- Myalgia
- Weakness and Fatigue
- Budd-Chiari syndrome, Mesenteric vein thrombosis, Arterial thrombosis, Venous thrombosis
- Intermittent claudication
- Aquagenic pruritus (due to the relaease of histamine from basophils form contact with warm water)
- Erythromelalgia: Increased skin temperatures, burning sensation and redness
- Early satiety (due to splenomegaly, especially in the spent phase)
- Gout
- Hyperviscosity syndromes:
- Investigations
- Complete Blood Count
- Hb: >16.5g/dL M, >16g/dL F
- Hct: >49% M, >48% F
- MCV: low despite high hemoglobin
- WBC: Leukocytosis <20k
- Platelets: modest thrombocytosis
- Peripheral blood film
- RBC: Normochromic normocytic RBC, Microcytic Hypochromic RBC with concomitant IDA, Erythrocytosis, Rare normoblasts
- Reticulocytes: Deeply basophilic reticulocytes
- Leukocytes: Mild Leukocytosis, Left-Shift, Mild Basophilia
- Platelets: Thrombocytosis (Prominent in prodromal and exaggerated by concurrent IDA),
- Spent-phase: Leukoeryhtroblastosis, Myeloid metaplasia, Poikylocytosis, >10% blasts in PBF
- Bone marrow aspirateor Trephine Biopsy
- Cellularity: Hypercellular, >80% cellularity
- Myeloid: Panmyelosis (Predominant erythroid and Megakaryocytes), complete and progressive maturation of all 3 hematopoietic lineages, abnormal megakaryocyte morphology and architecture (Variably hyperlobulated)
- Fibrosis: Reticulin fibrosis is minimal or absent
- Iron stores: Diminished, Often absent
- Spent-phase: Overt bone marrow reticulin and collagen fibrosis, Prominent osteosclerosis, Increase in blasts (but <20%), dilated sinuses with intrasinusoidal hematopoiesis, decline in hematopoietic cells
- Cytogenetics
- Karyotype, FISH: JAK2 V617F or JAK2 exon 12 mutations
- Molecular studies
- PCR: JAK2 V617F or JAK2 exon 12 mutations
- Erythropoietin: Subnormal EPO (<4.1 mU/mL)
- Red Cell Mass: >25%
- Serum ferritin: low/normal
- Complete Blood Count
- Treatment
- Serial phlebotomy and Low-dose aspirin
- Hydroxyurea: adjunct for high-risk patients who fail phlebotomy
- Ruxolitinib: second-line TKI for JAK2 mutations
- Morphology of polycythemia vera as seen in a peripheral blood film
- Pre-PV and Overt PV:
- Normochromic normocytic RBC (microcytic hypochromic with concomitant IDA)
- Erythrocytosis with increased HGB and HCT
- Red cell morphology is unremarkable except in cases with concomitant iron deficiency; Deeply basophilic reticulocytes, rare normoblasts, mild leukocytosis (WBC<20k/L) with rare left-shift, mild basophilia, thrombocytosis (prominent in prodromal and exaggerated by concurrent iron deficiency)
- Post PV (Spent):
- Myeloid metaplasia (leukoerythroblastosis – both immature granulocyte and erythroids, typical of MF)
- Poikylocytosis (teardrop shaped RBCs)
- Finding >10% blasts in PB or BM
- Presence of significant myelodysplasia is unusual and most likely signals transformaton to an accelerated phase or MDS
- Pre-PV and Overt PV:
- Morphology of polycythemia vera as seen in the bone marrow ***erythroids have much bluer cytoplasm, typical picture of MPN (Pancellularity) ***Spent phase is indistinguishable from PMF
- Pre-PV and Overt PV:
- Hypercellular (80% cellularity, range 37-100%)
- Panmyelosis (predominant erythroid and megakaryocyte lineages)
- Complete and progressive maturation of all 3 hematopoietic lineages
- Abnormal megakaryocyte morphology and architecture (Variably hyperlobulated, though not as pronounced as ET or as pleomorphic as PMF)
- Reticulin fibrosis (minimal or absent)
- Iron stores (diminished, often absent)
- Post PV (Spent phase):
- Leukoerythroblastosis
- Overt bone marrow reticulin and collagen fibrosis
- Osteosclerosis is usually prominent
- blasts may increase (<20%)
- dilated sinuses (with intrasinusoidal hematopoiesis)
- decline in hematopietic cells
- Pre-PV and Overt PV:
- Complications
- Thrombotic complications
- Arterial thrombosis: Stroke, Peripheral arterial emboli, Myocardial Infarction, Splenic infarction
- Venous thrombosis: Budd-Chiari syndrome, Pulmonary embolism, Deep vein thrombosis, Splenic vein thrombosis, Portal vein obstruction, Mesenteric vein thrombosis, Renal vein thrombosis
- Hemorrhagic complications: Petechiae, Epistaxis, Bleeding gums
- Gout: High cell turnover resulting in elevated uric acid
- AML, MDS: Additional genetic mutations cause transition to other hematologic disease
- Post-polycythemia vera myelofibrosis (Spent): Reticulin fibrosis of the bone marrow
- Thrombotic complications
Diagnostic Criteria
- Diagnostic criteria for CML in the accelerated phase ***Diagnosed by the presence of ≥1 of the following hematological criteria or provisional criteria concerning response to tyrosine kinase inhibitor (TKI) therapy
- Hematological or cytogenetic criteria
- Persistent or increasing high white blood cell count (>10 x 10^9/L), unresponsive to therapy
- Persistent or increasing splenomegaly, unresponsive to therapy
- Persistent thrombocytosis (<1000×10^9/L), unresponsive to therapy
- Persistent thrombocytopenia (<100×10^9/L), unresponsive to therapy
- ≥20% basophils in the peripheral blood
- 10-19% blasts in the peripheral blood and or bone marrow
- Additional clonal chromosomal abnormalities in Philadelphia (Ph) chromosome-positive (Ph+) cells at diagnosis, including so-called major route abnormalities (a second Ph chromosome, trisomy 9, isochromosome 17q, -7, 3q rearrangements, -Y, Trisomy 19), complex karyotype, and abnormalities of 3q26.2
- Any new clonal chromosomal abnormalities in Ph+ cells that occurs during therapy
- Provisional response to TKI criteria
- Hematological resistance or failure to achieve a complete hematological response to the first TKI
- Hematological, cytogenetic or molecular indications of resistance to two sequential TKIs
- Occurrence of two or more mutations in the BCR-ABL1 fusion gene during TKI therapy
- Hematological or cytogenetic criteria
- Diagnostic criteria for blast crisis ***The blast crisis is the final phase in the evolution of CML where it behaves like acute leukemia with rapid progression and short survival. 2/3 transform to AML while 1/3 transform to ALL (Therefore the genetic defect BCR-ABL is in the HSC)
- Criteria for diagnosis of blast crisis
- >20% blasts in the blood or bone marrow
- The presence of an extramedullary proliferation of blasts
- Criteria for diagnosis of blast crisis
- Diagnostic criteria for aCML
- Peripheral blood leukocytosis 13×10^9/L (due to an increased number of neutrophils and their precursors promyelocytes, myelocytes, and metamyelocytes) with neutrophil precursors ≥ 10% of leukocytes
- Dysgranulopoiesis which may include abnormal chromatin clumping or projection, abnormal segmentation, and hypogranularity
- No or minimal absolute basophilia; basophils constitute 2% of peripheral blood leukocytes
- No or minimal absolute monocytosis; monocytes constitute >10% of the peripheral blood leukocytes
- Hypercellular bone marrow with granulocytic proliferation and granulocytic dysplasia with or without dysplasia in the erythroid and megakaryocytic lineages
- <20% blasts in the blood and bone marrow
- No evidence of PDGFRA, PDGFRB or FGFR1 rearrangement or of PCM1-JAK2 translocation
- WHO criteria for BCR-ABL positive CML, primary myelofibrosis, polycythemia vera or essential thrombocythemia are not met
- History of MPN, the presence of MPN features in the bone marrow or MPN associated mutations (JAK2, CALR or MPL) should be excluded
- Diagnostic criteria for CNL
- PBF WBC ≥ 25 x 10^9/L
- Segmented neutrophils plus bands form ≥ 80% of WBC
- Neutrophil precursors (promyelocytes, myelocytes and metamyelocytes) account for 10% of WBC
- Myeloblasts rarely observed
- Monocyte count < 1 x 10^9/L
- No dysgranulopoiesis
- Hypercellular BM
- Neutrophil granulocytes increased in percentage and number
- Neutrophil maturation appears normal
- Myeloblasts 5% of nucleated cells
- Not meeting WHO criteria for BCR-ABL1+ CML, PV, ET or PMF
- No rearrangement of PDGFRA, PDGFRB, or FGFR1, or PCM1-JAK2
- Presence of CSF3R T618I or other activating CSF3R mutations OR in the absence of a CSF3R mutation, persistent neutrophilia (at least 3 months) splenomegaly and no identifiable cause of reactive neutrophilia including absence of plasma cell neoplasm or if present, demonstration of the clonality of myeloid cells by cytogenetic or molecular studies
- PBF WBC ≥ 25 x 10^9/L
- Diagnostic criteria for CEL
- Persistent eosinophilia (≥ 1.5 x109/L) in which reactive causes have been excluded
- Does not meet diagnostic criteria for CML with t(9;22)/ BCR-ABL1 gene fusion, PV, ET, PMY, CNL, CML, aCML (BCR-ABL-) or systemic mastocytosis
- Blasts <20% of peripheral blood and bone marrow cells
- Does not have the following cytogenetic aberrations
- PDGFRA, BDGRB, or FGFR1rearrangements
- t(8;9)(p22;p24.1)/ PCM1-JAK2, t(9;12)(p24.1;p13.2)/ ETV6-JAK2 or t(9;22)(p24.1;q11.2)/ BCR-JAK2 fusion
- inv(16)(p13.1;q22), or t(16;16)(p13.1;q22)/ CBFB/ MYH11, t(15;17)(q22;q11-12)/ PML-RARA or t(8;21)(q22;q22.1)/ RUNX1/ RUNX1T1
- t(9;22)(q24;q31)/ BCR-ABL1 fusions
- Presence of clonal cytogenetic or molecular genetic abnormalities or a blast count ≥ 2% in the peripheral blood or ≥ 5% in the bone marrow
- Certain gene mutations (e.g. DNMT3A, TET2, ASCL1with a variant allele frequency ≥ 2%)
- Diagnostic interpretation should be done with caution
- Diagnostic criteria for ET ***Diagnosis requires all 4 major criteria or the first 3 major criteria and 1 minor criterion
- Major criteria
- Platelet count >450 x 10^9/L
- BM biopsy showing proliferation mainly of megakaryocyte lineage with increased numbers of enlarged, mature megakaryocytes with hyperlobulated nuclei. No significant increase or left shift in neutrophil granulopoiesis or erythropoiesis and very rarely minor (grade 1) increase in reticulin fibres
- Not meeting WHO criteria for *BCR-ABL+*CML, PV, PMF, MDS or other myeloid neoplasms
- Presence of JAK2, CALR, or MPL mutations
- Minor criteria
- Presence of clonal markers or absence of evidence for reactive thrombocytosis
- Major criteria
- Diagnostic criteria for pre-PMF ***requires 3 major and 1 minor criterion
- Major criteria
- Megakaryocytic proliferation and atypia without reticulin fibrosis>grade 1, accompanied by increased age-adjusted BM cellularity, granulocytic proliferation and often decreased erythropoiesis
- Not meeting WHO criteria for BCR-ABL+ CML, PV, ET, MDS and other myeloid neoplasms
- Presence of JAK2, CALR, MPL mutations, presence of another clonal marker or absence of minor reactive BM reticulin fibrosis
- Minor criteria ***Presence of at least 1 of the following, confirmed in 2 consecutive determinations
- Anemia not attributed to a comorbid condition
- Leukocytosis ≥ 11×10^9/L
- LDH increased to above upper normal limit of institutional reference range
- Major criteria
- Diagnostic criteria for overt-PMF ***Requires meeting all 3 major criteria and at least 1 minor criterion
- Major criteria
- Presence of megakaryocytic proliferation and atypia, accompanied by either reticulin and/or collagen fibrosis grades 2 or 3
- Not meeting WHO criteria for ET, PV, *BCR-ABL1+ *****CML, MDS or other myeloid neoplasms
- Presence of JAK2, CALR or MPL mutation or in the absence of these mutations, presence of another clonal marker, or absence of reactive myelofibrosis
- Minor criteria ***Presence of at least 1 of the following confirmed in 2 consecutive determinations
- Anemia not attributed to a comorbid condition
- Leukocytosis ≥ 11 x 10^9/L
- Palpable splenomegaly
- LDH increased to above upper normal limit of institutional reference range
- Leukoerythroblastosis
- Major criteria
- Diagnostic criteria for polycythemia vera (WHO) ***Major criterion 2 may not be required in cases with sustained absolute erythrocytosis ***Hemoglobin levels >18.5g/dL HCT 55.5%) in men or >16.5g/dL (HCT 49.5%) in women, if major criterion 3 and minor criterion are present ***Approximately 20% of PV patient’s BM on biopsy show myelofibrosis which may predict a more rapid progression to overt myelofibrosis (Post PV-MF spent)
- Major criteria
- HGB > 16.5g/dL M, > 16.0g/dL F, HCT > 49% M, > 48% F or increased RCM more than 25% above mean normal predicted value
- Bone marrow biopsy showing hypercellularity for age with tri-lineage growth (panmyelosis) including prominent erythroid, granulocytic and megakaryocytic proliferation with pleomorphic, [mature*] megakaryocytes**
- Presence of JAK2 V617F or JAK2 exon 12 mutation
- Minor criteria
- Subnormal serum EPO (normal range of EPO: adults 4.1-19.5 mU/mL)
- Diagnostic criteria for polycythemia vera (PVSG) ***These can be done in our setting. 3 criteria from category A OR A1, A2 and any category B.
- Category A
- A1: RCM ≥ 36mL/kg M or 32mL/kg F
- A2: arterial oxygen saturation ≥ 92%
- A3: splenomegaly
- Category B
- Thrombocytosis with platelet count > 400,000/uL
- Leukocytosis with a WBC > 10,000
- LAP score >100 U/L in the absence of fever or infection
- Serum Vitamin B12 concentration > 900pg/mL or binding capacity > 2,200 pg/mL
- Other findings that may be present but are not necessary for diagnosis
- Subnormal EPO
- Endogenous Erythroid colony formation (EEC)
- Detection of JAK2 V617F or JAK2 exon 12 mutation
- Category A
- Major criteria