- The document provides information on the diagnosis and management of myeloproliferative neoplasms (MPN), including polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF).
- Diagnosis involves evaluating blood counts, bone marrow morphology, cytogenetics, and molecular testing for mutations in genes like JAK2, CALR, and MPL. Presenting symptoms vary between diseases.
- PV is characterized by elevated red blood cell counts. ET by elevated platelet counts. MF involves bone marrow fibrosis with extramedullary hematopoiesis and organomegaly. Each has distinct diagnostic criteria.
- Proper diagnosis distinguishes MPNs
This document discusses myeloproliferative neoplasms (MPNs), which are clonal stem cell disorders characterized by excessive proliferation of one or more myeloid cell lines in the bone marrow and peripheral blood. MPNs include chronic myeloid leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). CML is driven by the Philadelphia chromosome and BCR-ABL fusion gene. PV, ET and PMF are typically caused by a mutation in the JAK2 gene known as JAK2 V617F. The clinical features, diagnostic criteria, complications and treatment approaches for each MPN subtype are described.
MPNs are clonal hematopoietic stem cell disorders characterized by overproduction of one or more myeloid cell lineages in the bone marrow and blood. The key subtypes include CML, PV, PMF, and ET. CML is driven by the Philadelphia chromosome and BCR-ABL1 fusion gene. PV is characterized by elevated red blood cell counts and the JAK2 V617F mutation in over 95% of cases. Without treatment, MPNs can progress to more advanced stages including myelofibrosis, leukemia, or transformation. Molecular testing plays an important role in diagnosis and classification.
Thrombophilias are hypercoagulable conditions that can be acquired or inherited. Most important hypercoagulable conditions =, testing procedures, duration of anticoagulation will be discussed here. Useful for Internal Medicine Boards and Hematology boards. Some aspects on duration of anticoagulation, HIT are high-yield for USMLE exams.
This document discusses the classification of acute myeloid leukemia (AML). It provides an overview of classifications proposed over time including the French-American-British (FAB) classification from 1976 based on morphology and cytochemistry. The 2008 World Health Organization classification expanded genetic subtypes and incorporated cytogenetic and molecular information along with morphology. Accurate classification involves evaluating blast percentage, cell morphology, dysplasia, immunophenotyping, cytogenetics and molecular genetics to identify distinct biological entities of AML.
Myeloproliferative neoplasms (MPNs) are a group of disorders where the bone marrow produces too many red or white blood cells. The presentation outlines the history, classification, signs and symptoms, causes related to genetic mutations like JAK2, diagnosis through blood and bone marrow tests, and treatments including medications, radiation, surgery, and stem cell transplant. MPNs include chronic myeloid leukemia, polycythemia vera, essential thrombocythemia, myelofibrosis, and rare disorders like chronic neutrophilic leukemia and mast cell disease.
Paroxysmal Nocturnal Hemoglobinuria (PNH) is a rare, acquired hemolytic anemia caused by a loss of proteins that regulate the complement pathway, making red blood cells sensitive to complement-mediated lysis. It is characterized by intravascular hemolysis that is worse at night due to relative acidosis during sleep. Affected cells lack proteins like CD59 and CD55 on their surface. Diagnosis involves flow cytometry to detect absent or decreased CD59 and CD55.
This document discusses myeloproliferative neoplasms (MPNs), which are clonal stem cell disorders characterized by excessive proliferation of one or more myeloid cell lines in the bone marrow and peripheral blood. MPNs include chronic myeloid leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). CML is driven by the Philadelphia chromosome and BCR-ABL fusion gene. PV, ET and PMF are typically caused by a mutation in the JAK2 gene known as JAK2 V617F. The clinical features, diagnostic criteria, complications and treatment approaches for each MPN subtype are described.
MPNs are clonal hematopoietic stem cell disorders characterized by overproduction of one or more myeloid cell lineages in the bone marrow and blood. The key subtypes include CML, PV, PMF, and ET. CML is driven by the Philadelphia chromosome and BCR-ABL1 fusion gene. PV is characterized by elevated red blood cell counts and the JAK2 V617F mutation in over 95% of cases. Without treatment, MPNs can progress to more advanced stages including myelofibrosis, leukemia, or transformation. Molecular testing plays an important role in diagnosis and classification.
Thrombophilias are hypercoagulable conditions that can be acquired or inherited. Most important hypercoagulable conditions =, testing procedures, duration of anticoagulation will be discussed here. Useful for Internal Medicine Boards and Hematology boards. Some aspects on duration of anticoagulation, HIT are high-yield for USMLE exams.
This document discusses the classification of acute myeloid leukemia (AML). It provides an overview of classifications proposed over time including the French-American-British (FAB) classification from 1976 based on morphology and cytochemistry. The 2008 World Health Organization classification expanded genetic subtypes and incorporated cytogenetic and molecular information along with morphology. Accurate classification involves evaluating blast percentage, cell morphology, dysplasia, immunophenotyping, cytogenetics and molecular genetics to identify distinct biological entities of AML.
Myeloproliferative neoplasms (MPNs) are a group of disorders where the bone marrow produces too many red or white blood cells. The presentation outlines the history, classification, signs and symptoms, causes related to genetic mutations like JAK2, diagnosis through blood and bone marrow tests, and treatments including medications, radiation, surgery, and stem cell transplant. MPNs include chronic myeloid leukemia, polycythemia vera, essential thrombocythemia, myelofibrosis, and rare disorders like chronic neutrophilic leukemia and mast cell disease.
Paroxysmal Nocturnal Hemoglobinuria (PNH) is a rare, acquired hemolytic anemia caused by a loss of proteins that regulate the complement pathway, making red blood cells sensitive to complement-mediated lysis. It is characterized by intravascular hemolysis that is worse at night due to relative acidosis during sleep. Affected cells lack proteins like CD59 and CD55 on their surface. Diagnosis involves flow cytometry to detect absent or decreased CD59 and CD55.
Chronic myeloid leukemia (CML) is a type of leukemia characterized by the Philadelphia chromosome, which is formed from the translocation of chromosomes 9 and 22. This translocation results in the BCR-ABL fusion gene which leads to increased proliferation of myeloid cells. CML progresses from a chronic phase to accelerated and blast crisis phases without treatment. Imatinib is now the standard first-line treatment for CML, achieving high rates of response. Resistance can develop through BCR-ABL mutations requiring other tyrosine kinase inhibitors. Allogeneic stem cell transplant remains the only potentially curative option but has risks.
This document summarizes recent changes in the classification of myeloproliferative neoplasms according to the 2016 World Health Organization classification. It discusses the reclassification of chronic myeloid leukemia as chronic myeloid leukemia and updates to the diagnostic criteria for conditions such as polycythemia vera, essential thrombocythemia, primary myelofibrosis, and chronic neutrophilic leukemia. New genetic markers and provisions for incorporating treatment response are included. Representative images of peripheral blood smears and bone marrow biopsies are also presented.
1. Polycythemia vera (PV) is a chronic myeloproliferative neoplasm characterized by an overproduction of red blood cells without an identifiable stimulus. It commonly presents with erythrocytosis, splenomegaly, thrombosis, and pruritus.
2. The main cause of PV is a mutation in the JAK2 gene, but some patients have mutations in exon 12. Diagnosis requires tests to distinguish absolute from relative erythrocytosis. Treatment focuses on phlebotomy and medications to control symptoms and prevent complications.
3. Primary myelofibrosis (PMF) is a chronic myeloproliferative neoplasm involving clonal proliferation and
The document discusses hematopoietic neoplasms and myeloproliferative disorders. It describes how hematopoietic neoplasms can be classified based on lineage, chronicity, and location. It then focuses on chronic myeloproliferative disorders including chronic myelogenous leukemia, polycythemia vera, essential thrombocythemia, myelofibrosis, and their characteristics and diagnostic criteria. Acute myelogenous leukemia is also discussed.
This document provides an overview of myelodysplastic syndrome (MDS). It discusses the history and changing definitions of MDS, current WHO classification, clinical features, pathogenesis involving genetic and epigenetic abnormalities, dysplastic changes seen in the bone marrow, and identification of blast cells. MDS is a heterogenous stem cell disorder characterized by cytopenias, dysplasia, and increased risk of acute myeloid leukemia. The disease results from acquired mutations in hematopoietic stem/progenitor cells and involves dysregulated apoptosis, ineffective hematopoiesis, and genetic and epigenetic changes.
The document discusses various myeloproliferative neoplasms (MPNs) including classic MPNs such as polycythemia vera, essential thrombocythemia, and primary myelofibrosis as well as atypical MPNs. It provides details on the diagnostic criteria, signs and symptoms, genetic mutations involved, and treatment approaches for these different MPNs. Chronic myelogenous leukemia is also examined as it represents a distinct MPN characterized by the Philadelphia chromosome genetic abnormality.
This document provides an overview of hemophagocytic lymphohistiocytosis (HLH). It begins by introducing HLH and describing its characteristics such as fever, hepatosplenomegaly, and cytopenias. It then discusses the classification of primary and secondary HLH, epidemiology, genetic causes, clinical features, diagnostic guidelines, treatment protocols, and long-term follow up recommendations. For the patient presented, the document recommends following the HLH-2004 treatment protocol initially and considering continuation therapy or stem cell transplant depending on the disease response and severity.
Congenital dyserythropoietic anemia (CDA) is a rare blood disorder characterized by ineffective red blood cell production resulting in anemia. There are four main types of CDA which are inherited in an autosomal recessive pattern. Patients with CDA require frequent blood transfusions and iron chelation therapy to remove excess iron from the body. Bone marrow transplant and gene therapy may cure CDA but carry risks. Recent gene therapy trials have shown promise in curing beta-thalassemia.
The document provides information on evaluating and diagnosing thrombocytopenia, including:
1) Normal platelet counts range from 150,000-450,000/microL and are slightly higher in females and younger people. Thrombocytopenia is defined as a platelet count below 150,000/microL.
2) The basic mechanisms of thrombocytopenia include decreased platelet production, ineffective production, increased destruction, increased consumption, and sequestration.
3) Diagnosing thrombocytopenia involves ruling out pseudothrombocytopenia, examining the blood counts, bone marrow, and performing additional lab tests to determine the underlying cause and guide treatment.
acute leukemia
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This document discusses myeloproliferative disorders (MPDs), including polycythemia vera, essential thrombocythemia, and primary myelofibrosis. MPDs are clonal stem cell disorders characterized by excessive proliferation of one or more myeloid cell lineages. Common features include increased proliferation, extramedullary hematopoiesis, marrow fibrosis, and peripheral blood cytopenias. The document defines each type of MPD and discusses their pathogenesis, morphology, clinical features, complications, investigations, and treatments.
This document discusses the diagnostic approach and classification of myeloproliferative neoplasms according to the 2008 WHO criteria. It describes the differential diagnosis and clinical features of polycythemia vera, essential thrombocythemia, and primary myelofibrosis. It discusses diagnostic criteria, disease course, prognosis, and treatment approaches for these chronic myeloproliferative disorders.
This document discusses thrombotic thrombocytopenic purpura (TTP). It begins by presenting a case of a 32-year-old woman presenting with headaches, difficulty speaking and moving her tongue, and numbness. Her exam and labs show thrombocytopenia and schistocytes. The document then discusses the differential diagnosis, epidemiology, terminology, definitions, types, presentations, investigations, and treatment of TTP, with a focus on plasma exchange therapy to remove antibodies and replace deficient ADAMTS13 protease.
This document provides information about multiple myeloma, including its definition, epidemiology, pathogenesis, clinical presentation, diagnostic criteria, staging system, imaging, laboratory findings, and treatment options. Key points include:
- Multiple myeloma is a neoplastic plasma cell disorder characterized by clonal proliferation of malignant plasma cells in the bone marrow.
- It accounts for 1% of cancers and 13% of hematological malignancies in Western countries. Median age at diagnosis is 70 years.
- Pathogenesis involves genetic alterations in plasma cells following activation in lymph nodes, resulting in monoclonal protein production and bone marrow homing.
- Clinical features include bone lesions, hypercalcemia, renal impairment, anemia, and infections.
Pancytopenia refers to decreases in all peripheral blood cell lineages. The initial evaluation of pancytopenia includes history, physical exam, screening labs including CBC and peripheral smear. This helps identify potential causes and emergencies requiring prompt treatment or hematology referral. Bone marrow testing may identify primary hematologic disorders but is sometimes unhelpful and specialized testing is preferred in some cases involving peripheral cell destruction.
This document discusses Myelodysplastic Syndromes (MDS), including definitions, classification systems, predisposing factors, cytogenetic abnormalities, theories of pathophysiology, clinical manifestations, laboratory/pathology findings, and morphological abnormalities. Key points:
- MDS are clonal stem cell disorders characterized by ineffective hematopoiesis leading to cytopenias from defects in maturation. There have been many historical names and classification schemes, now defined by WHO.
- Predisposing factors include aging, genetic syndromes, chemotherapy/radiation, and environmental exposures. Cytogenetic abnormalities impact prognosis.
- Pathophysiology involves genetic/epigenetic changes, telomere dysfunction, altered micro
This document defines and describes myeloproliferative disorder (myelofibrosis). It discusses the etiology, pathogenesis, clinical features, investigations, complications, prognosis, and management of myelofibrosis. Myelofibrosis is a clonal disorder of hematopoietic stem cells characterized by bone marrow fibrosis, extramedullary hematopoiesis, and splenomegaly. The cause is unknown but genetic mutations are involved in many cases. Symptoms include anemia, splenomegaly, and constitutional symptoms. Diagnosis involves blood tests and bone marrow biopsy showing fibrosis. Management focuses on controlling symptoms and complications through medications, transfusions, radiation therapy, or stem cell transplant.
This document describes myelodysplastic syndromes (MDS), a group of clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis leading to peripheral blood cytopenias. It discusses the history of MDS classification including the French-American-British (FAB) and World Health Organization (WHO) systems. Key features of the different MDS subtypes are outlined along with associated cytogenetic abnormalities, predisposing factors, theories of pathophysiology, clinical manifestations, and diagnostic evaluation.
The document discusses myeloproliferative disorders (MPDs), which are clonal stem cell disorders characterized by increased blood cell counts and enlarged spleen and bone marrow. It focuses on chronic myeloid leukemia (CML), describing it as a MPD caused by a genetic mutation that results in uncontrolled white blood cell growth. CML progresses through chronic, accelerated, and blast phases, with symptoms ranging from fatigue to organ enlargement. Diagnosis involves blood and bone marrow tests detecting elevated white and platelet counts and the Philadelphia chromosome genetic abnormality associated with CML.
Myeloproliferative disorders include polycythemia vera, essential thrombocytosis, myelofibrosis, and chronic myeloid leukemia. Polycythemia vera is a neoplastic stem cell disorder characterized by erythrocytosis, thrombocytosis, and leukocytosis. Treatment involves phlebotomy and myelosuppressive drugs like hydroxyurea. Essential thrombocytosis is characterized by elevated platelet counts over 600,000 and enlarged, abnormal megakaryocytes. It can cause thrombosis. Myelofibrosis features bone marrow fibrosis, splenomegaly, anemia, and thrombocytopenia. Chronic myeloid leukemia is a malignant disorder caused by the Philadelphia chromosome resulting from a
Chronic myeloid leukemia (CML) is a type of leukemia characterized by the Philadelphia chromosome, which is formed from the translocation of chromosomes 9 and 22. This translocation results in the BCR-ABL fusion gene which leads to increased proliferation of myeloid cells. CML progresses from a chronic phase to accelerated and blast crisis phases without treatment. Imatinib is now the standard first-line treatment for CML, achieving high rates of response. Resistance can develop through BCR-ABL mutations requiring other tyrosine kinase inhibitors. Allogeneic stem cell transplant remains the only potentially curative option but has risks.
This document summarizes recent changes in the classification of myeloproliferative neoplasms according to the 2016 World Health Organization classification. It discusses the reclassification of chronic myeloid leukemia as chronic myeloid leukemia and updates to the diagnostic criteria for conditions such as polycythemia vera, essential thrombocythemia, primary myelofibrosis, and chronic neutrophilic leukemia. New genetic markers and provisions for incorporating treatment response are included. Representative images of peripheral blood smears and bone marrow biopsies are also presented.
1. Polycythemia vera (PV) is a chronic myeloproliferative neoplasm characterized by an overproduction of red blood cells without an identifiable stimulus. It commonly presents with erythrocytosis, splenomegaly, thrombosis, and pruritus.
2. The main cause of PV is a mutation in the JAK2 gene, but some patients have mutations in exon 12. Diagnosis requires tests to distinguish absolute from relative erythrocytosis. Treatment focuses on phlebotomy and medications to control symptoms and prevent complications.
3. Primary myelofibrosis (PMF) is a chronic myeloproliferative neoplasm involving clonal proliferation and
The document discusses hematopoietic neoplasms and myeloproliferative disorders. It describes how hematopoietic neoplasms can be classified based on lineage, chronicity, and location. It then focuses on chronic myeloproliferative disorders including chronic myelogenous leukemia, polycythemia vera, essential thrombocythemia, myelofibrosis, and their characteristics and diagnostic criteria. Acute myelogenous leukemia is also discussed.
This document provides an overview of myelodysplastic syndrome (MDS). It discusses the history and changing definitions of MDS, current WHO classification, clinical features, pathogenesis involving genetic and epigenetic abnormalities, dysplastic changes seen in the bone marrow, and identification of blast cells. MDS is a heterogenous stem cell disorder characterized by cytopenias, dysplasia, and increased risk of acute myeloid leukemia. The disease results from acquired mutations in hematopoietic stem/progenitor cells and involves dysregulated apoptosis, ineffective hematopoiesis, and genetic and epigenetic changes.
The document discusses various myeloproliferative neoplasms (MPNs) including classic MPNs such as polycythemia vera, essential thrombocythemia, and primary myelofibrosis as well as atypical MPNs. It provides details on the diagnostic criteria, signs and symptoms, genetic mutations involved, and treatment approaches for these different MPNs. Chronic myelogenous leukemia is also examined as it represents a distinct MPN characterized by the Philadelphia chromosome genetic abnormality.
This document provides an overview of hemophagocytic lymphohistiocytosis (HLH). It begins by introducing HLH and describing its characteristics such as fever, hepatosplenomegaly, and cytopenias. It then discusses the classification of primary and secondary HLH, epidemiology, genetic causes, clinical features, diagnostic guidelines, treatment protocols, and long-term follow up recommendations. For the patient presented, the document recommends following the HLH-2004 treatment protocol initially and considering continuation therapy or stem cell transplant depending on the disease response and severity.
Congenital dyserythropoietic anemia (CDA) is a rare blood disorder characterized by ineffective red blood cell production resulting in anemia. There are four main types of CDA which are inherited in an autosomal recessive pattern. Patients with CDA require frequent blood transfusions and iron chelation therapy to remove excess iron from the body. Bone marrow transplant and gene therapy may cure CDA but carry risks. Recent gene therapy trials have shown promise in curing beta-thalassemia.
The document provides information on evaluating and diagnosing thrombocytopenia, including:
1) Normal platelet counts range from 150,000-450,000/microL and are slightly higher in females and younger people. Thrombocytopenia is defined as a platelet count below 150,000/microL.
2) The basic mechanisms of thrombocytopenia include decreased platelet production, ineffective production, increased destruction, increased consumption, and sequestration.
3) Diagnosing thrombocytopenia involves ruling out pseudothrombocytopenia, examining the blood counts, bone marrow, and performing additional lab tests to determine the underlying cause and guide treatment.
acute leukemia
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This document discusses myeloproliferative disorders (MPDs), including polycythemia vera, essential thrombocythemia, and primary myelofibrosis. MPDs are clonal stem cell disorders characterized by excessive proliferation of one or more myeloid cell lineages. Common features include increased proliferation, extramedullary hematopoiesis, marrow fibrosis, and peripheral blood cytopenias. The document defines each type of MPD and discusses their pathogenesis, morphology, clinical features, complications, investigations, and treatments.
This document discusses the diagnostic approach and classification of myeloproliferative neoplasms according to the 2008 WHO criteria. It describes the differential diagnosis and clinical features of polycythemia vera, essential thrombocythemia, and primary myelofibrosis. It discusses diagnostic criteria, disease course, prognosis, and treatment approaches for these chronic myeloproliferative disorders.
This document discusses thrombotic thrombocytopenic purpura (TTP). It begins by presenting a case of a 32-year-old woman presenting with headaches, difficulty speaking and moving her tongue, and numbness. Her exam and labs show thrombocytopenia and schistocytes. The document then discusses the differential diagnosis, epidemiology, terminology, definitions, types, presentations, investigations, and treatment of TTP, with a focus on plasma exchange therapy to remove antibodies and replace deficient ADAMTS13 protease.
This document provides information about multiple myeloma, including its definition, epidemiology, pathogenesis, clinical presentation, diagnostic criteria, staging system, imaging, laboratory findings, and treatment options. Key points include:
- Multiple myeloma is a neoplastic plasma cell disorder characterized by clonal proliferation of malignant plasma cells in the bone marrow.
- It accounts for 1% of cancers and 13% of hematological malignancies in Western countries. Median age at diagnosis is 70 years.
- Pathogenesis involves genetic alterations in plasma cells following activation in lymph nodes, resulting in monoclonal protein production and bone marrow homing.
- Clinical features include bone lesions, hypercalcemia, renal impairment, anemia, and infections.
Pancytopenia refers to decreases in all peripheral blood cell lineages. The initial evaluation of pancytopenia includes history, physical exam, screening labs including CBC and peripheral smear. This helps identify potential causes and emergencies requiring prompt treatment or hematology referral. Bone marrow testing may identify primary hematologic disorders but is sometimes unhelpful and specialized testing is preferred in some cases involving peripheral cell destruction.
This document discusses Myelodysplastic Syndromes (MDS), including definitions, classification systems, predisposing factors, cytogenetic abnormalities, theories of pathophysiology, clinical manifestations, laboratory/pathology findings, and morphological abnormalities. Key points:
- MDS are clonal stem cell disorders characterized by ineffective hematopoiesis leading to cytopenias from defects in maturation. There have been many historical names and classification schemes, now defined by WHO.
- Predisposing factors include aging, genetic syndromes, chemotherapy/radiation, and environmental exposures. Cytogenetic abnormalities impact prognosis.
- Pathophysiology involves genetic/epigenetic changes, telomere dysfunction, altered micro
This document defines and describes myeloproliferative disorder (myelofibrosis). It discusses the etiology, pathogenesis, clinical features, investigations, complications, prognosis, and management of myelofibrosis. Myelofibrosis is a clonal disorder of hematopoietic stem cells characterized by bone marrow fibrosis, extramedullary hematopoiesis, and splenomegaly. The cause is unknown but genetic mutations are involved in many cases. Symptoms include anemia, splenomegaly, and constitutional symptoms. Diagnosis involves blood tests and bone marrow biopsy showing fibrosis. Management focuses on controlling symptoms and complications through medications, transfusions, radiation therapy, or stem cell transplant.
This document describes myelodysplastic syndromes (MDS), a group of clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis leading to peripheral blood cytopenias. It discusses the history of MDS classification including the French-American-British (FAB) and World Health Organization (WHO) systems. Key features of the different MDS subtypes are outlined along with associated cytogenetic abnormalities, predisposing factors, theories of pathophysiology, clinical manifestations, and diagnostic evaluation.
The document discusses myeloproliferative disorders (MPDs), which are clonal stem cell disorders characterized by increased blood cell counts and enlarged spleen and bone marrow. It focuses on chronic myeloid leukemia (CML), describing it as a MPD caused by a genetic mutation that results in uncontrolled white blood cell growth. CML progresses through chronic, accelerated, and blast phases, with symptoms ranging from fatigue to organ enlargement. Diagnosis involves blood and bone marrow tests detecting elevated white and platelet counts and the Philadelphia chromosome genetic abnormality associated with CML.
Myeloproliferative disorders include polycythemia vera, essential thrombocytosis, myelofibrosis, and chronic myeloid leukemia. Polycythemia vera is a neoplastic stem cell disorder characterized by erythrocytosis, thrombocytosis, and leukocytosis. Treatment involves phlebotomy and myelosuppressive drugs like hydroxyurea. Essential thrombocytosis is characterized by elevated platelet counts over 600,000 and enlarged, abnormal megakaryocytes. It can cause thrombosis. Myelofibrosis features bone marrow fibrosis, splenomegaly, anemia, and thrombocytopenia. Chronic myeloid leukemia is a malignant disorder caused by the Philadelphia chromosome resulting from a
This document provides an overview of myeloproliferative diseases other than chronic myeloid leukemia. It defines myeloproliferative diseases as disorders characterized by proliferation of one or more hematologic cell lines. The document discusses classifications, clinical presentations, diagnostic criteria, genetic mutations, outcomes, and treatment options for several myeloproliferative diseases including polycythemia vera, essential thrombocythemia, and primary myelofibrosis.
Recent updates in classification of mds and myeloid neoplasmDrChirag Parmar
The document summarizes key changes in the revised 2016 WHO classification of myeloid neoplasms and acute leukemia from the previous 2008 classification. Some notable changes include: incorporating new genetic entities for several myeloid neoplasms based on recent molecular findings; refining diagnostic criteria for certain myeloproliferative neoplasms and myelodysplastic/myeloproliferative neoplasms to improve accuracy; and stratifying chronic myelomonocytic leukemia into three subgroups based on blast percentage which provides more precise prognostication. The revision aims to incorporate new knowledge obtained since 2008 while maintaining most of the original disease categories.
This document summarizes four types of chronic myeloproliferative disorders: chronic myelogenous leukemia, polycythemia vera, essential thrombocytosis, and primary myelofibrosis. It provides details on chronic myelogenous leukemia such as its description, clinical course, Philadelphia chromosome translocation, and treatment options including BCR-ABL kinase inhibitors and allogenic bone marrow transplant. For polycythemia vera, it notes the clonal disorder of pluripotent stem cells, symptoms, complications including thrombosis and bleeding, and diagnostic criteria.
Chronic myeloid leukemia (CML) is a type of leukemia characterized by the increased and unregulated growth of myeloid cells in the bone marrow. It results from a reciprocal translocation between chromosomes 9 and 22, known as the Philadelphia chromosome, which generates the BCR-ABL fusion gene. This fusion gene encodes for a constitutively active tyrosine kinase that drives the overproduction of white blood cells. CML progresses through chronic, accelerated and blast crisis phases and can be diagnosed by blood and bone marrow tests and identification of the Philadelphia chromosome. Treatment involves tyrosine kinase inhibitors like imatinib, dasatinib or nilotinib, stem cell transplant, or other drugs and monitoring response based on blood counts
This document summarizes a case study of a 45-year-old female patient presenting with abdominal distention, leg swelling, and decreased urine output over the past several months. Her examination and test results indicate hepatosplenomegaly, anemia, thrombocytopenia, and a markedly elevated white blood cell count with myeloblasts in the blood and bone marrow. A bone marrow biopsy shows features consistent with chronic myeloid leukemia in lymphoid blast crisis. She is started on symptomatic treatment by the medical oncologist.
The document discusses several myeloproliferative disorders including polycythemia vera, essential thrombocytosis, and myelofibrosis. Polycythemia vera is a neoplastic stem cell disorder characterized by erythrocytosis and can lead to symptoms like pruritus, erythromelalgia, and thrombosis. Diagnosis involves meeting criteria such as increased red blood cell mass and the presence of a JAK2 mutation. Treatment options include phlebotomy, hydroxyurea, interferon alpha, and alkylating agents. Essential thrombocytosis is characterized by a platelet count over 600,000 and risks include thrombosis, erythromelalgia and hemorrhage. Myelofibrosis involves
This document discusses LAMP (loop-mediated isothermal amplification), a diagnostic technique for visual virus detection. LAMP offers advantages over PCR like higher sensitivity, specificity, speed, and simplicity. It can detect as little as 10 femtograms of DNA under isothermal conditions in 60 minutes. The document reviews the ideal properties of diagnostic tests, different isothermal amplification techniques, LAMP primers and enzymes, result interpretation methods, LAMP stability and applications for detecting various animal viruses. While sensitive, LAMP is prone to product cross-contamination; solutions to address this like closed-tube reactions and pre-made mixtures are proposed to make LAMP suitable for field-level pathogen diagnosis.
Monitoring of Minimal Residual Disease Principles and Applicationsspa718
This document discusses methods for monitoring minimal residual disease (MRD) in acute myeloid leukemia (AML) patients, including polymerase chain reaction (PCR) to detect leukemic fusion genes or mutations, and multiparameter flow cytometry (FCM) to identify aberrant myeloid precursors. MRD detection can provide prognostic information, help evaluate treatment effectiveness, guide risk-adjusted therapy, and predict relapse. Both methods have advantages and limitations, and more standardization is needed. MRD remains a promising tool to improve AML patient outcomes by guiding personalized therapy.
This document discusses minimal residual disease (MRD) in acute myeloid leukemia (AML). Some key points:
1) Most AML patients achieve remission with initial treatment but most will eventually relapse, so detecting MRD could help predict relapse and allow preemptive treatment.
2) Methods for detecting MRD include multiparameter flow cytometry, PCR for genetic mutations, and measuring markers like WT1. Challenges include a lack of standardized methods and thresholds.
3) Studies show detecting MRD after induction and consolidation chemotherapy provides strong prognostic information, with higher MRD levels predicting poorer outcomes. Detecting MRD early also provides a window to intervene before clinical relapse.
4) In
LAMP PCR is a nucleic acid amplification technique that uses a DNA polymerase with strand displacement activity. It requires 4-6 designed primers that recognize 6 distinct regions on the target gene. Amplification occurs isothermally without temperature cycling. It produces stem-loop DNA structures with dumbbell ends that are amplified quickly using loop primers. LAMP has advantages over PCR like higher specificity, greater detection limit, simpler operation without expensive equipment, and ability to use crude samples. It is a sensitive, specific and cost-effective technique used for diagnosing infectious diseases.
Cytogenetic analysis in Hematological Malignanciesspa718
1. Cytogenetic analysis identifies recurrent chromosomal abnormalities in hematological malignancies that are important for diagnosis, classification, risk stratification, and treatment selection.
2. Specific abnormalities seen in cancers include t(9;22) in CML, t(8;21), t(15;17), and others in AML, and t(4;11) and others in ALL. Abnormalities in MDS include -Y, del(11q), and -7.
3. Cytogenetic testing aids in diagnosis, determining prognosis, assessing treatment response over time, and detecting relapse in diseases like CML, AML, MDS, lymphoma, CLL and MM.
Dr. adhra al mawali - immunophenotyping and mrd of acute myeloid leukemiaHitham Esam
This document discusses multiparameter flow cytometry techniques for detecting leukaemia-associated phenotypes (LAPs) and minimal residual disease (MRD) in acute myeloid leukemia (AML). It finds that 64% of AML patients displayed LAPs, which were independent markers for predicting poor response to induction chemotherapy and relapse. The document also describes methods for detecting MRD, including multiparameter flow cytometry and polymerase chain reaction, and how MRD detection could facilitate early detection of relapse and guide risk-adapted therapies.
Ohio State's ASH Review 2017 - Myeloproliferative DisordersOSUCCC - James
Katherine Walsh, MD
Assistant Professor of Clinical Internal Medicine
The Ohio State University Comprehensive Cancer Center -
Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
The document discusses a case of a 66-year-old woman presenting with a transient ischemic attack and laboratory findings consistent with a myeloproliferative neoplasm (MPN). MPNs are chronic clonal hematopoietic stem cell diseases characterized by overproduction of one or more blood cell lines. Common MPNs discussed include polycythemia vera, essential thrombocythemia, and primary myelofibrosis. Treatment options for each MPN are summarized.
This document discusses surgical site infections (SSIs), including their definition, incidence, microbiology, pathogenesis, diagnosis, risk factors, prevention, and treatment. Some key points:
1. The CDC revised the definition of "wound infection" in 1992 to distinguish between surgical incision infections and traumatic wound infections.
2. SSIs are usually caused by the patient's skin flora or bacteria introduced during surgery. They occur within 30 days of an operation or 1 year if an implant is inserted.
3. Risk factors include age, diabetes, obesity, smoking, and surgical factors like wound class and duration. Prevention focuses on patient optimization, skin antisepsis, tight glucose control, and appropriate
01.13.09: Chronic Myeloid Leukemia and other Myeloproliferative Neoplasms (MPNs)Open.Michigan
Slideshow is from the University of Michigan Medical
School's M2 Hematology / Oncology sequence
View additional course materials on Open.Michigan: openmi.ch/med-M2Hematology
Mutations in genes like BCR-ABL, JAK2, MPL, and KIT can cause myeloid neoplasms by promoting proliferation or blocking differentiation. BCR-ABL, found in chronic myeloid leukemia (CML), encodes a fusion protein with constitutive tyrosine kinase activity. The JAK2 V617F mutation is present in the majority of polycythemia vera and a significant portion of essential thrombocythemia and primary myelofibrosis cases. MPL mutations like MPLW515L can also drive essential thrombocythemia and primary myelofibrosis. These genetic abnormalities activate signaling pathways that dysregulate myeloid cell growth and maturation.
1) This patient presented with fever, weight loss, anemia, leukocytosis, and thrombocytopenia. Bone marrow examination found increased myeloblasts and monoblasts.
2) He was diagnosed with acute monocytic leukemia (AML M5) based on over 30% monoblasts found on bone marrow biopsy.
3) AML M5 is a subtype of acute myeloid leukemia characterized by a proliferation of monocytic cells in the bone marrow. Workup includes blood tests, bone marrow aspiration and biopsy, and cytogenetic studies to further characterize the disease.
Leukemia is the most common pediatric malignancy, accounting for 1/3 of all childhood cancers. It is defined as the malignant clonal proliferation of lymphoid or myeloid precursor cells in the bone marrow and infiltration of other organs. The presentation includes general symptoms like fever, fatigue, and pallor as well as hematological effects from bone marrow invasion including anemia, neutropenia, and thrombocytopenia. Diagnosis involves blood tests, bone marrow examination, and other investigations. Treatment consists of induction chemotherapy followed by consolidation and maintenance therapy to achieve remission and prevent relapse.
This document discusses myeloproliferative disorders, which are clonal stem cell disorders characterized by overproduction of one or more myeloid cell lines. The common bcr-abl negative myeloproliferative disorders discussed are polycythemia vera, essential thrombocythemia, and myelofibrosis. JAK2 mutations are involved in the pathogenesis of many of these disorders. The document also discusses mast cell disease, hypereosinophilia, and other related rare conditions.
This document summarizes several myeloid disorders including myelodysplastic syndrome (MDS), chronic myeloid leukemia (CML), polycythemia vera (PV), and essential thrombocythemia (ET). MDS is a heterogeneous group of malignant stem cell disorders characterized by dysplastic and ineffective blood cell production with a risk of progressing to acute myeloid leukemia. CML is caused by the Philadelphia chromosome and results in excessive granulocyte production. PV is characterized by an elevated red blood cell mass and is caused by a JAK2 mutation. ET involves a sustained increased in platelet count due to megakaryocyte proliferation. These conditions are diagnosed based on blood tests, bone marrow biopsy, and genetic
This document discusses kidney cancer (renal cell carcinoma). It covers the epidemiology, etiology, hereditary forms, VHL disease, histology, staging, diagnosis, and screening recommendations. Some key points:
1. RCC incidence is increasing with a peak age of 60-70. Risk factors include smoking, obesity, and family history. Clear cell RCC is the most common type.
2. VHL disease is a hereditary form associated with clear cell RCC and other tumors. It is caused by a defective VHL gene.
3. Diagnosis is often incidental but may involve flank pain, hematuria, or mass. Imaging includes ultrasound, CT, MRI, and PET
The document summarizes recent changes to the World Health Organization's classification of myeloid neoplasms and acute leukemias based on advances since the 2008 classification. Key changes include new entities recognized based on unique biomarkers identified by gene expression analysis and sequencing. Entities were modified to better incorporate prognostic markers. Notable revisions include changes to criteria for chronic myeloid leukemia, myeloproliferative neoplasms, and myelodysplastic/myeloproliferative neoplasms. The classification of myelodysplastic syndromes was also updated to focus more on dysplasia levels than specific cytopenias. Recognition of myeloid neoplasms with germline predisposition was another major change.
This document discusses the case of a 35-year-old female patient presenting with fever, fatigue, and shortness of breath. Her medical history includes a hysterectomy for menorrhagia and treatment for genitourinary tuberculosis. On examination, she has pallor and tachycardia. Laboratory tests show pancytopenia and blasts in her peripheral blood smear. A bone marrow biopsy confirms the diagnosis of acute myeloid leukemia. The discussion reviews the epidemiology, etiology, classification, clinical presentation, diagnostic workup, and initial treatment evaluation for AML.
This document provides an overview of acute myeloid leukemia (AML). It discusses the historical background, classification, clinical features, risk stratification, diagnostic evaluation, and treatment regimens for AML. Key points include that AML is characterized by infiltration of blood and bone marrow by proliferative myeloid cells, the WHO classification system is based on clinical features, morphology, cytogenetics and molecular abnormalities, risk is stratified by cytogenetics and molecular markers, and treatment involves supportive care, induction chemotherapy, and consideration of novel targeted therapies or stem cell transplant depending on risk factors.
This presentation offers an in-depth exploration of Myelodysplastic Syndromes (MDS), a group of bone marrow disorders. I will cover MDS basics, symptoms, diagnosis, and treatment options. Join us to uncover the complexities of MDS subtypes, their impact on patients, and the latest medical advancements. Whether you're a healthcare professional specially hematologist/oncologist or simply curious, this presentation sheds light on MDS's intricacies and the importance of early intervention
Leukemia is a group of cancers that affect the blood and bone marrow. This document discusses the main types of leukemia:
1. Acute myelogenous leukemia (AML) is characterized by increased proliferation of immature myeloid cells in the bone marrow. It accounts for about one-third of adult leukemias.
2. Acute lymphoblastic leukemia (ALL) is most common in children and is characterized by increased lymphoblasts in the bone marrow. About 85% of ALL cases are B-cell ALL.
3. Chronic myelogenous leukemia (CML) is a myeloproliferative neoplasm characterized by increased and unregulated growth of predominantly granulocytic
This case report describes a 3-year-old female patient presenting with bleeding symptoms including rashes, nosebleeds, gum bleeding, and bloody stools. Initial investigations revealed pancytopenia. The peripheral smear and bone marrow findings were suggestive of idiopathic thrombocytopenic purpura with evidence of infection rather than acute promyelocytic leukemia due to the absence of features such as organomegaly and specific immunophenotyping or cytogenetic findings. The patient was treated with antibiotics and supportive care and diagnosed with idiopathic thrombocytopenic purpura complicated by infection based on clinical presentation, investigations, and differential diagnosis workup.
This document summarizes key information about polycythemia vera (PV), including signs and symptoms, diagnostic criteria, prognosis, treatment options, and risk of hematologic transformation. It presents two clinical vignettes and questions to assess understanding of PV diagnosis and management. Common initial findings in PV include hypertension, splenomegaly, pruritus, and erythromegaly. The 2016 WHO diagnostic criteria require meeting major criteria of elevated hematocrit/hemoglobin or increased red cell mass, along with bone marrow biopsy and JAK2 mutation status. Prognosis is best in low-risk PV treated with phlebotomy and aspirin, while high-risk disease requires additional cytoreductive therapy like
LEUKEMIC DISEASES AND THE EYE.pptx. This talks about the ocular manifestation...BARNABASMUGABI
This document provides an overview of leukemic diseases and their ocular manifestations. It discusses the different types of leukemia including acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, and chronic lymphocytic leukemia. It covers the pathogenesis, classification, signs and symptoms, diagnostic testing including blood counts, bone marrow examination, and cytochemical staining. It also describes the various ocular changes that can occur due to anemia, thrombocytopenia, hyperviscosity, thrombosis, infiltration of tissues, and metabolic abnormalities associated with leukemias.
Chronic myelogenous leukemia ( CML )
Tests to be done in order to differentiate CML from other dieases with common clinical features.
It's pathogenesis, clinical presentation and features of diagnostic tests.
Methods of treatment. Prognosis of a disease according to "Sokal" score
Chronic myelogenous leukemia (CML) is a myeloproliferative disorder characterized by increased proliferation of granulocytic cells. The initiating factor of CML is an acquired genetic translocation that fuses the BCR gene on chromosome 22 and the ABL gene on chromosome 9, producing the Philadelphia chromosome and the BCR-ABL fusion gene. This gene encodes for an unregulated tyrosine kinase that drives uncontrolled proliferation of myeloid cells. CML progresses through chronic, accelerated, and blast phases as the disease advances and more immature cells appear in the blood and bone marrow over time. Diagnosis is confirmed by detecting the Philadelphia chromosome or BCR-ABL fusion using techniques like fluorescence in situ hybrid
Dr. Sachin Verma is a young, diligent and dynamic physician. He did his graduation from IGMC Shimla and MD in Internal Medicine from GSVM Medical College Kanpur. Then he did his Fellowship in Intensive Care Medicine (FICM) from Apollo Hospital Delhi. He has done fellowship in infectious diseases by Infectious Disease Society of America (IDSA). He has also done FCCS course and is certified Advance Cardiac Life support (ACLS) and Basic Life Support (BLS) provider by American Heart Association. He has also done a course in Cardiology by American College of Cardiology and a course in Diabetology by International Diabetes Centre. He specializes in the management of Infections, Multiorgan Dysfunctions and Critically ill patients and has many publications and presentations in various national conferences under his belt. He is currently working in NABH Approved Ivy super-specialty Hospital Mohali as Consultant Intensivists and Physician.
MDS and myeloproliferative disorders are heterogeneous groups of clonal stem cell disorders characterized by ineffective or excessive blood cell production. MDS involves dysplastic and ineffective hematopoiesis that can progress to acute leukemia, while myeloproliferative disorders feature overgrowth of one or more myeloid cell lines. Key disorders discussed include MDS, polycythemia vera involving excessive red blood cell production, essential thrombocytosis with marked thrombocytosis, myelofibrosis with bone marrow fibrosis, and chronic myeloid leukemia characterized by the Philadelphia chromosome translocation. Diagnosis and classification of these disorders has evolved with new genetic and molecular testing.
This document provides an overview of hematological disorders including:
1. Leukemias are classified as either myeloid or lymphoid and acute or chronic based on the affected cell lineage and speed of onset. Acute myeloid leukemias are characterized by a rapid accumulation of blast cells in the bone marrow.
2. Myeloproliferative disorders involve the overproliferation of terminally differentiated myeloid cells and can transform into acute myeloid leukemia. Chronic myeloid leukemia is caused by the Philadelphia chromosome translocation.
3. Acute lymphoblastic leukemia is the most common childhood leukemia and is characterized by uncontrolled proliferation of lymphocyte precursors in the bone marrow presenting as p
Acute lymphoblastic leukemia (ALL) is a cancer of the lymphoid line of blood cells characterized by the proliferation of immature lymphocytes in the bone marrow. Diagnosis requires identifying at least 20% lymphoblasts in the bone marrow. Testing includes bone marrow biopsy and aspiration with immunophenotyping, cytogenetics, lumbar puncture and other studies. Proper classification is important for determining prognosis and selecting optimal treatment strategies.
Polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis are related myeloproliferative neoplasms. PV is characterized by excessive production of all blood cell lines including red blood cells, white blood cells, and platelets independent of erythropoietin. The JAK2 mutation is present in almost all PV cases. ET involves increased megakaryocytes and platelet counts without elevated thrombopoietin. Myelofibrosis features abnormal stem cells leading to bone marrow fibrosis, extramedullary hematopoiesis, and a leukoerythroblastic blood smear.
Similar to DIAGNOSIS AND MANAGEMENT OF MYELOPROLIFERATIVE NEOPLASMS (20)
3. INTRODUCTION (I)
• MPN- rare disorders of the bone marrow that
cause an increase in the number of blood
cells.
• Median age 60y, also in young, rare in children
• Incidence varied: ET 0.6-2.3/105,MF 0.5-1/105
PV is more prevalent in Europe 1.05/100000.G J.
Titmarsh et al. American Journal of Hematology, 2014
• Progression to acute leukaemia .
4. The history of myeloproliferative disorders: before and after Dameshek
A Tefferi Leukemia 2008.
1845:
Bennett- CML
1879:
Heuck- PMF
1892:
Vaquez- PV
1934:
Estein &
Goedel-
ET
1951:Dameshek- MPD
1953: DNA structure
1960: Nowel- Crom.Ph
1967: PVGS. Stem cell
origin
1982-1990
Molecular and oncogenic
characterization of
BCR-ABL
1996: Imatinib
2005:
JAK2 V617F exon 14.
2006: MPL
2007: JAK2 exon12.
2013: CALR
Present:
Molecular therapy
INTRODUCTION (II):a little of history
10. INTRODUCTION (VIII): Aetiology
• Dec ´13: CALR Exon 9 mutation described in: ET, PMF, MDS/MPN
overlap disorder, and RARS-T.
• Mutually exclusive of JAK2 and MPL. Longest survival in MF.
• Triple negative patients identified.
11. DIAGNOSIS: when suspect MPN?
• Erythrocytosis or thrombocytosis without
other causes---- think in PV & ET.
• Unusual thrombosis ( portal or hepatic vein
thrombosis)--- think in PV.
• Leucoerythroblastic blood film, splenomegaly,
anemia--- think in MF.
• Aquagenic pruritus, extramedullar
haematopoiesis and bone marrow fibrosis---
think in MPN.
12. Polycythaemia Vera –PV
• Raised Htc >0.52 M, > 0.48 F for> 2 months*
• Incidence 0.2-28/106, median age 60y, youngest
(5% < 50yo**)
• Median survival >10y
• RF survival: advanced age, leucocytosis,
thrombosis and abnormal karyotype.
• Leukaemia progression 10% in 20y. Fibrotic
transformation is slightly higher.
• JAK2 V617F presents over 95%, exon 12
mutation ~ 3%, exon14 mutation ~ 3%.
*BSH guidelines , **Passamonti et al. Haematologica
13. PV Diagnosis (I)
• Clinical presentation:
– Recurrent headaches, blurred vision- hyperviscosity
– Dyspnoea, gout
– Aquagenic pruritus, Erythromelalgia, Plethoric
appearances,
– Splenomegaly- 70%
– Haemorrhage or thrombosis ( arterial or venous):
• first manifestation (MI, stroke, DVT)
• 20%,
• unusual places: mesenteric, portal or splenic
• causes of dead
– Asymptomatic
15. FBC • Raised Hb, htc, red cell count and red cell volume
• Thrombocytosis 50% , neutrophilia 2/3 patients –
smokers have neutrophilia ( upper limit
12.5x109/L).
Ferritin & Vit B12 • Low serum ferritin
• Absence iron stores in BM
• Elevated B12 ( transcobalamin release from
increased granulocytic mass)
Red cell mass • Increased ( >25% for age, sex and weight- less usage now)
U&E, LFT´s and Ca profile • Essential to exclude secondary causes.
Sat O2 • Indicator of tissue hypoxia
• Measure can be misleading in high affinity Hb,
SAS, carbon monoxide poisoning---- measure
COHb, p50
• Consider respiratory tests
EPO • Reduce, also in idiopathic erythrocytosis
Adapted for the Guidelines for the diagnosis, investigation and management of PV/ erythrocytosis, BSH, 2005
PV Diagnosis (III): laboratory findings
16. BM Aspirate • Dense particles and cellular trials
• Marked erythroid hyperplasia with moderate
hyperplasia of granulopoiesis and
megakaryopoesis.
• Wide MK size ( large with hyperlobated nuclei)
• Iron stores absent.
BM trephine • Hypercellular for age and panmyelosis ( trilineage
proliferation)
• Erythroid maturation maintained and
normoblastic
• Erythroid nests abnormally located trabeculae
• Granulocyte maturation maintained
• Increased MK, large size , reduce lobulation
• Clusters MK pleomorphic
• Mild to moderate stromal reticulin ( gr 2-3)
PV Diagnosis (IV): laboratory findings
Adapted for the Guidelines for the diagnosis, investigation and management of PV/ erythrocytosis, BSH, 2005
18. PV Diagnosis (VI): laboratory findings
Molecular studies • JAK2 V617F, Exon 12 and exon 14
• Less frequency MPL, CALR
Karyotype • 10-20% pat: trisomy in chr8 and 9, del (20q), del
(13q) and del (1p).
Culture studies of BFU-E • Not usually found in normal individuals
• Expensive not standardised
EPO receptor, VHL gene
mutation analysis, PRV-1
& other genes
• Unexplained erythrocytosis and low serum EPO
levels
• VHL gene mutation related Chuvash disorder
• PRV-1 ( novel cell surface receptor)- overexpressed
in granulocytes in PV
• c-MPL protein found in platelets of PV
Adapted from the Guidelines for the diagnosis, investigation and management of PV/erythrocytosis, BSH, 2005
19. PV diagnosis (VII) Masked PV
• JAK2+ with PV-characteristic BM morphology
despite lower Hb levels ( <16-18.5g/l men and
15-16.5g/l women).
• Distinguish to ET– Hb optimal cutoff level:
16.5g/L and htc 49% for men and Hb 16g/L and
htc 48% women.
• Therapeutic implication- risk of thrombotic
complications associated with borderline
increased Htc
• ? Modified WHO criteria diagnosis
A.Tefferi and T.Barbui, AJH 2015.
20. 2008 WHO criteria 2014 Proposed revision
Either both major criteria and one minor
criterion or the first major criterion and
two minor criteria.
Requires meeting either all three major
criteria or the first two major criteria and
one minor criterion.
Major criteria Major criteria
• Hb >18.5 g/dL (men), >16.5
g/dL (women)
• Presence of JAK2V617F or JAK2
exon 12 mutation .
• Hb >16.5 g/dL (men), >16 g/dL
(women) or Hct >49% (men), >
48% (women)
• BM trilineage myeloproliferation
with pleomorphic MK
• Presence of JAK2 mutation.
Minor criteria Minor criteria
• BM trilineage myeloproliferation
• Subnormal serum EPO level
• Endogenous erythroid colony
growth
• Subnormal serum EPO
Table adapted from Bhee-Jin Kim et al, Blood Research 2014
PV criteria diagnosis
21. Essential Thrombocythaemia- ET
• Raised platelets > 450x109/L
• Discard secondary causes.
• Median survival ~ 20y, pat >60 y increases to 33 y.
• RF survival: advanced age, leucocytosis and
thrombosis.
• Causes of dead: haemorrhage and/or thrombosis
• Leukaemia progression 5% in 20y, higher rates for
fibrotic transformation
• JAK2 V617F presents over 60%, CALR 20%, MPL
3%, triple negative 20%
22. ET diagnosis (I)
• Clinical presentation:
– Thrombosis ( venous and arterial)
– Haemorrhage event: nosebleeding, mucosa bleeds,
blood stool, bruising.
– Asymptomatic – 25-33%
– Mild splenomegaly ( 50%) and hepatomegaly 15-
20%. Splenic atrophy due to infarction.
– Erythromelalgia , microvascular occlusion,
numbness and tingling in hands/feet, headache,
dizziness, weakness, vision changes.
– Pregnancy complications: spontaneous abortions,
placental infarctions,
23. ET diagnosis (II)
THROMBOCYTOSIS
Iron deficiency,
Haemolysis.
Infection/inflammation
Haemorrhage
Trauma
Post surgery,
Splenectomy,
Connective tissue diseases
Solid cancer,
Other MPN or MDS
Guidelines for the diagnosis, investigation and management of PV/erythocytois, BSH,
2005
ASH imagebank
24. FBC • Raised plat.
• Marked anisocytosis in platelets and atypical
granulation, occ MK fragments ,
• Features of iron deficiency ( haemorrhage
episodes)
• WBC can be elevated. Leucoerythroblastic film
and tear drops are unusual.
Clotting screening and
platelets aggregation
study
• Usually normal
• Bleeding time may or may not be prolonged.
• Abnormal platelets aggregation, acquired Von-
Willebrand
Ferritin and vit b12 • Low serum ferritin if iron deficiency associated.
• Increased vitamin b12 -25%
U&E, LFT´s, CRP,ESR
LDH
• Essential to exclude secondary causes.
• Elevated LDH correlation with fibrotic
transformation
Adapted from the Guidelines for diagnosis and management of thrombocytosis , BSH, 2010 and P.Beer Blood, 2011
ET Diagnosis (III): laboratory findings
25. BM Aspirate • Normocellular for age or mildly hypercellular.
• MK increased in number, spectrum morphology:
large or giants with hyperlobulated ( staghorn),
occ small forms and normal MK.
• No significant hyperplasia in erythroid and
myeloid series.
• Iron stores may be reduced. Siderotic granulation
is normal,
BM trephine • MK similar description as in aspirate.
• MK distribution is disperse, may occur in loose
clusters within the interstitium.
• Reticulin generally no increased ( gr 0-2/4 or 0/3).
• Proliferation of erythroid is haemorrhages.
ET Diagnosis (IV): laboratory findings
Adapted from the Guidelines for diagnosis and management of thrombocytosis , BSH, 2010 and P.Beer Blood, 2011
26. ET diagnosis (V)morphology features
Blood film
Hyperlobulated MK in BM
Hypercellular BM
Clusters MK in BM
ASH imagebank
27. ET Diagnosis (VI): laboratory and radiology
findings
Molecular studies • JAK2 V617F, CALR, MPL.
• Triple negative 20%
• BCR-ABL
Karyotype • No required in routine test, useful as marker of
disease progression.
Radiology tests • Splenomegaly and/or hepatomegaly
• Thrombosis
• To discard other causes of thrombocytosis
Adapted from the Guidelines for diagnosis and management of thrombocytosis , BSH, 2010 and P.Beer Blood, 2011
28. 2008 WHO criteria 2014 Proposed revision
Meeting all four major criteria. Meeting all four major criteria or first three
major criteria and one minor criterion.
Major criteria Major criteria
• Platelet count ≥450×109/L
• MK proliferation with large and
mature morphology.
• Not meeting WHO criteria for CML,
PV, PMF, MDS or other myeloid
neoplasm
• Demonstration of JAK2V617F or other
clonal marker or no evidence of
reactive thrombocytosis
• Platelet count ≥450×109/L
• MK proliferation with large and mature
morphology.
• Not meeting WHO criteria for CML, PV, PMF,
MDS or other Myeloid neoplasm
• Presence of JAK2, CALR or MPL mutation
Minor criteria Minor criteria
No minor criteria. • Presence of a clonal marker (e.g. abnormal
karyotype) or absence of evidence for
reactive thrombocytosis.
ET Criteria diagnosis
Table adapted from Bhee-Jin Kim et al, Blood Research 2014
29. Myelofibrosis (MF)
• Characterized by marked reticulin fibrosis and
osteosclerosis with extramedullary hematopoiesis
and organomegaly.
• Primary MF or secondary to PV ( PPV-MF) and ET (
PET-MF).
• Median age 65y, incidence 0.5-1.5 /100,000 per
year.
• Median survival in pat<60y is 15y. Leukaemia
transformation 10-20%.
• JAK2 +60%, CALR 25% ( superior survival) and MPL
7%
31. MF diagnosis (II)
MYELOFIBROSIS
Splenomegaly
• Haematology diseases:
• Lymphoma, leukaemia, myeloma
• Portal hypertension
• Autoimmune disorders:
• SLE, RA
• Infections
Leucoerithrobalastic film
• Bone marrow infiltration
• AL, Lymphoma, MPN, MDS
• Solid cancer
• Hematopathologies
• Sepsis
• Massive haemolysis
Fatigue
Weight loss
32. FBC • Anemia, WBC and plat higher at initial diagnosis
and pancytopenia is common at advance stages.
• Leucoerythroblastic film and tear drops.
LDH • Elevated
Radiology tests(US, CT) • Splenomegaly and other organomegalies.
Molecular and
cytogenetic studies
• JAK2 V617F, CALR, MPL.
• Triple negative~ 10%
• BCR-ABL
• ASXL1 ( associated to inferior survival)
• Abnormal karyotype 50-60% : +8, -7/7q, inv (3),
etc.
Adapted from the Guidelines for diagnosis and management of myelofibrosis , BSH, 2012 and Cervantes F, Blood, 2014
MF Diagnosis (III): laboratory and radiology
findings
33. BM Aspirate • Dry ( 50%)
• Hypocellular
BM trephine • Prefibrotic phase:
- hypercellular with increased neutrophils and
atypical MK( enlarged). Erythroid is reduced.
- MK dense clusters of variable size and
adjacent to vascular sinuses and bone
trabecule.
- Reticulin fibrosis is reduce.
• Fibrotic phase:
- Normo or hypocelluar with patches of active
haematopoiesis.
- Atypical MK large clusters.
- Dense reticulin or collagen fibrosis.
- 10-19% blasts detected by cytometry.
MF Diagnosis (IV): laboratory findings
Adapted from the Guidelines for diagnosis and management of myelofibrosis , BSH, 2012 and Cervantes F, Blood, 2014
35. 2008 WHO criteria 2014 Proposed revision
Meeting all three major criteria and two minor
criteria.
Meeting all three major criteria or the first
two major criteria and all three minor criteria
Major criteria Major criteria
• MK proliferation and atypia, accompanied
by either reticulin and/or collagen fibrosis.
• Not meeting WHO criteria for CML, PV, MDS
or other myeloid neoplasm.
• Demonstration of JAK2V617F or other
clonal marker or no evidence of reactive BM
fibrosis.
• MK proliferation and atypia, accompanied
by either reticulin and/or collagen fibrosis.
• Not meeting WHO criteria for CML, PV,
MDS or other myeloid neoplasm
• Presence of JAK2, CALR or MPL mutation
Minor criteria Minor criteria
• Leukoerythroblastosis
• Increased serum LDH level
• Anemia
• Palpable splenomegaly
• Presence of a clonal marker (e.g.
abnormal karyotype) or absence of
evidence for reactive BM fibrosis
• Presence of anemia or palpable
splenomegaly
• Presence of leukoerythroblastosis or
increased LDH level.
MF Criteria diagnosis
Table adapted from Bhee-Jin Kim et al, Blood Research 2014
36. Practical Algorithm for Diagnosis of MPN
JAMA Oncol. 2015;1(1):97-105. doi:10.1001/jamaoncol.2015.89
37. MK IN MPN
PV ET MF
• Mk varied size ( mostly
large ) and hypolobulated
• Loose clusters or adjacent
to endosteum
• MK large to giants and
deep lobulated – staghorn
like nuclei
• Loose clusters or
dispersed
Prefibrotic phase:
• Atypical MK –cloud like
or hyperchromatic nuclei
• Dense clusters adjacent
to endosteum or sinosids
Fibrotic phase:
• Atypical MK mostly small
MK
• Large clusters or sheets
No reticulin increased No reticulin increased Reticulin increased
38. MANAGEMENT OF MPN: OBJECTIVES
• Reduce the risk of thrombosis and haemorrhage.
• Reduce the risk of transformation to MF and/or
AL.
• Manage constitutional symptoms and
complications associated ( thrombosis,
haemorrhage, pruritus, infections).
• Manage cardiovascular risk factors
• Manage MPN in special situations like pregnancy
39. Conventional risk stratification International polycythemia vera study
stratification.1
High risk PV - ANY ONE of the following: Risk factors (weight)
• Age >60 years
• Previous documented thrombosis,
• Erythromelagia (if refractory to aspirin)
Platelets > 1000x109/L*
• Diabetes or hypertension requiring
pharmacological therapy*
• Significant (i.e. >5 cm below costal margin
on palpation) or symptomatic (pain, early
satiety) splenomegaly
• Age ≥67 years (5 points)
• Age 57-66 years (2 points)
• Leukocyte count ≥15x109/L (1 point)
• Venous thrombosis (1 point),
• Abnormal karyotype (identified but no
weight)
Low-risk PV Risk categories
• Patients not having any of the above risk
factors.
• Low-risk (sum of scores 0 points)
• Intermediate-risk (sum of scores 1 or 2
points)
• High-risk (sum of scores ≥3 points
Table adapted from C.Harrison EHA 2014
Risk stratification in MPN: PV
40. Risk stratification in MPN: ET
Conventional risk stratification2 Intermediate
risk ET**
International Prognostic Score for
ET – ( IPSET A novel risk stratification
based upon histopathologically defined
ET3)
High risk ET- ANY ONE of the following: • Patients 40-60
years lacking
any of the
above markers
of high risk
disease
Risk factors (weight)
• Age ≥60 years (2 points)
• Leukocyte count ≥11x109/L (1 point)
• Prior thrombosis (1 point)
• Age >60 years
• Platelet count >1500x109/L
• Previous thrombosis,
• Erythromelagia (if refractory to
aspirin)
• Previous hemorrhage related to ET
• Diabetes or hypertension requiring
pharmacological therapy*
Low-risk ET** Risk categories
• Patients under 40 years lacking any of
the above markers of high-risk
disease
• Low-risk (sum of scores 0 points)
• Intermediate-risk (sum of scores 1 or
2 points)
• High-risk (sum of scores ≥3 points
Table adapted from C.Harrison EHA 2014
41. Risk stratification in MPN: MF (I)
IPSS prognostic score DIPSS
Prognostic variables 0 1 Prognostic variables 0 1 2
• Age in years <65 >65 • Age in years <65 >65
• WBC count
x109/L
<25 >25• WBC count x109/L <25 >25
• Hemoglobin g/l - <10 • Hemoglobin g/l - - <10
• Peripheral blasts% <1 >1 • Peripheral blood
%
<1 >1
• Constitutional
symptoms
No Yes • Constitutional
symptoms
No Yes
Risk assignment: Low = 0, Intermediate
1 = 1, Intermediate 2 = 2 High = 3+.
Median survivals are 135, 95, 48 and
27 months, respectively.
Risk assignment: Low = 0; Intermediate 1 = 1 or 2;
Intermediate 2 = 3 or 4; High = 5 or 6.
Median survival: not reached, 14.2, 4, and 1.5
years, respectively
Table adapted from C.Harrison EHA 2014
42. DIPSS plus prognostic score
Points for DIPPS 0 1 2 3
DIPSS prognositic group points Low risk 0 Intermidate-1 Intermidate-2 High risk
To the DIPSS prognostic group add one point for:
• Platelets count x109/L • - • <100 • - • -
• Red cell trasnfusion required • No • Yes • - • -
• Unfavorable karyotype (includes
+8, -7/7q-, i(17q), inv(3), -5/5q-,
12p-. 11q23 rearrangements and
complex karyotypes. )
• No • yes
Risk assignment number of points Low = 0; Intermediate 1 = 1; Intermediate 2 = 2 or 3;
High = 4 to 6. Corresponding median survival
estimates: 185, 78, 35 and 16m.
Risk stratification in MPN: MF (II)
Table adapted from C.Harrison EHA 2014
43. Risk stratification in MPN: MF (III)
Tefferi A. et al, JAMA network, 2015
• CALR mutations associated favourable survival
(10.4y), ASXL1 unfavourable survival (2.3y)
independent of DIPSS-plus risk
• New prognostic models:
– MIPSS- mutation enhanced international prognostic
scoring system.
– GPSS- genetics based prognostic system.
44. Recommendation of Treatment in PV (I)
ALL PATIENTS HIGH RISK ( age>60y and/or
presence thrombosis)
PV in pregnacy
• Assess and manage CV risk • Assess and manage CV risk • Low risk: Aspirin low dose
and Phlebotomy
• Cytoreductive treatment no
recommended in low risk
patients
• >60y:
• Hydroxyurea,
• Second line: Ruxolitinib,
Interferon , Busulfan (
>75y), clinical trial.
• <60y :
• Interferon, Anagrelide,
clinical trial
• Cytoreduction therapy if High
risk : Interferon and
phlebotomy
• Aspirin low dose, unless CI,
• If Jak2+ and CV risk:
Aspirin bd.
• Determinate ristocetin
cofactor activity >30% if
high platetets
• Monitor closely pat with
abnormal bleeding
diathesis.
• Low dose of aspirin
• Phlebotomy hto target<0.45 • Phlebotomy hto target<0.45
Table adapted from C.Harrison EHA 2014 and A.Tefferi AJH 2015
45. Recommendation of Treatment in PV (II)
• Ruxolitinib- Indicate in patients inadequate response to or are
intolerant of hydroxyurea.
• Approved in Europe in 2015.
• Control hematocrit and PV-related symptoms
• Reduce spleen volume
Verstovsek s et all. ASCO meeting 2011
46. Recommendation of Treatment in ET
ALL PATIENTS HIGH RISK ( age>60y and/or presence
thrombosis)
ET in pregnacy
• Assess and manage CV risk • Assess and manage CV risk • Low risk: Aspirin
low dose
• Cytoreductive treatment no
recommended in low risk
patients
• >60y:
• Hydroxyurea,
• Second line: Interferon, anagrelide
, Busulfan ( >65y), clinical trial.
• <60y :
• Hydroxyurea or Interferon,
• Second line: clinical trial,
interferon, Anagrelide,
combination
• Cytoreduction
therapy if High risk
: Interferon
• Observation or
• Aspirin low dose unless CI,
• If Jak2+ and CV risk:
Aspirin bd.
• Determinate ristocetin
cofactor activity >30% if
high platetets
• Monitor closely pat with
abnormal bleeding
diathesis.
• Low dose of aspirin
Table adapted from C.Harrison EHA 2014 and A.Tefferi AJH 2015
47. Recommendation of Treatment in MF (I)
Intermediate 2 and high-risk patients
• AlloHSCT DIPSS-plus high or int-2 risk pat.
High mort-morb ( 50%pat)
5y survival 37% SCTmatched
Graft-vs-host 43% SCT matched
? Cord blood transplatation
• Cytoreductive agents Hydroxiurea
Interferon (early phase)
• Mangement of anemia Transfusion if symptomatic anaemia
Erythropoiesis-stimulating agents
Androgens
Immunomodulatory agents
Prednisolone
Danazol
• Splenomegaly Splenectomy
Radiotherapy
HU
Ruxolitinib
Table adapted from Guidelines BSH 2012, C.Harrison EHA 2014 and A.Tefferi AJH 2015
48. Recommendation of Treatment in MF (II)
Ruxolitinib High risk and/or int-2 risk pat.
COMFORT studies:
• reduced splenomegaly
• increased in volume spleen in 5dl, increase risk of death
9%,
• improve constitutional symptoms and QOL
• Survival benefit- response maintaned after 3yFU (hazard
ratio, 0.48; 95% CI, 0.28-0.85; log-rank test, P = .009)
Heam toxicities: anemia and thrombocytopenia.
Increase risk of infections
Other JAK inhibitors
& combination
therapies
Fedratinib – halted due to Wernicke´s encephalopathy
Pacrinitib- JAK2 and FTL3 inh.
Momelotinib- ph3, improve in anaemia, symptoms and
splenomegaly.
Imetelstat- telomerase inhibitor
Pomalidomide & Rux
LDE225 & Rux
Panobinostat & Rux
Buparlisib, Everolimus, PRM-151….
Table adapted from Guidelines BSH 2012, C.Harrison EHA 2014 and A.Tefferi AJH 2015
51. SUMMARY
• Knowledge of MPN pathogenesis has rapidly changed in
last decade and continues evolving.
• New molecular markers to be included in criteria diagnosis
and risk factor prognosis.
• ? WHO criteria diagnosis to be reviewed.
• Consider ongoing clinical trials as option for high risk pat
or resistance/intolerance to previous conventional
therapies.
• Future target therapies focus on new molecular pathways.
• Further clinical trials are required for promising agents to
clarify adverse events and molecular and histopathology
response.
52. What is past is prologue. The best is yet to be...
Thanks