Myloproliferative diseases Flashcards
CML is charecterized by
- Philadelphia chromosome which is a
- shortened chromosome 22 resultant from 2
- t(9,22) that consists of a mutant gene
- the brc-able which produces a
- p210 mutant tyrosine kinase that phosphorylates intracellular targets leading to proliferation of the clone
clonal disorders of hematopoiesis
- acquired disorders
- expansion of pluripotent hematopoietic stem cell
- abnormal production of mature blood cells
- predisposition to leukemia transformation
Chronic myeloproliferative disorders
charecterized by:
- hepatosplenomegaly
- hypermetabolism
- clonal increase in numbers of one or more circulating mature blood cell types
- clonal hematopoiesis without dysplasia
- predisposition to evolution to acute leukemia
Hyperluekocytosis
- symptoms
- signs
SYMPTOMS: Dyspnea, Dizziness, Slurred speech, Visual Blurriness, Diplopia, Decreased Hearing, Tinnitus, Confusion
SIGNS: Retinal Hemorrhages, Papilledema,
Priapism, Neurologic Findings
clinical features of CML
symptoms:
signs:
**symptoms: **
Fatigue
Anorexia
Abdominal Discomfort
Early Satiety
Weight Loss
Diaphoresis
Arthritis
Leukostasis
Abdominal Pain
Urticaria
** SIGNS:**
Pallor
Splenomegaly
Sternal Tenderness
lab findings for CML
- hematologic
Neutrophilic Leukocytosis
Anemia
Thrombocytosis
Myeloid Cells at All Stages of Development
Basophilia
Eosinophilia
Hypersegmentation
Decreased leukocyte Alkaline Phosphatase
Functional Abnormalities
lab findings for CML
2) marrow
Hypercellularity
Increased Myelopoiesis
Increased Megakaryocytes
Reticulin Fibrosis
Increased Progenitors
Cytogenetics
Accelerated phase of CML
definition:
path:
clinical features:
DEFINITION:
Transformation to a More Malignant Phenotype
**PATHOGENESIS: **
Additional Chromosomal abnormalities
Disordered Growth
Diminished Maturation
CLINICAL FEATURES:
Fever, Diaphoresis,Weight Loss, Splenomegaly, Adenopathy, Extramedullary Blast Crisis
Accelerated phase of CML
- lab features
Anemia
Leukopenia or Leukocytosis
Basophilia
Thrombocytopenia
Blasts (typically myloid blasts)
CML accelerated phase therapy
- Supportive Care
- Chemotherapy
- Interferons
- Leukapheresis
- Splenectomy
- Radiotherapy
- Bone Marrow Transplantation
predictors for adverse outcome after allogenic transplant for CML
Advanced age of recipient
Prolonged duration of CML
Advanced stage of CML
T-cell depletion
Persistence of molecular positivity after transplant
Absence of a/c GvHD
Mechanism of oncogenesis for CML
Constitutive activation of bcr-abl tyrosine kinase
-Intracellular signaling pathway activation
Altered proliferation, adhesion, survival
Drug for CML
Imatinib mesylate
Therapeutic milestones in management of CML
Hematologic Remission
Cytogenetic Remission
Molecular Remission
Management of the sub-optimal response
- Timing of transplant viz. second-line therapy
therapeutic managment of CML-disease monitoring
- *Hematologic**
- Weekly until stable, and thereafter every 2-4 weeks until complete cytogenetic response is achieved, then every 4-6 weeks until molecular response, and then every 6 weeks
Cytogenetic
- Every 3-6 months until CCyR, then every 12-18months
Histopathologic
Molecular
Every 3 months
histopathologic
molecular
- every 3 months
Polycythemia vera
def:
info:
DEFINITION:
Hematopoietic Stem Cell Disorder
Sustained Erythrocytosis
Increased RBC Mass
Cellular Proliferation
PREVALENCE: 0.5-2.6 per 100,000
AGE: Peak Onset Age 50-60
**SEX: ** Male > Female
Ethnic Predisposition: Less common in Asians, more common in Ashkenazi Jews
Polycythemia vera
clinical features
symptoms
signs
**SYMPTOMS: **
insidious:
Headache
Dizziness
Vertigo
Visual Disturbances
Angina
Claudication
Early Satiety
Abdominal Pain
Pruritus
Thrombosis
Hemorrhages
**SIGNS: **
Plethora
Retinal Hemorrhages
Splenomegaly
Hepatomegaly
Polycythemia vera
Other lab findings
Normal Arterial O2 Saturation (Normal FiO2)
Elevated B12 and B12- Binding Capacity
Hyperuricemia
Decreased Erythropoietin Level
Evidence of Clonality
- G6PD isoenzyme analysis
- JAK2 mutation
Established criteria for P.vera
Elevated RCM
Absence of secondary causes
Splenomegaly-palp.
Clonality
Thrombocytosis
Neutrophilia
Splenomegaly-other
Low Epo/EEC growth
Treatment for P. vera
Phlebotomy-
Goals are PCV (packed cell volume) of 45 in men, 42 in women, and 37 in late pregnancy
Radioactive Phosphorus
Other Myelosuppressive Agents
Antihistamines
Allopurinol
Aspirin, 100 mg daily is routine
Other therapies for P. vera
Hydroxyurea
- Leukemogenic potential, cytopenias, mucositis
Alpha-Interferon
- Cost, inconvenience, toxicity
Anagrelide
- Mixed results on bleeding, vascular, erythromelalgia features; uncertain value viz. thrombosis. Vasodilatory effects may dissipate
- Conventional alkylators
- Piprobroman
Course and prognosis for p. vera
Acute leukemia (1%)
“Spent Phrase” of Polycythemia Vera
Thrombosis
Special issues:
Pregnancy
Evolution to Acute Leukemia
Primary thrombocythemia
definition
clinical features
DEFINITION:
- Clonal Disorder of Platelet Production
- Persistent Elevation in Platelet Count
- Exclusion of Other Myeloproliferative Diseases
CLINICAL FEATURES:
Age 50-70
M=F
Usually Asymptomatic
Occasionally:
Hemorrhagic Manifestations
Erythromelalgia
Neurologic Manifestations
Thrombosis
Lab findings in thrombocythemia
hematologic:
increased Hematocrit
increased RBC Mass
Normal to Increased Plasma volume Occasionally Microcytosis
Neutrophilia
Thrombocytosis
Marrow:
Hypercellular
Increased Megakaryocytes
Myeloid and Erythroid Hyperplasia
Absent Stainable Iron
Thrombocythemia
lab features:
hematologic:
Thrombocytosis > 600 x 109/Liter
Neutrophilia
Basophilia
marrow:
Hypercellularity
Increase in All Cell Lines
Pathophysiology of essential thrombocythemia
Clonality is evident by G6PD isoenzyme analysis
JAK2 mutation is seen in 30-50%
EEC growth is noted
Hypersensitivity to thrombopoietic agents
Acquired MPL 515 mutation is seen in 1% of patients, often coexisting with JAK2 mutation
Clinical course of essential thrombocythemia
Predictors of adverse events
- Age over 60, Leukocytosis, smoking, DM
Thrombohemorrhagic risk
- Age over 60, platelets > 1500K, cardiovascular risk factors
- Anagrelide/ASA associ with greater risk of arterial thrombosis, but lower risk of venous when compared to HU/ASA
- Risk of AML transformation
Other myeloproliferative diseases
Chronic idiopathic myelofibrosis
Hypereosinophilic syndrome
Chronic eosinophilic leukemia
Mastocytosis
- Cutaneous mastocytosis
- Systemic mastocytosis
- Aggressive systemic mastocytosis
Hypereosinophilic syndrome
Sustained eosinophilia > 1500/cu.mm
End-organ manifestations of tissue infiltration
Absence of secondary causes of eosinophila
- Allergy
- Metazoan parasitic infection/chronic infection
- Hypersensitivity pneumonitis
- Collagen vascular disease
- Neoplasia
- CML, Mastocytosis, AML, other MPD
hypereosiniphilc syndrome
molecular path
- Interstitial deletion of chromosome 4q12
- FIP1L1-PDGFRα fusion tyrosine kinase
- This fusion typically confers sensitivity to imatinib
- Other partner genes may be PDGFRβ or c-kit, or KIF5b-PDGFRα
Mastocytosis
Distinguished by site and degree of involvement
- Cutaneous
- Systemic
- Aggressive systemic
Somatic clonal mutations may involve c-kit(D816V) of FIP1L1-PDGFRα
Elevated serum tryptase
