9 - Chronic Myeloid Leukemia and Myeloproliferative Neoplasms Flashcards
Myeloproliferative Neoplasms - Specific disorders
Chronic Myeloid Leukemia Polycythemia Vera Essential Thrombocytosis Primary Myelofibrosis Chronic Eosinophilic Leukemia Systemic Mastocytosis
Myeloproliferative Neoplasms
Excess of mature myeloid cells
Usually of single lineage
Often some overlap
Activating mutations in Tyrosine Kinases are common
Chronic Myeloid Leukemia - Epi
Presents 45 - 55, but incidence increases with age. 12 - 30% are >60
M>F (1.3:1)
50% diagnosed by routine labs
85% diagnosed during chronic phase
Chronic Myeloid Leukemia - Symptoms
Fatigue
Abdominal fullness
Fever, Chills, Sweats, Weight Loss
Chronic Myeloid Leukemia - Physical Findings
Hepatosplenomegaly
Ecchymoses
Chronic Myeloid Leukemia - Common Labs
Increased mature and immature myeloid cells
Basophilia
Anemia
Thrombocytosis
Chronic Myeloid Leukemia - Peripheral Blood Smear
Immature cells in the myeloid lineage
More committed than the blast cells, but still immature
Chronic Myeloid Leukemia - Bone Marrow
Hypercellular with increased Myeloid-to-Erythroid ratio
Chronic Myeloid Leukemia - Genetics
The Philadelphia Chromosome
t(9;22)
BCR-ABL gene fusions
Quantitative Reverse Transcriptase PCR detecting BCR-ABL can evaluate disease burden
Chronic Myeloid Leukemia Response to Therapy - Hematologic Response
Complete:
Normal peripheral blood count
WBC
Chronic Myeloid Leukemia Response to Therapy - Cytogenetic Response
Major:
Complete: 0% Ph+ cells
Partial: 1% - 35% Ph+ cells
Minor: 36% - 95% Ph+ cells
Chronic Myeloid Leukemia Response to Therapy - Molecular Response
MR3 (“Major”): >3 log reduction in BCR-ABL transcripts from baseline
MR4.5 (“Complete”): >4.5 log reduction
CML Survival
4ish years median surivval
CML Phases
Chronic (Median 4 -6 years)
Accelerated (Variable duration)
Blast Crisis (Median survival 3 - 6 months)
CML - If a patient responds to Interferon treatment
The prognosis from then on is usually good!
CML - If a patient doesn’t respond to Interferon treatment
The prognosis is as if they had no treatment at all
The only way to cure CML
Allogeneic Stem Cell Transplant
Imatinib - Mechanism of action
Binds to the ATP binding site of ABL, preventing the transfer of phosphate groups to other proteins, blocking downstream signaling!
Imatinib - Side Effects
Bone marrow suppression:
Leukopenia
Anemia
Thrombocytopenia
GI:
Nausea
Vomiting
Diarrhea
Imatinib - Metabolism
Well absorbed PO
Hepatic metabolism
Cytochrome P450
Majority excreted in biliary tract as metabolites with only a small percent unchanged
Doses must be adjusted in patients with severe liver disease.
CML - Patients who attain MR3 with Imatinib treatment
Have better survival
What can cause imatinib resistance?
DDIs
Adherence issues
Multiple copies of the Ph chromosome
Mutations in ABL
Clinical indications of Imatinib and other TK inhibitors
Ph+ diseases (ABL) CML Ph+ ALL C-kit diseases GIST
Polycythemia Vera
Elevated Hgb/Hct on lab testing
Thrombosis
Polycythemia Vera - Symptoms
Pruritus - especially after showering
Plethora (Ruddy complexion)
Abdominal fullness/early satiety (splenomegaly)
Polycythemia Vera - Most common mutation
JAK2 in the Pseudokinase domain
Results in downstream anti-apoptotic signaling through JAK2 in the absence of Erythropoietin
Polycythemia Vera - Bone Marrow
Moderate to marked hypercellularity Increased hematopoiesis Maturation intact Large clustered megakaryocytes Decreased/absent iron stores Increased reticulin fibers in a minority of cases
Polycythemia Vera - Diagnostic criteria
Major:
Hgb > 18.5 in men or > 16.5 in women or other evidence of increased RBC volume
Presence of JAK2V617F or JAK2 exon 12 mutation
Minor:
Hypercellular bone marrow with trilineage hematopoiesis
Low serum erythropoietin
Endogenous enrythroid colony formation in vitro
Diagnosis requires both major criteria of elevated Hgb & 2 minor criteria
Polycythemia Vera - Differential
Chronic Hypoxia (Altitude, cigarettes, sleep apnea, pulmonary disease) Erythropoietin abuse Familial erythrocytosis (mutation in Epo R)
Polycythemia Vera - Clinical Course
Overall mortality 3% per year
Thrombosis (increased by age >65 and prior thrombosis)
Bleeding
Transformation to AML (influenced by duration of disease)
Myelofibrosis (“spent phase”) - More common in age>70
Polycythemia Vera - Management
Therapeutic phlebotomy (Maintain Hct
Polycythemia Vera - Management - Cytoreduction
Consider cytoreduction if:
Patient is intolerant of phlebotomy
Thrombosis develops
Symptomatic or progressive splenomegaly
age 40: Hydroxyurea (Hydroxycarbamide)
Essential Thrombocythemia (Essential Thrombocytosis) - Clinical presentation
Elevated PLT on labs
Thrombosis
Symptoms:
Pruritus - Especially after showering
Erythromelagia (Severe pain in hands/feet)
Abdominal fullness/early satiety (splenomegaly)
Essential Thrombocythemia - Genetics
50% of cases - JAK2 mutation, similar to Polycythemia vera
Why the same mutation leads to two diseases is unclear, but may have to do with allele burden.
5% have point mutations in mpl
Essential Thrombocythemia - Diagnosis
Sustained platelet count > 450,000/μL for at least 2 months
Bone marrow showing primarily megakaryocytic proliferation
No evidence of WHO diagnosis of Polycythemia Vera, Primary myelofibrosis, CML (BCR-ABL translocation), MDS or other myeloid neoplasms
JAK2V617F mutation or other clonal marker (mpl mutation) or in the absence of a clonal marker, no evidence of reactive thrombocytosis
Essential Thrombocythemia - Differential Diagnosis
Reactive elevation of platelet count: Iron deficiency Inflammation/Infection Surgery Splenectomy Connective tissue disease Metastatic cancer Lymphoproliferative disease
Polycythemia Vera
Chronic Myeloid Leukemia
Essential Thrombocythemia - Clinical Course
Uncertain if ET compromises life span
Thrombosis (higher in patients > 60 w/previous history of thrombosis, cardiovascular risk factors, JAK2V617F mutation)
Bleeding - Higher in patients with plt>1,500,000
Myelofibrosis (4 - 8% at 10 years)
AML (1% in untreated patients)
Essential Thrombocythemia - Management
All: Aggressive management of cardiovascular risk factors
Low risk: (Age 60, prior thrombosis, cardiovascular risk factors)
Low dose aspirin + hydroxyurea
Consider anagrelide or interferon alfa if hydroxyurea intolerant
Primary Myelofibrosis - Clinical Presentation
Abdominal fullness (due to splenomegaly)
Splenomegaly (due to extramedullary hematopoiesis)
Symptoms of anemia (Fatigue, pallor, dyspnea on exertion)
Bleeding/bruising
Infection
Cachexia
Primary Myelofibrosis - Bone marrow
Hypercellular
Megakaryocytic hyperplasia
Pleomorphism of megakaryocytes
Granulocytic/erythroid maturation intact
Fibrotic phase - Loss of hematopoiesis (megakaryocytes spared)
Osteosclerosis - Increased osteoclasts and osteoblasts
Primary Myelofibrosis - Peripheral blood smear
Teardrop RBCs Leukoerythroblastic features (peripheral blood looks like marrow)
Primary Myelofibrosis - Major Diagnostic Criteria
Major:
Hypercellular marrow with megakaryocytic atypia and reticulin and/or collagen fibrosis
WHO diagnostic criteria for Polycythemia Vera, CML, ET, MDS or other myeloid neoplasms excluded
Presence of JAK2V617 or other clonal marker OR in the absence of a clonal marker, no evidence of reactive fibrosis
Minor: Leukoerythroblastosis Elevated LDH Anemia Splenomegaly
Diagnosis requires all major criteria AND 2 minor criteria
Primary Myelofibrosis - Clinical Course
Variable life expectancy - Average 5 years
Months to decades
Risk factors: Age > 65 yo Hgb 25k/μL Blasts > 1% Constitutional symptoms RBC transfusion dependence Unfavorable karyotype (eg +8, abnl 7 or 5, 12p-, inv3, 11q23 rearrangement) Plt
Calreticulin
Target of autoantibodies in SLE and Sjogrens
Major calcium storage protein in the ER
Inhibits binding to Glucocorticoid Response Element in the nucleus
Regulates gene transcription
Primary Myelofibrosis - Calreticulin mutation
Better survival than with JAK2 mutation or mpl
Primary Myelofibrosis - Management
Supportive measures:
Erythropoietin/transfusions
Hyrdroxyurea
Splenectomy/splenic radiation
Active Therapy:
Stem cell transplant
Thalidomide/corticosteroids
Jak inhibitors
Primary Myelofibrosis - Ruxolitinib
Reduces splenomegaly and improves survival
