Myelodysplastic Syndromes Flashcards
Acute Leukemia: Etiology
Factors:
Clonal diseases = derived from a single, genetically aberrant cell that continues to change
• Critical genes are ones controlling proliferation, differentiation, epigenetic regulation
Host factors
• Increase susceptibility to accumulate genetic injury (Ex: Fanconi’s anemia)
Environment: drugs, chemicals, radiation, chemotherapy
• Ex: benzene in petroleum products and industrial solvents
Time (age): allows accumulation of events
Acute Leukemia: types
Normally = proliferation and differentiation
• If proliferation without differentiation → more undifferentiated cells (blasts) without “expiration” date → pancytopenia
Ex:
• Acute Myeloid Leukemia (AML) = accumulation of myeloid blasts
• Acute Lymphoblastic Leukemia (ALL) = accumulation of lymphoid blasts
Acute Leukemia: clinical features
Bone marrow failure
• Anemia → pallor, fatigue, dyspnea
• Neutropenia → fever, infections
• Thrombocytopenia → bruises, bleeding
Organ infiltration
• Bone pain, lymphadenopathy, meningeal signs (CNS problems) & intracerebral bleeding, testicular swelling, skin rash, pulmonary infiltrates
Emergencies:
• Coagulopathy (acute promyelocytic leukemia)
• Tumor lysis syndrome
• Hypercalcemia
• Neutropenic sepsis (susceptible to infections)
• Leukostasis (large dysfunctional cells clog small vessels)
• Pulmonary failure
• Severe pancytopenia
Acute Myeloid Leukemia (AML): Epidemiology
- More common as people age (median age 67)
* 50% more common in men
Acute Myeloid Leukemia (AML): pathology
- Auer rods = aggregates of myeloperoxidase-containing granules
- Cell surface markers: CD13, CD33
- Immunohistochemistry = express myeloperoxidase
Acute Myeloid Leukemia (AML): molecular pathophysiology
Ex: translocation between Chromosomes 8 and 21 [t(8;21)]
• “Core-binding factor (CBF)” leukemia
• Normally = TF’s CBFα and CBFβ bind → attract transcriptional activators → gene transcription (IL-3, GM-CSF, M-CSF) → neutrophil maturation
• With translocation = CBFα onto ETO gene on chromosome 8 → transcription of hybrid CBFα-ETO mRNA → chimeric TF → attracts repressor proteins → blocked myeloid differentiation
• Result: cell division and proliferation but no neutrophil maturation
Ex: Acute Promyelocytic Leukemia (APML)
• Translocation putting retinoic acid receptor alpha on chromosome 17 → PML gene on chromosome 15 [t(15;17)]
• Associated with severe DIC
• Favorable prognosis = responds to treatment with all trans retinoic acid → induces leukemic cell differentiation → remission
Acute Lymphoblastic Leukemia (ALL): epidemiology
• Childhood disease (median age 13)
Acute Lymphoblastic Leukemia (ALL): pathology
Cell surface markers: • B cell ALL = CD19, CD22, CD10 • T cell ALL = CD7, CD3, CD2 • Lymphoid lineage = TdT enzyme Molecular analysis = clonal
Acute Myeloid Leukemia (AML): prognosis
Best:
t(8;21)
inv(16;16)
t(15;17)
Intermediate:
Normal Cytogenetics
Trisomy 8
Worst:
Chromosome 5, 7
11q23 abnl
Complex
Acute Lymphoblastic Leukemia (ALL): prognosis
Best: t(12;21)
Hyperdiploid
Worst:
t(9;22)
Hypodiploid
t(4;11)
Cytogenetic analysis: ALL vs. AML
AML:
CD 13/ CD33
Auer Rods (highly specific)
Germline Immunoglobulin/TCR genes
ALL:
B-ALL = CD19, CD22, CD10, TdT
T-ALL = CD7, CD3, CD2, TdT
Clonal Immunoglobulin/TCR genes
Describe the principles of treatment of acute leukemia.
Supportive care: Maintain blood counts • Red cell and platelet transfusions • Cannot reliably transfuse neutrophils (because short survival) Treat/Prevent infections • Bacterial and fungal infections common due to neutropenia (ANC below 500 cells/ul) Control Coagulopathy Control metabolic problems • Tumor lysis syndrome
Treatment
Some = curative with aggressive, high-dose and extended chemotherapy
• More success in younger rather than older
• Treatment carries significant risks
Bone marrow transplantation
• May be curative
• Indicated for high risk and relapsed diseases
Chronic myelogenous leukemia (CML): etiology
o Most cases = unknown
o Increased risk with ionizing radiation and benzene exposure
o Most patients = 25-60 years old
Chronic myelogenous leukemia (CML): pathophysiology
“Philadelphia chromosome”
• Reciprocal translocation between chromosome 9 and 22 → t(9;22)
Results: c-abl oncogene (from chromosome 9) next to bcr gene on chromosome 22
• Abl = cytoplasmic and nuclear tyrosine kinase
• Fusion of c-abl and bcr → new protein kinase that’s constitutively active
Note: t(9;22) also found in some cases of AML and ALL
o Poor prognosis
Chronic myelogenous leukemia (CML): pathology
Affects all 3 myeloid cell lines
Peripheral blood = granulocytic precursor cells in all levels of development
• Numerous eosinophils and basophils = distinguishes CML from reactive leukocytosis
• WBC count may be >300,000/μl
• Usually elevated platelets
• Hematocrit normal or low
Chronic myelogenous leukemia (CML): clinical features
Often asymptomatic → incidental diagnosis
Marked leukocytosis common: • Weight loss (hypermetabolic) • Massive splenomegaly • Gout (hyperuricemia) • Anemia (pallor, fatigue, dyspnea)
Thrombocytosis → unusual clotting or bleeding
Chronic myelogenous leukemia (CML): clinical course
Chronic phase:
• Median 5-6 years stabilization
• Symptoms: fever, night sweats, fatigue (hypermetabolism), anorexia, abdominal pain from enlarged spleen
Accelerated phase:
• Transformation to more aggressive phase if not treated
• Median duration = 6-9 months
• Progressive block in differentiation
Blast crisis
• Disease = acute leukemia
• Median survival: 3-6 months
• Blasts replace WBCs in blood and marrow
• Can be myeloblastic (70%) or lymphoblastic (30%)
• Almost always fatal
Chronic myelogenous leukemia (CML): treatment
Imatinib mesylate = suppresses malignant clone
• Inhibits tyrosine kinase activity from fusion gene
• Reduces leukemic cell burden
Excellent survival and lower risk of developing blast crisis
o NOT a cure
HLA-matched stem cell transplantation curative
Be able to distinguish CML from benign causes of leukocytosis.
CML:
o LAP (leukocyte alkaline phosphatase) negative
o Increased basophils
o Granulocytes with t(9;22) mutation
These features not present in reactive neutrophilic leukocytosis due to infection
Define and list the Myeloproliferative Disorders
From increased proliferation with differentiation
• Renewing stem cell with unrestrained proliferation → too many RBCs, WBCs, platelets, stroma
Ex:
• Chronic Myeloid Leukemia (too many myeloid cells)
• Polycythemia Vera (too many RBCs)
• Essential Thrombocythemia (too many platelets)
• Primary Myelofibrosis (marrow replaced by fibrous tissue)
Polycythemia Vera: Description
o Increased RBC volume
o 100% cases = JAK2 V617F mutation
o Important to distinguish from Secondary polycythemia or pseudopolycythemia
Polycythemia Vera vs. Secondary Polycythemia
Causes of Secondary Polycythemia: Diseases stimulating physiologic EPO: o Chronic hypoxia o CO poisoning o R to L shunts o High affinity Hgb o High altitudes Diseases causing inappropriate or ectopic EPO production: o Renal tumors o Liver tumors o Blood vessel tumors Exogenous EPO
Secondary polycythemia vs. Polycythemia vera:
PV: Normal SaO2; decreased EPO
Reactive polycythemia (Physiologic EPO): Decreased SaO2; increased EPO
Reactive polycythemia (Inappropriate production of EPO): Normal SaO2; increased EPO
Polycythemia Vera: Clinical features
- Hyperviscosity
- Hypervolemia
- Hypermetabolism
Polycythemia Vera: symptoms & signs
Symptoms: • Headache • Weakness • Pruritis (aquagenic = brought on by showering) • Dizziness • Diaphoresis • Visual disturbance • Weight loss
Signs: • Splenomegaly • Skin plethora • Hepatomegaly • Conjunctival plethora • Systolic HT
Polycythemia Vera: disease course
- Increased risk of thromboembolic complications (31%): MI, stroke, deep venous thrombosis (especially portal vein thrombosis)
- Progression to AML (19%)
- Other cancer (15%)
- Hemorrhage (6%)
- Myelofibrosis (4%)
Polycythemia Vera: treatment
Reduce hematocrit
• Phlebotomy: goal <400/μl
Polycythemia Vera: prognosis
- Long natural history
* Years to decades = slow growing
Essential Thrombocythemia: description
Increased platelet count (>600,000/μl)
• Often also leukocytosis, but hematocrit is not increased
Essential Thrombocythemia: causes
- Clonal stem cell disorder
* JAK2, CaIR, MPL gene mutations
Essential Thrombocythemia: clinical features
- Most = asymptomatic
- Abnormal clotting or bleeding
- Erythromelalgia (burning in hands and feet)
Essential Thrombocythemia vs. Secondary thrombocytosis
Secondary thrombocytosis due to: • Iron deficiency • Chronic infections/inflammation • Acute hemorrhage • Malignancy • Connective tissue diseases (ex: rheumatoid arthritis) • Post-splenectomy
Essential Thrombocythemia: treatment
Evaluate risk for clotting because treatment risk may be greater than disease risk
Prevent thrombosis
• Reduce risk factors (smoking, HT)
• Aspirin
Prevent bleeding
• High platelets sequester clotting factors
Reduce platelet count
• Hydroxyurea
Essential Thrombocythemia: prognosis
- Long natural history (years to decades)
* Increased risk of developing marrow fibrosis and AML
Myelofibrosis: description
o Fibrosis of the bone marrow often with atypical appearing megakaryocytes
o Growth factors abnormally shed from clonally expanded megakaryocytes → Nonclonal fibroblastic proliferation and hyperactivity → Bone marrow fibrosis
• Fibroblasts are NOT the malignant cells (just proliferate in response to abnormal growth factors from neoplastic hematopoietic stem cells)
• JAK 2 V617F mutation in about 50% of cases
Myelofibrosis: clinical presentation
- Often with massive splenomegaly
- Early = Anemia, elevated WBC and platelets
- Late = Anemia, lower WBC and platelets due to marrow failure and splenomegaly
Myelofibrosis: pathology
Blood smear is characteristic
• “Teardrop” RBC
• Precursor cells (nucleated RBCs, giant platelets, megakaryocytes, neutrophil precursors)
Marrow biopsy = fibrotic (staining for reticulin)
• Shows dense CT and trapped megakaryocytes
Myelofibrosis: treatment
Palliative
Control spleen size
• Ruxolitinib (to inhibit JAK2), hydroxyurea, radiation, surgery
Control inflammatory symptoms
• Ruxolitinib
Cure
• Hematopoietic cell transplantation
Myelofibrosis: prognosis
- Worst prognosis of the 3 MPDs
* Median survival 3.5 years
Describe the role of the JAK2 mutation in the pathophysiology of the chronic myeloproliferative disorders.
JAK2 = on chromosome 9
o Signal transduction protein used by EPO receptor
Normally = binding EPO to receptor → dimerization of receptors → JAK2 phosphorylation
o Enters nucleus
o Generates growth and survival signals
In polycythemia vera (and others) = valine replaced by phenylalanine at position 617 (JAK2 V617F mutation)
o Constitutively active → promotes RBC production
• Also involved in regulating platelet and granulocyte production
Define “myelodysplasia.”
• Under-production of one or more cell lines in conjunction with ineffective erythropoiesis and abnormal cell differentiation
o Self-renewing cells but damaged → poor proliferation and differentiation control with cell death (apoptosis) occurring = bone marrow filled with cells but being killed → pancytopenia
• Ex: Myelodysplastic syndromes
Myelodysplastic syndromes: Epidemiology
Causes: anything interfering with normal hematopoietic cell differentiation
• Ex: ionizing radiation and cytotoxic chemotherapy
• MDS = long term complication of treating cancer
• But most cases = unknown cause
Older patients = median age 65-70 years
Myelodysplastic syndromes: clinical presentation
Pancytopenia (diverse presentation)
• Anemia (usually macrocytic), thrombocytopenia, neutropenia
Ineffective hematopoiesis
• Paradox of hyper cellular marrow, but low blood counts
Potential evolution to AML
• For many but not all
• Higher risk if have higher proportion of blast cells in marrow
Myelodysplastic syndromes: pathology
Pseudo Pelger-Huet cells (hypolobated neutrophils)
Ring Sideroblast
• Iron deposition around nucleus with Prussian blue stain
• From iron accumulation in mitochondria
• Indicates disordered heme synthesis
Cytogenic analysis = often shows chromosome 5 or 7 abnormalities
Myelodysplastic syndromes: prognosis
International Prognostic Scoring System (IPSS)
“Risk” (death or AML) – predicted by:
1) Proportion of blasts in the bone marrow
• High blast count is bad (greater than 5%)
2) Cytogenetics
• Normal is good
• Loss of chromosome 7 is bad
• Loss of chromosome 5 short arm (q) = long survival
3) Severity of pancytopenia
• Just anemia is good
• All counts down is bad
Myelodysplastic syndromes: treatment
High risk MDS: median survival of months
• Chemotherapy
• Bone marrow transplant
Low risk: median survival 6-8 years • Improve counts (EPO) • Quality of life • Prevent iron overload • Lenalidomide (better response if MDS due to 5q deletion)
