Acute Leukemias Flashcards
What is the two hit model of leukemogenesis?
- First hit: Loss of function of transcription factors needed for differentiation leading to differentiation block
- Second hit: gain of function mutations of tyrosine kinases leading to enhanced proliferation
Both together lead to acute leukemia
What are the differences between acute and chronic leukemia?
Acute:
-rapid onset
-malignant clonal event and block to differentiation =blasts
-increase in immature cells (blasts) that do not differentiation/mature
Chronic:
-months to years chronic onset
-malignant clonal event without block=mature or differentiated cells
-increase in mature cells that do not die/undergo apoptosis
What are the causes of acute leukemias?
Idiopathic (most) Underlying hematologic disorders Chemicals, drugs Ionizing radiation Viruses (HTLV I) Hereditary/genetic conditions
What is the epidemiology of acute leukemia?
ALL: -mainly children -M>F -hispanics have higher incidence, normally rare disease in US -curable in 70% of children -not so curable in adults AML: -mainly adults -M>F -curable in minority of adults 40-50%
What is the clinical presentation of acute leukemias?
Bone Marrow Failure: Blasts crowd out normal hematopoiesis
- Anemia = weakness, fatigue
- Thrombocytopenia = bleeding
- Neutropenia/Leukopenia = infection
Organ/tissue infiltration
- Enlargement of liver, spleen, lymph nodes
- Gum hypertrophy
- Bone pain
- Other organs: CNS, skin, testis, any organ
Constitutional symptoms
-Fever, sweats, ± weight loss
How are acute leukemias diagnosed?
- Defined as >20% blasts in marrow
- Confirmation:
- Immunophenotyping via flow cytomery
- -myeloid: CD13, CD33
- -Lymphoid, CD5, CD7, CD19
- molecular genetics
- cytogenetics
How are AML and ALL morphologically different?
AML: -peripheral smear has myeloblasts -Auer rods due to MPO crystallization ALL -peripheral smear with lymphoblasts with higher N:C ratio
What are prognostic features of AML?
Patient specific: -performance status/co morbidities -prior hematologic disorder: AML may arise from myelodysplastic syndrome -increasing age, >65 very low cure rate -prior chemotherapy Leukemia specific: -leukocytosis -cytogenetics -molecular markers: FLT3, NPM1
Describe the features of acute promyelocytic leukemia.
- t(15;17) PML-RARa fusion gene that causes maturation arrest
- associated with DIC
- -lots of purple granules, low fibrinogen, abnormal coats, granules initiate coat cascade
- flow cytometry: CD13, CD33 positive, DR negative
- 90% cure rate with ATRA, a vitamin A analog that induces differentiation of blocked cells
Describe the features of ALL.
- most common pediatric malignancy
- 9:22 philadephia translocation
- mostly B cell ALL
- T cell ALL has poor prognosis
- Treatment regimen: intense and prolonged chemo with CNS coverage and prolonged maintenance
What are the prognostic features of ALL.
High risk
1. Pre-T
2. Pro B
3. Age >35 years old
4. WBC >30g/L in B-ALL and >100g/l in T all
5. no remission after 4 weeks of induction therapy
Very high risk
-Philadephia chromosome translocation BCR-ABL positive
What are the phases of ALL treatment?
- induction
- intensification
- CNS prophylaxis
- Maintenance: may involve steroids or low dose chemo (continued for months)
What are the phases of AML treatment?
- Induction
2. consolidation (post remission therapy) to keep AML from coming back
What are the complications in the course of managing acute leukemias?
- DIC
- leukostasis
- Sepsis
- tumor lysis
What is the standard remission induction therapy in newly diagnosed AML, excluding APL?
7+3 chemotherapy schedule
-Cytarabine for 7 days with an anthracycline for 3 days
What is the most common mutation in AML?
FLT3 mutation 30%
-has a negative prognostic factor
What mutation has a good prognostic factor in AML?
NPM1
What is the role of hematopoietic stem cell transplantation in AML treatment?
- used in patients with AML after 1st remission in those with poor/intermediate prognostic factors
- relapsed AML
What is leukostasis? what problems does it cause? and how do you treat it?
- WBC>100,000 mostly
- commonly in M4/M5 leukemia
- blast cells being less deformable than mature myeloid cells–>intravascular plug develops
- high metabolic activity of blast cells and local production of various cytokines contribute to underlying hypoxia
- Common symptoms: dyspnea, chest pain, CNS (headaches, altered mentation, CN palsies, ocular symptoms, priapism, MI
- Treatment: chemo with induction agents or high dose hydroxyurea, avoid PRBC transfusion to not contribute to blood viscosity, leukapheresis is second option for those unable to undergo immediate chemotx (renal insufficiency, metabolic derangements, etc)
What is Tumor Lysis Syndrome?
- commonly seen in malignancies with high rates of cell proliferation, including AML
- Characterized by metabolic derangements caused by massive release of cellular components following lysis of malignant cells (due to chemotx)
- high phosphate, low calcium, high uric acid, potassium, and uremia (from breakdown products of cells)
- Release of intracellular proteins →catobilized to hypoxanthine → xanthine → uric acid → Crystalization of uric acid and in renal tubules → impaired renal function
- Release of phosphate from malignant cells → calcium phosphate precipitation and further renal impairment along with hypocalcemia and resultant symptoms from ↓Ca
How do you treat tumor lysis syndrome?
- IV hydration to promote excretion of uric acid and phosphate
- allopurinol–>competitive inhibitor for xanthine oxidase to decrease conversion of purine metabolites to uric acid
- recombinant urate oxidase
- dialysis in severe cases
- give allopurinol before starting chemotherapy to prevent
How is relapse defined in AML? What is the most important predictive factor for outcome in relapsed/refractory AML?
> 5% blasts in bone marrow
-most important predictive factor=duration of 1st remission
