Clinical Aspects of Leukemia Flashcards
Types of leukemia
Acute leukemia – maturation arrest = accumulation of immature cells in the bone marrow and frequently in the peripheral blood
- AML = accumulation of myeloblasts
- ALL = accumulation of lymphoblasts
- Take up space in the bone marrow and interrupt normal hematopoeisis –> decreased production of RBCs, platelets and WBCs = medical emergency
Chronic leukemia – maturation is preserved –> hypercellular bone marrow with mature granulocytes
- Not a medical emergency
- Preservation of normal hematopoeisis
- Can become acute if not treated
Blood counts in diagnosing/differentiating leukemias
- WBC
- Hgb
- Platelet count
- Differential
- If they’re anemic and thrombocytopenic –> probably AML = emergency
- Differential –> what kind of cells are in the blood
- If these are all preserved, the patient is likely not acutely ill
Leukemia emergenices
- Hyperleukocytosis –> very high WBC count (>100,000)
- Tx = leukapheresis, hydroxyrea - Infection –> Tx = antibiotics
- Bleeding (mucosal) –> Tx = platelets
- DIC (common in APL) –> Tx = cryoprecipitate, platelets
- Hyperuricemia (esp. ALL) –> Tx = allopurinol, rasburicase
- Tumor lysis –> Tx = electrolytes, rasburicase, hemodialysis
Diagnosis/prognosis of leukemia
- Morphology
- Immunophenotype –> determined by looking at different cell surface antigens via flow cytometry
- Cytogenetic analysis
- Molecular studies
Treatment outcome definitions
- complete remission
- cytogenetic remission
- molecular remission
- relapse
- complete remission = normal blood counts, normal morphology
- cytogenetic remission = normal blood counts, normal marrow morphology, normal cytogenetics
- molecular remission = normal blood counts, normal marrow morphology, normal cytogenetics, negative RT-PCR
- relapse = reappearance of leukemia - can be morphologic, cytogenic or molecular
AML
Biologically, cytogenetically and molecularly diverse –> this diversity is used to assign prognosis, stratify treatment and develop targeted treatments
- More common in adults
- About 40% have a normal karyotype
- Many molecular abnormalities have been identified
- Most important is FLT3 internal tandem duplication –> 30% have this mutation
- constitutive activation of the FLT3 receptor TK and its growth related signaling pathway
- FLT3 mutation not resistant to chemotherapy, but the disease comes right back
- Currently developing FLT3 inhibitors
- FLT3 is a poor prognostic marker
AML treatment
- Remission induction
- goals = induce complete remission
- options = chemo +/- targeted therapy OR low intensity regiments - Post remission
- goals = delay/prevent relapse, eradicate minimal residual disease, cure
- options = consolidation or intensification (high dose chemo or HSCT)
AML remission induction chemotherapy
- Cytarabine (AraC) by continuous infusion for 7 days
- Daunorubicin daily x 3 days
- ~70% remission rate
AML post remission therapy
- High dose cytarabine
- Allogeneic hematopoietic stem cell transplantation
- Autologous hematopoietic stem cell tranplantation (HSCT)
AML treatment regimens based on risk stratification
- Favorable risk –> induction chemo then intensification chemo
- Intermediate risk –> induction chemo then intensification chemo or transplant
- Unfavorable risk –> Induction chemo then transplant, or clinical trial
Acute promyelocytic leukemia (APL)
Young patient with low blood counts and bleeding/bruising
- have lots of granules = pro-coagulants –> trigger DIC
- molecular marker = PML/RARalpha
- high cure rate with ATRA + arsenic trioxide
CML
Present with elevated WBC count with predominance of granulocytes
- not anemic or thrombocytopenic
- biologically and cytogenetically uniform
- this uniform disease is the model for targeted therapy in oncology
- targeted therapy has revolutionized treatment and outcome of CML
CML is characterized by the philadelphia chromosome = t(9;22) = BcrAbl –> fusion protein with TK activity
- targeted with imatinib mesylate = gleevac –> blocks binding of ATP to BCR-ABL TK, inhibiting its activity
Phases
- present in the chronic phase = ~4 years
- accelerated phase ~ 6 months
- blast phase ~ 3 months
- –> goal is to eradicate it in the chronic phase
ALL
- immature cells
- common form of leukemia in children
- adults with ALL don’t do as well as children
- ~1/3 of cases are Ph+
ALL treatment
- Remission induction
- goal = induce chronic remission
- options = chemo +/- BCR-ABL inhibitor (if Ph+) - Post remission
- goal = delay/prevent relapse, eradicate minimal residual disease, cure
- options = consolidation or intensification
- intensification
- –> high dose chemo
- –> HSCT
- –> CNS prophylaxis = radiation, intrathecal chemo, high dose methotrexate
- –> maintenance for 2-3 years
Blinatumomab
- New bispecific, single-chain antibody construct specific for CD19 and CD3
- Designed to target CD19-expressing cells and to recruit CD3 cytotoxic T cells to lyse CD19-expressing B cells
- High rate of complete response in adult patients with relapsed or refractory ALL
