Pharmacotherapy Vi - Acute Leukemia

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Acute Leukemia is a hematologic malignancy characterized by unregulated proliferation of blood forming cells in the bone marrow.

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Acute leukemia cells are immature proliferating blasts that physically crowd out or inhibit normal cellular maturation of the bone marrow.

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This is the leading cause of cancer related death in persons younger than age 35.

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Acute Myelogenous Leukemia accounts for the majority acute leukemia
ALL approximately 10 years old
AML approximately 65 years old

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AML has 8 subtypes based on which cell type is affected. (Myelopblast, promyelocytic, myelomonocytic, monoblastic etc)

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M3 subtype has the best prognosis (promyelocytic)

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What are the risk factors for AML?

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Chemical exposure (benzene)
Radiation exposure (ionizing radation)
Medications (alkylating agents)
Social habits (cigarette smoking, material alcohol/marijuana use)

Genetic conditions (down's syndrome)

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Symptoms of AML =

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Fever
Infection
Cough
Fatigue
Easy bruising, bleeding

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Signs and laboratory values in AML =

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Leukocytosis WBC > 50,000
Leukopenia WBC < 10
Anemia Hgb < 10
Thrombocytopenia Plts < 20

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Induction Chemotherapy =

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Goal is to rapidly induce a compete hematologic remission (eradicate leukemia blasts and restore normal hematopoiesis)
You want disappearance of bone marrow blasts to < 5% (blasts count in marrow > 20% is indicative of acute leukemia)
You want to return WBC and Platelets to normal limits

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Prognostic variables =

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> 60 years old - worse
Cytogenetics - t (8;21); inversion (16) = favorable
Del(5q); inversion(3p) = poor
some patients will have a complete remission, some will have partial remission, some will have no remission - this is based on prognostic variables (do not have to know specific variables)

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AML

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is typically considered to be acute aggressive disease

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Treatment options for AML

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First line Induction therapy (not M3 subtype)
combination chemotherapy (daunorubicin or idarubicin over 3 days and cytarabine over 7 days)

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Toxicities

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CINV - Anti-emetic regimen
Cardiotoxicity - baseline/periodic ECHO
Myelosuppression (GCSF not recommended - stimulates myeloid blasts)
Mucositis - good oral hygiene/mouth rinses
Alopecia

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Goal of therapy

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Curative intent induction chemtherapy

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Monitoring

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Day + 14 repeat bone marrow biopsy after chemotherapy.
You want to ensure patient will progress to achieve count recovery with < 5% blasts in marrow and peripheral blood.

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Risk of Tumor Lysis Syndrome?

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Yes - associated with cytotoxic therapy resulting in rapid tumor response. Rapid cells death --> release of cell nucleus contents into blood stream.

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Metabolic abnormalities due to tumor lysis

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Hyperuricemia - rasburicase to get uric acid < 8, candidate to receive allopurinol for prophylaxis once the uric acid level is under control
Hyperkalemia
Hyperphosphatemia
Hypocalcemia
Increased SCr (decreased renal function

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Consolidation chemotherapy

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Administered once the patient has achieved a CR with induction chemotherapy

Patients are cured at this point, but disease relapse is inevitable without consolidation (because of residual clinically undetectable leukemia cells after induction therapy)

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Goal of Consolidation chemotherapy

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Eradicate residual clinically undetectable disease

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Consolidation chemotherapy = cytarabine with a much higher dose.
Toxicities =

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CINV
Mucositis
Ocular toxicities (conjunctivitis and corneal toxicity) - corticosteroid eye drops (prednisone)
Neurologic toxicities (cerebellar dysfunction - dizziness, gait disturbance, slurred speech)

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When there is a complete remission, there is no need to prescribe rasburicase because they are not at risk for tumor lysis syndrome.

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There is not a heavy tumor burden and the risk of rapid lysis.

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ALL Therapy - Induction chemotherapy and Consolidation are necessary.

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Patient also needs maintenance therapy to prevent relapse. This is a standard treatment for ALL. Maintenance has only been proven to be effective in lymphoid malignancies and not myeloid malignancies.

Maintenance therapy allows for long term drug exposure to slowly dividing cells

This will continue for a couple of years.

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Toxicities

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GI Disturbances
Myelosuppression
Dermatologic rash (methotrexate, mercaptopurine)
Sensory-motor neuropathies (vincristine)
Hyperglycemia - routine/periodic blood sugar checks
Hepatotoxicity (mercaptopurine)

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Lab tests

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CBC (WBC, Platelets)
Liver Function (Total bilirubin, AST/ALT)
Renal Function (SCr and CrCl - Methotrexate is renally eliminated)

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Goal in ALL

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Curative maintenance therapy
Patient was already cured of ALL after receiving induction and consolidation chemotherapy. Maintenance has been shown to maintain ALL remission and improve survival.
Efficacy - maintain remission with periodic blood cell count monitoring to show no evidence of blast cells. Minimize acute toxicities associated with treatment complications.

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Acute Leukemia Treatment

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To eradicate the malignant precursor cells in the bone marrow and peripheral blood and allow regeneration of normal cell lineages.

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Acute Leukemia Treatment

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Induction - AML, ALL
Consolidation - AML, ALL
Maintenance - ALL
CNS Prophylaxis - ALL

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Chronic Myeloid Leukemia

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Results from the malignant transoformation of a pluripotent stem cell which leads to clonal proliferation of progenitor myeloid cells and mature myeloid cells.

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Molecular Biology

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Translocation (9;22) - philadelphia chromosome (Ph +). This translocation forms bcr-abl fusion gene which stimulates cell proliferation (tyrosine phosphokinase activity is important for intracellular signal in cell proliferation)

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Symptoms

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Fever
Night Sweats
Unintentional weight loss
Fatigue
Organ infiltration (splenomegaly, hepatomegaly)
Lab findings (leukocytosis wbc > 100,000)

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3 phases

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Chronic phase (4-5 years) - usually asymptomatic
Accelerated phase (3-12 months) - fever, night sweats, weight loss, loss of efficacy of drug therapy and subsequent wbc increase, detectable blast cells in bone marrow (11-19%)
Blast crisis phase (3 months) - transformation to acute leukemia - blast cells populate bone marrow

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Counseling

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Medication is for your CML. It will help reduce your wbc and reduce your enlarged spleen and liver. Take with a meal and water.
Toxicities - NV, Fluid retention/edema, rash/itching, myelosuppression, hepatotoxicity

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How to explain the duration of therapy.

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Take medication daily
This medication is to control your CML
You will have to follow up with your oncologist to monitor your blood counts
You will be on this medication for several years as long as your CML responds to this treatment and the toxicities are tolerable.

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Imatinib metabolism

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Hepatic via CYP 3A4 - potential drug interactions

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Lab values to monitor

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CBC
LFT
Renal Function

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Efficacy

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CBC (WBC, Platelets)
Molecular monitoring to assess decreases in (Ph +) cells

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Goal in Chronic Leukemia

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Slow disease progression - Targeted therapies are used for cytoreduction and to slow CML from progressing into the accelerated and blast phase. The goal is also to maintain symptoms control (alleviate pain associated with large liver and spleen).
Efficacy is usually maintained over 5-7 years with targeted therapies for 90% of patients.

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First line therapy in chronic phase CML

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Imatinib 400 mg PO daily
Dasatinib 100 mg PO daily
Nilotinib 300 mg PO twice daily