PHARM 444: Leukemia

chronic myeloid leukemia is characterized by the expression of what?

BCR-ABL (oncogene) related to the presence of Philadelphia Chromosome

- translocation b/w the long arms of chr 9 and 22

- ABL gene (chr 9)

- BCR gene (chr 22)

- changed chr 22 = Philadelphia Chromosome

BCR-ABL gene leads to the production of an ...

abnormal tyrosine kinase = altered signalling cascade = CML cells to proliferate, avoid apoptosis & overpopulate the bone marrow so healthy functional cells are crowed out

CML Signs and Symptoms

- TYPICALLY asymptomatic

- Splenomegaly >>> anorexia, early satiety, unexplained weight loss

- bone pain

- fatigue

- Leukocytosis (WBC > 25) or Leukostasis (WBC >100) >>> visual disturbances, stroke or MI

Leukostasis

WBC >100

infiltration of WBCs into tissues of major organs, compromising the organ's ability to function normally

what are 3 phases of CML?

1. Chronic Phase = < 10% blasts in peripheral blood/ bone marrow

2. Accelerated Phase = 10 to 19% blasts in peripheral blood/ bone marrow

3. Blast Phase = ≥ 20% blasts in peripheral blood/ bone marrow

what are pts typically given if they have Leukostasis?

Hydroxyurea

Hydroxyurea

- Rapidly lowers WBCs

- inhibits RNA reductase = blocks DNA synthesis. = prevents conversion of ribonucleotides to deoxyribonucleotides

- does NOT affect course of disease

Hydroxyurea may be given with ______ to prevent rumour lysis syndrome

allopurinol

BCR-ABL Tyrosine Kinase Inhibitors

a) MOA

b) 1st gen (1)

c) 2nd gen (3)

d) 3rd gen (1)

e) AE

f) INDICATION

a) competitively binds to ATP binding site on BCR-ABL kinase. = inhibits the phosphorylation of proteins involved with signal transduction

b) Imatinib

c)

- Dasatinib

- Nilotinib

- Bosutinib

d) Ponatinib

e)

- myelosuppression (neutropenia, thrombocytopenia)

- N/V (mild)

- fluid retention (peripheral edema or periorbital)

- drug rash

- hepatotoxicity

- QT prolongation

- diarrhea

- vascular risk

f) CML

what should pts taking a BCR-ABL TKI consider limiting the dose of due to hepatotoxicity risk?

acetaminophen (2-3 g/day INSTEAD of usual 4g/day)

BCR-ABL TKIs are all substrates for ...

CYP3A4

what BCR-ABL TKIs are not pH dependent

imatinib

what BCR-ABL TKI has a black box warning about QT prolongation

Nilotinib

which BCR-ABL TKI has a higher risk of vascular events like hypertension

Ponatinib

if a pt has a T31 151 mutation which is the only effective BCR-ABL TKI for treating it

Ponatinib

can you discontinue any BCR-ABL TKI after 2-3 years?

yes -- however ~1/2 of patients will relapse

what can cause resistance to BCR-ABL TKI

Reactivation of BCR-ABL activity >>>> b/c point mutations in ABL kinase domain

Acute Lymphoblastic Leukemia (ALL) Signs & Symptoms:

- "B" symptoms = Fevers, night sweats, unintentional weight loss

- Cytopenias = Neutropenia (causing infections), Anemia, Thrombocytopenia (causing easy bruising and bleeding)

- pain in joints/ bones

- CNS manifestations e.g. confusion, lethargy, gait abnormalities

what is the most common pediatric cancer?

ALL (acute lymphoblastic leukemia)

________ lymphoblasts required for a diagnosis of ALL

20%

what workup would be done prior to a diagnosis of ALL?

- lab tests (CBC w/ diff, coagulation studies, K+, creatine, uric acid, calcium, phosphate)

- peripheral blood smear

- bone marrow biopsy

- lumbar puncture

- echocardiogram/ MUGA

what are sanctuary sties in ALL?

sites in the body where chemotherapy drugs do not penetrate effectively, allowing leukaemia cells to persist and cause relapses. (i.e. CNS & testes)

if a pt has ALL & are BCR-ABL positive then what agent will be added onto chemo?

BCR-ABL TKI

Initial treatment of ALL typically combines some or most of the following agents:

- anthracycline (IV)

- Vincristine (IV)

- Corticosteroids (PO)

- Asparaginase (SC or IM)

what agent is considered and why might they want to do CNS prophylaxis in ALL?

- high dose IV methotrexate

- intrathecal chemo

* CNS is high risk site for relapse b/c it is a sanctuary site*

After remission, maintenance therapy for ALL typically includes more oral agents like: (3)

1. corticosteroid

2. Mercaptopurine

3. Methotrexate

Asparaginase

a) MOA

b) 3 different formulations

c) AE

a) hydrolyzes L- asparagine to L-aspartic acid & ammonia = depletes ALL cells of this necessary amino acid = cannot produce proteins

b)

- Asparaginase

- Erwinia asparaginase

- Peg-asparaginase

c)

- Severe Hypersensitivity Reactions

- Hepatic toxicity

- pancreatitis

- hyperglycemia

- hypertriglyceridemia

- VTE

can Asparaginase be interchanged between the different formulations?

NO!!! different dosing schedules & dosages

Methotrexate

a) drug class

b) MOA

c) why is it high dosed

d) eliminated via

e) pts may recieve what due to fear of precipitation & kidney damage?

f) AE

g) DI (3)

h) drug rescue

a) Folate Antagonist

b) Inhibits dihydrofolate reductase required to convert folic acid to tetrahydrofolate which is required for purine and thymidylate synthesis

c) to be able to cross BBB

d) kidneys

e) hydration & sodium bicarbonate

f)

- Myelosuppression

- Organ toxicities - nephrotoxicity, hepatotoxicity, neurotoxicity

g)

- PPis = reduce methotrexate clearance

- NSAIDs = additive renal toxicity

- Penicillins = impair methotrexate clearance

h) LEUCOVORIN

Must receive doses of leucovorin ______ until levels undetectable to "rescue" patient from life threatening myelosuppression/ other toxicities

q6h

what chemo is given intrathecally for ALL ? (3)

- Cytarabine

- Methotrexate

- Hydrocortisone

What is Tumour Lysis Syndrome?

- Complication of massive cell breakdown

- Release of intracellular contents into the bloodstream

What metabolic abnormalities may you see with tumour lysis syndrome? (4)

- hyperuricemia

- hyperkalemia

- hyperphosphatemia

- hypocalcaemia

what are risk factors for Tumour Lysis Syndrome

• tumour burden (i.e. elevated LDH, elevated WBC, large lymphoma > 10 cm)

• Elevated baseline SCr

• Elevated uric acid

• High Chemosensitivity

• aggressive lymphomas or leukemias

Tumour lysis syndrome signs and symptoms

- N/V

- Acute Kidney Injury

- Decreased urine output

- Edema (fluid overload, CHF)

- Lethargy

- Hypertension

- ECG changes (arrhythmias)

- Muscle twitching, cramping, and numbness

- Weakness

- Tetany

- Confusion & seizures

what pharmacological agents are given to combat tumour lysis syndrome? (2)

Allopurinol & Rasburicase

Allopurinol MOA

Inhibits xanthine oxidase preventing conversion of hypoxanthine to xanthine to uric acid (i.e. inhibits formation of uric acid)

Rasburicase MOA

Recombinant urate-oxidase enzyme which converts uric acid to allantoin (inactive/ SOLUBLE metabolite) >>> Degrades uric acid already formed

hyperkalemia treatment in TLS?

a) asymptomatic

b) symptomatic

a) sodium polystyrene sulphonate

b) rapid acting insulin + 25% dextrose infusion

what is AML?

hematologic malignancy characterized by the clonal expansion of myeloid blasts in the peripheral blood, bone marrow, & other tissues (MOST COMMON acute leukemia)

AML signs and symptoms

- cytopenias (anemia, thrombocytopenia, neutropenia)

- high blast count

Important predictors of outcomes in adult AML patients:

- age (Better outcomes < 60 years old)

- performance status

- duration of first remission

- cytogenetics & molecular abnormalities (MOST IMPORTANT)

AML Induction Goals

1) complete remission

- bone marrow w/ normal cellularity < 5% blasts

- no blasts in peripheral blood

2) restoration of normal hematopoiesis

- neuts ≥1.0

- Plt >100

in AML induction what is the 7+3 regimen

3 days of IV anthracycline

7 days of continuous IV cytarabine

what is a common toxicities are seen with cytarabine

- rash

- ocular toxicity = excessive tearing, pain, photophobia and sensation of foreign body

- cerebellar toxicity

what is the neurologic assessment done to test for Cerebellar Toxicity with cytarabine ...

handwriting assessment

what type of eye drops should always be prescribed with the drug cytarabine?

dexamethasone or prednisolone (start before chemo)

after giving "induction" chemo pts experience a very deep & extended period of neutropenia therefore what needs to occur?

Prophylaxis of opportunistic infections

AML consolidation drug regimen

(hint: HIDAC)

HIgh Dose Ara-C(cytarabine)

what is the purpose of an Allogeneic HSCT. (3)

- rescue recipient from myeloablative therapy

- replace the abnormal hematopoietic component

- establish a graft-versus-leukemia (tumor) effect >>>> donor cells recognize & destroy residual malignant cells in host which is an (++++) over autologous HSCT

stem cell sources (3)

- bone marrow

- peripheral blood

- umbilical cord blood

dasatinib and ponatinib cause what AE associated with fluid retention?

pleural effusion