HEMATOLOGIC MALIGNANCIES PART 2 LEUKEMIAS Flashcards
Chronic Myeloid Leukemia
results from an acquired mutation that leads to a clonal myeloproliferative expansion
of transformed, primitive hematopoietic progenitor cells
- CML is characterized by the presence of Philadelphia Chromosome
- translocation between the long arms of chromosomes
9 and 22 t(9;22) - This joining of a portion of the ABL gene of
chromosome 9 and the BCR gene of chromosome 22
leads to the formation of the BCR-ABL fusion
oncogene - The changed chromosome 22 is known as the
“Philadelphia chromosome” (Ph+)
*
Philadelphia Chromosome and BCR-ABL
The BCR–ABL gene leads to production of the BCR-ABL protein, an abnormal Tyrosine Kinase
The BCR-ABL tyrosine kinase has an ATP binding site which can transfer a phosphate group
to a protein substrate causing a signalling cascade for CML cells to proliferate and avoid
apoptosis.
The multitude of CML cells (immature myeloid precursor cells) that develop overpopulate the
bone marrow so healthy functional cells (functional WBC, platelets, RBC) are crowded out
CML Signs and Symptoms
Up to half of patients are asymptomatic due to the initial indolent phase of the
disease.
Splenomegaly (up to half of patients)
The spleen is a storage site for white blood cells. Some patients may have early satiety (due to
splenomegaly), anorexia, unexplained weight loss
Impact on hematopoiesis (other cell lines from bone marrow)
Patients may have bone pain and/or fatigue
Leukocytosis (WBC > 25)
Some patients may have leukostasis (WBC >100)
Leukostasis can allow infiltration of WBCs into tissues of major organs, compromising the organ’s
ability to function normally
infiltration of lungs or CNS, visual disturbances, stroke, or MI
Bone Marrow Biopsy
understanding diagnosis
Often done outpatient
Take sample from iliac crest
Hematopathologist reviews the samples from the bone marrow and peripheral blood to
confirm disease and phase
Cytogenetics
Review of the chromosomes in the cells from the bone marrow sample – is the
philadelphia chromosome present?
Molecular Testing
QPCR (Quantitative Reverse Transcriptase Polymerase Chain Reaction)
Very sensitive and is able to quantitatively measures the BCR-ABL gene
Count how much BCR-ABL gene is present if its there
Chronic, Accelerated, or Blast Crisis?
These tests take some time!
CML – Three Phases (simplified)
Chronic Phase (CP)
* < 10% blasts in the peripheral blood or bone marrow
* NOTE – 90% of CML patients present in this phase.
* Patient may feel asymptomatic
* splenomegaly
* 3 to 5 years
Accelerated Phase (AP)
* 10 to 19% blasts in peripheral blood and/or nucleated bone marrow cells
OR
* Persistent leukocytosis, thrombocytosis, thormbocytopenia, splenomegaly unresponsive to treatment
* Anemia, bone pain, fever, night sweats, and weight loss may occur. few months
Blast Crisis (BC)
* ≥ 20% blasts in peripheral blood white blood cells or nucleated bone marrow cells
- Similar to an acute leukemia
- days to weeks before death without treatment.
- cause of death is typically infection or hemorrhage
CML - Leukostasis
Give a bit of shor-term help
Does not treat CML
Patients with leukostasis require prompt initiation of anti-leukemic therapy to reduce WBC to safer level
Cytogenetic testing to provide a diagnosis will take some time
Hydroxyurea
Rapidly lowers WBCs
inhibits RNA reductase which blocks DNA synthesis
prevents conversion of ribonucleotides to deoxyribonucleotides
20-40 mg/kg/day in divided doses
Continue until WBC count in is controlled and CML therapy is initiated
Hydroxyurea is not Ph+ specific so will not affect course of disease
Give JJ some Hydroxyurea while we wait for test results
Hydroxyurea will cause massive cell breakdown. Give with allopurinol to prevent Tumour Lysis Syndrome
NOTE – Hydroxyurea is also used for other myeloproliferative neoplasms such as polycythemia vera and
essential thrombocytosis
BCR-ABL Tyrosine Kinase Inhibitors
First Generation:
Imatinib
Second Generation:
Dasatinib
Nilotinib
Mechanism of Action
competitively binds to the ATP binding site on BCR-ABL kinase
inhibits the phosphorylation of proteins involved with signal transduction
(CML clone proliferation)
Targeted Therapy!!!!! for CML
Help stop signal to keep growing
CML – Goals of Therapy
Chronic Phase (CP)
Maintain/Induce remission
Prevent progression to AP or BC
Minimize toxicity from therapy
Accelerated Phase (AP) or Blast Crisis (BC)
Induce second chronic phase
Cant say it is curable, need to keep them in remission
With no detectable BCR-ABL for the rest of their lives
Why did Imatinib change practice?
IRIS (n= 1106)
Imatinib 400 mg po daily vs. Interferon (IFN) + low dose cytarabine
Results at 18 months:
87% of Imatinib patients had a MCyR (< 35% Ph+) vs. only 35% of IFN +
Cytarabine patients
Estimated 76.2% of Imatinib patients had CCyR (0 Ph+) vs. only 14.5% of patients
on IFN + Cytarabine
Imatinib was better tolerated than IFN + Cytarabine
IRIS 60 months (5 year) follow up
estimated OS of 89% in imatinib patients!!!
BCR-ABL TKI – Side Effects
Myelosuppression
Neutropenia
increases risk of infection, encourage infection prevention and monitoring for fever
Thrombocytopenia
increases risk of bleeding, bruising, etc
If neutrophil count or platelet count become too low, may need to hold the TKI or consider a dose
reduction
Nausea/Vomiting (mild)
Imatinib and Dasatinib – Take with food to reduce nausea
Nilotinib – Take on an empty stomach due to increased bioavailability when taken with food
May be given an antinauseant to take 30-60 minutes before TKI dose and as needed. Typically
patients become tolerant and can stop the antinauseant after a few weeks.
Need to limit the amout of acetaminophen they use
Using tylenol and these drugs compounds liver toxicity
Stick to less than 2-3 g /day
BCR-ABL TKI – Side Effects cont’d
Fluid Retention
Peripheral edema or periorbital swelling, manage with diuretics
Dasatinib – pleural effusions. Manage with diuretics, steroids, consider switching agents.
Drug Rash
Mild rash is common and can be managed with mild creams, antihistamines, or topical steroids
Hepatotoxicity
Monitor LFT’s
Limit use of acetaminophen to lower doses (especially with imatinib)
QT prolongation
Nilotinib has a black box warning. Can also occur with Dasatinib
Baseline ECG recommended.
Vascular Risk Assessment
Assess for presence of obesity, hypertension, diabetes, hyperlipidemia, and smoking
Important to mitigate risk factors by appropriately controlling these risk factors (example – achieving targets
and smoking cessation as applicable)
Diarrhea
Dose related. Usually managed with loperamide
BCR-ABL TKIs
imatinib
Take with food to reduce
nausea
CYP 3A4 Substrate
CYP 3A4 Inhibitor
Absorption not affected by
food.
inhibition of acetaminophen
O-glucoronidation
Dasatinib
Take with food to reduce
nausea
CYP 3A4 Substrate
Acid dependant
absorption
Absorption not affected
by food.
Can increase QT interval
Can cause pleural
effusions
Nilotinib
Take on an empty stomach due to
increased bioavailability when taken
with food
CYP 3A4 Substrate
P-GP Substrate
CYP 3A4, 2D6 inhibitor
Acid dependant absorption
AUC increases by 82% if with high
fat meal
QT prolongation BLACK BOX
warning
Compliance
Keep in mind that CML is a chronic disease requiring daily chronic
therapy. Compliance is incredibly important!
Imatinib, Dasatinib, and Nilotinib can only be effective at maintaining
remission and preventing progression to accelerated phase and/or
blast crisis (acute leukemia) if patients take them!
Studies have shown that compliance can decrease over time and
impact outcomes.
Compliance must be assessed diligently at each visit!
Reasons for Treatment Failure:
Compliance!
The drug can’t work if the person doesn’t take it (or takes it incorrectly)
Drug Interactions!
Reduction in drug exposure could reduce efficacy
Keep in mind that drug interactions can also be the reason for heightened toxicities
Resistance
Reactivation of BCR-ABL activity
Can be due to point mutation in ABL kinase domain
Consider mutational analysis in appropriate patients to help direct therapy
decisions (you don’t want to switch to an agent that the patient is also resistant to)
Can BCR-ABL TKIs be discontinued?
Several trials have explored discontinuation.
In patients that have sustained undetectable disease (ie undetectable by QPCR) for 2-3
years, discontinuing TKI will lead to about half of patients relapsing.
AHS recommendation:
Can trial TKI discontinuation in patients that have been on BCR-ABL TKI for at least 5 years and have
achieved undetectable disease for at least 2 consecutive years. Must monitor QPCR very closely
(q1month) and if BCR-ABL QPCR is rising, reinstitute therapy
Otherwise, Allogeneic Stem Cell Transplant remains the only cure for CML
Rarely employed for treatment of AML due to tremendous efficacy of BCR-ABL TKIs
Allo - transplant is associated with many toxicities and not everyone has a donor.
– Acute Lymphoblastic Leukemia
ALL is a heterogeneous hematologic disease characterized by the
proliferation of immature lymphoid cells in the bone marrow,
peripheral blood, and other organs
Signs and Symptoms:
“B” symptoms
Fevers
night sweats
unintentional weight loss
Cytopenias
Neutropenia causing infections
Anemia causing fatigue, weakness and palpitations
Thrombocytopenia causing easy bruising and bleeding
Pain in joints or bone pain
CNS manifestations
ALL – Workup and Diagnosis
Laboratory Tests
CBC with differential, Coagulation studies
Electrolytes and chemistries including potassium, creatinine, uric acid, calcium, phosphate
Peripheral blood smear and bone marrow biopsy
Examination
Immunophenotyping, cytogenetics, molecular genetics
Lumbar puncture (LP)
Examination and evaluation of CSF
Consider Echocardiogram/MUGA
May need anthracycline within the therapy protocol
DIAGNOSIS
BLASTS = BAD!
20% lymphoblasts required for a diagnosis of ALL
CNS manifestations
Lumbar puncture or spinal tap
Blasts should not being hanging out
Treatment of ALL
Treatment Goals:
Cure - CURABLE
Prevent Relapse
Sanctuary sites – CNS and Testes
Minimize and/or manage therapy toxicities
Chemotherapy
ALL Chemotherapy protocols are complex and have several stages:
Induction, Intensification (Early and Late), Maintenance
One example - Modified Dana-Farber Protocol – most commonly used in AHS
BCR-ABL positive occurs in 25% of adult ALL cases
25% has Philadelphia crossover
These patients need a BCR-ABL TKI in addition to chemotherapy
Need to figure out it is a blast crisis or ALL?
Supportive Care and Symptom Management
Tumour Lysis Syndrome!
Infections
Chemotherapy related toxicities-
ALL Chemotherapy
All ALL protocols have the same backbone:
Anthracycline - IV
Vincristine - IV
Corticosteroids – PO
Other common agents used:
Asparaginase (most) – SC or IM
CNS prophylaxis – Patients require prophylactic therapy to prevent CNS disease because of the high risk of
CNS relapse (sanctuary site)
High Dose Methotrexate and/or Chemotherapy administered intrathecally
Anthracycline (doxorubicin or daunorubicin)
Maintenance phase
Mercaptopurine oral and Methotrexate oral
Appropriate patients will be transitioned to work up and conditioning for allogeneic
stem cell transplant
Asparaginase
Three DIFFERENT formulations that are NOT interchangeable
Asparaginase (L-asparaginase isolated from E.coli)
Erwinia asparaginase (L-asparaginase isolated from Erwinia chrysanthemi)
Peg-asparaginase (L-asparaginase isolated from E.coli and attached to polyethylene glycol)
Mechanism of Action:
L-asparagine is required for DNA synthesis and cell survival.
Regular cells can produce their own L-asparagine, but ALL cells cannot.
Asparaginase hydrolyzes L-asparagine to L-aspartic acid and ammonia and hence depletes ALL cells of this necessary amino acid.
Needed to make dna
Cancer cells can’t make it, but healthy cells can make asparagine
Asparaginase depletes asparage so cancer cells don’t have means of survival
Does not impact healthy cells
Adverse Effects:
Severe Hypersensitivity Reactions.
Asparaginase (E. Coli) has highest incidence - up to 35% of patients
Intradermal test dose is recommended for asparaginase
Not interchangeable, diff way they are dosed, how they work in protocol
Intradermal test dose needd for hyersensitivity
“High Dose” Methotrexate
MOA
MOA: Folate Antagonist
Inhibits dihydrofolate reductase that is required to convert folic acid to tetrahydrofolate
Tetrahydrofolate is required for purine and thymidylate synthesis
Doses of 3000 mg/m2 or higher (around 5-6 grams) to cross the Blood Brain Barrier
Consider this as compared to a rheumatology dose of only 25 mg
Pharmacokinetics:
Mainly eliminated via the kidneys. Precipitation of methotrexate in the urine can
cause renal injury
Methotrexate is more soluble in an alkaline environment.
Important to keep the urine alkaline to prevent methotrexate induced kidney damage
Patients will receive hydration as well as sodium bicarbonate IV or po starting the day before the infusion
SUPER HIGH DOSE
5-6 g to cross BBB]
Dont want it to precipitate in kidneys
Gvie them sod bicarb so urine is alkaline
“High Dose” Methotrexate
Toxicities:
drug int
Myelosuppression
Organ toxicities – nephrotoxicity, hepatotoxicity, neurotoxicity (chemo brain)
Patients require rescue with LEUCOVORIN
Drug Interactions:
PPIs reduce methotrexate clearance
NSAIDS can have additive renal toxicity
Penicillins can compete for renal tubular secretion impairing Methotrexate clearance
Need to do TDM
Need to hold PPI or it doesnt come down as fast
Leucovorin “Rescue”
Measure methotrexate levels daily
(serum drug monitoring) starting the
day after the infusion.
Must receive doses of leucovorin
q6h until levels undetectable to
“rescue” patient from life
threatening myelosuppression and
other toxicities
Need to give them leucovorin as methotrexate so toxic in this dose
Can expose themt o 24 h and healthy cells need to be rescued
Leucovorin helps to restart the cycle so healthy cells don’t suffer
Lumbar Puncture and Intrathecal Chemo
Intrathecally administered chemotherapy
Cytarabine, Methotrexate, Hydrocortisone
Sterility and safety incredibly important as it is an injection into the CSF
Patients may experience headache after administration
Vincristine deadly if given intrathecal route, pt will die within 3 days
Tumour Lysis Syndrome
Complication of massive cell breakdown
Release of intracellular contents into the bloodstream
Metabolic abnormalities include: hyperuricemia, hyperkalemia,
hyperphosphatemia, and hypocalcaemia
Can lead to: critical electrolyte imbalance, cardiac arrhythmias, renal
failure, and acute respiratory distress syndrome, seizures, death
Tumour Lysis Syndrome
Risk Factors:
Tumour burden
Bulky lymphatic disease (>10cm)
Elevated LDH
Elevated WBC count
Elevated baseline SCr
Elevated uric acid
High Chemosensitivity
Aggressive Lymphomas or
Leukemias
TLS Signs and Symptoms
Nausea, vomiting
Acute Kidney Injury (rising SCr)
Decreased urine output
Edema (fluid overload, CHF)
Lethargy
Hypertension
ECG changes (arrhythmias)
Muscle twitching, cramping, and
numbness
Weakness
Tetany
Confusion and seizures
TLS – Monitoring
Laboratory tests – look at electrolytes and remember 4 H’s
Hyperkalemia
Hyperuricemia
Hyperphosphatemia
Hypocalcemia
Renal function (SCr)
Fluid status – ins and outs, weight
Vital signs, ECG (if needed)
Blood work done q6h commonly
TLS - Management
Prevention (important) and treatment (if needed)
High risk patients – monitor lab work frequently (as often as
q6h for high risk patients on initial chemotherapy)
Hydration
Pharmacotherapy – Allopurinol, Rasburicase
In severe cases, dialysis may be required
TLS - Pharmacotherapy
Prevention with Allopurinol
Inhibits xanthine oxidase, the enzyme responsible for the conversion of hypoxanthine to xanthine to uric acid
It inhibits the formation of uric acid
Dose range of 300-600 mg po daily for 7-21 days with first cycle
Prevention and/or Treatment with Rasburicase
Recombinant urate-oxidase enzyme which converts uric acid to allantoin (an inactive and SOLUBLE metabolite of uric
acid)
Degrades the uric acid already formed
Treatment of Electrolyte Disturbances
Hyperkalemia:
asymptomatic - oral or rectal sodium polystyrene
sulphonate
symptomatic - rapid acting insulin and a 25% dextrose
infusion
Stop the progession of turning into something insoluble, leep it soluble
