Download L-Asparaginase

Peg-asparginase in the treatment
protocol of Acute Lymphoblastic
Leukemia
Muhammad Qayash Khan
PhD in Zoology
Ist Semester 2013
Leukemia
Leukemia is a cancer of the
marrow and blood.
---The four major types:
 Acute Myeloid Leukemia
 Chronic myeloid leukemia
 Acute Lymphoblastic
Leukemia
 Chronic lymphocytic
leukemia.

Acute leukemia
---A rapidly progressing
disease that produces cells
(blasts) that are not fully
developed.

Epidemiology
Most common childhood cancer
 Demographics:
---Males more commonly than females
---Whites more than blacks
---More commonly in patients with Down
Syndrome

Incidence
Etiology and Pathophysiology
ALL stems from mutations
–Radiation
–Chemicals
–Other
 Malignant immature white blood cells (WBCs).
–Lymphoblast crowd out the bone marrow.
–This includes crowding out of platelets, RBCs, and mature WBCs.

ALL Symptoms






Anemia
Bleeding and bruising
Bone and joint pain
Fever
Weight loss
Petechia
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Blood and Bone Marrow
hematology comparison in ALL
Bone Marrow Pathology
Etiology… stem cells
Symptoms
Diagnosis
Bone marrow biopsy
–>25% lymphoblast in the bone marrow
 Lumbar puncture
–CSF cytology
 Imaging/scans

Pegasparaginase (Oncaspar) for
ALL

PEGylated L-asparaginase for the treatment
of ALL in patients who are hypersensitive to
the native unmodified form of L-asparaginase
(obtained from Escherichia coli and Erwinia
chrysanthemi). The drug was recently
approved for front line use by FDA in 2007.
Oncaspar


Pegylated L-asparagine amidohydrolase from
E. coli.
C1377H2208N382O442S17
Pharmacodynamics


The malignant cells are dependent on an
exogenous source of asparagine for survival.
Normal cells, however, are able to synthesize
asparagine and thus are affected less by the
rapid depletion produced by treatment with the
enzyme asparaginase. Oncaspar exploits a
metabolic defect in asparagine synthesis of
some malignant cells.
Mechanism of action

Pegaspargase, more effective than native
asparaginase, converts asparagine to aspartic
acid and ammonia. It facilitates production of
oxaloacetate which is needed for general
cellular metabolism. Some malignant cells lose
the ability to produce asparagine and so the
loss of exogenous sources of asparagine leads
to cell death.
L-Asparaginase –
Mechanism of Action




Catalyzes the conversion of L-asparagine to aspartic acid and
ammonia.
Reversal of L-asparagine synthetase activity.
Results in rapid and complete depletion of L-asparagine.
Lack of intracellular asparagine results in decrease of protein
synthesis and apoptosis.
L-asparaginas in Normal Cells
L-asparaginase in Tumor Cells
L-asparginase action
Protein PEGylation
Use of Different nanoparticles for
drug delivery to the target
PEGylation, successful approach
to drug delivery

PEGylation is the process of covalent attachment
of polyethylene glycol (PEG) polymer chains to another
molecule, normally a drug or therapeutic protein..
PEGylation
The molecular weight of a molecule increases
which impart several significant pharmacological
advantages over the unmodified form, such as
 Improved drug solubility
 Reduced dosage frequency, without
diminished efficacy with potentially
reduced toxicity.
PEGylation
Extended circulating life
 Increased drug stability
 Enhanced protection from proteolytic degradation
------PEGylated drugs have the following commercial
advantages also:
 Opportunities for new delivery formats and dosing
regimens
 Extended patent life of previously approved drugs

Different types of PEGylation
L-Asparaginase –
Mechanisms of Resistance



Selective pressure of lymphoid cells that
overexpress asparagine synthetase gene.
Increase in L-asparagine synthetase due to a
decrease in intracellular levels of L-asparagine.
Formation of asparaginase antibodies that alter
L-asparaginase pharmacokinetics.
L-Asparaginase –
Pharmacokinetics

Absorption
–
–

Not given orally because of intestinal degradation
Intramuscular administration results in 50% lower peak blood
levels than IV route
Distribution
–
–
Primarily to intravascular space
Minimal blood-brain penetration


CSF levels are 1% of plasma concentration but depletion of
plasma asparagine levels leads to an antileukemic effect in CNS
Metabolism
–
Not known
Half-lives of different L Asparaginase
preparations Intramuscular

Elimination

Asselin et al half-life (hours) Dose:25,000 IU i.m
– T ½ is variable with dose, disease status, renal or
hepatic function, age, or gender
Depends on preparation
PEG-Asparaginase(Oncaspar®)
E.coli L-Asparaginase (Crasnitin®/Elspar®)
E. chrysanthemi L-Aspa. (Erwinase®)




137.5 ± 77.8 hours
29.8 ± 4.1 hours
15.6 ± 3.1 hours
Half-lives of different L Asparaginase
preparations intravenous IV

Werber et al. Elimination half life (hours) Dose:10,000IU
PEG-Asparaginase(Oncaspar ®)
no data
E.coli L-Asparaginase (Crasnitin ®/Elspar ®) 17.7 ± 2.5 hours

E. chrysanthemi L-Aspa. (Erwinase ®)


7.2 ± 4.1 hours
L-Asparaginase –
Dosage adjustment

Patients with hepatic impairment
–
–

Specific guidelines for dosage adjustments in
hepatic impairment are not available
These patients may be at increased risk for toxicity
Patients with renal impairment
–
–
Specific guidelines for dosage adjustments in renal
impairment are not available
No dosage adjustments are needed
L-Asparaginase –
Impaired Protein Synthesis

Decreased production of insulin
–
–
Resultant hyperglycemia secondary to hypoinsulinemia
Hyperglycemia usually transient and resolves upon
discontinuation

–
Patients with diabetes mellitus at increased risk of adverse
reactions due to alteration in insulin production or pancreatic
insults


Fatal diabetic ketoacidosis has occurred
Blood sugar should be closely monitored
Decreased production of albumin
–
Hypoalbuminemia can be severe resulting in peripheral edema
or ascites

Patients with limited hepatic synthetic function may be unable to
tolerate the effects of L-asparaginase
L-Asparaginase –
Impaired Protein Synthesis

Decreased production of vitamin K-dependent clotting
factors and endogenous anticoagulants such as
proteins C and S and antithrombin III
–
–
–
–
Coagulopathies, thrombosis, or bleeding due to impaired
protein synthesis may occur
Monitor coagulation parameters during L-asparaginase
therapy
Use cautiously in patients with a preexisting coagulopathy (e.g.
hemophilia) or hepatic disease
Intramuscular injections may cause bleeding, bruising, or
hematomas due to coagulopathy
L-Asparaginase –
Toxicities

Mild nausea/vomiting
–

Tumor Lysis Syndrome (TLS)
–
–
–

Anorexia, abdominal cramps, general malaise, weight loss
Hyperkalemia, hyperphosphatemia, hyperuricemia, hypocalcemia,
and decreased urine output
severe renal insufficiency
Appropriate TLS measures must be taken following chemotherapy
administration in patients with large chemosensitive tumors
Minor bone marrow suppression effects
–
–
–
Generally transient
Greatest potential is for slight anemia to occur
Marked leukopenia has been reported and white blood cell counts
should be monitored
L-Asparaginase –
Other Toxicities

Hepatic adverse reactions
–
–

Elevated AST, ALT, serum alkaline phosphatase, gamma
globulin, hyperammonemia, and hyperbilirubinemia or jaundice
Occurs within 2 weeks of starting therapy
Pancreatitis
–
–
Caused by necrosis and inflammation of pancreatic cells
Hemorrhagic and/or fatal pancreatitis can occur despite normal
amylase and lipase concentrations because of impaired
protein synthesis


Pancreatic toxicity is dose-related
Necessitates change of formulation or discontinuation of Lasparaginase therapy
L-Asparaginase –
Contraindications/Precautions


Contraindicated in patients with history of
pancreatitis because of risk of acute
pancreatitis.
E. coli preparation is contraindicated in patients
with history of anaphylactic reactions to
products derived from E. coli sources.
L-Asparaginase –
Drug Interactions

L-Asparaginase and methotrexate
–
Therapeutic synergistic and antagonistic effects depend on the
schedule of administration

If methotrexate is given 3—24 hours prior to L-asparaginase,
L-asparaginase decreases methotrexate toxicity
–

If methotrexate is given after L-asparaginase, the efficacy of methotrexate
is decreased
–

Due to blocking the antifolate effects of methotrexate
Due to:
 Inhibition of protein synthesis preventing progression to the S-phase of
the cell cycle
 Blocking of methotrexate polyglutamation
Recommended to give L-asparaginase at least 10—14 days prior to
methotrexate or shortly after methotrexate administration
–
–
Cells are refractory to methotrexate for up to 10 days following a single dose of
L-asparaginase
Period of increased DNA synthesis after L-asparaginase protein inhibition that
leads to increased sensitivity to methotrexate
L-Asparaginase –
Drug Interactions

L-asparaginase and vincristine
–
If L-asparaginase given concurrently or prior to vincristine, may result in
decreased hepatic metabolism of vincristine and cause additive neurotoxicity


L-asparaginase and corticosteroids
–
Result in additive hyperglycemia because L-Asparaginase inhibits insulin
production


Insulin therapy may be required in some cases
L-asparaginase and cytarabine
–

Vincristine should be given 12—24 hours prior to L-asparaginase
Acute pancreatitis with use of cytarabine in patients that have received prior
treatment with L-asparaginase
Anticoagulants, platelet inhibitors, NSAIDs, or thrombolytic agents
–
Due to the risk of bleeding and coagulopathy during L-asparaginase therapy
patients should not receive other agents that may increase the risk of bleeding
L-Asparaginase –
Monitoring Parameters









Blood glucose
CBC with differential
D-dimer
Fibrinogen
LFTs
Prothrombin time
Serum albumin
Serum creatinine/BUN
Serum uric acid
Conclusion and future perspective


Asparaginase is an important component of chemotherapy in ALL
treatment protocol.
With pediatric patients the incidence of severeallergic reactions,
thrombosis, pancreatitis and hepatic injury are prominent.

The incidence of these toxicities increases with age.

Future perspective……
To reduce the toxicity level and drug efficiency
in Adult ALL.

References





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Dinndorf PAF et al. 2007. DA drug approval summary: pegaspargase (oncaspar) for the
first-line treatment of children with acute lymphoblastic leukemia (ALL). Oncologist. 2007
Aug;12(8):991-8.
AsselinBL,WhitinJC,CoppolaDJ,RuppIP,SallanSE,CohenHJ.Comparativepharmacokineticstudi
esofthreeasparaginasepreparations.JClinOncol.1993;11:1780-1786.2
0.AlbertsenBK,JakobsenP,SchroderH,SchmiegelowK,CarlsenNT.PharmacokineticsofErwiniaas
paraginaseafterintravenousandintramuscularadministration.CancerChemotherPharmacol.2001;
48:77-82.2
1.WerberG.DrugmonitoringvonAsparaginaseimRahmendespädiatrischenTherapieprotokollsder
ALL/NHL-BFM90Studie.Inaugural-Dissertation,Münster.1995.2
2.HoDH,BrownNS,YenA,HolmesR,KeatingM,AbuchowskiA,etal.Clinicalpharmacologyofpolyeth
yleneglycol-L-asparaginase.DrugMetabDispos.1986;14:349-352.2
3.BoosJ,WerberG,AhlkeE,Schulze-WesthoffP,Nowak-GottlU,WurthweinG
etal.Monitoringofasparaginaseactivityandasparaginelevelsinchildrenondifferentasparaginasepre
parations.EurJCancer.1996;32A:1544-155