Peg-asparginase in the treatment protocol of Acute Lymphoblastic Leukemia

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Peg-asparginase in the treatment protocol of
Acute Lymphoblastic Leukemia

• Muhammad Qayash Khan
• PhD in Zoology
• Ist Semester 2013

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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.

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Epidemiology

• Most common childhood cancer
• Demographics
• ---Males more commonly than females
• ---Whites more than blacks
• ---More commonly in patients with Down Syndrome

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Incidence
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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.

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ALL Symptoms

• Anemia
• Bleeding and bruising
• Bone and joint pain
• Fever
• Weight loss
• Petechia

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Fonts - Bad

• If you use a small font, your audience wont be
  able to read what you have written
• CAPITALIZE ONLY WHEN NECESSARY. IT IS DIFFICULT
  TO READ
• Dont use a complicated font

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Blood and Bone Marrow hematology comparison in ALL
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Bone Marrow Pathology
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Etiology stem cells
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Symptoms
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Diagnosis

• Bone marrow biopsy
• gt25 lymphoblast in the bone marrow
• Lumbar puncture
• CSF cytology
• Imaging/scans

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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.

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Oncaspar

• Pegylated L-asparagine amidohydrolase from E.
  coli.
• C1377H2208N382O442S17

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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.

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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.

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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.

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L-asparaginas in Normal Cells
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L-asparaginase in Tumor Cells
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L-asparginase action
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Protein PEGylation
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Use of Different nanoparticles for drug delivery
to the target
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PEGylation, successful approachto drug delivery

• PEGylation is the process of covalent attachment
  of polyethylene glycol (PEG) polymer chains to
  another molecule, normally a drug or therapeutic
  protein..

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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.

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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

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Different types of PEGylation
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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.

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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

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Half-lives of different L Asparaginase
preparations Intramuscular

• Elimination
• Asselin et al half-life (hours) Dose25,000 IU
  i.m
• T ½ is variable with dose, disease status, renal
  or hepatic function, age, or gender
• Depends on preparation
• PEG-Asparaginase(Oncaspar) 137.5 77.8 hours
• E.coli L-Asparaginase (Crasnitin/Elspar) 29.8
  4.1 hours
• E. chrysanthemi L-Aspa. (Erwinase) 15.6 3.1
  hours

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Half-lives of different L Asparaginase
preparations intravenous IV

• Werber et al. Elimination half life (hours)
  Dose10,000IU
• 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

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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

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L-Asparaginase Impaired Protein Synthesis

• Decreased production of insulin
• Resultant hyperglycemia secondary to
  hypoinsulinemia
• Hyperglycemia usually transient and resolves upon
  discontinuation
• Fatal diabetic ketoacidosis has occurred
• Patients with diabetes mellitus at increased risk
  of adverse reactions due to alteration in insulin
  production or pancreatic insults
• 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

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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

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L-Asparaginase Toxicities

• Mild nausea/vomiting
• Anorexia, abdominal cramps, general malaise,
  weight loss
• Tumor Lysis Syndrome (TLS)
• 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

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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 L-asparaginase therapy

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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.

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L-Asparaginase Drug Interactions

• L-Asparaginase and methotrexate
• Therapeutic synergistic and antagonistic effects
  depend on the schedule of administration
• If methotrexate is given 324 hours prior to
  L-asparaginase,
• L-asparaginase decreases methotrexate toxicity
• Due to blocking the antifolate effects of
  methotrexate
• If methotrexate is given after L-asparaginase,
  the efficacy of methotrexate is decreased
• 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 1014
  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

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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
• Vincristine should be given 1224 hours prior to
  L-asparaginase
• 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
• 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

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L-Asparaginase Monitoring Parameters

• Blood glucose
• CBC with differential
• D-dimer
• Fibrinogen
• LFTs
• Prothrombin time
• Serum albumin
• Serum creatinine/BUN
• Serum uric acid

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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.

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References

• 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
  Aug12(8)991-8.
• AsselinBL,WhitinJC,CoppolaDJ,RuppIP,SallanSE,Cohen
  HJ.Comparativepharmacokineticstudiesofthreeasparag
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• 0.AlbertsenBK,JakobsenP,SchroderH,SchmiegelowK,Car
  lsenNT.PharmacokineticsofErwiniaasparaginaseafteri
  ntravenousandintramuscularadministration.CancerChe
  motherPharmacol.20014877-82.2
• 1.WerberG.DrugmonitoringvonAsparaginaseimRahmendes
  pädiatrischenTherapieprotokollsderALL/NHL-BFM90Stu
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• 2.HoDH,BrownNS,YenA,HolmesR,KeatingM,AbuchowskiA,e
  tal.Clinicalpharmacologyofpolyethyleneglycol-L-asp
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• 3.BoosJ,WerberG,AhlkeE,Schulze-WesthoffP,Nowak-Got
  tlU,WurthweinG etal.Monitoringofasparaginaseactivi
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