Drugs for CML Treatment – Imatinib, Nilotinib, Dasatinib, Bosutinib, Ponatinib

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IMATINIB

imatinib

  • Formerly referred to as STI571 or CGP57148B.
  • Represents  the paradigm of a new class of anticancer agents, so-called small molecules.
  • This “targeted” approach was found to dramatically alter the natural history of CML, improving 10-year overall survival from approximately 20% to 80–90%.

Mechanism of Action

  • Binds with inactive BCR-Abl TK with the DFG motif adopting an ‘out’ conformation, utilizing three binding pockets.
  • Imatinib selectively inhibits all the ABL tyrosine kinases, including BCR-ABL,v-ABL, TEL-ABL, and Abelson-related gene (ARG).
  • It potently inhibits the tyrosine kinase activity of the α- and β-platelet derived growth factor receptors (PDGFR) and the receptor for stem cell factor (c-KIT; CD117).

Pharmacokinetics

  • Imatinib is well absorbed after oral administration with Cmax achieved within 2-4 hours post-dose.
  • Mean absolute bioavailability is 98%.
  • Elimination half-lives of imatinib and its major active metabolite, the N-demethyl derivative (CGP74588) 18 and 40 hours, respectively.
  • CYP3A4 is the major enzyme responsible for metabolism of imatinib.
  • Imatinib elimination is predominately in the feces.
  • 81% of the dose is eliminated within 7 days

Indications

  • Ph+ CML Chronic phase(CP)
  • Ph+ CML Accelerated phase(AP) and Blast crisis(BP)
  • Ph+ ALL
  • Myelodysplastic/Myeloproliferative Diseases (MDS/MPD)
  • Aggressive Systemic Mastocytosis (ASM)
  • Hypereosinophilic Syndrome (HES) and/or Chronic Eosinophilic Leukemia (CEL)
  • Dermatofibrosarcoma Protuberans (DFSP)
  • Gastrointestinal Stromal Tumors (GIST)

Dosage and Administration

  • Doses of 400 mg or 600 mg should be administered once daily, whereas a dose of 800 mg should be administered as 400 mg twice a day.
  • Dose should be administered orally, with a meal and a large glass of water.
  • In children, Gleevec treatment can be given as a once-daily dose or alternatively the daily dose may be given- once in the morning and once in the evening.

Adult Patients with Ph+ CML CP, AP and BC

  • 400 mg/day for adult patients in chronic phase CML
  • 600 mg/day for adult patients in accelerated phase or blast crisis.
  • A dose increase can be done if no severe adverse affects occur or no severe non-leukemia related neutropenia or thrombocytopenia.

Pediatric Patients with Ph+ CML

  • Newly diagnosed Ph+ CML is 340 mg/m2/day (not
    to exceed 600 mg)
  • 260 mg/m2/day for children with Ph+ chronic phase CML recurrent after stem cell transplant

Ph+ ALL

  • 600 mg/day

MDS/MPD (associated with PDGFR gene re-arrangements)

  • 400 mg/day

Aggressive Systemic Mastocytosis (ASM)

(without the D816V c-Kit mutation or with c-Kit mutational status unknown)

  • 400 mg/day
  • ASM associated with eosinophilia(fusion kinase FIP1L1-PDGFRα)
    • 100 mg/day

HES/CEL

(FIP1L1-PDGFRα fusion kinase)

  • 100 mg/day

DFSP

  • 800 mg/day

GIST

  • 400 mg/ day in advanced GISTs
  • 800 mg/ day advanced GISTs carrying KIT exon 9 mutations.

Dosage forms and Strengths

  • 100 mg film coated tablets
  • 400 mg film coated tablets
  • Very dark yellow to brownish orange

Dose Modifications

Concomitant Strong CYP3A4 inducers

  • eg., dexamethasone, phenytoin,carbamazepine, rifabutin, rifampacin, phenobarbital
  • Best avoided
  • Increase by atleast 50%

Renal Impairment

  • Moderate renal impairment (CrCL = 20-39 mL/min)
      • 50% decrease in the recommended starting dose and increased as tolerated.
      • For patients with moderate renal
        impairment doses greater than 400 mg are not recommended.
  • Doses greater than 600 mg are not recommended in patients with mild renal impairment (CrCL = 40-59 mL/min).

Hematologic Adverse Reactions

  • Chronic phase, absolute neutrophil count (ANC) <1.0 x 10^9/L, and/or platelets <50 x 10^9/L:
      • Hold imatinib until ANC ≥1.5 x 10^9/L and platelets
        ≥75 x 10^9/L, then resume imatinib at the starting dose of 400 mg.
  • If recurrence of ANC <1.0 x 10^9/L and/or platelets <50 x 10^9/L:
      • hold drug until ANC ≥1.5 x 10^9/L and platelets ≥75 x 10^9/L, then resume imatinib at reduced dose of 300 mg.
  • Accelerated phase and blast phase, ANC <0.5 x 10^9/L and/or platelets <10 x 10^9/L:
      • If cytopenia is unrelated to disease, reduce dose to 400 mg.
      • If cytopenia persists for 2 weeks, reduce dose further to 300 mg.
      • If cytopenia persists for 4 weeks, stop imatinib until ANC ≥1.0 x 10^9/L and platelet count ≥20 x 10^9/L and then resume treatment at 300 mg.
      • Growth factors can be used in combination with imatinib for patients with resistant neutropenia.

Adverse Reactions

Most frequently reported adverse reactions (> 10%) were edema, nausea, vomiting, muscle cramps, musculoskeletal pain, diarrhea, rash, fatigue and abdominal pain.

  • Edema and severe fluid retention
      • MC :: periorbital / in lower limbs
      • Probability increases with dose and age (>65)
      • Weigh patients regularly and manage unexpected rapid weight gain by drug interruption and diuretics .
  • Cytopenias, particularly anemia, neutropenia, and thrombocytopenia ( depend on stage of disease & age)
      • Manage with dose reduction or dose interruption and in rare cases discontinuation of treatment.
      • Perform complete blood counts weekly for the first month, biweekly for the second month, and periodically thereafter.
  • Severe congestive heart failure and left ventricular dysfunction
      • In patients with comorbidities and risk factors.
  • Grade 3/4 hemorrhage
      • newly diagnosed CML and GIST.
      • GI tumor sites may be the source of GI bleeds in GIST.
  • Gastrointestinal perforations.
  • Bullous dermatologic reactions (e.g., erythema multiforme and Stevens-Johnson syndrome)
  • Hypothyroidism has been reported in thyroidectomy patients undergoing levothyroxine replacement.
      • Closely monitor TSH levels in such patients
  • Severe hepatotoxicity may occur.
      • Assess liver function before initiation of treatment and monthly thereafter or as clinically indicated.
      • Monitor liver function when combined with chemotherapy known to be associated with liver dysfunction.
  • Cardiogenic shock/left ventricular dysfunction
      • At initiation of Gleevec in patients with conditions associated with high eosinophil levels (e.g., HES, MDS/MPD and ASM).
      • Echocardiogram and determination of serum troponin should therefore be considered in patients.
      • If either is abnormal, the prophylactic use of systemic steroids (1-2 mg/kg) for one to two weeks concomitantly with Gleevec should be considered.
      • Reversible with the administration of systemic steroids, circulatory support measures and temporarily withholding Gleevec.

NILOTINIB

nilotinib

Mechanism of Action

  • Nilotinib is shown to have a 10- to 50-fold increased potency against unmutated Bcr-Abl
    compared with imatinib.
  • Importantly, nilotinib also has considerable activity against most imatinib-resistant Bcr-Abl mutations.
  • In addition to Bcr-Abl, nilotinib also inhibits tyrosine kinases KIT, platelet-derived growth factor receptor (PDGFR), and discoidin domain receptor 1 (DDR1).
  • Nilotinib is also found to inhibit the non-tyrosine kinase NAD(P)H:quinone oxidoreductase (NQO2).

Pharmacokinetics

  • Peak concentrations of nilotinib are reached 3 hours after oral administration.
  • The bioavailability of nilotinib is increased when given with a meal.
  • Compared to the fasted state, the (AUC) increased by 82% when the dose is given 30 minutes after a high fat meal.
  • Daily serum exposure to nilotinib following 400 mg twice daily dosing at steady state is 35% higher than with 800 mg once daily dosing.
  • The elimination half-life is 17 hours.
  • Steady state conditions are achieved by Day 8.

Indications and Usage

  • Newly diagnosed Ph+ CML-CP
      • dose is 300 mg orally twice daily.
  • Resistant or intolerant Ph+ CML-CP and CML-AP
      • dose is 400 mg orally twice daily
  • Twice a day at approximately 12 hour intervals and not to be taken with food.
  • Swallow the capsule as a whole with water.
  • Do not consume food for at least 2 hours before and one hour after the dose is taken.
  • If a dose is missed, the patient should not take a make-up dose, but should resume taking the next prescribed daily dose

Dosage Forms and Strengths

  • 150 mg red opaque hard gelatin capsules
  • 200 mg light yellow opaque hard gelatin capsules

Dose Adjustments and Modifications

QT Prolongation

  • ECGs with a QTc > 480 msec
      • Withhold Tasigna
      • serum potassium and magnesium analysis
      • to be resumed within 2 weeks at prior dose if QTcF returns to <450 msec and to within 20 msec of baseline.
  • If QTcF is between 450 msec and 480 msec after 2 weeks reduce the dose to 400 mg once daily.
  • If, following dose-reduction to 400 mg once daily, QTcF returns to >480 msec, discontinue Tasigna

An ECG should be repeated approximately 7 days after any dose adjustment.

Neutropenia and Thrombocytopenia

  • Chronic or accelerated phase, ANC <1.0 x 10^9/L, and/or platelets <50 x 10^9/L:
      • Hold nilotinib and monitor blood counts.
      • Resume within 2 weeks at prior dose if ANC >1.0 x 10^9/L and platelets >50 x 10^9/L.
      • reduce dose to 400 mg once daily If blood counts remain low for >2 weeks

Elevated serum lipase, amylase, bilirubin, or hepatic transaminases grade ≥3

  • Hold
  • Resume nilotinib at 400 mg once daily if serum levels return to grade ≤1.
  • Test serum lipase, amylase, bilirubin, or hepatic transaminases monthly.

Peripheral arterial occlusive disease (PAOD)

  • Associated with an increased risk of vascular adverse events.
  • Patients with a history of PAOD, nilotinib should be permanently discontinued.

Concomitant Strong CYP3A4 Inhibitors

  • Avoid the concomitant use of strong CYP3A4 inhibitors
  • Reduce the dose to 300 mg once daily in patients with intolerant or resistant Ph+ CML .
  • 200 mg once daily in patients with Ph+ CML-CP newly diagnosed
  • Close monitoring for prolongation of the QT interval is indicated

Concomitant Strong CYP3A4 Inducers

  • Loss is unlikely to be compensated on increasing the dose when co-administered with such agents

Adverse Reactions/Toxicities

MC side effects :: rash, pruritus, headache, nausea, fatigue, myalgia, thrombocytopenia, neutropenia and anemia, nasopharyngitis, constipation, diarrhea, abdominal pain, vomiting, arthralgia, back pain, cough, and asthenia.

Myelosuppression:

  • Associated with neutropenia, thrombocytopenia and anemia.
  • CBC should be done every 2 weeks for the first 2 months, then
    Reversible by withholding dose.

QT Prolongation:

  • Tasigna prolongs the QT interval.
  • Obtain ECGs at baseline, 7 days after initiation, and periodically thereafter, as well as following any dose adjustments.
  • QT interval may be significantly prolonged when drug is inappropriately taken with food, and/or with strong CYP3A4 inhibitors

Sudden deaths:

  • Sudden deaths have been reported in patients with resistant or intolerant Ph+ CML receiving nilotinib.
  • Some contribution may be due to ventricular repolarization abnormalities.

Elevated Serum Lipase

  • Check serum lipase periodically.
  • If lipid elevations are accompanied by abdominal symptoms, interrupt doses and rule out pancreatitis.
  • Caution is recommended in patients with history of pancreatitis.

Electrolyte abnormalities:

  • Can cause hypokalemia, hypophosphatemia, hyperkalemia, hyponatremia and hypocalcemia
  • Correct electrolyte abnormalities prior to initiating therapy and monitor periodically during therapy.

DASATINIB

Dasatinib

Mechanism of Action

  • Dasatinib was discovered by and named after Jagabandhu Das as part of an effort to develop
    potent inhibitors of SRC family kinases (SFKs).
  • Targets the SRC family of kinases (SRC, LCK, HCK, YES, FYN, FGR, BLK, LYN, FRK), receptor tyrosine kinases (c-KIT, PDGFR, DDR1 and 2, c-FMS, ephrin receptors), and TEC family kinases (TEC and BTK).
  • Dasatinib inhibits BCR-ABL with greater potency compared to other BCR-ABL inhibitors.
  • In malignancies, in which BCR-ABL is not the critical kinase, the role of dasatinib has still to be defined.

Pharmacokinetics

  • Maximum plasma concentrations (Cmax) of dasatinib between 0.5 and 6 hours following oral administration.
  • The overall mean terminal half-life of dasatinib is 3–5 hours.
  • 100-mg dose of dasatinib 30 minutes following consumption of a high-fat meal results in a 14% increase in the mean AUC of dasatinib.
  • CYP3A4 is the primary enzyme responsible for the formation of the active metabolite. Active metabolite of dasatinib is unlikely to play a major role in the observed pharmacology of the drug.
  • Dasatinib is a weak inhibitor of CYP3A4.
  • Elimination is primarily via the feces.

Indications

  • Ph+ CML Chronic phase(CP)
  • Ph+ CML Accelerated phase(AP) and Blast crisis(BP)
  • Ph+ ALL
  • Chronic, Accelerated, or Myeloid or Lymphoid blast phase Ph+ CML with resistance or intolerance to prior therapy including imatinib.

Dosage and Administration

  • Chronic phase CML
      • 100 mg administered orally once a day
  • Accelerated phase CML, myeloid or lymphoid blast phase CML, or Ph+ ALL
      • 140 mg administered orally once a day
  • Tablets should be swallowed whole, should not be crushed or cut
  • Can  be taken either in the morning or in the evening, with or without a meal

Dosage Forms and Strengths

  • Tablets: 20 mg, 50 mg, 70 mg, 80 mg, 100 mg, and 140 mg.
  • White to off-white, biconvex, round, film-coated tablets.

Precautions

  • Simultaneous administration with antacids should be avoided.
  • The antacid dose should be administered at least 2 hours prior to or 2 hours after the dose .
  • Long-term suppression of gastric acid secretion by H2 antagonists or proton pump inhibitors (eg, famotidine and omeprazole) is likely to reduce dasatinib exposure.

Dose Modifications

Dose escalation to 140 mg once daily (chronic phase CML) or 180 mg once daily (advanced phase CML and Ph+ ALL) is allowed in patients who do not achieve a hematologic or cytogenetic response.

Concomitant Strong CYP3A4 inducers

  • a dose decrease to 20 mg daily should be considered for patients taking 100 mg daily.
  • a dose decrease to 40 mg daily should be considered for patients taking 140 mg daily.

Chronic phase

  • ANC <0.5 x 10^9/L or platelets ≤50 x 10^9/L:
      • Hold dasatinib until ANC ≥1.0 x 10^9/L and platelets ≥50 x 10^9/L, then resume dasatinib at the starting dose if recovery occurs in ≥7 days.
  • If platelets <25 x 10^9/L or recurrence of ANC <0.5 x 10^9/L for >7 days,
      • Hold drug until ANC ≥1.0 x 10^9/L and platelets ≥50 x 10^9/L, then resume at reduced dose of 80 mg once daily for second episode.
  • For third episode
      • Reduce dose to 50 mg once a day (newly diagnosed patients) or discontinue the drug

Accelerated phase and Blast phase

ANC <0.5 x 10^9/L and/or platelets <10 x 10^9/L:

  • If cytopenia is unrelated to disease, hold the drug until platelets ≥20 x 10^9/L and ANC ≥1.0 x 10^9/L, and resume at original starting dose. If recurrence, hold dasatinib until ANC ≥1.0 x 10^9/L and platelets ≥20 x 10^9/L, and resume dasatinib at 100 mg once a day (second episode) or 80 mg once a day (third episode).
  • If cytopenia is related to leukemia, consider dose escalation to 180 mg once daily.

Adverse Reactions/Toxicities

  • The most frequently reported adverse reactions myelosuppression, fluid retention events (pleural effusion, superficial localized edema, generalized edema), diarrhea, headache, musculoskeletal pain, and rash.
  • Most frequently reported serious adverse reactions include pleural effusion (2%), hemorrhage (2%), congestive heart failure (1%), and pyrexia (1%).
  • Pleural effusion (2%), hemorrhage (2%), congestive heart failure (1%), and pyrexia (1%).
  • The most frequently reported serious adverse reactions in patients with resistance or intolerance to prior imatinib therapy included
    • pleural effusion (11%),
    • gastrointestinal bleeding (4%),
    • febrile neutropenia (4%),
    • diarrhea (3%),
    • congestive heart failure/cardiac dysfunction (2%),
    • pericardial effusion (1%),
    • CNS hemorrhage (1%).
  • Myelosuppression
    • More frequent in patients with advanced phase CML or Ph+ ALL
    • Grade 3 or 4 myelosuppression is reported less frequently in patients treated with 100 mg once daily.
    • Perform complete blood counts weekly for the first 2 months and then monthly thereafter.
    • Myelosuppression is generally reversible and usually managed by withholding SPRYCEL temporarily or dose reduction.
  • QT Prolongation
    • Caution in patients with
      • hypokalemia or hypomagnesemia,
      • patients with congenital long QT syndrome,
      • patients taking anti-arrhythmic medicines
      • cumulative high-dose anthracycline therapy.
  • Congestive Heart Failure, Left Ventricular Dysfunction, and Myocardial Infarction
  • Laboratory Abnormalities
      • Grade 3 or 4 elevations of transaminase or bilirubin and Grade 3 or 4 hypocalcemia, hypokalemia, and hypophosphatemia are reported
  • Pulmonary arterial hypertension:
    • Dasatinib may increase the risk of developing pulmonary arterial hypertension (PAH).
    • PAH may be reversible on discontinuation of dasatinib.
    • If PAH is confirmed, dasatinib should be permanently discontinued.

BOSUTINIB

bosutinib

Mechanism of Action

  • Acts as a dual inhibitor of Src and ABL kinases. Interestingly, distinctly lower concentrations of bosutinib are required to ablate BCR-ABL phosphorylation when compared to the first-generation tyrosine kinase inhibitor.
  • Bosutinib has the potency to induce deep and fast responses in second- and third-/fourth-line treatment.

Pharmacokinetics

  • Following administration of a single dose of BOSULIF (500 mg) with food in patients with cancer, the median time-to-peak concentration was 4-6 hours.
  • Bosutinib is primarily metabolized by CYP3A4.

Indications and Usage

  • Indicated for the treatment of adult patients with chronic, accelerated, or blast phase Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML) with resistance or intolerance to prior therapy.

Dosing

  • 500 mg orally once daily with food.

Dosage Forms and Strengths

  • 100 mg tablet
  • 500 mg tablet

Dose Adjustments

  • Consider dose escalation to 600 mg once daily with food in patients who do not reach
      • complete hematological response (CHR) by week 8
      • a complete cytogenetic response (CCyR) by week 12,
      • who are currently taking 500 mg daily and did not have Grade 3 or higher adverse reactions
  • ANC <1.0 x 109/L or platelets <50 x 109/L:
      • Hold bosutinib until ANC ≥1.0 x 109/L and platelets ≥50 x 109/L.
      • Resume treatment with bosutinib at the same dose if recovery occurs within 2 weeks.
      • If blood counts remain low for greater than 2 weeks, upon recovery reduce dose by 100 mg and resume treatment.
      • If cytopenia recurs, reduce dose by an additional 100 mg upon recovery and resume treatment.
  • Liver transaminases >5 x IULN:
      • Hold bosutinib until recovery to ≤2.5 x IULN and resume dose at 400 mg once daily thereafter.
      • If recovery takes longer than 4 weeks, discontinue bosutinib.
      • If transaminase elevations ≥3 x IULN occur concurrently with bilirubin >2 x IULN and alkaline phosphatase <2 x IULN discontinue bosutinib.
      • For other clinically significant, moderate, or severe non-hematologic toxicity, withhold bosutinib until the toxicity resolves, then consider resuming at 400 mg once a day.
      • If clinically appropriate, consider increasing the dose of bosutinib to 500 mg once a day.
  • In patients with pre-existing mild, moderate, and severe hepatic impairment, the recommended dose of BOSULIF is 200 mg daily.
  • Diarrhea:
      • For NCI CTCAE Grade 3-4 diarrhea (increase of ≥7 stools/day over baseline/pretreatment), withhold bosutinib until recovery to Grade ≤1.
      • Bosutinib may be resumed at 400 mg once daily.

Adverse Reactions/Toxicities

Most Common

      • Diarrhea, nausea, thrombocytopenia, vomiting, abdominal pain, rash, anemia, pyrexia, and fatigue.

Gastrointestinal Toxicity

      • Diarrhea, nausea, vomiting, and abdominal pain.
      • The median time to onset for diarrhea (all grades) was 2 days and the median duration per event was 1 day.

Myelosuppression

      • Complete blood count should be performed weekly for the first month and then monthly thereafter.

Hepatic Toxicity

      • 20% of the patients experienced an increase in either ALT or AST.
      • Most cases of transaminase elevations occurred early in treatment.
      • Perform monthly hepatic enzyme tests for the first three months of treatment with BOSULIF and as clinically indicated.

Fluid Retention(3%)

      • Manifest as pericardial effusion, pleural effusion, pulmonary edema, and/or peripheral edema.

PONATINIB

ponatinib

All  first- and second-generation inhibitors are ineffective against the BCR-ABL T315I ‘‘gatekeeper’’ mutation. In order to overcome this issue and to further improve the inhibitory effect, the third generation inhibitor ponatinib was developed. 

Mechanism of Action

  • The exchange of threonine at position 315 for the more bulky isoleucine leads to a steric hindrance, inhibiting binding of all these inhibitors. Unable to bind the kinase, most Abl inhibitors lose their ability to block the BCR-ABL function. Twenty percent of patients who are imatinib resistant because of a BCR-ABL mutation bear the T315I ‘‘gatekeeper’’ mutation.
  • The small molecule ponatinib was developed specifically to overcome resistance based on the T315I mutation. The integration of a linear carbon–carbon triple bond into the structure of the molecule to link two functional groups avoids the blocking effect of the isoleucine in the context of the T315I mutation

Pharmacokinetics

  • Peak concentrations of ponatinib are observed within 6 hours after oral administration.
  • Drugs that elevate the gastric pH may reduce ponatinib bioavailability.
  • CYP3A4 involved in the phase I metabolism of ponatinib.
  • Ponatinib is also metabolized by esterases and/or amidases. Ponatinib is mainly eliminated via feces.

Indications and Usage

Adult  patients with chronic myeloid leukemia (CML) resistant or intolerant to prior tyrosine kinase inhibitor therapy

  • chronic phase,
  • accelerated phase, or
  • blast phase

Dosage and Administration

  • 45 mg administered orally once daily with or without food.
  • Tablets should be swallowed whole.
  • 15 mg and 45 mg round, white, film-coated tablets.

Dose Modifications

Myelosuppression

  • ANC <1.0 x 10^9/L or platelets <50 x 10^9/L
  • First occurrence: Hold ponatinib until ANC ≥1.5 x 10^9/L and platelets ≥75 x 10^9/L and resume at initial dose of 45 mg.
  • Second occurrence: Hold ponatinib until ANC ≥1.5 x 10^9/L and platelets ≥75 x 10^9/L and resume at 30 mg after recovery.
  • Third occurrence: Hold ponatinib until ANC ≥1.5 x 10^9/L and platelets ≥75 x 10^9/L and resume at 15 mg after recovery.

Serum lipase elevation

  • Grade 1 or 2 (asymptomatic): Consider dose interruption or reduction.
  • Grade 3 or 4 (>2 x IULN) (asymptomatic) or asymptomatic radiologic pancreatitis: Hold drug until serum levels are <1.5 x ULN. Resume at lower dose after recovery (30 mg if patient receiving 45 mg; 15 mg if patient receiving 30 mg.Discontinue ponatinib if patient receiving 15 mg).

Pancreatitis (symptomatic)

  • Grade 3:
      • Hold drug until serum lipase levels are ≤grade 1.
      •  Resume at lower dose after recovery (30 mg if patient receiving 45 mg; 15 mg if patient receiving 30 mg). Discontinue ponatinib if patient receiving 15 mg.
  •  Grade 4: Discontinue ponatinib.

Liver transaminase

  •  >3 x ULN (grade ≥2):
      •  Hold drug until serum levels are <3 x IULN. Monitor hepatic function. Resume at lower dose after recovery
  • AST or ALT ≥3 x ULN concurrent with bilirubin >2 x ULN and alkaline phosphatase <2 x ULN:
      • Discontinue ponatinib

Geriatric Use

  • Patients of age ≥ 65 years may be more likely to experience adverse reactions including decreased platelet count, peripheral edema, increased lipase, dyspnea, asthenia, muscle spasms, and decreased appetite. 
  • In general, dose selection for an elderly patient should be cautious.

Adverse Effects/Toxicities

  • The most common non-hematologic adverse reactions (≥ 20%) were
    hypertension, rash, abdominal pain, fatigue, headache, dry skin, constipation,
    arthralgia, nausea, and pyrexia.
  • Hematologic adverse reactions included
    thrombocytopenia, anemia, neutropenia, lymphopenia, and leukopenia

Thrombosis and Thromboembolism

Arterial thrombosis

  • Cardiovascular, cerebrovascular, and peripheral vascular thrombosis, including fatal myocardial infarction and stroke have occurred in 8%
    patients.
  • Myocardial infarction or worsening coronary artery disease 
      • most common arterial thrombosis event and occurred in 5% of patients.
      •  50% of these patients developed congestive heart failure concurrent or subsequent to the myocardial ischemic event.
  • Serious cerebrovascular events were reported in 2% (8/449). 
      • hemorrhagic conversion of the initial ischemic event. 
      • stenosis of large arterial vessels of the brain (e.g., carotid, vertebral, middle cerebral artery).
  • Serious peripheral arterial events were reported in 2% . (digital
    or distal extremity necrosis, peripheral arterial disease and required
    amputations).
  • Myocardial  infarction, coronary artery disease, angina, stroke, transient ischemic attack, hypertension, diabetes mellitus, hyperlipidemia, and smoking are associated with increased risk of arterail thrombosis.

Venous thromboembolism : events occurred in 3% patients

  • deep venous thrombosis 
  • pulmonary embolism 
  • portal vein thrombosis
  • retinal vein thrombosis

Congestive Heart Failure (4%)

Pancreatitis

      • occurred in 6% of patients 
      • pancreatitis resolved within 2 weeks with dose interruption or reduction.
      • incidence of treatment-emergent lipase elevation is 41%.
      • In cases where lipase elevations are accompanied by abdominal symptoms, interrupt treatment.

Hemorrhage

      • Serious bleeding events, occurred in 5%.
      • Bleeding events is higher in patients with AP-CML, BP-CML, and Ph+ALL. 
      • Cerebral hemorrhage and gastrointestinal hemorrhage were the most commonly reported serious bleeding events.
      • Most hemorrhagic events occurred in patients with grade 4 thrombocytopenia

Fluid Retention

      • Fluid  retention occurred in 23% of the patients. 
      • most common fluid retention events were peripheral edema
        pleural effusion  and pericardial effusion .

Cardiac Arrhythmias

Myelosuppression

Tumor Lysis Syndrome

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