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Chronic myeloid leukaemia imatinib

Patients with leukaemia should be considered for inclusion into clinical trials. Link to ALLG website and ANZCTR website.

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Drug Dose Route
Imatinib 400 mg ONCE a day * PO

* The dose listed above is the standard starting dose for chronic phase CML. The higher starting dose of imatinib 600 mg once daily is commonly used in Australasia. This dose is generally tolerable and may be more efficacious.rr The starting dose of imatinib 800 mg may induce faster molecular responses but is associated with a higher discontinuation rate due to toxicities.rrr Starting dose for accelerated and blast phase CML is 600 mg once a day, however the ELN guidelines recommend a higher dose which may be used.r

Continuous as long as there is no evidence of progressive disease or unacceptable toxicity. If suboptimal or inadequate response is achieved, dose may be escalated or an alternative TKI considered.

Drug status:

Under the PBS, a patient can be prescribed imatinib, dasatinib or nilotinib within the initial 18 month treatment period, as long as only one agent is used at a time and providing the patient has not failed to respond to any one of these TKIs. Imatinib is only available on the PBS as a first-line TKI agent.

If a patient fails an adequate trial of imatinib as first line therapy, dasatinib or nilotinib may be prescribed as second or third-line agents.

Imatinib: (PBS authority)

Imatinib is available as 100 mg and 400 mg tablets.

Cost:
~ $1,680 per month (400 mg dose), ~ $2,600 per month (600 mg dose) "How this cost is calculated"

The cost displayed on the protocol is intended as rudimentary guide only for the Australian context.

The cost includes antineoplastic drugs only (not antiemetics or other supportive medications), unless otherwise indicated.

Drug unit costs are taken directly from the Pharmaceutical Benefits Scheme (PBS) website (www.pbs.gov.au), MIMS Online and other sources. These costs are reviewed and updated on eviQ at 6 monthly intervals.

Where there are differing unit costs based on vial sizes and tablet strengths, the mean unit cost is used. The cost of oral continuous therapy is based on 28 day month.

The protocol cost is derived from drug dose calculations based upon a default body surface area (BSA) of 1.8 m2; weight of 75 kg; and creatinine clearance of 75 mL/min.

One off loading doses are not included in protocol cost calculations.

The cost displayed is the actual drug cost and does not necessarily reflect the cost incurred by the patient as many antineoplastic drugs are reimbursed on the PBS.

The supportive therapies (e.g. antiemetics, premedications, etc.), infusion times, diluents, volumes and routes of administration, if included, are listed as defaults. They may vary between institutions and can be substituted to reflect individual institutional policy.

Antiemetics if included in the treatment schedule are based upon recommendations from national and international guidelines. These are defaults only and may be substituted to reflect individual institutional policy. Select here for recommended doses of alternative antiemetics.

Continuous treatment
Imatinib 400 mg (PO) ONCE a day with food

Note: the dose listed above is the standard starting dose for chronic phase CML. The higher starting dose of imatinib 600mg once daily is commonly used in Australasia. This dose is generally tolerable and may be more efficacious.rr The starting dose of imatinib 800mg may induce faster molecular responses but is associated with a higher discontinuation rate due to toxicities.rrr Starting dose for accelerated and blast phase CML is 600 mg once a day, however the ELN guidelines recommend a higher dose which may be used.r

Continuous as long as there is no evidence of progressive disease or unacceptable toxicity. If suboptimal or inadequate response is achieved, dose may be escalated or an alternative TKI considered.

Drug Dose Route
Imatinib 400 mg ONCE a day * PO

* The dose listed above is the standard starting dose for chronic phase CML. The higher starting dose of imatinib 600 mg once daily is commonly used in Australasia. This dose is generally tolerable and may be more efficacious.rr The starting dose of imatinib 800 mg may induce faster molecular responses but is associated with a higher discontinuation rate due to toxicities.rrr Starting dose for accelerated and blast phase CML is 600 mg once a day, however the ELN guidelines recommend a higher dose which may be used.r

Continuous as long as there is no evidence of progressive disease or unacceptable toxicity. If suboptimal or inadequate response is achieved, dose may be escalated or an alternative TKI considered.

Drug status:

Under the PBS, a patient can be prescribed imatinib, dasatinib or nilotinib within the initial 18 month treatment period, as long as only one agent is used at a time and providing the patient has not failed to respond to any one of these TKIs. Imatinib is only available on the PBS as a first-line TKI agent.

If a patient fails an adequate trial of imatinib as first line therapy, dasatinib or nilotinib may be prescribed as second or third-line agents.

Imatinib: (PBS authority)

Imatinib is available as 100 mg and 400 mg tablets.

Cost:
~ $1,680 per month (400 mg dose), ~ $2,600 per month (600 mg dose) "How this cost is calculated"

The cost displayed on the protocol is intended as rudimentary guide only for the Australian context.

The cost includes antineoplastic drugs only (not antiemetics or other supportive medications), unless otherwise indicated.

Drug unit costs are taken directly from the Pharmaceutical Benefits Scheme (PBS) website (www.pbs.gov.au), MIMS Online and other sources. These costs are reviewed and updated on eviQ at 6 monthly intervals.

Where there are differing unit costs based on vial sizes and tablet strengths, the mean unit cost is used. The cost of oral continuous therapy is based on 28 day month.

The protocol cost is derived from drug dose calculations based upon a default body surface area (BSA) of 1.8 m2; weight of 75 kg; and creatinine clearance of 75 mL/min.

One off loading doses are not included in protocol cost calculations.

The cost displayed is the actual drug cost and does not necessarily reflect the cost incurred by the patient as many antineoplastic drugs are reimbursed on the PBS.

The supportive therapies (e.g. antiemetics, premedications, etc.), infusion times, diluents, volumes and routes of administration, if included, are listed as defaults. They may vary between institutions and can be substituted to reflect individual institutional policy.

Antiemetics if included in the treatment schedule are based upon recommendations from national and international guidelines. These are defaults only and may be substituted to reflect individual institutional policy. Select here for recommended doses of alternative antiemetics.

Continuous treatment
Imatinib 400 mg (PO) ONCE a day with food

Note: the dose listed above is the standard starting dose for chronic phase CML. The higher starting dose of imatinib 600mg once daily is commonly used in Australasia. This dose is generally tolerable and may be more efficacious.rr The starting dose of imatinib 800mg may induce faster molecular responses but is associated with a higher discontinuation rate due to toxicities.rrr Starting dose for accelerated and blast phase CML is 600 mg once a day, however the ELN guidelines recommend a higher dose which may be used.r

Continuous as long as there is no evidence of progressive disease or unacceptable toxicity. If suboptimal or inadequate response is achieved, dose may be escalated or an alternative TKI considered.

  • Philadelphia chromosome (BCR-ABL) positive chronic myeloid leukaemia
Caution with oral antineoplastic agents

Select link for information on the safe prescribing, dispensing and administration of orally administered antineoplastic agents. 

Read more about oral anticancer therapy
Emetogenicity LOW/MODERATE

Although this treatment is classified as having MODERATE emetogenicity, in clinical practice, the administration of oral metoclopramide or prochlorperazine may be sufficient to control nausea.

Consider metoclopramide 10 mg three times a day when necessary (maximum of 30 mg/24 hours, up to 5 days) OR

Prochlorperazine 10 mg PO or 12.5 mg IV every 6 hours when necessary.

Read more about preventing antineoplastic induced nausea and vomiting
Cardiac toxicity

Imatinib has been associated with cardiac complications (i.e. left ventricular ejection fraction (LVEF) dysfunction and heart failure). For patients with pre existing cardiac disease, measure LVEF at baseline and as clinically indicated. Monitor patient for signs and symptoms of congestive heart failure.

In patients with hypereosinophilic syndrome and cardiac involvement, cardiogenic shock and left ventricular dysfunction have been associated with initiation of imatinib. The condition was reported to be reversible with the administration of systemic steroids, circulatory support measures, and temporary withholding of imatinib.

Read more about cardiac toxicity associated with antineoplastic agents
Hypothyroidism

Hypothyroidism has been reported in thyroidectomy patients undergoing thyroxine replacement during treatment with imatinib.

Monitor for signs and symptoms of hypothyroidism in thyroidectomy patients. 
Fluid retention/oedema

Patients may experience an increased incidence of fluid retention and periorbital oedema. Monitor for signs and symptoms of fluid retention and if severe fluid retention occurs treatment should be withheld until resolved. Periorbital oedema is a common side effect of imatinib which is usually mild to moderate and managed conservatively.
Diarrhoea

Antidiarrhoeals (e.g. loperamide) are usually prescribed with this treatment.
Cytogenetic and molecular tests

CBA (chromosome banding analysis) and qualitative PCR (polymerase chain reaction test) at diagnosis.
RQ-PCR (real-time quantitative polymerase chain reaction test) every 3 months until MMR has been achieved then every 3 to 6 months.

In addition it is acceptable to perform CBA at 3, 6, 12 months until CCyR has been achieved but after this it is most practical to use PCR for monitoring or FISH (fluorescence in situ hybridization) on blood cells can be used.

More frequent testing is recommended if response is suboptimal. RQ-PCR, mutational analysis and CBA is recommended if progression or treatment failure occurs. Immunophenotyping is recommended for failure/progression in blast phase.

Select link to see the European LeukaemiaNet recommendations for the management of chronic myeloid leukaemia  
Blood tests

FBC, EUC, LFTs and TSH at baseline. Repeat FBC weekly for the first month, then every second week for the second month, then every 2 to 3 months. Repeat LFTs monthly or as clinically indicated. TSH  as clinically indicated and monitor for signs and symptoms of hypothyroidism in thyroidectomy patients. INR at baseline and as clinically indicated.
Hepatitis B screening and prophylaxis

Routine screening for HBsAg and anti-HBc is recommended prior to initiation of treatment. Prophylaxis should be determined according to individual institutional policy.

Read more about hepatitis B screening and prophylaxis in cancer patients requiring cytotoxic and/or immunosuppressive therapy
Vaccinations

Live vaccines, including BCG, MMR, zoster and varicella vaccines, are contraindicated in cancer patients receiving immunosuppressive therapy and/or who have poorly controlled malignant disease.

Refer to the recommended schedule of vaccination for immunocompromised patients, as outlined in the Australian Immunisation Handbook.
Pregnancy and TKIs

Pregnancy must be avoided while a female patient is on tyrosine kinase inhibitor (TKI) therapy. Adequate contraception is required. There is no increased risk of pregnancy-associated complications in the partners or offspring of men receiving imatinib. Men on imatinib can safely start a family without interruption of treatment (Palani et al, 2015). There are very few reports of pregnancy outcome in partners of men receiving second or third generation TKIs. The safety of these drugs has not been proven and therefore pregnancy should be avoided. Fertility preservation options should be discussed with all patients commencing tyrosine kinase inhibitor therapy. Please see links for more information regarding the effects of TKIs on fertility.

Read more about the effect of cancer treatment on fertility

Link to Palani et al reference

Evidence for dose modifications is limited, and the recommendations made on eviQ are intended as a guide only. They are generally conservative with an emphasis on safety. Any dose modification should be based on clinical judgement, and the individual patient’s situation including but not limited to treatment intent (curative vs palliative), the antineoplastic regimen (single versus combination therapy versus chemotherapy versus immunotherapy), biology of the cancer (site, size, mutations, metastases), other treatment related side effects, additional co-morbidities, performance status and patient preferences. Suggested dose modifications are based on clinical trial findings, product information and reference committee consensus. Non-haematological gradings are based on Common Terminology Criteria for Adverse Events (CTCAE) unless otherwise specified. Renal and hepatic dose modifications have been standardised where possible. For more information see dosing considerations & disclaimer.
Haematological toxicity
Dose adjustment is based upon:
  • the haematological, cytogenetic and molecular response to therapy; if response is inadequate, change to an alternative TKI may be considered
  • consideration of toxicity (specifically the development of dose-limiting neutropenia or thrombocytopenia).

NOTE: The following dose modifications are taken from the imatinib product information
Chronic phase (starting dose 400 mg once daily)
ANC less than 1.0 x 109/L and/or
platelets less than 50 x 109/L
  1. Cease imatinib until ANC is greater than or equal to 1.5 x 109/L and platelets are greater than or equal to 75 x 109/L
  2. Resume imatinib at original starting dose (i.e. before severe adverse reaction)
  3. In the event of recurrence of ANC less than 1.0 x 109/L and/or platelets less than 50 x 109/L, repeat step 1 and resume imatinib at a reduced dose of 300 mg daily
Accelerated phase and blast crisis
ANC less than 0.5 x 109/L and/or
platelets less than 10 x 109/L
  1. Check if cytopenia is related to leukaemia (marrow aspirate or biopsy)
  2. If cytopenia unrelated to leukaemia, reduce dose of imatinib to 400 mg
  3. If cytopenia persists for 2 weeks, further dose reduce to imatinib 300 mg
  4. If cytopenia persists for 4 weeks and is still unrelated to leukaemia, stop imatinib until ANC greater than or equal to 1 x 109/L and platelets greater than or equal to 20 x 109/L, then resume imatinib at 300 mg
Renal impairment
Imatinib and its metabolites are not significantly excreted via the kidney, therefore a decrease in free drug clearance is not expected in renal insufficiency. The product information does however recommend that patients with renal dysfunction start with a reduced daily dose of 400 mg.
Hepatic impairment
Mild Use a starting dose of imatinib 400 mg daily
Moderate Use a starting dose of imatinib 400 mg daily
Severe Use a starting dose of imatinib 300 mg daily
Elevated bilirubin and hepatic transaminases
Bilirubin greater than 3 x ULN or
Transaminases greater than 5 x ULN		 Cease imatinib until bilirubin less than 1.5 x ULN and transaminases less than 2.5 x ULN. Resume at reduced dose of imatinib 300 mg daily (if starting dose was 400 mg), 400 mg daily (if starting dose was 600 mg) or 600 mg daily (if starting dose was 800 mg).
Non-Haematological toxicity
If a severe non-haematological adverse drug reaction develops imatinib should be withheld until the event has resolved. Thereafter, treatment can be resumed as appropriate depending on the initial severity of the event.

References & Disclaimer

Imatinib
  Interaction Clinical management
Gemfibrozil Increased toxicity OR reduced efficacy of imatinib possible due to inhibition of CYP2C8-mediated metabolism of imatinib OR reduced imatinib absorption and impaired CYP2C8-mediated conversion of imatinib to its active metabolite by gemfibrozil Avoid combination

Caution advised if other CYP2C8 inhibitors are to be used (e.g. trimethoprim, glitazones, montelukast etc.)
CYP3A4 inhibitors (e.g. aprepitant, azole antifungals, clarithromycin, erythromycin, grapefruit juice, ritonavir etc.) Increased toxicity of imatinib possible due to reduced clearance Monitor for imatinib toxicity
CYP3A4 inducers (e.g. carbamazepine, phenytoin, phenobarbitone, rifampicin, St John’s wort etc.) Reduced efficacy of imatinib possible due to increased clearance Avoid combination or monitor for decreased clinical response to imatinib
Drugs metabolised by CYP3A4 (e.g. atorvastatin, benzodiazepines, calcineurin inhibitors, clarithromycin, dihydroergotamine, simvastatin, etc.) Increased effect/toxicity of these drugs possible due to inhibition of CYP3A4 by imatinib resulting in reduced clearance Avoid combination or monitor for increased effect/toxicity of interacting drugs
Levothyroxine (thyroxine, Oroxine®, Eutroxsig®) Reduced efficacy of thyroid replacement therapy resulting in hypothyroid symptoms; possibly due to induction of levothyroxine metabolism by imatinib and subsequent TSH elevation Monitor closely for signs and symptoms of hypothyroidism, serum thyroxine and TSH levels; increase levothyroxine dose if needed
Paracetamol Risk of liver toxicity due to inhibition of metabolism of paracetamol by imatinib Avoid combination or monitor liver function closely
General
  Interaction Clinical management
Warfarin Antineoplastic agents may alter the anticoagulant effect of warfarin Monitor INR regularly and adjust warfarin dosage as appropriate; consider alternative anticoagulant (e.g. LMWH or unfractionated heparin)
Direct oral anticoagulants (DOACs) e.g. apixaban, rivaroxaban, dabigatran

Interaction with both CYP3A4 and P-gp inhibitors /inducers.

DOAC and antineoplastic levels may both be altered, possibly leading to loss of efficacy or toxicity (i.e. increased bleeding).

Apixaban: avoid concurrent use with strong CYP3A4 and P‑gp inhibitors. If treating VTE, avoid use with strong CYP3A4 and P‑gp inducers. 

Rivaroxaban: avoid concurrent use with strong CYP3A4 and P‑gp  inhibitors.

Dabigatran: avoid combination with strong P‑gp inducers and inhibitors.

If concurrent use is unavoidable, monitor closely for efficacy/toxicity of both drugs.
Digoxin Antineoplastic agents can damage the lining of the intestine; affecting the absorption of digoxin Monitor digoxin serum levels; adjust digoxin dosage as appropriate
Antiepileptics Both altered antiepileptic and antineoplastic levels may occur, possibly leading to loss of efficacy or toxicity Where concurrent use of an enzyme-inducing antiepileptic cannot be avoided, monitor antiepileptic serum levels for toxicity, as well as seizure frequency for efficacy; adjust dosage as appropriate.
Also monitor closely for efficacy of the antineoplastic therapy
Antiplatelet agents and NSAIDs Increased risk of bleeding due to treatment related thrombocytopenia Avoid or minimise combination.
If combination deemed essential, (e.g. low dose aspirin for ischaemic heart disease) monitor for signs of bleeding
Serotonergic drugs, including selective serotonin reuptake inhibitors (SSRIs e.g. paroxetine) and serotonin noradrenaline reuptake inhibitors (SNRIs e.g. venlafaxine) Increased risk of serotonin syndrome with concurrent use of 5-HT3 receptor antagonists (e.g. palonosetron, ondansetron, granisetron, tropisetron, dolasetron, etc.) Avoid combination.
If combination is clinically warranted, monitor for signs and symptoms of serotonin syndrome (e.g. confusion, agitation, tachycardia, hyperreflexia).
For more information link to TGA Medicines Safety Update
Vaccines Diminished response to vaccines and increased risk of infection with live vaccines Live vaccines (e.g. BCG, MMR, zoster and varicella) are contraindicated in patients on immunosuppressive therapy. Use with caution in patients on non-immunosuppressive therapy.
For more information; refer to the recommended schedule of vaccination for cancer patients, as outlined in the Australian Immunisation Handbook

Administration

This is an oral treatment

Safe handling and waste management (reproductive risk only)

Safe administration (reproductive risk only)

General patient assessment prior to each treatment.

Any toxicity grade 2 or greater may require dose reduction, delay or omission of treatment and review by medical officer before recommencing treatment.

Pre treatment medication

Verify antiemetics taken or administer as prescribed.

Imatinib

  • administer orally ONCE a day 
  • to be swallowed whole; do not break, crush or chew
  • to be taken with a large glass of water and food to minimise GI irritation
  • if difficulty is experienced swallowing the tablet advise patient to:
    • place tablets in a glass of water or apple juice (using ~50 mL for 100 mg tablet, ~200 mL for 400 mg tablet)
    • stir until tablet dissolves
    • drink straight away
    • rinse glass and drink this too

Note: missed doses should not be replaced; if a dose is forgotten or vomited, normal dosing should be resumed at the next scheduled dose.

Continue safe handling precautions (reproductive risk only) for 7 days after completion of drug(s).

Discharge information

Imatinib tablets
  • With written instructions on how to take them .
  • Advise patients to weigh themselves regularly and to report any increase by more than 1 to 2 kg in a week.
Antiemetics
  • Antiemetics as prescribed.
Antidiarrhoeals
  • Antidiarrhoeals as prescribed.
Patient information
  • Ensure patient receives patient information sheet.

The side effects listed below are not a complete list of all possible side effects for this treatment. Side effects are categorised into the approximate onset of presentation and should only be used as a guide.

Immediate (onset hours to days)
Nausea and vomiting

Read more about prevention of treatment induced nausea and vomiting
Flu-like symptoms
Headache

Mild headache is common with this treatment.

Early (onset days to weeks)
Neutropenia

Abnormally low levels of neutrophils in the blood. This increases the risk of infection. Any fever or suspicion of infection should be investigated immediately and managed aggressively. 

Read more about neutropenia
Thrombocytopenia

A reduction in the normal levels of functional platelets, increasing the risk of abnormal bleeding.  

Read more about thrombocytopenia
Haemorrhage
Diarrhoea

Read more about treatment induced diarrhoea
Fluid retention and oedema

An excess amount of fluid around the cells, tissues or serous cavities of the body, leading to swelling.
Arthralgia and myalgia

Generalised joint pain or and/or stiffness and muscle aches, often worse upon waking or after long periods of inactivity. Can improve with movement. May be mild or severe, intermittent or constant and accompanied by inflammation. 

Read more about arthralgia and myalgia
Skin rash

Antineoplastic agents can cause a number of changes in the skin with maculo-papular rash the most common type of drug-induced skin reaction. 

Read more about skin rash
Fatigue

Read more about fatigue
Abdominal pain

Dull ache, cramping or sharp pains are common with some antineoplastic drugs. These are caused by either increased or decreased gastrointestinal motility and can be associated with diarrhoea or constipation.
Anorexia

Loss of appetite accompanied by decreased food intake.

Read more about anorexia
Photosensitivity

Increased sensitivity to ultraviolet (UV) light resulting in an exaggerated sunburn-like reaction accompanied by stinging sensations and urticaria.
Oral mucositis

Erythematous and ulcerative lesions of the gastrointestinal tract (GIT). It commonly develops following chemotherapy, radiotherapy to the head, neck or oesophagus, and high dose chemotherapy followed by a blood and marrow transplant (BMT).

Read more about oral mucositis
Hepatotoxicity

Antineoplastic agents administered either alone or in combination with other drugs and/or radiation may cause direct or indirect hepatotoxicity. Hepatic dysfunction can alter the metabolism of some drugs resulting in systemic toxicity.
Cardiotoxicity

Cardiotoxicity may manifest as asymptomatic reduction in left ventricular ejection fraction (LVEF), arrhythmia, cardiomyopathy, hypertension, cardiac ischaemia and congestive heart failure (CHF). The risk of cardiotoxicity is increased by a number of factors, particularly a history of heart disease and electrolyte imbalances.

Read more about cardiotoxicity associated with antineoplastic agents

Late (onset weeks to months)
Anaemia

Abnormally low levels of red blood cells (RBCs) or haemoglobin in the blood. 

Read more about anaemia
Alopecia - partial

Hair thinning and/or patchy hair loss. Patients can also experience mild to moderate discomfort of the hair follicles, and rarely pain as the hair is falling out.

Read more about alopecia
Periorbital oedema

Accumulation of fluid in the tissue surrounding the eye sockets (orbits).
Muscle cramps

Cramping in the hands, calves and/or thighs associated with hypomagnesaemia (low magnesium) and/or hypocalcaemia (low calcium). 

Imatinib has proven efficacy in chronic, accelerated and blast phases of chronic myeloid leukaemia (CML).

CHRONIC PHASE (CP)

The evidence supporting this protocol is provided by a phase III multicentre international randomised trial (IRIS).r 1106 patients with untreated chronic phase Ph-positive CML were treated with imatinib or interferon alfa plus cytarabine. Between June 2000 and January 2001, 553 patients were randomised to receive imatinib 400 mg orally daily and 553 patients randomised to receive interferon alfa at a daily target dose of 5 million U/m2 plus 10-day cycles of cytarabine 20 mg/m2 daily every month. Patients receiving imatinib who did not have a complete haematological response within 3 months or whose bone marrow contained more than 65% Ph-positive cells at 12 months were able to increase the dose to 400 mg twice daily. The primary end point was event-free survival and secondary end points were the rate of complete haematological response, cytogenetic response, progression to the accelerated phase or blast crisis, overall survival, safety and tolerability. After a follow-up at 5 years, imatinib as initial therapy was found to induce durable responses in a high proportion of patients: the event-free survival was 83%, 93% of patients had no progression to AP or BP and the estimated overall survival was 95% for patients treated with imatinib (see Figure 4 below).r

© NEJM 2006

After a follow up at almost 11 years, imatinib as initial therapy proved to remain efficacious without significant late toxic or cumulative side effects.r The cumulative rate of major cytogenetic response (Ph+ cells 1-35%) with imatinib was 89%, and the rate of complete cytogenetic response (no detectable Ph+ cells) was 82.8%. Among 204 patients who had molecular assessments and could be evaluated at 10 years, 190 (93.1%) had a major molecular response and 129 (63%) had a MR4.5.r

Within the imatinib group, 38 patients (6.9%) progressed to AP or BP, compared with 71 patients (12.8%) in the IFN-α plus cytarabine group. This culminated in a 10 year event-free survival rate of 79.6% in the imatinib group compared to 56.6% in the IFN-α plus cytarabine group (See Figure 2  below). 260 patients (47%) were still alive at 10 years and receiving treatment, while 89 patients had died from any cause. The most common causes were CML, either without haematopoietic stem cell transplantation (n=37) or following transplantation (n=13), and second malignancies (n=11). This translates to a 10 year overall survival rate of 83.3% among those in the imatinib group. Those with a high Sokal score had a poorer 10 year overall survival (68.6%) compared to those with a low Sokal score (89.9%).r 

© NEJM 2017

The TIDEL-II trial,r evaluated the effect of dose escalating imatinib and/or switching from imatinib to nilotinib in patients who had suboptimal molecular responses. 210 patients with CP-CML were divided into 2 equal and sequential cohorts across 23 Australasian centres. All patients started treatment with imatinib 600 mg/day and dose escalated to 800 mg/day if the imatinib trough levels were <1000 ng/mL. Time-dependent MR targets were set: BCR-ABL =10%, =1% and =0.1% (IS) at 3, 6 and 12 months. In Cohort 1, patients who failed to meet these targets were dose escalated to imatinib 800 mg/day. Patients who failed to have improved molecular response or were already on imatinib 800 mg/day switched to nilotinib 400 mg twice a day. In Cohort 2, patients who failed these targets switched to nilotinib directly. Also, patients who experienced severe toxicities switched from imatinib to nilotinib. The primary end-point was confirmed MMR at 12 months. This was achieved by 64% of all patients, with no significant difference between the two cohorts, and at 24 months it was 73%. At 3 years, overall survival was 96%.r  Thirty percent of patients switched from imatinib to nilotinib, however an early switch to nilotinib did not overcome the adverse outcome for patients who failed to achieve early molecular response on imatinib. Furthermore, the study showed that treatment with optimised imatinib (involving a higher dose and blood tests every 28 days) upfront with a switch to nilotinib for toxicities achieved similar results to studies using second generation TKIs. Although 400mg is the approved starting dose, the TIDEL-II trial shows that a higher starting dose of 600mg has comparable efficacy to 2nd generation TKIs.r

The outcomes of patients treated with imatinib for CP-CML are summarised in Table 3 below.r A recent data review of imatinib as first line therapy reported no new clinically relevant late side effects or complications. Imatinib combination therapies were also reviewed and although some studies reported a higher MMR and MR rate, none of the combination studies reported a superior PFS or OS.r

© Blood 2013

More recently, due to the increase in literature and experience surrounding imatinib and second generation TKIs, the ELN 2009 recommendations were reviewed and updated. The ELN 2013 recommendations state that imatinib, nilotinib or dasatinib can be given as initial treatment. Furthermore, the responses that should be achieved at 3, 6 and 12 months were redefined (see cytogenetic and molecular tests in the clinical information section). In the case of treatment failure an alternate second generation TKI could be used second line.r

Successful stopping of imatinib therapy (for >5 years) was observed in a subgroup of patients who achieved a durable deep molecular response (molecular response 4, molecular response 4.5, or undetectable BCR-ABL1 transcripts), with approximately 39 to 45% of patients remaining in remission for 3 years or longer.r

ACCELERATED PHASE (AP)

Rea et al. conducted a multicentre retrospective analysis that reported on the benefit of imatinib in newly diagnosed accelerated phase (AP)-CML patients. 42 patients were treated with either 600 mg or 400 mg of imatinib daily for a median duration of 24 months. The rates of CHR, MCyR and CCyR did not differ significantly between patients who received 600 mg and 400 mg/day. However 64.3% patients who started on 400 mg/day underwent dose escalation to 600 mg/day. After a follow up of 24 months, favourable rates of OS 87.8%, PFS 87.2% and FFS 54.2% were achieved. Front-line imatinib for AP-CML is effective for patients with haematological acceleration without chromosomal abnormalities in addition to the Philadelphia chromosome and patients solely with additional chromosomal abnormalities (ACAs).r

© Leukemia 2012

BLAST PHASE (BP)

Palandri et al. conducted a phase II trial of imatinib 600 mg daily in patients with chronic myeloid leukaemia in blast crisis (BC-CML). From June 2000 to April 2001, 92 patients with confirmed Ph-positive BC-CML were enrolled into a prospective study. The primary end point was event-free survival or progression-free survival. Imatinib was effective and safe in the short-term treatment of BC-CML but did not significantly influence the longer-term outcomes (see Figure 1 below).r

© Haematologica 2008

Toxicity

After a median follow-up of 60 months, the most common adverse events experienced by patients receiving imatinib on the IRIS study were oedema (including peripheral and periorbital oedema; 60%), muscle cramps (49%), diarrhoea (45%), nausea (50%), musculoskeletal pain (47%), rash and other skin problems (40%), abdominal pain (37%), fatigue (39%), joint pain (31%) and headache (37%). Congestive heart failure was reported as being drug-related in one patient <1%.r Grade 3 and 4 events are summarised in ‘Table 2’ below.

© New England Journal of Medicine 2006

At the 11 year follow up analysis, 51 patients (9.3%) had a serious adverse event, most commonly abdominal pain. Serious adverse events related to imatinib were most common in the first year of treatment and then declined over time. Serious cardiac events of any cause were seen in 39 patients (7.1%) and secondary neoplasms (malignant or benign) were reported in 62 patients (11.3%).  No new safety issues were identified since the 5 year interim analysis.r

The side effects of imatinib therapy have also been documented in randomised trials comparing imatinib with dasatinib or nilotinib.rr The tables below summarise the most common side effects.

© New England Journal of Medicine 2010

© New England Journal of Medicine 2010

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Version 3

Date Summary of changes
09/11/2008 Review and reformatting of patient information sheet.
14/01/2010 Review, new dose modifications and transferred to eviQ
12/04/2012 New format to allow for export of protocol information
Protocol version number changed to V.2
Antiemetics and premedications added to the treatment schedule
Additional Clinical Information, Key Prescribing table and Key Administration table combined into new section titled Clinical Considerations
Drug specific information placed behind the drug name link
26/06/2012 Protocol updated to align with PBS changes. From 1 April 2012, under the PBS, a patient will be able to be prescribed any of imatinib mesylate, dasatinib or nilotinib within the initial 18 month treatment period, as long as only one agent is used at a time and providing the patient has not failed to respond to any one of these TKIs.
Evidence section removed as outdated and will be reviewed by the Haematology Reference Committee.
29/01/2014 Protocol discussed at Haematology Reference Committee meeting 31 August 2012. Consensus to have one imatinib protocol for the treatment of CML, therefore included information on all three phases.
Evidence section updated and rewritten as per current 2013 European LeukemiaNet (ELN) and NCCN guidelines.
08/04/2014 Information regarding taking paracetamol for pain and headaches in the 'patient information FAQs' section was edited to reflect the interaction between paracetamol and imatinib.
20/05/2016 

Reviewed at the Haematology Reference Committee meeting:

- cost updated
- cardiac toxicity, cytogenetic and pregnancy preclin added
- evidence updated.

31/05/2017

Transferred to new eviQ website. Version number change to V.3.
21/09/2018

Protocol reviewed at Haematology Reference Committee meeting. Minor updates to:

- Treatment schedule: removed 'in the morning' from detail tab
- Dose modifications 
- Administration: removed 'in the morning' from imatinib administration instructions
- Evidence
11/12/2018 Clinical information: 'Emetogenicity low' amended to 'Emetogenicity low/moderate' to align with ID 7- Prevention of chemotherapy induced nausea and vomiting document.

The information contained in this protocol is based on the highest level of available evidence and consensus of the eviQ reference committee regarding their views of currently accepted approaches to treatment. Any clinician (medical oncologist, haematologist, radiation oncologist, medical physicist, radiation therapist, pharmacist or nurse) seeking to apply or consult this protocol is expected to use independent clinical judgement in the context of individual clinical circumstances to determine any patient's care or treatment. Use is subject to eviQ’s disclaimer available at www.eviQ.org.au

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The currency of this information is guaranteed only up until the date of printing, for any updates please check:

https://www.eviq.org.au/p/362

22 May 2019