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Acute lymphoblastic leukaemia Ph+ maintenance therapy (daSATinib prednisolone vinCRISTine)

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

This protocol is based on limited evidence; refer to the evidence section of this protocol for more information.

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Cycle 1 and further cycles

Drug Dose Route Day
daSATinib 100 mg ONCE a day PO 1 to 28
Prednisolone 200 mg ONCE a day PO 1 to 5
vinCRISTine 2 mg IV infusion 1
Frequency:
28 days 
Cycles:
Continuous for a total of 2 years (24 months); dasatinib is then continued indefinitely as a sole agent.
Notes:

In the original trial by Ravandi et al.r, maintenance treatment was interrupted with two intensifications of Hyper CVAD and imatinib during months 6 and 13; it is the consensus of the Haematology Reference Committee to omit these intensifications from the eviQ protocol.

Drug status:

Dasatinib is PBS authority

All other drugs are on the PBS general schedule

Dasatinib is available as 20 mg, 50 mg, 70 mg and 100 mg tablets
Prednisolone is available as 25 mg, 5 mg and 1 mg tablets

Cost:
~ $4,170 per cycle "How this cost is calculated"

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

The cost includes anti-cancer drugs only (not antiemetics, supportive medications or consumables), 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 a 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 and ongoing maintenance 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 anti-cancer 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.

Cycle 1 and further cycles

Day 1
daSATinib 100 mg (PO) ONCE a day with or without food.
Prednisolone 200 mg (PO) ONCE a day on days 1 to 5. Take in the morning with food.
vinCRISTine 2 mg (IV infusion) in 50 mL sodium chloride 0.9% over 5 to 10 minutes

via minibag
Day 2 to 5
daSATinib 100 mg (PO) ONCE a day with or without food.
Prednisolone 200 mg (PO) ONCE a day on days 1 to 5. Take in the morning with food.
Day 6 to 28
daSATinib 100 mg (PO) ONCE a day with or without food.
Frequency:
28 days 
Cycles:
Continuous for a total of 2 years (24 months); dasatinib is then continued indefinitely as a sole agent.

Cycle 1 and further cycles

Drug Dose Route Day
daSATinib 100 mg ONCE a day PO 1 to 28
Prednisolone 200 mg ONCE a day PO 1 to 5
vinCRISTine 2 mg IV infusion 1
Frequency:
28 days 
Cycles:
Continuous for a total of 2 years (24 months); dasatinib is then continued indefinitely as a sole agent.
Notes:

In the original trial by Ravandi et al.r, maintenance treatment was interrupted with two intensifications of Hyper CVAD and imatinib during months 6 and 13; it is the consensus of the Haematology Reference Committee to omit these intensifications from the eviQ protocol.

Drug status:

Dasatinib is PBS authority

All other drugs are on the PBS general schedule

Dasatinib is available as 20 mg, 50 mg, 70 mg and 100 mg tablets
Prednisolone is available as 25 mg, 5 mg and 1 mg tablets

Cost:
~ $4,170 per cycle "How this cost is calculated"

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

The cost includes anti-cancer drugs only (not antiemetics, supportive medications or consumables), 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 a 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 and ongoing maintenance 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 anti-cancer 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.

Cycle 1 and further cycles

Day 1
daSATinib 100 mg (PO) ONCE a day with or without food.
Prednisolone 200 mg (PO) ONCE a day on days 1 to 5. Take in the morning with food.
vinCRISTine 2 mg (IV infusion) in 50 mL sodium chloride 0.9% over 5 to 10 minutes

via minibag
Day 2 to 5
daSATinib 100 mg (PO) ONCE a day with or without food.
Prednisolone 200 mg (PO) ONCE a day on days 1 to 5. Take in the morning with food.
Day 6 to 28
daSATinib 100 mg (PO) ONCE a day with or without food.
Frequency:
28 days 
Cycles:
Continuous for a total of 2 years (24 months); dasatinib is then continued indefinitely as a sole agent.
  • Philadelphia chromosome positive (Ph+) acute lymphoblastic leukaemia maintenance therapy after completion of Hyper CVAD Parts A and B with dasatinib
Safety alert vincristine administration

For safe administration of vincristine refer to the safety alert issued by the Australian Commission on Safety and Quality in Health Care
Venous access required

IV cannula (IVC) or central venous access device (CVAD) is required to administer this treatment.

Read more about central venous access device line selection
Caution with oral anti-cancer drugs

Select links for information on the safe prescribing, dispensing and administration of orally administered anti-cancer drugs. 

Read more about the COSA guidelines and oral anti-cancer therapy
Emetogenicity LOW

Antiemetics are not routinely required; however should a patient experience emesis:

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

Prochlorperazine 10 mg PO every 6 hours when necessary may be administered.

Read more about preventing anti-cancer therapy induced nausea and vomiting
Administration details

Long-term suppression of gastric secretions may decrease the absorption of some tyrosine kinase inhibitors (TKIs). Patients should avoid taking H2-receptor antagonists or proton-pump inhibitors while undergoing therapy with this TKI. Antacids may be used instead, but should be avoided within 2 hours of the TKI dose.
Prolongation of QT interval

This treatment may prolong the QT interval and increase the risk of cardiac arrhythmia. Use with caution in patients with a congenital long QT syndrome, patients treated with a high cumulative dose of anthracycline therapy, patients taking medications that may prolong the QT interval and those with electrolyte disturbances. Risk factors (e.g. electrolyte abnormalities) should be corrected, where possible, prior to commencement of treatment and the concurrent use of drugs that may prolong the QT interval should be avoided. Baseline and periodic monitoring of electrocardiogram (ECG) and electrolytes (potassium, magnesium, calcium) should be considered in patients at high risk of QT prolongation.

Read more about drugs that may prolong QTc interval
Cardiac toxicity

Tyrosine kinase inhibitors have been associated with cardiac complications of varying degrees and severity.

Patients, especially those with pre-existing cardiovascular disease, should have a baseline cardiac assessment of echocardiogram (ECHO), electrocardiogram (ECG) and biochemistry and be closely monitored. Cardiac assessment should be repeated as clinically indicated.

Read more about cardiac toxicity associated with anti-cancer drugs
Pulmonary complications

Clinicians should evaluate patients for signs and symptoms of underlying cardiopulmonary disease before starting treatment and during treatment.

Pleural effusions are dose dependent events and dose interruption, reduction or steroids should be considered. They are more common with dasatinib than with imatinib and may be bilateral or unilateral. Up to 35 % of patients treated with dasatinib on phase I/II studies developed pleural effusions, most often exudative. 

Pulmonary arterial hypertension (PAH) is an uncommon but serious complication. Echocardiogram is recommended in symptomatic patients (i.e. dyspnoea, cough, fatigue) and those with pleural effusions. Dasatinib should be withheld during evaluation if symptoms are severe, and permanently discontinued if PAH is confirmed i.e. not rechallenged.

Pneumonitis and interstitial lung disease has also been reported.
Fluid retention/oedema

Dasatinib may cause severe fluid retention, including pleural and pericardial effusions, severe ascites, severe pulmonary oedema, and generalised oedema. This may be dose-related.

Risk increases in patients greater than 65 years, patients with hypertension or prior cardiac history and those treated with twice daily dosing. (Note: once daily dosing is the recommended dosing schedule for all phases).

Monitor regularly for signs and symptoms of fluid retention. Chest x-ray is recommended for symptoms suggestive of pleural effusion (eg. cough, dyspnoea).
Gastrointestinal toxicity

Diarrhoea is a common side effect of tyrosine kinase inhibitors (TKI) (e.g imatinib and dasatinib). If severe diarrhoea occurs, discontinue TKI until condition improves or resolves.

Constipation has also been commonly reported with these regimens possibly related to the use of vinca alkaloids. 

Patients should be monitored closely, and prophylactic or symptom control anti-diarrhoeal/laxatives prescribed accordingly. 
Efficacy of therapy

Measure efficacy of therapy using a standardised RT-PCR assay for BCR-ABL transcripts. Assess after the first cycle, at 2 to 4 month intervals while on hyper CVAD, and at 4 to 6 month intervals thereafter. Alternate therapies should be considered for patients who do not achieve a major molecular remission (defined as BCR-ABL less than 0.1% in the marrow) by 3 months and for those who lose their initial response on serial monitoring.
Corticosteroids

Diabetic patients should monitor their blood glucose levels closely. To minimise gastric irritation, advise patient to take immediately after food. Consider the use of a H2 antagonist or proton pump inhibitor if appropriate.

Read more about acute short term effects from corticosteroids
Peripheral neuropathy

Assess prior to each treatment. Based on clinical findings, temporary omission, dose reduction or cessation of the vinca alkaloid may be indicated; review by medical officer before commencing treatment.

Read more about peripheral neuropathy

Link to chemotherapy-induced peripheral neuropathy screening tool
Pneumocystis jiroveci pneumonia (PJP) prophylaxis

PJP prophylaxis is recommended e.g. trimethoprim/sulfamethoxazole 160/800 mg PO one tablet twice daily, twice weekly (e.g. on Mondays and Thursdays) OR one tablet three times weekly (e.g. on Mondays, Wednesdays and Fridays).

Read more about prophylaxis of pneumocystis jiroveci (carinii) in cancer patients
Antifungals and antivirals

There are no specific recommendations for the use of antifungal or antiviral prophylaxis with this treatment. The use of prophylaxis should be at the discretion of the treating clinician and based on patient risk factors and local guidelines.

Read more about antifungal and antiviral prophylaxis
Blood tests

FBC, EUCs (including phosphate levels), LFTs at baseline and repeat prior to each treatment (consider weekly FBC for the first month of maintenance treatment). TSH and BSLs at baseline and regularly throughout treatment 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.

Read more about COVID-19 vaccines and cancer.
Effects of cancer treatment on fertility

Cancer treatment can have harmful effects on fertility and this should be discussed with all patients of reproductive age prior to commencing treatment.

Read more about the effect of cancer treatment on fertility
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 anti-cancer 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.

Note:

  • All dose reductions are calculated as a percentage of the starting dose
  • All dasatinib dose modifications are taken directly from the dasatinib product information and should be considered at the discretion of the treating Haematologist
Haematological toxicity
Dasatinib starting dose 100 mg once daily 
ANC less than 0.5 x 109/L and/or
platelets less than 10 x 109/L
  1. Stop dasatinib until ANC ≥ 1.0 x 109/L and platelets  ≥ 50 x 109/L 
  2. Resume at the original starting dose of dasatinib
  3. If platelets < 25 x 109/L and/or recurrence of ANC < 50 x 109/L for > 7 days, repeat step 1 and resume at a reduced dose of 80 mg once daily for 2nd episode. For 3rd episode further reduce dose to 50 mg once daily ( for newly diagnosed patients) or discontinue (patients resistant or intolerant to prior therapy including imatinib)

Note: The effects of dasatinib on platelet activation may also contribute to bleeding in addition to the thrombocytopenia

Renal impairment
Dasatinib and its metabolites are not significantly excreted via the kidney (<4%), therefore a decrease in total body clearance is not expected in renal insufficiency. 
Hepatic impairment
Patients with mild, moderate or severe hepatic impairment may receive the recommended starting dose of dasatinib. However, dasatinib is metabolised extensively in the liver and caution is recommended.
Peripheral neuropathy
Grade 2 which is present at the start of the next cycle Reduce vincristine by 50%
Grade 3 or Grade 4 Omit vincristine
Non-Haematological toxicity 
Severe Interrupt until resolved, then resume as appropriate at a reduced dose depending on the severity and recurrence of the event.

References & Disclaimer

The drug interactions shown below are not an exhaustive list. For a more comprehensive list and for detailed information on specific drug interactions and clinical management, please refer to the specific drug product information and the following key resources:  

Dasatinib
  Interaction Clinical management
H2 blockers (e.g. famotidine, ranitidine etc.) and Proton Pump Inhibitors (e.g.omeprazole, pantoprazole, rabeprazole etc.) and Antacids Reduced efficacy of dasatinib due to decreased absorption when gastric acid secretion suppressed (dasatinib requires acidic environment for absorption) Avoid combination; acid neutralising antacids, e.g. Gastrogel®, Mylanta® (which have a shorter duration of action), may be used if separated from dasatinib administration by at least 2 hours
CYP3A4 inhibitors (e.g. aprepitant, azole antifungals, clarithromycin, erythromycin, grapefruit juice, ritonavir etc.) Increased toxicity of dasatinib possible due to reduced clearance Avoid combination or monitor for dasatinib toxicity and reduce the dose appropriately
CYP3A4 inducers (e.g. carbamazepine, phenytoin, phenobarbitone, rifampicin, St John’s wort etc.) Reduced efficacy of dasatinib possible due to increased clearance Avoid combination or monitor for decreased clinical response to dasatinib
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 dasatinib resulting in reduced clearance Avoid combination or monitor for increased effect/toxicity. (e.g. simvastatin exposure can be increased by 20%; heightening the risk of QT prolongation)
Drugs that may prolong the QTc interval (e.g. azole antifungals, tricyclic antidepressants, antiarrhythmics etc.) Additive effect with dasatinib; may lead to torsades de pointes and cardiac arrest Avoid combination or minimise additional risk factors (e.g. correct electrolyte imbalances) and monitor ECG for signs of cardiac arrhythmia
Paracetamol Risk of liver toxicity due to inhibition of metabolism of paracetamol by dasatinib Avoid combination or monitor liver function closely
Prednisolone
  Interaction Clinical management
Antidiabetic agents (e.g. insulin, glibenclamide, glicazide, metformin, pioglitazone, etc) The efficacy of antidiabetic agents may be decreased Use with caution and monitor blood glucose
Azole antifungals (e.g. fluconazole, itraconazole, ketoconazole, posaconazole) Increased toxicity of prednisolone possible due to reduced clearance Avoid combination or monitor for prednisolone toxicity
Oestrogens (e.g. oral contraceptives) Increased toxicity of prednisolone possible due to reduced clearance Avoid combination or monitor for prednisolone toxicity. Dose reduction of prednisolone may be required
Ritonavir Increased toxicity of prednisolone possible due to reduced clearance Avoid combination or monitor for prednisolone toxicity
Vincristine
  Interaction Clinical management
CYP3A4 and P-gp inhibitors (e.g. amiodarone, aprepitant, azole-antifungals, ritonavir, lapatinib, nilotinib, sorafenib, macrolides, ciclosporin, grapefruit juice etc.) Increased toxicity of vincristine possible due to reduced clearance Monitor for vincristine toxicity (esp. neurotoxicity, paralytic ileus)
CYP3A4 inducers (e.g. carbamazepine, phenytoin, phenobarbitone, rifampicin, St John’s wort etc.) Reduced efficacy of vincristine possible due to increased clearance Monitor for decreased clinical response to vincristine
Mitomycin Acute shortness of breath and severe bronchospasm has occurred following use of vincristine in patients who had received mitomycin simultaneously or within 2 weeks Use combination with caution
Ototoxic drugs (e.g. cisplatin, aminoglycosides, frusemide, NSAIDs) Additive ototoxicity Avoid combination or perform regular audiometric testing
General
  Interaction Clinical management
Warfarin Anti-cancer drugs may alter the anticoagulant effect of warfarin. Monitor INR regularly and adjust warfarin dosage as appropriate; consider alternative anticoagulant.
Direct oral anticoagulants (DOACs) e.g. apixaban, rivaroxaban, dabigatran

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

DOAC and anti-cancer drug 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 Anti-cancer drugs 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 anti-cancer drug 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 anti-cancer 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

Day 1

Approximate treatment time: 30 minutes

General patient assessment prior to each day of treatment.

Peripheral neuropathy assessment tool

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

Prime IV line(s).

Insert IV cannula or access TIVAD or CICC.

  • baseline weight

Pre treatment medication

Verify antiemetics taken or administer as prescribed.

 Dasatinib

  • administer orally ONCE a day
  • to be swallowed whole with a glass of water; do not break, crush or chew
  • may be taken with or without food.

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

Prednisolone

  • administer orally ONCE a day on days 1 to 5
  • to be taken in the morning with or immediately after food

Note: if a dose is forgotten or vomited, contact treating team.

Vincristine

Administer vincristine (vesicant)
  • via a minibag over 5 to 10 minutes
  • ensure vein is patent and monitor for signs of extravasation throughout administration
  • flush with ~150 mL of sodium chloride 0.9%.

Remove IV cannula and/or deaccess TIVAD or CICC. 

Continue safe handling precautions until 7 days after completion of drug(s)

Day 2 to 5

This is an oral treatment

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.

  • weigh patient on each visit 

Pre treatment medication

Verify antiemetics taken or administer as prescribed.

 Dasatinib

  • administer orally ONCE a day
  • to be swallowed whole with a glass of water; do not break, crush or chew
  • may be taken with or without food.

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

Prednisolone

  • administer orally ONCE a day on days 1 to 5
  • to be taken in the morning with or immediately after food

Note: if a dose is forgotten or vomited, contact treating team.

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

Day 6 to 28

This is an oral treatment

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.

  • weigh patient on each visit 

 Dasatinib

  • administer orally ONCE a day
  • to be swallowed whole with a glass of water; do not break, crush or chew
  • may be taken with or without food.

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

Dasatinib tablets
  • Dasatinib tablets with written instructions on how to take them.
Prednisolone tablets
  • Prednisolone tablets with written instructions on how to take them.
Prophylaxis medications
  • Prophylaxis medications (if prescribed) e.g. PJP prophylaxis, antifungals, antivirals.
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
Taste and smell alteration

Read more about taste and smell changes

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
Constipation
Side effects of corticosteroids

Insomnia, oedema, increased risk of infection e.g. oral thrush, gastric irritation, worsening of peptic ulcer disease, increased blood sugar levels, loss of diabetic control, mood and behavioural changes - including anxiety, euphoria, depression, mood swings, increased appetite and weight gain, osteoporosis and fractures (long term use), bruising and skin fragility are associated with corticosteroid use.
Fatigue

Read more about fatigue
Abdominal pain

Dull ache, cramping or sharp pains are common with some anti-cancer drugs. These are caused by either increased or decreased gastrointestinal motility and can be associated with diarrhoea or constipation.
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 anti-cancer drugs
Fluid retention and oedema

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

Anti-cancer drugs 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.
Oral mucositis

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

Read more about oral mucositis
Skin rash

Anti-cancer drugs 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
Peripheral neuropathy

Typically symmetrical sensory neuropathy, affecting the fingers and toes, sometimes progressing to the hands and feet.  It is associated with several classes of anti-cancer drugs. These include taxanes, platinum-based compounds, vinca alkaloids and some drugs used to treat multiple myeloma.

Read more about peripheral neuropathy
Photosensitivity

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

Tinnitus and hearing loss may occur due to damage in the inner ear. Tinnitus is usually reversible, while hearing loss is generally irreversible. Hearing loss is dose-related, cumulative and may be worse in those with pre-existing hearing problems.

Read more about ototoxicity - tinnitus and hearing loss

Late (onset weeks to months)
Anaemia

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

Read more about anaemia
Periorbital oedema

Accumulation of fluid in the tissue surrounding the eye sockets (orbits).
Depression
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
Cognitive changes (chemo fog)

Changes in cognition characterised by memory loss, forgetfulness and feeling vague. This is also referred to as 'chemo brain' or 'chemo fog'.

Read more about cognitive changes (chemo fog) 

Evidence and Efficacy

Dasatinib has significant clinical activity in patients with Philadelphia chromosome positive (Ph+) acute lymphoblastic leukaemia (ALL) who are resistant to imatinib. Ravandi et al. examined the efficacy and safety of combining Hyper CVAD chemotherapy with dasatinib for 35 newly diagnosed patients, median age 53 (21-79). Dasatinib 50 mg twice a day or 100 mg once a day was given orally for the first 14 days of each 8 cycles of alternating Hyper CVAD, and high-dose cytarabine and methotrexate. Patients who achieved complete remission (CR) were given maintenance of daily dasatinib and monthly vincristine and prednisone for 2 years, followed by dasatinib indefinitely. 94% of patients achieved CR and a median disease-free survival and median overall survival had not been reached at a median follow-up of 14 months, with an estimated 2-year survival of 64%.r

A follow up study confirmed long-term efficacy of the Hyper CVAD chemotherapy in combination with dasatinib. 72 patients, median age 55 (21-80) with Philadelphia chromosome positive (Ph+) acute lymphoblastic leukaemia (ALL), either untreated or 1 or 2 prior cycles of therapy, were enrolled between 2006 and 2012. This study established dose equivalence between dasatinib 50 mg orally twice daily and dasatinib 100 mg daily and also further amended the protocol to give dasatinib 100 mg daily in the first 14 days of the first cycle followed by 70 mg daily continuously from the second cycle.  Maintenance with dasatinib, vincristine and prednisone was given monthly to patients who achieved CR for 2 years followed by dasatinib indefinitely. Allogeneic stem cell transplant (SCT) was given in first CR to eligible patients.r 

 69 patients (96%) achieved CR of which 57 (83%) achieved cytogenetic (CG) CR after 1 cycle and 64 (93%) a major molecular response (MMR) at a median of 4 weeks (range, 2 – 38 weeks). At a median of 3 weeks (range, 2–37), minimal residual disease by flow cytometry was negative in 65 (94 %) patients. At a median follow-up of 67 months (range, 33–97), 33 patients (46%) were alive and 30 (43%) in CR. 12 patients received an allogeneic SCT and 39 patients died. The median disease free and overall survival was 31 months (range, 0.3 to 97) and 47 months (range, 0.2 to 97) respectively. Seven relapsed patients had ABL mutations including 4 with T315I.r

© Cancer 2015

Furthermore, a multicentre trial found the addition of dasatinib in combination with chemotherapy followed by an allogeneic haematopoietic cell transplant (HCT) in patients with Philadelphia chromosome positive (Ph+) acute lymphoblastic leukaemia (ALL) was feasible. Hyper CVAD + dasatinib treatment was administered and of the 83 (88%) patients who achieved first complete remission (CR1), 41 patients received an allogeneic HCT where a donor was available, followed by daily dasatinib 100mg starting from day 100. 33 patients actually received dasatinib post-HCT and 30 (91%) of them required at least one dose reduction. Others received maintenance therapy with vincristine and prednisone for 2 years and dasatinib indefinitely. At median follow-up of 36 months (range, 9 - 63) for the overall cohort, overall survival (OS) was 69%, event-free survival (EFS) 55%, and relapse-free survival (RFS) 62%. The 12-month RFS was 71% and OS 87% after transplant.r

Source Study & Year Published Supports Use Is the dose and regimen consistent with the protocol? Comments
Phase II trials Ravandi et al 2010r Yes Yes  -
Phase II trials  Ravandi et al 2015r Yes  Yes  -
Phase II trials  Ravandi et al 2016r Yes  Yes  Hyper CVAD + dasatinib followed by allogeneic HCT
Guidelines Date published/revised Supports Use Is the dose and regimen consistent with the protocol? Comments
NCCN

Acute lymphoblastic leukaemia
Version 1.2018

 Yes Yes  -
BCCA N/A N/A N/A
CCO N/A N/A N/A   

Toxicity

Dasatinib was discontinued in 12 patients due to pleural effusions (n=6), pulmonary artery hypertension (n=2), gastrointestinal bleeding (n=2), skin cancer (n=1) and subdural bleeding(n=1)r

Dasatinib-related grade 3 and 4 adverse events included bleeding, pleural/ pericardial effusions, and elevated transaminases.

© Cancer 2015

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Flinders Filters has partnered with eviQ to build reliable, robust search filters to retrieve core high level evidence on topics of significance to eviQ. The project goal is the provision of a sustainable model for evidence retrieval to ensure ongoing currency of content.

These search filters have been developed to retrieve the most up to date evidence from PubMed, in real time, using specifically designed search filters built to meet our needs.

Searches can be used when a protocol is scheduled for review or at any time you choose. Please click on the Specific, Balanced and Sensitive tabs below to access the Pubmed searches.

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is the middle ground between sensitive and specific searches.

retrieves all clinically relevant evidence - generally a broader search on a given topic.

Access Flinders Filters, a division of the Flinders Digital Health Research Centre at Flinders University to read more about research solutions to searching problems.

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Version 1

Date Summary of changes
21/09/2018 New protocol proposed at Haematology Reference Committee meeting. Developed  out of session (discussed electronically via email).
15/05/2019 Approved and published on eviQ V1. Review in 1 year. 
05/08/2019 Drug status of dasatinib changed to reflect PBS update. 
23/10/2020 Protocol reviewed electronically by Haematology Reference Committee, no changes. Review in 2 years. 

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23 Sep 2021