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DASA

Cancer Type: Hematologic, Leukemia - Chronic Myeloid (CML)  Intent: Palliative
Regimen Category: Evidence-Informed
Funding:
Exceptional Access Program
    daSAtinib - Ph+ CML in the chronic phase, with specific criteria
Exceptional Access Program
    daSAtinib - Accelerated phase or blast phase Ph+ CML with documented resistance or intolerance to imatinib, with specific criteria
A - Regimen Name

DASA Regimen
Dasatinib


Disease Site
Hematologic - Leukemia - Chronic Myeloid (CML)

Intent
Palliative

Regimen Category
Evidence-Informed :

Regimen is considered appropriate as part of the standard care of patients; meaningfully improves outcomes (survival, quality of life), tolerability or costs compared to alternatives (recommended by the Disease Site Team and national consensus body e.g. pan-Canadian Oncology Drug Review, pCODR).  Recommendation is based on an appropriately conducted phase III clinical trial relevant to the Canadian context OR (where phase III trials are not feasible) an appropriately sized phase II trial. Regimens where one or more drugs are not approved by Health Canada for any indication will be identified under Rationale and Use.


Rationale and Uses
  • Treatment of adult patients with Philadelphia chromosome positive (Ph+) chronic, accelerated, or blast phase chronic myeloid leukemia (CML) with resistance or intolerance to prior therapy, including imatinib mesylate
  • Treatment of adults with newly diagnosed Philadelphia chromosome positive (Ph+) CML in chronic phase.
  • Health Canada approval was based on hematologic and cytogenetic response rates; overall survival benefit has not been demonstrated.

Supplementary Public Funding

daSATinib
Exceptional Access Program (daSAtinib - Ph+ CML in the chronic phase, with specific criteria) (EAP Website) (does not exclude treatment-naïve patients )

daSATinib
Exceptional Access Program (daSAtinib - Accelerated phase or blast phase Ph+ CML with documented resistance or intolerance to imatinib, with specific criteria) (EAP Website)

 
B - Drug Regimen

Chronic Phase:

daSATinib
100 mg PO Daily
(Outpatient prescription in multiples of 20mg, 50mg, 70mg, 80mg, 100mg and 140mg tablets)  If an adequate hematologic or cytogenetic response is not observed, the dose of dasatinib may be increased to 140 mg PO daily.
 

Accelerated Phase or Blast Crisis:

daSATinib
140 mg PO Daily
(Outpatient prescription in multiples of 20mg, 50mg, 70mg, 80mg, 100mg  and 140mg tablets)  If an adequate hematologic or cytogenetic response is not observed, the dose of dasatinib may be increased to 180 mg PO daily.
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C - Cycle Frequency

CONTINUOUS TREATMENT

In the absence of disease progression or unacceptable toxicities

 
D - Premedication and Supportive Measures

Antiemetic Regimen:

Minimal – No routine prophylaxis; PRN recommended

Other Supportive Care:

  • Patients should be tested for HBV infection prior to initiating treatment.  Carriers of HBV must be monitored for signs and symptoms of active HBV infection throughout therapy and for several months following termination of therapy.
     

Also refer to CCO Antiemetic Recommendations.

Electrolyte abnormalities should be corrected before starting dasatinib.

 
E - Dose Modifications

Doses should be modified according to the protocol by which the patient is being treated. The following recommendations have been adapted from clinical trials or product monographs and could be considered.

Dosage with toxicity

 

Dosage with Myelosuppression:

Indication

Blood Counts  (x 109/L)

Action
Chronic phase CML
(starting dose 100mg QD)
 
ANC <0.5
and/or
Platelets <50
  1. Hold until ANC ≥1 and platelets ≥ 50,
  2. Resume treatment at the original starting dose.
  3. If platelets < 25 and/or recurrence of ANC < 0.5 for > 7 days, repeat step 1 and resume at a reduced dose of 80mg QD (second episode). Third episode:  ↓ to 50 mg QD (newly diagnosed patients) or discontinue (patients resistant or intolerant to prior therapy including imatinib)

Accelerated, blast phase CML; Ph+ALL                          (starting dose 140mg QD)

ANC <0.5
and/or
Platelets <10

If related to leukemia (bone marrow biopsy), consider ↑ to 180 mg OD.  If unrelated:

  1. Hold until ANC ≥1 and platelets ≥20,
  2. Resume treatment at the original starting dose.
  3. Second episode: repeat step 1 and resume at a reduced dose of 100mg QD
  4. Third episode: repeat step 1 and resume at a reduced dose of 80 mg QD
  5. Fourth episode:  Discontinue

Dosage with non-hematologic toxicity:

Toxicity

Severity

Action

Fluid retention

Any grade

Hold if appropriate until recovery and treat with diuretics or other supportive measures.

Pulmonary hypertension

Severe

Hold and investigate. Discontinue if confirmed.

Mucocutaneous skin reactions

Severe or any grade SJS

Discontinue (if no other etiology)

Other non-hematologic toxicity

Severe

Hold until recovery. Restart at a reduced dose if appropriate. 



Hepatic Impairment

Dasatinib has not been studied in hepatic impairment within the indicated dosing range.  Hepatic metabolism / excretion is significant; caution should be exercised and dose modification considered especially for moderate or severe hepatic impairment. 


Renal Impairment

Studies in renal impairment have not been conducted. Dasatinib is not excreted via the kidney to a significant extent and reduced dasatinib clearance is not expected.

 


Dosage in the Elderly

Patients aged 65 and older are more likely to experience commonly reported adverse events, such as diarrhea, fatigue, cough, dyspnea, fluid retention (including pericardial and pleural effusion), dizziness, pneumonia, hypertension, arrhythmia, heart failure, and gastrointestinal bleeding, as well as less frequently reported events such as pulmonary edema, lung infiltration, arthritis and urinary frequency. Imatinib resistant or intolerant chronic phase CML patients are less likely to have major cytogenetic response.  Monitor closely.

 

 

 


 
F - Adverse Effects

Refer to dasatinib drug monograph(s) for additional details of adverse effects


Very common (≥ 50%)

Common (25-49%)

Less common (10-24%)

Uncommon (< 10%),

but may be severe or life-threatening

 
  • Headache
  • Musculoskeletal pain
  • Infection (including atypical infections, HBV re-activation)
  • Diarrhea (may be severe)
  • Fatigue
  • Myelosuppression
  • Fluid retention (may be severe)
  • Cough, dyspnea
  • Rash (may be severe)
  • Hemorrhage (may be severe)
  • Nausea, vomiting
  • Abdominal pain
  • Constipation
  • Dizziness
  • Neuropathy
  • Abnormal electrolytes
  • Mucositis
  • Weight changes
  • Depression
  • Arrhythmia, prolonged QTc
  • Venous / arterial thromboembolism
  • Cardiotoxicity
  • Myocarditis, pericarditis
  • Pulmonary hypertension
  • Hypersensitivity
  • Pneumonitis, ARDS
  • Pancreatitis
  • Tumour lysis syndrome
  • PRES, seizure
  • Increased LFTs
  • Renal failure
  • Rhabdomyolysis
  • Pure red cell aplasia

 

 
G - Interactions

Refer to daSATinib drug monograph(s) for additional details


  • Dasatinib is primarily metabolized by CYP3A4 and is susceptible to interactions with inhibitors and inducers of this isoenzyme.
  • Avoid strong CYP3A4 inhibitors; if cannot be discontinued, consider a dasatinib dose reduction.
  • Avoid strong CYP3A4 inducers; if cannot be discontinued, caution and monitor for reduced efficacy.
  • Avoid CYP3A4 substrates with a narrow therapeutic index; dasatinib inhibits CYP3A4
  • Avoid use with other drugs that prolong the QT interval.
  • Avoid concomitant use with drugs that increase gastric pH; separate administration by at least 2 hours.
  • Caution and monitor for increased risk of bleeding with anticoagulants and antiplatelet agents.
 
H - Drug Administration and Special Precautions

Refer to daSATinib drug monograph(s) for additional details


Administration:

  • Prescribed dose should be administered orally, swallowed whole with or without food once daily
  • Tablets should not be crushed or cut.
  • Antacids should be avoided; if required, they should be taken up to 2 hours before or 2 hours after the administration of dasatinib.
  • Avoid grapefruit, starfruit, Seville oranges, their juices or products during treatment.
  • If a dose is missed, skip this and give the next dose as scheduled. Do not double the dose to make up for the forgotten one.
  • Pregnant women should avoid exposure to crushed and/or broken tablets.
  • Store at room temperature (15°C to 30°C)

 

Contraindications:

 

• Patients with hypersensitivity to dasatinib or its components

 

 

Warnings/precautions:

  • Contains lactose; carefully consider use in patients with hereditary galactose intolerance, severe lactase deficiency or glucose-galactose malabsorption.
  • Consultation with a liver disease expert is recommended prior to starting dasatinib in chronic HBV carriers (including those with active disease), and for patients who test positive for HBV infection while on treatment
  • Avoid in patients with increased QTc or who are at risk (low potassium/magnesium, congenital QT prolongation, anti-arrhythmics, other QTc prolonging agents, prior anthracyclines).
  • Avoid concomitant use of warfarin or antiplatelet agents, especially with thrombocytopenia. Exercise caution in patients at risk of bleeding or who are taking concurrent anticoagulants, as dasatinib has been shown to inhibit platelet aggregation and increase bleeding time.
  • Caution in patients with hepatic impairment and cardiac risk factors.
  • Use with extreme caution when fluid loading/transfusing.

Pregnancy and lactation:

  • Highly effective contraception (<1% failure rate) should be used by both sexes during treatment and for at least 6 months after dasatinib cessation.
  • Breastfeeding is contraindicated

 

 
I - Recommended Clinical Monitoring

Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.

Recommended Clinical Monitoring

  • CBC; chronic phase CML: baseline and every 2 weeks for 12 weeks, then every 3 months or as clinically indicated
  • CBC; advanced phase CML: baseline and weekly for the first 8 weeks, then monthly or as clinically indicated
  • ECG; baseline and as clinically indicated
  • Liver and renal function tests (including electrolytes) and creatinine; baseline and every 2 weeks for the first 2 months, then monthly and as clinically indicated
  • LVEF evaluation, in patient with cardiac risk factors; baseline and as clinically indicated
  • HBV infection status: Prior to starting treatment; consult infectious disease if positive
  • For carriers of HBV:  signs and symptoms of active HBV infection; At each visit during treatment and for several months after treatment discontinues
  • Clinical toxicity assessment for signs and symptoms of bleeding, infection, cardiotoxicity, muscle pain, rash, GI, pulmonary hypertension, pleural effusion, and fluid retention; at each visit
  • Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version

     

Suggested Clinical Monitoring

  • Consider LVEF evaluation in patients without cardiac risk factors; baseline and as clinically indicated

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J - Administrative Information

Outpatient prescription for home administration


 
K - References

Kantarjian H, Shah NP, Hochhaus A, et al. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2010 Jun 17;362(24):2260-70.

Shah NP, Kantarjian HM, Kim DW, et al. Intermittent target inhibition with dasatinib 100 mg once daily preserves efficacy and improves tolerability in imatinib-resistant and -intolerant chronic-phase chronic myeloid leukemia. Blood 2008; 26(19); 3204-12.

Dasatinib drug monograph, Cancer Care Ontario.

May 2019 Updated emetic risk category


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M - Disclaimer

Regimen Abstracts
A Regimen Abstract is an abbreviated version of a Regimen Monograph and contains only top level information on usage, dosing, schedule, cycle length and special notes (if available). It is intended for healthcare providers and is to be used for informational purposes only. It is not intended to constitute or be a substitute for medical advice, and all uses of the Regimen Abstract are subject to clinical judgment. Such information is provided on an “as-is” basis, without any representation, warranty, or condition, whether express, or implied, statutory or otherwise, as to the information’s quality, accuracy, currency, completeness, or reliability, and Cancer Care Ontario disclaims all liability for the use of this information, and for any claims, actions, demands or suits that arise from such use.
Information in regimen abstracts is accurate to the extent of the ST-QBP regimen master listings, and has not undergone the full review process of a regimen monograph.  Full regimen monographs will be published for each ST-QBP regimen as they are developed.
Regimen Monographs
Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.
The information set out in the drug monographs, regimen monographs, appendices and symptom management information (for health professionals) contained in the Drug Formulary (the "Formulary") is intended for healthcare providers and is to be used for informational purposes only. The information is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects of a particular drug, nor should it be construed to indicate that use of a particular drug is safe, appropriate or effective for a given condition. The information in the Formulary is not intended to constitute or be a substitute for medical advice and should not be relied upon in any such regard. All uses of the Formulary are subject to clinical judgment and actual prescribing patterns may not follow the information provided in the Formulary.
The format and content of the drug monographs, regimen monographs, appendices and symptom management information contained in the Formulary will change as they are reviewed and revised on a periodic basis. The date of last revision will be visible on each page of the monograph and regimen. Since standards of usage are constantly evolving, it is advised that the Formulary not be used as the sole source of information. It is strongly recommended that original references or product monograph be consulted prior to using a chemotherapy regimen for the first time.
Some Formulary documents, such as the medication information sheets, regimen information sheets and symptom management information (for patients), are intended for patients. Patients should always consult with their healthcare provider if they have questions regarding any information set out in the Formulary documents.
While care has been taken in the preparation of the information contained in the Formulary, such information is provided on an “as-is” basis, without any representation, warranty, or condition, whether express, or implied, statutory or otherwise, as to the information’s quality, accuracy, currency, completeness, or reliability.
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