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VENE

Cancer Type: Hematologic, Leukemia - Chronic Lymphocytic (CLL)  Intent: Palliative
Regimen Category: Evidence-Informed
Funding:
Exceptional Access Program
    Treatment of chronic lymphocytic leukemia/ small lymphocytic lymphoma according to clinical criteria
A - Regimen Name

VENE Regimen
Venetoclax


Disease Site
Hematologic - Leukemia - Chronic Lymphocytic (CLL)

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

Monotherapy for treatment of patients with chronic lymphocytic leukemia (CLL) with 17p deletion who have received at least one prior therapy, or patients with CLL without the 17p deletion who have received at least one prior therapy and for whom there are no other available treatment options.

Note:  Approval is based on response rate results from interim analyses of single-arm studies.  Clinical trial data in patients without the 17p deletion are limited.

 


Supplementary Public Funding

venetoclax
Exceptional Access Program (Treatment of chronic lymphocytic leukemia/ small lymphocytic lymphoma according to clinical criteria)

 
B - Drug Regimen

Ramp-up Dosing Schedule:

Week Daily dose*
1 20 mg
2 50 mg
3 100 mg
4 200 mg

 

THEN

venetoclax
400 mg PO Once Daily

*Venetoclax is available as 10 mg, 50 mg, and 100 mg tablets and also as a starter pack (for the 1st 4 weeks). 

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C - Cycle Frequency

CONTINUOUS TREATMENT

Until disease progression or unacceptable toxicity.

 
D - Premedication and Supportive Measures

Antiemetic Regimen:

Low – No routine prophylaxis; PRN recommended

Other Supportive Care:

Also refer to CCO Antiemetic Recommendations.

Tumour lysis prophylaxis is required for all patients.
 

Recommended TLS Prophylaxis Based on Tumour Burden

Tumour Burden

Prophylaxis

Blood Chemistry Monitoringc,d

 

Hydrationa

Anti-hyperuricemics

Setting and Frequency of Assessments

Low

All LN < 5 cm

AND

ALC < 25 x 109/L

Oral

(1.5 to 2 L)

Allopurinolb

Outpatient:

  • Pre-dose, 6 to 8 hours, 24 hours at first dose of 20 mg and 50 mg
  • Pre-dose at subsequent ramp-up doses, and post-dose at clinical discretion

Medium

Any LN 5 cm to < 10 cm

OR

ALC ≥ 25 x 109/L

 

Oral

(1.5 to 2 L) and consider additional IV

Allopurinol

Outpatient:

  • Pre-dose, 6 to 8 hours, 24 hours at first dose of 20 mg and 50 mg
  • Pre-dose at subsequent ramp-up doses, and post-dose at clinical discretion
  • Consider hospitalization if CrCl < 80 mL/min at first dose of 20 mg and 50 mg; see below

 

 

Tumour Burden Prophylaxis Blood Chemistry Monitoringc,d

High

Any LN ≥ 10 cm

OR

ALC ≥ 25 x 109/L AND any LN ≥ 5 cm

Oral (1.5 to 2 L) and IV (150 to 200 mL/hr, as tolerated)

Allopurinol; consider rasburicase if elevated uric acid at baseline

In hospital at first dose of 20 mg and 50 mg

  • Pre-dose, 4, 8, 12 and 24 hours

Outpatient at subsequent ramp-up doses

  • Pre-dose, 6 to 8 hours, 24 hours

ALC= absolute lymphocyte count; LN= lymph node

a.  Administer IV hydration if unable to tolerate oral
b.  Start allopurinol or xanthine oxidase inhibitor for 2-3 days prior to starting venetoclax
c.  Evaluate blood chemistries (potassium, phosphorus, uric acid, calcium, creatinine); review in real time.
d.  For patients at continued risk of TLS, monitor blood chemistries at 6 to 8 hours and at 24 hours at each subsequent ramp-up dose

 

 
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 may be considered.

See section G for dosing when co-administered with CYP3A4 or PGP inhibitors.

Dosage with toxicity

For dose interruption

  • > 1 week during the first 5 weeks of ramp-up phase; reassess for risk of TLS to determine if reduced dose necessary
  • > 2 weeks when at the steady-state daily dose of 400mg


Dose Modification for Toxicity During Treatment:

Dose at Interruption (mg) Restart Dose (mg)a
400 300
300 200
200 100
100 50
50 20
20 10

a Continue the reduced dose for 1 week before increasing the dose.
 

Dose Modification for Tumour Lysis Syndrome 

Event Action
Blood chemistry suggests TLS

Hold next day's dose

If resolved within 24-48 hours; resume at same dose

Clinical TLS or blood chemistry changes for ≥ 48 hours Hold until resolved; resume at a reduced dose (see restart dose above) and follow TLS prophylaxis


Dose Modification for Other Toxicities:

Toxicity

Action*

Any Grade 3 or 4 non-hematological

1st Occurrence:

Hold until ≤ Grade 1 or baseline; resume at same dose

2nd and Subsequent Occurrence(s):

Once resolved, follow dose reduction levels above.  A larger dose reduction may be selected at the discretion of the physician.

≥ Grade 3 neutropenia** with infection or fever

Grade 4 hematological toxicities (except lymphopenia)

*if dose reductions < 100 mg for > 2 weeks, consider discontinuing

**G-CSF may be administered with venetoclax if clinically indicated



Hepatic Impairment

A trend for increased adverse events was observed in patients with moderate hepatic impairment; monitor closely for toxicity at initiation and during ramp-up phase. 

 

 

Hepatic impairment Dosing Recommendation
Mild to Moderate
(total bilirubin > 1.5 to 3 x ULN)
No dose adjustment
Severe
(total bilirubin > 3 x ULN)
Not Recommended

 


Renal Impairment

In clinical trials the incidence of TLS was higher in patients with moderate renal impairment (6%) compared to those with normal renal function (4.4%).  Patients with reduced renal function (CrCl < 80 mL/min) may require more intensive TLS prophylaxis and monitoring.

 

 

Renal impairment Dosing Recommendation
Mild to Moderate (CrCl ≥ 30 mL/min)  No dose adjustment
Severe (CrCl < 30 mL/min) or dialysis Recommended dose not determined

 


Dosage in the Elderly

No dose adjustment required; no overall differences in efficacy or safety were observed between patients ≥ 65 years of age and younger patients.  Age does not have an effect on pharmacokinetics, based on population PK analyses.


 
F - Adverse Effects

Refer to venetoclax 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

 

 

  • Myelosuppression ± infection/bleeding (may be severe)
  • Diarrhea
  • Nausea, vomiting
  • Fatigue
  • Fever
  • Hyperphosphatemia
  • Infection
  • Headache
  • Hypokalemia
  • Back pain
  • Constipation
  • Autoimmune hemolytic anemia
  • Tumour lysis syndrome
  • Secondary malignancy
 
G - Interactions

Refer to venetoclax drug monograph(s) for additional details


  • Strong CYP3A4 inhibitors during ramp-up is contraindicated; reduce venetoclax dose by at least 4-fold if concomitant use unavoidable once on a steady daily dose. Resume previous venetoclax dose 2 to 3 days after stopping the inhibitor.
     
  • Avoid concomitant use of moderate CYP3A4 inhibitors during initiation and ramp-up phase; reduce venetoclax dose by at least 2-fold if concomitant use is unavoidable. Resume previous venetoclax dose 2 to 3 days after stopping the inhibitor.
     
  • Avoid concomitant use of P-gp inhibitors. If unavoidable, reduce the venetoclax dose by at least 2-fold; resume dose used prior to P-gp inhibitor 1 day after discontinuation.
     
  • Avoid concomitant use with both strong and moderate CYP3A4 inducers; consider alternative treatments.
     
  • Avoid P-gp and BCRP substrates with a narrow therapeutic index (i.e. digoxin); if must be used, take at least 6 hours before venetoclax.
     
  • Warfarin concentrations may be increased; monitor INR closely if used together.
 
H - Drug Administration and Special Precautions

Refer to venetoclax drug monograph(s) for additional details


Administration: 

Note:  Venetoclax is only available through pharmacies that are part of AbbVie's managed distribution program

  • Take orally once daily with a meal and water at approximately the same time each day.
  • Tablets should be swallowed whole and not chewed, crushed, or broken prior to swallowing.
  • If a dose is missed, it should be taken as soon as possible (within 8 hours of the time it is normally taken).  If > 8 hours, the dose should be skipped and the usual dosing schedule resumed the following day.
  • If the patient vomits after taking a dose, no additional dose should be taken.  The next dose should be taken at the usual time.
  • Avoid grapefruit products, Seville oranges, and starfruit during treatment.
  • Store between 2 and 30oC

 

Contraindications:

  • Patients who have a hypersensitivity to this drug or any of its components
  • Concomitant use with strong CYP3A inhibitors at initiation and during ramp-up phase
  • Safety and efficacy of live attenuated vaccines during or after treatment have not been studied.  Live vaccines should not be administered during treatment and thereafter until B-cell recovery. 

 

Other Warnings/Precautions:

  • Tumour lysis syndrome (see dosing section for prophylaxis).
  • Patients should be advised that vaccinations may be less effective.


Pregnancy and Lactation:

  • Venetoclax is not recommended for use in pregnancy.  Women of childbearing potential should undergo pregnancy testing before initiating treatment; adequate contraception should be used by both sexes during treatment, and for at least 30 days after the last dose.Breastfeeding: Unknown
  • Breastfeeding is not recommended; it is unknown whether venetoclax or metabolites are excreted in human milk.
  • Fertility effects are likely; testicular germ cell depletion was observed in animals; male fertility may be compromised.

 

 
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

  • Tumour burden assessment; Prior to starting treatment
  • CBC; Baseline and at each visit
  • Blood chemistry (TLS- potassium, uric acid, phosphorous, calcium, creatinine); Before starting, at 6 to 8 hours post-dose, and 24 hours post-dose for the first dose of 20 mg and 50 mg, and pre-dose at subsequent ramp-up doses
  • Liver and renal function tests; Baseline and at each visit
  • INR; Baseline and at each visit, or as clinically indicated (for patients taking warfarin)
  • Pregnancy test (for women of childbearing potential); Before starting treatment
  • Skin evaluation for non-melanoma skin cancer; Regular
  • Clinical toxicity assessment for myelosuppression, fever, infection, GI effects, fatigue, electrolyte imbalances, back pain, and headache; Baseline and at each visit
  • Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version


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J - Administrative Information

Outpatient prescription for home administration


 
K - References

Stilgenbauer S, Eichhorst B, Schetelig J, et al.  Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion: a multicentre, open-label, phase 2 study.  Lancet Oncol 2016;17:768-78.

Venetoclax Drug Monograph, Cancer Care Ontario.

June 2019 Updated emetic risk category, added EAP funding info


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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.
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