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CHLO+OBIN

Cancer Type: Hematologic, Leukemia - Chronic Lymphocytic (CLL)  Intent: Palliative
Regimen Category: Evidence-Informed
Funding:
New Drug Funding Program
    Obinutuzumab - Previously Untreated Chronic Lymphocytic Leukemia
ODB - General Benefit
    chlorambucil
A - Regimen Name

CHLO+OBIN Regimen
Chlorambucil-oBINutuzumab


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

For the treatment of previously untreated (no prior anti-CD20 antibody or any other treatment) chronic lymphocytic leukemia (CLL). Funded by NDFP in patients with adequate renal function and for patients in whom fludarabine use is inappropriate.


Supplementary Public Funding

oBINutuzumab
New Drug Funding Program (Obinutuzumab - Previously Untreated Chronic Lymphocytic Leukemia) (NDFP Website)

chlorambucil
ODB - General Benefit (chlorambucil) (

ODB Formulary

)

 
B - Drug Regimen

chlorambucil
0.5 mg /kg PO Day 1 and 15 of each cycle

 

WITH

Cycle 1:

 

oBINutuzumab
1000* mg IV Days 1, 8 and 15

 

*Cycle 1 first dose may be split over 2 days (100 mg IV  day 1 and 900 mg IV day 2). See drug administration section for infusion rate recommendations.

THEN,

Cycles 2 to 6:

 

oBINutuzumab
1000 mg IV Day 1

 

 

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C - Cycle Frequency

REPEAT EVERY 28 DAYS

For a usual total of 6 cycles unless disease progression or unacceptable toxicity occurs

 
D - Premedication and Supportive Measures

Antiemetic Regimen:

Minimal

Obinutuzumab:

Hepatitis B screening should be performed prior to treatment for all patients.

Patients at risk for tumour lysis syndrome should receive adequate hydration and uricostatics or alternative starting 12 to 24 hours prior to infusion.

Consider withholding antihypertensives (if applicable) 12 hours prior to infusion, during infusion and for the first hour after drug administration, and withholding concomitant medications that increase bleeding risk, especially in the first cycle.

Patients with neutropenia should receive antimicrobial prophylaxis; consider use of G-CSF, antiviral and antifungal prophylaxis.

Premedication recommendations:

Treatment cycle, day

Patients

Premedication

Cycle 1, Day 1

All

IV corticosteroid* completed at least 1 hr prior to infusion &

PO analgesic/antipyretic** & antihistamine*** at least 30 min prior to infusion

 

Subsequent infusions

Patients with no prior IR during previous infusion

PO analgesic/antipyretic** at least 30 min prior to infusion

 

 

Patients with grade 1 or 2 IR with previous infusion

PO analgesic/antipyretic** & antihistamine*** at least 30 min prior to infusion

 

 

Patients with grade 3 IR with previous infusion OR

patients with lymphocyte counts > 25 x 109/L prior to next treatment

IV corticosteroid* completed at least 1 hr prior to infusion &

PO analgesic/antipyretic** & antihistamine*** at least 30 min prior to infusion

*e.g. 100 mg prednisone or 20 mg dexamethasone. Hydrocortisone should not be used as it has not been effective in reducing IR rates.

**e.g. 1000 mg acetaminophen

***e.g. 50 mg diphenhydramine

 
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 and product monographs and may be considered.

 

Dosage with toxicity

No dose reductions are recommended for obinutuzumab. The infusion may be discontinued, held or its rate reduced as appropriate. Do not re-escalate reduced doses of chlorambucil. Do not treat until ANC and hemoglobin ≤ grade 2 and platelets and non-hematologic toxicity ≤ grade 1.

Toxicity
 
Obinutuzumab dose*, **
Chlorambucil dose** (% previous dose)
Grade 4 hematologic toxicity, febrile neutropenia or thrombocytopenic bleeding
Hold until ≤ grade 2, restart at usual dose.
 
Discontinue if no recovery within 4 weeks.
 
Hold until ≤ grade 2. Administer G-CSF as required.
Day 1:
1st episode: upon recovery restart at 75%
2nd episode: upon recovery restart at 50%
3rd episode: discontinue
Day 15: Omit
Grade 2 or 3 related organ/non-hematologic toxicity
 
Hold until ≤ grade 1
 
Discontinue if no recovery within 4 weeks.
 
 
Hold until ≤ grade 1
 
Discontinue if no recovery within 4 weeks.
 
Grade 4 related organ/non-hematologic toxicity
 
Discontinue
Viral hepatitis or other serious infections; reactivation of hepatitis B
 
Discontinue
Suspected PML
 
Hold and refer to neurologist for diagnosis and treatment.  Discontinue if confirmed.
Grade 1-2 infusion reaction (IR)
Reduce infusion rate and treat symptoms.
Restart once resolved. Escalate*** infusion rate as tolerated at increments appropriate for treatment dose (see drug admin section).
 
No change
Grade 3 IR
Hold infusion and treat symptoms.
Restart once resolved at no more than half the previous rate. Escalate*** infusion rate as tolerated at increments appropriate for treatment dose (see drug admin section).
No change
Grade 4 IR OR
2nd episode of grade 3 IR (during same or subsequent infusion), acute life-threatening respiratory symptoms
OR
Anaphylaxis/ serum sickness
Discontinue
Discontinue
 * Missed doses may be administered later at physician discretion; the q28 day interval should be maintained.
**Hold up to 4 weeks. Before retreatment, major organ toxicities should recover to ≤ grade 1 (or as specified in table above), platelets ≥ 100 x 109/L and ANC ≥ 1.5 x 109/L. If chlorambucil is discontinued due to related toxicity, may continue obinutuzumab based on physician discretion.
***For CLL patients receiving cycle 1, day 1 dose split over 2 days, the infusion rate may be increased back to 25 mg/hr after 1 hr, but not increased further.



Hepatic Impairment

Safety and efficacy of obinutuzumab have not been established in patients with hepatic impairment. For chlorambucil, dose adjustment required with severe hepatic impairment; no details found.


Renal Impairment

For obinutuzumab, patients who have a creatinine clearance < 50mL/min in the pivotal study experienced more serious adverse events, including fatal ones than those with creatinine ≥ 50 mL/min.

CrCl (mL/min)
Obinutuzumab dose
Chlorambucil (% previous dose)
> 30 but < 50 mL/min
No change; use with caution
75%
10 to ≤ 30
No data; omit
75%
<10
No data; omit
50%

Dosage in the Elderly

Obinutuzumab:

No dose adjustment is required. CLL patients ≥ 75 years experienced more serious adverse effects than younger patients. No efficacy differences were observed between older and younger patients.

Chlorambucil:

No overall differences in safety or effectiveness were observed between younger patients and patients ≥ 65 years. Use with caution due to possible decreases in hepatic, renal, or cardiac function.


 
F - Adverse Effects

Refer to oBINutuzumab, chlorambucil, 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

  • Infusion-related reaction (may be severe; immediate or delayed)

 

  • Myelosuppression +/- infection (including atypical, viral reactivation), bleeding (may be severe)
  • Increased LFTs (may be severe)
  • Increased creatinine (may be severe)

 

  • Cough, dyspnea
  • Rash (may be severe)
  • Arterial / venous thromboembolism
  • Cardiotoxicity
  • Arrhythmia
  • Tumour lysis syndrome
  • Secondary malignancy
  • Hemolysis
  • Capillary leak syndrome
  • Pancreatitis
  • Pneumonitis, ARDS
  • PML
  • GI perforation
 
G - Interactions

Refer to obinutuzumab, chlorambucil drug monograph(s) for additional details


  • No clinical drug interaction studies have been conducted with obinutuzumab.
  • Consider withholding antihypertensives (if applicable) 12 hours prior to obintuzumab infusion, during infusion and for the first hour after drug administration, and withholding concomitant medications that increase bleeding risk, especially in the first cycle.
  • Drugs that cause immunosuppression may increase the risk of myelosuppression and infections.
  • Phenylbutazone may increase the toxicity of chlorambucil; consider dosage adjustment.
  • Co-administration of chlorambucil with succinylcholine may cause prolonged sleep apnea; decrease succinylcholine dose.

 

 
H - Drug Administration and Special Precautions

Refer to obinutuzumab, chlorambucil drug monograph(s) for additional details


Drug administration

Obinutuzumab:

Treatment cycle

Obinutuzumab dose*

Infusion rate**

Cycle 1, day 1

100 mg

25 mg/hr over 4 hours

Cycle 1, day 2 (or day 1 continued)

900 mg

50 mg/hr if no IR on day 1. May escalate as tolerated by 50 mg/hr q 30 min to max of 400 mg/hr.

25 mg/hr if previous IR. May escalate as tolerated by up to 50 mg/hr q 30 min to max of 400 mg/hr.

Cycle 1, day 8

1000 mg

100 mg/hr if no IR at rates ≥ 100mg/hr on day 2. May escalate as tolerated by 100 mg/hr q 30 min to max of 400 mg/hr.

50 mg/hr if previous IR. May escalate as tolerated by 50 mg/hr q 30 min to max of 400 mg/hr.

Cycle 1, day 15

1000 mg

Cycles 2 to 6, day 1

1000 mg q 28 days

*Two infusion bags should be prepared for the first 1000 mg infusion (100 mg for day 1, 900 mg for day 2). If the first bag is completed without needing modifications of infusion rate, the second bag may also be administered on day 1 without a dose delay, if possible.

**For infusion rate modifications in the case of IR, see dosage with toxicity section

  • Obinutuzumab should be administered only as an IV infusion through a dedicated line.  Do not administer as an IV push or bolus.
  • Withdraw required amount of diluent from vial and dilute in 250 ml PVC or non-PVC polyolefin bags containing 0.9% sodium chloride. See product monograph for details.
  • The initial 1000 mg dose should be prepared in two infusion bags of different sizes (i.e. 100 mg in 100 mL and 900 mg in 250 mL NS) to ensure differentiation of the 100 mg dose for day 1 and the 900 mg dose for day 2 (or day 1 continued)
  • Gently invert the IV bag to mix. Do not shake.
  • If a planned dose is missed, it should be administered as soon as possible; do not wait until the next planned dose. The planned treatment interval should then be maintained between doses.
  • Compatible with sodium chloride 0.9%. Do not mix with other IV solutions.

Chlorambucil:

  • Administer chlorambucil orally, preferably on an empty stomach at least 1 hour before or 2 hours after a meal.
  • Keep refrigerated, but do not freeze.

Contraindications

  • Patients who are resistant to chlorambucil or who have developed hypersensitivity to chlorambucil, obinutuzumab or any of its components; there may be cross-sensitivity between chlorambucil and other alkylating agents (especially rash).  
  • Chlorambucil should not be used within 4 weeks of a full course of radiation therapy or chemotherapy.

Precautions

  • Do not give to patients who have an active infection.
  • Administer chlorambucil with caution if bone marrow is severely depressed and in patients with seizure disorders.
  • Avoid live vaccines during treatment and until B-cell recovery. Following vaccination, do not start treatment until protective antibody titres have been reached.
  • Use with extreme caution in patients who are positive for hepatitis.
  • Use with caution in patients with recurrent or chronic infections.
  • Patients with a history of cardiovascular or respiratory disease should be monitored closely during and after obinutuzumab infusions. Use caution when hydrating patients with history of cardiovascular disease, to prevent fluid overload.
  • Patients at acute risk of hypertensive crisis should be assessed for the risk vs benefit of withholding anti-hypertensives.

Pregnancy & lactation

  • Obinutuzumab and Chlorambucil are not recommended for use in pregnancy. Adequate contraception should be used by both sexes during treatment, and for at least 18 months after the last dose of obinutuzumab. In case of exposure to obinutuzumab during pregnancy, newborns should be monitored for B-cell depletion and live vaccines postponed until B cell recovery. 
  • Breastfeeding is not recommended until at least 18 months after the last dose.
 
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

  • Cardiac tests for all patients with cardiac risk factors; baseline and as clinically indicated.
  • CBC; baseline, before each dose and as clinically indicated following treatment completion
  • Liver and renal function tests, electrolytes; baseline and before each cycle.
  • Infusion-related reactions; during and after the infusion
  • Clinical toxicity assessment for infection, bleeding, tumour lysis syndrome, thromboembolism, GI, neurologic, cardiac and respiratory effects; at each visit
  • Hepatitis B screening prior to treatment for all patients. Monitor for signs and symptoms of hepatitis B during treatment. Seropositive patients should see hepatologist and be closely monitored for several months after the last infusion.
  • 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 (chlorambucil)


Approximate Patient Visit
CLL: 5 hours; FL: 3 hours
Pharmacy Workload (average time per visit)
18.249 minutes
Nursing Workload (average time per visit)
74.833 minutes
 
K - References

Chlorambucil and obinutuzumab drug monographs, Cancer Care Ontario.

Goede V, Fischer K, Busch R, et al. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med. 2014 Mar 20;370(12):1101-10.

November 2018 Updated supportive measures, dose modifications, adverse effects, drug administration, precautions, monitoring sections


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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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