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A - Regimen Name

ALEM+RITU Regimen
Alemtuzumab-Rituximab


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 relapsed or refractory chronic lymphocytic leukemia (CLL)

 
B - Drug Regimen

Week 1:

alemtuzumab

a, b, c

3 mg IV / SC (first dose)
alemtuzumab

a, b, c

10 mg IV / SC (second dose)
alemtuzumab

a, b, c

30 mg IV / SC (third dose)
(This drug is not publicly funded. Universal compassionate access program is available. )

Weeks 2 to 13:

alemtuzumab

a, b, c

30 mg IV / SC 3 times per week
(This drug is not publicly funded. Universal compassionate access program is available. )


Can start either concurrently with alemtuzumab (on week one) or after alemtuzumab has already begun:

riTUXimab

 d

375 mg /m² IV Once weekly for 4 weeks
(This drug is not currently publicly funded for this regimen and intent)

a. Although not approved by Health Canada, alemtuzumab has been given subcutaneously instead of intravenously; the incidence of infusion reactions may be lower.

b. Gradual dose escalation is required at the initiation of therapy and after treatment interruptions of 7 days or more. In most patients, escalation to 30mg can be accomplished in 3-7 days.   Initial doses can be administered in various ways; sequentially (daily on days 1 to 3) and on alternate days (i.e. days 1, 3, and 5).  Both schedules were used in clinical trials.

c. Single doses of alemtuzumab greater than 30 mg or cumulative weekly doses of greater than 90 mg should not be administered since higher doses are associated with an increased incidence of pancytopenia.

d. The rituximab dose may be split over 2 days for patients with elevated absolute lymphocyte counts.

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C - Cycle Frequency

Alemtuzumab: For a usual total of 13 weeks (1 week dose escalation, 12 weeks maintenance) unless disease progression or unacceptable toxicity occurs.

Rituximab: For a usual total of 4 weeks unless disease progression or unacceptable toxicity occurs. 

 
D - Premedication and Supportive Measures

Antiemetic Regimen:

Minimal (infusion-related event)

Other Supportive Care:

• Diphenhydramine 50mg PO and acetaminophen 650mg PO 30 minutes before infusion; add meperidine 25mg IV and hydrocortisone 200mg IV with ≥ grade 3 reaction with prior infusion

• Trimethoprim/sulfamethoxazole DS twice daily three times per week and famciclovir (or equivalent) 250mg bid during treatment and for 2 months after or until CD4+ count ≥ 200 cell/uL

• Allopurinol and hydration to reduce the risk of tumour lysis syndrome are recommended.

• Consider prophylaxis with G-CSF for patients at risk of febrile neutropenia

Rituximab premedication:

• acetaminophen 650mg po

• diphenhydramine 50mg po

• If high volume disease, consider steroids and prophylaxis for tumour lysis

 
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

Alemtuzumab:
Toxicity (grade or 109)
1st Occurrence*
2nd Occurrence*
3rd Occurrence
ANC < 0.25 and/or
platelet ≤ 25
Hold, restart at same dose when ANC ≥ 0.5 and platelets  ≥ 50
Hold, restart at 10mg when ANC ≥ 0.5 and platelets ≥ 50
Discontinue
If baseline ANC ≤ 0.25, and/or platelet ≤ 25 and ↓ 50%
Hold, restart at same dose when ≥ baseline
Hold, restart at 10mg when ≥ baseline
Discontinue
≥ Grade 3 non-hematologic toxicity, including serious infections and CMV viremia
Hold until ≤ grade 2. Consider dose modification 
 
 
≥ Grade 3 infusion reaction
Hold.  Add meperidine and hydrocortisone as pre-medications.
 
 
Autoimmune disorders
Discontinue
 
 
PML, autoimmune anemia or thrombocytopenia
Discontinue
 
 
*If delay between dosing is ≥ 7 days, must re-escalate starting from 3mg
Do not modify dose for lymphopenia

Rituximab:

Toxicity
Rituximab Dose** / Infusion Rate
Myelosuppression 
No adjustment required.
Grade 1-2 Infusion-related
  • Stop or slow infusion; exclude respiratory symptoms; treat symptomatically.
  • Restart at 50% previous rate after resolution of symptoms.
≥ Grade 3 Infusion-related or pulmonary
  • Discontinue
  • Manage appropriately; monitor patient until complete resolution.
Other grade 3 toxicity
Delay infusion until ≤ grade 2
  • Other grade 4  toxicity
  • Severe mucocutaneous toxicity
  • Serious/life-threatening cardio-pulmonary events
  • Reactivation of tuberculosis or hepatitis B
  • PML / PRES/ RPLS
Discontinue

**Missed or delayed doses may be administered at a later time point, based on physician’s discretion.



Hepatic Impairment

No dosage adjustment required for rituximab. Discontinue if evidence of hepatitis. No information available for alemtuzumab.  


Renal Impairment

 No dosage adjustment required for rituximab. No information available for alemtuzumab. 


Dosage in the Elderly

No dosage adjustment required. Limited experience with alemtuzumab. For rituximab, older patients are more likely to experience serious adverse events (including cardiac, pulmonary, or other grade 3 or 4 toxicity).


 
F - Adverse Effects

Refer to alemtuzumab, riTUXimab drug monograph(s) for additional details of adverse effects

 

 


Very common (≥ 50%)

Less common (10-24%)

Uncommon (< 10%),

but may be severe or life-threatening

  • Hypersensitivity (may be severe)
  • Myelosuppression +/- infection (including atypical infections, viral reactivation), bleeding (may be severe)
  • Grade 1 or 2 local skin reaction (SC alemtuzumab)
  • Fatigue
  • Hypotension
  • Nausea, vomiting
  • Headache
  • Rash (may be severe)
  • Flu-like symptoms

 

  • Arrhythmia
  • Cardiotoxicity
  • Tumor lysis syndrome
  • Venous thromboembolism
  • Arterial thromboembolism
  • GI obstruction, perforation
  • Disseminated intravascular coagulation (DIC)
  • Vasculitis
  • Cholecystitis
  • Nephrotoxicity
  • Pancreatitis
  • Pneumonitis
  • Secondary malignancy
  • Autoimmune disorders
  • Transfusion associated GVHD
  • Posterior reversible encephalopathy syndrome (PRES)
  • Leukoencephalopathy (PML)
 
G - Interactions

Refer to alemtuzumab, riTUXimab drug monograph(s) for additional details


  • Additive effects with medications that can increase risk of bleeding
  • Additive effects with medications that can cause hypotension (especially at time of infusion)
 
H - Drug Administration and Special Precautions

Refer to alemtuzumab, riTUXimab drug monograph(s) for additional details


Administration

Alemtuzumab:

  • See the Product Monograph for full details of preparation and administration.
  • Full resuscitation facilities and experienced personnel should be available.
  • Do not administer as an intravenous push or bolus. Although not approved by Health Canada, alemtuzumab has been given subcutaneously in phase II studies
  • Mix in 100mL IV bag (5% Dextrose or Normal Saline). Gently invert the bag to mix the solution. Infuse the admixture over 2 hours.
  • Other drug substances should not be added or simultaneously infused through the same intravenous line

Rituximab:

  • Rituximab infusions should be administered in a setting where full resuscitation facilities are immediately available, and under the close supervision of someone experienced and capable of dealing with severe infusion-related reactions.
  • DO NOT administer as an IV push or bolus.
  • Dilute to a final concentration of 1-4 mg/mL in normal saline or D5W.
  • To avoid foaming, gently invert the bag to mix the solution.
  • Do not admix with other drugs.
  • Administer rituximab through a dedicated line.
  • Compatible with PVC or polyethylene bags.
  • Keep vials refrigerated; do not freeze.  Protect from light.
  •   Infusion rates:
  • Consider a slower infusion rate or split dosing over days 1-2 for any cycle where bulky disease present or WBC > 25 x 109/L.
  • First infusion: initial rate of 50 mg/h, then escalate rate in 50 mg/h increments every 30 minutes, to a maximum of 400 mg/h.
  • Subsequent infusions:
  • Initial rate of 100 mg/h, then escalate rate in 100 mg/h increments every 30 minutes, to a maximum of 400 mg/h as tolerated.
  • Published data suggest that a 90 minute infusion (20% of the dose in the first 30 min then the remaining 80% over 60 min) can be used for second and subsequent infusions if no reaction occurred with the first infusion.

Contraindications

  • Patients with known hypersensitivity and anaphylactic reactions to ritxuimab, proteins of similar mouse or human origin, to Chinese Hamster Ovary (CHO) cell proteins or to alemtuzumab or any components of MabCampath
  • Patients who have or have had PML, have active and/or severe infections, active hepatitis B, or severely immunocompromised (e.g. AIDS patients with very low CD4 or CD8 counts), or active secondary malignancies
  • Avoid the use of live vaccines.

Other warnings/precautions:

  • Gradual dose escalation of alemtuzumab to the recommended maintenance dose is required at the initiation of therapy and after interruption of therapy for more than 7 days. Alemtuzumab can result in serious and even fatal infusion reactions.
  • Single doses of alemtuzumab greater than 30mg or cumulative doses of more than 90mg per week should not be administered, as they are associated with a higher incidence of pancytopenia.
  • Exercise caution in patients with a history of recurring or chronic infections or with underlying conditions which may further predispose patients to serious infection.
  • Anti-viral and anti-Pneumocystis carinii pneumonia prophylaxis are strongly recommended.
  • Prior to starting rituximab in HBV seropositive patients, consultation with a liver disease expert is recommended to determine ongoing monitoring of HBV reactivation and its management.
  • Exercise caution in patients with neutrophil counts < 1.5 x 109/L and/or platelets < 75 x 109/L due to limited experience in this patient group.
  • Use with extreme caution in patients with pre-existing cardiovascular disease or in patients with high tumour burden.
  • Consider steroids ± slow infusions or infusions split over 2 days for patients with bulky disease or > 25 x 109/L circulating malignant cells.
  • Use with caution in patients with pulmonary insufficiency or lung tumour infiltration
  • alemtuzumab should be given to pregnant women only if the benefits outweigh the risks to the mother and fetus; rituximab should not be used during pregancy. Women of childbearing potential and men of reproductive potential should use effective contraceptive methods during treatment and for a minimum of six months following alemtuzumab therapy.
  • IgG is secreted in human milk; therefore, breastfeeding should be discontinued for at least three months after cessation of therapy.

 

 
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; baseline and before each treatment
  • Liver and renal function tests; baseline and before each treatment
  • CD4+ counts should be assessed after treatment until recovery to ≥ 200 cells/μL
  • Hepatitis B screening prior to treatment; seropositive patients should see hepatologist and be closely monitored for up to 12 months after the last ritxuimab infusion
  • Clinical assessment of hypersensitivity reactions, tumour lysis syndrome, hypotension, infection, bleeding, GI, pulmonary, skin, CNS, cardiovascular side effects; at each visit
  • Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version

Suggested Clinical Monitoring

  • Monitor closely for cardiovascular symptoms for patients who have cardiac conditions
  • Consider CMV monitoring

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J - Administrative Information

Approximate Patient Visit
RITU: 3 to 5 hours; ALEM (IV): 2.5 to 3 hours; ALEM (SC): 0.5 to 1 hour
Pharmacy Workload (average time per visit)
11.482 minutes
Nursing Workload (average time per visit)
40.019 minutes
 
K - References

Alemtuzumab, rituximab drug monographs, Cancer Care Ontario.

Brown JR, Messmer B, Werner L, et al. A phase I study of escalated dose subcutaneous alemtuzumab given weekly with rituximab in relapsed chronic lymphocytic leukemia/small lymphocytic lymphoma.  Hematologica. 2013; 98(6): 964-970.

Faderl S, Ferrajoli A, Wierda W, et al. Alemtuzumab by continuous intravenous infusion followed by subcutaneous injection plus rituximab in the treatment of patients with chronic lymphocytic leukemia recurrence. Cancer. 2010 May 15;116(10):2360-5.

Faderl S, Thomas DA, O’Brien S, et al. Experience with alemtuzumab plus rituximab in patients with relapsed and refractory lymphoid malignancies. Blood. 2003;101:3413-3415.

Lundin J, Kimby E, Bjorkholm M, et al. Phase II trial of subcutaneous anti-CD52 monoclonal antibody alemtuzumab (Campath-1H) as first-line treatment for patients with B-cell chronic lymphocytic leukemia (B-CLL). Blood 2002;100(3):768-773.

Zent CS, Call TG, Shanafelt TD, et al. Early treatment of high-risk chronic lymphocytic leukemia with alemtuzumab and rituximab. Cancer. 2008 Oct
15;113(8):2110-8.


PEBC Advice Documents or Guidelines

December 2017 Noted alemtuzumab as compassionate supply, rituximab as unfunded


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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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