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CHOP+R

Cancer Type: Hematologic, Lymphoma - Non-Hodgkin's High Grade, Lymphoma - Non-Hodgkin's Intermediate Grade  Intent: Curative, Palliative
Regimen Category: Evidence-Informed
Funding:
ODB - General Benefit
    prednisone
New Drug Funding Program
    Rituximab (SC) - Aggressive Histology Lymphoma
New Drug Funding Program
    Rituximab (SC) - HIV-Related - Aggressive Histology - B-cell Lymphoma
New Drug Funding Program
    Rituximab - Aggressive Histology Lymphoma
New Drug Funding Program
    Rituximab - HIV-Related, Aggressive Histology, B-cell Lymphoma
A - Regimen Name

CHOP+R Regimen
Cyclophosphamide-Hydroxyldaunorubicin (DOXOrubicin)-ONCOVIN® (VinCRIStine)-Prednisone-riTUXimab


Disease Site
Hematologic - Lymphoma - Non-Hodgkin's High Grade
Hematologic - Lymphoma - Non-Hodgkin's Intermediate Grade

Intent
Curative
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

Therapy for previously untreated patients with agressive histology CD20-positive B-cell lymphomas (Diffuse Large B-Cell Lymphoma (DLBCL) or a variant of DLBCL such as mediastinal sclerosing B-cell lymphoma, T-cell–rich B-cell lymphoma, Burkitt-like lymphoma, or intravascular lymphoma), including  previously untreated HIV-associated lymphomas (provided CD4 count ≥ 50 mm3), who are candidates for curative treatment and have not previously received rituximab.

There is insufficient evidence for maintenance rituximab in aggressive histology B-cell lymphomas.


Supplementary Public Funding

prednisone
ODB - General Benefit (prednisone) (

ODB Formulary

)

riTUXimab (subcut)
New Drug Funding Program (Rituximab (SC) - Aggressive Histology Lymphoma)

riTUXimab (subcut)
New Drug Funding Program (Rituximab (SC) - HIV-Related - Aggressive Histology - B-cell Lymphoma)

riTUXimab
New Drug Funding Program (Rituximab - Aggressive Histology Lymphoma)

riTUXimab
New Drug Funding Program (Rituximab - HIV-Related, Aggressive Histology, B-cell Lymphoma)

 
B - Drug Regimen

Cycle 1:  All patients must receive their first dose of rituximab by IV infusion.

prednisone
100 mg PO daily Days 1 to 5*

*(On Day 1 to be given as part of premedication before riTUXimab)
 

riTUXimab
375 mg /m² IV Day 1
vinCRIStine
1.4 mg /m² IV (max 2 mg) Day 1
DOXOrubicin
50 mg /m² IV Day 1
cyclophosphamide
750 mg /m² IV Day 1

 

Cycle 2 and onwards (For a usual total of 6-8 cycles including initial IV rituximab cycle(s) )

Rituximab IV:

riTUXimab
375 mg /m² IV Day 1

 

OR

Rituximab (subcut): 
The subcutaneous formulation must only be given at the second or subsequent cycles, if the patient has previously received at least one full rituximab IV dose.

riTUXimab (subcut)
1400 mg Subcut Day 1


Plus CHOP chemotherapy

prednisone
100 mg PO daily Days 1 to 5*

*(On Day 1 to be given as part of premedication before riTUXimab) 

vinCRIStine
1.4 mg /m² IV (max 2 mg) Day 1
DOXOrubicin
50 mg /m² IV Day 1
cyclophosphamide
750 mg /m² IV Day 1
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C - Cycle Frequency

REPEAT EVERY 21 DAYS

For a usual total of 6 to 8 cycles unless disease progression or unacceptable toxicity occurs.

 
D - Premedication and Supportive Measures

Antiemetic Regimen:

Moderate


Febrile Neutropenia Risk:

Moderate

Other Supportive Care:

Also refer to CCO Antiemetic Summary

Rituximab premedication:

  • Acetaminophen 650mg PO
  • Diphenhydramine 50mg PO/IV
  • Give day 1 prednisone as part of pre-medication before rituximab
  • If high volume disease, consider steroids and prophylaxis for tumour lysis

HBsAg positive patients should receive antiviral prophylaxis during and after rituximab. HBsAg negative, but HBcAb positive patients should be considered for antiviral prophylaxis and be closely monitored for viral reactivation by a HBV expert.


 

 
E - Dose Modifications

Screen patients for hepatitis B prior to starting treatment. See premedication and monitoring sections for supportive care, screening and monitoring recommendations. Doses should be modified according to the protocol by which the patient is being treated. 

Dosage with toxicity

Hematologic and Non-Hematologic Toxicities:  

 
Toxicity

Doxorubicin1 (% previous dose)

Vincristine1 (% previous dose)

Cyclophosphamide1 (% previous dose)

Rituximab IV or Subcut1,2 (% previous dose)

Grade 4 hematological, febrile neutropenia, bleeding

75%, or G-CSF for low ANC

100%

75%, or G-CSF for low ANC

100%
Grade 3 non-hematological toxicity
75%
100%
75%

100% or delay

Neurotoxicity

 

100%

Mild: 67%;
Moderate:  Hold until  recovery, then ↓ 50%;
SevereDiscontinue

100%
100%
Cystitis 100% 100% Hold until resolution 100%
Grade 4 organ toxicity Discontinue Discontinue Discontinue Discontinue
  • Severe rash
  • Serious/life-threatening cardio- pulmonary events
  • PML/RPLS; Reactivation of TB or hepatitis B
  • Evidence of active hepatitis
Discontinue
Discontinue
Discontinue
Discontinue
1Prior to retreatment, major organ toxicity should have recovered to ≤ grade 2 and ANC to ≥ 1.5 x 109/L and platelets ≥ 100 x 109/L.
2Missed or delayed doses may be administered at a later time point, based on physician’s discretion
 

Rituximab Infusion or Administration-Related Reactions:

Toxicity Rituximab IV Rituximab Subcut
Grade 1-2 Hypersensitivity/ acute reactions  
or Subcut administration-related reactions (if applicable)
  • Stop or slow infusion; exclude respiratory symptoms; treat symptomatically.
  • Restart at 50% previous rate after resolution of symptoms.
  • Hold administration if intolerable. Exclude respiratory symptoms; treat symptomatically. 
  • Cold compresses and topical steroids may be helpful for local cutaneous  reactions.


 

Grade ≥3 Hypersensitivity/ acute reactions  
or Subcut administration-related reactions (if applicable)
  • Discontinue
  • Manage appropriately; monitor patient until complete resolution.
  • Hold administration if possible.  Discontinue if hypersensitivity, pulmonary-related or based on physician discretion.
  • Manage appropriately; monitor patient until complete resolution.
 



Hepatic Impairment

Consider dose modification for doxorubicin and vincristine for severe increase in transaminases.
 
Bilirubin

Doxorubicin (% previous dose)

Vincristine
(% previous dose)

Cyclophosphamide
(% previous dose)

Rituximab

1 – 2 X ULN

50%
50%
100%
No adjustment required; discontinue if hepatitis
 

2 – 4 x ULN

25%
25%
Caution

> 4 ULN

OMIT
OMIT
Caution

 


Renal Impairment

Creatinine Clearance (mL/min)

Doxorubicin
(% previous dose)

Vincristine
(% previous dose)
Cyclophosphamide
(% previous dose)
Rituximab

>50

No dose adjustment required

No dose adjustment required

100%

No dose adjustment required

10-50

75%

< 10

Use with extreme caution or discontinue


Dosage in the Elderly

No dose adjustment required. Exercise caution as older patients are more likely to experience serious adverse events, including cardiac, pulmonary, neurotoxicity or other grade 3/4 toxicity. 

 


 
F - Adverse Effects

Refer to riTUXimab, riTUXimab (subcut), vinCRIStine, DOXOrubicin, cyclophosphamide 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 and hypersensitivity  reactions (may be severe; with IV rituximab)
  • Alopecia
  • Myelosuppression +/- infection (including atypical, viral reactivation), bleeding (may be severe)
  • Nausea, vomiting
  • Peripheral neuropathy (may be severe)
  • Administration-related reactions, including cutaneous (with rituximab subcut)
  • Mucositis
  • Fatigue
  • Headache, flu-like symptoms
  • Rash (may be severe)
  • Diarrhea
  • Constipation
  • Steroid effects (weight gain, GI irritation, hyperglycemia, insomnia, mood changes, myopathy, cataracts)
  • Arterial / venous thromboembolism
  • Arrhythmia, prolonged QTc
  • Cardiotoxicity
  • GI obstruction / perforation
  • Hepatotoxicity
  • Veno-occlusive disease
  • Pancreatitis
  • Pneumonitis
  • Nephrotoxicity
  • Cystitis
  • Bladder fibrosis
  • Tumour lysis syndrome
  • SIADH
  • Optic and cranial nerve disorder
  • Autonomic neuropathy
  • PML, PRES/ RPLS
  • Hemolysis
  • Vasculitis
  • Hyperviscosity
  • Secondary malignancies
  • Radiation recall reaction
  • Photosensitivity
  • Infertility
 
G - Interactions

Refer to riTUXimab, riTUXimab (subcut), vinCRIStine, DOXOrubicin, cyclophosphamide drug monograph(s) for additional details


  • Consider withholding antihypertensive medication 12 hours prior to and during rituximab administration. 

  • Avoid using stavudine or zidovudine with doxorubicin

  • Avoid use of calcium channel blockers with doxorubicin due to cardiotoxicity

  • Monitor serum digoxin levels when used with doxorubicin

  • Caution with use of CYP3A4 inhibitors and cyclophosphamide; avoid grapefruit for 48 hours before and on day of cyclophosphamide

  • Avoid combination of vincristine and verapamil or nifedipine; monitor closely if given concurrently

  • Monitor serum phenytoin levels when used with vincristine, and adjust phenytoin dose prn

 
H - Drug Administration and Special Precautions

Refer to riTUXimab, riTUXimab (subcut), vinCRIStine, DOXOrubicin, cyclophosphamide drug monograph(s) for additional details


Administration

Rituximab IV and subcutaneous formulations are not interchangeable. The dosing and concentrations of these products are different.
Rituximab 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.

 

Rituximab (IV)

  • 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.

  •   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 (about 4.25 hours in total).

  • 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 (about 3.25 hours in total).

  • 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.

 

Rituximab (Subcut):

Refer to Safety Considerations for the Implementation of Subcutaneous Rituximab Formulation

  • Rituximab SC must not be self-administered.

  • Rituximab SC is given subcutaneously into the abdominal wall only. Do not give in areas where the skin is red, tender, hard, bruised, or where there are moles or scars.

  • Non-Hodgkin’s lymphoma: Give SC over approximately 5 minutes

  • Observe for at least 15 minutes after administration.

  • If there are other SC medications, they should be given at separate sites.

  • Compatible with polypropylene or polycarbonate syringes.

 

VinCRIStine:

FOR INTRAVENOUS USE ONLY.  Vincristine is lethal if given intrathecally. No successful antidotes have been described.  Syringes containing this product should be labelled “WARNING – FOR INTRAVENOUS USE ONLY.  FATAL if given by other routes.” 

  • Direct IV push not recommended, due to risk of inadvertent intrathecal administration.

  • For intermittent IV use, may mix in small volume minibag (ie. 50mL NS or D5W for adults).

  • Infuse IV via gravity. Infusion pumps should not be used peripherally, since they deliver infusions at higher pressures and may continue to infuse when extravasation occurs.

  • During the infusion, suggest nurse to remain present with the patient to observe the IV site for extravasation.

 

DOXOrubicin:

  • Slow push through sidearm of free flowing IV (5% Dextrose or Normal Saline). Depending on the dose volume and vein condition, administer the dose between 3 to 10 minutes to minimize thrombosis risk or perivenous extravasation.

  • Doses <100mg may be mixed in a minibag (Normal Saline, 5% dextrose); infuse through sidearm of free flowing IV (dilution volume and infusion duration depend on institution protocol).

  • Do not admix with other drugs unless data are available; precipitates with fluorouracil and heparin.

  • Avoid contact with alkaline solutions as this can lead to hydrolysis of doxorubicin

  • Slow down injection rate if erythematous streaking or facial flushing occurs.

  • If any signs or symptoms of extravasation occur, the injection or infusion should be immediately terminated and restarted in another vein. Any known or suspected extravasation should be managed promptly.

 

Cyclophosphamide:

  • Oral hydration is strongly encouraged; for IV cyclophosphamide: 2-3 L of fluid/day; poorly hydrated patients may need more IV hydration.

  • Inadequate total hydration may result in dose-related hemorrhagic cystitis.  Patients should be encouraged to empty their bladder frequently to minimize dwell times.

  • Infuse in 250 mL sodium chloride 0.9% over 30 minutes.

  • Use sodium chloride 0.9% to reconstitute cyclophosphamide

  • Do not reconstitute or dilute with benzyl alcohol-containing solutions (ie. Bacteriostatic sodium chloride), since it may catalyse the decomposition of cyclophosphamide

  • Avoid the use of aluminum-containing preparation and administration equipment, since darkening of aluminum and gas production have been reported.


Contraindications

  • Patients who have a hypersensitivity to any of the drug(s) or any of its components, other anthracyclines or anthracenediones (i.e. epirubicin, daunorubicin, mitoxantrone or mitomycin C), or known hypersensitivity and anaphylactic reactions to proteins of similar mouse or human origin, to Chinese Hamster Ovary (CHO) cell proteins

  • 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).

  • Avoid the use of live vaccines.

  • Vincristine intrathecal administration is absolutely contraindicated.

  • (vincristine) patients with the demyelinating form of Charcot-Marie-Tooth Syndrome, childhood polio or with hypersensitivity to vinca alkaloids.

  • (doxorubicin) Patients with severe myocardial insufficiency, arrhythmias or history of cardiac disease or recent myocardial infarction

  • (doxorubicin) Patients with previous treatment with maximum cumulative doses of doxorubicin, other anthracyclines or anthracenediones

  • (cyclophosphamide) patients with urinary outflow obstruction

 

Warning/Precautions

  • Exercise caution in patients with a history of recurring or chronic infections or with underlying conditions which may further predispose patients to serious infection. Patients may have increased risk of infection following rituximab treatment.

  • 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 of rituximab in this patient group.

  • Use rituximab with extreme caution in patients with pre-existing cardiovascular disease or in patients with high tumour burden. Consider steroids ± rituximab 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, and in patients with myelosuppression.

  • Reduced immunogenicity may occur with use of inactivated vaccines.

  • Use vincristine with caution with other neuromuscular disorders, neurotoxic/ototoxic drugs, in leukopenia, complicating infection, or and in patients with Guillain-Barre Syndrome.

  • Vincristine should not be given to patients who are receiving radiation that includes liver portals.

  • Use cyclophosphamide with caution in patients with adrenal insufficiency or when used in combination with neuromuscular blockers


Pregnancy/Lactation 

  • IgGs are known to pass the placental barrier. There have been reports of infants with transient B-cell depletion and lymphocytopenia.  CHOP+R should not be used during pregnancy. Adequate contraception is recommended for both sexes with childbearing potential, during treatment and up to 12 months after the last dose.

  • Breastfeeding is not recommended during treatment and until rituximab drug levels are no longer detectable.

  • Fertility may be affected.

 
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 cycle

  • Liver function tests; baseline and before each cycle

  • Renal functions tests; baseline and before each cycle

  • The Hematology Disease Site group recommends screening patients for hepatitis B surface antigen (HBsAg) and core antibody (HBcAb) prior to starting treatment. If seropositive, consult with an expert in HBV and monitor closely.

  • Baseline and regular cardiac examination for patients with cardiac risk factors (including prior therapy with epirubicin, mitoxantrone, or other cardiotoxic drug) and cumulative doxorubicin doses > 450mg/m2.

  • Monitor patients during and for at least 15 minutes after each rituximab dose, longer in patients at higher risk of hypersensitivity reactions

  • Clinical assessment of hypersensitivity/infusion reactions, tumour lysis syndrome, infection, bleeding, GI, pulmonary, skin, CNS, cardiovascular effects, neurotoxicity and cystitis; 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 or recurrent cardiac events with rituximab

 


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J - Administrative Information

Approximate Patient Visit
First cycle: 6 hours; subsequent cycles: 2 to 5 hours
Pharmacy Workload (average time per visit)
46.499 minutes
Nursing Workload (average time per visit)
89.833 minutes
 
K - References

Coiffier B, Lepage E, Briere J, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 2002;346:235-42.

Feugier P, Van Hoof A, Sebban C, et al. Long-term results of the R-CHOP study in the treatment of elderly patients with diffuse large B-cell lymphoma: a study by the Groupe d’Etudes des Lymphomes de l’Adulte. J Clin Oncol 2005;23(18):4117-26.

Habermann TM, Weller EA, Morrison VA, et al. Rituximab-CHOP versus CHOP alone or with maintenance rituximab in older patients with diffuse large B-cell lymphoma. J Clin Oncol 2006;24(19):3121-7.

Rituximab drug monograph, Cancer Care Ontario.

Salar A, Casao D, Cervera M, et al. Rapid infusion of rituximab with or without steroid-containing chemotherapy: 1-yr experience in a single institution. Eur J Haematol 2006: 77: 338–40.

Sehn LH, Donaldson J, Filewich A, et al. Rapid infusion rituximab in combination with corticosteroid-containing chemotherapy or as maintenance therapy is well tolerated and can safely be delivered in the community setting. Blood 2007;109(10):4171-3.

Lugtenburg P, Avivi I, Berenschot H et al. Efficacy and safety of subcutaneous and intravenous rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone in first-line diffuse large B-cell lymphoma: the randomized MabEase study. Haematologica. 2017;102(11):1913-1922.

Rummel M, Kim TM, Aversa F et al. Preference for subcutaneous or intravenous administration of rituximab among patients with untreated CD20+ diffuse large B-cell lymphoma or follicular lymphoma: results from a prospective, randomized, open-label, crossover study (PrefMab). Ann Oncol 2017;28(4):836-842.


PEBC Advice Documents or Guidelines

February 2019 Expanded regimen abstract to full regimen monograph; edited rationale section


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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.
CCO and the Formulary’s content providers shall have no liability, whether direct, indirect, consequential, contingent, special, or incidental, related to or arising from the information in the Formulary or its use thereof, whether based on breach of contract or tort (including negligence), and even if advised of the possibility thereof. Anyone using the information in the Formulary does so at his or her own risk, and by using such information, agrees to indemnify CCO and its content providers from any and all liability, loss, damages, costs and expenses (including legal fees and expenses) arising from such person’s use of the information in the Formulary.