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Fludarabine, cyclophosphamide, and rituximab (FCR) for chronic lymphocytic leukemia[1]

Fludarabine, cyclophosphamide, and rituximab (FCR) for chronic lymphocytic leukemia[1]
Cycle length: 28 days.
Drug Dose and route Administration Given on days
Cycle 1
Rituximab* 375 mg/m2 IV Dilute in 0.9% NS or D5W to a final concentration of 1 to 4 mg/mL. Start at 50 mg/hour; escalate in 50 mg/hour increments every 30 minutes to a maximum of 400 mg/hour, as tolerated. Day 1
Fludarabine 25 mg/m2 IV Dilute in 100 mL NS or D5W and administer over 30 minutes. Days 2 to 4
Cyclophosphamide 250 mg/m2 IV Dilute in 250 mL NS or D5W and administer over 30 to 60 minutes.Δ Days 2 to 4
Cycles 2 to 6
Rituximab* 375 to 500 mg/m2 IV Dilute in 0.9% NS or D5W to a final concentration of 1 to 4 mg/mL. Start at 100 mg/hour and escalate in 100 mg/hour increments every 30 minutes to a maximum of 400 mg/hour, as tolerated.◊ Day 1
Fludarabine 25 mg/m2 IV Dilute in 100 mL NS or D5W and administer over 30 minutes. Days 1 to 3
Cyclophosphamide 250 mg/m2 IV Dilute in 250 mL NS or D5W and administer over 30 to 60 minutes.Δ Days 1 to 3
Pretreatment considerations:
Hydration
  • Patients receiving cyclophosphamide should maintain adequate oral hydration (2 to 3 L/day) and void frequently to reduce risk of hemorrhagic cystitis.[2]
  • Refer to UpToDate topic on "Hemorrhagic cystitis in cancer patients".
Emesis risk
  • MODERATE (30 to 90% frequency of emesis). Prophylaxis is indicated on the days that cyclophosphamide is given.
  • Refer to UpToDate topic on "Prevention and treatment of chemotherapy-induced nausea and vomiting in adults".
Prophylaxis for infusion reactions
  • Premedicate with acetaminophen and diphenhydramine, with or without an H2 blocker, 30 minutes prior to at least the first and second infusions of rituximab.[3]
  • Refer to UpToDate topic on "Infusion-related reactions to therapeutic monoclonal antibodies used for cancer therapy".
Vesicant/irritant properties
  • Cyclophosphamide is classified as an irritant, and not a true vesicant.
  • Refer to UpToDate topic on "Extravasation injury from chemotherapy and other non-antineoplastic vesicants".
Prophylaxis for tumor lysis syndrome
  • Due to the significant risk of tumor lysis syndrome during the first cycle, all patients should be well hydrated prior to and during therapy and receive allopurinol 300 mg orally once daily beginning the day prior to the first dose of rituximab and continuing for 14 days.[4]
  • Refer to UpToDate topic on "Tumor lysis syndrome: Prevention and treatment".
Infection prophylaxis
  • The rate of severe (grade 3/4) infection was 25%.[1] As such, we suggest prophylactic hematopoietic growth factors. In addition, due to the risk of developing Pneumocystis jirovecii pneumonia and other opportunistic infections, consider the use of antimicrobial, antifungal, and antiviral prophylaxis.
  • Refer to UpToDate topics on "Overview of infectious complications following purine analog therapy" and "Use of granulocyte colony stimulating factors in adult patients with chemotherapy-induced neutropenia and conditions other than acute leukemia, myelodysplastic syndrome, and hematopoietic cell transplantation".
Dose adjustment for baseline liver or renal dysfunction
  • Adjustment of initial cyclophosphamide and fludarabine may be required for renal dysfunction.[2,5-7] In addition, dose adjustments of cyclophosphamide may be needed for liver dysfunction.
  • Refer to UpToDate topics on "Chemotherapy nephrotoxicity and dose modification in patients with renal insufficiency: Conventional cytotoxic agents" and "Chemotherapy hepatotoxicity and dose modification in patients with liver disease: Conventional cytotoxic agents" and "Chemotherapy hepatotoxicity and dose modification in patients with liver disease: Molecularly targeted agents".
Hepatitis screening
  • Patients should be screened for hepatitis B and C virus infection prior to starting rituximab, and if positive, considered for prophylaxis.
  • Refer to UpToDate topics on "Chemotherapy hepatotoxicity and dose modification in patients with liver disease: Conventional cytotoxic agents" and "Chemotherapy hepatotoxicity and dose modification in patients with liver disease: Molecularly targeted agents" and "Hepatitis B virus reactivation associated with immunosuppressive therapy".
Monitoring parameters:
  • CBC with differential and platelet count weekly during treatment and as clinically indicated.
  • Assess renal and hepatic function prior to each cycle and as clinically indicated.
  • Assess serum creatinine, potassium, phosphate, calcium, uric acid, and LDH daily during treatment for patients at risk for tumor lysis syndrome.
  • Carriers of hepatitis B or C should be monitored for clinical and laboratory signs of active infection during and following completion of therapy. Rituximab should be discontinued if reactivation occurs.
  • Refer to UpToDate topic on "Chemotherapy hepatotoxicity and dose modification in patients with liver disease: Conventional cytotoxic agents" and "Chemotherapy hepatotoxicity and dose modification in patients with liver disease: Molecularly targeted agents".
Suggested dose modifications for toxicity:
Myelosuppression
  • Treatment should be delayed until ANC >1000/microL and platelet count is >80,000/microL. If blood counts do not recover to ANC >1000/microL or platelets >80,000/microL within five weeks from the last course of therapy, the daily dose of fludarabine should be reduced to 20 mg/m2 and the daily dose of cyclophosphamide should be reduced to 200 mg/m2 for subsequent cycles. During these subsequent cycles, if blood counts do not recover to ANC >1000/microL or platelets >80,000/microL within five weeks from the last course of therapy, the daily dose of fludarabine should be reduced to 15 mg/m2 and the daily dose of cyclophosphamide should be reduced to 150 mg/m2 for any remaining cycles.
If there is a change in body weight of at least 10%, doses should be recalculated.
This table is provided as an example of how to administer this regimen; there may be other acceptable methods. This regimen must be administered by a clinician trained in the use of chemotherapy, who should use independent medical judgment in the context of individual circumstances to make adjustments, as necessary.
IV: intravenous; NS: normal saline; D5W: 5% dextrose in water; CBC: complete blood count; LDH: lactate dehydrogenase; ANC: absolute neutrophil count.
* Although initial studies of the FCR regimen utilized higher doses (500 mg/m2) of rituximab in cycles 2 to 6, there have been no prospective studies that indicate that this increased dose is necessary. Some clinicians use the standard dose of rituximab (375 mg/m2) for all six cycles of FCR.
¶ Diluent solutions should not be modified without consulting a detailed reference due to potential incompatibility(ies).
Δ The volume and rate of administration varies between institutions.
◊ A subcutaneous formulation (rituximab-hyaluronidase) that uses a fixed dose and a shorter administration time is an acceptable alternative for patients who have tolerated at least one full dose of intravenous rituximab.[8] Dosing varies by histology and clinicians should refer to the US Prescribing Information for details.
References:
  1. Hallek M, et al. Lancet 2010; 376:1164.
  2. Cyclophosphamide injection. United States Prescribing Information. US National Library of Medicine. (Available online at: https://dailymed.nlm.nih.gov/dailymed/, accessed October 23, 2019).
  3. Rituximab injection. United States Prescribing Information. US National Library of Medicine. (Available online at https://dailymed.nlm.nih.gov/dailymed/, accessed October 23, 2019).
  4. Keating MJ, et al. J Clin Oncol 2005; 23:4079.
  5. Wierda W et al. J Clin Oncol 2005; 23:4070.
  6. Cooper K, Bennett WM. Nephrotoxicity of common drugs used in clinical practice. Arch Intern Med 1987; 147:1213.
  7. Fludarabine injection. United States Prescribing Information. US National Library of Medicine. (Available online at https://dailymed.nlm.nih.gov/dailymed/, accessed October 23, 2019).
  8. Rituximab and hyaluronidase human injection for subcutaneous use. United States Prescribing Information. US National Library of Medicine. (Available online at https://dailymed.nlm.nih.gov/dailymed/, accessed October 23, 2019).
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