Regimen: Rituximab with Hyperfractionated Cyclophosphamide + Vincristine + Doxorubicin + Dexamethasone (R-Hyper-CVAD) Alternating with Rituximab with Methotrexate + Cytarabine (R-MC)
Romaguera JE et al. J Clin Oncol 2005;23:7013–7023
Wang M et al. Cancer 2008;113:2734–2741
If indicated: Prophylaxis against tumor lysis syndrome during the first cycle:
Hydration with 2500–3000 mL/day, as tolerated; administer intravenously at 100–125 mL/hour
Notes:
Sodium bicarbonate is added to parenteral hydration solutions in the presence of plasma uric acid >9 mg/dL to maintain urine pH >7.0, but pH <8. The choice of hydration fluid and amount of sodium bicarbonate added to the fluid should NOT EXCEED the sodium concentration present in 0.9% sodium chloride injection (154 mEq/L); for example:
5% Dextrose/0.45% sodium chloride injection with sodium bicarbonate 50–75 mEq/1000 mL, or
5% Dextrose/0.2% sodium chloride injection with sodium bicarbonate 100–125 mEq/1000 mL, or
5% Dextrose injection with sodium bicarbonate 125–150 mEq/1000 mL
Potassium is NOT added to parenteral hydration solutions during the first few days of induction therapy unless serum potassium decreases to <3.0 mEq/dL
Furosemide 20–40 mg; administer intravenously every 12–24 hours to maintain fluid balance
Diuresis is maintained for at least the first 72 hours after starting chemotherapy in the absence of metabolic aberrations, or after metabolic complications normalize
Allopurinol 300 mg/day; administer orally for 7 consecutive days on days 1–7 (longer treatment may be needed)
Persons who express a variant human leukocyte antigen allele, HLA-B✫58:01, are at increased risk for severe cutaneous adverse reactions from allopurinol (Hershfield MS et al. Clin Pharmacol Ther 2013;93:153–158; Zineh I et al. Pharmacogenomics 2011;12:1741–1749)
R-Hyper-CVAD (odd-numbered cycles; ie, 1, 3, 5, ±7)
Premedication for rituximab:
Acetaminophen 650–1000 mg; administer orally, plus
Diphenhydramine 25–50 mg; administer orally or intravenously 30–60 minutes before starting rituximab
Rituximab 375 mg/m2 per dose; administer intravenously in 0.9% sodium chloride injection (0.9% NS) or 5% dextrose injection (D5W), diluted to a concentration within the range of 1–4 mg/mL on day 1, for 3–4 cycles, cycles 1, 3, 5 (±7). Cycle duration is 21 days (total dosage/cycle = 375 mg/m2)
Notes on rituximab administration:
Infuse initially at 50 mg/h. If hypersensitivity or infusion reactions do not occur during the first 30 minutes, increase the rate by 50 mg/h every 30 minutes, as tolerated, to a maximum rate of 400 mg/h. Subsequently, if previous administration was well tolerated, start at 100 mg/h and increase by 100 mg/h every 30 minutes, as tolerated, to a maximum rate of 400 mg/h
Interrupt rituximab administration for fever, chills, edema, congestion of the head and neck mucosa, hypertension, and other serious adverse events. Resume rituximab administration after adverse events abate
Patients with evidence of peripheral blood involvement (as determined by flow cytometric analysis at the time of initial presentation) may have their first dose of rituximab delayed or omitted when they are believed to be at risk for tumor lysis syndrome or cytokine-release syndrome
Cyclophosphamide 300 mg/m2 per dose; administer intravenously in 500 mL 0.9% NS over 3 hours, every 12 hours for 6 doses, on days 2, 3, and 4, for 3–4 cycles, cycles 1, 3, 5 (±7). Cycle duration is 21 days (total dosage/cycle = 1800 mg/m2)
Mesna 600 mg/m2 per day; administer by continuous intravenous infusion over 24 hours in 1000–2000 mL 0.9% NS on days 2, 3, and 4, starting 1 hour before cyclophosphamide and continuing until 12 hours after the last dose of cyclophosphamide, for 3–4 cycles, cycles 1, 3, 5 (±7). Cycle duration is 21 days (total duration of mesna administration per cycle is approximately 76 hours; total dosage/cycle is approximately 1900 mg/m2)
Vincristine 1.4 mg/m2 per dose (maximum single dose = 2 mg); administer by intravenous injection over 1–2 minutes for 2 doses, 12 hours after the last dose of cyclophosphamide on day 5 and on day 12, for 3–4 cycles, cycles 1, 3, 5 (±7). Cycle duration is 21 days (total dosage/cycle = 2.8 mg/m2; maximum total dose/cycle = 4 mg)
Doxorubicin 16.6 mg/m2 per day; administer by continuous intravenous infusion over 24 hours in 25–250 mL 0.9% NS or D5W for 3 consecutive days starting 12 hours after the last dose of cyclophosphamide, on days 5, 6, and 7, for 3–4 cycles, cycles 1, 3, 5 (±7). Cycle duration is 21 days (total dosage/cycle ~50 mg/m2)
Dexamethasone 40 mg/day; administer orally or intravenously in 25–150 mL 0.9% NS or D5W over 15–30 minutes for 8 doses, on days 2–5 and days 12–15 for 3–4 cycles, cycles 1, 3, 5 (±7). Cycle duration is 21 days (total dosage/cycle = 320 mg)
R-MC (even-numbered cycles; ie, 2, 4, 6, ±8)
Premedication for rituximab:
Acetaminophen 650–1000 mg; administer orally, plus
Diphenhydramine 25–50 mg; administer orally or intravenously, 30–60 minutes before starting rituximab
Rituximab 375 mg/m2 per dose; administer intravenously in 0.9% NS or D5W diluted to a concentration within the range of 1–4 mg/mL on day 1 for 3–4 cycles, cycles 2, 4, 6 (±8). Cycle duration is 21 days (total dosage/cycle = 375 mg/m2)
Notes on rituximab administration:
Infuse initially at 100 mg/h. If hypersensitivity or infusion reactions do not occur during the first 30 minutes, increase the rate by 100 mg/h every 30 minutes, as tolerated, to a maximum rate of 400 mg/h. Subsequently, if previous administration was well tolerated, start at 100 mg/h and increase by 100 mg/h every 30 minutes, as tolerated, to a maximum rate of 400 mg/h
Interrupt rituximab administration for fever, chills, edema, congestion of the head and neck mucosa, hypertension, and other serious adverse events. Resume rituximab administration after adverse events abate
Hydration with 2500–3000 mL/day, as tolerated; administer intravenously at 100–125 mL/hour
Notes:
Sodium bicarbonate is added to parenteral hydration solutions in the presence of plasma uric acid >9 mg/dL to maintain urine pH ≥7.0, but pH <8. The choice of hydration fluid and amount of sodium bicarbonate added to the fluid should NOT EXCEED the sodium concentration present in 0.9% sodium chloride injection (154 mEq/L); for example:
5% Dextrose/0.45% sodium chloride injection with sodium bicarbonate 50–75 mEq/1000 mL, or
5% Dextrose/0.2% sodium chloride injection with sodium bicarbonate 100–125 mEq/1000 mL, or
5% dextrose injection with sodium bicarbonate 125–150 mEq/1000 mL
Methotrexate 200 mg/m2; administer intravenously in 250 mL to >1000 mL 0.9% NS or D5W (or saline and dextrose combinations) over 2 hours, followed by:
Methotrexate 800 mg/m2; administer intravenously in 250 mL to >1000 mL 0.9% NS or D5W (or saline and dextrose combinations) over 22 hours, on day 2, for 3–4 cycles, cycles 2, 4, 6 (±8). Cycle duration is 21 days (total dosage/cycle [not including intrathecal methotrexate] = 1000 mg/m2)
Notes on methotrexate administration:
Patients with an initial serum creatinine level >1.5 mg/dL (>133 μmol/L), reduce the dose of methotrexate by 50%
Patients with evidence of third spacing of fluids, remove the fluid as completely as possible or, if this is not possible, repeat rituximab plus hyper-CVAD until third spacing of fluid is resolved
Cytarabine 3000 mg/m2 per dose; administer intravenously in 50–500 mL 0.9% NS or D5W over 2 hours, every 12 hours, for 4 doses, on days 3 and 4, for 3–4 cycles, cycles 2, 4, 6 (±8). Cycle duration is 21 days (total dosage/cycle [not including intrathecal cytarabine] = 12,000 mg/m2)
Notes on cytarabine administration:
Reduce the cytarabine dose to 1000 mg/m2 in patients whose age is ≥60 years and in those with a serum creatinine level >1.5 mg/dL (>133 μmol/L)
Administer a 1% ophthalmic solution of, at a rate of 2 drops in each eye 4 times daily, beginning on day 3 at the start of cytarabine infusion and continue for 7 days to prevent chemical conjunctivitis
Leucovorin calcium 50 mg; administer intravenously in 10–100 mL 0.9% NS or D5W over 10–20 minutes, on day 3, 36 hours after methotrexate administration began (12 hours after completing methotrexate), followed 6 hours later by:
Leucovorin calcium 15 mg; administer orally or intravenously in 10–100 mL 0.9% NS or D5W over 10–20 minutes, every 6 hours, for 8 doses or until blood methotrexate concentrations is <0.1 μmol/L
If methotrexate elimination is delayed or attenuated, both the dose and administration schedule for leucovorin calcium are escalated, thus: leucovorin calcium 100 mg/dose intravenously every 3 hours, if serum methotrexate concentrations are:
If methotrexate elimination is delayed, measure serum methotrexate concentrations at daily intervals and continue leucovorin administration until serum methotrexate concentration is ≤0.05 μmol/L (≤5 × 1028 mol/L) or undetectable
Treatment Duration:
Patients who achieved a CR after the first 2 cycles (1 cycle with rituximab plus hyper-CVAD and 1 cycle with rituximab plus methotrexate and cytarabine) received 4 more cycles, for a total of 6 cycles
Patients who achieved a partial response (PR) after 2 cycles and a complete remission after 6 cycles received 2 more cycles, for a total of 8 cycles
Patients with evidence of disease after 6 cycles did not receive further therapy
Patients whose disease was responding could be referred at any time during treatment for consolidation with stem cell transplantation
Supportive Care
Antiemetic prophylaxis for R-Hyper-CVAD (cycles 1, 3, 5, ±7)
Emetogenic potential on day 1 is MINIMAL
Emetogenic potential on days 2, 3, and 4 is MODERATE
Emetogenic potential on days 5, 6, and 7 is LOW–MODERATE
Emetogenic potential on day 12 is MINIMAL
See Chapter 39 for antiemetic recommendations
Antiemetic prophylaxis for R-MC (cycles 2, 4, 6, ±8)
Emetogenic potential on day 1 is MINIMAL
Emetogenic potential on day 2 is MODERATE
Emetogenic potential on days 3 and 4 is MODERATE
See Chapter 39 for antiemetic recommendations
Hematopoietic growth factor (CSF) prophylaxis (all cycles)
Primary prophylaxis is indicated with:
Filgrastim (G-CSF) 5 mcg/kg per day; administer by subcutaneous injection for 10 days
See Chapter 43 for more information
Antimicrobial prophylaxis
Risk of fever and neutropenia is HIGH
Antimicrobial primary prophylaxis is recommended:
See Chapter 47 for more information
Infusion reactions associated with rituximab
Fevers, chills, and rigors
Interrupt rituximab administration for severe symptoms, and give:
Acetaminophen 650 mg orally for fever. For persistent or recurrent symptoms, repeat administration every 4–6 hours as needed during rituximab administration
Diphenhydramine 25–50 mg orally or by intravenous injection for pruritus, hypotension, or angioedema. For persistent or recurrent symptoms, repeat administration every 4–6 hours as needed during rituximab administration
Meperidine 12.5–25 mg; by intravenous injection every 10–20 minutes as needed for shaking chills (generally, cumulative doses >100 mg are not needed; use repeated doses with caution in persons with moderate or more severely impaired renal function)
If rituximab administration was interrupted, resume infusion at a slower rate than the maximum rate previously attempted. Rate escalation may be reattempted at smaller incremental steps with close monitoring. Do not exceed the maximum recommended rate of 400 mg/h
Dyspnea or wheezing without allergic findings (urticaria, or tongue or laryngeal edema)
Interrupt rituximab administration immediately
Give hydrocortisone 100 mg by intravenous injection (or an alternative steroid with equivalent glucocorticoid potency)
Give a histamine (H2) receptor antagonist (ranitidine 50 mg, cimetidine 300 mg, or famotidine 20 mg) intravenously over 15–30 minutes
After symptoms resolve, resume rituximab administration at 25 mg/h with close monitoring. Do not increase the administration rate
Steroid-associated gastritis
Add a proton pump inhibitor during steroid use to prevent gastritis and duodenitis
Decreased bowel motility prophylaxis
Give stool softeners in a scheduled regimen, and saline, osmotic, and lubricant laxatives, as needed to prevent constipation for as long as vincristine use continues. If needed, circumspectly add stimulant (irritant) laxatives in the least amounts and for the briefest durations needed to produce defecation