BC Cancer Protocol Summary for the Treatment of Relapsed or

Refractory Advanced Stage Aggressive B-Cell Non-Hodgkin’s

Lymphoma with Ifosfamide, CARBOplatin, Etoposide and riTUXimab

Protocol Code LYRICE

Tumour Group Lymphoma

Contact Physician Dr. Laurie Sehn

ELIGIBILITY:
Patients must:
• Be greater than or equal to 18 years of age,
• Have aggressive histology lymphoma in the WHO classification including
o diffuse large B-cell lymphoma
o mediastinal large B-cell lymphoma
o T-cell rich B-cell lymphoma
o intravascular large B-cell lymphoma, and
• Have relapsed disease

Patients should have:

• ECOG Performance Status 0,1,2 or 3, and
• Adequate renal, hepatic, and bone marrow function

TESTS:
• Baseline (required before first treatment): CBC & diff, platelets, total bilirubin, ALT,
alkaline phosphatase, LDH, creatinine, calcium
• Baseline (required, but results do not have to be available to proceed with first
treatment; results must be checked before proceeding with cycle 2):, Hepatitis B and
C serology (HBsAg, anti-HBsAg, anti-HBcore Ab, anti-HepC), HIV, pregnancy test for
women of childbearing age
• Prior to each cycle: CBC and diff, platelets, total bilirubin, LDH, creatinine
• Prior to each ifosfamide treatment on days 1, 2, and 3: urine dipstick for blood. – if
positive at any time, notify doctor, send urine sample for urinalysis for verification and
accurate measurement of hematuria.

PREMEDICATIONS:
• Antiemetic protocol for highly emetogenic chemotherapy (see protocol SCNAUSEA)

BC Cancer Protocol Summary LYRICE Page 1 of 6

Activated: 1 Aug 2006 Revised: 1 Mar 2023 (premedications updated, carboplatin dosing clarified)
Warning: The information contained in these documents are a statement of consensus of BC Cancer professionals regarding their views of currently accepted approaches to treatment. Any clinician seeking to
apply or consult these documents is expected to use independent medical judgement in the context of individual clinical circumstances to determine any patient's care or treatment. Use of these documents is at
your own risk and is subject to BC Cancer's terms of use available at www.bccancer.bc.ca/terms-of-use.
For riTUXimab portion
• For intravenous infusion:
diphenhydrAMINE 50 mg PO prior to riTUXimab IV and then q 4 h during the IV
infusion, if the infusion exceeds 4 h
acetaminophen 650-975 mg PO prior to riTUXimab IV and then q 4 h during the IV
infusion, if the infusion exceeds 4 h

• For subcutaneous injection:

diphenhydrAMINE 50 mg PO prior to riTUXimab subcutaneous
acetaminophen 650-975 mg PO prior to riTUXimab subcutaneous

SUPPORTIVE MEDICATIONS:
If HBsAg or HBcoreAb positive, start lamiVUDine 100 mg PO daily for the duration of
chemotherapy and continue for one year from treatment completion for patients who are
HBsAg positive and for six months for patients who are HBcoreAb positive.

TREATMENT:

Drug Dose¥ BC Cancer Administration Guideline

Ifosfamide§ 1667 mg/m2/day IV in 500 mL NS over 2 hours on days 1,2,3
(total dose per cycle = 5000 mg/m2)
mesna (IV)§ 1667 mg/m2/day IV in 500 mL NS over 2 hours on days 1,2,3
(total dose per cycle = 5000 mg/m2)
mesna (PO) 2000 mg PO 2 h and 4 h after completion of ifosfamide
infusion on days 1,2,3
CARBOplatin AUC 5 x (GFR¶ + 25) IV in 100 to 250 mL NS over 1 hour on day 1
(maximum dose 800 mg)
etoposide 100 mg/m2/day IV in 250 to 1000 mL NS over 45 min to 1 hour 30 min
(total dose per cycle = 300 mg/m2) on days 1,2,3
(Use non-DEHP equipment with 0.2 micron in-line
filter)
375 mg/m2 IV in 250 to 500 mL NS over 1 hour 30 minutes-8
hours* day 1 (or day 2 or day 3)
If IV infusion tolerated (no severe reactions requiring early termination), subsequent
riTUXimab**†
doses can be given by subcutaneous administration
subcutaneous over 5 minutes into abdominal wall‡
1400 mg (fixed dose in 11.7 mL)
Observe for 15 minutes after administration
§ Ifosfamide and Mesna infused concurrently via Y- site connector placed immediately before
injection site
¥ Consider dose reduction to 75% for ifosfamide, IV mesna, CARBOplatin and etoposide in

patients greater than 70 years of age.

BC Cancer Protocol Summary LYRICE Page 2 of 6

Activated: 1 Aug 2006 Revised: 1 Mar 2023 (premedications updated, carboplatin dosing clarified)
Warning: The information contained in these documents are a statement of consensus of BC Cancer professionals regarding their views of currently accepted approaches to treatment. Any clinician seeking to
apply or consult these documents is expected to use independent medical judgement in the context of individual clinical circumstances to determine any patient's care or treatment. Use of these documents is at
your own risk and is subject to BC Cancer's terms of use available at www.bccancer.bc.ca/terms-of-use.
¶The lab reported GFR (MDRD formula) may be used as an alternative to the Cockcroft-
Gault estimate of GFR. When a nuclear renogram is available, this clearance would
take precedence. Maximum CARBOplatin dose is 800 mg.

Note: The same method of estimation should be used throughout the treatment course
(i.e. if lab reported GFR was used initially, this should be used for dosing in all
subsequent cycles and not the Cockcroft-Gault estimate).

*Start the (first dose) initial infusion at 50 mg/h and, after 1 hour, increase by 50 mg/h
every 30 minutes until a rate of 400 mg/h is reached. For all subsequent treatments,
infuse 50 mL (or 100 mL) of the dose over 30 minutes then infuse the remaining 200 mL
(or 400 mL) (4/5) over 1 hour (total infusion time = 1 hour 30 min). Development of an
allergic reaction may require a slower infusion rate. See hypersensitivity below.

**The risk of cytokine release syndrome is low but is increased when the peripheral
blood lymphocyte count is greater than 30 to 50 x 109 /L. While there is no requirement
to withhold riTUXimab based on lymphocyte count, clinicians may wish to pre-medicate
patients with high tumour burden with steroids prior to riTUXimab infusion or omit the
riTUXimab from the first cycle of treatment.

†Patients must receive first dose by IV infusion (using the IV formulation) because the
risk of reactions is highest with the first infusion. IV administration allows for better
management of reactions by slowing or stopping the infusion.

‡During treatment with subcutaneous riTUXimab, administer other subcutaneous drugs

at alternative injection sites whenever possible.

Repeat every 3 weeks for up to 6 cycles.

DOSE MODIFICATIONS:

1. Hematological

ANC (X 109/L) DOSE MODIFICATION

greater than or equal to 0.8 100%

less than 0.8 100% plus Filgrastim* 5mcg / kg subcutaneous daily x 5-10
days, starting on day 7

The patient should be treated with filgrastim (G-CSF) in doses sufficient to allow full dose
treatment on schedule. Note: this guideline applies only if the treatment is potentially curative
and after experience with one or more cycles of treatment indicate filgrastim (G-CSF) is
required. (See Pharmacare guidelines and submit special authority request to Pharmacare for
filgrastim coverage)
BC Cancer Protocol Summary LYRICE Page 3 of 6
Activated: 1 Aug 2006 Revised: 1 Mar 2023 (premedications updated, carboplatin dosing clarified)
Warning: The information contained in these documents are a statement of consensus of BC Cancer professionals regarding their views of currently accepted approaches to treatment. Any clinician seeking to
apply or consult these documents is expected to use independent medical judgement in the context of individual clinical circumstances to determine any patient's care or treatment. Use of these documents is at
your own risk and is subject to BC Cancer's terms of use available at www.bccancer.bc.ca/terms-of-use.
*Filgrastim 300 mcg: up to 75 kg
480 mcg: 76 kg to 110 kg
600 mcg: greater than 110 kg

Platelet Count (PLT) (x 109/L) DOSE MODIFICATION

Greater than or equal to 75 100%

less than 75 Hold treatment until PLT greater than or equal to 75

x109/L and then administer at 100% dosing
(on treatment day)

Consider RBC transfusion support in individuals that have an expected hemoglobin nadir
below 70 to 80 g/L and platelet transfusions to keep platelets greater than 20 x 109/L.

2. Renal dysfunction: Check renal function prior to each cycle and adjust dose of
CARBOplatin accordingly. Discontinue protocol if CrCl less than 60 mL/min.

PRECAUTIONS:
1. Neutropenia: Fever or other evidence of infection must be assessed promptly and
treated aggressively.
2. Thrombocytopenia: Support with platelet transfusion may be required.
3. Extravasation: etoposide causes pain and tissue necrosis if extravasated. Refer to
BC Cancer Extravasation Guidelines.
4. Hypersensitivity: Hypersensitivity reactions including anaphylaxis have been
reported with etoposide. Monitor etoposide infusion for 15 minutes for signs of
hypotension. Refer to BC Cancer Hypersensitivity Guidelines. riTUXimab can cause
allergic type reactions during the IV infusion such as hypotension, wheezing, rash,
flushing, alarm, pruritus, sneezing, cough, fever or faintness. For the first dose,
patients are to be under constant visual observation during all dose increases and
for 30 minutes after infusion is completed. For all subsequent doses, constant visual
observation is not required. Vital signs are not required unless symptomatic.
Because transient hypotension may occur during infusion, consider withholding
antihypertensive medications 12 hours prior to riTUXimab infusion. If an allergic
reaction occurs, stop the infusion and the physician in charge should determine a
safe time and rate to resume the infusion. A reasonable guideline is as follows. After
recovery of symptoms, restart riTUXimab infusion at one infusion rate below the rate
at which the reaction occurred and continue with escalation of infusion rates on the
appropriate schedule above. If the infusion must be stopped a second time, restart
after clearance of symptoms, at one infusion rate lower and continue at that rate
without further escalation. Fatal cytokine release syndrome can occur (see below).
See BC Cancer Hypersensitivity Guidelines.

BC Cancer Protocol Summary LYRICE Page 4 of 6

Activated: 1 Aug 2006 Revised: 1 Mar 2023 (premedications updated, carboplatin dosing clarified)
Warning: The information contained in these documents are a statement of consensus of BC Cancer professionals regarding their views of currently accepted approaches to treatment. Any clinician seeking to
apply or consult these documents is expected to use independent medical judgement in the context of individual clinical circumstances to determine any patient's care or treatment. Use of these documents is at
your own risk and is subject to BC Cancer's terms of use available at www.bccancer.bc.ca/terms-of-use.
5. Fatal Cytokine Release Syndrome has been reported. It usually occurs within
1-2 hours of initiating the first infusion. Initially, it is characterised by severe dyspnea
(often with bronchospasm and hypoxia) in addition to fever, chills, rigors, urticaria
and angioedema. Pulmonary interstitial infiltrates or edema visible on chest x-ray
may accompany acute respiratory failure. There may be features of tumour lysis
syndrome such as hyperuricemia, hypocalcemia, acute renal failure and elevated
LDH. For severe reactions, stop the infusion immediately and evaluate for tumour
lysis syndrome and pulmonary infiltration. Aggressive symptomatic treatment is
required. The infusion can be resumed at no more than one-half the previous rate
once all symptoms have resolved, and laboratory values and chest x-ray findings
have normalized. The risk of cytokine release syndrome is low but is increased when
the peripheral blood lymphocyte count is greater than 30 to 50 x 109 /L. While there
is no requirement to withhold riTUXimab based on lymphocyte count, clinicians may
wish to pre-medicate patients with high tumour burden with steroids prior to
riTUXimab infusion or omit the riTUXimab from the first cycle of treatment.
6. Rare Severe Mucocutaneous Reactions: (similar to Stevens-Johnson Syndrome)
have been anecdotally reported. If such a reaction occurs, riTUXimab should be
discontinued.
7. Urotoxicity: Ifosfamide can cause hemorrhagic cystitis, hematuria and
nephrotoxicity. No dose modifications for ifosfamide is required for transient or
persistent hematuria. Administration with MESNA and ample hydration is required
for gross hematuria. Avoid concurrent nephrotoxic drugs.
8. CNS toxicity: Ifosfamide can cause encephalopathy (manifest as confusion,
lethargy, seizures or coma). Avoid CNS depressant medications. If drowsiness
develops while receiving ifosfamide, discontinue all sedating medications and
continue ifosfamide. If patient is confused, not arousable or comatose, discontinue
ifosfamide. If ifosfamide is the cause of CNS depression, then it should not be given
again. If the CNS changes are not due to ifosfamide, then ifosfamide can be re-
instituted providing the previous medications contributing to CNS toxicity are not given
again with it. If a seizure occurs on ifosfamide, then that cycle should be discontinued.
Further cycles may be given if the patient is on anticonvulsants.
9. Hepatitis B Reactivation: All lymphoma patients should be tested for both HBsAg
and HBcoreAb. If either test is positive, such patients should be treated with
lamiVUDine during chemotherapy and continue for one year from treatment
completion for patients who are HBsAg positive and for six months for patients who
are HBcoreAb positive. Such patients should also be monitored with frequent liver
function tests and hepatitis B virus DNA at least every two months. If the hepatitis B
virus DNA level rises during this monitoring, management should be reviewed with
an appropriate specialist with experience managing hepatitis and consideration
given to halting chemotherapy.
10. Gastrointestinal Obstruction or Perforation: There have been rare reports of
gastrointestinal obstruction or perforation, sometimes fatal, when riTUXimab is given
in combination with other chemotherapy, occurring 1 to 12 weeks after treatment.
Symptoms possibly indicative of such complications should be carefully investigated
and appropriately treated.

BC Cancer Protocol Summary LYRICE Page 5 of 6

Activated: 1 Aug 2006 Revised: 1 Mar 2023 (premedications updated, carboplatin dosing clarified)
Warning: The information contained in these documents are a statement of consensus of BC Cancer professionals regarding their views of currently accepted approaches to treatment. Any clinician seeking to
apply or consult these documents is expected to use independent medical judgement in the context of individual clinical circumstances to determine any patient's care or treatment. Use of these documents is at
your own risk and is subject to BC Cancer's terms of use available at www.bccancer.bc.ca/terms-of-use.
11. Medication Safety: riTUXimab is formulated differently for IV versus subcutaneous
administration. Use caution during prescribing, product selection, preparation and
administration. IV formulation is supplied as 10 mg/mL solution which must be
diluted prior to administration. Subcutaneous formulation is supplied as a fixed dose
of 1400 mg/11.7 mL ready-to-use solution which contains hyaluronidase to facilitate
injection.
12. Increased drug absorption by hyaluronidase: other subcutaneous medications
should not be injected at the same site as subcutaneous riTUXimab. Increased
systemic effects are unlikely to be clinically significant with topical applications of
EMLA, hydrocortisone, or diphenhydrAMINE.

Call Dr. Laurie Sehn or tumour group delegate at (604) 877-6000 or 1-800-663-3333
with any problems or questions regarding this treatment program.

BC Cancer Protocol Summary LYRICE Page 6 of 6

Activated: 1 Aug 2006 Revised: 1 Mar 2023 (premedications updated, carboplatin dosing clarified)
Warning: The information contained in these documents are a statement of consensus of BC Cancer professionals regarding their views of currently accepted approaches to treatment. Any clinician seeking to
apply or consult these documents is expected to use independent medical judgement in the context of individual clinical circumstances to determine any patient's care or treatment. Use of these documents is at
your own risk and is subject to BC Cancer's terms of use available at www.bccancer.bc.ca/terms-of-use.