BC Cancer Protocol Summary for Treatment of Lymphoma with Dose-

Adjusted Etoposide, DOXOrubicin, vinCRIStine, Cyclophosphamide,

predniSONE and riTUXimab with Intrathecal Methotrexate
Protocol Code LYEPOCHR

Tumour Group Lymphoma

Contact Physician Dr. Laurie Sehn

Dr. Kerry Savage

ELIGIBILITY:
 Patients with an aggressive B-cell lymphoma and the presence of a dual translocation of
MYC and BCL2 (i.e., double-hit lymphoma). Histologies may include DLBCL, transformed
lymphoma, unclassifiable lymphoma, and intermediate grade lymphoma, not otherwise
specified (NOS).
 Patients with Burkitt lymphoma, who are not candidates for CODOXM/IVACR (such as those
over the age of 65 years, or with significant co-morbidities)
 Ensure patient has central line

EXCLUSIONS:
 Cardiac dysfunction that would preclude the use of an anthracycline.

TESTS:
 Baseline (required before first treatment): CBC and diff, platelets, BUN, creatinine, bilirubin.
AST, ALT, LDH, uric acid
 Baseline (required, but results do not have to be available to proceed with first treatment):
results must be checked before proceeding with cycle 2): HBsAg, HBcoreAb
 Day 1 of each cycle: CBC and diff, platelets, PTT, INR (and serum bilirubin if elevated at
baseline; serum bilirubin does not need to be requested before each treatment, after it has
returned to normal)
 Day 4 of each cycle: PTT, INR
 CBC and diff, platelets starting Day 4 and then twice-weekly (i.e., Monday and Thursday)
continuously during cycle. NB: twice-weekly CBC & diff, platelets are used to determine the
nadir information which is required for dosing in the subsequent cycle and for the ANC
recovery post nadir which is required to determine the duration of the filgrastim treatment in
the current cycle.
 Proceed with methotrexate intrathecal injection if
 PTT less than or equal to the upper limit of normal, within 48 hours
 INR less than 1.3 within 48 hours
 Platelets greater than or equal to 50 x 109/L within 48 hours
 Filgrastim (G-CSF) Usage Form - cycle 1
 VICTORY Program Enrolment Form for filgrastim – cycle 1
 Reassess all sites of disease after cycles 4 and 6 to determine response

PREMEDICATIONS:
BC Cancer Protocol Summary LYEPOCHR Page 1 of 9
Activated: 1 Jul 2015 (as interim) Revised: 1 Sep 2018 (Rituximab dosing schedule)
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/legal.htm
For etoposide, prednisone, vinCRIStine, cyclophosphamide, DOXOrubicin portion (i.e., EPOCH
portion)
* Antiemetic protocol for highly emetogenic chemotherapy (see protocol SCNAUSEA)

For riTUXimab portion

• diphenhydrAMINE 50 mg PO prior to riTUXimab and then q4h during the IV infusion, if
infusion exceeds 4 h
• acetaminophen 650-975 mg PO prior to riTUXimab and then q4h during the IV infusion, if
infusion exceeds 4 h
• predniSONE as ordered for the ULYEPOCHR

SUPPORTIVE MEDICATIONS:
• If HBsAg or HBcoreAb positive, start lamiVUDine 100 mg daily PO for the duration of
chemotherapy and for six months afterwards
• cotrimoxazole 1 DS tab PO 3 times each week (Monday, Wednesday and Friday)
• lansoprazole 30 mg PO daily (or equivalent)
• docusate and senna (sennosides 8.6 mg) 2 tablets PO twice daily prn constipation

Prevention of Tumor Lysis Syndrome (TLS) - Cycle 1 only:

Prophylaxis suggested for high-risk patients:
 High tumour burden,
 Elevated uric acid level
 Lymphocyte count greater than 25 x 109/L, or
 CrCl less than 70 mL/min

Suggested prophylactic treatment:

 Monitor electrolytes (including potassium, calcium, and phosphate), creatinine and uric acid
 Ensure adequate hydration. Intravenous fluids should be given as indicated based on
overall risk of tumour lysis syndrome. Suggest hospitalization for high-risk patients for cycle
1 with aggressive hydration (2-3 L/m2/24 h) to achieve urine output greater than 100 mL/h.
 allopurinol 300 mg PO daily (to decrease urate formation)
 If phosphate becomes elevated, add AMPHOJEL® (aluminum hydroxide) 15-30 mL PO q4h
 rasburicase (FASTURTEC®) can be considered on a case by case basis

BC Cancer Protocol Summary LYEPOCHR Page 2 of 9

Activated: 1 Jul 2015 (as interim) Revised: 1 Sep 2018 (Rituximab dosing schedule)
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/legal.htm
TREATMENT:

Drug Dose BC Cancer Administration Guideline

Cycle 1 to Cycle 6, on Day 1 to

Day 4 inclusive:

etoposide 50 mg/m2/day

(total dose per cycle = 200 mg/m2)

IV in the same 500-1000 mL non-DEHP

NS infusion bag by continuous infusion
Cycle 1 to Cycle 6, on Day 1 to over 24 h daily; for a total of 96 hours
Day 4 inclusive: per cycle (use non-DEHP equipment
with in-line filter and protect infusion bag
DOXOrubicin 10 mg/m2/day from light)
(total dose per cycle = 40 mg/m2)

- 500 mL non-DEHP NS for etoposide

less than or equal to 125 mg
Cycle 1 to Cycle 6: on Day 1 to
- 1000 mL non-DEHP NS for
Day 4 inclusive:
etoposide greater than 125 mg
0.4 mg/m2*/day
vinCRIStine
(*no cap on dose)

(total dose per cycle = 1.6 mg/m2)

Cycle 1 to Cycle 6: on Day 5: IV in 100 to 250 mL NS over 1 hour

2
cyclophosphamide 750 mg/m (*use 250 mL for doses greater than
1000 mg)

Cycle 1 to Cycle 6: on Day 1 to

Day 5 inclusive:

Total daily dose = 120 mg/m2 i.e.,

PO with food
60 mg/m2 BID (round off dose to
predniSONE nearest 25 mg) (On day of riTUXimab, ensure morning
predniSONE taken prior to riTUXimab
infusion)
Note: may reduce predniSONE
dose per physician discretion
based on patient tolerance

BC Cancer Protocol Summary LYEPOCHR Page 3 of 9

Activated: 1 Jul 2015 (as interim) Revised: 1 Sep 2018 (Rituximab dosing schedule)
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/legal.htm
Drug Dose BC Cancer Administration Guideline

Cycle 1 to Cycle 6: on Day 1

2
375 mg/m IV in 250 mL NS over 1 hour 30 min*
(doses between 500 to 1000 mg can be prepared in either
250 mL or 500 mL NS)
riTUXimab**† If patient received IV riTUXimab in the past with no severe reactions requiring
early termination, or if patient received SC riTUXimab in the past, riTUXimab
doses can be given by SC administration†

1400 mg (fixed SC over 5 minutes into abdominal wall‡

dose in 11.7 mL) Observe for 15 minutes after administration

Prophylaxis

Cycle 3 to 6: on Day 2 and Day 5:

12 mg (total 8 treatments)

Note:

Physician may start intrathecal

methotrexate*** chemotherapy with Cycle 1 if high
risk of CNS disease Intrathecal qs to 6 mL with preservative-
free NS
Physician may change the days of
intrathecal chemotherapy

Ensure dose is given twice in 1

week, with a minimum of 48 hours
between doses
Treatment of Meningeal
Lymphoma****

Cycle 1 to Cycle 6: Starting on

Day 6

filgrastim DAILY until ANC recovery (5.0 x

109/L past the nadir) subcutaneously

300 mcg: up to 75 kg

480 mcg: greater than 75 kg

*Start the (first dose of riTUXimab) 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.

BC Cancer Protocol Summary LYEPOCHR Page 4 of 9

Activated: 1 Jul 2015 (as interim) Revised: 1 Sep 2018 (Rituximab dosing schedule)
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/legal.htm
**The risk of cytokine release syndrome is low but is increased when the peripheral blood lymphocyte
9
count is greater than 30 to 50 x 10 /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. If patient tolerated IV riTUXimab (no severe reactions requiring early termination)
i.e., in active treatment or maintenance treatment or if patient tolerated SC riTUXimab previously i.e.,
active treatment or maintenance treatment the patient can receive all subsequent treatment using SC
riTUXimab.

‡During treatment with subcutaneous riTUXimab, administer other subcutaneous drugs at alternative
injection sites whenever possible.

***Concurrent use of co-trimoxazole and methotrexate may result in an increased risk of methotrexate
toxicity. The tumour group believes this drug interaction is not clinically significant with IT methotrexate 12
mg.

****Treatment of leptomeningeal Lymphoma

If the CSF is cytologically positive for malignant cells at the start of therapy, the CSF should be
treated with methotrexate and/or cytarabine as soon as possible. Suggested treatment as
follows:

Induction- intrathecal methotrexate (12 mg by lumbar route) alternating with cytarabine (50 mg
by lumbar route). Administer induction treatment twice a week for 2 weeks past negative
cytology with a minimum of 4 weeks treatment.

Consolidation- Following induction, change frequency to weekly x 6, alternating methotrexate

and cytarabine.

Maintenance- Following consolidation, change frequency to monthly x 4 (with either

methotrexate or cytarabine).

Due to unforeseeable events, the above therapy may be modified as clinically indicated. In
some cases it may be necessary to administer radiation to the head and/or spine. Patients who
fail to clear or relapse in the CSF should be considered for alternate therapies and/or radiation.
Substitution with liposomal cytarabine can be considered, but schedule should be determined in
consultation with a BC Cancer pharmacist. Note: liposomal cytarabine is accessed via the
Health Canada Special Access Programme (SAP) on a patient-specific basis.

Repeat protocol every 21 days for 6 cycles

Discontinue if no response after 2 cycles

BC Cancer Protocol Summary LYEPOCHR Page 5 of 9

Activated: 1 Jul 2015 (as interim) Revised: 1 Sep 2018 (Rituximab dosing schedule)
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/legal.htm
DOSE MODIFICATIONS:

Hematological:

a) On treatment day: Day 1

ANC (x109/L) Dose Modification

greater than or equal to 1 100%

filgrastim 5 mcg/kg x 1 day then treat the following day if ANC is

less than 1
greater than 1

Platelets (x109/L) Dose Modification

greater than or equal to 75 100%

less than 75 delay until platelets are greater than 75

Patients with bone marrow involvement should be treated irrespective of the ANC and platelet
counts based on physician discretion.

Dose levels are adjusted based on nadir ANC and platelet count of last cycle:

Nadir ANC (x 109/L) Nadir Platelet (x 109/L) Dose Level

Increase by one dose level

greater than or equal to 0.5 and greater than or equal to 25
above last cycle *

less than 0.5 on one or two Maintain same dose level as

and greater than or equal to 25
measurements last cycle

less than 0.5 on 3 or more Decrease by one dose level

or less than 25
measurements below last cycle **
*Dose adjustments ABOVE level 1 apply to etoposide, DOXOrubicin and cyclophosphamide
**Dose adjustments BELOW level 1 apply to cyclophosphamide only

Note: Rarely, patients may develop prolonged neutropenia (ANC less than 0.5) for over seven days or
life-threatening infections associated with organ failure or prolonged morbidity. In these cases, clinicians
should use their clinical judgement regarding dose reduction. No need to reduce doses for:
- non-life threatening infections
- non-life threatening neutropenia or thrombocytopenia in patients with bone marrow compromise due
to marrow involvement by lymphoma

BC Cancer Protocol Summary LYEPOCHR Page 6 of 9

Activated: 1 Jul 2015 (as interim) Revised: 1 Sep 2018 (Rituximab dosing schedule)
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/legal.htm
 Etoposide Dose Level

–2 –1 1* 2 3 4 5 6
2 2 2 2 2 2 2 2
50 mg/m 50 mg/m 50 mg/m 60 mg/m 72 mg/m 86 mg/m 104 mg/m 124 mg/m

*starting dose level

DOXOrubicin Dose Level*

–2 –1 1* 2 3 4 5 6
2 2 2 2 2 2 2 2
10 mg/m 10 mg/m 10 mg/m 12 mg/m 14 mg/m 17 mg/m 21 mg/m 25 mg/m

*starting dose level

Cyclophosphamide Dose Level*

–2 –1 1* 2 3 4 5 6
2 2 2 2 2 2 2 2
480 mg/m 600 mg/m 750 mg/m 900 mg/m 1080 mg/m 1296 mg/m 1555 mg/m 1866 mg/m

*starting dose level

Note: Individual drug doses may be reduced per physician discretion (rather than according to dose level)

Elderly Patients (age greater than 75 years):

As per clinical judgment, a suggested approach is to administer Cycle 1 with 75% dosing of
cyclophosphamide and DOXOrubicin. Further treatment should be given at the maximum dose
tolerated by the patient, trying to escalate up to full doses.

Ileus: vinCRIStine only

Note: constipation commonly occurs and stool softeners should be used

Clinical ileus Dose of vinCRIStine

Less than 8 days with abdominal pain requiring narcotics

and/or 75%
persistent nausea/vomiting greater than 2 days

8-12 days with abdominal pain requiring narcotics

and/or 50%
persistent nausea/vomiting greater than 2 days

Greater than 12 days with abdominal pain requiring narcotics

and/or Hold on next cycle. Restart at 50%
dose on subsequent cycle.
persistent nausea/vomiting greater than 2 days
BC Cancer Protocol Summary LYEPOCHR Page 7 of 9
Activated: 1 Jul 2015 (as interim) Revised: 1 Sep 2018 (Rituximab dosing schedule)
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/legal.htm
Neurotoxicity: vinCRIStine only:

Toxicity Dose of vinCRIStine

Dysesthesias, areflexia only 100 %
Abnormal buttoning, writing 67%
Motor neuropathy, moderate 50%
Motor neuropathy, severe omit

Hepatic toxicity: vinCRIStine only

Bilirubin on Day 1 Dose of vinCRIStine

1.5-3.0 x ULN 75%
Greater than 3.0 x ULN 50%

Cardiotoxicity: DOXOrubicin only: see PRECAUTIONS

PRECAUTIONS:
1. Neutropenia: Fever or other evidence of infection must be assessed promptly and treated
aggressively.
2. Cardiac Toxicity: DOXOrubicin is cardiotoxic and must be used with caution, if at all, in
patients with severe hypertension or cardiac dysfunction. Cardiac assessment is
recommended if lifelong dose of 450 mg/m2 is to be exceeded. (BC Cancer Cancer Drug
Manual)
3. Extravasation: DOXOrubicin and vinCRIStine cause pain and tissue necrosis if
extravasated. Refer to BC Cancer Extravasation Guidelines.
4. Hypersensitivity: If applicable, monitor etoposide infusion for the first 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 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
BC Cancer Protocol Summary LYEPOCHR Page 8 of 9
Activated: 1 Jul 2015 (as interim) Revised: 1 Sep 2018 (Rituximab dosing schedule)
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/legal.htm
 rate without further escalation. Fatal cytokine release syndrome can occur (see below). See
BC Cancer Hypersensitivity Guidelines.
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.
6. Rare Severe Mucocutaneous Reactions: (similar to Stevens-Johnson Syndrome) have
been anecdotally reported. If such a reaction occurs, riTUXimab should be discontinued.
7. 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 100
mg/day orally, for the entire duration of chemotherapy and for six months afterwards. 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.
8. 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.

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

References:
1. Dunleavy et al. Low-intensity therapy in adults with Burkitt’s lymphoma. NEJM 2013;369(20):1915-25.
2. Dunleavy et al. Dose-adjusted EPOCH-rituximab therapy in primary mediastinal B-cell lymphoma. NEJM
2013;369(20):1408-16.
3. Wilson et al. Dose-adjusted EPOCH chemotherapy for untreated large B-cell lymphomas: a pharmacodynamic
approach with high efficacy. Blood 2002;99:2685-93.
4. Petrich et al. Impact of induction regimen and stem cell transplantation on outcomes in double-hit lymphoma: a
multicenter retrospective analysis. Blood, 9 October 2014; Volume 124; Number 15
5. Dunleavy et al. 395 Preliminary Report of a Multicenter Prospective Phase II Study of DA-EPOCH-R in MYC-
Rearranged Aggressive B-Cell Lymphoma. ASH 2014 Oral Abstract.Session 623. December 8, 2014
6. Leukemia/Bone Marrow Transplant Program of British Columbia. Leukemia/BMT Manual. E-Edition ed.
Vancouver, British Columbia: Vancouver Hospital and Health Sciences Centre/BC Cancer Agency; 2013. p. 102-
104.

BC Cancer Protocol Summary LYEPOCHR Page 9 of 9

Activated: 1 Jul 2015 (as interim) Revised: 1 Sep 2018 (Rituximab dosing schedule)
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/legal.htm