Lymphoma group

R-Hyper-CVAD / R-MA

INDICATION

Aggressive lymphomas, including acute lymphoblastic leukaemia / lymphoma.

Omit rituximab if CD20-negative.

Consider omitting intrathecals if treating mantle cell lymphoma.

TREATMENT INTENT

Curative or Disease modification (depending on disease type).

PRE-ASSESSMENT

1. Ensure histology is confirmed prior to administration of chemotherapy and document in notes.

2. Record stage of disease - CT scan (neck, chest, abdomen and pelvis) or PET/CT, presence or
absence of B symptoms, clinical extent of disease. Consider bone marrow aspirate and
trephine if clinically indicated.
3. Blood tests - FBC, U&Es, LDH, urate, calcium, magnesium, creatinine, LFTs, glucose, Igs, β2
microglobulin, hepatitis B core antibody and hepatitis BsAg, hepatitis C antibody, EBV, CMV,
VZV, HIV 1+2 after consent, group and save.
4. A number of drugs can interfere with tubular secretion of methotrexate. These include
penicillins, aspirin and NSAIDs. Tazocin should NOT be used during high dose methotrexate
administration or rescue. Consider using meropenem or other alternative. Review indications
for aspirin and NSAIDs and consider stopping during methotrexate treatment.
5. Patients MUST NOT receive co-trimoxazole, starting from the week before the first
methotrexate infusion. Consider pentamidine treatment if considered at risk from
Pneumocystis infection.
6. Urine pregnancy test - before cycle 1 of each new chemotherapy course for women of child-
bearing age unless they are post-menopausal, have been sterilised or undergone a
hysterectomy.
7. ECG +/- Echo - if clinically indicated.
8. Record performance status, height and weight.
9. Consent - ensure patient has received adequate verbal and written information regarding their
disease, treatment and potential side effects. Document in medical notes all information that
has been given. Obtain written consent on the day of treatment.
10. Fertility - it is very important the patient understands the potential risk of infertility, all patients
should be offered fertility advice by referring to the Oxford Fertility Unit.
11. Hydration - in patients with bulky disease pre-hydrate with sodium chloride 0.9% 1 litre over 4-
6 hours. Patients at high risk of tumour lysis refer to tumour lysis protocol.
12. Consider dental assessment / Advise dental check is carried out by patient's own dental
practitioner before treatment starts.
13. Arrange insertion of double-lumen central venous catheter.
14. Treatment should be agreed in the relevant MDT.
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L.51 Authorised by Lymphoma lead Published: May 2014 Version
R-Hyper-CVAD / Dr. Graham Collins Reviewed: May 2018 1.2
R-MA Date: May 2018 Review: May 2020
Lymphoma group

DRUG REGIMEN

R-Hyper-CVAD - Cycles 1, 3, 5, 7:
Day 0 METHOTREXATE 12 mg INTRATHECAL.
Day 1 Pre-med with Chlorphenamine 10 mg IV, paracetamol 1 g 30 minutes before
rituximab. Give day 1 dexamethasone at least 30 minutes prior to rituximab.
RITUXIMAB 375 mg/m2 IV infusion daily in 500 mL sodium chloride 0.9%.
Days 1 to 3 MESNA 600 mg/m2 per day IV continuous infusion in 1000 mL sodium chloride
0.9% over 24 hours (to begin 1 hour before cyclophosphamide and stopping 12
hours after final dose).
Days 1 to 3 CYCLOPHOSPHAMIDE 300 mg/m2 twice a day IV infusion in 250 mL sodium
chloride 0.9% over 2 hours for 6 doses.
Days 1 to 4 DEXAMETHASONE 40 mg PO/IV daily (2 mg tablets).
Day 4 DOXORUBICIN 50 mg/m2 IV infusion daily in 100 mL sodium chloride 0.9% over
2 hours.
Day 4 VINCRISTINE 1.4 mg/m2 (maximum 2 mg) IV infusion in 50 mL sodium chloride
0.9% over 10 minutes. Consider capping at 1 mg in the over 70 year old age
group.
Day 5 G-CSF as per local policy. Continue until neutrophils >1.0 x 109/L for 3
consecutive days.
Day 7 CYTARABINE 100 mg INTRATHECAL.
Days 8 to 11 DEXAMETHASONE 40 mg PO/IV daily (2 mg tablets).
Day 11 VINCRISTINE 1.4 mg/m2 (maximum 2 mg) IV infusion in 50 mL sodium chloride
0.9% over 10 minutes. Consider capping at 1 mg in the over 70 year old age
group.

R-MA - Cycles 2, 4, 6, 8:
Day 0 Hydration / Alkalinisation - Pre methotrexate (starting T= -12 hours). Refer to
sections below.
Day 1 RITUXIMAB 375 mg/m2 IV infusion daily in 500 mL sodium chloride 0.9%.
Day 1 (T=0) METHOTREXATE 1 g/m2 IV infusion [start at 10.00 hrs] Day 1 in exactly 500 mL
sodium chloride 0.9% over 24 hrs.
Calcium folinate (Folinic acid) post methotrexate (starting 36 hours from the
start of methotrexate). Refer to sections below.
Day 2 METHOTREXATE 12 mg INTRATHECAL (following completion of IV
methotrexate).
Days 3 & 4 CYTARABINE* 3 g/m2 IV infusion (at 24, 36, 48 and 60 hours after completion of
IV methotrexate) in 500 mL sodium chloride 0.9% over 2 hours.
Day 5 G-CSF as per local policy. Continue until neutrophils >1.0 x 109/L for 3
consecutive days.
Day 7 CYTARABINE 100 mg INTRATHECAL.
NB: * Patients aged 60 years or more, reduce cytarabine to 1 g/m2.

This is a controlled document and therefore must not be changed or photocopied 2 of 7

L.51 Authorised by Lymphoma lead Published: May 2014 Version
R-Hyper-CVAD / Dr. Graham Collins Reviewed: May 2018 1.2
R-MA Date: May 2018 Review: May 2020
Lymphoma group

INTRAVENOUS HYDRATION

Start: T = -12 hours.

Fluid: 1000 mL glucose 2.5%, sodium chloride 0.45% with potassium chloride 20 mmol and
sodium bicarbonate 100 mmol added. Following completion of methotrexate infusion, decrease
amount of sodium bicarbonate in fluids to 50 mmol/L.
Flow rate: 200 mL/hour (or 150 mL/hour if BSA less than 1.6 m2).
Duration: Continue fluids during methotrexate infusion (run concurrently with methotrexate,
through one arm of Y extension). Administer fluids until methotrexate level <0.1 micromol/L.

METHOTREXATE INTRAVENOUS INFUSION

Start: T = 0 (aim to start at 10.00 am)

Levels: Check 48 hours after the start of the methotrexate infusion, and every 24 hours thereafter
until methotrexate level less than 0.1 micromol/L.

URINE OUTPUT

Check: Every 4 hours.

Aim: 400 mL/m2/4 hours (approx. 700 mL over 4 hours).
Furosemide: Administer 20-40 mg to maintain urine output.

FOLINIC ACID RESCUE

Start: 36 hour from start of methotrexate infusion.

Dose: 30 mg every 3 hours for 5 doses, then every 6 hours until methotrexate level is less than 0.1
micromol/L.
Administration: Give intravenous boluses for at least the first 4 doses then change to oral if the
patient is compliant and not vomiting.

GLUCARPIDASE – reversal agent

NHS England will fund Glucarpidase (unlicensed in UK) for adults receiving high-dose
methotrexate chemotherapy (doses >1g/m2)
- Who develop significant deterioration in renal function (>1.5x ULN and rising, or the
presence of oliguria) OR
- Have toxic plasma methotrexate level AND
- Have been treated with all standard rescue and supportive measures AND
- At risk of life-threatening methotrexate-induced toxicities

The recommended dose is one single intravenous injection of 50units/kg

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L.51 Authorised by Lymphoma lead Published: May 2014 Version
R-Hyper-CVAD / Dr. Graham Collins Reviewed: May 2018 1.2
R-MA Date: May 2018 Review: May 2020
Lymphoma group

CYCLE FREQUENCY

Maximum of 4 complete cycles, i.e. 4 x R-HyperCVAD and 4 x R-MA alternating.

Start next course if neutrophil count is >1.0 x 109/L and platelet count is >60 x 109/L.
Continue G-CSF until count is >1.0 x 109/L for 3 consecutive days.
24 hours after stopping G-CSF if neutrophil count is >1.0 x 109/L start next course.
If the neutrophil count is >1.0 x 109/L but platelets are <60 x 109/L, continue G-CSF until neutrophil
count is >1.0 x 109/L for 3 consecutive and await platelet recovery.

RESTAGING

Re-stage with CT or CT PET neck, chest, abdomen, pelvis (with contrast) after maximum of 2 x R-
hyperCVAD and 2 x R-MA alternating.

DOSE MODIFICATIONS

Hyper-CVAD

Cyclophosphamide:
Renal impairment Hepatic impairment
GFR (mL/min) Dose Clinical decision. Exposure to active
>20 100% metabolites may not be increased, suggesting
10-20 75% dose reduction may not be necessary.
<10 50%
Clinical decision – consider whether patient is
being treated with high dose treatment.

Doxorubicin:
Renal impairment Hepatic impairment
Discuss with consultant if renal Bilirubin micromol/L Dose
impairment severe 20-51 50%
51-85 25%
>85 omit
If AST 2-3 x normal, give 75% dose
If AST >3x ULN, give 50% dose
Doxorubicin maximum cumulative dose (additive to other anthracyclines):
450-550 mg/m2 (in normal cardiac function)
400 mg/m2 (in patients with cardiac dysfunction or exposed to mediastinal irradiation).
Consider dose reduction in the event of cardiac impairment.

This is a controlled document and therefore must not be changed or photocopied 4 of 7

L.51 Authorised by Lymphoma lead Published: May 2014 Version
R-Hyper-CVAD / Dr. Graham Collins Reviewed: May 2018 1.2
R-MA Date: May 2018 Review: May 2020
Lymphoma group

Vincristine:
Renal impairment Hepatic impairment
No dose reduction Bilirubin 26-51 micromol/L or ALT/AST 60-180 u/L 50% dose
necessary Bilirubin >51 micromol/L & normal ALT/AST 50% dose
Bilirubin >51 micromol/L & ALT/ AST >180 u/L omit
Vincristine In the presence of motor weakness or severe sensory symptoms, discuss reducing or
withholding vincristine with a consultant.

MA

Methotrexate: clinical judgment discuss with consultant.

A fluid space, e.g. pleural effusion or ascites, is potentially very dangerous as methotrexate can
accumulate and cause prolonged toxicity. High dose methotrexate should not be given in such cases.

Renal impairment Hepatic impairment

GFR > 80 mL/min 100% dose Bilirubin < 50 micromol/L and AST < 180 u 100% dose
GFR 60 mL/min 65% dose Bilirubin 51 - 85 micromol/L or AST >180 75% dose
GFR 45 mL/min 50% dose Bilirubin > 85 micromol/L - contraindicated / discuss with
GFR < 30 mL/min contra-indicated consultant.

High dose methotrexate expected to cause raised

transaminases and occasionally hyperbilirubinemia,
lasting up to 2 weeks after infusion, and are not
considered toxicity requiring discontinuation of repeated
administration of methotrexate.

Persistent hyperbilirubinemia and / or grade 3-4 raised

transaminases for longer than 3 weeks should result in
discontinuation of the drug. Contraindicated in severe
hepatic impairment.
Reduce methotrexate dose by 50-75% if there is delayed excretion & / or nephrotoxicity with
previous cycle.

Cytarabine:
Renal impairment
Hepatic impairment
(dose reduction may not be necessary)
High dose 1-3 g/m2 consider Bilirubin > 34 micromol/L give 50% dose
GFR 46-60 mL/min 60% dose Escalate doses in subsequent cycles in the
GFR 31-45 mL/min 50% dose absence of toxicity.
GFR < 30mL/min omit

Dexamethasone: Omit dexamethasone for severe proximal myopathy.

INVESTIGATIONS

FBC, U&Es, LFTs: as for in-patient care.

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L.51 Authorised by Lymphoma lead Published: May 2014 Version
R-Hyper-CVAD / Dr. Graham Collins Reviewed: May 2018 1.2
R-MA Date: May 2018 Review: May 2020
Lymphoma group

CONCURRENT MEDICATION

Allopurinol 300 mg daily for 7 days starting 24-48 hours prior to

chemotherapy (first course / cycle only)
Consider rasburicase if high risk for tumour lysis syndrome
Ranitidine (or PPI if specifically Daily for the duration of treatment
indicated - discuss with consultant)
Fluconazole 50 mg daily for the duration of treatment
Aciclovir 200 mg three times a day for duration of treatment and for 3
months after completion

Norethisterone 5 mg three times a day PO as appropriate.

Prednisolone 0.5-1% eye drops For MA cycles only

Or
Dexamethasone 0.1% eye drops Starting from Day 3, one drop to each eye QDS. Continue
(depending on local formulary) for 5 days after cytarabine (due to risk of cytarabine-induced
conjunctivitis). In the event of conjunctivitis, consider
increasing the frequency to 2 hourly until resolution of
symptoms. Liaison with ophthalmologists may be necessary
in this situation.
Co-trimoxazole 480 mg daily Mon, Wed, Fri after final cycle of
chemotherapy, methotrexate level is < 0.1 micromol/L and
when neutrophils >2x109/L. Continue for 3 months.

Patients MUST NOT receive co-trimoxazole during

treatment. Consider pentamidine treatment if considered at
risk from Pneumocystis infection.
G-CSF As per local policy starting from Day 5.

A number of drugs can interfere with tubular secretion of methotrexate. These include penicillins,
aspirin and NSAIDs. Tazocin should NOT be used during high dose methotrexate administration or
rescue. Consider using meropenem or other alternative. Review indications for aspirin and NSAIDs
and consider stopping during methotrexate treatment.

EMETIC RISK

Hyper-CVAD Days 1 to 4: High to moderate

MA Day 1-2: High
Days 3 to 4: High to moderate

This is a controlled document and therefore must not be changed or photocopied 6 of 7

L.51 Authorised by Lymphoma lead Published: May 2014 Version
R-Hyper-CVAD / Dr. Graham Collins Reviewed: May 2018 1.2
R-MA Date: May 2018 Review: May 2020
Lymphoma group

ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS

Cyclophosphamide may irritate the bladder. Encourage patient to drink a minimum of 3 litres per
24 hours.
Cardiotoxicity - monitor cardiac function. Doxorubicin may be stopped in future cycles if signs of
cardiotoxicity, e.g. cardiac arrhythmias, pericardial effusion, tachycardia with fatigue.
Vincristine may cause neurotoxicity.
Rituximab - severe cytokine release syndrome is characterised by severe dyspnoea, often
accompanied by bronchospasm and hypoxia, in addition to fever, chills, rigors, urticaria, and
angioedema.

EXTRAVASATION RISK

Cyclophohsphamide: neutral
Cytarabine: neutral
Doxrubicin: vesicant
Etoposide: irritant
Methotrexate: inflammatory agent
Vincristine: vesicant
Rituximab: neutral

TREATMENT RELATED MORTALITY

2-5%.

REFERENCES

1. Khouri IF, Romaguera J, Kantarjian H, Palmer JL, Pugh WC, Korbling M, et al. Hyper-CVAD and high-
dose methotrexate/cytarabine followed by stem-cell transplantation: an active regimen for aggressive
mantle-cell lymphoma. J Clin Oncol. 1998 Dec;16(12):3803-9.
2. Thomas DA, Cortes J, O'Brien S, Pierce S, Faderl S, Albitar M, et al. Hyper-CVAD program in Burkitt's-
type adult acute lymphoblastic leukemia. J Clin Oncol. 1999 Aug;17(8):2461-70.
3. Kantarjian HM, O'Brien S, Smith TL, Cortes J, Giles FJ, Beran M, et al. Results of treatment with hyper-
CVAD, a dose-intensive regimen, in adult acute lymphocytic leukemia. J Clin Oncol. 2000 Feb;18(3):547-
61.
4. Romaguera JE, Fayad L, Rodriguez MA, Broglio KR, Hagemeister FB, Pro B, et al. High rate of durable
remissions after treatment of newly diagnosed aggressive mantle-cell lymphoma with rituximab plus
hyper-CVAD alternating with rituximab plus high-dose methotrexate and cytarabine. J Clin Oncol. 2005
Oct 1;23(28):7013-23.
5. Thomas DA, Faderl S, O'Brien S, Bueso-Ramos C, Cortes J, Garcia-Manero G, et al.
Chemoimmunotherapy with hyper-CVAD plus rituximab for the treatment of adult Burkitt and Burkitt-type
lymphoma or acute lymphoblastic leukemia. Cancer. 2006 Apr 1;106(7):1569-80.
6. O'Brien S, Thomas DA, Ravandi F, Faderl S, Pierce S, Kantarjian H. Results of the hyperfractionated
cyclophosphamide, vincristine, doxorubicin, and dexamethasone regimen in elderly patients with acute
lymphocytic leukemia. Cancer. 2008 Oct 15;113(8):2097-101.
7. Department of Health (2008) Updated national guidance on the safe administration of intrathecal
chemotherapy, Health Service Circular, HSC 2008/001.
8. UCLH - Dosage Adjustment for Cytotoxics in Hepatic Impairment (Version 3 - updated January 2009).
9. UCLH - Dosage Adjustment for Cytotoxics in Renal Impairment (Version 3 - updated January 2009).
This is a controlled document and therefore must not be changed or photocopied 7 of 7
L.51 Authorised by Lymphoma lead Published: May 2014 Version
R-Hyper-CVAD / Dr. Graham Collins Reviewed: May 2018 1.2
R-MA Date: May 2018 Review: May 2020