INDICATION CD20-positive high-grade non-hodgkin Lymphoma in patients in which R-CHOP is not indicated TREATMENT INTENT Curative or Disease Modification. PRE-ASSESSMENT 1. Ensure histology is confirmed prior to administration of chemotherapy and document in notes. 2. Record stage of disease - contrast enhanced CT scan (neck, chest, abdomen and pelvis) and/or PET scan, presence or absence of B symptoms, clinical extent of disease, cardiac function, bone marrow trephine. 3. Blood tests - FBC, U&Es, LDH, ESR, urate, calcium, magnesium, creatinine, LFTs, glucose, Igs, hepatitis B core antibody and hepatitis BsAg, hepatitis C antibody, EBV, CMV, VZV, HIV 1+2 after consent, group and save. 4. Cerebrospinal fluid examination if clinically indicated or lymphomatous involvement in bone marrow, orbit, nasal/paranasal sinuses, orbit, testis, peripheral blood and bone. 5. Urine pregnancy test - before cycle 1 of each new chemotherapy course for women of childbearing age unless they are post-menopausal, have been sterilised or undergone a hysterectomy. 6. ECG and Echo. 7. Record performance status (WHO/ECOG). 8. Record vital signs, 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% rate as per clinician discretion 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. Treatment should be agreed in the relevant MDT. This is a controlled document and therefore must not be changed or photocopied 1 of 5
DRUG REGIMEN Day 1 Pre med - Paracetamol 1g PO, Chlorphenamine 10 mg IV, and Day 1 Prednisolone 30 minutes before rituximab. RITUXIMAB 375 mg/m 2 IV infusion daily in 500 ml sodium chloride 0.9%. VINCRISTINE 1.4 mg/m 2 (maximum 2 mg*) IV infusion in 50 ml sodium chloride 0.9% over 10 minutes. CYCLOPHOSPHAMIDE 750 mg/m 2 IV bolus GEMCITABINE** 750 mg/m 2 IV infusion in 250 ml sodium chloride 0.9% Days 1 to 5 PREDNISOLONE 100mg PO daily. (Give first dose before rituximab as pre-med). Day 8 GEMCITABINE** 750 mg/m 2 IV infusion in 250 ml sodium chloride 0.9% * Max. Vincristine dose 2 mg (consider capping at 1 mg in over 70 year old patients). ** The Gemcitabine dose is escalated to 875 mg/m 2 for cycle 2 and then 1 g/m 2 for successive cycles if no toxicity is observed. Primary G-CSF prophylaxis should be used according to local policy (e.g. filgrastim for 7 days starting on day 9). CYCLE FREQUENCY Cycle repeats every 21 days for 6 cycles. RESTAGING Re-stage with Interim CT scan after 4 courses of treatment to ensure response. PET/CT or contrast enhanced CTat completion of treatment. Consider repeat Bone Marrow Biopsy at end of treatment if initially involved and clinically appropriate This is a controlled document and therefore must not be changed or photocopied 2 of 5
DOSE MODIFICATIONS Toxicity 1. Haematological Toxicity ANC (x10 9 /L) Platelets (x10 9 /L) Gemcitabine 1.0 75 100% 100% 0.5 - <1.0 50 - <75 75% 75% <0.5 <50 Day 1: Delay until ANC 1 and platelets 75, then 100% dose. Day 8: Omit dose Cyclophosphamide & Vincristine Delay until ANC 1 and platelets 75, then 100% dose. *Dose modifications due to haematological toxicities should only be made according to the blood count on the day of treatment. Febrile neutropenia Haemorrhage with thrombocytopenia 2. Non-haematological Toxicity Grade 3 (expect nausea & vomiting, alopecia) Grade 4 Delay until recovery. If recurrent, then 75% dose in subsequent courses. Delay until recovery, then 75% dose in subsequent courses. Delay until recovery. If recurrent, then 75% dose in subsequent courses. Delay until recovery, then 75% dose in subsequent courses. 75% in subsequent courses. 75% in subsequent courses. Delay until recovery, then 50% in subsequent courses. Delay until recovery, then 50% in subsequent courses. Gemcitabine: CrCl <30 ml/min consider dose reduction - Clinical decision Gemcitabine: limited information, consider dose reduction if bilirubin elevated - e.g. if bilirubin >27 micromol/l, consider initiating at 80% dose. Vincristine: Bilirubin 26-51 micromol/l or ALT/AST 60-180 u/l 50% dose 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. This is a controlled document and therefore must not be changed or photocopied 3 of 5
Cyclophosphamide: GFR (ml/min) Dose >20 100% 10-20 75% <10 50% Clinical decision consider whether patient is being treated with high dose treatment. Clinical decision. Exposure to active metabolites may not be increased, suggesting dose reduction may not be necessary. INVESTIGATIONS FBC, renal and liver profiles, only FBC result essential prior to administration of chemotherapy. CONCURRENT MEDICATION Allopurinol Co-trimoxazole Ranitidine or PPI Aciclovir G-CSF 300 mg daily for 7 days starting 24-48 hours prior to chemotherapy (first course / cycle only) 480 mg OD PO (Mon, Wed and Fri) to treatment end plus 3 months Daily for the duration of steroid treatment in regimen 200 mg TDS until 3 months after last course from Day 9 as per local policy. EMETIC RISK Moderate. ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Cyclophosphamide may irritate the bladder mucosa. Patients should be encouraged to drink a minimum of three litres of fluid per 24 hrs. Vincristine may cause neurotoxicity. Gemcitabine may cause elevation of liver transaminases (AST and ALT), increased bilirubin and alkaline phosphatise, haematuria, oedema/peripheral oedema. Rituximab may cause patient chillness, fever, headache, tiredness, aching muscles and joints, itching redness of skin, nausea and mild drop in blood pressure. Hepatitis B reactivation. Steroid side effects monitor BMs. This is a controlled document and therefore must not be changed or photocopied 4 of 5
TREATMENT RELATED MORTALITY 2-5% REFERENCES 1. Fields P, Webb A, Pocock CFE, Townsend W, Smith P, Kirkwood A, El-Mehiki N, Johnson PW, Radford J, Linch DC, Cunningham D. First Analysis of a Phase II Study of Rituximab-Gemcitabine, Cyclophosphamide, Vincristine and Prednisolone () for Diffuse Large B Cell Lymphoma (DLBCL) Patients Considered Unsuitable for Anthracycline Containing Chemo-Immunotherapy. An NCRI Lymphoma Clinical Studies Group Trial. Blood (ASH Annual Meeting Abstracts), Nov 2011; 118: 1634. 2. UCLH - Dosage Adjustment for Cytotoxics in Hepatic Impairment ( 3 - updated January 2009). 3. UCLH - Dosage Adjustment for Cytotoxics in Renal Impairment ( 3 - updated January 2009). This is a controlled document and therefore must not be changed or photocopied 5 of 5