O-CVP with maintenance Obinutuzumab

Transcription

1 with maintenance Obinutuzumab INDICATION Follicular Lymphoma: 1 st line treatment in advanced symptomatic patients (NICE TA513 for FLIPI score 2 or higher - BLUETEQ required) TREATMENT INTENT Disease modification. 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), presence or absence of B symptoms, clinical extent of disease, consider bone marrow aspirate and trephine. 3. Blood tests - FBC, DAT, U&Es, LDH, ESR, urate, calcium, magnesium, creatinine, LFTs, glucose, Igs, β 2 microglobulin, hepatitis B core antibody and hepatitis BsAg, hepatitis C antibody, EBV, CMV, VZV, HIV 1+2 after consent, group and save. 4. 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. 5. ECG +/- Echo - if clinically indicated. 6. Record performance status (WHO/ECOG). 7. Record height and weight. 8. 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. 9. 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. 10. Hydration - in patients with bulky disease pre-hydrate with sodium chloride 0.9% 1 litre over 4-6 hours. For patients at high risk of tumour lysis, refer to the tumour lysis protocol. 11. Withhold antihypertensive treatment 12 hours before, during and 1 hour after Obinutuzamb infusion. Patients at acute risk of hypertensive crisis should be evaluated for the benefits and risks of withholding their anti-hypertensive medicine 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. 1 of 4

2 DRUG REGIMEN Make sure that the patient receives adequate hydration. For cycle 1 day 1 administer 500mL normal saline 0.9% over 1 hour before administering Obinutuzumab. INDUCTION Day 1 Days 1 to 5 Days 8 and 15 (CYCLE 1 ONLY) MAINTENANCE Day 1 Pre med:** At least 60 minutes prior to infusion: Prednisolone 100mg PO (Given as Day 1 prednisolone part of the regimen) At least 30 minutes prior to infusion paracetamol 1g PO and chlorphenamine 10mg IV OBINUTUZUMAB 1000mg IV infusion in 250mL sodium chloride 0.9% VINCRISTINE 1.4 mg/m 2 (max 2 mg*) IV infusion in 50 ml sodium chloride 0.9% over 10 minutes. CYCLOPHOSPHAMIDE 750 mg/m 2 IV bolus. * Patients >70 years use 1 mg vincristine. **See premedication administration guidance summary table below. See Infusion Rate section below PREDNISOLONE 100mg PO daily. (Day 1 to be given as a pre-med 1 hour prior to starting Obinutuzumab infusion) Pre med** At least 60 minutes prior to infusion: Prednisolone 100mg PO At least 30 minutes prior to infusion paracetamol 1g PO and chlorphenamine 10mg IV OBINUTUZUMAB 1000mg IV infusion in 250mL sodium chloride 0.9% Pre med:** At least 60 minutes prior to infusion: Prednisolone 100mg PO At least 30 minutes prior to infusion paracetamol 1g PO and chlorphenamine 10mg IV OBINUTUZUMAB 1000mg IV infusion in 250mL sodium chloride 0.9% PREMEDICATION Pre-meds required Prednisolone 100mg PO. Completed at least 60 minutes prior to infusion Chlorphenamine 10mg IV. At least 30 minutes prior to infusion Paracetamol 1g PO. At least 30 minutes prior to infusion steroid pre-med is recommended in FL on cycle 1 day 1. Hydrocortisone should not be used as it has not been effective in reducing rates of IRR. If the Prednisolone part of the chemotherapy regimen is due to be administered on the same day as Obinutuzumab, the corticosteroid can be administered as as the oral prednisolone if given at least 60 minutes prior to Obinutuzumab, Cycle 1 Days 1 All Patients Subsequent infusions Cycle 1 Days 8 & 15 and Cycles 2-8 Patients without Patients with grades 1-2 any IRR Symptoms (mild to moderate) IRR with the previous infusions Patients with a grade 3 (severe) IRR with the previous infusion OR with a lymphocyte count >25 x 10 9 /L prior to next treatment 2 of 4

3 INFUSION RATE These are the recommended starting infusion rates assuming the patient has not experience infusion related reactions in the prior infusion; otherwise the infusion rate should be no more than half the previous rate. Cycle 1 Day 1 Subsequent infusions Administer at 50mg/hr. The rate of infusion can be escalated in 50mg/hr increments every 30 minutes to a maximum of 400mg/hr. If no infusion related reactions or if an IRR Grade 1 occurred during the prior infusion when the final infusion rate was 100mg/hr or faster, infusions can be started at a rate of 100mg/hr and increased by 100mg/hr increments every 30 minutes to a maximum of 400mg/hr. Note: For guidance on infusion rates in the case of infusion related reactions. See adverse effects section below. CYCLE FREQUENCY Induction: Cycle repeats every 21 days for up to to 6-8 cycles Maintenance: Obinutuzumab is given every 2 months for 2 years RESTAGING Give 4 courses and restage with CT. If progressive disease, consider other treatment. Consider maintenance if PR or CR after 6-8 cycles Re-stage at the end of maintenance with CT or PET/CT DOSE MODIFICATIONS Haematological toxicity: Neutrophils x 10 9 /L Platelets x 10 9 /L Cyclophosphamide Vincristine Prednisolone >1.5 and % 100% 100% and % 100% 100% and/or % 100% 100% <0.5 and/or <50 0% 100% 100% Renal/Hepatic Impaitment: Vincristine Renal impairment No dose reduction necessary Hepatic impairment Bilirubin micromol/l or ALT/AST 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. 3 of 4

4 Obinutuzumab: Renal impairment No dose adjustment is required in patients with mild to moderate renal impairment (CrCl ml/min). The safety and efficacy has not been established in patients with severe renal impairment (CrCl < 30 ml/min). Patients with renal impairment (CrCl < 50 ml/min) are more at risk of IRRs, neutropenia and thrombocytopenia. Cyclophosphamide: Renal impairment GFR (ml/min) Dose >20 100% % <10 50% Clinical decision consider whether patient is being treated with high dose treatment. Hepatic impairment The safety and efficacy of Obinutuzumab in patients with impaired hepatic function has not been established. No specific dose recommendations can be made. Hepatic impairment Clinical decision. Exposure to active metabolites may not be increased, suggesting dose reduction may not be necessary. INVESTIGATIONS FBC, renal and liver profiles. CONCURRENT MEDICATION Allopurinol Ranitidine (or PPI if specifically indicated - discuss with consultant) Aciclovir Mesna (in patients with pre-existing bladder disorders) 300 mg daily for 7 days starting hours prior to chemotherapy (first course / cycle 1 only) Daily for the duration of steroid treatment in regimen 200 mg three times a day for duration of treatment and for 3 months after completion The oral dose of mesna is 40% of the intravenous bolus dose of the Cyclophosphamide given on 3 occasions at intervals of 4 hours beginning 2 hours before the Cyclophosphamide injection; thus a total dose of mesna equivalent to 120% of the Cyclophosphamide is given. In patients at high-risk of urothelial toxicity a shorter interval may be left between oral mesna doses, or the number of doses increased, or both. Alternatively, the initial dose of mesna (20% of the dose of the Cyclophosphamide) may be given intravenously at the same time as the antineoplastic, followed by two oral doses (each 40% of the dose of the Cyclophosphamide) given 2 and 6 hours after the intravenous dose. 4 of 4

5 EMETIC RISK Induction: Moderate. Maintenance: minimal EXTRAVASATION RISK Cyclophosphamide: neutral Vincristine: vesicant Obinutuzumab: nuetral 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. Steroid side effects monitor BMs. Anti-CD20 antibody therapy may re-activate hepatitis B Main side effects of Obinutuzumab: Infusion-related reaction, tumour lysis syndrome, neutropenia, thrombocytopenia, anaemia, hepatitis B reactivation, worsening of pre-existing cardiac condition, upper respiratory infections, diarrhoea and constipation. Infusion-related Toxicity: - Obinutuzumab should be administered as per infusion protocol. Infusion-related sideeffects such as rashes, allergic and anaphylactic reactions or cytokine release syndrome (dyspnoea, bronchospasm and hypoxia, in addition to fever, chills, rigors, urticaria and angiooedema) should be treated promptly. It is recommended, that the infusion should be temporarily interrupted or slowed until the adverse event has subsided and then re-started at 50% of the previous dose. - Patients who have pre-existing cardiac or pulmonary conditions should be monitored carefully throughout the infusion and the post-infusion period. Hypotension may occur during intravenous infusions. Therefore, withholding of antihypertensive treatments should be considered for 12 hours prior to and throughout each infusion and for the first hour after administration. Patients at acute risk of hypertensive crisis should be evaluated for the benefits and risks of withholding their anti-hypertensive medicin - Ensure there is a doctor and experienced nurse available during administration of all doses on cycle 1 and subsequent doses if the patient previously reacted - Monitor the patient closely during the infusion. - Have symptomatic rescue medication readily available for administration in case of occurrence of IRRs. - Have emergency resuscitation facilities available during infusion. - Management of IRRs may require temporary interruption, reduction in the rate of infusion, or treatment discontinuations as outlined below: 5 of 4

6 IRR grade Grade 4 (life threatening) Grade 3 (severe) Grade 1-2 (mild to moderate) Recommendation Infusion must be stopped and therapy must be permanently discontinued. Infusion must be temporarily stopped and symptoms treated Upon resolution of symptoms, the infusion can be restarted at no more than half the previous rate (the rate being used at the time that the IRR occurred) If the patient does not experience any IRR symptoms, the infusion rate escalation can resume at the increments and intervals as appropriate for the treatment dose. if the patient experiences a second occurrence of a Grade 3 IRR, the infusion must be stopped and therapy permanently discontinued The infusion rate must be reduced and symptoms treated Upon resolution of symptoms, the infusion can be restarted at no more than half the previous rate (the rate being used at the time that the IRR occurred) If the patient does not experience any IRR symptoms, the infusion rate escalation can resume at the increments and intervals as appropriate for the treatment dose. TREATMENT RELATED MORTALITY Approximately 1% REFERENCES 1. R. Marcus, A. Davies, K. Ando, W. Klapper, S. Opat, C. Owen, E. Phillips, R. Sangha, R. Schlag, J.F. Seymour, W. Townsend, M. Trneny, M. Wenger, G. Fingerle-Rowson, K. Rufibach, T. Moore, M. Herold, and W. Hiddemann. Obinutuzumab for the first-line Treatment of Follicular Lymphoma. N Engl J Med. (2017) 377; NICE. TA513 Obinutuzumab for untreated advanced follicular lymphoma. Published 21/03/2018. Available at 3. Roche. Summary of Product Characteristics Gazyvaro 1000mg. Updated 07 Dec Accessed on 13/02/2018 via 4. UCLH - Dosage Adjustment for Cytotoxics in Hepatic Impairment ( 3 - updated January 2009). 5. UCLH - Dosage Adjustment for Cytotoxics in Renal Impairment ( 3 - updated January 2009). 6 of 4