Lymphoma group

ESHAP and R-ESHAP

INDICATION

Chemosensitive relapsed / refractory Hodgkin and non-. Omit rituximab if CD20-negative.

TREATMENT INTENT

Disease Modification.

PRE-ASSESSMENT

1. Ensure histology is confirmed prior to administration of and document in notes. 2. Record stage of disease - contrast enhanced CT scan (neck, chest, abdomen and pelvis), and/or PET-CT scan, presence or absence of B symptoms, clinical extent of disease. Bone marrow trephine if clinically indicated in Non Hodgkins lymphoma. 3. Blood tests - FBC, ESR, U&Es, LDH, urate, calcium, magnesium, creatinine, LFTs, glucose, hepatitis B core antibody and hepatitis B surface Ag, hepatitis C antibody 4. Send a "group and save" sample to transfusion and inform patient and transfusion laboratory that they will require irradiated blood products for 7 days before harvest. See ‘Guidelines for the use of blood components in adult haematology' for details. Ensure irradiation card is attached to the patient's notes and copy given to the patient. 5. 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. 6. ECG +/- Echo - if clinically indicated. 7. Record performance status, 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 prior to treatment. 9. Fertility - it is very important the patient understands the potential risk of reduced fertility. 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. Advise dental check is carried out by patient's own dental practitioner before treatment starts. 12. Liaise with BMT nurse co-ordinator for timing of harvest and possible transplant slot. 13. Venous access should be assessed well in advance of collection. Every effort should be made not to use antecubital fossa veins in the run up to harvest. 14. If good antecubital fossa veins, insert Hickman line. Apheresis line to be inserted if poor antecubital veins. 15. Treatment should be agreed in the relevant MDT. 16. This is usually delivered during an inpatient stay but can be used in ambulatory setting for patient(s) meeting criteria. Refer to local Ambulatory Care Operational Policy. 17. Ensure the peripheral stem cell harvest / final donor clearance form (form FRM3721/1) is sent within 30 days of scheduled harvest date, via nhs.net mail to NHSBT STS, to confirm eligibility for PBSCH.

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Lymphoma group

NB: Infective agent screen. Peripheral blood stem cells for autologous transplant are cryopreserved in liquid nitrogen. In order to eliminate the risk of transmitting infective agents during the storage of marrow, virology testing is mandatory within 30 days of the harvesting procedure and results must be known before priming.

Bottles and consent form provided by NBS Oxford. Please send to the stem cell laboratory Oxford. Address provided on consent form.

DRUG REGIMEN

This is an infusional regimen given over a total of 5 days.

Day 1: Hydration regimen: Pre 1L sodium chloride 0.9% + 20 mmol KCl + 8 mmol MgSO4 infusion over 2 hours. 100 mL Mannitol 10% intravenous infusion over 15 minutes. Furosemide 40 mg may be added if there is weight gain >2kg during infusion or other clinical evidence of fluid overload. CISPLATIN 25 mg/m2/day. For inpatients: in 1L sodium chloride 0.9% IV infusion over 22 hours (total dose = 100 mg/m2 over 4 days) For outpatients: continuous IV infusion via pump (e.g. Baxter 2C1008KP LV2 Infusor) over 96 hours (total dose = 100 mg/m2) and encourage oral hydration – at least 3 litres per day 40 mg/m2 IV infusion OD in 250-500 mL sodium chloride 0.9% over 1 hour. Can be given alongside cisplatin via a different lumen. METHYLPREDNISOLONE 500 mg IV infusion OD in 100 mL sodium chloride 0.9% over 15 min (OR orally). Can be given alongside cisplatin via a different lumen. Pre-med - Paracetamol 1 g PO, Chlorphenamine 10 mg IV, Hydrocortisone 100 mg IV (or the steroid component of the regimen). RITUXIMAB 375 mg/m2 IV infusion daily in 500 mL sodium chloride 0.9%. NB: Rituximab may be administered on Day 2. Can be given alongside cisplatin via a different lumen.

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Days 2-4: Hydration regimen: Pre Cisplatin 1L sodium chloride 0.9% + 20 mmol KCl + 8 mmol MgSO4 infusion over 2 hours. 100 mL Mannitol 10% intravenous infusion over 15 minutes. Furosemide 40 mg may be added if there is weight gain >2kg during infusion or other clinical evidence of fluid overload. CISPLATIN 25 mg/m2/day. For inpatients: in 1L sodium chloride 0.9% IV infusion over 22 hours (total dose = 100 mg/m2 over 4 days) For outpatients: continuous IV infusion via pump (e.g. Baxter 2C1008KP LV2 Infusor) over 96 hours (total dose = 100 mg/m2) ETOPOSIDE 40 mg/m2 IV infusion OD in 250-500 mL sodium chloride 0.9% over 1 hour. Can be given alongside cisplatin via a different lumen. METHYLPREDNISOLONE 500 mg IV infusion OD in 100 mL sodium chloride 0.9% over 15 min (OR orally).

Day 5: METHYLPREDNISOLONE 500 mg IV infusion OD in 100 mL sodium chloride 0.9% over 15 min (OR orally). 2 g/m2 OD in 250 mL sodium chloride 0.9% over 3 hours.

When used for priming: Days 6 to 15 Daily G-CSF as per local policy. Continue until mobilisation completed. *G-CSF should be discontinued after completion of stem cell harvesting. (Pegfilgrastim must NOT be used)

When not used for priming: Days 6 to 12 Daily G-CSF as per local policy.

HARVESTING (if used for priming)

Stem cell collection performed days 15 and 16. Aim to collect minimum of 2.0 x 106 with target of 4.0 x 106 CD34-positive cells/kg.

CYCLE FREQUENCY

Courses are repeated every 3-4 weeks depending on blood count recovery (neuts >1.0 and Platelets > 75) to a maximum of 3 courses.

RESTAGING

After 1-2 cycles with CT or PET-CT.

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DOSE MODIFICATIONS

Haematolological Prior to each cycle, the following criteria must be met: 1. Neutrophil count ≥ 1 x 109/L 2. Platelet count > 75 x 109/L

Cytarabine: Renal impairment Hepatic impairment GFR (mL/min) Dose Bilirubin >34 micromol/L: 50% dose. >60 100% Escalate doses in subsequent cycles in the absence 46-60 60% of toxicity. 31-45 50% <30 Contra-indicated

Cisplatin: Renal impairment Hepatic impairment GFR (mL/min) Dose No dose reduction necessary. >60 100% 45-59 75% <45 Consider carboplatin Ototoxicity: Consider omitting the platinum agent.

Etoposide: * Renal impairment Hepatic impairment CrCl (mL/min) Dose Discuss with consultant. Consider: >50 100% Bilirubin 26-51 micromol/L or AST 60-180 u/L: 50% dose 15-50 75% Bilirubin >51 micromol/L or AST >180 u/L: clinical decision <15 50% Subsequent doses should be based on clinical response. * If hepatic function is impaired but renal function good, it may not be necessary to dose reduce etoposide.

INVESTIGATIONS

 Twice weekly FBC, U&Es, creatinine, LFTs, Mg++ and Ca++ - ensure Hb > 100g/L, platelets > 20 x 109/L, and Mg and Ca are within normal limits prior to harvest, arranging replacements as necessary and updating NHSBT STS with current plan.  Check blood sugar daily when on methylprednisolone

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CONCURRENT MEDICATION

Allopurinol 300 mg od for 7 days starting 24 hours before first dose of (if first cycle after relapse) chemo Ranitidine (or PPI ) 150mg twice daily for the duration of treatment 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 Prednisolone 0.5 -1% eye drops Starting from Day 5, 1 drop into both eyes QDS for 7 days. or In the event of conjunctivitis, consider increasing the dexamethasone 0.1% eye drops frequency to 2 hourly until resolution of symptoms. Liaison (depending on local formulary) with ophthalmologists may be necessary in this situation.

G-CSF Daily SC as per local policy. See “Drug Regimen”.

EMETIC RISK

Days 1 to 3: High Days 3 to 4: High - Moderate Beware of delayed emesis with Cisplatin

EXTRAVASTATION RISK

Cisplatin: exfoliant Cytarabine: neutral Etoposide: irritant Rituximab: neutral

ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS

Drug Main adverse effects General Myelosuppression, emesis, alopecia, mucositis Cisplatin Neuropathy, nephrotoxicity, ototoxicity Cytarabine CNS toxicity, conjunctivitis, flu-like syndrome Etoposide Hypotension on rapid infusion, hyperbilirubinaemia Methylprednisolone Weight gain, GI disturbance, hyperglycaemia, CNS disturbance, cushingoid changes Rituximab Chillness, fever, headache, tiredness, aching muscles and joints, itching redness of skin, nausea and mild drop in blood pressure. Hepatitis B reactivation – see pathway for treatment and management of HBV positive patient.

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Lymphoma group

TREATMENT RELATED MORTALITY

2-5%.

REFERENCES

1. Velasquez WS, McLaughlin P, Tucker S, Hagemeister FB, Swan F, Rodriguez MA, Romaguera J, Rubenstein E, Cabanillas F. ESHAP--an effective chemotherapy regimen in refractory and relapsing lymphoma: a 4-year follow-up study. J Clin Oncol. 1994 Jun;12(6):1169-76. 2. Kintzel PE, Dorr RT. Anticancer drug renal toxicity and elimination: dosing guidelines for altered renal function. Cancer Treat Rev. 1995 Jan;21(1):33-64. 3. Harting R, Venugopal P, Gregory SA, O'Brien T, Bogdanova E. Efficacy and safety of rituximab combined with ESHAP chemotherapy for the treatment of relapsed/refractory aggressive B-cell non-Hodgkin lymphoma. Clin Lymphoma Myeloma. 2007 May;7(6):406-12. 4. Kim MK, Kim S, Lee SS, Sym SJ, Lee DH, Kim SW, Jang S, Park CJ, Chi HS, Huh J, Suh C. Rituximab-ESHAP as a mobilization regimen for relapsed or refractory B-cell lymphomas: a comparison with ESHAP. Transfusion. 2007 Aug; 47(8):1447-54. 5. British Oncology Pharmacy Association. Dosage Adjustment for Cytotoxics in Hepatic and Renal Impairment. S Daniels, Guy's & St Thomas' NHS Trust. November 2003. 6. UCLH - Dosage Adjustment for Cytotoxics in Hepatic Impairment (Version 3 - updated January 2009). 7. UCLH - Dosage Adjustment for Cytotoxics in Renal Impairment (Version 3 - updated January 2009).

Review Name Revision Date Version Review date Cheuk-kie Jackie Cheung Annual protocol review May 2017 2.1 (Haematology Pharmacist)

NSSG Lymphoma Group, Annual protocol review. May 2019 2.2 May 2021 Cheuk-kie Jackie Cheung Ambulatory care information (Haematology Pharmacist) added.

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