LD-ARA-C and Clofarabine

Transcription

1 LD-ARA-C and Clofarabine INDICATION Induction plus consolidation chemotherapy for patients with acute myeloid leukaemia (AML). Its use is particularly for patients over 60 years of age but it can be applied to other patients according to clinicians' assessment. Individual Funding approval is required. TREATMENT INTENT Palliative / disease control PRE-ASSESSMENT 1. Ensure diagnosis is confirmed prior to administration and document in notes. 2. Record clinical impact of disease, blood film, bone marrow aspirate and trephine, immunophenotype, cytogenetic results and calculate IPSS score. 3. Blood tests - FBC, DCT, U&Es, LDH, ESR, urate, calcium, magnesium, creatinine, LFTs, glucose, Igs, Hep B&C, EBV, CMV, VZV, HIV 1+2 after consent, group and save. 4. Send a "group and save" sample to transfusion and inform patient and transfusion laboratory that they will require irradiated blood products for all future transfusions. Ensure card is attached to the patient's notes and copy given to the patient. See Guidelines for the use of blood components in adult haematology. 5. Pregnancy Test - for all women of childbearing age before each new chemotherapy course. 6. ECG +/- Echo - if clinically indicated. 7. Record performance status (WHO/ECOG). 8. Record 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 and ensure this is in the hospital record prior to treatment. 10. Fertility - it is very important the patient understands the potential risk of infertility; all patients should be offered fertility advice (see fertility guidelines). 11. Hydration and tumour lysis prevention; 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. Central venous access should be used, e.g. Hickman line or PICC. In urgent cases it may be necessary to start chemotherapy via a peripheral cannula. 14. Treatment should be agreed in the relevant MDT 1 of 5

2 DRUG REGIMEN Hydration: ensure patients receive adequate hydration throughout clofarabine administration. CYCLE 1: INDUCTION Days 1 to 5 Days 1 to 10 CLOFARABINE 20mg/m 2 daily in 100 ml sodium chloride 0.9% intravenous infusion over 1 hour (via a 0.2micron end-line filter) CYTARABINE 20mg TWICE daily (every 12 hours) subcutaneously (to start 3-6 hours after the start of clofarabine infusion) CYCLES 2 & 3: CONSOLIDATION Days 1 to 3 Days 1 to 7 CLOFARABINE 20mg/m 2 daily in 100 ml sodium chloride 0.9% intravenous infusion over 1 hour (via a 0.2micron end-line filter) CYTARABINE 20mg TWICE daily (every 12 hours) subcutaneously (to start 3-6 hours after the start of clofarabine infusion) Note: Subcutaneous cytarabine can be administered in the out-patient setting providing patients/carers have been trained, assessed and confirmed competent for self-administration. Refer to CYCLE FREQUENCY/RESTAGING Cycles repeated every 4-7 weeks depending on neutrophil and platelet count recovery and resolution of non-haematological toxicities. Support with GCSF where necessary. Patients could receive up to 2 cycles of induction if CR was not achieved after cycle 1. Proceed with cycle 2 when the response to the first cycle has been assessed i.e. bone marrow aspirate (see below). DOSE MODIFICATIONS Proceed to the next cycle when neutrophils 0.75 x 10 9 /L and platelets 50 x 10 9 /L and resolution of non-haematological toxicities to Grade 1 or lower (see below). Haematological toxicity: Discuss with consultant. If the ANC does not recover by 6 weeks from the start of a treatment cycle, a bone marrow aspirate / biopsy should be performed to determine possible refractory disease. If refractory consider 2 nd induction (if the patient has had only one induction cycle) or patient to come off protocol. If persistent leukaemia (>5% blasts) is not evident and the marrow is hypocellular; wait until 2 of 5

3 regenrration (platelet count >50x10 9 /L and neutrohplis >0.75x10 9 /L) and dose reduce for the next cycle by 25% of the previous dose. Should patients experience an ANC < /l for more than 4 weeks from the start of the last cycle, it is recommended that the dose for the next cycle be reduced by 25%. Non-haematological toxicity: Subsequent doses of clofarabine and cytarabine were reduced by 25% for grade 3 drug related non-haematologic toxicities. If a patient experiences one or more severe toxicities (US National Cancer Institute (NCI) Common Toxicity Criteria (CTC) Grade 3 toxicities excluding nausea and vomiting), treatment should be delayed until the toxicities resolve to baseline parameters or to the point where they are no longer severe and the potential benefit of continued treatment with clofarabine outweighs the risk of such continuation. It is then recommended that clofarabine be administered at a 25% dose reduction. Should a patient experience the same severe toxicity on a second occasion, treatment should be delayed until the toxicity resolves to baseline parameters or to the point where it is no longer severe and the potential benefit of continued treatment with clofarabine outweighs the risk of such continuation. It is then recommended that clofarabine be administered at a further 25% dose reduction. Any patient who experiences a severe toxicity on a third occasion, a severe toxicity that does not recover within 14 days (see above for exclusions), or a life-threatening or disabling toxicity (US NCI CTC Grade 4 toxicity) should be withdrawn from treatment with clofarabine. Clofarabine Discuss with Consultant Renal impairment CrCl ml/min discuss with consultant and consider 50% dose reduction Avoid in severe renal impairment. The limited data available indicate that clofarabine may accumulate in patients with decreased creatinine clearance. Cytarabine Discuss with consultant Renal impairment No dose modifications for renal impairment. Hepatic impairment Use with caution with mild-moderate hepatic impairment Avoid in severe hepatic impairment. There is no experience in patients with hepatic impairment (serum bilirubin > 1.5 x ULN plus AST and ALT > 5 x ULN) Hepatic impairment Reduce dose by 50% for bilirubin >34micromols/L. INVESTIGATIONS FBC, Coagulation screen. U&E, Creatinine clearance and LFT. Recent bone marrow aspirate. 3 of 5

4 CONCURRENT and SUPPORTIVE MEDICATION Avoid concomitant administration of hepatotoxic and nephrotoxic medication and clofarabine. Drug Allopurinol Fungal prophylaxis Aciclovir Proton pump inhibitor Hydrocortisone Dose and duration 300 mg daily for first 14 days of initial induction chemotherapy. (If a remission is attained, the subsequent use of allopurinol is not required). **Refer to tumour lysis protocol in patients with high WCC>100x10 9. As per local protocol. Withhold antifungal azoles during days of clofarabine therapy to minimize the risk of hepatotoxicity. 200 mg tds Daily if clinically indicated Hydrocortisone 100mg/m 2 iv days 1-3 as required for the prevention of SIRS ANTI-EMETICS Moderate-High emetic risk. ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Clofarabine Cytarabine Myelosuppression, Nausea, vomiting, diarrhea, CNS side-effects have been described (including agitation, anxiety and somnolence, in case of neurotoxicity the infusion time of clofarabine should be increased to 120 minutes), febrile neutropenia, headaches, pruritus, dermatitis, acute vascular leak syndrome, deranged LFTs, nephrotoxicity, plantar-palmar erythrodysaethesia. Systemic Inflammatory Response Syndrome (SIRS), capillary leak syndrome: Clofarabine should be discontinued immediately if patients show early signs or symptoms of SIRS. The use of prophylactic Hydrocortisone 100 mg/m2 on Days 1-3 may be of benefit in preventing signs or symptoms of SIRS or capillary leak.. Haematologic toxicity see above. Nausea. Diarrhea. Oral ulceration. Hepatic dysfunction. Fatigue. Rarely at this dose maculopapular rash, conjunctivitis and malaise. Injection site reactions. MORTALITY 4 and 8 week mortality rates of 3% and 7%, respectively. 4 of 5

5 REFERENCES 1. Tapan M. Kadia, MD; Stefan Faderl, MD; Farhad Ravandi, MD; Elias Jabbour, MD; Guillermo Garcia-Manero, MD; Gautam Borthakur, MD; Alessandra Ferrajoli, MD; Marina Konopleva, MD, PhD; Jan Burger, MD, PhD; Xuelin Huang; Xuemei Wang; Sherry Pierce; Mark Brandt; Jennie Feliu; Jorge Cortes, MD; and Hagop Kantarjian, MD. Final Results of a Phase 2 Trial of Clofarabine and Low-Dose Cytarabine Alternating With Decitabine in Older Patients With Newly Diagnosed Acute Myeloid Leukemia. Cancer July 15, Stefan Faderl, MD; Farhad Ravandi, MD; Xuelin Huang, PhD; Xuemei Wang, MS; Elias Jabbour, MD; Guillermo Garcia-Manero, MD; Tapan Kadia, MD; Alessandra Ferrajoli, MD; Marina Konopleva, MD; Gautam Borthakur, MD; Jan Burger, MD; Jennie Feliu, RN; and Hagop M. Kantarjian, MD. Clofarabine Plus Low-Dose Cytarabine Followed by Clofarabine Plus Low-Dose Cytarabine Alternating With Decitabine in Acute Myeloid Leukemia Frontline Therapy for Older Patients. Cancer September 15, Koichi Takahashi, Hagop Kantarjian, Guillermo Garcia-Manero,Gautam Borthakur, Tapan Kadia, Courtney DiNardo, Elias Jabbour, Sherry Pierce, Zeev Estrov, Marina Konopleva, Michael Andreeff, Farhad Ravandi, Jorge Cortes. Clofarabine Plus Low-Dose Cytarabine Is as Effective as and Less Toxic Than Intensive Chemotherapy in Elderly AML Patients. Clinical Lymphoma, Myeloma & Leukemia, Vol. 16, No. 3, March. 4. Stefan Faderl, Farhad Ravandi, Xuelin Huang, Guillermo Garcia-Manero, Alessandra Ferrajoli, Zeev Estrov,Gautam Borthakur, Srdan Verstovsek, Deborah A. Thomas, Monica Kwari, and Hagop M. Kantarjian. Arandomized study of clofarabine versus clofarabine plus low-dose cytarabine as front-line therapy for patients aged 60 years and older with acute myeloid leukemia and high-risk myelodysplastic syndrome. BLOOD, 1 SEPTEMBER 2008 VOLUME 112, NUMBER 5 5. Clofarabine (Evoltra ) Summary of Product Characteristic. Last updated 28/09/. Available on: REVIEW Name Revision Date Version Review date Nadjoua Maouche and Prof New Document v.1.0 Paresh Vyas of 5