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1 AZACITIDINE NICE TA218 Treatment of adults not eligible for haematopoietic stem cell transplantation who have: Intermediate-2 and high-risk MDS according to the International Prognostic Scoring System (IPSS) or CMML with 10 29% marrow blasts without myeloproliferative disorder or AML with 20 30% blasts and multilineage dysplasia, according to the WHO classification and Azacitidine is provided via a company led PAS scheme NICE criteria are based on IPSS MDS. For more information see [link]. TREATMENT INTENT Disease modifying PRE-ASSESSMENT 1. Blood tests - FBC, coagulation screen, DAT, U&Es, urate, creatinine, egfr, LFTs, glucose, Hepatitis B core antibody and Hepatitis BsAg, Hepatitis C antibody after consent, group and save 2. Ensure histology is confirmed prior to administration of chemotherapy and document in notes 3. Record clinical impact of disease, blood film, bone marrow aspirate and trephine, immunophenotype, cytogenetic results and calculate IPSS score 4. Record stage of disease 5. Urine pregnancy test - before cycle 1 of each new chemotherapy course in women aged years of age unless they have been sterilised or undergone a hysterectomy 6. ECG 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 on the day of treatment 10. Consider dental assessment / advise dental check is carried out by patient's own dental practitioner before treatment starts 11. Treatment should be agreed in the relevant MDT 1 of 5

2 DRUG REGIMEN / CYCLE FREQUENCY Start Cycle 1 regardless of baseline haematology laboratory values. Treat for a minimum of 6 cycles. Continue as long as the patient continues to benefit or until disease progression. Schedule 1 AZACITIDINE 75 mg/m 2 SC once daily for 7 days, then 21 days rest, of 28 day cycle Schedule 2 (5-2-2 regimen)* AZACITIDINE 75 mg/m 2 SC once daily Days 1 to 5 (Monday to Friday), weekend rest, then AZACITIDINE 75 mg/m 2 SC once daily Days 8 to 9 (Monday to Tuesday), of 28 day cycle Schedule 3 (5 day regimen)* AZACITIDINE 100 mg/m 2 SC once daily Days 1 to 5 (Monday to Friday), of 28 day cycle * Unlicensed. It is acceptable where day case care is unavailable or local policy. There is no maximum number of cycles. 50% of responding patients do so by Cycle 3 and 90% by Cycle 6. Responding patients continue azacitidine until response is lost. When patients become cytopenic after response, this is usually due to either a hypocellular marrow (drug toxicity) or recurrent disease. EVALUATION OF FIRST RESPONSE If there is no clinical response, consider a bone marrow after completion of Cycle 6 GUIDANCE FOR STOPPING AZACITIDINE 1. If there is clinical response, continue Azacitidine and re-evaluate blood response after every cycle 2. SD - unknown if Azacitidine improves survival; the decision to continue is at physician s and patient s discretion 3. Progressive disease at any stage - stop Azacitidine FURTHER EVALUATION BEYOND EVALUATION OF FIRST RESPONSE Perform bone marrow when response is lost 2 of 5

3 DOSE MODIFICATIONS The below are recommended by the SPC. Clinician judgement should be exercised in their use. = nadir when Platelets 50 x 10 9 /L and/or ANC 1 x 10 9 /L Recovery = blood count nadir count + (0.5 x [baseline count nadir count]) If baseline WBC 3 x 10 9 /L, ANC 1.5 x 10 9 /L, Platelets 75 x 10 9 /L prior to Cycle 1 ANC 1x 10 9 /L and / or Platelets 50 x 10 9 /L Modification recovery occurs within 14 days, no dose adjustment is needed. Next cycle should be delayed until Platelet and ANC recovery. 50% dose in the next cycle if recovery is not achieved within 14 days If baseline WBC < 3 x 10 9 /L or ANC < 1.5 x 10 9 /L or Platelets < 75 x 10 9 /L prior to Cycle 1 WBC or ANC or Platelet decrease 50% from baseline, or > 50% but with improvement in any cell line differentiation WBC or ANC or Platelet decrease > 50% from baseline, with no improvement in cell line differentiation Renal / Hepatic Impairment Modification Next cycle should not be delayed and no dose adjustment made. recovery occurs within 14 days, no dose adjustment is necessary. recovery has not been achieved within 14 days, determine bone marrow cellularity. Recovery > 21 days and bone cellularity 15-50% dose at 50% Recovery > 21 days and bone cellularity < 15% dose at 33% Renal impairment After Cycle 1, if serum bicarbonate levels < 20 mmol/l, dose at 50% in the next cycle. If Cr or blood urea nitrogen 2 x baseline and > ULN, next cycle should be delayed until values return to normal or baseline and dose at 50% in the next cycle. Hepatic impairment Carefully monitor in severe impairment. Subsequent dose modifications should be based on haematology laboratory values. Contraindicated in advanced malignant hepatic tumours 3 of 5

4 CONTRAINDICATIONS Hypersensitivity to the active substance or to any of the excipients Advanced malignant hepatic tumours Breast-feeding SPECIAL WARNINGS / PRECAUTIONS / MONITORING particularly during the first 2 cycles Hepatic impairment Patients with extensive tumour burden due to metastatic disease have been reported to experience progressive hepatic coma and death during Azacitidine treatment, especially in such patients with baseline serum albumin < 30g/L. Cardiac and pulmonary disease Patients with a known history of cardiovascular or pulmonary disease have shown significantly increased incidence of cardiac events with Azacitidine Necrotising fasciitis Azacitidine should be discontinued in patients who develop necrotising fasciitis and appropriate treatment should be promptly initiated. CONCURRENT MEDICATION Drug ALLOPURINOL Dose / Duration 300mg PO once daily for 7 days ACICLOVIR 200mg PO three times a day if ANC < 1 x 10 9 /L ANTIFUNGAL PROPHYLAXIS Refer to local antifungal guideline FLUCONAZOLE 50mg PO once daily if ANC < 1 x 10 9 /L TRANEXAMIC ACID Consider POSACONAZOLE 300mg PO once daily if compatible with local guidelines 1.5g PO three times a day if clinical evidence of wet mucosal bleeding and Platelet < 50 x 10 9 /L ANTI-EMETICS Moderate - High emesis risk INTERACTIONS No formal studies have been conducted. 4 of 5

5 ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Very commonly reported: pneumonia, nasopharyngitis, febrile neutropenia, neutropenia, leukopenia, thrombocytopenia, anaemia, anorexia, decreased appetite, hypokalemia, insomnia, dizziness, headache, dyspnoea, epistaxis, diarrhoea, vomiting, constipation, nausea, abdominal pain, petechiae, pruritus, rash, ecchymosis, arthralgia, musculoskeletal pain, pyrexia, fatigue, asthenia, chest pain, injection site erythema, injection site pain, injection site reaction (unspecified), weight decreased For all others adverse effects, refer to SPC. MORTALITY Drug related mortality is less than 1% REFERENCES 1. NICE (2011) TA 218, Accessed 12/03/ Celgene (2016) Azacitidine Summary of product characteristics. Accessed 12/03/ Thames Valley SCN (2016) Cancer Chemotherapy Guidelines Antiemetic for Prophylaxis of Chemotherapy & Radiotherapy Induced Nausea and Vomiting in Adults v8.1a. Accessed 12/03/ Lyons et al (2009) Hematologic response to three alternative dosing schedules of azacitidine in patients with myelodysplastic syndromes. JCO 27: Fenaux et al (2009) Efficacy of azacitidine compared with that of conventional care regimens in the treatment of high-risk myelodysplastic syndrome: a randomized, open-label, phase III study. Lancet Oncol 10(3): Greenberg et al (1997) International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 89(6): Greenberg et al (2012) Revised International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 120(12): REVIEW Name Revision Date Version Review date Julia Wong, Prof Vyas Revised (re-draft) March Mach 2019 Cheuk-kie Cheung General formatting May March of 5