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Clofarabine for acute myeloid leukaemia in older adults for whom - containing combination is inappropriate – first line

February 2012

This technology summary is based on information available at the time of research and a limited literature search. It is not intended to be a definitive statement on the safety, efficacy or effectiveness of the health technology covered and should not be used for commercial purposes.

The National Horizon Scanning Centre Research Programme is part of the National Institute for Health Research

February 2012

Clofarabine for acute myeloid leukaemia in older adults for whom anthracycline-containing combination chemotherapy is inappropriate – first line

Target group • Acute myeloid leukaemia (AML): untreated, adults aged ≥60 years – first line, where anthracycline-containing combination chemotherapy is inappropriate.

Technology description Clofarabine (Evoltra; Clofarex; Clofaribine; Clolar) is a hybrid analogue that is transported into cells and phosphorylated to clofarabine triphosphate. It inhibits the growth of tumour cells by inhibiting ribonucleotide reductase, and inhibiting DNA polymerase α and ε leading to clofarabine insertion into the DNA. This inhibits DNA synthesis, produces strand breaks, and initiates a chain of events resulting in the release of cytochrome C from mitochondria, stimulating apoptosis. Clofarabine has been designed to resist inactivation by deamination and phosphorolysis1; overcoming the dose- limiting neurotoxicity of other anti-leukaemic halogenated nucleoside analogues, which are susceptible to enzymatic cleavage2. Clofarabine offers enhanced cytotoxicity, resulting from prolonged intracellular clofarabine triphosphate retention1. Clofarabine is intended as monotherapy for the treatment of AML in adults aged 60 years and over for whom anthracycline-containing combination chemotherapy is inappropriate. It is administered by intravenous (IV) infusion over 1 hour at 20mg/m2 daily for 5 days, repeated at 28- to 42-day intervals for up to 4 cycles.

Clofarabine is licensed for the treatment of acute lymphoblastic leukaemia (ALL) in paediatric patients who have relapsed or are refractory after receiving at least two previous regimens, and where there is no other treatment option expected to result in a durable response3. Clofarabine has completed a phase II for the second line treatment of myelodysplastic syndrome (MDS).

When used for its licensed indications, clofarabine is associated with significant immunosuppression and renal, neurological, cardiovascular, respiratory, dermatological, gastrointestinal, hepatobiliary and other toxic effects4.

Innovation and/or advantages If licensed, clofarabine could offer this group of patients a much needed additional active therapy with an intermediate toxicity profile (associated with significant potential adverse effects but not as toxic as anthracycline-based regimens).

Developer Genzyme Therapeutics.

Availability, launch or marketing dates, and licensing plans In phase III clinical trials.

NHS or Government priority area This topic is relevant to Improving Outcomes: A Strategy for Cancer (2011).

2 February 2012

Relevant guidance • NICE technology appraisal in development. for the treatment of newly diagnosed acute myeloid leukaemia for whom intensive chemotherapy is considered inappropriate. Expected date of issue to be confirmed5. • NICE technology appraisal. for the treatment of myelodysplastic syndrome, chronic myelomonocytic leukaemia and acute myeloid leukaemia. 20116. • NICE cancer service guideline. Haemato-oncology. 20037.

• National Comprehensive Cancer Network (NCCN). . 20108. • European Society for Medical Oncology (ESMO). Acute myeloblastic leukemia in adult patients: ESMO Clinical Recommendations for diagnosis, treatment and follow-up. 20099. • British Committee for Standards in Haematology: Guidelines on the management of acute myeloid leukaemia in adults. 200610.

Clinical need and burden of disease The UK incidence of adults with AML is 10 per 100,000 population, with around 2,200 adults diagnosed every year11. AML affects all ages, however its incidence increases with age, with a median age of onset of 70, and two thirds of all cases diagnosed in the UK are in those aged over 60 years12. The incidence is slightly higher in males than in females7.

The majority of elderly patients will either not achieve a remission or will suffer a relapse13. Remission occurs in 40-65% of those over 60 years14. The median duration of disease-free survival is less than 12 months8. Older people with AML have a higher incidence of unfavourable cytogenetics, a higher rate of primary drug resistance associated with a multi-drug resistance phenotype (i.e. overexpression of P-glycoprotein), and an increased frequency of disease evolution from a pre-existing and, probably unrecognised MDS15. These features are associated with a lower response rate to intensive chemotherapy, a shorter duration of remission and diminished overall survival16.

Increasing frailty and co-morbidity limits the number of older patients who can tolerate intensive chemotherapy16. Patients unsuitable for anthracycline-containing chemotherapy include those with a poor performance status, aged over 75 years, and/or with cardiac co- morbidity, which equates to at least half of those aged over 60 yearsa. However, many of these patients could not also tolerate an intermediate level of chemotherapy toxicity that resulted in prolonged neutropeniaa.

In England and Wales, there were 2,493 deaths from AML registered in 2010 of which 2,145 were in those aged 60 years old or over17. In 2010-2011 there were 31,719 admissions for AML in England, resulting in 120,390 bed days. This includes 21,398 finished consultant episodes for patients 60 years and over18 (ICD10 C92.0).

Existing comparators and treatments The options for the management of patients with AML over the age of 60 years are10,19,20: • For patients with a good performance statusa: . Standard induction therapy – 10+3 regimen with 10 days of (Ara-C) and 3 days of an anthracycline such as , ,

a Expert communication. 3 February 2012

or , with or without – achieves complete remission in 60% with a median survival of 5-10 months. . Some patients may be eligible for myeloblative haemopoietic stem cell transplantation (‘bone marrow transplant’, BMT) with reduced intensity conditioning.

• For patients who cannot tolerate anthracycline-containing combination chemotherapya: . Non-palliative treatment – low dose cytarabine (LDAC), , 6- or etoposide – median survival of 2- 3 months.

• For patients who are very frail or elderlya: . Best supportive care.

Efficacy and safety Trial CLASSIC I, NCT00317642, NCT00454480, CDR0000526121, CLO34100405, 2008-001043-19; UHW-AML16, EU-20677, cytarabine with clofarabine or placebo; ISRCTN11036523, EUDRACT-2005- phase III. 002846-14, MREC-CU106; clofarabine or low dose cytarabine, alone or in combination with mylotarg or ; phase III.

Sponsor Genzyme. Cardiff University, Wales. Status Published. Ongoing. Source of Press release21, Trial registry22, Trial registry23, manufacturer. information manufacturer. Location EU, USA and Canada. UK. Design Randomised, placebo-controlled. Randomised, active-controlled. Participants n=326; ≥55 years; AML; first or second n=2,000 (planned); ≥60 years; AML or and schedule relapse (after 2 prior regimens) or high risk MDS. refractory to not more than 1 prior Randomised to: combination chemotherapy; ECOG PS Arm I: LDAC subcutaneously (SC) 0-2b. 20mg/m2 twice daily on days 1-10. Randomised to cytarabine 1g/m2 per day Arm II: LDAC SC 20mg/m2 twice daily with clofarabine 40mg/m2 per day or on days 1-10, combined with mylotargc cytarabine 1g/m2 per day with placebo, 3mg/m2 IV over 2 hours on day 1. both daily for 5 days, repeated within Arm III: clofarabine 20mg/m2 over 1 28- to 42-days for ≤3 cycles (induction, hour once daily on days 1-5. re-induction (if necessary) and Arm IV: LDAC SC 20mg/m2 twice daily consolidation cycles). on days 1-10 combined with arsenic trioxide 0.25mg/kg IV over 1-2 hours on days 1-5, 9, and 11. All regimens repeated every 4-6 weeks for 4 courses. Follow-up 60-months. 6-months and 1-year. Primary Overall survival (OS). Efficacy and toxicity. outcome Secondary Overall response rate (ORR), complete Relevance of cytogenetic abnormalities, outcomes response (CR), event-free survival molecular markers and protein status on b The ECOG PS (Eastern Cooperative Oncology Group Performance Status) scale assesses a patient’s disease progression, living abilities, and determines appropriate treatment and prognosis. c Gemtuzumab ozogamicin. 4 February 2012

(EFS), disease-free survival (DFS), 4- treatment outcomes; evaluation of month EFS and safety. methods of minimal residual disease monitoring; association between gene methylation status and treatment. Key results For clofarabine with cytarabine, ORR -. 47%. For clofarabine with cytarabine vs. cytarabine alone: 37% improvement in event-free survival; overall 30-day mortality, 16% vs. 5%. Adverse effects Grade 3-4 treatment-emergent adverse - (AEs) events reported in ≥5% of patients included: febrile neutropenia, hypokalaemia, thrombocytopenia, pneumonia, anaemia, neutropenia, abnormal enzymes, bacteraemia hypertension, diarrhoea, leukopenia, fatigue, , hyperglycaemia, renal failure, acute hyponatraemia, , increased bilirubin, increased lipase and hypocalcaemia. Expected - August 2012. reporting date

Trial NCT00924443, BIOV-121; clofarabine; UWCM-001; clofarabine; phase II. phase II. Sponsor Genzyme. Cardiff University, Wales. Status Published. Published. Source of Publication24,25, trial registry26, Publication24, manufacturer. information manufacturer. Location EU (inc UK) and Italy. UK. Design Non-randomised, single arm. Non-randomised, single arm. Participants n=66; ≥65 years; AML; previously n=40; ≥70 years, or 60-69 years with and schedule untreated; unsuitable for intensive WHO performance score ≥2, or a history chemotherapy treatment. of cardiac disease; AML; previously Clofarabine 30mg/m2 daily for 5 days, untreated; unsuitable for intensive repeated every 28- to 42-days at daunorubicin or cytarabine 20mg/m2 for up to an additional 2 chemotherapy treatment. cycles. Clofarabine 30mg/m2 daily for 5 days, repeated every 28 days for up to 4 cycles. Amended to 20mg/m2 for all cycles in final 11 patients. Follow-up 31 months. Primary ORR, CR and CRid. outcomes Secondary Duration of CR, time to CR, OS. outcomes Key results ORR 48% (CR 32%, CRi 16%); 19 patients (18%) died within 30 days. Adverse effects Diarrhoea, , , cardiac, hepatic, skin and renal toxicity all reported. (AEs) For trial BIOV-121, 6/14 deaths were considered drug-related and 37.9% experienced AEs, including neutropenic sepsis and renal failure.

d CR with incomplete peripheral blood count recovery 5 February 2012

Trial CLASSIC II, NCT00088218, 2004- Clofarabine with ara-c; NCT00373529, 0183; clofarabine with or phase II. CLO24300606; without low dose clofarabine; phase II. cytarabine; phase II. Sponsor Genzyme. Genzyme. Genzyme. Status Published. Published. Published. Source of Publication27, trial Publication29, trial Publication31, information registry28, manufacturer registry30, manufacturer. manufacturer. Location USA. USA. USA. Design Non-randomised, single Randomised, active- Non-randomised, single arm. controlled, open-label. arm. Participants n=116; ≥ 60 years; AML; n=70; ≥ 60 years; AML; n=60; ≥50 years; AML; and schedule previously untreated; previously untreated. previously untreated. unlikely to benefit from Randomised to Ara-c 1g/m2, given by IV standard induction clofarabine 30mg/m2 infusion daily for 5 days, therapy. given by IV infusion daily with clofarabine 40mg/m2 Clofarabine 30mg/m2 for 5 days for up to 2 given by IV infusion daily given by IV infusion daily induction cycles, and for 5 days, starting on day for 5 days, repeated every daily for 3 days for up to 2. 28 days at 20mg/m2 for up 12 consolidation cycles; to 5 additional cycles. with or without LDAC Cycles repeated every 4-6 20mg/m2, given weeks depending on subcutaneously for 14 response. Maximum of 3 days in the induction induction cycles or until cycles, and for 7 days in CR, CRpe or partial for the consolidation response (PR) achieved. cycles. Responders receive up to 6 additional maintenance Cycles were of variable courses: clofarabine 40 length, being repeated mg/m2 daily for 3 days every 4-7 weeks followed by ara-c at 1 depending on response. g/m2 daily. Follow-up 85 weeks. 23 months. - Primary ORR (complete remission CR and CRp. ORR, CR and CR outcomes within 2 cycles). duration. Secondary Duration of remission; OS. PR. outcomes DFS; OS; safety and tolerability. Key results ORR 46% (CR 38%, CRp For all patients (n=70), ORR 60% (CR 52%, CRp 8%). ORR 59% (CR 56%, CRi 8%); 20 patients (33%) 3%); had resistant disease and 4 patients (7%) died during Clofarabine (n=16) vs. induction. For 35 patients clofarabine and LDAC > 60 years, ORR 63%. (n=54), respectively: EFS, 7.1 vs. 1.7 months (p=0.04); treatment failure, 6% vs. 8% (p=0.046).

Adverse effects Nausea, vomiting, febrile Diarrhoea, nausea, Diarrhoea, nausea, (AEs) neutropenia, diarrhoea, vomiting, vomiting, mucositis, skin rash, fatigue, headache, hyperbilirubinaemia, reactions, liver test e CR with incomplete recovery 6 February 2012

, anorexia, mucositis, mucositis, liver test abnormalities and infusion pruritus and hepatobiliary abnormalities headache, related facial flushing and toxicity all reported. oedema, anorexia, acute headaches all reported. renal failure, fatigue, Myelosuppression was atrial fibrillation, skin common. reactions facial flushing, pruritus and chest tightening, all reported.

Estimated cost and cost impact The cost of clofarabine has not yet been determined for this indication. However, the cost of clofarabine for the treatment of ALL and the cost of other selected treatments are32:

Drug Dose4,10 Costf Clofarabine 40mg/m2 IV £19,604 per 5-day cycle Cytarabine 1g/m2 IV £329 per 5-day cycle LDAC 20mg/m2 IV £26 per 10-day cycle Daunorubicin 45mg/m2 IV £632 per 3-day cycle

Claimed or potential impact – speculative

Patients  Reduced mortality or increased  Reduction in associated morbidity Quicker, earlier or more accurate length of survival or improved quality of life for diagnosis or identification of patients and/or carers disease Other: None identified

Services Increased use Service organisation Staff requirements

Decreased use Other:  None identified

Costs  Increased unit cost compared to Increased costs: more patients Increased costs: capital alternative coming for treatment investment needed New costs: Savings: Other:

Other issues Clinical uncertainty or other research question identified:  None identified

References

1Agura E, Cooper B, Holmes H et al. Report of a phase II study of clofarabine and cytarabine in de novo and relapsed and refractory AML patients and in selected elderly patients at high risk for anthracycline toxicity. Oncologist 2011;16(2):197-206. 2 Zhenchuk A, Lotfi K, Juliusson G et al. Mechanisms of anti-cancer action and pharmacology of clofarabine. Biochemal Pharmacology 2009;78(11):1351-9. 3 Evoltra Summary of Product Characteristics. Electronic Medicines Compendium. http://www.medicines.org.uk/EMC/medicine/18023/SPC/Evoltra+1mg+ml+concentrate+for+solution+for+ infusion/ Accessed 30 January 2012. 4 The electronic Medicine Compendium (eMC). Summary of Product Characteristics, Evoltra. Genzyme f Based on an average surface area of 1.7m2. 7 February 2012

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30ClinicalTrials.gov. Clofarabine vs clofarabine in plus with low-dose Ara-C in previously untreated patients with acute myeloid leukemia (aml) and high-risk myelodysplastic syndromes (MDS). http://www.clinicaltrials.gov/ct2/show/NCT000882181 Accessed 27 January 2012. 31Faderl S, Verstovsek S, Cortes J et al. Clofarabine and cytarabine combination as induction therapy for AML in patients 50 years of age or older. Blood 2006;108 (1): 45-51. 32British Medical Association and Royal Society of Great Britain. British National Formulary. No.62, BMJ Group and RPS Publishing. London; September 2011.

The National Institute for Health Research National Horizon Scanning Centre Research Programme is funded by the Department of Health. The views expressed in this publication are not necessarily those of the NHS, the NIHR or the Department of Health

The National Horizon Scanning Centre, Department of Public Health and Epidemiology University of Birmingham, 90 Vincent Drive, Edgbaston, Birmingham, B15 2SP, England Tel: +44 (0)121 414 7831 Fax +44 (0)121 414 2269 www.haps.bham.ac.uk/publichealth/horizon

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