Horizon Scanning Centre January 2015

Pegaspargase (Oncaspar) for acute lymphoblastic leukaemia

SUMMARY NIHR HSC ID: 3888

Pegaspargase (Oncaspar) in combination with chemotherapy is intended for the treatment of acute lymphoblastic leukaemia (ALL) in children, adolescents and adults. If licensed, pegaspargase will offer an additional treatment option for such patients and has the potential to improve safety, and reduce toxicity through the pegylation of Escherichia coli asparaginase (compared to non-pegylated asparaginase). Pegaspargase is an antineoplastic agent formed by linking Escherichia coli asparaginase with This briefing is polyethylene glycol (PEG). Linking the two may extend the duration the based on drug’s activity while reducing the potential for immunogenic reactions. information Pegaspargase (in combination with chemotherapy) is licensed in Germany available at the time and Poland for the treatment of ALL in children, adolescents and adults with of research and a known hypersensitivity to native L-asparaginases. limited literature search. It is not ALL is the only form of leukaemia that is more common in childhood (under intended to be a 15 years of age) and is characterised by a bimodal age pattern, with a peak definitive statement incidence at one to four years of age and a second increase in incidence in on the safety, those aged over 60 years. In the case of childhood ALL, there is an overall efficacy or survival rate of 80% at five years, but in adults the survival rate falls to 35% effectiveness of the at five years. In England there were 529 new diagnoses of ALL registered in health technology 2012. In the same year there were 202 deaths due to ALL registered in covered and should England. not be used for commercial Treatment of ALL consists of three phases: induction phase, consolidation purposes or phase and continuation treatment. Central nervous system (CNS) commissioning prophylaxis is also administered concurrently throughout treatment. Patients without additional typically receive chemotherapy for 2.0–2.5 years. In adults, stem cell information. transplantation and chemotherapy are considered equal treatment options. Allogeneic haemopoietic stem cell transplantation is an option for children with very high risk or persistent disease, and high risk adults in remission. Pegaspargase is currently in a number of phase III clinical trials comparing its effect on overall survival, complete response, and adverse effects against treatment with various other antineoplastic treatment regimens. These trials are expected to complete between 2019 and 2021.

This briefing presents independent research funded by the National Institute for Health Research (NIHR). The views expressed are those of the author and not necessarily those of the NHS, the NIHR or the Department of Health.

NIHR Horizon Scanning Centre, University of Birmingham Email: [email protected] Web: http://www.hsc.nihr.ac.uk NIHR Horizon Scanning Centre

TARGET GROUP

• Acute lymphoblastic leukaemia (ALL): children, adolescents and adults - in combination with chemotherapy.

TECHNOLOGY

DESCRIPTION

Pegaspargase (Oncaspar; asparaginase macrogol; PEG-asparaginase; PEG-L- asparaginase; PEGLA) is an antineoplastic agent formed by linking Escherichia coli asparaginase with polyethylene glycol (PEG). By conjugating the immunogenic E. coli asparaginase to PEG, the duration of activity of the drug may be extended while reducing the potential for immunogenic reactions. Asparaginase hydrolyses asparagine to L- aspartic acid and ammonia, leading to asparagine depletion, and cell death.

In the phase III clinical trial, pegaspargase is administered by intravenous injection (IV) at 2,500units/m2 or 3,500units/m2 on day 1 of the continuation phase of treatment, days 1 and 15 of the reinduction I phase, and days 1 and 15 of the reinduction II phase; all in combination with chemotherapy which varied depending on risk stratification. Pegaspargase (in combination with chemotherapy) is licensed in Germany and Poland for the treatment of ALL in children, adolescents and adults with known hypersensitivity to native L- asparaginases.

INNOVATION and/or ADVANTAGES

If licensed, pegaspargase will offer an additional treatment option for children, adolescents and adults with ALL. Pegaspargase has the potential to improve safety through the pegylation of Escherichia coli asparaginase.

DEVELOPER

Pfizer; Sigma-Tau Pharmaceuticals Ltd (EU licensee).

AVAILABILITY, LAUNCH OR MARKETING

The company submitted a Marketing Authorisation Application to the EU in July 2014.

PATIENT GROUP

BACKGROUND

ALL is a malignancy of lymphocytes and lymphocyte-producing cells. In persons with ALL, there is excess production of immature lymphocyte-precursor cells, called blast cells, in the bone marrow. Eventually this overgrowth affects normal haemopoiesis, and there is a reduction in the numbers of red cells, white cells and platelets in the blood1. The most common symptoms of ALL are2: • Anaemia, which results in fatigue and breathlessness. • Low platelet counts, which may result in bruising and bleeding from mucous membranes and the gut.

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• Low white cell counts, high numbers of abnormal cells and high metabolic rate, resulting in persistent infections and fever that is often present even in the absence of clear indications of infection.

NHS or GOVERNMENT PRIORITY AREA

This topic is relevant to: • Improving Outcomes: A Strategy for Cancer (2011). • NHS England. 2013/14 NHS Standard Contract for Cancer: Chemotherapy (Adult). B15/S/a. • NHS England. 2013/14 NHS Standard Contract for Cancer: Chemotherapy (Children, Teenagers and Young Adults). B12/S/b. • NHS England. 2013/14 NHS Standard Contract for Cancer: Radiotherapy (All Ages). B01/S/a. • NHS England. Clinical Commissioning Policy: Haematopoietic Stem Cell Transplantation. NHSCB/B04/P/a. April 2013.

CLINICAL NEED and BURDEN OF DISEASE

ALL is the only form of leukaemia that is more common in childhood (under 15 years of age)1, accounting for 75% of leukaemia diagnoses in paediatric patients3. ALL is characterised by a bimodal age pattern, with a peak incidence at one to four years of age and a second increase in incidence at ages over 60 years4. In the case of childhood ALL, there is an overall survival rate of 80% at five years, but in adult patients the survival rate is reduced to approximately 35% at five years5. In England there were 529 new diagnoses of ALL registered in 20126. In the same year there were 202 deaths due to ALL registered in England7. In 2012, there were 25,330 hospital admissions for ALL (ICD10 C91.0) in England, resulting in 40,642 bed-days and 26,027 finished consultant episodes8. The population likely to be eligible to receive pegaspargase could not be estimated from available published sources.

PATIENT PATHWAY

RELEVANT GUIDANCE

NICE Guidance

• NICE Clinical Guideline. Referral for suspected cancer (CG27). June 2005. • NICE Cancer Service Guidance. Improving outcomes in haemato-oncology cancer; the manual. October 2003.

Other Guidance

• National Comprehensive Cancer Network. Acute Lymphoblastic Leukaemia 20139. • The European Group for Blood and Marrow Transplantation. Handbook on Haemopoietic Stem Cell Transplantation. Revised edition 201210. • The American Society for Blood and Marrow Transplantation Executive Committee. The role of cytotoxic therapy with haematopoietic stem cell transplantation in the treatment of adult acute lymphoblastic leukaemia: update of the 2006 evidence based-review. 201211.

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CURRENT TREATMENT OPTIONS

Treatment for ALL aims to induce clinical remission (induction phase), target cells that are clinically undetectable (consolidation phase) and maintain the patient in remission (continuation treatment). Additional CNS prophylaxis, which consists of concurrent chemotherapy, is also given throughout the entire period of treatment3. Patients typically receive chemotherapy for 2.0–2.5 years12. In adults, stem cell transplantation and chemotherapy are considered equal treatment options. Allogeneic haemopoietic stem cell transplantation is an option for children with very high risk or persistent disease, and high risk adults in remission13,14,15,16.

EFFICACY and SAFETY

The tables below contain details of a number of phase II and III clinical trials of pegaspargase for the treatment of ALL. In addition to the trials listed, there are a large number of other investigator-led studies on regimens containing pegaspargase for the treatment of ALL.

Trial NCT00549848; children NCT01117441; UKALL14, EudraCT 2009- aged up to 18 years; pegaspargase with 012717-22; pegaspargase higher dose PEG- chemotherapy; phase III. with chemotherapy; phase asparaginase vs III. conventional dose PEG- asparaginase, both in combination with chemotherapy; phase III. Sponsor and St. Jude Children's University of Schleswig- University College London. collaborators Research Hospital; Holstein; Deutsche National Cancer Institute Krebshilfe e.V., Bonn (NCI); Enzon (Germany); Sigma-Tau Pharmaceuticals, Inc. Pharma Limited; medac GmbH. Status Ongoing. Ongoing. Ongoing. Source of Trial registry17, Trial registry18, Trial registry19, information manufacturer. manufacturer. publication20, manufacturer. Location USA. EU (not UK), Australia, UK. and Israel Design Randomised, active- Randomised, active- Randomised, active- controlled. controllled. controlled. Participants n=420 (planned); aged n=4,750 (planned); aged n=720 (planned); aged ≤18 years; precursor B-cell ≥1 year and <18 years; ≥25 and ≤65 years; newly or precursor T-cell ALL; newly diagnosed ALL; no diagnosed, previously limited prior therapy, Philadelpia (Ph) positive untreated ALL; no known including systemic (BCR/ABL or t(9;22)- HIV infection; no blast glucocorticoids for ≤ 1 positive) ALL. Within the transformation of CML; no week, 1 dose of vincristine, study, participants were mature B-cell leukemia emergency radiation assigned to one of 3 e.g. Burkitt’s disease therapy to the research questions based t(8;14) and all disorders mediastinum and 1 dose of upon risk stratification. amplification of c-myc e.g. intrathecal chemotherapy. Patients with precursor B- t(2;8), t(8;22). cell, medium risk ALL are assigned to research question R2 - Can the clinical outcome be improved by protracted

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asparagine depletion achieved through application of intensified PEG-L-asparaginase during reintensification and early maintenance? Schedule Trial consists of 3 phases: Participants in R2 arm Trial consists of 5 phases: remission induction, randomised to, induction, consolidation, consolidation, and Experimental R2 arm: interim maintenance, continuation. Participants pegaspargase 2,500IU/m2 delayed intensification, received induction and single dose IV (maximal and maintenance. consolidation therapy single dose 3,750IU) Participants received a (including pegaspargase) on days 12, 26 of protocol chemotherapy regimen that varied depending on IA, days 8, 22 of protocol that varied depending on risk stratification. IIA, days 36, 50 of protocol risk stratification, In the continuation phase IIB, and every second Philadelphia chromosome participants randomised to week of maintenance status and age. pegaspargase 3,500IU/m2 protocol (6 doses); or Participants received: 2 IV on day 1 of continuation Control R2 arm: Pegaspargase 1,000IU/m 2 phase, 3,500IU/m IV on pegaspargase 2,500IU/m2 IV on days 4 and 18 of days 1 and 15 of single dose IV (maximal induction (only on day 18 if reinduction I phase, and single dose 3,750IU) on participant >40 years of a 3,500IU/m2 IV on days 1 days 12, 26 of protocol IA, age) , on days 2 and 16 of and 15 of reinduction II and day 8 of protocol IIA. intensification, and day 5 phase; or pegaspargase of consolidation phase 2,500IU/m2 IV on day 1 of during cycle 1, and day 4 continuation phase, of consolidation phase 2,500IU/m2 IV on days 1 cycle 3 . and 15 of reinduction I phase, and 2,500IU/m2 IV on days 1 and 15 of reinduction II; both in combination with chemotherapy. Follow-up Active treatment for 135 Follow-up 10 years. Follow-up until death. weeks, follow-up indefinite with 5 and 10 year event- free survival (EFS) and overall survival (OS) updates. Primary Continuous complete EFS; disease-free survival EFS, toxicity related to outcome/s remission. (DFS); rate of MRD highly pegaspargase, mucositis positive patients. score Secondary EFS; OS; minimal residual OS; treatment-related OS, complete remission outcome/s disease (MRD) on the 15th mortality; AEs; MRD. No (CR), tolerability of day of remission induction; quality of life measurement pegaspargase in induction time to CNS relapse or the included in trial outcomes. treatment of all patients; last follow up since anti-asparaginase antibody diagnosis. levels; MRD; AEs. Adverse - - Interim results from effects (AEs) induction phase (n=91): induction mortality 19.8%; pegaspargase related cause of death was “definitely or probably” implicated in 11/18 induction deaths; non-fatal a Following a protocol amendment Philadelphia positive patients do not receive any pegaspargase during induction phase.

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pegaspargase toxicity during induction, 36.7%; abnormal liver function test, 24.5%; coagulopathy, 7.7%; thrombosis, 5.6%. Expected Study completion date Study completion date Not reported. reporting reported as November reported as December date 2019. 2021.

Trial UKALL 2011, ISRCTN64515327, ALL2008, NCT00819351; intermittent vs EudraCT 2010-020924-22; pegaspargase continuous pegaspargase, both with with chemotherapy; phase III. chemotherapy; phase III. Sponsor and University of Birmingham. Rigshospitalet, Denmark; collaborators Nordic Society for Pediatric Hematology and Oncology. Status Ongoing. Ongoing. Source of Trial registry21, manufacturer. Trial registry22, manufacturer. information Location Ireland, UK. EU (not UK), and Iceland. Design Randomised, active-controlled. Randomised, active-controlled. Participants n=2,430 (planned) aged ≥1 year and ≤24 n=1,000 (planned); aged ≥1 year and ≤45 years; first diagnosis of ALL or years; ALL; no bilineage ALL; no pre- lymphoblastic lymphoma (T-NHL or SmIg treatment with glucocorticoids or other negative precursor B-NHL); no B-ALL antileukemic agents for ≥1 week; no ALL (Burkitt-like, t(8;14), L3 morphology, SmIg predisposition syndromes; no previous positive); no Philadelphia-positive ALL cancer; no off protocol administration of (t(9;22) and no BCR/ABL positive); additional chemotherapy during induction no prior therapy for ALL or lymphoblastic therapy; no allergic reactions to lymphoma except, a single dose of pegaspargase. intrathecal methotrexate at the time of diagnostic lumbar puncture, or glucocorticoid (dexamethasone or prednisolone) for ≤7 days, or emergency cytoreduction with glucocorticoid (dexamethasone or prednisolone) for ≤7 days and/or ≤ 300mg/m2 cyclophosphamide in the previous 7 days b . Schedule Trial consists of 5 phases: induction, Randomised to: consolidation, interim maintenance, pegaspargase 1,000IU/m2 IM every six delayed intensification, and maintenance. weeks from week 13 after diagnosis; or Participants received therapy (including pegaspargase 1,000IU/m2 IM every two pegaspargase) that varied depending on weeks from week 13 after diagnosis; both risk stratification. in combination with high dose Randomised to: methotrexate, vincristine, Pegaspargase 1,000IU/m2 intramuscular dexamethasone, 6-mercaptopurine, (IM) injection for 3 doses (regimen A); doxorubicin, and intrathecal pegaspargase 1,000IU/m2 IM for 3 doses chemotherapy. (regimen B); or pegaspargase 1,000IU/m2 IM for 8 doses (regimen C). Follow-up Follow-up 5 years. Active treatment for 33 weeks after diagnosis, follow-up 6 years.

Primary OS; AEs. EFS. outcome/s b Only in patients with NHL or lymphomatous presentation of T-ALL who receive cytoreduction with glucocorticoid and/or cyclophosphamide due to concerns over respiratory compromise or thoracic outlet obstruction.

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Secondary Remission rate; EFS; treatment related AEs; toxicity; the formation of silent outcome/s mortality and morbidity; quality of life. antibodies; the influence of antibody production on the EFS. Expected Not reported. Study completion date reported as June reporting 2017. date

Trial NCT01920737; NCT00905034; NCT00973752; PEG- daunorubicin, vincristine, methotrexate, vincristine, asparaginase and prednisolone, PEG- pegylated-L-asparaginase clofarabine, in combination asparaginase, and dexamethasone with a multi-drug regimen; methotrexate, (MOAD) in ALL salvage; phase II. mercaptopurine, phase II. cyclophosphamide, cytarabine, leucovorin, and dexamethasone; phase II. Sponsor and Memorial Sloan-Kettering M.D. Anderson Cancer Massachusetts General collaborators Cancer Center; Sigma-Tau Center; Sigma Tau Hospital; Dana-Farber Research, Inc.; Duke Pharmaceuticals, Inc. Cancer Institute; Beth University; Weill Medical Israel Deaconess Medical College of Cornell Center; Enzon University. Pharmaceuticals, Inc.; Genzyme. Status Ongoing. Ongoing. Ongoing. Source of Trial registry23, Trial registry24, Publication25, trial information manufacturer. manufacturer. registry26, manufacturer. Location USA. USA. USA. Design Single arm, uncontrolled. Single arm, uncontrolled. Single arm, uncontrolled. Participants n=39 (planned); aged 18- n=60 (planned); aged ≥1 n=30 (planned); aged 51- 60yrs; previously untreated years; previously treated 75 years; ALL, excluding Ph negative precursor B- ALL (including Burkitt's known mature B-cell ALL cell or T-cell ALL or T-cell lymphoma) or by the presence of any of lymphoblastic lymphoma, lymphoblastic lymphoma in the following: surface even if the bone marrow is relapse or primary immunoglobulin, L3 not involved; ECOG refractory, both without morphology, performance status of 0-2; viable stem cell transplant t(8;14)(q24;q32), t(8;22), adequate renal and option; previously treated or t(2;8), and hepatic function; normal Ph positive ALL; chronic lymphoblastic lymphoma; cardiac function; patients myeloid leukemia (CML) in no prior anti-leukaemic with CNS involvement by blast phase; zubrod therapy except <1 week of ALL are eligible and may performance status ≤3; no glucocorticoids, emergent receive concomitant prior history of allergic radiation therapy to the treatment with radiation reaction, serious mediastinum, hydroxyurea therapy and/or intrathecal pancreatitis, hemorrhagic or emergent chemotherapy in or thrombotic event with leukopheresis; ejection accordance with standard PEG-L-asparaginase or its fraction >45%, creatinine medical practice. components; adequate <2.0mg/dl, total bilirubin liver and kidney function; <3.0mg/dl; ECOG score 0- for paediatric patients, 2. Lansky performance status ≥50, and second or subsequent relapse. Schedule Regimen has 6 cycles; Methotrexate 200mg/m2 IV Induction - prednisolone induction phase I, on days 1 and 15 of a 28 orally on days 1-21, (for induction phase II, day cycle; vincristine participants aged <60), or intensification I, re- 1.4mg/m2 IV on days 1, 8, days 1-7 (for participants induction I, intensification and 15; PEG-L- aged ≥60); vincristine IV II, re-induction II; each asparaginase 2,500IU/m2 on days 1, 8, 15, and 22;

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over a period of 4-6 IV on days 2 and 16; doxorubicin IV on days 1 weeks; interval between dexamethasone and 2; PEG-asparaginase cycles ranges between 1-3 40mg IV or orally daily IV on days 7 and 21; weeks; cycles consist of, days 1-4 and 15-18; and cytarabine intrathecally on daunorubicin (doxorubicin rituximab 375mg/m2 IV on day 1; methotrexate may be used as a days 1 and 15 (first 4 intrathecally on day 29; substitute), vincristine, cycles) for CD20 positive and imatinib orally on days prednisolone, PEG- patients. 14-29 (Ph positive ALL). asparaginase, Consolidation 1 - methotrexate, prednisolone orally days 1- mercaptopurine (6-MP), 5; clofarabine IV days 1-5; cyclophosphamide, PEG-asparaginase IV cytarabine, leucovorin, days 1 and 15; and and dexamethasone. imatinib orally daily (Ph Pegaspargase was positive ALL). administered: CNS therapy - vincristine 2 2,000IU/m IV on day 15 of IV on day 1; doxorubicin IV induction phase I, on day 1; 6 2,000IU/m2 IV on day 15 of mercaptopurine orally on induction phase II, days 1-14; prednisolone 2,000IU/m2 IV on day 16 of orally on days 1-5; PEG- both intensification I and II, asparaginase IV on days 1 and 2,000IU/m2 IV on day and 15; 15 of both re-induction methotrexate/cytarabine/ phase I and II. prednisolone intrathecally weekly for 3 weeks; and imatinib orally daily (Ph positive ALL). Consolidation 2 – for 8 cycles, vincristine IV on day 1; doxorubicin IV on day 1; 6 mercaptopurine orally on days 1-14; prednisolone orally days 1- 5; PEG-asparaginase orally on days 1 and 15 (first cycle only); imatinib orally daily (Ph positive ALL). Continuation - vincristine IV on day 1; 6-MP orally on days 1-14; prednisolone orally on days 1-5; methotrexate IV on day 15; and imatinib orally daily (Ph positive ALL). Follow-up Active treatment for 6 Active treatment for 6 Active treatment until cycles, follow-up cycles (24 weeks), follow- participant has been in (maintenance) 36 months. up until death. remission for 2 years, follow-up indefinite. Primary Rate of molecular CR (normalisation of Feasibility, toxicity and outcome/s remission (MRD negative peripheral blood and bone efficacy of aggressive status after phase I marrow with ≤5% blasts in treatment regimen. induction). a normocellular or hypercellular marrow, a granulocyte count of ≥1 x 109/L, platelet count of ≥100 x 109/L, complete

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resolution of all sites of extramedullary disease). c Secondary Complete remission (CR) ; - OS; CR; DFS. outcome/s OS; EFS; DFS; MRD; AEs. Key results - - CR, 66%; OS at one year, 62%. Adverse - - The most common grade effects (AEs) 3-4 toxicities included transaminitis and hyperbilirubinemia, cytopenias, hypophosphatemia, hyperglycemia, and neutropenic fever. Expected Study completion date Study completion date Study completion date reporting reported as August 2016. reported as September reported as December date 2016. 2014.

ESTIMATED COST and IMPACT

COST

The cost of pegaspargase is not reported but pegaspargase (used off-label) is currently reimbursed by NHS England Specialised Services.

IMPACT - SPECULATIVE

Impact on Patients and Carers

 Reduced mortality/increased length of survival  Reduced symptoms or disability

 Other  No impact identified

Impact on Health and Social Care Services

 Increased use of existing services  Decreased use of existing services

 Re-organisation of existing services  Need for new services

 Other  None identified

Impact on Costs and Other Resource Use

 Increased drug treatment costs  Reduced drug treatment costs

 Other increase in costs  Other reduction in costs

 Other: uncertain unit cost compared to  None identified existing treatments

c All criteria must be met for clinical CR: absolute neutrophil count ≥1,000/μl (without growth factor support), platelet count ≥100,000/μl (without transfusions), no circulating blasts; bone marrow cellularity approximately normal with evidence of maturation of all cell lineages and <5% blasts; extramedullary leukemia, such as CNS or soft tissue involvement, must not be present.

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Other Issues

 Clinical uncertainty or other research question  None identified identified

REFERENCES

1 National Institute for Health and Clinical Excellence. Dasatinib for acute lymphoblastic leukaemia. Health technology appraisal final scope: August 2008. 2 Adult acute lymphoblastic leukaemia patients (25 and over) October 2011. https://leukaemialymphomaresearch.org.uk/booklet/adult-acute-lymphoblastic-leukaemia-all Accessed 12 December 2014. 3 Donnan JR, Ungar WJ, Mathews M et al: Health technology assessment of thiopurine methyltransferase testing for guiding 6-mercaptopurine doses in pediatric patients with acute lymphoblastic leukemia. Toronto: Technology Assessment at SickKids (TASK). TASK Health Technology Assessments 2010-02. March 2010. 4 Lauw M, Hubers L, van Ommen C, et al. Prophylaxis for venous thromboembolism during asparaginase therapy in patients treated for acute lymphoblastic leukemia. Cochrane Database of Systematic Reviews 2012; Issue 9. Art. No: CD010049. 5 Bassan, Renato, and Hoelzer D. Modern therapy of acute lymphoblastic leukemia. Journal of Clinical Oncology 2011;29(5):532-543. 6 Office for National Statistics. Cancer Registration Statistics, England (Series MB1), No. 43, 2012. www.ons.gov.uk 7 Cancer Research UK. Data Table: Cancer deaths and rates by country in the UK 2012. http://publications.cancerresearchuk.org/publicationformat/data_tables/dtmortcountries.html 8 Health & Social Care Information Centre. Hospital episode statistics for England. Inpatient statistics, 2012-13. www.hscic.gov.uk/hes 9 National Comprehensive Cancer Network. Acute Lymphoblastic Leukemia. Fort Washington, PA: NCCN; 2013. 10 The European Group for Blood and Marrow Transplantation. Editors: J. Apperley, E. Carreras, E. Gluckman, T. Masszi. Handbook on Haemopoietic Stem Cell Transplantation. Revised edition 2012. 11 The American Society for Blood and Marrow Transplantation Executive Committee. The role of cytotoxic therapy with haematopoietic stem cell transplantation in the treatment of adult acute lymphoblastic leukaemia: update of the 2006 evidence based-review. Biology of Blood Marrow Transplant 2012;18:16-7. 12 Pui CH, Leslie LR, and Look AT. Acute lymphoblastic leukaemia. Lancet 2008;371(9617):1030- 1043. 13 Inaba H, Greaves M, and Mullighan CG. Acute lymphoblastic leukaemia. Lancet 2013;381(9881)1943-1955. 14 Map of medicine. Acute lymphoblastic leukaemia in adults – management. http://app.mapofmedicine.com/mom/1/page.html?department-id=6&specialty-id=1032&pathway- id=3397&page-id=15284&pathway-prov-cert=/attachments/17208_provcert.pdf Accessed 09 January 2014. 15 Ashfaq K, Yusuf BJ, Jilani AZ et al. Stem cell transplantation for high risk acute lymphoblastic leukaemia in paediatric patients in first remission. The Cochrane Library 2013; Issue 2. Art. No: CD010348. 16 National Institute of Health Research (NIHR) Horizon Scanning Centre. Inotuzumab ozogamicin for acute lymphoblastic leukaemia – second or subsequent line. University of Birmingham, March 2014. http://www.hsc.nihr.ac.uk/ 17 Clinicaltrials.gov. Total therapy study XVI for newly diagnosed patients with acute lymphoblastic leukemia. http://clinicaltrials.gov/ct2/show/NCT00549848 Accessed 11 December 2014 18 Clinicaltrials.gov. International collaborative treatment protocol for children and adolescents with acute lymphoblastic leukemia. https://clinicaltrials.gov/ct2/show/study/NCT01117441 Accessed 12 December 2014. 19 Clinicaltrialsregister.eu. UKALL14 - A randomized trial for adults with newly diagnosed acute lymphoblastic leukemia. https://www.clinicaltrialsregister.eu/ctr-search/trial/2009-012717-22/GB Accessed 22 January 2015.

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20 Patel B, Kirkwood A, Dey A, et al. Feasibility of pegylated-asparaginase (peg-asp) during induction in adults with acute lymphoblastic leukaemia (ALL): results from the UK phase 3 multicentre trial UKALL 14. Blood 2013:122(21);3900-3900. 21 Clinicaltrialsregister.eu. United Kingdom national randomised trial for children and young adults with acute lymphoblastic leukaemia and lymphoma 2011. www.clinicaltrialsregister.eu/ctr- search/trial/2010-020924-22/GB Accessed 22 January 2015. 22 Clinicaltrials.gov. ALL2008 protocol for childhood acute lymphoblastic leukemia intermittent versus continuous PEG Asparaginase https://clinicaltrials.gov/ct2/show/NCT00819351 Accessed 22 January 2015. 23 Clinicaltrials.gov. A novel "pediatric-inspired" regimen with reduced myelosuppressive drugs for adults (aged 18-60) with newly diagnosed Ph negative acute lymphoblastic leukemia. http://clinicaltrials.gov/ct2/show/NCT01920737 Accessed 15 December 2014. 24 Clinicaltrials.gov. Methotrexate, vincristine, pegylated l-asparaginase and dexamethasone (MOAD) in acute lymphoblastic leukemia (ALL) salvage. http://clinicaltrials.gov/ct2/show/study/NCT00905034 Accessed 15 December 2014. 25 Fathi A, DeAngelo D, Stevenson K, et al. Intensified chemotherapy for older patients with acute lymphoblastic leukemia (ALL): A phase II study from the Dana Farber Cancer Institute (DFCI) ALL consortium. Blood 2014;124 (21). 26 Clinicaltrials.gov. Treatment of older adults with acute lymphoblastic leukemia. http://clinicaltrials.gov/ct2/show/study/NCT00973752 Accessed 12 December 2014.

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