1. Leukaemia for shared care centres Workshop session Caroline Osborne & Julia Hitchin (Alder Hey) NPPG conference 11 th November 2012

2. Workshop content  Presentation Children’s Cancer Measures Children’s Cancer Measures Shared care levels for POSCUs Shared care levels for POSCUs Clinical Trial Issues Clinical Trial Issues Background – other trial results (UK and international) Background – other trial results (UK and international) Objectives of UKALL 2011 Objectives of UKALL 2011 UKALL 2011 trial summary UKALL 2011 trial summary IMPs/NIMPs IMPs/NIMPs Pharmacy responsibilities Pharmacy responsibilities  UKALL 2011 Prescription verification exercise  Open discussion

3. Aims of session   Have an understanding of the UKALL 2011 clinical trial   Understand the implications of this trial for your POSCU   Be aware of your responsibilities in dispensing for this clinical trial

4. Children’s Cancer Measures   2005 NICE Improving Outcomes Guidance in Children and Young People with Cancer  2009 Manual for Cancer Services, Children’s Cancer Measures. Part of National Cancer Peer Review Programme.  2011 - V2.1  Birth to 16 years

5. Children’s Cancer Measures  Principle Treatment Centre (PTC) – 20, linked to CCLG  Paediatric Oncology Shared Care Unit (POSCUs)  Self assessment, Internal Validation, external review

6. Shared care levels for POSCUs  Level 1 Supportive care Supportive care Out patient Oral chemo Out patient Oral chemo Out patient IV bolus Out patient IV bolus  Level 2 As level 1 PLUS As level 1 PLUS Day case infusional chemo Day case infusional chemo  Level 3 As level 2 plus inpatient 24 hour chemotherapy Everything except diagnosis, trial enrolment, BMT etc As level 2 plus inpatient 24 hour chemotherapy Everything except diagnosis, trial enrolment, BMT etc

7. Clinical Trial Issues  IMP = Investigational Medicinal Product a pharmaceutical form of an active substance or placebo being tested or used as a reference in a clinical trial, including products already with a marketing authorisation but used or assembled in a way different from the authorised form, or when used for an unauthorised indication, or when used to gain further information about the authorised form a pharmaceutical form of an active substance or placebo being tested or used as a reference in a clinical trial, including products already with a marketing authorisation but used or assembled in a way different from the authorised form, or when used for an unauthorised indication, or when used to gain further information about the authorised form  NIMP = Non-Investigational Medicinal Product (i.e. any other drug used within protocol)

8. IMP management  IMPs may be licensed medication that only becomes IMP once taken off shelf to dispense OR  Trial specific products that must be ordered, stored and recorded specifically for the trial  Drug accountability is required for all IMPs  Labelling – need to attach a trial specific label (supplied by trial sponsor) to each container of IMP dispensed as well as dispensing label

9. Background  Results of UKALL 2003 show an improvement in EFS of 6% (87%)  Among the best reported to date internationally  Various recent international trials (COG and BFM) have been reviewed whilst making the changes to UKALL 2011  UKALL 2011 aims to further improve survival and quality of survival by addressing 4 main issues apparent from UKALL 2003

10. UKALL 2003 4 main areas of concern  Treatment related morbidity and mortality too high in context of DFS 87% 100 non-relapse deaths in CR, 25% all patients have at least 1 SAE 100 non-relapse deaths in CR, 25% all patients have at least 1 SAE Marked reduction in QoL Marked reduction in QoL TRM commonest during induction and delayed intensive (Dexamethasone) TRM commonest during induction and delayed intensive (Dexamethasone)  Very poor prognosis of early marrow relapse <20% survive even after transplant <20% survive even after transplant

11. UKALL 2003 4 main areas of concern  Concerns over efficacy and burden of therapy of CNS prophylaxis (i.e. IT’s)  Superior outcome for young adults treated on paediatric protocol Up to age 24. Previously treatment depended on place of presentation/choice Up to age 24. Previously treatment depended on place of presentation/choice Needs more uniform approach so all young adults get treated the same Needs more uniform approach so all young adults get treated the same

12. Aims & Objectives of UKALL 2011  Reduce toxicity through introduction of short 14- day course high dose dexamethasone instead of conventional 28 day lower dose (randomised)  More effective CNS prophylaxis and reduce burden of therapy by introducing high dose IV methotrexate and by omission of vincristine and dex pulses (randomised)  Decrease toxicity and reduce burden of therapy by administering a single delayed intensification to all patients (non-randomised)

13. UKALL 2011 Inclusion  Age 1 year to < 25 years  First diagnosis of acute lymphoblastic leukaemia or:  Lymphoblastic lymphoma (T-NHL or precursor negative B-NHL)

14. Regimen A (Standard risk) Induction  B cell precursor ALL < 10 years of age and highest WCC <50  All Downs syndrome patients  Randomised to standard dexamethasone (IMP) 6mg/m 2 /day in 2 doses (capped at 10mg/day) for 28 days then taper over next 7 days  OR short dexamethasone (IMP) 10mg/m 2 /day in 2 doses (not capped & no taper) for 14 days  Weekly vincristine  PEG Asparaginase  Intrathecal Methotrexate

15. Regimen B (High risk) Induction  B cell precursor ALL > 10 years of age and/or highest WCC >50  All T cell ALL and T cell lymphoblastic lymphoma  Randomised to standard dexamethasone (IMP) 6mg/m2/day in 2 doses (capped at 10mg/day) for 28 days then taper over next 7 days  OR short dexamethasone (IMP) 10mg/m2/day in 2 doses (not capped & no taper) for 14 days (NB >10 years “short dex” get 2 x 7 day blocks weeks 1 & 3 – reduced risk osteonecrosis) (NB >10 years “short dex” get 2 x 7 day blocks weeks 1 & 3 – reduced risk osteonecrosis)  Weekly daunorubicin and vincristine  PEG Asparaginase  Intrathecal Methotrexate

16. Day 29 MRD  Low risk – continue regimen A or B as allocated for induction  Risk – augmented BFM consolidation regimen C  No result – determine post induction therapy based on early response

17. Post induction treatment – Regimen A

18. Post induction treatment – reg B

19. Interim maintenance (standard arm)  As in UKALL 2003 (ALL IMPS) Dexamethasone 5 day pulse each month Dexamethasone 5 day pulse each month Vincristine monthly Vincristine monthly Continuous oral mercaptopurine 75mg/m 2 /day for 8 weeks Continuous oral mercaptopurine 75mg/m 2 /day for 8 weeks Oral methotrexate weekly omitting in weeks when get intrathecals Oral methotrexate weekly omitting in weeks when get intrathecals Intrathecal methotrexate monthly Intrathecal methotrexate monthly

20. Protocol M – High Dose methotrexate (experimental arm)  ALL IMPs Oral mercaptopurine 25mg/m 2 /day for 8 weeks (NB much lower dose than elsewhere) Oral mercaptopurine 25mg/m 2 /day for 8 weeks (NB much lower dose than elsewhere) IV Methotrexate 5g/m 2 every 14 days for 4 doses IV Methotrexate 5g/m 2 every 14 days for 4 doses Intrathecal methotrexate – within 2 hours of start of IV Methotrexate Intrathecal methotrexate – within 2 hours of start of IV Methotrexate

21. Delayed Intensive (reg A week 18 – 24) (reg B week week 20-26) All NIMPs  As per UKALL 2003 except no Intrathecals in part 2  Part 1 - Vinc, Dox, PEG, IT day 1, Dex 10mg/m 2 /day for 7 days week 1 & 3  Part 2 - Cyclo, Cytarabine, oral Mercaptopurine 60mg/m 2 /day for 14 days

22. Maintenance  All patients get Oral Mercaptopurine (NIMP) 75mg/m 2 /day continuous (adjusted for counts) Oral Mercaptopurine (NIMP) 75mg/m 2 /day continuous (adjusted for counts) Oral Methotrexate (NIMP) 20mg/m 2 once a week (omitted week of IT & adjusted for counts) Oral Methotrexate (NIMP) 20mg/m 2 once a week (omitted week of IT & adjusted for counts)  Pulses (randomised to receive or not) Dexamethasone (IMP) 6mg/m 2 /day for 5 days every 4 weeks Dexamethasone (IMP) 6mg/m 2 /day for 5 days every 4 weeks Vincristine (IMP) 1.5mg/m 2 every 4 weeks Vincristine (IMP) 1.5mg/m 2 every 4 weeks  Intrathecals (IMP) (NOT for patients who got protocol M) IT Methotrexate day 15 of each 12 week cycle IT Methotrexate day 15 of each 12 week cycle  NB Septrin continues throughout

23. Regimen C  Induction Only for reg A subsequently found to have high risk cytogenetics OR Downs syndrome with SER Only for reg A subsequently found to have high risk cytogenetics OR Downs syndrome with SER Continue Dex as randomised Continue Dex as randomised Continue Vinc Continue Vinc Daunorubicin day 16 & 23 (higher dose than reg B) Daunorubicin day 16 & 23 (higher dose than reg B)

24. Post induction treatment – reg C

25. Capizzi interim maintenance (standard arm) (all IMPs)  As UKALL 2003  Vincristine every 10 days with escalating IV Methotrexate doses  PEG Asparaginase  Intrathecal methotrexate

26. Protocol M-A (experimental arm) (all IMPs)  As reg A/B with addition of Peg Asp

27. Delayed Intensive – reg C (weeks 24-31) All NIMPs  As per UKALL 2003  As regimen A/B

28. Special IMPs  Mercaptopurine 10mg tabs and PEG Asparaginase, licensed in Germany, must use Medice (Medac UK) for both  Methotrexate liquid for IMP is trial specific from Stockport  In NIMP phase use special from Stockport  Mercaptopurine suspension – is now a licensed product (NOVA) but initially this is trial specific IMP from NOVA  When NIMP must use licensed NOVA product

29. Pharmacy Responsibilities  Maintaining pharmacy file and signing relevant delegation logs  IMP ordering, ensuring only approved preparations are used  IMP storage in controlled temperature environment  Drug accountability of all IMPs  Ensure prescription is identified as clinical trial and IMPs are highlighted  Identification of IMP by approved trial label in addition to dispensing label  Recording returns and safely disposing of them

30. Useful Links  NPPG and POP group  Your local cancer network –see the Department of Health website for a full list www.dh.gov.uk www.dh.gov.uk  www.bopawebsite.org – learning centre: Verification of Chemotherapy Prescriptions in Paediatrics Module www.bopawebsite.org  www.macmillan.org.uk – aimed at public but lots of useful information www.macmillan.org.uk  www.cclg.org.uk www.cclg.org.uk  www.cquins.nhs.uk – children's cancer measures www.cquins.nhs.uk