Leukaemia for Leukaemia for shared care centresshared care centres

Workshop sessionWorkshop session

Caroline Osborne & Julia Hitchin (Alder Hey)Caroline Osborne & Julia Hitchin (Alder Hey)NPPG conferenceNPPG conference

1111thth November 2012 November 2012

Workshop contentWorkshop content PresentationPresentation

• Children’s Cancer MeasuresChildren’s Cancer Measures• Shared care levels for POSCUsShared care levels for POSCUs• Clinical Trial IssuesClinical Trial Issues• Background – other trial results (UK and international)Background – other trial results (UK and international)• Objectives of UKALL 2011Objectives of UKALL 2011• UKALL 2011 trial summaryUKALL 2011 trial summary• IMPs/NIMPsIMPs/NIMPs• Pharmacy responsibilitiesPharmacy responsibilities

UKALL 2011 Prescription verification UKALL 2011 Prescription verification exerciseexercise

Open discussionOpen discussion

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

Children’s Cancer MeasuresChildren’s Cancer Measures 2005 NICE Improving Outcomes Guidance in

Children and Young People with Cancer 2009 Manual for Cancer Services , Children’s 2009 Manual for Cancer Services , Children’s

Cancer Measures. Part of National Cancer Peer Cancer Measures. Part of National Cancer Peer Review Programme.Review Programme.

2011 - V2.1 2011 - V2.1 Birth to 16 yearsBirth to 16 years

Children’s Cancer MeasuresChildren’s Cancer Measures Principle Treatment Centre (PTC) – 20, linked to Principle Treatment Centre (PTC) – 20, linked to

CCLGCCLG Paediatric Oncology Shared Care Unit Paediatric Oncology Shared Care Unit (POSCUs) (POSCUs)

Self assessment, Internal Validation, external Self assessment, Internal Validation, external reviewreview

Shared care levels for POSCUs Shared care levels for POSCUs Level 1Level 1

Supportive careSupportive care Out patient Oral chemoOut patient Oral chemo Out patient IV bolusOut patient IV bolus

Level 2Level 2 As level 1 PLUSAs level 1 PLUS Day case infusional chemo Day case infusional chemo

Level 3Level 3 As level 2 plus inpatient 24 hour chemotherapy As level 2 plus inpatient 24 hour chemotherapy

Everything except diagnosis, trial enrolment, BMT etc Everything except diagnosis, trial enrolment, BMT etc

Clinical Trial IssuesClinical Trial Issues IMP = Investigational Medicinal ProductIMP = Investigational Medicinal Product

a pharmaceutical form of an active substance or placebo a pharmaceutical form of an active substance or placebo being tested or used as a reference in a clinical trial, being tested or used as a reference in a clinical trial, including products already with a marketing authorisation including products already with a marketing authorisation but used or assembled in a way different from the but used or assembled in a way different from the authorised form, or when used for an unauthorised authorised form, or when used for an unauthorised indication, or when used to gain further information about indication, or when used to gain further information about the authorised formthe authorised form

NIMP = Non-Investigational Medicinal NIMP = Non-Investigational Medicinal Product (i.e. any other drug used within Product (i.e. any other drug used within protocol)protocol)

IMP managementIMP management IMPs may be licensed medication that only IMPs may be licensed medication that only

becomes IMP once taken off shelf to becomes IMP once taken off shelf to dispense ORdispense OR

Trial specific products that must be ordered, Trial specific products that must be ordered, stored and recorded specifically for the trialstored and recorded specifically for the trial

Drug accountability is required for all IMPsDrug accountability is required for all IMPs Labelling – need to attach a trial specific label Labelling – need to attach a trial specific label

(supplied by trial sponsor) to each container (supplied by trial sponsor) to each container of IMP dispensed as well as dispensing labelof IMP dispensed as well as dispensing label

BackgroundBackground Results of UKALL 2003 show an improvement in Results of UKALL 2003 show an improvement in

EFS of 6% (87%)EFS of 6% (87%) Among the best reported to date internationallyAmong the best reported to date internationally Various recent international trials (COG and Various recent international trials (COG and

BFM) have been reviewed whilst making the BFM) have been reviewed whilst making the changes to UKALL 2011changes to UKALL 2011

UKALL 2011 aims to further improve survival UKALL 2011 aims to further improve survival and quality of survival by addressing 4 main and quality of survival by addressing 4 main issues apparent from UKALL 2003issues apparent from UKALL 2003

UKALL 2003UKALL 20034 main areas of concern4 main areas of concern

Treatment related morbidity and mortality too Treatment related morbidity and mortality too high in context of DFS 87%high in context of DFS 87% 100 non-relapse deaths in CR, 25% all patients have 100 non-relapse deaths in CR, 25% all patients have

at least 1 SAEat least 1 SAE Marked reduction in QoLMarked reduction in QoL TRM commonest during induction and delayed TRM commonest during induction and delayed

intensive (Dexamethasone)intensive (Dexamethasone) Very poor prognosis of early marrow relapseVery poor prognosis of early marrow relapse

<20% survive even after transplant<20% survive even after transplant

UKALL 2003UKALL 20034 main areas of concern4 main areas of concern

Concerns over efficacy and burden of Concerns over efficacy and burden of therapy of CNS prophylaxis (i.e. IT’s)therapy of CNS prophylaxis (i.e. IT’s)

Superior outcome for young adults treated Superior outcome for young adults treated on paediatric protocolon paediatric protocol Up to age 24. Previously treatment depended Up to age 24. Previously treatment depended

on place of presentation/choiceon place of presentation/choice Needs more uniform approach so all young Needs more uniform approach so all young

adults get treated the sameadults get treated the same

Aims & Objectives of UKALL 2011Aims & Objectives of UKALL 2011

Reduce toxicity through introduction of short 14-Reduce toxicity through introduction of short 14-day course high dose dexamethasone instead of day course high dose dexamethasone instead of conventional 28 day lower dose (randomised)conventional 28 day lower dose (randomised)

More effective CNS prophylaxis and reduce More effective CNS prophylaxis and reduce burden of therapy by introducing high dose IV burden of therapy by introducing high dose IV methotrexate and by omission of vincristine and methotrexate and by omission of vincristine and dex pulses (randomised)dex pulses (randomised)

Decrease toxicity and reduce burden of therapy Decrease toxicity and reduce burden of therapy by administering a single delayed intensification by administering a single delayed intensification to all patients (non-randomised)to all patients (non-randomised)

UKALL 2011UKALL 2011InclusionInclusion

Age 1 year to Age 1 year to < 25 years< 25 years First diagnosis of acute lymphoblastic First diagnosis of acute lymphoblastic

leukaemia or:leukaemia or: Lymphoblastic lymphoma (T-NHL or Lymphoblastic lymphoma (T-NHL or

precursor negative B-NHL)precursor negative B-NHL)

Regimen A (Standard risk) Regimen A (Standard risk) InductionInduction

B cell precursor ALL < 10 years of age and B cell precursor ALL < 10 years of age and highest WCC <50highest WCC <50

All Downs syndrome patientsAll Downs syndrome patients Randomised to standard dexamethasone Randomised to standard dexamethasone (IMP)(IMP)

6mg/m6mg/m22/day in 2 doses (capped at 10mg/day) for /day in 2 doses (capped at 10mg/day) for 28 days then taper over next 7 days28 days then taper over next 7 days

OR short dexamethasone OR short dexamethasone (IMP)(IMP) 10mg/m 10mg/m22/day in /day in 2 doses (not capped & no taper) for 14 days2 doses (not capped & no taper) for 14 days

Weekly vincristineWeekly vincristine PEG AsparaginasePEG Asparaginase Intrathecal MethotrexateIntrathecal Methotrexate

Regimen B (High risk) InductionRegimen B (High risk) Induction B cell precursor ALL > 10 years of age and/or highest B cell precursor ALL > 10 years of age and/or highest

WCC >50WCC >50 All T cell ALL and T cell lymphoblastic lymphomaAll T cell ALL and T cell lymphoblastic lymphoma Randomised to standard dexamethasone Randomised to standard dexamethasone (IMP)(IMP)

6mg/m2/day in 2 doses (capped at 10mg/day) for 28 6mg/m2/day in 2 doses (capped at 10mg/day) for 28 days then taper over next 7 daysdays then taper over next 7 days

OR short dexamethasone OR short dexamethasone (IMP)(IMP) 10mg/m2/day in 2 10mg/m2/day in 2 doses (not capped & no taper) for 14 daysdoses (not capped & no taper) for 14 days

(NB >10 years “short dex” get 2 x 7 day blocks weeks 1 & 3 – (NB >10 years “short dex” get 2 x 7 day blocks weeks 1 & 3 – reduced risk osteonecrosis)reduced risk osteonecrosis)

Weekly daunorubicin and vincristineWeekly daunorubicin and vincristine PEG AsparaginasePEG Asparaginase Intrathecal MethotrexateIntrathecal Methotrexate

Day 29 MRDDay 29 MRD

Low risk – continue regimen A or B as Low risk – continue regimen A or B as allocated for inductionallocated for induction

Risk Risk – augmented BFM consolidation – augmented BFM consolidation regimen Cregimen C

No result – determine post induction No result – determine post induction therapy based on early responsetherapy based on early response

Post induction treatment – Post induction treatment – Regimen ARegimen A

Post induction treatment – reg BPost induction treatment – reg B

Interim maintenance Interim maintenance (standard arm)(standard arm)

As in UKALL 2003 As in UKALL 2003 (ALL IMPS)(ALL IMPS) Dexamethasone 5 day pulse each monthDexamethasone 5 day pulse each month Vincristine monthlyVincristine monthly Continuous oral mercaptopurine 75mg/mContinuous oral mercaptopurine 75mg/m22/day /day

for 8 weeksfor 8 weeks Oral methotrexate weekly omitting in weeks Oral methotrexate weekly omitting in weeks

when get intrathecalswhen get intrathecals Intrathecal methotrexate monthlyIntrathecal methotrexate monthly

Protocol M – High Dose Protocol M – High Dose methotrexate (experimental arm)methotrexate (experimental arm)

ALL IMPsALL IMPs Oral mercaptopurine 25mg/mOral mercaptopurine 25mg/m22/day for 8 /day for 8

weeks (NB much lower dose than elsewhere)weeks (NB much lower dose than elsewhere) IV Methotrexate 5g/mIV Methotrexate 5g/m22 every 14 days for 4 every 14 days for 4

dosesdoses Intrathecal methotrexate – within 2 hours of Intrathecal methotrexate – within 2 hours of

start of IV Methotrexatestart of IV Methotrexate

Delayed Intensive (reg A week 18 – 24) Delayed Intensive (reg A week 18 – 24) (reg B week week 20-26) (reg B week week 20-26) All NIMPsAll NIMPs

As per UKALL 2003 except no Intrathecals As per UKALL 2003 except no Intrathecals in part 2in part 2

Part 1 - Vinc, Dox, PEG, IT day 1, Dex Part 1 - Vinc, Dox, PEG, IT day 1, Dex 10mg/m10mg/m22/day for 7 days week 1 & 3/day for 7 days week 1 & 3

Part 2 - Cyclo, Cytarabine, oral Part 2 - Cyclo, Cytarabine, oral Mercaptopurine 60mg/mMercaptopurine 60mg/m22/day for 14 days /day for 14 days

MaintenanceMaintenance All patients getAll patients get

Oral Mercaptopurine Oral Mercaptopurine (NIMP)(NIMP) 75mg/m 75mg/m22/day continuous /day continuous (adjusted for counts)(adjusted for counts)

Oral Methotrexate Oral Methotrexate (NIMP)(NIMP) 20mg/m 20mg/m22 once a week once a week (omitted week of IT & adjusted for counts)(omitted week of IT & adjusted for counts)

Pulses (randomised to receive or not)Pulses (randomised to receive or not) Dexamethasone Dexamethasone (IMP)(IMP) 6mg/m 6mg/m22/day for 5 days every 4 /day for 5 days every 4

weeksweeks Vincristine Vincristine (IMP)(IMP) 1.5mg/m 1.5mg/m22 every 4 weeks every 4 weeks

Intrathecals Intrathecals (IMP)(IMP) (NOT for patients who got (NOT for patients who got protocol M)protocol M) IT Methotrexate day 15 of each 12 week cycleIT Methotrexate day 15 of each 12 week cycle

NB Septrin continues throughoutNB Septrin continues throughout

Regimen CRegimen C

InductionInduction Only for reg A subsequently found to have Only for reg A subsequently found to have

high risk cytogenetics OR Downs syndrome high risk cytogenetics OR Downs syndrome with SERwith SER

Continue Dex as randomisedContinue Dex as randomised Continue VincContinue Vinc Daunorubicin day 16 & 23 (higher dose than Daunorubicin day 16 & 23 (higher dose than

reg B)reg B)

Post induction treatment – reg CPost induction treatment – reg C

Capizzi interim maintenance Capizzi interim maintenance (standard arm) (standard arm) (all IMPs)(all IMPs)

As UKALL 2003As UKALL 2003 Vincristine every 10 days with escalating Vincristine every 10 days with escalating

IV Methotrexate dosesIV Methotrexate doses PEG AsparaginasePEG Asparaginase Intrathecal methotrexateIntrathecal methotrexate

Protocol M-A (experimental arm) Protocol M-A (experimental arm) (all IMPs)(all IMPs)

As reg A/B with addition of Peg AspAs reg A/B with addition of Peg Asp

Delayed Intensive – reg C Delayed Intensive – reg C (weeks 24-31) (weeks 24-31) All NIMPsAll NIMPs

As per UKALL 2003As per UKALL 2003 As regimen A/BAs regimen A/B

Special IMPsSpecial IMPs Mercaptopurine 10mg tabs and PEG Mercaptopurine 10mg tabs and PEG

Asparaginase, licensed in Germany, must use Asparaginase, licensed in Germany, must use Medice (Medac UK) for bothMedice (Medac UK) for both

Methotrexate liquid for IMP is trial specific from Methotrexate liquid for IMP is trial specific from StockportStockport

In NIMP phase use special from StockportIn NIMP phase use special from Stockport Mercaptopurine suspension – is now a licensed Mercaptopurine suspension – is now a licensed

product (NOVA) but initially this is trial specific product (NOVA) but initially this is trial specific IMP from NOVAIMP from NOVA

When NIMP must use licensed NOVA productWhen NIMP must use licensed NOVA product

Pharmacy ResponsibilitiesPharmacy Responsibilities Maintaining pharmacy file and signing relevant Maintaining pharmacy file and signing relevant

delegation logsdelegation logs IMP ordering, ensuring only approved preparations are IMP ordering, ensuring only approved preparations are

usedused IMP storage in controlled temperature environmentIMP storage in controlled temperature environment Drug accountability of all IMPsDrug accountability of all IMPs Ensure prescription is identified as clinical trial and IMPs Ensure prescription is identified as clinical trial and IMPs

are highlightedare highlighted Identification of IMP by approved trial label in addition to Identification of IMP by approved trial label in addition to

dispensing labeldispensing label Recording returns and safely disposing of themRecording returns and safely disposing of them

Useful LinksUseful Links NPPG and POP groupNPPG and POP group Your local cancer network –see the Department Your local cancer network –see the Department

of Health website for a full list of Health website for a full list www.dh.gov.uk www.bopawebsite.org – learning centre: – learning centre:

Verification of Chemotherapy Prescriptions in Verification of Chemotherapy Prescriptions in Paediatrics ModulePaediatrics Module

www.macmillan.org.uk – aimed at public but lots – aimed at public but lots of useful informationof useful information

www.cclg.org.uk www.cquins.nhs.uk – children's cancer measures – children's cancer measures