Single Technology Appraisal Pegaspargase for treating acute lymphoblastic leukaemia Committee ...

498 Pages·2016·7.44 MB·English

by  Jeremy Powell

Single Technology Appraisal

Pegaspargase for treating acute
lymphoblastic leukaemia

Committee Papers
NATIONAL INSTITUTE FOR HEALTH AND CARE EXCELLENCE

SINGLE TECHNOLOGY APPRAISAL

Pegaspargase for treating acute lymphoblastic leukaemia [ID863]

Contents:

1. Pre-Meeting Briefing

2. Final Scope and Final Matrix of Consultees and Commentators

3. Company submission from Baxalta (now part of Shire)

4. Clarification letters
 NICE request to the company for clarification on their submission
 Company response to NICE’s request for clarification

5. Patient group, professional group and NHS organisation submission
from:
 Leukaemia CARE
 Royal College of Pathologists endorsed by clinical expert Professor
A Vora
 National Cancer Research Institute, Association of Cancer
Physicians and Royal College of Physicians joint submission
endorsed by clinical expert Dr C Rowntree

6. Evidence Review Group report prepared by Kleijnen Systematic Reviews

7. Evidence Review Group report – factual accuracy check

8. Evidence Review Group report – erratum

9. Evidence Review Group report – erratum 2

Any information supplied to NICE which has been marked as confidential, has been
redacted. All personal information has also been redacted.
CONFIDENTIAL
NATIONAL INSTITUTE FOR HEALTH AND CARE
EXCELLENCE
Premeeting briefing
Pegaspargase for treating acute lymphoblastic
leukaemia
This premeeting briefing presents:
 the key evidence and views submitted by the company, the consultees and their
nominated clinical experts and patient experts and
 the Evidence Review Group (ERG) report.
It highlights key issues for discussion at the first Appraisal Committee meeting and
should be read with the full supporting documents for this appraisal.
Please note that this document includes information from the ERG before the
company has checked the ERG report for factual inaccuracies.
Key issues for consideration
Clinical effectiveness
 Is there sufficient evidence available to assume equal effectiveness between
pegaspargase, native E. coli derived asparaginase and Erwinia-derived
asparaginase in the paediatric or adult populations?
 How generalisable are the results from the trials to clinical practice? The UKALL
protocols form the basis of current clinical practice in England, with pegaspargase
being administered at a dose of 1,000 IU/m2. This is lower than all of the
comparative evidence available for pegaspargase (2,500 IU/m2) and that
recommended in the Summary of product characteristics.

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Cost effectiveness
 Is treatment sequencing a valid approach to modelling? The ERG commented
that the comparison of pegaspargase followed by Erwinia derived asparaginase
versus Erwinia derived asparaginase followed by pegaspargase does not inform
the decision at hand, that is should pegaspargase be recommended for routine
use within the NHS.
 Does the company’s economic model reflect clinical practice in England?
 In the model the paediatric population received 1 course of treatment at the
maintenance and 2 courses at the delayed intensification treatment periods.
The ERG stated that in the most recent paediatric treatment protocols specify
only 1 course of treatment at the maintenance and delayed intensification
treatment periods.
 The model used a rate of 6 doses of E.coli derived asparaginase or Erwinia
derived asparaginase for each dose of pegaspargase but the ERG considered
that 4 doses was a better estimate.
 Is it appropriate to use the rates of hypersensitivity to reflect the proportion of
patients who require a treatment switch as a result of hypersensitivity?
 With respect to the hypersensitivity to native E. coli derived asparaginase, the
ERG agreed with the company that 20% can be considered as a reliable and
conservative estimate. However, there is no evidence that the percentages
used for hypersensitivity to pegaspargase and Erwinia derived asparaginase
also reflect the proportion of patients who require a treatment switch. Based on
alternative data sources which explicitly report the rate of treatment switching,
the ERG used 13.2% and 9% for pegaspargase and Erwiniaderived
asparaginase, respectively, in the ERG base case.

1 Remit and decision problems
1.1 The remit from the Department of Health for this appraisal was: To
appraise the clinical and cost effectiveness of pegaspargase within its
marketing authorisation for treating acute lymphoblastic leukaemia.
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Table 1 Decision problem
Final scope issued by Decision problem Comments from the company Comments from the ERG
NICE addressed in the
submission
Pop. People with acute Newly diagnosed people As the use of asparaginase in the The patient population described
lymphoblastic leukaemia with ALL UK is driven by the UKALL in the final scope are: “People
(ALL) protocols, the patient population with acute lymphoblastic
whose chemotherapeutic regimen leukaemia”. This is in line with
is underpinned by asparaginase is the patient population described
the newly-diagnosed cohort, as per in the licence indication for
the protocols. Patients who pegaspargase: "Oncaspar is
experience a relapse or are older indicated as a component of
than 65 would have regimens that antineoplastic combination
do not include pegaspargase therapy in acute lymphoblastic
leukaemia (ALL) in paediatric
patients from birth to 18 years,
The submission therefore meets
and adult patients".
the scope in that it considers
patients of relevance to decision-
makers in the NHS.
Int. Pegaspargase plus As per scope N/A The intervention described in the
standard chemotherapy company submission matches
the intervention described in the
final scope: pegaspargase plus
standard chemotherapy.
However, the dose used in the
economic model is not the
recommended dose.
Com. Non-pegylated forms of: As per scope Asparaginase treatment will be The comparators are in line with
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 Escherichia coli- Treatment sequences given as part of 1st line ALL the final NICE scope
derived L- modelled: treatment, and in cases of
asparaginase 1. Pegaspargase >> hypersensitivity reactions, a switch
plus standard Erwinia-derived to an alternative (2nd line)
chemotherapy asparaginase asparaginase will be necessary.
 Erwinia 2. Native E. coli-derived Although the licence for
chrysanthemi- asparaginase >> Erwinia- pegaspargase does not preclude
derived L- derived asparaginase its use as a 2nd line asparaginase
asparaginase therapy there is not currently a
3. Erwinia-derived
(crisantaspase) clinical scenario in the UK in which
asparaginase >>
plus standard pegaspargase would be used in
Pegaspargase
chemotherapy this setting, since patients would
4. Erwinia-derived
not receive native E. coli- or
asparaginase >> Native E.
Erwinia-derived asparaginase as a
coli-derived asparaginase 1st line asparaginase.
In addition, with the availability of
Erwinia-derived asparaginase,
patients experiencing
hypersensitivity to pegylated or
native E. coli enzyme would in
practice no longer be switched to
the other E. coli enzyme because
of the risk of cross reactivity, and
subsequent hypersensitivity. In UK
clinical practice, UKALL protocols
mandate a switch to Erwinia-
derived enzyme following
hypersensitivity to pegaspargase
A further complication in this field is
that native E. coli-derived
asparaginase is not licensed for
use in the UK. Unavailability in the
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United States has seen it removed
from United States treatment
guidelines (NCCN 2015).
Erwinia derived asparaginase is
licensed in the UK and, although
the wording of its indication does
not limit its use to a specific line of
asparaginase therapy, the product
is only positioned in treatment
protocols as a 2nd line
asparaginase.
Hence, with this context in mind,
the current standard of care
treatment pathway in the UK is
pegaspargase 1st line followed by
Erwinia-derived enzyme in cases of
hypersensitivity, and this treatment
sequence has been modelled.
Although not currently part of UK
clinical practice and unrealistic
given the current unavailability of
native E. coli enzyme and the 2nd
line positioning of Erwinia,
alternative switching scenarios of
native to Erwinia, Erwinia to
pegylated, and Erwinia to native
could be clinically possible, and are
also modelled.
Out. The outcome measures As per scope except for Event free survival was used in All outcomes in the scope are
to be considered progression-free survival many studies and this outcome will included in the company
include: which wasn’t included incorporate progression free submission, except for
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 Overall survival survival. progression-free survival which
 Progression-free In addition, there are a large wasn’t reported in any of the
survival amount of patients, especially included studies. Instead, event
paediatric patients, who are cured free survival was used in many
 Treatment
and as such do not progress studies and this outcome
response rates
incorporates progression free
 Event-free survival according to the
survival company.
 Asparaginase
activity
 Adverse effects
of treatment
 Health-related
quality of life

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2 The technology and the treatment pathway
2.1 Pegaspargase (Oncaspar, Baxalta) is a polyethylene glycol conjugate
of Escherichia coli derived L-asparaginase. L- asparaginase is an
enzyme that hydrolyses asparagine (an amino acid) leading to cell
death. Pegaspargase received its marketing authorisation in January
2016. It is given intravenously. In September 2008, pegylated L-
asparaginase was granted orphan status by the European Medicines
Agency for the treatment of ALL.
2.2 The specific treatment regimens, drug selection, dosages, and
treatment duration differ depending on patient age (adults and
younger patients), and among different subtypes of ALL, but multi-
agent chemotherapy is generally used and treatment is grouped into
three main phases:
 Remission/Induction: The aim of treatment is to clear as many
leukaemic cells as possible and achieve bone marrow remission
(less than 5% blasts). Drugs used in this phase include vincristine,
corticosteroid (e.g. prednisone), cyclophosphamide, anthracyclines
(e.g. doxorubicin), and asparaginase (3 types are available: native E
coli derived asparaginase, Erwinia derived asparaginse and
pegaspargase).
 Intensification/consolidation: The aim of treatment is to irradiate
residual disease. Drugs used during this phase are cytarabine,
methotrexate and 6-mercaptopurine.
 Maintenance. The aim of treatment is to prevent disease relapse.
Drugs used during this phase are 6-mercaptopurine, methotrexate,
corticosteroids, and vincristine.
2.3 Treatment decisions also take into account patient’s disease risk
category:
 Low-risk ALL: Aged between age 1 and 10 years, less than 50,000
white blood cells per cubic millimetre (mm3) of blood when
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diagnosed, leukaemia cells with chromosome changes that respond
well to treatment, negative central nervous system status (low
amount of leukemic cells in spinal fluid), rapid early response to
induction treatment.
 High-risk ALL: Aged less than age one or older than ten years,
more than 50,000 white blood cells/mm3 of blood when diagnosed,
positive CNS status (high amount of leukemic cells in spinal fluid)
leukemia cells with chromosome changes that are more difficult to
treat (mixed-lineage leukaemia gene rearrangement).
 Very high-risk ALL: Patient also has leukaemia cells that have
parts of chromosome 9 and chromosome 22 fused together
(Philadelphia chromosome) or leukaemia cells which have too few
chromosomes (hypodiploid).
 Standard risk ALL: patient does not share any features with the
low-risk or high-risk groups.
2.4 According to the company, pegaspargase has been included in NHS
England baseline commissioning since April 2013. In addition,
pegaspargase has been the first line asparaginase in UK practice
mandated since 2003, being adopted in UKALL protocols for children,
adolescents and young adults (UKALL 2003, which completed
enrolment in 2010; UKALL 2011) and for adults (UKALL14). The
company stated as such although the marketing authorisation for
pegaspargase does not preclude its use as a second line
asparaginase therapy, there is not currently a clinical scenario in
which pegaspargase would be used as a second line asparaginase
therapy, since patients would not receive native E. coli-or Erwinia
derived asparaginase as a first line asparaginase. The company
highlighted that UKALL protocols have seen clinicians adopt
pegaspargase at a dose of 1,000 IU/m2 lower than the summary of
product characteristics recommended dose of 2,000-2,500 IU/m2.
2.5 The treatment pathway for pegaspargase for the treatment of ALL is
shown in figure 1.and the treatment protocols for UKALL 2003,
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