Future Treatments in Acute Myeloid Leukaemia (AML) - A Guide for Patients
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Future Treatments in Acute Myeloid Leukaemia (AML) A Guide for Patients
Introduction
The main treatment for acute myeloid leukaemia (AML) is
chemotherapy, including targeted therapy where cancer
drugs attack specific components of the leukaemia
cells. This might be followed by a stem cell transplant.
Surgery and radiation therapy may be used in special
circumstances. New therapies are being developed and
investigated every day. Several of these new drugs for the
treatment of AML are described in this booklet.
If you need specific advice or professional who is specialised
have any questions about this in leukaemia, Dr Emmanouil
treatment, please contact your Nikolousis. We are also grateful to
medical team or Clinical Nurse a leukaemia patient, Julie Quigley,
Specialist (CNS). for her valuable contribution as a
reviewer.
Booklet compiled by our Patient
Information Writer, Isabelle Leach
and peer reviewed by a medical
If you would like any information on the sources
used for this booklet, please email
communications@leukaemiacare.org.uk
for a list of references.
Version 1
Printed: 10/2018
2 www.leukaemiacare.org.uk Review date: 10/2020In this booklet
Introduction 2
In this booklet 3
About Leukaemia Care 4
Drug approval and recommendations 6
Clofarabine 8
Gilteritinib 12
Quizartinib 18
Venetoclax 22
Vyxeos 28
Glossary 32
Useful contacts and further support 35
Helpline freephone 08088 010 444 3About Leukaemia Care
Leukaemia Care is a national charity dedicated to ensuring
that people affected by blood cancer have access to the
right information, advice and support.
Our services found on our website at www.
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Our helpline is available 9.00am - resources/information-booklets/
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information booklets like had blood cancer themselves
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has been affected by a blood way. You can speak to someone
cancer. A full list of titles – both who knows what you are going
disease specific and general through. For more information
information titles – can be on how to get a buddy call
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Website to www.leukaemiacare.org.uk/
You can access up-to-date communication-preferences/
information on our website,
www.leukaemiacare.org.uk, as
well as speak to one of our care
advisers on our online support
Helpline freephone 08088 010 444 5Drug approvals and
recommendations
Information on when new drugs https://www.daiichisankyo.
are approved by the European com/media_investors/
Medicines Agency (EMA), the media_relations/press_
medicines regulatory authority releases/detail/006846.
for Europe, are available on the html). Preliminary trial results,
EMA website under the Human strategies on submission for
Medicines tab. A European Public drug approval, and Orphan
Assessment Report (EPAR) for Designation on the company’s
each drug that is approved drugs are often shared.
is provided on the website,
together with its Summary of
2. ClinicalTrial.gov (https://
clinicaltrials.gov) is a website
Product Characteristics (SPC),
database of approximately
which details everything that is
276,190 clinical trials studies
available on the drug.
in over 204 countries. The
If a drug is not on the website, phases of the studies and
then it is being developed and their estimated completion
investigated by the sponsor dates will indicate the stage of
pharmaceutical company (e.g. development of the drug. Phase
Daiichi Sankyo in the case of 1 and 2 trials investigate how
quizartinib which is not yet the drug behaves in healthy
approved in Europe; for more volunteers and which are
information, go to the quizartinib the best doses to use. Phase
section in this booklet starting on 3 clinical trials investigate
page 18). To find out more on the the efficacy and safety of
stage of development of a drug the drug in large numbers
that is not approved, two websites of patients with the disease.
are very helpful: Positive results in a Phase 3
trial will allow the sponsor
1. The Sponsor pharmaceutical pharmaceutical company to
company website provides
submit for approval to the EMA.
regular press releases (e.g.
6 www.leukaemiacare.org.ukThe National Institute for Health
and Care Excellence (NICE) issues
recommendation guidelines
based on the best available
evidence of which drugs work and
what their costs are. Decisions on
which topics to develop guidelines
on, and in what order, are based
on suggestions by commissioners
and professional organisations,
and organisations for people
using services, their families
and carers. The final decision is
made in conjunction with NHS
England and the Department
of Health and Public Health.
Published guidelines are available
on the NICE website at https://
www.nice.org.uk/guidance/
published?type=cg. Checks
on whether a guideline needs
updating is usually undertaken
by NICE every two years and
is always undertaken at least
every four years from the date of
guideline publication. A list of the
guidance in the various stages
of development with estimated
completion dates are available
on the NICE website at https://
www.nice.org.uk/guidance/
Helpline freephone 08088 010 444 7Clofarabine
What is clofarabine? treatment with a stem cell
transplant
Clofarabine (developed
by Genzyme) is a type of •• Patients with myelodysplastic
chemotherapy drug known as a syndrome (MDS) which is a
DNA synthesis inhibitor, which group of conditions where the
stops cancer cells making DNA, bone marrow does not make
thereby preventing them from enough normal blood cells
growing and multiplying.
The bone marrow of patients with
Clofarabine is indicated for the MDS makes blood cells which
treatment of children and adults are not fully developed and do
up to 21 years of age with relapsed not work normally. The cause
or refractory acute lymphoblastic is not known, but exposure to
leukaemia (ALL), who have the chemical benzene (present
received at least two previous in petrol and cigarette smoke)
regimens. or treatment with radiotherapy
or chemotherapy have been
Clofarabine was approved for implicated. Patients with MDS
the treatment of relapsed or are commonly aged between 65
refractory ALL by the Food and to 70 years, with only 20% being
Drug Administration (FDA) on 28 younger than 50 years old.
December 2004 and is marketed
under the name of Clolar®. It was Who receives
approved for the same indication clofarabine?
in Europe, Australia and New
Zealand on 29 May 2006, and is Clofarabine is approved for
marketed as Evoltra®. the treatment of children and
adolescents (1 to 18 years of age)
In addition, clofarabine is also and adults up to 21 years of age
being investigated as a treatment with relapsed or refractory acute
for: lymphoblastic leukaemia when at
least two other types of treatment
•• Older patients with AML have failed. There is no experience
who cannot have high dose
8 www.leukaemiacare.org.ukof the safety and efficacy of 2. The cycle is then repeated every
clofarabine for children less than two to six weeks as soon as the
one year of age or adults greater number of blood cells return to
than 21 years of age. normal. Dosage used is based
on the patient’s body surface
Clofarabine should not be given to
area, calculated using the
patients with the following:
actual height and weight before
•• Known hypersensitivity the start of each cycle.
reaction to the constituents
Extra fluids are given through
of clofarabine (clofarabine,
the drip to prevent the build-up
sodium chloride and water for
of uric acid which occurs as the
injections)
cancer cells are broken down
•• Severe renal and hepatic by clofarabine. Medications to
impairment prevent nausea and vomiting
will be given if required. Liver
•• Pregnant or breast-feeding and kidney function will be
women monitored during the five days of
clofarabine infusion. Clofarabine,
How is clofarabine like fludarabine, will require the
administered? administration of irradiated
Clofarabine is available as a blood products for up to one
single-use vial containing 20mg year after receiving clofarabine
of clofarabine in 20mL of normal (and this will be indefinite if
saline. It is administered by the patient undergoes stem cell
intravenous infusion. transplantation).
1. For the first cycle, the What are the side
recommended paediatric dose effects of clofarabine?
of 52mg/m2 is administered as
an intravenous infusion over The most common side effects
two hours every day for five reported in more than 10% of
consecutive days. patients during clinical trials with
with clofarabine were:
Helpline freephone 08088 010 444 9Clofarabine (cont.)
•• Nausea company. No expanded access
trials, which enable patients who
•• Vomiting cannot participate in a clinical
•• Febrile (feverish) neutropenia trial to gain access to a medical
product not yet approved by the
•• Headache regulatory authority, are available
•• Rash for clofarabine at present.
•• Diarrhoea More details of the criteria that
patients need to have to take part
•• Itching (pruritus) in the trials, and locations of the
centres for the clinical trials can
•• High temperature (pyrexia) be found at https://clinicaltrials.
•• Palmar-plantar gov
erythrodysaesthesia syndrome
(reddening, swelling, numbness Phase 3 trials of
and skin peeling on palms of clofarabine for the
the hands and soles of the feet) treatment of patients
•• Fatigue with AML
•• Anxiety NCT00703820
•• Mucosal membrane ••Title of trial: Clofarabine plus
Cytarabine versus Conventional
inflammation (areas that
Induction Therapy and a
produce mucus to filter out
Study of Natural Killer Cell
bacteria swell up)
Transplantation in Newly
•• Flushing Diagnosed Acute Myeloid
Leukaemia
What trials have there
been for clofarabine? ••Status of trial: Active, not
recruiting
Four Phase 3 clinical trials of
clofarabine in patients with AML ••Enrolment/estimated
enrolment: 324 patients
are ongoing. All these trials are
sponsored by Genzyme, a Sanofi ••Study start date: 4 August
10 www.leukaemiacare.org.uk2008 enrolment: 727 patients
••Estimated study completion ••Study start date: 28 December
date: June 2020 2010
NCT00317642 ••Estimated study completion
••Title of trial: A Study of date: September 2018
Clofarabine and Cytarabine for
NCT01471444
Older Patients with Relapsed or
Refractory Acute Myelogenous ••Title of trial: Fludarabine-IV
Leukaemia (AML), (CLASSIC I) Busulfan ± Clofarabine and
Allogeneic Hematopoietic Stem
••Status of trial: Completed, Cell Transplantation for Acute
results available Myeloid Leukaemia (AML) and
Myelodysplastic Syndrome
•• Enrolment/estimated (MDS)
enrolment: 326 patients
••Status of trial: Active, not
••Study start date: 1 August recruiting
2006
••Enrolment/estimated
••Estimated study completion enrolment: 250 patients
date: January 2012
••Study start date: 2 November
NCT02085408 2011
••Title of trial: Clofarabine or ••Estimated study completion
Daunorubicin Hydrochloride
and Cytarabine Followed by date: November 2020
Decitabine or Observation in
Treating Older Patients with
Newly Diagnosed Acute Myeloid
Leukaemia
••Status of trial: Active, not
recruiting
••Enrolment/estimated
Helpline freephone 08088 010 444 11Gilteritinib
What is gilteritinib? 1. FLT3-ITD is a FLT3 mutation
that includes an internal
Gilteritinib (manufactured tandem duplication (ITD) which
by Astellas) is a cancer drug is a small doubling up of amino
which is being investigated for acids in the membrane of the
the treatment of patients with receptor. Amino acids are the
relapsed or refractory AML. building block for proteins.
Tyrosine kinase receptors 2. FLT3-TKD is a point mutation
are receptors present in the in a single amino acid in the
membranes of all of the body’s tyrosine kinase domain (TKD).
cells, and they carry information
to and from complex cell networks The FLT3-ITD mutations are
such as the bone marrow, present in the AML cells of 20%
amongst others. FMS-like tyrosine to 30% of newly diagnosed
kinase 3 (FLT3) is a member of patients and point mutations in
the class 3 receptor tyrosine the tyrosine kinase domain are
kinase family, and mutations in present in 7% of patients.
the FLT3 gene are known to be
In October 2017, the FDA granted
involved in the development of
gilteritinib Fast Track Designation
AML. FLT3s mutations are found
for the treatment of adult
in approximately one third of
patients with FLT3 mutation-
all patients with AML, and these
positive relapsed or refractory
mutations are associated with
AML. This Fast Track program
relapsed and refractory cases of
enables Astellas to accelerate
AML.
the development, review, and
Gilteritinib is known to inhibit approval of gilteritinib for the
both FLT3 mutations involved in treatment of AML.
AML and it is being developed
In January 2018, gilteritinib was
for treatment of patients with
granted Orphan Designation
relapsed or refractory AML who
for the treatment of AML by the
have these mutations. These two
European Commission. Orphan
FLT3 mutations are FLT3-ITD and
Designation is given to drugs
FLT3-TKD:
that may be of significant benefit
12 www.leukaemiacare.org.ukto patients with rare conditions of patients with relapsed or
(affecting less than 5 in 10,000 refractory AML who have these
people). This status makes it mutations.
easier for a drug to be approved,
and the company developing it How is gilteritinib
receives scientific advice and administered?
funding.
A dose-finding, first-in-human
On 23 March 2018, a new drug trial of gilteritinib which
application for marketing investigated oral daily doses of
approval of gilteritinib in Japan gilteritinib ranging from 20mg
was submitted by Astellas to 450mg in 252 patients with
Pharma Inc for the treatment relapsed or refractory acute
of adult patients with FLT3 myeloid leukaemia showed that
mutation-positive relapsed or gilteritinib 120mg gave the best
refractory AML. On 29 March 2018, combination of activity against
Astellas also submitted new AML (consistent FLT3 inhibition)
drug application for approval of and a good safety profile. Based
gilteritinib in the same patient on this data, gilteritinib 120mg
population to the FDA. once daily is being tested in Phase
3 trials.
Who receives
In the ongoing Phase 3 ADMIRAL
gilteritinib? study, which compares gilteritinib
Currently, gilteritinib is being with salvage chemotherapy
investigated in adults with FLT3 (chemotherapy given to a
mutation-positive relapsed patient when other options are
or refractory AML. There is no exhausted) in 371 adult patients
experience of the safety and with FLT3-positive relapse/
efficacy of gilteritinib for those refractory AML, gilteritinib 120mg
under 18 years of age. is administered orally once daily.
Gilteritinib is known to inhibit What are the side
two of the FLT3 mutations
(FLT3-ITD and FLT3-TKD) and is
effects of gilteritinib?
being developed for treatment Early experience of the safety of
Helpline freephone 08088 010 444 13Gilteritinib (cont.)
gilteritinib comes from a first- relapse/refractory AML. The study
in-human trial of 252 patients which started in October 2015
with relapsed or refractory acute has recruited 371 patients and
myeloid leukaemia. The three is estimated to be completed by
most common side effects November 2020.
that patients experienced with
Six other Phase 3 clinical trials
gilteritinib were diarrhoea (37%
of gilteritinib in patients with
of patients), anaemia (34%)
AML are also ongoing. All these
and fatigue (33%). Other side
trials are sponsored by Astellas
effects included abnormal liver
Pharma Global Development,
enzyme tests, pneumonia, acute
Inc. Two expanded access trials
renal failure and pyrexia (high
are available alongside the other
temperature).
trials.
What trials have there More details of the criteria that
been for gilteritinib? patients need to have to take part
Gilteritinib is currently being in the trials and locations of the
investigated in large numbers of centres for the clinical trials can
patients (Phase 3 trials) and is be found at https://clinicaltrials.
showing consistent inhibition of gov
FLT3 mutations in patients with
relapsed or refractory AML, as well
Phase 3 and expanded
as being well tolerated by these access trials of
patients. gilteritinib for the
The new drug applications treatment of patients
submitted in Japan and the with AML
US for gilteritinib are based on NCT02752035
data from the ongoing Phase 3
ADMIRAL study (NCT02421939), ••Title of trial: A Study of ASP2215
which is comparing gilteritinib (Gilteritinib) by Itself, ASP2215
with salvage chemotherapy in Combined with Azacitidine
adult patients with FLT3-positive or Azacitidine by Itself to
Treat Adult Patients who have
14 www.leukaemiacare.org.ukRecently Been Diagnosed with ••Estimated study completion
Acute Myeloid Leukaemia with date: March 2024
a FLT3 Gene Mutation and
who Cannot Receive Standard NCT02997202
Chemotherapy ••Title of trial: A Trial of the
FMS-like Tyrosine Kinase 3
••Status of trial: Recruiting (FLT3) Inhibitor Gilteritinib
••Enrolment/estimated Administered as Maintenance
enrolment: 540 patients Therapy Following Allogeneic
Transplant for Patients
••Study start date: 1 August with FLT3/Internal Tandem
2016 Duplication (ITD) Acute Myeloid
Leukaemia (AML)
••Estimated study completion
date: March 2022 ••Status of trial: Recruiting
NCT02957262 ••Enrolment/estimated
••Title of trial: A Study of ASP2215 enrolment: 346 patients
(Gilteritinib), Administered as
Maintenance Therapy Following
••Study start date: 7 June 2017
Induction/Consolidation ••Estimated study completion
Therapy for Subjects with FMS- date: August 2024
like Tyrosine Kinase 3 (FLT3/ITD)
Acute Myeloid Leukaemia (AML) NCT03182244
in First Complete Remission ••Title of trial: A Study of ASP2215
versus Salvage Chemotherapy
••Status of trial: Recruiting in Patients with Relapsed
••Enrolment/estimated or Refractory Acute Myeloid
enrolment: 354 patients Leukaemia (AML) with FLT3
Mutation
••Study start date: 10 January
2017 ••Status of trial: Recruiting
Helpline freephone 08088 010 444 15Gilteritinib (cont.)
••Enrolment/estimated If you wish to have
enrolment: 318 patients
further information on
••Study start date: 15 January AML, please view our
2018 collection of patient
information booklets
••Estimated study completion that are available on
date: June 2020 our website at www.
NCT02421939 leukaemiacare.org.uk
••Title of trial: A Study of ASP2215
versus Salvage Chemotherapy
in Patients with Relapsed
or Refractory Acute Myeloid
Leukaemia (AML) with FMS-like
Tyrosine Kinase (FLT3) Mutation
(ADMIRAL trial)
••Status of trial: Active, not
recruiting
••Enrolment/estimated
enrolment: 371 patients
••Study start date: 20 October
2015
••Estimated study completion
date: February 2020
16 www.leukaemiacare.org.ukHelpline freephone 08088 010 444 17
Quizartinib
What is quizartinib? Who receives
Quizartinib (developed by Daiichi quizartinib?
Sankyo) is a selective FLT3 Quizartinib is an investigational
receptor tyrosine kinase inhibitor agent that is not currently
that is being investigated for the approved for any indication in any
treatment of adult patients with country. Safety and efficacy have
relapsed/refractory AML. not been established.
Quizartinib has shown promising Patients with a FLT3-ITD mutation
activity against leukaemia in AML have a lower overall survival
relapsed and refractory patients rate and an increased rate of
in a large Phase 2 study. It is relapse compared with patients
currently being investigated in with AML but without this
two international Phase 3 trials mutation. Therefore, Daiichi
for the treatment of AML with Sankyo are investigating
FLT3-ITD mutations for relapsed/ quizartinib for the treatment
refractory patients (QuANTUM-R of relapsed/refractory AML in
trial) and newly-diagnosed patients with FLT3-ITD mutations
patients (QuANTUM-First trial). in their international QuANTUM-R
Results from the QuANTUM-R trial Phase 3 trial. These patients will
will form the basis of worldwide be the first to receive quizartinib
regulatory submissions for once it is approved.
quizartinib in AML leukaemia.
How is quizartinib
Quizartinib has been granted administered?
Fast Track Designation by the FDA
In Phase 1 and 2 trials, quizartinib
for the treatment of relapsed/
has been administered as an oral
refractory AML. It has also been
solution once daily. In a Phase 1
granted Orphan Drug Designation
dose-finding trial, the maximum
by the FDA and EMA for the
tolerated dose of quizartinib
treatment of AML.
was determined as 60mg daily.
Increases in the QT interval on the
ECG tracing, which may lead to
18 www.leukaemiacare.org.ukheart rhythm disturbances, were carried by the red blood cells)
noticed at the maximum tolerated
dose of 60mg daily. •• Thrombocytopenia (decrease
in the levels of platelets, which
To prevent the occurrence of any are small blood cells that help
heart rhythm disturbances, the the body form clots to stop
starting dose of quizartinib in the bleeding)
QuANTUM-R Phase 3 trial will be
30mg daily until the QT interval •• Increased QT interval on the ECG
tracing (this may lead to heart
on the ECG has been checked, and
rhythm disturbances)
then the doses will be increased
to 60mg daily. •• Leukopenia (decrease in
numbers of all white blood cells)
What are the side
effects of quizartinib? •• Pneumonia
The most common side effects What trials have there
reported in patients during
Phase 1 and 2 clinical trials with
been for quizartinib?
quizartinib were: Quizartinib has shown promising
results in relapsed/refractory
•• Febrile neutropenia (decrease in patients in a large Phase 2 study.
numbers of neutrophils, which It is currently being studied
are white blood cells involved in in two large Phase 3 studies
fighting disease, together with a (QuANTUM-R and QuANTUM-First),
temperature) which are detailed below.
•• Neutropenia (decrease in QuANTUM-R
numbers of neutrophils which
This trial is due to end in July 2019
are white blood cells involved in
and the results will be used to
fighting disease)
support worldwide submissions
•• Anaemia (low level of red blood for the approval of quizartinib in
cells and haemoglobin which is the treatment of AML leukaemia.
Helpline freephone 08088 010 444 19Quizartinib (cont.)
The trial compares quizartinib maintenance therapy.
with salvage chemotherapy in
More details of the criteria that
patients with AML who are FLT3-
patients need to have to take part
ITD positive.
in the trials, and locations of the
Preliminary results from the centres for the clinical trials, can
global QuANTUM-R Phase 3 trial be found at https://clinicaltrials.
were released by Daiichi Sankyo in gov
May 2018. The QuANTUM-R Phase
3 trial showed that quizartinib Phase 3 trials of
significantly prolonged overall quizartinib for the
survival compared with salvage treatment of patients
chemotherapy in patients with
FLT3-ITD mutation-positive
with AML
relapsed or refractory AML. Safety NCT02039726
was consistent with that observed
in Phase 2 trials of quizartinib.
••Title of trial: (QuANTUM-R): An
Open-label Study of Quizartinib
QuANTUM-First Monotherapy vs Salvage
Chemotherapy in Acute Myeloid
This trial is still recruiting Leukemia (AML) Subjects who
patients and is due to be are FLT3-ITD Positive
completed in November
2020. Details of recruitment ••Status of trial: Active, not
can be found at https:// recruiting
quantumfirststudy.com/
••Enrolment/estimated
The trial compares quizartinib enrolment: 367 patients
and chemotherapy with placebo
and chemotherapy in newly ••Study start date: April 2014
diagnosed patients with FLT3- ••Estimated study completion
ITD mutation-positive AML. The date: July 2019
two treatments will be compared
for effectiveness as induction/
consolidation therapy and
20 www.leukaemiacare.org.ukNCT02668653
••Title of trial: Quizartinib with
Standard of Care Chemotherapy
and as Maintenance Therapy in
Patients with Newly Diagnosed
FLT3-ITD (+) Acute Myeloid
Leukaemia (AML) (QuANTUM-
First)
••Status of trial: Recruiting
••Enrolment/estimated
enrolment: 536 patients
••Study start date: September
2016
••Estimated study completion
date: November 2020
Leukaemia Care offers nationwide support groups for
people affected by a diagnosis of a blood or lymphatic
cancer. Visit www.leukaemiacare.org.uk, or call
08088 010 444, to find out more and to find a group
near you.
Helpline freephone 08088 010 444 21Venetoclax
What is venetoclax? The approval is conditional to
the European Medicines Agency
Venetoclax (marketed as reviewing any additional data as
Venclyxto® in Europe and and when it is available.
Venclexta® in the US by
AbbVie/Genentech) is a B-cell On 8 June 2018, the FDA in the
lymphoma-2 (BCL2) inhibitor. US granted regular approval
BCL2 cells are found in high to venetoclax for patients with
numbers among chronic chronic lymphocytic leukaemia
lymphocytic leukaemia (CLL) (CLL) or small lymphocytic
cancer cells. Venetoclax attaches lymphoma (SLL), with or without
itself to these BCL2 cancer 17p deletion, who have received at
cells, blocking their actions and least one prior therapy.
causing them to die.
Who receives
On 6 December 2012, venetoclax venetoclax?
was designated an Orphan Drug
because of the low number of Venetoclax is conditionally
patients with CLL. indicated for the treatment of CLL.
On 5 December 2016, venetoclax There is no experience of the
received conditional approval for safety and efficacy of venetoclax
the treatment of CLL for: for children.
•• Patients with 17p deletion Patients with AML
or TP53 mutations who are Although there is currently no
unsuitable for, or have failed indication for venetoclax in the
treatment with, a B-cell receptor treatment of AML, early Phase 1
pathway inhibitor. and 2 trials are investigating the
•• Patients without 17p deletion or combination of venetoclax with
TP53 mutations who have failed decitabine or azacitidine in the
treatment with both chemo- treatment of elderly patients with
immunotherapy and a B-cell AML.
receptor pathway inhibitor. A Phase 1b trial in 57 elderly
22 www.leukaemiacare.org.ukpatients with AML (median age combination of drugs achieved
of 75 years), for whom intensive complete remission or complete
chemotherapy was not an option, remission with incomplete
reported that 61% of patients marrow recovery. Based on this
receiving the combination trial, enrolment has begun in a
of drugs achieved complete Phase 3 trial to confirm these
remission or complete remission results in a greater number of
with incomplete marrow recovery. patients.
Moreover, nine of the patients
went on to receive stem cell How is venetoclax
transplants while in remission, administered?
suggesting that venetoclax with
Venetoclax is available in film-
decitabine or azacitidine may be
coated tablets containing either
a step forward to achieving cure.
venetoclax 10mg, 50mg or 100mg.
It is also shown that patients with
The tablets are administered
the IDH2 mutation can have a
orally once daily according to the
better response to venetoclax.
following dosing schedule. They
On their own, decitabine or should be swallowed whole, with a
azacitidine do not achieve a meal and water.
cure (less than 30% remission);
The starting dose is venetoclax
however, when combined with
20mg once daily for seven days.
venetoclax, which has a low
The dose is then gradually
toxicity profile, the results are
increased over a period of five
greatly improved. Large Phase 3
weeks up to the recommended
trials are needed to confirm these
daily dose of 400mg as shown on
results.
the next page:
Similar results have been
reported when combining
venetoclax and cytarabine in 71
patients ≥65 years with previously
untreated AML. Results showed
that 62% of patients receiving the
Helpline freephone 08088 010 444 23Venetoclax (cont.)
Week Venetoclax tomography scan) and blood
Daily Dose chemistry (potassium, uric
acid, phosphorus, calcium
One 20mg and creatinine) levels will be
Two 50mg performed, and any abnormalities
corrected to decrease risk of
Three 100mg
tumour lysis syndrome.
Four 200mg
Five and 400mg
What are the side
onwards effects of venetoclax?
The most common side effects
This five-week dose-titration
reported in more than 20% of
schedule is designed to reduce
patients during clinical trials with
the size of the tumour gradually
venetoclax for the treatment of
and decrease the risk of tumour
CLL include:
lysis syndrome, which is when
tumour cells release their •• Diarrhoea
contents into the bloodstream
leading to metabolic disturbances •• Nausea
which can progress to clinical •• Vomiting
toxic effects, including kidney
(renal) problems, heart rate •• Constipation
disturbances, seizures, and death
due to multi-organ failure.
•• Fatigue
The risk of tumour lysis syndrome
•• Anaemia (low level of red cells
and haemoglobin which red
is greater with a rapid decrease of
cells carry)
a large tumour, and if the patient
has poor renal function or any •• Neutropenia (decrease in
other serious diseases. Before numbers of neutrophils which
treatment with venetoclax is are white blood cells involved in
started by an experienced cancer fighting disease)
physician, assessment of the
tumour (X-ray and computed •• Thrombocytopenia (decrease
24 www.leukaemiacare.org.ukin the levels of platelets, which The study is estimated to be
are small blood cells that help completed in August 2020.
the body form clots to stop
In the second trial
bleeding)
(NCT03069352), venetoclax
•• Upper respiratory tract combined with low dose
infections cytarabine is being compared
with low dose cytarabine alone
•• Hyperphosphataemia in treatment-naïve patients
(abnormally high levels of
with AML who are ineligible
phosphate in the blood)
for intensive chemotherapy.
The study is estimated to be
What trials have there completed in November 2019.
been for venetoclax?
More details of the criteria that
Venetoclax is currently being
patients need to have to take part
investigated in two large Phase
in the trials, and locations of the
3 trials for the treatment of
centres for the clinical trials, can
patients with AML who are
be found at https://clinicaltrials.
ineligible for standard induction,
gov
and in patients with AML who
are ineligible for intensive
Phase 3 and expanded
chemotherapy. Both trials are
sponsored by AbbVie. An expanded access trials of
access trial (NCT03123029) is venetoclax for the
available alongside these trials. treatment of patients
In the first trial (NCT02993523), with AML
venetoclax combined with NCT02993523
azacitidine is being compared
with azacitidine alone in ••Title of trial: A Study of
Venetoclax in Combination with
treatment-naïve patients with
Azacitidine versus Azacitidine
AML (those who have never had
in Treatment Naïve Subjects
treatment) who cannot have
with Acute Myeloid Leukaemia
standard induction therapy.
Helpline freephone 08088 010 444 25Venetoclax (cont.)
who are Ineligible for Standard ••Status of trial: Expanded
Induction Therapy access available
••Status of trial: Recruiting ••Enrolment/estimated
enrolment: N/A
••Enrolment/estimated
enrolment: 400 patients ••Study start date: N/A
••Study start date: 3 April 2017 ••Estimated study completion
date: N/A
••Estimated study completion
date: 5 August 2020
NCT03069352
••Title of trial: A Study of
Venetoclax in Combination with
Low Dose Cytarabine versus
Low Dose Cytarabine Alone
in Treatment Naïve Patients
with Acute Myeloid Leukaemia
who are Ineligible for Intensive
Chemotherapy
••Status of trial: Recruiting
••Enrolment/estimated
enrolment: 175 patients
••Study start date: 23 May 2017
••Estimated study completion
date: 25 November 2019
NCT03123029
••Title of trial: Expanded Access
to Venetoclax
26 www.leukaemiacare.org.ukHelpline freephone 08088 010 444 27
Vyxeos
What is Vyxeos? granted Vyxeos approval for the
treatment of adults with newly
Vyxeos® is the registered name diagnosed t-AML or AML-MRC.
for the combination of two This is the first FDA-approved
cancer drugs (daunorubicin treatment specifically for these
and cytarabine) which has been conditions. The approval was
formulated for intravenous based on preliminary data from
injection. Daunorubicin and Study CLTR0310301 which is
cytarabine are already licensed being conducted in 309 patients
for the treatment of patients with (aged 60-75 years) with newly-
AML, and both act by damaging diagnosed t-AML or AML-MRC.
the DNA of cancer cells in the
blood stream and bone marrow. Who receives Vyxeos?
Vyxeos is being investigated by Vyxeos is approved for the
Jazz Pharmaceuticals for the treatment of adults with newly
treatment of adult patients with diagnosed t-AML or AML-MRC.
two types of newly diagnosed AML: There is no experience of the
safety and efficacy of Vyxeos for
1. Therapy-related AML (t-AML) those below 18 years of age.
– This is a recognised illness
which occurs as a complication Vyxeos should not be given to
of a patient having had patients with the following:
cytotoxic and/or radiation
therapy.
•• Known hypersensitivity reaction
to daunorubicin and cytarabine
2. AML with myelodysplasia
related changes (AML-
•• Impaired cardiovascular
function
MRC) – Patients who have
previously had other types •• Severe renal and hepatic
of blood disorders have AML impairment
with myelodysplasia related
changes. •• Very low blood cell counts which
may lead to haemorrhage
On 3 August 2017, the FDA
28 www.leukaemiacare.org.uk•• Pregnant or breast-feeding of body surface area of the
women patient) and cytarabine 100mg/
m2 in a liposome by intravenous
How is Vyxeos infusion over 90 minutes on
administered? days one, three and five of the
cycle.
Vyxeos is administered in a
liposome, which is a small ball- •• If required, the same dose can
like structure made from a thin be given on days one and three
cell membrane that combines of a second induction cycle.
the doses of daunorubicin and
cytarabine and is formulated for For the first induction cycle of
intravenous infusion. the treatment, administration of
Vyxeos by intravenous infusion
The aim of administering Vyxeos commonly requires a stay in a
is to achieve remission when all hospital of three to five weeks,
the leukaemia cells in the blood depending upon whether
or bone marrow are removed and remission can be achieved
the normal bone marrow develops and how well side effects can
again. be tolerated. Patients typically
receive the entire treatment cycle
To bring about or induce
during their stay in hospital. In
remission, patients receive
some cases, the intravenous
an induction cycle of Vyxeos.
infusions which are on days one,
Occasionally, the first induction
three and five of the cycle can be
chemotherapy does not destroy
administered in an outpatient
all the leukaemia cells and a
infusion centre allowing the
second induction cycle may be
patient to go home afterwards.
required.
However, the patient must be
•• For the first induction cycle, the admitted to the hospital after the
recommended dose of Vyxeos completion of all the infusions for
is combined daunorubicin the remainder of the induction
44mg/m2 (mg of drug per meter cycle as they will have very low
Helpline freephone 08088 010 444 29Vyxeos (cont.)
blood cell counts that require consolidation therapy cycle.
special monitoring.
Consolidation therapy can be
Your consultant will often perform given in an outpatient infusion
a bone marrow biopsy 14 to 21 centre, allowing the patients to
days after starting your treatment return home when therapy is
and, according to the results of finished.
the biopsy, you can proceed to
In total, the duration of therapy
consolidation chemotherapy for
may last between four to six
the next cycle of treatment.
months, depending upon how
Once patients are in remission, you respond to the treatment,
they receive consolidation how well you tolerate it, the
chemotherapy with the aim number of consolidation
of eliminating any leukaemia chemotherapy cycles required,
cells that are still present after and the availability of a stem cell
induction chemotherapy, as transplant.
this will help reduce the risk
of the leukaemia returning. What are the side
Consolidation chemotherapy is effects of Vyxeos?
given between five to eight weeks
The most common side effects
after the last induction cycle
which occurred in more than 25%
and once blood cell counts have
of patients during clinical trials
reverted to normal.
with Vyxeos were:
•• The recommended dose for •• Haemorrhage events
each consolidation cycle is
combined daunorubicin 29mg/ •• Febrile (feverish) neutropenia
m2 and cytarabine 65mg/m2
in a liposome via intravenous •• Rash
infusion over 90 minutes on •• Oedema (build-up of fluid in the
days one and three. body)
•• A second consolidation therapy •• Nausea
cycle may be required as
the same dose as the first •• Mucositis
30 www.leukaemiacare.org.uk•• Diarrhoea The Phase 3 trial (NCT01696084)
which provided the preliminary
•• Constipation data that led to the approval of
•• Musculoskeletal pain Vyxeos for the treatment of adult
patients with newly diagnosed
•• Fatigue t-AML or AML-MRC, is still ongoing.
•• Abdominal pain The study started in November
2012 and is due to be completed
•• Dyspnoea (difficult or laboured by November 2019. FDA approval
breathing) was achieved on the strength of
data on overall survival, which
•• Headache was 9.56 months for patients who
•• Cough received Vyxeos and 5.95 months
for patients daunorubicin and
•• Decreased appetite cytarabine in separate infusions.
•• Arrhythmia (abnormal heart A Phase 4 trial (NCT03526926)
rhythms) titled ‘A Post-Marketing
•• Pneumonia Observational Study of VYXEOS™
to Assess the Incidence of
•• Bacteraemia (infection of the Infusion-Related Reactions in
blood) Adult Patients’ is due to start
soon. Jazz Pharmaceuticals plan
•• Chills to recruit 50 patients, and they
•• Sleep disorders estimate that the trial will be
completed by January 2019.
•• Vomiting
More details of the criteria that
What trials have there patients need to have to take part
been for Vyxeos? in the trials and locations of the
centres for the clinical trials can
There are currently no ongoing, or
be found at https://clinicaltrials.
planned Phase 3 trials of Vyxeos
gov
for the treatment of patients with
a diagnosis of AML.
Helpline freephone 08088 010 444 31Glossary
Acute Myeloid Leukaemia (AML) of a trial.
Acute myeloid leukaemia (AML) is ClinicalTrials.gov
a type of blood cancer that starts
ClinicalTrials.gov is a database
from young white blood cells
of trials and includes details of
called granulocytes or monocytes
276,190 research studies in all 50
in the bone marrow.
states and in 204 countries.
Amino acids
Cytotoxic drugs
Organic molecules which are
Drugs that are toxic to cancer
the building blocks for making
cells and prevent their growth and
proteins.
replication.
Blast cells
Deoxyribonucleic Acid (DNA)
Immature cells found in the
A molecule that carries the
bone marrow. They are not fully
genetic instructions used in the
developed and therefore do not
growth development, functioning
carry any particular function
and reproduction of all living
within the body. In normal
organisms.
humans, up to 5% of the cells
found in the bone marrow are Generic drug
blast cells.
A pharmaceutical drug that is
Chemotherapy the equivalent to a brand name
product in dosage, strength, route
A form of cancer treatment that
of administration, quality and
uses one or more anticancer
performance and intended use.
drugs as part of a standardised
chemotherapy regime. Mutation
Clinical trial The changing of the structure
of a gene, resulting in a variant
A medical research study
form which may be transmitted to
involving patients with the aim of
subsequent generations, caused
improving treatments and their
by the alteration of single base
side effects. You will always be
units in DNA, or the deletion,
informed if your treatment is part
32 www.leukaemiacare.org.ukinsertion, or rearrangement different dosages and by using
of larger sections of genes or the drug in combination with
chromosomes. other drugs.
Myelodysplasia Phase 4 trial
Myelodysplastic syndrome is a Phase 4 trials are conducted once
group of conditions where the a drug has been granted a license
bone marrow does not make to find out more about a drug’s
enough normal blood cells. The side effects, its long-term risks
blood cells made are not fully and benefits, or how well it works
developed and not able to work when it’s used more widely.
normally. These blood cells
include red blood cells which Platelets
supply oxygen to the body’s A disc-shaped element in the
tissues, white blood cells which blood that assists in blood
fight infection and platelets which clotting. During normal blood
help blood clot. clotting, the platelets clump
together (aggregate).
Palmar-plantar
erythrodysaesthesia syndrome Red Blood Cell
Reddening, swelling, numbness The blood cell that carries oxygen.
and desquamation (skin Red cells contain haemoglobin,
sloughing or peeling) on palms which permits them to transport
of the hands and soles of the oxygen (and carbon dioxide).
feet (and, occasionally, on the
knees, elbows, and elsewhere),
Relapse
chemotherapy-induced. The return of a disease or the
signs and symptoms of a disease
Phase 3 trial after a period of improvement.
A Phase 3 trial is a large clinical
trial (more than 100 patients)
Remission
that collects information on a A period of time when the illness
drug’s safety and effectiveness is less severe or is not affecting
using different populations and someone.
Helpline freephone 08088 010 444 33Glossary (cont.)
Refractory disease Tyrosine Kinase Inhibitor (TKI)
Refractory describes a disease or A drug which blocks the action
condition which does not respond of a tyrosine kinase (a particular
to attempted forms of treatment. type of enzyme in the cell). In CML
A cancer is said to be refractory it works mainly by blocking the
when it does not respond to (or is activity of the BCR-ABL protein.
resistant to) cancer treatment.
White blood cell
Salvage chemotherapy One of the cells the body makes
Chemotherapy given to a patient to help fight infections. There are
when other options are exhausted. several types of white blood cells.
The two most common types are
Targeted therapy the lymphocytes and neutrophils.
Drugs that specifically interrupt
the ability of the leukaemia to
grow in the body. These drugs do
not simultaneously harm healthy
tissue the way conventional
chemotherapy agents do.
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34 www.leukaemiacare.org.ukUseful contacts
and further support
There are a number of helpful Bloodwise
sources to support you during Bloodwise is the leading charity
your diagnosis, treatment and into the research of blood cancers.
beyond, including: They offer support to patients,
•• Your haematologist and their family and friends through
healthcare team patient services.
•• Your family and friends 020 7504 2200
•• Your psychologist (ask your www.bloodwise.org.uk
haematologist or CNS for a
referral)
Cancer Research UK
Cancer Research UK is a leading
•• Reliable online sources, charity dedicated to cancer
such as Leukaemia Care
research.
•• Charitable organisations 0808 800 4040
There are a number of www.cancerresearchuk.org
organisations, including
ourselves, who provide expert Macmillan
advice and information. Macmillan provides free practical,
medical and financial support for
Leukaemia Care
people facing cancer.
We are a charity dedicated to
0808 808 0000
supporting anyone affected by
www.macmillan.org.uk
the diagnosis of any blood cancer.
We provide emotional support Maggie’s Centres
through a range of support Maggie’s offers free practical,
services including a helpline, emotional and social support
patient and carer conferences, to people with cancer and their
support group, informative families and friends.
website, one-to-one buddy
service and high-quality patient 0300 123 1801
information. We also have a nurse www.maggiescentres.org
on our help line for any medical Citizens Advice Bureau (CAB)
queries relating to your diagnosis.
Offers advice on benefits and
Helpline: 08088 010 444 financial assistance.
www.leukaemiacare.org.uk
support@leukaemiacare.org.uk 08444 111 444
www.adviceguide.org.uk
Helpline freephone 08088 010 444 35Leukaemia Care is a national charity dedicated to providing information, advice and support to anyone affected by a blood cancer. Around 34,000 new cases of blood cancer are diagnosed in the UK each year. We are here to support you, whether you’re a patient, carer or family member. Want to talk? Helpline: 08088 010 444 (free from landlines and all major mobile networks) Office Line: 01905 755977 www.leukaemiacare.org.uk support@leukaemiacare.org.uk Leukaemia Care, One Birch Court, Blackpole East, Worcester, WR3 8SG Registered charity 259483 and SC039207
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