ATRA and ATO for Acute Promyelocytic Leukaemia (APL) - A Guide for Patients
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ATRA and ATO for Acute Promyelocytic Leukaemia (APL) A Guide for Patients
Introduction
In this booklet, we describe the use of all-trans retinoic
acid (ATRA), also known as tretinoin, and arsenic trioxide
(ATO) for the treatment of acute promyelocytic leukaemia
(APL).
This booklet was originally put
together by Saloua Najjam, PhD
and peer reviewed by Dr Steve
Knapper, University of Wales,
Cardiff. It has then been updated
by our Patient Information Writer,
Isabelle Leach. We are also
grateful to leukaemia patients
Bruce Bain and John Pointon for
their valuable contributions.
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 2
Printed: 05/2020
2 www.leukaemiacare.org.uk Review date: 05/2022In this booklet
Introduction 2
In this booklet 3
About Leukaemia Care 4
What is ATRA and ATO therapy? 6
Who receives ATRA and ATO therapy? 8
How is ATRA and ATO therapy administered? 10
What are the side effects of ATRA and ATO therapy? 12
What happens if ATRA and ATO therapy doesn’t
work? 14
Glossary 15
Useful contacts and further support 19
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.
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Helpline freephone 08088 010 444 5What is ATRA and ATO
therapy?
ATRA and ATO therapy is a ATRA blocks the effect of the
combination treatment of all- PML-RARA gene that prevents
trans retinoic acid (ATRA) and the promyelocyte cells maturing
arsenic trioxide (ATO) which is into normal white blood cells.
now recognised as the first-line Until recently, ATRA, which is an
treatment for acute promyelocytic active by-product of vitamin A,
leukaemia (APL). A first-line was given with chemotherapy
treatment is accepted as the best drugs called anthracyclines. It
initial treatment for a given type was given in combination with an
and stage of a disease. anthracycline to prevent any drug
resistance to ATRA. Anthracycline
APL is a rare sub-type of acute
drugs, such as daunorubicin or
myeloid leukaemia (AML) in which
idarubicin, interfere with the DNA
there is an increased production
and reproduction of white blood
of immature, abnormal white
cells, including the leukaemia
blood cells called promyelocytes
cells.
in the bone marrow. It is a
special type of AML in that it is In 2018, NICE approved ATO for
nearly always associated with the first-line treatment of APL in
a specific gene called the PML- previously untreated patients,
RARA (ProMyelocytic Leukaemia- with low-to-intermediate risk
Retinoic Acid Receptor Alpha) disease, and patients with APL
gene. When treated with ATRA and that was refractory (did not
ATO, it has an excellent prognosis; respond to chemotherapy) or
better than other sub-types of patients who had relapsed (APL
AML. returned after chemotherapy).
The PML-RARA gene is the result ATRA and ATO are not
of the swapping of the PML gene chemotherapy drugs, but drugs
on chromosome 15 and the RARA called differentiating agents. They
gene on chromosome 17 which encourage the promyelocytic cells
fuse to become the PML-RARA to differentiate (mature) into
gene. normal white blood cells. They
6 www.leukaemiacare.org.ukalso have complementary actions
in that ATRA breaks down the PML- For further details on
RARA gene and ATO encourages the causes, symptoms,
the abnormal APL cells to self- diagnosis and clinical
destruct. features of APL, you
can read our booklet
on our website at www.
leukaemiacare.org.uk.
Alternatively, you can
order a copy by calling
our helpline on 08088
010 444.
Helpline freephone 08088 010 444 7Who receives ATRA and ATO
therapy?
Patients suspected of having • Patients with high-risk APL can
APL should start ATRA treatment be given either of the following
immediately, even before the regimens because studies have
diagnosis is fully confirmed, shown that neither was superior
because they can quickly develop to the other:
potentially life-threatening
bleeding or blood clotting • ATRA plus ATO
with cytoreductive
symptoms. A confirmed diagnosis
chemotherapy such as
of APL using genetic testing can
cytarabine (cytoreductive
be performed later, and treatment
means that the
can be discontinued if APL is not
chemotherapy reduces
confirmed.
the number of cells, which
Based on recent studies in the case of APL are
comparing ATRA plus ATO with abnormal promyelocytes)
ATRA plus chemotherapy, the
European Medicines Agency • ATRA plus an anthracycline
(EMA) have approved ATO for the However, using ATO for high-risk
treatment of newly diagnosed patients may be difficult because
patients with low-to-intermediate the EMA has only approved ATO for
risk APL who are defined as low-to-intermediate risk APL, but
patients with a white blood not for high-risk APL as of yet.
cell (WBC) count of 10000 cells
per microlitre of blood or less.
Patients with APL and a WBC
count higher than this are
considered to be high-risk.
To achieve remission (induction
therapy) and re-enforce remission
(consolidation therapy):
• Patients with low-to-
intermediate risk APL can be
given ATRA plus ATO
8 www.leukaemiacare.org.ukHelpline freephone 08088 010 444 9
How is ATRA and ATO therapy
administered?
ATRA and ATO therapy should be bone marrow is collected from
started as soon as possible and the chest or hip bone, generally
monitored under the supervision under local anaesthetic,
of a doctor experienced in the using a bone marrow surgical
use of chemotherapeutic agents instrument. The sample is then
who will explain the use of this examined for abnormal cells.
combination therapy to you.
You will then need to read and
Before starting treatment with sign a consent form summarising
ATRA and ATO, the following the receipt of verbal and written
clinical assessments will be information about your disease,
carried out: treatment and potential side
effects.
• Measurement of your weight
and height. All patients will start induction
treatment as an inpatient but very
• Full blood count, liver function few will remain inpatients all the
tests, and urea/electrolyte levels
way through the eight weeks it
as a measure of kidney function.
takes to deliver ATO induction. The
These tests will be performed
latter part of these weeks will be
before each treatment cycle.
given to you as an outpatient once
• A pregnancy test will be carried you are completely stable and
out on all female patients responding well to treatment.
of child-bearing age before
Depending on the Haematology
starting treatment.
Unit in your hospital, you
• Electrocardiogram (ECG) to will probably be able to have
check that your heart is working consolidation treatment on an
normally. outpatient basis. As this is a
combination treatment, your
• Bone marrow biopsy to check consultant will decide the best
how many cancer cells there are combination regimen in terms
in your bone marrow. In a bone of the doses and the frequency
marrow biopsy, a sample of of administration for you. As an
10 www.leukaemiacare.org.ukoutpatient, you may be told to
monitor your temperature as this
can be a sign of infection. If your
temperature is above 37.5°C, then
please contact your doctor or
nurse.
In addition to induction
treatment, patients with APL
require supportive care such as
blood product transfusions to
maintain the platelet count and
the blood clotting indicators
as normal as possible. Blood
chemical levels (particularly
potassium and magnesium
which are important for electrical
conduction in the heart) will be
monitored closely. Sometimes
it is necessary to also give
potassium and/or magnesium
supplements.
For consolidation treatment,
patients will be given seven
courses of ATRA (with a two-week
break between courses) and four
consolidation courses of ATO
(with a four-week break between
courses) are recommended by the
latest guidelines.
Helpline freephone 08088 010 444 11What are the side effects of
ATRA and ATO therapy?
Everyone will experience different • Weight gain
side effects with ATRA and ATO
therapy. However, because they Pseudotumour cerebri
have a high white blood cell count, This non-serious increase in
high-risk patients are more likely pressure in the skull is seen with
to experience side effects. It is both ATRA and ATO, and is more
important to report side effects common when both drugs are
to your doctor or nurse so that given together. It can be treated
they can be managed and treated with steroids and by decreasing
differently. The most common the dose of ATRA. Symptoms
side effects when ATRA and ATO include:
are given together are shown
below. • Headaches and dizziness
Side effects in patients with • Eye problems, including
swelling of the optic disk and/or
APL treated with ATRA or ATO are
double vision
similar and include:
Differentiation syndrome • Confusion
This occurs during the first Heart rhythm disturbance
weeks of treatment when the (prolongation of the QT interval)
differentiating agents ATRA which can be seen on the ECG
and ATO start allowing the Treatment may cause heart
promyelocyte cells to mature. It problems, especially for patients
is usually associated with a rise with existing heart disease. ECG
in the white blood cell count. monitoring before and twice a
Differentiation syndrome can week throughout treatment is
usually be treated with steroids. recommended. Patients with this
Symptoms include: condition should have treatment
• Fever, cough, fluid in the lungs stopped and then restarted when
the heart rhythm disturbances
and difficulty breathing
subside.
• Fluid in the tissues and kidney
damage
12 www.leukaemiacare.org.ukOther side effects include: of the pancreas/abdominal pain,
inflammation of the lips, hair loss,
• Harmful liver effects. increased sweating and chills.
• Changes to mood: Confusion, Fertility, pregnancy and
anxiety and depression.
breastfeeding
• Fatigue: Normally mild, you can There are no animal or human
feel you have a lack of energy. studies into the effect of ATO or
Also, you may feel tiredness and ATRA on fertility.
weakness.
There are no studies into the use
• Nausea and vomiting: This can of ATO or ATRA in pregnant women.
be easily managed with anti- However, ATRA is a retinoid, and
sickness medication. other retinoid drugs are known
• Diarrhoea and/or constipation. to cause abnormalities to the
baby when exposed to the drugs
• Changes to skin: problems with during pregnancy. ATO has been
your skin can include rashes, shown to cause abnormalities
dry skin, itching and your skin for the baby in animal studies.
tone appearing flushed. Women receiving ATO or ATRA
are therefore advised to avoid
• Bone and muscle pain. pregnancy by using effective
• Numbness and tingling in contraception during and for at
fingers and toes. least one month after finishing
treatment with ATO or ATRA.
ATO is also linked to excess of
glucose and changes in mineral Women who are taking ATO
levels in the blood. From ATO or ATRA are advised not to
therapy, you may also experience breastfeed.
swelling of the hands and feet,
due to a build-up of fluid.
ATRA is also linked to a loss of
appetite, difficultly sleeping, dry
mouth and nose, inflammation
Helpline freephone 08088 010 444 13What happens if ATRA and ATO
therapy doesn’t work?
For patients with APL who have have relapsed after achieving
had an early diagnosis and been remission, your consultant is the
treated without delay, excellent best person to discuss what other
cure rates of over 90% for low-to- treatments are available, and
intermediate risk patients and help you decide the next course of
85% for high-risk patients have action. Knowledge of your genetic
been reported. results, your physical condition
and any new treatments which
If following your treatment with
may help you will guide your
ATRA and ATO, your APL has
consultant’s recommendations.
not gone into remission or you
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.
14 www.leukaemiacare.org.ukGlossary
Acute Myeloid Leukaemia (AML) Bone Marrow Biopsy
A rapid and aggressive cancer A collection of a sample of bone
of the myeloid cells in the bone marrow from the hip bone,
marrow. generally under local anaesthetic.
A bone marrow surgical
Amino Acids instrument with a cylindrical
Organic molecules which are blade, called a trephine, is used to
the building blocks for making remove a one to two-centimetre
proteins. core of bone marrow in one piece.
Anthracyclines Bone Marrow Failure
An antibiotic derived from the The term used when the bone
bacteria Streptomyces peucetius marrow is unable to keep up with
and found to be an effective the body’s need for white and red
anticancer drug. blood cells and platelets.
Autologous Stem Cell Chemotherapy
Transplant Drugs that work in different ways
A transplant of stem cells derived to stop the growth of cancer cells,
from part of the same individual. either by killing the cells or by
stopping them from dividing.
Bone Marrow
The soft blood-forming tissue Chromosomes
that fills the cavities of bones Thread-like structures which carry
and contains fat, immature and the genes, and are located in the
mature blood cells, including nuclei of every cell in the body.
white blood cells, red blood cells There are 46 chromosomes (23
and platelets. pairs) in humans.
Helpline freephone 08088 010 444 15Glossary (cont.)
Complete Remission that help conduct electrical
impulses in the body. They include
Complete remission has occurred
sodium, potassium, chloride and
when:
bicarbonate among others.
• Blood cell counts have returned First-line Treatment
to normal
The first treatment given for
• Less than 5% of abnormal, a disease. It is generally the
leukaemia cells are still present treatment accepted by the
in the bone marrow medical profession as the best
Consolidation Treatment initial treatment for a given type
and stage of cancer.
Treatment following remission
intended to kill any cancer cells Genes
that may be left in the body. Genes are made up of DNA which
DNA (Deoxyribonucleic Acid) stores the genetic information
required to make human proteins.
A thread-like chain of amino acids
found in the nucleus of each cell Induction Treatment
in the body which carries genetic The first treatment after diagnosis
instructions used in the growth, intended to kill the majority of
development and functioning of the leukaemia cells and stimulate
the individual’s cells. remission.
Electrocardiogram (ECG) Leukaemia
The test that records the electrical A group of cancers that usually
signals in your heart to detect any begin in the bone marrow
heart problems and monitor the and result in high numbers of
heart’s status. abnormal blood cells. These cells
Electrolytes are not fully developed and are
called blasts or leukaemia cells.
Salts and minerals in the blood
16 www.leukaemiacare.org.ukDepending on the type of blood Relapse Condition
cell involved, there are different
Relapse occurs when a patient
types of leukaemia with varying
initially responds to treatment,
characteristics, such as being
but after six months or more,
acute (develops quickly) or
the response stops. This is also
chronic (develop slowly).
sometimes called a recurrence.
Maintenance
Stem Cell
The treatment given to prevent
The most basic cell in the body
cancer from coming back after it
that has the ability to develop
has disappeared following first-
into any of the body’s specialised
line treatment.
cell types, from muscle cells to
Myeloid brain cells. However, what make
these stem cells reproduce
Relates to the bone marrow.
uncontrollably, as in cancer,
Platelets is thought to be linked to
chromosome abnormalities.
One of the types of blood cells
which help to stop bleeding. Stem Cell Transplantation
Red Blood Cells The transplant of stem cells
derived from part of the same
The small blood cells that contain
individual or a donor.
haemoglobin and carry oxygen
and other substances to all Urea
tissues of the body.
The breakdown product of
Refractory Condition proteins in the body which is
excreted in the urine.
A condition for which treatment
does not result in a remission. White Blood Cells
However, the condition may be
White blood cells are one of the
stable.
types of cells found in the blood
Helpline freephone 08088 010 444 17Glossary (cont.)
and bone marrow, along with
red blood cells and platelets. For more definitions
White blood cells create an of terms that you may
immune response against both come across during
infectious disease and foreign your blood cancer
invaders. Granulocyte white blood journey, you can
cells include the neutrophils download our booklet
(protect against parasites and A to Z of Leukaemia
allergens) and basophils (create from our website at
the inflammatory reactions www.leukaemiacare.
during an immune response). org.uk
Other white blood cells include
the lymphocytes (recognise
bacteria, viruses and toxins, to
which they produce antibodies)
and monocytes (clear infection
products from the body).
18 www.leukaemiacare.org.ukUseful contacts
and further support
There are a number of helpful Blood Cancer UK
sources to support you during Blood Cancer UK is the leading
your diagnosis, treatment and charity into the research of blood
beyond, including: cancers. They offer support to
• Your haematologist and patients, their family and friends
healthcare team through patient services.
• Your family and friends 0808 169 5155
• Your psychologist (ask your www.bloodcancer.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 19Leukaemia 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 Leukaemia Care is registered as a charity in England and Wales (no.1183890) and Scotland (no. SCO49802). Company number: 11911752 (England and Wales). Registered office address: One Birch Court, Blackpole East, Worcester, WR3 8SG
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