Relapse in Acute Lymphoblastic Leukaemia (ALL) - A Guide for Patients
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Relapse in Acute Lymphoblastic Leukaemia (ALL) A Guide for Patients
Introduction
A relapse is the return of leukaemia after treatment.
Specifically, this booklet is about a relapse in acute
lymphoblastic leukaemia (ALL).
The booklet was written by our
Patient Information Writer,
Isabelle Leach, and peer reviewed
by Dr. Richard Kaczmarski at
The Hillington Hospital NHS
Foundation Trust, Dr Mark
Mansour at University College of
London Cancer Institute and Dr
David O’Connor at GOSH. We are
also grateful to our reviewer, Kerri
Baker, whose son had a relapse in
ALL, for their contribution.
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: 01/2019
2 www.leukaemiacare.org.uk Review date: 01/2021In this booklet
Introduction 2
In this booklet 3
About Leukaemia Care 4
What is Acute Lymphoblastic Leukaemia? 6
What is a relapse? 8
Symptoms and diagnosis of relapsed ALL 12
How is relapsed ALL treated? 14
Glossary 20
Useful contacts and further support 23
Helpline freephone 08088 010 444 3About Leukaemia Care
Leukaemia Care is a national charity dedicated to ensuring
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right information, advice and support.
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Helpline freephone 08088 010 444 5What is Acute Lymphoblastic
Leukaemia?
In acute lymphoblastic leukaemia •• Five-year survival is
(ALL), high numbers of abnormal, approximately 90% in children,
immature lymphocytes called but only 30% to 40% in adults
blasts start over-multiplying in and elderly patients.
the bone marrow. Lymphocytes
are white blood cells involved in In children with ALL:
the immune response. There are •• 80% to 85% of ALL consists
two types of lymphocytes: of early B-cells (also called
precursor B-cell)
1. B-cells (formed in the bone
marrow) which produce •• 15% are early T-cells
antibodies that seek out and
immobilise bacteria, viruses, •• Approximately 2% are mature
B-cells
and toxins which invade the
body. In adults with ALL:
2. T-cells (formed in the thymus •• 75% of cases are early B-cells
gland, behind the sternum)
which destroy the invading •• 25% are malignant early T-cells
organisms that have been
Prognostic risk factors
tagged by the B-cells as well
as any cells that have become Prognostic risk factors at initial
cancerous. presentation, which can also be
used to inidicate a poor outcome
ALL has different rates of or the chances of a relapse
occurrence, survival and type of occurring, include:
lymphocytes involved in children
and adults: •• Age at diagnosis: younger than
6 months and older than 60
•• Approximately 50% of patients years
with ALL are children under 15
years of age (with a peak from •• Male sex, possibly because of
two to five years of age), and the impact of a major relapse
the remaining 15% of ALL cases site being in the testicles
are adults, mainly aged over 50
years.
•• High white blood cell count of
6 www.leukaemiacare.org.ukgreater than 300,000 white
blood cells x 106 cells/L
•• T-cell lymphocyte ALL rather
than B-cell lymphocyte ALL
•• Spread of ALL to the central
nervous system (CNS)
Certain abnormal gene
rearrangements can also act as
prognostic risk factors. These
include:
•• t(9;22) BCR-ABL1 (Philadelphia
chromosome)
•• MLL (KMT2A) translocations
•• t(17;19) TCF3-HLF
•• Near haploidy (24-30
chromosomes). Haploidy is
having only half of the normal
number of 46 chromosomes
•• Low hypodiploidy (31–39
chromosomes). Hypodiploidy
is having less than the normal
number of 46 chromosomes
Helpline freephone 08088 010 444 7What is a relapse?
What is a relapse? in their bone marrow after
treatment. This is called refractory
Relapse in ALL is the return of ALL.
ALL in patients who have already
undergone treatment and reached Between 10% and 20% of patients,
complete remission. who have achieved complete
remission after initial treatment
For complete remission to have for ALL, will have a relapse. In
occurred, the following conditions children, the relapse rate is near
will have been met: to 10%, while in adults relapse rate
•• Blood cell counts returned to is closer to 50%. Relapse of ALL
normal generally occurs within two years
of initial treatment, although
•• Less than 5% of blasts it may occur several months to
(abnormal, immature, early years after the initial remission.
lymphocytes) are still present in
the bone marrow Why does relapse
•• There is no leukaemia present happen?
elsewhere in the body Patients with ALL are known to
have a number of characteristics
When a relapse occurs, as with that make them more likely to
newly-diagnosed ALL, the blasts, relapse. Patients with a likelihood
which begin in the bone marrow, or risk that they will have a
start over-multiplying again, relapse after treatment can be
reaching high levels beyond subdivided into well-defined
levels considered appropriate for risk groups according to these
remission. This is also called a characteristics.
recurrence.
By way of an example, there is a
While a large number of patients well-established risk stratification
go into remission after induction for ALL patients, which is used by
therapy, there are subsets of many doctors, shown below. This
patients who do not at all, and risk stratification is for children
still have numerous blast cells since the majority of patients with
8 www.leukaemiacare.org.ukALL are children. Chromosomes are thread-like
structures which carry the genes
National Cancer and are located in the nuclei
Institute/Rome criteria of every cell. Genes are made
for children up of DNA (deoxyribonucleic
acid) which stores the genetic
The National Cancer Institute/ information required to make
Rome criteria uses only patients’ human proteins.
ages and white blood cell counts
to determine their risk, and The presence of abnormal gene
predict relapse and outcome. rearrangements alone cannot
predict a relapse rate in patients,
Standard risk - Both of the but the relationship between
following criteria must be genetic rearrangements and the
present: prognosis of the first occurrence
•• White blood cell count less than of ALL can.
50 x 109 cells/L
How often does relapse
•• Age of patient between one and occur?
nine years
Despite the fact that around 85%
High risk - Both of the following of cases of ALL occur in children,
criteria must be present: its presence in the remaining
•• White blood cell count greater 15% of adults who get ALL carries
a much more serious prognosis
than 50 x 109 cells/L
than the children.
•• Age of patient younger than one In children, although complete
year or older than nine years
remission occurs in 97 to 99% of
Since this risk classification patients following initial multi-
was established, numerous agent chemotherapy treatment,
other risks factors for relapse between 15 and 20% will have a
have been found, none more relapse.
so than the implications of
faulty chromosomes and genes. In adults, despite complete
Helpline freephone 08088 010 444 9What is a relapse? (cont.)
remission rates of between 78%
and 93%, relapse will occur in 60-
70% of patients.
In addition to different rates of
relapse for ALL patients according
to their age at diagnosis, other
prognostic factors at initial
presentation can also indicate
those patients where relapse
occurs more often.
Although not having any of the
prognostic risk factors at initial
presentation predicts less chance
of relapse and a better outcome,
there is always a risk of relapse
irrespective of a patient’s age or
prognostic factors.
10 www.leukaemiacare.org.ukHelpline freephone 08088 010 444 11
Symptoms and diagnosis of
relapsed ALL
What are the platelets. In a relapse, ALL patients
have lower-than-expected red
symptoms of relapsed blood cells and platelets.
ALL?
A peripheral blood smear
The symptoms of relapsed ALL
are the same as those for newly A sample of blood is viewed under
diagnosed ALL, and include: a microscope to count different
circulating blood cells and to see
•• Anaemia whether the cells look normal. In
relapsed ALL patients, there are
•• Bruising or petechiae (small red too many blast cells.
spots on the skin)
•• Fever Bone marrow aspiration and
biopsy
•• Recurrent infections The aspiration procedure removes
•• Abdominal pain a liquid marrow sample and the
biopsy removes a small amount
•• Bone and joint pain of bone filled with marrow.
•• Swollen lymph nodes (showing Medication is given to numb the
up as lumps and bumps on your area, or a general anaesthetic is
neck, armpits and groin) performed, to remove a sample
from the hip bone. The following
•• Dyspnoea (difficulty in can be examined:
breathing)
•• Percentage of ALL cells are in
How is relapsed ALL your bone marrow
diagnosed? •• Any abnormalities of the ALL
To make a diagnosis of relapsed cells
ALL, your doctor will carry out the
Immunophenotyping
following tests:
This procedure identifies the
Full blood count (FBC) types of proteins on the surface of
This will show the number of red the cell to find out if the ALL cells
blood cells, white blood cells and are B-cells or T-cells.
12 www.leukaemiacare.org.ukLumbar puncture
This will determine if the ALL cells
are in your CNS.
Chromosomal analysis (also
called cytogenetic analysis)
The blood smear sample can
also be used to identify certain
changes in the number and size
of chromosomes within cells that
might have led to the relapse.
Other tests and scans
X-rays are used to monitor the
presence of ALL in any organs.
Helpline freephone 08088 010 444 13How is relapsed ALL treated?
Patients with relapsed ALL remain another complete remission.
curable despite the failure of the The treatment of relapsed ALL is
initial course of treatment. The normally more intensive than for
treatment strategies for adult newly diagnosed ALL. Treatment
patients with ALL are similar to outcome depends on the time of
those for children with ALL. the patient’s relapse and the type
of ALL:
The mainstay of the treatment
for relapse ALL is chemotherapy, •• For patients who relapse
often given with steroids to during, or just after finishing
improve the effectiveness. If chemotherapy, another course
required, novel target therapy of chemotherapy is unlikely to
drugs which attack specific achieve a cure. An ASCT in the
components of the leukaemia second remission period is the
cells can be given. High-risk only way to cure these patients
patients are frequently offered an with ALL, and should be the
allogeneic stem cell transplant main focus whenever possible.
(ASCT) because the likelihood of a
cure with chemotherapy alone is •• For patients who relapse six
months or longer after finishing
very low.
treatment, many patients can
Chemotherapy achieve a second remission
with therapy similar to that
Chemotherapy for ALL used in initial treatment.
normally consists of induction,
consolidation, and long-term •• For patients with B-cell ALL
maintenance therapy, with CNS with a late first bone marrow
prophylaxis treatment to prevent relapse and low levels of MRD,
blast cells entering the brain or chemotherapy can achieve a
spinal cord, often given during the positive outcome. In addition,
first year of treatment. the dual specific antibody,
blinatumumab, is known to
After a first relapse, patients inactivate the T-cell immune
should receive re-induction response against B-cells and
therapy to try and achieve
14 www.leukaemiacare.org.ukdirectly activate T-cells against prognosis for both children and
the ALL blasts. Blinatumumab is adults. It only occurs in 3% to
recommended by the National 5% of patients with ALL, but less
Institute for Health and Care than 40% of them are cured with
Excellence (NICE) as an option intensive chemotherapy.
for treating Philadelphia
A young person who is
chromosome-negative relapsed
Philadelphia chromosome-
or refractory B-cell precursor
positive will be a candidate for
ALL in adults. A recent study of
an ASCT in the first remission.
113 adults with B-cell precursor
Patients who relapse but achieve
ALL in complete haematological
a second complete remission
remission showed that
may also benefit from an
blinatumumab achieved a
ASCT. However, the success
complete MRD response in 78%
of tyrosine kinase inhibitors
of patients. However, an ASCT,
in chronic myeloid leukaemia
particularly for those patients
(CML) has encouraged their use
with unfavourable genetic
in Philadelphia chromosome-
factors and/or who are MRD-
positive ALL patients. The
positive, offers a significant
tyrosine kinase inhibitor,
benefit.
imatinib, has achieved complete
•• For patients with T-cell remission rates of 90%-100% for
ALL, intensive multi-agent patients who have Philadelphia
chemotherapy can achieve good chromosome-positive ALL with
outcomes. relatively low toxicity. However,
the combination of a tyrosine
Discovery of abnormal gene
kinase inhibitor with standard
rearrangements in patients
chemotherapy has led to a longer
with ALL will also influence
survival in both adults and
the choice of treatment. The
children.
Philadelphia chromosome (BCR-
ABL) is the most common genetic Relapses can result from a
abnormality associated with lack of response to standard
adult ALL and has a very poor chemotherapy agents. In patients
Helpline freephone 08088 010 444 15How is relapsed ALL treated?
(cont.)
with refractory ALL, or patients Clinical trials of CAR T-cell therapy
who have had several relapses, for relapsed or refractory B-cell
multidrug treatment is often cancers, such as B-cell leukaemia
used with the aim of eliminating and lymphoma, and several solid
blast cells and targeting therapy- tumors, have shown promising
resistant cells that could cause results. The anti-CD19 CAR T-cell
further episodes of relapse. therapy has achieved remission
in up to 90% of patients with
Introduction of new treatments
B-cell ALL. CD19 is a B-cell receptor
from trials for high-risk patients
associated protein present on
is an option for improving
the surface of B-cells. However,
outcome. Other possibilities
relapse after CAR T-cell therapy is
which can also be explored
still a problem, often because the
include the following:
ALL cells lose expression of CD19.
•• Ground-breaking combinations The anti-CD19 agent
of chemotherapy drugs
tisagenlecleucel (Kymriah) is
•• Antibodies directed against the the first CAR T-cell therapy to be
leukaemia approved in the United States for
the treatment of patients up to 25
•• Drugs that stimulate the body’s years of age with B-cell ALL that
immune system to attack the is refractory or in second or later
leukaemia relapse. In Europe, this anti-CD19
CAR T-cell drug has been approved
Chimeric Antigen Receptor
by the European Medicines
(CAR) T-cell therapy:
Agency and NICE.
This new cancer treatment
works by removing the patient’s Chemotherapy for T-cell ALL,
own immune cells, genetically paying special attention to the
modifying them to recognise the patient’s responses to previous
tumour cells, and then re-infusing treatments, has also resulted in
them back into the patient so they good survival rates. Patients with
can target the cancer cells. mature T-cell ALL have a better
outcome than those with early
16 www.leukaemiacare.org.ukT-cell ALL. Careful selection of SCT for ALL
patients is important to achieve
A major challenge in the future
the best outcomes. Human
treatment of ALL will be to devise
leukocyte antigen (HLA)-matched
less toxic regimens for patients
sibling donors are recognised as
with low-risk disease and high
the best option, but this is only
cure potential, with the ultimate
available for 30% of patients.
goal of improving their quality of
Alternative sources of stem cells
life.
for the remaining 70% of patients
include matched unrelated adult
Allogeneic stem cell volunteer donor, a haploidentical
transplantation donor or a cord blood unit.
High-risk patients are frequently
ASCTs are increasingly performed
offered an ASCT because
due to the improved availability
the likelihood of a cure with
of alternative donors and
chemotherapy alone is very
refinement of indications
low. Currently an ASCT is an
according to the NHS England
established treatment for high-
Clinical Commissioning Policy
risk acute leukaemia.
for Haematopoietic Stem Cell
Patients who have a bone Transplantation. In addition, the
marrow relapse following advent of the haploidentical stem
initial chemotherapy treatment cell transplantation (HID-SCT),
may benefit from a stem cell where the donor matches exactly
transplant (SCT); however, this half of the HLA, offers another
is not uniformly recommended. option for patients, although
General procedure for ASCT in this option only accounts for
ALL patients involves total body approximately 10% of ASCTs in the
irradiation, because outcomes are UK.
improved in patients who undergo
Adults with Philadelphia
transplant after achieving a low
chromosome-negative ALL in
MRD status.
their first complete remission
Helpline freephone 08088 010 444 17How is relapsed ALL treated?
(cont.)
will benefit from an HLA-matched Adults with ALL who relapse have
donor ASCT or a HID-SCT. a poor prognosis. Young adults
Moreover, children with T-cell ALL less than 30 years old with a first
benefit from ASCTs, including complete remission of two years
HID-SCT. or more may have the chance of
long-term survival; however, older
Philadelphia chromosome-
patients (>30 years) who relapse
positive ALL patients who
early do not have realistic survival
have received a HLA-matched
options with current therapies.
donor ASCT compared to those
who had a HID-SCT showed Despite the great improvements
similar results in studies with in the treatment of ALL in children,
children and adults. In a study with a five-year overall survival of
of 82 Philadelphia chromosome- approximately 90%, the prognosis
positive ALL Chinese patients, is still much lower for children
HID-SCT was associated with a who have relapsed, compared
meaningful lower relapse rate with newly diagnosed ALL.
compared with HLA-matched
donor ASCT (44.8 vs. 19.1%,
If you would like some
respectively), although overall
survival times were the same. support or advice
about your relapse,
If an HLA-identical sibling donor
you can speak to the
is not available, the probability of
finding a fully matched unrelated Patient Advocacy
donor should be estimated to help team by calling
inform the decision on whether 08088 010 444 or
to search for an unrelated donor emailing support@
or find an alternative source
leukaemiacare.org.uk
of haematopoietic stem cells
(haploidentical donor or cord
blood unit).
Prognosis
18 www.leukaemiacare.org.ukHelpline freephone 08088 010 444 19
Glossary
Allogeneic Stem Cell Transplant to stop the growth of cancer cells,
either by killing the cells or by
Transplant of stem cells from a
stopping them from dividing.
matching donor.
Chromosomes
Antibody
Thread-like structures include
Blood protein produced by the
an individual’s genes, and are
B-cell lymphocytes in response
located in the nuclei of every
to, and counteracting, a specific
cell in the body. There are 46
antigen such as a bacteria, virus,
chromosomes (23 pairs) in
or foreign substance.
humans.
Autologous Stem Cell
CNS3 status
Transplant
CNS3 status occurs when the
Transplant of stem cells derived
cerebrospinal fluid sample
from part of the same individual.
contains equal to or greater
Blasts than 5 white blood cells/µL with
identifiable blasts, or there is the
These white blood cells are not
presence of a cerebral (brain)
fully developed and are called
mass or cranial palsy.
blasts or leukaemia cells.
Complete Remission
Bone Marrow Relapse
Complete remission occurs when
Bone marrow relapse is defined
the following conditions have
as the presence of 25% of
been met:
lymphoblasts or more in a bone
marrow aspirate following the •• Blood cell counts returned to
first complete remission. normal
Central Nervous System (CNS) •• Less than 5% of blasts
Part of the nervous system which (abnormal, immature, early
includes the brain and spinal lymphocytes) are still present in
cord. the bone marrow
Chemotherapy •• There is no leukaemia present
elsewhere in the body
Drugs that work in different ways
20 www.leukaemiacare.org.ukCranial Nerve Palsy Hypodiploidy
Weakness and impaired function Hypodiploidy is having less
(palsy) of one or more of the than the normal number of 46
twelve cranial nerves caused by chromosomes.
tumours, trauma, impaired blood
flow, and infections. The condition Lymph nodes
may also be congenital. Components of the lymphatic
system (part of the body’s
DNA (deoxyribonucleic acid) immune system) that contain
Thread-like chain of amino acids lymphocytes which produce
found in the nucleus of each cell antibodies and macrophages to
in the body which carries genetic digest dead cells. Lymph nodes
instructions used in the growth, are swollen with cell fragments
development and functioning of if infection or cancer occurs.
the individual. Lymph nodes are located mainly
in the spleen, but also in the neck,
Genes armpit and groin.
Genes are made up of DNA which
stores the genetic information Minimal Residual Disease
required to make human proteins. (MRD)
Measure of the presence of
Haploidentical Stem Cell leukaemia at a molecular level
Transplantation (HID-SCT) rather than at a cell level. It
Type of allogeneic transplant is measured using molecular
of stem cells where the donor techniques such as flow
matches exactly half of the cytometry and polymerase chain
human leukocyte antigens. reaction analysis.
Leukaemia Petechiae
A group of cancers that usually Red or purple, flat, pinhead spots
begin in the bone marrow under the skin.
and result in high numbers of
abnormal white blood cells known Philadelphia chromosome
as blasts. (BCR-ABL1)
BCR-ABL1 is a cancer gene formed
Helpline freephone 08088 010 444 21Glossary (cont.)
by the fusion of chromosomes 9 Relapse
and 22 [t(9;22) (q34;q11)]. BCR-
A relapse is when a patient
ABL1 is found in all patients with
initially responds to therapy
chronic myeloid leukaemia and
but, after six months or more,
some patients with ALL.
response stops. This is also
Platelets sometimes called a recurrence.
Platelets are one of the types of Thymus Gland
blood cells which help to stop
Main organ of the lymphatic
bleeding.
system, located behind the
Precursor Cell sternum and between the lungs,
where the T-cell lymphocytes
Precursor cells are a type of
develop and mature.
partially differentiated stem
cell which has the capacity to Tyrosine Kinase Receptors
differentiate into only one cell
Receptors present in the
type (B-cell or T-cell).
membranes of all of the body’s
Refractory (leukaemia) cells which contain the enzyme
tyrosine kinase that carries
Refractory leukaemia is a
information to and from complex
leukaemia that does not result
cell networks. It functions as an
in a remission or that gets
‘on’ or ‘off’ switch in many cellular
worse within six months of the
functions.
last treatment. However, the
leukaemia may be stable.
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22 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
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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,
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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.
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support@leukaemiacare.org.uk 08444 111 444
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Helpline freephone 08088 010 444 23Leukaemia 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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