Download The importance of minimal residual disease (MRD)

The importance of minimal residual disease
(MRD) in blood cancer
Key take-aways
Blood cancers are the fifth most common cause of cancer death worldwide and lymphoma,
leukaemia and myeloma are the main types.1
Minimal residual disease (MRD) is a term used in blood cancer, meaning that small number of
cancer cells remain in the patients’ blood or bone marrow following treatment. MRD is a major
cause of relapse for patients with blood cancer.2
Assessing MRD is important as it allows physicians to assess the extent to which a treatment is
working, whether a patient is likely to relapse or if they have achieved a deep remission.
MRD is also significant as it is a novel, innovative endpoint which promises to predict longer-term
outcomes in people with blood cancers, such as overall survival.2
Blood cancers: incurable diseases of the blood and bone marrow
Blood cancer is an umbrella term
for cancers that affect the blood,
bone marrow and lymphatic
system. Approximately one person
is diagnosed with blood cancer
every 35 seconds and one person
dies of blood cancer every minute
worldwide.1
There are three main categories
of blood cancer, and some types
are more common than others:
Lymphoma – e.g. Non Hodgkin's lymphoma (NHL),
which is the tenth most common cancer worldwide3
Leukaemia – e.g. Chronic lymphocytic leukaemia (CLL),
which is the most prevalent type of leukaemia4
While blood cancer can affect anyone at any stage of life, the risk of
developing blood cancers such as NHL and CLL increases with age,
meaning they predominantly affect the elderly.5,6
Myeloma – e.g. Multiple myeloma (MM), a less
common type of blood cancer
Although blood cancers can develop slowly and treatments can
keep the disease under control for many years, many are incurable.7
Blood cancer treatment and Minimal Residual Disease (MRD)
By reducing the number of cancer cells in a
patient’s blood, bone marrow or lymph nodes to
the lowest attainable level, patients can live as
normal a life as possible and without symptoms.
This is called remission.6
Patients can appear to respond well to treatment,
so achieving ‘complete remission’, meaning
there is no evidence of cancer in the body using
standard tests and the patient shows no signs or
symptoms of disease. However, patients may be
left with a tiny number of cancer cells within the
blood or bone marrow which can regrow and
after a few weeks or months, may cause them to
relapse. This tiny population of remaining or
residual cancerous cells in the body are termed
‘Minimal Residual Disease’ (MRD) and are a
major cause of relapse in patients with CLL, MM
and follicular lymphoma (FL, a subtype of NHL).2
Bone marrow with
cancerous
B-lymphocytes in an
untreated CLL patient
Few cancer cells left
in the bone marrow
(MRD) in a CLL
patient
No cancer cells left
in the bone marrow
(negative MRD)
How do we detect residual cancer cells?
8
A minute proportion of cancerous cells still present in a patient
can cause them to relapse in the future – so measuring MRD is
crucial for physicians to assess how well a patient is responding to
treatment.
Testing for these cancerous cells previously relied upon
microscopes and small numbers of remaining cancer cells after
treatment could not always be detected. In these patients, these
cells were given the opportunity to regrow and so may have
caused the patient to relapse.
Recent advances in scientific knowledge and medical technology
have enabled us to detect these residual cells after treatment with
greater accuracy. A patient is said to be ‘MRD-negative’ when
even these highly sensitive tests are not able to detect remaining
cancer cells.
This means they have achieved a ‘deep’ remission and are also
more likely to sustain a longer-term disease control compared to
patients with residual cancer (MRD) after treatment. Importantly,
deep remissions are associated with prolonged progression free
survival (PFS) and overall survival (OS).2
Using a microscope, it can be
possible to find roughly
one harmful cell in 100
healthy cells, which is a very
high level of disease.
New technology is able to
increase the level of
detection to one in
10,000.8
How are the cancer cells
sampled for testing?
Samples of blood or tissue from the bone
marrow can be taken and the very low levels
of residual cancer cells measured. Although a
more invasive sampling method, MRD levels
are usually higher in the bone marrow
compared to blood, as the bone marrow is
harder to clear of the cancer cells.
Blood sample
An analogy of MRD testing: Leaves in a swimming pool9
A standard bone marrow test is like
taking a sample from a swimming pool.
If leaves are found in the bucket, it
suggests there are likely to be leaves
floating elsewhere in the pool – or with
blood cancer, a notable number of cancer
cells remaining in the body.
MRD testing is like examining the sample
of water in the bucket for tiny fragments
of substances that exist only in leaves.
These tiny fragments represent MRD, or
the tiny number of blood cancer cells
remaining in the body after treatment,
which are only detectable with highly
sensitive tests.
Thus, a negative finding with MRD testing
provides much greater confidence that
the blood or bone marrow is clear of the
abnormal cells.
Bone marrow sample
Why is testing for MRD in CLL, MM and FL important for
patients in both the short- and long-term?
Critically, accurate detection of MRD enables physicians to:8
1. Reduce the risk of relapse, as the likelihood of relapse can be assessed and follow-up treatment given, as needed.
Identify patients who achieve a deep or MRD-negative remission and require no further treatment, so avoiding unnecessary side
2. effects and time on treatment.
3. Indicate how effectively a treatment is working and predict whether continued treatment is likely to improve a patient’s longer term
outcomes.
Roche is leading the way in novel clinical trial design, using MRD as both a primary and secondary endpoint to show superiority of one
treatment over another. Importantly, the European Medicines Agency (EMA) has recently published guidelines on the use of MRD in
clinical trials as an indicator of the likelihood of a patient achieving longer endpoints such as progression free survival (PFS) or overall
survival (OS).2
Meanwhile, the U.S. Food and Drug Administration (FDA) is also considering MRD as a meaningful endpoint, using which the
effectiveness of a treatment can be assessed earlier, helping to decrease lengthy development timelines and reduce delay in patient
access to more effective treatment options.
What is MRD?
People with blood cancer can respond to
treatment to varying degrees, ranging
from no response, to some reduction in
the level of disease, to achieving
“complete remission” and showing no
signs of the disease.
MRD is a condition where a small, or
minimal, number of cancer cells remain
in the patients’ blood or bone marrow
following treatment, and is the main
cause of relapse in blood cancer.
Achieving ‘MRD negativity’ means a
patient is in a deep remission and has no
detectable cancer cells, even using
modern, more sensitive tests.
Patient 1
Non responder with disease progression
Key:
Depth of remission
Patient 2
Stable disease
Treatment
Relapse
Patient 3
Partial responder to treatment
Patient 4
Complete responder to treatment
Complete
MRD
Patient 5
Complete responder with MRD negative disease
Time
No relapse
References
1. Globocan (2012) Estimated incidence, mortality and 5-year prevalence: both sexes. Available at:
http://globocan.iarc.fr/Pages/fact_sheets_population.aspx (Last accessed November 2015).
2. European Medicines Agency (2014) Guideline on the use of minimal residue disease as an endpoint in chronic lymphocytic leukaemia
studies. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2014/12/WC500179047.pdf (Last
accessed November 2015).
3. Cancer Research UK. Non-Hodgkin lymphoma incidence statistics. Available at:
http://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/non-hodgkin-lymphoma/incidence#
heading-Five (Last accessed November 2015).
4. Byrd JC et al. Introduction to a series of reviews on chronic lymphocytic leukemia. Blood 2015: 126 (4); 427.
5. Cancer.net. Leukemia - Chronic Lymphocytic - CLL: Risk Factors. Available at:
http://www.cancer.net/cancer-types/leukemia-chronic-lymphocytic-cll/risk-factors (Last accessed November 2015).
6. Cancer.net. Lymphoma - Non-Hodgkin: Risk Factors. Available at:
http://www.cancer.net/cancer-types/lymphoma-non-hodgkin/risk-factors (Last accessed November 2015).
7. Liu Q et al. Improvement of Overall and Failure-Free Survival in Stage IV Follicular Lymphoma: 25 Years of Treatment Experience at The
University of Texas M.D. Anderson Cancer Center. J Clin Oncol 2006: 24 (10); 1582-9.
8. Boldeanu F et al. Minimal Residual Disease - Generalities and Perspectives. TMJ 2011: 61; 3 – 4.
9. Lymphomation.org. Minimum Residual Disease (MRD) with PCR ("molecular photocopying") of blood or marrow samples. Available at:
http://www.lymphomation.org/MRD.htm (Last accessed November 2015).
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