Minimal Residual Disease
the greatest risk for a poor outcome.
“It’s very clear that pediatric ALL patients
who have high levels of MRD at the end of
the first month of therapy – using 10-4 or 0.01
percent as the common definition of ‘high’
MRD – do significantly worse than those that
are negative at that point,” Dr. Hunger said.
“Most groups and physicians will intensify
treatment after the first month for those who
are MRD-positive.”
But, some believe even earlier testing
could be a benefit, as Dr. Pui demonstrated in
his recent study in The Lancet Oncology, where
patients who tested MRD-positive (>1%) after
just 19 days of remission induction therapy
had significantly worse 10-year EFS.1
“For most centers, I think the best timing
is really two weeks into induction,” Dr. Pui
stated. At this point, he explained, falsepositives are unlikely and oncologists can
make decisions about whether to back off or
intensify treatment even earlier.
But measuring MRD at only one time
point may not be enough – especially considering the heterogeneity among ALL subtypes.
For instance, T-cell patients have a slower
response than patients with precursor B-cell
ALL, according to Paul Gaynon, MD, profes-
“Everybody is comfortable with the
idea that MRDpositive patients
must get different
treatment, but [we
don’t know] if giving these patients
more therapy
improves their
outcomes.”
—MICHAEL J. BOROWITZ, MD, PhD
sor of pediatrics at Children’s Hospital Los
Angeles. “In T-cell ALL, many patients were
slow responders by day 29 but then rallied by
day 85,” he said. “They had good responses
and did quite well.”2
According to Dr. Hunger, there is also
significant evidence that testing again at later
time points could be valuable – particularly
for patients who test MRD-positive at the
one-month mark. “Research has shown that
people who test positive after induction, but
test negative at three months do substantially
better than those who are still positive at three
months,” he said.4
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ASH Clinical News
Many physicians also rely on MRD measurements to evaluate the best timing to perform a
stem cell transplantation. If patients are MRDpositive going into transplant, Dr. Borowitz said,
data have shown that their outcomes are much
worse than patients who are MRD-negative
before transplant.5 For this reason, oncologists
may want to take MRD into consideration when
deciding on whether transplant is needed, as
well as thinking about using additional therapy
to get patients to an MRD-negative state if transplant is deemed necessary.
as an equivalent of relapse (before a morphologic relapse is determined) is that physicians do
not want to expose patients to unnecessary morbidity and mortality associated with additional
therapy or stem cell transplants.
“Until there is more proof that persistent
or recurrent MRD during treatment is predictive of impending relapse – highly predictive,
not just ‘suggested’ – people are not really
willing to act on that information by and
large,” Dr. Hunger said.
The Search for a New Surrogate
Endpoint Continues
So, is there a “safe” level of MRD? That is still
unclear, but newer technology such as nextgeneration sequencing could provide more
answers in the near future. Dr. Hunger, however, cautioned that immunoglobular T-cell
receptor-based technologies get down to such
a low level of measurement that it is not always
possible to distinguish between a pre-leukemic
ancestral clone and a fully leukemic clone.
“We really do not know what some of
these very low levels mean yet,” he said.
While we do know that ALL patients who
don’t have MRD at earlier points in their
therapy tend to have the best prognosis, researchers are still trying to determine the best
way to treat patients who appear to be in remission based on morphologic examinations
but who still have MRD. Consensus about
whether MRD can be used as an endpoint in
clinical trials, or whether oncologists should
be monitoring MRD to signal relapse, have yet
to be reached.
Currently, it seems that the unanswered
questions surrounding MRD in ALL outweigh
the answered ones.
Is MRD monitoring in ALL all it’s cracked up
to be? There was a common refrain among all of
the experts we spoke with: Despite previous and
ongoing research, it’s still too soon to call.
As research forges ahead, finding the
answers to these questions will be the key in
ultimately understanding the true power of
MRD.—By Jill Sederstrom ●
Patients who have MRD do worse than those
who don’t – that much is clear. But despite its
significant prognostic properties, using MRD
as a clinical endpoint is still under dispute.
“There are some well-known examples of
cases where therapy has improved outcomes
but didn’t change MRD,” Dr. Hunger said. “It
makes people a little leery about this idea.”
For example, an open-label randomized
trial comparing the effect of mitoxantrone
with idarubicin in children with first relapse
of ALL found that, although the mitoxantrone-treated patients had a lower relapse rate,
there was no apparent difference in MRD between the two drugs in the intermediate-risk
group – leading researchers to believe that the
decrease in relapse was unrelated to the kinetics of disease clearance.6
“To enable the quick assessment of the
number of new drugs now in the pipeline, study
designs are incorporating the use of MRD as
a surrogate marker of outcome,” lead author
Catriona Parker, PhD, and co-authors wrote. “If
we had opted to use such a study design, mitoxantrone would have been discarded.”
The hope, Dr. Gaynon said, was that if
there was no difference in MRD levels after
the one-month time point, there would also
be no difference in EFS in the long run, but
evidence has failed to support this hypothesis.
“Sadly, MRD is not a surrogate for efficacy,” he said.
An Early Indicator for Relapse?
While researchers tend to agree that MRD has
clear prognostic properties, its role after remission in predicting a relapse is less clear. “This
is an ongoing research question,” Dr. Pui cautioned. “Nothing has been definitively proven.”
MRD appears to be a significant risk factor for relapse in adult patients: A 2009 study
published in Blood found that MRD analysis
du ring early post-remission therapy improves
risk definitions and helps improve risk-oriented treatment strategies. Patients who were
MRD-negative had five-year overall survival
and disease-free survival rates of 0.75 and 0.72,
respectively, compared with rates of just 0.33
and 0.14 in MRD-positive patients. Presence of
MRD, then, was the most significant risk factor
for relapse, with a hazard ratio of 5.22.7
According to Dr. Hunger, MRD is far from a
perfect predictor of relapse: Some patients who
are MRD-negative will still relapse, and others
who are MRD-positive will not. The main reason for the hesitation to adopt rising MRD levels
What We Still Don’t Know
References
1. Pui CH, Pei D, Coustan-Smith E, et al. Clinical utility
of sequential minimal residual disease measurements
in the context of risk-based therapy in childhood acute
lymphoblastic leukaemia: a prospective study. Lancet Oncol.
2015;16:465-74.
2. Parekh C, Gaynon PS, Abdel-Azim H. End of induction
minimal residual disease alone is not a useful determinant
for risk stratified therapy in pediatric T-cell acute lymphoblastic leukemia. Pediatr Blood Cancer. 2015 May 14. [Epub
ahead of print]
3. National Cancer Institute. Comparison of laboratory test
results of minimal-residual disease in samples from patients
with acute myeloid leukemia (NCT01498302). Accessed
August 14, 2015 from https://clinicaltrials.gov/ct2/show/
NCT01498302.
4. van Dongen JJM, van der Velden VHJ, Bruggeman M,
Orfao A. Minimal residual disease diagnostics in acute
lymphoblastic leukemia: need for sensitive, fast, and standardized technologies. Blood. 2015;125:3996-4009.
5. Eckert C, Biondi A, Seeger K, et al. Prognostic value of
minimal residual disease in relapsed childhood acute lymphoblastic leukaemia. Lancet. 2001;358:1239-41.
6. Parker C, Waters R, Leighton C, et al. Effect of mitoxantrone on outcome of children with first relapse of acute
lymphoblastic leukaemia (ALL R3): an open-label randomised trial. Lancet. 2010;376:2009-17.
7. Bassan R, Spinelli O, Oldani E, et al. Improved risk classification for risk-specific therapy based on the molecular
study of minimal residual disease (MRD) in adult acute
lymphoblastic leukemia (ALL). Blood. 2009;113:4153-62.
September 2015