Minimal Residual Disease:
ALL It’s Cracked Up to Be?
Monitoring minimal residual disease (MRD)
has become the standard of care in pediatric
patients with acute lymphocytic leukemia
(ALL) based on evidence that it is a strong
prognostic factor for patient outcomes – patients who test negative for MRD have better
outcomes than those who test positive.
However, MRD monitoring isn’t a panacea. There are still many unanswered questions about what MRD is able to tell us, and
what it isn’t – especially in adult patients with
ALL. The use of MRD monitoring in adult
patients is much less prevalent due to a lack of
clear evidence and inconsistencies among the
labs that conduct the tests.
Despite some lingering questions, there
is no doubt that the movement toward MRD
monitoring is in full swing. ASH Clinical News
spoke with several experts about MRD monitoring in pediatric and adult ALL, its role in
signaling a relapse, and whether its results can
help doctors avoid overtreating low-risk patients and identifying high-risk patients who
would benefit from more intensive therapy.
Measuring MRD
In the pediatric realm, MRD measurement
is replacing routine bone marrow tests as
64
ASH Clinical News
the standard in assessing persistent disease,
even as oncologists place less emphasis on
the results from what has in the past been the
standard of bone marrow biopsies.
“I don’t trust it,” Ching-Hon Pui, MD,
chair of the department of oncology at St.
Jude Children’s Research Hospital in Memphis, Tennessee, told ASH Clinical News. “I
don’t rely on my eye to tell me whether or not
a patient has a leukemic cell.”
Although he still performs morphologic
bone marrow tests, Dr. Pui no longer depends
on them. MRD monitoring is able to provide
greater sensitivity and identify disease not
found on bone marrow tests, without adding
significant costs.
There are several ways to test for MRD,
and often the technique chosen depends on
the lab where the test is being conducted.
In the United States, the most common
method for detecting MRD is flow cytometry:
leukemia-associated immunophenotypes that
are not found on normal hematopoietic cells
are identified through a process of reacting
live cells with inked antibodies that fluoresce
when illuminated with a laser.
In Europe, the common approach is using
polymerase chain reaction (PCR) to screen and
amplify a DNA in the immuglobulin gene or Tcell receptor to identify a clone associated with
leukemia. Next, specific primers or molecules
that will only bind to this clone are made to test
later samples for the presence of this clone. So,
the test is only looking for that specific clone
present in that particular leukemia.
Each method has its own set of advantages and disadvantages. Flow cytometry, for
instance, is less expensive, can often report
quantitative results within a day, and has a
larger evidence base (having been used in
most U.S.-based trials). PCR is said to be
more sensitive, although researchers say it
isn’t clear yet how critical it is to have that
lower detection.
“Studies have compared these two
methods head-to-head, and they are quite
concordant, particularly in higher levels of
MRD,” said Stephen Hunger, MD, chief of the
division of pediatric oncology and director
of the center for childhood cancer research at
Children’s Hospital of Philadelphia.
There is an emerging technique on the horizon: next-generation sequencing. Essentially,
it works on the same principle as PCR but,
instead of only amplifying one sequence and
making a specific primer, next-generation se-
September 2015