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● ● ● MYELOID NEOPLASIA
Comment on Sobrinho-Simões et al, page 1329
Remission
in CML: is DNA useful?
---------------------------------------------------------------------------------------------------------------François-Xavier Mahon
UNIVERSITÉ VICTOR SÉGALEN BORDEAUX 2
Imatinib is the current standard of care for patients with CML; however, the ability
of imatinib to eradicate the CML clone is uncertain. Indeed, according to in vitro
studies, leukemic stem cells are seemingly resistant to imatinib-induced apoptosis.1
Thus, imatinib treatment would not appear to be curative. Most patients in longterm remission after allogeneic stem cell transplantation would be considered
“cured,” in spite of very occasionally being found positive for low-level BCR-ABL
mRNA detected by RT-PCR.2
n this issue of Blood, Sobrinho-Simões and
colleagues describe a patient-specific quantitative polymerase chain reaction (PCR) strategy using genomic DNA designed to test
minimal residual disease in chronic myeloid
leukemia (CML) patients in complete molecular response (CMR) after either allogeneic
stem cell transplantation (SCT) or imatinib.3
This shrewd strategy needs the patientspecific genomic BCR-ABL fusion sequence
to be characterized. Indeed, in CML the
genomic breakpoints in the BCR and ABL
gene are dispersed over intervals of 3.0 kb and
150 kb, respectively. The variability on the
genomic DNA located in the introns is very
important. Using this technique, each leukemic fusion sequence is therefore unique, unlike the mRNA transcript in which the variable intronic sequences containing the
breakpoints are spliced out leading to 2 types
of transcripts. Generally, to evaluate and
monitor the response after treatment, the
“BCR-ABL load ”—that is, the amount of
BCR-ABL mRNA in the peripheral blood—is
measured as a ratio of BCR-ABL to a control
gene. To perform this analysis, the quantitative reverse transcriptase–PCR technique is
routinely used and major molecular response
is defined as a 3-log reduction in BCR-ABL
mRNA. The CMR with no detectable residual
disease corresponds to 4- to 5-log reduction of
BCR-ABL due to the limit of the reverse
transcriptase–PCR sensitivity compared with
diagnosis.4
BCR-ABL DNA is unique and may be
detected by PCR after sequencing and so provides a patient-specific marker of minimum
residual disease. Although this technique cannot be used as a routine test (appropriate primers and probes need to be designed), the usefulness of this approach is nicely illustrated by
I
1192
Sobrinho-Simões and colleagues. Hence, it
was applied to trace the persistence of the
original leukemic clone in 12 patients who had
received allogeneic SCT (9 in long-term molecular remission) and 5 imatinib-treated patients in confirmed CMR. The results show
that: (1) in patients on imatinib, the leukemic
clone is detectable after achievement of CMR
(5/5) although it may disappear with continued therapy (4/5) and (2) in patients in longterm remission after SCT, the original leukemic clone almost invariably seems to disappear
although Bcr-Abl–transcript positivity may
occasionally occur.
Regarding imatinib treatment, even in patients who are in CMR (ie, with undetectable
Bcr-Abl transcripts) there is likely to be a residual population of CML cells which could be
detected by specific PCR on DNA. It has been
reported previously that Bcr-Abl transcript
numbers continue to decrease for some years
after initiating treatment with imatinib, and
that increasing numbers of patients achieve
transcript-undetectable status.5 This report
goes further and demonstrates that continuing
imatinib therapy after achieving CMR leads to
further reduction in residual disease. It has
also been reported that discontinuation may be
possible for patient CMR maintained strictly
for more than 2 years.6
In a pilot study, 50% of patients previously treated by interferon were in sustained
CMR after discontinuation of imatinib. In a
multicenter study entitled “Stop Imatinib”
(STIM), these results were confirmed:
CMR persisted after imatinib discontinuation in approximately 40% of patients only
treated with imatinib.7 In these 2 studies,
sustained CMR was defined as BCR-ABL/
ABL levels below a detection threshold corresponding to at least a 5-log reduction and
undetectable signal using real-time quantitative PCR for at least 2 years. By specific
PCR on DNA it would be possible to define
more strict criteria and increase the proportion of patients in sustained CMR after discontinuation. Concerning allogeneic SCT,
this work confirms that the rare late relapse
corresponds to the same disease. In only 1 of
9 patients in long-term remission after SCT
was there evidence for the survival of the
original leukemic clone, which is consistent
with the low risk of relapse observed many
years after SCT.
Finally, even with a single molecular abnormality such as BCR-ABL, CML is a heterogeneous disease and we still do not know
whether the variability of the DNA breakpoint
may influence the disease, although not demonstrated using RNA. The complexity of
patient-specific DNA PCR may limit the use
of this method for the routine monitoring of
CML, but taking into account both progress
and rapidity of DNA sequencing, this kind of
investigation would be able to provide useful
information about residual disease in selected
patients.
Conflict-of-interest disclosure: The author
declares no competing financial interests. ■
REFERENCES
1. Graham SM, Jørgensen HG, Allan E, et al. Primitive,
quiescent, Philadelphia positive stem cells from patients
with chronic myeloid leukemia are insensitive to STI571 in
vitro. Blood. 2002;99(1):319-325.
2. Kaeda J, O’Shea D, Szydlo RM, et al. Serial measurement of BCR-ABL transcripts in the peripheral blood after
allogeneic stem cell transplantation for chronic myeloid
leukemia: an attempt to define patients who may not require
further therapy. Blood. 2006;107(10):4171-4176.
3. Sobrinho-Simões M, Wilczek V, Score J, Cross NC,
Apperley JF, Melo JV. In search of the original leukemic
clone in chronic myeloid leukemia patients in complete molecular remission after stem cell transplantation or imatinib.
Blood. 2010;116(8):1329-1335.
4. Hughes TP, Branford S. Monitoring disease response to
tyrosine kinase inhibitor therapy in CML. Hematology Am
Soc Hematol Educ Program. 2009;477-487.
5. Branford S, Seymour JF, Grigg A, et al. BCR-ABL
messenger RNA levels continue to decline in patients with
chronic phase chronic myeloid leukemia treated with imatinib for more than 5 years and approximately half of all
first-line treated patients have stable undetectable BCRABL using strict sensitivity criteria. Clin Cancer Res.
2007;13(23):7080-7085.
6. Rousselot P, Huguet F, Rea D, et al. Imatinib mesylate
discontinuation in patients with chronic myelogenous leukemia in complete molecular remission for more than two
years. Blood. 2007;109(1):58-60.
7. Mahon FX, Rea D, Guilhot F, et al. Discontinuation of
imatinib therapy after achieving a molecular response in
chronic myeloid leukemia patients [abstract]. Blood (ASH
Annual Meeting Abstracts). 2009;114(22):Abstract 859.
26 AUGUST 2010 I VOLUME 116, NUMBER 8
blood
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
2010 116: 1192
doi:10.1182/blood-2010-05-286310
Remission in CML: is DNA useful?
François-Xavier Mahon
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