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BACKGROUND
The first generation of Tyrosine Kinase Inhibitor (TKI), Imatinib, has
revolutionized the treatment of Chronic Myeloid Leukemia (CML) leading to a
significant reduction of the Breakpoint Cluster Region-Abelson murine Leukemia
1 (BCR-ABL1) transcript levels in peripheral blood [1]. Hematological and
molecular responses, especially BCR-ABL1 transcripts in peripheral blood, are
prognostic and treatment planning parameters used to assess the level of
reduction of leukemic cells [2-4] BCR-ABL RQ-PCR represents the scientific
paradigm for successful molecular diagnostic monitoring of the targeted cancer
therapy. Furthermore, achieving Major Molecular Response (MMR), defined as
BCR-ABL1 transcripts ≤ 0.1%, is the goal of treatment with Imatinib due to the
association between this level of response and the greater likelihood of
disease-free progression [5,6]. However, patients with CML can exhibit various
treatment responses including the resistance to Imatinib and they have a higher
risk of disease progression [7,8]. The optimal frequency of molecular
monitoring after the first generation of TKI of patients with CML has been
established [3]. The standardization is needed to properly use for success in
therapy.
HEMATOLOGICAL AND MOLECULAR RESPONSE
The simplest treatment
monitoring is a hematological response. To achieve Complete Hematological
Response (CHR), peripheral blood counts and spleen size must be normal. Blood
counts and differentials are required biweekly until CHR has been achieved and
confirmed at least every three months thereafter. The treatment goal is to
achieve CHR within one to three months after the start of treatment [7].
CLINICAL MOLECULAR MONITORING
Quantitative reverse transcription PCR is the
most sensitive tool for assessing disease burden in patients with CML.
Quantitative BCR-ABL results are usually expressed as a percentage ratio
related to an internal control transcript. RT Q-PCR BCR-ABL with its increased
sensitivity and dynamic range has become the main tool used to monitor CML patients. The long-term molecular follow-up studies of these
patients would make it possible to evaluate the major molecular response rates
and the prognostic effect of different levels of BCR-ABL transcript reduction
given the same complete cytogenetic result [8].
As emerging evidence suggests that the slope of the initial BCR-ABL1
decline may add prognostic information, some studies routinely send blood for
RT Q-PCR in all newly diagnosed patients [9,10]. Once TKI therapy has been
initiated, RT Q-PCR should be done every 3 months until MMR has been achieved
and at the interval of 3 to 6 months thereafter [3,11]. Clinical judgment is
needed to determine the appropriate testing interval. For example, it is good
practice to monitor patients with adherence issues every 3 months even if they
have achieved MMR or a deep molecular response [12].
The European Leukemia Network (ELN) established response goals to be
achieved in different intervals of drug exposure, particularly in the chronic
phase of CML. Molecular response is assessed with standardized RT Q-PCR at 3, 6
and 12 months. BCR-ABL1 transcript levels ≤ 10% at 3 months, <1% at 6 months
calls and ≤ 0.1% from 12 months onward define optimal response, whereas >10%
at 6 months and >1% from 12 months onward define failure, mandating a change
in treatment. Between optimal and failure, there is an intermediate warning
zone requiring more frequent monitoring (Table
1) [3]. Because cutoff values are subjected to fluctuation in case of
molecular data close to the indicated values, repetition of the tests is
recommended.
Molecular
testing must be performed by RQ-PCR on buffy coat of more than 10 mL of blood
to measure BCR-ABL1 transcript level expressed as BCR-ABL1% on International
Scale (IS) [6]. IS refers to a system based on the conversion of
laboratory-specific numerical values to conform to a universal scale [12]. IS
as the ratio of BCR-ABL1 transcripts to ABL1 transcripts or other
internationally recognized controls transcripts and it is expressed and
reported as BCR-ABL1% on a log scale, where 10%, 1%, 0.1%, 0.01%, 0.0032% and
0.001% correspond to the decrease of 1, 2, 3, 4, 4.5 and 5 logs, respectively
[3].
The first MR
(Molecular Response) level shown to be associated with subsequent outcome was a
3 log reduction of BCR-ABL1 transcripts (MR3.0) or BCR-ABL1 ≤ 0.1%. This is
termed Major Molecular Response (MMR). MR4.0, MR4.5 and MR5.0 refer to 4.0 log,
4.5 log and 5.0 log transcript reductions expressed on IS. Good laboratories
are able to measure MR4.5or even MR5.0 using conventional technology [12]. The
five-year follow-up in the IRIS study showed that no patients progressed to the
accelerated or blast phase after 12 months if MMR was achieved [7]. Failure to
achieve MMR during Imatinib therapy was associated with inferior outcomes
including a significantly shorter PFS.
Complete Molecular
Response (CMR) occurs when there is no detectable BCR-ABL mRNA level in the
blood, or term as molecularly undetectable leukemia. These definitions depend
on the ability of laboratories, as well as their ability to PCR sensitivity
required for BCR-ABL1 detection.
RT Q-PCR methodology
is complex and requires considerable attention of details to ensure
reproducible results. Hence, variation among methods, methodological
shortcomings such as suboptimal procedures, performance problems, and operator
error may impact on the accuracy and reproducibility of BCR-ABL testing.
Although BCR-ABL monitoring is recommended for monitoring signs of relapse and
therapy resistance, test accuracy and variability issues are a potential reason
why molecular monitoring is not recommended for more extensive use in treatment
decisions.
After 12 months, if
MMR is achieved, the response can be assessed by RQ-PCR every 3 to 6 months and
cytogenetics is required only in case of failure or if standardized molecular
testing is not available. MMR is optimal for survival but that deeper response
is likely to be required for successful treatment [3].
Patients who
discontinue TKIs are usually monitored prospectively on an intended schedule of
monthly blood quantitative PCR BCR-ABL1 for 3 months, quarterly for 12 months
and every 6 months thereafter until the loss of MMR. However, less frequent
monitoring of BCR-ABL1 does not appear to affect outcomes and that
discontinuation of TKIs used as first-line treatment or beyond after resistance
or intolerance to first-line treatment appears feasible [13].
CONCLUSION
Molecular response is assessed with standardized
quantitative PCR at 3, 6 and 12 months. RT Q-PCR should be done every 3 months
until MMR has been achieved and at the interval of 3 to 6 months thereafter.
MMR is a 3 log reduction of BCR-ABL1 transcripts (MR3.0) or BCR-ABL1
≤ 0.1%. After 12 months, if MMR is achieved, the response can be assessed by
every 3 to 6 months.
1.
Hehlmann R, Hochhaus A,
Baccarani M; European LeukemiaNet (2007) Chronic myeloid leukaemia. Lancet Lond
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2.
O’Brien SG, Guilhot F,
Larson RA, Gathmann I, Baccarani M, et al. (2003) Imatinib compared with
interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic
myeloid leukemia. N Engl J Med 348: 994-1004.
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Baccarani M, Deininger
MW, Rosti G, Hochhaus A, Soverini S, et al. (2013) European LeukemiaNet
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872-884.
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Baccarani M, Saglio G,
Goldman J, Hochhaus A, Simonsson B, et al. (2006) Evolving concepts in the
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Branford S, Rudzki Z, Hochhaus A, et al. (2003) Frequency of major molecular
responses to imatinib or interferon alfa plus cytarabine in newly diagnosed
chronic myeloid leukemia. N Engl J Med 349: 1423-1432.
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Hochhaus A, Branford S, Radich J, et al. (2006) Monitoring CML patients responding
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harmonizing current methodology for detecting BCR-ABL transcripts and kinase
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Giles FJ (2011)
Molecular monitoring of BCR-ABL Transcripts — Standardization needed to
properly use, and further investigate the value of, a critical surrogate marker
for success in therapy of chronic myeloid leukemia. US Oncol Hematol 7:
138-142.
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Iacobucci I, Saglio G,
Rosti G, Testoni N, Pane F, et al. (2006) Achieving a major molecular response
at the time of a complete cytogenetic response (CCgR) predicts a better
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Branford S, Yeung DT,
Parker WT, Roberts ND, Purins L, et al. (2014) Prognosis for patients with CML
and >10% BCR-ABL1 after 3 months of imatinib depends on the rate of BCR-ABL1
decline. Blood.
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Hanfstein B, Shlyakhto
V, Lauseker M, Hehlmann R, Saussele S, et al. (2014) Velocity of early BCR-ABL
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Molecular monitoring in CML and the prospects for treatment-free remissions.
ASH Educ Program Book, pp: 257-263.
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Kong JH, Winton EF,
Heffner LT, Chen Z, Langston AA, et al. (2017) Does the frequency of molecular
monitoring after tyrosine kinase inhibitor discontinuation affect outcomes of
patients with chronic myeloid leukemia? Cancer 123: 2482-2488.
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