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Blue Cross and Blue Shield of Montana may consider BCR/ABL1 qualitative testing for the presence of the fusion gene medically necessary for diagnosis of chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL).
BCR/ABL1 testing for messenger RNA transcript levels by quantitative real-time reverse transcription-polymerase chain reaction at baseline prior to initiation of treatment and at appropriate intervals during therapy may be considered medically necessary for monitoring of chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL) to evaluate treatment response and remission.
Evaluation of ABL kinase domain point mutations to evaluate patients for tyrosine kinase inhibitor (TKI) resistance may be considered medically necessary when there is inadequate initial response to treatment or any sign of loss of response, and/or when there is progression of the disease to the accelerated or blast phase.
BCBSMT considers evaluation of ABL kinase domain point mutations experimental, investigational, and unproven when monitoring for advanced signs of treatment failure or disease progression.
Various types of laboratory tests involving BCR/ABL1 detection are associated with chronic myelogenous leukemia (CML) and have different clinical uses. Briefly, these are:
- Diagnosis: patients who do not have the BCR/AB1L fusion gene by definition do not have CML. In contrast, identification of the BCR/ABL1 fusion gene is necessary, although not sufficient, for diagnosis. Relevant test technologies are cytogenetics (karyotyping; recommended) or fluorescence in situ hybridization (FISH; acceptable in the absence of sufficient sample for karyotyping).
- Monitoring BCR/ABL1 RNA transcripts for residual disease during treatment/disease remission; relevant, standardized test technology is quantitative reverse transcription-polymerase chain reaction (RT-PCR). Note that a baseline measurement after confirmation of CML diagnosis and before treatment begins is strongly recommended.
- Identification and monitoring of mutations for drug resistance at response failure/disease progression; various test technologies are in use (not standardized).
While the diagnosis of CML is based on the presence of characteristic cellular abnormalities in bone marrow, the presence of the Philadelphia chromosome (Ph) and/or confirmation of the BCR/ABL1 fusion gene is essential to diagnosis. The initial evaluation of chronic phase CML should include bone marrow cytogenetics, not only to detect the Ph chromosome, but to detect other possible chromosomal abnormalities. (18) If bone marrow is not available, FISH analysis with dual probes for BCR and ABL genes or qualitative reverse transcriptase PCR (RT-PCR can provide qualitative confirmation of the fusion gene and its type. (18) Baseline measurement of BCR/ABL transcript levels are recommended as part of the initial evaluation, providing confirmation of the fusion gene, ensuring that it is detectable (rare variants requiring non-standard probes may occur), as well as a baseline for monitoring response to treatment. (18)
Monitoring for residual disease during treatment/disease remission
Quantitative RT-PCR measurement of BCR/ABL1 RNA transcript levels is the method of choice for measuring response to treatment because of the high sensitivity of the method and strong correlation with outcomes. (3) Compared to conventional cytogenetics, quantitative PCR (qRT-PCR) is more than 3 logs more sensitive (19) and can detect one CML cell in the background of >100,000 normal cells. Quantitative RT-PCR testing can be conducted on peripheral blood, eliminating the need for bone marrow sampling. The goal of treatment is complete molecular response (CMR; no detectable BCR/ABL transcript levels by qRT-PCR). However, only a small minority of patients achieve CMR on imatinib. (20) More often, patients achieve a major molecular response (MMR; a 3-log reduction from the standardized baseline of the International Scale (not from the actual baseline level of the individual patient). Results from the IRIS trial showed that patients who had a CMR or MMR had a negligible risk of disease progression at 1 year, and a significantly lower risk of disease progression at 5 years compared to patients who had neither. (21) At 8 years’ follow-up, none of the patients who achieved a MMR at 1 year progressed to the accelerated phase of disease or to a blast crisis. Similar near absence of progression in patients who achieved an MMR has been reported in registration studies of nilotinib and dasatinib. (5, 6, 20)
The degree of molecular response has been reported to correlate with risk of progression in patients treated with imatinib. (22) Timing of the molecular response is also important; the degree of molecular response at early time points predicts the likelihood of achieving CMR or MMR and predicts improved rates of progression-free and event-free survival. (23-26) While early and strong molecular response predicts durable long-term remission rates and progression-free survival, studies have not been conclusive that molecular response is predictive of overall survival. (27-29)
Based on imatinib follow-up data, it is recommended that for patients with a complete cytogenetic response, molecular response to treatment be measured every 3 months for 3 years, then every 3-6 months thereafter. (3, 30) Without complete cytogenetic response (CCyR), continued monitoring at 3-month intervals is recommended. It has been assumed that the same time points for monitoring imatinib are appropriate for dasatinib and nilotinib as well, (3) and will likely also be applied to bosutinib and ponatinib.
Rising BCR/ABL1 transcript levels are associated with increased risk of mutations and of treatment failure. (31-36) However, the amount of rise that is considered clinically significant for considering mutation testing is not known. Factors affecting the clinically significant change include the variability of the specific assay used by the laboratory, as well as the level of molecular response achieved by the patient. Thresholds used include 2- to 10-fold increases, and increases of 0.5-1 log. (3, 30, 37) Because of potential variability in results and lack of agreement across studies for an acceptable threshold, rising transcript levels alone are not viewed as sufficient to trigger mutation testing or changes in treatment. (38)
Standardization of BCR/ABL1 quantitative transcript testing. A substantial effort has been made to standardize the BCR/ABL1 qRT-PCR testing and reporting across academic and private laboratories. In 2006, the National Institute of Health Consensus Group proposed an International Scale (IS) for BCR/ABL1 measurement. (39) The IS defines 100% as the median pretreatment baseline level of BCR/ABL1 RNA in early chronic-phase CML as determined in the pivotal IRIS trial, MMR is defined as a 3-log reduction relative to the standardized baseline, or 0.1% BCR/ABL1 on the IS. (40) In the assay, BCR/ABL1 transcripts are quantified relative to one of 3 recommended reference genes (e.g., ABL) to control for the quality and quantity of RNA and to normalize for potential differences between tests. (41, 42) Percent ratios on the IS are determined at local labs by a test-specific conversion factor (IS % ratio=local % ratio x conversion factor). Until reference standards become broadly available, patient specimens must be exchanged between the local laboratory and an IS Reference Laboratory to establish a laboratory-specific conversion factor. In the U.S., many laboratories offer BCR/ABL quantitative testing (e.g., Quest, ARUP, LabCorp and Mayo) and most specify on their websites that results are standardized to the IS.
Identification of ABLkinase domain mutations (mutations associated with TKI-resistance)
Screening for BCR/ABL1 kinase domain point mutations (i.e. single nucleotide polymorphisms) in chronic phase CML is recommended for patients with inadequate initial response to tyrosine kinase inhibitor (TKI) treatment, those with evidence of loss of response, and for patients who have progressed to accelerated or blast phase CML. (3) The purpose of testing for kinase domain point mutations is, in the setting of potential treatment failure, to help select among other possible TKI treatments or allogeneic stem-cell transplantation. The following discussion focuses only on kinase domain point mutations.
In 2010, the Agency for Healthcare Research and Quality published a systematic review on BCR/ABL1 pharmacogenetic testing for tyrosine kinase inhibitors in CML. (43) The report concluded that the presence of any BCR/ABL1 mutation does not predict differential response to TKI therapy, although the presence of the T315I mutation uniformly predicts TKI failure. However, during the public comment period, the review was strongly criticized by respected pathology organizations for lack of attention to several issues that were subsequently insufficiently addressed in the final report. Importantly, the review grouped together studies that used kinase domain mutation screening methods with those that used targeted methods, and grouped together studies that used mutation detection technologies with very different sensitivities. The authors dismissed the issues as related to analytic validity and beyond the scope of the report. However, in this clinical scenario assay with different intent (screening vs. targeted) and assays of very different sensitivities may lead to different clinical conclusions and an understanding of these points is critical.
Point Mutation Detection Methods
Currently, methods for detecting drug resistance mutations are not standardized; clinical laboratories may choose among several different methods. The methods can detect either specific, known mutations (e.g., targeted mutation analysis) or screen for all possible mutations (e.g., direct sequencing); sensitivity also varies by method.
The particular methods to detect BCR/ABL kinase domain mutations will have great influence on the detection frequency, analytical sensitivity and the clinical impact of testing. The various mutation detection methods available have widely different analytic sensitivities, from the least sensitive direct Sanger sequencing to the highly sensitive mutation-specific quantitative polymerase chain reaction (PCR) methods.
Direct Sanger sequencing screens for all possible mutations but has low sensitivity, detecting a mutation present in approximately 1 in 5 BCR/ABL1 transcripts. Denaturing high-performance liquid chromatography (DHPLC) is also a screening method with initially higher sensitivity to detect the presence or absence of any mutations. Follow-up Sanger sequencing of positive samples is required to identify the mutations present; final sensitivity of this method is the sensitivity of sequencing. Targeted methods, used either to screen for only the most common, clinically relevant mutations or to monitor already identified mutations after a therapy change, can offer either limited sensitivity (e.g., pyrosequencing) or very high sensitivity (e.g., allele-specific PCR).
Kinase Domain Point Mutations and Treatment Outcomes
Branford et al. (44) have summarized much of the available evidence regarding kinase domain mutations detected at imatinib failure, and subsequent treatment success or failure with dasatinib or nilotinib. The studies referenced used direct Sanger sequencing, with or without DHPLC screening, to identify mutations at low sensitivity. The authors conducted a survey of mutations detected in patients at imatinib failure at their own institution and compared it with a collation of mutations derived from the literature. For both, the T315I mutation was most common; although about 100 mutations have been reported, the 7 most common (at residues T315, Y253, E255, M351, G250, F359, and H396) accounted for 60-66% of all mutations in both surveys. Detection of the T315I mutation at imatinib failure is associated with lack of subsequent response to high-dose imatinib, or to dasatinib or nilotinib. For these patients, allogeneic stem-cell transplantation remained the only available treatment until the advent of new agents such as ponatinib. (45) ‘Most common,’ however, does not necessarily correspond to clinically significant. Based on the available clinical studies, the majority of imatinib-resistant mutations remain sensitive to dasatinib and nilotinib. However, preexisting or emerging mutations T315A, F317L/I/V/C, and V299L are associated with decreased clinical efficacy with dasatinib treatment following imatinib failure. Similarly, preexisting or emerging mutations Y253H, E255K/V, and F359V/C have been reported for decreased clinical efficacy with nilotinib treatment following imatinib failure. In the survey reported by Branford et al., a total of 42% of patients tested had T315I or one of these dasatinib- or nilotinib-resistant mutations. (44) As a result, guidelines recommend mutation analysis only at treatment failure, and use of the T315I mutation and the identified dasatinib- and nilotinib-resistant mutations to select the subsequent treatment. (3, 38) In the absence of any of these actionable mutations, various treatment options are available. Note that these data have been obtained from studies in which patients were all initially treated with imatinib. No data are available regarding mutations developing during first-line therapy with dasatinib or nilotinib. (46)
ABL kinase domain mutational analysis is recommended if there is inadequate initial response (failure to achieve complete hematologic response at 3 months, only minor cytological response at 6 months or major [rather than complete] cytogenetic response at 12 months) or any sign of loss of response (defined as hematologic relapse, cytogenetic relapse or 1 log increase in BCR/ABL1 transcript ratio and therefore loss of major molecular response). Mutation testing is also recommended for progression to accelerated or blast phase CML. Treatment recommendations based on mutation(s) are shown in Table 1.
Table 1: Treatment Options Based on BCR/ABL1 KD Point Mutation Status at Imatinib Treatment Failure:
Ponatinib*, hematopoietic stem-cell transplantation,
or clinical trial
V299L, T315A, F317L/V/I/C
Consider nilotinib or bosutinib* rather than dasatinib
Y253H, E255K/V, F359V/C/I
Consider dasatinib or bosutinib* rather than nilotinib
Any other mutation
Consider high-dose imatinib, or dasatinib, nilotinib, or bosutinib*
*Recently approved; added in advance of National Comprehensive Cancer Network (NCCN) update, from which guidelines for this table were modified. Bosutinib active across BCR/ABL1 mutations including dasatinib- and nilotinib-resistant mutations except T315I, and after treatment failure with imatinib, dasatinib, or nilotinib (47, 48); Ponatinib active in treatment-resistant patients with T315I mutation. (45, 49)
Since only a small number of mutations have been recommended as clinically actionable, targeted assays may also be used to screen for the presence of actionable mutations at treatment failure. Quantitative, targeted assays may also be used to monitor levels of already identified clinically significant mutations after starting a new therapy following initial treatment failure. Targeted assays use different technologies, which can be made very sensitive to pick up mutated cell clones at very low frequencies in the overall malignant population. Banked samples from completed trials have been studied with high-sensitivity assays to determine if monitoring treatment can detect low-level mutations that predict treatment failure well in advance of clinical indications. While some results have been positive, not all mutations detected in advance predict treatment failure and more study is recommended before these assays are used for monitoring in advance of treatment failure. (38, 44) A direct correlation of low-sensitivity and high-sensitivity assays and a limited correlation with clinical outcomes supports recommendations of sequencing, with or without DHPLC screening, for identification of mutations. (50) Although high-sensitivity assays identified more mutations than did sequencing, the clinical impact of the additional mutations was viewed as uncertain.
Other types of mutations in addition to point mutations can be detected in the BCR/ABL1 gene, including alternate splicing, insertions, deletions and/or duplications. The clinical significance of such altered transcripts is unclear, and reporting such mutations is not recommended. (4, 46)
Ongoing Clinical Trials
Over 100 ongoing clinical trials resulted from a search of online site ClinicalTrials.gov for ‘BCR/ABL1 and CML’; many of these trials are treatment regimen-related.
Five ongoing trials were found that have direct genetic testing/molecular testing involvement:
- The Multicenter Trial Estimating the Persistence of Molecular Remission in Chronic Myeloid Leukaemia in Long Term After Stopping Imatinib (STIM 2) will measure the rate of molecular relapse defined by the rate of patients having a significant increasing of BCR/ABL transcript for 2 years after stopping treatment. Secondary outcomes include overall survival, molecular profile of patient, treatment costs, and event-free survival. NCT01343173.
- A Study of Complete Molecular Response for Chronic Myeloid Leukemia in Chronic Phase Patients, Treated With Dasatinib (CMR-CML) will measure the rate of complete molecular response (CMR) after treatment with dasatinib. Secondary outcomes include progression-free survival, and number of participants with adverse events. NCT01342679
- Nilotinib Versus Standard Imatinib (400/600 mg QD) Comparing the Kinetics of Complete Molecular Response (CMR) for CML-CP (chronic phase) Pts With Evidence of Persistent Leukemia by RQ-PCR will measure the rate of confirmed best cumulative Complete Molecular Response within the first year of study therapy with imatinib or nilotinib. Secondary outcomes include kinetics of CMR achieved in both treatment arms, progression-free survival, EFS (event-free survival) and OS (overall survival) between the two arms, and kinetics of CMR achieved after cross-over. NCT00760877
- Validation of Digital-PCR Analysis Through Programmed Imatinib Interruption in PCR Negative CML Patients will measure the negative predictive value ratio (rNPV) of dPCR over qRT-PCR. Secondary outcomes include rate of molecular and cytogenetic relapse, rate of dPCR (digital PCR)-positive patients, rate of dPCR negative patients, rate of patients who are maintaining dPCR negativity for 36 month, time to molecular relapse, overall survival, quality of life, and rate of patients progressing or developing resistance. NCT01578213
- Extending Molecular Responses With Nilotinib in Newly Diagnosed Chronic Myeloid Leukemia (CML) Patients in chronic phase (CP) will evaluate efficacy, using molecular response, of nilotinib 300 mg BID in the treatment of newly diagnosed CML-CP patients. No secondary outcomes were defined. NCT01580059
Extensive clinical data have led to the development of congruent recommendations and guidelines developed both in North America and in Europe concerning the use of various types of molecular tests relevant to the diagnosis and management of chronic myelogenous leukemia (CML). These tests are also useful in the accelerated and blast phases of this malignancy. Appropriate uses are summarized as follows:
Although CML is diagnosed primarily by clinical and cytogenetic methods, qualitative molecular testing is needed to confirm the presence of the BCR/ABL1 fusion gene, particularly if the Philadelphia chromosome (Ph) was not found, and to identify the type of fusion gene, as this information is necessary for subsequent quantitative testing of fusion gene messenger RNA transcripts. If the fusion gene is not confirmed, then the diagnosis of CML is called into question.
Monitoring during treatment with tyrosine kinase inhibitors:
Quantitative determination of BCR/ABL1 transcript levels during treatment allows for a very sensitive determination of the degree of patient response to treatment. Evaluation of trial samples has consistently shown that the degree of molecular response correlates with risk of progression. In addition, the degree of molecular response at early time points predicts improved rates of progression-free and event-free survival. Conversely, rising BCR/ABL1 transcript levels predict treatment failure and the need to consider a change in management. Quantitative polymerase-chain reaction (PCR)-based methods and international standards (IS) for reporting have been recommended and adopted for treatment monitoring.
The presence of ABL kinase domain point mutations are associated with treatment failure; a large number of mutations have been detected, but extensive analysis of trial data with low-sensitivity mutation detection methods has identified a small number of mutations that are consistently associated with treatment failure with specific tyrosine kinase inhibitors; guidelines recommend testing for, and using information regarding these specific mutations in subsequent treatment decisions. The recommended method is sequencing with or without denaturing high-performance liquid chromatography (DHPLC) screening to reduce the number of samples that need to be sequenced. Targeted methods that detect the mutations of interest for management decisions are also acceptable if designed for low sensitivity. High sensitivity assays are not recommended.
While the existing evidence is associational in nature, the body of evidence that has been accumulated and the consequences of the management decisions involved, along with international agreement on recommendations of the use of molecular assays, support the medical necessity of the use of the assays as described. Other uses and other types of assays is considered experimental, investigational, and unproven.
Policy Guidelines and Position Statements
The NCCN Practice Guidelines v.3.2013 Chronic Myelogenous Leukemia (3) and the NCCN Practice Guideline v.1.2013 Acute Lymphoblastic Leukemia (51) outline recommended methods for diagnosis and treatment management of CML and ALL, including BCR/ABL1 tests for diagnosis, monitoring, and ABL kinase domain mutations, and were referred to extensively in these documents. The European LeukemiaNet management recommendations for CML are very similar to those of NCCN and have also been cited in this document. (30) The U.S. Association for Molecular Pathology (4) and European LeukemiaNet recommendations for kinase domain mutation analysis (38) have been referenced; both provide very similar guidelines.
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