Clinical Advances in Hematology & Oncology
July 2013, Volume 11, Issue 7
Luke P. Akard, MD, FACP, Maher Albitar, MD, Charles E. Hill, MD, PhD, and Javier Pinilla-Ibarz, MD, PhD
Dr. Akard is Co-Director of the Stem Cell Transplantation Program at Indiana Blood and Marrow Transplantation in the Franciscan St. Francis Hospital and Health Centers in Indianapolis, Indiana. Dr. Albitar is Chief Medical Officer and Director of Research & Development at NeoGenomics Laboratories in Irvine, California. Dr. Hill is Director of the Molecular Diagnostics Laboratory at Emory University School of Medicine in Atlanta, Georgia. Dr. Pinilla-Ibarz is a Medical Oncologist at the H. Lee Moffitt Cancer Center & Research Institute in Tampa, Florida.
Introduction
The approval of the first BCR-ABL1 tyrosine kinase inhibitor (TKI) for the treatment of Philadelphia chromosome–positive (Ph+) chronic myeloid leukemia (CML) more than a decade ago represented a major advancement in the management of patients with CML. For most patients with CML in the chronic phase (CML-CP), BCR-ABL1 TKIs can reduce disease burden to extremely low, sometimes undetectable, levels. The effectiveness of BCR-ABL1 TKIs has had far-reaching effects on CML management, affecting methods of disease monitoring, expectations for treatment response,1 and clinical study design.2
The National Comprehensive Cancer Network (NCCN) has kept up with the rapid pace of research in CML, issuing updates and revisions to the NCCN Clinical Practice Guidelines in Oncology for CML (NCCN Guidelines) biannually to reflect current, evidence-based, best practices. The guidelines were updated in July 2012 (version 1.2013).3 Additional updates were made in September and November 2012 and in February 2013 in order to fine-tune version 1.2013 and include 3 newly approved compounds: the BCR-ABL1 TKIs bosutinib (Bosulif, Pfizer) and ponatinib (Iclusig, ARIAD Pharmaceuticals), as well as the protein synthesis inhibitor omacetaxine (Synribo, Teva Pharmaceutical Industries).4 The majority of these recent updates relate to specifications for the timing and methodology used to monitor disease. Notably, the NCCN Guidelines (v4.2013)4 now include recommendations for deeper responses to first-line TKI therapy, a change that will affect treatment response goals.
Because these revisions represent arguably the most substantive changes to practice guidelines in a decade, clinicians may have questions about the clinical evidence supporting the new guidelines. This review outlines the more substantive changes to the NCCN Guidelines, describes clinical data that support these changes, and provides an overview of the implications of these changes for routine clinical practice that might not be covered by these new guidelines.
Rationale Behind the Major Changes to the NCCN Guidelines
The major changes in the NCCN Guidelines v1.2013 (carried over in v2.2013, v3.2013, and v4.2013) are summarized in Table 1.
The International Scale (IS)
The IS was established in the IRIS (International Randomized Study of Interferon and STI571) trial to facilitate the direct comparison of quantitative reverse-transcription polymerase chain reaction (QPCR) data generated from the 3 investigating laboratories.5 Each laboratory calculated a median value of BCR-ABL1 level for a common set of 30 pretreatment samples, and independently set that median value to 100% on the IS. Then, subsequent log reductions in BCR-ABL1 level were expressed as a reduction in percent on the IS (eg, 1-log reduction is equivalent to 10% IS). Since the IRIS study, there has been a global effort to promote the adoption of the IS,6-9 including the development and validation by the World Health Organization (WHO) of a set of reference materials consisting of a freeze-dried panel of 4 dilution levels of K562 cells diluted in HL60 cells that laboratories can use to align themselves to the IS. Unfortunately, only a limited supply of these reference materials is available. It was envisioned that these materials would be furnished to manufacturers of secondary reference materials, thus maintaining a chain of traceability to the original WHO IS-standardized materials.9 Recently, several commercial laboratories have developed tests that use reference materials standardized to the IS. Some of these laboratories have developed kits or are developing compact testing systems that can rapidly evaluate BCR-ABL1 levels (IS). It is hoped that these new products will be evaluated and approved by the US Food and Drug Administration (FDA) to allow wider access and routine use of IS-standardized testing for all patients with CML.
Some laboratories have found it difficult to convert to the IS because the conversion process is labor-intensive and the currently available IS-calibrated tests are labeled for research use only. In the absence of IS standardization, these laboratories may establish their own standardized baseline against which subsequent BCR-ABL1 values can be compared. Although the use of laboratory-specific baselines can serve the purpose of standardization, unless the standardization is validated against IS-approved materials, the test results from such laboratories may be difficult to interpret.
IS-standardized QPCR is the preferred method of measuring treatment response and monitoring residual disease in CML. In the absence of access to IS-standardized QPCR assays, the NCCN Guidelines recommend the use of bone marrow cytogenetic testing to assess response to TKI therapy. Although cytogenetic testing is less sensitive than QPCR, the use of non-IS–standardized QPCR assays, as mentioned, yields results that may be difficult to interpret and not suitable for making decisions regarding treatment.
Minimum Sensitivity Threshold of QPCR Assay for Undetectable BCR-ABL1 Levels
The NCCN Guidelines (v4.2013) now defines the term complete molecular response (CMR) as undetectable BCR-ABL1 levels by measurement using QPCR assays that have a sensitivity threshold of 4.5 log or higher.4 This specification acknowledges that CMR, by itself, is an imprecise term that varies by assay (ie, method, technology, and limit of detection). This specification of assay sensitivity in the NCCN Guidelines is also consistent with a recent shift in the way molecular response (MR) is reported in the literature—that is, MR labeled with the limit of detection of the assay (eg, MR4=detectable BCR-ABL1 level of ≤0.01% [IS] or ≥4-log reduction; CMR4=undetectable BCR-ABL1 transcripts with ≥10,000 control transcripts detected). Note that when BCR-ABL1 transcripts are undetectable, the control gene copy number should be reported1 as an indication that the QPCR assay was not technically flawed, and that BCR-ABL1 transcripts would have been detected had they been present in the sample.
Acceptable Samples for QPCR Molecular Monitoring
The NCCN Guidelines (v4.2013) now indicate that the use of either peripheral blood or bone marrow samples for QPCR assay is acceptable.4 Bone marrow sampling is considered an invasive procedure, which may pose a barrier to performing monitoring every 3 months, as recommended in the NCCN Guidelines. Allowing the use of peripheral blood samples for QPCR assays could alleviate some of the burden of performing quarterly molecular monitoring of response.
In a recent study by Lima and associates, a significant correlation was found between QPCR results using paired bone marrow samples versus peripheral blood samples (n=64 paired samples; r=0.869; P<.0001) from patients with CML (all stages) treated with a TKI or with omacetaxine mepesuccinate.10 Similarly, a post-hoc analysis of the RIGHT (Rationale and Insight for Gleevec High-Dose Therapy) study also found a significant correlation between peripheral blood and bone marrow QPCR results (n=170 paired samples; r=0.9256; P<10-4).11 Lima and colleagues further determined that the costs associated with bone marrow biopsies (including professional and technical costs, and fees associated with conscious sedation) in the first 18 months after diagnosis of CML were more than 4 times those associated with peripheral blood drawings (including professional and technical costs, and fees associated with phlebotomies).10
The 3-Month Treatment Response Milestone
In the current NCCN Guidelines (v4.2013), criteria for satisfactory response to TKI therapy at 3 months were changed from achievement of complete hematologic response (CHR) to BCR-ABL1 transcript level of 10% or less (IS) (≥1-log reduction) or partial cytogenetic response (PCyR; 1–35% Ph+).4 There is considerable clinical evidence that TKIs elicit significantly higher rates of molecular response than pre-TKI standard treatment modalities, such as interferon alfa. In the IRIS study, the rate of major molecular response (MMR) at 1 year (BCR-ABL1 ≤0.1% [IS] or ≥3-log reduction from baseline; 39% vs 2%, P<.001) was significantly higher with imatinib (Gleevec, Novartis) than with the control regimen of interferon alfa plus cytarabine.5 Likewise, the newer BCR-ABL1 TKIs have improved rates of MMR over imatinib. In the phase III randomized ENESTnd (Evaluating Nilotinib Efficacy and Safety in Clinical Trials – Newly Diagnosed Patients) study, the rate of MMR at 1 year (44% vs 22%; P<.001),12 and the rates of MR4 and MR4.5 at 1, 2, and 3 years were significantly higher with nilotinib (Tasigna, Novartis) 300 mg twice daily than with imatinib.13,14 In the DASISION (Dasatinib Versus Imatinib Study in Treatment-Naïve CML Patients) trial, the rate of MMR at 1 year (46% vs 28%; P<.0001),15 and the rates of MR4.5 at 2 and 3 years were significantly higher with dasatinib (Sprycel, Bristol-Myers Squibb) than with imatinib.16,17
In the BELA (Bosutinib Efficacy and Safety in Newly Diagnosed CML) study, the rate of MMR at 12 months was higher with bosutinib than with imatinib (41% vs 27%; P<.001), although the rate of complete cytogenetic response (CCyR) at 12 months was similar with either TKI.18 This change in treatment response expected at 3 months recognizes that the previous criterion of CHR at 3 months was neither sufficiently sensitive nor specific in distinguishing patients who might need closer evaluation or follow-up from those with satisfactory response to first-line treatment, because nearly all patients treated with TKI therapy achieve CHR at 3 months (eg, median time to CHR with imatinib in the IRIS study was 1 month19). The updated response criteria at 3 months, namely BCR-ABL1 levels of 10% or less (IS; ≥1-log reduction) or partial cytogenetic response (PCyR), should identify a greater proportion of patients who do not respond adequately to first-line TKI therapy, compared with the previous 3-month response criterion of CHR.
The new response criteria are based on findings of landmark analyses linking early cytogenetic or molecular responses with long-term outcomes. In the IRIS study, achievement of cytogenetic response at 3 months predicted durable response at 8 years.20 Furthermore, the achievement of cytogenetic responses has been associated with fewer CML-related events and longer survival without disease progression to accelerated phase (AP) or blast crisis (BC) in the IRIS study,20,21 as well as in other studies of first-line imatinib.22-24 Similarly, other studies have shown that the achievement of CCyR at 3, 6, and 12 months is associated with improved event-free survival (EFS) and overall survival (OS),25 and the achievement of at least PCyR at 3 months predicts significantly better 5-year OS than lower levels of cytogenetic response.26
The update of the NCCN Guidelines for expected treatment response at 3 months also reflects a considerable body of clinical research showing that the achievement of BCR-ABL1 levels of 10% or less (IS; ≥1-log reduction) at 3 months significantly predicts favorable long-term outcome27-34 (Table 2). The first of these studies to show a significant correlation between molecular response at 3 months and prolonged OS was a landmark analysis conducted by Marin and colleagues, in which unselected patients treated at a single center with first-line imatinib who achieved BCR-ABL1 up to 9.84% (IS) at 3 months had significantly higher rates of CCyR, MMR, and CMR, as well as higher rates of OS, progression-free survival (PFS), and EFS at 8 years than patients with higher BCR-ABL1 levels at 3 months.31
In addition, multivariate analysis identified the BCR-ABL1 level at 3 months (≤9.84% vs >9.84%) to be the only independent predictor of OS, PFS, EFS, and current CCyR survival (the probability of being alive and in CCyR at a given time) at 8 years. In a landmark analysis of the randomized, controlled German CML IV study, achievement of early molecular response (BCR-ABL1 ≤10% [IS] at 3 months and BCR-ABL1 ≤1% [IS] at 6 months) was associated with significantly higher rates of PFS and OS at 5 years.26 Independent validation of the prognostic significance of early molecular response to imatinib was conducted in a group of patients who were treated with imatinib in the IRIS study. In agreement with the findings of the German CML IV landmark analysis, IRIS patients with BCR-ABL1 levels up to 10% (IS) at 3 months had a higher rate of OS at 8 years than patients with BCR-ABL1 levels greater than 10% (IS) at 3 months (93% vs 81%).26 Because their data predicted poorer prognosis for patients without early molecular response, the German CML Study Group considers an early switch in TKI therapy in these so-called “slow-responding” patients to be justified.
Although not as mature as the imatinib data, landmark analyses of the ENESTnd, DASISION, and BELA studies show that early response to nilotinib, dasatinib, and bosutinib, respectively, correlate with higher rates of future response,33,35,36 higher rates of OS35,36 and PFS,33 and lower incidences of disease progression to AP/BC.33,36 Notably, half of the progression events occurring in patients in the ENESTnd study with BCR-ABL1 levels above 10% (IS) occurred between 3 and 6 months,36 which further supports the concept that the 3-month mark is an important decision point. Some of the landmark analyses—particularly those of imatinib—have followed patients for many years and have shown significant survival differences. The more recent analyses have demonstrated a higher likelihood of attaining CCyR and MMR for early responders, and a higher likelihood of reaching the 3-month molecular target with the newer TKIs than with imatinib. As a whole, the findings of these landmark analyses point to the importance of achieving rapid response to first-line TKI therapy for improving long-term outcome.
Practical Considerations of the Updated NCCN Guidelines
Goals of Therapy
The new 3-month treatment response milestone—BCR-ABL1 levels less than or equal to 10% (IS; ≥1-log reduction)—underscores the importance of achieving rapid response to first-line TKI therapy, based on the significant prognostic link between rapid response and improved long-term OS. The NCCN Guidelines have consistently recommended regular monitoring of treatment response and minimal residual disease, acknowledging the need for constant vigilance in detecting potential signs of disease progression. Preventing the progression of CML to advanced stages (CML-AP and CML-BC) is an important goal of therapy. First-line TKI therapy significantly reduces the frequency of disease progression relative to previous standard treatment modalities. In the IRIS study, patients treated with imatinib had a significantly higher rate of freedom from progression at 12 months than patients treated with interferon alfa plus cytarabine (98.5% vs 93.1%; P<.001).19 In the ENESTnd study, the time to progression to CML-AP/BC was significantly longer with nilotinib (either dose) than with imatinib at 1 year,12 and the rate of freedom from progression was significantly higher at 2 years13 and at 3 years.14 In both the DASISION15,17 and BELA18 studies, the number of patients who progressed to CML-AP/BC while on treatment was lower with dasatinib and bosutinib than with imatinib. Given the relatively poor prognosis of patients with advanced CML—especially CML-BC37,38—and the dearth of effective treatment options for patients with CML-BC, delaying disease progression may ultimately improve EFS and OS; however, longer-term follow-up of clinical studies involving TKIs is needed.
First-Line TKI Treatment Choice
At present, there are 3 BCR-ABL1 TKIs approved for the treatment of patients with newly diagnosed Ph+ CML-CP: imatinib, nilotinib, and dasatinib. (Bosutinib and ponatinib were approved in 2012 for treatment after TKI failure.) The NCCN Guidelines characterize each first-line–approved TKI as a valid treatment option and do not recommend one over the others in the first-line setting. The only exception is for patients who are classified as intermediate- or high-risk by the Sokal and Hasford models. Then, the NCCN Guidelines suggest that nilotinib or dasatinib may be preferred over imatinib as initial therapy, based on observations that most patients in the imatinib arms of the ENESTnd and DASISION studies who progressed to CML-AP/BC had intermediate- or high-risk scores. In addition, the acknowledged importance of achieving rapid response to first-line therapy could highlight nilotinib or dasatinib as potentially more suitable options than imatinib. In the landmark analysis of the ENESTnd study,36 9% of evaluable patients on nilotinib 300 mg twice daily versus 33% of patients on imatinib had BCR-ABL1 levels above 10% (<1-log reduction) at 3 months. In the DASISION study,33 16% of evaluable patients on dasatinib versus 36% of patients on imatinib had BCR-ABL1 levels above 10% (<1-log reduction) at 3 months (Table 2). These observations indicate that considerably fewer patients treated with nilotinib or dasatinib versus imatinib experienced responses considered unsatisfactory by the updated NCCN criteria for the 3-month point. Thus far, there have been no significant differences in EFS or OS with nilotinib and imatinib in the ENESTnd study,14 or in PFS or OS with dasatinib and imatinib in the DASISION17 study.
Management of Patients With BCR-ABL1 Levels Above 10% (<1-Log Reduction) at 3 Months
For patients with BCR-ABL1 levels above 10% (<1-log reduction) at 3 months, the current NCCN Guidelines recommend first evaluating for adherence to therapy and drug-drug interactions and conducting BCR-ABL1 mutational analysis before considering a switch in TKI treatment, evaluating for hematopoietic stem cell transplant, or enrolling in a clinical study.4 There are currently no published studies evaluating the effect of second-line TKIs in patients who do not achieve BCR-ABL1 levels of 10% or less (≥1-log reduction) at 3 months with first-line imatinib. None of the studies shown in Table 2 had included in their protocols any provision to switch therapy during the first year of treatment upon failure to achieve specific molecular targets. Instead, the patients in these studies switched treatment based on study parameters that typically included failure to achieve hematologic or cytogenetic response, or relapse after achievement of response. These studies thus reflect the outcomes of patients who had a delayed (rather than early) switch in treatment following inadequate response to first-line TKI therapy. It remains to be determined whether switching therapy early, at the time of the 3-month evaluation, would result in better outcome.
Instead, there are clinical studies of second-line nilotinib, dasatinib, and bosutinib that might provide clues to the likely outcomes of patients who require second-line TKI therapy. First, clinical studies in patients with resistance to or intolerance of first-line imatinib show that roughly half of patients achieve cytogenetic and molecular response with second-line TKIs, and high rates of long-term PFS and OS are achievable.39-53 In general, these studies suggest that the second-line TKI therapy elicited higher response rates in patients with intolerance to imatinib than with resistance to imatinib, which implies that an earlier switch in TKI therapy may lead to improved outcomes.
Second, there are a small number of clinical studies that have compared outcomes of patients who were switched sooner versus later to second-line therapy. In a retrospective pooled analysis comparing outcomes of patients who were switched to second-line dasatinib after the loss of cytogenetic response versus after the loss of both cytogenetic and hematologic response to first-line imatinib, the group that was switched sooner had higher cumulative rates of CHR, CCyR, and MMR, as well as higher rates of 24-month EFS, transformation-free survival, and OS compared to the group that was switched later.50 In the TIDEL-II (Therapeutic Intensification in De Novo) study,54 patients with newly diagnosed CML-CP on first-line imatinib who failed to meet specific treatment response milestones were either switched to nilotinib directly or given high-dose imatinib for 3 months before switching to nilotinib. Patients switched to nilotinib directly had a higher rate of MR4.5 at 12 months, but not at 24 months, than patients who were switched later. In aggregate, these observations suggest favorable odds that patients with unsatisfactory response to first-line imatinib who are switched to second-line nilotinib or dasatinib will have good long-term prognosis.
At this time, whether patients who receive first-line nilotinib or dasatinib have long-term clinical outcomes as favorable as patients who receive second-line TKI therapy after first-line imatinib failure is not known, although the findings of the ENESTnd extension study might provide some insight. In that study, patients with resistance (not intolerance) to first-line nilotinib 300 mg twice daily or imatinib 400 mg (once or twice daily) were eligible to receive nilotinib 400 mg twice daily.45 It is important to note that resistance was defined by the European LeukemiaNet (ELN) criteria for suboptimal response or treatment failure at 6, 12, and 18 months,55 not by the NCCN criterion of BCR-ABL1 levels above 10% (<1-log reduction) at 3 months. By the ELN criteria, 18 patients (6.4%) on nilotinib 300 mg twice daily and 31 patients (11.0%) on imatinib had suboptimal response or treatment failure. Of the 31 imatinib-resistant patients, 7 patients achieved MMR on nilotinib 400 mg twice daily in the extension study. Thus, there remained 24 patients (8.5% of patients in the imatinib arm of the ENESTnd study) without molecular response following 2 lines of therapy, a proportion similar to the proportion of patients with resistance to first-line nilotinib (6.4%). This suggests that patients who received a first-line, second-generation TKI may have outcomes at least as favorable as patients who received a second-line, second-generation TKI after failure of first-line imatinib. These findings are provocative, although follow-up of the ENESTnd extension study is ongoing and final results are not yet available. A new clinical study to be conducted in the United Kingdom, in which newly diagnosed patients will start on first-line imatinib and switch to a different TKI treatment if their BCR-ABL1 levels are greater than 10% (IS) at 3 months, should address this clinical question.
Applying the updated 3-month treatment response milestone in the NCCN Guidelines, would patients with unsatisfactory response to first-line imatinib have fared better (or at least as well) if nilotinib or dasatinib had been given in the first-line setting? Table 2 summarizes the available 3-month molecular response data for more than 1,600 imatinib-treated patients and more than 900 patients treated with a newer TKI. Based on these data, the number of patients treated with first-line imatinib who failed to meet the 3-month response target was approximately 31%, and the number treated with a first-line, second-generation TKI (considered as a single group) was approximately 13% (Figure 1). For patients with inadequate imatinib response who are switched to second-line TKI therapy to achieve the same degree of response as patients who received a second-generation TKI in the first-line setting, 58% of patients switched would need to respond to second-line therapy. Data show, however, that for patients who switch from imatinib to a newer TKI because of imatinib resistance, only approximately 50% achieve CCyR. There are very few data on the response to second-line therapy in patients who are switched at 3 months for BCR-ABL1 levels above 10% (IS; <1-log reduction). The TIDEL-II study did include a group of patients who switched from imatinib to nilotinib at 3 months for BCR-ABL1 levels greater than 10% (IS; <1-log reduction), and only 27% of patients achieved MMR at 12 months after the switch.56 Based on these preliminary calculations, patients who are switched to second-line TKI therapy are unlikely to achieve the same degree of overall response as patients who are treated with a newer TKI as first-line therapy.
The gap in overall response rates achievable in patients who start on imatinib and switch to nilotinib/dasatinib versus patients who start on nilotinib/dasatinib may be even greater, because patients who do not achieve early molecular response to first-line nilotinib or dasatinib could also switch to another TKI at 3 months. Therefore, the proportion of patients who fail both first-line nilotinib or dasatinib and second-line TKI therapy is likely to be less than 13%. At present, there are very few second-line clinical data available on patients with resistance to or intolerance of first-line nilotinib, dasatinib, or bosutinib. In a small series of patients treated at MD Anderson Cancer Center in Houston, Texas,57 23 of 172 patients on first-line nilotinib or dasatinib discontinued treatment, 12 of 23 patients subsequently received a second-line TKI, and 5 of 12 patients (42%) achieved MMR on second-line imatinib, nilotinib, or dasatinib. An estimate of the ultimate failure rate in patients treated with imatinib or a second-generation TKI in the first-line setting is shown in Figure 1.
Starting with a second-generation TKI would be associated with fewer ultimate TKI treatment failures compared to starting with imatinib, assuming that: 1) 31% of patients fail first-line imatinib and 13% of patients fail first-line second-generation TKI; 2) 50% of patients with first-line imatinib failure and 60% of patients with first-line second-generation TKI failure will also fail second-line therapy; and 3) in the third-line setting, the rate of response is about half the rate of response in the second-line setting (ie, 25% of patients who started on imatinib and 20% of patients who started on a second-generation TKI would respond to TKI therapy in the third-line setting). For patients starting with imatinib to reach the same degree of ultimate response to TKI therapy as patients starting with a second-generation TKI, the failure rate of first-line imatinib would need to decrease to 16%, the failure rate of second-line TKI therapy would need to decrease to 26%, or the failure rate of third-line therapy would need to decrease to 38% (Figure 2). As this is highly unlikely, the provocative conclusion is that starting with second-generation TKIs as first-line treatment would result in greater long-term success. In other words, the strategy of starting with first-line imatinib and then switching to a second-generation TKI is unlikely to be superior to starting all patients on a second-generation TKI.
Patient Evaluations Between 3 and 12 Months
For patients with satisfactory response to first-line TKI therapy at 3 months, the NCCN Guidelines recommend quarterly molecular monitoring but no other specific treatment response evaluation until 12 months. For patients with an unsatisfactory response at 3 months who are subsequently switched to alternative TKI therapy, treatment evaluation before the 12-month mark is advisable. Although not addressed in the NCCN Guidelines, the ELN guidelines include provisional criteria for suboptimal response to and failure of second-line nilotinib and dasatinib.55 These criteria were based on a study that found the BCR-ABL1 level at 3 months after the start of second-line nilotinib or dasatinib to be significantly correlated with rates of MMR and MCyR at 24 months.58 Thus, it is advisable that response to second-line treatment be evaluated at the 6-month mark, or 3 months after the start of second-line therapy following an early switch, because that would allow timely intervention if there is no response to 2 successive lines of TKI therapy (which we approximated could occur in approximately 15% of imatinib-treated patients).
Regular Molecular Monitoring of BCR-ABL1
The overarching message is the importance of regular molecular monitoring of disease burden every 3 months, and more frequently when there are signs that suggest relapse or disease progression.59 An increase in BCR-ABL1 transcript level of as little as 0.5 log (~3.2-fold) has been shown to significantly predict the occurrence of relapse (defined as loss of CHR, loss of CCyR, or progression to CML-AP/BC) in patients who achieved CCyR on imatinib.60 In another study, a 1-log increase in BCR-ABL1 level, particularly in patients who had achieved CCyR but not MMR, and in patients who had lost MMR at the time of BCR-ABL1 increase, significantly predicts disease progression (defined as loss of CHR, loss of CCyR, transformation to CML-AP/BC, or death).61 The NCCN Guidelines recommend that patients with MMR who experience a 1-log increase in BCR-ABL1 level undergo repeat QPCR testing within 1–3 months, and patients who experience a 1-log increase with concomitant loss of MMR should have BCR-ABL1 kinase domain mutational analysis performed.4
Despite the importance of regular molecular monitoring as a means to monitor response, and to detect minimal residual disease and potential signs of eventual disease progression, evidence shows that patients with CML are routinely monitored less frequently than recommended.62-64 The recent updates to the NCCN Guidelines and concerted efforts to adopt the IS in QPCR testing are expected to increase awareness of the importance of regular molecular monitoring by QPCR.
Commercial Reference Laboratory Choice
At present, the majority of commercial laboratories do not use IS-standardized QPCR assays.65 When laboratories use either their own standard baselines or no baselines, clinicians may be challenged to make sense of inconsistent, potentially confusing test results, or to compare test results reported across laboratories. In addition, there are currently no minimum requirements for QPCR test reporting, so reports from one laboratory may differ from those of another laboratory.
The use of IS standardization in QPCR testing, as recommended in the current NCCN Guidelines, may alleviate potential problems that could complicate patient care. For example, universally interpretable data might facilitate the use of a uniform set of treatment decision criteria,7 such as those outlined in the NCCN Guidelines, which in turn could standardize the treatment of CML across practices. Furthermore, the transfer of patients from one practice to another would be less problematic7 because IS-standardized molecular monitoring could continue more seamlessly, even if a different testing laboratory is used. Most importantly, IS standardization allows for easier interpretation of QPCR data for individual patients (ie, reduces variability in serial monitoring in individual patients) and across patients within a practice, as well as aggregate data across clinical studies.7
Summary and Conclusions
The most recent set of updates to the NCCN Guidelines in CML (v1.2013, v2.2013, v3.2013, and v4.2013) includes some sweeping changes that affect routine clinical practice, particularly goals of therapy, molecular monitoring of BCR-ABL1 level, and management of patients with unsatisfactory response to first-line TKI. Updated clinical practice guidelines issued by the ELN, which were last updated in 2009,55 are also expected in the coming months. It is important for clinicians to be aware of both sets of guidelines, as they form the basis of response criteria used in modern CML clinical study designs, and of the recent and forthcoming updates, because they represent evidence-based best practices and reflect broader shifts in the management of CML.
The durable, deep molecular responses now possible with TKI therapy allow for the management of CML as a chronic disease, in which patients are stably maintained in CP for extended periods of time with TKI therapy. Whether patients who stably maintain undetectable BCR-ABL1 levels on TKI therapy can safely stop treatment is the subject of current clinical research in CML. Evidence suggests that achievement and maintenance of MR4 (IS) or better for at least 2 years may be an important criterion for safely stopping TKI therapy.66-68 The current NCCN Guidelines with specifications for the use of QPCR assays should ease the identification of patients who meet this inclusion criterion. With a larger pool of patients potentially eligible for clinical studies of safe cessation of TKI therapy, the CML community may one day realize its ultimate goal of having as many patients as possible living in treatment-free remission.
Acknowledgments
Financial support for medical editorial assistance was provided by Novartis Pharmaceuticals Corporation. The authors would like to thank Anna Lau, PhD, and Claudette Knight, PharmD, of Percolation Communications LLC for medical editorial assistance.
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