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Keywords:

  • chronic myeloid leukemia;
  • early response;
  • imatinib;
  • dasatinib;
  • nilotinib;
  • BCR-ABL1;
  • polymerase chain reaction;
  • molecular response

Abstract

  1. Top of page
  2. Abstract
  3. Predicting Long-Term Outcomes Using Early Responses to First-Line Imatinib Therapy
  4. Competing Risks in Nonresponding Patients: Probability of Response and Risk of Progression
  5. Benefits of Early Switch to Newer BCR-ABL1 Inhibitors
  6. Second-Generation TKIs as First-Line Therapy
  7. Conclusions
  8. FUNDING SOURCES
  9. REFERENCES

Chronic myeloid leukemia (CML) depends on the kinase activity of the BCR-ABL1 fusion protein. This dependency has led to the development of BCR-ABL1 inhibitors, such as imatinib, dasatinib, and nilotinib, which have proved to be highly efficacious treatments for CML. The European LeukemiaNet guidelines have established the importance of achieving a certain depth of response at different time points during imatinib therapy for patients with newly diagnosed CML in chronic phase. Patients who achieve a complete cytogenetic response by 12 months or a major molecular response by 18 months are classified as optimal responders and deemed to have excellent long-term outcomes. Conversely, failing to achieve such milestones is associated with an increased risk of worse long-term outcomes, such as loss of response, disease progression, or death. With ongoing treatment, patients not in complete cytogenetic response face a decreasing probability of ever achieving a complete cytogenetic response or major molecular response and increasing risk of disease progression. Available data therefore support treatment recommendations based on achieving defined levels of response within a specified duration of treatment. Recent data have shown that dasatinib and nilotinib used as frontline CML therapy result in higher response rates that are achieved at earlier time points compared with standard-dose imatinib therapy. Future analyses will need to determine whether these higher rates of deep and fast responses translate into improved long-term survival. Cancer 2011;. © 2011 American Cancer Society.

Chronic myeloid leukemia (CML) is a malignant hematologic disorder in which clonal expansion of leukemic stem cells depends on constitutive expression of the BCR-ABL1 oncoprotein. BCR-ABL1 is a fusion protein encoded in most patients by the Philadelphia chromosome (Ph), formed by reciprocal translocations between chromosomes 9 and 22.1

Almost 10 years ago, CML therapy was radically changed by the introduction of imatinib (formerly STI571), a BCR-ABL1–targeting tyrosine kinase inhibitor (TKI).2-4 Imatinib 400 mg once daily became rapidly established as the preferred first-line therapy for patients with newly diagnosed CML in chronic phase (CML-CP) after showing superior efficacy and safety compared with interferon-α (IFNα) plus cytarabine, the previous standard of care.3 This was demonstrated in the pivotal IRIS (International Randomized Study of Interferon and STI571) trial, in which the cumulative rate of complete cytogenetic response (complete cytogenetic response; ie, 0% Ph+ metaphase cells in bone marrow) was 69% by 12 months.5 Major molecular response rates were also calculated, that is, the proportion of patients who had a 3-log reduction in BCR-ABL1 transcript level (0.1% ratio) compared with a standardized baseline (established in 3 laboratories as the median BCR-ABL1 level among 30 trial participants before treatment). Major molecular response rates were significantly better for imatinib compared with IFNα (estimated 12-month major molecular response rates: 39% vs 2% in the control arm; P < .001).5 Imatinib was associated with a superior rate of transformation-free survival, that is, survival without progression to accelerated phase (AP) or blast phase (BP) (97% vs 91% for IFNα plus cytarabine at 19 months; P < .001).3 On the basis of the predictive importance of complete cytogenetic response and major molecular response observed in the IRIS trial, these have become important milestones in patients with CML-CP receiving TKI therapy.4, 6 The definition of an optimal response to first-line imatinib, as published by the European LeukemiaNet, includes complete cytogenetic response by 12 months and major molecular response by 18 months (Table 1).6

Table 1. Established Response Milestones During First-Line Imatinib Treatment for Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase6
Evaluation Time, moResponse
 OptimalSuboptimalFailure
  1. Abbreviations: CCA, clonal chromosomal abnormalities; CCyR, complete cytogenetic response; CHR, complete hematologic response; CyR, cytogenetic response; MMR, major molecular response; NA, not applicable; PCyR, partial cytogenetic response; Ph+, Philadelphia chromosome positive.

BaselineNANANA
3CHR and at least a minor CyR (≤65% Ph+)No CyR (>95% Ph+)Less than CHR
6At least a PCyR (≤35% Ph+)Less than PCyR (>35% Ph+)No CyR (>95% Ph+)
12CCyRPcyR (1%-35% Ph+)Less than PcyR (>35% Ph+)
18MMRLess than MMRLess than CCyR
Any time during therapyStable/improving MMRLoss of MMR, imatinib-sensitive mutationsLoss of CHR or CCyR, CCA

Several different methods exist for assessing cytogenetic or molecular responses, potentially complicating comparisons of data from different institutions. Conventional cytogenetic testing of bone marrow aspirates is performed by assessing Ph positivity in at least 20 Giemsa-stained metaphase cells. In patients who have not achieved a complete cytogenetic response, the degree of cytogenetic response is classified as partial (1%-35% Ph+ metaphases), minor (36%-65% Ph+ metaphases), or minimal (66%-95% Ph+ metaphases). A more sensitive detection method uses fluorescence in situ hybridization (FISH) to assess the Ph chromosome in peripheral blood interphase cells, thereby evaluating a higher number of cells than conventional cytogenetic testing. Parallel analyses of patients with CML using conventional analysis, interphase or metaphase FISH, and real-time quantitative polymerase chain reaction (RT-Q-PCR) have found a high, albeit not perfect, degree of correlation between BCR-ABL1 transcript level and cytogenetic assessments.7

A recent study by the GIMEMA (Gruppo Italiano Malattie Ematologiche Adulto) CML Working Party examined how closely interphase FISH and RT-Q-PCR correlated with conventional cytogenetic testing. Of patients defined as having a complete cytogenetic response using conventional testing, the majority (83%) had <1% of nuclei positive for BCR-ABL1 in interphase FISH analysis, which is broadly accepted as a false-positive threshold with modern dual-color dual-fusion FISH probes. Of patients who had <1% positive nuclei by interphase FISH, 98% had a complete cytogenetic response using conventional chromosome banding analysis. Major molecular response rates were significantly higher in patients with <1% positivity by interphase FISH compared with patients with positivity rates of 1% to 5% (67% vs 52%, P < .001). These data show that interphase FISH is more sensitive than conventional cytogenetics and may potentially be useful for monitoring patients who have achieved complete cytogenetic response by conventional cytogenetic analysis.8 However, because established response categories are based on conventional cytogenetics and because FISH does not detect other clonal chromosomal abnormalities, conventional testing remains the recommended approach for establishing complete cytogenetic response. FISH is recommended for identifying the minority of patients with CML who have PhBCR-ABL1–positive disease.4, 9

In molecular monitoring, the level of BCR-ABL1 transcripts is calculated by normalizing the absolute value obtained by RT-PCR to that of a housekeeping gene. However, the choice of housekeeping gene varies between laboratories and includes ABL1, BCR, GUS, G6PDH, and β2M, which complicates interlaboratory comparisons.10 Efforts are ongoing to standardize molecular responses derived in different laboratories using an International Scale, which uses ABL1 as the housekeeping gene.10, 11 Expressing quantitative RT-PCR values on the International Scale using an individual conversion factor unique to each laboratory may facilitate comparisons of molecular response data.

The current focus on complete cytogenetic response and major molecular response for evaluating patients is based on the finding that these responses are predictors of how patients are likely to fare during long-term treatment. This has been demonstrated in the IRIS trial, in which patients who achieved a complete cytogenetic response had a lower annual incidence of events (loss of response, transformation to AP/BP, or death) than the overall group after 5 years of follow-up.12 With 8-year follow-up, no patient who had complete cytogenetic response and major molecular response at 12 months had progressed to AP or BP.13 Importantly, achievement of complete cytogenetic response has been associated with improved survival, whereas achievement of major molecular response has been associated with improved probability of event-free survival (EFS) but not overall survival (OS).

The importance of complete cytogenetic response has been further illustrated by IRIS data showing that achieving a complete cytogenetic response on imatinib (unlike on IFNα plus cytarabine) enabled patients to overcome the poorer prognosis associated with an intermediate or high Sokal score. The Sokal score is an established prognostic method in newly diagnosed CML-CP that uses 4 baseline factors (age, spleen size, platelet count, and percentage of blast cells in peripheral blood).14 Although low, intermediate, and high Sokal scores were predictive for 5-year rates of complete cytogenetic response (89% vs 82% vs 69%, respectively; P < .001) and transformation to AP/BP (3% vs 8% vs 17%; P = .002) in the imatinib arm of IRIS, patients within the different Sokal groups who achieved a complete cytogenetic response had similar rates of transformation-free survival (95% vs 95% vs 99%, respectively).12 The Hasford risk score is an alternative prognostic system that includes percentages of eosinophils and basophils in addition to the variables used by the Sokal method when deriving risk score.15 In general, the Hasford method categorizes fewer patients as high risk compared with the Sokal method.3 Although Hasford scores have similar prognostic value to Sokal scores, it has not been formally confirmed that achieving a complete cytogenetic response also overcomes a high/intermediate Hasford categorization.

Recently, initial data have been reported from trials of the more potent BCR-ABL1 inhibitors dasatinib and nilotinib compared with imatinib as first-line treatment for patients with newly diagnosed CML-CP.16, 17 In both trials, the newer agents showed superior efficacy over imatinib, although follow-up is currently relatively short (18-24 months). A key question is whether these early data will translate into superior long-term outcomes. In the remainder of this article, analyses from various sources investigating the predictive value of early responses to first-line imatinib treatment are reviewed, and the implications of emerging data with newer agents are discussed.

Predicting Long-Term Outcomes Using Early Responses to First-Line Imatinib Therapy

  1. Top of page
  2. Abstract
  3. Predicting Long-Term Outcomes Using Early Responses to First-Line Imatinib Therapy
  4. Competing Risks in Nonresponding Patients: Probability of Response and Risk of Progression
  5. Benefits of Early Switch to Newer BCR-ABL1 Inhibitors
  6. Second-Generation TKIs as First-Line Therapy
  7. Conclusions
  8. FUNDING SOURCES
  9. REFERENCES

The use of complete cytogenetic response and major molecular response as milestones for treatment response is based on various landmark analyses that have been performed using data from the IRIS trial and other studies of first-line imatinib. Landmark analyses are performed by grouping patients according to their response status at a specific time point during treatment, then evaluating subsequent outcome in each group typically using the Kaplan-Meier method. To avoid statistical bias, patients who discontinue treatment before the chosen landmark or who are not assessed at (or close to) the landmark are excluded from the analysis.18, 19 However, it is worth emphasizing that landmark analyses are often performed as post hoc or exploratory analyses. Although the P values reported provide a description of any difference in outcome, they do not account for multiplicity of analysis and so do not provide an accurate indication of statistical significance. Also, when performing landmark analyses, patients who are lost before the chosen time point are discarded, thus the best patients for the analyses are always selected.

Different types of long-term outcome have been considered during landmark analyses of imatinib treatment, which is an important consideration when interpreting findings. Although OS is ultimately the most important outcome, the prolonged survival of patients with CML-CP in the TKI era means that very long periods of follow-up may be needed before significant differences in survival become apparent. Alternative endpoints, including progression-free survival (PFS), transformation-free survival, and EFS, are frequently used (almost interchangeably) when referring to long-term outcomes in studies of patients with CML-CP, although it is important to note the precise definition used in each study or analysis. Because transformation to AP or BP is associated with decreased survival,20 transformation-free survival (ie, survival without progression to AP/BP) is a commonly used and important endpoint. In some analyses, time to progression to AP or BP (ie, distinct from transformation-free survival because death is not considered) has been reported. EFS was defined in the IRIS trial as survival without transformation to AP/BP, loss of complete hematologic or major cytogenetic response, or increasing white cell count while on TKI therapy.3, 12 Thus, discontinuation of TKI therapy for toxicity or for other reasons is not considered an event (15%-20% of patients); patients are censored at the time of discontinuing TKI therapy, and their subsequent outcome is not captured, except in the event of death. Because loss of response typically precedes disease transformation, and patients who experience hematologic or cytogenetic relapse after an initial response have lower rates of survival or progression to AP/BP,21-23 EFS is potentially a more sensitive endpoint than transformation-free survival. Confusingly, EFS was called PFS in early reports from IRIS, and the definition of EFS in other analyses may incorporate additional events such as treatment discontinuation after toxicity. Depending on the individual study/publication, PFS has been defined using the definitions stated above for EFS or transformation-free survival.

Landmark analyses assessing the predictive value of complete cytogenetic response or molecular responses at different time points during first-line treatment are reviewed below. To avoid confusion, endpoint definitions for studies other than IRIS are specified instead of using inconsistent terminology.

Predictive value of complete cytogenetic response

Across various clinical studies in the first-line setting, standard-dose imatinib treatment (400 mg/d) resulted in a complete cytogenetic response in 45% to 59% of patients by 6 months, 57% to 72% by 12 months, and 76% by 18 months.3, 12, 16, 17, 24-26 A recent update of the IRIS study with 8-year follow-up included landmark analyses based on level of cytogenetic response at 3, 6, 12, and 18 months of treatment. Across all time points, patients who had achieved a complete cytogenetic response had the lowest rates of events or transformation to AP/BP during long-term follow-up compared with patients who had achieved inferior levels of cytogenetic response (Table 2). Of patients who were assessable at 12 months, the rates of events and transformation to AP/BP in patients who had achieved complete cytogenetic response by 8 years were 6% and 3%, respectively, compared with 20% and 5% in patients who had achieved only a partial cytogenetic response, and 62% and 37% in patients who did not achieve complete cytogenetic response or partial cytogenetic response at 12 months. Thus, patients who had only achieved a partial cytogenetic response at 12 months had a >3-fold higher incidence of events during long-term follow-up compared with patients who had achieved a complete cytogenetic response.13 Similar findings from landmark analyses were published in earlier reports from the IRIS trial.12, 27

Table 2. Outcomes of Patients Receiving Imatinib Therapy in the IRIS Trial at 8 Years According to Cytogenetic Response at 3, 6, 12, and 18 Months13
Cytogenetic Response3 Months6 Months12 Months18 Months
% Stable CCyREstimated Event Rate (%)%AP/BP% Stable CCyREstimated Event Rate (%)% AP/BP% Stable CCyREstimated Event Rate% AP/BP% Stable CCyREstimated Event Rate (%)% AP/BP
  1. Abbreviations: AP, acute phase; BP, blast phase; CCyR, complete cytogenetic response; IRIS, International Randomized Study of Interferon and STI571; PCyR, partial cytogenetic response; Ph+, Philadelphia chromosome positive.

CCyR (0% Ph+)9073848387639041
PCyR (>0%- 35% Ph+)721046317557205293120
Minor (>35%- 65% Ph+)553010353811146237
Minimal (>65%- 95% Ph+)373213254520
None (>95% Ph+)324016323617

Landmark analyses based on cytogenetic response at 12 and 18 months have also been performed using data from single centers. In an analysis of 204 patients with newly diagnosed CML-CP treated with imatinib at the Hammersmith Hospital in London, United Kingdom, patients who had not achieved a complete cytogenetic response at 12 months had significantly lower rates of survival without transformation to AP/BP (74%) and OS (74%) than patients who had achieved a complete cytogenetic response at 12 months (96% [P = .007] and 98% [P = .03], respectively). This study was an intention-to treat analysis, thus providing a more realistic estimation of clinical practice.25 In a further analysis from the same institution, patients with a suboptimal response at 12 months (ie, partial cytogenetic response but not complete cytogenetic response) had significantly worse rates of survival without transformation to AP/BP and OS than patients with an optimal response (complete cytogenetic response) at 12 months.21 Further validation was provided by an independent cohort of 280 patients treated with imatinib at The University of Texas MD Anderson Cancer Center in Houston, Texas; patients who achieved a complete cytogenetic response at 12 and 18 months had significantly higher rates of long-term survival without transformation to AP/BP or loss of hematologic or cytogenetic response than patients who had achieved a partial cytogenetic response. However, no significant difference in OS was observed within the available follow-up. Patients who had achieved at least a partial cytogenetic response by 6 or 12 months did show significantly higher OS rates than patients who had not achieved a partial cytogenetic response.23 In a subsequent analysis of suboptimal versus optimal responders at 12 months performed at the same institution, a difference was seen in long-term rates of events (26% vs 8%, respectively) but not transformation to AP/BP (both 5%).28 These studies thus show that earlier responses are associated with improved EFS, with trends for better survival free from transformation to AP/BP, but with little if any improved OS, at least within available follow-up.

An alternative insight into the value of early responses has been obtained through the TOPS (Tyrosine Kinase Inhibitor Optimization and Selectivity) trial, a phase 3 randomized study of imatinib 400 mg/d versus 800 mg/d in patients with newly diagnosed CML-CP. Although the 800 mg/d arm had higher complete cytogenetic response rates than the 400 mg/d arm at 6 months (45% vs 57%; P = .015), rates were similar at 12 months (66% vs 70%; P = .347).24 After 24 months of follow-up, rates of EFS (95% vs 95%; event = death, transformation to AP/BP, or loss of complete hematologic response or major cytogenetic response), survival without transformation to AP/BP (97% vs 98%), and OS (97% vs 98%) were similar for both arms.29

Predictive value of major molecular response

Across multiple first-line studies of standard-dose imatinib (400 mg/d), a major molecular response was achieved in 12% to 40% by 12 months and 50% to 52% by 18 months.16, 17, 24, 25, 29 Analyses into the value of achieving major molecular response (BCR-ABL1 transcript reduction to 0.1% on the International Scale) during imatinib treatment have reported inconsistent findings across different series. Although the first report from the IRIS trial suggested that among patients with a complete cytogenetic response, those who had achieved a major molecular response had the best probability of survival free from events or transformation,2 with longer follow-up and larger number of patients assessed, the significance of achieving a 12-month major molecular response was lost, as shown by 7-year EFS rates of 92% versus 91% for patients with transcript levels ≤0.1% (ie, major molecular response) or >0.1 to 1% (ie, grossly equivalent to complete cytogenetic response without major molecular response), respectively. However, the prognostic impact for EFS of achieving major molecular response is maintained at 18 months, as patients who achieved complete cytogenetic response without major molecular response by 18 months had a significantly poorer 7-year EFS than those who achieved complete cytogenetic response and major molecular response (86% vs 95%; P = .01).3 However, the difference in the probability of survival free from transformation to AP or BP is narrower (96% vs 99%, P = .054).3 Achievement of both complete cytogenetic response and major molecular response by 18 months was predictive for complete cytogenetic response duration; only 3% of patients lost their complete cytogenetic response by 7 years compared with 26% of patients who had a complete cytogenetic response but no major molecular response at 18 months (P < .001). No significant difference in long-term outcomes was seen in analyses of these levels of response at 6 months.30

Other analyses, mostly from single-institution studies of patients in complete cytogenetic response at 12 or 18 months, have also found no advantage in survival without transformation to AP/BP or OS associated with achieving complete cytogenetic response plus major molecular response versus achieving only complete cytogenetic response.21, 23, 25, 28 However, prolonged durability of complete cytogenetic response associated with achieving major molecular response has been confirmed. In an analysis from Hammersmith Hospital of patients with a complete cytogenetic response, only 0% to 3% of patients who achieved a major molecular response at 12 or 18 months subsequently lost their complete cytogenetic response compared with 24% to 25% of patients who did not achieve a major molecular response.21 In a separate analysis, a stable complete cytogenetic response lasting at least 12 months was associated with an improved rate of survival without loss of hematologic or cytogenetic response, transformation to AP/BP, or death from any cause (P < .001).23

Molecular responses at early time points

Regardless of the prognostic importance of obtaining a major molecular response, the probability of achieving such response may be concluded from the depth of molecular response obtained at very early time points during TKI therapy. An analysis of a subset of patients from the IRIS trial showed that those who failed to achieve a 1-log reduction of BCR-ABL1 level (compared with the standardized baseline) by 3 months or a 2-log reduction by 6 months had a significantly lower probability of achieving a major molecular response by 24 months compared with those who achieved these responses. Achieving a 2-log reduction by 6 months also predicted a lower occurrence of events.31 In a single-institution analysis, the probability of achieving a major molecular response after approximately 5 years of follow-up could be predicted using the BCR-ABL1/ABL transcript ratio at 3 months; 84% of patients who had a transcript ratio of >0.1% to 1% achieved a major molecular response, compared with 53% who had a transcript ratio of >1% to 10%, and 33% who had a transcript ratio of >10%. The probabilities of eventually achieving major molecular response based on achieving these BCR-ABL1 transcript ratios at 6 months were 69%, 44%, and 15%, respectively. Median time to major molecular response was also longer in patients with inferior BCR-ABL1 reductions at these time points.32

Competing Risks in Nonresponding Patients: Probability of Response and Risk of Progression

  1. Top of page
  2. Abstract
  3. Predicting Long-Term Outcomes Using Early Responses to First-Line Imatinib Therapy
  4. Competing Risks in Nonresponding Patients: Probability of Response and Risk of Progression
  5. Benefits of Early Switch to Newer BCR-ABL1 Inhibitors
  6. Second-Generation TKIs as First-Line Therapy
  7. Conclusions
  8. FUNDING SOURCES
  9. REFERENCES

It is clear that during imatinib treatment, the proportion of patients who have achieved a response at any time, that is, cumulative response rates, continues to increase during long-term treatment.12, 25 For example, in the imatinib arm of the IRIS study, estimated complete cytogenetic response rates were 69% at 12 months and 87% at 60 months. These rates, however, do not reflect the proportion of patients who remained in complete cytogenetic response at 60 months (65%-67%); annual rates of treatment failure during years 1 through 4 after complete cytogenetic response had been achieved were in 5.5%, 2.3%, 1.1%, and 0.4%, respectively.12 These data suggest that 80% of patients who are destined to achieve a complete cytogenetic response on imatinib do so within the first 12 months of treatment. Similar cumulative increases in major molecular response rates over time have also been reported.25, 33

An analysis by The University of Texas MD Anderson Cancer Center examined the long-term outcomes of patients with CML-CP who did not achieve complete cytogenetic response and/or major molecular response during the first 12 months of treatment.32 Patients who had not achieved complete cytogenetic response after 3, 6, or 12 months of imatinib therapy exhibited a trend toward higher rates of events (loss or response, disease transformation, or death) over time. In parallel, the probability of achieving a complete cytogenetic response significantly decreased, as did the probability of reaching major molecular response (Table 3). At 3 and 6 months, the probability of achieving complete cytogenetic response remained greater than the probability of an event occurring (P < .001), whereas at 12 months, nonresponding patients had similar probabilities of eventually achieving a complete cytogenetic response or experiencing an event (42% vs 38%; P = .15). Furthermore, the risks of achieving a complete cytogenetic response or major molecular response, or having an event can be concluded from the level of BCR-ABL1 transcripts measured at early time points during imatinib therapy. Patients with the lowest levels of BCR-ABL1 transcripts at 3, 6, and 12 months had a higher probability of achieving a complete cytogenetic response and major molecular response and the lowest probability of having an event (Table 4).

Table 3. Outcome of Patients in CCyR and Not in CCyR at Specific Time Points During Imatinib Therapy32
Months on TreatmentPatients in CCyR (%)Patients Not in CCyR (%)Percentage Eventually Achieving Outcome if Not in CCyR at Specified Time
CCyRMMREvent
  1. Abbreviations: CCyR, complete cytogenetic response; MMR, major molecular response.

3143 (56)109 (43)756223
6190 (79)47 (20)574334
12200 (85)26 (12)423138
P value  .002.0040.16
Table 4. Probability of Achieving Major Molecular Response and the Risk of Developing a Progression Event According to the Reduction of BCR-ABL1 Transcripts at Fixed Time Points32
BCR-ABL1:ABL Transcript RatioPercentage Probability of Outcome According to Transcript Ratio at Specified Time Points (Median Months to Outcome)
MMR (BCR-ABL1:ABL <0.05%)Event
3 Months6 Months12 Months3 Months6 Months12 Months
≤0.1%100 (3)96 (6)97 (12)4 (13)1 (38)3 (40)
>0.1%-1%84 (6)69 (12)61 (18)3 (46)7 (30)2 (48)
>1%-10%53 (17)44 (18)20 (33)11 (21)9 (34)8 (47)
>10%33 (15)15 (18)7 (46)13 (47)23 (14)50 (19)

It can be hypothesized that the increasing risk of events in nonresponding patients over time may be a consequence of continuous unopposed BCR-ABL1 activity, which can result in genomic instability and may lead to advanced phases of CML.34 Not surprisingly, patients who achieve undetectable levels of BCR-ABL1 have a negligible risk of disease progression.12, 13

Overall, clinical data indicate that first-line treatment should not be continued indefinitely in nonresponding patients in the hope that treatment goals will be achieved eventually, thus supporting the use of response milestones during therapy, such as those established by the European LeukemiaNet guidelines.6

Benefits of Early Switch to Newer BCR-ABL1 Inhibitors

  1. Top of page
  2. Abstract
  3. Predicting Long-Term Outcomes Using Early Responses to First-Line Imatinib Therapy
  4. Competing Risks in Nonresponding Patients: Probability of Response and Risk of Progression
  5. Benefits of Early Switch to Newer BCR-ABL1 Inhibitors
  6. Second-Generation TKIs as First-Line Therapy
  7. Conclusions
  8. FUNDING SOURCES
  9. REFERENCES

For patients who fail imatinib, follow-up treatment options include second-generation BCR-ABL1 inhibitors (dasatinib or nilotinib), or in good candidates, allogeneic stem cell transplantation.6 The timing of the switch to second-generation TKIs upon failure of imatinib therapy has been shown to affect long-term treatment outcome. A single-institution analysis found that patients who received dasatinib or nilotinib after cytogenetic relapse on imatinib had higher survival rates than patients who were treated after hematologic relapse (3-year survival of 92% vs 52%).22 This observation was investigated in more detail in a retrospective analysis of patients in 3 clinical trials of dasatinib who had previously experienced loss of response on imatinib. Patients were grouped according to whether they received dasatinib after loss of cytogenetic response on imatinib (earlier intervention) or after loss of both cytogenetic and hematologic response on imatinib (later intervention). During dasatinib treatment, complete cytogenetic response was achieved by 72% of patients with earlier intervention compared with loss of 42% of patients with later intervention. Respective 2-year rates of survival without transformation to AP/BP, loss of complete hematologic response or major cytogenetic response, and increased white cell count were 89% versus 29%, and rates of survival without transformation to AP/BP were 98% versus 93%.35 These data suggest that continuing imatinib treatment until hematologic relapse in patients who have already experienced cytogenetic relapse is associated with worse outcomes on subsequent treatment, supporting earlier treatment switch in patients failing TKI therapy. This analysis refers to patients who have experienced failure on therapy. Whether interventions such as dose increase or change of therapy alter the outcome of patients who have only a suboptimal response has not been documented.

Second-Generation TKIs as First-Line Therapy

  1. Top of page
  2. Abstract
  3. Predicting Long-Term Outcomes Using Early Responses to First-Line Imatinib Therapy
  4. Competing Risks in Nonresponding Patients: Probability of Response and Risk of Progression
  5. Benefits of Early Switch to Newer BCR-ABL1 Inhibitors
  6. Second-Generation TKIs as First-Line Therapy
  7. Conclusions
  8. FUNDING SOURCES
  9. REFERENCES

Dasatinib and nilotinib, 2 agents with increased inhibitory activity against BCR-ABL1 kinase, have been approved for the treatment of CML after failure of imatinib therapy. Dasatinib is 325-fold more potent than imatinib against unmutated BCR-ABL1 in vitro.36 Dasatinib has a chemical structure unrelated to that of imatinib and binds to BCR-ABL1 at a different although overlapping binding site.37 Nilotinib is 20-fold more potent than imatinib in vitro. Nilotinib was developed by modifying the chemical structure of imatinib and therefore binds to a binding site nearly identical to the imatinib binding site within BCR-ABL1, albeit with an improved topological fit.36, 38 After the demonstration of the efficacy of dasatinib and nilotinib in patients with resistance or intolerance to imatinib,39 early single-arm trials assessed the activity of these agents in the frontline setting. These trials found that first-line treatment with dasatinib or nilotinib resulted in higher rates of complete cytogenetic response and major molecular response at early time points relative to historical data for imatinib.40-42

Recently, primary data have been published from 2 randomized multicenter phase 3 trials comparing the activity of either dasatinib or nilotinib with that of imatinib as first-line treatment for patients with newly diagnosed CML-CP. In the ENESTnd trial (Evaluating Nilotinib Efficacy and Safety in clinical Trials of Newly Diagnosed Ph+ CML patients), 2 different doses of nilotinib were assessed (300 mg twice daily and 400 mg twice daily). The primary endpoint was the major molecular response rate at 12 months.17 At 12 months, major molecular response rates for nilotinib (44% with 300 mg twice daily, 43% with 400 mg twice daily) were significantly higher than those achieved with imatinib treatment (22%; P < .001 vs both nilotinib arms). In addition, complete cytogenetic response rates by 12 months were also significantly higher for the nilotinib arms compared with imatinib (80% for nilotinib 300 mg twice daily, 78% for nilotinib 400 mg twice daily, 65% for imatinib; both P < .001). Complete cytogenetic response rates at 6 months showed a similar trend (67% vs 63% vs 45%, respectively). Kaplan-Meier analysis showed that in the total group, median time to major molecular response was 8.6 months with nilotinib 300 mg, 11.0 months with nilotinib 400 mg, and not reached with imatinib. Rates of BCR-ABL1 transcript reduction to 0.0032% or less (the limit of sensitivity of the PCR assay) by data cutoff were 13%, 12%, and 4%, respectively. Improvements were seen in rates of transformation to AP/BP for patients who received nilotinib compared with those who received imatinib (<1% with nilotinib 300 mg and 400 mg vs 4% with imatinib; P = .01 and P = .004, respectively, based on an analysis of time to transformation to AP/BP). The benefit of achieving a major molecular response was demonstrated in both the nilotinib and the dasatinib trials, in which no patient who had achieved major molecular response progressed to AP/BP at last follow-up.

In the DASISION trial (Dasatinib vs Imatinib Study in Treatment-Naive CML Patients), complete cytogenetic response and major molecular response rates by 12 months were significantly higher with dasatinib 100 mg once daily compared with imatinib 400 mg once daily (complete cytogenetic response: 83% vs 72%, P = .0011; major molecular response: 46% vs 28%, P < .0001).16 The primary study endpoint, rate of confirmed complete cytogenetic response by 12 months (defined as complete cytogenetic response detected on 2 consecutive assessments), was also significantly superior with dasatinib compared with imatinib (77% vs 66%, respectively; P = .0067). Furthermore, patients who received dasatinib reached complete cytogenetic response and major molecular response faster than those who received imatinib. At 3 months, complete cytogenetic response rates were 54% with dasatinib versus 31% with nilotinib, increasing to 73% versus 59%, respectively, at 6 months. Kaplan-Meier analyses of time to response showed that patients in the dasatinib arm had an approximate 50% increase in probability of complete cytogenetic response and 100% increase in probability of major molecular response at any time compared with imatinib (hazard ratios were 1.5 for complete cytogenetic response and 2.0 for major molecular response; both P < .0001).16 Among the subgroup of patients who achieved major molecular response, median time to major molecular response was 6.3 months for dasatinib and 9.2 months for imatinib. At last follow-up, 1.9% of patients who received dasatinib and 3.5% of those who received imatinib had progressed to AP/BP.16

These results led to the US Food and Drug Administration and European approval in 2010 of nilotinib 300 mg twice daily and dasatinib 100 mg once daily for first-line treatment of newly diagnosed CML-CP. Overall, the results reported by the ENESTnd and DASISION studies suggest that frontline therapy with second-generation TKIs produces higher rates of cytogenetic and molecular responses compared with standard-dose imatinib, and that these responses are achieved at earlier time points. On the basis of data derived from the IRIS trial highlighting the prognostic importance of achieving early complete cytogenetic response and major molecular response, it is reasonable to expect that the use of nilotinib or dasatinib in the frontline setting might render higher rates of EFS and transformation-free survival, but this remains to be proven. Whether the latter translate into improved OS remains to be determined, and longer-term follow-up is needed to confirm these predictions.

Conclusions

  1. Top of page
  2. Abstract
  3. Predicting Long-Term Outcomes Using Early Responses to First-Line Imatinib Therapy
  4. Competing Risks in Nonresponding Patients: Probability of Response and Risk of Progression
  5. Benefits of Early Switch to Newer BCR-ABL1 Inhibitors
  6. Second-Generation TKIs as First-Line Therapy
  7. Conclusions
  8. FUNDING SOURCES
  9. REFERENCES

Long-term follow-up of patients treated with imatinib for CML-CP indicates that early achievement of complete cytogenetic response or major molecular response during first-line therapy is a favorable predictive factor and is associated with prolonged protection against transformation to AP/BP. This benefit of early response can be seen within the first few months after initiation of imatinib treatment. However, in patients who have not achieved these responses, the probability of complete cytogenetic response or major molecular response with imatinib gradually decreases over time with a concurrent increase in the risk of disease progression over time. Landmark analyses have demonstrated that achieving a complete cytogenetic response by 12 months is associated with improved transformation-free survival and EFS, and although analyses of major molecular response have been inconsistent, available data also suggest that patients who achieve an major molecular response by 18 months are more likely to have a favorable EFS compared with those failing to achieve such response. It might be predicted that newer agents that are able to provide higher rates of earlier complete cytogenetic response or major molecular response are also likely to provide a long-term benefit. Whether this is confirmed with additional follow-up will likely depend on whether superior response rates observed with early treatment are maintained with longer follow-up. In the TOPS trial, improved response rates at 6 months but not at 12 months during imatinib treatment did not result in improved 24-month rate of survival without transformation to AP/BP. Lastly, it must be noted that given the very high rates of EFS, transformation-free survival, and OS reported in the 8-year update of the IRIS trial with the use of imatinib 400 mg daily and the available effective salvage therapy for patients who develop resistance to imatinib, any potential improvement on such metrics derived from the use of second-generation TKIs in the frontline setting may require a very long follow-up time for it to be detected.

FUNDING SOURCES

  1. Top of page
  2. Abstract
  3. Predicting Long-Term Outcomes Using Early Responses to First-Line Imatinib Therapy
  4. Competing Risks in Nonresponding Patients: Probability of Response and Risk of Progression
  5. Benefits of Early Switch to Newer BCR-ABL1 Inhibitors
  6. Second-Generation TKIs as First-Line Therapy
  7. Conclusions
  8. FUNDING SOURCES
  9. REFERENCES

StemScientific, funded by Bristol-Myers Squibb, provided writing and editing support. Bristol-Myers Squibb did not influence the content of the article, nor did the authors receive financial compensation for authoring the article. The authors take full responsibility for the content of this article and confirm that it reflects their viewpoint and medical expertise.

CONFLICT OF INTEREST DISCLOSURES

Drs Cortes and Kantarjian have received research support from Novartis and Bristol-Myers Squibb.

REFERENCES

  1. Top of page
  2. Abstract
  3. Predicting Long-Term Outcomes Using Early Responses to First-Line Imatinib Therapy
  4. Competing Risks in Nonresponding Patients: Probability of Response and Risk of Progression
  5. Benefits of Early Switch to Newer BCR-ABL1 Inhibitors
  6. Second-Generation TKIs as First-Line Therapy
  7. Conclusions
  8. FUNDING SOURCES
  9. REFERENCES
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