Chronic myeloid leukemia (CML) is caused by formation of the BCR–ABL1 fusion protein. Tyrosine kinase inhibitors (TKI) that target BCR–ABL1 are now the standard of care for patients with CML. Molecular monitoring of residual BCR–ABL1 mRNA transcripts, typically performed using real-time quantitative PCR, has improved treatment management, particularly for patients with CML in chronic phase. Major molecular response (MMR; i.e., a ≥3-log reduction in BCR–ABL1 transcript levels) is used in current treatment guidelines to assess prognosis. Recent evidence suggests that deeper molecular responses (≥4-log reductions in BCR–ABL1 transcript levels), particularly when attained early during treatment, may have even better correlation with long-term outcomes, including survival and disease progression. Furthermore, achieving deep molecular response is a requirement for entering trials evaluating treatment-free remission (TFR). In this review, we discuss the evolving definition of minimal residual disease and the various levels of molecular response under evaluation in current clinical studies. In addition, the available clinical data on achieving MMR and deeper levels of molecular response with TKI therapy, the prognostic value of deep molecular response, and factors that may predict a patient's ability to achieve and sustain a deep molecular response on TKI therapy are also discussed. Available data from TFR studies are addressed. We discuss current knowledge of the ideal conditions for attempting treatment discontinuation, factors predictive of molecular relapse, when TKI therapy should be restarted, and which therapeutic strategies (when administered in the first-line setting and beyond) are expected to best enable successful TFR. Clin Cancer Res; 20(2); 310–22. ©2013 AACR.

Dysregulated protein tyrosine kinase (PTK) activity is the hallmark of multiple neoplasms (1). Over the past decade, a broad array of drugs designed to selectively inhibit PTKs [i.e., tyrosine kinase inhibitors, (TKI)] have emerged as novel therapies for patients with cancer (2). Perhaps the most well-known PTK target to date is the BCR–ABL1 oncoprotein, which is critical to the pathogenesis of chronic myeloid leukemia (CML; ref. 3). The successful treatment of patients with CML with the BCR–ABL1 TKI imatinib has definitively validated this therapeutic strategy and established CML as a model disease for targeted cancer treatment (4).

With over a decade of imatinib use as first-line therapy in patients with CML, surrogate markers that strongly correlate with prognosis have been identified (5). The validation of surrogate endpoints for treatment effectiveness, such as complete hematologic response (CHR) and complete cytogenetic response (CCyR), has improved treatment management (6, 7). Most patients, particularly those with CML in chronic phase (CML-CP), will achieve these endpoints on a BCR–ABL1 TKI (8–10). The progress of molecular biology has presented the opportunity to look beyond CHR and CCyR and monitor residual disease on a molecular level (11, 12). Current clinical practice recommendations for CML advocate monitoring patients for hematologic response (i.e., blood counts returning to normal values), cytogenetic response (i.e., disappearance of the Philadelphia chromosome), and molecular response (i.e., reduction in BCR–ABL1 gene expression; refs. 6 and 7). Molecular monitoring is typically performed using real-time quantitative PCR (RQ-PCR), a simple technique that can be performed on peripheral blood samples and is both more sensitive and more convenient than conventional cytogenetics (13). The first level of response evaluated on the molecular scale, a major molecular response (MMR), corresponds to a 3-log reduction in BCR–ABL1 transcript levels from a standardized baseline (≤0.1% BCR–ABL1 on the International Scale [BCR–ABL1IS]; refs. 11 and 14). MMR has been found to be associated with improved progression-free survival (PFS; refs. 15 and 16) and event-free survival (EFS; refs. 17–19), although its prognostic value is still debated.

The European LeukemiaNet (ELN) defines response to TKI therapy based on molecular and cytogenetic milestones achieved at 3, 6, and 12 months, or beyond (6). The ELN recommends evaluating molecular response using buffy coat from peripheral blood every 3 months until MMR is achieved, and then every 3 to 6 months. Cytogenetic response should be assessed using bone marrow at 3, 6, and 12 months, and then every 12 months once CCyR is achieved. Some patients (e.g., patients with monosomy 7, del[7q] or clonal chromosomal abnormalities) may require additional long-term bone marrow follow-up.

Until recently, deep molecular responses beyond the level of MMR have remained largely unexplored, given a lack of standardized assay techniques (20). Several recent studies have demonstrated that some patients with such responses can achieve treatment-free remission (TFR), thereby challenging the dogma that CML cannot be cured without allogeneic bone marrow transplantation (21, 22). The overall goals of therapy in CML—disease remission, reduced risk of progression, and improved overall survival (OS)—are clear; however, many questions remain about the impact of molecular response on achieving these goals. Recent data, to be discussed herein, suggest that in select populations, obtaining a deep molecular response should be considered a primary therapeutic goal.

The development of the International Scale for BCR–ABL1 RQ-PCR assessment has enabled quantification of molecular response in relation to a standardized baseline (14, 23). The definition of MMR as BCR–ABL1IS ≤0.1% originates from the International Randomized Study of Interferon Versus STI571 (IRIS; ref. 15). However, standardization of deeper levels of molecular response has proven less straightforward and is urgently needed to facilitate improved interpretation of clinical results. Deeper levels of molecular response may also be defined according to the International Scale, wherein MR4 indicates ≥4.0-log reduction (BCRABL1IS ≤0.01%), MR4.5 indicates ≥4.5-log reduction (BCR–ABL1IS ≤0.0032%), and MR5 indicates ≥5.0-log reduction (BCR–ABL1IS ≤ 0.001%; Fig. 1; ref. 11). However, the observation of undetectable BCR–ABL1 transcripts is inherently linked to the sensitivity of the PCR method, as well as the control gene, used. An ongoing European Treatment and Outcome Study (EUTOS) collaboration aims to facilitate standardization of deep molecular response across laboratories by establishing recommendations for response definitions and quality control (11).

Figure 1.

Levels of molecular response in CML. MCyR, major cytogenetic response; MR, molecular response.

Figure 1.

Levels of molecular response in CML. MCyR, major cytogenetic response; MR, molecular response.

Close modal

Varying definitions of complete molecular response (CMR) have been reported. For example, the National Comprehensive Cancer Network (7) defines CMR as “no detectable BCR–ABL1 chimeric mRNA as assessed by RQ-PCR using the International Scale with a sensitivity of 4.5-log reduction or more from the standardized baseline,” whereas the ELN (6) recommends using the term “molecularly undetectable leukemia” instead of “CMR” and notes the importance of specifying control gene copy number when reporting this level of response. Undetectable minimal residual disease indicates a negative RQ-PCR result and must be associated with a defined PCR assay sensitivity; however, leukemic cells may still be present even if RQ-PCR results are negative (24). Notably, current RQ-PCR methodology is largely optimized for detection of so-called “typical” BCR–ABL1 transcripts, or those involving the major breakpoint cluster region, and may fail to detect atypical transcripts derived from other breakpoints (25); thus, assessment of transcript type at baseline is essential to ensure accurate interpretation of RQ-PCR results.

Deep molecular responses have been assessed in multiple ongoing clinical trials of TKIs in patients with newly diagnosed CML-CP (Table 1). Given the current lack of standardization of PCR sensitivity, rates of CMR reported in these studies are not necessarily comparable. Discrepancies in rates of deep molecular response may also result from differences in assay techniques or study design. For example, PCR may be assessed using blood or bone marrow, and response may be defined by a PCR result at a single time point or confirmed by multiple samples. Other variables include the study population (e.g., the proportion of high-risk patients), median follow-up at time of analysis, and type and dose of TKI therapy received. Although several studies have shown that imatinib can elicit deep molecular responses in some patients, second-generation TKIs, such as nilotinib and dasatinib, have demonstrated higher rates of deep molecular response attained within shorter time periods (Table 1). The combination of TKI therapy with interferon (IFN), which may help drive leukemic stem cells (LSC) into the cell cycle (26), thereby inducing deep molecular response, has also been explored. Rates of deep molecular response were higher with this combination versus imatinib alone in one study using pegylated IFN (26), but similar in another study using IFN-α (Table 1; ref. 27).

Table 1.

Clinical trials of TKI therapy reporting deep molecular responses (MR4 or deeper) occurring in patients with newly diagnosed CML-CP

TrialSamples, naAssay sensitivity (IS standardized?)Median f/u, moTreatment→MR endpoints assessed
IRIS (15, 24) ≥4.5 logs (established the IS) 25 IM 400 mg qd (n = 333) → CMR at 12 mo = 4%b 
   81 IM 400 mg qd (n = 29c) → MR4/MR4.5 by 81 mo = 70%/52%. MR4.5 at 81 mo = 45% 
ID-01_151 (66) ≥5 logs (No) 15 IM 400 mg b.i.d. (n = 112) → CMR = 28% 
de Lavallade et al. (67) ≥2 consecutive NR (Yes) 38 IM 400 mg qd (n = 204d) → CMR = 5% 
RIGHT (68) ≥4.5 logs (Noe17f IM 400 mg b.i.d. (n = 115) → CMR by 6, 12, 18 mo = 39%, 44%, 55% 
Verma et al. (29) ≥4.5 logs (NR) 65 IM 400 mg qd (n = 73) or 800 mg qd (n = 208) → CMR = 44% 
SPIRIT (26) g(Yes) 47h IM 400 mg qd (n = 159) → MR4 at 12, 24 mo = 14%, 21%. CMR at 24 mo = 9% 
    IM 400 mg qd + AraC (n = 158) → MR4 at 12, 24 mo = 15%, 26%. CMR at 24 mo = 8% 
    IM 400 mg qd + PEG-IFN (n = 159) → MR4 at 12, 24 mo = 30%, 38%. CMR at 24 mo = 16% 
    IM 600 mg qd (n = 160) → MR4 at 12, 24 mo = 17%, 26%. CMR at 24 mo = 8% 
CML Study IV (27) NR (Yes) 43 IM 400 mg qd (n = 324) → MR4 by 12, 24, 36 mo = 8%, 31%, 46% 
   48 IM 400 mg qd + IFN-α (n = 350) → MR4 by 12, 24, 36 mo = 12%, 30%, 41% 
   28 IM 800 mg qd (n = 338) → MR4 by 12, 24, 36 mo = 20%, 43%, 57% 
ENESTnd (10) i(Yes) Min 36 NIL 300 mg b.i.d. (n = 282) → MR4 by 1, 3 y = 20%, 50%. MR4.5 by 1, 3 y = 11%, 32% 
    NIL 400 mg b.i.d. (n = 281) → MR4 by 1, 3 y = 15%, 44%. MR4.5 by 1, 3 y = 7%, 28% 
    IM 400 mg qd (n = 283) → MR4 by 1, 3 y = 6%, 26%. MR4.5 by 1, 3 y = 1%, 15% 
ENEST1st (69) NR (Yes) 6.5f NIL 300 mg b.i.d. (n = 205) → MR4 by 3, 6 mo = 5%, 20% 
GIMEMA (70, 71) 1; stable, 3 × 4 mo apart ≥4 logs (Yes) 48 NIL 400 mg b.i.d. (n = 73) → MR4 at 12, 24, 36 mo = 12%, 27%, 25% 
   51 NIL 400 mg b.i.d. (n = 73) → Stable MR4 = 25% 
MDACC NIL phase II (72) ≥5 logs (Yes) 17.3 NIL 400 mg b.i.d. (n = 51) → CMR by 6, 12, 30 mo = 4%, 11%, 15% 
Nicolini et al. (73) NR (Yes) 13.6 NIL 300 mg b.i.d. + PEG-IFN (n = 40) → MR4 at 6, 12, 15 mo = 23%, 57%, 80%. MR4.5 at 6, 12, 15 mo = 10%, 21%, 50%. MR5 at 6, 12, 15 mo = 10%, 15%, 40% 
DASISION (9) NR (Yes) Min 24 DAS 100 mg qd (n = 259) → MR4.5 by 2 y = 17% 
    IM 400 mg qd (n = 260) → MR4.5 by 2 y = 8% 
S0325 (74) NR (j36 DAS 100 mg qd (n = 99) → MR4/MR4.5 at 1 y = 27%/21% 
    IM 400 mg qd (n = 91) → MR4/MR4.5 at 1 y = 21%/15% 
MDACC DAS phase II (75) ≥5 logs (Yes) 24 DAS 100 mg qd or 50 mg b.i.d. (n = 50) → CMR at 6, 12, 30 mo = 0%, 7%, 0% 
BELA (76) ≥4 logs (Yes) 13.8f BOS 500 mg qd (n = 250) → MR4 at 12 mo = 12% 
    IM 400 mg qd (n = 252) → MR4 at 12 mo = 3% 
TrialSamples, naAssay sensitivity (IS standardized?)Median f/u, moTreatment→MR endpoints assessed
IRIS (15, 24) ≥4.5 logs (established the IS) 25 IM 400 mg qd (n = 333) → CMR at 12 mo = 4%b 
   81 IM 400 mg qd (n = 29c) → MR4/MR4.5 by 81 mo = 70%/52%. MR4.5 at 81 mo = 45% 
ID-01_151 (66) ≥5 logs (No) 15 IM 400 mg b.i.d. (n = 112) → CMR = 28% 
de Lavallade et al. (67) ≥2 consecutive NR (Yes) 38 IM 400 mg qd (n = 204d) → CMR = 5% 
RIGHT (68) ≥4.5 logs (Noe17f IM 400 mg b.i.d. (n = 115) → CMR by 6, 12, 18 mo = 39%, 44%, 55% 
Verma et al. (29) ≥4.5 logs (NR) 65 IM 400 mg qd (n = 73) or 800 mg qd (n = 208) → CMR = 44% 
SPIRIT (26) g(Yes) 47h IM 400 mg qd (n = 159) → MR4 at 12, 24 mo = 14%, 21%. CMR at 24 mo = 9% 
    IM 400 mg qd + AraC (n = 158) → MR4 at 12, 24 mo = 15%, 26%. CMR at 24 mo = 8% 
    IM 400 mg qd + PEG-IFN (n = 159) → MR4 at 12, 24 mo = 30%, 38%. CMR at 24 mo = 16% 
    IM 600 mg qd (n = 160) → MR4 at 12, 24 mo = 17%, 26%. CMR at 24 mo = 8% 
CML Study IV (27) NR (Yes) 43 IM 400 mg qd (n = 324) → MR4 by 12, 24, 36 mo = 8%, 31%, 46% 
   48 IM 400 mg qd + IFN-α (n = 350) → MR4 by 12, 24, 36 mo = 12%, 30%, 41% 
   28 IM 800 mg qd (n = 338) → MR4 by 12, 24, 36 mo = 20%, 43%, 57% 
ENESTnd (10) i(Yes) Min 36 NIL 300 mg b.i.d. (n = 282) → MR4 by 1, 3 y = 20%, 50%. MR4.5 by 1, 3 y = 11%, 32% 
    NIL 400 mg b.i.d. (n = 281) → MR4 by 1, 3 y = 15%, 44%. MR4.5 by 1, 3 y = 7%, 28% 
    IM 400 mg qd (n = 283) → MR4 by 1, 3 y = 6%, 26%. MR4.5 by 1, 3 y = 1%, 15% 
ENEST1st (69) NR (Yes) 6.5f NIL 300 mg b.i.d. (n = 205) → MR4 by 3, 6 mo = 5%, 20% 
GIMEMA (70, 71) 1; stable, 3 × 4 mo apart ≥4 logs (Yes) 48 NIL 400 mg b.i.d. (n = 73) → MR4 at 12, 24, 36 mo = 12%, 27%, 25% 
   51 NIL 400 mg b.i.d. (n = 73) → Stable MR4 = 25% 
MDACC NIL phase II (72) ≥5 logs (Yes) 17.3 NIL 400 mg b.i.d. (n = 51) → CMR by 6, 12, 30 mo = 4%, 11%, 15% 
Nicolini et al. (73) NR (Yes) 13.6 NIL 300 mg b.i.d. + PEG-IFN (n = 40) → MR4 at 6, 12, 15 mo = 23%, 57%, 80%. MR4.5 at 6, 12, 15 mo = 10%, 21%, 50%. MR5 at 6, 12, 15 mo = 10%, 15%, 40% 
DASISION (9) NR (Yes) Min 24 DAS 100 mg qd (n = 259) → MR4.5 by 2 y = 17% 
    IM 400 mg qd (n = 260) → MR4.5 by 2 y = 8% 
S0325 (74) NR (j36 DAS 100 mg qd (n = 99) → MR4/MR4.5 at 1 y = 27%/21% 
    IM 400 mg qd (n = 91) → MR4/MR4.5 at 1 y = 21%/15% 
MDACC DAS phase II (75) ≥5 logs (Yes) 24 DAS 100 mg qd or 50 mg b.i.d. (n = 50) → CMR at 6, 12, 30 mo = 0%, 7%, 0% 
BELA (76) ≥4 logs (Yes) 13.8f BOS 500 mg qd (n = 250) → MR4 at 12 mo = 12% 
    IM 400 mg qd (n = 252) → MR4 at 12 mo = 3% 

Abbreviations: AraC, cytarabine; BELA, Bosutinib Efficacy and Safety in Chronic Myeloid Leukemia; b.i.d., twice daily; BOS, bosutinib; DAS, dasatinib; DASISION, Dasatinib Versus Imatinib Study in Treatment-Naive CML patients; ENEST1st, Evaluating Nilotinib Efficacy and Safety in Clinical Trials as First-Line Treatment; ENESTnd, Evaluating Nilotinib Efficacy and Safety in Clinical Trials–Newly Diagnosed Patients; f/u, follow-up; GIMEMA, Gruppo Italiano Malattie Ematologiche dell'Adulto; IM, imatinib; IRIS, International Randomized Interferon Versus STI571; IS, International Scale; MDACC, MD Anderson Cancer Center; min, minimum; MR, molecular response; NIL, nilotinib; NR, not reported; qd, daily; PEG-IFN, pegylated interferon α-2a; qd, once daily; RIGHT, Rationale and Insight for Gleevec High-Dose Therapy; SPIRIT, STI571 Prospective Randomized Trial; SWOG, Southwest Oncology Group.

aNumber of samples required to meet criteria for response.

bPatients with CCyR only.

cSubgroup analysis of patients enrolled in the IRIS study in Australia and New Zealand from June 2000 to February 2007.

dNote: 17 of these patients were also in the IRIS study.

eBaseline BCR–ABL1/ABL1 ratio based on prestudy samples from participating laboratory.

fMedian exposure.

g≥25,000 copies of ABL were required for a sample to be considered adequate.

hFor all patients; 48 mo for patients alive as of data cutoff.

i≥3,000 copies of ABL were required for a sample to be considered adequate.

jStandardized to SWOG-specific BCR–ABL1 baseline level.

Defining the value of achieving deep molecular response in patients with CML is an active area of ongoing research. There is conflicting evidence about whether achieving an MMR provides additional benefit beyond a CCyR (20). The leukemic cell burden is similar in patients with MMR and CCyR (only 1-log difference in BCR–ABL1 levels), and this difference may be too small to impact long-term outcomes such as PFS and OS. Events like progression or death are quite infrequent with frontline TKI therapy; therefore, long-term follow-up and large cohorts of patients would be required to definitively demonstrate any added benefit to achieving MMR.

However, deeper molecular responses provide more separation from CCyR in terms of residual disease burden; therefore, it may be easier to distinguish the unique benefits of such responses. Patients who achieve deep molecular response seem less likely to lose MMR, and several studies have shown that deep molecular responses correlate with better long-term clinical outcomes, such as EFS, PFS, and OS, and a low risk of progression and disease relapse (Table 2; refs. 28 and 29). For example, a study by Etienne and colleagues (30) found that EFS and PFS were longer in patients with CMR than those with CCyR, regardless of MMR status; OS was not significantly different between these groups. Another study by Falchi and colleagues (31) showed that patients with undetectable BCR-ABL1 levels by 18 or 24 months had 100% rates of OS, EFS, and transformation-free survival (TFS) at 6 years. In the German CML study IV, life expectancy in patients with MR4 or MR4.5 was the same as that in an age-matched population, and only 4 of 792 patients (0.5%) who achieved MR4 had disease progression (32).

Table 2.

Clinical outcomes of patients with newly diagnosed CML-CP who achieved deep molecular responses with TKI therapy

Outcomes for patients with or without deep molecular response, %
Trial descriptionNMedian f/u, moComparatorsEFS ratePFS rateOS rateTFS rate
Etienne et al. (30): first-line IM 400 mg 266 53.2 CCyR + MMR + CMRa CCyR + MMR − CMRa CCyR − MMR 956528 988256 OS was not different among the 3 groups NRNRNR 
Falchi et al. (31): first-line IM (400 mg, n = 83; 800 mg, n = 204), NIL (n = 106), or DAS (n = 102) 495 73 No MR at 18 moMMR at 18 moMR4 at 18 moMR4.5 at 18 moUndetectable BCR-ABLb at 18 moNo MR at 24 moMMR at 24 moMR4 at 24 moMR4.5 at 24 mo 78 (6 y)94 (6 y)97 (6 y)93 (6 y)100 (6 y)80 (6 y)90 (6 y)97 (6 y)95 (6 y) NRNRNRNRNRNRNRNRNR 93 (6 y) 98 (6 y) 97 (6 y) 95 (6 y) 100 (6 y) 92 (6 y) 97 (6 y) 100 (6 y) 97 (6 y) 90 (6 y) 100 (6 y) 100 (6 y) 100 (6 y) 100 (6 y) 90 (6 y) 100 (6 y) 100 (6 y) 100 (6 y) 
   Undetectable BCR-ABLb at 24 mo 100 (6 y) NR 100 (6 y) 100 (6 y) 
CML study IV (32): first-line IM 400 mg, IM 400 mg + IFN-α, IM 400 mg + AraC, IM after IFN-α failure, or IM 800 mg 1,525 67.5 After a median duration of MR4 of 3.7 y, only 4 of 792 patients with CMR4 (0.5%) progressed; life expectancy with MR4 and MR4.5 was identical to that of the age-matched population 
Kantarjian et al. (28): retrospective analysis. IM (400 mg, n = 71; 800 mg, n = 205) 276 48 Durable CMRb (≥6 mo) Nondurable CMRb (<6 mo) NR NR 100 (5 y) 98 (5 y) NR NR NR NR 
Verma et al. (29): retrospective analysis. First-line IM (400 mg, n = 73; 800 mg, n = 208) 281 65 CCyR + MMR + CMRb at 2 y CCyR + MMR − CMRb at 2 y CCyR − MMR − CMRb at 2 y 100 (5 y) 96 (5 y) 86 (5 y) NR NR NR NR NR NR 100 (5 y) 96 (5 y) 91 (5 y) 
Press et al. (77): all patients achieved CCyR on IM and had ≥2 measurements of BCR–ABL1 level after achieving CCyR 90 49 MMR + CMRc MMR − CMRc NR NR Not reachedd 44 mod NR NR NR NR 
Outcomes for patients with or without deep molecular response, %
Trial descriptionNMedian f/u, moComparatorsEFS ratePFS rateOS rateTFS rate
Etienne et al. (30): first-line IM 400 mg 266 53.2 CCyR + MMR + CMRa CCyR + MMR − CMRa CCyR − MMR 956528 988256 OS was not different among the 3 groups NRNRNR 
Falchi et al. (31): first-line IM (400 mg, n = 83; 800 mg, n = 204), NIL (n = 106), or DAS (n = 102) 495 73 No MR at 18 moMMR at 18 moMR4 at 18 moMR4.5 at 18 moUndetectable BCR-ABLb at 18 moNo MR at 24 moMMR at 24 moMR4 at 24 moMR4.5 at 24 mo 78 (6 y)94 (6 y)97 (6 y)93 (6 y)100 (6 y)80 (6 y)90 (6 y)97 (6 y)95 (6 y) NRNRNRNRNRNRNRNRNR 93 (6 y) 98 (6 y) 97 (6 y) 95 (6 y) 100 (6 y) 92 (6 y) 97 (6 y) 100 (6 y) 97 (6 y) 90 (6 y) 100 (6 y) 100 (6 y) 100 (6 y) 100 (6 y) 90 (6 y) 100 (6 y) 100 (6 y) 100 (6 y) 
   Undetectable BCR-ABLb at 24 mo 100 (6 y) NR 100 (6 y) 100 (6 y) 
CML study IV (32): first-line IM 400 mg, IM 400 mg + IFN-α, IM 400 mg + AraC, IM after IFN-α failure, or IM 800 mg 1,525 67.5 After a median duration of MR4 of 3.7 y, only 4 of 792 patients with CMR4 (0.5%) progressed; life expectancy with MR4 and MR4.5 was identical to that of the age-matched population 
Kantarjian et al. (28): retrospective analysis. IM (400 mg, n = 71; 800 mg, n = 205) 276 48 Durable CMRb (≥6 mo) Nondurable CMRb (<6 mo) NR NR 100 (5 y) 98 (5 y) NR NR NR NR 
Verma et al. (29): retrospective analysis. First-line IM (400 mg, n = 73; 800 mg, n = 208) 281 65 CCyR + MMR + CMRb at 2 y CCyR + MMR − CMRb at 2 y CCyR − MMR − CMRb at 2 y 100 (5 y) 96 (5 y) 86 (5 y) NR NR NR NR NR NR 100 (5 y) 96 (5 y) 91 (5 y) 
Press et al. (77): all patients achieved CCyR on IM and had ≥2 measurements of BCR–ABL1 level after achieving CCyR 90 49 MMR + CMRc MMR − CMRc NR NR Not reachedd 44 mod NR NR NR NR 

Abbreviations: AraC, cytarabine; DAS, dasatinib; f/u, follow-up; IM, imatinib; MR, molecular response; NIL, nilotinib; NR, not reported.

aCMR was defined as undetectable BCR–ABL1 transcripts with a sensitivity of ≥4.5 logs on 2 consecutive analyses ≥2 mo apart.

bMinimum sensitivity 4.5 logs.

cMinimum sensitivity 4 logs.

dData shown are median relapse-free survival, defined as progression to accelerated phase/blast crisis, loss of complete hematologic response, or loss of CCyR.

These results provide encouraging evidence that achievement of deep molecular response is an important clinical goal and prompt the question: should patients with CCyR, who do not achieve these deep levels of molecular response, be switched to an alternate therapy? The ongoing Evaluating Nilotinib Efficacy and Safety in Clinical Trials–CMR (ENESTcmr) study aims to address this question by randomizing patients with detectable BCR–ABL1 transcripts after ≥2 years on imatinib to either continue on imatinib or switch to nilotinib (33). After 12 and 24 months of follow-up, more patients achieved MR4.5 and undetectable BCR–ABL1 (≥4.5-log RQ-PCR assay sensitivity) on nilotinib compared with continued imatinib (33). Yet perhaps the most convincing reason to strive for sustained deep molecular response in patients with CML-CP is the possibility that it may enable eventual achievement of TFR.

Reports of imatinib discontinuation in patients without sustained deep molecular responses have shown high and rapid rates of disease relapse (34–37). In contrast, a small pilot study of imatinib discontinuation with the stringent entry criteria of sustained CMR for ≥2 years on imatinib showed promising results, with 6 of 12 patients remaining in molecular remission after a median 18 months of follow-up (38). This proof of concept inspired numerous clinical studies of imatinib discontinuation in patients with stable, deep molecular responses on TKI therapy (Table 3). In all cases, many patients were able to remain relapse-free off therapy.

Table 3.

Clinical trials of TKI discontinuation in patients with CML-CP and deep molecular response

TrialTreatment before d/c (response required for d/c)Definition of relapseRelapse-free pts, % (median f/u, mo)Patients responding to TKI after relapse
Trials of IM d/c 
STIM (ref. 40; N = 100) IM for ≥36 mo (MR5 for ≥24 mo) Confirmed loss of MR5 39% (30) 56/61 regained MR5 
ALLG CML8/TWISTER (ref. 55; N = 40) IM for ≥36 mo (MR4.5 for ≥24 mo) Confirmed loss of MR4.5 45% (42) 22/22 regained MMRa 
According to STIM (ref. 41; N = 66) IM for ≥36 mo (MR4.5 for ≥24 mo) Loss of MMR 64% (23) 24/24 regained MMRa 
Korean study (ref. 78; N = 48) IM for ≥36 mo (CMR for ≥24 mo) Confirmed loss of MMR 81% (15.8) 8/9 regained MMRa 
Yhim et al. (ref. 54; N = 14) IM for median 56.4 mo; range, 26.2–82.0 (CMR for ≥12 mo) Confirmed loss of CMR 28.6% at 12 mo (23) 7/10 regained CMR 
Keio STIM (ref. 79; N = 40) IM for median 98 mo; range, 24–126 (UMRDb for ≥24 mo) Loss of UMRDb 55.4% at 12 mo (15.5) 17/18 regained CMR 
Takahashi et al. retrospective analysis (ref. 80; N = 43) IM for median 45.2 mo; range, 4.5–92.7 [UMRD (≥4-log sensitivity) by RQ-PCR, RT-PCR, or TMA] Molecular recurrence after d/c of IM for ≥6 mo 56% (22.4) 17/17 regained MMRa 
STIM 2c (ref. 57; N = 200) IM (MR5 for ≥2 y) Loss of MMR and/or >1-log increase in BCR–ABL1 Study ongoing Study ongoing 
Trials of NIL d/c 
Nilo post-STIMc (ref. 57; N = 70) NIL for ≥2 y in patients who failed TFR in STIM or STIM 2 (confirmed CMR after 2 y of NIL) Loss of MR5 on 2 consecutive assessments Study ongoing Study ongoing 
ENESTFreedomc (ref. 57; N = 175) First-line NIL for ≥2 y and 1 y NIL on study (MR4.5 for ≥1 y) Loss of MMR Study ongoing Study ongoing 
ENESTopc (ref. 57; N = 117) TKI therapy for ≥3 y, including ≥2 y of second-line NIL and 1 y NIL on study (MR4.5 for ≥1 y) Confirmed loss of MR4 or any loss of MMR Study ongoing Study ongoing 
ENESTgoalc (ref. 57; N = 300) IM for ≥1 y and NIL on study (MR4.5 for 1 or 2 y) Confirmed loss of MR4 Study ongoing Study ongoing 
ENESTPathc (ref. 57; N = 1,058) IM for ≥2 y and NIL on study (MR4 for 1 or 2 y) Loss of MR4 Study ongoing Study ongoing 
TIGERc (ref. 57; N = 652) First-line NIL + PEG-IFN-α vs. NIL for ≥2 y on study, then PEG-IFN-α vs. NIL maintenance therapy (stable MR4Loss of MMR Study ongoing Study ongoing 
Trials of DAS d/c 
DASFREEd (57) (N = 75) DAS for ≥2 y (MR4.5 for ≥1 y) Loss of MMR Study ongoing Study ongoing 
Trials of TKI d/c 
STOP 2G-TKI (ref. 42; N = 34) NIL or DAS for ≥36 mo (UMRD for ≥24 mo, with ≥20,000 ABL1 copies) Loss of MMR 58.3% at 12 mo (14) 13/15 regained MMR 
    10/13 regained CMR 
EURO-SKId (ref. 57; N = 500) TKI therapy (first-line or second-line) for ≥3 y (MR4 for ≥1 y) Loss of MMR Study ongoing Study ongoing 
DESTINYd (ref. 57; N = 168) IM, NIL, or DAS for ≥3 y and half-standard dose of TKI for 1 y on study (MMR or MR4 for ≥1 y at therapeutic dose and 1 y at half-standard dose) Loss of MMR Study ongoing Study ongoing 
NCT00573378c (ref. 57; N = 40) NIL or IM for ≥3 y, with stable dose for ≥1 y and same TKI + PEG-IFN-α for 2 y on study (NR) NR Study ongoing Study ongoing 
TrialTreatment before d/c (response required for d/c)Definition of relapseRelapse-free pts, % (median f/u, mo)Patients responding to TKI after relapse
Trials of IM d/c 
STIM (ref. 40; N = 100) IM for ≥36 mo (MR5 for ≥24 mo) Confirmed loss of MR5 39% (30) 56/61 regained MR5 
ALLG CML8/TWISTER (ref. 55; N = 40) IM for ≥36 mo (MR4.5 for ≥24 mo) Confirmed loss of MR4.5 45% (42) 22/22 regained MMRa 
According to STIM (ref. 41; N = 66) IM for ≥36 mo (MR4.5 for ≥24 mo) Loss of MMR 64% (23) 24/24 regained MMRa 
Korean study (ref. 78; N = 48) IM for ≥36 mo (CMR for ≥24 mo) Confirmed loss of MMR 81% (15.8) 8/9 regained MMRa 
Yhim et al. (ref. 54; N = 14) IM for median 56.4 mo; range, 26.2–82.0 (CMR for ≥12 mo) Confirmed loss of CMR 28.6% at 12 mo (23) 7/10 regained CMR 
Keio STIM (ref. 79; N = 40) IM for median 98 mo; range, 24–126 (UMRDb for ≥24 mo) Loss of UMRDb 55.4% at 12 mo (15.5) 17/18 regained CMR 
Takahashi et al. retrospective analysis (ref. 80; N = 43) IM for median 45.2 mo; range, 4.5–92.7 [UMRD (≥4-log sensitivity) by RQ-PCR, RT-PCR, or TMA] Molecular recurrence after d/c of IM for ≥6 mo 56% (22.4) 17/17 regained MMRa 
STIM 2c (ref. 57; N = 200) IM (MR5 for ≥2 y) Loss of MMR and/or >1-log increase in BCR–ABL1 Study ongoing Study ongoing 
Trials of NIL d/c 
Nilo post-STIMc (ref. 57; N = 70) NIL for ≥2 y in patients who failed TFR in STIM or STIM 2 (confirmed CMR after 2 y of NIL) Loss of MR5 on 2 consecutive assessments Study ongoing Study ongoing 
ENESTFreedomc (ref. 57; N = 175) First-line NIL for ≥2 y and 1 y NIL on study (MR4.5 for ≥1 y) Loss of MMR Study ongoing Study ongoing 
ENESTopc (ref. 57; N = 117) TKI therapy for ≥3 y, including ≥2 y of second-line NIL and 1 y NIL on study (MR4.5 for ≥1 y) Confirmed loss of MR4 or any loss of MMR Study ongoing Study ongoing 
ENESTgoalc (ref. 57; N = 300) IM for ≥1 y and NIL on study (MR4.5 for 1 or 2 y) Confirmed loss of MR4 Study ongoing Study ongoing 
ENESTPathc (ref. 57; N = 1,058) IM for ≥2 y and NIL on study (MR4 for 1 or 2 y) Loss of MR4 Study ongoing Study ongoing 
TIGERc (ref. 57; N = 652) First-line NIL + PEG-IFN-α vs. NIL for ≥2 y on study, then PEG-IFN-α vs. NIL maintenance therapy (stable MR4Loss of MMR Study ongoing Study ongoing 
Trials of DAS d/c 
DASFREEd (57) (N = 75) DAS for ≥2 y (MR4.5 for ≥1 y) Loss of MMR Study ongoing Study ongoing 
Trials of TKI d/c 
STOP 2G-TKI (ref. 42; N = 34) NIL or DAS for ≥36 mo (UMRD for ≥24 mo, with ≥20,000 ABL1 copies) Loss of MMR 58.3% at 12 mo (14) 13/15 regained MMR 
    10/13 regained CMR 
EURO-SKId (ref. 57; N = 500) TKI therapy (first-line or second-line) for ≥3 y (MR4 for ≥1 y) Loss of MMR Study ongoing Study ongoing 
DESTINYd (ref. 57; N = 168) IM, NIL, or DAS for ≥3 y and half-standard dose of TKI for 1 y on study (MMR or MR4 for ≥1 y at therapeutic dose and 1 y at half-standard dose) Loss of MMR Study ongoing Study ongoing 
NCT00573378c (ref. 57; N = 40) NIL or IM for ≥3 y, with stable dose for ≥1 y and same TKI + PEG-IFN-α for 2 y on study (NR) NR Study ongoing Study ongoing 

Abbreviations: ALLG, Australasian Leukaemia and Lymphoma Group; DAS, dasatinib; d/c, discontinuation; f/u, follow-up; IM, imatinib; MR, molecular response; NIL, nilotinib; NR, not reported; PEG-IFN-α, pegylated interferon-α; RT-PCR, nested reverse transcriptase PCR; TMA, transcription-mediated amplification; UMRD, undetectable minimal residual disease.

aPatients achieved this level of response or better.

bUMRD defined as <100 copies by TMA; thus, loss of UMRD was >100 copies by TMA.

cCurrently recruiting participants.

dNot yet recruiting participants.

Importantly, molecular relapse, the trigger for reintroduction of TKI therapy in these studies, was often defined differently. For example, in the Stop Imatinib (STIM) study, molecular relapse was defined as positive RQ-PCR results on 2 consecutive assessments (39, 40), whereas in the STIM study, molecular relapse was less stringently defined as loss of MMR at any time (41). In According to STIM, all 24 patients who relapsed regained a response of MMR or better once imatinib was reintroduced (41); therefore, waiting until a patient loses MMR to reinitiate TKI therapy does not seem to be detrimental. This suggests that BCR–ABL1 positivity after TKI cessation does not necessarily equal disease relapse (22). However, the optimal molecular response threshold for triggering restart of TKI therapy remains to be established.

Data on discontinuation of second-generation TKIs are limited; however, the ongoing STOP 2G-TKI study has shown similar results to those of imatinib discontinuation trials (Table 3; ref. 42). Thus, available results suggest that stopping TKI therapy in patients with sustained deep molecular response can be safe and associated with prolonged TFR. Given the preliminary nature of available clinical data on TFR, both the ELN and the National Comprehensive Cancer Network currently recommend that patients remain on TKI therapy indefinitely and that TKI discontinuation only be attempted in controlled clinical trials (6, 7).

Achievement of BCR–ABL1IS ≤10% at 3 or 6 months after initiating first-line imatinib has been shown to be predictive of long-term molecular response and improved outcomes (19, 43, 44), whereas delayed cytogenetic and molecular response on imatinib is associated with increased risk of progression (45). Landmark studies of second-generation TKIs have found BCR–ABL1 levels at 3 months to be similarly predictive (46, 47). A retrospective analysis of patients treated with second-line nilotinib, dasatinib, or bosutinib found that BCR–ABL1IS ≤10% at 3 months from start of second-line treatment was associated with significantly higher cumulative incidence of MMR and CMR and improved OS, PFS, and EFS (48). An online database of patients with CML-CP treated with first-line imatinib in Japan found that patients with an MMR at 12 months were significantly more likely than those without to achieve undetectable BCR–ABL1 transcripts by 72 months (49). Another study found a similar association in patients treated with first-line or second-line imatinib (24).

Other factors that may affect achievement of deep molecular response include risk score, sex, adherence to treatment, and dose intensity. For example, in the Evaluating Nilotinib Efficacy and Safety in Clinical Trials–Newly Diagnosed Patients (ENESTnd) phase III trial of first-line nilotinib versus imatinib, rates of deep molecular response were lowest among patients with high Sokal score, although more high-risk patients achieved MR4.5 by 3 years on nilotinib than imatinib (24%, 27%, and 9% in the nilotinib 300 mg b.i.d., nilotinib 400 mg b.i.d., and imatinib arms, respectively; ref. 10). Univariate analysis of a study in patients treated with first-line imatinib showed that females were more likely than males to achieve stable undetectable BCR–ABL1 (with a RQ-PCR sensitivity of ≥4.5 log) by 8 years (68% vs. 30%, respectively; ref. 50). Multivariate analysis of a study in Japanese patients found adherence to standard-dose imatinib to be predictive of CMR achievement (51). Another study reported adherence to standard-dose imatinib as the only independent predictor of CMR; poor adherence and failure to achieve MMR predicted treatment discontinuation and eventual loss of CCyR (52, 53).

The high rates of and rapidity of disease relapse observed in patients who discontinue TKI therapy without deep molecular response (34–37) suggest that the main factor influencing relapse risk off therapy is the level of residual molecular disease present when TKI therapy is stopped. However, even among patients with sustained, undetectable disease on TKI therapy, a significant percentage of patients have experienced disease relapse (40), and several studies have evaluated factors potentially contributing to a patient's ability to achieve successful TFR.

Studies of imatinib discontinuation have found an association between Sokal score and relapse risk (39, 40, 54, 55), suggesting that patients with high Sokal risk may have inherent biologic attributes that drive development of disease relapse once BCR–ABL1 inhibition is relieved. The duration of deep molecular response before TKI discontinuation and the overall duration of prior TKI treatment also seem to be important (39, 40, 56). Based on this, the majority of ongoing studies require patients to maintain a deep molecular response for ≥2 years and have had ≥3 years of prior TKI treatment before attempting discontinuation. More rapid achievement of deep molecular response may also be predictive of successful TFR (54, 55).

In the STIM study, the only factors associated with lower risk of relapse were low/intermediate Sokal score and duration of imatinib treatment >5 years (39, 40). Another study identified a subgroup of patients with increased risk of molecular relapse following imatinib discontinuation, characterized by the following: high Sokal score, >24 months to CMR, and <33 months of imatinib after achieving CMR; patients with any of these characteristics had a 0% probability of CMR persistence at 1 year, compared with 80% probability in patients without these characteristics (54). Several other ongoing TKI discontinuation studies aim to determine other factors that may play a role in relapse off treatment (Table 3). For example, the large, phase III EURO-SKI study (NCT01596114) will explore factors associated with molecular relapse in patients with stable MR4 who stop TKI therapy, and STIM 2 (NCT01343173) will evaluate factors predictive of sustained deep molecular response after imatinib discontinuation (57). Current data suggest that deep molecular response is heterogeneous, and different patients may have differing levels of residual disease burden despite having undetectable disease (22).

Most, if not all, patients with sustained CMR have persistent BCR–ABL1-positive cells (based on PCR at a DNA level; ref. 55 and 58); however, this persistence does not necessarily lead to relapse after treatment discontinuation. Furthermore, the kinetics of relapse after treatment discontinuation vary, with early and late molecular relapses observed (39). This discrepancy may reflect the heterogeneity of CML at the stem cell level. The development of highly sensitive techniques like ultra-deep sequencing (UDS) and massive parallel sequencing (MPS) may help clarify these differences. Indeed, both UDS and MPS detected more complex mutation dynamics in TKI-resistant patients than conventional Sanger sequencing (59, 60).

Mathematical modeling of the kinetics of molecular relapse in patients in the STIM study has led to a hypothesis that selective pressure exerted by imatinib treatment results in an increased frequency of LSC clones with slower growth and differentiation than the predominant clone at baseline (61). Imatinib therapy may affect the ability of LSCs to produce differentiated populations and may affect the cell division of progenitors and differentiated leukemic cells (61). The effects of imatinib on leukemia-initiating cells (LIC) may differ from patient to patient, and these differences may manifest in varying times to molecular relapse in patients with deep molecular response who stop imatinib treatment (Fig. 2).

Figure 2.

Hypothesis for variability in duration of deep molecular response in patients who discontinue imatinib. Imatinib treatment has differing effects on LICs that introduce variability in times to molecular relapse after imatinib discontinuation. A, in some patients, imatinib treatment may successfully eradicate LICs, leaving only a small population of quiescent LSCs that is undetectable by conventional RQ-PCR (≈5-log sensitivity), enabling prolonged TFR. B, in other patients, populations of LICs with variable growth kinetics remain. Patients with faster-growing residual LICs experience more rapid molecular relapse on discontinuation of imatinib treatment, whereas patients with slower-growing residual LICs experience later molecular relapse. Inset graphs show the Kaplan–Meier estimate of relapse-free survival in the STIM study (relapse defined as confirmed loss of molecular response ≥5-log reduction) based on a median follow-up of 30 months (40).

Figure 2.

Hypothesis for variability in duration of deep molecular response in patients who discontinue imatinib. Imatinib treatment has differing effects on LICs that introduce variability in times to molecular relapse after imatinib discontinuation. A, in some patients, imatinib treatment may successfully eradicate LICs, leaving only a small population of quiescent LSCs that is undetectable by conventional RQ-PCR (≈5-log sensitivity), enabling prolonged TFR. B, in other patients, populations of LICs with variable growth kinetics remain. Patients with faster-growing residual LICs experience more rapid molecular relapse on discontinuation of imatinib treatment, whereas patients with slower-growing residual LICs experience later molecular relapse. Inset graphs show the Kaplan–Meier estimate of relapse-free survival in the STIM study (relapse defined as confirmed loss of molecular response ≥5-log reduction) based on a median follow-up of 30 months (40).

Close modal

It remains to be established whether the ultimate goal of treatment for patients with CML-CP will be a “clinical cure” (i.e., the absence of relapse) or a “biological cure” (i.e., absence of all leukemic cells, including LSCs; refs. 22, 62, 63). Multiple strategies for specifically targeting the LSC reservoir in patients with CML are under investigation, including combination of a BCR–ABL1 TKI with other targeted agents, such as inhibitors of the Hedgehog, Wnt/B-catenin, or Notch signaling pathways, or immunomodulatory agents, such as IFN (22, 62, 63). In one study, maintenance therapy with peglyated IFN following imatinib discontinuation led to retained or improved molecular responses in the majority of patients, most of whom did not have deep molecular responses (64). This may represent a viable strategy for patients who wish to stop TKI therapy in the absence of deep molecular response; the ongoing TIGER study is further investigating this approach (Table 3). Quantification of a patient's residual LSC reservoir and the effect of such combination treatments on LSCs remains a challenge (22, 65). Given the potential diversity in disease burden and relapse risk in patients who discontinue TKI therapy, rigorous long-term follow-up is essential, and discontinuation should only be attempted in clinical trials.

Molecular monitoring affords a precise, convenient method for monitoring residual disease burden in patients with CML-CP. As TKIs have improved patient outcomes, clinical trial designs have begun to evaluate deeper levels of molecular response. Deep molecular responses are associated with improved rates of PFS, EFS, and OS, and reduced risk of progression to advanced disease. Furthermore, a sustained deep molecular response is an essential entry criterion for studies of TFR. The ability to achieve deep molecular response on therapy, and sustain this response off therapy, may be affected by a variety of factors, including disease characteristics, risk score, and adherence to and time on treatment. As more is learned about the optimal criteria for successful TKI discontinuation, patients may have increased chances of achieving treatment-free disease control, a first step toward the elusive cure for CML.

F.-X. Mahon has received commercial research grants from Bristol-Myers Squibb and Novartis Pharma. F.-X. Mahon is a consultant/advisory board member of Bristol-Myers Squibb, Novartis Pharma, and Ariad. G. Etienne is a consultant/advisory board member of Bristol-Myers Squibb, Novartis, Pfizer, and Ariad.

Conception and design: F.-X. Mahon, G. Etienne

Development of methodology: F.-X. Mahon

Writing, review, and/or revision of the manuscript: F.-X. Mahon, G. Etienne

The authors thank K. Miller-Moslin, PhD, and P. Tuttle, PhD (Articulate Science), for medical editorial assistance.

Financial support for medical editorial assistance was provided by Novartis Pharmaceuticals Corporation.

1.
Van Etten
RA
,
Shannon
KM
. 
Focus on myeloproliferative diseases and myelodysplastic syndromes
.
Cancer Cell
2004
;
6
:
547
52
.
2.
Natoli
C
,
Perrucci
B
,
Perrotti
F
,
Falchi
L
,
Iacobelli
S
Consorzio Interuniversitario Nazionale per Bio-Oncologia (CINBO)
. 
Tyrosine kinase inhibitors
.
Curr Cancer Drug Targets
2010
;
10
:
462
83
.
3.
Druker
BJ
. 
Translation of the Philadelphia chromosome into therapy for CML
.
Blood
2008
;
112
:
4808
17
.
4.
Melo
JV
,
Barnes
DJ
. 
Chronic myeloid leukaemia as a model of disease evolution in human cancer
.
Nat Rev Cancer
2007
;
7
:
441
53
.
5.
Hernandez-Boluda
JC
,
Cervantes
F
. 
Prognostic factors in chronic myeloid leukaemia
.
Best Pract Res Clin Haematol
2009
;
22
:
343
53
.
6.
Baccarani
M
,
Deininger
MW
,
Rosti
G
,
Hochhaus
A
,
Soverini
S
,
Apperley
JF
, et al
European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013
.
Blood
2013
;
122
:
872
84
.
7.
National Comprehensive Cancer Network
. 
NCCN Clinical Practice Guidelines in Oncology: Chronic Myelogenous Leukemia
.
Version 4.2013. [cited 2013 Jul 12]. Available from
: http://www.nccn.org/professionals/physician_gls/pdf/cml.pdf.
8.
Deininger
M
,
O'Brien
SG
,
Guilhot
F
,
Goldman
JM
,
Hochhaus
A
,
Hughes
TP
, et al
International randomized study of interferon vs. STI571 (IRIS) 8-year follow up: sustained survival and low risk for progression or events in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) treated with imatinib
.
Blood
2009
;
114
:
462
(
abstr 1126
).
9.
Kantarjian
HM
,
Shah
NP
,
Cortes
JE
,
Baccarani
M
,
Agarwal
MB
,
Undurraga
MS
, et al
Dasatinib or imatinib in newly diagnosed chronic phase chronic myeloid leukemia: 2-year follow-up from a randomized phase 3 trial (DASISION)
.
Blood
2012
;
119
:
1123
9
.
10.
Larson
RA
,
Hochhaus
A
,
Hughes
TP
,
Clark
RE
,
Etienne
G
,
Kim
DW
, et al
Nilotinib vs. imatinib in patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase: ENESTnd 3-year follow-up
.
Leukemia
2012
;
26
:
2197
203
.
11.
Cross
NCP
,
White
H
,
Müller
MC
,
Saglio
G
,
Hochhaus
A
. 
Standardized definitions of molecular response in chronic myeloid leukemia
.
Leukemia
2012
;
26
:
2172
5
.
12.
Tibes
R
,
Mesa
RA
. 
Evolution of clinical trial endpoints in chronic myeloid leukemia: efficacious therapies require sensitive monitoring techniques
.
Leuk Res
2012
;
36
:
664
71
.
13.
Cortes
J
,
Quintas-Cardama
A
,
Kantarjian
HM
. 
Monitoring molecular response in chronic myeloid leukemia
.
Cancer
2011
;
117
:
1113
22
.
14.
Hughes
T
,
Deininger
M
,
Hochhaus
A
,
Branford
S
,
Radich
J
,
Kaeda
J
, et al
Monitoring CML patients responding to treatment with tyrosine kinase inhibitors: review and recommendations for harmonizing current methodology for detecting BCR-ABL transcripts and kinase domain mutations and for expressing results
.
Blood
2006
;
108
:
28
37
.
15.
Hughes
TP
,
Kaeda
J
,
Branford
S
,
Rudzki
Z
,
Hochhaus
A
,
Hensley
ML
, et al
Frequency of major molecular responses to imatinib or interferon-α plus cytarabine in newly diagnosed chronic myeloid leukemia
.
N Engl J Med
2003
;
349
:
1423
32
.
16.
Press
RD
,
Love
Z
,
Tronnes
AA
,
Yang
R
,
Tran
T
,
Mongoue-Tchokote
S
, et al
BCR-ABL mRNA levels at and after the time of a complete cytogenetic response (CCR) predict the duration of CCR in imatinib mesylate-treated patients with CML
.
Blood
2006
;
107
:
4250
6
.
17.
Cortes
J
,
Talpaz
M
,
O'Brien
S
,
Jones
D
,
Luthra
R
,
Shan
J
, et al
Molecular responses in patients with chronic myelogenous leukemia in chronic phase treated with imatinib mesylate
.
Clin Cancer Res
2005
;
11
:
3425
32
.
18.
Pavlovsky
C
,
Giere
I
,
Moiraghi
B
,
Pavlovsky
MA
,
Aranguren
PN
,
Garcia
J
, et al
Molecular monitoring of imatinib in chronic myeloid leukemia patients in complete cytogenetic remission: does achievement of a stable major molecular response at any time point identify a privileged group of patients? A multicenter experience in Argentina and Uruguay
.
Clin Lymphoma Myeloma Leuk
2011
;
11
:
280
5
.
19.
Hughes
TP
,
Hochhaus
A
,
Branford
S
,
Muller
MC
,
Kaeda
JS
,
Foroni
L
, et al
Long-term prognostic significance of early molecular response to imatinib in newly diagnosed chronic myeloid leukemia: an analysis from the International Randomized Study of Interferon Versus STI571 (IRIS)
.
Blood
2010
;
116
:
3758
65
.
20.
Breccia
M
,
Alimena
G
. 
The significance of early, major and stable molecular responses in chronic myeloid leukemia in the imatinib era
.
Crit Rev Oncol Hematol
2011
;
79
:
135
43
.
21.
Mahon
FX
. 
Is going for cure in chronic myeloid leukemia possible and justifiable?
Hematology Am Soc Hematol Educ Program
2012
;
2012
:
122
8
.
22.
Rea
D
,
Rousselot
P
,
Guilhot
J
,
Guilhot
F
,
Mahon
FX
. 
Curing chronic myeloid leukemia
.
Curr Hematol Malig Rep
2012
;
7
:
103
8
.
23.
Branford
S
,
Fletcher
L
,
Cross
NC
,
Muller
MC
,
Hochhaus
A
,
Kim
DW
, et al
Desirable performance characteristics for BCR-ABL measurement on an international reporting scale to allow consistent interpretation of individual patient response and comparison of response rates between clinical trials
.
Blood
2008
;
112
:
3330
8
.
24.
Branford
S
,
Seymour
JF
,
Grigg
A
,
Arthur
C
,
Rudzki
Z
,
Lynch
K
, et al
BCR-ABL messenger RNA levels continue to decline in patients with chronic phase chronic myeloid leukemia treated with imatinib for more than 5 years and approximately half of all first-line treated patients have stable undetectable BCR-ABL using strict sensitivity criteria
.
Clin Cancer Res
2007
;
13
:
7080
5
.
25.
Burmeister
T
,
Reinhardt
R
. 
A multiplex PCR for improved detection of typical and atypical BCR-ABL fusion transcripts
.
Leuk Res
2008
;
32
:
579
85
.
26.
Preudhomme
C
,
Guilhot
J
,
Nicolini
FE
,
Guerci-Bresler
A
,
Rigal-Huguet
F
,
Maloisel
F
, et al
Imatinib plus peginterferon α-2a in chronic myeloid leukemia
.
N Engl J Med
2010
;
363
:
2511
21
.
27.
Hehlmann
R
,
Lauseker
M
,
Jung-Munkwitz
S
,
Leitner
A
,
Muller
MC
,
Pletsch
N
, et al
Tolerability-adapted imatinib 800 mg/d versus 400 mg/d versus 400 mg/d plus interferon-alpha in newly diagnosed chronic myeloid leukemia
.
J Clin Oncol
2011
;
29
:
1634
42
.
28.
Kantarjian
H
,
O'Brien
S
,
Shan
J
,
Huang
X
,
Garcia-Manero
G
,
Faderl
S
, et al
Cytogenetic and molecular responses and outcome in chronic myelogenous leukemia: need for new response definitions?
Cancer
2008
;
112
:
837
45
.
29.
Verma
D
,
Kantarjian
HM
,
Shan
J
,
O'Brien
S
,
Verma
A
,
Jabbour
E
, et al
Sustained complete molecular response to imatinib in chronic myeloid leukemia (CML): a target worth aiming and achieving?
Blood
2009
;
114
(
abstr 505
).
30.
Etienne
G
,
Nicolini
FE
,
Dulucq
S
,
Schmitt
A
,
Hayette
S
,
Lippert
E
, et al
Achieving a complete molecular remission under imatinib therapy is associated with a better outcome in chronic phase chronic myeloid leukaemia patients on imatinib frontline therapy
.
Blood
2012
;
120
(
abstr 3754
).
31.
Falchi
L
,
Kantarjian
HM
,
Quintas-Cardama
A
,
O'Brien
S
,
Jabbour
EJ
,
Ravandi
F
, et al
Clinical significance of deeper molecular responses with four modalities of tyrosine kinase inhibitors as frontline therapy for chronic myeloid leukemia
.
Blood
2012
;
120
(
abstr 164
).
32.
Hehlmann
R
,
Lauseker
M
,
Hanfstein
B
,
Müller
MC
,
Schreiber
A
,
Proetel
U
, et al
Complete molecular remission (CMR 4.5) of CML is induced faster by dose—optimized imatinib predicts better survival—results from the randomized CML-study IV
.
Blood
2012
;
120
(
abstr 67
).
33.
Hughes
TP
,
Lipton
JH
,
Spector
N
,
Leher
B
,
Pasquini
R
,
Clementino
N
, et al
Switching to nilotinib is associated with continued deeper molecular responses in CML-CP patients with minimal residual disease after ≥2 years on imatinib: ENESTcmr 2-year follow-up results
.
Blood
2012
;
120
(
abstr 694
).
34.
Cortes
J
,
O'Brien
S
,
Kantarjian
H
. 
Discontinuation of imatinib therapy after achieving a molecular response
.
Blood
2004
;
104
:
2204
5
.
35.
Mauro
MJ
,
Druker
BJ
,
Maziarz
RT
. 
Divergent clinical outcome in two CML patients who discontinued imatinib therapy after achieving a molecular remission
.
Leuk Res
2004
;
28
(
suppl 1
):
S71
3
.
36.
Merante
S
,
Orlandi
E
,
Bernasconi
P
,
Calatroni
S
,
Boni
M
,
Lazzarino
M
. 
Outcome of four patients with chronic myeloid leukemia after imatinib mesylate discontinuation
.
Haematologica
2005
;
90
:
979
81
.
37.
Michor
F
,
Hughes
TP
,
Iwasa
Y
,
Branford
S
,
Shah
NP
,
Sawyers
CL
, et al
Dynamics of chronic myeloid leukaemia
.
Nature
2005
;
435
:
1267
70
.
38.
Rousselot
P
,
Huguet
F
,
Rea
D
,
Legros
L
,
Cayuela
JM
,
Maarek
O
, et al
Imatinib mesylate discontinuation in patients with chronic myelogenous leukemia in complete molecular remission for more than 2 years
.
Blood
2007
;
109
:
58
60
.
39.
Mahon
FX
,
Rea
D
,
Guilhot
J
,
Guilhot
F
,
Huguet
F
,
Nicolini
F
, et al
Discontinuation of imatinib in patients with chronic myeloid leukaemia who have maintained complete molecular remission for at least 2 years: the prospective, multicentre stop imatinib (STIM) trial
.
Lancet Oncol
2010
;
11
:
1029
35
.
40.
Mahon
F
,
Rea
D
,
Guilhot
J
,
Guilhot
F
,
Huguet
F
,
Nicolini
FE
, et al
Discontinuation of imatinib in patients with chronic myeloid leukemia who have maintained complete molecular response: update results of the STIM study
.
Blood
2011
;
118
(
abstr 603
).
41.
Rousselot
P
,
Charbonnier
A
,
Cony-Makhoul
P
,
Agape
P
,
Nicolini
F
,
Varet
B
, et al
Loss of major molecular response is accurate for restarting imatinib after imatinib discontinuation in CP-CML patients with long lasting CMR: importance of fluctuating values of MRD and interferon
.
Haematologica
2012
;
97
(
s1
):
77
(
abstr 194
).
42.
Rea
D
,
Rousselot
P
,
Guilhot
F
,
Tulliez
M
,
Nicolini
FE
,
Guerci-Bresler
A
, et al
Discontinuation of second generation (2G) tyrosine kinase inhibitors (TKI) in chronic phase (CP)-chronic myeloid leukemia (CML) patients with stable undetectable BCR-ABL transcripts
.
Blood
2012
;
120
(
abstr 916
).
43.
Marin
D
,
Hedgley
C
,
Clark
RE
,
Apperley
J
,
Foroni
L
,
Milojkovic
D
, et al
Predictive value of early molecular response in patients with chronic myeloid leukemia treated with first-line dasatinib
.
Blood
2012
;
120
:
291
4
.
44.
Hanfstein
B
,
Muller
MC
,
Hehlmann
R
,
Erben
P
,
Lauseker
M
,
Fabarius
A
, et al
Early molecular and cytogenetic response is predictive for long-term progression-free and overall survival in chronic myeloid leukemia (CML)
.
Leukemia
2012
;
26
:
2096
102
.
45.
Quintas-Cardama
A
,
Kantarjian
H
,
Jones
D
,
Shan
J
,
Borthakur
G
,
Thomas
D
, et al
Delayed achievement of cytogenetic and molecular response is associated with increased risk of progression among patients with chronic myeloid leukemia in early chronic phase receiving high-dose or standard-dose imatinib therapy
.
Blood
2009
;
113
:
6315
21
.
46.
Hochhaus
A
,
Guilhot
F
,
Haifa Al-Ali
K
,
Rosti
G
,
Nakaseko
C
,
Antonio De Souza
C
, et al
Early BCR-ABL transcript levels predict future molecular response and long-term outcomes in newly diagnosed patients with CML-CP: analysis of ENESTnd 3-year data
.
Haematologica
2012
;
97
(
s1
):
237
(
abstr 0584
).
47.
Hochhaus
A
,
Boque
C
,
Bradley Garelik
MB
,
Manos
G
,
Steegmann
JL
. 
Molecular response kinetics and BCR-ABL reductions in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) receiving dasatinib versus imatinib: DASISION 3-year follow-up
.
Haematologica
2012
;
97
(
s1
):
609
(
abstr 1537
).
48.
Milojkovic
D
,
Apperley
JF
,
Gerrard
G
,
Ibrahim
AR
,
Szydlo
R
,
Bua
M
, et al
Responses to second-line tyrosine kinase inhibitors are durable: an intention-to-treat analysis in chronic myeloid leukemia patients
.
Blood
2012
;
119
:
1838
43
.
49.
Tauchi
T
,
Kizaki
M
,
Okamoto
S
,
Tanaka
H
,
Tanimoto
M
,
Inokuchi
K
, et al
Seven-year follow-up of patients receiving imatinib for the treatment of newly diagnosed chronic myelogenous leukemia by the TARGET system
.
Leuk Res
2011
;
35
:
585
90
.
50.
Branford
S
,
Ross
D
,
Prime
J
,
Field
C
,
Altamura
H
,
Yeoman
A
, et al
Early molecular response and female sex strongly predict achievement of stable undetectable BCR–ABL1, a criterion for imatinib discontinuation in patients with CML
.
Blood
2012
;
120
(
abstr 165
).
51.
Yoshida
C
,
Komeno
T
,
Hori
M
,
Kimura
T
,
Fujii
M
,
Okoshi
Y
, et al
Adherence to the standard dose of imatinib, rather than dose adjustment based on its plasma concentration, is critical to achieve a deep molecular response in patients with chronic myeloid leukemia
.
Int J Hematol
2011
;
93
:
618
23
.
52.
Marin
D
,
Bazeos
A
,
Mahon
FX
,
Eliasson
L
,
Milojkovic
D
,
Bua
M
, et al
Adherence is the critical factor for achieving molecular responses in patients with chronic myeloid leukemia who achieve complete cytogenetic responses on imatinib
.
J Clin Oncol
2010
;
28
:
2381
8
.
53.
Ibrahim
AR
,
Eliasson
L
,
Apperley
JF
,
Milojkovic
D
,
Bua
M
,
Szydlo
R
, et al
Poor adherence is the main reason for loss of CCyR and imatinib failure for chronic myeloid leukemia patients on long term therapy
.
Blood
2011
;
117
:
3733
6
.
54.
Yhim
HY
,
Lee
NR
,
Song
EK
,
Yim
CY
,
Jeon
SY
,
Shin
S
, et al
Imatinib mesylate discontinuation in patients with chronic myeloid leukemia who have received front-line imatinib mesylate therapy and achieved complete molecular response
.
Leuk Res
2012
;
36
:
689
93
.
55.
Ross
DM
,
Branford
S
,
Seymour
JF
,
Schwarer
AP
,
Arthur
C
,
Yeung
DT
, et al
Safety and efficacy of imatinib cessation for CML patients with stable undetectable minimal residual disease: Results from the TWISTER study
.
Blood
2013
;
122
:
515
22
.
56.
Lee
SE
,
Choi
SY
,
Bang
JH
,
Kim
SH
,
Jang
EJ
,
Choi
M
, et al
BCR-ABL kinetics after discontinuation of imatinib in CML patients with MR4.5 or undetectable molecular residual disease
.
Haematologica
2012
;
97
(
s1
):
80
(
abstr 200
).
57.
U.S. National Institutes of Health
.
Clinicaltrials.gov
.
[cited 2013 Sept 12]. Available from
: http://www.clinicaltrials.gov/.
58.
Ross
DM
,
Branford
S
,
Seymour
JF
,
Schwarer
AP
,
Arthur
C
,
Bartley
PA
, et al
Patients with chronic myeloid leukemia who maintain a complete molecular response after stopping imatinib treatment have evidence of persistent leukemia by DNA PCR
.
Leukemia
2010
;
10
:
1719
1724
.
59.
Eyal
E
,
Tohami
T
,
Amir
A
,
Cesarkas
K
,
Jacob-Hirsch
J
,
Volchek
Y
, et al
Detection of BCR–ABL1 mutations in chronic myeloid leukaemia by massive parallel sequencing
.
Br J Haematol
2013
;
160
:
477
86
.
60.
Soverini
S
,
De Benedittis
C
,
Machova Polakova
K
,
Brouckova
A
,
Horner
D
,
Iacono
M
, et al
Unraveling the complexity of tyrosine kinase inhibitor-resistant populations by ultra-deep sequencing of the BCR-ABL kinase domain
.
Blood
2013
;
122
:
1634
48
.
61.
Tang
M
,
Foo
J
,
Gonen
M
,
Guilhot
J
,
Mahon
FX
,
Michor
F
. 
Selection pressure exerted by imatinib therapy leads to disparate outcomes of imatinib discontinuation trials
.
Haematologica
2012
;
97
:
1553
61
.
62.
Chomel
JC
,
Turhan
AG
. 
Chronic myeloid leukemia stem cells in the era of targeted therapies: resistance, persistence and long-term dormancy
.
Oncotarget
2011
;
2
:
713
27
.
63.
Ross
DM
,
Hughes
TP
,
Melo
JV
. 
Do we have to kill the last CML cell?
Leukemia
2011
;
25
:
193
200
.
64.
Burchert
A
,
Muller
MC
,
Kostrewa
P
,
Erben
P
,
Bostel
T
,
Liebler
S
, et al
Sustained molecular response with interferon alfa maintenance after induction therapy with imatinib plus interferon alfa in patients with chronic myeloid leukemia
.
J Clin Oncol
2010
;
28
:
1429
35
.
65.
Chu
S
,
McDonald
T
,
Lin
A
,
Chakraborty
S
,
Huang
Q
,
Snyder
DS
, et al
Persistence of leukemia stem cells in chronic myelogenous leukemia patients in prolonged remission with imatinib treatment
.
Blood
2011
;
118
:
5565
72
.
66.
Kantarjian
H
,
Talpaz
M
,
O'Brien
S
,
Garcia-Manero
G
,
Verstovsek
S
,
Giles
F
, et al
High-dose imatinib mesylate therapy in newly diagnosed Philadelphia chromosome-positive chronic phase chronic myeloid leukemia
.
Blood
2004
;
103
:
2873
8
.
67.
de Lavallade
H
,
Apperley
JF
,
Khorashad
JS
,
Milojkovic
D
,
Reid
AG
,
Bua
M
, et al
Imatinib for newly diagnosed patients with chronic myeloid leukemia: incidence of sustained responses in an intention-to-treat analysis
.
J Clin Oncol
2008
;
26
:
3358
63
.
68.
Cortes
JE
,
Kantarjian
HM
,
Goldberg
SL
,
Powell
BL
,
Giles
FJ
,
Wetzler
M
, et al
High-dose imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: high rates of rapid cytogenetic and molecular responses
.
J Clin Oncol
2009
;
27
:
4754
9
.
69.
Hochhaus
A
,
Rosti
G
,
le Coutre
PD
,
Ossenkoppele
G
,
Griskevicius
L
,
Rea
D
, et al
ENEST1st: nilotinib in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP): a European and EUTOS clinical initiative for standardization of molecular response
.
Haematologica
2012
;
97
(
s1
):
74
(
abstr 0188
).
70.
Gugliotta
G
,
Castagnetti
F
,
Breccia
M
,
Levato
L
,
Capucci
A
,
Tiribelli
M
, et al
Early CP CML, nilotinib 400 mg twice daily frontline: beyond 3 years, results remain excellent and stable (A GIMEMA CML Working Party trial)
.
Blood
2011
;
116
(
abstr 2756
).
71.
Rosti
G
,
Gugliotta
G
,
Castagnetti
F
,
Breccia
M
,
Levato
L
,
Rege-Cambrin
G
, et al
Five-year results of nilotinib 400 mg BID in early chronic phase chronic myeloid leukemia (CML): high rate of deep molecular response—update of the GIMEMA CML WP trial CML0307
.
Blood
2012
;
120
(
abstr 3784
).
72.
Cortes
JE
,
Jones
D
,
O'Brien
S
,
Jabbour
E
,
Konopleva
M
,
Ferrajoli
A
, et al
Nilotinib as front-line treatment for patients with chronic myeloid leukemia in early chronic phase
.
J Clin Oncol
2010
;
28
:
392
7
.
73.
Nicolini
FE
,
Etienne
G
,
Dubruille
V
,
Roy
L
,
Huguet
F
,
Legros
L
, et al
Pegylated interferon-α 2a in combination to nilotinib as first line therapy in newly diagnosed chronic phase chronic myelogenous leukemia provides high rates of MR4.5. Preliminary results of a phase II study
.
Blood
2012
;
120
(
suppl; abstr 166
).
74.
Radich
JP
,
Kopecky
KJ
,
Applebaum
FR
,
Kamel-Reid
S
,
Stock
W
,
Malnassy
G
, et al
A randomized trial of dasatinib 100 mg vs imatinib 400 mg in newly diagnosed chronic phase chromic myeloid leukemia
.
Blood
2012
;
120
:
3898
905
.
75.
Cortes
JE
,
Jones
D
,
O'Brien
S
,
Jabbour
E
,
Ravandi
F
,
Koller
C
, et al
Results of dasatinib therapy in patients with early chronic-phase chronic myeloid leukemia
.
J Clin Oncol
2010
;
28
:
398
404
.
76.
Cortes
JE
,
Kim
DW
,
Kantarjian
HM
,
Brummendorf
TH
,
Dyagil
I
,
Griskevicus
L
, et al
Bosutinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: results from the BELA trial
.
J Clin Oncol
2012
;
30
:
3486
92
.
77.
Press
RD
,
Galderisi
C
,
Yang
R
,
Rempfer
C
,
Willis
SG
,
Mauro
MJ
, et al
A half-log increase in BCR-ABL RNA predicts a higher risk of relapse in patients with chronic myeloid leukemia with an imatinib-induced complete cytogenetic response
.
Clin Cancer Res
2007
;
13
:
6136
43
.
78.
Lee
S
,
Choi
SY
,
Bang
J
,
Kim
S
,
Jang
E
,
Byeun
J
, et al
Predictive factors for successful imatinib cessation in chronic myeloid leukemia patients treated with imatinib
.
Am J Hematol
2013
;
88
:
449
54
.
79.
Matsuki
E
,
Ono
Y
,
Tonegawa
K
,
Sakurai
M
,
Kunimoto
H
,
Ishizawa
J
, et al
Detailed investigation on characteristics of Japanese patients with chronic phase CML who achieved a durable CMR after discontinuation of imatinib—an updated result of the Keio STIM study
.
Blood
2012
;
120
(
abstr 2788
).
80.
Takahashi
N
,
Kyo
T
,
Maeda
Y
,
Sugihara
T
,
Usuki
K
,
Kawaguchi
T
, et al
Discontinuation of imatinib in Japanese patients with chronic myeloid leukemia
.
Haematologica
2012
;
97
:
903
6
.