Current Oncology Reports

, Volume 14, Issue 5, pp 379–386

Chronic Myeloid Leukemia: State of the Art in 2012

Authors

  • Carmen Fava
    • Division of Hematology and Internal Medicine, Department of Clinical and Biological Sciences of the University of TurinSan Luigi Hospital
  • Giovanna Rege-Cambrin
    • Division of Hematology and Internal Medicine, Department of Clinical and Biological Sciences of the University of TurinSan Luigi Hospital
    • Division of Hematology and Internal Medicine, Department of Clinical and Biological Sciences of the University of TurinSan Luigi Hospital
Leukemia (A Aguayo, Section Editor)

DOI: 10.1007/s11912-012-0253-9

Cite this article as:
Fava, C., Rege-Cambrin, G. & Saglio, G. Curr Oncol Rep (2012) 14: 379. doi:10.1007/s11912-012-0253-9

Abstract

The prognosis of Philadelphia positive (Ph+) chronic myeloid leukemia (CML) has been revolutionized since the discovery of the pathogenetic role of BCR-ABL and the invention of tyrosine kinase inhibitors (TKIs). With a follow-up of 8 years, patients had an OS of 85 % and, with second generation TKIs, dasatinib and nilotinib, almost 50 % of the resistant patients gained a remission with an OS over 90 % at 2 years. Currently the challenge is preventing resistance leading to progression to advance phases that have still few chances of effective treatment. Another objective, derived from the needs of our patients, beside the pride of the scientist, is the discontinuation of the treatment. Second generations TKIs applied to the first line setting seem to be a good option either to avoid progression and to achieve deeper rates of molecular response, necessary for the cure.

Keywords

CMLImatinibDasatinibNilotinibSuboptimal responseEarly cytogenetic responsePrognostic factorsDiscontinuation

Introduction

Philadelphia positive (Ph+) chronic myeloid leukemia (CML) is a chronic disease with a tendency of progression into an accelerated and a blastic phase. When the disease becomes advanced, it is almost incurable. Fortunately, the discovery of the pathogenetic role of BCR-ABL and the invention of molecules with a tyrosine kinase inhibiting activity achieved the great goal of freezing the disease in the chronic phase. Furthermore, above all expectations, these drugs obtained a complete cytogenetic remission (CCyR) for most of the patients, and this population showed to have a long survival. A great majority of the patients in CCyR also obtain a major molecular remission defined as a BCR-ABL transcript lower than 0.1 % expressed in International Scale, that was a way of the Scientific Community to agree on the same results and to confer a prognostic significance universally shared. All these results were obtained first with imatinib-mesylate (STI571; Novartis Pharmaceuticals, Basel, Switzerland), a tyrosine kinase inhibitor (TKI) that showed its superiority to α-interferon and Ara-C as front line therapy for CML. Since the first results of the IRIS study became available, imatinib became the standard front-line treatment for patients diagnosed of CML in early chronic phase (CP). The 8-year update of the IRIS trial confirmed the long-term efficacy and safety of imatinib [1•], with a cumulative CCyR rate of 83 %, an event-free survival (EFS) of 81 %, and the estimated overall survival (OS) rate of 85 %. It is well recognized, however, that with continued treatment, a significant number of patients shows resistance to imatinib. Almost one-third of the patients discontinued treatment for intolerance or resistance [1•].

Response to Second Generation TKIs

Vigilant monitoring (Table 1) [2•], aids prompt detection of imatinib failure, and ensures that patients receive the most suitable therapy as early in the disease course as possible. Treatment failure, as defined by the ELN recommendation, indicates that treatment at the current schedule is no longer appropriate for a patient and a change in therapy is indicated [3]. Several highly potent next-generation BCR-ABL inhibitors have been developed as strategies to overcome imatinib resistance and improve the prognosis of patients with CML. These include novel and more potent multi-tyrosine kinase inhibitors such as dasatinib (Sprycel, BMS-354825; Bristol-Myers Squibb, New York, NY) and nilotinib (AMN107; Novartis Pharmaceuticals) [46].
Table 1

Responses and response assessments according to the ELN recommendations [2]

Response

Monitoring

Optimal response

Suboptimal response

Failure

Hematologic

Check every 2 weeks until CHR achieved and confirmed; subsequently at least every 3 months unless clinically required

CHR at 3 months

/

Less than CHR at 3 months; loss of CHR

Cytogenetic

Check at 3 and 6 months, then at least every 6 months until CCyR achieved and confirmed; subsequently every 12 months

At least minor CyR at 3 months; at least PCyR at 6 months; CCyR at 12 months

No CyR at 3 months; less than PCyR at 6 months; less than CCyR at 12 months

No CyR at 6 months; less than PCyR at 12 months; less than CCyR at 18 months; loss of CCyR; additional chromosomal abnormalities on the Ph-positive clone

Molecular

Check every 3 months until confirmed MMR, then at least every 6 months; perform mutational analysis following failure, suboptimal response, or transcript level increase

MMR at 18 months

Less than MMR at 18 months; loss of MMR

/

Dasatinib, a piperazinyl derivative that targets many tyrosine kinases, was selected for its potent inhibitory activity against Src and Abl kinases, including most mutated forms [5]. The drug was shown to be effective for the treatment of Ph + leukemias [4], and was registered for the treatment of patients with imatinib-intolerant and imatinib-resistant disease who have Ph + CML in CP, accelerated phase (AP), and blast phase (BP). In patients with imatinib-resistant disease in CP, after a minimum 2-year follow-up, the major cytogenetic response (MCyR) and the CCyR rates were 53 % and 47 %, respectively [710], the progression-free survival (PFS) was greater than 80 %, and the OS was greater than 90 %. Dasatinib treatment of patients with or without mutations resulted in notable response rates and durable PFS (70 % vs 80 %) [11]. MCyRs were rapidly achieved in patients with the most commonly mutated amino acids, except T315I and F317L. The approved dasatinib dose in CP CML is 100 mg once daily, which was obtained following a phase III dose-optimization trial demonstrating similar efficacy compared with other doses tested and a significantly reduced occurrence of AEs [12•].

Nilotinib is an aminopyrimidine derivative that inhibits the tyrosine kinase activity of the unmutated and most mutated forms of BCR-ABL more potently and more selectively than imatinib [6, 1315]. Nilotinib is effective for the treatment of Ph + leukemias and was registered for treating imatinib-intolerant and imatinib-resistant patients with Ph + CML in CP and in AP at a dose of 400 mg twice daily [6]. In 226 patients in CP who had imatinib-resistant disease, the MCyR and the CCyR rates were 56 % and 41 %, respectively [15], and the 2-year OS was 95 % with a PFS of 64 %. No difference in response was observed between patients with or without mutations, with the exception of patients with Y253H, E255V/K, F359V/C, and T315I who had less favorable responses [16, 17•].

Second Generation TKIs in the Front Line Setting

On the basis of the efficacy showed by these two drugs in the second line setting, nilotinib and dasatinib were tested on newly diagnosed CP-CML patients, in single arm and randomized double or triple arm studies.

Ninety-three newly-diagnosed CP CML patients were treated with dasatinib 50 mg twice daily (BID) or 100 mg once daily (QD) at the M. D. Anderson Cancer Center, with a median follow-up of 29 months (3–67 months) [18•, 19]. The primary endpoint was the attainment of MMR at 12 months. Most patients achieved a rapid CCyR (94 % at 6 months), with a cumulative CCyR ratio of 95 % among 87 evaluable patients. MMR has been achieved in 75 patients (86 %), including 54 patients (67 %) with complete molecular response (CMR; ≤0.0032 % IS). At 6 and 12 months, 68 % and 73 % of patients had achieved a MMR. The toxicity profile with dasatinib front line was favorable, with a better tolerability with dasatinib QD vs BID dosing, along with similar efficacy. In order to perform a full comparison of imatinib and next-generation TKIs, randomized phase III trials have been initiated in patients with newly diagnosed CP CML without prior treatment. Three ongoing trials are comparing dasatinib and imatinib. In CA180-056 (DASISION) [20••], an international trial, and SPIRIT2 [21], a UK-based trial, patients are randomized to receive either dasatinib 100 mg QD or imatinib 400 mg QD. In addition, a US-based randomized phase II study is comparing dasatinib with imatinib 400 mg [22].

In the DASISION trial patients were randomized to receive either dasatinib 100 mg QD or imatinib 400 mg QD. The primary endpoint was attainment of CCyR at 12 months. After a minimum follow-up of 12 months, the rate of confirmed CCyR (cCCyR) was in fact higher with dasatinib than with imatinib (77 % vs 66 %, p = 0.007), as was the rate of CCyR observed on at least 1 assessment (83 % vs 72 %, p = 0.001). The rate of MMR was higher with dasatinib than with imatinib (46 % vs 28 %, p <0.0001), and responses were achieved in a shorter time with dasatinib (P < 0.0001). By 24 months 77 % and 75 % remained on dasatinib and imatinib, respectively; response rates for dasatinib vs imatinib were: cCCyR 80 % and 74 %; CCyR 86 % and 82 %, MMR 64 % and 46 % (P < 0.0001); BCR-ABL ≤ 0.0032 % (MR4.5, ≥ 4.5-log reduction) was achieved in 17 % vs 8 % (P = 0.002), respectively. The transformation rate to accelerated/blast phase was 2.3 % vs 5 %. At 24 months, PFS rates (defined as survival without loss of response or transformation to AP/BP) for dasatinib vs imatinib were 93.7 % vs 92.1 %. OS rates, including follow-up beyond first line treatment, for dasatinib vs imatinib, were 95.3 % vs 95.2 %, although survival data are still immature. Among patients who discontinued the study treatment, a BCR-ABL mutation was detected in 10 patients in each arm. Patients on dasatinib developed the T315I mutation (7 patients), the F317L mutation (2 patients), and a concomitant F317I/V299L in 1 patient, which are known to be resistant to dasatinib and were also common in the second line studies. Instead 9 different mutations developed during treatment with imatinib. Both drugs were very well tolerated; thrombocytopenia grade 3–4 was more common with dasatinib compared with imatinib. Discontinuations due to AEs occurred in 7 % with dasatinib and 5 % with imatinib. Fifty-two percent of the patients treated with dasatinib and 36 % of those with imatinib had dose reduction and/or interruption for AE management at the 24-month update. Grade 3–4 nonhematologic AE rates in the DASISION study were ≤1 %. After a minimum follow-up of 24 months, 14 % of the 258 dasatinib-treated patients experienced pleural effusion; only 1 % had grade 3–4. The occurrence of pleural effusion and management interventions did not negatively affect the achievement of CCyR or MMR.

Two phase II studies demonstrated substantial activity of nilotinib 400 mg BID in newly diagnosed patients in CP. One hundred patients were treated with nilotinib at the M. D. Anderson Cancer Center for a median of 24 months [23•]. CCyR rates in evaluable patients after 3, 6, 12, and 24 months were 78 %, 92 %, 97 %, and 98 %, respectively, and after 12 and 24 months, 86 % and 88 % had achieved a MMR [24]. Seventy-three newly-diagnosed CP CML patients were treated with nilotinib across 18 GIMEMA centres with a median follow-up of 48 months [25•, 26]. The CCyR rate was 78 % at 3 months, 96 % at 6 and 12 months, 95 % at 18 months, 92 % at 24 months. MMR rates (named in this study as MR3.0) were 52 %, 66 %, 85 %, 81 % and 82 %, respectively. The overall estimated probability of MR4.0 was 79 %, while the rates of MR4.0 at 12, 24 and 36 months were 12 %, 27 % and 25 %, respectively. MR4.0 was defined as undetectable transcript levels with ≥ 10,000 Abl transcripts. To investigate the therapeutic potential of sequential TKI treatment, an exploratory phase II study is in progress (GIMEMA CML0408) evaluating treatment with sequential 3-month treatment blocks of nilotinib followed by 3 months of imatinib, with EFS at 24 months as the primary endpoint. The cumulative response rates were superior compared with the historical data of imatinib alone. However, if compared with the excellent results of second generation TKI as monotherapy, the study did not support an alternating schedule [27]. First-line treatment with nilotinib and imatinib is being compared in the CAMN107A2303 (ENESTnd) trial, an international phase III trial with 3 arms: 846 CP-CML patients were randomized to receive nilotinib 300 mg BID vs nilotinib 400 mg BID vs imatinib 400 mg/day [28••, 29]. Data from ENESTnd have shown that nilotinib (300 mg or 400 mg BID) was superior to imatinib, with a significantly higher 12-month MMR (44 % [P <0.0001] vs 43 % [P <0.0001] vs 22 %). By 24 months, still significantly more patients had a MMR with nilotinib than with imatinib: 71 % with nilotinib 300 mg twice daily, 67 % with nilotinib 400 mg twice daily, and 44 % with imatinib (P <0.0001 for both comparisons). Significantly more patients in the nilotinib groups achieved a CMR (named as MR4.5, defined as a reduction of Bcr–Abl levels ≤ 0.0032 %) at any time than did those in the imatinib group (26 % with nilotinib 300 mg twice daily, 21 % with nilotinib 400 mg twice daily, and 10 % with imatinib; P < 0.0001 for nilotinib 300 mg twice daily vs imatinib, P = 0.0004 for nilotinib 400 mg twice daily vs imatinib). Progression to AP/BC (excluding clonal evolution [CE]) on treatment was significantly lower for nilotinib vs imatinib (2 pts and 3 pts with nilotinib 300 mg BID [P = 0.0059] and 400 mg BID [P = 0.0196]), respectively, vs 12 pts with imatinib. At 24 months, survival was comparable in all treatment groups, but fewer CML-related deaths had occurred in both the nilotinib groups than in the imatinib group (5 with nilotinib 300 mg twice daily, 3 with nilotinib 400 mg twice daily, and 10 with imatinib). Approximately twice as many BCR-ABL mutations developed in the imatinib arm (20) vs nilotinib arms (10 and 8 for 300 mg BID and 400 mg BID), and most of these were detected within the first 12 months. The majority of mutations in the nilotinib arms were less sensitive (Y253H, E255K, F359V) or resistant (T315I) to nilotinib, while both nilotinib-sensitive and insensitive mutations were detected in the imatinib arm. The T315I mutation emerged in 8 patients: 3 on nilotinib 300 mg BID, 2 on nilotinib 400 mg BID, and 3 on imatinib. Nilotinib had superior efficacy to imatinib across all Sokal risk groups. Discontinuations due to AEs were lowest for nilotinib 300 mg BID (9 %).

In summary, compared with imatinib, nilotinib appears to eradicate more rapidly the bulk of CML cells, inducing high rate of CCyR and MMR after a very short period of treatment. Grade 3–4 AEs in first line studies were manageable with appropriate dose adaptations: hematologic toxicity was less frequent than in the salvage, and nonhematologic adverse events were generally infrequent. The only grade 3 or 4 nonhematologic adverse events reported in at least 2.5 % of patients in any treatment group were headache and rash. One patient in the imatinib group and one in the nilotinib 400 mg twice daily group discontinued the study because of acute pancreatitis; no patient discontinued because of hyperglycaemia. At the 24-month data cutoff, no patient in either of the nilotinib groups had a QTcF greater than 500 ms. No patient had a decrease in left ventricular ejection fraction of less than 45 %. Six patients had a peripheral arterial occlusive disease event within 24 months of follow-up, 3 (1 %) in each nilotinib group. All 6 of these events occurred in patients with preexisting risk factors for the disease and only one of these events was judged to be related to the study drug by the investigator.

Based on the results of the randomized studies dasatinib and nilotinib have both been approved by FDA and EMEA for the treatment of newly diagnosed adult patients with CML-CP, with a recommended dose of 100 mg/d for dasatinib and 300 mg twice daily for nilotinib.

Prognostic Factors: Response to TKIs

As a significant proportion of patients become resistant to imatinib, earlier use of nilotinib or dasatinib (ie, as a front-line therapy) in CP CML may be beneficial in two potential ways: by promoting an early response, thereby potentially improving prognosis; and/or by avoiding the development of treatment resistance. The clinical challenge in this setting would be to accurately identify patients who are likely to fail treatment with TKIs by using clinical risk factors and genetic testing as predictive factors.

The 12-month cytogenetic response to imatinib was predictive of prognosis either in the IRIS trial or in unsponsored studies [3032]. At 60 months, 97 % of patients with a CCyR after 12 months of imatinib had not progressed to the AP or BP, vs 93 % and 81 % of patients with a PCyR or absence of a MCyR, respectively (P < 0.001; P = 0.20 for the comparison between patients with a CCyR and those with a PCyR) [32]. Patients not in CCyR continuously face the competing possibility of eventually achieving a cytogenetic response vs progressing. In patients who failed to achieve a CCyR by 12 months, the probability of eventually achieving a CCyR was only 42 %, which was similar to the probability of losing response, disease progression, or death (38 %) [33•]. Suboptimal responders at 6 months (Table 1) are “cytogenetic” suboptimal responders, with a significantly lower probability of eventually achieving a CCyR and a MMR compared with patients with an optimal response, and EFS and transformation-free survival (TFS) similar to those of patients responding to criteria for failure at the same time point [34•]. Furthermore, compared with patients who achieved a CCyR by 6 months in the IRIS study, the rates of events at 6 years was about 2-fold higher in patients with a PCyR (EFS 85 % vs 91 %), and around 5-fold higher in patients with only a minor/minimal cytogenetic remission or no cytogenetic remission (EFS 58-59 % versus 91 %). Suboptimal response at 12 months defined a group with a similar TFS as those with optimal response, but with worse EFS. In contrast, patients with a suboptimal response at 18 months (“molecular” suboptimal responders) had outcomes that were similar to those patients with an optimal response [34•]. Analogue results were obtained analyzing a cohort of 224 patients treated with imatinib front line in London. Suboptimal responders defined at 6 and 12 months had a significant poorer PFS and lower probability of CCyR, whereas the 18-month criteria failed to identify patients with worse OS or PFS [35•]. Across all time-points, patients who had achieved a CCyR had lower rates of events or transformation to AP/BP compared with patients who had achieved inferior levels of cytogenetic response. The correlation between the achievement of an early CCyR and EFS and OS was evaluated in sequential phase II trials run at the MD Anderson Cancer Center in patients with newly diagnosed CML in CP treated with imatinib 400 mg daily, imatinib 400 mg BID, and new generation TKIs. Patients with 3, 6, and 12 months CCyR had, statistically, a significantly better outcome in terms of 3-year EFS and OS rates. There was no difference in EFS and OS in patients who achieved a CCyR whether they received 1 treatment or the others, remaining the achievement of an early CCyR a major determinant for outcome of patients with early CP CML. However, the new drugs induced higher rates of CCyR and MMR than imatinib and the median time to CCyR was 6 months with standard-dose imatinib and 3 months with second generation TKIs [36•]. The high rates of CCyR obtainable with imatinib led to molecular monitoring of BCR-ABL transcript levels with real-time quantitative polymerase chain reaction (RQ-PCR) as one of the preferred methods to assess the residual amount of disease in patients, particularly those experiencing CCyR. This technique may allow patients with CCyR to be further stratified into subgroups with different outcome features, although not in terms of overall survival [35, 36•, 37]. The molecular monitoring is essential for the establishment of the quality of a response. In particular the obtainment of a stable MMR translates into a longer CCyR and a better EFS, with a very low progression rate [38]. Categories of molecular response were associated with EFS in a time-dependent manner. At the 6-month landmark, patients with a poor molecular response had lower EFS rates compared with patients who achieved better molecular responses. Thus, patients with a BCR-ABL >10 % had 84-month EFS rates that were reduced (56 %) compared with patients with a BCR-ABL <0.1 %, BCR-ABL >0.1 % to ≤1.0 %, and those with BCR-ABL >1 % to ≤ 10 %, all of whom had an EFS rate >85 % at 84 months. At 12 months, the achievement of an MMR appeared to be a clinically significant event. At the 12-month landmark, patients with an MMR, and those with a BCR-ABL level at >0.1 % to ≤1.0 %, had similar 84-month EFS rates, while those with a worse molecular response had an EFS of <65 %. Lastly, after 18 months, the significance of MMR became more pronounced. In fact, the EFS for patients with an MMR was 95 %, compared with 86 % in patients achieving the next lower category of response of >0.1 % to ≤1.0 % [37].

Because the achievement of MMR has been associated with improved probability of durable Cytogenetic Remission and EFS [37, 38], the long-term outcome of patients not in MMR according to the BCR-ABL transcript levels at different time points during the first 12 months of imatinib therapy have been analyzed at the MD Anderson Cancer Center. By 3 months, patients with a transcript >10 % had a probability of eventually achieving a CCyR of 67 %, significantly lower than patients with a transcript ≤ 10 %. As time goes by, the outcome of patients with transcript levels >10 % worsens, with decreasing probabilities of MMR and increasing probabilities of developing an event [33•]. Two hundred and eighty-two patients with a molecular analysis available at 3 months were analyzed at the Hammersmith Hospital. Patients with transcript levels of more than 9.84 % at 3 months had significantly lower 8-year probabilities of OS (56.9 % vs 93.3 %; P < 0.001), progression-free survival, cumulative incidence of CCyR, and Complete Molecular Response (CMR) than those with higher transcript levels [39••]. Among 289 German patients, 203 were found with a BCR-ABL level <10 % and 86 with a transcript >10 %. A total of 20 failures (defined according to the ELN criteria) have been observed in 20 patients after 12 months, and 29 after 18 months. A stratification into 3 groups at 3 months revealed a significant difference concerning treatment failure between patients with BCR-ABL levels <10 % and those with BCR-ABL >10 % [40••]. The median BCR-ABL transcript level decreased faster in the dasatinib and in the nilotinib arm compared with the imatinib arm. By 3 months, 84 % and 64 % of evaluable patients in the dasatinib vs imatinib arm, respectively, had achieved a BCR-ABL level ≤ 10 % [41••]. A landmark analysis found that patients who had achieved BCR-ABL ≤ 10 % at 3 months had a higher probability of achieving CCyR and MMR by 18–24 months, a higher probability of 24-PFS, and a lower probability of transformation to AP/BP, both in the dasatinib and imatinib arms. However, probabilities of subsequent CCyR and MMR among patients who had a BCR-ABL level ≤10 % at 3 months showed a higher trend in dasatinib-treated patients compared with imatinib-treated patients. Also the findings from the UK SPIRIT 2 study agreed that patients who achieved a transcript level ≤ 10 % after 3 months of dasatinib had higher probability of eventually achieving CCyR, compared with patients with higher transcript levels (89.1 % vs 50.2 %; P = 0.02) [21].

Curative Therapy In CML: Is This A Reality?

The achievement of a fast MMR correlates with a higher probability of achievement of a CMR [42]. The definition of CMR is currently confusing and under revision because the meaning of “complete” is dependent on the sensitivity that can be reached in a given sample. Therefore, the term CMR in the next future, will be substituted by the indication of the real amount of residual disease present in the samples, and the results will be expressed as MR4, MR4,5 and MR5, which correspond respectively to a decrease of 4-, 4.5-, or 5-logs with respect to the median standard baseline at diagnosis, and to a percentage of 0.01 %, 0.0032 %, or 0.001% of BCR-ABL according to the IS [43•]. The achievement of a CMR represents the only possibility for our patient to discontinue the therapy with no further reappearance of the disease. Currently there is no indication to discontinue therapy out of clinical studies. We have few experiences on discontinuations. The first 12 patients were enrolled in France from March 2004 to July 2005. Eleven patients had CP CML and 1 patient had AP. Previous therapies comprised interferon in 10 of 12 patients and autologous hematopoietic stem cell transplantation in 2 patients. Imatinib was started at 400 mg in CP-CML and at 600 mg in AP-CML. The median interval from imatinib to molecular remission was 10 months. Imatinib therapy was then maintained during a median of 32 months, which corresponds to a median of 45 months of treatment. After discontinuation, a molecular relapse (without cytogenetic or hematologic relapse) occurred in 6 patients by the fifth month. Imatinib was reintroduced in all 6 patients with a new decline in residual disease [44]. A prospective, multicenter, non-randomized Stop Imatinib (STIM) study has followed. Imatinib treatment of >2 years duration was discontinued in patients with CML who were in CMR (>5-log reduction). One hundred patients were enrolled, with a median follow-up of 30 months. After imatinib was discontinued, a molecular relapse occurred in 61 patients with 58 relapses occurring during the first 7 months and 3 late relapses at months 19, 20, and 22, respectively. The overall probability of maintenance of CMR at 24 and 36 months was 39 %. All patients who relapsed (Bcr–Abl/Abl >0.001 % indicating the increase [at least 1 log] confirmed by a second analysis point) responded to reintroduction of imatinib. Independent prognostic factors of prognosis were sex, Sokal risk group, and imatinib treatment duration: highest Sokal score and female sex were predictive of worsened prognosis, whereas a long duration of imatinib was predictive of improved prognosis [45, 46].

Patients who obtain a stable CMR are a minority of imatinib-treated patients. Second generation TKIs induce a deeper and faster molecular response. However, despite the outstanding efficacy of these drugs, their curative potential remains uncertain. In fact, most TKI-treated patients retain residual leukemic cells detected by means of RTQ-PCR and termination of TKI therapy under such circumstances usually leads to disease relapse. We still do not have experience on big numbers of patients who discontinued second generation TKIs. Results of 16/25 patients followed for a minimum of 6 months were reported again by the French group during the last ASH meeting; approximately half of the patients were on dasatinib or nilotinib, with a median duration of treatment of 32 months and a median duration of sustained CMR of 27 months. MMR was lost in 31 % (5/16) of patients after a median time off-therapy of 4 months (1–5). Both MMR and CMR were rapidly regained upon TKI re-introduction. Eleven patients (68.75 %) remained off-therapy at the last follow-up after a median of 13 months (7–20) [47].

It is generally accepted that allogeneic stem cell transplantation can “cure” CML although occasional patients relapse more than 10 years after the transplant procedure. Such cures presumably result from the combined effects on leukemia stem cells (LSCs) of the conditioning regimen and the graft vs leukemia (GvL) effect mediated by donor-derived T lymphocytes. The advent of imatinib has revolutionized the management of patients with CML, but much evidence suggests that it does not eradicate all LSCs, which theoretically remain a potential source of relapse to chronic phase or advanced phase disease [48]. The existence of a threshold with a minimum residual number of leukemic cells required to reconstitute leukemic hematopoiesis was postulated. Once suppressed below this threshold, the Ph + clone may lose its reconstitution potential; certain immunological mechanisms may control it or it may finally become extinct by chance.

Conclusions

According to the ELN recommendations, failure to imatinib strongly demands a change in treatment, including a switch to one of the available second-generation TKIs, dasatinib or nilotinib. Achieving a CCyR is associated with a favorable long-term prognosis. The identification early into the course of therapy of patients at high risk of not achieving a CCyR is thus relevant. The best therapeutic strategy for patients with cytogenetic suboptimal response has not been clearly established. However, reports that responders at 6 months have final outcomes not so dissimilar from those of manifest failures, the good results obtained with second-generation TKIs, and these agents’ good tolerability are progressively moving many clinicians to favor switching to second-generation TKIs. MMR provides more stable disease control. Assessment of molecular response after 3 months of first-line imatinib therapy in patients with CML-CP found that molecular response was predictive for EFS/OS. All 3 TKIs, imatinib, dastinib, and nilotinib, are approved for initial treatment of CML-CP. Nilotinib and dasatinib demonstrated superior CCyR, MMR, and CMR4.5, compared with imatinib, with fewer rates of progression to AP/BC in all risk groups, although a longer follow-up is required to support the superiority of these drugs in terms of OS. The achievement of MMR is an important target because it anticipates and predicts for the achievement of CMR. The achievement of a CMR is the only condition that preludes the decision of treatment interruption. The Sokal score and the duration of targeting Ph + stem cells have been related to a higher probability of remaining in remission after treatment discontinuation. Dasatinib and nilotinib were superior to imatinib in all categories of risk, potentially increasing the number of patients eligible for discontinuation.

Disclosure

C. Fava: none; G. Rege-Cambrin: none; G. Saglio: consultancy and speakers’ bureaus (Novartis and BMS).

Copyright information

© Springer Science+Business Media, LLC 2012