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Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Statistical analysis
  6. Results
  7. Discussion
  8. Author Contributions
  9. References

Second generation tyrosine kinase-inhibitors (TKI) have been claimed to represent now the first-choice therapy for chronic myeloid leukemia (CML). Indeed, they generally induce faster and deeper molecular responses compared to imatinib that, however, is equally effective in at least 50% of patients. Moreover, some recent reports have questioned the long term safety of dasatinib and nilotinib. Therefore, upfront imatinib with early shift to second generation TKI for patients with slow/incomplete response might be as effective as front-line second generation TKI, with a possibly better safety profile. We retrospectively evaluated 91 chronic phase CML patients (median follow-up 57 months, median age 61 years), treated front-line with standard-dose imatinib and early therapy modifications (at 3–12 months) in case of unsatisfactory response or intolerance. Thirty-three patients (24 with unsatisfactory response, 9 intolerant) changed therapy, either by increasing imatinib dose (11/91) or by switching to second generation TKI (22 directly, 4 after high-dose imatinib). Globally, our strategy led to complete cytogenetic response (CCyR) in 98% of the patients, major molecular response (MMR) in 88% and molecular response 4 logs (MR4.0) in 62%. Three patients in CCyR (3%), 2 of them in MMR too, suddenly progressed to blastic phase. At the last follow-up nine patients had died, seven of CML-unrelated causes and two only of CML progression. These results suggest that our strategy could be as effective as front line second generation TKI, with most of patients still receiving imatinib, a drug of better known long-term side effects and lower cost. Am. J. Hematol. 88:838–842, 2013. © 2013 Wiley Periodicals, Inc.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Statistical analysis
  6. Results
  7. Discussion
  8. Author Contributions
  9. References

In the past 12 years, tyrosine kinase inhibitors (TKI) have dramatically changed the clinical outcome of chronic myeloid leukemia (CML) patients in chronic phase [1, 2]. In particular, most clinical trials with imatinib reported a 70–80% of patients achieving a durable complete cytogenetic response (CCyR) [3-5]. Second generation TKI have been successful in inducing CCyR in 40–50% of patients failing imatinib treatment [6-9]. Therefore, only 10% of patients who started imatinib treatment in early chronic phase progressed to accelerated/blastic phase or died of CML at 8–10 years from diagnosis [10].

More recently, second generation TKI employed as first-line treatment, have determined earlier CCyR and higher proportions of patients achieving a major molecular response (MMR) [11-13]. This has been defined as a BCR-ABL transcript level of 0.1% or lower on the International Scale corresponding to a reduction in the BCR-ABL transcript level by at least 3 logs from the standardized baseline level [14, 15]. In phase III studies comparing second generation TKI to standard imatinib treatment, a lower proportion of patients progressing to the accelerated/blastic phase was observed with second generation TKI compared to imatinib treatment; however, that difference reached a statistically significance with nilotinib but not with dasatinib or bosutinib therapy [16-19]. Dasatinib and nilotinib have been approved, both in Europe and USA, for first-line CML treatment and are claimed by some authors to represent now the standard front-line CML therapy [20], in spite of their higher costs and some uncertainty on their long-term side effects [21-27], compared to imatinib.

However, some discrepancies in the proportions of patients achieving CCyR (ranging from 98% in phase II to about 75% in phase III trials) have been observed in different studies with both nilotinib and dasatinib [11-13, 16, 17]. Moreover, recent surveys evidenced equally excellent long-term results (about 95% progression-free survival) for both imatinib and nilotinib/dasatinib-treated patients who achieved an early molecular response: BCR-ABL/ABL transcript <10% I.S., after 3 months of therapy [28-30]. In some previous reports too, “optimal responders” to 3–6 months of imatinib therapy, according to European Leukemia Net (ELN) definitions [31], obtained very good long-term therapeutic results [32-35], comparable to those achievable with front-line second generation TKI. Indeed, recent guidelines by the European Society of Medical Oncology (ESMO) advised an early TKI shift for patient with a BCR-ABL transcript >10% I.S. after 3 months of therapy [36].

Therefore, two different strategies can now be considered for chronic phase CML: either a front-line use of second generation TKI or still an imatinib-based treatment with early shift to second generation TKI in the case of suboptimal molecular /cytogenetic response after 3–6 months of therapy [37-43]. However, no clinical study has yet directly compared the two strategies or clearly evaluated the efficacy of an early therapy change in suboptimal responders to imatinib.

In our center, starting from 2005 before ENL guidelines were available, almost all CML patients who displayed resistance or suboptimal cytogenetic/molecular response to standard imatinib treatment underwent an early shift to either an increased imatinib dosage or, more recently, to dasatinib or nilotinib. Here, we report the favorable long-term outcome of 91 consecutive CML patients, diagnosed from January 2005 and treated according to that strategy.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Statistical analysis
  6. Results
  7. Discussion
  8. Author Contributions
  9. References

Patients

Ninety-one patients were diagnosed with chronic phase BCR-ABL + CML according to standard morphological, cytogenetic, and molecular procedures, from January 2005 to March 2012. All patients were treated front-line with standard-dose imatinib and early therapy modifications were introduced in cases of intolerance or suboptimal response. We did not include in this study six patients diagnosed in that period because of either severe co-morbidities at the time of CML diagnosis (advanced lung cancer in one, severe vascular dementia in another patient), or early loss from follow-up (two patients who left Italy), or inadequate imatinib intake (<300 mg/day in two patients) for lack of compliance.

Table 1 illustrates the main clinical features of our patients. Median age at diagnosis was 61 years (range, 18–86 years). Sokal “score,” available for 83 patients was “low risk” in 36, “intermediate risk” in 34, “high risk” in 13.

Table 1. Baseline Characteristics of the Patients
  
Sex, n (%) 
Male49 (54)
Female42 (46)
Age (years) 
Median (range)61 (18–86)
Sokal score, n (%) 
Low36 (43)
Intermediate34 (41)
High13 (16)

All the patient gave an informed consent to make their clinical data available.

Treatment

All patients began imatinib 400 mg daily within 3 weeks from diagnosis. Six elderly patients started the therapy with a reduced dosage of 300 mg daily but increased it to 400 mg/day after 1–3 months. Starting from 2005, it has been our policy to increase imatinib dosage to 600–800 mg daily for patients who had not reached at least a partial cytogenetic response after 6 months and a CCyR after 12 months of therapy. Since the publication of 2009 ENL guidelines [31], the same approach was applied to all “suboptimal responders” according to ENL criteria. In the last 2 years of the study, all patients without an “optimal response” to imatinib according to ENL criteria were immediately shifted to dasatinib or nilotinib treatment. More recently, we apply the same approach to patients with a BCR-ABL transcript >10% I.S. after 3 months of therapy.

Response evaluation

Response monitoring was performed by standard blood counts and morphology, cytogenetic analysis, and quantitative “real-time” PCR. Cytogenetic and molecular tests were performed in the central pathology service of our hospital. Molecular tests have been standardized according to Italian Labnet procedures. Cytogenetic analysis on bone marrow aspirates was performed every 3 months until CCyR achievement and then every 2 years or at the time of therapy shift for unsatisfactory response. We relayed on double color F.I.S.H analysis on interphase bone marrow cells if less than 20 mitosis were available in standard cytogenetics. Quantitative PCR was routinely performed on whole peripheral blood leucocytes every 3 months until a confirmed complete molecular response (PCR negativity) and every 6 month thereafter.

Cytogenetic and molecular responses were defined according to ELN definitions [31]. In particular, CCyR: absence of detectable Philadelphia chromosome in 20 mitosis and /or <1% BCR-ABL + cells by interphase F.I.S.H. analysis on 300 cells; MMR: BCR-ABL transcript ≤0.1% I.S.; “Molecular response 4 logs” (MR4.0): BCR-ABL transcript ≤0.01% I.S. (with at least 1 × 104 copies of control ABL gene transcript in the PCR reaction) [44]. In a 86 years old patient, cytogenetic analysis was not performed and CCyR was defined as BCR-ABL transcript <1% I.S. [45]. Response to therapy has been defined as “optimal,” “suboptimal,” or “failure” according to 2009 ELN criteria [31].

We performed final patients' evaluation in April 2013.

Statistical analysis

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Statistical analysis
  6. Results
  7. Discussion
  8. Author Contributions
  9. References

The primary end points of the study were overall survival and cumulative incidence (CI) of CCyR, MMR and MR4.0. Overall survival from diagnosis until death from any cause or disease-related death was calculated by the Kaplan–Meier method.

The incidence of CCyR, MMR, and MR4.0 was calculated by the cumulative function; death without achieving these responses was considered a competing event.

Data were analyzed as of April 2013 by NCSS 2007.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Statistical analysis
  6. Results
  7. Discussion
  8. Author Contributions
  9. References

Median follow-up of living patients is 57 months (range 15–98 months).

Eighty-six percent (78/91) of the patients reached a CCyR with imatinib standard dose. In one patient cytogenetic analysis was not performed because of poor clinical condition and she died of ab-ingestis pneumonia before completing 12 months of therapy.

As a result of this first line treatment 64% of patients (58/91) also achieved a MMR and 49% (45/91) a MR4.0. Five patients in imatinib treatment (5.5%) later lost the CCyR and were shifted to second generation TKI.

Fifty-four patients (59%) maintained imatinib standard dose. The reasons for therapy modification in the other patients are shown in table 2. In particular, five patients with MR4.0 (four of them with undetectable BCR-ABL transcript) tried imatinib discontinuation: one resumed imatinib for loss of MR4.0 and soon regained it, four maintained a stable MR4.0 without any therapy.

Table 2. Reasons for Therapy Change
  
  1. a

    Suboptimal molecular and cytogenetic responses were defined according to 2009 European Leukemia Net guidelines.

  2. b

    Resistance defined as: less than a complete hematologic response after 3 months of therapy, no cytogenetic response after 6 months, less than a partial cytogenetic response after 12 months, and less than a complete cytogenetic response after 18 months.

  3. c

    Progression defined as: loss of complete hematologic response, loss of complete cytogenetic response, clonal evolution, or progression to accelerated or blastic phase.

Therapy change33
Intolerance9
Suboptimal response (molecular)a12
Suboptimal response (cytogenetic)a4
Resistanceb3
Progressionc5

Thirty-three patients (36%) changed therapy, either by increasing imatinib dose or by switching to second generation TKI. In particular, nine patients (10%) changed TKI because of intolerance to imatinib: five for grade 3 toxicities (one hepatic, one pulmonary, and three cutaneous) and four patients for several grade 2 extra-hematological side effects.

In the other 24 cases (26%), therapy modification was determined by unsatisfactory imatinib response: 12 patients had a molecular suboptimal response, four a cytogenetic suboptimal response, three were cytogenetically resistant, and five had disease progression (one a cytogenetic relapse, one a hematologic relapse, one a cytogenetic resistance with clonal evolution, and two a sudden lymphoid blastic crisis).

Eleven patients with “suboptimal response” increased imatinib dose to 600 or 800 mg per day: seven achieved an optimal response (3 MR4.0, 4 MMR) whereas four subsequently switched to a second generation TKI, one for intolerance and three because of a still unsatisfactory response.

Thirteen patients with unsatisfactory response to imatinib 400 mg daily shifted directly to second generation TKI.

On the whole, 26 patients (10 for imatinib intolerance, 14 for unsatisfactory response, and two for progression to blastic phase) switched either to dasatinib (14) or nilotinib (11) or bosutinib (1). Four of these patients subsequently showed intolerance to one of second generation TKI and further shifted to the other one or restarted imatinib. Seventy-three percent of the patients treated with second generation TKI in chronic phase (16/22) achieved a stable MMR (10 MR 4.0), 23% (6/22) achieved a CCyR only, one did not respond and underwent allogeneic stem cell transplantation, another one achieved a MMR with nilotinib but later progressed to a sudden lymphoid blast crisis. Two patients switched to second generation TKI after progression to blastic phase during imatinib treatment. Both of them achieved a complete hematological and cytogenetic response but later relapsed.

Therapeutic changes are detailed in Fig. 1.

image

Figure 1. Schematic representation of the treatments received by the 91 patients with chronic phase CML.

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Globally, our “early-switch” strategy led to a CCyR in 98% of the patients (89/91), with a CI of CCyR of 86% at 12, and 93% at 24 months (Fig. 2). MMR was achieved by 88% of the patients (80/91) with a MMR rate of 44, 69, and 87% at 12, 24, and 48 months, respectively (Fig. 2). Fifty-six patients (62%) reached a MR4.0 (CI: 32% at 24 months and 60% at 48 months) (Fig. 2).

image

Figure 2. Cumulative incidence of CCyR, MMR (defined by a BCR-ABL transcript ≤ 0.1% I.S. [44]) and MR4.0 (defined by a BCR-ABL transcript ≤0.01% I.S [44]) in the 91 CML patients treated with up-front imatinib and “early shift” strategy. Black line: cumulative incidence of CCyR; grey line: cumulative incidence of MMR; dotted line: cumulative incidence of MR4.0.

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Another patient did not respond to any TKI and reached MR4.0 after allogeneic hematopoietic stem cell transplantation (alloHSCT): he was censored at the time of transplantation.

Twenty-one patients actually obtained an undetectable BCR-ABL transcript; however, we could not formally define these responses MR4.5 or deeper because of the inadequate number of control gene copies in the PCR reaction (<32.000) [44]. No significant differences in the final outcome were observed among the patients of the three Sokal score groups.

Three patients suddenly progressed to the blastic phase after reaching CCyR and, in two cases, MMR too. In all the cases, blasts were of B lymphoid lineage and evolutions occurred after 15, 20, and 70 months, from diagnosis, respectively. The first patient was on imatinib 400 mg/ day at the time of progression; then she received chemotherapy and dasatinib, underwent alloHSCT and died of relapse a few months later. The second patient was receiving imatinib 400 mg/day; hence she was switched to bosutinib, underwent alloHSCT and eventually died of relapsing disease. The last patient was receiving nilotinib 800 mg daily when the progression occurred, then he was switched to dasatinib and chemotherapy with unsatisfactory response and he is currently receiving ponatinib.

At the last follow-up nine patients (10%) had died. Seven patients, all aged more than 60, died of CML unrelated causes, six while in CCyR and one before reaching it. In particular, the cause of death was solid cancer in five patients (two lung, one gastric, one pancreatic, and one glioblastoma), cardiovascular surgery in one and “ab-ingestis” pneumonia in the other one.

The other two patients died of disease progression, after 28 and 80 months, respectively, from diagnosis.

The projected overall survival rate is 92% at 5 years and 80% at 8 years. If we consider only disease-related deaths 8 years survival is projected at 95% (Fig. 3).

image

Figure 3. Overall survival of the 91 CML patients treated with up-front imatinib and “early shift” strategy. Black line: all deaths considered; gray line: only CML-related deaths considered.

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Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Statistical analysis
  6. Results
  7. Discussion
  8. Author Contributions
  9. References

In the past few years, several studies evaluated the activity of second generation TKI as first-line therapy for chronic phase CML and confirmed their more potent anti-leukemic activity compared to imatinib. However, a significant fraction of CML patients (at least 50–60%) are very sensitive to imatinib too and display early cytogenetic and molecular responses [28-30], comparable to those achievable with front-line second generation TKI. Second generation TKI can rescue to CCyR 40–50% only of truly imatinib-resistant patients [6-9]; therefore, it has been suggested that a therapeutic strategy involving front-line imatinib and second generation TKI in cases of cytogenetic/hematologic resistance to the first drug could not achieve the same results obtained with front-line use of the new TKI [20]. However, results might be different if a switch to second generation TKI is performed before a clear imatinib resistance has developed, i.e., in cases of slow imatinib response, and both ENESTnd and DASISION studies did not employ this kind of strategy for the imatinib arm. Indeed, in the TIDEL-II study, the strategy of early imatinib dose increase and eventual shift to nilotinib in the cases of less than optimal response reported excellent results in terms of CCyR, MMR and progression-free survival [46]. Spanish PETHEMA group also reported very good final outcomes with a strategy involving either an increased imatinib dose or interferon addition to imatinib 400 mg daily and eventually a shift to second generation TKI in cases of suboptimal hematologic or cytogenetic response [47].

Our present study retrospectively evaluated patients who have been treated according to a somewhat similar strategy: front line standard-dose imatinib, then early shift (at 3–12 months) to higher imatinib dose and/or second generation TKI in cases with unsatisfactory response. We excluded from our survey CML patients with a diagnosis before 2005 since in the previous years the early shift to high dose imatinib was not routinely considered for suboptimal responders and second generation TKI were not available. We included in the study 91 CML patients in chronic phase treated in the two hematological Institutions from 2005, irrespectively of age: indeed the median age of our casistics (61 years) is 12–15 years higher than the median age reported in trials with either imatinib or second generation TKI and reflects the actual age of CML patients in our country. Patients' distribution according to Sokal score was also similar to that previously observed in a large CML observational study in Italy [48].

Optimal responses to imatinib were in the range of the best reported in literature [10] and most of these patients continued that drug. Conversely, 11 and 18% of patients underwent an early shift to second generation TKI because of intolerance and unsatisfactory response, respectively. The final outcome of the whole casistics was the achievement of CCyR by all but two patients (one early death and one with cytogenetic resistance) and of MMR and MR4.0 by the large majority of them. Indeed, the proportions of patients achieving MMR and MR4.0 at 2 and 4 years from diagnosis were similar to those reported in studies with first-line second generation TKI in younger patients [11-13, 16-19]. Most of responses were maintained at a median follow-up of 57 months, with three patients only progressing to a “sudden” blastic phase. These events occurred unexpectedly in patients in CCyR ± MMR, without a previous hematological relapse in chronic phase. The same was true for one of the two cases of blastic phase we observed in imatinib era before 2005. Intriguingly, all these cases of “unexpected” blastic crisis involved B-lymphoid lineage.

It has been reported that the earlier responses and the lower incidence of BCR-ABL mutations achievable with front-line second generation TKI could significantly reduce the incidence of progressions to blastic phase and CML-related deaths, compared to imatinib [16-19]. However, this has been proven true with nilotinib only in the ENESTnd study [16]. Moreover, at a 2–3 years follow-up, both in ENESTnd and DASISION studies the incidence of evolution to accelerated/blastic phase ranged between 2.1 and 3.5% of patients who started the second generation TKI [16, 17]. It has not been reported whether these events occurred in patients in CCyR and involved lymphoid lineage as in our casistics or represented the progression of a cytogenetic resistant or relapsing disease. Although our casistics was too limited to accurately assess the incidence of blastic phase progressions, these events were observed in a small percentage (3.3%) of our patients, comparable to that reported in ENESTnd and DASISION studies with a shorter follow-up.

Recently, some reports have questioned the long term safety of second generation TKIs. In particular several observations suggest that nilotinib has a proatherogenic activity, since patients treated with this drug seem to be at higher risk of developing peripheral artery occlusive disease, stroke and other vascular diseases [21-24]. Other studies showed that dasatinib, in addition to causing pleural and pericardial effusion in a consistent proportion of patients might increase the risk of pulmonary arterial hypertension [25-27]. On the other hand, imatinib has been used worldwide for more than 12 years and it has demonstrated a safe long-term profile. Thus, it appears more cautious to choose imatinib as a first line treatment, at least unless a clear survival advantage of up-front second generation TKI has been proved.

In conclusion, our results suggest that a therapeutic strategy involving front-line imatinib and early shift to second generation TKI in cases of intolerance or suboptimal cytogenetic/molecular response could be as effective as front line second generation TKI in terms of MMR, MR4.0, and progression-free survival, with the majority of patients maintained in a therapy of better known long-term side effects [49], lower costs and, in Italy, easier prescription procedure. However, our study was a retrospective one, involving a not very large number of patients. We think that the issue of the optimal up-front strategy in CML therapy should be worthy to be evaluated in a prospective, possibly randomized study. It would be also interesting to evaluate the possibility of therapy discontinuation in complete molecular response that has been hypothesized, but not demonstrated yet, to be greater with up-front use of second generation TKI than with imatinib [50].

Author Contributions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Statistical analysis
  6. Results
  7. Discussion
  8. Author Contributions
  9. References

MC analyzed data and wrote the paper. EC performed statistical analysis and wrote the paper; DF ideated the study and wrote the paper. PP followed the patients and reviewed the paper. PR and CA followed the patients and collected data. MB supervised the research and provided funds.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Statistical analysis
  6. Results
  7. Discussion
  8. Author Contributions
  9. References
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