Originally published as JCO Early Release 10.1200/JCO.2007.15.8154 on June 2 2008

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Imatinib for Newly Diagnosed Patients With Chronic Myeloid Leukemia: Incidence of Sustained Responses in an Intention-to-Treat Analysis

Hugues de Lavallade, Jane F. Apperley, Jamshid S. Khorashad, Dragana Milojkovic, Alistair G. Reid, Marco Bua, Richard Szydlo, Eduardo Olavarria, Jaspal Kaeda, John M. Goldman, David Marin

From the Department of Haematology, Hammersmith Hospitals Trust, Imperial College London, London, United Kingdom

Corresponding author: David Marin, MD, Department of Haematology, Imperial College London, Du Cane Rd, London W12 0NN, United Kingdom; e-mail: d.marin{at}imperial.ac.uk

	ABSTRACT

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Purpose Imatinib is remarkably effective in treating newly diagnosed patients with chronic myeloid leukemia (CML) in chronic phase (CP). To date, most of the available data come from a single multicenter study in which some of the patients were censored for diverse reasons. Here, we report our experience in treating patients at a single institution in a setting where all events were recorded.

Patients and Methods A total of 204 consecutive adult patients with newly diagnosed CML in CP received imatinib from June 2000 until August 2006. Response (hematologic, cytogenetic, and molecular), progression-free survival (PFS) and survival were evaluated.

Results At 5 years, cumulative incidences of complete cytogenetic response (CCyR) and major molecular response (MMR) were 82.7% and 50.1%, respectively. Estimated overall survival and PFS were 83.2% and 82.7%, respectively. By 5 years, 25% of patients had discontinued imatinib treatment because of an unsatisfactory response and/or toxicity. The 5-year probability of remaining in major cytogenetic response while still receiving imatinib was 62.7%. Patients achieving a CCyR at 1 year had a better PFS and overall survival than those failing to reach CCyR, but achieving a MMR conferred no further advantage. The identification of a kinase domain mutation was the only factor predicting for loss of CCyR.

Conclusion Imatinib is highly effective in most patients with CML-CP; patients who respond are likely to live substantially longer than those treated with earlier therapies. Achieving CCyR correlated with PFS and overall survival, but achieving MMR had no further predictive value. However, approximately one third of patients still need better therapy.

	INTRODUCTION

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Imatinib is remarkably effective therapy for newly diagnosed patients with chronic myeloid leukemia (CML) in chronic phase (CP).¹ Most of the available data on the efficacy of imatinib in these patients are based on results of a single multicenter trial, the International Randomized Study of Interferon (IRIS) study, carried out under the supervision of the manufacturer.^1-3 In the IRIS study, the majority of patients achieved a durable complete cytogenetic response (CCyR) and the estimated overall survival (OS) was 89% at 5 years; furthermore, these responses seemed to be sustained.³ However, 20% of patients were censored for various reasons, and event-free survival and progression to accelerated or blastic phase were evaluated only for those patients still receiving the study drug. This means that the overall results may differ from those obtained in an analysis performed on an intention-to-treat basis.⁴ We present here a single-institution experience in the treatment with imatinib of newly diagnosed patients with CML.

	PATIENTS AND METHODS

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Patient Characteristics and Treatment
Between June 2000 and August 2006, 204 consecutive adult patients with BCR-ABL–positive CML in CP received imatinib as first-line therapy. Imatinib was started within 6 months of diagnosis. The patients had received no prior treatment for leukemia other than hydroxyurea. Seventeen of these patients were included in the IRIS study. The research ethics committee reviewed the study protocol, and patients gave written informed consent to participate. CP and complete hematologic responses (CHRs) were defined by conventional criteria.^1,5 Patients received imatinib 400 mg/d by mouth, and the dose was adjusted according to tolerance and response.^1,3 Dose was reduced in the presence of grades 3 to 4 toxicity⁶ with the aim of maintaining imatinib at or greater than 300 mg/d. Initially, the criteria for dose escalation were applied as in the IRIS study,^1,3 but as more evidence emerged, dose increases reflected those recommended by the European LeukemiaNet.⁷ Similarly, the criteria for discontinuing imatinib varied as new tyrosine kinase inhibitors became available.

Bone marrow morphology and cytogenetics were assessed at diagnosis and then every 3 months until patients achieved CCyR. Thereafter, patients were monitored by real-time quantitative polymerase chain reaction (PCR) and annual bone marrow examinations. CCyR was defined by the failure to detect any Philadelphia chromosome (Ph)-positive metaphases in two consecutive bone marrow examinations with a minimum of 30 metaphases examined; major cytogenetic response (MCyR) was defined by combining the number of complete and partial cytogenetic responses ( 35% Ph-positive metaphases). Cytogenetic relapse (loss of CCyR) was defined by the detection of one or more Ph-positive marrow metaphases, also confirmed by a subsequent study. Bone marrow examination was triggered by a rise in BCR-ABL transcript numbers to a level consistent with cytogenetic relapse.⁸

Detection of BCR-ABL Transcripts
BCR-ABL transcripts were measured in the blood at 6- to 12-week intervals using quantitative real-time PCR (RQ-PCR) as described previously.^8-11 Results were expressed as percent ratios relative to an ABL internal control and as log₁₀ reductions compared with a standardized median value for the 30 untreated patients used in the IRIS study.^2,9 Major molecular response (MMR) was defined as a 3-log reduction in transcript levels² on the basis of two consecutive molecular studies; complete molecular response (CMR) was defined as two consecutive samples with no detectable transcripts.

BCR-ABL Kinase Domain Mutations
Samples obtained for RQ-PCR from August 2003 were also analyzed every 6 months on a routine basis for kinase domain (KD) mutations, and more often if resistance to imatinib was suspected. The criteria for triggering an unscheduled screen for a mutation were (1) loss of CHR or progression to advanced phase, (2) loss of MCyR or CCyR, (3) an increase by a factor of 2 in the transcript level,¹³ and (4) failure to achieve a CHR by 12 weeks. Samples obtained before August 2003 were analyzed retrospectively using the same criteria. Samples were not available from 12 patients (6%). Once a mutation was detected the result was confirmed using pyrosequencing¹² and the earlier samples were then analyzed to determine the time at which the mutation first became detectable and its subsequent kinetics.

Statistical Methods
Probabilities of OS and progression-free survival (PFS) were calculated using the Kaplan-Meier method. PFS was defined as survival without evidence of accelerated or blastic phase disease.⁵ The probabilities of cytogenetic response and cytogenetic relapse were calculated using the cumulative incidence procedure, in which cytogenetic response or relapse were the events of interest, and death and disease progression were the competitors. For survival and PFS analysis, patients were censored at the time of stem-cell transplantation; for cytogenetic responses patients were censored at imatinib discontinuation. Univariate analyses to identify prognostic factors for OS, PFS, cytogenetic response, and cytogenetic relapse were carried out using the log-rank test. Variables found to be significant at the P < .25 level were entered into a proportional hazards regression analysis; a forward stepping procedure was employed to find the best model. The influence of KD mutations on the different outcomes was studied in a time-dependent Cox model. P values were two sided and 95% CIs computed.

	RESULTS

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Patients and Treatment
Patient characteristics are detailed in Table 1. Patients still alive had a median follow-up of 38 months (range, 12 to 85 months); no patient was lost to follow-up. At the time of data analysis 54 patients (26%) had permanently discontinued imatinib after a median time of 15.5 months (range, 0.5 to 64 months). Reasons for discontinuation included adverse events (n = 7), loss of CHR or progression to accelerated or blastic phase (n = 26), loss of MCyR (n = 3), and failure to achieve MCyR while still in CHR (n = 18). After discontinuing imatinib, 18 patients underwent allogeneic stem-cell transplantation (four while still in CP) and the remaining 36 received one or more of hydroxyurea, interferon-, dasatinib, nilotinib, or other agents. Imatinib toxicity was comparable with that described in the literature (data not shown).^1,3 The dose of imatinib was increased in 75 patients (37%).

View larger version (20K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Cumulative incidence of best cytogenetic and molecular responses to imatinib. At 1 year, the cumulative incidence of complete hematologic response (CHR) was 97.1%, of major cytogenetic response (MCyR) was 71.1%, of complete cytogenetic response (CCyR) 57.4%, of MMR 12.3%, of a 4-log reduction in transcript levels 2.9%, and of complete molecular response (CMR) 0.5%. At 5 years, the cumulative incidence of CHR was 98.5%, of MCyR was 85.1%, of CCyR 82.7%, of MMR 50.1%, of a 4-log reduction in transcript levels 19.9%, and of CMR 8.3%. Vertical lines indicate censored patients.

We found an association between the dose of imatinib received during the first 6 months of therapy and the probability of achieving CCyR in the 193 patients still in chronic phase at 12 months. Patients who received an average dose more than 350 mg/d (n = 160) had a higher cumulative incidence of CCyR at 5 years than did those who received lower doses (89.3% v 61.8%; P = .003).

During follow-up, 80 patients (39%) achieved an MMR, which was sustained in 72 (35%). Only 10 patients (5%) achieved CMR, which proved durable in six (3%; Fig 1). One hundred forty-five patients achieved and maintained a CCyR, but 10 of these subsequently had an increase in transcript levels of at least 0.5-log greater than nadir¹⁵ without losing CCyR. Figure 2 shows the kinetics of the molecular responses in the remaining 135 patients.

View larger version (16K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Evolution of transcript levels in the 135 responders in stable complete cytogenetic response (CCyR). The vertical lines indicate the 25 and 75 percentiles. The solid blue circles indicate the median values.

View larger version (15K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 3. Cumulative incidence of best complete cytogenetic response (CCyR) according to the cytogenetic response at (A) 3 and (B) 6 months. Ph+, Philadelphia chromosome.

PFS, OS, and Event Free-Survival
Figure 4 shows the 5-year probabilities of PFS, loss of CHR, event free-survival (EFS), and survival on an intention-to- treat basis. Eight of the 18 patients who experienced progression to advanced phase did so within the first year. We found a correlation between grade 3 and 4 bone marrow toxicity and early progression, because four of the 29 patients with myelosuppression progressed compared with four of 175 without myelosuppression (P = .016).

View larger version (19K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 4. Overall survival, progression-free survival (PFS), probability of remaining in complete hematologic response (CHR) and of event-free survival (EFS) by intention-to-treat analysis. During follow-up, 11 patients died (one as a result of a leukemia-unrelated cause while still in complete cytogenetic response), 18 patients progressed to accelerated or blastic phases (n = 16 blastic phase), and 26 lost their CHR. At 5 years, the probability of survival was 83.2%, of PFS 2.7%, and of remaining in CHR 81.0%. The term EFS as defined for this study reflects the probability of stable cytogenetic response with imatinib at 5 years (62.7%). The figure also shows the probability of loss of major cytogenetic response (MCyR); of the 171 patients who achieved a MCyR 14 lost the response. The 5-year probability of losing a MCyR was 16%. The vertical lines indicate censored patients.

Effects of Response on Outcome
Cytogenetic response had an important influence on the probabilities of survival and PFS. Figure 5 shows the results of a landmark analysis according to cytogenetic response at 1 year. At 1 year, 193 patients were still in CP, and 121 had achieved CCyR. These 121 individuals had better OS and PFS than did the 72 patients who had failed to achieve CCyR, namely 98.0% versus 74.1% (P = .03) and 96.0% versus 74.0% (P = .007), respectively. When we subclassified the patients achieving CCyR at 1 year (n = 121) or at 18 months (n = 106) by whether they had also achieved MMR at those time points (n = 30 at 1 year; n = 38 at 18 months) we found no significant difference in PFS or OS (data not shown).

View larger version (14K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 5. Landmark analysis of progression-free survival (PFS) on the basis of cytogenetic response to imatinib at 1 year. At 1 year, 193 patients were still in chronic phase and could be subclassified according to cytogenetic response; 121 (62.6%) had achieved complete cytogenetic response (CCyR) and 72 (37.4%) had failed to do so. The patients who had achieved CCyR had a better 5-year PFS than those who had not (96% v 74%; P = .007) and also better survival. Vertical lines indicate censored patients.

Development of KD Mutations
Twelve different KD mutations were detected in 11 patients during follow-up. The median time to detection was 10.5 months (range, 4.3 to 53 months). The 5-year cumulative incidence was 8.6% (95% CI, 4.5% to 15.8%). Of the 11 patients, four never achieved any degree of cytogenetic response during follow-up; in two patients, the mutation was detected while still in CHR (M244V and E453V), and in two others at the time of progression to advanced phase (D276G and F311I). In the remaining seven patients, the mutation were detected while in CCyR; six patients lost their CCyR (T315I, F359V, M351T, S417F, L387M, E459K) and one of them progressed to blastic phase (E459K); the 11th patient eventually achieved CMR (S438C). The median time between the detection of mutation and loss of CCyR was 16.5 months (range, 1 to 38.5 months). In five of the six patients who lost their CCyR after detection of the mutation, the percentage of the mutated clone increased from less than 20% to more than 80% as the transcript levels increased. The development of KD mutations significantly predicted for loss of CCyR (RR = 13.4; P < .0001) but not for loss of CHR, PFS, or OS.

The only significant predictor for developing a mutation was the Sokal score; of the 11 patients, seven had high scores, three intermediate scores, and one a low score (P = .02). The cumulative incidence of mutations in the high risk group was 16.0% versus 4.5% in the pooled intermediate and low groups (P = .02).

	DISCUSSION

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The introduction of imatinib in 1998 has revolutionized the treatment of CML in CP.^1,3,16 Survival seems substantially prolonged in the majority of patients,^17,18 though the extent of this prolongation is not yet established. The IRIS trial showed a cumulative incidence of CCyR at 60 months of 87%, an EFS of 83%, and an OS of 89%. The comparable values in this study, namely 82.7%, 81.3%, and 83.2%, respectively, are similar. The minor differences are best explained by the fact that 20% of patients in the IRIS study were censored for diverse reasons including unsatisfactory response (11%), consent withdrawal (5%), and adverse events (4%).^3,4 There is no evidence that discontinuation was random; patients with a worse prognosis may have been more likely to have been censored for these reasons. Consequently, the real impact of imatinib therapy can be assessed only by an intention-to-treat analysis.^3,4 In practice, the proportion of patients who discontinued imatinib was very similar in both studies, namely 25% in our study versus 28% in IRIS (P = NS).

It is difficult to define imatinib failure, in part because some patients achieve hematologic response rapidly but take substantial time to achieve a CCyR. However, it may be inappropriate to wait indefinitely for a CCyR.⁷ In the IRIS study, those patients who failed to achieve a MCyR but who discontinued imatinib before loss of a CHR or progression were not scored as imatinib failures. Moreover, patients who discontinued imatinib treatment because of adverse effects were censored. Consequently, EFS as defined in the IRIS study is likely to be an overestimate. When these failures are considered appropriately, as in an intention-to-treat analysis, the real response rate to imatinib at 5 years is 62.7%.

KD mutations have been detected in patients with acquired resistance to tyrosine kinase inhibitors, especially in advanced phases.^19-21 However, we detected KD mutations in only 11 of the patients in this series, of whom 10 had resistant leukemia. Thus, we found mutations in four (9%) of the 45 patients with primary resistance (failure to achieve a CCyR) and in six (43%) of the 14 patients with secondary resistance (who achieved CCyR but subsequently lost it). The incidence of KD mutations in resistant patients in this series is therefore comparable with that reported by others.^21-23 The detection of KD mutations was the only factor predicting for loss of CCyR. We found an association between the development of KD mutations and Sokal risk group, which supports the hypothesis that development of mutations is related to the biology of the disease rather than merely being a random event, thus possibly reflecting a higher degree of genomic instability in the high-risk patients.

In our study, patients who remained more than 95% Ph-positive at 6 months had a low probability of achieving CCyR during subsequent follow-up (Fig 3B) and were identifiable at 3 months (Fig 3A); patients already in MCyR at 6 months and patients with a minimal cytogenetic response (36% to 95% Ph-positive) had a similar cumulative incidence of CCyR at 5 years, although the responses in the second group were slower. This result may be explained by the fact than 54% of the patients in the second group had their dose of imatinib increased (data not shown). We found that the Sokal score significantly predicted for the achievement of CCyR (low score) and loss of CHR (high score) in our population, but failed to reach significance for PFS and survival (data not shown). This disparity may be explained by the fact that some of the nonresponding patients discontinued imatinib before progression and fared well with second-line therapy, thus delaying any subsequent event. Our observation that KD mutations predicted for loss of CCyR but not for loss of CHR, PFS, or OS may be explained on the same basis. The median dose of imatinib during the first 6 months was an important factor in achieving CCyR. One possible explanation is the previously postulated relationship between myelosuppression and the lack of an expandable Ph-negative hematopoiesis.^24-26 A similar explanation could apply to the relationship between early progression and hematologic toxicity. The major predictor for OS and PFS was the cytogenetic response at 1 year, as reported previously.^2,3 We found no additional benefit of achieving MMR at 1 year or 18 months for the patients in CCyR, which accords with the 5-year data in the IRIS study.³ This observation calls into question the use of MMR at a predetermined time point as a surrogate marker for outcome of therapy for CML.

	AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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The author(s) indicated no potential conflicts of interest.

	AUTHOR CONTRIBUTIONS

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Conception and design: Hugues de Lavallade, Jane F. Apperley, Jamshid S. Khorashad, Dragana Milojkovic, Alistair G. Reid, Marco Bua, Richard Szydlo, Eduardo Olavarria, Jaspal Kaeda, John M. Goldman, David Marin

Data analysis and interpretation: Richard Szydlo, David Marin

Manuscript writing: Hugues de Lavallade, Jane F. Apperley, Jamshid S. Khorashad, Dragana Milojkovic, Alistair G. Reid, Marco Bua, Richard Szydlo, Eduardo Olavarria, Jaspal Kaeda, John M. Goldman, David Marin

Final approval of manuscript: Hugues de Lavallade, Jane F. Apperley, Jamshid S. Khorashad, Dragana Milojkovic, Alistair G. Reid, Marco Bua, Richard Szydlo, Eduardo Olavarria, Jaspal Kaeda, John M. Goldman, David Marin

	ACKNOWLEDGMENTS

 
We thank Robert Gale, MD, for critical reading of the manuscript and the many members of the medical, nursing, and technical staff who contributed to patient care and production of laboratory data.

	NOTES

 
published online ahead of print at www.jco.org on June 2, 2008.

Supported by the National Institute for Health Research Biomedical Research Centre Funding Scheme and a grant from the "Fondation de France" (H. de L.).

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

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Submitted December 17, 2007; accepted March 12, 2008.

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