Tolerability-Adapted Imatinib 800 mg/d Versus 400 mg/d Versus 400 mg/d Plus Interferon-α in Newly Diagnosed Chronic Myeloid Leukemia
Publication: Journal of Clinical Oncology
Abstract
Purpose
Treatment of chronic-phase (CP) chronic myeloid leukemia (CML) with imatinib 400 mg/d can be unsatisfactory. Optimization of treatment is warranted.
Patients and Methods
In all, 1,014 newly diagnosed CP-CML patients were randomly assigned to imatinib 800 mg/d (n = 338), imatinib 400 mg/d (n = 325), or imatinib 400 mg/d plus interferon alfa (IFN-α; n = 351). Dose adaptation to avoid higher-grade toxicity was recommended. First primary end point was major molecular remission (MMR) at 12 months.
Results
A higher rate of MMR at 12 months occurred with tolerability-adapted imatinib 800 mg/d than with imatinib 400 mg/d (59% [95% CI, 53% to 65%] v 44% [95% CI, 37% to 50%]; P < .001) or imatinib 400 mg/d plus IFN-α (59% v 46% [95% CI, 40% to 52%]; P = .002). Median dose in the 800-mg/d arm was 628 mg/d with a maximum dose of 737 mg/d during months 4 to 6 and a maintenance dose of 600 mg/d. All three treatment approaches were well tolerated with similar grade 3 and 4 adverse events. Independent of treatment approach, MMR at 12 months showed better progression-free survival (99% v 94%; P = .0023) and overall survival (99% v 93%; P = .0011) at 3 years when compared with > 1% on the international scale or no MMR but showed no difference in 0.1% to < 1% on the international scale, which closely correlates with complete cytogenetic remission.
Conclusion
Treatment of early-phase CML with imatinib can be optimized. Early high-dose therapy followed by rapid adaptation to good tolerability increases the rate of MMR at 12 months. Achievement of MMR by month 12 is directly associated with improved survival.
Introduction
Recommended initial therapy for chronic-phase (CP) chronic myeloid leukemia (CML) is imatinib 400 mg/d.1 Imatinib has been shown to be superior to the previous standard therapy with interferon alfa (IFN-α) with regard to remission rates, survival, and tolerability.2 After 8 years, imatinib was discontinued for adverse events in 6% of patients, for lack of efficacy in 22%, and for other reasons in 17%.3 Optimization of the standard approach of imatinib 400 mg/d is warranted.
Because of different modes of action of imatinib and IFN-α4,5 and 10-year survival rates with IFN-α up to 60%6–8 (which is better than with any other drug treatment except imatinib), a combination of imatinib and IFN-α appeared to be a rational option.
The optimal dose of imatinib for first-line therapy has not been determined. Dose-escalation in nonresponding patients has shown efficacy in CP-CML.9,10 Higher imatinib doses are effective in the accelerated phase (AP) and blast crisis (BC).11,12 Observational studies13,14 suggested a more rapid induction of remission by imatinib 800 mg/d in patients with CP-CML. Analysis of patients randomly assigned to high-dose imatinib in early CP-CML appeared to be an appropriate next step.
Therefore, the German CML Study Group conducted a randomized treatment optimization trial to compare imatinib at 800 mg/d, imatinib 400 mg/d plus IFN-α, and imatinib 400 mg/d in newly diagnosed patients with CP-CML with regard to cytogenetic and molecular remission rates, survival, and toxicity. The first primary end point was the rate of major molecular remission (MMR) at 12 months.
Patients and Methods
Study Design and Goals
The pilot phase of CML Study IV15 compared monotherapy with imatinib 400 mg/d versus imatinib 400 mg/d in combination with IFN-α versus imatinib 400 mg/d in combination with low-dose cytarabine versus imatinib after IFN-α therapy failed. Only low- and intermediate-risk patients were randomly assigned to therapy with primary IFN-α, whereas high-risk patients were randomly assigned to the other study arms and, from November 2003 on, to imatinib 800 mg/d instead. Because the protocol determined that the study arms using imatinib plus cytarabine and imatinib after failure of IFN-α could be terminated early under defined conditions (feasibility and compliance), random assignment to these arms was terminated after 3 years (in 2005), and imatinib 800 mg/d was extended to low- and intermediate-risk patients.
The main phase of CML Study IV compares monotherapy imatinib 400 mg/d versus imatinib 400 mg/d combined with IFN-α versus imatinib 800 mg/d. Patients in the pilot phase who were receiving imatinib 400 mg/d, imatinib 400 mg/d plus IFN-α, or imatinib 800 mg/d were retained for the analysis of the main phase.
The first primary goal of the main phase was the MMR rate at 12 months. Other primary end points were hematologic remission, complete cytogenetic remission (CCR), and complete molecular remission (CMR) rates; adverse events; and overall survival (OS) and progression-free survival (PFS). Secondary end points included long-term toxicity and survival. The outcome of patients who received transplantations has already been published.16
Treatment
Initial treatment in all study arms was imatinib 400 mg/d in one dose. If no complete hematologic remission was reached after 2 months or no partial cytogenetic remission was reached after 6 months, a dose increase to 600 mg/d or 800 mg/d was permitted.
In the imatinib 800 mg/d arm, the full 800 mg/d dose was given after a 6-week run-in period with imatinib 400 mg/d to avoid excessive cytopenias. In case of imatinib intolerability, it was recommended to split imatinib into two doses of 200 mg/d or two doses of 400 mg/d. A dose reduction was permitted to achieve good tolerability, but a reduction to < 300 mg/d was discouraged. Higher-grade adverse events (WHO grades 3 and 4) were to be avoided. Treatment interruptions were discouraged and permitted only for grades 3 and 4 adverse events. Simultaneous CYP3A4 inhibitors were avoided. If imatinib treatment failed, either stem-cell transplantation or risk-adapted drug treatment was recommended. After approval of second-generation tyrosine kinase inhibitors (TKIs) for second-line treatment, either nilotinib or dasatinib was recommended. In older patients who were not eligible for transplantation, hydroxyurea was recommended if second-generation TKIs were not effective.
In the imatinib plus IFN-α arm, IFN-α was added 6 weeks after the start of imatinib at an initial dose of 1.5 mill. U three times per week and increased up to 3 mill. U three times per week, according to tolerability. The IFN-α dose was adapted to avoid WBC < 2,000/μL and platelets < 50,000/μL. The IFN-α dose was halved at WBC < 1,000/μL or platelets < 100,000/μL and was interrupted at WBC < 500/μL or platelets < 50,000/μL at a constant imatinib dose.
Definitions and End Points
Definitions followed the recommendations published by the European LeukemiaNet.1 Risk assignment was made by using the EuroSCORE criteria.17 Starting date for all time-to-event analyses was the date of diagnosis. All living patients were censored at the time of their last visit. PFS was defined by survival free of AP and BC. Death for any cause, with or without TKIs, was counted as an end point. No patient was taken off study except at the patient's request (n = 2).
Statistical Analysis
Comparisons of MMR rates at 12 months between treatment arms were performed by the χ2 test. Patients had to have an analysis within an interval of 9 to 15 months. If a patient's treatment had failed before that point (progression or death), this was counted as no MMR. A group sequential design with three analyses (two interim, one final) according to O'Brien and Fleming18 was chosen (2007, 2008, and 2009). On the basis of MMR rates of 25% and 50% at 12 months after random assignment and a significance level of 4.507% at the final analysis (two-sided), 68 patients randomly assigned in a 1:1 ratio between imatinib 800 mg/d and the two 400 mg/d arms would detect a 25% difference with a power of 80% (χ2 test). To allow recognition of a survival difference of 5% between treatments, a sample size of 400 patients per treatment arm was needed. Probabilities of OS and PFS were calculated by the Kaplan-Meier method and compared by log-rank statistics. Cumulative incidences were calculated under consideration of competing risks19 defined by AP, BC, and death. Comparisons between cumulative incidences were performed by the Gray test. Analyses were according to intention-to-treat; only adverse events were analyzed as treated. Level of significance was 0.05. All calculations were performed with SAS software Version 9.1.3 (SAS Institute, Cary, NC).
Cytogenetic and Molecular Analyses
Cytogenetic analyses were performed after short-term culture (24 hours, 48 hours, or both) with standard G-banding or fluorescence R-banding techniques. For follow-up analyses of CCR, at least 20 marrow cell metaphases were evaluated. Molecular diagnostics for residual BCR-ABL mRNA followed the procedures of Hughes et al20 and Cross et al21 and were performed in standardized laboratories only.22 Transcripts with breakpoints outside the major breakpoint cluster region were considered separately.
Ethics
The protocol followed the Declaration of Helsinki and was approved by the ethics committee of the Medizinische Fakultät Mannheim and by local ethics committees of participating centers. Written informed consent was obtained from all patients before they entered the study.
Results
Patients
From July 2002 to April 30, 2009, a total of 1,022 patients were randomly assigned (Fig 1). In all, 1,012 patients were evaluable. Data entry was closed on April 15, 2010.
Patients' characteristics at diagnosis are listed in Table 1. The variables were similar between treatment groups without significant differences. Median follow-up was 28 months in the imatinib 800 mg/d arm, 43 months in the 400 mg/d arm, and 48 months in the imatinib plus IFN-α arm. The difference is due to the later start of the 800 mg/d arm. Drug dosages and dose adaptation are provided in Table 1. The median doses of imatinib were 628 mg/d in the high-dose arm and 400 mg/d in the 400 mg/d with or without IFN-α arms. The dose intensities during the first 12 months showed acceptable adherence. To analyze the dynamics of dose adaptation in the 800 mg/d arm, doses were analyzed per 3- and 6-month periods during the first 24 months of treatment. The dosage in the first 3-month period reflects the run-in period of 6 weeks with imatinib at 400 mg/d. The highest median dosage was reached in the second 3-month period (737 mg/d) before the dosage decreased to around 600 mg/d, which reflected adaptation to tolerability.
| Characteristic | Imatinib 800 mg/d(n = 338) | Imatinib 400 mg/d(n = 325) | Imatinib + Interferon-α(n = 351) | ||||
|---|---|---|---|---|---|---|---|
| No. | % | No. | % | No. | % | ||
| Age, years | |||||||
| Median | 52 | 54 | 54 | ||||
| Range | 18-86 | 16-88 | 16-83 | ||||
| Sex | |||||||
| Female | 41 | 40 | 39 | ||||
| Hemoglobin, g/dL | |||||||
| Median | 12.1 | 12.4 | 12.2 | ||||
| Range | 5.0-16.7 | 6.4-17.5 | 6.8-17.7 | ||||
| WBC × 109/L | |||||||
| Median | 76.7 | 75.0 | 91.3 | ||||
| Range | 2.6-488 | 3.8-574 | 2.8-525 | ||||
| Platelets × 109/L | |||||||
| Median | 388 | 381 | 341 | ||||
| Range | 48-2,582 | 58-2,419 | 49-3,020 | ||||
| EuroSCORE | |||||||
| Low | 37 | 35 | 34 | ||||
| Intermediate | 49 | 53 | 55 | ||||
| High | 14 | 12 | 11 | ||||
| Median time from diagnosis to random assignment, days | 16 | 17 | 16 | ||||
| Median observation time, months | 28 | 43 | 48 | ||||
| Dose per actual therapy day, mg* | |||||||
| Median | 628 | 400 | 400 | ||||
| Range | 208-800 | 279-720 | 179-608† | ||||
| Dose Intensity During the First 12 Months, mg/d | (n = 275) | (n = 318) | |||||
| 800 | 46 | ||||||
| > 700 | 121 | 44.0 | |||||
| 601-700 | 34 | 12.4 | |||||
| 501-600 | 46 | 16.7 | 6 | 1.9 | |||
| 401-500 | 66 | 24.0 | 41 | 14.9 | |||
| ≤ 400 | 8 | 2.9 | 247 | 77.7 | |||
| 301-399 | 22 | 6.9 | |||||
| < 300 | 2 | 0.7 | |||||
| Median dose during the first 24 months, mg/d | |||||||
| Per 3-month interval (months) | |||||||
| 1-3 | 555 | 400 | |||||
| 4-6 | 737 | 400 | |||||
| 7-9 | 613 | 400 | |||||
| 10-12 | 600 | 400 | |||||
| Per 6-month interval (months) | |||||||
| 13-18 | 600 | 400 | |||||
| 19-24 | 600 | 400 | |||||
Abbreviation: EuroSCORE, European System for Cardiac Operative Risk Evaluation.
*
Number of patients for whom this information was available: imatinib 800 mg/d (n = 279); imatinib 400 mg/d (n = 318); imatinib (n = 334) plus interferon-α (n = 253).
†
Interferon-α median, 1.8 mill.U; range, 0.3-6.0 mill.U.
Molecular Response
MMR by 12 months was reached significantly more rapidly with imatinib 800 mg/d than with imatinib 400 mg/d alone or imatinib 400 mg/d in combination with IFN-α (55%, 31%, or 35%, respectively; Fig 2A, Table 2). The differences in cumulative incidences were particularly prominent during the 6- to 24-month period with up to 24% by 12 months. At month 12 (± 3 months), 758 patients (78%) of 970 had a molecular analysis. The incidence of MMR at 12 months was also significantly higher with imatinib 800 mg/d: 59% (95% CI, 53% to 65%; 153 of 259) versus 45% (95% CI, 40% to 49%; 224 of 499; P < .001) compared with the combined imatinib 400 mg/d–based arms, 59% versus 44% (95% CI, 37% to 50%; 108 of 246; P < .001) compared with imatinib 400 mg/d alone, and 59% versus 46% (95% CI, 40% to 52%; 116 of 253; P = .0020) compared with imatinib plus IFN-α. If missing data (including data from nonstandardized laboratories) and patients with atypical transcripts were counted as failures and patients with MMR before and after (if there was no measurement during) the interval were counted as successes, the rates were lower, but the incidence of MMR at 12 months remained significantly higher with imatinib 800 mg/d. The incidence was 46% (95% CI, 40% to 51%; 154 of 338) versus 34% (95% CI, 30% to 37%; 228 of 674; P < .001) compared with the combined imatinib 400 mg/d–based arms, 46% versus 34% (95% CI, 29% to 39%; 110 of 324; P = .0018) compared with imatinib 400 mg/d alone, and 46% versus 34% (95% CI, 29% to 39%; 118 of 350; P = .0025) compared with imatinib plus IFN-α.
| Time After Start of Treatment (months) | Imatinib 400 mg/d(n = 306) | Imatinib 800 mg/d(n = 328) | Imatinib 400 mg/d + Interferon-α(n = 336) | |||||
|---|---|---|---|---|---|---|---|---|
| % | 95% CI | Δ* | % | 95% CI | Δ* | % | 95% CI | |
| MMR | ||||||||
| 6 | 8.6 | 5.2 to 11.3 | 9.5 | 18.1 | 13.8 to 22.9 | 9.7 | 8.4 | 5.2 to 11.0 |
| 12 | 30.8 | 26.6 to 36.1 | 24.0 | 54.8 | 48.7 to 59.7 | 20.1 | 34.7 | 29.0 to 39.2 |
| 18 | 50.3 | 44.0 to 55.5 | 18.1 | 68.4 | 62.2 to 73.0 | 14.3 | 54.1 | 48.4 to 59.4 |
| 24 | 63 | 56.7 to 68.0 | 13.0 | 76.0 | 70.5 to 80.6 | 13.2 | 62.8 | 56.7 to 67.6 |
| 36 | 79.3 | 73.9 to 83.7 | 2.3 | 81.6 | 76.0 to 86.0 | 10.9 | 70.7 | 64.6 to 75.1 |
| CMR4 | ||||||||
| 6 | 3 | 1.2 to 4.9 | 0.7 | 3.7 | 1.6 to 5.4 | 1.3 | 2.4 | 0.9 to 4.1 |
| 12 | 7.5 | 4.8 to 10.8 | 12.3 | 19.8 | 15.2 to 24.0 | 7.4 | 12.4 | 8.8 to 15.8 |
| 18 | 21.2 | 16.6 to 26.1 | 12.2 | 33.4 | 28.0 to 39.0 | 9.8 | 23.6 | 19.0 to 28.5 |
| 24 | 30.7 | 24.9 to 35.8 | 12.3 | 43 | 36.8 to 49.0 | 13 | 30.0 | 24.9 to 35.3 |
| 36 | 45.5 | 38.7 to 51.0 | 11.3 | 56.8 | 49.4 to 63.5 | 16.3 | 40.5 | 34.6 to 46.3 |
| CCR† | ||||||||
| 6 | 21.3 | 16.4 to 25.8 | 10.2 | 31.5 | 25.9 to 36.6 | 12.0 | 19.5 | 15.0 to 23.8 |
| 12 | 49.4 | 42.6 to 54.4 | 13.5 | 62.9 | 56.4 to 67.9 | 13.2 | 49.7 | 43.5 to 54.9 |
| 18 | 66.0 | 59.4 to 70.9 | 8.9 | 74.9 | 68.6 to 79.3 | 5.7 | 69.2 | 63.4 to 74.3 |
| 24 | 74.3 | 67.6 to 78.9 | 8.0 | 82.3 | 77.0 to 86.6 | 5.8 | 76.5 | 70.3 to 80.7 |
Abbreviations: MMR, major molecular remission; CMR4, complete molecular remission4; CCR, complete cytogenetic remission.
*
Difference between imatinib 800 mg/d and imatinib 400 mg/d, or imatinib 800 mg/d and imatinib 400 mg/d plus interferon-α.
†
Number of patients with cytogenetic evaluations: imatinib 400 mg/d (n = 303); imatinib 800 mg/d (n = 311); imatinib plus interferon-α (n = 326); compare with Fig. 1.
Rapid remissions were observed in low- and intermediate-risk but not in high-risk patients (EuroSCORE). The median times to MMR for imatinib 800 mg/d, imatinib 400 mg/d, and imatinib plus IFN-α in low-risk patients were 8.9, 15.3, and 15.7 months; in intermediate-risk patients, they were 10.1, 18.9, and 17.5 months; and in high-risk patients they were 22.5, 15.6, and 17.9 months, respectively. The Cochran-Mantel-Haenszel test resulted in a significant difference (P < .001). A significant difference (P < .001) was also found for the Sokal score.
Cytogenetic Response
CCR was reached at a significantly more rapid rate with imatinib 800 mg/d over the first 24 months. The differences in cumulative incidences of CCR reached a maximum of 13.5% after 12 months and decreased thereafter (Table 2). CCR versus no CCR at 12 months was associated with better survival (96% v 91% at 5 years; P = .0154).
Adverse Events
Adverse events (all grades) were more frequent with imatinib 800 mg/d (edema and GI problems) and with imatinib 400 mg/d plus IFN-α (neurologic problems and fatigue; Table 3). If only WHO grades 3 and 4 were analyzed, the rates were low with virtually no differences between treatments.
| Adverse Events | Total | Imatinib 800 mg/d(n = 323)* | Imatinib 400 mg/d(n = 321)* | Imatinib + Interferon-α(n = 336)* | ||||
|---|---|---|---|---|---|---|---|---|
| No. | % | No. | % | No. | % | No. | % | |
| WHO grades 1 to 4 | ||||||||
| Edema | 38 | 28 | 21 | |||||
| Myalgia | 26 | 19 | 20 | |||||
| Neurologic | 17 | 14 | 21 | |||||
| GI | 48 | 31 | 32 | |||||
| Fatigue | 17 | 13 | 18 | |||||
| WHO grades 3 and 4 | ||||||||
| Anemia | 4 | 5 | 1 | |||||
| Leukopenia | 5 | 3 | 6 | |||||
| Thrombopenia | 9 | 5 | 4 | |||||
| Edema | 2 | 1 | 1 | |||||
| Myalgia | 2 | 3 | 2 | |||||
| Neurologic | 3 | 2 | 4 | |||||
| GI | 4 | 2 | 4 | |||||
| Fatigue | 2 | 0 | 3 | |||||
| Progressions | (n = 338) | (n = 324) | (n = 350) | |||||
| Progressions including death from any cause | 49 | 4.8 | 21 | 6.2 | 16 | 4.9 | 12 | 3.4 |
| Deaths | 30 | 3.0 | 11 | 3.3 | 9 | 2.8 | 10 | 2.9 |
| Causes | ||||||||
| CML related | 15 | 6 | 4 | 5 | ||||
| Transplantation related | 4 | 1 | 2 | 1 | ||||
| Second neoplasia | 4 | 1 | 1 | 2 | ||||
| Infection in CP | 4 | 2 | 1 | 1 | ||||
| Cardio-renal | 2 | 1 | 1 | 0 | ||||
| Suicide | 1 | 0 | 0 | 1 | ||||
| Survival probability at 24 months | 96.6 | 96.0 | 96.9 | 96.8 | ||||
Abbreviations: CML, chronic myeloid leukemia; CP, chronic phase.
*
Numbers of patients for whom an analysis was available. Thirty-two patients were not evaluable because of an early second-generation tyrosine kinase inhibitor (n = 5), early stem-cell transplantation (n = 3), early death (n = 1), lack of compliance (n = 4), no treatment according to protocol (eg, hydroxyurea only; n = 11), or unclear or no documentation (n = 8).
Progression and Survival
At 3 years, OS of all patients was 95% (95% CI, 93% to 97%) and PFS was 94% (95% CI, 92% to 95%) with no differences between treatment arms (Fig 3A), including progression and numbers and causes of death (Table 3).
Independent of treatment approach, MMR versus no MMR at 12 months was associated with better PFS (99% [95% CI, 97% to 100%] v 95% [95% CI, 93% to 97%]; P = .0143) and OS (99% [95% CI, 97% to 100%] v 95% [95% CI, 93% to 97%]; P = .0156) at 3 years (Fig 3B). Similarly, MMR versus > 1% on the international scale at 12 months showed better PFS (99% [95% CI, 97% to 100%] v 94% [95% CI, 90% to 97%]; P = .0023) and OS (99% [95% CI, 97% to 100%] v 93% [95% CI, 90% to 96%]; P = .0011) at 3 years (Fig 3C). No difference was observed in the group with 0.1% to < 1% on the international scale, which is closely correlated with CCR (PFS, 97% [95% CI, 94% to 99%]; OS, 98% [95% CI, 95% to 100%]; Fig 3C).
Discussion
Our data indicate that the approach of using a standard initial dose of imatinib 400 mg/d for patients with CP-CML can be improved. More patients reached MMR by month 12, and MMR, CMR, and CCR were reached more rapidly with tolerability-adapted imatinib 800 mg/d. Patients with MMR by month 12 were associated with better OS compared with those who reached MMR later or not at all. This is in agreement with the rationale that early and effective inhibition of BCR-ABL and BCR-ABL–induced DNA damage and impairment of DNA repair should reduce progression and improve survival. The findings agree well with mono- and multicentric observations,14 which found higher molecular and cytogenetic remission rates with imatinib 800 mg/d when compared with historical controls or with patients from the International Randomized Study of Interferon and STI571 (IRIS) study who were treated with imatinib 400 mg/d.24,25 In suboptimal responders to imatinib 400 mg/d, dose-escalation to 600 or 800 mg/d increased MMR and CCR rates.26 Our results differed in some respects from those of another randomized trial,27 which found an advantage for imatinib 800 mg/d only during the first 9 months. The difference might be due to a more flexible dose reduction in our study (Table 1), which avoids higher-grade toxicity (Table 3) to facilitate compliance. Adherence to therapy has indeed been reported as a critical factor for achieving molecular remission.28 Our 6-week run-in period with imatinib 400 mg/d before the start of the portion of the study with doses of 800 mg/d could explain our low hematologic grade 3 and 4 toxicity with imatinib 800 mg/d which, in contrast to the results of other studies,27 is similar to that in the 400 mg/d arms.
Another randomized trial compared imatinib 400 mg/d and 800 mg/d in Sokal high-risk patients only29 and found no advantage for higher-dose imatinib except in an as-treated analysis. This agrees with our study, which did not observe an advantage for high-dose imatinib in high-risk patients (EuroSCORE or Sokal). That a more rapid induction of remission was seen in low- and intermediate-risk patients but not in high-risk patients can be explained by a higher degree of BCR-ABL independence in high-risk patients and by the known lower efficacy of imatinib in later-stage CML.30 It is expected that the earlier and more rapid remissions with tolerability-adapted high-dose imatinib, as observed in this study, will translate into better survival later on. At present, follow-up is too short.
A possible advantage of high-dose therapy is supported by the higher rate of CCR during the first 2 years, which is an accepted surrogate marker for OS, and by the high CMR rates, which demonstrate the depth of molecular remissions. Patients who achieve stable CMR are candidates for treatment discontinuation within clinical trials and may reach durable off-treatment remissions and possibly cure.31
WHO grades 3 and 4 adverse events were similar between treatment arms (Table 3) with an overall median dose in the high-dose arm of 628 mg/d, an increase to 737 mg/d during the second quarter of year 1, and a reduction to 600 mg/d from the fourth quarter of year 1 onward (Table 1). We suggest that the superior remission rates in the high-dose arm are due to the strategy applied (high dose early on, with a maintenance dose of around 600 mg/d according to tolerability). Hughes et al26 in evaluating the impact of dose-escalation on cytogenetic response rates, suggest a threshold dose of approximately 600 mg/d for early CML.
MMR has not been a validated surrogate marker for OS thus far. To the best of our knowledge, this is the first study to demonstrate a significant advantage of OS for patients who achieved an MMR by month 12. This is important for patients, because MMR can be determined from peripheral blood thus avoiding the need for a bone marrow puncture. In addition, if performed in a standardized manner by standardized laboratories,22 molecular monitoring should be more reliable than cytogenetics. Although the prognostic power of MMR at 12 months seems to be no better than that of CCR at 12 months, the data demonstrate that MMR and molecular response of 0.1% to < 1% on the international scale can be used in the future as surrogate markers of survival in patient care and in clinical trials. Optimization of time points for prognostic prediction by molecular monitoring and validation by sufficiently long observation periods are in progress.
The high MMR rate at 12 months with tolerability-adapted high-dose imatinib compares well with the recently published results32,33 regarding the second-generation TKIs dasatinib and nilotinib as first-line therapy. The molecular remission rates depicted in Figure 2 and Table 2 were calculated by the competing-risk technique, which results in lower rates when compared with calculations that use the Kaplan-Meier method.
Imatinib is currently the treatment of choice for first-line treatment of CP-CML. It has a clear advantage with regard to long-term safety. During the past 10 years, imatinib has shown remarkably low adverse event rates and good efficacy. Virtually no severe toxicity has surfaced. This remains to be shown for second-generation TKIs. We suggest that our data with an optimized dose schedule are in support of the current role of imatinib in first-line CML treatment.
Progression to advanced phase and death (any cause) is low during the first 24 months at 2.4% per year with currently no difference between treatment arms. This rate is similar to those observed previously with imatinib 400 mg/d (2%)2 or with second-generation TKIs (< 1% with nilotinib; 1.9% with dasatinib).32,33 These early treatment failures most likely reflect BCR-ABL–independent transformation and underscore the need for early monitoring in CP-CML to detect treatment failure and facilitate early transplantation.1,16
That imatinib 800 mg/d induced remissions more rapidly, when compared with the combination of imatinib with IFN-α, supports the efficacy of high-dose imatinib but does not exclude the possibility of a better survival rate later on with the combination compared with imatinib 400 mg/d alone, as would be expected from the complementary action of these two drugs.4,5 It should be noted that pegylated IFN34–36 might have an advantage over conventional IFN-α, which was used in this study.
In this context, it should be remembered that early and intensive treatment improved outcome in patients with CML in the past37 (as observed in those who have had transplantations and who relapsed after intensive chemotherapy with and without autografting),38 and more recently with early high-dose imatinib in the case of inadequate response,39 probably due to early reduction of BCR-ABL and thereby reduction of cells at risk for genetic instability and progression.
In summary, imatinib remains the first choice for patients with early-phase CML, but its application can be improved. Early high-dose followed by rapid dose-adaptation to good tolerability increases the rate of MMR at 12 months. Achievement of MMR by month 12 is directly associated with improved survival.
Acknowledgment
We thank Angelika Adler, Gabriele Bartsch, Ute Berger, Sabine Dean, Matthias Dumke, Christine Folz, Michaela Hausmann, Ute Kossak, Elke Matzat, Barbara Müller, Regina Pleil-Lösch, Nicole Schomber, Inge Stalljann, P. Schrotz-King, Cornelia Willersinn, and all CML centers (Appendix) for their contributions.
Presented in part at the 51st Annual Meeting of the American Society of Hematology, New Orleans, LA, December 5-8, 2009; at the 46th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, June 4-7, 2010; and at the Annual Meeting of the European Hematology Association, Barcelona, Spain, June 9-11, 2010.
See accompanying Comments and Controversies on page 1512
Written on behalf of the Swiss Group for Clinical Cancer Research (SAKK) and the German Chronic Myeloid Leukemia (CML) Study Group.
Clinical trial information can be found for the following: NCT00055874.
Authors' Disclosures of Potential Conflicts of Interest
Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Employment or Leadership Position: Claudia Haferlach, Munich Leukemia Laboratory (C) Consultant or Advisory Role: Joerg Hasford, Novartis Pharmaceuticals (C); Andreas Hochhaus, Novartis (C), Bristol-Myers Squibb (C) Stock Ownership: None Honoraria: Rüdiger Hehlmann, Novartis, Bristol-Myers Squibb; Martin C. Müller, Novartis, Bristol-Myers Squibb; Stefan W. Krause, Novartis; Joerg Hasford, Novartis Pharmaceuticals; Andreas Hochhaus, Novartis, Bristol-Myers Squibb Research Funding: Rüdiger Hehlmann, Novartis; Martin C. Müller, Novartis, Bristol-Myers Squibb; Stefan W. Krause, Novartis; Joerg Hasford, Novartis Pharmaceuticals; Andreas Hochhaus, Novartis, Bristol-Myers Squibb Expert Testimony: None Other Remuneration: Armin Leitner, Novartis; Stefan W. Krause, Novartis
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Appendix
Participating centers of the German CML Study Group:
Aarau: Kantonspital: M. Wernli, M. Bargetzi; Amberg: Klinikum St. Marien: V. Großß, L. Fischer von Weikersthal; Ansbach: Praxis: S. Müller, M. Hahn; Augsburg: Klinikum: G. Schlimok; Aurich: Praxis: D. Reichert, J. Janssen; Bad Friedrichshall: Klinikum am Plattenwald: J. Furkert, T. Mandel; Bad Hersfeld: Klinikum R. Paliege, P.-J. Majunke; Bad Saarow: Helios Klinikum: P. Reichert, C. Hammer; Baden-Baden: Stadtklinik: H.-J. Staiger; Basel: Universitätsspital: A. Gratwohl, D. Heim, A. Tichelli; Bergisch-Gladbach: Vinzenz-Pallotti-Hospital: S. Korsten, D. Henesser; Berlin: Praxis: Ch. Sperling, C. Schelenz; Praxis: A. Koschuth, D. Kingreen; Vivantes- Klinikum am Urbahn: J. Beyer, E. Dahmen; Vivantes Klinikum Neukölln: M. de Wit, G. Büschel; Charité Campus Virchow: R. Arnold, P. Le Coutre; Praxis: I. Blau, H. Ihle; St. Hedwig-Krankenhaus: K.-M. Derwahl, H.-J. Englisch; Praxis: F. Ludwig; Charité - Campus Benjamin Franklin: E. Thiel, I. Blau, M. Notter; Praxis: J. Heßßling; HELIOS Klinikum Berlin-Buch: W.-D. Ludwig, C. Teutsch; Bern: Inselspital: B. Lämmle, G. Baerlocher, E. Oppliger, A. Tobler; Bielefeld: Praxis: M. Just, E. Schäfer; Bochum: Knappschaftskrankenhaus W. Schmiegel, C. Teschendorf; Augusta-Kranken-Anstalt: D. Behringer, M. Brandt; Bonn: Universitätsklinikum: T. Sauerbruch, I. Schmidt-Wolf; Praxis: W. Verbeek, H.A. Vaupel; Johanniter-Krankenhaus: Y.D. Ko, S. Weidenhöfer; Bottrop: Knappschaftskrankenhaus: G. Trenn, M. van der Linde; Brandenburg: Städtisches Klinikum: W. Pommerien; Braunschweig: Klinikum: F. Lordick, G. Fritsch; Bremen: Klinikum: B. Hertenstein; Praxis: G. Doering, H. Munziger; DIAKO: K.-H. Pflüger: J. Kullmer, C. Diekmann; Brno: Fakultni nemocnice: J. Mayer, D. Zackova; Brühl: Praxis: S. Stier; Bünde: Lukas-Krankenhaus: B. Wejda, F. Möller-Faßßbender; Chemnitz: Klinikum: M. Hänel, A. Morgner; Coburg: Klinikum: W. Matek, D. Eichmann; Praxis: T. Zöller; Datteln: St. Vincenz-Krankenhaus: R. Grün, B. Koch; Daun: Krankenhaus Maria Hilf: D. Marth, A. Henzel; Deggendorf: Klinikum: S. Wagner, E. Woska; Delmenhorst: Städtische Kliniken: F. Neumann; Dernbach: Praxis: M. M. Hoffknecht; Dresden: Universitätsklinikum: G. Ehninger, A. Kiani; Praxis: T.Illmer: T. Wolf; Duisburg: St. Johannes-Hospital: C. Aul, A. Giagounidis; Düren: Krankenhaus: M. Flasshove, F. Henneke, T. Moritz; Ehingen: Praxis: M. Simon; Emden: Hans-Susemihl-Krankenhaus: L. Müller; Erkelnz: Praxis: R. Janz; Erlangen: Universitätsklinikum: A. Mackensen, S.W. Krause; Praxis: M.J. Eckart, B. Häcker; Eschweiler: St. Antonius Hospital: P. Staib, F. Schlegel; Essen: Universitätsklinikum: D.W. Beelen, R. Trenschel, A. Hüttmann, J. Novotny; Evangelisches Krankenhaus: W. Heit, F.-K. Baur; Praxis: R. Rudolph; Ettlingen: Praxis: A. Lindemann; Euskirchen: Praxis: D. Linck; Frankfurt: Universitätsklinikum: H. Serve, O.G. Ottmann; Krankenhaus Nordwest: E. Jäger, S.-E. Al-Batran; Freiburg: Universitätsklinikum: C. Waller, A. Kühnemund; Praxis: D. Semsek; Fulda: Klinikum H.-G. Höffkes; Garmisch-Partenkirchen: Klinikum: H. Lambertz, L. Schulz; Geilenkirchen: Praxis: K. Tajrobehkar; Germering: Praxis: J. Mittermüller; Gießßen: Universitätsklinikum: H. Pralle, M.J. Rummel; Goch: Wilhelm-Anton-Hospital: V. Runde, J. Westheider; Goslar: Asklepios Klinik: A. Hoyer; Onkologische Kooperation Harz: H.W. Tessen; Göttingen: Universitätsmedizin: L. Trümper, C. Binder; Greifswald: Universitätsklinikum: G. Dölken, C. Hirt; Gummersbach: Kreiskrankenhaus: M. Sieber; Güstrow: Praxis: H. Eschenburg, S. Wilhelm; Güterloh: Praxis: R. Depenbusch, S. Rösel; Hagen: Katholisches Krankenhaus: H. Eimermacher, H.-W. Lindemann; Halle: Praxis: C. Spohn, R. Moeller; Martin Luther Universität: H.-J. Schmoll, H.-H. Wolf; Hamburg: Universitätsklinikum: D. Hossfeld, C. Bokemeyer, P. Schafhausen; Praxis U.R. Kleeberg, E. Engel und Partner; Asklepios Klinik Altona: D. Braumann, P. Hoelzer; Asklepios Klinik St. Georg: N. Schmitz, M. Nickelsen; Praxis: H. Köster; Hamm: Evangelisches Krankenhaus: J. Schubert, E. Lange; St. Marien-Hospital: H.A. Dürk; Praxis: A. Grote-Metke, B. Bechtel, H. Weischer; Hannover: Medizinische Hochschule: A. Ganser, D. Peest; Krankenhaus Siloah: H. Kirchner, M. Sosada; Heidelberg: Universitätsklinikum: A.D. Ho, J. Dengler; Heidenheim: Praxis: V. Petersen; Heilbronn: Praxis: P. Porowski; Herford: Klinikum: S. Bildat, J.G. Lange; Herne: Praxis: L. Hahn; Herrsching-Ammersee: Praxis: H. Dietzfelbinger; Hersbruck: Praxis: W. Gröschel; Hildesheim: St. Bernward Krankenhaus: U. Kaiser; Praxis: W. Freier; Homburg: Universitätsklinkum: M. Pfreundschuh, K. Adam; Idar-Oberstein: Klinik: A. Fauser, M.-L. Valverde; Ingolstadt: Klinikum: J. Menzel; Iserlohn: Praxis: J. Kemper; Jena: Universitätsklinikum: A. Hochhaus, P. La Rosée; Kaiserslautern: Westpfalz-Klinikum: H. Link, S. Mahlmann; Praxis: R. Hansen, M. Reeb; Karlsruhe: Städtisches Klinikum: M. Bentz, M. Schmier; St. Vincentius-Kliniken: J. Mezger, M. Schat; Kempten: Klinikum: O. Prümmer, J. Gatter; Kiel: Universitätklinikum: M. Kneba, R. Schoch, U. Strack; Koblenz: Praxisklinik: J. Heymanns; Köln: Universitätklinikum: C. Scheid; Praxis: S. Schmitz, H.T. Steinmetz, K. Severin; Krefeld: Klinikum: T.F. Frieling, M. Planker; Praxis Krefeld: A. Lollert, M. Neise; Kronach: Praxis: M. Stauch; Landau: Vinzentius Krankenhaus: U. Karbach, M. Schröder; Landshut: Praxis: U. Vehling-Kaiser, D. Greif; Klinikum: B. Kempf, W. März; Lebach: Caritaskrankenhaus: S. Kremers; Leer: Praxis: L. Müller; Limburg: St. Vincenz Krankenhaus: T. Neuhaus, H. Martin; Lippe-Lemgo: Klinikum: F. Hartmann, H. Middeke; Lübeck: Klinik f. Hämatologie/Onkologie: S. Fetscher, J. Schmielau; Lüdenscheid: Klinikum: G. Heil; Praxis: D. Kämpfe; Ludwigshafen: Klinikum: M. Uppenkamp, B. Weißß; Lüneburg: Praxis: B. Goldmann, P.Heinkele; Luzern: P. Thum, W. Wuillemin; Mainz: Johannes Gutenberg-Universität: T. Fischer, M. Theobald, S. Thomas; Mannheim: Medizinische Fakultät Mannheim, Universität Heidelberg: R. Hehlmann, S. Saußßele, A. Leitner; Praxis: J. Brust, C. Plöger; Praxis: U. Hieber; Marburg: Klinikum der Philipps-Universität: A. Neubauer, A. Burchert; Minden: Klinikum: H.-J. Tischler, M. Griesshammer; Praxis: M. Becker; Mönchengladbach: Kliniken Maria Hilf: U. Graeven, C. Lange; Mühlheim: Praxis: C. Lunscken; Muhr am See: Praxis: B. Göttler, G. Schmidt; München: Klinikum Großßhadern: H.-J. Kolb, W. Hiddemann, K. Spiekermann; Klinikum Schwabing: Ch. Nerl, Ch. Fischer; Krankenhaus Harlaching: L. Lutz, M. Hentrich; Praxis: S. J. Völkl; Praxis: C. Scheidegger; Praxis: H. Hitz; Praxis: O. Stötzer; Praxis: H.-D. Schick, B. Schmitt; Klinikum Dritter Orden: P. Weidinger, S. Weidenhöfer; Münster: Universitätsklinikum: W.E. Berdel, S. Koschmieder, A. Koppelle; Praxis: J. Wehmeyer; Neumarkt: Praxis: M. Gnad, E. Ladda; Neunkirchen: Praxis: P. Schmidt; Norderstedt: Praxis: R. Hoffmann; Nürnberg: Klinikum Nord: M. Wilhelm, C. Falge; Oldenburg: Klinikum: C. H. Köhne, C. Schweiger; Praxis: D. Reschke, I. Zirpel; Olpe: Martinus-Hospital: M. Sauer, G. Lenk; Praxis: H. Eimermacher, C. Müller-Naendrup; Osnabrück: Paracelsus Klinik: S. Frühauf; Penzberg: Krankenhaus: K. Ranft; Pforzheim: Klinikum: B. Sandritter; Medizinisches Versorgungszentrum: Y. Dencausse; Pinneberg: Praxis: G. Baake; Recklinghausen: Elisabeth Krankenhaus: O. Kloke, D. Wacker; Regensburg: Krankenhaus Barmherzige Brüder: E.D. Kreuser, M. Schenk, A. Schlenska-Lange; Universitätsklinikum: R. Andreesen, S. Krause, M. Edinger; Praxis: R. Dengler; Remscheid: Sana-Klinikum: A. Wehmeier; Reutlingen: Kreisklinik: B. Braun, E. Günther; Rosenheim: Praxis: R. Pihusch; Rüdersdorf: Krankenhaus u. Poliklinik: K. Stahlhut; Rüsselsheim: Praxis: M. Baldus; Saarbrücken: Caritasklinik St. Theresia: A. Matzdorff; Schwäbisch Gmünd: Klinikum: W. Grimminger, H. Hebart; Schwäbisch Hall: Diakonie-Krankenhaus: T. Geer; Siegen: St. Marien-Krankenhaus: W. Gassmann; Kreisklinikum, Haus Hüttental: S. Schanz, C. Jurßß; Sigmaringen: Kreiskrankenhaus: G. Käfer, J. Hohemaier; St. Gallen: Kantonsspital: T. Czerny, U. Hess; Stadthagen: Praxis: C. Priebe-Richter; Straubing: Praxis: M. Demandt, G. Freunek; Stuttgart: Klinikum Stuttgart Bürgerhospital: H.-G. Mergenthaler, D. Hoffmann; Diakonie-Klinikum: E. Heidemann, R. Mück; Klinikum Stuttgart Katharinenhospital: H.-G. Mergenthaler, J. Schleicher, D. Assmann; Praxis für Innere Medizin: H. Fiechtner, G. Springer; Marienhospital: C. Denzlinger; Triberg: Asklepiosklinik: G. Adam; Trier: Klinikum Mutterhaus der Borromäerinnen: M. Clemens, A. Waladkhani; Praxis: B. Rendenbach, H.-P. Laubenstein; Troisdorf: Praxis: H. Forstbauer; Tübingen: Universitätsklinikum: M. Sökler, U. Bross-Bach, C. Dorn; Praxis: S.H. Jacki; Ulm: Universitätsklinikum: H. Döhner, F. Stegelmann; Velbert: Praxis: N. Kalhori, A. Nusch; Verden: Praxis: F. Muller; Waldbröl: Kreiskrankenhaus: S. Brettner; Weiden: Praxis: J. Weißß; Wendlingen: Praxis: T. Kamp, R. Eckert; Wesel: Praxis: C. Schadeck-Gressel; Wiesbaden: Deutsche Klinik für Diagnostik: R. Schwerdtfeger; Praxis: K.M. Josten; Wuppertal: Praxis: W. Fett; Helios Klinikum: A. Raghavachar; Praxis: H. Strotkötter; Würselen: Praxis: C. Maintz, M. Groschek; W ürzburg: Universitätsklinikum: V. Kunzmann, M.-E. Goebeler; Praxis: R. Schlag, B. Schöttker; Zürich: Univ. Spital: J. Gmür; Zwickau: Praxis: W. Elsel
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© 2011 by American Society of Clinical Oncology.
History
Published online: March 21, 2011
Published in print: April 20, 2011
Authors
Author Contributions
Conception and design: Rüdiger Hehlmann, Markus Pfirrmann, Stefan W. Krause, Christoph Nerl, Hans Pralle, Alois Gratwohl, Dieter K. Hossfeld, Joerg Hasford, Andreas Hochhaus, Susanne Saußele
Administrative support: Rüdiger Hehlmann, Andreas Hochhaus, Susanne Saußele
Provision of study materials or patients: Rüdiger Hehlmann, Armin Leitner, Martin C. Müller, Claudia Haferlach, Brigitte Schlegelberger, Leopold Balleisen, Mathias Hänel, Stefan W. Krause, Christoph Nerl, Hans Pralle, Alois Gratwohl, Dieter K. Hossfeld, Andreas Hochhaus, Susanne Saußele
Collection and assembly of data: Rüdiger Hehlmann, Michael Lauseker, Susanne Jung-Munkwitz, Armin Leitner, Martin C. Müller, Nadine Pletsch, Ulrike Proetel, Claudia Haferlach, Brigitte Schlegelberger, Markus Pfirrmann, Christoph Nerl, Alois Gratwohl, Joerg Hasford, Andreas Hochhaus, Susanne Saußele
Data analysis and interpretation: Rüdiger Hehlmann, Michael Lauseker, Susanne Jung-Munkwitz, Armin Leitner, Martin C. Müller, Nadine Pletsch, Ulrike Proetel, Markus Pfirrmann, Stefan W. Krause, Hans Pralle, Alois Gratwohl, Dieter K. Hossfeld, Joerg Hasford, Andreas Hochhaus, Susanne Saußele
Manuscript writing: All authors
Final approval of manuscript: All authors
Disclosures
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
Funding Information
Supported by Grants No. 106642 from Deutsche Krebshilfe, Novartis, Nürnberg, Germany; No. BMBF 01GI0270 from Deutsches Kompetenznetz für Akute and Chronische Leukämien; No. DJCLS H09/01f, H06/04v, H03/01 from Deutsche José-Carreras Leukämiestiftung; No. LSHC-CT-2004-503216 from the European LeukemiaNet; and by Roche, Grenzach-Wyhlen, Germany; and Essex Pharma, München, Germany.
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Tolerability-Adapted Imatinib 800 mg/d Versus 400 mg/d Versus 400 mg/d Plus Interferon-α in Newly Diagnosed Chronic Myeloid Leukemia. JCO 29, 1634-1642(2011).
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Journal of Clinical Oncology 2011 29:12, 1634-1642
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