• Open Access

Long-term outcome following imatinib therapy for chronic myelogenous leukemia, with assessment of dosage and blood levels: the JALSG CML202 study

Authors


  • Name of trial register: JALSG CML202. Registration no. C000000153, UMIN Clinical Trials Registry.

To whom correspondence should be addressed.

E-mail: kohnishi@hama-med.ac.jp

Abstract

A prospective multicenter Phase II study was performed to examine the efficacy and safety of imatinib therapy in newly diagnosed Japanese patients with chronic-phase CML. Patients were scheduled to receive imatinib 400 mg daily. Plasma imatinib concentrations were measured by liquid chromatography–tandem mass spectrometry. In 481 evaluable patients, estimated 7-year overall survival (OS) and event-free survival (EFS) at a median follow-up of 65 months were 93% and 87%, respectively. Because imatinib dosage was reduced in many patients due mainly to adverse events, subgroup analysis was performed according to the mean daily dose during the first 24 months of treatment: ≥360 mg (400-mg group; n = 294), 270–359 mg (300-mg group; n = 90) and <270 mg (200-mg group; n = 67). There were no significant differences in OS and EFS between the 300- and 400-mg groups; however, cumulative rates of complete cytogenetic and major molecular responses differed significantly between the two groups. There were no significant differences in mean imatinib trough levels between these two groups for the patients in whom trough levels had been measured. Survival and efficacy in the 200-mg group were markedly inferior to the former two groups. These results suggest that, although a daily dose of 400 mg imatinib is associated with better outcomes, 300 mg imatinib may be adequate for a considerable number of Japanese patients who are intolerant to 400 mg imatinib. Blood level monitoring would be useful to determine the optimal dose of imatinib. (Cancer Sci 2012; 103: 1071–1078)

Imatinib mesylate, a selective BCR-ABL1 kinase inhibitor, has demonstrated remarkable long-term efficacy in the treatment of chronic-phase (CP) CML[1] and now is the standard therapy for this disease.[2] An 8-year follow-up during the International Randomized Study of Interferon and STI571 (IRIS) on newly diagnosed CP CML demonstrated that continuous imatinib therapy exhibited superior efficacy and improved survival.[3] In Japan, imatinib was approved for the treatment of CML in 2001, and a multicenter prospective Phase II study of imatinib therapy (CML202 study) for newly diagnosed CP CML was immediately initiated by the Japan Adult Leukemia Study Group (JALSG). Herein, we report on the results of this study after a median follow-up period of 65 months.

In the present study, although the daily dose of imatinib was set at 400 mg, because of adverse events in many patients the dosage was reduced to less than 400 mg. Nevertheless, the overall efficacy and outcomes were excellent compared with that reported in other studies.[1, 4, 5] The relatively smaller body size of Japanese patients may explain why a daily dose of < 400 mg imatinib was adequate in some patients.[6] To confirm this assumption, we measured plasma trough levels of imatinib in patients receiving 400 or 300 mg imatinib daily and evaluated the association between plasma concentrations of imatinib and the efficacy, as well as long-term outcome, in these patients.

Materials and Methods

Study design and treatment

The present study was a prospective multicenter Phase II study on previously untreated, newly diagnosed patients with CP CML, with patients receiving a daily dose of 400 mg imatinib. The primary endpoint was overall survival (OS). Secondary endpoints included the rate of a complete hematologic response (CHR), the rate of a cytogenetic response, progression-free survival (PFS), event-free survival (EFS), and safety. The study was registered with the UMIN Clinical Trials Registry (http://www.umin.ac.jp/ctr/index/htm, accessed 10 Sep 2005; registration no. C000000153, the JALSG CML202 study).

Patients

Patients were eligible for inclusion in the study if they were 15 years or older, had de novo Philadelphia (Ph)-chromosome positive CP CML and had not received interferon-α treatment for CML. Further eligibility criteria were adequate liver function (serum bilirubin level ≤2.0 mg/dL and serum liver aminotransferase less than threefold the upper limit of normal), kidney function (serum creatinine ≤2.0 mg/dL), heart and lung function, an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0–3, and no prior or concurrent malignancy. Written informed consent was obtained from all patients prior to registration. The study protocol was reviewed and approved by the institutional review board of all the participating centers and the study was conducted in accordance with the Declaration of Helsinki.

Dose modification of imatinib

Patients were scheduled to receive imatinib at an oral daily dose of 400 mg. Lower dose of < 400 mg daily were permitted at the start of imatinib therapy in patients who were old and/or had a small body size, but it was planned to increase the dose of imatinib to 400 mg within the first month if patients tolerated the reduced dose. Dose escalation to 600 mg was implemented if patients failed to achieve a complete hematologic response (CHR) at 3 months or a major cytogenetic response at 6 months in the absence of dose-limiting adverse events. If patients did not exhibit a CHR at 6 months, they were switched to alternative therapy. If patients achieved a major cytogenetic response within 9 months, imatinib at 400 mg or the adjusted dose was maintained until disease progression.

If Grade 2 non-hematologic toxicities occurred and did not resolve spontaneously, imatinib was interrupted until the toxicities had been ameliorated to Grade 1 or less, and then resumed at the preceding dose. If Grade 3 or 4 non-hematologic or hematologic toxicities occurred, imatinib was interrupted until the toxicities had been ameliorated to Grade 1 or less, and then resumed at a reduced daily dose of 300 mg. Imatinib therapy was discontinued in the event of failure to achieve a CHR at 6 months, intolerance to imatinib, or disease progression to an accelerated phase (AP) or blast crisis (BC).

Definitions

The phases of CML (i.e. CP, AP, or BC) were defined as described previously in the IRIS study.[7] A CHR was defined as a reduction in the leukocyte count to <10 × 109/L and a reduction in the platelet count to <450 × 109/L that persisted for at least 4 weeks. Cytogenetic responses were evaluated by G-banding of at least 20 marrow cells in metaphase and were categorized as complete (CCyR; no cells positive for the Ph chromosome) and partial (PCyR; 1–35% of cells positive for the Ph chromosome). A major cytogenetic response (MCyR) was defined as complete or partial responses.[2] A major molecular response (MMR) was defined as a 3-log reduction or more in BCR-ABL1 transcripts compared with median baseline levels, as measured by reverse-transcription real-time quantitative polymerase chain reaction (RQ-PCR)[8, 9] or the transcription-mediated amplification and hybridization protection assay (TMA-HPA)[10, 11] (For details, refer to Fig. S1 and the Data S1 available as online Supplementary Material for this paper).

Event-free survival was defined as the time between registration and the earliest occurrence of any of the following events: death due to any cause, progression to AP or BC, and/or loss of MCyR or CHR. Progression-free survival was defined as the time between registration and the earliest occurrence of any of the following events: death due to any cause or progression to AP or BC. Overall survival was defined as the time between the date of registration and death due to any cause. Hematopoietic stem cell transplantation (HSCT) was not censored. Adverse events were assessed according to the National Cancer Institute–Common Toxicity Criteria version 2.0 (http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm, accessed 15 Mar 2012). The mean daily dose of imatinib in a designated period was defined as the total of the doses administered divided by the total number of days on which it was administered.

Measurement of trough plasma levels of imatinib

Blood samples were obtained within 24 ± 2 h after the last imatinib administration from patients who had been receiving 300 or 400 mg imatinib daily without any dose modification for at least 2 years. Plasma was immediately separated at 4°C and at 5000g for 10 min by centrifugation and stored at −80°C until measurement. Plasma imatinib concentrations were measured at the Toray Research Center (Tokyo, Japan), as reported previously.[12] Briefly, sample extracts were analyzed using reverse-phase chromatography with a Waters Symmetry column (Waters, Milford, MA, USA), followed by detection with a Sciex API 3000 mass spectrometer (PE Biosystems, Foster City, CA, USA). The lower limit of quantification was 4 ng/mL imatinib mesylate and the assay was fully validated. The precision from validation ranged from 99 ± 5% to 108 ± 5% over the concentration range 4–10 000 ng/mL.[13] The internal standard, imatinib mesylate, was provided by Novartis Pharma (Basel, Switzerland) and the assay system was approved by Novartis Pharma.

Statistical analysis

The Kaplan–Meier method and 95% confidential intervals (CI) were used to analyze OS, PFS, and EFS. Differences between subgroups of patients were evaluated using the log-rank test. Cumulative rates of CHR and cytogenetic responses were estimated according to the competing risk method, in which discontinuation of imatinib was evaluated as competing risk. Comparisons of baseline characteristics in the subgroups were made using the chi square test or Fisher's exact test for categorical variables, and with the Mann–Whitney U-test for continuous variables. All statistical analyses were performed using JMP software (SAS Institute, Cary, NC, USA) and R software (http://www.r-project.org, accessed 15 Feb 2011). Two-sided P < 0.05 was considered significant.

Results

Patients

Between April 2002 and April 2006, 489 patients from 86 hospitals belonging to the JALSG were enrolled in the CML202 study. Of these patients, three were deemed to be ineligible for inclusion because they were in AP, and a further five were excluded because of insufficient data. The characteristics of the remaining 481 evaluable patients at the time of registration are given in Table 1. The median follow-up time was 65.2 months (range 0.4–95.1 months). Eighty-two of 481 patients (17%) discontinued imatinib therapy or were switched to other therapy (Table 2).

Table 1. Patient characteristics
  1. Data are presented as the mean ± SD, as the median with the range given in parentheses, or as the number of patients in each group with percentages given in parentheses, as appropriate. †The presence of additional chromosomal abnormalities was not an exclusion criterion for the present study. BSA, body surface area; ECOG PS, Eastern Cooperative Oncology Group performance status; Hb, hemoglobin; PB, peripheral blood; WBC, white blood cells.

Total no. patients489
No. evaluable patients481
Age (years)52 (15–88)
No. patients ≥60 years of age (%)141 (29)
Sex (M/F, %)310/171 (64/36)
ECOG PS
0441 (92)
136 (8)
24 (1)
30 (0)
Duration from diagnosis (months)0.4 (0–8.3)
Sokal risk group (%)
Low253 (53)
Intermediate163 (34)
High65 (14)
Hasford risk group (%)
Low202 (42)
Intermediate227 (47)
High39 (8)
Unknown13 (3)
Additional chromosomal abnormalities (%)
Yes†51 (11)
Trisomy 84 (0.8)
Double Ph3 (0.6)
Loss of sex chromosome3 (0.6)
Others41 (8.5)
Splenomegaly (%)
Yes127 (27)
≥10 cm below the costal margin29 (6)
WBC (×109/L)36.7 (4.5–634.7)
Hb (g/dL)12.9 (4.8–19.1)
Platelets (×109/L)473 (96–2916)
PB blast (%)0 (0–13.0)
PB basophils (%)5.0 (0–19.0)
Body weight (kg)
All patients61.8 ± 12.1
Men 66.9 ± 10.9
Women52.6 ± 8.2
BSA (m2)
All patients1.621 ± 0.187
Men 1.714 ± 0.148
Women1.453 ± 0.121
Table 2. Patients' treatment status
 No. patients (%)
  1. HSCT, hematopoietic stem cell transplantation.

Continued imatinib treatment399 (83.0)
Discontinued imatinib treatment82 (17.0)
Reasons for discontinuation and/or change in therapy
Adverse events34 (7.1)
Disease progression11 (2.3)
Unsatisfactory therapeutic effect12 (2.5)
HSCT6 (1.2)
Death2 (0.4)
Lost to follow-up7 (1.5)
Withdrawal of consent8 (1.7)
Unknown2 (0.4)

Efficacy

For all 481 evaluable patients, the estimated cumulative rate of CHR was 96% at 7 years, whereas the rates for MCyR and CCyR were 94% and 90%, respectively (Fig. 1a). The BCR-ABL1 transcript was measured in 428 patients using TMA-HPA and/or RQ-PCR. Levels of the BCR-ABL1 transcript decreased to <100 copies/μg mRNA (i.e. MMR) in 39% of patients at 18 months and in 79% of patients after 7 years from the start of imatinib (Fig. 1b). According to the Sokal scoring system,[14] the cumulative rates of CCyR were 93%, 84%, and 82% in the low-, intermediate-, and high-risk groups, respectively. There was a significant difference in the rates of CCyR between the low- and intermediate/high-risk groups (= 0.006).

Figure 1.

Cumulative best (a) cytogenetic and (b) molecular responses and (c) survival of patients on imatinib therapy for chronic phase CML. Cumulative rates of responses were estimated according to the competing risk method. Discontinuation of imatinib was evaluated as a competing risk. CHR, complete hematologic response; MCyR, major cytogenetic response; CCyR, complete cytogenetic response; MMR, major molecular response; OS, overall survival; PFS, progression-free survival; EFS, event-free survival.

Long-term outcomes

The estimated 7-year rates (with 95% CI) of OS, PFS, and EFS were 93% (90–96%), 93% (90–95%), and 87% (84–91%), respectively (Fig. 1c). The estimated rate of freedom from progression to AP/BC was 97% (95% CI 96–99%) and the estimated 7-year rates of OS according to the Sokal scoring system for patients in the low-, intermediate-, and high-risk groups were 95%, 90%, and 91%, respectively. Patients in the low-risk group exhibited significantly better OS (= 0.016) and EFS (= 0.022) than those in the intermediate- or high-risk groups. In the landmark analysis, patients who had achieved a CCyR at 12 months or an MMR at 18 months exhibited significantly better PFS than those without CCyR or MMR (= 0.0005 and = 0.012, respectively).

Safety

The adverse events observed in all patients are listed in Table 3. Grade 3 or 4 hematologic adverse events were neutropenia (18%), thrombocytopenia (12%), and anemia (6%). Grade 3 or 4 non-hematologic adverse events included skin eruption (8%) and peripheral edema (0.6%). Grade 3 or 4 liver dysfunction was reported in 4% of patients. Congestive heart failure (Grade 3) developed in one patient and interstitial pneumonitis (Grade 3) developed in another patient. Grade 3 or 4 thrombocytopenia and skin eruptions occurred more frequently in the present study than in the IRIS study.[7]

Table 3. Adverse events associated with imatinib therapy
Adverse eventaNo. patients (%)
All patients (n = 481)400-mg group‡ (n = 294)300-mg group‡ (n = 90)200-mg group‡(n = 67)
All gradesGrade 3 or 4Grade 3 or 4Grade 3 or 4Grade 3 or 4
  1. a

    Adverse events were assessed according to the National Cancer Institute–Common Toxicity Criteria version 2.0. ‡Mean daily doses in the 400-, 300-, and 200-mg groups were ≥360, 270–359, and < 270 mg imatinib, respectively. ALT, alanine aminotransferase; AST, aspartate aminotransferase.

Non-hematologic
Superficial edema234 (48.6)3 (0.6)03 (3.3)0
Nausea/vomiting106 (22.0)4 (0.8)2 (0.7)1 (1.1)1 (1.5)
Anorexia94 (19.5)5 (1.0)2 (0.7)2 (2.2)1 (1.5)
Muscle cramps81 (16.8)1 (0.2)01 (1.1)0
Musculoskeletal pain (myalgia)100 (20.8)5 (1.0)2 (0.7)02 (3.0)
Arthralgia47 (9.8)1 (0.2)000
Rash192 (39.9)37 (7.7)7 (2.4)10 (11.1)14 (20.9)
Fatigue114 (23.7)0 (0)000
Diarrhea75 (15.6)2 (0.4)1 (0.3)00
Headache36 (7.5)1 (0.2)000
Hemorrhage24 (5.0)3 (0.6)2 (0.7)01 (1.5)
Pyrexia49 (10.0)1 (0.2)1 (0.3)00
Depression 25 (5.2)0 (0)000
Infection35 (7.3)8 (1.7)5 (1.7)02 (3.0)
Interstitial pneumonitis3 (0.6)1 (0.2)001 (1.5)
Hematologic
Anemia197 (41.0)28 (5.8)12 (4.1)4 (4.4)10 (14.9)
Neutropenia188 (39.1)85 (17.7)36 (12.2)25 (27.8)18 (26.9)
Thrombocytopenia199 (41.4)59 (12.3)19 (6.5)20 (22.5)16 (23.9)
Biochemical
Elevated ALT/AST99 (20.6)18 (3.7)3 (1.0)6 (6.7)7 (10.4)
Renal dysfunction37 (7.7)1 (0.2)1 (0.3)00

Efficacy and outcomes in relation to imatinib dosage

Although it was planned to administer imatinib to patients at a dose of 400 mg daily, 82 patients (17%) discontinued imatinib or were switched to other treatment mainly because of adverse events or unsatisfactory efficacy (Tables 2, 3). Dose reduction or interruption were required in 223 (46%) patients, with escalated doses given to 10 patients (2%) during the first 24 months. Among all 481 patients, the initial dose of imatinib was 400 mg in 458 patients (95.2%), 300 mg in 10 patients (2.1%), 200 mg in 11 patients (2.3%), 100 mg on one patient, and 600 mg in one patient. The mean daily dose during the first 24 months of treatment was ≥360 mg in 294 patients (61%; designated the “400-mg group”), 270–359 mg in 90 patients (19%; designated the “300-mg group”), and < 270 mg in 67 patients (14%; designated the “200-mg group”). Thirty patients (6%) discontinued imatinib during the first 24 months. Regarding the safety profile, Grade 3 or 4 neutropenia, thrombocytopenia, liver dysfunction, and skin eruptions tended to be observed more frequently in the 300- and 200-mg groups because dose reductions from the scheduled dose of 400 mg imatinib daily were mostly made for patients in these groups because of adverse events (Table 3). The patients in the 300-mg group were significantly more likely to be female, older, have a lower body weight (BW), and a smaller body surface area (BSA) than patients in the 400-mg group (Table 4). Patients in the 300- and 200-mg groups had significantly higher Sokal risk than patients in the 400-mg group (= 0.001). Of the patients in the 400- and 300-mg groups, age (= 0.0024) and sex (= 0.0077) were significant independent predictors for OS, as determined by multivariate analysis; however, dosage was not a significant predictor of OS (= 0.64).

Table 4. Patient characteristics in each of the mean daily dose groups during the first 24 months of treatment
 Imatinib daily dose group†P-value
400 mg300 mg 200 mg Discontinued
  1. Unless indicated otherwise, data are given as the mean ± SD or as the median with the range given in parentheses. †Mean daily doses in the 400-, 300-, and 200-mg groups were ≥360, 270–359, and <270 mg imatinib, respectively. BSA, body surface area; NA, not applicable.

No. patients294906730 
Daily dose (mg)398 ± 17310 ± 23187 ± 68NA 
No. men/women212/8246/4430/3722/8<0.0001
Age (years)48 (16–81)57 (19–79)63 (19–87)52.5 (15–88)<0.0001
Body weight (kg)64.6 ± 11.857.6 ± 10.555.3 ± 10.061.8 ± 15.3<0.0001
BSA (m2)1.67 ± 0.181.55 ± 0.161.51 ± 0.171.61 ± 0.22<0.0001
Sokal risk group (n)
Low180392311<0.0001
Intermediate84303213 
High3021126 
Dose reduction (n)16959NA 
Interruption (n)65218NA 
Dose escalation (n)1000NA 

Efficacy and survival were analyzed according to the mean daily dose during the first 6, 12, and 24 months. During each period, the estimated cumulative rate of CCyR or MMR was significantly higher for patients in the 400- and 300-mg groups than for patients in the 200-mg group (< 0.001 and < 0.0001, respectively). There was a significant difference in achieving CCyR or MMR between the 400- and 300-mg groups (= 0.018 and = 0.017, respectively; Fig. 2a,b). There were no significant differences in OS and EFS between the 400- and 300-mg groups during the first 24 months (= 0.77 and = 0.49, respectively). However, the OS and EFS of the 200-mg group were significantly inferior to those of the 400- and 300-mg groups during the same periods (= 0.009 and = 0.002, respectively; Fig. 3a,b). Survival was analyzed according to the mean daily dosage of imatinib during the first 24 months per BW (Table 5). Patients who received a mean dose of imatinib per BW that was >5.0 mg/day/kg showed significantly superior OS and EFS than those receiving ≤5.0 mg/day/kg (= 0.0012 and = 0.0016, respectively; Fig. 4). These results indicate that patients who had relatively high daily dosage per BW had better OS and EFS, although the actual daily dose had been lower than 400 mg imatinib.

Figure 2.

Cumulative rates of best responses according to the mean daily dose during the first 24 months of treatment with imatinib. (a) Cumulative rates for complete cytogenetic responses (CCyR). (b) Cumulative rates of major molecular responses (MMR). Mean daily doses in the 400- (n = 294), 300- (n = 90), and 200-mg (n = 67) groups were ≥360, 270–359, and <270 mg imatinib, respectively.

Figure 3.

(a) Overall and (b) event-free survival according to the mean daily dose during the first 24 months. Mean daily doses in the 400- (n = 294), 300- (n = 90), and 200-mg (n = 67) groups were ≥360, 270–359, and < 270 mg imatinib, respectively.

Figure 4.

(a) Overall and (b) event-free survival according to the mean daily dose during the first 24 months per body weight. The cut-off value was set at >5.0 mg/day/kg (e.g. if a patient whose body weight was <60 kg received imatinib at a mean daily dose of 300 mg).

Table 5. Number of patients and survival according to the mean daily dose of imatinib during the first 24 months per body weight
 Mean daily dose/body weight (mg/day/kg)P-value
>5.0a≤5.0
Actual bodyweight (kg)No. patientsActual bodyweight (kg)No. patients
  1. a

    The cut-off value was set at >5.0 mg/day/kg (e.g. the mean daily dose of imatinib during the first 24 months (300 mg) divided by body weight [<60 kg]). ‡Mean daily doses in the 400-, 300-, and 200-mg groups were ≥360, 270–359, and <270 mg imatinib, respectively. Patients who discontinued imatinib were not included in the analysis. EFS, event-free survival; OS, overall survival.

Imatinib daily dose group‡
400 mg<80266≥8028 
300 mg<6063≥6027 
200 mg<405≥4062 
Estimated 7-year OS96%89%0.0012
Estimated 7-year EFS88%76%0.0016

Plasma trough levels of imatinib according to the daily dose

Plasma trough levels (Cmin) of imatinib were determined in 50 patients who continuously received imatinib at a daily dose of 300 mg (n = 24) or 400 mg (n = 26) without any dose modification (Table 6). The patients receiving 300 mg imatinib tended to be older and to have a smaller BSA than patients in the 400-mg group. These tendencies did not different from those of the entire study population (Tables 4 and 6). There was no significant difference in mean Cmin between the two groups (= 0.673). The Cmin in 15 of 24 patients (63%) receiving 300 mg imatinib and in 15 of 26 patients (58%) receiving 400 mg imatinib were distributed above 1000 ng/mL, and the ratio of patients >1000 ng/mL Cmin did not differ significantly between the two groups (= 0.10). However, the Cmin in patients receiving 300 mg imatinib was distributed towards lower concentrations compared with those receiving 400 mg imatinib. There was a significant correlation between Cmin and age only in the 400-mg group (= 0.034), with weak correlations between Cmin and BW or BSA. These results indicate that small, elderly, and/or female patients receiving 300 mg imatinib daily had almost the same Cmin as patients receiving 400 mg daily.

Table 6. Patient characteristics and plasma trough levels of imatinib according to the daily dose of imatinib
 Imatinib daily dose†P-value
400 mg300 mg
  1. Unless indicated otherwise, data are given as the mean ± SD, as the median with the range given in parentheses, or as the number of patients in each group with percentages given in parentheses, as appropriate. †Imatinib at a daily dose of 400 or 300 mg without any dose modification. BSA, body surface area; CCyR, complete cytogenetic response; Cmin, plasma trough level; MCyR, major cytogenetic response; MMR, major molecular response.

No. patients2624 
No. men/women19/712/120.092
Age (years)49 (17–79)58 (33–76)0.012
Body weight (kg)65.2 ± 10.659.5 ± 10.70.062
BSA (m2)1.68 ± 0.171.57 ± 0.170.034
Sokal risk group (n)
Low18130.357
Intermediate66 
High25 
Cmin (ng/mL)
Mean ± SD1165 ± 4451113 ± 4260.673
Median (range)1035 (710–2420)1130 (439–2140) 

% Patients on >1000 

ng/mL imatinib

57.7 (15/26)62.5 (15/24)0.1
Best response (%)
MCyR26 (100)23 (96) 
CCyR26 (100)22 (92) 
MMR24 (92)23 (96) 

Discussion

In the present study (CML202), the best cumulative rates of MCyR and CCyR 7 years after the start of imatinib were 94% and 90%, respectively, and the estimated 7-year OS and EFS rates were 93% and 87%, respectively. The Sokal risk showed favorable prognostic significance in low-risk patients compared with intermediate- or high-risk patients. These results are comparable to those reported in the IRIS trial and others studies in Western countries.[3-5] In terms of baseline characteristics, there was a tendency for fewer patients with a high-risk Sokal score in the present study compared with the IRIS study. We believe this is due to the Japanese medical system, in which a considerable number of people undergo annual medical check-ups.

Imatinib is currently established as the first-line therapy for patients with CP CML. Nevertheless, several controversial issues remain,[15] with the dose of imatinib as one of the most important.[6, 16-21] In the present study, many patients received a lower dose of imatinib than the planned initial dose of 400 mg. Therefore, we performed subgroup analysis according to the mean daily dose during the first 6, 12, and 24 months of treatment. The rate of achieving CCyR or MMR differed significantly between the 300- and 400-mg groups during the first 24 months. Even so, there were no significant differences in OS, PFS, and EFS between the 300- and 400-mg groups during the first 6, 12, or 24 months of treatment. Conversely, the 200-mg group showed markedly inferior cytogenetic and/or molecular responses, as well as inferior survival, compared with the 300- and 400-mg groups. We also analyzed outcomes according to the mean daily dosage during the first 24 months per BW, with the results suggesting that patients who had relatively high daily dosage per BW were likely to have better OS and EFS even though the actual daily dose had been lower than 400 mg imatinib. The OS and EFS in the 300-mg group in the present study were not inferior compared with rates reported in the IRIS study (85% at 7 years vs. 83% at 6 years), which suggests that a considerable number of Japanese patients who received doses lower than 400 mg demonstrated an adequate response. A prospective comparative study would be necessary to confirm this observation.

Two recent studies showed a correlation between the plasma trough levels (Cmin) and response, suggesting that maintaining Cmin above approximately 1000 ng/mL was associated with improved outcomes.[22, 23] In the present study, the mean daily dose was 331 ± 108 mg during the first 24 months and the relatively high dosage of imatinib per BW was associated with better OS and EFS, whereas in the IRIS study the mean daily dose among the patients who continued receiving imatinib was 382 ± 50 mg.[1] On the basis of our results, we assume that the relatively small body size of Japanese patients compared with their Western counterparts may have affected Cmin, although differences in the metabolism of imatinib because of ethnicity cannot be ruled out either. Therefore, we measured the Cmin of imatinib in a group of patients who had received imatinib continuously at a daily dose of either 300 or 400 mg. The patients from whom blood samples were collected showed almost similar background characteristics to the entire study population. There was no significant difference in the mean Cmin between patients receiving 300 or 400 mg imatinib, and there was no significant difference in the ratio of patients whose Cmin was higher than 1000 ng/mL between the two groups. When pharmacokinetic analyses of patients receiving 400 mg imatinib in the present study are compared with the IRIS study, the Cmin in the present study was distributed at higher concentrations than in the IRIS study (mean Cmin 1165 vs. 979 ng/mL, respectively); however, the distribution of Cmin in patients receiving 300 mg imatinib was similar between the studies.[23] Larson et al. reported a weak correlation between Cmin and age, BW, or BSA in the IRIS study, but also suggested that the effects of body size and age on Cmin were not likely to be of clinical significance because Cmin showed large interpatient variability.[23] However, the Cmin in their female patients was significantly higher than that in male patients, and they speculated that this may be due to the small body size of the female patients. The same tendency was seen in the present study, especially in terms of age and gender. Therefore, a small body size among Japanese old and/or female patients may partly account for the higher Cmin of imatinib. Regarding the plasma concentration of imatinib in Japanese patients, there are other reports showing sufficient Cmin in patients receiving imatinib at doses lower than 400 mg,[6, 24] but it remains uncertain whether there are any individual or ethnic differences in the metabolism of imatinib.[24, 25]

Another possible reason for the satisfactory outcomes seen for patients in the 300-mg group could be that, at this dose, imatinib could be administered continuously to some patients without serious adverse events. A recent study regarding imatinib dosage in Japanese patients reported that, based on multivariate analysis, older age and lower BW are significant risk factors for the discontinuation of imatinib therapy and that patients with these factors were less likely to achieve a CCyR.[18] Continuous and adequate dosage is essential for optimal outcome, and adherence to imatinib therapy is critical.[26, 27]

In conclusion, the long-term follow-up of the JALSG CML202 study revealed almost similar excellent outcomes to those of the IRIS study and others. There were no significant differences in OS and EFS between the 300- and 400-mg imatinib groups. However, cumulative rates of cytogenetic or molecular responses in the 300-mg group were inferior to those in the 400-mg group. The results of the present study suggest that imatinib at a dose of 400 mg may be optimal for Japanese patients, but that 400 mg imatinib is not tolerable in a considerable number of patients, and that the measurement of Cmin is useful in finding the optimal dose, especially in elderly and/or female patients. Nevertheless, excessive dose reductions to <300 mg imatinib should be avoided even in patients who are intolerant to 400 mg imatinib or have a small body size. We hope our findings are useful for the treatment of CML patients in other Asian countries.

Acknowledgments

This work was supported by a grant from the Japanese Ministry of Health, Labour and Welfare. The authors thank the participating doctors and other medical staff of the 86 hospitals who enrolled patients in the present study and provided the necessary data to make the study possible. The authors are indebted to Dr Ryuzo Ohno (Aichi Cancer Center, Nagoya, Japan) for his contribution to the study and in the preparation of manuscript.

Disclosure Statement

KO, YM, HK, and TN received research funding from Novartis. The other authors declare no competing financial interests.

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