Continuous infusion intermediate-dose cytarabine, mitoxantrone, plus etoposide for refractory or early relapsed acute myelogenous leukemia

Leukemia Research 30 (2006) 204–210

Continuous infusion intermediate-dose cytarabine, mitoxantrone, plus etoposide for refractory or early relapsed acute myelogenous leukemia Je-Hwan Lee a,∗ , Seong-Jun Choi a , Jung-Hee Lee a , Young-Shin Lee a , Miee Seol a , Seong-Gil Ryu a , Seongsoo Jang b , Chan-Jeoung Park b , Hyun-Sook Chi b , Jung-Shin Lee a , Woo-Kun Kim a , Kyoo-Hyung Lee a a

Departments of Internal Medicine, Asan Medical Center, University of Ulsan, College of Medicine, 388-1 Pungnap-2dong, Songpa-gu, Seoul 138-736, South Korea b Departments of Laboratory Medicine, Asan Medical Center, University of Ulsan, College of Medicine, Seoul, South Korea Received 20 May 2005; received in revised form 20 June 2005; accepted 21 June 2005 Available online 1 August 2005

Abstract For refractory and early relapsed AML, this prospective phase II clinical trial evaluated a salvage chemotherapy regimen, which was consisted of continuous infusion intermediate-dose cytarabine (1 g/m2 /day, 24 h i.v. infusion × 5), mitoxantrone (12 mg/m2 /day × 3), and etoposide (150 mg/m2 /day × 3). We treated 33 patients and 17 (51.5%) achieved CR with a median duration of 117 days. Median overall survival was 219 days. Our results suggest that continuous infusion intermediate-dose cytarabine, together with mitoxantrone and etoposide, may induce CR in a significant proportion of patients with refractory or early relapsed AML, although remission duration was short. © 2005 Elsevier Ltd. All rights reserved. Keywords: Continuous infusion; Intermediate dose cytarabine; Early relapse; Refractory; Acute myelogenous leukemia

1. Introduction Despite significant progress in the treatment of acute myelogenous leukemia (AML), 20–40% of adult patients still fail to achieve initial complete remission (CR) with standard induction chemotherapy [1,2] and 50–70% of the patients in first CR will eventually relapse [3]. The prognosis for patients with refractory or early relapsed disease is very poor. Although a number of single agents and drug combinations have been tested, the CR rate is much lower in these patients than in patients with untreated or late relapsed AML, and the remission is usually short-lived [4–7]. There are few longterm survivors, and only a minority could be salvaged with allogeneic or, possibly, autologous hematopoietic cell transplantation [10]. ∗

Corresponding author. Tel.: +82 2 3010 3218; fax: +82 2 3010 6961. E-mail address: [email protected] (J.-H. Lee).

0145-2126/$ – see front matter © 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.leukres.2005.06.013

The clinical failure in patients with refractory or relapsed AML generally results from the resistance of leukemic cells to chemotherapeutic agents. Resistance to anthracyclines was shown to be associated with increased expression and activity of multi-drug resistance proteins [9,10]. However, several different mechanisms may be involved in the resistance to cytarabine, including intracellular depletion of deoxycytidine kinase, increased levels of cytidine deaminase, and decreased numbers of nucleoside transport sites [11]. Cytarabine, an important component of chemotherapy regimens for AML, is most frequently administered at standard doses (100–200 mg/m2 /day) by continuous infusion or at intermediate to high doses (0.5–3.0 g/m2 once or twice daily) by short infusion (1–6 h) [12–14]. As most patients with refractory or relapsed AML become resistant to standard dose cytarabine, many salvage regimens for these patients have included short infusion of intermediate- to high-dose cytarabine, increasing its extracellular concentration to 20–80 ␮M and leading to

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increased intracellular accumulation of its active metabolite, ara-C 5 -triphosphate (ara-CTP) [15–21]. Since cytarabine is S phase-specific, its therapeutic efficacy may be influenced by the duration of drug exposure as well as by its extracellular concentration [13]. There have been few studies, however, involving continuous infusion of intermediateto high-dose cytarabine to increase the duration of drug exposure. In pediatric AML patients, continuous infusion of intermediate-dose cytarabine was administered along with fludarabine or cladribine [22–25], but these studies focused on the effects of fludarabine or cladribine on the intracellular accumulation of ara-CTP. In a previous report, we retrospectively analyzed the efficacy of salvage chemotherapy regimen, including continuous infusion of intermediate-dose cytarabine plus idarubicin and etoposide, on patients with refractory or relapsed AML [26]. We found that 7 (37%) of 19 patients achieved CR, with a median remission duration of 6.7 months, and two patients survived long-term without transplantation [26]. Due to these promising results, we have conducted a prospective phase II clinical trial to evaluate the efficacy and toxicity of continuous infusion intermediatedose cytarabine, together with mitoxantrone and etoposide, in patients with refractory or early relapsed AML. In this study, idarubicin was replaced with mitoxantrone because many patients had already received idarubicin as front-line induction chemotherapy.

2. Patients and methods 2.1. Eligibility criteria This study included adult patients, aged 15 years or older, with refractory or relapsed acute myelogenous or mixed leukemia. Refractory leukemia was defined as a failure to achieve CR after two cycles of initial induction chemotherapy (primary refractoriness) or after chemotherapy for leukemia relapse (refractory relapse). Early relapsed leukemia was defined as a relapse within 12 months of initial CR (early relapse). This study also included patients who relapsed after allogeneic hematopoietic cell transplantation (posttransplant relapse), or who relapsed two or more times (multiple relapses). However, patients whose initial CR lasted for ≥12 months were excluded from this study. A Karnofsky performance score of 60 or higher and adequate cardiac, hepatic, and renal functions were required. Written informed consent was obtained from all patients. 2.2. Protocol outline This study was approved by the Institutional Review Board of the Asan Medical Center, Seoul, Korea. The salvage chemotherapy regimen consisted of cytarabine (1 g/m2 /day intravenously [i.v.] as a 24 h continuous infusion on days 1 through 5), mitoxantrone (12 mg/m2 /day i.v. over 30 min on days 1 through 3), and etoposide (150 mg/m2 /day i.v. over

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5 h on days 1 through 3). A second course of induction chemotherapy was given to patients who achieved partial remission, but less than CR, after the first course, with at least 4 weeks between the start of the first course and the start of the second course. At the discretion of the attending physician, hematopoietic growth factor could be given to a patient to facilitate recovery from myelosuppression after confirmation of hypocellular marrow at interim bone marrow examination. Patients who achieved CR could be given one or two cycles of consolidation chemotherapy using the same regimen, and allogeneic hematopoietic cell transplantation was planned according to donor availability. 2.3. Evaluation of salvage chemotherapy Blood was drawn everyday for complete blood count, including reticulocyte count, until full hematologic recovery. Blood chemistry was performed twice weekly, or more frequently as necessary, and blood coagulation tests were performed once weekly, or more frequently as necessary. Bone marrow examination for evaluation of remission status was performed 14 days after salvage chemotherapy and on the day the patient showed full hematologic recovery. All patients were monitored for the occurrence of adverse events, including chemotherapy-induced toxicities. Toxicities were graded according to NCI Common Terminology Criteria for Adverse Events (CTCAE) v3.0, which classifies each toxicity as grades I through V. Grades III–V toxicities were recorded as severe. CR was defined as fewer than 5% blasts in an aspirate sample with marrow spicules and hematologic recovery, measured as an absolute neutrophil count ≥1000 ␮L−1 and a platelet count ≥100,000␮L−1 . In addition, there should be no blasts with Auer rods or persistence of extramedullary disease [27]. Cause of treatment failure was subdivided into three categories [27]. Treatment failure due to resistant disease included appropriately treated patients who survived ≥1 week following the completion of the initial course of treatment, but whose last peripheral blood smear and/or bone marrow showed persistent leukemia. Treatment failure due to complications of aplasia included patients who survived ≥1 week following the completion of the initial course of treatment and died while cytopenic, but whose last post-treatment bone marrow was aplastic or hypoplastic without evidence of leukemia. Treatment failure of indeterminate cause included patients who died less than 1 week after the completion of the initial course of treatment and patients who died ≥1 week following the completion of treatment, whose most recent peripheral blood smear did not show persistent leukemia, and who did not have a bone marrow examination subsequent to therapy. Relapse after CR was defined as reappearance of leukemic blasts in the peripheral blood or ≥5% blasts in the bone marrow that was not attributable to any other cause, such as bone marrow regeneration after consolidation therapy, or appearance of extramedullary leukemic involvement [27].

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2.4. Statistical analysis

Table 1 Patient characteristics

Various clinico-pathologic parameters were analyzed for potential prognostic significance for CR achievement, remission duration, and overall survival. Univariable analyses of associations between CR achievement and each categorical variable were performed using the χ2 test. In patients who achieved CR, remission duration was measured from the time of CR to the time of relapse. Overall survival was calculated from the first date of salvage chemotherapy to the time of death. The probabilities of remission duration and overall survival were calculated according to the Kaplan–Meier method and compared by the log–rank test. Multivariable analysis was made by a stepwise multiple logistic regression for CR achievement and by the Cox’s proportional hazard model for remission duration and overall survival.

Characteristic

3. Results 3.1. Patient characteristics We enrolled all 33 consecutive patients who were eligible between May 1999 and February 2003 (Table 1). Twentyeight had AML and five had acute mixed leukemia. Median age was 34 years (range, 20–59 years). At the time of salvage chemotherapy, 19 patients (57.6%) had refractory leukemia, 16 with primary refractoriness and three with refractory relapse, whereas 14 (42.4%) had relapsed leukemia, 10 with early relapse, three with multiple relapses, and one with posttransplant relapse. Cytogenetic analyses were successfully performed in 27 patients at diagnosis and four additional patients showed normal karyotype at the time of salvage chemotherapy. Risk groups were classified according to the criteria of the Southwest Oncology Group/Eastern Cooperative Oncology Group Study [28]: two patients (6.1%) had favorable cytogenetics [t(8;21) in two], 16 (48.5%) had intermediate cytogenetics [normal in 10 and +8, −13, +11/−13, del(13q), t(4;6), t(7;11) in one each], and 13 had poor cytogenetics [complex karyotype containing three or more chromosomal changes in six, t(9;22) in three, and del(7q), del(7q)/del(9q), t(6;9), 11q23 abnormalities in one each]. Assay for multi-drug resistance activity of leukemic cells, as measured by the rhodamine-123 efflux assay [29], was performed at the time of salvage chemotherapy in 22 patients, and it was positive in 15 (68%). The front-line induction chemotherapy regimens used included standard-dose cytarabine plus idarubicin in 15 patients (45.5%), standard-dose cytarabine plus daunorubicin in 14 (42.4%), and others in 4 (12.1%). In 17 patients, an initial CR had been induced by the front-line induction chemotherapy, with the median remission duration being 236 days (range, 73–567 days). The patients, who had attained their first CR with front-line induction chemotherapy, had received median three cycles (range, 1–7) of consolidation chemotherapy consisting of high-dose cytarabine in all patients except one patient who

Number of patients

Sex Male Female

18 15

Age at treatment, year 35 or less Over 35

17 16

Disease status at treatment Refractory Relapsed

19 14

Cytogenetic risk group at diagnosis Good/intermediate Poor Unknown

18 13 2

Number of previous chemotherapy cycles 3 or less More than 3

21 12

Response to front-line induction chemotherapy CR No CR

17 16

Duration of first CR, day 210 or less Over 210

7 10

Karnofsky performance score at treatment 80 or less 90–100

9 24

WBC at treatment (×103 /mm3 ) 20.0 or less Over 20.0

27 6

% Circulating blasts at treatment 40% or less Over 40%

25 8

% Blood neutrophils at treatment 10% or less Over 10%

9 24

% Blood lymphocytes at treatment 20% or less Over 20%

13 20

% Bone marrow blasts at treatment 30% or less Over 30%

6 24

Uric acid at treatment, mg/dL 7.0 or less Over 7.0

28 5

% MDR activity at treatment Less than 10 10 to less than 30 30 or more

7 9 6

had Philadelphia chromosome. The median number of previous chemotherapy cycles per patient, including consolidation therapy, was three (range, 1–8). The median time from diagnosis of acute leukemia to salvage chemotherapy was 150 days (range, 28–977 days).

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3.2. Efficacy of salvage chemotherapy All patients received the planned dose of salvage chemotherapy. CR was attained in 15 patients after one cycle of salvage chemotherapy. A second cycle of the same salvage chemotherapy was administered to four patients, two of whom attained CR. Overall, 17 (51.5%; 95% confidence interval [CI], 34.4–68.6%) of 33 patients achieved CR at a median of 42 days (range, 27–130 days) after salvage chemotherapy. Six patients received one or two cycles of consolidation chemotherapy using the same regimen. Five patients underwent allogeneic hematopoietic cell transplantation, two using a sibling donor, and three using an unrelated donor. In the 16 patients who did not achieve CR, the cause of treatment failure was resistant leukemia in 13 and indeterminate in three. Thirteen of the 17 patients who achieved CR relapsed, with the median CR duration being 117 days (range, 38–993+ days). The site of relapse was the blood and bone marrow in 11 patients, the central nervous system in one, and the lymph nodes in one. Four of five patients who underwent allogeneic hematopoietic cell transplantation after CR with salvage chemotherapy relapsed. Two patients died in remission due to the complications of aplasia after consolidation chemotherapy. 3.3. Toxicities after salvage chemotherapy

Table 2 Non-hematologic toxicities of salvage chemotherapy Grades I–II

Grades III–V

15.2 18.2 69.7 27.3 33.3 0 27.3 6.1 15.1 42.4 42.4

3.0 9.1 27.3 0 21.2 87.9 9.1 51.5 9.1 6.1 6.1

Toxicities were graded by CTCAE v3.0.

abnormalities (51.5%), gastrointestinal toxicities (27.3%), and hepatic toxicities (21.2%). Three patients experienced severe neurologic toxicity, and one of these patients experienced seizure attacks, which were controlled with medication. 3.4. Overall survival

Myelosuppression was the main toxicity observed. GCSF was administered to 13 patients, starting on median day 15 (range, day 10–30), for a median of 10 days (range, 1–31 days). Absolute neutrophil counts recovered to over 500 ␮L−1 in 28 patients on median day 28 (range, day 20–44), and unsupported platelet counts recovered to over 20,000 ␮L−1 in 22 patients on median day 29 (range, day 14–49). A median of eight units (range, 2–18 units) of packed red blood cells and a median of 100 units (range, 10–566 units) of platelets were required after salvage chemotherapy. Non-hematologic toxicities after salvage chemotherapy were graded by CTCAE v3.0 (Table 2). The most common severe non-hematologic toxicity was febrile neutropenia (87.9%). Other common severe toxicities were metabolic

Cardiovascular toxicities (%) Respiratory toxicities (%) Gastrointestinal toxicities (%) Renal toxicities (%) Hepatic toxicities (%) Infection (%) Hemorrhage (%) Metabolic abnormalities (%) Neurologic toxicities (%) Skin toxicities (%) Pain (%)

Fig. 1. Overall survival curve. The median overall survival was 219 days, and survival probability at 3 years was 5.5%.

Three patients remained alive, with a median overall survival of 219 days (Fig. 1). Two surviving patients were in CR 664 and 1145 days, respectively, after salvage chemotherapy, and one was alive with disease 474 days after salvage chemotherapy. One of the two surviving patients without disease underwent unrelated hematopoietic cell transplantation, whereas the other did not receive any type of post-remission therapy. 3.5. Prognostic factor analysis Several clinico-laboratory and treatment-related variables were analyzed to determine their prognostic significance for CR achievement, duration of CR, and overall survival. Univariable analysis of CR achievement showed that disease status at salvage chemotherapy (refractory versus relapsed; 36.8% versus 71.4%; P = 0.049), initial CR duration (<210 days versus ≥210 days; 28.6% versus 80.0%; P = 0.034), and Karnofsky performance score (<90 versus ≥90; 22.2% versus 62.5%; P = 0.039) were statistically significant prognostic factors. Total leukocyte counts (≤20,000 ␮L−1 versus >20,000 ␮L−1 ; 59.3% versus 16.7%; P = 0.059), percentage of circulating blasts (≤40% versus >40%; 60.0% versus 25.0%; P = 0.085), and percentage of peripheral blood lymphocytes (≤20% versus >20%; 30.8% versus 65.0%; P = 0.055) were marginally significant. All of these factors, except for initial CR duration, were entered into a stepwise multiple logistic regression analysis, which showed

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Table 3 Multivariate analyses of prognostic factors for CR achievement, remission duration, and overall survival Variable

Odds ratio

95% confidence interval

P-value

0.002–0.640

0.024a

1.434–130.434

0.023a

CR achievement Total leukocyte counts ≤20,000 ␮L−1 0.033 vs. >20,000 ␮L−1 Disease status Refractory vs. 13.675 relapsed Duration of CR Uric acid level ≤7.0 mg/dL vs. 8.068 >7.0 mg/dL Overall survival Percentage of circulating blasts ≤40% vs. >40% 2.941

1.764–36.893

0.007b

1.489–5.809

0.002b

Karnofsky performance score <90 vs. ≥90 0.444

0.212–0.927

0.031b

a b

Stepwise multiple logistic regression analysis. Cox’s proportional hazard model.

that total leukocyte counts (odds ratio [OR], 0.033; 95% confidence interval [CI], 0.002–0.640; P = 0.024) and disease status at salvage chemotherapy (OR, 13.675; 95% CI, 1.434–130.434; P = 0.023) were independent prognostic factors for CR achievement (Table 3). Although initial CR duration is commonly prognostic for relapsed patients [6], it was omitted in the multivariable analysis because it could be analyzed only in the 17 patients who had attained CR after front-line induction chemotherapy. Univariable analysis of remission duration showed that the percentage of circulating blasts (≤40% versus >40%; 249 days versus 48 days; P = 0.016) and uric acid concentration (≤7.0 mg/dL versus >7.0 mg/dL; 249 days versus 38 days; P = 0.007) were statistically significant prognostic factors. When these factors were entered into a Cox’s proportional hazard model, uric acid concentration (OR, 8.068; 95% CI, 1.764–36.893; P = 0.007) was the only independent prognostic factor for remission duration (Table 3). Univariable analysis of overall survival showed that Karnofsky performance score (<90 versus ≥90; 93 days versus 244 days; P = 0.011) and percentage of circulating blasts (≤40% versus >40%; 244 days versus 81 days; P = 0.054) were statistically or marginally significant prognostic factors. When these factors were entered into a Cox’s proportional hazard model, both Karnofsky performance score (OR, 0.444; 95% CI, 0.212–0.927; P = 0.031) and percentage of circulating blasts (OR, 2.941; 95% CI, 1.489–5.809; P = 0.002) were independent prognostic factors for overall survival (Table 3). 4. Discussion Many retrospective, phase II (single agent or combination), and phase III studies that have addressed the effi-

cacy of various chemotherapy regimens for refractory or relapsed AML have reported CR rates of 8–68% [3–5,7]. This wide range of response rates may reflect the efficacy of different regimens or the heterogeneity of study populations. Observations made from these studies have consistently identified initial CR duration as an important prognostic factor in patients with relapsed AML. As duration of initial CR decreases, CR rates and disease-free survival following salvage chemotherapy decreases continuously [6]. Intermediate- to high-dose cytarabine-based regimens have been most frequently adopted for refractory or relapsed AML. Among the regimens, various combinations of fludarabine, cytarabine, and granulocyte colony stimulating factor (G-CSF) (FLAG regimen) [30–33] and combinations of etoposide, mitoxantrone, and cytarabine [8,34,35] have been widely investigated. Although CR rates over 50% were reported with these regimens, subgroup analyses showed that CR rates were much lower in patients with refractory or early relapsed disease than in those with late relapsed disease [8,31,35]. Using various high dose cytarabine-containing salvage regimens, the CR rate was shown to be only 11% among patients whose initial CR lasted less than 12 months or whose AML failed to respond to standard induction chemotherapy regimen, but was over 50% among patients who relapsed more than 12 months after their first CR [6]. Our study included adult AML patients with refractory disease (n = 19), early relapse (n = 10), initial CR duration less than 12 months), multiple relapses (n = 3), or posttransplant relapse (n = 1), but excluded patients with late relapsed disease. Taking into account the adverse features of the patients in our study, our CR rate (51.5%) was at least comparable to results obtained using FLAG or other regimens. While most studies using intermediate- to high-dose cytarabine as therapy for acute leukemia have employed intermittent short infusions, we administered intermediate-dose cytarabine (1 g/m2 /day) as a continuous infusion, thereby prolonging the duration of drug exposure as well as increasing plasma drug concentration. By a 72 h continuous infusion, 2 g/m2 /day of cytarabine is expected to attain a mean plasma cytarabine concentration of 5.1 ␮M/L [36], which represents the lower limit of achieving maximum rates of ara-CTP accumulation [14]. Because the majority (76%) of our patients who experienced treatment failure did so due to resistant leukemia, the efficacy of our regimen may be improved by increasing the daily dose of cytarabine to 2 g/m2 /day, or combining cytarabine with a cytarabine metabolism modulator such as fludarabine [11,37]. Several recent reviews of refractory or relapsed AML have stated that there is still no generally accepted and successful treatment of this disease [3–5,7]. Despite the relatively high CR rates attained by several chemotherapy regimens, none resulted in durable remission or improved overall survival. Furthermore, regimens with higher CR rates are generally associated with prolonged myelosuppression and severe mucosal toxicities. In our study, significant proportion of

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the patients experienced severe non-hematologic toxicities, which were manageable in most cases, and there were no hypoplastic deaths. However, median remission duration was only 4 months and median overall survival was 7 months. Thus, although we could not monitor minimal residual disease, the quality of CR was apparently not good. Cytogenetic abnormalities and multi-drug resistance activity, which are important prognostic factors in untreated AML [38,39], did not have any significant influence on treatment outcomes in our study. This finding suggests that leukemic cells from the patients included in our study were highly resistant to chemotherapy, regardless of their cytogenetic or multi-drug resistance status. Thus, a fraction of resistant cells may survive after salvage chemotherapy even in those patients who attained CR. Regarding cytogenetics, our study has some limitation because we used the cytogenetic results at diagnosis, which might have different prognostic impact from those at relapse [40]. The short remission duration observed in our study may also be related to inadequate post-remission therapy, which was not performed in 11 patients. However, there was no difference in remission duration between patients who received any type of post-remission therapy and those who did not. Furthermore, four of five patients who underwent allogeneic hematopoietic cell transplantation after CR relapsed. Thus, a more innovative approach is needed to improve the overall outcome of these refractory patients. Several new anti-leukemic agents, most of which target specific pathways involved in leukemogenesis, are being developed [3–5]. Investigators can find an opportunity to test new agents in patients who are expected to gain negligible advantage from a conventional salvage chemotherapy [6]. Recent advances in knowledge and techniques for minimal residual disease have made it possible to detect molecular relapses prior to obvious clinical or hematological relapses. Among the acute leukemias, acute promyelocytic leukemia is, currently, the only indication for treatment of molecular relapse by monitoring of PML/RAR␣ hybrid transcripts [41,42]. Evidences have been accumulated that monitoring of AML1/ETO and CBF␤/MY11 hybrid transcripts could predict hematologic relapse [43,44]. Immunophenotyping investigation of minimal residual disease may also predict relapse in AML patients [45]. Thus, it is likely that, in the near future, therapeutic decisions will be made on the basis of molecular evidence of disease prior to obvious clinical relapse, which may help improve overall treatment outcomes of AML. In summary, we have shown that a combination of continuous infusion intermediate-dose cytarabine, mitoxantrone, and etoposide could induce CR in a significant portion of patients with refractory or early relapsed AML, but with a short remission duration. Continued efforts to improve treatment outcomes in patients with refractory or relapsed AML should be made through well-designed clinical trials using new agents or new therapeutic strategies.

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Acknowledgments Contributions. Je-Hwan Lee designed the study, analyzed the data, and wrote the paper. Seong-Jun Choi and Jung-Hee Lee contributed to conception of the study and performed the research programs of Hematology division at the Asan Medical Center. Miee Seol, Young-Shin Lee, and Seong-Gil Ryu collected the clinical data. Seongsoo Jang, Chan-Jeoung Park and Hyun-Sook Chi supported the collection of laboratory data. Jung-Shin Lee, Woo-Kun Kim, and Kyoo-Hyung Lee were involved in revising the manuscript critically for important intellectual content. Kyoo-Hyung Lee gave the final approval for the submission of this manuscript.

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