Ann Hematol DOI 10.1007/s00277-015-2389-9
ORIGINAL ARTICLE
Comparison of consolidation strategies in acute myeloid leukemia: high-dose cytarabine alone versus intermediate-dose cytarabine combined with anthracyclines Dae Sik Kim 1 & Ka-Won Kang 1 & Se Ryeon Lee 1 & Yong Park 1 & Hwa Jung Sung 1 & Seok Jin Kim 2 & Chul Won Choi 1,3 & Byung Soo Kim 1
Received: 5 October 2014 / Accepted: 21 April 2015 # Springer-Verlag Berlin Heidelberg 2015
Abstract We compared the efficacy of high-dose cytarabine alone to that of intermediate-dose cytarabine combined with anthracyclines as consolidation therapy. Patients enrolled in the Korea University acute myeloid leukemia (AML) registry received remission induction chemotherapy with the same standard induction regimen (idarubicin and cytarabine 3+7). Postremission therapy was performed for three or four cycles according to one of the following regimens: high-dose cytarabine (3 g/m2) or combination of intermediate-dose cytarabine (1 g/m 2) with anthracyclines (idarubicin or mitoxantrone). Among the 443 AML patients enrolled in the registry, 145 patients received consolidation chemotherapy. The median overall survival (OS) and relapse-free survival (RFS) in the high-dose cytarabine group were significantly longer than those in the anthracycline combination group (OS, not reached vs. 16.6 months, p=0.045; RFS, 38.6 months vs. 11.0 months, p=0.011). The median duration of neutropenia was longer in the anthracycline combination group than in the high-dose cytarabine group (8 vs. 10 days, p=0.001). This study suggests that high-dose cytarabine consolidation may * Yong Park [email protected] * Chul Won Choi [email protected] 1
Division of Hematology-Oncology, Department of Internal Medicine, Korea University School of Medicine, 73 Inchon-ro, Seongbuk-gu, Seoul 136-705, Republic of Korea
2
Division of Hematology-Oncology, Department of Internal Medicine, Sungkyunkwan University School of Medicine, Seoul, South Korea
3
Division of Hematology-Oncology, Department of Internal Medicine, Korea University School of Medicine, 148 Guro-dong-ro, Guro-gu, Seoul 152-703, Republic of Korea
produce superior outcomes than combination treatment with intermediate-dose cytarabine and anthracyclines and that the addition of anthracyclines during AML consolidation has limited value as compared to cytarabine intensification. Keywords Acute myeloid leukemia . Consolidation chemotherapy . High-dose cytarabine . Anthracyclines
Introduction Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy characterized by the rapid clonal expansion of myeloid blasts in peripheral blood, bone marrow, and other tissues [1]. Standard treatment of AML is composed of anthracycline-based remission induction chemotherapy followed by postremission consolidation (cytarabine-based chemotherapy or stem cell transplantation) [2, 3]. Standard induction chemotherapy based on a backbone of cytarabine and anthracycline, so called the 3+7 regimen, was established in the 1981 Cancer and Leukaemia Group B (CALGB) study [4]. Over recent years, there have been significant advances in induction treatment for young patients using anthracycline dose intensification [5, 6]. Regarding the consolidation strategies, high-dose cytarabine chemotherapy (3 g/m2 every 12 h on D1, D3, and D5) has been established since the CALGB 1994 trial. However, the CALGB 1994 trial only demonstrated that high-dose cytarabine alone was superior to low-dose cytarabine alone (100 mg/m2 on D1–5 or 400 mg/m2 on D1–5), with no assessment of combination regimens. Therefore, efforts have been made to determine further effective consolidation strategies such as establishment of intermediate-dose cytarabine consolidation to reduce toxicities and cytarabine combined with other drugs to increase efficacy. However, the overall
Ann Hematol
results were not as impressive as those of recent trials for induction chemotherapy. Furthermore, the benefit of high-dose cytarabine has not been clearly demonstrated in recently published prospective randomized studies [7, 8]. Based on such studies, intermediate-dose cytarabine chemotherapy was suggested as a more appropriate treatment option as consolidation therapy than high-dose cytarabine chemotherapy because of less toxicities and similar efficacy [9]. In addition, controversies remain on whether multiagent combination chemotherapy is superior to high-dose cytarabine monotherapy as consolidation strategy. Recent prospective randomized studies comparing high-dose cytarabine monotherapy and multiagent chemotherapy, which include lower-dose cytarabine, showed no statistically significant differences in outcome between regimens [7, 10–12]. Therefore, there is currently no consensus on a single Bbest^ postremission treatment regimen, and several multiagent combination chemotherapies as well as high-dose cytarabine chemotherapy are still used as consolidation regimens, with most combination consolidation regimens including anthracyclines. Therefore, a key question regarding the best consolidation regimen is whether anthracyclines provide a benefit, because anthracyclines show a powerful antileukemic effect in the induction phase. In this context, two consolidation strategies, high-dose cytarabine monotherapy (3 g/m2 per 12 h on D1, D3, and D5) or anthracyclines combined with intermediatedose cytarabine (1 g/m2 per 12 h on D1–3), are used in our institution. The choice of consolidation regimen is made according to the physicians in charge. To the best of our knowledge, no randomized controlled trials or retrospective analyses have compared high-dose cytarabine consolidation and our combination consolidation schedule. This study compared the efficacy and toxicities of high-dose cytarabine (3 g/m2 per 12 h on D1, D3, and D5) alone and intermediate-dose cytarabine (1 g/m 2 per 12 h on D1–3) combined with anthracyclines as postremission consolidation therapy in patients who achieved complete remission by the same induction chemotherapy (3+7 regimen).
Materials and methods Patients From September 2001, all patients with newly diagnosed AML were enrolled in the AML registry of three hospitals (Anam, Guro, and Ansan) affiliated with the Korea University. This Korea University—AML registry (KU-AML) is a database including data on demographic characteristics, performance status, comorbidities, type of leukemia, cytogenetic risk category, molecular markers, and baseline laboratory findings of newly diagnosed AML patients. In addition,
monthly updated treatment outcomes are also recorded. All registrations were performed by a trained data manager. A diagnosis of AML with morphologic and immunophenotypical analysis according to the WHO 2008 classification was made by a specialist from the Department of Laboratory Medicine and Pathology. Inclusion criteria of this study were as follows: (1) complete remission (CR) achieved in the first induction by standard 3+7 regimen, (2) three to four cycles of postremission therapy in transplant noncandidates according to one of the following regimens: highdose cytarabine (HiDAC) or anthracycline and intermediatedose cytarabine combination (AIDAC), and (3) one to three cycles of postremission therapy in transplant candidates according to the same regimen before proceeding to stem cell transplantation. Patients who were treated with supportive care or low-intensity chemotherapy such as low-dose cytarabine or decitabine were excluded. Patients with de novo AML or secondary AML were included, but patients with acute promyelocytic leukemia (APL) were excluded. Before chemotherapy, all patients were screened according to the Eastern Cooperative Oncology Group (ECOG) performance status and Charlson comorbidity risk index [13]. Baseline laboratory evaluation and cytogenetic analysis were performed to determine prechemotherapy status and risk. Patients were classified as favorable, intermediate risk, or poor risk according to previously published criteria [14]. This study was approved by the Korea University Hospital institutional review board. Treatment All patients received remission induction chemotherapy with standard 3 + 7 regimen (idarubicin 12 mg/m2 on D1–3 + cytarabine 100 mg/m2 on D1–7). To evaluate response, a follow-up bone marrow evaluation was performed at the time of bone marrow recovery at around day 30 from the start of chemotherapy. Response was evaluated according to the recommendations by the Standard National Cancer Institute [15]. Postremission therapies were performed for three to four cycles by one of the following regimens: HiDAC (cytarabine 3 g/m2 per 12 h on D1, D3, and D5) or AIDAC (cytarabine 1 g/m2 per 12 h on D1–3 combined with idarubicin 12 mg/m2 or mitoxantrone 12 mg/m2 on D1 and D2). Idarubicin and mitoxantrone were administered alternately for each cycle. Dose reduction was permitted according to performance status of patients. Patients with favorable cytogenetic risk received only three to four cycles of consolidation chemotherapy and no further therapy. However, in patients with intermediate or poor risk cytogenetics, allogeneic stem cell transplantation was considered during the first CR to patients with a HLAmatched donor. Patients who relapsed after CR received salvage chemotherapy, and some of relapsed patients underwent allogeneic stem cell transplantation.
Ann Hematol
Statistical analysis
Results
Data analysis was performed using the IBM Statistical Package for Social Sciences (SPSS) version 21.0. Differences among treatment groups were compared by the Student’s t test and the chi-square test. Treatment outcomes according to consolidation regimen were compared. Overall survival (OS) was defined as the time interval from the date of diagnosis to the date of death. Relapse-free survival (RFS) for patients who had achieved CR was defined as the time interval from the date that CR was achieved to documentation of relapse or death. RFS and OS were calculated using the Kaplan–Meier method and compared by the log-rank test. Univariate analyses for prognostic factors of survival were performed by logrank test. For multivariate analyses, the proportionality assumption was tested by including a time-dependent covariate for each factor. However, the result indicated no differential effects over time, and thus, the final multivariate model was built using a Cox proportional hazard model. The Cox proportional hazard model was analyzed using the following variables: age, performance status, comorbidities (Charlson’s risk index), type of leukemia, cytogenetic risk categories, consolidation regimen, laboratory findings on diagnosis, and allogeneic stem cell transplantation. A p value of less than 0.05 was considered significant.
Patient selection and baseline characteristics
Fig. 1 Flow diagram for patient selection from the KU-AML registry
The selection process of patients enrolled in this study from the KU-AML registry is summarized in Fig. 1. Briefly, among a total of 443 AML patients, 260 non-APL patients received remission induction chemotherapy. In the induction phase, treatment-related early death (within 30 days after start of chemotherapy) occurred in 29 patients and 55 patients failed to achieve CR. A total of 145 patients received consolidation chemotherapy, 58 of which were treated with HiDAC consolidation and 87 with AIDAC consolidation chemotherapy. The median age of enrolled patients was 45 years (range, 15– 75 years). There were no significant differences between the two groups in terms of demographic features, PS, comorbidities, type of leukemia, cytogenetic risk, LDH, blast count, or other baseline laboratory findings. The baseline characteristics and laboratory results of enrolled patients are shown in Table 1. Treatment outcomes After remission induction chemotherapy, CR was achieved in 176 of the 260 eligible patients (67.7 %), with seven patients
Ann Hematol Table 1
Baseline characteristics and laboratory results
Characteristic
No. of patients (%) HiDAC (n=58)
Age (years) Median Range Sex Male Female ECOG PS 0–1 ≥2 Charlson risk index Low >Intermediate Type of leukemia De novo Secondary Cytogenetic risk Better Intermediate Poor Hb (g/dL) ≥8.0
ORIGINAL ARTICLE
Comparison of consolidation strategies in acute myeloid leukemia: high-dose cytarabine alone versus intermediate-dose cytarabine combined with anthracyclines Dae Sik Kim 1 & Ka-Won Kang 1 & Se Ryeon Lee 1 & Yong Park 1 & Hwa Jung Sung 1 & Seok Jin Kim 2 & Chul Won Choi 1,3 & Byung Soo Kim 1
Received: 5 October 2014 / Accepted: 21 April 2015 # Springer-Verlag Berlin Heidelberg 2015
Abstract We compared the efficacy of high-dose cytarabine alone to that of intermediate-dose cytarabine combined with anthracyclines as consolidation therapy. Patients enrolled in the Korea University acute myeloid leukemia (AML) registry received remission induction chemotherapy with the same standard induction regimen (idarubicin and cytarabine 3+7). Postremission therapy was performed for three or four cycles according to one of the following regimens: high-dose cytarabine (3 g/m2) or combination of intermediate-dose cytarabine (1 g/m 2) with anthracyclines (idarubicin or mitoxantrone). Among the 443 AML patients enrolled in the registry, 145 patients received consolidation chemotherapy. The median overall survival (OS) and relapse-free survival (RFS) in the high-dose cytarabine group were significantly longer than those in the anthracycline combination group (OS, not reached vs. 16.6 months, p=0.045; RFS, 38.6 months vs. 11.0 months, p=0.011). The median duration of neutropenia was longer in the anthracycline combination group than in the high-dose cytarabine group (8 vs. 10 days, p=0.001). This study suggests that high-dose cytarabine consolidation may * Yong Park [email protected] * Chul Won Choi [email protected] 1
Division of Hematology-Oncology, Department of Internal Medicine, Korea University School of Medicine, 73 Inchon-ro, Seongbuk-gu, Seoul 136-705, Republic of Korea
2
Division of Hematology-Oncology, Department of Internal Medicine, Sungkyunkwan University School of Medicine, Seoul, South Korea
3
Division of Hematology-Oncology, Department of Internal Medicine, Korea University School of Medicine, 148 Guro-dong-ro, Guro-gu, Seoul 152-703, Republic of Korea
produce superior outcomes than combination treatment with intermediate-dose cytarabine and anthracyclines and that the addition of anthracyclines during AML consolidation has limited value as compared to cytarabine intensification. Keywords Acute myeloid leukemia . Consolidation chemotherapy . High-dose cytarabine . Anthracyclines
Introduction Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy characterized by the rapid clonal expansion of myeloid blasts in peripheral blood, bone marrow, and other tissues [1]. Standard treatment of AML is composed of anthracycline-based remission induction chemotherapy followed by postremission consolidation (cytarabine-based chemotherapy or stem cell transplantation) [2, 3]. Standard induction chemotherapy based on a backbone of cytarabine and anthracycline, so called the 3+7 regimen, was established in the 1981 Cancer and Leukaemia Group B (CALGB) study [4]. Over recent years, there have been significant advances in induction treatment for young patients using anthracycline dose intensification [5, 6]. Regarding the consolidation strategies, high-dose cytarabine chemotherapy (3 g/m2 every 12 h on D1, D3, and D5) has been established since the CALGB 1994 trial. However, the CALGB 1994 trial only demonstrated that high-dose cytarabine alone was superior to low-dose cytarabine alone (100 mg/m2 on D1–5 or 400 mg/m2 on D1–5), with no assessment of combination regimens. Therefore, efforts have been made to determine further effective consolidation strategies such as establishment of intermediate-dose cytarabine consolidation to reduce toxicities and cytarabine combined with other drugs to increase efficacy. However, the overall
Ann Hematol
results were not as impressive as those of recent trials for induction chemotherapy. Furthermore, the benefit of high-dose cytarabine has not been clearly demonstrated in recently published prospective randomized studies [7, 8]. Based on such studies, intermediate-dose cytarabine chemotherapy was suggested as a more appropriate treatment option as consolidation therapy than high-dose cytarabine chemotherapy because of less toxicities and similar efficacy [9]. In addition, controversies remain on whether multiagent combination chemotherapy is superior to high-dose cytarabine monotherapy as consolidation strategy. Recent prospective randomized studies comparing high-dose cytarabine monotherapy and multiagent chemotherapy, which include lower-dose cytarabine, showed no statistically significant differences in outcome between regimens [7, 10–12]. Therefore, there is currently no consensus on a single Bbest^ postremission treatment regimen, and several multiagent combination chemotherapies as well as high-dose cytarabine chemotherapy are still used as consolidation regimens, with most combination consolidation regimens including anthracyclines. Therefore, a key question regarding the best consolidation regimen is whether anthracyclines provide a benefit, because anthracyclines show a powerful antileukemic effect in the induction phase. In this context, two consolidation strategies, high-dose cytarabine monotherapy (3 g/m2 per 12 h on D1, D3, and D5) or anthracyclines combined with intermediatedose cytarabine (1 g/m2 per 12 h on D1–3), are used in our institution. The choice of consolidation regimen is made according to the physicians in charge. To the best of our knowledge, no randomized controlled trials or retrospective analyses have compared high-dose cytarabine consolidation and our combination consolidation schedule. This study compared the efficacy and toxicities of high-dose cytarabine (3 g/m2 per 12 h on D1, D3, and D5) alone and intermediate-dose cytarabine (1 g/m 2 per 12 h on D1–3) combined with anthracyclines as postremission consolidation therapy in patients who achieved complete remission by the same induction chemotherapy (3+7 regimen).
Materials and methods Patients From September 2001, all patients with newly diagnosed AML were enrolled in the AML registry of three hospitals (Anam, Guro, and Ansan) affiliated with the Korea University. This Korea University—AML registry (KU-AML) is a database including data on demographic characteristics, performance status, comorbidities, type of leukemia, cytogenetic risk category, molecular markers, and baseline laboratory findings of newly diagnosed AML patients. In addition,
monthly updated treatment outcomes are also recorded. All registrations were performed by a trained data manager. A diagnosis of AML with morphologic and immunophenotypical analysis according to the WHO 2008 classification was made by a specialist from the Department of Laboratory Medicine and Pathology. Inclusion criteria of this study were as follows: (1) complete remission (CR) achieved in the first induction by standard 3+7 regimen, (2) three to four cycles of postremission therapy in transplant noncandidates according to one of the following regimens: highdose cytarabine (HiDAC) or anthracycline and intermediatedose cytarabine combination (AIDAC), and (3) one to three cycles of postremission therapy in transplant candidates according to the same regimen before proceeding to stem cell transplantation. Patients who were treated with supportive care or low-intensity chemotherapy such as low-dose cytarabine or decitabine were excluded. Patients with de novo AML or secondary AML were included, but patients with acute promyelocytic leukemia (APL) were excluded. Before chemotherapy, all patients were screened according to the Eastern Cooperative Oncology Group (ECOG) performance status and Charlson comorbidity risk index [13]. Baseline laboratory evaluation and cytogenetic analysis were performed to determine prechemotherapy status and risk. Patients were classified as favorable, intermediate risk, or poor risk according to previously published criteria [14]. This study was approved by the Korea University Hospital institutional review board. Treatment All patients received remission induction chemotherapy with standard 3 + 7 regimen (idarubicin 12 mg/m2 on D1–3 + cytarabine 100 mg/m2 on D1–7). To evaluate response, a follow-up bone marrow evaluation was performed at the time of bone marrow recovery at around day 30 from the start of chemotherapy. Response was evaluated according to the recommendations by the Standard National Cancer Institute [15]. Postremission therapies were performed for three to four cycles by one of the following regimens: HiDAC (cytarabine 3 g/m2 per 12 h on D1, D3, and D5) or AIDAC (cytarabine 1 g/m2 per 12 h on D1–3 combined with idarubicin 12 mg/m2 or mitoxantrone 12 mg/m2 on D1 and D2). Idarubicin and mitoxantrone were administered alternately for each cycle. Dose reduction was permitted according to performance status of patients. Patients with favorable cytogenetic risk received only three to four cycles of consolidation chemotherapy and no further therapy. However, in patients with intermediate or poor risk cytogenetics, allogeneic stem cell transplantation was considered during the first CR to patients with a HLAmatched donor. Patients who relapsed after CR received salvage chemotherapy, and some of relapsed patients underwent allogeneic stem cell transplantation.
Ann Hematol
Statistical analysis
Results
Data analysis was performed using the IBM Statistical Package for Social Sciences (SPSS) version 21.0. Differences among treatment groups were compared by the Student’s t test and the chi-square test. Treatment outcomes according to consolidation regimen were compared. Overall survival (OS) was defined as the time interval from the date of diagnosis to the date of death. Relapse-free survival (RFS) for patients who had achieved CR was defined as the time interval from the date that CR was achieved to documentation of relapse or death. RFS and OS were calculated using the Kaplan–Meier method and compared by the log-rank test. Univariate analyses for prognostic factors of survival were performed by logrank test. For multivariate analyses, the proportionality assumption was tested by including a time-dependent covariate for each factor. However, the result indicated no differential effects over time, and thus, the final multivariate model was built using a Cox proportional hazard model. The Cox proportional hazard model was analyzed using the following variables: age, performance status, comorbidities (Charlson’s risk index), type of leukemia, cytogenetic risk categories, consolidation regimen, laboratory findings on diagnosis, and allogeneic stem cell transplantation. A p value of less than 0.05 was considered significant.
Patient selection and baseline characteristics
Fig. 1 Flow diagram for patient selection from the KU-AML registry
The selection process of patients enrolled in this study from the KU-AML registry is summarized in Fig. 1. Briefly, among a total of 443 AML patients, 260 non-APL patients received remission induction chemotherapy. In the induction phase, treatment-related early death (within 30 days after start of chemotherapy) occurred in 29 patients and 55 patients failed to achieve CR. A total of 145 patients received consolidation chemotherapy, 58 of which were treated with HiDAC consolidation and 87 with AIDAC consolidation chemotherapy. The median age of enrolled patients was 45 years (range, 15– 75 years). There were no significant differences between the two groups in terms of demographic features, PS, comorbidities, type of leukemia, cytogenetic risk, LDH, blast count, or other baseline laboratory findings. The baseline characteristics and laboratory results of enrolled patients are shown in Table 1. Treatment outcomes After remission induction chemotherapy, CR was achieved in 176 of the 260 eligible patients (67.7 %), with seven patients
Ann Hematol Table 1
Baseline characteristics and laboratory results
Characteristic
No. of patients (%) HiDAC (n=58)
Age (years) Median Range Sex Male Female ECOG PS 0–1 ≥2 Charlson risk index Low >Intermediate Type of leukemia De novo Secondary Cytogenetic risk Better Intermediate Poor Hb (g/dL) ≥8.0
