Therapeutic strategy of untreated de novo acute myeloid leukemia in the elderly: the efficacy of continuous drip infusion with low dose cytarabine and etoposide
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- Tsurumi, H., Kanemura, N., Hara, T. et al. J Cancer Res Clin Oncol (2007) 133: 547. doi:10.1007/s00432-007-0203-3
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To evaluate the efficacy and safety of a novel low dose chemotherapy as a remission induction regimen for elderly de novo AML patients ineligible for intensive chemotherapy.
Fifty consecutive patients aged 60 to 85 with untreated de novo AML were enrolled. Patients with poor PS or defined non-hematological complications were given continuous drip infusion of low dose cytarabine (Ara-C), 20 mg/body and etoposide (VP-16), 50 mg/body for 10 days (AV group). Patients without those cormobidities were given intensive induction therapy (S group). After achieving complete remission (CR), S group patients and those with improved PS in AV group received consolidation chemotherapy with intensive regimen (S-S or AV-S group), and other patients received AV regimen repeatedly (AV-AV group).
Eighteen (64%; 95% confidence interval (CI), 0.47–0.82) of 28 patients in AV group and 16 (73%; 95% CI, 0.54–0.91) of 22 patients in S group achieved CR, respectively. The 1-year OS rates of the patients in the AV-AV group (n = 9), AV-S group (n = 9), and S-S group (n = 16) were 22, 81, and 78%, respectively. Although the sample size was small, no significant difference was observed for the 1-year OS rate between the AV-S and S-S groups. Regimen related death were 4 patients in S group, while no patient in AV group.
Therapeutic strategy consisting of remission induction using AV regimen and consolidation using intensive regimen after improving PS is beneficial in the management of elderly AML patients who have difficulty in tolerating for intensive induction chemotherapy.
KeywordsElderlyAMLLow dose cytarabineEtoposide
The incidence of acute myeloid leukemia (AML) increases with age and more than half of all patients are over 60 years of age at the time of diagnosis (Deschler and Lubbert 2006). Despite some reports of improved chemotherapeutic response and disease free survival in adults with AML (Berman et al. 1991; Wiernik et al. 1992; Yates et al. 1982), advanced age remains a significantly poor prognostic factor for both complete remission and survival. The optimal management strategy for those patients is still a controversial issue with opinions frequently diverse between intensive chemotherapy and conservative therapy. In fact, we cannot often help hesitating to select intensive chemotherapy for elderly patients due to prolonged myelosuppression, complex karyotypic abnormalities, preexisting myelodysplasia, underlying non-hematological complications, a poor performance status (PS) and organodysfunction with aging in comparison to younger patients.
We have tried to develop a therapeutic strategy for elderly patients with untreated de novo AML according to the presence of PS and non-hematological complications at the diagnosis. Accordingly, we treated those elderly patients with a new combination chemotherapy using continuous drip infusion of low dose cytarabine (Ara-C) and etoposide (VP-16) (AV therapy). We thus consider that administering Ara-C and etoposide by continuous intravenous infusion might possibly extend the contact time for drugs and leukemic cells, thereby enhancing the anti-leukemic effect (Koyama et al 1990). While, the patients without comorbidities received the intensive chemotherapy in a similar manner to younger patients with good PS. The present study aimed to evaluate the efficacy and safety of AV therapy as a remission induction regimen for elderly de novo AML patients ineligible standard intensive chemotherapy.
Patients and methods
The eligibility for enrollment included patients aged 60–85 with previously untreated de novo AML as defined by French–American–British (FAB) classification criteria (Bennett et al 1976). We only enrolled patients with a poor PS as defined by the WHO criteria 3 and 4, or non-hematological complications such as metabolic disease, an active infection without respiratory failure, a mild liver dysfunction due to a hepatic viral infection, and/or other malignant diseases. The exclusion criteria were as follows: (1) patients with acute promyelocytic leukemia (APL); (2) patients with antecedent myelodysplastic syndrome (MDS); (3) patients with therapy related AML; (4) patients with prior treatment for AML including chemotherapy, radiation, stem cell transplantation, and cytokines like as granulocyte colony-stimulating factor (G-CSF); and (5) obvious organ dysfunction (serum bilirubin level > 2 × upper normal limit, creatinine clearance < 50 ml/min and cardiac ventricular ejection fraction < 40%). The enrollment period was from July 1995 to December 2000. Written informed consent was obtained from all eligible patients before undergoing remission induction therapy. The study was approved by the institutional review board of our university.
Low dose Ara-C and VP16 regimen (AV therapy); patients either with a poor PS or defined non-hematological complications were given continuous drip infusion of low dose Ara-C, 20 mg/body/day and VP-16, 50 mg/body/day for 10 days. If marrow hypoplasia or a reduction of leukemic blasts of less than 5% could not been obtained on day 10, both Ara-C and VP-16 were added for another 4 days. If a complete remission (CR) could not been achieved, then the patients received the re-induction therapy which was the same as the first regimen.
Intensive regimen; the patients without a poor PS or any other complications were given the intensive regimen consisting of daunorubicin (DNR), 30 mg/m2, by bolus infusion on days 1, 2, and 3, behenoyl Ara-C (BHAC), 150 mg/m2, by drip infusion for 10 days and 6-mercaptopurine (6—MP), 70 mg/m2, orally for 10 days. If marrow hypoplasia or a reduction of leukemic blasts of less than 5 % could not been obtained on day 7, then DNR was added on days 8 and 9. If CR could not been achieved, then the patients received the re-induction therapy which was the same as the first regimen.
After achieving CR, patients received three courses of intensive post-remission chemotherapy. The first course consisted of Ara-C, 150 mg/m2, by continuous infusion for 7 days and mitoxantrone, 6 mg/m2, by bolus infusion on days 1, 2, and 3. The second course consisted of DNR, 30 mg/m2 for 3 days, VP-16 70 mg/m2, by drip infusion for 5 days, and BHAC, 150 mg/m2, for 7 days. The third course consisted of aclarubicin, 14 mg/m2, by bolus infusion and BHAC, 150 mg/m2 for 7 days. These courses were applied for patients who achieved CR by intensive induction regimen, and for those who obtained CR by AV regimen and recovered PS. Patients, who achieved CR by AV therapy but still had a poor PS, again received three courses of AV therapy.
The response criteria were defined as follows: a CR included normalization of previous cytologic abnormalities in the bone marrow (blasts < 5%, normal proportion of erythropoiesis) and normalization of peripheral blood counts (disappearance of blasts, neutrophil > 1.5 × 109/l and platlets > 100 × 109/l). It was essential to maintain the condition of the peripheral blood for 4 weeks except for beginning the next chemotherapy in order to confirm CR. A relapse was determined in the event of an increase of blasts in the marrow (>10%) or the appearance of them in the peripheral blood. For CR patients, the duration of remission [disease free survival (DFS)] was defined from the date of bone marrow examination associated with CR until either relapse, death, or the final data acquisition (August 31, 2005). The overall survival (OS) was defined from the date of diagnosis until death or the final data acquisition.
A comparison of the variables between the two treatment groups at baseline was performed either by Student’s t test or Fisher’s exact test. The effects of age, sex, PS, FAB classification, chromosomal abnormality, hemoglobin, white blood cell (WBC) count, lactate dehydrogenase (LDH) level, nucleated cell count of bone marrow, CD7 and CD34 expression of blasts and regimen of induction chemotherapy were analyzed for the CR rates using the chi-square test. Survival analyses for OS and DFS were performed using the log-rank test based on the Kaplan-Meier method. A multivariate analysis was performed using the Cox regression technique to define the prognostic significance of selected variables. A P value of less than 0.05 was considered to be significant.
Patient’s characteristics at enrollment to this study
No. of patients (%)
Age (median, range)
(P < 0.01)
Defined non-hematological complications
(P < 0.01)
Intermadiate or Favorable
Unfavorable or Unknown
Data not available
Response to treatment and survival
Only a poor PS was identified as an adverse prognostic factor associated with CR based on univariate analysis. Regarding OS, a univariate analysis identified the following factors have an adverse prognostic effect: poor PS, leukocytosis (>30 × 109/l), elevated LDH (>1,000 IU/l), hypoalbuminemia (<3.5 g/dl), and no achievement of CR. A multivariate analysis of prognostic factors associated with OS identified the following factors to demonstrate independent adverse significance: poor PS (RR 0.27, 95% CI 0.44–0.91, P < 0.001) and no achievement of CR (RR 0.63, 95% CI 0.16–0.45, P < 0.05). A multivariate analysis for DFS identified no prognostic factors. In this study, age, chromosomal abnormality, surface markers, and the regimen of induction were not identified as prognostic factors for either the CR rates or OS.
Non-hematological adverse effects at first induction in AV group (n = 28)
NCI-CTCAEa version 3.0 grading system
How to treat elderly patients with AML still remains an important topic of debate regardless more than half of the all AML patients are older than 60 years of age (Estey 2000). Although the beneficial effects of intensive chemotherapy for elderly patients were reported (Lowenberg et al. 1989; Rees et al. 1996) and thereby recommended (Chen et al 2005; Hiddemann et al. 1999), many oncologists feel uncomfortable of offering intensive chemotherapy to elderly patients with a poor PS or comorbidity because of the high risk of induction mortality. For those patients, various regimens to reduce the toxicity associated with intensive chemotherapy have been proposed such as dose attenuation and/or use of cytokines like as G-CSF. A low dose Ara-C regimen has been extensively studied and it is currently regarded as one of the representative therapies for advanced MDS and AML patients in the elderly (Tilly et al. 1990; Visani et al. 2004), because of the assumption that it is less toxic than conventional intensive treatments. These studies have shown CR rates about 30–50% and a lower number of early deaths. Combination therapy of low dose Ara-C with other cytotoxic drugs therefore seems to be more promising to improve CR rates. Based on this point of view, we therefore employed AV therapy for elderly AML patients.
In this study, the CR rates were not different between the AV group and S group, in spite of an unfavorable selection of patients for AV group. The CR rate in the AV group (64%) was higher than those in other studies on older patients with AML (Lowenberg et al. 1989; Tilly et al. 1990; Goldstone et al. 2001). Moreover, the DFS and OS rates in the AV-S group who had achieved CR by AV therapy and received intensive consolidation were in a similar range to those reported for younger adults (Mayer et al 1994).
In addition, a clear observation in this study is the importance of post-remission chemotherapy. Usually, PS consists of two factors: namely, host-related factors such as comorbidity, and leukemia-related factors such as leukocytosis or infection as associated complications. Leukemia-related factors can be improved by achieving CR regardless of the induction regimen, and as a result, patient’s PS after CR must also improved. In this study, half of all patients who achieved CR in the AV group were able to receive standard intensive consolidation chemotherapy after an improvement of PS. This fact suggested that leukemia-related factors were important elements of the PS, and moreover, that standard intensive chemotherapy was possible for those with a poor PS if they once achieved CR. The findings that there was no difference in the OS and DFS rates between the AV-S group and the S-S group suggests that intensive consolidation chemotherapy contributes to an improvement of survival. In addition, the compliance of the intensive approach was generally acceptable probably due to the good PS. In contrast, if the PS of patients is poor after the achievement of CR, low dose post-remission chemotherapy could thus be one option. However, the optimal intensity of consolidation regimen is still open to debate (Stone et al. 2001; Anderson et al. 2002) and thus requires further study.
Recently, large retrospective studies on the treatment outcome of elderly patients with AML and MDS have been reported (Chen et al. 2005; Kantarjian et al. 2006). Kanterjian et al. proposed prognostic models, based on standard readily available characteristics such as age, PS, leukocytosis and an unfavorable karyotype, which may assist in therapeutic and investigational decisions (Kantarjian et al. 2006). However, in our study, some parameters such as age, chromosomal abnormality, leukocytosis, and regimen of induction were not identified as prognostic factors for CR rates and/or OS. These results probably reflect the lower statistical power of our sample size. In our study, a few patients survived longer than 5 years in AV-S group. Those patients had lower blasts percentages in the marrow at first in comparison to other patients. The disease characteristics of the patients tend to mostly MDS rather than AML. As a result, the AV regimen was thus speculated to be effective for patients with such diseases as overt leukemia with slowly growing blasts. In the future, the selection of adequate induction chemotherapy based on such prognostic models should be considered in elderly AML patients. In poor-risk group, the mortality during induction chemotherapy with standard intensive regimens was still high, and thereby it seems adequate to recommend AV therapy as an option for AML patients who have difficulty in tolerating intensive chemotherapy.
Febrile neutropenia (FN) occurred in 57% of the patients in the AV group as a major toxicity in the first induction therapy. In addition, myelosuppression was an important adverse effect during the induction therapy, but no life-threatening sepsis or hemorrhaging was observed. As a result, no patients required withdrawal, and all safely concluded the AV regimen.
In conclusion, AV therapy was found to be effective, at least as a remission induction therapy and well tolerated by elderly patients with a poor PS or some non-hematological complications. In addition, therapeutic strategy consisting of remission induction using low dose regimens such as AV therapy and consolidation therapy using an intensive regimen should therefore be taken into consideration in the management of such AML patients.