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Table of Contents
ORIGINAL ARTICLE
Year : 2018  |  Volume : 1  |  Issue : 2  |  Page : 61-65

Intensified versus non-intensified induction therapy with cytarabine and daunorubicin for patients with newly diagnosed acute myeloid leukemia


1 Hematology and Medical Oncology Department, Cancer Research Center, Cancer Institute of Iran, Imam Khomeini Hospital Complex, Tehran, Iran
2 Department of Hematology, Thrombosis Hemostasis Research Center, Tehran, Iran
3 Department of Hematology and Oncology, Hematopoietic Stem Cell Transplantation Research Center, Shariati Hospital, Tehran University of Medical Science (TUMS), Tehran, Iran

Date of Web Publication31-Dec-2018

Correspondence Address:
Sahar Tavakoli
Department of Hematology and Oncology, Hematopoietic Stem Cell Transplantation Research Center, Shariati Hospital, North Kargar Street, Tehran
Iran
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/JCO.JCO_8_18

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  Abstract 

Background: The purpose of this study was to compare the efficacy and adverse effects of intensified dose of daunorubicin (DNR) and cytarabine (Ara-C) versus their standard dose in induction therapy for patients with newly diagnosed acute myeloid leukemia (AML). Materials and Methods: In a retrospective review, patients with AML in Hematology and Oncology Department of Imam Khomeini Hospital, Tehran, Iran, who underwent induction therapy with standard dose of Ara-C and DNR (100mg/m2 for 7 days and 45mg/m2 for 3 days, respectively) were compared in terms of overall survival (OS) rate, disease-free survival (DFS) rate, and treatment-related complications with those who underwent double-intensified induction (i.e., Ara-C, 200mg/m2 for 7 days and DNR, 60mg/m2 for 3 days). Results: Among 123 patients, the standard-dose regimen was used for 49 patients, and 74 patients received the dose-intensified regimen. The rate of 2-year DFS, 2-year recurrence rate of the disease, and treatment-related mortality improved significantly in the latter group (P < 0.05). However, between the two groups, OS rate, bone marrow blast cell percentage 14 days after treatment, the number of antibiotics received, fungal infection rate, and the need for bone marrow transplants did not significantly differ. On the other hand, the risk of heart failure significantly increased in the dose-intensified group (P < 0.05). Conclusion: Treatment of AML using combined dose-intensified induction significantly improved DFS rate and decreased the disease-recurrence rate but did not significantly improve OS rate, and more side effects were encountered.

Keywords: Acute myeloid leukemia, cytarabine, daunorubicin, induction therapy


How to cite this article:
Mirzania M, Safaee Nodehi SR, Sharifian RA, Shahi F, Emami AH, Esfandbod M, Togeh GR, Tavakoli S. Intensified versus non-intensified induction therapy with cytarabine and daunorubicin for patients with newly diagnosed acute myeloid leukemia. J Curr Oncol 2018;1:61-5

How to cite this URL:
Mirzania M, Safaee Nodehi SR, Sharifian RA, Shahi F, Emami AH, Esfandbod M, Togeh GR, Tavakoli S. Intensified versus non-intensified induction therapy with cytarabine and daunorubicin for patients with newly diagnosed acute myeloid leukemia. J Curr Oncol [serial online] 2018 [cited 2019 Jan 21];1:61-5. Available from: http://www.journalofcurrentoncology.org/text.asp?2018/1/2/61/249062


  Introduction Top


Acute myeloid leukemia (AML) is the most common type of leukemia in adults.[1] The most frequent induction chemotherapy regimen consists of combination therapy with cytarabine (Ara-C) for 7 days of continuous infusion plus 3 days of intravenous injection of daunorubicin (DNR).[2],[3]So far, many studies have been carried out comparing different doses of the standard drugs used in induction chemotherapy of AML. Increasing the dosage of Ara-C to 200mg/m2 per day, extending its infusion period to 10 days (10+3), or adding oral thioguanine (100mg/m2) twice per day on days 1–7 (7+3 + 7) did not additionally improve the results.[4]

Since 1980s, different doses of DNR, which ranged from 45 to 90mg/m2 of body surface area, have been studied.[5] Studies have indicated that overall survival (OS) rate increases considerably in patients who received higher doses versus those who received lower doses of DNR.[2] On the other hand, continuous 3-day infusion of DNR has been preferred to its continuous 2-day infusion.[4]

Historically, comparing results after receiving 100 and 200mg/m2 doses of Ara-C has manifested that survival rate of patients younger than 60 years improved.[3] However, further studies indicated that dose increment of Ara-C or increasing the days of its injections resulted in increased toxicity without improving the effectiveness of treatment.[6],[7]On the other hand, a newly published systematic review concluded that high-dose Ara-C in induction improves long-term disease control and OS rate in adults <60 years of age with de novo AML and also is a clear benefit on relapse-free survival in induction therapy, especially for the favorable-risk group.[8]

In this study, we evaluated the results of a dose increment in not only one but two main drugs used in the induction therapy of patients with AML, considering the synergistic effects of the combination of DNR and Ara-C.


  Materials and Methods Top


In a retrospective review, we studied the documents of 123 patients with AML of 16–60 years of age treated in hematology department of Imam Khomeini Hospital, Tehran, Iran, since January 2011 to February 2015. Data analysis was performed on March 2017. Patients more than 60 years of age and cases of acute promyelocytic leukemia were excluded from the study. The diagnosis of AML was established on the basis of morphological, cytochemical, immunophenotypic, and cytogenetic analyses on a bone marrow (BM) aspiration specimen. The patients were categorized as unfavorable-, intermediate-, and favorable-risk groups according to their cytogenetic analyses.[9] Moreover, molecular survey was performed using polymerase chain reaction method for recognizing possible mutations affecting the prognosis. Pathology material from BM biopsy for all cases was also reviewed. To avoid technical bias, the mentioned analyses were performed by a single team in the pathology department of Imam Khomeini Hospital.

Treatment plan

Between January 2011 and January 2013, the patients had received standard dose of Ara-C (i.e., continuous infusion of 100mg/m2 for 7 days) and DNR (i.e., 45mg/m2 for 3 days) and from February 2013 to February 2015, they had received intensified doses of Ara-C (i.e., continuous infusion of 200mg/m2 for 7 days) and DNR (i.e., 60mg/m2 for 3 days).

On the 8th day of chemotherapy, all patients received Granulocyte-colony stimulating factor (10 µg/kg intravenously) for more than 48h until their absolute neutrophil count reached at least 1500/µL. On the 14th day, BM aspiration and biopsy were performed. If less than 5% blast cells were observed, the patient was monitored until 28th day. However, if the blast cells were between 5% and 25%, the patient underwent another 24-h infusion of Ara-C at the dose of 100mg/m2 for 5 days and DNR at 45mg/m2 for 3 days. If blast cells were more than 25%, the patient was considered as refractory and underwent salvage regimens. These three mentioned groups were categorized as favorable response, partial response, and resistant groups, respectively. BM aspiration and biopsy were repeated on the 28th day of treatment and when the blast cells were less than 5% in the presence of more than 50% of marrow cellularity, complete response (CR) to treatment was achieved. The patients were categorized into two groups according to their cytogenetic risk and initial white blood cell (WBC) count. Good-risk group was selected to receive high-dose Ara-C consolidation at the dose of 3g/m2 twice a day for 3 days and a maximum of four courses every 28 days. Medium- or poor-risk group was scheduled for a BM transplant. The patients who had more than 5% blast cells on the 28th day of treatment, considered as resistant to treatment, thus proceeded to salvage regimens.

Supportive care

If initial WBC count was >100,000/µL, the patients were treated with 2g of hydroxyurea every 6h for 36h in addition to proper hydration.

At each outpatient visit, the patients were examined entirely for any disease or treatment-related complications, and their peripheral blood smear was observed for possible recurrences.

Infection management

During the neutropenic period, if fever (i.e., core temperature ≥38°C for more than an hour or ≥38.3°C at any time) was detected, first line of broad-spectrum antibiotics (ceftazidime and amikacin) was initiated. After 48h, if fever continued, vancomycin was added. If the fever did not drop off, an antifungal drug (i.e., amphotericin B) would be added and the addition of other antibiotics was made according to the conditions of each patient.

Data analysis

Data were inserted in Statistical Package for Social Sciences (SPSS) software, released 2007 for Windows, Version 16.0. Chicago, SPSS Inc, for analysis. Frequencies were calculated for qualitative variables and mean ± standard deviation was calculated for quantitative variables. Data analysis was carried out using two independent sample t-test, and wherever necessary, Fisher’s exact test was used. Later, Kaplan–Meier estimate was used for survival analysis and logrank test was used to compare survival curves.


  Results Top


Among the 123 patients, 49 received the standard dose and 74 received the dose-intensified regimen. [Table 1] shows the descriptive characteristics of the two groups. The median time of follow-up was 25 months. The mean age of patient was 40.8±13.7 years (ranging from 16 to 60 years). The mean age of the two groups did not show any significant statistical difference. In general, AML type was specified in 57 patients (on the basis of the evidences in their medical files). In both groups, the most common subtype was M4. No significant difference was observed in the distribution of AML subtypes in both groups.
Table 1: Descriptive statistics of two groups that received different treatment regimens

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Cardiac toxicity occurrence was compared between the two groups. A statistically significant difference was observed between them and higher levels of heart failure occurred in patients who received the dose-intensified regimen (P > 0.011).

From 2011 to 2013, a total of 26 patients died: 12 (46.1%) died during the time of treatment initiation until they reached CR, and 8 (30.7%) died after reaching CR, either during consolidation phase or after a recurrence. Between 2014 and 2016, a total of 32 patients died, of which 20 (62.5%) died during the induction phase until reaching CR and 12 (37.5%) died after reaching CR.

The survival rate for the standard-dose regimen and the dose-intensified regimen after 2 years was 28% and 47%, respectively. Median-survival time for the first and the second group was 12.93 and 12.97 months, respectively. The result of logrank test showed no significant statistical difference between the survival rates of two regimens [Figure 1].
Figure 1: Comparing the survival rates in patients with AML of two groups

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  Discussion Top


The outcome of patients with AML is significantly impacted by their characteristics and disease and the type of therapy. The combination of Ara-C plus an anthracycline has been a common-induction regimen for patients with AML for decades.[10],[11]Nonetheless, little advancement in this treatment has been reported since it was developed. Different groups have addressed the question of whether anthracycline intensification during induction can improve OS in de novo AML.[12],[13]On the other hand, several studies assessed the effect of high-dose Ara-C application in the induction and consolidation therapy of patients with AML.[8] As a therapeutic challenge, we aimed to examine the efficacy of dose intensification of both the drugs in increasing the survival rate of patients despite the side effects of drugs. This study shows that the patients with AML who received the dose-intensified regimen of Ara-C and DNR in their induction therapy had significantly better disease-free survival (DFS) rates compared to those who received the standard-dose regimen. Moreover, the less than a year relapse rate and the mortality rate were lower after the intensified-dose treatment. However, no significant statistical difference was observed between the OS of the two groups. Studies conducted by Bishop et al.[14] and Weick et al.[15] also indicated that although increasing the dose of Ara-C resulted in decreasing the probability of AML recurrence, it led to an increased toxicity; moreover, there was no change in OS rate. Vaezi et al.[16] carried out a research to compare the results of 60 and 80mg/m2 doses of DNR. It was shown in their study that CR, OS, and DFS were all the same in both the groups. Toxicity and safety were also the same in both the groups. Similar to our study, they indicated that no difference was found considering the frequency of febrile neutropenia occurrence, the duration of antibiotic use, and the spread of invasive fungal infections between the two groups.

In our study, dose intensification of the drugs resulted in an increase in heart failure occurrence. Other studies have also shown that higher doses of the mentioned drugs or increasing the days of their injection may result in increased toxicity without more effectiveness.[6],[17]

The limitations of the study are the small sample size, numerous missing data, short follow-up time, and heterogeneity in AML subtypes.


  Conclusion Top


Dose intensification of DNR and Ara-C in the induction regimen of the patients with AML will lead to a significant improvement in DFS rate and a reduction of disease recurrence. However, it does not improve the OS rate. In the future, more comprehensive studies with larger study population are needed to clarify the advantages and shortcomings of each treatment regimen and the optimal drug dose for patients with AML.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

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Li W, Gong X, Sun M, Zhao X, Gong B, Wei H, et al. High-dose cytarabine in acute myeloid leukemia treatment: A systematic review and meta-analysis. PLoS One 2014;9:e110153.  Back to cited text no. 8
    
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Döhner H, Estey EH, Amadori S, Appelbaum FR, Büchner T, Burnett AK, et al.; European LeukemiaNet. Diagnosis and management of acute myeloid leukemia in adults: Recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood 2010;115:453-74.  Back to cited text no. 9
    
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Yates JW, Wallace HJ Jr., Ellison RR, Holland JF. Cytosine arabinoside (NSC-63878) and daunorubicin (NSC-83142) therapy in acute nonlymphocytic leukemia. Cancer Chemother Rep 1973;57:485-8.  Back to cited text no. 10
    
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Yates J, Glidewell O, Wiernik P, Cooper MR, Steinberg D, Dosik H, et al. Cytosine arabinoside with daunorubicin or adriamycin for therapy of acute myelocytic leukemia: A CALGB study. Blood 1982;60:454-62.  Back to cited text no. 11
    
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Bishop JF, Matthews JP, Young GA, Szer J, Gillett A, Joshua D, et al. A randomized study of high-dose cytarabine in induction in acute myeloid leukemia. Blood 1996;87:1710-7.  Back to cited text no. 14
    
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Weick JK, Kopecky KJ, Appelbaum FR, Head DR, Kingsbury LL, Balcerzak SP, et al. A randomized investigation of high-dose versus standard-dose cytosine arabinoside with daunorubicin in patients with previously untreated acute myeloid leukemia: A Southwest Oncology Group Study. Blood 1996;88:2841-51.  Back to cited text no. 15
    
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Vaezi M, Bahar B, Mousavi A, Yaghmai M, Kasaeian A, Souri M, et al. Comparison of 60 and 80mg/m2 of daunorubicin in induction therapy of acute myeloid leukaemia. Hematol Oncol 2017;35:101-5.  Back to cited text no. 16
    
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Heil G, Mitrou PS, Hoelzer D, Freund M, Link H, Ehninger G, et al. High-dose cytosine arabinoside and daunorubicin postremission therapy in adults with de novo acute myeloid leukemia. Long-term follow-up of a prospective multicenter trial. Ann Hematol 1995;71:219-25.  Back to cited text no. 17
    


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