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ORIGINAL ARTICLE
Year : 2019  |  Volume : 15  |  Issue : 7  |  Page : 1471-1476

Decitabine: An effective and safe treatment for myelodysplastic syndrome and acute myeloid leukemia


1 Department of Hematology, The Affiliated Hospital of Qingdao University, Qingdao, China
2 Department of Hematology, Shandong Jining No. 1 People's Hospital, Jining, China
3 Department of Neurology, The Affiliated Hospital of Qingdao University, Qingdao, China

Date of Submission10-Aug-2016
Date of Decision07-Sep-2016
Date of Acceptance13-Sep-2016
Date of Web Publication13-Jan-2020

Correspondence Address:
Dr. Xianqi Feng
Department of Hematology, The Affiliated Hospital of Qingdao University, Qingdao 266555
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.204849

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 > Abstract 


Objective: Decitabine is reported to be valuable in treating multiple malignant blood diseases. However, the application of decitabine in myelodysplastic syndromes (MDSs) and acute myeloid leukemia (AML) has not been fully examined. Thus, our study aimed to investigate the clinical efficacy and safety of decitabine in treating such patients.
Materials and Methods: Clinical data of MDS or AML patients treated with decitabine were retrospectively analyzed. All the patients were regularly followed up, and the risk factors affecting clinical efficacy were also detected.
Results: A total of 36 patients (MDS, n = 27; AML, n = 9) were included in the study. The response rate of MDS patients was 55%, and there were three cases (15%) of complete remission (CR), three cases (15%) of marrow CR, and five cases (15%) of hematologic improvement. It was about three cycles to achieve the best efficiencies. Gender, age, percentage of blasts in bone marrow, International Prognostic Scoring System risk group, and cytogenetic factors were not associated with response rate. The median overall survival of MDS patients was 8 (1–44) months. Agranulocytosis (P = 0.037) and severe anemia (P = 0.044) were the independent factors for prognosis. The complete response rate of AML was 33.3%. From the investigation, infection was the most common complication in our cohort, especially lung infection with the incidence of 27.8%.
Conclusions: Our data demonstrated that decitabine was effective and relatively safe in treating MDS and AML. Patients with agranulocytosis and severe anemia were prone to have poor survival, which should be monitored in clinical practice.

Keywords: Acute myeloid leukemia, chemotherapy, clinical efficacy, decitabine, myelodysplastic syndromes, safety


How to cite this article:
Feng X, Chen X, Nie S, Chang Y, Meng F, Zhou J, Mao C, Li T, Yan X, Huang J, Liu S, Gao Y, Xiao S. Decitabine: An effective and safe treatment for myelodysplastic syndrome and acute myeloid leukemia. J Can Res Ther 2019;15:1471-6

How to cite this URL:
Feng X, Chen X, Nie S, Chang Y, Meng F, Zhou J, Mao C, Li T, Yan X, Huang J, Liu S, Gao Y, Xiao S. Decitabine: An effective and safe treatment for myelodysplastic syndrome and acute myeloid leukemia. J Can Res Ther [serial online] 2019 [cited 2020 Jan 27];15:1471-6. Available from: http://www.cancerjournal.net/text.asp?2019/15/7/1471/275634

X ianqi Feng and X i angyun Chen contributed equally to this work.





 > Introduction Top


The myelodysplastic syndromes (MDSs) have a relatively high risk for progressing into acute myeloid leukemia (AML), which are a heterogeneous group of clonally hematopoietic stem cell disorders associated with bone marrow failure and peripheral cytopenias.[1],[2] Patients with MDS most commonly suffer from anemia and usually feel fatigue, and then develop infectious complications and bleeding due to agranulocytosis and thrombocytopenia, respectively. For many years, best supportive care was the main treatment option for MDS, which could alleviate the symptoms and improve life quality. The curative treatment is allogeneic hematopoietic stem cell transplantation, but this is only appropriate for a highly selected group of patients.

Recently, DNA methyltransferase inhibitors 5-AZA-2′-deoxyctidine (DAC or decitabine) and 5-azacitidine (5-AZA or azacitidine or Vidaza) which can reverse abnormal DNA methylation have been proved to be able to efficiently treat patients with MDS,[1] enriching the current treatment modalities for MDS. Genetic silencing of potential tumor suppressor genes play an important role in the development of multiple types of human cancers,[2] and it was thought to participate in the progression of MDS.[3],[4] Loss of gene expression and gene silencing was caused by DNA methylation,[5] and hypermethylation has been validated in many tumors. Azanucleosides, after its incorporation into DNA in dividing cells, may modulate differentiation, growth, and apoptosis through upregulating genes that are silenced by DNA methylation. The common potent inhibitors of DNA methylation include azacitidine and decitabine,[6] which are of clinical significance for patients with MDS.[7],[8],[9] So far, several randomized trials reveal that either 5-AZA or decitabine could achieve an overall response rate of 40%–60% and a longer overall survival (OS) in patients with MDS compared to best supportive care.[7],[9],[10],[11],[12],[13],[14] However, previous studies have not fully elaborated the safety of decitabine and were mostly conducted in Western countries, as it is known that geographical distribution may manifest unique clinical features. Thus, we retrospectively analyzed clinical data of patients treated by decitabine in our department to clarify the efficacy and adverse reaction in patients with MDS and AML, which is usually developed from MDS.


 > Materials and Methods Top


Patients

From November 2014 to March 2015, a total of 36 patients with MDS or AML were treated with decitabine in our department, and the clinical and hematologic data were retrieved from our computerized database. All the patients had received the laboratory inspection of cell morphologic, flow cytometry, and karyotype analysis. MDS and AML categories were determined according to the WHO classification. International Prognostic Scoring System (IPSS) risk score was measured at the start of the treatment protocol. All the patients provided informed consent before enrolling in the study, and our study was approved by the Ethics Committee of Qingdao University.

There were 22 men and 14 women. There were 27 cases of MDS (19 men; 8 women) and 9 cases of AML (3 men; 6 women). WHO subtype included refractory anemia (RA, n = 1), refractory cytopenia with multilineage dysplasia (n = 12), RA with excess of blasts-I (RAEB-I, n = 6), RAEB-II (n = 8), AML transformed from MDS (MDS/AML, n = 2), AML-M5 (n = 5), and AML-M2 (n = 2). The details are shown in [Table 1].
Table 1: Demographic and clinical characteristics

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Decitabine treatment

Among the patients with MDS, 16 cases received 25 mg/m 2 decitabine for days 1–4 every 6 weeks, and 4 cases used the dosage of 12 mg/m 2 decitabine for days 1–8 with 4 weeks a cycle. Other seven cases used 20 mg/m 2 decitabine for days 1–5 every 4 weeks. The total dosage of all the three regimens of decitabine was 100 mg/(m 2 × courses). The dosage of decitabine among all the AML cases was 25 mg/m 2 decitabine for days 1–4 and repeated every 4 weeks as a cycle. Three cases used decitabine monotherapy, and six cases used decitabine combined with traditional chemotherapy of idamycin/ arabinoside-cytosine (IA), homoharringtonine/ arabinoside-cytosine/ granulocyte colony-stimulating Factor (HAG), and half of HAG.

Toxicity

The toxicity was evaluated by the WHO toxicity grade. All the patients were closely monitored. Toxicity included infection, liver toxicity, nausea and vomiting, cardiovascular effects, and mucositis.

Clinical efficacy

Responses were estimated according to the modified International Working Group (IWG) response criteria.[15] The condition of <5% of blast cells found in the bone marrow with a normal hemoglobin concentration, and cell count for neutrophilic granulocytes and platelets was defined as complete remission (CR). The overall response rate includes complete CR, partial response (PR), marrow CR (mCR), and hematologic improvement (HI). The category “stable disease” was only used in patients with RAEB-I, RAEB-II, or secondary AML (sAML) while patients with low-risk MDS who did not show any HI were classified in the category of “no response”. If nonresponders advanced into a higher WHO subtype or sAML or died during treatment before bone marrow evaluation without any HI, the treatment was considered to be a failure. HI was assessed according to the modified IWG response criteria.[15]

Survival analysis

OS was defined as the time from start of treatment to death. Factors such as age, gender, severe anemia (hemoglobin <60 g/L), agranulocytosis (absolute neutrophil count <0.5 × 109/L), thrombocytopenia (platelet count <30 × 109/L), cell line deficiency (≥2 cell lines), and the karyotypes were involved in the analysis of prognostic risk factors.

Statistical analysis

Statistical analyses were done using SPSS software (version 17.0, SPSS Inc, Chicago, IL, USA). P values < 0.05 were considered statistically significant. Response rates were compared using the Fisher's exact test. Survival rates were estimated by Kaplan–Meier method and median survival times were reported with the range. Log-rank test was sensitive to long survive; on the contrary, Breslow test had a high sensibility to short survive. Subgroups were compared using log-rank test or Breslow test. Multivariate analyses were performed using Cox regression analysis.


 > Results Top


Follow-up status

Due to the last follow-up on July 2015, 20 cases still survived, 14 died, and 2 were lost to follow-up. The median follow-up time was 8 (1–44) months. Eight of the 27 patients with MDS progressed to AML during therapy with the response rate of 29.6%, and the median time for the progression to AML was 4.5 (2.5–26) months. Among the nine patients with AML, there were seven cases who still survived and two cases who died. One case got CR after two courses of induction therapy and received the allogeneic hematopoietic stem cell transplantation. From November 2014 to March 2015, 14 (38.9%) deaths occurred among all the 36 patients. Four patients died of pneumonia (n = 2) and bleeding (n = 2) during the course of treatment. Two deaths were attributed to primary disease progression, and other eight deaths were caused by infection (n = 3) and unknown reasons (n = 5). Except primary disease progression, infection and bleeding were the most common death causes. The deaths of three patients were not disease related.

Clinical efficacy and the potential influential factors

In 27 patients with MDS, seven patients were not evaluable for response. These seven patients received only one cycle of therapy without signs of disease progression. One of them refused further therapy and six had persistent cytopenia, therefore not being qualified for next cycle. At last, the data of twenty patients were available for evaluation. Considering the best clinical efficiency in all the patients, the overall response rate was 55% with the CR rate of 15%. They all achieved the best efficiency at the third course. Although the response rate of patients with intermediate (INT) and poor karyotypes was higher than those with good karyotypes, no significant differences were seen between the two groups (60% vs. 53.8%). Using the Fisher's exact test analysis, other factors that potentially affect the clinical efficiency including age, gender, severe anemia, agranulocytosis, thrombocytopenia, and cell line deficiency were analyzed. However, none of the parameters shown in [Table 2] were predictive for a response to decitabine. Male and female patients had comparable response rate (56.3% vs. 50%). Elderly patients over 65 years had a higher response rate, but the difference was not statistically significant. The bone marrow blast count, WHO classification, and IPSS risk groups were considered in our analysis. Our results showed that higher risk was not associated with poorer response.
Table 2: Univariate analysis on response rate

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Among nine AML patients treated with decitabine, three cases (33.3%) got CR, two cases died due to disease progression, and four cases changed therapeutic regimen because of poor efficacy. Age, sex, primary white blood cell count, and cytogenetics were not significantly predictive for good response to decitabine therapy.

Survival analysis

Survival analysis showed that higher bone marrow blast count was associated with longer OS, but there was no significant difference. In our study, sex (P = 0.017) and agranulocytosis (P = 0.026) could significantly affect OS [Table 3]. Men had a longer OS than women (9 months vs. 7.25 months). The patients with no agranulocytosis had a longer OS than patients with agranulocytosis (10.5 months vs. 6 months). Multivariate analysis for survival according to the defined risk factors was carried out by Cox proportional hazards model [Table 4]. We observed a significant contribution of agranulocytosis and severe anemia to survival, and platelets showed no contribution to survival. Agranulocytosis (P = 0.037, Exp (B) = 0.219) and severe anemia (P = 0.044, Exp (B) = 18.308) were statistically correlated with OS. OS of nine patients with AML was 7.5 (4–16) months. Because of small sample size, we did not analyze the prognostic factors for the survival of AML patients.
Table 3: Univariate analysis on patients' survival

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Table 4: Multivariate analysis on the risk factors for survival

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The OS of all the 36 patients is shown in [Figure 1]a. The median survival time of all the 27 patients with MDS was 8 (1–44) months, with 1-year OS rate of 68.2% and 2-year OS rate of 43%. The 1-year OS rate of the nine patients with AML was 66.7%. The survival status of patients with MDS or AML was not greatly different after they accepted the therapy of decitabine [Figure 1]a. We also compared the survival between responders and nonresponders, and a significant survival advantage in responders in the short term was observed (P = 0.015) [Figure 1]b.
Figure 1: Overall survival of patients with myelodysplastic syndrome and acute myeloid leukemia (a), and of responders and nonresponders (b) was analyzed, respectively. The survival status of patients with myelodysplastic syndrome or acute myeloid leukemia was not significantly improved by decitabine treatment, but a significant increased survival rate in responders in the short term was observed (P = 0.015)

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Toxicity

In general, the toxicity was very mild and the most common was myelosuppression. Most of them had Grade 3 or 4 hematologic toxicity. The agranulocytosis could last for 16.7 (7–30) days. During the period of myelosuppression, most patients needed blood transfusion. The median transfusion unit of red blood cell and platelet was 10U and 60U, respectively. Most patients could pull through the period of myelosuppression under the supportive treatment of blood transfusion, administration of hematopoietic-stimulating factors (granulocyte colony-stimulating factor, interleukin-11, thrombopoietin, erythropoietin), and active anti-infection. Infectious complications occurred in 15 (41.7%) patients during the treatment of decitabine, and the proportion of pneumonia was 27.8% [Table 5]. All patients received antiemetic prophylaxis so that no obvious nausea or vomiting was observed except in one case. Two cases (5.6%) had liver toxicity, who recovered well once decitabine treatment was stopped. No patients had cardiovascular and renal failure.
Table 5: Toxicity

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 > Discussion Top


At present, bone marrow transplantation and standard supportive care have poor effectiveness in treating MDS patients with advanced age. Therefore, great attention has now been focused on new pharmacologic interventions with agents including inhibitors of DNA methyltransferases such as 5-AZA or its congener decitabine.[16] Nowadays, many multicenter studies have been conducted, and several randomized trials obtained favorable response rate, good survival, reduced transformation to acute leukemia, and improved quality of life.[17] In this paper, we analyzed 36 patients including 27 MDS cases and 9 AML cases. Seven of them could not be included in the follow-up analysis. The CR rate of the 20 patients with MDS was 15%, and the overall response rate [15] was 55%, which was consistent with published data of 101 patients with MDS and chronic myelomonocytic leukemia by Lee et al.[18] The published data were 55%, including CRs (n = 13, 13%), mCRs with or without HI (n = 23, 23%), PRs (n = 1, 1%), and HI (n = 19, 19%). The rate was also comparable to the overall rate of patients with the treatment of 5-AZA.[7],[19]

A randomized Phase III trial carried out by Kantarjian et al.[10] reported that the overall response rate of patients with decitabine treatment was 30%, which was 7% under best supportive care. Our study also supported that decitabine was more effective than supportive care for the treatment of MDS. Patients treated with decitabine had a higher response rates. It was about 3 (2–5) cycles for the achievement of best clinical efficacy. Among all the 27 patients, the median cycles of decitabine treatment was 4 (2–21). By July 2015, among the patients who had a response to decitabine, most patients (6/11) achieved stable disease. Wijermans et al.[20] reviewed the data of three European Phase II studies and the data from a single center that participated in the US Phase II study and concluded that the overall response rate was almost 50%, even in those patients with extremely bad prognostic characteristics including high-risk cytogenetic abnormalities who could get good response with decitabine. In our study, patients with INT/poor karyotype have a higher response rate than patients with good karyotype, but the difference was not significant.

Among the 27 patients with MDS, there were eight cases (29.6%) who progressed to AML during therapy, and the median time progressed to AML was 4.5 (2.5–26) months. The statistic data of morphologic, immunologic, and cytogenetic [21] cooperation demonstrated that about 21% could finally progress into AML. Morel et al.[22] and Lee et al.[23] ever observed that the rate of progression was 22% and 17%, respectively, and the progression time was different between eastern and Western countries. Lee et al.[23] found that the time in Korean patients was 6 (1–45) months. Our patients had shorter progression time, and perhaps it was related to the poor compliance which could accelerate the progression to AML. Compared with Kantarjian et al.'s study,[10] decitabine treatment reduced AML transformation.

The median OS of all the 27 patients was 8 (1–44) months. IPSS score is well acknowledged as an indication for good survival. Wijermans et al.[20] found that this risk score correlated with survival in patients being treated with decitabine, which could be explained by the duration of response. Low-risk patients with longer response duration had better survival than high-risk patients. However, our study found that sex and agranulocytosis could significantly affect the OS of patients (P < 0.05). We came to a conclusion that the OS was shorter among patients who had agranulocytosis, while men had longer OS than women. According to Cox regression analysis, we did not find the risk score correlated with survival, due to the presence of random error or systematic error in our data. We observed a significant contribution of agranulocytosis and severe anemia to survival, suggesting that perhaps more attention should be paid on the agranulocytosis and severe anemia. We also found that responders had better prognosis than nonresponders in short term (P < 0.05). In our cohort, patients with AML transformed from MDS and patients with complex karyotype had poorer prognosis.

Scandura et al.[24] confirmed the safety and feasibility of decitabine combined with standard induction chemotherapy (daunorubicin/ cytosine arabinoside (DA) 3 + 7) among patients with AML. Fifty-seven percent of patients got CR and the toxicity was comparable to that of DA. Both decitabine monotherapy and combined therapy with standard chemotherapy could be used in treating patients with AML. In our study, among the nine AML patients treated with decitabine, three cases accepted decitabine monotherapy, and six cases underwent decitabine combined with traditional chemotherapy. Three cases with monotherapy (33.3%) received CR, and two cases with combined therapy received CR. Although our CR rate was lower than the rate reported by Scandura et al.,[24] it could be obviously seen that the combination therapy could elevate CR rate and overall response rate among AML patients.

The most common toxicity of decitabine was myelosuppression. Steensma et al.[25] in the alternative dosing for outpatient treatment trial reported that the incidence of pneumonia was 11%, which was lower than 27.8% in our study. This prompted that we should pay special attention to infectious complications during the period of myelosuppression and antibiotics could be administrated together with decitabine.[26] Decitabine treatment had a high response rate in patients with MDS and AML, which could improve life quality, alleviate symptoms such as fatigue and physical function, and reduce the occurrence of relapse and progression and mortality.


 > Conclusions Top


Taken together, regular decitabine treatment had higher response rate but lower toxicity in MDS or AML patients, which can improve life quality. Patients with agranulocytosis and severe anemia are prone to had poor survival, who should be closely monitored in clinical practice. In addition, the optimal decitabine regimen for treating MDS and AML and the potential molecular mechanism should be further investigated in future.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

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Kantarjian HM, O'Brien S, Huang X, Garcia-Manero G, Ravandi F, Cortes J, et al. Survival advantage with decitabine versus intensive chemotherapy in patients with higher risk myelodysplastic syndrome: Comparison with historical experience. Cancer 2007;109:1133-7.  Back to cited text no. 14
    
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Cheson BD, Greenberg PL, Bennett JM, Lowenberg B, Wijermans PW, Nimer SD, et al. Clinical application and proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia. Blood 2006;108:419-25.  Back to cited text no. 15
    
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Ghoshal K, Bai S. DNA methyltransferases as targets for cancer therapy. Drugs Today (Barc) 2007;43:395-422.  Back to cited text no. 16
    
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Wijermans PW, Lübbert M, Verhoef G, Klimek V, Bosly A. An epigenetic approach to the treatment of advanced MDS; the experience with the DNA demethylating agent 5-aza-2'-deoxycytidine (decitabine) in 177 patients. Ann Hematol 2005;84 Suppl 1:9-17.  Back to cited text no. 20
    
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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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