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ORIGINAL CONTRIBUTION - CLINICS IN PEDIATRIC HEMATOLOGY
Year : 2017  |  Volume : 4  |  Issue : 3  |  Page : 164-168

Low dose Metronomic Chemotherapy in Patients of Acute Myeloid Leukemia


1 Department of Medicine, SMS Medical College, Jaipur, Rajasthan, India
2 Department of Pathology, Datta Meghe Institute of Medical Sciences, Wardha, Maharashtra, India

Date of Web Publication30-Jan-2018

Correspondence Address:
Akash Mathur
C-201, Trimurti Apartment, Malviya Nagar, Jaipur, Rajasthan
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/astrocyte.astrocyte_53_17

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  Abstract 


Background: Standard aggressive treatment of AML is expensive, requires significant supportive care (blood and platelet support) and toxic with significant morbidity and mortality. The metronomic approach refers to repetitive low doses of chemotherapy drugs and serves as one of the options of treatment for the patients who are unable to arrange the supportive care and those who are ineligible for intensive chemotherapy. Material and Methods: This is a hospital based observational single arm pilot study in which newly diagnosed 36 patients of AML who were unable to take standard aggressive chemotherapy were started on low dose metronomic chemotherapy and its effects evaluated over a period of 12 months. Results: Observed overall response rate (OR) was 21.87% (6.25% CR and 15.62% PR), mean survival was 3.58 months. 43.75% patients had non-hematological drug toxicities, 40.62% patients developed hematological toxicity, 3.12% developed hepatotoxicity and 9.32% patients developed febrile illness. Out of expired patients at the end of 1 year duration 70% died at their home with cause of death unidentified however rest 30% died in hospital (23% from bleeding and 7% from infection). On FACT-L questionnaire overall improvements were elicited in well being along with 43% improvement in additional concerns (including night sweats, pains, weight loss, tiredness). Conclusion: Data from our small study suggests that oral PEM metronomic chemotherapy for patients of AML with treatment possible on OPD basis itself appears to be an effective regimen with acceptable toxicities.

Keywords: Acute myeloid leukemia, chemotherapy, metronomic


How to cite this article:
Singh G, Mathur A, Rastogi N, Malhotra H. Low dose Metronomic Chemotherapy in Patients of Acute Myeloid Leukemia. Astrocyte 2017;4:164-8

How to cite this URL:
Singh G, Mathur A, Rastogi N, Malhotra H. Low dose Metronomic Chemotherapy in Patients of Acute Myeloid Leukemia. Astrocyte [serial online] 2017 [cited 2020 Mar 28];4:164-8. Available from: http://www.astrocyte.in/text.asp?2017/4/3/164/224196




  Introduction Top


Most patients with acute myeloid leukemia (AML) cannot bear the cost of conventional chemotherapy and supportive care, especially in resource-poor countries such as India, and die untreated. Patients with AML have a very poor prognosis; therefore, rationally designed new therapies, such as metronomic chemotherapy regimen, are being investigated as potential treatments. Standard aggressive treatment of AML with daunorubicin and cytarabine is expensive, requires significant supportive care (blood and platelet support), and is toxic with significant morbidity and mortality. The metronomic approach refers to repetitive low doses of chemotherapy drugs designed to target the microvasculature and tumor stroma rather than the cancer cell. It serves as one of the options of treatment for the patients who are unable to arrange the supportive care and those who are ineligible for intensive chemotherapy. The metronomic approach was initially proposed and tested by Dr. Timothy Browder in Dr. Judah Folkman's lab at Harvard.[1] Metronomic chemotherapy is designed to target the tumor endothelium as opposed to targeting the tumor. This low-dose oral chemotherapy regimen has low incidence of treatment-related side effects and potentially delays the development of resistance.[1] In India, only <30% patients are eligible for standard-of-care aggressive treatment due to various factors. Data from Leukemia Lymphoma Clinic at RKBC Cancer Centre, SMS Hospital, Jaipur, Rajasthan, India reveal that out of the 94 patients of AML with a median age of 48 years and 22 patients of <20 years age attending the clinic between 1992 and 2010, only 16 patients received standard-of-care chemotherapy. Majority of the patients were not eligible for standard-of-care chemotherapy due to financial constrains, lack of supportive care, logistic issues, or associated comorbidities. Hence in an attempt to develop novel therapeutic approaches for them to control leukemia requiring less supportive care apart from being affordable, we have treated such patients of AML with oral metronomic therapy based on prednisolone, etoposide, and 6-mercaptopurine (PEM).


  Materials and Methods Top


This is a hospital-based observational single-arm pilot study in which newly diagnosed 36 patients of AML attending medical outpatient department (OPD) and wards and Leukemia Lymphoma Clinic at Birla Cancer Centre, SMS Hospital, Jaipur, Rajasthan, India who were unable to take standard aggressive chemotherapy due to poor general condition, inability to arrange supportive care (blood, platelets, etc.), inability to arrange funds, or refusal for aggressive treatment were started on low-dose metronomic chemotherapy and its effects evaluated over a period of 12 months. Selection of patients was done based on the following inclusion and exclusion criteria.

Inclusion criteria

  • Newly diagnosed chemo-naive patients of AML who were not eligible for standard-of-care aggressive treatment
  • Patients who gave informed consent


Exclusion criteria

  • Patients of AML who had received any chemotherapy previously
  • Patients of AML-M3 (patients of APML)
  • Patients unwilling to give informed consent
  • Patients who had severe systemic cardiovascular, hepatic/renal disease, or uncontrolled infection
  • Pregnant females


Subsequently, the recruited patients were started on low-dose oral metronomic chemotherapy as prednisolone 40 mg/m 2/day, etoposide 50 mg/m 2/day, and 6-mercaptopurine 75 mg/m 2/day given orally on outpatient basis continuously for 21 days every month following which necessary investigations such as the percentage of blast cells, renal and liver function tests, and complete blood count were done. Data were then subjected to statistical analysis.

Statistical analysis

Statistical analysis was done using the software Statistical Package for the Social Sciences, version 20.0 (IBM, NY, USA). Descriptive statistics is used to describe demographic variables and clinical characteristics. Chi-square test is used for discrete data; unpaired Student's t-test and analysis of variance is used for continuous data. Statistical significance has been set at P < 0.05.


  Results Top


There were 20 male and 16 female patients with male to female ratio of 1.25 in favor of males. Mean age of patients was 34.80 years (range 6–70 years) [Table 1] and [Figure 1]. Median follow-up period was between 1 and 12 months, with the mean of 4.31 months. Out of 32, 7 patients showed response either in the form of complete remission (2 patients) or partial remission (5 patients). Thus, overall response rate was 21.87%. Response rate in the form of complete remission rate (CR) was 6.25% and in the form of partial remission rate (PR) was 15.62%. Those patients who had complete remission achieved it after 6–9 cycles of metronomic chemotherapy. One patient achieved CR after 6 cycles of metronomic chemotherapy and another patient achieved CR after 9 cycles of metronomic chemotherapy. Those patients who had PR achieved it after 3–6 cycles of metronomic chemotherapy with mean of 4.4 cycles. Progression-free survival for patients who achieved CR was 3–6 months, while it was 1–7 months for those who achieved PR. Out of 30 patients, only those 2 patients who achieved CR were alive at the end of 1 year of follow-up. So overall survival (OS) rate was 6.25%. Survival time in patients who achieved PR was 3–7 months with the mean of 4.4 months, while it was 1–6 months with the mean of 2.76 months in patients who achieved neither PR nor CR. Overall mean survival time was 3.58 months, while median survival time was between 7 and 8 months [Table 2] and [Figure 2]. Fourteen patients (43.75%) developed one or more kind of drug toxicities. Thirteen patients (40.62%) developed myelosuppression, one patient (3.12%) developed hepatotoxicity, and three patients (9.32%) developed febrile illness. Out of 13 patients who developed myelosuppression, 5 patients were elderly (>40 years) and these patients had myelosuppression in early follow-up (up to fourth follow-up). Out of 30 patients who could not survive, 21 patients (70%) died at their home only, of which exact cause of death remained unidentified. Nine patients (30%) were admitted to hospital before death, out of which 7 patients (23%) died due to bleeding and 2 patients (7%) died due to infection. Excluding the patients who were lost in follow-up, totally 24 patients required transfusions. Out of these patients, 12 patients required packed red cells (PRC), 11 patients required random donor platelets (RDP), and only 1 patient required single donor platelets (SDP). Thirteen patients were hospitalized during follow-up and average one person required less than 1 day (0.78 day) of stay in hospital. On FACT-L questionnaire, the following improvement in quality of life index was observed:
Table 1: Demographic profile of newly diagnosed chemo-naive AML patients

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Figure 1: Age and sex wise distribution of patients.

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Table 2: Table showing survival of patients using Kaplan Meier Method

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Figure 2: Bar diagram showing survival of patients using Kaplan Meier method.

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  1. Overall 41% improvement in physical well-being was elicited
  2. Overall 57% improvement in social well-being was seen
  3. Overall 79% improvement in emotional well-being was observed
  4. Overall 28% improvement in functional well-being was noticed
  5. Overall 43% improvement in additional concern (including night sweats, pains, weight loss, tiredness) well-being was found Table & graph showing age and sex wise distribution of patients


On EORTC questionnaire, the following improvement in quality of life was seen (including about sexual life, worry about future life, traveling ability, etc.):

  1. Overall 31% improvement was seen during the past week
  2. Overall 37% improvement was observed during the past 4 weeks


Best improvement in quality of life was seen in second follow-up in both EORTC and FACT-L questionnaires.


  Discussion Top


The concept of metronomic chemotherapy for patients of AML includes:

  1. The individual's need for better treatment according to his/her affordability and requirement of less supportive care
  2. To minimize the risk of adverse effects of aggressive chemotherapy
  3. Reducing frequent hospitalizations
  4. Good tolerability of oral treatment


In this study, patients were evaluated at the start of the chemotherapy and subsequently. The median survival for untreated or refractory AML is usually a few weeks to 2–3 months.[2] In our study median survival time was found between 7 and 8 months. In a study done by Claude et al. using standard intravenous chemotherapy, the CR rate was 57%, but in our study CR rate was 6.25%. In their study the estimated OS was 27% at 2 years and 12% at 4 years.[3] In our study at 12th follow-up, it was 6.31%, and maximum cumulative survival rate was 81.25%, which was found during second follow-up. Majority of patients died at fourth follow-up, so minimum survival rate of 71.42% was found during this follow-up. In their study median OS was 12 months. In our study median survival time was found between 7 and 8 months. These differences can be attributed to either a smaller sample size or higher efficacy of standard aggressive chemotherapy, although with a significantly higher economic and noneconomic burden, which makes most of the patients ineligible for the same, especially in resource-poor countries such as India.

Huang et al. (2014)[4] observed that 98.3% patients of AML during intensive chemotherapy developed agranulocytosis. Atallah et al. (2015)[5] observed that all patients who received intensive chemotherapy developed cytopenias during therapy and more than 90% had febrile episode. In our study out of 36 patients, 14 patients developed various toxicities. Among them, 13 (40.62%) showed myelosuppression (cytopenias), one (3.12%) developed hepatotoxicity, and 3 (9.37%) patients developed febrile episodes. Overall toxicity rate was found to be 43.75%. Out of these, majority of 5 (35.71%) patients showed myelosuppression in third follow-up, 3 (21.42%) in second follow-up, 2 (14.28%) in seventh follow-up, and 1 (7.14%) each in fourth, fifth, sixth, and eighth follow-up. These results significantly establish the better safety profile of the metronomic chemotherapy along with a significantly lower economic and noneconomic burden on the patient. Jacob et al. in their study observed that depending on prognostic factors, the disease-free survival (DFS) was 6–9 months and an OS was 7–10 months.[6] In our study Overall event-free survival was 0.62 month (<1 month) and OS was 4.2 months. In a study done by Barbosa et al.[7] using conventional chemotherapy on 272 days median follow-up, CR was 63.6%, 5-year estimated DFS was 34%, and 20.5% OS was seen. In our study on 365 days follow-up, CR was 6.31%, maximum event-free survival 71.87% was found during second follow-up, 35.93% during third follow-up, 10.26% during fourth follow-up, and 2.73% during fifth follow-up. Event-free survival rate reduces with each successive follow-up. Overall event-free survival was 0.62 month (<1 month). In a study done by Tandon et al.,[8] the cancer and leukemia group B (CALGB) in 8525 trials observed that individuals aging <60 years had a CR rate of 73% and 4-year DFS rate of 31%, whereas patients who were aged >60 years had a CR rate of 47% and DFS rate of 14% in patients who received metronomic chemotherapy. In our study patients on metronomic chemotherapy with age <60 years had a CR rate of 6.25% and event-free survival rate of 0.0%. Based on previous data, Mukhopadhyay et al. also reported DFS and OS at 19 months of follow-up were 18 and 32%, respectively. In our study these were 0.0 and 6.31%, respectively. Shripad Banavali et al. in their study observed that 10 out of 11 patients received at least 1 cycle of prednisolone, etoposide, 6-thioguanine chemotherapy, of which 9 achieved CR. Only 2 patients required admission, four of them received HD-Ara-C after achieving CR, 2 of them died in remission at 6 and 11 months, the other 2 were alive in CR at 36 and 14 months. The median OS was 20 months for those who continued treatment.[9] In our study 36 patients received PEM chemotherapy, of which 2 achieved CR, 5 patients achieved PR, and 24 patients required admission. None of them received any intravenous chemotherapy. The OS was 4.2 months. Progression-free survival for CR patients was 66.66% and progression-free survival for PR patients was found to be 33.33%. Excluding the patients who were lost in follow-up, 24 patients in total required transfusions. Out of these patients, 12 patients required PRC, 11 patients required RDP, and only 1 patient required SDP. Thirteen patients were hospitalized during follow-up. Patients who developed myelosuppression associated with febrile episodes showed maximum (4 days) stay in hospital and on average 1 person required less than 1 day (0.78 day) of stay in hospital. More recently, the AML-10 trial and the German AML-Intergroup conducted a cross-sectional survey of AML survivors 1 year from the end of treatment and at least 5 years from CR, respectively. Of the 481 patients in the AML-10 trial, measured at 1 year, most patients reported problem with emotional (75%), social (56%), cognitive functioning (53%), and many with problems in physical (41%) and role functioning (35%).[9] Patients were evaluated for quality of life by using FACT-L questionnaire and EORTC questionnaires. On FACT-L questionnaire, the improvement in the form of mean quality of life index in physical well-being was 41%, social well-being was 57%, emotional well-being was 79%, functional well-being was 28%, and in additional concerns was 43%. On EORTC questionnaire at the start of the treatment and subsequently, the mean quality of life score was calculated and improvement in the form of mean quality of life index was 31% during the past week and 37% during the past 4 weeks. Best improvement in quality of life is seen in second follow up including both EORTC and FACT-L questionnaires. These results support the fact that the metronomic regimen leads to improvement in the quality of life of cancer patients.


  Conclusion Top


Our study signifies that the metronomic chemotherapy although a bit less efficacious than the standard aggressive treatment holds the advantage in terms of significantly better safety profile along with improvement in the quality of life indices with lesser economic and noneconomic burden on the patient, thereby putting the patient at advantage, especially in resource-poor countries such as India. Data from our small study suggest that oral PEM metronomic chemotherapy for patients of AML appears to be an effective regimen with acceptable toxicities. It is possible to give the treatment on an OPD basis. Hence this regimen could be considered in patients of AML who are not candidates for aggressive standard-of-care therapy on grounds of cost, lack of supportive care, and/or significant comorbidities. Larger multicenter studies are, however, needed to confirm our findings and evaluate the role of this regimen in the treatment of this category of AML patients, who otherwise have limited treatment options.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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Wang D, Margalit O, DuBois R. Metronomic topotecan for colorectal cancer: A promising new option. Gut 2012;62:190-1.  Back to cited text no. 1
    
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Pagnano KB, Traina F, Takahashi T, Oliveira GB, Rossini MS, Lorand-Metze I, et al. Conventional chemotherapy for acute myeloid leukemia: A Brazilian experience. Sao Paulo Med J 2000;118:173-8.  Back to cited text no. 7
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Tandon N, Banavali S, Menon H, Gujral S, Kadam PA, Bakshi A. Is there a role for metronomic induction (and maintenance) therapy in elderly patients with acute myeloid leukemia? A literature review. Indian J Cancer 2013;50:154-8.  Back to cited text no. 8
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Banavali SD, Goyal L, Padhye B, Khadwal A, Nair CN, Gujral S, et al. A Novel Therapeutic Approach Yields Excellent Results in Minimally Differentiated Acute Myeloid Leukemia (AML-M0): Time to Think out of the box. Blood 2005;106:4615.  Back to cited text no. 9
    


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