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 » Introduction
 » Case Report
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  Table of Contents  
Year : 2013  |  Volume : 50  |  Issue : 2  |  Page : 154-158

Is there a role for metronomic induction (and maintenance) therapy in elderly patients with acute myeloid leukemia? A literature review

1 Department of Medical Oncology, Tata Memorial Hospital, Parel, Mumbai, Maharashtra, India
2 Department of Hemato Pathology, Tata Memorial Hospital, Parel, Mumbai, Maharashtra, India
3 Department of Cytogenetics, Tata Memorial Hospital, Parel, Mumbai, Maharashtra, India
4 Department of Medical Oncology, L.H. Hiranandani Hospital, Powai, Mumbai, Maharashtra, India

Date of Web Publication27-Aug-2013

Correspondence Address:
S Banavali
Department of Medical Oncology, Tata Memorial Hospital, Parel, Mumbai, Maharashtra
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0019-509X.117033

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 » Abstract 

Acute myeloid leukemia (AML) in older adults differs biologically and clinically from that in younger patients and is characterized by adverse chromosomal abnormalities, stronger intrinsic resistance, and lower tolerance to chemotherapy. In patients over age 60 with AML, cure rates are under 10% despite intensive chemotherapy, and most of them die within a year of diagnosis. Over the last decade, metronomic chemotherapy has emerged as a potential strategy to control advanced/refractory cancer. Here, we report a case of a 68-year-old gentleman having AML with high-risk cytogenetic features, who achieved complete remission on our oral metronomic PrET (PrET: Prednisolone, etoposide, thioguanine) protocol on an outpatient basis. He was later treated with standard high-dose (HD) cytosine arabinoside (Ara-C) consolidation followed by maintenance with etoposide, thioguanine, and sodium valproate. Presently, the patient is nearly 35 months since diagnosis and 21 months off treatment. This case report and review highlights that the combination of oral low-intensity metronomic therapy, followed by standard HD consolidation therapy and metronomic maintenance therapy may be well tolerated by elderly patients especially with less proliferative, high (cytogenetic)-risk AML who are otherwise deemed to be unfit for intensive intravenous induction chemotherapy regimens. References for this review were identified through searches of Pubmed for recent publications on the subject as well as searches of the files of the authors themselves. The final list was generated on the basis of originality and relevance to this review.

Keywords: Elderly acute myeloid leukemia, metronomic therapy, metronomics, oral etoposide, oral 6TG

How to cite this article:
Tandon N, Banavali S, Menon H, Gujral S, Kadam P A, 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

How to cite this URL:
Tandon N, Banavali S, Menon H, Gujral S, Kadam P A, 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 [serial online] 2013 [cited 2022 Aug 19];50:154-8. Available from:

 » Introduction Top

Acute myeloid leukemia (AML) is a disease of older adults with a median age of diagnosis of over 65 years. Advances in our understanding of the biology of the pathogenesis and prognosis of AML have not been matched with clinical improvements. AML in older adults differs biologically and clinically from that in younger patients and is characterized by adverse chromosomal abnormalities, stronger intrinsic resistance, and lower tolerance to chemotherapy. [1],[2] The prognosis of elderly AML patients remains poor despite recent therapeutic advances. [3] In patients over age 60 with AML, cure rates are under 10% despite intensive chemotherapy, and most of them die within a year of diagnosis. [3],[4] The small percentage of patients who are cured and the high rate of treatment-related mortality in elderly patients with AML give rise to the question: Which patients would benefit from a primary curative approach, and which should be treated with a palliative approach? [5]

Based on the clinical and biological features, older AML patients are generally offered one of the four different treatment options: 'Standard' induction with infusional cytarabine and an anthracycline; 'low-intensity' induction with low-dose cytarabine, or more recently a hypomethylating agent like decitabine; 'supportive care' with hydrea, antibiotics, and transfusions; or enrollment on a 'clinical trial'. [4] Regardless of treatment, however, outcomes for older AML patients generally remain unsatisfactory. The wishes and expectations of the patient after thorough information about the risks and outlooks of the various therapeutic strategies ultimately guide the final therapy decisions in an individual patient. [3]

Over the last decade, metronomic chemotherapy - the chronic administration of chemotherapy at relatively low, minimally toxic doses on a frequent schedule of administration, with no prolonged drug-free breaks - has emerged as a potential strategy to control advanced/refractory cancer disease. [6],[7] At the Tata Memorial Hospital, we have developed an oral metronomic protocol for the treatment of AML in children and young adults. [8],[9],[10] Here we report a case of a 68-year-old gentleman who achieved complete remission with this same protocol on an outpatient basis and was later treated with standard high-dose (HD) cytosine arabinoside (Ara-C) (HDAC) consolidation followed by metronomic maintenance. Appropriate literature justifying the use of low-dose oral therapies in the treatment of elderly AML patients has been reviewed. References for the review were identified through searches of Pubmed with the search terms 'acute myeloid leukemia' and 'elderly' alone or in combination in recent years. Articles were also identified through searches of files of the authors themselves. Only papers published in English were included. The final list was generated on the basis of originality and relevance to this review.

 » Case Report Top

A 68-year-old gentleman presented at our hospital on 21 June, 2010 with complaints of generalized weakness and dry cough of a duration of one and one-half months. Complete blood count (CBC) done outside was suggestive of 'myeloproliferative disorder' and thus he was referred to our hospital for further workup and treatment. The patient was a known case of hypertension not on any medication and was an old tobacco chewer, smoker, and an alcoholic.

On examination at our hospital, he had an Eastern Cooperative Oncology Group performance status (ECOG PS) of 1/4. There was no evidence of infection or bleeding from any site. He had pallor but no gum hypertrophy, lymphadenopathy, or organomegaly. His CBC revealed hemoglobin (Hb) of 10.1 g%, platelet count of 9.0 × 10 9 /L, and total leukocyte count of 8.0 × 10 9 /L with neutrophils (N): 24%, lymphocytes (L): 50%, monocytes (M): 25%, and myelocytes: 1%. The liver and renal function tests were essentially within normal range and lactate dehydrogenase (LDH) was marginally elevated at 232 U/L. The bone marrow examination showed 22% myeloperoxidase (MPO)-positive blasts which were positive for CD13 (CD: Cluster of differentiation), CD33, CD34, and human leukocyte antigen (HLA)-DR with a morphology similar to AML-M2 by the French-American-British (FAB) classification. The conventional katyotype analysis revealed that of 17 cells analyzed, four cells showed abnormal pseudodiploid karyotype pattern with clonal abnormalities of 5q deletion [(46 XY, del (5) (q15q21)] and 7q inversion [(46 XY, inv (7) (q11.2q q35)] in two cells each. The patient and his relatives were explained about the benefits and drawbacks of intensive standard induction chemotherapy versus oral metronomic low-intensity induction chemotherapy in view of age, comorbidities, and poor-risk cytogenetics. The patient opted for oral metronomic chemotherapy.

The patient was started on our institutional PrET (PrET: Prednisolone, etoposide, 6-thioguanine) chemotherapy. [8] He received oral prednisolone 30 mg twice a day (BD), etoposide (50 mg) 1 once a day (OD) and 1 BD every alternate days, and 6TG (40 mg) 1 q at bedtime (HS). This was given for 21 days every 28 days for two cycles, followed by another two cycles of just etoposide and 6TG. All chemotherapy was given on an outpatient basis and he did not require any admission during this period. The patient received five units of packed cells and six single-donor platelet transfusions during this period. The counts normalized by the end of the second cycle. The CBC in November 2010 showed Hb: 9.3, platelets: 110 × 10 9 /L, white blood cells (WBCs): 6.4 × 10 9 /L, absolute neutrophil count (ANC): 3.22 × 10 9 /L, and the bone marrow aspiration showed remission marrow with no excess of blasts.

As the patient had achieved morphological remission and had good performance status, he was given the option of continuing with oral palliative metronomic chemotherapy versus receiving standard high-dose cytarabine consolidation with the possibility of cure. The patient opted for the second option and he received two cycles of HDAC with 2 g/m 2 Ara-C every 12 hours on days 1, 3, and 5 (total 12 g/m 2 ) on 25 November 2010 and 03 January 2011. Overall, the patient tolerated HDAC well, though he required admission for febrile neutropenia during these cycles.

After completion of HDAC consolidation, he received oral metronomic maintenance therapy with etoposide 50 mg OD and 6TG 40 mg OD for 21 days every month along with sodium valproate 500 mg BD everyday for another six months. After completion of approximately one year of therapy, all treatment was stopped in July 2011. The off-treatment bone marrow evaluation done on 10 August 2011 showed no excess of blasts with a normal male diploid karyotype. Presently, he is on regular follow-up and his last CBC done on 04/06/2013 showed Hb: 14.8 g/dL, platelets: 294.0 × 10 9 /L, and WBC: 8.9 × 10 9 /L, with ANC of 5.60 × 10 9 /L.

Overall, the patient tolerated oral metronomic therapy well with no admission during this period and minimal monitoring with CBC and biochemical evaluation just once prior to each cycle. Very importantly, after completion of HDAC consolidation, the patient received the entire maintenance therapy at his hometown in rural India.

 » Discussion Top

Unsatisfactory outcomes persist for the majority of patients with AML, particularly the elderly, [11] in whom there is no universally accepted standard of care as this patient population is clinically heterogeneous, and currently available therapies are largely ineffective. [4] Unsurprisingly, very few elderly AML patients have prolonged survival. [4] The United States Surveillance, Epidemiology and End Results (SEER) data from 2000 through 2007 showed that the median survival was two months for the untreated group versus six months for the treated group (P < 0.01). [12]

Elderly patients, defined in the literature as age > 60 years, historically have lower complete remission (CR) and relapse-free survival (RFS) rates than their younger counterparts. [5],[13] In a study of 211 patients by the South West Oncology Group, it was observed that there was a notably high frequency of secondary AML (24%), unfavorable cytogenetics (32%), multidrug resistance protein 1 (MDR1 protein) expression by leukemic blasts (71%), and functional drug efflux (58%) in elderly AML patients. [14] The Medical Research Council (MRC) AML8 trial, in which younger and older patients with AML received the same therapy, demonstrated a CR rate of 70% among individuals aged < 50, a CR rate of 52% for patients 60-69 years of age, and a dismal CR rate of 26% for individuals aged > 70. [15] Similar age-related differences were seen in the Cancer and Leukemia Group B (CALGB) 8525 trial, [16] in which individuals aged < 60 had a CR rate of 73% and four-year disease-free survival (DFS) rate of 31%, whereas patients who were aged > 60 had a CR rate of 47% and four-year DFS of 14%. Multiple novel agents like gemtuzumab ozogamicin (GO), multidrug resistance modulators, farnesyltransferase inhibitors, clofarabine, cloretazine, and FLT3 inhibitors have been tried alone or in combination with cytarabine, but none have showed to improve survival in this age group. [17],[18],[19],[20],[21] Also, the poor performance status and the presence of multiple comorbidities frequently preclude the use of intensive chemotherapy in patients aged > 60 years.

Achieving CR in leukemia is a requisite end point for prolonged survival, and the data from large population registries have validated the use of intensive induction approaches over less-intensive therapies in patients up to the age of 80 years. [22] For patients not fit for intensive treatment, intermediate intensity options are available. Low-dose cytarabine (20 mg subcutaneous BD for 10 days) repeated every four weeks was considered as a 'standard' nonintensive treatment for elderly AML patients. [23] However, with the availability of newer agents, things are changing. [24],[25] Also low-dose cytarabine was not found to be effective in patients with high-risk cytogenetics. [23]

Decision about fitness for treatment should not be made on the basis of age alone, but should arise from a comprehensive assessment of the patient as well as the biology of the disease. It has recently been discovered that patients with less proliferative AML (defined as a bone marrow blast percentage of 30% or less) stand to benefit from treatment with hypomethylating drugs such as 5-azacytidine and decitabine, which partially revert the aberrant methylation of cyctosine remnants in the DNA of leukemic cells. [26] Interestingly, patients with high-risk cytogenetic aberration also responded to hypomethylating agents. [27],[28]

There have been small single-center studies which have evaluated the use of low-dose chemotherapy regimens for elderly patients with AML. Herousseave and colleagues demonstrated a 40% CR rate using idarubicin alone and a similar CR rate using idarubicin in continuation with low-dose Ara-C. [29] Ruutu and colleagues observed a CR of 60% when using a combination of etoposide, idarubicin, and thioguanine. [30] In another study by Jackson et al., of 25 elderly AML patients not considered fit enough to tolerate intensive intravenous (IV) chemotherapy, who received a combination of oral etoposide and idarubicin, nine achieved CR. [31] Interestingly, autologous dendritic cells plus cytokine-induced killer cells were also shown to synergize with low-dose chemotherapy [response rate (RR) of 71.4 vs. 39.1% for controls]. [32]

In our elderly patient with comorbodities and high-risk cytogenetics, we gave oral metronomic induction because of the choice of the patient and based on our previous experience. [8],[9],[10] The combination of oral metronomic chemotherapeutic agents was not only well tolerated, but our patient also did not require any hospitalization during induction. Moreover, it was successful in achieving morphological and hematological CR. Angiogenesis seems to be important for both leukemogenesis and susceptibility to intensive chemotherapy, and antiangiogenic strategies are therefore now being considered for the treatment of AML. [33],[34],[35] Though recently other mechanisms of action have also been reported, metronomic therapies are believed to work primarily through antiangiogenic mechanisms. [6],[7] For the large group of elderly patients affected, intensive strategies are not possible because of high treatment-related mortality. In these patients, cytokine-directed antiangiogenic metronomic therapy maybe tried to increase the antileukemic effects of conventional intensive therapies. [33]

If only low-intensity treatment is given, then only a handful of patients would be long-term survivors. Buchner et al. have shown that postremission therapy is a prerequisite for long-term DFS. [36] Patients who do achieve a CR usually receive one to several cycles of consolidation therapy, often based on cytarabine in varying doses among different protocols, with older patients receiving fewer courses and lower doses in each course because of CNS toxicity. [3] Considering this, we offered our patient treatment with two courses of HDAC with an interval chance of achieving long-term DFS. The patient tolerated full doses of HDAC well with just one admission for febrile neutropenia in each cycle.

There is no adequate evidence for the use of maintenance treatment outside of clinical trials in AML. [37] Some patients do receive maintenance therapy post consolidation therapy, based on either chronic cytotoxic drugs or experimental drugs. Based on our past experience, [8],[9],[10],[38] we also gave our patient another six months of oral maintenance with etoposide and 6TG. Sodium valproate was added as an HDAC inhibitor in view of the upcoming data in AML patients and especially in view of high-risk cytogenetic features in our patient. [39],[40] Both valproic acid as well as 6TG have been shown to have antiangiogenic activity. [41],[42] The antiangiogenic activity of 6TG, together with its antimetabolite activity toward tumor cells, may contribute to its action during maintenance therapy in AML. [42] Our patient has been off treatment since 21 months and so far has an overall survival (OS) of 35 months and continues to be in complete hematological remission. Based on our previous data, Mukhopadhyay et al. also had treated 100 patients of AML > 50 years of age (median age: 65 years) with similar therapy. [43] In their series, 38% patients had a complete hematological response after six courses. The DFS and OS at 19 months of follow-up were reported at 18 and 32%, respectively.

This case report highlights that the combination of oral low-intensity metronomic therapy, followed by standard HD consolidation therapy and metronomic maintenance therapy maybe well tolerated by elderly patients especially with less proliferative, high (cytogenetic)-risk AML who are otherwise deemed to be unfit for intensive intravenous induction chemotherapy regimens. Thus, elderly patients even with comorbidities or even advanced-risk cytogenetics should not be left devoid of treatment.

 » Conclusion Top

Improving outcomes in older adults with AML remains a formidable challenge. There are limited treatment options and prognosis remains poor, thereby warranting the development of novel, less toxic treatment approaches with broader applicability. Combination of oral metronomic therapies and drug repositioning (e.g., sodium valproate as HDAC inhibitor)-an approach termed metronomics, [6] maybe especially of use in low-income and middle-income countries like India, where newer targeted agents (like azacytadine or GO) or low-intensity allotransplants are beyond the reach of most patients. Prospective, controlled studies are needed to support our findings.

 » References Top

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