Hypomethylating Agents in AML Treatment

A major determinant of chemotherapeutic treatment is whether a patient’s risks of severe side effects would outweigh their benefit from the therapy. In this post, I will look into how the effectiveness of hypomethylating agents in Acute Myeloid Leukemia compares to their promise, especially in older patients who have lower rates of survival and are more susceptible to side effects of treatment. Often these patients do not receive any form of intensive treatment, since the toxicity is not worth the cancerous cell death. The standard AML treatment of high doses of cytarabine, an antimetabolite which inhibits DNA synthesis during the S phase of mitosis, also damages healthy cells with its high toxicity. The American Cancer Society reports the average AML patient age as 66 years old, so the majority of patients with this type of leukemia would not be ideal recipients of the standard-of-care treatment (1).

In response to cancers caused by hypermethylation of tumor suppressor genes, a hypomethylating drug that can remove the methyl groups and allow their transcription would seem to be a clear solution. Azacitidine and decitabine are the two hypomethylating agents currently approved by the FDA for Myelodysplastic Syndromes (MDS). 1 out of 3 cases of MDS can progress into AML, and they share the symptoms of having a high percentage of abnormal or immature hematopoeitic stem cells in bone marrow (2). Recent studies have shown these two drugs to also be effective in treating AML, especially in the cases that are due to aberrant DNA methylation, such as with the mutation of methyltransferase DNMT3a, which I have been focusing on.

For groups of untreated AML patients over 60, randomized phase III trials demonstrated significant improval in the tested endpoints when compared to the control treatments. Median survival outcome was 24.5 months with azacitidine vs. 16 months with the control, and complete remission was 18% with decitabine vs. the 8% with the control (3). This paper then contrasts the effectiveness of azacitidine to decitabine, but these two main studies on the drugs’ use in AML are not yet comparable because they use different criteria for selecting participants and focus on different endpoints. At the mechanistic level, the two drugs inhibit DNA methylation in different ways, so are not interchangeable. As a ribonucleoside, azacitidine mainly incorporates itself into RNA, rather than just DNA as in the deoxyribonucleoside decitabine (3). Therefore decitabine is only present to bind to methyltransferase and inhibit its function in the S phase of mitosis, while azacitidine incorporated into the RNA can be active throughout the entire cell cycle and also inhibit protein production. This may be a reason explaining why azacitidine's effects were apparent sooner than decitabine's in trials, with global reduction of methylation levels occurring within the first treatment cycle (3). The paper didn’t provide evidence that these mechanistic differences directly show in comparisons of the drugs, but brought up important distinctions that may be more observable in the future as follow-up studies are conducted.

The NCCN also reports on the same two clinical trials, stating that their adverse effects are thrombocytophenia, anemia, and neutropenia, which are all conditions caused by the lack of healthy blood cells (4). These side effects are seen in the control cytarabine treatment as well, and suggest that they are also due to systemic death of blood cells undergoing mitosis. The complication of relying on hypomethylating agents is that the epigenetic effects of methyltransferase mutations do not solely result in the excessive addition of methyl groups to DNA, so the treatment targets a limited aspect of the cancer. There isn't a defined or consistent methylation pattern caused by the frequent DNMT3a mutations that can be targeted. Besides age and DNMT3a mutation, other factors to be taken into account when determining whether this treatment is appropriate are comorbid conditions, the percentage of blood cells that are the immature myeloblasts, and if the AML is a secondary cancer or recurrence (3).

Despite similar side effects, the NCCN panel actually considers azacitidine and decitabine to be less-intensive forms of chemotherapy, compared to the standard drugs used (anthracycline, cytarabine, clofarabine) and recommends it for older AML patients, as well as patients with less severe conditions. If azaciditine and decitabine will be used with the purpose of being less aggressive options, it’s important to focus on their toxicity to determine balanced dosage. Since AML is known to maintain reservoirs of leukemic cells that reappear after remission, it would also be crucial to find out the level of resistance to the drugs. Though they are not cures and require further research, so far it appears hopeful that these hypomethylating agents will be more useful in improving the quality of life for these patients in addition to the AML patients with DNMT3a mutations. 

Sources:

1. "Leukemia--Acute Myeloid (Myelogenous)." American Cancer Society. N.p., n.d. Web. 21 May 2014.
      <http://www.cancer.org/cancer/leukemia-acutemyeloidaml/detailedguide/index>. 

2. "Myelodysplastic Syndrome Overview." American Cancer Society. N.p., 3 Apr. 2014. Web. 21 May 2014. 
      <http://www.cancer.org/cancer/myelodysplasticsyndrome/overviewguide/ myelodysplastic-syndromes-
      overview-what-is-myelodysplastic-syndrome>. 

3. Al-Ali, Haifa Kathrin, Nadja Jaekel, and Dietger Niederwieser. "The role of hypomethylating agents in
      the treatment of elderly patients with AML." Journal of Geriatric Oncology 5.1 (2014): 89-105. Journal
      of Geriatric Oncology. Web. 21 May 2014. <http://www.geriatriconcology.net/ article/S1879-4068(13)
      00086-6/fulltext>. 

4. National Comprehensive Cancer Network. "NCCN Guidelines Version 2.2014 Acute Myeloid Leukemia."
      Mar. 2014. PDF file.