Richard T. Silver MD Myeloproliferative Neoplasms Center

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DNA Hypomethylating Agents (DHAs)

DNA Hypomethylating Agents (DHAs) change the way cells express genes and can disrupt unregulated cancer cell growth. In order to understand how DHAs work, it's important to understand how DNA works. The human genome is the long sequence of DNA letters that defines us. As humans, each of our individual genomes is 99.6% to 99.9% identical to everyone else’s genome. Virtually all cells within our bodies share the exact same sequence of letters—the same genetic code written in our DNA. The genome alphabet is limited to just four letters and, like this writing, it is the organization of these letters, the grammar and the punctuation that makes the alphabet useful and understandable. Whereas the string of DNA letters is the same in every cell type, the words and the punctuation can be very different in one cell type compared to another. This packaging and organization of the genetic code is what allows a brain neuron to (hopefully) perform very different functions than a fat cell or a toe nail. So, if a human genome is the sequence of letters, the “epigenome” is the words and punctuation.

Although the cells of your body should all share the same DNA code, MPN cells always have important changes in their DNA known as “mutations”. You are not born with these mutations; they occur later in life and only in certain cell types. Although some DNA mutations are always found in MPN cells, the epigenomic packaging of the DNA code is always abnormal in MPNs too. In fact, the number of abnormalities in the epigenome far outnumber the DNA mutations in MPN cells. These epigenomic abnormalities “epimutations” help the MPN cells survive and grow in the body. We know less about epi-mutations and how they work but what we do know indicates that these abnormalities are very important. Although we cannot currently fix the DNA mutations, there are drugs that can help convert the epi-mutations back to normal. This is an active area of research.

One frequently altered epigenomic “punctuation” mark is called DNA methylation. MPN cells commonly have excess or inappropriate DNA methylation. In diseases closely related to MPNs—myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML)—abnormal DNA methylation is known to help the cancer cells survive and take over the blood forming sites of your body such as in the bone marrow. Less is known about the function of DNA methylation abnormalities in MPNs but it is thought to be important in these diseases also.

Drugs that block DNA methylation are called DNA hypomethylating agents (DHA). Clinical trials showed that DHAs are very effective for the treatment of MDS and AML. The FDA has approved the use of two DHAs, Azacitidine (Vidaza) and Decitabine (Dacogen), for treatment of MDS, AML, chronic myelomonocytic leukemia (CMML) and myelodysplastic/myeloproliferative (MDS/MPN) overlap diseases. These drugs and newer cousins are currently being tested in other MPNs.

The DHAs Azacitidine (Vidaza) and Decitabine (Dacogen) can be given in the vein (intravenous, IV) or under the skin (subcutaneous). Newer, oral versions of these drugs are being tested in clinical trials. Current DHAs, work by switching off a protein called DNA methyltransferase. This prevents myeloid cancer cells from growing and dividing and in so doing reducing the number of abnormal blood cells. They are generally well tolerated drugs but, like all chemotherapy, they can cause side effects. There is still a lot of research being done to learn how best to use HMAs. DHAs are not appropriate for all patients and prior to starting an HMA, it is important to discuss this option in detail with your treating physicians.

Side Effects

Common side effects of DHA use can include: lowering of blood counts increased risk of infection, bruising and bleeding, diarrhea, headaches, muscle of joint pain, chest pain and breathlessness, difficulty sleeping, nose bleeds, fatigue and weakness, fevers, and chills. Occasional side effects of DHA use can include: sore mouth, allergic reaction, stroke, bloody stool, runny nose, and sinus pain. Rare side effects of DHA use can include: red, painful skin, and inflammation of the bowel.

Richard T. Silver MD Myeloproliferative Neoplasms Center 525 East 70th St., Starr Pavillion, 3rd Floor New York, NY 10021 SilverMPNCenter@med.cornell.edu