What Are Hypomethylating Agents And How Do They Treat CMML?

Hypomethylating agents (HMAs) are a class of medications that treat chronic myelomonocytic leukemia (CMML) by blocking DNA methylation (a chemical process that regulates gene expression in DNA). This reprograms cancer cells and impedes their growth. They are the only FDA-approved treatment for CMML. However, they are less effective for proliferative CMML subtypes with RAS mutations.

How Do HMAs Work?

HMAs are considered the standard treatment for CMML. They can improve blood cell counts and decrease the need for transfusions.

• By reversing the DNA methylation, they can reprogram tumor cells.
• They can activate genes that help healthy cells mature.
• They can kill cells that are dividing abnormally quickly.
• HMAs are believed to re-express tumor suppressors.
• Patients who progress to acute myeloid leukemia (AML) after responding to HMAs have a median overall survival of 8 months.

However, HMAs can also induce cytopenias (low levels of red blood cells/white blood cells/platelets), especially in the early stages of treatment. This can lead to dose restrictions, treatment delays, or discontinuation. Other side effects include nausea and vomiting, diarrhea or constipation, weakness, and fatigue. Adding growth factors to HMA treatment may help prevent this.

How Are HMAs Used?

HMAs are often preferred for patients who are not eligible for transplant. Treatment usually starts when CMML is symptomatic or progressive and is typically administered by IV infusion. HMAs stop DNA methyltransferase (DNMT- an enzyme that adds methyl groups to DNA molecules). This re-expresses tumor suppressors and triggers the death of leukemic cells. 

• Azacitidine (Vidaza): has effects on both DNA and RNA.
• Decitabine (Dacogen): acts only at the DNA level.
• Decitabine and Cedazuridine (Inqovi).

Other Treatments For CMML

• Hydroxyurea: A chemotherapy drug that can help some CMML patients live longer.
• Pembrolizumab: A humanized monoclonal antibody that may be effective in patients who failed HMA treatment.
• A combination of HMAs and Venetoclax has shown good results in CMML, with an overall response rate of 62%.
• In 2023, the FDA granted fast-track designation to IO-202 for treating patients with relapsed/refractory CMML. This anti-LILRB4 monoclonal antibody is being investigated as an immunotherapy for blood cancers. As of 2024, at the American Hematology Association, updates from a phase 1 trial showed promising results. 

Conclusion

Hypomethylating agents (HMAs) are the standard of care for treating CMML as chemotherapy. Currently, immunotherapy for CMML is not available. Therefore, using HMAs after being diagnosed can be more effective.

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Source: 

• Are Hypomethylating Agents the Best First-Line Choice for Treating CMML?