Chronic myelomonocytic leukaemia (CMML) is a complex blood cancer that sits at the crossroads between two types of bone marrow disorders, making treatment decisions particularly important. While CMML cannot be cured in most cases, many people can maintain a good quality of life through carefully chosen therapies that control symptoms, slow disease progression, and reduce the risk of transformation to more aggressive forms of leukaemia.

Understanding Treatment Goals in CMML

When someone receives a diagnosis of chronic myelomonocytic leukaemia, understanding what treatment can and cannot achieve becomes essential for making informed decisions. The primary goals of treating CMML focus on managing symptoms, maintaining quality of life, slowing the progression of the disease, and reducing the risk that it will transform into acute myeloid leukaemia, which happens in approximately 15 to 20 percent of cases over a period of three to five years.^[3][10]

Treatment approaches for CMML depend heavily on several factors unique to each patient. These include the specific subtype of CMML, whether the disease presents with features that are more dysplastic (problems with blood cell development) or proliferative (excessive production of abnormal cells), the number of blast cells present, the patient’s age and overall health, and whether any other medical conditions exist.^[1][6] Because CMML primarily affects older adults—with a median age at diagnosis between 70 and 75 years—treatment plans must carefully balance effectiveness against potential side effects and impact on daily life.^[8][10]

Medical societies and expert groups have established standard treatments that have been tested and approved for use in CMML. However, because this is a rare and complex disease affecting fewer than 1 in 100,000 people, ongoing research continues to explore new therapies through clinical trials.^[13] These trials investigate innovative approaches that may offer better outcomes or fewer side effects than current standard treatments.

Standard Treatment Approaches for CMML

Standard treatment for chronic myelomonocytic leukaemia involves several established therapeutic approaches that doctors have used successfully to manage the disease. The choice of treatment depends on whether a patient needs immediate intervention or can be safely monitored without active therapy.

Watchful Waiting and Supportive Care

Many people with CMML, especially those diagnosed through routine blood tests without noticeable symptoms, may not require immediate treatment. In these cases, doctors recommend a period of observation with regular monitoring through blood tests and clinical examinations.^[6][11] This approach allows healthcare teams to track the disease’s behaviour and begin treatment if and when it becomes necessary.

Even without specific anti-cancer treatment, most people with CMML need supportive care to manage the effects of abnormal blood cell counts. Supportive treatment addresses specific symptoms and complications as they arise. Blood transfusions become necessary when red blood cell counts drop too low, causing fatigue and weakness. These transfusions help restore energy levels and improve oxygen delivery throughout the body.^[11] Similarly, platelet transfusions may be needed if platelet counts fall dangerously low, particularly if bleeding problems develop.

Repeated blood transfusions can lead to iron accumulation in the body because each transfused red blood cell contains iron. Over time, excess iron can damage vital organs including the heart and liver. To prevent this complication, doctors may prescribe iron chelation therapy—medicines that help remove excess iron from the body.^[11]

Infections pose a significant risk for CMML patients because the disease affects the normal function of white blood cells. Antibiotics play a crucial role both in treating active infections and, in some cases, preventing them from occurring in the first place.^[6][11] Patients may also receive growth factors—substances that stimulate the bone marrow to produce more blood cells. Erythropoietin, for example, encourages red blood cell production and may reduce the need for blood transfusions in some patients.^[11]

Chemotherapy with Hypomethylating Agents

When CMML requires active treatment, hypomethylating agents represent the most commonly used class of drugs. These medications work by switching off a protein called DNA methyltransferase, which in turn activates genes that help control abnormal cell growth and division.^[11] The most widely used drug in this category is azacitidine (also known by the brand name Vidaza).

Azacitidine is typically given as an injection just under the skin (subcutaneously) and is usually administered at a hospital or clinic setting. The treatment follows a specific schedule, with patients receiving injections over several days each month.^[11] While azacitidine has been approved for managing CMML and related conditions, it’s important to understand that response rates range between 40 and 50 percent, and true complete remissions occur in fewer than 20 percent of patients.^[10]

An important characteristic of hypomethylating agents is that they work by restoring more normal blood cell production through epigenetic changes—alterations in how genes are expressed—rather than by eliminating the underlying genetic mutations that cause CMML. This means that even in patients who respond well to treatment, the disease-causing mutations remain present, and progression is eventually inevitable.^[10] However, the treatment can provide meaningful periods of disease control and symptom relief.

Research has shown that certain genetic profiles predict better responses to azacitidine. Patients with mutations in the TET2 gene but without mutations in the ASXL1 gene tend to respond better to this therapy. Conversely, the treatment appears less effective in patients with proliferative forms of CMML who have mutations in RAS pathway genes.^[10]

Other Chemotherapy Options

Another chemotherapy drug used in CMML management is hydroxycarbamide (also called hydroxyurea). This medication helps control high white blood cell counts, which is particularly useful in the proliferative subtype of CMML where excessive production of abnormal cells causes problems.^[11] Hydroxycarbamide is taken as a tablet, making it more convenient than injectable therapies for some patients.

The duration of chemotherapy treatment varies significantly depending on how well the disease responds, how the patient tolerates the medications, and whether the disease progresses. Some patients may continue treatment for months or even years if they experience benefit without intolerable side effects. Treatment is typically continued as long as it provides benefit and remains tolerable.

Side Effects of Standard Treatments

Like all cancer treatments, therapies for CMML can cause side effects, though not everyone experiences them and severity varies from person to person. Common side effects of azacitidine and other chemotherapy drugs include fatigue, nausea, injection site reactions (redness, pain, or swelling where the medicine was injected), and temporary worsening of blood counts, which can increase the risk of infection or bleeding.^[11] Healthcare teams carefully monitor blood counts during treatment and provide supportive care to manage these effects.

Patients should report any new or worsening symptoms to their medical team promptly. Fever, unusual bleeding or bruising, severe fatigue, or signs of infection require immediate medical attention.

Stem Cell Transplantation

Allogeneic stem cell transplantation—where healthy stem cells from a donor are used to replace the patient’s diseased bone marrow—remains the only treatment approach with the potential to cure CMML.^[10][13] However, this intensive procedure carries significant risks and requires that patients be healthy enough to tolerate the treatment.

Given that the median age at CMML diagnosis is around 73 years, and many patients have other health conditions, stem cell transplantation is suitable for only about 10 percent of people diagnosed with CMML.^[10] Younger patients in relatively good health are most likely to be considered for this approach. The procedure involves intensive chemotherapy or radiation to eliminate diseased cells, followed by infusion of healthy donor stem cells. Recovery requires several months, and potential complications include infection, graft-versus-host disease (where the donor cells attack the patient’s body), and organ damage.

When appropriate patients undergo successful stem cell transplantation, they have the possibility of long-term disease-free survival. However, the decision to proceed with transplantation requires careful discussion between patients, their families, and the medical team about potential benefits and risks.

Innovative Treatments in Clinical Trials

Because current standard treatments for CMML have significant limitations—with many patients not responding or experiencing only temporary benefit—researchers worldwide are actively investigating new therapeutic approaches through clinical trials. These studies test promising drugs and treatment strategies that may offer better outcomes than existing options.

Understanding Clinical Trial Phases

Clinical trials for new cancer treatments typically progress through three phases, each designed to answer specific questions about a new therapy. Phase I trials primarily assess safety, determining what dose of a new drug can be given safely and what side effects might occur. These trials usually involve small numbers of patients. Phase II trials expand to larger groups and focus on whether the treatment shows signs of effectiveness against the disease while continuing to monitor safety. Phase III trials compare the new treatment directly with current standard treatments to determine if it offers superior outcomes, equivalent results with fewer side effects, or other advantages.

Targeted Therapies Based on Genetic Mutations

One of the most promising areas of CMML research involves developing drugs that target specific genetic mutations found in the disease. Scientists have identified that CMML is associated with mutations in several genes, most commonly TET2 (found in about 60 percent of cases), ASXL1 (40 percent), SRSF2 (50 percent), and RAS pathway genes (30 percent).^[8][10] Understanding which mutations drive disease in individual patients opens the door to personalized treatment approaches.

Researchers are investigating drugs that specifically inhibit the effects of these mutations. For example, clinical trials are exploring inhibitors of IDH1 and IDH2 enzymes, which are sometimes mutated in CMML. Other studies examine drugs targeting the RAS signalling pathway, which becomes overactive when RAS genes are mutated. These targeted approaches aim to interfere with the specific molecular abnormalities driving cancer cell growth while potentially causing less harm to normal cells than traditional chemotherapy.

Immunotherapy Approaches

Immunotherapy—treatment that harnesses the body’s immune system to fight cancer—represents another area of active investigation in CMML. Some clinical trials are testing immune checkpoint inhibitors, drugs that remove brakes on the immune system, allowing immune cells to recognize and attack cancer cells more effectively. These medications have shown remarkable success in some other cancer types, and researchers are evaluating whether they might benefit CMML patients.

Other immunotherapy approaches being studied include vaccines designed to stimulate immune responses specifically against CMML cells and adoptive cell therapies where a patient’s own immune cells are collected, modified in the laboratory to better recognize cancer cells, and then returned to the patient’s body.

Novel Hypomethylating Strategies

While azacitidine and similar drugs form the backbone of current CMML treatment, researchers continue to develop newer versions of hypomethylating agents that might work better or differently. Some clinical trials test these newer drugs alone, while others combine them with additional medications to enhance their effectiveness. For instance, studies are evaluating combinations of hypomethylating agents with targeted drugs or with drugs that affect other aspects of cancer cell metabolism and survival.

JAK Inhibitors and Other Signal-Blocking Drugs

Some CMML cases, particularly the proliferative subtype, involve mutations in genes that lead to overactivity of cellular signalling pathways. JAK inhibitors—drugs that block the Janus kinase signalling pathway—have shown benefit in related blood cancers and are being investigated in CMML clinical trials. The JAK2V617F mutation, found in some proliferative CMML cases, makes this pathway continuously active, promoting excessive cell production.^[10] Blocking this pathway might help control the disease’s proliferative features.

Preliminary Results and Patient Eligibility

Early results from some clinical trials have shown encouraging signs, including improvements in blood counts, reductions in abnormal monocyte levels, decreased bone marrow blast cells, and symptom improvement in some patients. However, it’s crucial to understand that preliminary results require confirmation in larger studies before any new treatment can be considered a proven therapy.

Clinical trials for CMML are conducted at major cancer centres across the United States, Europe, and other regions worldwide. Patient eligibility for specific trials depends on factors including the CMML subtype, previous treatments received, genetic mutation profile, overall health status, and specific criteria set by each study.^[1] Patients interested in clinical trials should discuss this option with their haematology team, who can help identify appropriate studies and facilitate referral if suitable.

Most common treatment methods

• Watchful waiting (Active monitoring)
  • Regular blood tests and clinical examinations without active treatment
  • Appropriate for patients with no symptoms or mild symptoms
  • Treatment begins when disease progresses or symptoms develop
• Supportive care
  • Blood transfusions for low red blood cell counts (anaemia)
  • Platelet transfusions for low platelet counts and bleeding problems
  • Iron chelation therapy to remove excess iron from repeated transfusions
  • Antibiotics to treat and prevent infections
  • Growth factors like erythropoietin to stimulate red blood cell production
• Chemotherapy
  • Azacitidine (Vidaza) – a hypomethylating agent given by injection under the skin
  • Hydroxycarbamide (hydroxyurea) – helps control high white blood cell counts, taken as tablets
  • Treatment duration varies based on response and tolerance
  • Response rates to hypomethylating agents range from 40-50%
• Stem cell transplantation
  • Allogeneic stem cell transplant – the only potentially curative treatment
  • Involves intensive chemotherapy or radiation followed by donor stem cell infusion
  • Suitable for approximately 10% of patients due to age and health requirements
  • Carries significant risks including infection and graft-versus-host disease
• Clinical trial therapies
  • Targeted therapies against specific genetic mutations (TET2, ASXL1, SRSF2, RAS pathway)
  • Immunotherapy including immune checkpoint inhibitors
  • Novel hypomethylating agents and combination strategies
  • JAK inhibitors for proliferative CMML subtypes
  • Available at major cancer centres in the USA, Europe, and worldwide