Myelodysplastic Syndrome Transformation

Myelodysplastic syndrome (MDS) is a group of blood disorders that can progress to a more serious form of cancer. Understanding what happens when MDS transforms into acute myeloid leukemia and what affects the outcome can help patients and families prepare for the challenges ahead.

Table of contents

• What Is Myelodysplastic Syndrome Transformation?
• Risk Factors for Transformation
• Prognosis and Survival
• Treatment Approaches
• Clinical Features at Transformation

What Is Myelodysplastic Syndrome Transformation?

Myelodysplastic syndrome transformation refers to the progression of MDS to acute myeloid leukemia (AML), a more aggressive form of blood cancer. MDS is a collection of disorders affecting the bone marrow, the soft center of bones where blood cells are made. In MDS, the bone marrow does not produce enough healthy blood cells, and the cells that are made often don’t work properly.^[1]

Not all patients with MDS will experience transformation to leukemia. Some patients with MDS may progress to acute myeloid leukemia, which further complicates their clinical course. In fact, only about one-third of cases of MDS actually progress to leukemia.^[2] When transformation does occur, the bone marrow becomes filled with blasts, which are immature white blood cells that don’t function properly. By medical convention, MDS is reclassified as AML when the percentage of blasts in the blood or bone marrow reaches or exceeds 20 percent.^[9]

The transformation process involves the accumulation of additional genetic abnormalities over time. MDS develops from a series of changes in the genetic material of blood stem cells. As these cells continue to develop new mutations, they can eventually transform into leukemia cells.^[5]

Risk Factors for Transformation

Several factors influence whether MDS will transform into acute myeloid leukemia and how quickly this might happen. Understanding these risk factors helps doctors predict the course of the disease and plan appropriate treatment.

One important factor is the specific subtype of MDS. Patients with certain subtypes, particularly those classified as refractory anemia with excess blasts (RAEB) or RAEB in transformation (RAEB-t), have a higher risk of progressing to leukemia. In pediatric classifications, RAEB is defined as having 5 to 20 percent blasts in the bone marrow, while RAEB-t has 21 to 30 percent blasts.^[2]

The percentage of blasts in the bone marrow at the time of MDS diagnosis is directly related to prognosis. Higher blast percentages indicate a greater risk of transformation. Additionally, certain cytogenetic abnormalities—changes in the chromosomes of cells—play a significant role. Patients with high-risk cytogenetic abnormalities, such as complex karyotype or specific chromosomal deletions, face a higher risk of transformation.^[4]

The presence of specific genetic mutations also affects transformation risk. Patients with TP53 mutations, a change in a gene that normally helps prevent cancer, have particularly poor outcomes and higher rates of transformation to AML.^[4] The time from MDS diagnosis to transformation can also be an indicator of prognosis, with shorter transformation times generally associated with worse outcomes.^[4]

Prognosis and Survival

The prognosis for patients whose MDS transforms to acute myeloid leukemia varies considerably based on multiple factors. Prognosis is directly related to the number of bone marrow blast cells, certain cytogenetic abnormalities, and the amount of peripheral blood cytopenias—low counts of blood cells.^[9]

In a retrospective study of 52 patients whose MDS transformed to AML, patients were divided into good and poor prognosis groups based on survival beyond 12 months. The good prognosis group had 20 patients, while 32 patients fell into the poor prognosis group. The mean age was 64.5 years, and there was no significant difference in age between the two groups.^[4]

Several factors were identified as independent predictors of poor prognosis after transformation. These included an Eastern Cooperative Oncology Group (ECOG) performance status score of 2 or higher, which measures how well a patient can perform daily activities. Patients in the poor prognosis group had significantly lower performance status scores, meaning they had more difficulty with daily activities.^[4]

Other poor prognosis factors included higher International Prognostic Scoring System (IPSS) scores at MDS diagnosis, RAEB-1 or RAEB-2 subtypes, higher bone marrow blast percentage at transformation, TP53 mutation, and high-risk cytogenetic abnormalities. Each of these factors independently increased the risk of poor outcomes.^[4]

The acute leukemic phase that results from MDS transformation is less responsive to chemotherapy than leukemia that develops on its own (de novo AML). Many patients succumb to complications of low blood cell counts before progressing to the leukemic stage.^[9]

Treatment Approaches

Treatment for patients whose MDS has transformed to AML depends on several factors, including the patient’s age, overall health, specific disease characteristics, and personal goals. Currently, allogeneic hematopoietic stem cell transplantation—a procedure where healthy stem cells from a donor replace the patient’s diseased bone marrow—is the only potential cure for MDS, including cases that have transformed to AML. However, even this option is available only to a minority of qualified patients who have HLA-matched donors and are healthy enough to undergo the procedure.^[10]

For patients who are candidates for aggressive treatment, cytotoxic chemotherapy may be used. The usual combination treatment includes cytarabine plus an anthracycline, which yields a limited response rate of 30 to 40 percent.^[13] However, the response rates are generally lower than those seen in patients with de novo AML.

Treatment with hypomethylating agents—medications that help restore normal gene function—such as azacitidine or decitabine, is considered standard therapy for intermediate and high-risk MDS. This approach is especially useful in elderly patients, who experience high rates of complications with cytotoxic chemotherapy.^[13] Hypomethylating agents currently remain the only approved non-transplant option for higher-risk MDS and are the standard of care for patients not eligible for allogeneic hematopoietic stem cell transplantation.^[8]

Treatment response is an important prognostic factor. Studies have shown that patients who achieve complete remission or partial remission have significantly better outcomes than those who show no response to treatment. The response to initial therapy affects overall survival after transformation.^[4]

Supportive care remains an essential component of treatment for all patients. This includes blood transfusions to replace deficient cells, treatment of infections, and management of symptoms such as fatigue and bleeding. These measures help improve quality of life even when curative treatment is not possible.^[1]

Clinical Features at Transformation

When MDS transforms to acute myeloid leukemia, patients may experience changes in their symptoms and blood test results. At the time of transformation, patients in the poor prognosis group typically have higher white blood cell counts and higher bone marrow blast percentages compared to those with better outcomes.^[4]

The clinical features at MDS diagnosis can also provide clues about the likelihood of transformation. Patients who later develop poor outcomes often have worse International Prognostic Scoring System scores, higher bone marrow blast percentages, poorer cytogenetic risk, and shorter time to transformation at their initial MDS diagnosis.^[4]

Many patients experience fatigue, which is one of the most common symptoms. Up to 9 out of 10 people with MDS have lasting fatigue that doesn’t go away with rest. This can become more severe as the disease progresses or transforms to AML.^[14] Other common symptoms may include shortness of breath, unusual paleness due to low red blood cell count, easy bruising or bleeding due to low platelet count, and frequent infections due to low white blood cell count.^[3]

Regular monitoring through blood tests and bone marrow examinations is important for detecting transformation early. Healthcare providers can use these tests to track the percentage of blasts and identify changes that might indicate progression to AML.^[6]