Myelodysplastic Syndromes

I. What every physician needs to know.

Myelodyplastic Syndromes (MDS) is an acquired marrow failure syndrome caused by accumulated mutations in pluripotent stem cells responsible for production of blood cells. The mutations lead to ineffective dysplastic hematopoiesis.

Most cases of MDS arise denovo with a smaller number (~15%) secondary to exposure to DNA-damaging agents such as alkylating agents, topoisomerase II inhibitors or environmental exposures, such as benzenes.

MDS can progress to acute myeloid leukemia (AML) with the distinction being <20% marrow blasts in MDS and >20% marrow blasts in AML. In general, MDS progressing to AML carries a worse prognosis than denovo AML.

II. Diagnostic Confirmation: Are you sure your patient has Myelodysplastic Syndromes?

Diagnostic confirmation is made by examining the peripheral smear for cytopenias and dysplastic cells, and bone marrow examination. Below is a basic classification and some salient features listed:

1. Refractory cytopenia with unilineage dysplasia (RCUD):

Includes refractory anemia, refractory neutropenia and refractory thrombocytopenia.

Less than 1% blasts in periphery and less than 5% blasts in the marrow.

2. Refractory anemia with ringed sideroblasts (RARS):

No circulating blasts, 5% marrow blasts.

>15% erythroid precursors in marrow are ringed sideroblasts.

3. Refractory cytopenia with multilineage dysplasia (RCMD):

Less than 1% circulating blasts, less than 5% marrow blasts.

No Auer rods.

Comprises 30% of patients with MDS.

4. Refractory anemia with excess blasts, type 1 (RAEB-1):

Less than 5% circulating blasts, 5-9% marrow blasts.

No Auer rods.

Along with RAEB-2 comprises 40% of patients with MDS.

5. Refractory anemia with excess blasts, type 2 (RAEB-2):

5-19% circulating blasts, 10-19% marrow blasts.

Auer rods may be present.

6. MDS associated with isolated del(5q)

Less than 1% circulating blasts.
Isolated 5q31 chromosome deletion.
More common in women.
Lenolidamide leads to transfusion independence in 2/3rds of these patients.

7. MDS unclassifiable (MDS-U)

Less than 1% circulating blasts, less than 5% marrow blasts.
Does not fit other categories. Dysplasia or MDS-associated karyotype seen.

8. Refractory cytopenia of childhood (RCC):

Pancytopenia with less than 5% marrow blasts.

Flow cytometry and cytogenetics help to more precisely define the form of MDS and have both prognostic and treatment implications.

A. History Part I: Pattern Recognition:

Consider MDS in any elderly patient or any patient with a history of prior chemotherapy who present with reductions in at least one cell line. In almost all cases, patients will present with anemia – usually normocytic or macrocytic. In most cases they will also have reductions in granulocyte counts or even neutropenia. Thrombocytopenia can also be seen.

The signs and symptoms of MDS are the same non-specific signs of reductions in one or more of the cell lines: petechiae, pallor and occasionally systemic bacterial infections. The degree of symptoms might not correlate with the degree of cytopenias because dysplastic cells often have cellular dysfunction.

B. History Part 2: Prevalence:

MDS is usually seen in patients who have over time accumulated mutations in pluripotent stem cells. As such it is usually seen in the elderly or in patients previously exposed to chemotherapy. Median age at diagnosis is 70 years.

C. History Part 3: Competing diagnoses that can mimic MDS.

As the usual presenting feature is a normocytic/macrocytic anemia very often with decreased granulocytes and thrombocytopenia in an elderly patient, consider other common causes for depression of these cell lineages.

1. Macrocytic anemia

B12 and folate deficiency – evaluate for by checking B12, folate, homocystine and MMA levels.

2. Pancytopenia

Aplastic anemia – evaluate for by examining the marrow. In aplastic anemia, the marrow will be hypocellular as opposed to the often hypercellular marrow of MDS.
Myelofibrosis – evaluate for two key diagnostic features of myelofibrosis: splenomegaly and marrow fibrosis. Both will usually be present in myelofibrosis and both absent in MDS.
HIV, copper deficiency and alcohol abuse can cause cytopenias and dysplastic changes.
Bone marrow suppressive medications that can also lead to a macrocytic anemia.

D. Physical Examination Findings.

No classic physical exam findings except those associated with decreases in any of the cell lines that are often involved.

Anemia – pallor
Thrombocytopenia – petechiae

Also consider physical exam findings that are usually absent in MDS, but present in many hematologic malignancies:

Absent lymphadenopathy
Absent splenomegaly

E. What diagnostic tests should be performed?

As discussed above the most critical tests are:

Examination of the peripheral smear looking for dysplastic cells and blasts
Examination of the marrow looking for blasts
Flow cytometry can provide complementary information but cannot be used to establish a diagnosis

1. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

No radiologic studies are diagnostic.

III. Default Management.

A. Immediate management.

The most emergent complication is gram negative sepsis in the setting of neutropenia or hemorrhage from thrombocytopenia.

In patients not otherwise acutely ill, consideration will be made to starting chemotherapy or performing a bone marrow transplant. Hypomethylating agent’s azacitidine and decitabine are the usual chemotherapeutic agents used. Lenolidamide leads to transfusion independence in 2/3rds of MDS patients with 5q deletion.

Factors affecting outcomes age, comorbidities and IPSS score. Older age and more comorbidities have worse outcomes. IPSS score classifies people into four categories with worsening outcomes with increasing marrow blast count, specific karyotypes, >3 chromosomal anomalies and the number of peripheral blood cytopenias.

B. Physical Examination Tips to Guide Management.

Physical exam findings are not specific or diagnostic, but are usually related to deficencies in affected cell lines.

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

A CBC should be monitored daily while receiving therapy. Particular attention should be paid to the white blood count and more specifically, the neutrophil count, as patients with neutropenia require more careful monitoring in the event of fever. Platelets also must be followed closely with increased bleeding risk with counts below 10,000/μL.

D. Long-term management.

Long-term management is focused on supportive care.

In patients with persistent leukopenia, careful attention and treatment with antibiotics are necessary for early signs of infections such as fever.

MDS patients require frequent leukocyte-depleted blood transfusions and occasionally chelation therapy to prevent the risk for secondary iron overload.

The usefulness of colony-stimulating factors is less well proven. ESA (erythropoiesis-stimulating agents) and granulocyte-CSF in combination with ESAs can lead to response in about 40% of patients, particularly in RARS subtype of MDS. Thrombopoietin (TPO)-receptor agonists can raise the platelet count but are not FDA-approved because of concern for increasing the risk of AML progression.