- MDS with single lineage dysplasia (MDS-SLD)
- MDS with multi-lineage dysplasia (MDS-MLD)
- MDS with ring sideroblasts (MDS-RS)
- MDS with excess blasts (MDS-EB)
- MDS with isolated del(5q)
- A specific subtype that is amenable to treatment with a mediation called lenalidomide.
- Unclassifiable MDS (MDS-U)
Other classification systems include the International Prognostic Scoring System (IPSS) and French-American-British (FAB) system.
Primary MDS (90%)
- Risk factors include:
- Male sex
- Age >60 years
- Occurs on average 2-10 years after chemotherapy for other cancers
- Due to the DNA-damaging effects on the the bone marrow
- The risk is higher in patients treated for breast cancer, leukaemias, lymphomas, head and neck, GI, lung and prostate cancer.
- Patients may have more complex chromosomal abnormalities
- Similar as for chemotherapy, this is a late adverse effect of treatment due to irradiation of the bone marrow
- MDS occurs due to a failure of one, two or all three main cell lines in the bone marrow, usually at the stem cell level.
- These cell lines are erythrocytic (giving rise to RBCs), granulocytic (most WBCs) and megakaryocytic (platelets).
- MDS is therefore an umbrella term for a a quite heterogeneous group of disorders that occur due to different cytogenetic events, such as 5q deletion in the MDS-5q deletion subtype.
- RBCs, WBCs and platelets may all be affected by MDS, resulting in potentially life-threatening disease due to anaemia, increased risk of bleeding and infections.
- Additional genetic abnormalities can hence result in the transformation of MDS into acute myeloid leukaemia (AML).
If symptomatic, features may be non-specific, such as recurrent infections.
Generally, the symptoms depend on the cell line affected:
- Recurrent infections, especially bacterial infections of the skin
- Easy bruising, e.g. petechiae
- Recurrent bleeding, e.g. recurrent nosebleeds
- Hepatosplenomegaly is uncommon, but may occur due to extramedullary haematopoiesis (blood cell production in other places than the bone marrow in an attempt to compensate for cytopaenia)
- Low RBC, WBC and/or platelets
- Neutropaenia is often severe
- Peripheral blood film
- Nucleated RBCs
- Ringed sideroblasts
- Howell-Jolly bodies
- Basophilic stippling
- Hypolobulated or unlobulated neutrophil nuclei
- Large, agranular platelets and megakaryocytes
Once these initial tests support the suspicion of MDS, the following investigations are performed:
- Bone marrow biopsy (diagnostic)
- HypERcellular, dysplastic bone marrow with numerous cells of all three cell lines
- Blasts, megakaryotes, ringed sideroblasts, etc.
- Cytogenetic studies (indicated in all patients with suspected MDS having a bone marrow examination according to the British Society for Haematology)
- Common clonal changes are 5q deletion (5q-), monosomy 7 (-7 or 7q-), trisomy 8 (+8)
- Generally, most single genetic abnormalities indicate a good prognosis.
- This also identifies patients with a 5q deletion who respond to treatment with lenalidomide.
Haematological neoplasms that also present with cytopaenia:
- Myeloproliferative neoplasm that leads to bone marrow fibrosis, extramedullary haematopoiesis and splenomegaly
- Late phase may mimic MDS, as it presents with pancytopaenia and hence anaemia, recurrent infections and petechial bleeding
- Bone marrow biopsy would show extensive scarring rather than the bone marrow findings of MDS
- Aplastic anaemia
- Pancytopaenia caused by bone marrow insufficiency
- Idiopathic in >50%, but can be due to medications, toxins, ionising radiations, viral infections or inherited syndromes (e.g. Fanconi anaemia)
- Bone marrow biopsy would show a hypocellular, fat-filled marrow, rather than the hypercellularity in MDS
- Multiple myeloma
- Neoplasm of plasma cells
- Can also cause pancytopaenia due to bone marrow infiltration
- Check for blood immunoglobulins, urine Bence-Jones protein
- Bone marrow biopsy would show >10% clonal plasma cells
- All types can present with pancytopaenia
- Acute myeloid leukaemia (AML) may be a complication of MDS; blood film and bone marrow biopsy would show large blasts and Auer rods
- Chronic myeloid leukaemia (CML) may present first with a leukocytosis (midstage progenitor cells and myelocytes, basophilia, eosinophilia) and thrombocytosis, but advanced stages may be characterised by pancytopaenia and the disease may progress to AML; cytogenetic analysis shows the classical Philadelphia chromosome (t9;22)
- Acute lymphocytic leukaemia (ALL) is less likely in this age group but may present in adults with pancytopaenia, too
Other causes of cytopaenia:
- Chemotherapy and radiotherapy, through toxic effects on the bone marrow
- Drug-induced cytopaenia, e.g. methotrexate, alcohol
- Vitamin B12 or folate deficiency
- Immune-mediated cytopaenias (e.g. aplastic anaemia)
- Congenital anaemia syndromes (e.g. Fanconi anaemia, X-linked sideroblastic anaemia)
- HIV/AIDS infection
The mainstay of treatment is supportive care:
- Blood transfusions, especially RBC transfusions, based on an individualised haemoglobin cut-off
- Iron chelation therapy in transfusion iron overload (only for patients with good prognosis and certain subtypes), e.g. desferrioxamine, deferasirox
- Erythroid-stimulating agents (ESA) to relieve anaemia
- Antibiotics for recurrent infections
Further therapy may involve the following, depending on the patient's subtype, prognosis, and general health:
- Medical treatment
- Antithymocyte globulin (ATG) as immunosuppressant therapy (for younger patients with normal karyotype)
- Lenalidomide (for patients with del(5q) subtype)
- Azacitidine (hypomethyalting agent approved by NICE in 2011 for intermediate and high-risk MDS)
- Allogenous stem cell (bone marrow) transplant
- This is the only curative treatment option
- The patient's eligibility depends on type (for high-risk MDS) and general health; it should not depend on the age, but more on comorbidities and performance status.
- Bleeding (due to thrombocytopaenia)
- Risk of life-threatening haemorrhage
- E.g. intracranial, pulmonary, gastrointestinal
- Infections (due to leukocytopaenia)
- Atypical infections
- Neutropaenic sepsis
- Progression to AML
- Any of the above are more likely to occur once the disease progresses to AML, i.e. bleeding and infection
- 30% of patients with MDS progress to AML
- Groups at highest risk of transformation are MDS-EB, MDS-RS-MLD, MDS-MLD
Also consider treatment-related complications:
- Complications of chemotherapy
- Azacitidine: fever, N+V, diarrhoea or constipation, fatigue and weakness
- Lenalidomide: leukocytopaenia, thrombocytopaenia, diarrhoea or constipation, fatigue and weakness
- Cytarabine (for patients progressed to AML): hair loss, mouth sores, loss of appetite, N+V, pancytopaenia
- Complications of allogeneic bone marrow transplant
- Early side effects: bleeding, infection, pancytopaenia
- Late side effects: graft-versus-host disease (GVHD), recurrence
The overall recurrence rate following allogeneic transplantation is estimated to be 20-50%.
- Median survival is about 5 years, but varies with subtype and risk group (e.g. International Prognostic Scoring System risk groups).
- 30% progress to acute myeloid leukaemia (AML).
- This risk is higher with certain subtypes and findings in the bone marrow. You do not need to know the details here, again, but the principles are easy to understand.
- Presence of ringed sideroblasts = protective; in a UK-based study (Roman et al., 2016), only 5% progressed to AML.
- Presence of excess blasts (6-20% myeloblasts) = higher risk; 25% progressed to AML (Roman et al., 2016).