Bone Marrow Failure

How the marrow fails

Bone marrow is the soft tissue inside bones where blood-forming stem cells make all blood cells. Marrow failure occurs when:

• the stem cells are destroyed or suppressed (for example, by the immune system in aplastic anemia, or by chemotherapy)
• the stem cells are genetically faulty and cannot divide normally (inherited syndromes)
• abnormal cells crowd out or replace healthy ones (MDS, leukemia, cancers spreading to the marrow)

When all three cell lines are low, doctors call it pancytopenia.

Causes

Acquired

• Aplastic anemia: the classic cause. In most adults it is autoimmune, with T cells attacking stem cells, leaving an "empty" marrow.
• Myelodysplastic syndromes (MDS): abnormal, ineffective stem cells, mostly in people over 60. Can progress to leukemia.
• Paroxysmal nocturnal hemoglobinuria (PNH): often linked to aplastic anemia.
• Chemotherapy and radiation, usually temporary.
• Medicines: chloramphenicol, some antiseizure drugs, gold, and others in rare idiosyncratic reactions.
• Toxins: benzene and some pesticides.
• Viruses: hepatitis (non-A to E), Epstein-Barr virus, HIV, parvovirus B19 (red cells especially).
• Marrow infiltration: leukemia, lymphoma, myeloma, metastatic cancer, myelofibrosis.
• Nutritional: severe vitamin B12 or folate deficiency can mimic marrow failure and is easily reversible.
• Pregnancy rarely.

Inherited

Inherited syndromes can first appear in adulthood, so they are considered in younger adults with marrow failure.

Symptoms

Symptoms depend on which cells are low:

• Low red cells (anemia): fatigue, pale skin, breathlessness, fast heartbeat, dizziness
• Low white cells (neutropenia): frequent or severe infections, mouth ulcers, fevers
• Low platelets (thrombocytopenia): easy bruising, pinpoint red spots (petechiae), nosebleeds, bleeding gums, heavy periods

Diagnosis

1. Complete blood count and blood smear: shows which cells are low and whether they look abnormal.
2. Reticulocyte count: a low count shows the marrow is not making red cells.
3. Bone marrow aspirate and biopsy: shows whether the marrow is empty (aplastic anemia), full of abnormal cells (MDS, leukemia) or scarred.
4. Cytogenetics and gene mutation testing on marrow cells.
5. Flow cytometry for PNH.
6. Inherited syndrome testing: chromosome breakage tests for Fanconi anemia, telomere length testing, and gene panels.
7. Other blood tests: B12, folate, viral tests, liver function, autoimmune tests.

Treatment

Supportive care

• Red cell transfusions for symptomatic anemia, with iron chelation if many transfusions are needed.
• Platelet transfusions for bleeding or very low counts.
• Infection prevention and prompt antibiotics for fever.
• Growth factors (G-CSF) in some cases.

Treating the cause

• Aplastic anemia: immunosuppressive therapy with antithymocyte globulin (ATG), cyclosporine and eltrombopag, or stem cell transplant.
• MDS: depends on risk. Options include growth factors, luspatercept, hypomethylating agents such as azacitidine, and transplant.
• Drug- or toxin-related: stop the exposure.
• Nutritional: vitamin replacement.

Stem cell (bone marrow) transplant

Transplant from a matched sibling or unrelated donor replaces the faulty marrow and can cure aplastic anemia, many inherited syndromes and some MDS. It works best in younger, fitter patients and carries risks including graft-versus-host disease and infection.

Outlook

Outcomes depend on the cause, severity, age and treatment. Most younger people with severe aplastic anemia who have a matched sibling transplant are cured. Immunosuppression produces responses in most patients, though relapse or progression to MDS can occur. Inherited syndromes need lifelong monitoring for cancers and organ problems. Temporary marrow suppression from chemotherapy usually recovers within weeks.

Frequently asked questions

What are the symptoms of bone marrow failure?

Symptoms come from low blood counts: tiredness, pale skin and breathlessness from anemia, frequent or severe infections from low white cells, and easy bruising, nosebleeds, bleeding gums or tiny red spots from low platelets. Some people are diagnosed from a routine blood test before symptoms appear.

What causes bone marrow failure?

Common causes include aplastic anemia (usually autoimmune), myelodysplastic syndromes, chemotherapy and radiation, certain drugs and toxins, viral infections, and inherited conditions such as Fanconi anemia. Cancers like leukemia can also crowd out normal marrow.

Is bone marrow failure the same as leukemia?

No. Bone marrow failure means the marrow is not making enough normal cells. Leukemia is a cancer where abnormal cells multiply and crowd out normal ones, which is one cause of marrow failure. Some marrow failure conditions, such as MDS, can progress to leukemia.

Can bone marrow failure be cured?

Many cases can. Stem cell transplant can cure aplastic anemia, inherited marrow failure syndromes and some MDS. Immunosuppressive therapy controls aplastic anemia in most patients. Marrow suppression from drugs or chemotherapy often recovers once the cause is removed.

How is bone marrow failure diagnosed?

It starts with a complete blood count showing low cell counts. A bone marrow biopsy then shows whether the marrow is empty, abnormal or infiltrated. Genetic tests, PNH testing and other blood tests identify the specific cause.