Bone marrow failure syndromes

1

Describe the three main pathophysiological mechanisms of aplastic anemia.

• a.

  Direct damage to bone marrow

  • i.

    Typically iatrogenic because of cytotoxic drugs/chemotherapy, radiation therapy, and other myelosuppressive medications. Has also been seen with environmental toxins, including benzene (workplace toxin), now more common in low-income countries.

  • ii.

    Effects are dose-dependent and often associated with spontaneous recovery.

• b.

  Immune-mediated

  • i.

    Acquired aplastic anemia, when severe and acute, is most often associated with immune-mediated process as evidenced by response of blood counts to immunosuppressive therapies and dependence of counts after recovery on maintenance immunosuppression.

  • ii.

    This immune-mediated process is believed to be because of an aberrant T-cell immune response; as such, treatment designed to suppress T-cell response has been shown to be effective. This may have an identifiable viral trigger or can be associated with typable and nontypable hepatitis; however, in most cases, no trigger can be identified.

• c.

  Constitutional genetic defects

  • i.

    Less often, bone marrow failure is associated with genetic defects. Factors that suggest an inherited bone marrow failure syndrome include macrocytosis; physical anomalies; failed response to immunosuppressive therapy; past history of moderate, chronic pancytopenia; significant infectious history or family history of cytopenias; early death; myelodysplastic syndrome (MDS)/acute myelogenous leukemia (AML), or early cancer.

  • ii.

    Screening for causes of constitutional marrow failure is indicated for patients with aplastic anemia. If pancytopenia is severe and acute with no family history or clinical features on examination, screening is less likely to be positive.

2

What are the treatment options for idiopathic severe aplastic anemia?

In children, if a human leukocyte antigen (HLA)–matched, related donor is available, the treatment of choice is hematopoietic stem cell transplant (HSCT). If no such donor is available, patients can be treated with immunosuppressive therapy.

Immunosuppressive therapy has typically included horse antithymocyte globulin (ATG) and cyclosporine. In a randomized study, horse ATG was found to be superior to rabbit ATG in treatment of severe aplastic anemia based on improved hematological response and survival. Additionally, new trials have shown improved response in approximately 60% of patients with the addition of eltrombopag to an upfront immunosuppressive regimen.

If immunotherapy fails, matched unrelated donor transplant is a suitable option. Alternatively, haploidentical transplant or second-line immunosuppressive therapy can be used if an unrelated transplant donor is unavailable.

3

What is the underlying defect of paroxysmal nocturnal hemoglobinuria?

Paroxysmal nocturnal hemoglobinuria (PNH) is a clonal hematopoietic stem cell disease that is the result of an acquired defect in the PIG-A gene necessary for the synthesis of glycosylphosphatidylinositol, which anchors proteins to the surface of cells. The mutation leads to the loss of CD55 and CD59, inhibitors of the complement system, thereby leading to uncontrolled complement activation and both intravascular and extravascular hemolysis.

Patients with classic PNH present with symptoms of intravascular hemolysis, including elevated reticulocyte count, large population of PNH cells, elevated lactate dehydrogenase (LDH), hemoglobinuria, fatigue, smooth muscle dystonias, and thrombosis. More common to pediatric patients, an expanded PNH clone may be found in patients with acquired aplastic anemia. These patients may present with aplastic anemia and often a smaller number of PNH clones. Nevertheless, some will experience expansion of PIG-A mutation mutant clone and progress to classical PNH.

4

What is the therapy of choice for classical PNH and/or PNH complications?

In patients with classical PNH, HSCT and complement inhibition therapy are the only proven effective therapies. Complement inhibition therapy is the current first-line treatment of choice for severe classical PNH in children. It is highly effective in reducing intravascular hemolysis and reducing risk of thrombosis; however, it does not treat bone marrow failure. Patients with severe aplastic anemia should be considered for allogeneic transplant or immunosuppressive therapy if no HLA-matched sibling donor is available. Additionally, HSCT may be considered in patients with severe classical PNH with suboptimal response to complement inhibition therapy.

5

Describe the inheritance patterns, common genetic mutations, and treatment options associated with inherited bone marrow failure syndromes.