Acquired aplastic anemia in children and young adults

INTRODUCTION

• Injury to or loss of pluripotent hematopoietic stem cells, in the absence of infiltrative disease of the bone marrow, is the major pathophysiologic characteristic of the disease
• Acquired AA, characterized by pancytopenia and hypocellular bone marrow in the absence of abnormal infiltrates and without increased reticulum
• The major constitutional or inherited causes of pancytopenia and AA in children include Fanconi anemia, dyskeratosis congenita, Shwachman- Diamond syndrome, and amegakaryocytic thrombocytopenia

ETIOLOGY AND INCIDENCE

• The major identifiable etiologies are exposure to a wide variety of drugs and chemicals, ionizing radiation, and some viruses
• AA may also rarely complicate orthotopic liver transplantation; AA in this setting has a very poor outcome except in those patients who develop the disorder in the background of fulminant hepatic
• AA also has occurred in patients with other immune disorders such as systemic lupus erythematosus and, occasionally, in pregnancy

In one study in 213 children <17>

• Radiation Exposure - Exposure to large doses of external radiation
• Drugs - Numerous drugs, such as certain nonsteroidal antiinflammatory drugs (particularly phenylbutazone, which is now rarely used), chloramphenicol, gold, sulfonamides, certain of the antiepileptic agents, nifedipine, and cytotoxic drugs can be associated with
• Other chemical agents –
• Prolonged exposure to benzene is particularly notorious in this regard
• Infectious agents - Patients with bacterial or viral diseases may experience pancytopenia.
• This condition is usually transient and may relate to multiple factors, including the use of antibiotics and other medications
• The best documented virus is parvovirus B19. However, pancytopenia can occur, particularly in immunocompromised patients.
• Hepatitis - Hepatitis viruses and HIV can cause severe aplasia. The mechanism may involve T cell activation with release of cytokines. The responsible virus has not been identified; hepatitis A, B, C, and G do not appear to be involved
• Pregnancy - Aplastic anemia associated with pregnancy frequently is self-limited, ending with delivery
• Idiopathic - both immune system abnormalities as well as a genetic predisposition may play causative roles.

CLINICAL PRESENTATION AND DIAGNOSIS

The clinical presentation of AA is variable and includes symptoms and signs related to cytopenia in each of the three cell lineages:

• Hemorrhagic manifestations secondary to thrombocytopenia
• Fatigue, pallor, and cardiovascular complaints caused by progressive anemia.
• Fever, mucosal ulcerations, and bacterial infections resulting from neutropenia

Diagnosis

A diagnosis of AA is suggested by the presence of pancytopenia with absolute reticulocytopenia, suggestive of bone marrow failure. (

The red blood cells usually are normocytic but occasionally may be macrocytic (mean cell volume >100)

The peripheral blood smear shows that the remaining elements, while reduced, are morphologically normal.

The differential diagnosis

• Marrow replacement by fibrosis or tumor
• severe megaloblastosis
• paroxysmal nocturnal hemoglobinuria
• myelodysplastic syndromes
• Overwhelming infection caused by HIV or disorders associated with hemophagocytosis

The diagnosis of AA is established by bone marrow aspiration and biopsy. The characteristic findings include:

• The marrow is profoundly hypocellular with a decrease in all elements; the marrow space is now composed of fat cells and marrow stroma
• The residual hematopoietic cells are morphologically normal
• Malignant infiltrates or fibrosis are absent
• There is no megaloblastic hematopoiesis

Definitions of severity

• Moderate aplastic anemia
  Bone marrow cellularity <50>6 weeks as documented by an absolute neutrophil count <1200/microl,>
• Severe aplastic anemia
  A marrow biopsy showing less than 25 percent of normal cellularity or
  A bone marrow biopsy showing less than 50 percent normal cellularity in which fewer than 30 percent of the cells are hematopoietic and at least two of the following are present: absolute reticulocyte count <40,000/microl,>
• Very severe aplastic anemia - The patient is considered to have very severe aplastic anemia (vSAA) if the ANC is <200/microl.>

Unless patients with SAA or vSAA are successfully treated, over 70 percent will be dead within one year
Spontaneous recovery is rare.

TREATMENT

• Treatment includes withdrawal of offending agents (if any), supportive care, and some form of definitive therapy against the aplasia.
• Blood and platelet transfusions should be used selectively in candidates for hematopoietic cell transplantation in order to avoid sensitization
• Any blood products should be irradiated and CMV-negative, and should not be from family members
• Patients with severe neutropenia affected with fever require immediate evaluation, blood culture, and treatment with broad spectrum antibiotics
• Prophylactic antibiotics have no role

Severe AA— two major modalities for treatment of severe acquired AA are hematopoietic cell transplantation (HCT) and immunosuppressive therapy

For children with SAA or vSAA, including those with hepatitis- associated AA , the problems associated with HCT (eg, low frequency of matched sibling donors, graft failure, graft versus host disease) are outweighed by the advantages (eg, stable engraftment and hematopoiesis, low risk for clonal disorders such as myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML)). Therefore, HCT from a matched sibling donor is the treatment of choice, with long-term disease-free survival rates approaching 90 percent

Immunosuppressive therapy - Only 20 to 25 percent of children with AA have an HLA-matched sibling. For the remaining children, intensive immunosuppressive therapy is the preferred option.

Initial regimens often consisted of antithymocyte globulin (ATG) alone, or cyclosporine alone, with response rates of about 50 percent
However, response rates of 75 to 80 percent currently are achieved by the use of more intensive regimens consisting of ATG, cyclosporine, corticosteroids, and hematopoietic growth factors

We currently use the following regimen:

• Antithymocyte globulin (ATG) — 40 mg/kg per day for four days.
• Cyclosporine (CSA) — 12 to 15 mg/kg per day in divided doses begun on day five to maintain a blood trough of 200 to 250 ng/mL.
• Prednisone — 2 mg/kg (maximum 60 mg/day) for two weeks followed by a slow taper to prevent and control potential complications of serum sickness.
• Recombinant human G-CSF or GM-CSF (eg, G-CSF at 5 microg/kg per day SQ for 90 days)

The response to therapy may be slow, with granulocyte recovery occurring first, followed by stabilization of hemoglobin and a decline in transfusion requirements. Platelet recovery may take months to years. Long-term survivors may show persistent thrombocytopenia, red blood cell macrocytosis, and elevated hemoglobin F concentrations

A variety of acute or delayed complications may be observed following immunosuppressive therapy in children with AA:

• Serum sickness, occurring seven to 10 days after ATG therapy, is a common problem
• Fever associated with the administration of ATG typically develops on the first day of treatment and lasts from one to six days.
• Increased risk for opportunistic infections, particularly fungal infection
• Cyclosporine has a variety of frequent side effects, including hypertension, nephrotoxicity, hirsutism, and gingival hypertrophy

The rate of relapse of aplasia increases over time, with reported values ranging from 9 percent at five years to 35 percent at fourteen years
Relapses typically respond to a second course of immunosuppressive therapy and, in responders, is not associated with a survival disadvantage
Nonresponders to repeat therapy have a worse outcome
Other than relapse, late complications following successful immunosuppressive therapy include evolution of clonal disease such as MDS and AML
The reported rate of these disorders has ranged from 9 percent at five years to 19 percent at ten years

Moderate AA –
For patients with moderate aplastic anemia (MAA), treatment recommendations are unclear
With progressive cytopenias, particularly severe neutropenia and/or transfusion dependence, treatment with HCT or immunosuppression should be considered
Further studies are needed for this variant of AA.