Etiology and Epidemiology

Drugs, chemicals, toxins, infectious agents, radiation, and immune disorders can result in pancytopenia by direct destruction of hematopoietic progenitors, disruption of the marrow microenvironment, or immune-mediated suppression of marrow elements (Table 463-1). A careful history of exposure to known risk factors should be obtained for every child presenting with pancytopenia. Even in the absence of the classic associated physical findings, the possibility of a genetic predisposition to bone marrow failure should always be considered (Chapter 462). The majority of cases of acquired marrow failure in childhood are “idiopathic,” in that no causative agent is identified. These are probably immune-mediated through activated T lymphocytes and cytokine destruction of marrow progenitor cells. The overall incidence of acquired aplastic anemia is relatively low, with an approximate incidence in both children and adults in the USA and Europe of 2-6 cases/million/yr. The incidence is higher in Asia, with as many as 14 cases/million/yr in Japan.

Severe bone marrow suppression can develop after exposure to many different drugs and chemicals, including certain chemotherapeutic agents, insecticides, antibiotics, anticonvulsants, nonsteroidal anti-inflammatory agents, and recreational drugs. Some of the most notable agents are benzene, chloramphenicol, gold, and, most recently, 3,4,-methylenedioxymethamphetamine (Ecstasy).

A number of viruses can either directly or indirectly result in bone marrow failure. Parvovirus B19 is classically associated with isolated red blood cell (RBC) aplasia, but in patients with sickle cell disease or immunodeficiency, it can result in transient pancytopenia (Chapters 243 and 462). Prolonged pancytopenia can occur after infection with many of the hepatitis viruses, herpes viruses, Epstein-Barr virus (Chapter 246), cytomegalovirus (Chapter 247), and HIV (Chapter 268).

Patients with evidence of bone marrow failure should also be evaluated for paroxysmal nocturnal hemoglobinuria (PNH; Chapter 458) and collagen vascular diseases, although these are uncommon causes of pancytopenia in childhood. Pancytopenia without peripheral blasts may be caused by bone marrow replacement by leukemic blasts or neuroblastoma cells.

Pathology and Pathogenesis

The hallmark of aplastic anemia is peripheral pancytopenia, coupled with hypoplastic or aplastic bone marrow. The severity of the clinical course is related to the degree of myelosuppression. Severe aplastic anemia is defined as a condition in which 2 or more cell components have become seriously compromised (absolute neutrophil count [ANC] <500/mm³, platelet count <20,000/mm³, reticulocyte count <1% after correction for hematocrit) in a patient whose bone marrow biopsy material is moderately or severely hypocellular. Approximately 65% of patients who first present with moderate aplastic anemia (ANC 500-1,500/mm³, platelet count 20,000-100,000/mm³, reticulocyte count <1%) eventually progress to meet the criteria for severe disease if they are simply observed. Bone marrow failure may be a consequence of a direct cytotoxic effect on hematopoietic stem cells from a drug or chemical or may result from either cell-mediated or antibody-dependent cytotoxicity. There is strong evidence that many cases of idiopathic aplastic anemia are caused by an immune-mediated process, with increased circulating activated T lymphocytes producing cytokines (interferon-γ) that suppress hematopoiesis. Abnormal telomere length and telomerase activity in granulocytic precursors and increased expression of cell surface Flt3 ligand (a member of the class III receptor tyrosine kinase family) in the lymphocytes of patients with aplastic anemia suggest that early apoptosis of hematopoietic progenitors may play a role in the pathogenesis of this disease.

Clinical Manifestations, Laboratory Findings, and Differential Diagnosis

Pancytopenia results in increased risks of cardiac failure, infection, bleeding, and fatigue. Acquired pancytopenia is typically characterized by anemia, leukopenia, and thrombocytopenia in the setting of elevated serum cytokine values. Other treatable disorders, such as cancer, collagen vascular disorders, PNH, and infections that may respond to specific therapies (IV immune globulin for parvovirus), should be considered in the differential diagnosis. Careful examination of the peripheral blood smear for RBC, leukocyte, and platelet morphologic features is important. A reticulocyte count should be performed to assess erythropoietic activity. In children, the possibility of congenital pancytopenia must always be considered, and chromosomal breakage analysis should be performed to evaluate for Fanconi anemia (Chapter 462). The presence of fetal hemoglobin suggests congenital pancytopenia but is not diagnostic. To assess for the possibility of PNH, flow cytometric analysis of erythrocytes for CD55 and CD59 is the most sensitive test. Bone marrow examination should include both aspiration and a biopsy, and the marrow should be carefully evaluated for morphologic features, cellularity, and cytogenetic findings.

Treatment

The treatment of children with acquired pancytopenia requires comprehensive supportive care coupled with an attempt to treat the underlying marrow failure. For patients with an HLA-identical sibling marrow donor, allogeneic bone marrow transplantation (BMT) offers a 90% chance of long-term survival. The risks associated with this approach include the immediate complications of transplantation, graft failure, and graft versus host disease. Late adverse effects associated with transplantation may include secondary cancers, cataracts, short stature, hypothyroidism, and gonadal dysfunction (Chapters 131-133). Only 1 in 5 patients has an HLA-matched sibling donor, so matched-related BMT is not an option for the majority of patients.

For patients without a sibling donor, the major form of therapy is immunosuppression with antithymocyte globulin (ATG) and cyclosporine, with a response rate of 60-80%. The median time to response is 6 mo. As many as 25-30% of “responders” experience relapse after discontinuation of immunosuppression, and some patients must continue cyclosporine for several years to maintain a hematologic response. Among those who have relapse after immunosuppression, about 50% show response to a second course of ATG and cyclosporine. There is an increased risk of clonal bone marrow disease, such as leukemia, myelodysplasia (MDS), or PNH after immunosuppression. The exact risk of clonal disease after immunosuppression is probably <10%, and the abnormal karyotypes most frequently involve chromosomes 6, 7, and 8. To accelerate neutrophil recovery, a hematopoietic colony-stimulating factor (e.g., granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor) is sometimes added to ATG and cyclosporine for treatment of patients with very severe neutropenia (absolute neutrophil count <200/mm³), but there is no clear evidence that this treatment influences response rate or survival. In a few cases, tacrolimus has been given successfully with ATG for treatment of aplastic anemia in a patient unable to tolerate cyclosporine.

For patients who show no response to immunosuppression or who experience relapse after immunosuppression, matched unrelated donor marrow/stem cell transplant is a treatment option, with a response rate approaching 80% in later studies. Cord blood transplants have rarely lead to successful outcomes because of problems with non-engraftment. High-dose cyclophosphamide has been used successfully in the treatment of patients with newly diagnosed aplastic anemia and in patients without adequate response to immunosuppression. This therapy leads to prolonged severe pancytopenia, increasing the risk of life-threatening infection, especially fungal. Other therapies that have been used in the past with inconsistent results include androgens, corticosteroids, and plasmapheresis.

Complications

The major complications of severe pancytopenia are predominantly related to the risk of life-threatening bleeding from prolonged thrombocytopenia or to infection secondary to protracted neutropenia. Patients with protracted neutropenia due to bone marrow failure are at risk not only for serious bacterial infections but also for invasive mycoses. The general principles of supportive care that have evolved from the use of chemotherapy-related myelosuppression to treat patients with cancer should be fully extended to the care of patients with acquired pancytopenia (Chapter 171).

Prognosis

Spontaneous recovery from pancytopenia rarely occurs. If left untreated, severe pancytopenia has an overall mortality rate of approximately 50% within 6 mo of diagnosis and of >75% overall, with infection and hemorrhage being the major causes of morbidity and mortality. The majority of children with acquired severe aplastic anemia show response to allogeneic marrow transplantation or immunosuppression, leaving them with normal or near-normal blood cell counts.

Pancytopenia Caused by Marrow Replacement

Processes that either infiltrate or replace the bone marrow can manifest as acquired pancytopenia. Infiltration can be caused by malignancy (classically, neuroblastoma or leukemia) or occur as a consequence of myelofibrosis, MDS, or osteoporosis. Although uncommon, evidence of hypoplastic anemia can precede the onset of acute leukemia, generally by a few months. This relationship is important to appreciate in evaluating and monitoring children who present with what appears to be acquired aplastic anemia. Morphologic examination of the peripheral blood and bone marrow and marrow cytogenetic studies are critically important in making the diagnoses of leukemia, myelofibrosis, and MDS.

MDS is very rare in children, but when it occurs, its clinical course is more aggressive than the same category of MDS in adults. A number of inherited conditions are associated with an increased risk for development of MDS, including Down syndrome, Kostmann syndrome, Noonan syndrome, Fanconi anemia, trisomy 8 mosaicism, neurofibromatosis, and Schwachman syndrome. Significant clonal abnormalities are found within the marrow of approximately 50% of patients with MDS, with monosomy 7 and trisomy 8 being most common. The transition time from pediatric MDS to acute leukemia is relatively short, at 14-26 mo, so aggressive treatment, such as BMT, must be considered shortly after diagnosis. With allogeneic BMT, the survival rate is approximately 50%. One exception to such an aggressive therapeutic approach is MDS and acute myelocytic leukemia in children with Down syndrome, because this disease in this specific population is very responsive to conventional chemotherapy, with long-term survival rates >80%.

The decision on how to treat a child with MDS who lacks a suitable marrow donor should be made with the specific clonal abnormality found within the child’s marrow taken into consideration. Lenalidomide produces the best responses among patients who have the chromosomal abnormality, 5q−. Immunosuppressive therapy with ATG and cyclosporine is most effective in patients with trisomy 8, especially in the presence of a PNH clone. Imatinib mesylate targets mutations in the tyrosine kinase receptor family of genes found in patients with t(5;12) and del(4q12). The DNA hypomethylating agents azacitidine and decitabine have also been used in treating MDS without a known molecular target and have some effect.