ABSTRACT: The bone marrow failure states, aplastic anemia and myelodysplastic syndrome, are characterized by reticulocytopenic anemia, with variable neutropenia and thrombocytopenia. The bone marrow biopsy is very hypocellular in aplastic anemia, but it is usually hypercellular in myelodysplastic syndrome. Marrow cytogenetic abnormalities are present in approximately half of myelodysplastic syndrome patients but are absent in aplastic anemia. Allogeneic bone marrow transplantation is the treatment of choice for young patients with severe aplastic anemia. Immunosuppressive therapy with antithymocyte globulin (ATG) and cyclosporine is used when transplantation is not the initial therapeutic choice; it induces responses in 65% to 80% of patients. Treatment of myelodysplastic syndrome is dependent upon risk classification, and patient age and performance status. Allogeneic stem cell transplantation should be considered for younger myelodysplastic syndrome patients. An acute myelogenous leukemia (AML) type of induction chemotherapy may benefit high-risk patients with a good performance status for whom allogeneic transplantation is not an option. Patients achieving a complete remission to induction chemotherapy may be considered for autologous stem cell transplantation. However, aggressive therapy is an option for only a minority of myelodysplastic syndrome patients; most receive supportive care. Anemia, and its related symptoms, is the principal problem for most myelodysplastic syndrome patients. Erythropoietin administration ameliorates anemia in a minority of myelodysplastic syndrome patients. A wide variety of novel experimental approaches including immunosuppressive therapy, angiogenesis inhibitors, platelet growth factors, and demethylating agents are now under investigation for myelodysplastic syndrome. [ONCOLOGY 16(Suppl 10):153-161, 2002]
Aplastic anemia and myelodysplastic syndrome are sometimes grouped together as "bone marrow failure states." Although patients with these disorders all have one or more peripheral blood cytopenias, aplastic anemia and myelodysplastic syndrome are distinguished by epidemiology, natural history, bone marrow histopathology, and response to therapy.
Acquired aplastic anemia does not preferentially afflict any age group. Patients typically present with one or more symptoms related to pancytopenia. These may include fevers and chills, fatigue, dyspnea on exertion, mucosal bleeding, or petechial rash.
The peripheral blood counts usually are severely reduced, and the bone marrow biopsy is severely hypocellular. The remaining marrow elements usually consist of lymphocytes and plasma cells. Hypocellular myelodysplastic syndrome and hypocellular acute myeloid leukemia (AML) are excluded by performing flow cytometry and cytogenetics on the bone marrow. Increased numbers of myeloblasts or chromosomal abnormalities should not be observed in aplastic anemia.
In contrast to aplastic anemia, the incidence of myelodysplastic syndrome increases dramatically with age, and the majority of patients are elderly. They most commonly present with symptomatic anemia or incidentally noted peripheral blood abnormalities. Reticulocytopenic anemia is the most common laboratory abnormality; the red cells can be macrocytic, microcytic, or normocytic. Causes of megaloblastic anemia (vitamin B12 or folate deficiency) should be excluded when macrocytosis is present, and iron deficiency, anemia of chronic disease, or thalassemia minor should be considered in the setting of microcytosis.
Neutropenia and thrombocytopenia are variably present in myelodysplastic syndrome, but are more commonly associated with advanced disease. Thrombocytosis may occur in certain myelodysplastic syndrome subtypes, including those with an isolated 5q-cytogenetic abnormality or with increased numbers of ringed sideroblasts in the bone marrow.
The bone marrow biopsy is usually hypercellular for the patient’s age, although it is hypocellular in approximately 15% of cases. Erythroid dysplasia, including megaloblastic changes, binuclearity, or nuclear blebbing is a common feature of myelodysplastic syndrome. Ringed sideroblasts, abnormal erythroid precursors with iron-laden mitochondria ringing the nucleus, may be observed after Prussian blue staining.
Myeloid dysplasia may be characterized by increased numbers of immature forms (myeloid "left-shift"), or neutrophils with abnormal cytoplasmic granules or bilobed nuclei (pseudo-Pelger-Hut anomaly). Megakaryocytes may be abnormally small (micromegakaryocytes) or have abnormal nuclear morphology or ploidy. Increased numbers of bone marrow myeloblasts (> 5% of cellular elements) are present in more advanced myelo-dysplastic syndrome. Cytogenetics are abnormal in 50% to 60% of de novo cases of myelodysplastic syndrome and are useful in prognostication.
Although aplastic anemia and myelodysplastic syndrome are considered to be "bone marrow failure states" because of the defective production of mature peripheral blood cells, there are pathophysiologic differences between these two disorders.
The profound pancytopenia of aplastic anemia in association with the marked bone marrow hypocellularity suggests that there is a critical deficiency of hematopoietic progenitor cells. In most cases of acquired aplastic anemia, the hematopoietic progenitors are destroyed by autoreactive cytotoxic T lymphocytes. The trigger for this autoimmune process cannot be identified in approximately three-quarters of patients. Known causes of aplastic anemia include various medications, rheumatologic disorders, hepatitis, pregnancy, and exposure to benzene.
The concurrence of peripheral blood cytopenias and bone marrow hypercellularity with an increase in immature precursors in myelodysplastic syndrome suggests that there is defective production of mature functional cells. Increasing evidence suggests that the common mechanism governing this process is intramedullary apoptosis. Locally increased levels of tumor necrosis factor-alpha or Fas ligand may induce hematopoietic progenitors to "commit suicide" by altering the normal intracellular ratio of antiapoptotic and proapoptotic proteins.[2,3] Alternatively, cytotoxic T lymphocytes may directly induce apoptosis of the abnormal hematopoietic progenitors.
It has long been appreciated that a number of cytogenetic abnormalities (especially 5q-,7q- or -7, +8, or 20q-) are characteristically observed in myelodysplastic syndrome. The critical genes affected by these changes have not been identified, and therefore the mechanism of these cytogenetic defects on hematopoieis is unknown. The N-ras oncogene can be mutated in myelodysplastic syndrome, albeit infrequently, but this alteration may be of biological and clinical significance.
Patients with aplastic anemia are classified as having moderate, severe or very severe disease based on the number of lineages affected and the severity of the neutropenia (see Table 1). This classification is of prognostic significance for patients receiving medical therapy.[6,7] Bone marrow transplantation has typically been reserved for treatment of severe or very severe aplastic anemia.
The heterogeneity of myelodysplastic syndrome makes it a difficult disease to classify. The original French/American/British (FAB) classification was established to better characterize the morphologic features of myelodysplastic syndrome and to describe various subtypes. Subsequently, this classification (see Table 2) was found to have prognostic value. The prognostic scoring systems for myelodysplastic syndrome have been progressively refined.
The increasing availability of novel therapies for myelodysplastic syndrome requires accurate risk assessment for experimental subjects. One recent approach to improving prognostication in such patients is the World Health Organization (WHO) classification of myelodysplastic syndrome. This refinement of the FAB classification subdivides the low-risk subtypes (refractory anemia [RA] and refractory anemia with ringed sideroblasts [RARS]) into very-low-risk groups, which have dysplasia of only the red cell lineage, and a higher-risk group, called refractory cytopenia with trilineage dysplasia (see Table 3).
In addition, the 5q- syndrome was identified as a unique subset of refractory anemia with an excellent prognosis. The intermediate-risk group, refractory anemia with excess of blasts (RAEB), was stratified into lower- and higher-risk groups based on the percentage of bone marrow blasts. The highest-risk group, refractory anemia with excess of blasts in transformation (RAEB-t), was reclassified as AML because patients with 20% to 30% bone marrow blasts have outcomes that are similar to those with > 30% blasts. Chronic myelomonocytic leukemia (CMML) was reclassified as a myeloproliferative disorder that may or may not have associated dysplastic features. This proposal remains controversial and requires further validation.
A perhaps more widely embraced prognostic tool is the International Prognostic Scoring System (IPSS). This method assigns values to independent prognostic variables including percentage of bone marrow blasts, type of cytogenetic abnormality, and number of peripheral blood cytopenias, and generates a score that correlates with survival (see Tables 4 and 5). Many current clinical trials use this scoring system to establish enrollment criteria, or to stratify patients undergoing randomization.
Allogeneic Stem Cell Transplantation
The newly diagnosed aplastic anemia patient should be expeditiously assessed for the appropriateness of allogeneic stem cell transplantation and, if this is a suitable option, referred to a transplant center for treatment. Supportive care measures implemented prior to the transplant can significantly affect the outcome of the patient.
Unless there is an actively life-threatening requirement for transfusion of blood products, they should be absolutely minimized to prevent sensitization of the patient to alloantigens and minimize the risk of graft rejection. For the same reason, transfusion of blood products from family members must be prohibited.
All blood products should be seronegative for cytomegalovirus (CMV), leukocyte-reduced, and irradiated. The use of CMV-negative products should be continued unless the patient is seropositive for prior CMV exposure. Leukocyte reduction decreases the risk of allosensitization and decreases the risk of CMV transmission. Irradiation of blood products prevents the proliferation of alloreactive T lymphocytes that could potentially induce transfusion-related graft-vs-host disease (GVHD) in the patient posttransplant.
Allogeneic stem cell transplantation is appropriate as initial therapy for younger patients with severe aplastic anemia. Retrospective comparisons of allogeneic bone marrow transplantation (BMT) and immunosuppressive therapy for severe aplastic anemia have demonstrated a survival benefit of early transplantation in younger patients, although reports differ over whether age should be less than 20 years  or less than 40 years.
Transplantation remains appropriate initial therapy for older patients, especially if very severe disease is present or if the patient has not received prior transfusions. An alternative strategy is to administer immunosuppressive therapy first and reserve transplantation for patients who do not respond to treatment. Because immunosuppressive therapy takes several months to work, the principal risks of this approach relate to pancytopenia and allosensitization from the ongoing transfusion requirements.
The standard conditioning therapy prior to transplantation is cyclophosphamide (Cytoxan, Neosar) and antithymocyte globulin (ATG [Atgam]) for previously transfused patients, and cyclophosphamide alone for those who have not been transfused.[15,16] The survival following allogeneic BMT is 66% to 89% at 5 years.[16,17] Early risks of transplantation include graft failure (10%-15%), life-threatening (grade 3/4) acute GVHD (20%), and fatal infection or treatment-related organ failure (< 10%). Late risks include chronic GVHD (20%-40%) and late solid tumors (13%), especially squamous cell cancers.
Immunosuppression with ATG and cyclosporine (Neoral, Sandimmune) is well established as standard therapy for aplastic anemia. Concurrent treatment with both drugs is significantly more effective than use of either drug alone. The optimal duration of cyclosporine administration has not been evaluated systematically, but a minimum of 1 year of treatment, with gradual tapering over the subsequent year is recommended to minimize the risk of relapse. Renal function and transaminase levels should be monitored while patients are receiving cyclosporine and the drug dose should be adjusted if toxicity is observed.
The overall response to ATG/cyclosporine is 65% to 71% within 6 months of treatment. For patients achieving either a partial or complete response, survival is 57% after 10 years.[20-22] A randomized trial did not demonstrate a positive effect of granulocyte-colony stimulating factor (G-CSF, Neupogen), 5 µg/kg/d for 98 days, on the response rate or survival.
The major risk of immunosuppressive therapy is fatal infection or bleeding (approximately 10%) from the underlying disease while awaiting a response. Other risks include disease relapse (35%-41%) and the development of acute myeloid leukemia or of myelodysplastic syndrome (10%-15% at 10 years).[20,22,24] Paroxysmal nocturnal hemoglobinuria can also occur as a late complication of aplastic anemia. Recently, high-dose cyclophosphamide without stem cell transplantation has been reported as an effective alternative immunosuppressive regimen with a high response rate (73%) and low risk of relapse. However, preliminary data from a randomized trial comparing cyclophosphamide/cyclosporine to ATG/ cyclosporine found a higher rate of early death (20% vs 0%) for the cyclophosphamide group, but similar response rate (53% vs 81%) and relapse rate (25% vs 38%) for cyclophosphamide/cyclosporine compared to ATG/cyclosporine respectively. Therefore, cyclophosphamide should be used for routine treatment of aplastic anemia.
Relapsed aplastic anemia can respond to a second course of ATG/cyclosporine or cyclosporine alone. More than half of patients with relapsed aplastic anemia will respond to a second course of ATG. "Cyclosporine dependence," defined as relapse associated with cyclosporine withdrawal, is fairly common and indicates the need to taper the cyclosporine dose very slowly over to 1 to 2 years, if possible.
Other Therapeutic Options
Therapeutic options for aplastic anemia that does not respond to an initial course of immunosuppression include unrelated donor stem cell transplantation or a second course of ATG. Because the survival following an unrelated transplant is best for patients who are transplanted within 1 year of diagnosis, the decision regarding this treatment is best made early.
Conditioning therapy requires total body irradiation in addition to cyclophosphamide/ATG in order to minimize the risk of graft rejection. Improved survival 2 years after unrelated BMT has been reported for patients ≤ 20 years old (67%) compared to those > 20 years (43%) and for patients transplanted ≤ 1 year from diagnosis (73%), compared to 1 to 3 years (53%) or > 3 years (39%) after diagnosis.
Single institutions have reported high response rates using horse ATG (64%) or rabbit ATG (77%) in patients who have not responded to an initial course of standard immunosuppressive therapy, but these numbers are perhaps double the results usually reported.[28,29] Nevertheless, a second course of ATG should be considered if no response is observed within 6 to 8 months after the initial treatment.
Prolonged cyclosporine administration as a single agent is occasionally effective. Hematopoietic growth factors, especially stem cell factor in combination with G-CSF, have induced trilineage responses in occasional refractory patients. Chronic administration of a myeloid growth factor may be considered in patients with severe aplastic anemia and recurrent infections. A retrospective analysis showed no significantly increased risk of clonal hematologic disorders (myelodysplastic syndrome or AML) associated with G-CSF given for a median of 6 months.
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