What is myelodysplastic syndrome?
Historically, the myelodysplastic syndromes (MDS) have been referred to as oligoblastic leukemia, refractory anemia, smoldering acute leukemia, or preleukemia. They represent a heterogeneous hematopoietic disorder derived from an abnormal multipotent progenitor cell, and are characterized by a hyperproliferative bone marrow, dysplasia of the cellular elements, and ineffective hematopoiesis.
MDS can be indolent or aggressive, depending on the subclassification (discussed below). Recognition of this entity has increased over the past decade, and should be suspected in older adults with anemia, thrombocytopenia, leukopenia, or a combination of these abnormalities. Not surprisingly, morbidity and mortality result from anemia, bleeding, and infection, along with transformation to acute myelogenous leukemia (AML), which occurs in approximately one-third of patients.
MDS can be cured with bone marrow transplantation, a procedure prohibitively toxic in older patients with this diagnosis, and estimated to be available for only 5-10% of MDS patients. Thus, most treatments focus on alleviation of symptoms, reduction in transfusion requirements, and improvement of quality of life.
Signs and Symptoms
MDS often presents as a refractory cytopenia in an older adult who may be entirely asymptomatic. A macrocytic or normocytic anemia is found in nearly all MDS patients, and frequently is accompanied by thrombocytopenia, leukopenia, or both. Typical symptoms reflect underlying cytopenias: patients with anemia frequently complain of fatigue, shortness of breath, loss of appetite, and even exacerbation of underlying cardiac symptoms; patients with thrombocytopenia may have spontaneous bruising, the appearance of petechiae (particularly in dependent areas, such as the shins, or in areas exposed to minor trauma, such as skin under elastic waistbands), or bleeding of mucosal surfaces (including the gums when brushing teeth); and patients with leukopenia may have recurrent infections, particularly of the skin, mucosal surfaces (especially the oral and rectal mucosa), and lungs.
MDS can be associated with paraneoplastic syndromes related to autoimmune processes. These may be dermatologic (psoriasis or Sweet's syndrome); rheumatologic (vasculitis); hematologic (hemolytic anemia or Glanzmann's disease [an acquired glycoprotein IIB/IIIA inhibition resulting in abnormal platelet function); or endocrinologic (hypothyroidism, diabetes insipidus). In addition, a subset of MDS, chronic myelomonocytic leukemia, which actually represents an overlap syndrome with myeloproliferative disorders, may cause splenomegaly and subsequent complaints of left upper-quadrant abdominal pain and early satiety. Cytokine release (see Pathophysiology section, above) may result in constitutional symptoms, such as anorexia, weight loss, and even low-grade fevers.
Options for treatment of MDS range from supportive care (which includes blood product transfusions and the use of growth factors) to intensive therapy with allogeneic hematopoietic stem cell transplantation.
Allogeneic hematopoietic stem cell transplantation, the only potentially curative approach to MDS, is a realistic option for only about 5-10% of patients because MDS is diagnosed most commonly in patients in their seventh or eighth decade of life. Conditioning regimens typically consist of busulfan (Myleran) and cyclophosphamide (Cytoxan), and long-term (often 2-year) disease-free survival approaches 40%, although studies often include young MDS patients (with a median age between 30 and 45 years) with earlier stages of MDS. Treatment-related mortality may be as high as 40% to 50%. Newer approaches take advantage of non-myeloablative ("mini") conditioning regimens in an effort to reduce treatment-related mortality and to include older patients with MDS. This type of transplantation is still considered experimental, but can be offered to patients up to 70 years of age who otherwise are in good health.
Less-intensive (midrange) therapeutic options for patients with indolent MDS include the use of thalidomide (Thalomid), arsenic trioxide (Trisnox), amifostine (Ethyol), or immunosuppressive therapy. Thalidomide, whose effects may be mediated through inhibition of TNF-a, TGF-ß, and a decrease in microvessel density, appears to be more effective in patients without excess myeloblasts, in whom the response rate (defined as hematologic improvement and/or improvement in blood product transfusion requirements) may be as high as 31%. Many patients are intolerant of the medication's side effects, which include gastrointestinal toxicity (particularly constipation), somnolence, and neurotoxicity. A Thalidomide derivative, lenalidomide (Revlimid) has been investigated in two large Phase II trials in patients with the 5q- syndrome and in patients with non-5q- low-grade MDS. In a Phase I/II trial, 10/12 patients with the 5q- syndrome experienced complete responses, including cytogenetic remissions.
Arsenic trioxide works through both pro-differentiation and pro-apoptotic mechanisms, and as a single agent can yield response rates (defined as improvement in hematologic parameters) of 20-25%. This drug can also be used in patients with advanced MDS. Amifostine promotes the growth of hematopoietic cells, and in a phase II study, 30% of patients achieved a single or multilineage hematologic response. Symptoms of fatigue and gastrointestinal toxicity were experienced at higher drug doses. Immunosuppressive therapy (which includes the use of antithymocyte globulin (ATG, Atgam) and cyclosporine A (Neoral, Sandimmune)) takes advantage of the immune-mediated aspects of MDS and may be effective in the subset of patients with hypoplastic MDS—MDS that resembles aplastic anemia, with a hypocellular bone marrow. Improved hematologic counts and transfusion independence may be achieved in up to 33% of appropriately treated patients.
Another midrange therapy, 5-azacytidine (5-aza, azacitidine, Vidaza), deserves mention. This hypomethylating agent induces hematopoietic progenitor cell differentiation. In a recent phase III trial, responses occurred in 60% of patients treated with 5-aza compared with 5% of patients receiving supportive care, including 23% complete or partial remissions. Median survival, transformation to AML, and even quality of life was better for patients receiving 5-aza than for those receiving supportive care. This drug is the only one approved for the treatment of MDS. Though approved for all MDS subtypes (in the Summer of 2004), it is most effective in patients with advanced MDS. A similar class of drug, decitabine, has been investigated in a multi-center phase III study.
Patients with more indolent forms of MDS (without excess myeloblasts) who may be dependent on blood product transfusions may derive some benefit from the use of growth factors. Often, G-CSF (Filgrastim) or GM-CSF (Sargramostim) is combined with recombinant human erythropoietin (rHuEPO, Procrit or Epogen). One recent study demonstrated a response rate of 48% in MDS patients with use of a combined growth factor approach. Typical response rates, across a number of studies, are in the 15-20% range. Growth factor agents do need to be administered over a protracted period of time to maintain the cellular response. The National Comprehensive Cancer Network, which develops disease-specific clinical practice guidelines, recommends use of combination growth factor agents in low-risk MDS patients (with serum erythropoietin levels <500 U/L) as frequently as five times per week. In our experience, patients with serum erythropoietin levels <100 U/L tend to benefit from the use of growth factors, while those with levels >500 U/L do not. Darbepoetin alfa (Aranesp) is not recommended for the treatment of patients with MDS outside of the setting of a clinical trial.