The myelodysplastic syndromes (MDS) consist of a heterogeneous spectrum of myeloid clonal hemopathies. The Revised International Prognostic Scoring System (IPSS-R) provides a recently refined method for clinically evaluating the prognosis of patients with MDS. Molecular profiling has recently generated extensive data describing critical hematopoietic molecular and biologic derangements contributing to clinical phenotypes. Current molecular insights have demonstrated roles of specific somatic gene mutations in the development and clinical outcomes of MDS, including their propensity to progress to more aggressive stages, such as acute myeloid leukemia. This article focuses on these recently reported clinical and underlying pathogenetic findings. The discussion provides a synthesis of the prognostic clinical, molecular, and biologic abnormalities intrinsic to the aberrant marrow hematopoietic and microenvironmental influences in MDS.
Peter L. Greenberg
Chronic red blood cell transfusion support in patients with myelodysplastic syndromes (MDS) is often necessary but may cause hemosiderosis and its consequences. The pathophysiologic effects of iron overload relate to increased non-transferrin bound iron generating toxic oxygen free radicals. Studies in patients with MDS and thalassemia major have shown adverse clinical effects of chronic iron overload on cardiac function in patients who underwent polytransfusion. Iron chelation therapy in patients with thalassemia who were effectively chelated has prevented or partially reversed some of these consequences. A small group of patients with MDS who had undergone effective subcutaneous desferrioxamine (DFO) chelation for 1 to 4 years showed substantial hematologic improvements, including transfusion independence. However, because chronic lengthy subcutaneous infusions of DFO in elderly patients have logistic difficulties, this chelation therapy is generally instituted late in the clinical course. Two oral iron chelators, deferiprone (L1) and deferasirox (ICL670), provide potentially useful treatment for iron overload. This article reviews data indicating that both agents are relatively well tolerated, were at least as effective as DFO for decreasing iron burdens in comparative thalassemia trials, and (for deferiprone) were associated with improved cardiac outcomes. These outcomes could potentially alter the tissue siderosis-associated morbidity of patients with MDS, particularly those with pre-existing cardiac disease.
Rafael Bejar and Peter L. Greenberg
Jason Gotlib and Peter L. Greenberg
Levels of treatment for patients with myelodysplastic syndromes (MDS) fall within 3 broad categories: supportive care, low- and high-intensity therapy. Most approaches remain experimental, and supportive care remains the standard of treatment in MDS. In parallel with the growing knowledge of the multiple pathobiologic abnormalities in MDS, increasing numbers of low-intensity, biospecific agents that target these pathogenetic lesions have entered clinical trial testing. Although the term “biospecific” has been applied to many of these investigational drugs, they often exert pleiotropic effects, many of which remain to be identified. An ongoing challenge will be to more fully characterize the mechanisms of action of these drugs and to characterize biologic correlates of response. With these data in hand, it will be increasingly feasible to treat patients with combinations of biospecific drugs with non-overlapping actions and toxicities, a therapeutic approach that is likely required to effectively overcome the barriers posed by the biologic heterogeneity of MDS. This review focuses on recent therapeutic approaches using such biologic response modifiers to treat MDS.
Brady L. Stein, Susan O’Brien, Peter Greenberg and Ruben A. Mesa
Peter L. Greenberg, Leon E. Cosler, Salvatore A. Ferro and Gary H. Lyman
Guidelines for management of patients with myelodysplastic syndromes (MDS) have been generated by the National Comprehensive Cancer Network (NCCN) Myelodysplastic Syndromes Panel. Because MDS is a heterogeneous spectrum of disorders, these patients have been categorized into prognostic subgroups, predominantly using the International Prognostic Scoring System (IPSS). Several drugs have been used to treat these patients, and their selection and sequential recommended use by the panel depend on disease characteristics and responses to treatment. Recombinant erythropoietin alfa and darbepoetin alfa have been the mainstay of therapy for treating anemia associated with MDS. The FDA has recently approved several other drugs for treating MDS, including azacytidine and decitabine for all stages of disease, lenalidomide for low-risk anemic patients with del(5q) chromosomal abnormality, and deferasirox for treating iron overload. For iron chelation, deferoxamine is also used occasionally. Treatment with immunosuppressive therapy (antithymocyte globulin and cyclosporin) has been therapeutically beneficial for a subset of younger patients with MDS. Because the financial cost of these therapies are substantial and have received only limited attention, this article evaluates the costs of specific drugs and their sequential use in the lower-risk IPSS (low and intermediate-1) subgroups based on the NCCN guidelines. Results estimate an average annual cost for potentially anemia-altering drugs of $63,577 per patient, ranging from $26,000 to $95,000, depending on the specific therapies. In patients for whom the therapies fail, annual costs for iron chelation plus red blood cell transfusions are estimated to average $41,412. The economic impact of drug therapy should be weighed against the patient's potential for improvement in clinical outcomes, quality of life, and transfusion requirements.
Philippe E. Spiess, Simon Horenblas, Lance C. Pagliaro, Matthew C. Biagioli, Juanita Crook, Peter E. Clark, Richard E. Greenberg and Cesar E. Ercole
This review highlights the significant advances made in the diagnosis and management of penile cancer. This often-aggressive tumor phenotype has been characterized by its poor prognosis, mostly attributable to its late presentation and heterogeneity of surgical care because of the paucity of cases treated at most centers. Recent advances in understanding of the risk factors predisposing to penile cancer, including its association with the human papilloma virus (HPV), have brought forth the socioepidemiologic concept of HPV vaccination in certain high-risk populations and countries, which remains highly debated. The management of penile cancer has evolved in recent years with the adoption of penile-sparing and minimally invasive surgical approaches to the inguinal lymph nodes, which are a frequent site of regional spread for this malignancy. Lastly, this review highlights the importance of adopting a multimodal approach consisting of neoadjuvant systemic chemotherapy followed by consolidative surgical resection in patients presenting with bulky/locally advanced nodal metastases from penile cancer.
Peter L. Greenberg, Cynthia K. Rigsby, Richard M. Stone, H. Joachim Deeg, Steven D. Gore, Michael M. Millenson, Stephen D. Nimer, Margaret R. O'Donnell, Paul J. Shami and Rashmi Kumar
The National Comprehensive Cancer Network (NCCN) convened a multidisciplinary task force to critically review the evidence for iron chelation and the rationale for treatment of transfusional iron overload in patients with myelodysplastic syndromes (MDS). The task force was charged with addressing issues related to tissue iron toxicity; the role of MRI in assessing iron overload; the rationale and role of treating transfusional iron overload in patients with MDS; and the impact of iron overload on bone marrow transplantation. This report summarizes the background data and ensuing discussion from the NCCN Task Force meeting on transfusional iron overload in MDS.