Dr. Abdullah Kutlar is a Professor of Medicine in the Division of Hematology/Oncology and Stem Cell Transplantation and an Associate Professor in the College of Graduate Studies and serves as the Director of the MCG Sickle Cell Center.
Dr. Kutlar earned his MD degree from Ankara University Medical School, Ankara, Turkey, in 1971. Following residency and fellowship training in hematology, he focused primarily on red cell disorders including thalassemia and sickle cell disease. He also served as a Research Fellow at the Sickle Cell Center at the Georgia Health Sciences University, in 1982-1983. He returned to the Sickle Cell Center in Augusta in 1984 where he worked in the research laboratories until 1990 under the directorship of the late Professor Titus H.J. Huisman.
Because of his expertise and training, Dr. Kutlar was named Director of the Sickle Cell Center In 1994. Under his leadership, the Sickle Cell Center Laboratory has served as a core lab for NIH and pharmaceutical sponsored clinical trials as well as a clinical site for many multicenter, national, and international studies of sickle cell disease.
Dr. Kutlar has served on several NIH review panels, served as a member of DSMB, and serves on the Steering Committee of the Candidate-gene Association Resource (CARE) program of the NHLBI. Dr. Kutlar’s research interest in recent years has been in the area of genetic modifiers of SCD and the elucidation of risk factors for various complications. He is also interested in the development of novel therapies and evidence-based recommendations for the treatment of SCD.
Abstract
SICKLE CELL DISEASE: Lessons Learnt from Clinical Trials
The last three decades have witnessed a tremendous progress in our understanding of mechanisms contributing to the pathogenesis of sickle cell disease (SCD). This has led to advances in therapeutic approaches, especially in developed countries, with significant improvement in life expectancy to around the mid 50s. Despite this progress, huge global challenges remain: cure remains elusive; significant challenges to public health, especially in the developing world; health disparity, even in developed Western countries.
Progress in deciphering the mechanisms involved in the pathology of SCD has changed our understanding. The disease is no longer thought of as a process characterized by episodic microvascular occlusion leading to acute complications between which the affected individuals have a so called “steady state,” a state of relative normalcy. Rather, we now think of SCD as a chronic illness with an ongoing inflammatory state and chronic hemolysis punctuated by episodes of acute complications with heightened inflammation and microvascular occlusion ultimately leading to chronic organ damage, significant morbidity, and early mortality. Such an understanding requires a paradigm shift in our approach to therapy with emphasis changing from interventions aimed at acute symptomatic relief to disease modifying modalities. A major area of intense research has focused on unraveling the basis of phenotypic/clinical heterogeneity of SCD. Beyond the well known genetic modifiers (high Hb F, co-existing α-thalassemia), during the past decade of the human genome era, a large number of studies have tried to decipher the non-globin genetic modifiers of SCD. While some interesting results have emerged from candidate gene approaches and more recently from genome wide association studies, this field is still in its infancy.
In terms of therapy, with the exception of stem cell transplantation (limited availability) and gene therapy trials (very early stages), there are no available curative strategies. Thus, disease modifying approaches will form the mainstay of treatment for the foreseeable future. Foremost among these are anti-switching (Hb F inducing) therapies. Hydroxyurea (HU) has proven to be an effective treatment modality for the majority of patients with SCD. Recent trials of IMIDs, histone deacetylase (HDAC) inhibitors, and DMT1 (DNA methyl transferase 1) inhibitors appear promising. Approaches targeting downstream effects of “sickling” (RBC cation loss and dehydration, cell adhesion, inflammation, hemolysis) may be important; however, lessons from clinical trials in the past decade suggest that efficacy as single agents may be very limited and may best be used in conjunction with anti-switching therapies. It should also be noted that targeting “pain” as an endpoint in SCD clinical trials has proven risky. Similarly, composite endpoints should best be avoided in the design of such trials.