Ramon V. Tiu, MD | Aplastic Anemia and MDS International Foundation

Ramon V. Tiu, MD

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LFA-3/CD2 Pathway: Potential Target for Immunosuppressive Therapy in Aplastic Anemia
Original Research Center: 
Cleveland Clinic Lerner Research Institute
Pubmed Author Name: 
Tiu, RV
Current Position/Title: 
Assistant Professor of Molecular Medicine
2010
Final Report: 

Aplastic Anemia is a rare bone marrow failure disease that can affect both young and adult patients. Patients with this disease have an empty bone marrow and have low blood counts. The low blood count puts the patients at risk for infections and frequently necessitates the need for transfusions with blood products. The disease can develop from unknown causes (idiopathic) or can be due to drugs, toxins, chemotherapy (acquired). Idiopathic aplastic anemia is caused primarily by an abnormal immune system. Hematopoietic bone marrow transplant is a potential cure for idiopathic aplastic anemia patients. However, not all aplastic anemia patients can undergo hematopoietic bone marrow transplant. Drugs that suppress the immune system are the main treatment for patients with aplastic anemia who lack suitable donors or ineligible for bone marrow transplant. Horse Antithymocyte globulin (ATG) is the best first treatment for newly diagnosed severe aplastic anemia patients who are not candidates for transplant. However, some patients with aplastic anemia treated with ATG do not respond (refractory aplastic anemia) and others have an initial response but lose it again (relapsed aplastic anemia). Understanding this problem in treating aplastic anemia patients, we wanted to explore alternative immunosuppressive therapies for the treatment of patients with relapsed/refractory aplastic anemia.

Alefacept is a novel immunosuppressive agent that targets the CD2-LFA3 pathway.  The CD2-LFA3 pathway is important in the function of T lymphocytes, cells that play important roles in immunity and are thought to contribute to disease in aplastic anemia. This Phase I/II study was fully approved by the Institutional Review Board of the Cleveland Clinic and conducted in patients with relapsed/refractory aplastic anemia.

A total of four patients were successfully enrolled in this trial. All four patients had refractory aplastic anemia. None of the patients had a PNH clone at presentation. Improvements in blood counts were noted in three out of the four patients. Side effects were very mild and included cough, sore throat, and nasal congestion in one patient and mild muscle aches in a second. All side effects were temporary and disappeared after 2 weeks of treatment.  No severe side effects were reported. To date, three out of four patients who achieved improvements in blood counts continue to not require blood transfusions or any other immunosuppressive therapies such as cyclosporine. All four patients have not developed a PNH clone. In December 2011, Astellas Pharma US announced that the company has voluntarily discontinued the promotion, manufacturing, distribution and sales of alefacept because of business needs but not related to safety issues.  In conclusion, targeting CD2-LFA-3 pathway using alefacept is a safe option for treating patients with relapsed/refractory aplastic anemia.

Current Institution: 
Cleveland Clinic Lerner Research Institute

Ramon Tiu is an Assistant Professor of Molecular Medicine at Cleveland Clinic Lerner College of Medicine of Case Western Reserve University and is associate staff in the Department of Translational Hematology and Oncology Research and Department of Hematologic Oncology and Blood Disorders at Cleveland Clinic. He completed his medical school training at the University of Santo Tomas Faculty of Medicine and Surgery in the Philippines and subsequently pursued internal medicine training at Cleveland Clinic from 2003-2006. He pursued further research training in experimental hematology as a bone marrow failure research fellow at Cleveland Clinic under the tutelage of Dr. Jaroslaw P. Maciejewski, which he continued throughout his fellowship training in hematology and oncology at the same institution. He is well published in the area of single nucleotide polymorphism arrays, especially in their clinical application in myeloid malignancies like myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). He is a young investigator awardee from the MDS Foundation and the Aplastic Anemia and MDS International Foundation and a prior recipient of a T32 research award from Case Western Reserve University. He is involved in both clinical and translational research, focusing mainly on the field of myeloproliferative neoplasms and bone marrow failure syndromes. His laboratory research team recently identified a gene called SF3B1 to be frequently mutated in cases of MDS with ring sideroblasts, specifically refractory anemia with ring sideroblasts (RARS) and RARS associated with marked thrombocytosis (RARS-T). SF3B1 is a gene involved in an important physiologic post-transcriptional process called splicing. This is an unprecedented finding, as this is the first time that the spliceosome machinery has been implicated as a possible cause in blood cancers, particularly in MDS. Recently, his research team showed the first experimental evidence linking SF3B1 dysfunction and the formation of ring sideroblast in MDS. He is also very active in conducting clinical trials in bone marrow failure syndromes and myeloproliferative neoplasms (MPNs) and an active clinician seeing patients with MDS, MDS/MPN overlap syndromes, MPNs and rare bone marrow failure conditions like Aplastic Anemia, PNH and LGL leukemia. He is board certified in Internal Medicine, Hematology and Oncology.