Treatment of Aplastic Anemia MGR Review Treatment of Aplastic Anemia Department of Hemato-Oncology R4 손주웅/Prof. 윤휘중

Definition A disorder of hematopoiesis characterized by pancytopenia A marked reduction or depletion of erythroid, granulocytic, and megakaryocytic cells in bone marrow

Epidemiology Europe and Israel Thailand and China Two cases per million persons annually Thailand and China Five to seven cases per million persons annually Age distribution is biphasic first peak in the teens and twenties and second rise in the elderly

Etiology

Pathophysiology Immune-mediated injury Respond to immunosuppressive therapy 50~60% of syngeneic grafts fail to engraft Achieve hematologic reconstitution if adquate immunosuppression is given before a second transplant

Pathophysiology

Clinical features Progressive weakness, fatigue, headaches, dyspnea on exertion, petechia, ecchymoses, epistaxis, metrorrhagia, gum bleeding Caused by anemia and thrombocytopenia Infection is an unusual first symptom Prior drug use, chemical exposure, preceding viral illness

Laboratory studies Blood Bone marrow Large erythrocytes Paucity of platelets and granulocytes MCV is commonly increased Reticulocyte are absent or few Bone marrow Hypocellular with a decrease in all elements Fatty biopsy specimen Infiltration of the bone marrow with malignant cells or fibrosis is not present Hematopoietic cells occupying < 25% of the marrow space

Determination of severity Moderate aplastic anemia Bone marrow cellularity < 30% Absence of severe pancytopenia Depression of at least two of three blood elements Severe aplastic anemia : at least two of the following Granulocyte < 500/uL Platelet < 20,000/uL Corrected reticulocyte count < 1% Very severe aplastic anemia Severe aplastic anemia with granulocyte < 200/uL

Treatment three different treatment strategies, based on the level of cytopenia moderate cytopenia, not requiring transfusions Supportive care or outpatient treatment with anabolic steroids and/or low-dose steroids or cyclosporine Severe aplastic anemia either IST or BMT severity of the disease and patient age

Immunosuppressive treatment Antithymocyte globulin (ATG) Superior survival compared with supportive care The probability of becoming transfusion independent vary from 40% to 80% according to the IST regimen and the patient population Median time to achieve a response is 120 days Combinations with Cyclosporin A Improve the overall response rates

Cyclosporin dependence and relapse Current IST regimens including CsA for 6 months CsA is tapered, and it is unclear exactly when and how fast this should be done the Italian pediatric group it is safe to start taper CsA at 12 months of treatment (rather than 6 months) taper should be very slow (less than 10% of the dose/month) for at least 1 year, to minimize the risk of relapse

Growth factors The potential advantages of using G-CSF Disadvantages faster neutrophil recovery early identification of non-responders early referral for BMT Disadvantages expensive apparently does not improve survival at 3 years increased risk of clonal disorders

Relapse The risk of relapse after ATG is around 35% In some cases associated with cyclosporin withdrawal sometimes respond to re-introduction of cyclosporin If not, a second course of ATG would be appropriate

Algorithms for treatment of acquired aplastic anemia

Allogeneic hematopoietic stem cell transplantation Most effective therapy Usefulness declines with age because of fatal complications the International Bone Marrow Transplant Registry showed 77% 5-year survival children and patients who were minimally transfused, survival of 80–90% may be routinely achieved Acute grade II–IV GVHD occurs in about 20–30% chronic GVHD in 30–40%

The Treatment of Severe Acquired Aplastic Anemia Blood, Vol 85, No 12 (June 15). 1995: pp 3367-3377

Matched unrelated donor transplant the outcome for an unrelated donor HSCT remains less favorable compared with a matched-related transplant due to more GVHD mortality rate that is about twice that observed in matched sibling transplants long term survival of about 50% A multicenter prospective study compared the outcomes of a second course of IST to a MUD HSCT MUD HSCT had a higher failure free survival no difference in overall survival

Current concepts in the pathophysiology and treatment of aplastic anemia BLOOD, 15 OCTOBER 2006 VOLUME 108, NUMBER 8

Allogeneic Stem Cell Transplantation for Aplastic Anemia Biology of Blood and Marrow Transplantation 13:505-516 (2007)