Abstract
An 80-year old gentleman with very severe aplastic anemia was treated with standard combination therapy of equine antithymocyte globulin and cyclosporine A. His death shortly after treatment could be attributed to his advanced age, severe pancytopenia at diagnosis, absence of minor paroxysmal nocturnal hemoglobinuria clone and immunosuppressive therapy-related complications.
Introduction
Aplastic anemia (AA) is an acquired bone marrow failure syndrome characterised by fatty replacement and diminished production of haematopoietic precursor stem cells of the bone marrow. Immune-mediated destruction of hematopoietic stem cell precursors in AA is triggered by the activated cytotoxic T-cells which express a variety of inhibitory cytokines such as interferon-gamma through the Fas-dependent apoptosis pathway1. AA demonstrates a bimodal age distribution in which, it occurs most frequently in those aged between 20-30 and over 602. AA has an annual incidence of 2 per 1,000,000 population in the West but it is higher in Asia2. The common causes for aplastic anemia are exposure to toxic chemicals such as benzene, certain drugs such as chloramphenicol, ionizing radiation, history of cytotoxic chemotherapy, viral infections and autoimmune diseases3. Most AA diagnosed in the elderly are idiopathic and they do not exhibit any underlying secondary etiology4. Age over 60 years is an important independent risk factor for mortality in AA4. One should consider other possibilities such as hypoplastic myelodysplastic syndrome(h-MDS), paroxysmal nocturnal hemoglobinuria (PNH), nutritional deficiency, late onset telomeropathy and delayed onset inherited bone marrow failure syndromes when diagnosing AA in the elderly. Here, we describe a case of idiopathic very severe aplastic anemia in an 80-year old male who was treated with standard first line therapy but subsequently succumbed to severe infection.
Case presentation
An 80-year-old Chinese gentleman with no known prior medical illness presented to the department of hematology with lethargy, reduced effort tolerance, easy bruising, anorexia, and loss of weight for the past 6 weeks. He has no significant family history. He is a non-smoker, a teetotaler and does not consume any recreational or therapy-related drugs. He worked as a bank clerk previously. He is married with 5 children, whom are all healthy.
On examination, he was alert with a body weight of 75 kilogrammes. He demonstrated a Charlson comorbidity index (CCI) score of 4 (low risk) with an Eastern Cooperative Oncology group (ECOG) performance status of 0 (fully active). His blood pressure was 140/70 with a pulse rate of 96 beats per minute. He was afebrile. Visible cutaneous bruising was evident. His cardiovascular and respiratory system examinations were unremarkable. There was no palpable organomegaly or lymphadenopathy.
A complete blood count revealed severe pancytopenia. The blood parameters are tabulated in Table 1.
The peripheral blood film revealed erythrocyte anisopoikilocytosis and severe pancytopenia. The bone marrow aspiration (Figure 1A) was aparticulate and markedly hypocellular. No abnormal cells were seen. The bone marrow trephine biopsy (Figure 1B) revealed a hypocellular marrow which was replaced mainly with non-hematopoietic tissue such as fat. Flow cytometry analysis did not show any evidence of leukemia. Cytogenetic studies using Giemsa banding technique revealed -Y and trisomy 8 abnormalities. Multiparameter flow cytometry and Fluorescent aerolysin (FLAER) of erythrocytes, polymorphonuclear neutrophils and monocytes did not detect any paroxysmal nocturnal hemoglobinuria (PNH) clone. Whole-body CT imaging did not reveal any organomegaly or lymphadenopathy.
He was diagnosed with very severe idiopathic aplastic anemia (based on Camitta criteria, 1976).
In view of his advanced age, he was not suitable for an allogenic stem cell transplant. He was treated with triple therapy consisting of Intravenous equine Antithymocyte globulin (ATGAM) 40 mg/kg for 4 days, oral ciclosporin A (CsA) 75 mg twice daily (total daily dose of 2mg/kg per body weight) and concomitant upfront subcutaneous granulocyte-colony stimulating factor (G-CSF) 300mcg once daily. Serum sickness prophylaxis in the form of intravenous methylprednisolone 1mg/kg 30 minutes before and after the ATGAM was also administered. The oral CsA was titrated slowly to a maximum of 125mg twice daily (total daily dose of 3mg/kg per body weight) in view of the patient’s age and risk of nephrotoxicity in the elderly. He was also given a thrombopoietin receptor agonist, oral eltrombopag 50mg once daily and triple antimicrobial prophylaxis (acyclovir, trimethoprim/sulfamethoxazole, and fluconazole). However, he developed severe pneumonia and sepsis on Day 8 of ATGAM therapy which necessitated oxygen support. The chest radiograph (Figure 2) showed diffuse bilateral interstitial and nodular consolidation. The family opted for palliation. He succumbed to his illness on Day 10 of treatment.