Diagnosis and Treatment of Aplastic Anemia

Abstract

Acquired aplastic anemia (AA) is a rare, life-threatening bone marrow failure (BMF) disorder that affects patients of all ages and is caused by lymphocyte destruction of early hematopoietic cells. Diagnosis of AA requires a comprehensive approach with prompt evaluation for inherited and secondary causes of bone marrow aplasia, while providing aggressive supportive care. The choice of frontline therapy is determined by a number of factors including AA severity, age of the patient, donor availability, and access to optimal therapies. For newly diagnosed severe aplastic anemia, bone marrow transplant should be pursued in all pediatric patients and in younger adult patients when a matched sibling donor is available. Frontline therapy in older adult patients and in all patients lacking a matched sibling donor involves immunosuppressive therapy (IST) with horse antithymocyte globulin and cyclosporine A. Recent improvements in upfront therapy include encouraging results with closely matched unrelated donor transplants in younger patients and the emerging benefits of eltrombopag combined with initial IST, with randomized studies underway. In the refractory setting, several therapeutic options exist, with improving outcomes of matched unrelated donor and haploidentical bone marrow transplantation as well as the addition of eltrombopag to the non-transplant AA armamentarium. With the recent appreciation of frequent clonal hematopoiesis in AA patients and with the growing use of next-generation sequencing in the clinic, utmost caution should be exercised in interpreting the significance of somatic mutations in AA. Future longitudinal studies of large numbers of patients are needed to determine the prognostic significance of somatic mutations and to guide optimal surveillance and treatment approaches to prevent long-term clonal complications.

Keywords: Antithymocyte globulin; Aplastic anemia; Bone marrow failure; Bone marrow transplant; Clonal hematopoiesis; Cyclosporine A; Eltrombopag; Immunosuppressive therapy.

Figure 1. Approach to diagnosis and treatment of acquired aplastic anemia

Initial screening evaluation of a patient with aplastic anemia is required to document pancytopenia with a hypocellular marrow, followed by testing to exclude alternative diagnoses. Aplastic anemia severity and outcomes of a transplant evaluation factor into determining an optimal treatment strategy. Patients with Severe or Very Severe Aplastic Anemia (SAA/VSAA) 40 years of age or younger with an HLA-matched sibling donor should undergo an evaluation for an allogeneic bone marrow transplant; older patients or patients without an HLA-identical sibling donor should be evaluated for frontline immunosuppressive therapy (IST) with horse ATG and CsA. **Based on recent data showing superior hematologic outcomes with the addition of eltrombopag [4], addition of 6 months of eltrombopag to standard IST in patients without pre-existing cytogenetic abnormalities can be considered. Cyclosporine A should be continued for ~12 months of therapy, followed by a slow taper to reduce relapse rates. Salvage therapies include alternative transplant modalities and a variety of nontransplant options. AA, aplastic anemia; PNH, paroxysmal nocturnal hemoglobinuria; 6p CN-LOH, copy number-neutral loss of heterozygosity of chromosome arm 6p; alloSCT, allogeneic stem cell transplant; NSAA, nonsevere aplastic anemia; SAA, severe aplastic anemia; VSAA, very severe aplastic anemia. *Cellularity criteria are determined on adequate bone marrow biopsy, and hypoplastic marrow can either be diagnosed on total cellularity or on bone marrow biopsy with <50 percent normal cellularity in which < 30 percent of the cells are hematopoietic. HLA, human leukocyte antigen; alloBMT, allogeneic bone marrow transplant; IST, immunosuppressive therapy; hATG, horse antithymocyte globulin; CsA, cyclosporine A; CR, complete response; PR, partial response; Cy, cyclophosphamide; MRD, matched related donor; MUD, matched unrelated donor; haplo BMT, haploidentical bone marrow transplant.