Immunosuppressive treatment for aplastic anemia: are we hitting the ceiling?

Abstract

A plastic anemia is a heterogeneous disease, a form of marrow failure that presents with pancytopenia of abrupt or insidious onset and an empty marrow. There are marrow and peripheral blood criteria (bone marrow cellularity <30%; reticulocytes <20×10 9 /L, platelets <20×10 9 /L, and neutrophils <0.5×10 9 /L) to define the severity of the condition. 1 The disease is termed severe when two out of three peripheral blood criteria are met, moderate if less than two are met, and very severe if the neutrophil count is below 0.2×10 9 /L. Severity has long been established as a prognostic criterion as it has been difficult to keep patients with severe neutropenia alive. The reticulocyte criterion will have to be re-evaluated as results of modern automated reticulocyte counters overestimate reticulocyte counts at low levels and do not, therefore, correlate well with manual counting results obtained by brilliant cresyl blue staining. Obviously, the diagnostic criteria established by Bruce Camitta were defined at a time when automated counters were not available. In a study published in this issue of the journal the reticulocyte criterion was set at 60×10 9 /L using an automated counting method. The diagnostic work-up includes testing for paroxysmal nocturnal hemoglobinuria by flow cytometry and cytogenetics and exclusion of hereditary marrow failure syndromes. This work-up is becoming increasingly complex as new hereditary forms are being identified and because the search for a hereditary form should no longer be limited to the pediatric age group. 2 The interpretation of clonal cytogenetic anomalies such as trisomy 8 and monosomy 7 is equally difficult as patients with a classical presentation of severe aplastic anemia and clonal hematopoietic anomalies should not be diagnosed as having a myelodysplastic syndrome based on the cytogenetic anomaly alone. Aplastic anemia is rare. The incidence is 1-2 new cases per million per year. It occurs in all age groups but is found more commonly among the young. The incidence is higher in south-east Asia and in poor countries; this may be due to viral infections and exposure to toxins.A series of studies in the past established that the combination of anti-thymocyte globulin (ATG) of horse origin, obtained by sensitizing horses with human lymphocytes or thymocytes, and cyclosporine A (CSA) is the standard treatment for aplastic anemia in patients not eligible for marrow transplantation.3 Results of transplantation and immunosuppression are roughly equivalent with graft-versus-host disease and graft failure being problems associated with transplantation and treatment failure, relapse and secondary clonal disorders such as myelodysplastic syndromes, paroxysmal nocturnal hemoglobinuria and leukemia being associated with immunosuppressive treatment. [4][5][6] Immunosuppression to treat severe aplastic anemia was initially pioneered by Georges Mathé and Bruno Speck among others. It is of interest that the first patients so treated received haploidentical marrow along with ATG and it took a...

Immune suppression for childhood acquired aplastic anemia and myelodysplastic syndrome: where next?

“…While there has been no improvement in overall or failure-free survival rates in the last two decades following IST, 17 results of matched unrelated donor hematopoietic stem cell transplantation have improved dramatically over this period. This has been due to improvements in supportive care, the development of high resolution HLA typing and less toxic conditioning regimens.…”

Clinical outcomes in adult patients with aplastic anemia: A single institution experience

“…3 Outcomes with immunosuppressive therapies (ISTs) have improved considerably over four decades since their inception, with improved supportive care and better informed salvage therapies. 4 Although a majority of AA patients respond to ISTs, about 10%–25% remain unresponsive, either due to poor marrow regenerative capacity, or a different nonimmune based pathophysiological mechanism. 5 …”

Immunosuppressive therapies in the management of acquired immune-mediated marrow failures

“…4 [8,75,77,78]. h-ATG and cyclosporine remains the gold standard as IST regimen for aplastic anemia patients, resulting in 60-70% response rates and even higher survival; on the basis of recent experience, it is conceivable that this is close to the maximum benefit that we may expect from any IST [79]. Three alternative immunosuppressive agents have shown a substantial activity in aplastic anemia: r-ATG, alemtuzumab and cyclophosphamide.…”