Note: This review is based upon two presentations at the 2012 American Society of Hematology (ASH) Annual Meeting, December 7-10 in Atlanta, Georgia. The full abstracts may be viewed on the ASH Annual Meeting Web site. Search by entering the title in the search box. The abstract number is referenced to access the full report.
Mutations in genes that are key to the telomerase complex can lead to a variety of disorders, including bone marrow failure and liver and lung fibrosis. The lab led by Neal Young at the NHLBI presented two studies at the 2012 American Society of Hematology Meeting in Atlanta delineating the heterogeneity of bone marrow failure syndromes associated with telomere abnormalities and the role of telomere abnormalities in aplastic anemia.
Phillip Scheinberg, MD, Danielle M. Townsley, MD, MSc, Bogdan Dumitriu, MD, Olga Rios, RN, Barbara Weinstein, RN, Minoo Battiwalla, MD, MS, Richard Childs, MD, Cynthia E. Dunbar, MD, A. John Barrett, MD, Colin O. Wu and Neal S. Young, MD
In this poster presentation, the investigators evaluated the use of “moderate” dose cyclophosphamide for severe aplastic anemia for patients who do not have a compatible donor. In earlier studies, high dose cyclophosphamide (200mg/kg) had unacceptable toxicities (including death from aggressive fungal infections) compared to standard of care with horse-ATG/cyclosporine. These toxicities far outweighed the reduction in clonal evolution and relapse seen in the high dose cyclophosphamide single institution study. In a subsequent study of lower dose cyclophosphamide (30mg/kg/day x 4 days) plus cyclosporine, the benefits of cyclophosphamide were maintained with a reduction in toxicity. Based on these findings, this study aimed to assess the response to “moderate” dose cyclophosphamide defined as 30mg/kg/day for 4 days (=120mg/kg total dose) plus cyclosporine in first line severe aplastic anemia patients where no donor is available.
Both in this study and the companion protocol by the same group (investigating cyclophosphamide 60mg/kg plus fludarabine 125mg/m2), there were severe toxicities noted including profound neutropenia and frequent, severe infections (bacterial and fungal) despite adequate prophylaxis. The investigators concluded that “moderate” dosing of cyclophosphamide does not prevent the toxicities of severe infection and neutropenia. The potential benefits of cyclophosphamide and its activity in severe aplastic anemia are outweighed by the unacceptable toxicities, especially given that there are safer alternatives such as horse-ATG approved.