Immunomodulation Antithymocyte globulincyclosporine

Antithymocyte globulin (ATG) is derived from the serum of either rabbits or horses immunized with human thoracic duct lymphocytes. ATG suppresses cytotoxic and potentially inhibitory T lymphocytes, and also has an indirect effect on hematopoiesis through augmentation of hematopoietic growth factor release from T cells and stromal cells. ATG stimulates cellular differentiation, and has been successfully used to treat patients with aplastic anemia (AA).

Hypoplastic MDS, although a distinct entity from AA, has some pathophysiologic similarities, specifically T-cell-mediated immune suppression of hematopoiesis. There is evidence of an increase in cytotoxic T-cell activity, a higher percentage of CD8+ cells, as well as skewing of T-cell receptor Vp complimentarity-determining region 3 (CDR3). This immune dysfunction in MDS is also found in low-risk MDS patients, with fewer than 10% blasts. It is reasonable, therefore, to treat hypocel-lular MDS patients with the same immunomodulation therapy that has been used for patients with AA, i.e., ATG and cyclosporine. These patients showed favorable responses, especially patients with HLA-DR2, HLA-DR15, or those with a paroxysmal nocturnal hemoglobinuria (PNH) phenotype (i.e., CD55 and CD59 negative). Other factors that are predictive for response to ATG are thought to be bone marrow cellularity <30%, shorter duration of red cell transfusions, and age <60 years. This therapy has recently been extended to RA and RAEB-1 patients in several small trials.

In a trial by Molldrem et al., unselected MDS patients with RA and refractory anemia with excess blasts (RAEB) were given rabbit ATG 40 mg/kg/day for 4 days, with an overall response rate of 44%.59 Higher responses of 64% were seen in patients with RA, 81% of whom maintained transfusion independence for a median of 36 months. This included 48% of those with severe thrombocytopenia and 55% of those with severe neutropenia. A follow-up with a total of 61 patients was reported in 2002, with an overall response of 34%.60

Subsequently, in a study of a select group of 30 patients with low-risk MDS and <10% blasts, horse ATG 1.5 vials/10kg/day was given for 5 days.61 Ten of

20 evaluable patients responded and became transfusion independent, with a median duration of response of 15.5 months, and 62% of the RA patients responded. Only one patient had normal counts at the 6-month follow-up, and there was no relationship between age, gender, cytogenetic clone, bone marrow cellularity, and response.

In a trial of 32 unselected MDS patients (RA, RAEB/RAEB-T, or CMMoL) treated with ATG, cyclo-sporine, and prednisone, only one CR and four PRs were achieved (OR 16%).62 Another small phase II trial of eight MDS patients treated with ATG and pred-nisone showed no responses; although three patients had the HLA-DR15 allele, this did not improve responses, and toxicities were significant.63 The role of ATG therefore remains limited to patients with hypocellular MDS, especially those with specific phe-notypic features, as described above.

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