Anti-rIL-2 receptor antibodies and marrow aplasia

In this issue, Maciejewski and colleagues (page 3584) suggest an interesting new use for anti-interleukin-2 (IL-2) receptor antibody (daclizumab) in patients with moderate aplastic anemia (AA). According to their interpretation, 6 of 16 evaluable patients responded within 90 days from the last dose of daclizumab, although only 2 showed normal blood counts. One patient progressed under treatment; however, he did respond to subsequent treatment with antithymocyte globulin (ATG)/cyclosporine (CsA). This finding, together with available data reported in patients treated with ATG, suggests that the immunosuppressive/immunoregulatory effects induced by daclizumab may be inferior to ATG, the conventional modality for AA. Indeed, the incomplete response in many of the patients and the relapse already observed in one patient suggests that more effective immunosuppression may still be indicated for effective treatment of AA. The option of continuous treatment to prolong the beneficial effects of daclizumab may improve the long-term outlook, but is less preferable than achieving better results up front. Unfortunately, the results in the table summarizing the actual blood counts appear to be somewhat less impressive than the general conclusions, since 2 of 16 patients considered in complete remission (CR) did not show normal platelet counts or any dramatic increases in other values. Therefore, it appears that the authors' conclusions should be adopted with great caution, since the severity of the disease of the patients selected was moderate and the success rate of treatment, compared with conventional immunosuppressive modalities such as ATG, was less than optimal. However, it should be remembered that for patients, especially the young ones, with severe AA, allogeneic stem cell transplantation (SCT) still remains the treatment of choice. Also, since procedure-related toxicity and mortality are currently extremely low due to available reduced-intensity conditioning, SCT should be considered for patients with a fully matched donor available, even those who do not meet the full criteria of severe AA for patients. This possibility must be weighed against long-term immunosuppressive treatment, which is time consuming and frequently not effective. A most interesting observation noted by the authors was the relationship of responsiveness to daclizumab and the presence of interferon-γ: 5 of 6 tested positive and responded to daclizumab, whereas no response was observed in any of the 5 patients testing negative. Since similar observations were reported in another study in AA, such a test may be used to predict responsiveness, and may possibly serve as a guideline for choosing the proper protocol for patients who do not qualify for SCT. Also of interest is the implied role of IL-2 receptor activation, which could shed more light on the mechanisms controlling autoimmunity. Taken together, it appears that AA is a complicated multifactorial syndrome caused, perhaps, in patients who do respond to immunosuppressive treatment, by an autoimmune syndrome, and caused by other etiologies in patients who do not. A better understanding of the mechanisms of AA, including the role of lymphocyte subsets and their cytokines, will certainly help elucidate the etiology and thus improve treatment strategies.