Haplotype Donor-Generated Graft-Versus-Leukemia Responses: Serendipity Revisited

Abstract

This re-evaluation of a pilot study conducted nearly three decades ago (1965-1970), in which serendipity played a central role in favorable responses of hematologic malignancies to the administration of adoptive lymphocytes from both parents, has been motivated by clearer understanding. Temporary remissions marking LAK cell-driven graft-versus-leukemia (GvL) responses were observed in four of seven acute leukemia patients associated with unique self-limited graft-versus-host (GvH) reactions that were NK cell and cytokine related. Retinopathy not previously reported in a GvH setting was a consistent manifestation in these patients. Cure was achieved in an eighth patient with acute lymphoblastic leukemia after she had been given effective chemotherapy, an active role for the adoptive therapy indicated by the occurrence of a week of fever suggesting an abortive GvH reaction. Two of five patients with Hodgkin's disease also experienced favorable responses to parental leukocyte therapy, one exhibiting GvH manifestations almost identical to those seen in the acute leukemia patients when given the adoptive therapy successfully to spur recovery from severe herpes zoster that had interrupted curative radiation therapy. The GvH in the other patient was a more typical one, the key effect being an increase in circulating lymphocytes that may have contributed indirectly to cure with subsequent therapy. These and other attempts to apply GvL responses therapeutically, including those currently in favor, exemplify the shortcomings of partial mitogenic responses to alloactivation, which are dependent on engraftment, limited in scope, excessively toxic, and difficult to control. Treatment with mitogens such as PHA would be a superior alternative because of the abilities of these agents to regulate immune responses by simple modulations of dosage, scheduling, and modes of application.