Re: Allogeneic transplantation after nonmyelosuppressive conditioning—the effect of single-agent pentostatin (2004)

Reduced-intensity preparative regimens for allogeneic transplantation have been used to provide sufficient immunosuppression to allow for successful donor engraftment. In a recent article by Chan et al. [1Chan G.W. Foss F.M. Klein A.K. Sprague K. Miller K.B. Reduced-intensity transplantation for patients with myelodysplastic syndrome achieves durable remission with less graft-versus-host disease.Biol Blood Marrow Transplant. 2003; 9: 753-759Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar], 18 patients with myelodysplasia underwent allogeneic progenitor cell transplantation with a novel preparative regimen of extracorporeal photopheresis, total body irradiation, and pentostatin. The pentostatin was given by continuous infusion over 2 days at 4 mg/m2. The relative contribution of each agent in achieving immunosuppression of the donor was not assessed. Recent work suggests that successful nonmyeloablative regimens may be developed free of total body irradiation and that single-agent pentostatin may be sufficient to achieve donor chimerism. We initiated a phase I/II clinical trial to assess the feasibility and safety of related allogeneic progenitor cell transplantation after nonmyeloablative, reduced-intensity preparative conditioning with single-agent pentostatin. Four patients with metastatic renal cell cancer underwent conditioning with pentostatin 1.75 mg/m2 (3 patients) or 2.5 mg/m2 (1 patient) delivered by bolus intravenous injection every other day for 3 doses on days −7, −5, and −3 before infusion of granulocyte colony-stimulating factor-mobilized allogeneic hematopoietic progenitor cells. Posttransplantation immunosuppression consisted of cyclosporine started on day −1 at 3 mg/kg and continued at 2 mg/kg/d as a continuous infusion until day 30 or beyond as needed for development of graft-versus-host disease. Patients were observed by immunophenotype of lymphocyte subsets and for engraftment by either fluorescent in situ hybridization for Y chromosome if sex discordant, or restriction fragment length polymorphism if sex matched, weekly for 4 weeks and thereafter as clinically indicated. Patients were eligible for infusion of unstimulated donor leukocytes 1 month after transplantation for incomplete hematopoietic chimerism. Although the preparative regimen produced significant suppression of the CD4 count, there was no treatment-related myelosuppression despite the slow development of donor chimerism. At the lowest dose level of pentastatin full hematopoietic engraftment was demonstrated after unstimulated donor leukocyte infusion in 2 of 3 patients. At the 2.5 mg/m2 dose, unstimulated donor leukocyte infusion was given on day +51, when restriction fragment length polymorphism analysis showed mixed chimerism. The recipient achieved full donor chimerism by day +59. The regimen was not associated with myelosuppression, and among those who achieved full donor chimerism, a shift from recipient to donor hematopoiesis was gradual and not associated with appreciable neutropenia or thrombocytopenia. Furthermore, the pace of donor chimerism and time to development of graft-versus-host disease were delayed in all 3 patients who achieved evidence of engraftment, as demonstrated in Table 1. Table 1Renal Cancer TrialPatient No.Dose of Pentostatin (mg/m2 QOD × 3)No. of CD34+ Cells (× 10−6/kg)Donor Leukocyte Infusion (day after Transplantation)Dose of Donor Leukocytes (CD3 × 10−6/kg)Time to Full Donor Chimerism (day)Time to Onset of Acute GVHD (day)11.759.42+371.48+101+71+38+3921.754.18+521.47+63—∗Patient died of progressive metastatic renal carcinoma on day +66.+5331.754.11+585.86+59+60+64+65+212+21342.54.7+511.77+59+57+52+53QOD indicates every other day; GVHD, graft-versus-host disease.∗ Patient died of progressive metastatic renal carcinoma on day +66. Open table in a new tab QOD indicates every other day; GVHD, graft-versus-host disease. Notwithstanding the small number of patients, these results suggest that single-agent pentostatin may prove an acceptable preparative agent for reduced-intensity allogeneic transplantation, obviating the need for costly radiation-containing regimens. Such a single-agent preparative regiment may be of particular value for adoptive immunotherapy of solid tumors, such as metastatic renal cancer, in which chemotherapy may play a minimal role in antitumor responses [2Childs R.W. Nonmyeloablative blood stem cell transplantation as adoptive allogeneic immunotherapy for metastatic renal cell carcinoma.Crit Rev Immunol. 2001; 21: 191-203Crossref PubMed Google Scholar]. The preparative regimen may also be useful for therapy of nonmalignant conditions, because it may be given to outpatients and may not be associated with myelosuppression or significant regimen-related toxicity.