Bone Marrow Transplantation (2002) 30, 805–812  2002 Nature Publishing Group All rights reserved 0268–3369/02 $25.00 www.nature.com/bmt Mini-review Nonablative hematopoietic cell transplantation for the treatment of metastatic renal cell carcinoma RP Nelson Jr 1 , TF Logan 2 and R Abonour 1 1 Division of Hematology/Oncology, Hematological Malignancy Program/Immunology, Bone Marrow Transplant Program, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA; and 2 Division of Hematology/Oncology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA Summary: Nonablative hematopoietic cell transplantation (HCT) is becoming a preferred treatment for those recipients in whom the potential toxicity risk of standard ablative allogeneic therapy may be unacceptable. Graft-versus- malignancy effects may be generated against epithelial malignancies which are similar to the graft-versus-leu- kemia activity that is well documented in human hema- tological malignancies. Renal cell carcinoma has been shown to be responsive to immunotherapy with recom- binant human cytokines and may be an ideal model for exploring this novel therapy. Clinical investigations have demonstrated regression of metastatic renal cell carcinoma occurs in some patients following nonabla- tive allogeneic HCT. However, graft-versus-host disease remains a significant toxicity of nonablative transplan- tation, and further investigations are warranted to further evaluate this promising approach and to improve its safety. Bone Marrow Transplantation (2002) 30, 805–812. doi:10.1038/sj.bmt.1703740 Keywords: renal cell carcinoma; nonmyeloablative; hem- atopoietic cell transplantation Metastatic renal cell carcinoma Of the 30 000 cases of kidney cancer per year which are diagnosed in the United States, there are over 12 000 deaths. The incidence of renal cell carcinoma (RCC) has increased by 38% from 1976–1990 and occurs predomi- nantly in persons between the ages of 50 to 70. 1 Common sites of metastases include lung, soft tissue, bone, liver, skin and less commonly, the central nervous system. 2 The clini- cal behavior of RCC (either resected or metastatic) is extremely variable, recurring in some patients only many years following nephrectomy. A small percentage of patients with metastatic RCC experience a short-lived spon- Correspondence: Dr RP Nelson Jr, Hematological Malignancy Program/Immunology, Department of Internal Medicine, Indiana Univer- sity School of Medicine, 535 Barnhill Dr. 473, Indianapolis, IN 46202– 5289, USA taneous regression which typically follows nephrectomy. 3,4 Some metastases initially progress slowly, if at all, while others progress rapidly, making treatment difficult. Treat- ment for metastatic renal cancer is not usually successful and the median prognosis for survival despite added cyto- kine therapy is 10 months. 5 Therapy and survival Standard chemotherapeutic and hormonal approaches are generally unsuccessful. 6,7 Immunomodulator therapies util- izing interferon have been used with some success in patients with metastatic RCC. 8–12 Nephrectomy, followed by interferon alfa-2b, accomplishes longer survival among patients with metastatic RCC than does interferon therapy alone. 9 IL-2 is FDA-approved and considered standard ther- apy for metastatic renal cell carcinoma; however, many patients are not eligible because of poor performance status or concurrent organ dysfunction. Approximately 15–20% of patients have an objective response to therapy, and although the complete response (CR) rate is 5–7%, approxi- mately 80% of these complete responders will experience response duration of greater than 2 years. 13–16 Toxicity of high-dose IL-2 therapy is significant, although the treat- ment-related mortality is less than 1%. 14 The toxicities include hypotension requiring pressors, major organ failure, myocardial infarction and potentially fatal systemic capil- lary leak. Fisher reported that the median response duration of the original cohort of 255 RCC patients treated with high-dose IL-2 was 54 months (range, 3–131 months). 17,18 The median duration for complete responders was not reached, but was greater than or equal to 80 months (range, 7–131 months). Median survival for all 255 patients was 16.3 months, with 10–20% estimated to be alive 5–10 years post treatment. Regimens combining IL-2 and other agents appear to have similar response rates compared to IL-2 alone. 12,15 Low- to moderate-dose parenteral IL-2 may be associated with similar response rates and less toxicity. 19,20 However, a phase III study of the Cytokine Working Group found that treatment with high-dose IL-2 demonstrated a significantly higher objective response rate than did treat- ment with low-dose IL-2/interferon. 21 Conventional treat- ment options are summarized in Table 1.