Long-term Follow-up of Metastatic Renal Cancer Patients Undergoing Reduced-Intensity Allografting

1. Long-term follow-up of metastatic renal cancer patients undergoing reduced-intensity allografting M. Bregni, M. Bernardi, P. Servida, A. Pescarollo, R. Crocchiolo, E. Treppiedi, P. Corradini, F. Ciceri, and J. Peccatori Ospedale San Giuseppe, Milano; San Raffaele Scientific Institute, Milano Actual addresses: *Medical Oncology Unit, Ospedale San Giuseppe, Milano, Italy; **Istituto Oncologico Svizzera Italiana (IOSI), Bellinzona, CH; ***Ospedale Evangelico, Genova, Italy; Istituto Tumori Milano, Italy. Convegno Regionale SIE Senigallia, 23-24 ottobre 2008

2. Methods • From February 1999 to May 2005, 25 patients with cytokine-refractory RCC received a reduced-intensity allograft from an HLA-id sibling donor in the context of a IRB-approved, prospective Phase II study (nickname: Allorene)

3. Main eligibility criteria • Metastatic renal cancer • 18-65 year-old • Clear-cell histology • Resistant/refractory to at least one treatment line • Availability of an HLA-identical sibling donor • No active brain metastases • Life expectancy 6 months

4. Study Flow-chart

5. Patients Characteristics

6. Engraftment data • All evaluable patients (N=24) had a complete hematopoietic engraftment within one month from transplant • A full donor chimerism was achieved in all patients by day +60 after transplant. In one patient there was a late graft failure at +150 after transplant (lymphoid engraftment 20-25% donor, myeloid engraftment <40% donor), that was rescued by reinfusion of selected CD34+ cells from the original donor.

7. Immune data • Median CSA withdrawal day after BMT was 120 (21-351) days • Six patients received DLI at escalating doses for progressing or non-responding disease at a median of 360 (72-1095) days from transplant • Twelve patients had acute GVHD (grade I-II: ten; grade III-IV: two) • Nine patients had chronic GVHD (limited: seven; extensive: two)

8. Results • Six patients died because of TRM • Fourteen patients died of progressive disease • One-year-OS was 48% (95% CI: 28-68) and five-year-OS was 20% (95% CI: 4-36) • At a median observation time of 65 months, 5 patients are alive, one in CR, one in VGPR, and three with stable disease.

9. Overall survival Survival probability Follow-up days

10. Analysis of survival The following variables were analyzed: • Age at Transplant • Time from diagnosis to Transplant (days) • Corrected Calcium • LDH • CRP • Hemoglobin • Karnofsky PS • Infused CD34+/kg • Infused CD3+/kg • PD within +90 after Tx • aGvHD • cGvHD Motzer R, J Clin Oncol 2004; Peccatori J, Cancer 2005

11. Multivariate Analysis for Survival

12. OS according to early PD Survival probability All others, n=17 PD by +90, n=8 Days from landmark

13. Conclusions • Twenty percent of cytokine-refractory RCC patients are alive at a median 65 (40-72) months after allografting • All these patients have received >5x106 CD34+ cells/kg, and had stable or responding disease at +90 after transplant • Early progression appears to be the critical factor for survival • Three patients are receiving sorafenib or sunitinib, and two are in CR/VGPR without further therapies

14. Future programs: AlloTOR • Prospective single arm Phase I-II trial of sequential HLA-matched sibling donor allogeneic stem cell transplant, followed by temsirolimus given during post-transplant immune suppression • It is intended as a second-line treatment for patients with clear-cell RCC, relapsed after or resistant to TK inhibitor therapy • Endpoints: to avoid tumor progression during the immune suppression period, to reduce toxicity and transplant-related mortality, to maximise responses, and to prolong progression-free survival