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

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)

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

Study Flow-chart Treatment Day -6 -5 -4 -3 -2 -1 +1 +3 +6 +30 +60 +90   -6 -5 -4 -3 -2 -1 +1 +3 +6 +30 +60 +90 +120 Thiotepa 5 mg/kg BW X Fludarabine 30 mg/msq Cyclophosphamide 300 mg/msq Allogeneic stem-cell transplantation Sandimmun 1-2 mg/kg IV MTX 10-8 mg/msq IV

Patients Characteristics Value Median age (range) 53 (40-65) Sex (M/F) 18/7 Histology Clear cell Papillary 24 1 Previous treatments (range) 1 (0-3) ECOG PS 2 19 3 Patients with: LDH level >1.5 times ULN Hemoglobin level <LLN Corrected serum calcium level >10 mg/dL (2.5 mmol/L) Disease-free interval <1 yr 21 17 MSKCC score 0 risk factors 1 risk factor 2-3 risk factors 5

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.

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)

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.

Overall survival Survival probability Follow-up days

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

Multivariate Analysis for Survival Variable HR 95% C.I. P value Multivariate P value Age at Tx 0.99 0.93-1.06 0.87 Time diagnosis-Tx (days) 1.00 0.99-1.00 0.67 Corrected Calcium 1.33 0.30-5.80 0.71 LDH 10.99 0.99-121.24 0.05 CRP 6.29 1.98-19.97 0.002 0.012 Hemoglobin 1.82 0.42-7.94 0.42 Karnofsky PS 0.95 0.92-0.99 0.01 Infused CD34+/kg 0.17-1.07 0.07 0.015 Infused CD3+/kg 0.37-2.66 0.98 PD within +90 after Tx 27.74 2.77-277.49 0.005 0.010 aGvHD occurrence 2.05 0.75-5.60 0.16 cGvHD occurrence 0.75 0.24-2.31 0.62

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

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

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