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, 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 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 mg/kg BW X
Fludarabine mg/msq
Cyclophosphamide 300 mg/msq
Allogeneic stem-cell transplantation
Sandimmun 1-2 mg/kg IV
MTX 10-8 mg/msq IV

5. 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

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 ( ) 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
Variable HR
95% C.I.
P value
Multivariate P value
Age at Tx
0.99
0.87
Time diagnosis-Tx (days)
1.00
0.67
Corrected Calcium
1.33
0.71
LDH
10.99
0.05
CRP
6.29
0.002
0.012
Hemoglobin
1.82
0.42
Karnofsky PS
0.95
0.01
Infused CD34+/kg
0.07
0.015
Infused CD3+/kg
0.98
PD within +90 after Tx
27.74
0.005
0.010
aGvHD occurrence
2.05
0.16
cGvHD occurrence
0.75
0.62

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