Ematologia, Ospedali Riuniti, Bergamo

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Ematologia, Ospedali Riuniti, Bergamo Reduced-toxicity conditioning with Busulfan and Fludarabine and allogeneic stem cell transplant: chimerism evaluation and global outcome of 26 consecutive patients Alessandra Algarotti Ematologia, Ospedali Riuniti, Bergamo Senigallia, 24 Ottobre 2008

Reduced intensity or reduced toxicity conditioning regimens? RIC regimens have been used to offer an allogeneic transplant to otherwise inelegible patients RIC regimens are often associated with an increased proportion of disease relapse We investigated a reduced toxicity conditioning regimen with Busulfan and Fludarabine and we evaluated the outcome and the toxicity

Alyea EA: et al.: Blood, 2005, Vol. 105, 1810-1814 Comparative outcome of nonmyeloablative and myeloablative allogeneic hematopoietic cell transplantation for patients older than 50 years of age Alyea EA: et al.: Blood, 2005, Vol. 105, 1810-1814 Conditioning regimens “Nonmyeloablative” Fludarabine (30 mg/m2/d for 4 days) Busulfan (0.8 mg/kg/d iv for 4 days) on days -6, -5, -4, and -3. Myeloablative Cyclophosphamide (1800 mg/m2 for 2 days) and fTBI; 1400 cGy in 7 fractions over 4 days) Busulfan (16 mg/kg po divided over 4 days) and Cyclophosphamide a 152 patients: 71 nonmyeloablative and 81 myeloablative

Overall survival Event Free Survival Once Daily i.v. Busulfan and Fludarabine (i.v. Bu-Flu) Compares Favorably with i.v. Busulfan and Cyclophosphamide (i.v. BuCy2) as Pretransplant Conditioning Therapy in AML/MDS OS: Bu-Flu patients survived significantly longer (but shorter follow-up time). EFS: Bu-Flu patients had a longer EFS compared with the BuCy2 group (19,1 months versus 8,4 months) Overall survival Event Free Survival Andersson BS et al.: Biology of Blood and Marrow Transplantation 14:672-684 (2008)

Clinical findings Patients 26 Sex, M/F 15/11 Age,median (range) 53 (23-66) Diagnosis (n) AML 12 ALL 1 MDS 1 MM 7 HD 3 NHL 2 Disease status at transplant CR 9 (5 AML, 1 ALL, 2 NHL, 1 HD) GPR 7 (MM) PR 1 (HD) active disease 9 (7 AML, 1 MDS, 1 HD)

Transplantation Sibling/MUD 14/12 BM/PB 3/23 TNC x 10^8/Kg median (range) 9.16 (0.84-372.25) CD34 x 10^6/Kg median (range) 4.4 (1.4-11.8) CD3 x 10^6/Kg median (range) 202 (13-1206) Engraftment day, median (range) N > 500/mmc 16 (13-21) PLT > 20.000/mmc 14 (11-39)

BM BM Chimerism

PB Chimerism (CD 15, CD 3) P

Immunologic Reconstitution - CD3 p < 0.0001 Days from transplant

Immunologic Reconstitution - CD 4 p < 0.0001 Days from transplant

GVHD Acute GVHD 14/26 (54%) grade I 4 (15%) grade II-IV 10 (38%) Chronic GVHD 12/23 (52) mild 7 (30) extensive 5 (22)

Main transplantation outcomes Alive at last follow up 18 Alive in CR 15 Alive with active disease 3 Relapse/progression 4/6 Mortality NRM/RRM 1/7

Overall and Event Free Survival OS = 60% EFS = 55%

TRM and Risk to Relapse RRD = 40% TRM = 4% Competing risk analysis

Conclusion In our hands the FLU-Bu regimen confirms its remarkable tolerability and a significant antineoplastic activity Despite a low Fludarabine dosage, the chimerism full donor was obtained in most patients at 100 days after transplant Randomized clinical trials are needed to confirm these preliminary results

Studio AIFA per la ricerca indipendente 2006