Il trapianto allogenico da donatore alternativo dopo condizionamento a ridotta intensità Alessandro Rambaldi

The role of the conditioning regimen and Is the donor type (related or unrelated) still an issue in the setting of RIC allograft? The role of the conditioning regimen and GVHD prophylaxis

Perez-Simon et al: Blood. 2002;100:3121-3127 Nonmyeloablative transplantation with or without alemtuzumab: comparison between 2 prospective studies in patients with lymphoproliferative disorders Perez-Simon et al: Blood. 2002;100:3121-3127 Transplantation-related mortality

Perez-Simon et al: Blood. 2002;100:3121-3127 Nonmyeloablative transplantation with or without alemtuzumab: comparison between 2 prospective studies in patients with lymphoproliferative disorders Perez-Simon et al: Blood. 2002;100:3121-3127 The conditioning regimen fludarabine 150 mg/m2 + melphalan 140 mg/m2 Event Free Survival

Perez-Simon et al.: BBMT 14:664-671 (2008) Reduced-Intensity Conditioning Allogeneic Transplantation from Unrelated Donors: Evaluation of Mycophenolate Mofetil Plus Cyclosporin A as Graft versus- Host Disease Prophylaxis Two RIC regimens The lymphoid RIC regimen fludarabine 150 mg/m2 and melphalan 70 mg/m2 2) The myeloid RIC regimen fludarabine 150 mg/m2 and busulfan 1 mg/kg for 10 doses (days-6 to-4) total 10 mg/kg Perez-Simon et al.: BBMT 14:664-671 (2008)

Perez-Simon et al.: BBMT 14:664-671 (2008) Reduced-Intensity Conditioning Allogeneic Transplantation from Unrelated Donors: Evaluation of Mycophenolate Mofetil Plus Cyclosporin A as Graft versus- Host Disease Prophylaxis Perez-Simon et al.: BBMT 14:664-671 (2008)

Perez-Simon et al.: BBMT 14:664-671 (2008) Reduced-Intensity Conditioning Allogeneic Transplantation from Unrelated Donors: Evaluation of Mycophenolate Mofetil Plus Cyclosporin A as Graft versus- Host Disease Prophylaxis Perez-Simon et al.: BBMT 14:664-671 (2008)

OS for patients over age 50 after nonmyeloablative or myeloablative transplantation Alyea, E. P. et al. Blood 2005;105:1810-1814 Copyright ©2005 American Society of Hematology. Copyright restrictions may apply.

Factors having an impact on PFS Alyea, E. P. et al. Blood 2005;105:1810-1814 Copyright ©2005 American Society of Hematology. Copyright restrictions may apply.

Cumulative incidence of TRM and risk of relapse after nonmyeloablative or myeloablative transplantation for patients over the age of 50 Myeloablative TRM Nonmyeloablative relapse Nonmyeloablative TRM Myeloablative relapse Myeloablative relapse Alyea, E. P. et al. Blood 2005;105:1810-1814 Copyright ©2005 American Society of Hematology. Copyright restrictions may apply.

Eight-year experience with allogeneic stem cell transplantation for relapsed follicular lymphoma after nonmyeloablative conditioning with fludarabine, cyclophosphamide, and rituximab Khouri IF et al. Blood. 2008;111:5530-5536

Unrelated hematopoietic stem cell transplantation with reduced intensity regimens in high-risk patients for age or disease: results from two independent prospective GITMO studies for Gruppo Italiano Trapianti di Midollo Osseo (GITMO) and Italian Bone Marrow Donor Registry (IBMDR)

Patients who activated an UD search N = 326 Patients who underwent a UD allograft N = 121 (37%) Patients who stopped the UD search N = 171 (53%) Death, N=90 (28%) Another protocol, N=33 (10%) No longer eligible, N=33 (10%) Donor not available, N=9 (3%) Withdrawn consent, N=6 (2%) Patients who still have an ongoing search N = 34 (10%)

Patients characteristics by treatment strategy Univariate analyses.*Non parametric test for the medians; § Fisher exact test

Results of 121 patients actually allografted

Clinical results of allografted patients Program A: TBI+Alemtuzumab+Fludarabine+Melphalan; Program B: Thiotepa+Cyclophamide+ATG * Risk status at transplant defined as standard for 1st and 2nd CR or CML in Chronic Phase. High risk for 3rd CR or more, PR, refractory relapse, active disease, chemotherapy resistant † Defined as PMN > 500x109/L

Clinical results of allografted patients Program A: TBI+Alemtuzumab+Fludarabine+Melphalan; Program B: Thiotepa+Cyclophamide+ATG

OS OS EFS EFS OS OS EFS EFS All patients (N=121) Acute Leukemias (N=27) OS OS EFS EFS A B Non Hodgkin Lymphoma (N=30) Hodgkin Disease (N=41) OS OS EFS EFS C D

TRM TRM RR RR A B TRM TRM RR RR C D All patients (N=121) Acute Leukemias (N=27) TRM TRM RR RR A B Non Hodgkin Lymphoma (N=30) Hodgkin Disease (N=41) TRM TRM RR RR C D

Incidence of Acute and Chronic Graft versus Host Disease .2 .4 .6 .8 1 50 100 150 200 Days from transplant Grades 2-4: 44% Grades 3-4: 20% .2 .4 .6 .8 1 100 200 300 400 500 Days from transplant Acute GVHD Chronic GVHD Chronic GVHD: 25% Extensive GVHD: 9% A B

Impact of allogeneic transplant on Overall Survival by diagnosis (1) Multivariable Cox proportional hazard models. * Time-dependent covariate

Impact of allogeneic transplant on Overall Survival by diagnosis (2) Multivariable Cox proportional hazard models. * Time-dependent covariate

Prognostic factors for the prediction of Overall Survival Multivariable Cox proportional hazard model. * Time-dependent covariate

Protocollo GlobAl Confronto randomizzato tra regimi di condizionamento a ridotta intensità contenenti rispettivamente Globulina Anti Linfocitaria verso Alemtuzumab nel trapianto allogenico da donatore non familiare Sponsorizzato dal GITMO Gruppo Italiano Trapianto Midollo Osseo

Curve di reclutamento Il protocollo prevede l’arruolamento di 100-150 pazienti. I risultati della analisi ad interim saranno disponibili a metà Novembre e permetteranno di prendere una decisione sulla opportunità di chiudere la fase di reclutamento.

Decessi Follow-up post trapianto (mediana 6.0 mesi [0.4 – 25.7])

Conclusions The conditioning regimen The GVHD prophylaxis The patients you are selecting for the allograft