Graft-Versus-Host Disease, Hematological Malignancies
Conditions
Keywords
Allogeneic hematopoeitic cell transplantation, Graft-Versus-Host Disease, Prophylaxis, Reduced-intensity conditioning, Immunosuppressive regimen, HLA-matched donor, Progression free survival, Overall survival
Brief summary
The present project is a multicenter phase II trail aiming at comparing which of the two postgrafting immunosuppressive regimens proposed in this study will be best suited to prevent graft-versus-host disease (GVDH). The immunosuppressive regimens will consist of: Tacrolimus plus Mycophenolate Mofetil or Tacrolimus plus Sirolimus. Before grafting patients will undergo a reduced-intensity conditioning with Fludarabine/total body irradiation (TBI) or Fludarabine/Busulfan/anti-thymoglobuline. Following the interim analysis of October 2014, the protocol has been amended to allow inclusion only after Flu-TBI conditioning. The hypothesis is that the Tacrolimus plus Sirolimus regimen will be associated with better progression-free survival due to a lower incidence of relapse/progression.
Interventions
DRUGMycophenolate mofetil
Tablets. For HLA-identical sibling donors:15 mg/kg t.i.d from day 0 to day 28. For alternative donor: 15 mg/kg, from day 0 to day 42.
DRUGSirolimus
Tablets. 6 mg loading dose on day -3, followed by (1)-2 mg daily to a target trough level of 5 to 10 ng/mL. Full doses will be given until day 100 (sibling recipients) or 180 (alternative donor recipients). Doses will then be progressively tapered to be definitely discontinued by day 180 (sibling donors) or 365 (alternative donor recipients) in the absence of GVHD.
Sponsors
AZ Sint-Jan AV
Ziekenhuis Netwerk Antwerpen (ZNA)
Jules Bordet Institute
University Hospital, Gasthuisberg
AZ-VUB
Cliniques universitaires Saint-Luc- Université Catholique de Louvain
University Hospital, Antwerp
Cliniques Universitaires de Mont-Godinne
Hospital de Jolimont
University Hospital, Ghent
AZ Delta
University of Liege
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
16 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
1. Hematological malignancies confirmed histologically and not rapidly progressing: * Acute myeloid leukemia (AML) in complete remission (CR) (defined as ≤ 5% marrow blasts and absence of blasts in the peripheral blood); * Myelodysplastic syndromes (MDS) with ≤ 5% marrow blasts and absence of blasts in the peripheral blood; * Chronic myeloid leukemia (CML) in chronic phase (CP); * Myeloproliferative neoplasms not in blast crisis and not with extensive marrow fibrosis; * Acute lymphoid leukemia (ALL)in CR; * Multiple myeloma not rapidly progressing; * chronic lymphocytic leukemia (CLL); * Non-Hodgkin's lymphoma (aggressive NHL should have chemosensitive disease); * Hodgkin's disease with chemosensitive disease; 2. 10/10 HLA-A, -B, -C, DRB1 and DQBI allele-matched donor fit to/willing to donate PBSC. 3. Clinical situations: 1. Theoretical indication for a standard allotransplant, but not feasible because: * Age \> 50 yrs; * Unacceptable end organ performance; * At the physician's decision; * Patient's refusal. 2. Indication for a standard auto-transplant: perform mini-allotransplantation 2-6 months after standard autotransplant. 4. Other inclusion criteria: * Male or female; fertile patients must use a reliable contraception method; * Age ≤ 75 yrs (children of any age are allowed in the protocol); * Informed consent given by patient or his/her guardian if of minor age.
Exclusion criteria
* Any condition not fulfilling inclusion criteria; * HIV positive; * Non-hematological malignancy(ies) (except non-melanoma skin cancer) \< 3 years before nonmyeloablative hematopoietic cell transplantation (HCT); * Life expectancy severely limited by disease other than malignancy; * Administration of cytotoxic agent(s) for cytoreduction within three weeks prior to initiating the nonmyeloablative transplant conditioning (Exceptions are hydroxyurea and imatinib mesylate); * CNS involvement with disease refractory to intrathecal chemotherapy; * Terminal organ failure, except for renal failure (dialysis acceptable) 1. Cardiac: Symptomatic coronary artery disease or other cardiac failure requiring therapy; ejection fraction \<35%; uncontrolled arrhythmia, uncontrolled hypertension; 2. Pulmonary: DLCO \< 35% and/or receiving supplementary continuous oxygen; 3. Hepatic: Fulminant liver failure, cirrhosis of the liver with evidence of portal hypertension, alcoholic hepatitis, esophageal varices, a history of bleeding esophageal varices, hepatic encephalopathy, uncorrectable hepatic synthetic dysfunction evinced by prolongation of the prothrombin time, ascites related to portal hypertension, bacterial or fungal liver abscess, biliary obstruction, chronic viral hepatitis with total serum bilirubin \>3 mg/dL, and symptomatic biliary disease; * Uncontrolled infection; * Karnofsky Performance Score \<70%; * Patient is a fertile man or woman who is unwilling to use contraceptive techniques during and for 12 months following treatment; * Patient is a female who is pregnant or breastfeeding; * Any condition precluding the use of sirolimus or MMF; * One HLA mismatch with peripheral blood stem cells (PBSC) fit to/willing to donate.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free survival | 1 year after transplantation | To compare the 1-year progression-free survival between the 2 prophylactic arms (Tracolimus/Mycophenolate Mofetil and Tracolimus/Sirolimus) in the whole group of patients and separately in those conditioned with Fluradabine/TBI or Fluradabine plus Busulfan and anti-thymocyte globulin. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression free survival | 2 and 5 years after transplantation | To compare progression-free survival in the 2 phrophylactic arms (Tracolimus/Mycophenolate Mofetil and Tracolimus/Sirolimus) 2 and 5 years after HSCT, in the whole group of patients and separately in those conditioned with Fluradabine/TBI or Fluradabine plus Busulfan and anti-thymocyte globulin. |
| Engraftment | 1 year after transplantation | To compare hematopoietic (whole blood and T cell chimerism) engraftment and to evaluate the 1-year incidence of graft rejection in the 2 prophylctic arms (Tracolimus/Mycophenolate Mofetil and Tracolimus/Sirolimus), in the whole group of patients and separately in those conditioned with Fluradabine/TBI or Fluradabine plus Busulfan and anti-thymocyte globulin. |
| Acute GVDH | 6 months after transplantation | To compare the 6-mo incidence of grades II-IV and III-IV acute GVHD in the 2 prophylactic arms (Tracolimus/Mycophenolate Mofetil and Tracolimus/Sirolimus), in the whole group of patients and separately in those conditioned with Fluradabine/TBI or Fluradabine plus Busulfan and anti-thymocyte globulin. |
| Relapse rate; nonrelapse mortality and overall survival | 1, 2 and 5 years after transplantation | To compare relapse rate, nonrelapse mortality, and overall survival in the 2 prophyltic arms (Tracolimus/Mycophenolate Mofetil and Tracolimus/Sirolimus) 1, 2 and 5 years after hematopietic stem cell transplantation (HSCT) in the whole group of patients and separately in those conditioned with Fluradabine/TBI or Fluradabine plus Busulfan and anti-thymocyte globulin. |
| Immunological reconstitution | 3 mo, 6 mo, 1 yr, 2 yrs and 5 yrs after transplantation | To compare the quality and timing of immunologic reconstitution in the 2 prophylactic arms (Tracolimus/Mycophenolate Mofetil and Tracolimus/Sirolimus),in the whole group of patients and separately in those conditioned with Fluradabine/TBI or Fluradabine plus Busulfan and anti-thymocyte globulin. |
| Infection | 1 year after transplantation | To compare the 1-yr incidences of bacterial, fungal and viral infections in the 2 prophylactic arms (Tracolimus/Mycophenolate Mofetil and Tracolimus/Sirolimus), in the whole group of patients and separately in those conditioned with Fluradabine/TBI or Fluradabine plus Busulfan and anti-thymocyte globulin. |
| Chronic GVDH | 1 year after transplantation | To compare the 1-yr incidence of chronic GVHD in the phrophylactic 2 prophylactic arms (Tracolimus/Mycophenolate Mofetil and Tracolimus/Sirolimus), in the whole group of patients and separately in those conditioned with Fluradabine/TBI or Fluradabine plus Busulfan and anti-thymocyte globulin. |
Countries
Belgium
Outcome results
None listed