Acute Lymphoid Leukemia in Remission, Acute Myeloid Leukemia in Remission, Chronic Lymphoid Leukemia, Chronic Myeloid Leukemia in Remission, Hodgkin Lymphoma, Multiple Myeloma, Myelodysplastic Syndromes, Myeloproliferative Disorder, Myeloproliferative Syndrome, Non Hodgkin Lymphoma
Conditions
Keywords
hematological malignancies, Graft versus host disease, GVHD, Progression free survival, Allogeneic hematopoeitic cell transplantation, HLA-matched donor, reduced intensity conditioning, Overall survival, ATG PK, Immunosuppressive regimen, Prophylaxis
Brief summary
The present project aims at comparing two conditioning regimens (FM-PTCy vs FM-ATG). The hypothesis is that one or the two regimens will lead to a 2-year cGRFS rate improvement from 30% (the cGRFS rate with FM without ATG/PTCy) to 45% (Pick-a-winner phase 2 randomized study).
Detailed description
This study is a multicenter, randomized, open-label, phase II study pick-a-winner study, comparing 2 conditioning regimens. A total of 114 eligible patients with HLA-matched donors will be randomized 1:1 between the FM-PTCy arm and the FM-ATG arm, with stratification for donor type (related or unrelated). The recruitment period is 3 years with a 5-year follow-up plus a 10-year additional long-term follow-up (for GVHD status, disease status, second malignancy and QOL). The whole study will be completed within 18 years.
Interventions
DRUGThymoglobulin
ATG: 2.5 mg /kg/day on day -2 and -1 (day 0 is allogenic transplantation)
DRUGMelphalan
100mg/m² on day -2
DRUGFludarabine
30mg/m² on days -6, -5, -4, -3, and -2
DRUGCyclophosphamid
50 mg/kg on days +3 and +4.
Sponsors
Belgian Hematological Society
University of Liege
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
Patients V.1.1. Diseases Hematological malignancies confirmed histologically: * AML in morphological CR or not in morphological CR but not rapidly progressing (i.e. no need to give treatments such as hydroxyurea to maintain WBC count \< 10 000 x109/mL); * MDS; * CML in CP or AP; * MPD not in blast crisis, * MDS/MPD overlap, * ALL in CR; * Multiple myeloma; * CLL; * Non-Hodgkin's lymphoma (aggressive NHL should have chemosensitive disease); * Hodgkin's disease with chemosensitive disease or responding to checkpoint inhibitors. \* Clinical situations • Theoretical indication for a standard allo-transplant, but not feasible because: * Age \> 50 yrs; * Unacceptable end organ performance; * The physician's decision; * The patient's decision * Underlying 'lower risk' disease, for which Reduced Intensity Conditioning is preferred (eg CLL, MCL) \* Other inclusion criteria * Male or female; fertile patients must use a reliable contraception method; * Age 18-75 yrs (children of any age are not allowed in the protocol); * Informed consent given by patient or his/her guardian if indicated. Donors * Male or female; * Any age; * Human Leukocyte Antigen (HLA)-identical sibling donor or 10 of 10 (HLA-A, -B, -C, -DRB1, and -DQB1) HLA allele matched unrelated donor; * Weight \> 15 Kg (because of leukapheresis); * Fulfills criteria for allogeneic Peripheral Blood Stem Cell (PBSC) donation according to standard procedures; * Informed consent given by donor or his/her guardian if indicated, as per donor center standard procedures.
Exclusion criteria
Patients * Any condition not fulfilling inclusion criteria; * Human Immunodeficiency Virus positive; * Non-hematological malignancy(ies) (except non-melanoma skin cancer) active \< 3 years before Hematopoietic Cell Transplantation (HCT). * Life expectancy severely limited by disease other than malignancy; * Central Nervous System involvement with disease refractory to intrathecal chemotherapy. * Terminal organ failure, except for renal failure (dialysis acceptable) 1. Cardiac: Symptomatic coronary artery disease; ejection fraction \<40%; uncontrolled arrhythmia, uncontrolled hypertension; 2. Pulmonary: Diffusing Capacity of the Lung for Carbon Monoxide (DLCO)\< 40% and/or receiving supplementary continuous oxygen, Forced Expiratory Volume in 1 Second (FEV1)\< 40%; 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 melphalan or Thymoglobulin; Donors * Any condition not fulfilling inclusion criteria; * Unable to undergo leukapheresis because of poor vein access or other reasons.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Current GVHD-free, relapse-free survival (cGRFS) | 15 years (the primary endpoint will be first assessed after 191 events have been reached) | To assess the current GVHD-free, relapse-free survival (cGRFS) for patients in the 2 arms |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Relapse/progression rate | 15 years | To assess the relapse/progression rate for patients conditioned with FM-PTCy or FM-ATG |
| Rate aGVHD | 6 months | To assess rate of grade II-IV and III-IV acute GVHD (Graft-versus-host disease) in patients conditioned with FM or FM-ATG. |
| Rate cGVHD | 24 months | To assess rate of grade of moderate-severe chronic GVHD in patients conditioned with FM or FM-ATG. |
| cGRFS according donor | 15 years | To assess cGRFS for patients conditioned with FM-PTCy or FM-ATG separately in those transplanted with a related or an unrelated donor |
| Rate of Leukemia Free Survival (LFS) | 15 years | To assess rate of Leukemia Free Survival in patients conditioned with FM-PTCy or FM-ATG. |
| Rate of Overall Survival (OS) | 15 years | To assess rate of Overall Survival in patients conditioned with FM-PTCy or FM-ATG. |
| Proportion of patients alive | 15 years | To assess the proportion of patients alive without active disease and without systemic immunosuppression |
| Rate of Nonrelapse Mortality (NRM) | 15 years | To assess rate of Nonrelapse Mortality in patients conditioned with FM-PTCy or FM-ATG. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Assess ATG Pharmacokinetic in association with OS | 15 years | To assess kinetics of functional ATG serum levels (mg/L) in the FM-ATG arm in association with OS |
| Assess ATG Pharmacokinetic in association with Relapse/progression | 15 years | To assess kinetics of functional ATG serum levels (mg/L) in the FM-ATG arm in association with Relapse/progression |
| Hematopoietic engraftment | 2 years | To assess hematopoietic (whole blood and T cell chimerism) engraftment in the 2 arms. |
| Assess ATG Pharmacokinetic in association with immunologic reconstitution | 5 years | To assess kinetics of functional ATG serum levels (mg/L) in the FM-ATG arm in association with immunologic reconstitution (CD4 and NAIVE T cells counts) |
| Assess ATG Pharmacokinetic in association with Infections | 1 years | To assess kinetics of functional ATG serum levels (mg/L) in the FM-ATG arm in association with Infections |
| Quality of immunologic reconstitution | 5 years | To assess the quality of immunologic reconstitution in the 2 arms |
| Timing of immunologic reconstitution | 5 years | To assess the timing (days) of immunologic reconstitution in the 2 arms |
| Incidences of bacterial infections | 1 year | To assess the incidences of bacterial infections (number of episode, site, grade) in the 2 arms, in the whole group of patients |
| Incidences of fungal infections | 1 year | To assess the incidences of fungal infections (number of episode, site, grade) in the 2 arms, in the whole group of patients |
| Incidences of viral infections | 1 year | To assess the incidences of viral infections (number of episode, site, grade) in the 2 arms, in the whole group of patients |
| Assess Thymoglobulin (ATG) Pharmacokinetic | 10 days | To assess kinetics of functional ATG serum levels (mg/L) in the FM-ATG arm |
| Assess ATG Pharmacokinetic in association with cGRFS | 15 years | To assess kinetics of functional ATG serum levels (mg/L) in the FM-ATG arm in association with cGRFS |
| Assess ATG Pharmacokinetic in association with NRM | 15 years | To assess kinetics of functional ATG serum levels (mg/L) in the FM-ATG arm in association with NRM |
Countries
Belgium
Contacts
Primary ContactFrédéric Baron, MD,Ph
Outcome results
None listed