Acute Myelogenous Leukemia, Myelodysplastic Syndrome
Conditions
Keywords
Hematology, Acute Myelogenous Leukemia, Myelodysplasic syndrome, Allogeneic stem cell transplantation, Donor lymphocyte infusion, DLI, Azacytidine, Vidaza, Overall response rate, Relapse
Brief summary
The present project is a multicenter, phase II trial which aims at evaluating if the administration of azacytidine (Vidaza®) combined to donor lymphocyte infusion (DLI) could improve the response rate to DLI in the population of patients with relapsed acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) after allogeneic hematopoietic stem cell transplantation.
Detailed description
This is a prospective, multicenter, non-randomized phase II study. The aims at evaluating if the administration of azacytidine (Vidaza®) combined to donor lymphocyte infusion (DLI) could improve the response rate to DLI in the population of patients with relapsed acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) after allogeneic hematopoietic stem cell transplantation. Because the investigators focus our interest on relapsed MDS and low marrow blast count relapsed AML, the investigators postulate that one cycle at higher doses of azacytidine given at 100 mg/m² during 5 days is enough to induce temporary disease control, as suggested by the predictive value of the immediate response rate after the first cycle described in the study of Czibere et al. Starting with cycle 2, the investigators propose to administer DLI along with azacytidine to optimise the immunomodulatory effect. Because these immunomodulatory effects have been described at low dose, the investigators postulate that 35 mg/m² given during 5 days is enough to harness a graft-versus-leukemia effect and induce durable remissions without exacerbating GvHD. DLI will be given every other cycle following an escalated-dose regimen. The investigators have estimated a sample size of 50 patients to be recruited during 4 years with a 2-year follow-up and a 3-year long-term follow-up. The whole study will be completed within 9 years.
Interventions
BIOLOGICALDonor lymphocyte infusion
On day 1 of cycle 2, 4 and 6 of Azacytidine, patients will be infused with donor lymphocytes (ideally on day 1 but in case of organizational problems, DLI can be administered until day 5) . * Patients with a sibling donor will receive: * 5x10exp7 CD3+/kg on day 1 of cycle 2 * 5x10exp7 CD3+/kg on day 1 of cycle 4 * 10x10exp7 CD3+/kg on day 1 of cycle 6 * Patients with an unrelated donor will receive: * 1x10exp7 CD3+/kg on day 1 of cycle 2 * 5x10exp7 CD3+/kg on day 1 of cycle 4 * 10x10exp7 CD3+/kg on day 1 of cycle 6
DRUGAzacytidine
* Cycle 1: Subcutaneous administration of 100mg/m2/day for 5 days. * Cycle 2: Subcutaneous administration of 35mg/m2/day for 5 days. Cycles will be administered every 28 days. All patients will receive at least 6 cycles of Azacytidine except if progression requests additional disease-related treatment such as hydroxyurea or other chemotherapeutic agents. In such cases, the patient will be excluded from the study and only disease status and survival status will be reported during the 3-year follow-up period. In case of complete remission after cycle 5, 2 additional cycles will be administered after achievement of complete remission. In case of stable disease or partial response, Azacytidine will be continued until progression. In case of disease progression after cycle 6, Azacytidine will be stopped.
Sponsors
Celgene Corporation
Belgian Hematological Society
Carlos Graux, MD, PhD
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Patients: * Age ≥ 18 years * Be able to understand and sign informed consent * Fertile patients must use a reliable contraception method 2. Disease status at transplantation: * AML in first or subsequent complete remission (\< 5% marrow blasts) * MDS with less than 10% marrow blasts at the time of transplantation 3. Transplantation: * Allogeneic transplantation using a sibling or unrelated donor with matching in 10/10 alleles (HLA-A, B, C, DRB1, DQB1) or maximum of one allele or one antigen or 1 antigen + 1 allele or 1 antigen + 1 DQB1 antigen or 2 alleles mismatches. * Myeloablative or reduced-intensity conditioning * Second transplantation is allowed * Donor is willing to donate lymphocytes 4. Clinical situation: * Cytological relapse after allo-SCT defined as the recurrence of more than 5% blasts on bone marrow aspiration (AML) or evidence of MDS * Immunophenotypic relapse defined as the recurrence of an abnormal phenotype on flow cytometry in bone marrow aspirate (only in case of a specific phenotype). * Cytogenetic or molecular relapse defined as the persistence or recurrence of a cytogenetic abnormality or molecular marker in bone marrow aspiration or peripheral blood. WT1 expression is not considered as reliable marker for relapse in this protocol but FLT3-ITD, NPM1, CEBPA, or translocation-specific markers (such as MLL-PTD, AML-ETO, CBFB-MYH11) are. 5. Immunosuppressive therapy should have been stopped before inclusion.
Exclusion criteria
* More than 30% marrow blasts at the time of inclusion * Extramedullary relapse including CNS involvement * ECOG Performance status \> 2 * Active acute grade II-IV GvHD at the time of inclusion * Active chronic GvHD requiring systemic therapy at the time of inclusion * Uncontrolled infection * HIV positive * Acute or chronic heart failure (NYHA class III or IV) or symptomatic ischemic heart disease or ejection fraction \< 35% or uncontrolled arrhythmia * Severe liver failure (total bilirubin \> 3 mg/dL, SGPT \> 4 X upper normal limit) * Severe pulmonary failure (corrected DLCo \< 35%) * Terminal renal failure requiring dialysis * Severe neurological or psychiatric disorders * Concurrent investigational drug. * Other treatment for relapse, except for hydroxyurea but it should be stopped before inclusion in the study. * Female who is pregnant or breastfeeding
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Response rate | Will be evaluated at day 24 of cycle 1, 3 and 5. Then every 3 months for a year after cycle 6 thereafter at 1.5 and 2 years after cycle 6 | To assess the response rate to DLI by the combination with azacytidine in the population of patients with relapsed AML and MDS after allo-SCT. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Disease-free survival | 2 years after cycle 6 | Disease-free survival of patients |
| Overall survival | 2 years after cycle 6 | Overall survival of patients |
| Evaluation of the treatment Toxicity | At the beginning of each cycle and at the discretion of the investigator until cycle 6, then monthly for 6 months, thereafter every 3 months for 1.5 years | Evaluate haematological and non-haematological toxicities and safety of the planned therapy. |
| Incidence and severity of GvHD | At the beginning of each cycle and at the discretion of the investigator until cycle 6, then monthly for 6 months, thereafter every 3 months for 1.5 years | Incidence and severity of GvHD |
| Incidence and severity of infections | At the beginning of each cycle and at the discretion of the investigator until cycle 6, then monthly for 6 months, thereafter every 3 months for 1.5 years | Incidence and severity of infections |
Other
| Measure | Time frame | Description |
|---|---|---|
| Immune reconstitution | On day 1 of each cycle until cycle 6, then every 3 months for a year and at 1.5 and 2 years after cycle 6 | Immune reconstitution (hemoglobuline in g/dL) |
| Treg expansion | On day 1 of each cycle until cycle 6, then every 3 months for a year and at 1.5 and 2 years after cycle 6 | Treg expansion |
Countries
Belgium
Outcome results
None listed