VIDAZA-DLI Pre-emptive Azacitidine and Donor Lymphocyte Infusions Following Allogeneic Hematopoietic Stem Cell Transplantation for High Risk Acute Myeloid Leukemia and Myelodysplastic Syndrome

Acute Myeloid Leukemia Clinical Trial

— VIDAZA-DLI  

Official title:

Pre-emptive Azacitidine and Donor Lymphocyte Infusions Following Allogeneic Hematopoietic Stem Cell Transplantation for High Risk Acute Myeloid Leukemia and Myelodysplastic Syndrome

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01541280
• Other study ID #: BRD 10/07-H
• Status: Completed
• Phase: Phase 2
• First received: December 13, 2011
• Last updated: March 17, 2016
• Start date: November 2011
• Est. completion date: July 2015

Study information

• Verified date: February 2016
• Source: Nantes University Hospital
• Contact: n/a
• Is FDA regulated: No
• Health authority: France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
• Study type: Interventional

Clinical Trial Summary

Patients included in the study with high risk acute myeloid leukemia or myelodysplastic syndrome as defined will receive an allogeneic transplantation conditioned by either myeloablative or reduced regimen. Following allogeneic transplantation, patients will receive a maintenance regimen combining chemotherapy with azacitidine (aza) and immunotherapy with donor lymphocyte infusion.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 30
• Est. completion date: July 2015
• Est. primary completion date: July 2015
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 70 Years

Eligibility

Inclusion Criteria:

• Patients with high risk acute myeloid leukemia undergoing allogeneic transplantation with either a familial or an unrelated donor.

High risk AML is defined as :

• AML in CR1 with unfavorable cytogenetics defined by complex caryotype, autosomal monosomy combined or not with other cytogenetics abnormalities inv(3)/t(3,3), t(6;9), t(6;11), t(11;19), del(5q), del(7q).

• AML in CR2 or greater remission prior allogeneic transplantation

• AML in PR or relapse prior allogeneic transplantation

• Or Patients with high risk myelodysplastic syndrome undergoing allogeneic transplantation with either a familial or an unrelated donor.

High risk MDS is defined as :

• MDS with intermediate-2 group and higher risk group according to IPSS criteria

• Age 18 - 70 years.

• Availability of an HLA identical family donor or unrelated donor with matching in 10/10 alleles (HLA-A, B, C, DRB1, DQB1) or maximum of 1 allele or antigen mismatch OR family donor with maximum 1 allele mismatch.

• Conditioning regimen to allogeneic transplantation may be either myeloablative or reduced.

• Be able to understand and sign informed consent.

• Affiliation number to National Health Care System

• Men and women of childbearing potential must use effective contraception during and up to 3 months after treatment.

Exclusion Criteria:

• The presence of any one exclusion criteria renders the patient ineligible:

• Patient in full relapse post-transplant (>20% blasts in the bone marrow) following allogeneic transplant

• Documented leukemic infiltration of CNS/cerebrospinal fluid.

• Karnofsky performance score below 60%.

• Acute and chronic heart failure (NYHA Class III or IV) or symptomatic ischemic heart disease.

following allogeneic transplant

• Severe liver failure (bilirubin >30 µmoles/L, SGPT > 4 X upper limit of normal).

• Hepatic malignancy in advanced stage.

• Severe neurological or psychiatric disorders

• Acute GVHD grade II-III. Patient with grade I GVHD may be included (see annex 1 for GHVD grade definition).

• Active uncontrolled infection.

• Denied informed consent.

• Treatment with other investigational drugs following allogeneic transplantation.

• No effective contraception

• Lactating females

• Pregnant woman

Study Design

Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Acute Myeloid Leukemia
• Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute
• Myelodysplastic Syndrome
• Myelodysplastic Syndromes
• Preleukemia
• Syndrome

Intervention

Drug:
• Azacitidine
Azacitidine (AZA) is to be administered every 28 days beginning day +56 to 100 posttransplant for one year provided the patients has a platelet count of >15 x 109/L without transfusion for at least 2 successive days, and an absolute neutrophil count of >1 x 109/L without growth factor for at least 2 successive days, and no acute GVHD greater than grade I and no clinical evidence of life-threatening infection. AZA is given 32 mg /m²/day subcutaneously for 5 days every 28 days (

Other:
• DLI
Donor lymphocyte infusion (DLI) is to be given from day +126 (week 18) in patients without immunosuppressive therapy for at least one month and following 3 cycles of AZA, and without clinical signs of GVHD, and without uncontrolled infection and without a recent history of >grade 2 acute GVHD. DLI are schedules every 8 weeks. There are 3 DLI scheduled. If first cycle of AZA is postponed beyond day 56 (maximum to Day 100), all subsequent cycles and DLI will be post poned too.

Locations

Country	Name	City	State
France	University Hospital of Nantes	Nantes

Sponsors (1)

Lead Sponsor	Collaborator
Nantes University Hospital

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Evaluation of the cumulative incidence of relapse rate	An A'Hern procedure will be used (cf. 11.1): If the number of patients not relapsed at two year will be 18 or more out of 24 patients, the null hypothesis will be rejected and the relapse rate will be considered acceptable.	2 years	Yes
Secondary	Evaluation of disease-free survival (DFS) at 2 years from transplantation	Kaplan-Meier method	2 years	Yes
Secondary	Measure the overall survival rate at 2 years	Kaplan-Meier method	2 years	Yes
Secondary	Cumulative incidence death from leukemia, and non relapse mortality (NRM)	cumulative incidence function for disease free survival at 2 years from transplantation, GVHD, death from leukaemia and non-relapse mortality will be estimated (patients are at risk not only for relapse but can also be "removed" from possible relapse because of competing events such as death in remission (due to infection or GVHD)).	2 years	Yes
Secondary	Feasibility and safety of administrating maintenance azacitidine following allogenic transplantaton	To evaluate toxicity induced by the azacitidine and DLI, different parameters will be studied:Cell Blood Count with differential, liver function tests, serum creatinine, BUN and total protein will be performed weekly from the time of initiation of azacitidine administration until completion of the last DLI. Performance Status,Acute GVHD,Bone marrow aspiration with evaluation of morphological response as well as chimerism from peripheral blood will be performed prior starting azacitidine, following 3 cycles of azacitidine and after the seventh cycle and twelfth cycle of azacitidine.	2 years	Yes
Secondary	Feasibility and safety of performing prophylactic donor lymphocytes infusion	The relatedness of observed toxicity to DLI will be evaluated and documented: Maximum toxicity with respect to mucositis, liver, kidney, lung, heart, neurological system according to CTC criteria (cf. appendices).; Infections (bacteremia, fungemia, invasive fungal infection, CMV reactivation and disease, other viral reactivation or infection).; Grade of acute and chronic GVHD (cf. appendices); GVHD is classified according to clinical symptoms, irrespective to the time interval to DLI.; Bone marrow aspiration, as well as chimerism in PB.	2 years	Yes
Secondary	Incidence and severity of acute and chronic graft-versus-host disease	Symptoms related to GVHD should be reported within the GVHD section of the case reporting files. AE and SAE are documented in the patient's chart; on a daily basis, as long as the patient is on ward, and; on a weekly to two-monthly basis during outpatient follow up, depending on the frequency of outpatient visits on the respective patient.	2 years	Yes