Symptoms and General Pathology

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Myeloid Leukemia

Acute Myeloid Leukemia

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Acute Graft Versus Host Disease

Antineoplastic Agents

All Drugs and Chemicals

Antisickling Agents

Azacitidine

Hydroxyurea

Antimetabolites

Enzyme Inhibitors

Azacytidine will be administered subcutaneously for 5 days. During the first cycle, a dose of 100mg/m2/day will be used and for the following cycles a dose of 35mg/m2/day will be administered. Each cycle will consist in 28 days. All patients will receive at least 6 cycles of Azacytidine and the total number of cycles will depend on the response to treatment.

Donor lymphocyte infusion will be performed on day 1 of cycle 2, 4 and 6 of Azacytidine. The amount of cells infused will depend on donor origin.

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

Donor lymphocyte infusion

* 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.

Azacytidine

Xavier Poiré, MD

Carlos Graux, MD, PhD

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.

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.

Azacytidine and Lymphocytes in Relapse of AML or MDS After Allogeneic Stem Cell Transplantation.

Sequential Administration of 5-azacytidine (AZA) and Donor Lymphocyte Infusion (DLI) for Patients With Acute Myelogenous Leukemia (AML) and Myelodysplastic Syndrome (MDS) in Relapse After Allogeneic Stem Cell Transplantation.

Immune reconstitution (hemoglobuline in g/dL)

Immune reconstitution (ANC, ALC, platelet in cells/µL)

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.

Evaluate haematological and non-haematological toxicities and safety of the planned therapy.

Celgene Corporation

Belgian Hematological Society

Professor

Fludarabine

Fludarabine phosphate

Thymoglobulin

Busulfan

Alkylating Agents

Immunosuppressive Agents

Immunologic Factors

Antineoplastic Agents, Alkylating

Fludarabine (Fludara®): 30 mg/m2 on D-6, D-5, D-4, D-3 and D-2 Busulfan IV (Busilvex®) : 3.2 mg/kg/d on D-4 and D-3 Thymoglobuline®: 2.5 mg/kg/d on D-3 and D-2

Fludarabine (Fludara®): 30 mg/m² on D-6, D-5, D-4, D-3 and D-2 Busulfan IV (Busilvex®) : 3.2 mg/kg/d on D-5, D-4 and D-3 Thymoglobuline® : 2.5 mg/kg/d on D-3 and D-2

Fludarabine (Fludara®): 30 mg/m²on D-6, D-5, D-4, D-3 and D-2 Busulfan IV (Busilvex®) : 3.2 mg/kg/d on D-6, D-5, D-4 and D-3 Thymoglobuline® : 2.5 mg/kg/d on D-3 and D-2

BX4-Suspended

Dominique GENRE, MD

Jihane PAKRADOUNI, PharmD,PhD

Jihane PAKRADOUNI, PharmD, PhD

Didier BLAISE, MD PhD

Albeit the safety of the stem cell transplantation procedure has been greatly improved, further refining the intensity of the conditioning is an important issue to explore, especially in patients with poor prognosis, the goal being to maintain the very favorable safety profile and improve the disease control. This is the goal our prospective trial; we aim to prospectively evaluate in a prospective multicenter trial the efficacy of different conditioning regimens in patients with high-risk myeloid malignancies.

The study is a phase II trial randomizing patients between a prospective active control arm (BX2) and two experimental arms (BX3 and BX4). A standard group was kept in this clinical trial in order to avoid the limitations induced by the comparison with historical controls in the context of continuously improving practice. Each experimental arm will be conducted in parallel according to a standard phase II trial design.

In addition, this trial will associate four ancillary studies to the main clinical objective: 1/ a prospective assessment of the quality of life of the patients over a period of 2 years 2/ an analysis of the cost effectiveness of the procedure, assessed over a period of 2 years 3/ an observational busulfan pharmacokinetic study 4/ a busulfan pharmacogenomic study

Evaluation of 3 Different Doses of IV Busulfan

Prospective and Multicentre Evaluation of 3 Different Doses of IV Busulfan Associated With Fludarabine and Thymoglobuline in the Conditioning of Allogeneic Stem Cell Transplantation (SCT) From a Matched Related or Unrelated Donor in Patients With Poor Prognosis Myeloid Malignancies

Institut Paoli-Calmettes

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Azacytidine and Lymphocytes in Relapse of AML or MDS After Allogeneic Stem Cell Transplantation.	NCT02017457	Acute Myelogeno... Myelodysplastic...	Donor lymphocyt... Azacytidine	18 Years -	University Hospital of Mont-Godinne
Evaluation of 3 Different Doses of IV Busulfan	NCT01985061	Myelodysplastic... Acute Myeloid L...	BX2 BX3 BX4-Suspended	18 Years - 65 Years	Institut Paoli-Calmettes
Evaluation of 3 Different Doses of IV Busulfan	NCT01985061	Myelodysplastic... Acute Myeloid L...	BX2 BX3 BX4-Suspended	18 Years - 65 Years	Institut Paoli-Calmettes

Spots Global Cancer Trial Database for myelodysplasic syndrome