Dose-reduced Versus Standard Conditioning in MDS/sAML

Study Overview
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Brief Summary
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In this trial dose reduced conditioning is compared to standard conditioning followed by allogeneic stem cell transplantation from related or unrelated donors in patients with MDS or secondary AML. Conditioning is the very high dose chemotherapy treatment that is given in the days before the stem cell transplant. The hypothesis is that a dose reduced conditioning will reduce the non-relapse mortality from 40% to 20% at one year after allogeneic stem cell transplantation.

Official Title
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Dose-reduced Versus Standard Conditioning Followed by Allogeneic Stem Cell Transplantation in Patients With MDS or sAML: A Randomised Phase III Study (RICMAC)

Conditions
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Myelodysplastic Syndromes, Secondary Acute Myeloid Leukemia

Intervention / Treatment
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* Other: Reduced Intensity Conditioning
* Other: Myeloablative conditioning


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Disease: Cytologically proven primary or therapy-related myelodysplastic syndrome (MDS), either as refractory anaemia (RA) according FAB or RA with or without dysplasia according WHO, refractory anaemia with ringsideroblasts (RARS) according FAB or RARS with or without dysplasia according WHO, refractory anaemia with excess of blasts (RAEB) according FAB or RAEB I or RAEB II according WHO, refractory anaemia with excess of blast in transformation (RAEB T) according FAB, CMML (dysplastic type) according WHO, or secondary acute myeloid leukaemia (sAML). Blast count < 20 percent in bone marrow with or without chemotherapy at time of transplantation. Patient eligible for standard and dose-reduced conditioning as per local guideline. Patient age 18 - 60 years if donor is a HLA-matched unrelated donor (HLA-A, HLA-B, HLA-DRB1 and HLA-DQB1) (one mismatch allowed): Patient age 18 - 65 years if donor is a HLA-matched related donor ((HLA-A, HLA-B, HLA-DRB1 and HLA-DQB1) (one anti¬gen-mismatch allowed): No major organ dysfunction. Written informed consent of the patient. Exclusion Criteria: Blasts > 20 % in bone marrow at time of transplantation No written informed consent. Central nervous involvement. Severe irreversible renal, hepatic, pulmonary or cardiac disease, such as Total bilirubin, SGPT or SGOT > 2 times upper the normal level. Left ventricular ejection fraction < 30 %. Creatinine clearance < 30 ml/min. DLCO < 35 % and/or receiving supplementary continuous oxygen. Positive serology for HIV. Pregnant or lactating women. Patients with a life-expectancy of less than six months because of another debilitating disease. Serious psychiatric or psychological disorders. Invasive fungal infection at time of registration.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: A<br>Myeloablative conditioning | Other: Myeloablative conditioning<br>* Busilvex®: 12.8 mg/kg IBW i. v.; day -9: 0.8 mg/kg IBW x 4 (2 hour infusion every 6 hours) day -8: 0.8 mg/kg IBW x 4 (2 hour infusion every 6 hours) day -7: 0.8 mg/kg IBW x 4 (2 hour infusion every 6 hours) day -6: 0.8 mg/kg IBW x 4 (2 hour infusion every 6 hours) or (if i.v.-application is not available): Busulfan: 16.0 mg/kg BW p. o.; day -9: 4.0 mg/kg BW day -8: 4.0 mg/kg BW day -7: 4.0 mg/kg BW day -6: 4.0 mg/kg BW plus: Cyclophosphamide: 120 mg/kg BW i. v.; day -4: 60 mg/kg BW day -3: 60 mg/kg BW<br>* Other names: Endoxan;|
| Experimental: B<br>Reduced Intensity Conditioning | Other: Reduced Intensity Conditioning<br>* Busilvex®: 6.4 mg/kg IBW i. v. day -7: 0.8 mg/kg IBW x 4 (2 hour infusion every 6 hours) day -6: 0.8 mg/kg IBW x 4 (2 hour infusion every 6 hours) or (if i.v.-application is not available) Busulfan: 8.0 mg/kg BW p. o.: day -7: 4.0 mg/kg BW day -6: 4.0 mg/kg BW plus: Fludarabine: 5 x 30 mg/m² BS i. v.: day -7: 30 mg/m² BS day -6: 30 mg/m² BS day -5: 30 mg/m² BS day -4: 30 mg/m² BS day -3: 30 mg/m² BS<br>* Other names: 2-Fluoro-ara-AMP;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| non-relapse mortality |  | every 6 months for safety and in the final analysis at one year after allogeneic stem cell transplantation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| organ related toxicity of conditioning |  | every 6 months for safety and in the final analysis at day +30 after allogeneic stem cell transplantation | 
| Incidence of aGVHD |  | every 6 months for safety and in the final analysis at day +100 after allogeneic stem cell transplantation | 
| incidence of cGVHD |  | every 6 months for safety and in the final analysis at one year after allogeneic stem cell transplantation | 
| overall survival |  | every 6 months for safety and in the final analysis at 2 years after allogeneic stem cell transplantation | 
| event-free survival |  | every 6 months for safety and in the final analysis at 2 years after allogeneic stem cell transplantation | 
| cumulative incidence of relapse |  | every 6 months for safety and in the final analysis at 2 years after allogeneic stem cell transplantation | 
| VOD |  | every 6 months for safety and in the final analysis at day +100 after allogeneic stem cell transplantation | 
| infection incidence |  | every 6 months for safety and in the final analysis at day +100, 1 year and 2 years after allogeneic stem cell transplantation | 
| Haematopoeitic recovery |  | every 6 months for safety and in the final analysis at day +30 after allogeneic stem cell transplantation | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Reduced Intensity conditioning, Myeloablative conditionig, Allogeneic stem cell transplantation, MUD