Pilot Study of Reduced Intensity Haematopoietic Stem Cell Transplantation in Patients With Poor Risk Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukaemia (AML) Utilising Conditioning With Fludarabine, Busulphan and Thymoglobulin

Study Overview
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Brief Summary
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The purpose of this study is to determine the safety and feasibility of conditioning with fludarabine, busulphan and thymoglobuline in patients with myelodysplastic syndrome (MDS), myelodysplastic/myeloproliferative disorders (MDS/MPD) or acute myeloid leukaemia (AML) undergoing haematopoietic stem cell allograft with granulocyte colony-stimulating factor (G-CSF)-mobilised peripheral blood stem cells (PBSC) (or bone marrow) from HLA compatible sibling donors.

Official Title
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Pilot Study of Reduced Intensity Haematopoietic Stem Cell Transplantation in Patients With Poor Risk Myelodysplastic Syndrome and Acute Myeloid Leukaemia Utilising Conditioning With Fludarabine, Busulphan and Thymoglobulin

Conditions
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Myelodysplastic Syndromes, Leukemia, Myeloid, Acute

Intervention / Treatment
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* Drug: Fludarabine
* Drug: Busulphan
* Drug: Thymoglobuline (Anti-thymocyte globulin [rabbit]) - Genzyme
* Procedure: Haematopoietic stem cell infusion


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient Selection Availability of a HLA compatible sibling donor Age >18 years Myelodysplastic Syndromes with IPSS Intermediate-2 or High. Poor risk acute myeloid leukaemia, de novo or transformed from MDS Ineligibility for standard conditioning allograft due to age or co-existing morbidities Donor selection 1. Related donors compatible for HLA-A, B, C, DRB1 and DQB1 by molecular typing. Exclusion Criteria: Patient selection Cardiac insufficiency requiring treatment or symptomatic coronary artery disease. Hepatic disease, with AST > 2 times normal. Severe hypoxaemia, pO2 < 70 mm Hg, with decreased DLCO < 70% of predicted; or mild hypoxemia, pO2 < 80 mm Hg with severely decreased DLCO < 60% of predicted. Impaired renal function (creatinine > 2 times upper limit of normal or creatinine clearance < 50% for age, gender, weight). Patients who have received previous treatment with Thymoglobuline HIV-positive patients. Female patients who are pregnant or breast feeding due to risks to foetus from conditioning regimen and potential risks to nursing infants. Life expectancy severely limited by diseases other than MDS or MPD. Serious concurrent untreated infection Patients with limited life expectancy for other reasons Serious psychiatric/ psychological disorders Absence of /inability to provide informed consent Donor selection Age >75 years, unless independently assessed to be medically fit to donate Donors who for any reason are unable to tolerate the leukapheresis procedure and cannot undergo anaesthesia for marrow harvest. Donors who are HIV-positive, or hepatitis B or C PCR positive. Donors who are medically unsuitable to donate

Ages Eligible for Study
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Minimum Age: 18 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: FBATG<br>Haematopoietic stem cell transplantation utilising conditioning with Fludarabine, Busulphan and Thymoglobuline | Drug: Fludarabine<br>* Fludarabine 30mg/m2 intravenously daily on days -9 to -5 inclusive of stem cell infusion.<br>Drug: Busulphan<br>* Busulphan 0.8mg/kg intravenously 6 hourly on days -4 and -3 of stem cell infusion.<br>Drug: Thymoglobuline (Anti-thymocyte globulin [rabbit]) - Genzyme<br>* Thymoglobuline will be given intravenously over a minimum of 6 hours for the first two doses and 4 hours for the subsequent doses. Acute side effects of ATG appear to be reduced if a very low dose is given for the first injection. Thymoglobuline 0.5mg/kg iv on day -4, 1.5mg/kg/day on day -3; and 2mg/kg/day iv on day -2 to -1 inclusive.<br>Procedure: Haematopoietic stem cell infusion<br>* The source of stem cells will be PBSC wherever possible. Patients whose donors decline or are unable to donate PBSC will be transplanted with marrow cells.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment related mortality to Day 100 |  | Days 28, 56 and 100 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of single or multi-organ acute toxicity |  | Days 28, 56 and 100 | 
| Incidence of graft failure/rejection |  | Days 28, 56 and 100 | 
| Incidence of acute graft-versus-host disease |  | Days 28, 56, 100 and months 6, 9, 12, 18 and 24 | 
| Incidence of systemic infections |  | Days 28, 56, 100 and months 6, 9, 12, 18 and 24 | 
| EBV activation |  | Fortnightly for first 6 weeks after transplantation and then weekly for the first 6 months. | 
| Overall survival |  | Days 28, 56, 100 and months 6, 9, 12, 18 and 24 | 
| Disease free survival/relapse risk |  | Days 28, 56, 100 and months 6, 9, 12, 18 and 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Myelodysplastic Syndromes, Leukemia, Myeloid, Acute, Haematopoietic stem cell transplantation, Fludarabine, Busulphan, Thymoglobuline