FB-ATG: 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

Sponsor

King's College Hospital NHS Trust (Other)

Overall Status

Terminated

CT.gov ID

NCT00915811

Collaborator

(none)

Enrollment

Location

Arm

Duration (Months)

0.4

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Myelodysplastic Syndromes Leukemia, Myeloid, Acute	Drug: Fludarabine Drug: Busulphan Drug: Thymoglobuline (Anti-thymocyte globulin [rabbit]) - Genzyme Procedure: Haematopoietic stem cell infusion	Phase 2

Study Design

Study Type:

Interventional

Anticipated Enrollment :

20 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Study Start Date :

Jun 1, 2007

Actual Primary Completion Date :

Jun 1, 2011

Actual Study Completion Date :

Jun 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: FBATG Haematopoietic stem cell transplantation utilising conditioning with Fludarabine, Busulphan and Thymoglobuline	Drug: Fludarabine Fludarabine 30mg/m2 intravenously daily on days -9 to -5 inclusive of stem cell infusion. Drug: Busulphan Busulphan 0.8mg/kg intravenously 6 hourly on days -4 and -3 of stem cell infusion. Drug: Thymoglobuline (Anti-thymocyte globulin [rabbit]) - Genzyme 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. Procedure: Haematopoietic stem cell infusion 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.

Arm

Intervention/Treatment

Experimental: FBATG

Haematopoietic stem cell transplantation utilising conditioning with Fludarabine, Busulphan and Thymoglobuline

Drug: Fludarabine

Fludarabine 30mg/m2 intravenously daily on days -9 to -5 inclusive of stem cell infusion.

Drug: Busulphan

Busulphan 0.8mg/kg intravenously 6 hourly on days -4 and -3 of stem cell infusion.

Drug: Thymoglobuline (Anti-thymocyte globulin [rabbit]) - Genzyme

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.

Procedure: Haematopoietic stem cell infusion

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.

Outcome Measures

Primary Outcome Measures

Treatment related mortality to Day 100 [Days 28, 56 and 100]

Secondary Outcome Measures

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]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

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