Multicenter Study of Peritransplantation Immunosuppression for Mismatched Hematopoietic Cell Transplantation After Reduced Intensity Conditioning

Study Overview
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Brief Summary
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Feasibility and toxicity of peritransplantation immunosuppression with ATG, sirolimus, mycophenolate mofetil and rituximab in patients receiving mismatched allogeneic HCT after a reduced intensity conditioning regimen with fludarabine/treosulfan

Official Title
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Multicenter Phase II Study of Peritransplantation Immunosuppression Using ATG, Rituximab, Sirolimus and Mycophenolate Mofetil in Patient Receiving Mismatched Hematopoietic Cell Transplantation After Reduced Intensity Conditioning With Fludarabine and Treosulfan

Conditions
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Patients Receiving Mismatched Allogeneic HCT

Intervention / Treatment
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* Drug: immunosuppression


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients scheduled for mismatched allogeneic HCT Unrelated donor with maximal 2 antigen or allelic mismatches in HLA-I or HLA-II Age >=75, >=18 years Patients Age <=50 if a HCT-CI score > 2 [acc. to Sorror et al., 2005] Karnofsky Index >60% Patients with: Acute myeloid leukemia in CR (<5% blasts) Acute lymphoblastic leukemia in CR (< 5% blasts) Myelodysplastic syndrome with up to 20% blasts Osteomyelofibrosis Chronic lymphocytic leukemia High grade Non-Hodgkin Lymphoma in CR or PR Low grad Non-Hodgkin Lymphoma in CR or PR M. Hodgkin in CR or PR Chronic myeloid leukaemia in chronic phase or CR of blast crisis Exclusion Criteria: Patients with >5% blasts in BM at the time of transplantation Progressive or chemorefractory disease Less than 3 months after preceding HCT CNS involvement with disease Fungal infections with radiological progression after receipt of amphotericin B or active triazole for greater than 1 month. Liver function abnormalities with bilirubin >2 mg/dL and elevation of transaminases higher 2x upper limit of normal. Chronic active viral hepatitis Ejection fraction <40 % on echocardiography Patients with > grade II hypertension by CTC criteria Creatinine clearance <50 ml/min Proteinuria >800 mg/24 h Respiratory failure necessitating supplemental oxygen or DLCO <30% Allergy against murine antibodies Known allergy/intolerance against sirolimus or one of it's excipients HIV-Infection Female patients who are pregnant or breast feeding, or adults of reproductive potential not employing an effective method of birth control during study treatment and for at least 12 months thereafter. (Women of childbearing potential must have a negative serum pregnancy test at study entry) Concurrent severe and/or uncontrolled medical disease (e.g. uncontrolled diabetes, congestive heart failure, myocardial infarction within 6 months prior to the study, unstable and uncontrolled hypertension, chronic renal disease, or active uncontrolled infection) which could compromise participation in the study Patients with a history of psychiatric illness or condition which could interfere with their ability to understand the requirements of the study (this includes alcoholism/drug addiction) Patients unwilling or unable to comply with the protocol Unable to give informed consent Enrollment in an other trial interfering with the endpoints of this study

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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

| Intervention/Treatment |
| --- |
|Drug: immunosuppression|Conditioning with treosulfan 14 g/m2 day -6 to -4, fludarabine 30 mg/m2/24h day-6 to -2, ATG-Fresenius 20 mg/kg day -4 to -2, rituximab 500 mg/m2 day -1. Unmanipulated PBSC day 0. Postgrafting immunosuppression with mycophenolate mofetil (15 mg/kg TID) and sirolimus (2 mg QD).|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment related mortality |  | 12 months after HCT | 
| Treatment related mortality |  | 24 months after HCT | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Toxicity according CTC of protocol on day 100 |  | on day 100 | 
| Engraftment on day 100 |  | on day 100 | 
| Overall survival |  | 12 months after HCT | 
| Incidence of graft versus host disease |  | 3 months after HCT | 
| Incidence of infections |  | 2 years after HCT | 
| Immune reconstitution of CD3, CD3/CD4/CD8, CD56, CD19 cells |  | 3 months after HCT | 
| Overall survival |  | 24 months after HCT | 
| Incidence of graft versus host disease |  | 6 months after HCT | 
| Disease free survival |  | 24 months after HCT | 
| Disease response |  | 12 months after HCT | 
| Disease response |  | 24 months after HCT | 
| Immune reconstitution of CD3, CD3/CD4/CD8, CD56, CD19 cells |  | 6 months after HCT | 
| Immune reconstitution of CD3, CD3/CD4/CD8, CD56, CD19 cells |  | 12 months after HCT | 
| Immune reconstitution of CD3, CD3/CD4/CD8, CD56, CD19 cells |  | 24 months after HCT | 
| Incidence of graft versus host disease |  | 12 months after HCT | 
| Incidence of graft versus host disease |  | 24 months after HCT |