5-azacytidine Treatment Versus 5-azacytidine Followed by Allogeneic Stem Cell Transplantation in Elderly Patients With Myelodysplastic Syndrome (MDS)

Study Overview
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Brief Summary
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5-azacytidine treatment prolongs survival in patients with myelodysplastic syndrome (MDS), but does not cure the disease. Allogeneic stem cell transplantation is a curative treatment option but is associated with a high risk treatment-related morbidity and mortality. In the current trial allogeneic stem cell transplantation will be compared to 5-azacytidine only treatment according to donor availability in elderly patients with MDS (55-70 years).

Detailed Description
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5-azacytidine treatment prolongs survival in patients with myelodysplastic syndrome (MDS), but does not cure the disease. Allogeneic stem cell transplantation is a curative treatment option but is associated with a high risk treatment-related morbidity and mortality. Dose-reduced conditioning prior transplantation allows also treatment of elderly patients with MDS. In the current trial allogeneic stem cell transplantation will be compared to 5-azacytidine only treatment according to donor availability in elderly patients with MDS (55-70 years).

Official Title
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Comparison Between 5-azacytidine Treatment and 5-azacytidine Followed by Allogeneic Stem Cell Transplantation in Elderly Patients With Advanced MDS According to Donor Availability

Conditions
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Myelodysplastic Syndrome, Chronic Myelomonocytic Leukemia

Intervention / Treatment
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* Procedure: allogeneic stem cell transplantation
* Procedure: 5-azacytidine until progress


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with proven de novo or therapy-related MDS / CMML (WBC <13 GPT/l)according to FAB and risk profile according to IPSS: intermediate II- risk or high-risk or intermediate I with high-risk cytogenetic (according to IPSS, taking into account that IPSS, however, was not validated for t- MDS), patients with secondary AML (according to WHO) and blasts ≤ 30 % (= RAEB-t according to FAB) Previously untreated or maximal 1 cycle of 5-azacytidine (Vidaza®) Male or Female; Age 55 - 70 years Understand and voluntarily sign an informed consent form ECOG performance status of ≤ 2 at study entry Adequate renal and liver function: creatinine and bilirubin < 3 x the upper limit of normal Sufficient cardiac function (ejection fraction > 30 %) Exclusion Criteria: Blasts > 30 % in bone marrow at time of diagnosis Central nervous involvement Severe irreversible renal, hepatic, pulmonary or cardiac disease, such as Total bilirubin, SGPT or SGOT ≥ 3 times upper the normal level Left ventricular ejection fraction < 30 % Creatinine clearance < 30 ml/min DLCO < 35 % and/or receiving supplementary continuous oxygen Pregnant or breastfeeding female subject Patients with a life-expectancy of less than six months because of another debilitating disease Serious psychiatric or psychological disorders Uncontrolled invasive fungal infection at time of registration Known positive for HIV or acute infectious hepatitis, type A, B or C Participation in another study with ongoing use of unlicensed investigational product from 28 days before study enrollment until the end of the study

Ages Eligible for Study
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Minimum Age: 55 Years
Maximum Age: 70 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: Non-Randomized
Intervention Model: Factorial Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 5-azacytidine treatment until progress<br>5-azacytidine until progress | Procedure: 5-azacytidine until progress<br>* if no donor available 5-azacytidine until progress or toxicities<br>|
| Experimental: allogeneic stem cell transplantation<br>after 4 cycles 5-azacytidine and if donor available: allogeneic stem cell transplantation after reduced intensity conditioning | Procedure: allogeneic stem cell transplantation<br>* donor available, after 4 cycles 5-azacytidine allogeneic stem cell transplantation after reduced conditioning<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| overall survival | compare to overall survival of patients who receive after 4 cycles of 5-azacytidine either allogeneic stem cell transplantation or continuous 5-azacytidine if no compatible donor is available overall 230 patients | three years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| response | Comparison of response according to International Working Group Response Criteria between both arms: - Examinations of bone marrow (count of blasts) and peripheral blood (hematological improvement)after schedule of study assessments (after cycle 4 in both arms, after cycle 8 and after months 12-24-36 in the 5-azacytidine treatment and on day 100, day 180, months 12-24-36 after allogeneic stem cell transplantation | three years | 
| event-free survival | comparison of event free survival in both arms (230 pat.): - evaluation of survival status (relapse, date of relapse, alive or death) in the whole study period | three years | 
| overall survival | Comparison of overall survival between both arms (230 pat.). - evaluation of survival status (alive or death/date of death) in the whole study period | three years | 
| impact of Comorbidity-index on outcome | impact of comorbidity-index on outcome after study entry and prior to allogeneic stem cell transplantation (according definitions and weighted scores of comorbidities by Sorror et al): physical examination laboratory values(creatinine,Alt, AST, bilirubin, etc.) apparative diagnostics (echo,lufu,ECG) | three years | 
| Treatment-related mortality | compare treatment related mortality in both arms (230 pat.): - death according to treatment in both arms | three years | 
| Evaluation of toxicity | the evaluation of toxicity will be performed according to the reporting guidelines as per NCI CTCAE in the whole study period: adverse events grade 3 and 4 cytopenia grade 3 and 4 only be reported as AE which are judged by the investigator as clinically relevant | three years | 
| quality of life | Comparison of quality of life between both arms with the quality of life core questionnaire QLQ-C30 and the treatment specific high-dose chemotherapy module QLQ HD-C29 to assess the quality of life of cancer patient. The questionnaire has to be answered after the fourth cycle, 6 months, 1 year, 2 years and 3 years after both treatment arms | three years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MDS, CMML, allogeneic stem cell transplantation, 5-azacytidine