Dose-reduced Versus Standard Conditioning in MDS/sAML (RICMAC)

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

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.

Study Overview

• Status: Terminated
• Conditions: Myelodysplastic Syndromes; Secondary Acute Myeloid Leukemia
• Intervention / Treatment: Other: Myeloablative conditioning; Other: Reduced Intensity Conditioning

• Study Type: Interventional
• Enrollment (Actual): 129
• Phase: Phase 3

Contacts and Locations

Study Locations

• Germany
  • Düsseldorf, Germany
    • University Hospital
  • Halle, Germany
    • Martin-Luther-Universität Halle-Wittenberg
  • Hamburg, Germany
    • University Hospital Eppendorf
  • Heidelberg, Germany
    • University Hospital
  • Kiel, Germany
    • UKSH Campus Kiel
  • Köln, Germany
    • University Hospital
  • Leipzig, Germany
    • University Hospital
  • Munster, Germany
    • Universitatsklinikum Munster
  • Tübingen, Germany
    • University Hospital
• Italy
  • Alessandria, Italy
    • Santi Antonio e Biagio
  • Firenze, Italy
    • Ospedale di Careggi
  • Milano, Italy
    • Ospedale Maggiore di Milano
• Netherlands
  • Nijmegen, Netherlands
    • Radboud University MC
• Russian Federation
  • St. Petersburg, Russian Federation
    • SPb State I. Pavlov Medical University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: A; Myeloablative conditioning	Other: Myeloablative conditioning; 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; Other Names: Cytoxan; Endoxan; Myeloleukon; Claphene; Cyclophosphan; Cyclostin; Cytophosphan; Procytox; cyclophosphamide; Busulphan; Myleran; Sulphabutin; Leucosulfan; Citosulfan; Mielevcin; Milecitan
Experimental: B; Reduced Intensity Conditioning	Other: Reduced Intensity Conditioning; 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; Other Names: Beneflur; Fludara; Myeloleukon; Busulphan; Myleran; Fludura; FAMP; Sulphabutin; Leucosulfan; Citosulfan; Mielevcin; Milecitan; 2-Fluoro-ara-AMP

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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	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

Collaborators and Investigators

• Sponsor: European Society for Blood and Marrow Transplantation
• Collaborators: Pierre Fabre Medicament
• Investigators: Study Chair: Nicolaus Kröger, MD, Universitatsklinikum Hamburg-Eppendorf; Principal Investigator: Axel R Zander, MD, University Hospital Hamburg-Eppendorf, Germany; Principal Investigator: Ghulam J Mufti, MD, King's College Hospital London, United Kingdom; Principal Investigator: Marie Robin, MD, Hopital Saint-Louis Paris, France; Principal Investigator: Kathrin Haifa Al-Ali, MD, University Hospital Leipzig, Germany; Principal Investigator: Dietger Niederwieser, MD, University Hospital Leipzig, Germany; Principal Investigator: Giorgio Lambertenghi Deliliers, IRCCS Ospedale Maggiore of Milan, Italy; Principal Investigator: Domink Heim, Prof., University Hospital, Basel, Switzerland; Principal Investigator: Liisa Volin, MD, Helsinki University Central Hospital, Finland; Principal Investigator: Stefano Guidi, MD, Careggi Hospital - Florence, Italy; Principal Investigator: Augustin Ferrant, MD, Cliniques Universitaires St. Luc Bruxelles, Belgium; Principal Investigator: Afanasyer Boris, SPB Pavlov Medical Univ, St. Petersburg, Russia; Principal Investigator: Kai Hubel, University of Cologne; Principal Investigator: Peter Dreger, Univ Hospital Heidelberg - Germany; Principal Investigator: Martin Gramatzlle, University Hospital Münster - Germany; Principal Investigator: Gerhard Behre, Martin-Luther-Universitaet Halle-Wittenberg - Germany; Principal Investigator: Martin Gramatzlle, Univ Hospital Kiel - Germany; Principal Investigator: Allione Bernardino, Santi Antonio e Biagio

Publications and helpful links

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start: May 1, 2004
• Primary Completion (Actual): January 1, 2015
• Study Completion (Actual): February 1, 2015

Study Registration Dates

• First Submitted: September 15, 2010
• First Submitted That Met QC Criteria: September 15, 2010
• First Posted (Estimate): September 16, 2010

Study Record Updates

• Last Update Posted (Estimate): April 3, 2015
• Last Update Submitted That Met QC Criteria: April 2, 2015
• Last Verified: April 1, 2015

More Information

Terms related to this study

• Keywords: MUD; Allogeneic stem cell transplantation; Reduced Intensity conditioning; Myeloablative conditionig
• Additional Relevant MeSH Terms: Bone Marrow Diseases; Hematologic Diseases; Myelodysplastic Syndromes; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Cyclophosphamide; Fludarabine phosphate; Busulfan
• Other Study ID Numbers: 2005-002011-24; EBMT 42205525