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A phase I/ II study.
Efficacy and safety of alpha / betaT- /CD19B-cell depleted allogeneic haematopoietic stem cells transplantation in high risk or relapsed acute leukaemia / MDS followed by an innate donor lymphocyte infusion (iDLI).



- candidate number8321
- NTR NumberNTR2463
- ISRCTNISRCTN wordt niet meer aangevraagd.
- Date ISRCTN created
- date ISRCTN requested
- Date Registered NTR7-aug-2010
- Secondary IDs10-257 / NL33076.000.10 ; METC / ABR
- Public TitleA phase I/ II study.
Efficacy and safety of alpha / betaT- /CD19B-cell depleted allogeneic haematopoietic stem cells transplantation in high risk or relapsed acute leukaemia / MDS followed by an innate donor lymphocyte infusion (iDLI).
- Scientific TitleA phase I/ II study.
Efficacy and safety of alpha / betaT- /CD19B-cell depleted allogeneic haematopoietic stem cells transplantation in high risk or relapsed acute leukaemia / MDS followed by an innate donor lymphocyte infusion (iDLI).
- ACRONYMiDLI
- hypothesisPatients suffering from high risk or relapsed leukaemia or high risk MDS can only occasionally be cured with conventional chemotherapy. Allogeneic stem cell transplantation (allo-SCT) has substantially improved the outcome of such patients due to a potent graft versus leukaemia effect after transplantation, but still for the high price of severe and life-threatening GvHD. Also relapses are still observed after allo-SCT. This study aims therefore to improve the outcome of this potent treatment modality by combining T-cell depleted allo-SCT with reduced toxicity and post-allo-SCT immunomodulations in order to enhance the anti-tumor-effect.
- Healt Condition(s) or Problem(s) studiedMyelodysplastic syndrome (MDS), High risk acute leukemia
- Inclusion criteria1. Age 18-65 years;
2. Meeting the criteria for a allo-SCT and high risk disease * (see below);
3. WHO performance status ≤ 2;
4. Written informed consent.

*High risk disease as defined by:
1. AML with monosomal karyotype, abnormal 3q26, t(9;22) EVI-1-expression, or complex karyotype in first CR;
2. No CR after first induction cycle chemotherapy;
3. Relapsed AML (in case of second allo-SCT if relapse occurs 6 months after allo-SCT) in second or subsequent CR;
4. MDS with complex karyotype or -7, transfusion dependent or neutropenic with < 10% blasts or in CR after induction therapy;
5. ALL with t(9;22), t(4;11), and other 11q23 abnormalities, and hypodiploidy; complex abnormalities (≥ 5), excluding hyperdiploidy; high WBC at diagnosis (B-ALL > 30x109/l, T-ALL > 100x109/l) in first CR, or no CR after first induction but in CR after rescue chemotherapy;
6. Relapsed ALL (in case of second allo-SCT if relapse occurs 6 months after allo-SCT) in second or subsequent CR.
- Exclusion criteria1. Relapse of allo-SCT within 6 months after allo-SCT;
2. Relapse acute promyelocyten leukemia;
3. Bilirubin and/or transaminases > 2.5 x normal value;
4. Creatinine clearance < 40 ml/min;
5. Cardiac dysfunction as defined by:
A. Unstable angina;
B. Unstable cardiac arrhythmias.
6. Active, uncontrolled infection;
7. HIV positivity.
- mec approval receivedno
- multicenter trialno
- randomisedno
- groupParallel
- TypeSingle arm
- Studytypeintervention
- planned startdate 1-jan-2011
- planned closingdate1-jan-2016
- Target number of participants30
- InterventionsSelection of T cells and depletion of B-cell in the alloSCT. After that zolendronic acid administations and iDLI after immunosupressive medication is stopped. Normally there is no selection of T oor B-cells or IDLI.
- Primary outcomeFeasibility and safety of alpha/ betaT-/CD19 B-cell depleted allo-SCT in high risk or relapsed acute leukaemia / MDS followed by an innate donor lymphocyte infusion (iDLI) by assessing:
1. Time to neutrophil engraftment;
2. Time to platelet engraftment;
3. Time to donor engraftment (chimerism >95%);
4. Time to red blood cell transfusion independence;
5. Incidence and grade of acute GvHD;
6. Incidence and grade of chronic GvHD;
7. Ability to generate and apply an iDLI;
8. Incidence of infections;
9. Transplant related mortality (TRM).
- Secondary outcome1. Immune reconstitution by counting total number of CD3+ T cells, CD4+ and CD8+ subtyping of T cells, CD3-CD16/56+ (NK cells), alpha / beta T-cells at 3, 6, 12 and 24 months after transplantation;
2. Progression free survival (PFS, i.e. time from transplantation until progression/relapse or death from any cause, whichever comes first);
3. Overall survival (OS) calculated from transplantation. Patients still alive or lost to follow up are censored at the date they were last known to be alive.
- TimepointsDate form allo-SCT till 1 year after allo-SCT.
- Trial web siteN/A
- statusinclusion stopped: follow-up
- CONTACT FOR PUBLIC QUERIES L.C.J. Boome, te
- CONTACT for SCIENTIFIC QUERIESProf. Dr. J. Kuball
- Sponsor/Initiator University Medical Center Utrecht (UMCU)
- Funding
(Source(s) of Monetary or Material Support)
University Medical Center Utrecht (UMCU)
- PublicationsN/A
- Brief summaryRationale:
Patients suffering from high risk or relapsed leukaemia or high risk MDS can only occasionally be cured with conventional chemotherapy. Allogeneic stem cell transplantation (allo-SCT) has substantially improved the outcome of such patients due to a potent graft versus leukaemia effect after transplantation, but still for the high price of severe and life-threatening GvHD. Also relapses are still observed after allo-SCT. This study aims therefore to improve the outcome of this potent treatment modality by combining T-cell depleted allo-SCT with reduced toxicity and post-allo-SCT immunomodulations in order to enhance the anti-tumor-effect.

Objective:
To test feasibility and safety of alphabetaT-/CD19 B-cell depleted allo-SCT in high risk or relapsed acute leukaemia / MDS followed by an innate donor lymphocyte infusion (iDLI).

Study design:
Phase I/II study.

Study population:
Patients with high risk or relapsed acute leukaemia after high dose chemotherapy in remission and high risk MDS disease with less than 10% blasts in the bone marrow.

Intervention:
Myeloablative or non-myeloablative conditioning regime, alphabetaT-/CD19 B-cell depleted stem cell graft, short immunosuppression with ciclosporin, immunomodulation with zoledronic acid and innate donor lymphocyte infusion (iDLI).

Main study parameters/endpoints:
Feasibility with respect to engraftment, toxicity in terms of incidence of GvHD and infectious complications.

Nature and extent of the burden and risks associated with participation, benefit and group relatedness:
The protocol comprises a different processing of the donor stem cells source followed by innate DLI (iDLI). All other acts, measurements, follow-up and level of care are similar to off-study patients undergoing allo-SCT. The burden of the therapy is associated with the allo-SCT itself which is a necessary therapeutic intervention in all subjects. Possible increased risks of acute (a) and chronic (c) GvHD exist due to the earlier application of immune cells. There is a possible increased risk engraftment failure due to T cell depletion. However, we expect a lower mortality, secure engraftment, and less relapse and infection due to NK- and γδT-cell activity as well as a lower risk of aGvHD and cGvHD.
- Main changes (audit trail)
- RECORD7-aug-2010 - 12-jul-2012


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