• To assess feasibility and safety of a sequential treatment regime in which standard intensive chemotherapy (fludarabin-amsacrin-cytarabin) is directly followed by standard allogeneic stem cell transplantation (T cell depleted RIC alloSCT with…
ID
Source
Brief title
Condition
- Leukaemias
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
• The number of patients eligible for DLI at 6 months after transplantation
• Incidence of non-hematological grade 3-4 toxicity from the start of
chemotherapy until 9 months after transplantation
• Incidence of serious adverse events from the start of chemotherapy until 9
months after transplantation
• Incidence of severe grade 3 or 4 acute GvHD and incidence of extensive
chronic GvHD in the first 9 months after transplantation
• Non-relapse mortality at 3 and 12 months after transplantation
Secondary outcome
• 1-year progression free survival after transplantation
• 1-year overall survival after transplantation
Background summary
Elderly patients aged over 60 years with AML or high risk MDS have a poor
prognosis, the only way to achieve long term survival is transplantation with
an allogeneic donor after achieving complete remission with intensive
chemotherapy. Most patients starting with intensive chemotherapy are not
transplanted, due to not achieving a complete remission with intensive
chemotherapy, due to declining condition during the multiple courses of
intensive chemotherapy with long periods of neutropenia or due to early relapse
after chemotherapy. Patients that are in remission after the first induction
chemotherapy and stay in remission after the second induction chemotherapy are
good candidates for standard reduced intensity conditioning allogeneic stem
cell transplantation. Patients that are not in remission after the first
induction chemotherapy (50% of patients starting with induction chemotherapy)
have a poor prognosis even if they are treated with the intention to reach
allogeneic stem cell transplantation. They either stop with the chemotherapy
treatments due to declining condition, they relapse before transplantation, or
relapse early after transplantation.
In this study we want to explore the feasibility of the sequential use of
FLAMSA chemotherapy and our standard T cell depleted reduced intensity
conditioning allogeneic stem cell transplantation, followed by our standard
donor lymphocyte infusion regimen for high risk disease starting at 3 months
after transplantation. This treatment regimen combines a well known effective
induction regimen (amsacrine-cytarabine) with a relatively non-toxic allogeneic
transplantation conditioning regimen in combination with donor lymphocyte
infusion at 3 and 6 months after transplantation.
With this TCD FLAMSA-RIC alloSCT regimen we hope to cure patients that are not
in remission after the first induction therapy, a patient group known to have a
poor prognosis when treated with further chemotherapy courses followed by
allogeneic stem cell transplantation. Patients in remission after induction
chemotherapy and in continuous remission after consolidation therapy have a
good curative chance with standard RIC alloSCT and will therefore not be
included in the study.
Study objective
• To assess feasibility and safety of a sequential treatment regime in which
standard intensive chemotherapy (fludarabin-amsacrin-cytarabin) is directly
followed by standard allogeneic stem cell transplantation (T cell depleted RIC
alloSCT with donor lymphocyte infusion at 3 and 6 months) , in elderly
patients with AML or high risk myelodysplastic syndrome (IPSS >=1.5).
• To evaluate the incidence of non-relapse mortality.
• To evaluate progression free survival and overall survival
Study design
Phase 1-2 feasibility study.
Intervention
Patients will receive FLAMSA chemotherapy over the course of 5 days. After a 3
day rest, the conditioning of the allogeneic stem cell transplantation is
started. T cell depletion of the patient consists of alemtuzumab in patients
transplanted with a related donor and alemtuzumab in combination with rabbit
ATG (Thymoglobulin) in unrelated patients. No further immunosuppressive drugs
are given after transplantation. All patients are to be treated with donor
lymphocyte infusions at 3 and 6 months after transplantation. A total of 15
patients will be included in the study.
Study burden and risks
Elderly patients with AML or high risk MDS have a poor prognosis; the only way
to achieve long term survival is transplantation with an allogeneic donor. Most
patients starting with intensive chemotherapy are not transplanted, due to not
achieving a complete remission with intensive chemotherapy, due to declining
condition during the courses of intensive chemotherapy with long periods of
neutropenia or due to early relapse after achieving a complete remission.
Especially patients that are not in remission after the first induction
chemotherapy have a dismal prognosis with current therapies. In a retrospective
analysis of 20 patients not in remission after first induction chemotherapy, 16
patients received a second induction chemotherapy; 10 of these patients
achieved a CR, 7 patients received a third chemotherapy course for
consolidation, and 4 underwent RIC alloSCT. However, there were no long-term
survivors in this group of 20 patients.
At the moment our standard therapy for high risk acute myeloid leukemia is
induction chemotherapy followed by consolidation chemotherapy in case of the
achievement of a complete remission, followed by T cell depleted reduced
intensity allogeneic stem cell transplantation and donor lymphocyte infusion at
3 and 6 months after transplantation. Because of the dismal prognosis that
patients have when they are not in complete remission after the first
induction, even despite further intensive chemotherapy and allogeneic stem cell
transplantation, further treatment with standard chemotherapy and
transplantation protocols is questionable in these patients.
In this study we explore the feasibility of the sequential use of FLAMSA
chemotherapy and T cell depleted reduced intensity conditioning allogeneic stem
cell transplantation followed by donor lymphocyte infusion at 3 and 6 months
after transplantation in patients that are not in complete remission after the
first induction chemotherapy. This treatment regimen combines an effective
chemotherapy regimen (amsacrine-cytarabine) with a relatively non-toxic
allogeneic transplantation conditioning regimen and a short time between
chemotherapy and the time point of DLI administration (3 months). With this TCD
FLAMSA-RIC alloSCT regimen we hope to be able to treat and cure more elderly
patients with AML and high risk MDS with allogeneic transplantation. The
benefit this treatment offers is a chance of curation, the risk is non-relapse
mortality which will be between 10 and 20%.
Albinusdreef 2
Leiden 2333 ZA
NL
Albinusdreef 2
Leiden 2333 ZA
NL
Listed location countries
Age
Inclusion criteria
• Patients with AML or high risk MDS
• Not in remission after first intensive induction chemotherapy
• 60-75 years, inclusive
• HLA-identical sibling or unrelated donor completely matched (10/10 for HLA A, B, C, DR, DQ)
• WHO-performance status 0-2
• Written informed consent
Exclusion criteria
• Previous autologous or allogeneic SCT
• Acute promyelocytic leukemia
• Severe pulmonary dysfunction (CTCAE grade III-IV, see appendix B);
• Severe cardiac dysfunction (NYHA classification 3-4, see appendix C).
• Significant hepatic dysfunction (serum bilirubin or transaminases >= 3 times upper limit of normal);
• Significant renal dysfunction (creatinine clearance < 30 ml/min after rehydration);
• Concurrent severe and/or uncontrolled medical condition (e.g. uncontrolled diabetes, infection, hypertension, cancer, etc.);
• Severe neurological or psychiatric disease;
• Any psychological, familial, sociological and geographical condition potentially hampering compliance with the study protocol and follow-up schedule
• Patient known to be HIV-positive
Design
Recruitment
Medical products/devices used
metc-ldd@lumc.nl
metc-ldd@lumc.nl
Followed up by the following (possibly more current) registration
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Other (possibly less up-to-date) registrations in this register
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In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2012-004421-24-NL |
| CCMO | NL42222.058.13 |