Lymphoblastic Leukemia, Lymphoma, Multiple Myeloma, Myelodysplastic Syndrome, Myeloid Leukemia, Myeloproliferative Disorders
Conditions
Keywords
Haploidentical stem cell transplantation, Graft-versus-host disease, Immune reconstitution, Alloreactive T-cells, Photodepletion, TH9402, Transplant related mortality, Hematologic malignancy
Brief summary
The purpose of this study is to determine whether the administration of a donor lymphocyte preparation depleted of functional host alloreactive T-cells (ATIR) after a T-cell depleted stem cell transplant from a related, haploidentical donor enhances survival by improving the immune effect against infections while preventing graft-versus-host disease .
Detailed description
Allogeneic stem cell transplantation is the treatment of choice for many patients with leukemia and other hematologic malignancies. However, a major limitation of this therapy is that for a significant number of patients no fully HLA-matched donor can be found. The application of partially HLA-matched (haploidentical) family donors, who are virtually always available, has some complications. If there is no T-cell add-back it increases the risk for life-threatening infections and disease relapse, while in case of T-cell add-back the risk for graft-versus-host disease is raised. Kiadis Pharma has developed a method to selectively deplete host alloreactive T-cells through photodynamic therapy, using TH9402 ex vivo. The donor lymphocyte preparation depleted of functional host alloreactive T-cells (ATIR) is administered to the patient 28-42 days after the stem cell transplant.
Interventions
BIOLOGICALDonor lymphocyte preparation depleted of host functional alloreactive T-cells
Single intravenous infusion with 2x10E6 T-cells/kg
Sponsors
Kiadis Pharma
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
One of the following hematological malignancies: * Acute Myeloid Leukemia (AML) * Acute Lymphoblastic Leukemia (ALL) * Myelodysplastic Syndrome (MDS) * Ph-positive chronic myeloid leukemia (CML) * Non-Hodgkin Lymphoma (NHL) * Myelodysplastic Syndrome (MDS) * Chronic Myeloid Leukemia (CML) * Multiple Myeloma (MM) * Chronic Lymphocytic Leukemia (CLL) * Myeloproliferative Syndrome (MPS)
Exclusion criteria
* AML in 1st complete remission with good risk karyotypes * MM featuring concurrent extramedullar disease or being non-responsive to prior therapy * CML in blast crisis * CLL concurrently transformed into high-grade lymphoma and failing to demonstrate at least partial remission * NHL with concurrent bulky disease (≥ 5 cm) * Diffusing Capacity for Carbon Monoxide (DLCO) \< 40% predicted * Left ventricular ejection fraction \< 40% * AST/SGOT \> 2.5 x ULN * Bilirubin \> 1.5 x ULN * Creatinine \> 1.5 x ULN * HIV positive * Positive pregnancy test for women of childbearing age * Prior haploidentical peripheral blood stem cell or cord blood transplantation * Less than 2 years from a prior allogeneic stem cell transplantation * Estimated probability of surviving less than three months * Major anticipated illness or organ failure incompatible with survival from transplant * Severe psychiatric illness or mental deficiency sufficiently severe as to make compliance with the transplant treatment unlikely and informed consent impossible * Known allergy to any of the components of ATIR * Any other condition which, in the opinion of the investigator, makes the patient ineligible for the study Donor Inclusion Criteria: * Haploidentical family donor with 2 to 3 mismatches at the HLA-A, -B and/or DR loci of the unshared haplotype. * Male or female, age ≥ 16, ≤ 75 years. * Donors must be fit to receive G-CSF and undergo apheresis (normal blood count, normotensive and no history of stroke). * Donor must have Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less. * Donor must provide written informed consent. Donor
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Transplant Related Mortality | 6, 12 and 24 months after the transplantation | TRM is defined as death due to causes other than disease relapse or progression, or other causes which are unrelated to the transplantation procedure (e.g. accident, suicide) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival | Up to 24 months after the transplantation | — |
| Incidence and Severity of Bacterial, Viral or Fungal Infection | Up to 24 months after the transplantation | — |
| Incidence and Severity Graft-versus-host Disease (GVHD) | Up to 24 months after the transplantation | GVHD was graded according to standard criteria as referred to in the reference module (Filipovich et al. 2005; Przepiorka et al. 1995). |
| Health Status (Including Quality of Life) | Up to 24 months after the transplantation | — |
| Overall Survival | 6, 12, and 24 months after the transplantation | — |
| Immune Reconstitution | Up to 24 months after the transplantation | — |
Countries
Belgium, Canada, Germany, Italy, Netherlands, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| ATIR Donor lymphocyte preparation depleted of host functional alloreactive T-cells: Single intravenous infusion with 2x10E6 T-cells/kg | 40 |
| Total | 40 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 24 |
| Overall Study | Lost to Follow-up | 1 |
| Overall Study | Relapse | 1 |
| Overall Study | Study termination by sponsor | 12 |
Baseline characteristics
| Characteristic | ATIR |
|---|---|
| Age, Continuous | 45 years |
| Donor HLA compatibility (HLA-A, -B, -DR) Donor HLA compatibility (HLA-A, -B, -DR): 3/6 | 27 Participants |
| Donor HLA compatibility (HLA-A, -B, -DR) Donor HLA compatibility (HLA-A, -B, -DR): 4/6 | 13 Participants |
| Hematologic malignancy Acute lymphatic leukemia | 5 Participants |
| Hematologic malignancy Acute myeloid leukemia | 22 Participants |
| Hematologic malignancy Chronic myeloid leukemia | 1 Participants |
| Hematologic malignancy Myelodysplastic syndrome | 3 Participants |
| Hematologic malignancy Myeloproliferative syndrome | 1 Participants |
| Hematologic malignancy Other acute leukemia | 2 Participants |
| Hematologic malignancy Other leukemia | 3 Participants |
| Hematologic malignancy Plasma cell disorder | 3 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 36 Participants |
| Sex: Female, Male Female | 16 Participants |
| Sex: Female, Male Male | 24 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 15 / 40 |
| serious Total, serious adverse events | 9 / 40 |
Outcome results
Primary
Transplant Related Mortality
TRM is defined as death due to causes other than disease relapse or progression, or other causes which are unrelated to the transplantation procedure (e.g. accident, suicide)
Time frame: 6, 12 and 24 months after the transplantation
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| ATIR | Transplant Related Mortality | TRM at 6 months post HSCT | 33 Kaplan-Meier estimates (%) |
| ATIR | Transplant Related Mortality | TRM at 12 months post HSCT | 56 Kaplan-Meier estimates (%) |
| ATIR | Transplant Related Mortality | TRM at 24 months post HSCT | 71 Kaplan-Meier estimates (%) |
Secondary
Health Status (Including Quality of Life)
Time frame: Up to 24 months after the transplantation
Population: Data were not collected, premature termination of study
Secondary
Immune Reconstitution
Time frame: Up to 24 months after the transplantation
Population: Data were not collected, premature termination of study
Secondary
Incidence and Severity Graft-versus-host Disease (GVHD)
GVHD was graded according to standard criteria as referred to in the reference module (Filipovich et al. 2005; Przepiorka et al. 1995).
Time frame: Up to 24 months after the transplantation
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| ATIR | Incidence and Severity Graft-versus-host Disease (GVHD) | Grade II acute GVHD (moderate) | 7.5 Percentage of participants |
| ATIR | Incidence and Severity Graft-versus-host Disease (GVHD) | Grade III (moderate) or IV (severe) acute GVHD | 12.5 Percentage of participants |
| ATIR | Incidence and Severity Graft-versus-host Disease (GVHD) | Severe chronic GVHD | 5 Percentage of participants |
Secondary
Incidence and Severity of Bacterial, Viral or Fungal Infection
Time frame: Up to 24 months after the transplantation
Population: Data not collected, premature termination of study
Secondary
Overall Survival
Time frame: 6, 12, and 24 months after the transplantation
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| ATIR | Overall Survival | OS 6 months after the HSCT | 65 Kaplan-Meier estimates (%) |
| ATIR | Overall Survival | OS 12 months after the HSCT | 33 Kaplan-Meier estimates (%) |
| ATIR | Overall Survival | OS 24 months after the HSCT | 22 Kaplan-Meier estimates (%) |
Secondary
Progression Free Survival
Time frame: Up to 24 months after the transplantation
Population: Data were not collected, premature termination of study