Safety and Efficacy of Donor T-lymphocytes Depleted ex Vivo of Host Alloreactive T-cells (ATIR) in Patients With a Hematologic Malignancy Who Received a Hematopoietic Stem Cell Transplantation From a Haploidentical Donor

Conditions

Acute Lymphoblastic Leukemia, Acute Myeloid Leukemia, Myelodysplastic Syndrome

Keywords

Haploidentical stem cell transplantation, Graft-versus-host disease, Immune reconstitution, Alloreactive T-cells, Photodepletion, Photodynamic treatment, TH9402, Transplant-related mortality, Hematologic malignancy

Brief summary

The purpose of this study is to determine whether ATIR is safe and effective in reducing transplant-related mortality and improving overall survival, when infused in patients with a hematologic malignancy following a T-cell depleted stem cell graft from a related haploidentical donor.

Detailed description

Study CR-AIR-007 is an exploratory, open-label, multicenter study. After signing informed consent, patients will receive a hematopoietic stem cell transplantation (HSCT) from a related, haploidentical donor, followed by infusion with ATIR between 28 and 32 days after the HSCT (or later if required by the patient's medical condition). Patients will receive ATIR as a single infusion at a dose of 2x10E6 viable T-cells/kg. All patients treated with ATIR will be followed up until 12 months after the HSCT. Assessments will be performed at weekly visits from the day of ATIR infusion until 8 weeks after ATIR infusion, at monthly visits from 3 until 6 months after the HSCT, every 2 months from 6 until 12 months after the HSCT, and every 6 months from 12 until 24 months after the HSCT.

Denis‐Claude Roy, Irwin Walker, Johan Maertens, Philippe Lewalle, Eduardo Olavarría et al. (11 authors)

Blood2019-11-13

10.1182/blood-2019-128344

A Single Dose of Donor Lymphocytes Depleted of Alloreactive T Cells (ATIR101) after Haploidentical HSCT Is Well-Tolerated and Efficacious: Pooled Analysis of Two Phase II Studies

Denis‐Claude Roy, Irwin Walker, Johan Maertens, Philippe Lewalle, Eduardo Olavarría et al. (11 authors)

Biology of Blood and Marrow Transplantation2019-01-311 citations

10.1016/j.bbmt.2018.12.274

Efficacy and Safety of a Single Dose of Donor Lymphocytes Depleted of Alloreactive T-Cells (ATIR101) Following T-Cell-Depleted Haploidentical HSCT: A Pooled Analysis of Two Phase II Studies

Denis‐Claude Roy, Irwin Walker, Johan Maertens, Philippe Lewalle, Eduardo Olavarría et al. (11 authors)

Blood2018-11-293 citations

10.1182/blood-2018-99-119086

Donor Lymphocytes Depleted of Alloreactive T-Cells (ATIR101) Improve Event-Free Survival (GRFS) and Overall Survival in a T-Cell Depleted Haploidentical HSCT: Phase 2 Trial in Patients with AML and ALL

Denis‐Claude Roy, Silvy Lachance, Jean Roy, Irwin Walker, Johan Maertens et al. (16 authors)

Blood2016-12-029 citations

10.1182/blood.v128.22.1226.1226

Donor Lymphocytes Depleted of Alloreactive T-Cells (ATIR101) Reduce Transplant Related Mortality and Improve Overall Survival in Haploidentical HSCT for Patients with AML and ALL, Using an Immunosuppressant-Free Transplant Regimen

Denis‐Claude Roy, Silvy Lachance, Jean Roy, Irwin Walker, Johan Maertens et al. (17 authors)

Blood2015-12-033 citations

10.1182/blood.v126.23.4391.4391

Selective Photodepletion of Recipient-Alloreactive T-Cells Enables Safe and Efficacious Haploidentical HSCT: Initial Results from a Phase 2 Trial in Patients with AML, ALL, and MDS

Denis‐Claude Roy, Johan Maertens, Irwin Walker, Silvy Lachance, Jean Roy et al. (14 authors)

Blood2014-12-064 citations

10.1182/blood.v124.21.314.314

Interventions

BIOLOGICALATIR

Donor T-lymphocytes depleted ex vivo of host alloreactive T-cells using photodynamic treatment. Single intravenous infusion with 2x10E6 viable T-cells/kg.

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

* Any of the following hematologic malignancies: a) Acute myeloid leukemia (AML) in first remission with high-risk features or in second or higher remission b) Acute lymphoblastic leukemia (ALL) in first remission with high-risk features or in second or higher remission c) Myelodysplastic syndrome (MDS): transfusion-dependent, or intermediate or higher Revised International Prognostic Scoring System (IPSS-R) risk group * Eligible for haploidentical stem cell transplantation according to the investigator

Exclusion criteria

* Availability of a suitable matched related or unrelated donor following a donor search * In second or higher remission with the previous remission having lasted less than 6 months * Diffusing capacity for carbon monoxide (DLCO) \< 50% predicted * Left ventricular ejection fraction \< 50% (evaluated by echocardiogram or multiple gated acquisition \[MUGA\]) * Aspartate aminotransferase (AST) \> 2.5 x upper limit of normal (ULN)(CTCAE grade 2) * Bilirubin \> 1.5 x ULN (CTCAE grade 2) * Creatinine clearance \< 50 mL/min (calculated or measured) * Positive test for human immunodeficiency virus (HIV) * Positive pregnancy test (women of childbearing age only) * Prior allogeneic stem cell transplantation using stem cells from a matched sibling donor, a matched unrelated donor, a haploidentical donor, or a cord blood donor * Prior autologous stem cell transplantation * Stay at intensive care unit for more than 2 months in the preceding 12 months * Estimated probability of surviving less than 3 months * Known allergy to any of the components of ATIR (e.g., dimethyl sulfoxide) * 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 human leukocyte antigen (HLA)-A, -B and/or -DR loci of the unshared haplotype * Male or female, age ≥ 16 and ≤ 75 years * Eligible for donation according to the transplantation center Donor

Design outcomes

Primary

Measure	Time frame	Description
Transplant-related Mortality (TRM)	At 6 months post HSCT	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). The TRM rate is displayed as a function of time using the Kaplan-Meier method. The TRM rate at 6 months post HSCT is estimated from this analysis.

Secondary

Measure	Time frame	Description
Relapse-related Mortality (RRM)	6, 12 and 24 months post HSCT	Defined as death due to disease relapse or disease progression. The Kaplan-Meier analysis resulted in estimates and 95% confidence intervals (CI)s.
Overall Survival (OS)	6, 12 and 24 months post HSCT	Defined as the time from HSCT until death from any cause. The Kaplan-Meier analysis resulted in estimates and 95% CIs.
Immune Reconstitution	Up to 24 months post HSCT	Immunophenotyping on peripheral blood samples by means of flow cytometry assessment of immune subsets was done if the absolute lymphocyte count was higher than 0.1×10E9/l
Number of Participants With Viral, Fungal, and Bacterial Infections.	Up to 24 months post HSCT	—
Number of Participants With Graft Versus Host Disease (GVHD)	Up to 24 months post HSCT	—
Progression-free Survival (PFS)	6, 12 and 24 months post HSCT	Defined as the time from HSCT until relapse, disease progression, or death, whichever occurs first. The Kaplan-Meier analysis resulted in estimates and 95% CIs.

Countries

Belgium, Canada, Germany, United Kingdom

Participant flow

Participants by arm

Arm	Count
ATIR ATIR: Donor T-lymphocytes depleted ex vivo of host alloreactive T-cells using photodynamic treatment. Single intravenous infusion with 2x10E6 viable T-cells/kg.	23
Total	23

Withdrawals & dropouts

Period	Reason	FG000
Overall Study	ATIR batch rejected	2
Overall Study	ATIR manufacturing not possible	1
Overall Study	Death	14
Overall Study	Discontinued from active follow-up	1
Overall Study	Graft failure	1
Overall Study	Relapse	2
Overall Study	Relapse and rejection of ATIR batch	1

Baseline characteristics

Characteristic	ATIR	—
Age, Continuous	34 years	—
Human leukocyte antigen (HLA)-match n (%) 3/6	16 Participants	—
Human leukocyte antigen (HLA)-match n (%) 4/6	6 Participants	—
Human leukocyte antigen (HLA)-match n (%) 5/6	1 Participants	—
Race and Ethnicity Not Collected	—	— Participants
Sex: Female, Male Female	13 Participants	—
Sex: Female, Male Male	10 Participants	—

Adverse events

Event type	EG000 affected / at risk
deaths Total, all-cause mortality	— / —
other Total, other adverse events	4 / 23
serious Total, serious adverse events	3 / 23

Outcome results

Primary

Transplant-related Mortality (TRM)

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). The TRM rate is displayed as a function of time using the Kaplan-Meier method. The TRM rate at 6 months post HSCT is estimated from this analysis.

Time frame: At 6 months post HSCT

Arm	Measure	Value (NUMBER)
ATIR	Transplant-related Mortality (TRM)	13 Kaplan-Meier estimates (%)

Secondary

Immune Reconstitution

Immunophenotyping on peripheral blood samples by means of flow cytometry assessment of immune subsets was done if the absolute lymphocyte count was higher than 0.1×10E9/l

Time frame: Up to 24 months post HSCT

Arm	Measure	Group	Value (COUNT_OF_PARTICIPANTS)
ATIR	Immune Reconstitution	Number of participants with CD3 counts above 0.1×10E9/l at 24 months follow up	18 Participants
ATIR	Immune Reconstitution	Number of participants with CD3 counts above 0.2×10E9/l at 24 months follow up	13 Participants

Secondary

Number of Participants With Graft Versus Host Disease (GVHD)

Time frame: Up to 24 months post HSCT

Arm	Measure	Group	Value (NUMBER)
ATIR	Number of Participants With Graft Versus Host Disease (GVHD)	Any GVHD, from ATIR infusion to 100 days after HSCT.	0 participants
ATIR	Number of Participants With Graft Versus Host Disease (GVHD)	Any GVHD, from HSCT to ATIR infusion	2 participants
ATIR	Number of Participants With Graft Versus Host Disease (GVHD)	Any GVHD, from 100 days to 6 months after HSCT.	3 participants
ATIR	Number of Participants With Graft Versus Host Disease (GVHD)	Any GVHD, from 6 months to 1 year after HSCT.	3 participants
ATIR	Number of Participants With Graft Versus Host Disease (GVHD)	Any GVHD, from 1 year to 2 years after HSCT.	4 participants

Secondary

Number of Participants With Viral, Fungal, and Bacterial Infections.

Time frame: Up to 24 months post HSCT

Arm	Measure	Group	Value (NUMBER)
ATIR	Number of Participants With Viral, Fungal, and Bacterial Infections.	Any infection, from HSCT to ATIR infusion	17 participants
ATIR	Number of Participants With Viral, Fungal, and Bacterial Infections.	Any infection, from ATIR infusion to 6 months after HSCT	19 participants
ATIR	Number of Participants With Viral, Fungal, and Bacterial Infections.	Any infection, from 6 months to 1 year after HSCT	13 participants
ATIR	Number of Participants With Viral, Fungal, and Bacterial Infections.	Any infection, from 1 year to 2 years after HSCT	12 participants

Secondary

Overall Survival (OS)

Defined as the time from HSCT until death from any cause. The Kaplan-Meier analysis resulted in estimates and 95% CIs.

Time frame: 6, 12 and 24 months post HSCT

Arm	Measure	Group	Value (NUMBER)
ATIR	Overall Survival (OS)	6 months post HSCT	83 Kaplan-Meier estimates (%)
ATIR	Overall Survival (OS)	12 months post HSCT	61 Kaplan-Meier estimates (%)
ATIR	Overall Survival (OS)	24 months post HSCT	39 Kaplan-Meier estimates (%)

Secondary

Progression-free Survival (PFS)

Defined as the time from HSCT until relapse, disease progression, or death, whichever occurs first. The Kaplan-Meier analysis resulted in estimates and 95% CIs.

Time frame: 6, 12 and 24 months post HSCT

Arm	Measure	Group	Value (NUMBER)
ATIR	Progression-free Survival (PFS)	6 months post HSCT	78 Kaplan-Meier estimates (%)
ATIR	Progression-free Survival (PFS)	12 months post HSCT	61 Kaplan-Meier estimates (%)
ATIR	Progression-free Survival (PFS)	24 months post HSCT	39 Kaplan-Meier estimates (%)

Secondary

Relapse-related Mortality (RRM)

Defined as death due to disease relapse or disease progression. The Kaplan-Meier analysis resulted in estimates and 95% confidence intervals (CI)s.

Time frame: 6, 12 and 24 months post HSCT

Arm	Measure	Group	Value (NUMBER)
ATIR	Relapse-related Mortality (RRM)	6 months post HSCT	5 Kaplan-Meier estimates (%)
ATIR	Relapse-related Mortality (RRM)	12 months post HSCT	10 Kaplan-Meier estimates (%)
ATIR	Relapse-related Mortality (RRM)	24 months post HSCT	25 Kaplan-Meier estimates (%)

Safety and Efficacy of Donor T-lymphocytes Depleted ex Vivo of Host Alloreactive T-cells (ATIR) in Patients With a Hematologic Malignancy Who Received a Hematopoietic Stem Cell Transplantation From a Haploidentical Donor

Conditions

Keywords

Brief summary

Detailed description

Related papers

Interventions

Sponsors

Study design

Eligibility

Inclusion criteria

Exclusion criteria

Design outcomes

Primary

Secondary

Countries

Participant flow

Participants by arm

Withdrawals & dropouts

Baseline characteristics

Adverse events

Outcome results

Transplant-related Mortality (TRM)

Immune Reconstitution

Number of Participants With Graft Versus Host Disease (GVHD)

Number of Participants With Viral, Fungal, and Bacterial Infections.

Overall Survival (OS)

Progression-free Survival (PFS)

Relapse-related Mortality (RRM)