Total Lymphoid Irradiation Pre-HSCT in Severe Congenital Neutropenia
Primary Purpose
Severe Congenital Neutropenia, GATA2 Deficiency
Status
Not yet recruiting
Phase
Phase 2
Locations
Russian Federation
Study Type
Interventional
Intervention
conditioning with TLI
Sponsored by
About this trial
This is an interventional treatment trial for Severe Congenital Neutropenia
Eligibility Criteria
Inclusion Criteria:
- Clinical indications for HSCT in SCN: clinical diagnosis of SCN with (1) no adequate response to G-CST therapy or (2) with malignant transformation or (3) unfavorable mutations of known SCN genes
- GATA2 deficiency
- SCN patients age at HSCT 18 months - 21 years
- GATA2 deficiency patients age at HSCT more than 10 years
- Signed informed consent to participate in the study
- Presence of HLA-matched unrelated or HLA-mismatched related donor
Exclusion Criteria:
- Presence of HLA matched related donor in absence of pathologic SCN gene mutation
- Inability to perform TCRab/CD19 graft depletion
- Contraindications for HSCT due to patients somatic condition
Sites / Locations
- HSCT department
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
intervention/treatment
Arm Description
Total lymphoid irradiation 4 Gy (days -7, -6) in combination with: Fludarabine 150 mg/m2 (days-6, -5, -4, -3, -2) Cyclophosphamide 120 mg/kg (days -5, -4, -3) Thymoglogulin (Genzyme) 5 mg/kg (days -5, -4) Melphalan 180 mg/m2 (day -2) Rituximab 100 mg/m2 (day -1) Hematopoietic stem cell graft infusion after TCRab/CD19 depletion - day 0
Outcomes
Primary Outcome Measures
Overall survival
event free survival
events - death, graft failure, secondary malignancy, relapse of malignancy
Secondary Outcome Measures
Cumulative incidence of transplant related mortality
Cumulative incidence of graft failure
non-engraftment, secondary graft rejection, severe non-reversible bone marrow failure
Cumulative incidence of graft versus host disease
number of patients with donor chimerism
Incidence of secondary malignancies
number of patients
Cumulative incidence of engraftment
Incidence of early severe organ toxicity
number of patients
cumulative incidence of infectious complications
infectious complication - CMV, EVB, ADV reactivation
Full Information
NCT ID
NCT04844177
First Posted
April 9, 2021
Last Updated
April 9, 2021
Sponsor
Federal Research Institute of Pediatric Hematology, Oncology and Immunology
1. Study Identification
Unique Protocol Identification Number
NCT04844177
Brief Title
Total Lymphoid Irradiation Pre-HSCT in Severe Congenital Neutropenia
Official Title
Pilot Prospective Clinical Study of Safety and Efficacy of Conditioning Regimen With Total Lymphoid Irradiation Before Allogeneic Hematopoietic Stem Cell Transplantation With TCRab/CD19 Graft Depletion in Severe Congenital Neutropenia
Study Type
Interventional
2. Study Status
Record Verification Date
April 2021
Overall Recruitment Status
Not yet recruiting
Study Start Date
April 14, 2021 (Anticipated)
Primary Completion Date
April 2024 (Anticipated)
Study Completion Date
April 2026 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Federal Research Institute of Pediatric Hematology, Oncology and Immunology
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
5. Study Description
Brief Summary
Severe congenital neutropenia (SCN) is a group of primary immunodeficiencies caused by distinct gene mutations and characterized by neutrophil maturation impairment, which leads to neutropenia, predisposition to severe bacterial and fungal infections, and myeloid malignancies. Granulocyte-colony stimulation factor is used for pathogenetic therapy, however, no adequate response is seen in some patients.
The only curative option for SCN is hematopoietic stem cell transplantation (HSCT). An indication for HSCT in SCN is: no adequate response to G-CSF therapy, or development of malignancies, or found unfavorable mutations of SCN genes, leading to poor response to G-CSF and high risk of malignant transformation.
One of the major peculiarities of HSCT in SCN is a high risk of graft failure. That was described in few studies in SCN transplantation and was also observed in our SCN HSCT cohort. We also consider the role of TCRab/CD19 graft depletion, which is routinely used in our center for GVHD prophylaxis in increased risks of graft failure.
Another problem often observed in our patients is the relatively high risks of death of infections, developed after graft failure.
Due to predominantly early HSCT graft failure development, non-sufficient immuablation is presumed as the main reason for graft failure. Because of the low level of toxicity, associated with TCRab/CD19 depletion usage, this strategy is planned to be used in the current study. To increase an immunoablative potential of conditioning regimen in SCN, total lymphoid irradiation will be studied in combination with myeloablative agents and standardly used serotherapy.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Severe Congenital Neutropenia, GATA2 Deficiency
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
10 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
intervention/treatment
Arm Type
Experimental
Arm Description
Total lymphoid irradiation 4 Gy (days -7, -6) in combination with:
Fludarabine 150 mg/m2 (days-6, -5, -4, -3, -2)
Cyclophosphamide 120 mg/kg (days -5, -4, -3)
Thymoglogulin (Genzyme) 5 mg/kg (days -5, -4)
Melphalan 180 mg/m2 (day -2)
Rituximab 100 mg/m2 (day -1)
Hematopoietic stem cell graft infusion after TCRab/CD19 depletion - day 0
Intervention Type
Other
Intervention Name(s)
conditioning with TLI
Intervention Description
Total lymphoid irradiation 4 Gy (days -7, -6) in combination with:
Fludarabine 150 mg/m2 (days-6, -5, -4, -3, -2)
Cyclophosphamide 120 mg/kg (days -5, -4, -3)
Thymoglogulin (Genzyme) 5 mg/kg (days -5, -4)
Melphalan 180 mg/m2 (day -2)
Rituximab 100 mg/m2 (day -1)
Hematopoietic stem cell graft infusion after TCRab/CD19 depletion - day 0
Primary Outcome Measure Information:
Title
Overall survival
Time Frame
2 years post HSCT
Title
event free survival
Description
events - death, graft failure, secondary malignancy, relapse of malignancy
Time Frame
2 years post HSCT
Secondary Outcome Measure Information:
Title
Cumulative incidence of transplant related mortality
Time Frame
2 years post HSCT
Title
Cumulative incidence of graft failure
Description
non-engraftment, secondary graft rejection, severe non-reversible bone marrow failure
Time Frame
2 years post HSCT
Title
Cumulative incidence of graft versus host disease
Time Frame
2 years post HSCT
Title
number of patients with donor chimerism
Time Frame
2 years post HSCT
Title
Incidence of secondary malignancies
Description
number of patients
Time Frame
2 years post HSCT
Title
Cumulative incidence of engraftment
Time Frame
100 days post HSCT
Title
Incidence of early severe organ toxicity
Description
number of patients
Time Frame
100 days post HSCT
Title
cumulative incidence of infectious complications
Description
infectious complication - CMV, EVB, ADV reactivation
Time Frame
1 year after HSCT
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Months
Maximum Age & Unit of Time
21 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Clinical indications for HSCT in SCN: clinical diagnosis of SCN with (1) no adequate response to G-CST therapy or (2) with malignant transformation or (3) unfavorable mutations of known SCN genes
GATA2 deficiency
SCN patients age at HSCT 18 months - 21 years
GATA2 deficiency patients age at HSCT more than 10 years
Signed informed consent to participate in the study
Presence of HLA-matched unrelated or HLA-mismatched related donor
Exclusion Criteria:
Presence of HLA matched related donor in absence of pathologic SCN gene mutation
Inability to perform TCRab/CD19 graft depletion
Contraindications for HSCT due to patients somatic condition
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Dmitry Balashov, MD, PhD
Phone
84956647078
Email
Dmitriy.Balashov@fccho-moscow.ru
First Name & Middle Initial & Last Name or Official Title & Degree
Alexandra Laberko, MD
Phone
84956647078
Ext
6223
Facility Information:
Facility Name
HSCT department
City
Moscow
ZIP/Postal Code
117198
Country
Russian Federation
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Dmitry Balashov, MD, PhD
Phone
84956647078
Email
Dmitriy.Balashov@fccho-moscow.ru
12. IPD Sharing Statement
Learn more about this trial
Total Lymphoid Irradiation Pre-HSCT in Severe Congenital Neutropenia
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