Total Lymphoid Irradiation Pre-HSCT in Severe Congenital Neutropenia

Severe Congenital Neutropenia Clinical Trial

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

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT04844177
• Other study ID #: NCPHOI-2021-02
• Status: Not yet recruiting
• Phase: Phase 2
• Start date: April 14, 2021
• Est. completion date: April 2026

Study information

• Verified date: April 2021
• Source: Federal Research Institute of Pediatric Hematology, Oncology and Immunology
• Contact: Dmitry Balashov, MD, PhD
• Phone: 84956647078
• Email: Dmitriy.Balashov[@]fccho-moscow.ru
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 10
• Est. completion date: April 2026
• Est. primary completion date: April 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Months to 21 Years

Eligibility

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

Related Conditions & MeSH terms

• GATA2 Deficiency
• Neutropenia
• Severe Congenital Neutropenia

Intervention

Other:
• conditioning with TLI
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

Locations

Country	Name	City	State
Russian Federation	HSCT department	Moscow

Sponsors (1)

Lead Sponsor	Collaborator
Federal Research Institute of Pediatric Hematology, Oncology and Immunology

Country where clinical trial is conducted

Russian Federation, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall survival		2 years post HSCT
Primary	event free survival	events - death, graft failure, secondary malignancy, relapse of malignancy	2 years post HSCT
Secondary	Cumulative incidence of transplant related mortality		2 years post HSCT
Secondary	Cumulative incidence of graft failure	non-engraftment, secondary graft rejection, severe non-reversible bone marrow failure	2 years post HSCT
Secondary	Cumulative incidence of graft versus host disease		2 years post HSCT
Secondary	number of patients with donor chimerism		2 years post HSCT
Secondary	Incidence of secondary malignancies	number of patients	2 years post HSCT
Secondary	Cumulative incidence of engraftment		100 days post HSCT
Secondary	Incidence of early severe organ toxicity	number of patients	100 days post HSCT
Secondary	cumulative incidence of infectious complications	infectious complication - CMV, EVB, ADV reactivation	1 year after HSCT