Total Lymphoid Irradiation Pre-HSCT in Severe Congenital Neutropenia

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

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Severe Congenital Neutropenia; GATA2 Deficiency
• Intervention / Treatment: Other: conditioning with TLI

• Study Type: Interventional
• Enrollment (Anticipated): 10
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Dmitry Balashov, MD, PhD; Phone Number: 84956647078; Email: Dmitriy.Balashov@fccho-moscow.ru
• Study Contact Backup: Name: Alexandra Laberko, MD; Phone Number: 6223 84956647078

Study Locations

• Russian Federation
  • Moscow, Russian Federation, 117198
    • HSCT department
    • Contact: Dmitry Balashov, MD, PhD; Phone Number: 84956647078; Email: Dmitriy.Balashov@fccho-moscow.ru

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 21 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: intervention/treatment; 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	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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival		2 years post HSCT
event free survival	events - death, graft failure, secondary malignancy, relapse of malignancy	2 years post HSCT

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cumulative incidence of transplant related mortality		2 years post HSCT
Cumulative incidence of graft failure	non-engraftment, secondary graft rejection, severe non-reversible bone marrow failure	2 years post HSCT
Cumulative incidence of graft versus host disease		2 years post HSCT
number of patients with donor chimerism		2 years post HSCT
Incidence of secondary malignancies	number of patients	2 years post HSCT
Cumulative incidence of engraftment		100 days post HSCT
Incidence of early severe organ toxicity	number of patients	100 days post HSCT
cumulative incidence of infectious complications	infectious complication - CMV, EVB, ADV reactivation	1 year after HSCT

Collaborators and Investigators

• Sponsor: Federal Research Institute of Pediatric Hematology, Oncology and Immunology

Study record dates

Study Major Dates

• Study Start (Anticipated): April 14, 2021
• Primary Completion (Anticipated): April 1, 2024
• Study Completion (Anticipated): April 1, 2026

Study Registration Dates

• First Submitted: April 9, 2021
• First Submitted That Met QC Criteria: April 9, 2021
• First Posted (Actual): April 14, 2021

Study Record Updates

• Last Update Posted (Actual): April 14, 2021
• Last Update Submitted That Met QC Criteria: April 9, 2021
• Last Verified: April 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Bone Marrow Diseases; Hematologic Diseases; Genetic Diseases, Inborn; Agranulocytosis; Leukopenia; Leukocyte Disorders; Myelodysplastic Syndromes; Neutropenia; GATA2 Deficiency
• Other Study ID Numbers: NCPHOI-2021-02

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No