Total Lymphoid Irradiation Pre-HSCT in Severe Congenital Neutropenia

NCT04844177 | Not Yet Recruiting Phase 2

• 1 other identifier: NCPHOI-2021-02
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 1

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.

Conditions

Severe Congenital Neutropenia; GATA2 Deficiency

Outcome Measures

Primary Outcomes (2)

• Overall survival

  2 years post HSCT

• event free survival

  events - death, graft failure, secondary malignancy, relapse of malignancy

  2 years post HSCT

Secondary Outcomes (8)

• Cumulative incidence of transplant related mortality

  2 years post HSCT

• Cumulative incidence of graft 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

  2 years post HSCT

Study Arms (1)

intervention/treatment

EXPERIMENTAL

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

Interventions

conditioning with TLI OTHER

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/treatment

Eligibility Criteria

• Age: 18 Months - 21 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

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

Study Sites (1)

HSCT department

Moscow, 117198, Russia

Location

MeSH Terms

Conditions

Neutropenia, Severe Congenital, Autosomal Recessive 3; GATA2 Deficiency

Condition Hierarchy (Ancestors)

Myelodysplastic Syndromes; Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Central Study Contacts

Dmitry Balashov, MD, PhD

CONTACT

84956647078; Dmitriy.Balashov@fccho-moscow.ru

Alexandra Laberko, MD

CONTACT

84956647078

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 9, 2021
• First Posted: April 14, 2021
• Study Start: April 14, 2021
• Primary Completion: April 1, 2024
• Study Completion: April 1, 2026
• Last Updated: April 14, 2021

Record last verified: 2021-04

Locations

RU (1)