GATA2 Deficiency, Severe Congenital Neutropenia
Conditions
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.
Interventions
OTHERconditioning 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
Sponsors
Federal Research Institute of Pediatric Hematology, Oncology and Immunology
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Months to 21 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| event free survival | 2 years post HSCT | events - death, graft failure, secondary malignancy, relapse of malignancy |
| Overall survival | 2 years post HSCT | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cumulative incidence of graft failure | 2 years post HSCT | non-engraftment, secondary graft rejection, severe non-reversible bone marrow failure |
| Cumulative incidence of graft versus host disease | 2 years post HSCT | — |
| number of patients with donor chimerism | 2 years post HSCT | — |
| cumulative incidence of infectious complications | 1 year after HSCT | infectious complication - CMV, EVB, ADV reactivation |
| Cumulative incidence of engraftment | 100 days post HSCT | — |
| Incidence of early severe organ toxicity | 100 days post HSCT | number of patients |
| Incidence of secondary malignancies | 2 years post HSCT | number of patients |
| Cumulative incidence of transplant related mortality | 2 years post HSCT | — |
Countries
Russia
Contacts
Primary ContactDmitry Balashov, MD, PhD
Backup ContactAlexandra Laberko, MD
Outcome results
None listed