Total Lymphoid Irradiation Pre-HSCT in Severe Congenital Neutropenia

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Severe Congenital Neutropenia, GATA2 Deficiency

Intervention / Treatment
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* Other: conditioning with TLI


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Months
Maximum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: intervention/treatment<br>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<br>* 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<br>|

What is the study measuring?
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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 |