Treosulfan-Based Conditioning Regimen in Haematopoietic Stem Cell Transplantation with TCRαβ/CD19 Depletion in Nijmegen Breakage Syndrome.

Laberko, Alexandra; Sultanova, Elvira; Gutovskaya, Elena; Радыгина, С. А.; Deripapa, Elena; Кантулаева, А. К.; Trakhtman, Pavel; Brilliantova, Varvara; Starichkova, Julia; Shcherbina, Anna; Maschan, Michael; Maschan, Alexei

doi:10.1007/s10875-020-00811-9

Cited by 6 publications

(4 citation statements)

References 28 publications

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“…Taking into account a progressive immunodeficiency with deteriorating clinical state and extremely high risk of first and subsequent lymphoid malignancies with uncertain curative potential, allogeneic HSCT with RIC may be a rational therapeutic option for NBS patients with severe defects of immune function and for any NBS patients with lymphoid malignancy in first remission ( 14 ). However, the biggest Russian NBS study group reported that an RIC was a reason for a high level of graft failure and mixed chimerism in NBS patients ( 20 ).…”

Section: Discussionmentioning

confidence: 99%

Geographical Distribution, Incidence, Malignancies, and Outcome of 136 Eastern Slavic Patients With Nijmegen Breakage Syndrome and NBN Founder Variant c.657_661del5

et al. 2021

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Nijmegen breakage syndrome (NBS) is a DNA repair disorder characterized by combined immunodeficiency and a high predisposition to lymphoid malignancies. The majority of NBS patients are identified with a homozygous five base pair deletion in the Nibrin (NBN) gene (c.657_661del5, p.K219fsX19) with a founder effect observed in Caucasian European populations, especially of Slavic origin. We present here an analysis of a cohort of 136 NBS patients of Eastern Slav origin across Belarus, Ukraine, Russia, and Latvia with a focus on understanding the geographic distribution, incidence of malignancy, and treatment outcomes of this cohort. Our analysis shows that Belarus had the highest prevalence of NBS (2.3 per 1,000,000), followed by Ukraine (1.3 per 1,000,000), and Russia (0.7 per 1,000,000). Of note, the highest concentration of NBS cases was observed in the western regions of Belarus and Ukraine, where NBS prevalence exceeds 20 cases per 1,000,000 people, suggesting the presence of an “Eastern Slavic NBS hot spot.” The median age at diagnosis of this cohort ranged from 4 to 5 years, and delay in diagnosis was more pervasive in smaller cities and rural regions. A total of 62 (45%) patients developed malignancies, more commonly in males than females (55.2 vs. 34.2%; p=0.017). In 27 patients, NBS was diagnosed following the onset of malignancies (mean age: 8 years). Malignancies were mostly of lymphoid origin and predominantly non-Hodgkin lymphoma (NHL) (n=42, 68%); 38% of patients had diffuse large B-cell lymphoma. The 20-year overall survival rate of patients with malignancy was 24%. However, females with cancer experienced poorer event-free survival rates than males (16.6% vs. 46.8%, p=0.036). Of 136 NBS patients, 13 underwent hematopoietic stem cell transplantation (HSCT) with an overall survival of 3.5 years following treatment (range: 1 to 14 years). Indications for HSCT included malignancy (n=7) and immunodeficiency (n=6). Overall, 9% of patients in this cohort reached adulthood. Adult survivors reported diminished quality of life with significant physical and cognitive impairments. Our study highlights the need to improve timely diagnosis and clinical management of NBS among Eastern Slavs. Genetic counseling and screening should be offered to individuals with a family history of NBS, especially in hot spot regions.

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Section: Discussionmentioning

confidence: 99%

Geographical Distribution, Incidence, Malignancies, and Outcome of 136 Eastern Slavic Patients With Nijmegen Breakage Syndrome and NBN Founder Variant c.657_661del5

et al. 2021

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“…42,[93][94][95] A recent publication of a treosulfan-based conditioning regimen followed by TCRαβ/CD19depleted HSCT in 10 patients with Nijmegen breakage syndrome demonstrated a low level of early transplant-associated toxicity and enhanced graft function with stable donor chimerism. 96…”

Section: Dna-repair Defectsmentioning

confidence: 99%

Treosulfan-based conditioning for inborn errors of immunity

Slatter

Gennery

2021

Therapeutic Advances in Hematology

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Inborn errors of immunity (IEI) are inherited disorders that lead to defects in the development and/or function of the immune system. The number of disorders that can be treated by haematopoietic stem-cell transplantation (HSCT) has increased rapidly with the advent of next-generation sequencing. The methods used to transplant children with IEI have improved dramatically over the last 20 years. The introduction of reduced-toxicity conditioning is an important factor in the improved outcome of HSCT. Treosulfan has myeloablative and immunosuppressive properties, enabling engraftment with less toxicity than traditionally used doses of busulfan. It is firmly incorporated into the conditioning guidelines of the Inborn Errors Working Party of the European Society for Blood and Marrow Transplantation. Unlike busulfan, pharmacokinetically guided dosing of treosulfan is not part of routine practice, but data are emerging which indicate that further improvements in outcome may be possible, particularly in infants who have a decreased clearance of treosulfan. It is likely that individualized dosing, not just of treosulfan, but of all agents used in conditioning regimens, will be developed and implemented in the future. This will lead to a reduction in unwanted variability in drug exposure, leading to more predictable and adjustable exposure, and improved outcome of HSCT, with fewer late adverse effects and improved quality of life. Such conditioning regimens can be used as the basis to study the need for additional agents in certain disorders which are difficult to engraft or require high levels of donor chimerism, the dosing of individual cellular components within grafts, and effects of adjuvant cellular or immunotherapy post-transplant. This review documents the establishment of treosulfan worldwide, as a safe and effective agent for conditioning children with IEI prior to HSCT.

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“…Most patients received modified Fanconi RIC based on fludarabine, and cyclophosphamide with or without antithymocyte globulin therapy [2,3,53,54]. Laberko et al reported that a conditioning regimen with treosulfan 30 g/m 2 demonstrated a low level of early transplanted-associated toxicity, and enhanced graft function with stable donor chimerism in comparison to regimen with busulfan [55].…”

Section: Treatment Strategies Of Lymphoid Malignancies In Nbsmentioning

confidence: 99%

Diagnostic and therapeutic approach to children with Nijmegen breakage syndrome in relation to development of lymphoid malignancies

Filipiuk¹,

Kozakiewicz²,

Kośmider³

et al. 2021

Ann Agric Environ Med.

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Treosulfan-Based Conditioning Regimen in Haematopoietic Stem Cell Transplantation with TCRαβ/CD19 Depletion in Nijmegen Breakage Syndrome.

Cited by 6 publications

References 28 publications

Geographical Distribution, Incidence, Malignancies, and Outcome of 136 Eastern Slavic Patients With Nijmegen Breakage Syndrome and NBN Founder Variant c.657_661del5

Geographical Distribution, Incidence, Malignancies, and Outcome of 136 Eastern Slavic Patients With Nijmegen Breakage Syndrome and NBN Founder Variant c.657_661del5

Treosulfan-based conditioning for inborn errors of immunity

Diagnostic and therapeutic approach to children with Nijmegen breakage syndrome in relation to development of lymphoid malignancies

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