Outcome of hematopoietic cell transplantation for DNA double-strand break repair disorders

Slack, James L.; Albert, Michael H.; Balashov, Dmitry; Belohradsky, Bernd H.; Bertaina, Alice; Bleesing, Jack J.; Booth, Claire; Buechner, Jochen; Buckley, Rebecca H.; Marie, O; Deripapa, Elena; Drabko, Katarzyna; Eapen, Mary; Feuchtinger, Tobias; Finocchi, Andrea; Gaspar, H. Bobby; Ghosh, Sujal; Gillio, Alfred P.; González-Granado, Luis Ignacio; Grunebaum, Eyal; Güngör, Tayfun; Heilmann, Carsten; Helminen, Merja; Higuchi, Kohei; Imai, Kohsuke; Kałwak, Krzysztof; Kanazawa, Nubuo; Karasu, Gülsün; Kucuk, Zeynep Yesim; Laberko, Alexandra; Lange, Andrzej; Mahlaoui, Nizar; Meisel, Roland; Moshous, Despina; Muramatsu, Hideki; Parikh, Suhag; Pašić, Srdjan; Schmid, Irene; Schuetz, Catharina; Schulz, Ansgar; Schultz, Kirk R.; Shaw, Peter J.; Slatter, Mary; Sykora, Karl‐Walter; Tamura, Shinobu; Taskinen, Mervi; Wawer, Angela; Wolska-Kuśnierz, Beata; Cowan, Morton J.; Fischer, Alain; Gennery, Andrew R.; Transplantation, Marrow

doi:10.1016/j.jaci.2017.02.036

Cited by 85 publications

(77 citation statements)

References 40 publications

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“…Hence, there are only few reports of successful HSCT in NBS (29–32), describing less than the total of 30 patients transplanted worldwide. The reported HSCT survival in them is above 70%.…”

Section: Discussionmentioning

confidence: 99%

Prospective Study of a Cohort of Russian Nijmegen Breakage Syndrome Patients Demonstrating Predictive Value of Low Kappa-Deleting Recombination Excision Circle (KREC) Numbers and Beneficial Effect of Hematopoietic Stem Cell Transplantation (HSCT)

et al. 2017

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BackgroundNijmegen breakage syndrome (NBS) is a combined primary immunodeficiency with DNA repair defect, microcephaly, and other phenotypical features. It predominantly occurs in Slavic populations that have a high frequency of carriers with the causative NBN gene c.657_661del5 mutation. Due to the rarity of the disease in the rest of the world, studies of NBS patients are few. Here, we report a prospective study of a cohort of Russian NBS patients.Methods35 Russian NBS patients of ages 1–19 years, referred to our Center between years 2012 and 2016, were prospectively studied.ResultsDespite the fact that in 80% of the patients microcephaly was diagnosed at birth or shortly thereafter, the average delay of NBS diagnosis was 6.5 years. Though 80% of the patients had laboratory signs of immunodeficiency, only 51% of the patients experienced significant infections. Autoimmune complications including interstitial lymphocytic lung disease and skin granulomas were noted in 34%, malignancies—in 57% of the patients. T-cell excision circle (TREC)/kappa-deleting recombination excision circle (KREC) levels were low in the majority of patients studied. Lower KREC levels correlated with autoimmune and oncological complications. Fifteen patients underwent hematopoietic stem cell transplantation (HSCT), 10 of them were alive and well, with good graft function. Three patients in the HSCT group and five non-transplanted patients died; tumor progression being the main cause of death. The probability of the overall survival since NBS diagnosis was 0.76 in the HSCT group and 0.3 in the non-transplanted group.ConclusionBased on our findings of low TRECs in most NBS patients, independent of their age, TREC detection can be potentially useful for detection of NBS patients during neonatal screening. KREC concentration can be used as a prognostic marker of disease severity. HSCT is a viable treatment option in NBS and should be especially considered in patients with low KREC numbers early on, before development of life-threatening complications.

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Section: Discussionmentioning

confidence: 99%

Prospective Study of a Cohort of Russian Nijmegen Breakage Syndrome Patients Demonstrating Predictive Value of Low Kappa-Deleting Recombination Excision Circle (KREC) Numbers and Beneficial Effect of Hematopoietic Stem Cell Transplantation (HSCT)

et al. 2017

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“…Hematopoietic stem cell transplantation (HSCT) showed a successful preliminary outcome on lymphoma and even neurologic condition of Atm ‐deficient animal models . Nonetheless, allogeneic HSCT and pre‐emptive alloHSCT have been performed as potential therapeutic modality in few A‐T patients resulting in a poor survival rate of 25% during 3‐year follow‐up . Furthermore, the most debilitating feature of A‐T is the progressive neurodegeneration due to loss of Purkinje cells and malfunction of other neuronal cells, but theoretically HSCT is unable to cure neurodegenerative phenotype of this disorder .…”

Section: Management and Treatmentmentioning

confidence: 99%

Ataxia‐telangiectasia: A review of clinical features and molecular pathology

Amirifar

Ranjouri

Yazdani

et al. 2019

Pediatric Allergy Immunology

139

105

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Ataxia‐telangiectasia (A‐T) is an autosomal recessive primary immunodeficiency (PID) disease that is caused by mutations in ataxia‐telangiectasia mutated (ATM) gene encoding a serine/threonine protein kinase. A‐T patients represent a broad range of clinical manifestations including progressive cerebellar ataxia, oculocutaneous telangiectasia, variable immunodeficiency, radiosensitivity, susceptibility to malignancies, and increased metabolic diseases. This congenital disorder has phenotypic heterogeneity, and the severity of symptoms varies in different patients based on severity of mutations and disease progression. The principal role of nuclear ATM is the coordination of cellular signaling pathways in response to DNA double‐strand breaks, oxidative stress, and cell cycle checkpoint. The pathogenesis of A‐T is not limited to the role of ATM in the DNA damage response (DDR) pathway, and it has other functions mainly in the hematopoietic cells and neurons. ATM adjusts the functions of organelles such as mitochondria and peroxisomes and also regulates angiogenesis and glucose metabolisms. However, ATM has other functions in the cells (especially cell viability) that need further investigations. In this review, we described functions of ATM in the nucleus and cytoplasm, and also its association with some disorder formation such as neurologic, immunologic, vascular, pulmonary, metabolic, and dermatologic complications.

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“…Late effects are seen in 70% of Artemis patients with high rates of growth failure (particularly in those who receive alkylator-based conditioning), severe or recurrent infections, cGVHD/ autoimmunity, need for nutritional support, and death occurring greater than 2 years post-HSCT 30 . Effects uniquely observed in Artemis patients include dental anomalies, growth hormone deficiency, central hypothyroidism, type 1 diabetes mellitus, renal tubulopathy, exocrine pancreatic insufficiency, and pulmonary fibrosis 34 .…”

Section: Organ System Treatment Recommendationsmentioning

confidence: 99%

“…This is particularly important for RS-SCID before initiation of alkylator conditioning. Rapid identification of ADA deficiency allows prompt initiation of enzyme replacement therapy and consideration for gene therapy [34][35][36] . Gene therapy may also be offered as a treatment option for X-linked SCID [37][38] .…”

Section: Genetic Counselingmentioning

confidence: 99%

Mini Review: Screening and Management of Late Effects in Patients with Severe Combined Immunodeficiency after Allogeneic Hematopoietic Cell Transplantation

Heimall¹

2018

J Pediatrics & Pediatr Med

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Severe combined immunodeficiency (SCID) is a group of the most severe of primary immunodeficiencies and is typically fatal in the first year of life without hematopoietic cell transplantation (HCT). Improved transplantation techniques and supportive care measures have resulted in improved survival following HCT. Furthermore, patients are being diagnosed earlier since the widespread implementation of SCID newborn screening in the United States and moving on to transplantation before 3.5 months of age. As such, most SCID patients are now expected to live well into adulthood following successful HCT. Many centers are using conditioning with alkylating agents, including busulfan and melphalan, pre-transplantation to achieve full T and B cell immune reconstitution; however, significant concerns remain regarding the attendant risks of using chemotherapeutic agents in early infancy. Several long-term follow-up studies have demonstrated high rates of non-immunologic late effects depending on the conditioning regimen employed and SCID genotype. The full risk of conditioning in this patient population remains incompletely characterized, and further research on post-HCT outcomes is needed. It is imperative that all providers caring for SCID survivors both in childhood and adulthood be aware of the risk of late effects. Guidelines for long-term follow-up were recently published, and the recommendations are briefly summarized here.

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Outcome of hematopoietic cell transplantation for DNA double-strand break repair disorders

Abstract: RIC HCT resolves DNA repair disorder-associated immunodeficiency. Long-term follow-up is required for secondary malignancy surveillance. Routine HCT for AT is not recommended.

Cited by 85 publications

References 40 publications

Prospective Study of a Cohort of Russian Nijmegen Breakage Syndrome Patients Demonstrating Predictive Value of Low Kappa-Deleting Recombination Excision Circle (KREC) Numbers and Beneficial Effect of Hematopoietic Stem Cell Transplantation (HSCT)

Prospective Study of a Cohort of Russian Nijmegen Breakage Syndrome Patients Demonstrating Predictive Value of Low Kappa-Deleting Recombination Excision Circle (KREC) Numbers and Beneficial Effect of Hematopoietic Stem Cell Transplantation (HSCT)

Ataxia‐telangiectasia: A review of clinical features and molecular pathology

Mini Review: Screening and Management of Late Effects in Patients with Severe Combined Immunodeficiency after Allogeneic Hematopoietic Cell Transplantation

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