L‐leucine improves anemia and growth in patients with transfusion‐dependent Diamond‐Blackfan anemia: Results from a multicenter pilot phase I/II study from the Diamond‐Blackfan Anemia Registry

Vlachos, Adrianna; Atsidaftos, Evangelia; Lababidi, Mohammad Lutfi; Muir, Ellen; Rogers, Zora R.; Alhushki, Waseem; Bernstein, Jonathan; Glader, Bertil; Gruner, Barbara; Hartung, Helge; Knoll, Christine; Loew, Thomas; Nalepa, Grzegorz; Narla, Anupama; Panigrahi, Arun; Sieff, Colin A.; Walkovich, Kelly; Lipton, Jeffrey M.

doi:10.1002/pbc.28748

Cited by 16 publications

(17 citation statements)

References 15 publications

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“…In particular, the amino acid leucine is currently being explored as a potential modulator of protein synthesis in DBA patients 19 . Recently, results of the first clinical trial have been published, showing a partial or complete haematological response in 7/43 patients (16·3%), and more strikingly, positive effects on growth in 9/25 (height) and 11/25 (weight) patients, respectively 20 . How leucine exerts its effect on both erythropoiesis and growth remains to be defined, but it has been assumed that it involves upregulating of ribosome biosynthesis via the mTOR pathway, as well as improved translational efficiency through activation of translation‐initiation factors 21 .…”

Section: Discussionmentioning

confidence: 99%

Dried blood spot metabolomics reveals a metabolic fingerprint with diagnostic potential for Diamond Blackfan Anaemia

et al. 2021

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Summary The diagnostic evaluation of Diamond Blackfan Anaemia (DBA), an inherited bone marrow failure syndrome characterised by erythroid hypoplasia, is challenging because of a broad phenotypic variability and the lack of functional screening tests. In this study, we explored the potential of untargeted metabolomics to diagnose DBA. In dried blood spot samples from 18 DBA patients and 40 healthy controls, a total of 1752 unique metabolite features were identified. This metabolic fingerprint was incorporated into a machine‐learning algorithm, and a binary classification model was constructed using a training set. The model showed high performance characteristics (average accuracy 91·9%), and correct prediction of class was observed for all controls (n = 12) and all but one patient (n = 4/5) from the validation or ‘test’ set (accuracy 94%). Importantly, in patients with congenital dyserythropoietic anaemia (CDA) – an erythroid disorder with overlapping features – we observed a distinct metabolic profile, indicating the disease specificity of the DBA fingerprint and underlining its diagnostic potential. Furthermore, when exploring phenotypic heterogeneity, DBA treatment subgroups yielded discrete differences in metabolic profiles, which could hold future potential in understanding therapy responses. Our data demonstrate that untargeted metabolomics in dried blood spots is a promising new diagnostic tool for DBA.

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Section: Discussionmentioning

confidence: 99%

Dried blood spot metabolomics reveals a metabolic fingerprint with diagnostic potential for Diamond Blackfan Anaemia

et al. 2021

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“…17 Last, leu cine has been found to be effec tive in small num ber of patients with DBA. 18 New ther a peu tic options such as gene ther apy are prob a bly the most prom is ing option, 19,20 along with other targeted ther a pies. 21 Recently, some inno va tive ther a pies have been pro posed such as cal mod u lin inhib i tors 16 and met formin, 22 and it is likely that other new ther a peu tic options will emerge from trans la tional research (trial NCT03966053 with tri fluo per a zine).…”

Section: Dba Treat Ment: Take-home Mes Sagementioning

confidence: 99%

Diamond-Blackfan anemia

2021

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Diamond-Blackfan anemia (DBA) is an inherited bone marrow failure syndrome, characterized as a rare congenital bone marrow erythroid hypoplasia (OMIM#105650). Erythroid defect in DBA results in erythroblastopenia in bone marrow as a consequence of maturation blockade between the burst forming unit–erythroid and colony forming unit–erythroid developmental stages, leading to moderate to severe usually macrocytic aregenerative (<20 × 109/L of reticulocytes) anemia. Congenital malformations localized mostly in the cephalic area and in the extremities (thumbs), as well as short stature and cardiac and urogenital tract abnormalities, are a feature of 50% of the DBA-affected patients. A significant increased risk for malignancy has been reported. DBA is due to a defect in the ribosomal RNA (rRNA) maturation as a consequence of a heterozygous mutation in 1 of the 20 ribosomal protein genes. Besides classical DBA, some DBA-like diseases have been identified. The relation between the defect in rRNA maturation and the erythroid defect in DBA has yet to be fully defined. However, recent studies have identified a role for GATA1 either due to a specific defect in its translation or due to its defective regulation by its chaperone HSP70. In addition, excess free heme-induced reactive oxygen species and apoptosis have been implicated in the DBA erythroid phenotype. Current treatment options are either regular transfusions with appropriate iron chelation or treatment with corticosteroids starting at 1 year of age. The only curative treatment for the anemia of DBA to date is bone marrow transplantation. Use of gene therapy as a therapeutic strategy is currently being explored.

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“…L-leucine therapy resulted in a hematologic response in 16% of subjects with classical DBA accordingly to recently published results of the multicenter, phase I/II study. 16 L-leucine effects in DBA and models of cohesinopathies are attributed to activation of the mTOR pathway more than an influence on p53 and its target activity. [17][18][19] Here, we provide a description of two new patients with TP53 mutation and DBA-like phenotype.…”

Section: Discussionmentioning

confidence: 99%

De novo TP53 germline activating mutations in two patients with the phenotype mimicking Diamond–Blackfan anemia

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Ovsyannikova

Курникова

et al. 2022

Pediatric Blood & Cancer

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Diamond–Blackfan anemia (DBA) is an inherited bone marrow failure syndrome, associated with mutations in ribosomal protein (RP) genes. Growing data on mutations in non‐RP genes in patients with DBA‐like phenotype became available over recent years. We describe two patients with the phenotype of DBA (onset of macrocytic anemia within the first year of life, paucity of erythroid precursors in bone marrow) and germline de novo variants in the TP53 gene. Both patients became transfusion independent, probably due to L‐leucine therapy. The possible role of TP53 variants should be considered in patients with DBA‐like phenotype and no mutations in RP genes.

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L‐leucine improves anemia and growth in patients with transfusion‐dependent Diamond‐Blackfan anemia: Results from a multicenter pilot phase I/II study from the Diamond‐Blackfan Anemia Registry

Cited by 16 publications

References 15 publications

Dried blood spot metabolomics reveals a metabolic fingerprint with diagnostic potential for Diamond Blackfan Anaemia

Dried blood spot metabolomics reveals a metabolic fingerprint with diagnostic potential for Diamond Blackfan Anaemia

Diamond-Blackfan anemia

De novo TP53 germline activating mutations in two patients with the phenotype mimicking Diamond–Blackfan anemia

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