Nonsteroidal anti-inflammatory drugs as a targeted therapy for bone marrow failure in Ghosal hematodiaphyseal dysplasia

• Published in: Blood 2023-03, Vol.141 (13), p.1553-1559
• Main Authors: Brown, Timothy J., Barrett, Neil, Meng, Hu, Ricciotti, Emanuela, McDonnell, Ciara, Dancis, Andrew, Qualtieri, Julianne, FitzGerald, Garret A., Cotter, Melanie, Babushok, Daria V.
• Format: Article
• Language: English
• Subjects: Adult; Anemia - drug therapy; Anemia, Refractory - drug therapy; Anemia, Refractory - genetics; Anti-Inflammatory Agents, Non-Steroidal - therapeutic use; Bone Marrow Failure Disorders; Child; Humans; Pancytopenia; Prostaglandin H2; Syndrome
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.2022018667

•NSAIDs can normalize hematologic parameters and serum inflammatory markers in patients with Ghosal hematodiaphyseal dysplasia syndrome.•Prostaglandins and leukotrienes are aberrantly augmented in patients with Ghosal syndrome and are responsive to treatment with NSAIDs. [Display omitted] Advances in genomic diagnostics hold promise for improved care of rare hematologic diseases. Here, we describe a novel targeted therapeutic approach for Ghosal hematodiaphyseal dysplasia, an autosomal recessive disease characterized by severe normocytic anemia and bone abnormalities due to loss-of-function mutations in thromboxane A synthase 1 (TBXAS1). TBXAS1 metabolizes prostaglandin H2 (PGH2), a cyclooxygenase (COX) product of arachidonic acid, into thromboxane A2. Loss-of-function mutations in TBXAS result in an increase in PGH2 availability for other PG synthases. The current treatment for Ghosal hematodiaphyseal dysplasia syndrome consists of corticosteroids. We hypothesize that nonsteroidal anti-inflammatory drugs (NSAIDs), which inhibit COX-1 and COX-2, could ameliorate the effects of TBXAS1 loss and improve hematologic function by reducing prostaglandin formation. We treated 2 patients with Ghosal hematodiaphyseal dysplasia syndrome, an adult and a child, with standard doses of NSAIDs (aspirin or ibuprofen). Both patients had rapid improvements concerning hematologic parameters and inflammatory markers without adverse events. Mass spectrometry analysis demonstrated that urinary PG metabolites were increased along with proinflammatory lipoxygenase (LOX) products 5-hydroxyeicosatetraenoic acid and leukotriene E4. Our data show that NSAIDs at standard doses surprisingly reduced both COX and LOX products, leading to the resolution of cytopenia, and should be considered for first-line treatment for Ghosal hematodiaphyseal dysplasia syndrome. Ghosal hematodiaphyseal dysplasia (GHDD) is an extremely rare disorder associated with normocytic anemia and cortical bone thickening, caused by mutations in thromboxane A synthase 1 (TBXAS1). Marrow failure is thought to result from loss of thromboxane and a consequent increase in proinflammatory prostaglandin synthesis and is treated with corticosteroids. Brown and colleagues report on the treatment of 2 patients with nonsteroidal anti-inflammatory drugs, leading to cyclooxygenase inhibition and complete hematologic response, suggesting this should be first-line therapy for this rare disorder.