Treatment of inherited bone marrow failure syndromes beyond transplantation

Abstract

Despite significant progress in transplantation by the addition of alternative hematopoietic stem cell sources, many patients with inherited bone marrow failure syndromes are still not eligible for a transplant. In addition, the availability of sequencing panels has significantly improved diagnosis by identifying cryptic inherited cases. Androgens are the main nontransplant therapy for bone marrow failure in dyskeratosis congenita and Fanconi anemia, reaching responses in up to 80% of cases. Danazol and oxymetholone are more commonly used, but virilization and liver toxicity are major adverse events. Diamond-Blackfan anemia is commonly treated with corticosteroids, but most patients eventually become refractory to this treatment and toxicity is limiting. Growth factors still have a role in inherited cases, especially granulocyte colony-stimulating factor in congenital neutropenias. Novel therapies are warranted and thrombopoietin receptor agonists, leucine, quercetin, and novel gene therapy approaches may benefit inherited cases in the future.

Comparable Effects of the Androgen Derivatives Danazol, Oxymetholone and Nandrolone on Telomerase Activity in Human Primary Hematopoietic Cells from Patients with Dyskeratosis Congenita

“…DN, although it has a toxicity profile that has yet to be completely determined [ 18 , 31 ], might cause an attenuated degree of masculinization and might be more appropriate for the treatment of women. Moreover, liver toxicity appears to be more common with OX [ 16 ]. Consequently, this compound might be avoided in favor of DN or ND in patients with pre-existent liver damage.…”

“…However, various other mutations affecting helicases, namely poly (A)-specific ribonuclease ( PARN ) or regulator of telomere elongation helicase 1 ( RTEL1 ), or the ribosomal core component H/ACA ribonucleoprotein complex subunit DKC1 ( DKC1 ) are found [ 14 ]. The two currently established therapeutic options for patients with DKC and bone marrow failure (apart from symptomatic treatment) are allogenic hematopoietic stem cell transplantation (HSCT) or treatment with androgens derivatives (ADs) [ 16 ]. Unfortunately, due to the substantial treatment-associated morbidity and mortality, HSCT is frequently not an attractive option for patients with DKC.…”

“…In addition, patients often either lack a suitable HSC donor or a potential sibling donor albeit yet still asymptomatic is affected by the same inherited mutation (which is why telomere screening is recommended for family members). Even more importantly, severe affection of non-hematopoietic organs, such as the lungs or liver, often preclude DKC patients from using HSCT as treatment due to the risk of excess toxicity and morbidity [ 16 ].…”

Desenlace de los pacientes pediátricos con falla medular tratados en un centro de alta complejidad

“…Las opciones terapéuticas utilizadas se basaron en las guías de atención para pacientes con SFMA, dando un enfoque multidisciplinario, indicando como primera opción TPH si se contaba con donante idéntico o TIS en pacientes sin indicación de TPH o que no disponían de donante idéntico relacionado 6 . En el SFMC el tratamiento está basado en soporte transfusional, andrógenos y TPH en los casos severos o con mala respuesta 10 .…”

Reconsidering the indication of haematopoietic stem cell transplantation for dyskeratosis congenita

“…Allogeneic HSCT accelerates telomere shortening (Wynn et al , ), thereby increasing transplant–related toxicities, including pulmonary/liver complications in patients with DC. Moreover, the risk for developing solid tumours is higher in transplanted patients than in patients without transplants (Calado & Clé, ).…”