Hematological Landscape of Adult Patients with Diamond-Blackfan Anaemia Syndrome (DBAS): Results from the French DBA Cohort

Diamond-Blackfan anaemia syndrome (DBAS) is a congenital ribosomathy characterized by non-regenerative macrocytic anaemia, congenital malformations and cancer predisposition. Therapeutic approaches include corticosteroid, chronic red blood cells (RBC) transfusion, associated with early and aggressive chelation, and hematopoietic stem cell transplantation (HSCT). Diagnosis, therapeutic management and monitoring are based on recently updated international guidelines (Wlodarski et al. Diagnosis, treatment, and surveillance of Diamond-Blackfan anaemia syndrome: international consensus statement. Lancet Haematol 2024). Data on DBAS adult patients are limited. The aim of this study is to describe the hematological landscape of DBAS in adult patients.

Adult patients (pts) with DBAS registered in the French DBA cohort (OFABD) are analyzed. Pts aged 18 or over at 06/01/2024 were included. Outcome study cut-off was 01/06/2024.

One hundred and seventy-one pts were currently included, 86 (50%) being male. Median age at last follow-up (FU) was 35 years (yr) (range, 20-76). Molecular diagnosis screening was performed for 163 pts (95%); DBAS-associated gene was identified for 115 pts (67%) mainly RPS19 (n=45), RPL5 (n=22) and RPS26 (n=16). Sixty-one out of 158 evaluable pts (39%) had at least one congenital malformation. One hundred and nine pts (64%) were diagnosed in the 1st year of life, 19 (11%) between 1 and 18 years of age, and 7 (4%) in adulthood (NA: 39 pts). Median age at diagnosis for pts diagnosed in childhood and adulthood were respectively 2 months (range, 1-186) and 37.4 yr (range, 27.3-52.5). Eighteen pts (11%) developed at least one cancer at a median age of 37 yr (range, 4-49). At study cut-off, 10 pts (6%) were deceased: neoplasia: 7, severe iron overload: 1, head trauma: 1, NA: 1.

At last FU, 103/129 evaluable pts (80%) had anaemia, 34/112 (30%) neutropenia and 20/117 (17%) thrombocytopenia, severe (<50,000/µL) in 4 pts. Thirty-one out of 109 evaluable pts (28%) were both anemic and neutropenic 19/114 both anemic (17%) and thrombocytopenic and 13/105 (12%) were anemic, neutropenic and thrombocytopenic. No pt had clinically severe pancytopenia. Seven pts were diagnosed with myelodysplastic syndrome (MDS) without any reported acute myeloid leukemia (AML) evolution during FU.

Six pts with DBAS were transplanted, 5 for transfusion-dependency and 1 for MDS. Median age at HSCT was 10 yr (range, 2-51). Stem cell source, donor type and conditioning regimen were heterogenous. All 6 pts were alive at last FU but the pt with MDS had relapsed post HSCT.

Ninety-eight out of 150 evaluable pts (65%) had an history of RBC transfusion-dependency, with a median duration of 9 years (1-44); 86/138 (61%) had a history of long-term steroids exposure, with a median duration of 14,5 yr (range: 1-49) and a median dose of 5mg/d (range, 2-40). Seventy evaluable pts (50%) presented steroids-related adverse effects (AE), the main AE being growth delay (n=35), non-fractural osteoporosis (n=18) and weight gain (n=7).

At last FU, 68/159 evaluable (43%) patients were transfusion-dependent, 37 (23%) were on steroids, 6 (4%) on RBC transfusion and steroids, 4 (3%) were in remission after HSCT, and 43 (27%) were free of treatment. Among pts in therapeutic independence, 7 never received any DBAS-specific treatment, 13 had a history of RBC transfusion-dependency and 19 a history of steroids exposure (NA: 4 pts).

Ninety out of evaluable 147 pts (61%) had a history of iron overload, including 84 pts with a history of RBC transfusion-dependency. At last FU, 25/119 (21%) pts had iron overload, of whom 22 were on chelation therapy.

With a median FU from adulthood of 13 yr, the 10-yr and 20-yr overall survival (OS) estimates were 99% (95%; CI[[97.1-100]]) and 93% (95%; CI[86.7-100]), respectively. In a univariate Cox model, failure to identify a DBAS-associated mutation was associated with a shorter OS (HR 4.17, 95%CI[0.08-11.1], p=.0045).

We report here on the hematological evolution of a cohort of 171 adult patients with DBAS. As expected, 80% of patients were anemic at last FU but a significant proportion of patients had associated other cytopenias, as expected in an inherited bone marrow-failure syndrome. Nevertheless, no significant clinical impact was associated with neutropenia or thrombocytopenia in adult DBAS pts. Only 7 cases of MDS were reported, with no case of overt AML but the median age in this cohort is only 35 yr.

Sicre de Fontbrune:Alexion, AstraZeneca Rare Disease: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Samsung: Honoraria, Research Funding; Sobi: Honoraria, Research Funding. Forcade:Astellas: Research Funding; Novartis: Consultancy; Maat Pharma: Consultancy; Alexion: Other: Travel support, Speakers Bureau; Novartis: Other: Travel support, Speakers Bureau; Gilead: Other: Travel support, Speakers Bureau; Jazz: Speakers Bureau; GSK: Speakers Bureau; Sanofi: Other: Travel support, Speakers Bureau; Sobi: Speakers Bureau. Peffault de Latour:Apellis: Consultancy, Honoraria; Alexion: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Swedish Orphan Biovitrum AB (Sobi): Consultancy, Honoraria. Dalle:Teva: Current equity holder in private company; Orchard: Consultancy, Honoraria; Pierre Fabre Médicaments: Consultancy, Honoraria, Other: travels; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Vertex: Consultancy, Honoraria; Symbiopharm: Consultancy, Honoraria. Leblanc:Bristol Myers Squibb: Honoraria.