Outcomes of Immunosuppressive Therapy in Children Less Than Three Years of Age with Idiopathic Severe Aplastic Anemia: A North American Collaboration

Severe aplastic anemia (SAA) is characterized by pancytopenia and is either inherited or acquired (idiopathic). Accurate diagnosis is critical for proper treatment; however, the frequent overlap in clinical presentation between idiopathic SAA and inherited bone marrow failure syndromes (IBMFS) presents diagnostic and management challenges. For patients with idiopathic SAA, immunosuppressive therapy (IST) is considered the standard of care, when there is no available matched related donor. While 70-75% of pediatric patients with SAA respond to IST, patients with IBMFS do not. To our knowledge, there are no published data on a specific age cut-off that predicts a higher likelihood of an inherited disease, to guide treatment with IST or hematopoietic stem cell transplantation (HSCT). The aim of this study was to evaluate response to IST in children with SAA who are less than 3 years of age and to gain insight into the age below which response to IST is unlikely, suggesting an IBMFS.

In a retrospective cohort study, we extracted data of patients diagnosed with SAA between 2002 and 2021 from 3 ethics board-approved multicenter databases: (1) North American Pediatric Aplastic Anemia Consortium (NAPAAC; 2002-2014), (2) Canadian Aplastic Anemia and Myelodysplasia Study (CAMS) and (3) Canadian Inherited Marrow Failure Registry (CIMFR). Patient characteristics, treatment and outcomes were collected. Patients were included if diagnosed with acquired SAA before the age of 3 years and received IST as a first line treatment for at least 3 months. Patients were excluded if they had physical malformations suggestive of an IBMFS, a first-degree relative with a history of bone marrow failure, or insufficient available data. Response rate was compared with published literature on pediatric patients with SAA over the age of 3 years. Descriptive statistics were utilized (SPSS V25).

Among 31 patients aged 1.3-2.9 years (median 2.25) treated with IST as a first line therapy for SAA, 13 (42%) were male, 10 (32%) had hepatitis associated SAA, 3 (10%) had mild physical abnormalities (vesicoureteral reflux, patent ductus arteriosus, mild hearing impairment), none had short stature, and 7 (23%) had a family history of cancer (n=4), polycythemia vera (n=1), hyper-eosinophilic syndrome (n=1) or consanguinity (n=1).

Twenty-nine patients (93%) were treated with horse anti-thymocyte globulin (ATG) and cyclosporine A (CSA), while 2 (7%) were treated with cyclophosphamide (CTX). Of the 31 patients, 24 (77%) had a complete response (CR) to IST (including the 2 patients post CTX). Twelve (50%), 22 (92%) and 24 (100%) were transfusion independent by 3, 6 and 12 months from the start of IST, respectively. CSA was discontinued after a median time of 20.4 months (range 5.6-55). No relapse was reported during long-term follow up (median 79 months, range 29-233).

Seven patients (23%, age 1.95-2.83 years, median 2.44), had no response to a first IST course, 5 of whom received a second IST course with rabbit ATG. Of these 5 patients, 3 (age 1.95, 2.44 and 2.45 years) did not respond to the second IST and underwent HSCT, 1 (age 2.8 years) had a partial response and became transfusion-independent, 1 (age 2.83 years, who had a second IST with tacrolimus) achieved partial response and then switched to danazol with a CR. Two of the 7 patients who did not respond to the first IST did not receive a second IST before transplant; 1 of them (age 2.25 years) had an unsuccessful response to danazol and 1 (age 2.04 years) had no interim treatment.

Complications during the first 3 months post IST included infections (bacteremia/sepsis, n=5; cellulitis, n=2; viral gastroenteritis, n=1), gross hematuria (n=1), hypertension (n=4) and gum hyperplasia (n=1). In the 3-6 months post-IST interval, 2 patients had bleeding events (gross hematuria, oral bleed) and 1 had a bacteremia episode. In the 6-12 months post-IST interval, 1 patient had bacteremia, 2 had hypertension and 1 developed a chronic kidney injury secondary to CSA.

In conclusion, our study indicates for the first time a high complete response rate of 77% in SAA patients under 3 years of age who were treated with IST, a response rate comparable to what is reported in the literature for IST response in older pediatric patients. Although our study is limited by its retrospective nature and a relatively small cohort, due to the lack of previously published data, this research provides critical insight to help in managing this age group.

Corriveau-Bourque:Vertex: Honoraria. Rogers:Novartis: Consultancy, Honoraria. Olson:Pfizer: Membership on an entity's Board of Directors or advisory committees; Elixirgen: Membership on an entity's Board of Directors or advisory committees; bluebird bio: Consultancy; Medexus: Membership on an entity's Board of Directors or advisory committees; Akari: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Coates:Agios pharma: Consultancy, Honoraria; Chiesi pharma: Consultancy, Honoraria; Bristol Meyers Squibb: Consultancy, Honoraria. Chawla:bluebird bio: Current Employment, Current equity holder in publicly-traded company. Joshi:Fortrea, Inc.: Current Employment. Rothman:Agios: Consultancy, Research Funding; Blue Bird Bio: Research Funding; Dova: Research Funding; Novartis: Research Funding; Pfizer: Research Funding; Sobi: Research Funding. Glader:Agios Pharmaceuticals, Inc.: Consultancy. Walkovich:Horizon Pharma: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; X4 Pharma: Membership on an entity's Board of Directors or advisory committees; Sobi Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharming: Membership on an entity's Board of Directors or advisory committees. Thompson:Global Blood Therapeutics: Divested equity in a private or publicly-traded company in the past 24 months; Novartis: Research Funding; CRISPR/Vertex: Consultancy, Research Funding; Editas: Consultancy, Research Funding; bluebird bio: Consultancy, Research Funding; Beam Therapeutics: Consultancy, Research Funding. Hanna:AbbVie: Consultancy; Vertex: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; SOBI: Speakers Bureau; Sanofi: Consultancy. Williams:ExcellThera: Research Funding; Tessera Therapeutics: Consultancy; Verve Therapeutics: Consultancy; Biomarin: Membership on an entity's Board of Directors or advisory committees; Skyline Therapeutics (formerly Geneception): Membership on an entity's Board of Directors or advisory committees; Emerging Therapy Solutions: Membership on an entity's Board of Directors or advisory committees; Beam Therapeutics: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Orchard Therapeutics: Research Funding; Bluebird bio: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Vertex Pharmaceuticals: Consultancy. Shimamura:Fulcrum: Consultancy; X4 pharma: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees.