Genetic testing in severe aplastic anemia is required for optimal hematopoietic cell transplant outcomes

Abstract

Patients with severe aplastic anemia (SAA) can have an unrecognized inherited bone marrow failure syndrome (IBMFS) because of phenotypic heterogeneity. We curated germline genetic variants in 104 IBMFS-associated genes from exome sequencing performed on 732 patients who underwent hematopoietic cell transplant (HCT) between 1989 and 2015 for acquired SAA. Patients with pathogenic or likely pathogenic (P/LP) variants fitting known disease zygosity patterns were deemed unrecognized IBMFS. Carriers were defined as patients with a single P/LP variant in an autosomal recessive gene or females with an X-linked recessive P/LP variant. Cox proportional hazard models were used for survival analysis with follow-up until 2017. We identified 113 P/LP single-nucleotide variants or small insertions/deletions and 10 copy number variants across 42 genes in 121 patients. Ninety-one patients had 105 in silico predicted deleterious variants of uncertain significance (dVUS). Forty-eight patients (6.6%) had an unrecognized IBMFS (33% adults), and 73 (10%) were carriers. No survival difference between dVUS and acquired SAA was noted. Compared with acquired SAA (no P/LP variants), patients with unrecognized IBMFS, but not carriers, had worse survival after HCT (IBMFS hazard ratio [HR], 2.13; 95% confidence interval[CI], 1.40-3.24; P = .0004; carriers HR, 0.96; 95% CI, 0.62-1.50; P = .86). Results were similar in analyses restricted to patients receiving reduced-intensity conditioning (n = 448; HR IBMFS = 2.39; P = .01). The excess mortality risk in unrecognized IBMFS attributed to death from organ failure (HR = 4.88; P < .0001). Genetic testing should be part of the diagnostic evaluation for all patients with SAA to tailor therapeutic regimens. Carriers of a pathogenic variant in an IBMFS gene can follow HCT regimens for acquired SAA.

Graphical abstract

Figure 1.

Frequencies and genes identified in the SAA cohort. (A) Frequency of variant status across the full cohort of patients with aplastic anemia. Blue, no variant; red, carrier (single pathogenic variant in an autosomal recessive gene or X-linked recessive gene in females); green, unrecognized IBMFS. (B) The frequency of SAA patients with unrecognized IBMFS and (C) carrier status categorized by gene pathway. (D) The number of patients with pathogenic/likely pathogenic variants in an autosomal dominant gene and (E) the number of patients with pathogenic/likely pathogenic variants in autosomal recessive, X-linked, or dual inheritance gene. Red, hematopoiesis genes; blue, ribosome biology genes; green, telomere biology genes; purple, DNA damage response gene. Darker bars, unrecognized IBMFS; lighter bars, carriers.

Figure 2.

Genetic information by age and year of HCT of the 48 patients with SAA found to have an unrecognized IBMFS. Het, heterozygous; Comp het, compound heterozygous; Hemi, hemizygous; Hom, homozygous. *One patient had dual MPL and THPO inheritance. Note: HCT sample collection began in 1989, but the first patient in this group to have HCT was in 1991.

Figure 3.

Overall survival by variant status. Kaplan-Meier curve comparing 3 groups of patients, those with a previously unrecognized IBMFS (green), carriers (red), and those with no variants (blue).

Figure 4.

Survival probability after allogeneic HCT by IBMFS variant status and conditioning intensity. (A) Myeloablative and (B) reduced-intensity conditioning and nonmyeloablative Kaplan-Meier curve comparing 3 groups of patients, those with a previously unrecognized IBMFS (green), carriers (red), and those with no variants (blue).

Figure 5.

Posttransplant survival probability in patients with unrecognized IBMFS by gene group. (A) Telomere biology disorders. (B) Hematopoiesis disorders. (C) Ribosome biology disorders. (D) DNA damage response disorders. Kaplan-Meier curve comparing 3 groups of patients, those with a previously unrecognized IBMFS (green), carriers (red), and those with no variants (blue).