Hypomethylating Agents Are Associated with High Rates of Hematologic Toxicity in Patients with Secondary MDS/AML That Develops after Acquired Aplastic Anemia

Acquired aplastic anemia (AA) is an autoimmune bone marrow failure (BMF) associated with depletion of hematopoietic stem and progenitor cells. Approximately 15-20% of AA patients treated with immunosuppressive therapy (IST) develop late complications of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Little is known about managing patients with post-AA myeloid neoplasms (MN). We hypothesized that patients with post-AA MN may be particularly susceptible to hematologic toxicities from cytotoxic therapy because of stem cell deficits. To investigate our hypothesis, we retrospectively analyzed post-AA MN patients treated at our 2 institutions over the past 15 years. Fourteen post-AA MN patients were identified: 11 with MDS, 1 with AML, and 2 with clonal cytopenia of undetermined significance (CCUS). Patients with inherited BMF or allogeneic stem cell transplant (SCT) prior to MN diagnosis were excluded. The median age at MN was 56.5 years (range 5-75) with a median time of 5 years (range 0.25-30) between AA diagnosis and MN. At MN diagnosis, 12 of 14 patients (86%) had a partial or complete response of AA with 5 receiving cyclosporine (CSA) maintenance. Two patients (14%) were on CSA within 6 months of IST without response. After MN diagnosis, CSA was discontinued. Ten adults received hypomethylating agents (HMA) as first-line treatment in preparation for SCT. Three pediatric patients were treated with SCT with no prior HMA. One patient died before receiving treatment. The 10 post-AA patients who received HMA were matched in a 3:1 ratio with a similarly aged, randomly selected non-AA MDS cohort treated with HMA at our center during the same period (Table 1). Compared to patients with non-AA MDS, post-AA MN patients tolerated HMA poorly with frequent, severe complications. Their median per-cycle duration of grade 4 neutropenia was longer (9 v. 1.5 days, p = 0.044), as was median duration of grade 4 thrombocytopenia (13 v. 0 days, p = 0.003). Post-AA patients notably had lower baseline platelets prior to HMA (median 36.5 v. 115 k/mL, p =0.007). Following HMA, the post-AA cohort had higher rates of febrile neutropenia (80% v. 17%, RR 4.8, p < 0.001) and infections ≥ grade 3 (90% v. 13%, RR 6.8, p < 0.001). They also had higher rates of ≥ grade 3 bleeding (40% v. 7%, RR 6.0, p = 0.026) with 2 patients (20%) experiencing intracranial hemorrhage on HMA; no such events occurred in the non-AA cohort. Post-AA patients had more hospital admissions - 18 in