Eltrombopag restores trilineage hematopoiesis in refractory severe aplastic anemia that can be sustained on discontinuation of drug

Abstract

About a quarter of patients with severe aplastic anemia remain pancytopenic despite immunosuppressive therapy. We have previously demonstrated that eltrombopag has efficacy in this setting with 44% (11/25) of patients having clinically significant hematologic responses. We now report safety and efficacy data on a further 18 patients and long-term follow-up on the entire cohort of 43 patients. The overall response rate was 17 of 43 patients (40%) at 3 to 4 months, including tri- and bilineage responses. The majority of patients who remained on eltrombopag in an extension study (14/17) continued to show improvement, and 7 eventually had significant increases in neutrophil, red cell, and platelet lineages. Five patients with robust near-normalization of blood counts had drug discontinued at a median of 28.5 months after entry (range, 9-37 months), and all maintained stable counts a median of 13 months (range, 1-15 months) off eltrombopag. Eight patients, including 6 nonresponders and 2 responders, developed new cytogenetic abnormalities on eltrombopag, including 5 with chromosome 7 loss or partial deletion. None evolved to acute myeloid leukemia to date. Eltrombopag is efficacious in a subset of patients with aplastic anemia refractory to immunosuppressive therapy, with frequent multilineage responses and maintenance of normalized hematopoiesis off treatment. This study is registered at www.clinicaltrials.gov as #NCT00922883.

Figure 1

Responses to eltrombopag by lineage. These Venn diagrams show the numbers of patients with uni- and multilineage responses at response assessment (A) and best response at follow-up (B). All biological best responses are included in panel B, including a >1.5 g increase in hemoglobin, even if it began at >9 g/dL. The lineage affected is indicated by the shade of the circle.

Figure 2

Hematologic responses over time by lineage. Boxplots show erythroid response (A), neutrophil response (B), and platelet response (C).

Figure 3

Bone marrow cellularity in patients 1 and 2. The left panels (for both Patients 1 and 2) show cellularity in these robust responders at baseline. The middle panels show cellularity just prior to discontinuing eltrombopag. The right panels demonstrate that, for Patients 1 and 2, the marrows remain cellular. The images were taken on an Olympus BX41 microscope with an Olympus DP72 camera, using a 4× UPlanFL N Olympus objective (original magnification ×40).