L-leucine improves anemia and growth in patients with transfusion-dependent Diamond-Blackfan anemia: Results from a multicenter pilot phase I/II study from the Diamond-Blackfan Anemia Registry

Abstract

Background: Diamond-Blackfan anemia (DBA) is an inherited bone marrow failure syndrome characterized by anemia, short stature, congenital anomalies, and cancer predisposition. Most cases are due to mutations in genes encoding ribosomal proteins (RP) leading to RP haploinsufficiency. Effective treatments for the anemia of DBA include chronic red cell transfusions, long-term corticosteroid therapy, or hematopoietic stem cell transplantation. In a small patient series and in animal models, there have been hematologic responses to L-leucine with amelioration of anemia. The study objectives of this clinical trial were to determine feasibility, safety, and efficacy of L-leucine in transfusion-dependent patients with DBA.

Procedure: Patients ≥2 years of age received L-leucine 700 mg/m2 orally three times daily for nine months to determine a hematologic response and any improvement in growth (NCT01362595).

Results: This multicenter, phase I/II study enrolled 55 subjects; 43 were evaluable. There were 21 males; the median age at enrollment was 10.4 years (range, 2.5-46.1 years). No significant adverse events were attributable to L-leucine. Two subjects had a complete erythroid response and five had a partial response. Nine of 25, and 11 of 25, subjects experienced a positive weight and height percentile change, respectively, at the end of therapy.

Conclusions: L-leucine is safe, resulted in an erythroid response in 16% of subjects with DBA, and led to an increase in weight and linear growth velocity in 36% and 44% of evaluable subjects, respectively. Further studies will be critical to understand the role of L-leucine in the management of patients with DBA.

Keywords: Diamond-Blackfan anemia; L-leucine; clinical trial; erythropoiesis.

Conflict of interest statement

Conflict of Interest

The authors do not report any conflicts of interest.

© 2020 Wiley Periodicals LLC.

Figures

FIGURE 1.

Change in height percentiles in subjects receiving L-leucine. Comparison of pre- to post-L-leucine height percentiles in 11 patients with growth potential (males and females up to age 18 years and 16 years, respectively). Numbers above pre- and post- bars are the number of percentiles of accelerated growth during the study duration of 8–9 months. Each subject’s response to L-leucine is categorized below each set of bars. NR, no response; CR, complete response; PR, partial response.