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.

2020-10-06
Pediatric blood & cancer 67(12)
- Adrianna Vlachos
- Evangelia Atsidaftos
- Mohammad Lutfi Lababidi
- Ellen Muir
- Zora R Rogers
- Waseem Alhushki
- Jonathan Bernstein
- Bertil Glader
- Barbara Gruner
- Helge Hartung
- Christine Knoll
- Thomas Loew
- Grzegorz Nalepa
- Anupama Narla
- Arun R Panigrahi
- Colin A Sieff
- Kelly Walkovich
- Jason E Farrar
- Jeffrey M Lipton

PubMed: 33025707
DOI: 10.1002/pbc.28748

Study Design

Type: Clinical Trial
Sample size: n = 55
Population: 55 subjects with Diamond-Blackfan anemia (DBA); 43 evaluable; age ≥2 years; median age 10.4 years (range 2.5-46.1 years); 21 males
Methods: Multicenter phase I/II study; L-leucine 700 mg/m² orally three times daily for nine months
Blinding: Open-label
Duration: nine months
Funding: Unclear

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.

Research Insights

L-Leucine→Improved Erythroid Response
Two subjects had a complete erythroid response and five had a partial response.
Effect
Beneficial
Effect size
Small
Dose
700 mg/m^2 orally three times daily
L-Leucine→Improved Height Percentile
11 of 25 subjects experienced a positive height percentile change at the end of therapy.
Effect
Beneficial
Effect size
Small
Dose
700 mg/m^2 orally three times daily
L-Leucine→Improved Weight Percentile
Nine of 25 subjects experienced a positive weight percentile change at the end of therapy.
Effect
Beneficial
Effect size
Small
Dose
700 mg/m^2 orally three times daily

Adverse Events Reported

L-Leucine→Overall tolerability
No significant adverse events were attributable to L-leucine.
Finding
Reported