Initial experience with l-leucine therapy in myelodysplastic syndromes with associated chromosome 5q deletion

To the editor:

In murine and zebrafish preclinical models of Diamond-Blackfan anemia (DBA), supplementation with the essential amino acid l-leucine ameliorates defective erythropoiesis and alleviates anemia, probably via upregulation of the mammalian target of rapamycin signaling pathway.^1-3  In addition, at least a single European patient with DBA experienced improved hemoglobin levels during l-leucine supplementation.⁴  Because dysregulated ribosome biogenesis similar to that underlying DBA is present in cells from patients with myelodysplastic syndromes (MDSs) associated with deletion of chromosome 5q, it has been proposed that l-leucine might also improve MDS-associated anemia, especially in patients with the so-called 5q- syndrome, a lower-risk form of MDS associated with haploinsufficiency of ribosomal component ribosomal protein S14.^1,5  To date, no clinical experience with l-leucine in MDS has been reported, although the low cost, widespread availability, and excellent tolerability of this dietary supplement suggest that clinical trials should be undertaken.

Three consenting patients with World Health Organization–defined MDS with isolated del(5q) (a 71-year-old man, a 65-year-old woman, and a 58-year-old woman; 2 of whom were red cell transfusion–dependent and 1 of whom had no response to erythropoiesis-stimulating agent therapy) who were reluctant to initiate treatment with lenalidomide took l-leucine capsules obtained from a nutritional supplement store at a dose of 1500 mg orally 3 times daily for 2 to 3 months, approximating the 700 mg/m² dose chosen for a planned trial of l-leucine in transfusion-dependent patients with DBA. The DBA trial is registered at www.clinicaltrials.gov as #NCT01362595.

Although no adverse events were observed during l-leucine therapy, none of the patients experienced any improvement in their cytopenias or transfusion needs. Two of the 3 patients subsequently agreed to take lenalidomide, and both became transfusion-independent during that therapy.

DBA is a congenital disorder with germline associated with mutations in ribosomal genes. The goal of therapy is to improve red blood cell production from erythroid progenitor cells with dysfunctional ribosomes. In MDS with del(5q), patients have somatically acquired ribosomal protein S14 haploinsufficiency, as well as haploinsufficiency for multiple additional genes on chromosome 5q and additional somatic mutations. The goal of therapy in MDS is to eliminate the del(5q) clone or, potentially, to improve red blood cell production from the neoplastic clone or residual normal hematopoietic clones. Of note, an improvement in ribosome function could potentially improve the clonal advantage of the del(5q) MDS clone. An absence of response could be a result of an insufficient dose of l-leucine, a more general lack of response in patients with ribosomal dysfunction, or that l-leucine does not improve erythropoiesis more specifically in del(5q) MDS. We eagerly await results of the formal DBA clinical trial and additional clinical experience with l-leucine in the MDS setting.