L-leucine in Diamond Blackfan Anemia Patients

Therapeutic Use of the Amino Acid Leucine in the Treatment of Transfusion-Dependent Diamond Blackfan Anemia Patients

Diamond-Blackfan anemia (DBA) is a rare congenital syndrome associated with physical anomalies, short stature, red cell aplasia, and an increased risk of malignancy.

Mutations affecting genes encoding ribosomal proteins cause DBA. Genetic studies have identified heterozygous mutations in at least one of eight ribosomal protein genes in up to 50% of cases.

25% of patients carry a mutation in the ribosomal protein (RP)S19 gene, whereas mutations in RPS24, RPS17, RPL35A, RPL11, and RPL5 are rare.

p53 activation has been identified as a key component in the pathophysiology of DBA after cellular and molecular studies. Other potential mechanisms that warrant further investigation include impaired translation as the result of ribosomal insufficiency, which may be ameliorated by Leucine supplementation.

Despite significant improvements in understanding of the pathophysiology of Diamond Blackfan anemia (DBA), there have been few advances in therapy. The cornerstones of treatment remain corticosteroids,chronic red blood cell transfusions, and hematopoietic stem cell transplantation, each of which is fraught with complications. Other treatments have been shown to be effective in only a few patients or in individual case reports : IL-3, cyclosporine (alone or in combination with steroids), metaclopramide. Gene therapy is still a part of research programs.

There are some indications that the Amino Acid (AA) L-leucine, a translation enhancer, may have some efficacy in DBA and 5q-syndrome, which has the same altered ribosome functions as the DBA. L-leucine is an essential AA that is unique among the branched-chain AA acting as a nutrient regulator of protein synthesis in skeletal muscle and adipose tissue.

Several preclinical studies with DBA lymphocytes exposed to various L-leucine doses, have demonstrated that protein synthesis can be increased by using high doses L-leucine.

Recent clinical data on L-leucine therapeutic use have demonstrated increase the hemoglobin level and transfusion independence in patients with DBA and 5q-syndrom.

These data support the rationale for clinical trial on L-leucine use as a therapeutic agent for DBA patients.

Study Overview

• Status: Unknown
• Conditions: Diamond Blackfan Anemia
• Intervention / Treatment: Drug: L-leucine

Detailed Description

Experimental: one arm L-leucine , dose- 700mg/m2 , per os, 3 time a day, 6 months

• Study Type: Interventional
• Enrollment (Anticipated): 30
• Phase: Phase 2

Contacts and Locations

Study Locations

• Russian Federation
  • Moscow, Russian Federation, 117997
    • Recruiting
    • Federal Scientific Clinical Centre of Pediatric Hematology Oncology Immunology n.a. Dmitry Rogachev
    • Contact: Natalia - SMETANINA, MD, PhD; Phone Number: 13 05 +7 985 647 13 05; Email: Nataliya.smetanina@fccho-moscow.ru

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 20 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• signed Informed Consent Form
• diagnosed Diamond Blackfan Anemia
• transfusion dependenсe
• adequate renal function
• adequate liver function
• negative B-HCG and adequate contraception

Exclusion Criteria:

• known hypersensitivity to branched chain amino acids
• diagnosed AA metabolism disorder
• prior HSCT
• pregnancy or planning to become pregnant

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: L-leucine pills; L-leucine , dose- 700mg/m2 , per os, three time a day, course duration 6 months	Drug: L-leucine; L-leucine pills per os for 6 months

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hemoglobin level	Response to the treatment can be one of the following: Complete response (CR): Hb > 9 gm/dL and transfusion-independence as defined in DBA; Partial response (PR): Hb < 9 gm/dL, increased reticulocyte count > 1% and any increase in transfusion interval from baseline.; No response (NR): no change in transfusion requirements and no significant change in Hb or reticulocytes; Progression: worsening of disease as defined by the need for more frequent transfusions	every 4 weeks for 12 months

Secondary Outcome Measures

Outcome Measure	Time Frame
Side effects of L-leucine in transfusion-dependent DBA patients for one year	every 4 weeks for 12 moths

Collaborators and Investigators

• Sponsor: Federal Scientific Clinical Centre of Pediatric Hematology, Oncology and Immunology named after Dmitry Rogache
• Investigators: Principal Investigator: Natalia - SMETANINA, MD, PhD, FSCCPHOI, Outpatient Department

Study record dates

Study Major Dates

• Study Start: September 1, 2014
• Primary Completion (Anticipated): March 1, 2015
• Study Completion (Anticipated): March 1, 2016

Study Registration Dates

• First Submitted: February 18, 2015
• First Submitted That Met QC Criteria: March 5, 2015
• First Posted (Estimate): March 11, 2015

Study Record Updates

• Last Update Posted (Estimate): March 11, 2015
• Last Update Submitted That Met QC Criteria: March 5, 2015
• Last Verified: March 1, 2015

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Bone Marrow Diseases; Hematologic Diseases; Genetic Diseases, Inborn; Anemia, Hypoplastic, Congenital; Anemia, Aplastic; Congenital Bone Marrow Failure Syndromes; Bone Marrow Failure Disorders; Red-Cell Aplasia, Pure; Anemia; Anemia, Diamond-Blackfan
• Other Study ID Numbers: Ru0001