Acquired Pyruvate Kinase Deficiency In Clonal Myeloid Neoplasms

Acute Myeloid Leukemia Clinical Trial

Official title:

Characterization Of Acquired Pyruvate Kinase Deficiency In Clonal Myeloid Neoplasms

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04902833
• Other study ID #: 21-187
• Status: Recruiting
• Start date: February 1, 2022
• Est. completion date: December 31, 2025

Study information

• Verified date: March 2024
• Source: Massachusetts General Hospital
• Contact: Hanny Al-Samkari, MD
• Phone: (617) 643-6214
• Email: hal-samkari[@]mgh.harvard.edu
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

This cross-sectional prevalence assessment study involves a single blood draw in specific patient populations to assess for enzymatic and genomic evidence for acquired pyruvate kinase deficiency.

Description:

This cross-sectional prevalence assessment study involves a single blood draw in specific patient populations to assess for enzymatic and genomic evidence for acquired pyruvate kinase deficiency.

• Red cell pyruvate kinase enzyme activity and next-generation sequencing (NGS) hereditary hemolytic anemia panels will be performed on samples from all recruited participants.

• The study will recruit patients to two separate cohorts.

• Cohort 1 will recruit approximately 75 anemic (Hgb <11.0 g/dL) MDS participants without overt clinical evidence of hemolysis.

• Cohort 2 will recruit approximately 25 participants with clonal myeloid disorders of any type with evidence of non-immune, otherwise unexplained hemolytic anemia

• Participation in the study involves a single blood draw. Basic information about the participant's blood disorder will also be collected.

It is expected that about 100 people will take part in this research study

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 100
• Est. completion date: December 31, 2025
• Est. primary completion date: April 30, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Cohort 1

• Capable and willing to provide informed consent for participation in the study.

• Diagnosis of clonal cytopenia of undetermined significance (CCUS), myelodysplastic syndrome (MDS) or myelodysplastic/myeloproliferative neoplasm (MDS/MPN syndrome) according to 2016 World Health Organization (WHO) classification system.

• Anemia secondary to underlying clonal cytopenia of undetermined significance (CCUS), MDS or MDS/MPN syndrome, defined as a hemoglobin <11.0 g/dL measured within 30 days of study enrollment. Anemia should not be related to nutritional deficiency (such as iron, cobalamin, folate, or copper deficiencies), peripheral immune or non-immune hemolysis, or renal disease, in the opinion of the investigator.

• Age >18 years.

• Cohort 2

• Capable and willing to provide informed consent for participation in the study.

• Diagnosis of a clonal myeloid neoplasm, such as MDS, MDS/MPN syndrome, myeloproliferative neoplasm (MPN), acute myeloid leukemia (AML), clonal cytopenia of undetermined significance (CCUS), or other clonal myeloid neoplasm according to 2016 World Health Organization (WHO) classification system.

• A diagnosis of an otherwise unexplained Coombs-negative non-immune hemolytic anemia, according to the clinical judgement of the investigator. Some form of objective laboratory evidence must be present, including one or more of the following: negative direct antiglobulin (Coombs) test, reduced haptoglobin, elevated indirect bilirubin, elevated lactate dehydrogenase, elevated aspartate aminotransferase, or compatible findings on peripheral blood film. Results of all of these tests are not required to satisfy this criterion.

• Age >18 years.

Exclusion Criteria:

• Cohort 1

• Receipt of red cell transfusion within 60 days of study enrollment.

• Have a known untreated nutritional anemia or acquired disorder resulting in hemolysis, such as paroxysmal nocturnal hemoglobinuria (PNH). A known hereditary anemia (such as thalassemia trait) is not exclusionary if the patient's baseline hemoglobin has worsened significantly (in the opinion of the investigator) after development and diagnosis of MDS.

• Cohort 2

• Have a known hereditary anemic disorder, such as thalassemia, sickle cell disease, or hereditary enzyme deficiency, with the exception of hereditary X-linked glucose-6-phosphate dehydrogenase deficiency known not to cause chronic baseline hemolysis. Testing for these diagnoses is not required unless deemed clinically necessary.

• Have a known untreated nutritional anemia or acquired disorder resulting in hemolysis, such as paroxysmal nocturnal hemoglobinuria (PNH).

Related Conditions & MeSH terms

• Acute Myeloid Leukemia
• Anemia
• Anemia, Hemolytic
• Anemia, Hemolytic, Congenital
• Clonal Cytopenia of Undetermined Significance
• Cytopenia
• Hemolysis
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute
• Myelodysplastic Syndromes
• Myelodysplastic-Myeloproliferative Diseases
• Myelodysplastic/Myeloproliferative Neoplasm
• Myeloproliferative Disorders
• Myeloproliferative Neoplasm
• Neoplasms
• Preleukemia
• Pyruvate Kinase Deficiency

Intervention

Procedure:
• Blood Draw
Blood specimen 2-4 teaspoons

Locations

Country	Name	City	State
United States	Massachusetts General Hospital	Boston	Massachusetts

Sponsors (2)

Lead Sponsor	Collaborator
Massachusetts General Hospital	Agios Pharmaceuticals, Inc.

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Characterization of other possible factors involved in acquired PKD, including acquired epigenetic or gene expression factors		Day 1
Primary	Overall prevalence of possible or likely acquired pyruvate kinase deficiency	defined by PK enzyme activity or PK:HK ratio >1 SD below the control mean (healthy subject mean) as measured by enzyme assay, or potentially pathogenic mutations in the PKLR gene as found on PKLR sequencing	Day 1
Secondary	Overall prevalence of definite acquired pyruvate kinase deficiency	Defined by PK enzyme activity below normal (or a PK:HK ratio <8.7) as measured by enzyme assay, or known pathogenic mutations in the PKLR gene as found on PKLR sequencing	Day 1
Secondary	Red cell pyruvate kinase enzyme activity	Red cell pyruvate kinase enzyme activity in patients not receiving red cell transfusion in the 60 days prior to blood draw	60 days
Secondary	Red cell pyruvate kinase	hexokinase enzyme activity ratio in patients not receiving red cell transfusion in the 60 days prior to blood draw	60 Day
Secondary	Somatic mutations in PKLR (and other genes associated with acquired PKD) detected in the hematopoietic clone		Day 1
Secondary	Somatic mutations in other genes associated with hemolytic anemia detected in the hematopoietic clone		Day 1
Secondary	Characterization of pyruvate kinase-related red cell metabolites (ATP, 2,3-DPG) and pyruvate kinase-R protein in patients with clonal myeloid disorders		Day 1
Secondary	Impact of pyruvate kinase activators on PK activity in vitro		Day 1