Acquired Pyruvate Kinase Deficiency In Clonal Myeloid Neoplasms

Recruiting

• Conditions: Other Clonal Myeloid Neoplasm; Unexplained Coombs-negative Non-immune Hemolytic Anemia; Hereditary Hemolytic Anemia; Clonal Myeloid Neoplasm; Myeloproliferative Neoplasm; Pyruvate Kinase Deficiency; Clonal Cytopenia of Undetermined Significance; Pyruvate Kinase Deficiency Anemia; Myelodysplastic/Myeloproliferative Neoplasm; Myelodysplastic Syndromes
• Interventions: Procedure: Blood Draw

• Registration Number: NCT04902833
• Lead Sponsor: Massachusetts General Hospital

Brief 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.

Detailed 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

Study Timeline

• Study First Submitted: 2021-05-21
• Study First Submitted QC: 2021-05-21
• Study First Posted: 2021-05-26
• Study Start: 2022-02-01
• Status Verified: 2024-03
• Last Update Submitted: 2024-03-12
• Last Update Posted: 2024-03-13
• Primary Completion: 2025-04-30
• Study Completion: 2025-12-31

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 100

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).

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
Cohort I	Blood Draw	Approximately 75 anemic (Hgb \<11.0 g/dL) MDS Participants without overt clinical evidence of hemolysis. - Single Blood Draw
Cohort 2	Blood Draw	25 Participants with clonal myeloid disorders of any type with evidence of non-immune, otherwise unexplained hemolytic anemia -Single Blood Draw

Primary Outcome Measures

Name	Time	Method
Overall prevalence of possible or likely acquired pyruvate kinase deficiency	Day 1	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

Secondary Outcome Measures

Name	Time	Method
Red cell pyruvate kinase	60 Day	hexokinase enzyme activity ratio in patients not receiving red cell transfusion in the 60 days prior to blood draw
Overall prevalence of definite acquired pyruvate kinase deficiency	Day 1	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
Red cell pyruvate kinase enzyme activity	60 days	Red cell pyruvate kinase enzyme activity in patients not receiving red cell transfusion in the 60 days prior to blood draw
Somatic mutations in other genes associated with hemolytic anemia detected in the hematopoietic clone	Day 1
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
Impact of pyruvate kinase activators on PK activity in vitro	Day 1
Somatic mutations in PKLR (and other genes associated with acquired PKD) detected in the hematopoietic clone	Day 1

Trial Locations

Locations (1)

Massachusetts General Hospital; 🇺🇸 Boston, Massachusetts, United States