Acquired Pyruvate Kinase Deficiency In Clonal Myeloid Neoplasms

Characterization Of Acquired Pyruvate Kinase Deficiency In Clonal Myeloid Neoplasms

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.

Study Overview

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

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 Type: Observational
• Enrollment (Actual): 18

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Massachusetts General Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Probability Sample

Study Population

Cohort 1 will recruit approximately 50 anemic (Hgb <11.0 g/dL) MDS patients without overt clinical evidence of hemolysis. Cohort 2 will recruit approximately 50 patients with clonal myeloid disorders of any type with evidence of non-immune, otherwise unexplained hemolytic anemia.

Description

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 Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Cohort I; Approximately 75 anemic (Hgb <11.0 g/dL) MDS Participants without overt clinical evidence of hemolysis. - Single Blood Draw	Procedure: Blood Draw; Blood specimen 2-4 teaspoons
Cohort 2; 25 Participants with clonal myeloid disorders of any type with evidence of non-immune, otherwise unexplained hemolytic anemia -Single Blood Draw	Procedure: Blood Draw; Blood specimen 2-4 teaspoons

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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
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
Somatic mutations in PKLR (and other genes associated with acquired PKD) detected in the hematopoietic clone		Day 1
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

Other Outcome Measures

Outcome Measure	Time Frame
Characterization of other possible factors involved in acquired PKD, including acquired epigenetic or gene expression factors	Day 1

Collaborators and Investigators

• Sponsor: Massachusetts General Hospital
• Collaborators: Agios Pharmaceuticals, Inc.
• Investigators: Principal Investigator: Hanny Al-Samkari, MD, Massachusetts General Hospital

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2022
• Primary Completion (Actual): February 1, 2026
• Study Completion (Actual): February 1, 2026

Study Registration Dates

• First Submitted: May 21, 2021
• First Submitted That Met QC Criteria: May 21, 2021
• First Posted (Actual): May 26, 2021

Study Record Updates

• Last Update Posted (Actual): May 19, 2026
• Last Update Submitted That Met QC Criteria: May 15, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Acute Myeloid Leukemia; Myelodysplastic Syndromes; Myeloproliferative Neoplasm; Pyruvate Kinase Deficiency; Clonal Cytopenia of Undetermined Significance; Pyruvate Kinase Deficiency Anemia; Hereditary Hemolytic Anemia; Myelodysplastic/Myeloproliferative Neoplasm; Clonal myeloid neoplasm; Other clonal myeloid neoplasm; Unexplained Coombs-negative non-immune hemolytic anemia
• Additional Relevant MeSH Terms: Neoplasms; Genetic Diseases, Inborn; Neoplasms by Histologic Type; Hematologic Diseases; Leukemia, Myeloid; Bone Marrow Diseases; Anemia, Hemolytic; Anemia; Leukemia; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Hemic and Lymphatic Diseases; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Myeloproliferative Disorders; Myelodysplastic-Myeloproliferative Diseases; Anemia, Hemolytic, Congenital; Pyruvate Kinase Deficiency of Red Cells; Investigative Techniques; Specimen Handling; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Punctures; Surgical Procedures, Operative; Blood Specimen Collection
• Other Study ID Numbers: 21-187

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The Dana-Farber / Harvard Cancer Center encourages and supports the responsible and ethical sharing of data from clinical trials. De-identified participant data from the final research dataset used in the published manuscript may only be shared under the terms of a Data Use Agreement. Requests may be directed to Sponsor Investigator or designee. The protocol and statistical analysis plan will be made available on Clinicaltrials.gov only as required by federal regulation or as a condition of awards and agreements supporting the research.
• IPD Sharing Time Frame: Data can be shared no earlier than 1 year following the date of publication
• IPD Sharing Access Criteria: Contact the Partners Innovations team at http://www.partners.org/innovation
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No