Clinical Trial: Isoagglutinins in the Development of IVIG-associated Hemolysis

Study Status: Completed
Recruit Status: Completed
Study Type: Observational

Official Title: Elucidation of the Mechanism of IVIG-Associated Hemolysis

Brief Summary: Patients at high risk of IVIG-associated hemolysis (defined as receipt of a 28-day cumulative dose of ≥ 2 g/kg, adjusted for ideal body weight, and non-O blood group) will be prospectively monitored using a standardized protocol for signs of hemolysis, and will be undergo additional testing for variables that have been hypothesized to increase the risk of hemolysis. The goal of the study is to define the incidence and dynamics of IVIG-mediated hemolysis and identify patient and product-related factors that may predict which patients are especially at risk.

Detailed Summary:

All IVIG orders received by the blood transfusion service at participating sites will be screened for patient eligibility. All non-O blood group patients receiving a cumulative 28-day dose of IVIG ≥ 2 g/kg will be approached for enrolment. Exclusion criteria include the presence of an alternate cause of anemia, including blood loss, other drug-induced hemolysis, anemia associated with chemotherapy for cancer, or hemolysis associated with an underlying disease or participation in another ongoing study. Patients receiving repeated courses of therapy will be eligible for re-enrollment a maximum of 6 times. There are otherwise no exclusions on the basis of age, diagnosis, concurrent treatment, or specific brand of product received. Enrolment will occur at multiple Canadian health care facilities.

Upon enrolment,case report forms documenting the participant's previous medical history, IVIG treatments and adverse reactions, and concurrent medication use will be collected. Laboratory testing for hemolysis will be performed at baseline, immediately following the completed high-dose cycle (usually administered over 1-2 days), and then again at 5-10 days post-infusion. IVIG associated. Hemolysis will be defined and graded as per the criteria of the Canadian IVIG Pharmacovigilance Group. The pathophysiology of IVIG-associated hemolysis will be characterized by tracking changes in serum complement levels, performing extended cytokine profiling, and conducting mononuclear phagocyte activity assays using patient monocytes. Secretor gene status, ABO zygosity and FcR polymorphisms will also be determined. A predictive model incorporating both patient factors (eg., blood group, total dose prescribed, presence of pre-infusion inflammation) and product factors (eg., specific lot number) will then be developed.


Sponsor: Toronto Transfusion Medicine Collaborative

Current Primary Outcome: Hemolysis [ Time Frame: From initiation of IVIG therapy to 5-10 days after the completion of last IVIG infusion ]

Definition and grading of hemolysis adopted from the Canadian IVIG Hemolysis Pharmacovigilance Group


Original Primary Outcome: Hemolysis [ Time Frame: within 10 days of a course of IVIG ]

Primary outcome is the presence of haemolysis within 10 days of a course of IVIG. Hemolysis is defined as follows, adapted per the recommendations of the Canadian IVIG Hemolysis Pharmacovigilance Group5:

  1. Drop in hemoglobin of ≥ 10 g/L
  2. Positive result of direct antiglobulin test

  3. At least 2 of:

    • increased reticulocyte count (above upper limit of UHN reference range)
    • increased lactate dehydrogenase level (≥50% increase from baseline)
    • low haptoglobin level (below lower limit of UHN reference range)
    • unconjugated hyperbilirubinemia (≥50% increase from baseline)
    • presence of significant spherocytosis on peripheral blood film

Severity of the hemolysis will also be graded as per the recommendations of the Canadian IVIG Hemolysis Pharmacovigilance Group.



Current Secondary Outcome:

  • Adverse transfusion reaction [ Time Frame: From initiation of IVIG therapy to 5-10 days after the completion of last IVIG infusion ]
    Any patient symptom reported during or within 10 days of an IVIG infusion will be considered as a possible adverse transfusion reaction. Symptoms deemed to most likely indicate an adverse reaction include the development of fever, chills or rigours; allergic reactions (urticaria, angioedema or anaphylaxis); pain reactions (including headache); respiratory symptoms (cough, shortness of breath); and signs suggestive of anemia or hemolysis (pallor, fatigue, red-coloured urine, jaundice)
  • Descriptive analysis of risk factors [ Time Frame: From initiation of IVIG therapy to 5-10 days after the completion of last IVIG infusion ]

    Additional secondary outcomes will include a descriptive analysis of information collected on the initial case report form such as patient demographics, medical history, dose and lot of IVIG administered, infusion rate, patient blood group, and concurrent medications. In addition, patient samples will be sent for additional testing aimed at elucidating the mechanism of IVIG-mediated hemolysis. These include:

    1. Cytokine panel profiling
    2. C3, C4, ferritin and CRP levels
    3. Monocyte monolayer assay using patient monocytes and implicated lot of IVIG against AET-treated group A1, B, and O red cells
    4. Tests of eluted IgG antibody for subtype.
    5. ABO zygosity (PCR) and/or by Flow
    6. FcR polymorphisms by PCR
    7. Secretor status by PCR


Original Secondary Outcome:

  • Acute transfusion reaction [ Time Frame: 10 days following the completion of last IVIG infusion ]
    Acute transfusion reaction is defined as any unwanted reaction to a blood product (including all autologous blood products and fractionated plasma products such as albumin or IVIG), that occurs within 24 hours of infusion.Suspected acute transfusion reaction includes low risk fever, high risk fever, Minor allergic reaction(Urticaria/hives/pruritus affecting less than 2/3 of body surface area) major allergic reaction (Urticaria/hives/pruritus affecting more than 2/3 of body surface area), Severe allergic reaction (Urticaria affecting more than 2/3 of body surface area or mucosal surfaces involves and/or other signs or symptoms- hypotension, dyspnea, nausea, vomiting, pain), Hypoxic reaction (decrease in SpO2 of 5% or more). Secondary outcomes will also include any signs or symptoms need for hospitalization, or need for RBC transfusion.
  • Descriptive analysis of risk factors [ Time Frame: up to 10 days ]

    Additional secondary outcomes will include a descriptive analysis of risk factors measured in patients who developed IVIG-associated hemolysis.

    Patients experiencing IVIG-associated hemolysis (see Outcome Measurements) will undergo additional testing for additional risk factors (note: availability of these investigations may be dependent upon the date time at which samples are collected):

    1. Secretor status determination by Lewis genotyping or saliva testing for A and B substance by serology
    2. FACS or FLAER analysis for PNH phenotype6,7
    3. Tests of implicated lot of IVIG against AET-treated group A1, B, and O red cells +/- fresh AB serum.
    4. Tests of eluted IgG antibody for subtype.
    5. Serum test for Donath-Landsteiner antibody9
    6. ABO zygosity (PCR) and/or by Flow
    7. FcR polymorphisms by PCR


Information By: Toronto Transfusion Medicine Collaborative

Dates:
Date Received: August 29, 2014
Date Started: October 2014
Date Completion:
Last Updated: March 10, 2017
Last Verified: March 2017