HAEMOLYTIC STATE
SEVERE ANAEMIA
THROMBOEMBOLIC EVENTS

Due to chronic C1-activated haemolysis, many patients remain in a haemolytic state over 5 years1

In a population-based retrospective follow-up study of patients with CAD (n=86)*

Hb chart image
Bilirubin chart image
LDH chart image

In CAD, haemolytic markers, such as bilirubin and LDH, have been shown to correlate with anaemia severity, but not IgM levels2,3

    A population-based, retrospective follow-up study of 86 patients in Norway with CAD measured the change over time in concentrations of bilirubin, LDH and haemoglobin

    • The mean initial serum bilirubin level was 41 μmol/L and the corrected LDH level was 437 U/L, and the initial haemoglobin level at baseline was 9.2, demonstrating that these patients were in a haemolytic state at baseline
    • After a median follow-up time of 5 years, there were no significant overall changes in these parameters despite the majority of these patients receiving pharmacotherapies during the study time period (73% of patients received 1 to 8 courses of 1 to 5 different therapies)
    • There were, however, large individual differences with regard to the changes in individual biomarkers throughout the 5-year period based on the treatment that patients received. While a majority of patients who received therapy had a complete or partial response for some period of time, this study showed that those effects were not sustained over time
    • Based on the results, most patients with CAD in this study experienced haemolysis despite receiving pharmacotherapies
    • There were some patients on pharmacotherapies who experienced complete and partial response to their therapies

Severe anaemia events are unpredictable and can occur at any time throughout the disease course4

of patients had at least 1 severe anaemia event within the first year of follow-up

Data from a retrospective review of a healthcare system database in patients with CAD (n=29) who were included based on haemoglobin readings and follow-up

of patients had a severe anaemia event within the first 6 months of pharmacotherapy

Data collected from 18 patients with at least 6 months of follow-up after initial therapy in a retrospective review of a healthcare database

    Data collected from 18 patients with at least 6 months of follow-up after initial therapy in a retrospective review of a healthcare database

    • Haemoglobin at CAD onset was defined as the lowest haemoglobin value during the patients’ first haemolytic crisis, as defined in other studies
    • CAD-related therapies were characterised as corticosteroids, IV immunoglobulin, rituximab, immunosuppressants, antineoplastics or biologics
    • Each 6-month time period of patient follow-up is characterised by the lowest haemoglobin value during that time period and categorised as either “mild” (haemoglobin >10 g/dL), “moderate” (haemoglobin=8.1-10 g/dL), or “severe” (haemoglobin ≤8 g/dL)

    Study limitations

    • The database did not record reasons for loss to follow-up. Some patients with severe anaemia at disease onset could not be followed for a year
      or more
    • Given that the database captured data from the Stanford clinics, this study captured the minimum levels of care for this cohort of patients
      with CAD

CAD is associated with significant increased rate of life-threatening thromboembolic events (TEs)5

In a retrospective claims-database study and sensitivity analysis of patients with CAD (n=425) vs a matched non-CAD population (n=4126)†

TEs in parients with CAD chart image

Patients with CAD or CAS consistently experienced a significant increase in TEs over 10 years5

Cumulative incidence curve of first TE after index date‡ in patients with CAD or CAS§ (n=608) demonstrated a significant difference in the development of TEs over time vs a matched non-CAD or -CAS population (n=5873) (P<0.0001)||

Significant increase in TE risk chart image
  • The increased incidence of TEs in patients with CAD or CAS was noted from the time of identification through the entire 10-year follow-up period
  • The adjusted absolute risk difference calculation revealed a significant excess risk of TEs for patients with CAD or CAS vs patients without CAD or CAS at 1 year (11.9 per 100 patients; 95% CI: 11.7-12.1 per 100 patients) and 5 years (11.9 per 100 patients; 95% CI: 11.6-12.2 per 100 patients) after the index date

In another study of patients with CAD or CAS, life-threatening TE risk persisted, regardless of season6

In a retrospective claims analysis of 344 patients with CAD or CAS,§ risk of TEs was found to be consistent despite changes in season and weather

Risk of TEs by reason chart image

Additional studies are needed to further understand the risks associated with CAD

    In a US retrospective study, thromboembolic event risk in patients with CAD or CAS was evaluated vs matched comparisons

    US patients with CAD or CAS (n=608) vs a matched non-CAD or CAS population (n=5873)*

    • This study evaluated TE risk in patients with CAD and CAS over a 10-year period
    • While patients with both CAD and CAS were included in the primary analysis, sensitivity analyses were performed to evaluate the estimated risk of TEs among patients presumed to have CAD (not due to a secondary cause) by excluding patients with CAD with a coexisting diagnosis of any type of lymphoma (except Hodgkin disease), myelomas, chronic lymphocytic leukaemia, Waldenström macroglobinaemia and certain infections known to be associated with CAS (Mycoplasma pneumoniae, Epstein-Barr virus and cytomegalovirus)

    Study limitations

    • Claims-based data and TE diagnostic codes (ICD-9 and ICD-10) may be subject to coding errors
    • Database only included commercially insured patients
    • Lack of data on specific CAD treatments in relation to TE development
    • Patients with both CAD and CAS were likely included in the main analysis,* as the database did not allow for differentiation
    • Lack of data on the hereditary and acquired thrombotic risks that may also contribute to the occurrence and severity of these events
    • Only the first TE of each type was included, so the risk of TEs may have been underestimated
    • There may be some selection bias because patients with <1 year in the Optum system prior to the index date were not included. This may have excluded the most severely affected patients due to early death

    * Data used a Cox regression model adjusting for age, sex, race, region, active time in the Optum system, history of a prior TE, history of HIV/AIDS, history of malignant cancer except for melanoma skin cancer, history of organ failure, history of organ transplantation, history of chemotherapy use, history of radiation use, history of anticoagulant medication use, history of antiplatelet medication use and CCI score.

    CAD=Cold Agglutinin Disease; CAS=cold agglutinin syndrome; CCI=Charlson Comorbidity Index; ICD=International Classification of Diseases; TE=thromboembolic event.

    Retrospective study of a Japanese claims database of TE risk in patients with CAD or CAS was evaluated vs matched comparisons

    Japanese patients with CAD or CAS (n=344) vs matched comparisons (n=3440)

    • This study evaluated TE risk in patients with CAD or CAS in Japan during a 1-year period
    • In the main analysis, patients with both CAD and CAS were included. A sensitivity analysis was performed to evaluate the risk of TEs among patients assumed to have CAD (not due to a secondary cause) by excluding patients with an additional diagnosis code for any kind of non-Hodgkin lymphoma, myeloma, chronic lymphocytic leukaemia, Waldenström macroglobinaemia and certain infections known to be associated with CAS (Mycoplasma pneumoniae, Epstein-Barr virus and cytomegalovirus)

    Study limitations

    • The use of an administrative claims database limits the data to records from hospitals within that system only; claims that occurred in community settings were not included
    • The information related to potential risk factors for TE could only be obtained from claims analyses and was limited by the lack of clinical data, and because of the retrospective study design, it was difficult to ascertain causal relationships
    • Laboratory data were limited in this database, limiting the ability to correlate with findings

    CAD=Cold Agglutinin Disease; CAS=cold agglutinin syndrome; TE=thromboembolic event.

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There are specific criteria to diagnose CAD

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CAD can impact patients’ lives

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aHR=adjusted hazard ratio; CAS=cold agglutinin syndrome; CI=confidence interval; IgM=immunoglobulin M; LDH=lactate dehydrogenase; n.s.=not significant; OR=odds ratio; TE=thromboembolic event.

*Charts reflect mean haemolytic biomarker levels collected over 5 years. Throughout the study, for some patients, there were large individual differences in regard to changes in these biomarkers.
†Because the primary analysis included patients with both CAD and CAS, this sensitivity analysis was performed to evaluate the estimated risk of TEs among patients presumed to have CAD specifically. 183 and 1747 patients from the initial CAD and matched comparisons, respectively, were excluded due to the presence of diagnostic codes known to be associated with CAS.
‡The date of first mention of CAD for the diseased patient.
§Patients with both CAD and CAS were included in the primary analysis.
||With 95% confidence limits. Gray’s test P<0.0001.

References: 1. Berentsen S, Ulvestad E, Langholm R, et al. Primary chronic cold agglutinin disease: a population based clinical study of 86 patients. Haematologica. 2006;91(4):460-466. 2. Berentsen S. New insights in the pathogenesis and therapy of cold agglutinin-mediated autoimmune hemolytic anemia. Front Immunol. 2020;11:590. doi:10.3389/fimmu.2020.00590 3. Berentsen S, Barcellini W, D’Sa S, et al. Cold agglutinin disease revisited: a multinational, observational study of 232 patients. Blood. 2020;136(4):480-488. 4. Mullins M, Jiang X, Bylsma LC, et al. Cold agglutinin disease burden: a longitudinal analysis of anemia, medications, transfusions, and health care utilization. Blood Adv. 2017;1(13):839-848. doi:10.1182/bloodadvances.2017004390 5. Broome CM, Cunningham JM, Mullins M, et al. Increased risk of thrombotic events in cold agglutinin disease: a 10-year retrospective analysis. Res Pract Thromb Haemost. 2020;4(4):628-635. doi:10.1002/rth2.12333 6. Kamesaki T, Nishimura J-i, Wada H, et al. Demographic characteristics, thromboembolism risk, and treatment patterns for patients with cold agglutinin disease in Japan. Int J Hematol. 2020:112(3):307-315. doi:10.1007/s12185-020-02899-6

MAT-GLB-2201061-v1.0-05/2022