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Not an official event of the 64th ASH Annual Meeting and Exposition. This presentation is not sponsored or endorsed by ASH. Not CME-accredited. MAT-US-2208046-v1.0-11/2022

How to diagnose Cold Agglutinin Disease (CAD)

It’s important to recognize CAD as a cold autoimmune hemolytic anemia, so patients can receive optimal care

CAD is a rare type of chronic autoimmune hemolytic anemia that is dependent on classical complement pathway activation. CAD has potentially serious acute and chronic consequences due to C1-activated hemolysis in the classical complement pathway.1-4 Get a deeper look at the mechanism of hemolysis in CAD and how ENJAYMO works.

women doing yoga
20%
CAD makes up ≈20% of all
autoimmune hemolytic anemias2
60YEARS
CAD onset is typically near 60 years of age, but has been seen in patients as young as 302,5-7

CAD manifests with clinical symptoms due to both C1-activated hemolysis and cold-induced agglutination

Hemolytic anemia, profound fatigue, and circulatory symptoms are the most common CAD symptoms.2,8,9

Recognizing CAD2,5,10-14

Symptoms due to chronic hemolysis

Anemia

Anemia

Profound fatigue

Profound fatigue

Shortness of breath

Shortness of breath

Hemoglobinuria

Hemoglobinuria

Jaundice

Jaundice

Some symptoms of CAD are due to cold-induced agglutination including acrocyanosis, Raynaud’s phenomenon, and livedo reticularis.

Biomarkers that indicate active hemolysis and risk for hemolytic crisis in CAD include elevated bilirubin, LDH, and reticulocyte levels, as well as decreased haptoglobin levels8

How to diagnose CAD

It is important to recognize CAD as a cold autoimmune hemolytic anemia so patients can receive optimal care. CAD is a rare type of chronic autoimmune hemolytic anemia that is dependent on classical complement pathway activation at C1.1

In patients with CAD, cold agglutinins (IgM autoantibodies against RBC antigens) can cause clinical symptoms related to RBC agglutination in cooler parts of the body and hemolytic anemia. The hemolysis in CAD is driven by C1 activation in the classical complement pathway, when cold agglutinins recruit and activate C1, typically at body temperatures below 98.6 °F (37 °C).10

Considerations when diagnosing CAD in adults: Step by step6,8

Adapted from Berentsen S et al. Blood Rev. 2012. doi:10.1016/j.blre.2012.01.002 and Jäger U et al. Blood Rev. 2020. doi:10.1016/jblre.2019.100648

ANEMIA DETECTED

OR

COLD-INDUCED
CIRCULATORY SYMPTOMS
Acrocyanosis
HEMOLYSIS
arrow
YES
NO
POLYSPECIFIC DAT
arrow
POSITIVE
NEGATIVE
MONOSPECIFIC DAT
arrow
POSITIVE FOR C3d
NEGATIVE FOR C3d
COLD AGGLUTININ TITER
arrow
64
0 to 32
INFECTION OR OVERT MALIGNANCY
arrow
NONE
YES arrow arrow
ACUTE FEBRILE INFECTION
OVERT MALIGNANCY
ANEMIA ONSET BEFORE INFECTION? arrow
YES
NO
CAD CONFIRMED

Unlike cold agglutinin syndrome (CAS), CAD is not secondary to cancer or an acute infection

Differentiating CAD and CAS6,8

CAD
  • A chronic autoimmune hemolytic anemia*
  • Classical pathway-mediated hemolysis activated at C1
  • A clonal B-cell low-grade lymphoproliferative disorder without an underlying condition
  • Formerly known as primary CAD
CAS
  • A self-remitting autoimmune hemolytic anemia secondary to an underlying condition
  • Triggered by infections such as Mycoplasma pneumoniae or Epstein-Barr virus, rheumatologic and autoimmune disorders, or overt malignancies
  • Formerly known as secondary CAD

*Patients may have a B-cell clonal lymphoproliferative disorder detectable in blood or marrow but no clinical or radiological evidence of malignancy.

CAD is a chronic autoimmune hemolytic anemia with distinct symptoms driven by complement activation1,2

IMPORTANT SAFETY INFORMATION AND INDICATION

CONTRAINDICATIONS

ENJAYMO is contraindicated in patients with known hypersensitivity to sutimlimab-jome or any of the inactive ingredients.

WARNINGS AND PRECAUTIONS

Serious Infections

  • ENJAYMO may increase susceptibility to serious infections, including infections caused by encapsulated bacteria such as Neisseria meningitides (any serogroup), Streptococcus pneumoniae, and Haemophilus influenzae.
  • Serious infections (bacterial and viral) were reported in 17% (4/24) of patients receiving ENJAYMO in a single-arm open-label clinical trial.
  • Vaccinate patients for encapsulated bacteria according to the most current ACIP recommendations for patients with persistent complement deficiencies. Revaccinate patients in accordance with ACIP recommendations.
  • Immunize patients without a history of vaccination against encapsulated bacteria at least 2 weeks prior to receiving the first dose of ENJAYMO. If urgent ENJAYMO therapy is indicated in an unvaccinated patient, administer vaccine(s) as soon as possible.
  • If ENJAYMO treatment is administered to patients with active systemic infections, monitor closely for signs and symptoms of worsening infection. Some infections may become rapidly life-threatening or fatal if not recognized and treated promptly. Inform patients of these signs and symptoms and steps to be taken to seek immediate medical care.
    • Consider interruption of ENJAYMO treatment in patients who are undergoing treatment for serious infection.
    • Consider patients’ immune status when initiating treatment with ENJAYMO.

Infusion-Related Reactions

  • Administration of ENJAYMO may result in infusion-related reactions. In the CARDINAL study, 8% (2/24) of patients treated with ENJAYMO experienced infusion-related reactions.
  • Monitor patients for infusion-related reactions and interrupt if a reaction occurs.
  • Discontinue ENJAYMO infusion and institute appropriate supportive measures if signs of hypersensitivity reactions, such as cardiovascular instability or respiratory compromise, occur.

Risk of Autoimmune Disease

  • Based on its mechanism of action, ENJAYMO may potentially increase the risk for developing autoimmune diseases such as systemic lupus erythematosus (SLE). Development of SLE has been associated with inherited classical complement deficiency.
  • Monitor patients being treated with ENJAYMO for signs and symptoms and manage medically.

Recurrent Hemolysis After ENJAYMO Discontinuation

  • If treatment with ENJAYMO is interrupted, closely monitor patients for signs and symptoms of recurrent hemolysis, e.g., elevated levels of total bilirubin or lactate dehydrogenase (LDH) accompanied by a decrease in hemoglobin, or reappearance of symptoms such as fatigue, dyspnea, palpitations, or hemoglobinuria. Consider restarting ENJAYMO if signs and symptoms of hemolysis occur after discontinuation.

ADVERSE REACTIONS

  • The most common adverse reactions (10%) with ENJAYMO were respiratory tract infection, viral infection, diarrhea, dyspepsia, cough, arthralgia, arthritis, and peripheral edema.

INDICATION

ENJAYMO (sutimlimab-jome) is indicated to decrease the need for red blood cell (RBC) transfusion due to hemolysis in adults with cold agglutinin disease (CAD).


Please see full Prescribing Information.

See the full Medication Guide.

Learn more about Sanofi’s commitment to fighting counterfeit drugs.

CAD=Cold Agglutinin Disease; CAS=cold agglutinin syndrome; DAT=direct antiglobulin test; Hb=hemoglobin; IgG=immunoglobulin G; IgM=immunoglobulin M; LDH=lactate dehydrogenase; RBC=red blood cell.
References:
  1. Berentsen S, Beiske K, Tjønnfjord GE. Primary chronic cold agglutinin disease: an update on pathogenesis, clinical features and therapy. Hematology. 2007;12(5):361-370. doi:10.1080/10245330701445392
  2. 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
  3. 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
  4. Noris M, Remuzzi G. Overview of complement activation and regulation. Semin Nephrol. 2013;33(6):479-492. doi:10.1016/j.semnephrol.2013.08.001
  5. Berentsen S, Röth A, Randen U, Jilma B, Tjønnfjord GE. Cold agglutinin disease: current challenges and future prospects. J Blood Med. 2019;10:93-103. doi:10.2147/JBM.S177621
  6. Berentsen S, Tjønnfjord GE. Diagnosis and treatment of cold agglutinin mediated autoimmune hemolytic anemia. Blood Rev. 2012;26(3):107-115. doi:10.1016/j.blre.2012.01.002
  7. 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.
  8. Jäger U, Barcellini W, Broome CM, et al. Diagnosis and treatment of autoimmune hemolytic anemia in adults: recommendations from the First International Consensus Meeting. Blood Rev. 2020;41(100648):100648. doi:10.1016/j.blre.2019.100648
  9. Swiecicki PL, Hegerova LT, Gertz MA. Cold agglutinin disease. Blood. 2013;122(7):1114-1121. doi:10.1182/blood-2013-02-474437
  10. Berentsen S. Complement activation and inhibition in autoimmune hemolytic anemia: focus on cold agglutinin disease. Semin Hematol. 2018;55(3):141-149. doi:10.1053/j.seminhematol.2018.04.002
  11. Elharake M, Bors K. Cold agglutinin disease: a case report. W V Med J. 2017:1-4.
  12. Aljubran SA. Cold agglutinin disease clinical presentation. Medscape website. Updated February 7, 2022. Accessed March 22, 2022. emedicine.medscape.com/article/135327-clinical
  13. Hill QA, Stamps R, Massey E, Grainger JD, Provan D, Hill A; British Society for Haematology. The diagnosis and management of primary autoimmune haemolytic anaemia. Br J Haematol. 2017;176(3):395-411. doi:10.1111/bjh.14478
  14. Berentsen S, Randen U, Tjønnfjord GE. Cold agglutinin-mediated autoimmune hemolytic anemia. Hematol Oncol Clin North Am. 2015;29(3):455-471. doi:10.1016/j.hoc.2015.01.002
  15. Barcellini W, Fattizzo B. Clinical applications of hemolytic markers in the differential diagnosis and management of hemolytic anemia. Dis Markers. 2015;2015:1-7. doi:10.1155/2015/635670
  16. Farinade A. Lab values, normal adult. Medscape website. Updated May 14, 2019. Accessed September 29, 2022. https://emedicine.medscape.com/article/2172316-print
  17. Theis SR, Hashmi MF. Coombs test. National Library of Medicine. Updated September 16, 2021. Accessed August 4, 2022. https://www.ncbi.nlm.nih.gov/books/NBK547707/?report=printable
  18. Brugnara C, Berentsen S. Cold agglutinin disease. UpToDate website. Updated July 25, 2022. Accessed August 4, 2022. https://www.uptodate.com/contents/cold-agglutinin-disease/print
expand arrow

IMPORTANT SAFETY INFORMATION AND INDICATION

CONTRAINDICATIONS

ENJAYMO is contraindicated in patients with known hypersensitivity to sutimlimab-jome or any of the inactive ingredients.

WARNINGS AND PRECAUTIONS

Serious Infections

  • ENJAYMO may increase susceptibility to serious infections, including infections caused by encapsulated bacteria such as Neisseria meningitides (any serogroup), Streptococcus pneumoniae, and Haemophilus influenzae.
  • Serious infections (bacterial and viral) were reported in 17% (4/24) of patients receiving ENJAYMO in a single-arm open-label clinical trial.
  • Vaccinate patients for encapsulated bacteria according to the most current ACIP recommendations for patients with persistent complement deficiencies. Revaccinate patients in accordance with ACIP recommendations.
  • Immunize patients without a history of vaccination against encapsulated bacteria at least 2 weeks prior to receiving the first dose of ENJAYMO. If urgent ENJAYMO therapy is indicated in an unvaccinated patient, administer vaccine(s) as soon as possible.
  • If ENJAYMO treatment is administered to patients with active systemic infections, monitor closely for signs and symptoms of worsening infection. Some infections may become rapidly life-threatening or fatal if not recognized and treated promptly. Inform patients of these signs and symptoms and steps to be taken to seek immediate medical care.
    • Consider interruption of ENJAYMO treatment in patients who are undergoing treatment for serious infection.
    • Consider patients’ immune status when initiating treatment with ENJAYMO.

Infusion-Related Reactions

  • Administration of ENJAYMO may result in infusion-related reactions. In the CARDINAL study, 8% (2/24) of patients treated with ENJAYMO experienced infusion-related reactions.
  • Monitor patients for infusion-related reactions and interrupt if a reaction occurs.
  • Discontinue ENJAYMO infusion and institute appropriate supportive measures if signs of hypersensitivity reactions, such as cardiovascular instability or respiratory compromise, occur.

Risk of Autoimmune Disease

  • Based on its mechanism of action, ENJAYMO may potentially increase the risk for developing autoimmune diseases such as systemic lupus erythematosus (SLE). Development of SLE has been associated with inherited classical complement deficiency.
  • Monitor patients being treated with ENJAYMO for signs and symptoms and manage medically.

Recurrent Hemolysis After ENJAYMO Discontinuation

  • If treatment with ENJAYMO is interrupted, closely monitor patients for signs and symptoms of recurrent hemolysis, e.g., elevated levels of total bilirubin or lactate dehydrogenase (LDH) accompanied by a decrease in hemoglobin, or reappearance of symptoms such as fatigue, dyspnea, palpitations, or hemoglobinuria. Consider restarting ENJAYMO if signs and symptoms of hemolysis occur after discontinuation.

ADVERSE REACTIONS

  • The most common adverse reactions (10%) with ENJAYMO were respiratory tract infection, viral infection, diarrhea, dyspepsia, cough, arthralgia, arthritis, and peripheral edema.

INDICATION

ENJAYMO (sutimlimab-jome) is indicated to decrease the need for red blood cell (RBC) transfusion due to hemolysis in adults with cold agglutinin disease (CAD).


Please see full Prescribing Information.

See the full Medication Guide.

Learn more about Sanofi’s commitment to fighting counterfeit drugs.