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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

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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 Cold Agglutinin Disease so patients can receive optimal care

Cold Agglutinin Disease is a rare autoimmume hemolytic anemia with complement-mediated hemolysis via the classical pathway. Cold Agglutinin Disease has potentially serious acute and chronic consequences due to classical pathway–mediated hemolysis.1-4 Get a deeper look at the mechanism of hemolysis in Cold Agglutinin Disease and how ENJAYMO works.

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Cold Agglutinin Disease is a rare autoimmume hemolytic anemia with complement-mediated hemolysis and potentially serious acute and chronic consequences.1-3,5-7

up to30%
Cold Agglutinin Disease makes up to 30% of all autoimmune hemolytic anemias2,7,8
60YEARS
Cold Agglutinin Disease onset is typically near 60 years of age, but has been seen in patients as young as 302,7,9,10

Cold Agglutinin Disease manifests with clinical symptoms due to both complement-mediated hemolysis via the classical pathway and cold-induced agglutination2,5,11,12

Hemolytic anemia, profound fatigue, and circulatory symptoms are the most common Cold Agglutinin Disease symptoms.2,5,11

Recognizing Cold Agglutinin Disease7,12-15

Anemia

Anemia

Profound fatigue

Profound fatigue

Shortness of breath

Shortness of breath

Hemoglobinuria

Hemoglobinuria

Jaundice

Jaundice

Some symptoms of Cold Agglutinin Disease are due to cold-induced agglutination, including acrocyanosis, Raynaud’s phenomenon, and livedo reticularis.5

Biomarkers that indicate active hemolysis and risk for hemolytic crisis in Cold Agglutinin Disease include elevated bilirubin, LDH, and reticulocyte levels, as well as decreased haptoglobin levels11,16,17

How to diagnose Cold Agglutinin Disease (CAD)

It is important to consider a Cold Agglutinin Disease diagnosis in patients who present with hemolytic anemia. Up to 30% of all autoimmune hemolytic anemias are Cold Agglutinin Disease.2,7,8

In patients with Cold Agglutinin Disease, 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 Cold Agglutinin Disease 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).4,12

Considerations when diagnosing Cold Agglutinin Disease in adults: Step by step10,11

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
  • 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

Cold Agglutinin Disease should be distinguished from Cold Agglutinin Syndrome10,11,22

COLD AGGLUTININ DISEASE
  • A chronic autoimmune hemolytic anemia*
  • Classical complement-dependent hemolysis
  • Considered a well-identified clinicopathologic entity
  • A clonal B-cell low-grade lymphoproliferative disorder without an underlying condition
  • Formerly known as primary Cold Agglutinin Disease
COLD AGGLUTININ SYNDROME
  • A group of disorders with heterogeneous etiology and pathogenesis
  • 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 Cold Agglutinin Disease

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

Cold Agglutinin Disease is a chronic autoimmune hemolytic anemia with distinct symptoms of hemolysis driven by complement activation through the classical pathway1,2

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ENJAYMO HCP Indication and Important Safety Information

INDICATION

ENJAYMO® (sutimlimab-jome) is indicated for the treatment of hemolysis in adults with cold agglutinin disease (CAD).

IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS

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

WARNINGS AND PRECAUTIONS

Serious Infections Including Those Caused by Encapsulated Bacteria

  • ENJAYMO, a proximal classical complement C1s inhibitor, increases susceptibility to serious infections, including those caused by encapsulated bacteria e.g. Neisseria meningitidis (any serogroup, including non-groupable strains), Streptococcus pneumoniae, and Haemophilus influenzae type B.
  • Life-threatening and fatal infections with encapsulated bacteria have occurred in both vaccinated and unvaccinated patients treated with complement inhibitors.
  • Serious infections (bacterial and viral) were reported in 15% (10/66) of patients receiving ENJAYMO in the two phase 3 trials. These infections included urinary tract infection with sepsis, respiratory tract infection, pneumonia, otomastoiditis, and skin infections. One patient (1.5%) died due to Klebsiella pneumoniae.
  • Complete or update vaccination against encapsulated bacteria at least 2 weeks prior to administration of the first dose of ENJAYMO, according to the most current ACIP recommendations for patients receiving a complement inhibitor.
  • If urgent ENJAYMO therapy is indicated in a patient who is not up to date on their vaccine(s), administer as soon as possible.
  • Vaccination does not eliminate the risk of serious encapsulated bacterial infections. Closely monitor patients for early signs and symptoms of serious infection and evaluate patients immediately if an infection is suspected.
  • 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 two phase 3 trials, 29% (19/66) of patients treated with ENJAYMO experienced infusion-related reactions. One patient permanently discontinued ENJAYMO due to an infusion-related reaction.
  • 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.
  • In clinical trials, 4.5% (3/66) of patients developed a relapse or worsening of previously diagnosed autoimmune disease.
  • Monitor ENJAYMO patients 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, eg, 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 in the CADENZA trial (Part A) (incidence ≥18%) are rhinitis, headache, hypertension, acrocyanosis, and Raynaud’s phenomenon. The most common adverse reactions in the CARDINAL trial (incidence ≥25%) are urinary tract infection, respiratory tract infection, bacterial infection, dizziness, fatigue, peripheral edema, arthralgia, cough, hypertension, and nausea.

Please see full Prescribing Information.

See the full Medication Guide.

DAT=direct antiglobulin test; 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:10.1080/10245330701045392
  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. Swiecicki PL, Hegerova LT, Gertz MA. Cold agglutinin disease. Blood. 2013;122(7):1114-1121. doi:10.1182/blood-2013-02-474437
  6. Pham HP, Wilson A, Adeyemi A, et al. An observational analysis of disease burden in patients with cold agglutinin disease: results from a large US electronic health record database. J Manag Care Spec Pharm. 2022;28(12):1419-1428. doi:10.18553/jmcp.2022.28.12.1419
  7. 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
  8. Sokol RJ, Hewitt S, Stamps BK. Autoimmune haemolysis: an 18-year study of 865 cases referred to a regional transfusion centre. Br Med J (Clin Res Ed). 1981;282(6281):2023-2027. doi:10.1136/bmj.282.6281.2023
  9. 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.
  10. 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
  11. 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
  12. 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
  13. Elharake M, Bors K. Cold agglutinin disease: a case report. W V Med J. 2017:1-4. doi:10.21885/wvmj.2017.5
  14. Collie JC, Lockey RF. Cold agglutinin disease clinical presentation. Medscape. February 7, 2022. Accessed January 18, 2023. https://emedicine.medscape.com/article/135327-clinical
  15. 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.1447
  16. Berentsen S. How I treat cold agglutinin disease. Blood. 2021;137(10):1295-1303. doi:10.1182/blood.2019003809
  17. 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
  18. Röth A, Barcellini W, D'Sa S, et al. Sutimlimab in Cold Agglutinin Disease. N Engl J Med. 2021;384(14):1323-1334. doi:10.1056/NEJMoa2027760
  19. Farinde A. Lab values, normal adult. Medscape. Updated May 14, 2019. Accessed November 29, 2022. https://emedicine.medscape.com/article/2172316-print
  20. Berentsen S., Brugnara C. Cold agglutinin disease. UpToDate. Updated October 30, 2025. Accessed April 9, 2026. https://www.uptodate.com/contents/cold-agglutinin-disease/print
  21. Theis SR, Hashmi MF. Coombs test. National Library of Medicine. Updated September 12, 2022. Accessed April 8, 2026. https://www.ncbi.nlm.nih.gov/books/NBK547707/?report=printable
  22. Berentsen S. Cold agglutinin disease. Hematology Am Soc Hematol Educ Program. 2016;2016(1):226-231. doi:10.1182/asheducation2016.1.226
  23. Shi J, Rose EL, Singh A, et al. TNT003, an inhibitor of the serine protease C1s, prevents complement activation induced by cold agglutinins. Blood. 2014;123(26):4015-22. doi:10.1182/blood-2014-02-556027
  24. ENJAYMO. Prescribing information. Recordati Rare Diseases Inc.; 2024.
  25. Panicker S, Shi J, Rose EL. TNT009, a Classical complement pathway specific inhibitor, prevents complement dependent hemolysis induced by cold agglutinin disease patient autoantibodies. Blood. 2013;122(21):42-42. doi:10.1182/blood.V122.21.42.42
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ENJAYMO INDICATION

ENJAYMO® (sutimlimab-jome) is indicated for the treatment of hemolysis in adults with cold agglutinin disease (CAD).

IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS

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

WARNINGS AND PRECAUTIONS

Serious Infections Including Those Caused by Encapsulated Bacteria

  • ENJAYMO, a proximal classical complement C1s inhibitor, increases susceptibility to serious infections, including those caused by encapsulated bacteria e.g. Neisseria meningitidis (any serogroup, including non-groupable strains), Streptococcus pneumoniae, and Haemophilus influenzae type B…

NO COST TRIAL PROGRAM

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The ENJAYMO No Cost Trial Program is available regardless of your patient's insurance coverage or current treatment

Enroll your eligible patients* in the No Cost Trial Program

To get started:

Download the start form

*PROGRAM OVERVIEW

  • The No Cost Trial Program can provide a 30-day supply of ENJAYMO at no cost to eligible patients.
  • Eligibility for the No Cost Trial Program is contingent on patient enrollment in RRD Patient Solutions.
  • There is no obligation for your patient to continue use of ENJAYMO after the No Cost Trial Program has been completed.
  • Patients are eligible for the No Cost Trial Program only once per lifetime.
  • Shipment of the No Cost Trial Program product is contingent on patients receiving recommended vaccinations and scheduling the first infusion.
  • The provision of the No Cost Trial Program product may be disclosed in accordance with transparency reporting requirements in certain states (e.g., VT).
  • Recordati Rare Diseases reserves the right to change, modify, or discontinue this program at any time without notice.
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