Cold Agglutinin Disease

beau hilton, 2024-03-22

Cold Agglutinin Disease

beau hilton, 2024-03-22

Case presentation

72F, p/w hgb 3.8. A little tired.

Some discoloration of fingers, she says it’s worse (and painful) when it’s cold.

No notable icterus.

Elevated indirect bili.

LDH elevated. Hapto undetectable.

Retic elevated.

+RBC clumping on smear. Other cells normal in morphology and number.

DAT: IgG+ (weak), C3+

Cold agglutinin titre: way >64

Pathophysiology

Berentsen, Frontiers in Immunology, 2020

Confirming the diagnosis

flow cytometry
SPEP, SFLC (usu IgM kappa)
maximal thermal amplitude (>28C)
cold-temperature titre (>=64 @ 4C)
BMBx (sometimes)

Differential diagnosis

no B symptoms (may be difficult to separate from infx)
no extramedullary disease (may push you toward MZL)
CD5- (>50% CAD -ve for CD5), CD10- B cells: MZL vs IgM LPL (Waldenstrom)
MYD88 L265P -ve (usu + in LPL)
certain clusters of genomic and cytogenetic changes, e.g. KMT2D variant (69%) complete or partial gain of chromosome 3 (93%)
WHO 2022: CAD is now a distinct lymphoid neoplasm (CAD-associated LPD) (hopefully, more diagnostic consensus will follow)

Diagnostic algorithm

Berentsen, Fattizzo, Barcellini, Frontiers in Immunology, 2023

Case presentation

2010: p/w hemolytic anemia, eventually found to have cold agglutinin disease
2010 - 2015: rituximab, multiple cycles
2016: rituximab + fludarabine
2018: rituximab + bortezomib
2019: rituximab + bendamustine
2022: sutimlimab recommended

A jaunt through history

1200s

Johannes Actuarius, Constantinople court physician, publishes De Urinis, which notes: "Yea indeed an extremely black urine… signifies extreme chilliness."

(syphilis causes paroxysmal cold hemoglobinuria, so used to be much more common)

(but watch out for a resurgence - syphilis cases went up 80%, to 207,000 in 2022)

A jaunt through history

1800s

Trypanosomiasis (N’gana, sleeping sickness) is found to cause deep anemias, partially via hemolysis.

https://vetclinpathimages.com/2018/04/27/trypanosoma/

A jaunt through history

1898

Mssrs. Kanthack, Durham, and Blandford describe agglutination in red blood cells of animals infected with trypanosomes.

"Instead of forming rouleaux, the red corpuscles tend to clump into masses and to lose their outlines, especially when the anaemia is pronounced (rabbit, ass, and horse). The serum of such blood, when mixed with normal blood of the same species of animal, causes the red corpuscles to clump together also."

A jaunt through history

1903

Karl Landsteiner publishes "About Relationships Between the Blood Serum and the Body Cells" (Über Beziehungen zwischen dem Blutserum und den Körperzellen), which contains a description of blood agglutination at cold temperatures (thermal amplitude 0-5C).

He’s the guy who discovered blood types, under the term "iso-agglutination," and won the Nobel Prize in Medicine for this in 1930.

A jaunt through history

1918

Clough and Richter publish "A study of an autoagglutinin occurring in a human serum," first definite cases of cold agglutination in humans, describing the relationship between agglutination, hemolysis, and pneumonia.

A jaunt through history

1937

McCombs and McElroy note that the huge increase in surgical transfusions since Landsteiner’s discovery has revealed a number of cases of cold agglutination found in the blood bank (thermal amplitude 0-25 C), confusing technicians nation-wide.

(And occasionally leading to death)

A jaunt through history

1946

Lubinski and Goldbloom collect and describe 7 cases of cold agglutination with a thermal amplitude of 0-37C, all associated with hemolytic anemia (5 primary cases, 1 sepsis, 1 syphilis).

A jaunt through history

1957

Christenson et al perform the first isolation of a monoclonal protein, a cold agglutinin. One of the pts also has a cryoglobulin.

A jaunt through history

1964

Olesen publishes the first paper with a successful drug treatment for CAD, choosing chlorambucil based on the then-recent success of this drug in Waldenstrom macroglobulinemia. Follow-up in 1970 with 4 pts has similar results.

(One pt got cyclophosphamide for 4mo, switched to chlorambucil later on d/t drAE).

A jaunt through history

1997

Rituximab comes to market.

1998

Lee and Kueck try rituximab (375 x4) in a pt w CAD, and it works.

2001

Berentsen et al report on a small prospective ritux study: 1 CR, 3 PR, 2 no response.

2006, 2013

Berentsen et al retrospective study: ritux-based regimens RR 67-83%.

A jaunt through history

2017

Berentsen et al, prospective study using BR: 71% RR, 40% CR, 31% PR. 50% RR in the retreatment setting. TTR 2mo. 77% response rate at 5y. Median DOR >88mo.

2018

Rossi et al report on 2L bortezomib (GIMEMA) (single cycle): 32% RR, median DOR 16mo.

2020, 2021

Case reports on CAS d/t pembro (Atiq 2020) and atezo (Acikgoz 2021).

A jaunt through history

2021

Roth et al report (NEJM) on sutimlimab monotherapy (CARDINAL) (nonrandomized)

2022

Roth et al report (Blood) on sutimlimab monotherapy (CADENZA) (phase III placebo-controlled RCT)

A jaunt through history

Blood 2022, Roth et al

Tx options overview

Berentsen, Fattizzo, Barcellini, Frontiers in Immunology 2023

Tx sequencing overview

Berentsen, Fattizzo, Barcellini, Frontiers in Immunology 2023

Bibliography

Acikgoz, O., Bayramgil, A., Cavusoglu, G., & Sadri, S. (2021). Rare side effect caused by atezolizumab, an immune checkpoint inhibitor: Cold agglutinin disease. Journal of Oncology Pharmacy Practice: Official Publication of the International Society of Oncology Pharmacy Practitioners, 27(8), 2066–2068. https://doi.org/10.1177/10781552211033009

Atiq, O., Atiq, S. O., Atiq, Z. O., Patel, V., Atiq, M. O., & Atiq, O. T. (2020). Pembrolizumab-Induced Cold Agglutinin Disease. The American Journal of Case Reports, 21, e924283. https://doi.org/10.12659/AJCR.924283

Berentsen, S. (2016). Cold agglutinin disease. Hematology: The American Society of Hematology Education Program, 2016(1), 226–231.

Berentsen, S. (2020). New Insights in the Pathogenesis and Therapy of Cold Agglutinin-Mediated Autoimmune Hemolytic Anemia. Frontiers in Immunology, 11, 590. https://doi.org/10.3389/fimmu.2020.00590

Berentsen, S. (2021). How I treat cold agglutinin disease. Blood, 137(10), 1295–1303. https://doi.org/10.1182/blood.2019003809

Berentsen, S., Barcellini, W., D’Sa, S., & Jilma, B. (2022). Sutimlimab for treatment of cold agglutinin disease: Why, how and for whom? Immunotherapy, 14(15), 1191–1204. https://doi.org/10.2217/imt-2022-0085

Berentsen, S., Barcellini, W., D’Sa, S., Randen, U., Tvedt, T. H. A., Fattizzo, B., Haukås, E., Kell, M., Brudevold, R., Dahm, A. E. A., Dalgaard, J., Frøen, H., Hallstensen, R. F., Jæger, P. H., Hjorth-Hansen, H., Małecka, A., Oksman, M., Rolke, J., Sekhar, M., … Tjønnfjord, G. E. (2020). Cold agglutinin disease revisited: A multinational, observational study of 232 patients. Blood, 136(4), 480–488. https://doi.org/10.1182/blood.2020005674

Berentsen, S., Fattizzo, B., & Barcellini, W. (2023). The choice of new treatments in autoimmune hemolytic anemia: How to pick from the basket? Frontiers in Immunology, 14, 1180509. https://doi.org/10.3389/fimmu.2023.1180509

Berentsen, S., Tjønnfjord, G. E., Brudevold, R., Gjertsen, B. T., Langholm, R., Løkkevik, E., Sørbø, J. H., & Ulvestad, E. (2001). Favourable response to therapy with the anti-CD20 monoclonal antibody rituximab in primary chronic cold agglutinin disease. British Journal of Haematology, 115(1), 79–83. https://doi.org/10.1046/j.1365-2141.2001.03078.x

Berentsen, S., Ulvestad, E., Langholm, R., Beiske, K., Hjorth-Hansen, H., Ghanima, W., Sørbø, J. H., & Tjønnfjord, G. E. (2006). Primary chronic cold agglutinin disease: A population based clinical study of 86 patients. Haematologica, 91(4), 460–466.

Bibliography

Bhattacharyya, J., Mihara, K., Takihara, Y., & Kimura, A. (2012). Successful treatment of IgM-monoclonal gammopathy of undetermined significance associated with cryoglobulinemia and cold agglutinin disease with immunochemotherapy with rituximab, fludarabine, and cyclophosphamide. Annals of Hematology, 91(5), 797–799. https://doi.org/10.1007/s00277-011-1322-0

Broome, C. M. (2023). Complement-directed therapy for cold agglutinin disease: Sutimlimab. Expert Review of Hematology, 16(7), 479–494. https://doi.org/10.1080/17474086.2023.2218611

Christenson, W. N., Dacie, J. V., Croucher, B. E. E., & Charlwood, P. A. (1957). Electrophoretic Studies on Sera containing High-Titre Cold Haemagglutinins: Identification of the Antibody as the Cause of an Abnormal γ Peak. British Journal of Haematology, 3(3), 262–273. https://doi.org/10.1111/j.1365-2141.1957.tb05795.x

Clough, M. C., & Richter, I. M. (1918). A study of an autoagglutinin occurring in a human serum. Johns Hopkins Hosp Bull, 29, 86.

Cunha, B. A., & Pherez, F. M. (2009). Mycoplasma pneumoniae community-acquired pneumonia (CAP) in the elderly: Diagnostic significance of acute thrombocytosis. Heart & Lung: The Journal of Critical Care, 38(5), 444–449. https://doi.org/10.1016/j.hrtlng.2008.10.005

Donath, J., & Landsteiner, K. (1904). Über paroxysmale Hämoglobinurie. Münchener medizinische Wochenschrift, 51, 1590–1593.

Evans, R. S., Baxter, E., & Gilliland, B. C. (1973). Chronic Hemolytic Anemia Due to Cold Agglutinins: A 20-Year History of Benign Gammopathy With Response to Chlorambucil. Blood, 42(3), 463–470. https://doi.org/10.1182/blood.V42.3.463.463

Gelbenegger, G., Berentsen, S., & Jilma, B. (2023). Monoclonal antibodies for treatment of cold agglutinin disease. Expert Opinion on Biological Therapy, 23(5), 395–406. https://doi.org/10.1080/14712598.2023.2209265

Gertz, M. A. (2022). Updates on the Diagnosis and Management of Cold Autoimmune Hemolytic Anemia. Hematology/Oncology Clinics of North America, 36(2), 341–352. https://doi.org/10.1016/j.hoc.2021.11.001

Hippe, E., Jensen, K. B., Olesen, H., Lind, K., & Thomsen, P. E. B. (1970). Chlorambucil Treatment of Patients With Cold Agglutinin Syndrome. Blood, 35(1), 68–72. https://doi.org/10.1182/blood.V35.1.68.68

Bibliography

Horstmann, D. M., & Tatlock, H. (1943). COLD AGGLUTININS: A DIAGNOSTIC AID IN CERTAIN TYPES OF PRIMARY ATYPICAL PNEUMONIA. Journal of the American Medical Association, 122(6), 369–370. https://doi.org/10.1001/jama.1943.72840230003006a

Ito, S., Wang, D., Purcell, A., Chetlapalli, K., Lee, A. I., Cuker, A., & Goshua, G. (2023). Cost-Effectiveness of Sutimlimab Versus Standard-of-Care in Transfusion Dependent Patients with Primary Cold Agglutinin Disease in the United States. Blood, 142(Supplement 1), 2316. https://doi.org/10.1182/blood-2023-187270

Jacobs, J. W., Booth, G. S., Woo, J. S., Adkins, B. D., & Stephens, L. D. (2024). How the United States syphilis epidemic may portend a resurgence of an unusual hematologic condition: The connection between syphilis and paroxysmal cold hemoglobinuria. American Journal of Hematology, 99(3), 484–485. https://doi.org/10.1002/ajh.27190

Jäger, U., D’Sa, S., Schörgenhofer, C., Bartko, J., Derhaschnig, U., Sillaber, C., Jilma-Stohlawetz, P., Fillitz, M., Schenk, T., Patou, G., Panicker, S., Parry, G. C., Gilbert, J. C., & Jilma, B. (2019). Inhibition of complement C1s improves severe hemolytic anemia in cold agglutinin disease: A first-in-human trial. Blood, 133(9), 893–901. https://doi.org/10.1182/blood-2018-06-856930

Jain, M. D., Cabrerizo-Sanchez, R., Karkouti, K., Yau, T., Pendergrast, J. M., & Cserti-Gazdewich, C. M. (2013). Seek and you shall find--but then what do you do? Cold agglutinins in cardiopulmonary bypass and a single-center experience with cold agglutinin screening before cardiac surgery. Transfusion Medicine Reviews, 27(2), 65–73. https://doi.org/10.1016/j.tmrv.2012.12.001

Kanthack, A. A., Durham, H. E., & Blandford, W. F. H. (1898). On Nagana, or Tsetse Fly Disease. (Report, Made to the Tsetse Fly Committee of the Royal Society, of Observations and Experiments Carried out from November, 1896, to August, 1898). Proceedings of the Royal Society of London, 64, 100–118.

Khwaja, J., Japzon, N., Gabriel, M., Raju, K., Rajaratnam, V., Gupta, R., Rismani, A., Kyriakou, C., & D’Sa, S. (2024). Cold agglutinin disease and cryoglobulinaemia: A frequent coexistence with clinical impact. British Journal of Haematology, 204(2), e21–e24. https://doi.org/10.1111/bjh.19185

Bibliography

Landsteiner, K. (1903). Über Beziehungen zwischen dem Blutserum und den Körperzellen. Münchener medizinische Wochenschrift, 50, 1812–1814.

Lee, E. J., & Kueck, B. (1998). Rituxan in the Treatment of Cold Agglutinin Disease. Blood, 92(9), 3490–3491. https://doi.org/10.1182/blood.V92.9.3490

LUBINSKI, H., & GOLDBLOOM, A. (1946). ACUTE HEMOLYTIC ANEMIA ASSOCIATED WITH AUTOAGGLUTINATION WITH A THERMAL AMPLITUDE OF 0 TO 37 C. American Journal of Diseases of Children, 72(3), 325–333. https://doi.org/10.1001/archpedi.1946.02020320076009

Mbaya, A., Kumshe, H., & Okwudiri, C. (2012). The Mechanisms of Anaemia in Trypanosomosis: A Review. In D. Silverberg (Ed.), Anemia. InTech. https://doi.org/10.5772/29530

McCOMBS, R. P., & McELROY, J. S. (1937). REVERSIBLE AUTOHEMAGGLUTINATION WITH PERIPHERAL VASCULAR SYMPTOMS. Archives of Internal Medicine, 59(1), 107–117. https://doi.org/10.1001/archinte.1937.00170170113007

Nelson, R. (2023). Syphilis rates soar in the USA amid penicillin shortage. The Lancet, 402(10401), 515. https://doi.org/10.1016/S0140-6736(23)01665-3

Olesen, H. (1964). CHLORAMBUCIL TREATMENT IN THE COLD AGGLUTININ SYNDROME. Scandinavian Journal of Haematology, 1, 116–128. https://doi.org/10.1111/j.1600-0609.1964.tb00010.x

Rossi, G., Gramegna, D., Paoloni, F., Fattizzo, B., Binda, F., D’Adda, M., Farina, M., Lucchini, E., Mauro, F. R., Salvi, F., Marchetti, M., Fazi, P., Zaja, F., & Barcellini, W. (2018). Short course of bortezomib in anemic patients with relapsed cold agglutinin disease: A phase 2 prospective GIMEMA study. Blood, 132(5), 547–550. https://doi.org/10.1182/blood-2018-03-835413

Bibliography

Röth, A., Barcellini, W., D’Sa, S., Miyakawa, Y., Broome, C. M., Michel, M., Kuter, D. J., Jilma, B., Tvedt, T. H. A., Fruebis, J., Jiang, X., Lin, S., Reuter, C., Morales-Arias, J., Hobbs, W., & Berentsen, S. (2021). Sutimlimab in Cold Agglutinin Disease. New England Journal of Medicine, 384(14), 1323–1334. https://doi.org/10.1056/NEJMoa2027760

Röth, A., Barcellini, W., D’Sa, S., Miyakawa, Y., Broome, C. M., Michel, M., Kuter, D. J., Jilma, B., Tvedt, T. H. A., Weitz, I. C., Yoo, R., Jayawardene, D., Vagge, D. S., Kralova, K., Shafer, F., Wardȩcki, M., Lee, M., & Berentsen, S. (2023). Sustained inhibition of complement C1s with sutimlimab over 2 years in patients with cold agglutinin disease. American Journal of Hematology, 98(8), 1246–1253. https://doi.org/10.1002/ajh.26965

Röth, A., Barcellini, W., Tvedt, T. H. A., Miyakawa, Y., Kuter, D. J., Su, J., Jiang, X., Hobbs, W., Arias, J. M., Shafer, F., & Weitz, I. C. (2022). Sutimlimab improves quality of life in patients with cold agglutinin disease: Results of patient-reported outcomes from the CARDINAL study. Annals of Hematology, 101(10), 2169–2177. https://doi.org/10.1007/s00277-022-04948-y

Röth, A., Berentsen, S., Barcellini, W., D’Sa, S., Jilma, B., Michel, M., Weitz, I. C., Yamaguchi, M., Nishimura, J., Vos, J. M. I., Storek, M., Wong, N., Patel, P., Jiang, X., Vagge, D. S., Wardęcki, M., Shafer, F., Lee, M., & Broome, C. M. (2022). Sutimlimab in patients with cold agglutinin disease: Results of the randomized placebo-controlled phase 3 CADENZA trial. Blood, 140(9), 980–991. https://doi.org/10.1182/blood.2021014955

Röth, A., Broome, C. M., Barcellini, W., Tvedt, T. H. A., Miyakawa, Y., D’Sa, S., Cella, D., Bozzi, S., Jayawardene, D., Yoo, R., Shafer, F., Wardęcki, M., & Weitz, I. C. (2023). Long-term sutimlimab improves quality of life for patients with cold agglutinin disease: CARDINAL 2-year follow-up. Blood Advances, 7(19), 5890–5897. https://doi.org/10.1182/bloodadvances.2022009318

Ruzickova, S., Pruss, A., Odendahl, M., Wolbart, K., Burmester, G.-R., Scholze, J., Dörner, T., & Hansen, A. (2002). Chronic lymphocytic leukemia preceded by cold agglutinin disease: Intraclonal immunoglobulin light-chain diversity in V(H)4-34 expressing single leukemic B cells. Blood, 100(9), 3419–3422. https://doi.org/10.1182/blood.V100.9.3419

Bibliography

Schubothe, H. (1966). The cold hemagglutinin disease. Seminars in Hematology, 3(1), 27–47.

Steverding, D. (2008). The history of African trypanosomiasis. Parasites & Vectors, 1, 3. https://doi.org/10.1186/1756-3305-1-3

Swiecicki, P. L., Hegerova, L. T., & Gertz, M. A. (2013). Cold agglutinin disease. Blood, 122(7), 1114–1121. https://doi.org/10.1182/blood-2013-02-474437