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Cold Agglutinin Disease

beau hilton, 2024-03-22

current

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

No notes.

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

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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.

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