Cold agglutinin disease

Section editor
	Benjamin Tillman, MD Vanderbilt University Nashville, TN

4 regimens on this page 4 variants on this page

Guidelines

"How I Treat"

• 2021: Berentsen How I treat cold agglutinin disease

All lines of therapy

Bendamustine & Rituximab (BR)

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BR: Bendamustine, Rituximab

Regimen

Study	Evidence
Berentsen et al. 2017	Phase II

Chemotherapy

• Bendamustine 90 mg/m² IV once per day on days 1 & 2

Targeted therapy

• Rituximab (Rituxan) 375 mg/m² IV once on day 1

28-day cycle for 4 cycles

References

1. Berentsen S, Randen U, Oksman M, Birgens H, Tvedt THA, Dalgaard J, Galteland E, Haukås E, Brudevold R, Sørbø JH, Næss IA, Malecka A, Tjønnfjord GE. Bendamustine plus rituximab for chronic cold agglutinin disease: results of a Nordic prospective multicenter trial. Blood. 2017 Jul 27;130(4):537-541. Epub 2017 May 22. link to original article contains verified protocol PubMed NCT02689986

Eculizumab monotherapy

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Regimen

Study	Evidence
Röth et al. 2018 (DECADE)	Phase II, <20 pts

Eligible patients had symptomatic cold agglutinin-mediated hemolysis with a serum lactate dehydrogenase (LDH) level greater than or equal to 2 x upper limit of normal and a cold agglutinin titer greater than 1:64 at 4°C.

Immunosuppressive therapy

• Eculizumab (Soliris) as follows:
  • Cycle 1: 600 mg IV once per day on days 1, 8, 15, 22
  • Cycles 2 to 11: 900 mg IV once on day 1

Supportive medications

• Patients were vaccinated against Neisseria meningitidis or received "appropriate antibiotics" if vaccination occurred within 14 days of the first dose

28-day cycle for 1 cycle, then 14-day cycle for 11 cycles

References

1. DECADE: Röth A, Bommer M, Hüttmann A, Herich-Terhürne D, Kuklik N, Rekowski J, Lenz V, Schrezenmeier H, Dührsen U. Eculizumab in cold agglutinin disease (DECADE): an open-label, prospective, bicentric, nonrandomized phase 2 trial. Blood Adv. 2018 Oct 9;2(19):2543-2549. link to original article link to PMC article PubMed NCT01303952

FR

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FR: Fludarabine & Rituximab

Regimen

Study	Evidence	Efficacy
Berentsen et al. 2010	Phase II	ORR: 76%

Eligible patients had to be diagnosed with cold agglutinin disease and require therapy because of anemia, substantial cold-induced circulatory symptoms, or both.

Chemotherapy

• Fludarabine (Fludara) 40 mg/m² PO once per day on days 1 to 5

Targeted therapy

• Rituximab (Rituxan) 375 mg/m² IV once on day 1

28-day cycle for 4 cycles

References

1. Berentsen S, Randen U, Vågan AM, Hjorth-Hansen H, Vik A, Dalgaard J, Jacobsen EM, Thoresen AS, Beiske K, Tjønnfjord GE. High response rate and durable remissions following fludarabine and rituximab combination therapy for chronic cold agglutinin disease. Blood. 2010 Oct 28;116(17):3180-4. Epub 2010 Jul 15. link to original article contains verified protocol PubMed NCT00373594

Rituximab monotherapy

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Regimen

Study	Evidence	Efficacy
Berentsen et al. 2003	Phase II	ORR: 54%
Schöllkopf et al. 2006	Phase II	ORR: 45%

Patients in Berentsen et al. 2003 were required to have cold agglutinin disease, as defined by the combination of chronic hemolysis and a cold agglutinin titer of 1:64 or higher, and a typical pattern for the direct antiglobulin test (DAT).

Immunosuppressive therapy

• Rituximab (Rituxan) 375 mg/m² IV once per day on days 1, 8, 15, 22

28-day course

References

1. Berentsen S, Ulvestad E, Gjertsen BT, Hjorth-Hansen H, Langholm R, Knutsen H, Ghanima W, Shammas FV, Tjønnfjord GE. Rituximab for primary chronic cold agglutinin disease: a prospective study of 37 courses of therapy in 27 patients. Blood. 2004 Apr 15;103(8):2925-8. Epub 2003 Dec 30. link to original article contains verified protocol PubMed
2. Schöllkopf C, Kjeldsen L, Bjerrum OW, Mourits-Andersen HT, Nielsen JL, Christensen BE, Jensen BA, Pedersen BB, Taaning EB, Klausen TW, Birgens H. Rituximab in chronic cold agglutinin disease: a prospective study of 20 patients. Leuk Lymphoma. 2006 Feb;47(2):253-60. link to original article contains protocol PubMed

Sutimlimab monotherapy

Regimen

Targeted therapy

• Sutimlimab 6.5 g (for patients who weighed less than 75 kg at baseline) and 7.5g (for patients who weighed 75 kg or more)

7 day course for cycle 1 then every 14 days for 26 weeks

Study	Evidence	Efficacy
Röth et al. 2021	Phase II	ORR: 54%