Cold agglutinin disease

Section editor
	Benjamin Tillman, MD Vanderbilt University Nashville, TN LinkedIn

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)

BR: Bendamustine, Rituximab

Regimen

Study	Evidence
Berentsen et al. 2017 (CAD5)	Phase 2

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. CAD5: 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 dosing details in manuscript PubMed Clinical Trial Registry

Eculizumab monotherapy

Regimen

Study	Evidence
Röth et al. 2018 (DECADE)	Phase 2, <20 pts

Note: 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 therapy

• 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 Clinical Trial Registry

Fludarabine & Rituximab (FR)

FR: Fludarabine & Rituximab

Regimen

Study	Evidence	Efficacy
Berentsen et al. 2010	Phase 2	ORR: 76%

Note: 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 dosing details in manuscript PubMed Clinical Trial Registry

Rituximab monotherapy

Regimen

Study	Evidence	Efficacy
Berentsen et al. 2003	Phase 2	ORR: 54%
Schöllkopf et al. 2006	Phase 2	ORR: 45%

Note: 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 dosing details in manuscript 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 dosing details in abstract PubMed

Sutimlimab monotherapy

Regimen

Study	Evidence	Efficacy
Röth et al. 2021 (CARDINAL)	Phase 2	ORR: 54%

Immunosuppressive therapy

• Sutimlimab (Enjaymo) by the following weight-based criteria:
  • Patients who weighed less than 75 kg at baseline: 6500 mg IV once on day 1
  • Patients who weighed 75 kg or more: 7500 mg IV once on day 1

7-day cycle, then 14-day cycle for 12 cycles (26 weeks)

References

1. CARDINAL: Röth A, Barcellini W, D'Sa S, Miyakawa Y, Broome CM, Michel M, Kuter DJ, Jilma B, Tvedt THA, Fruebis J, Jiang X, Lin S, Reuter C, Morales-Arias J, Hobbs W, Berentsen S. Sutimlimab in Cold Agglutinin Disease. N Engl J Med. 2021 Apr 8;384(14):1323-1334. link to original article PubMed Clinical Trial Registry
2. CADENZA: Röth A, Berentsen S, Barcellini W, D'Sa S, Jilma B, Michel M, Weitz IC, Yamaguchi M, Nishimura JI, Vos JMI, Storek M, Wong N, Patel P, Jiang X, Vagge DS, Wardęcki M, Shafer F, Lee M, Broome CM. Sutimlimab in patients with cold agglutinin disease: results of the randomized placebo-controlled phase 3 CADENZA trial. Blood. 2022 Sep 1;140(9):980-991. link to original article PubMed Clinical Trial Registry

Investigational agents

• Sutimlimab (BIVV009)