Cold agglutinin disease

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Last updated on 2024-07-23:5 regimens on this page
5 variants on this page
=All lines of therapy=
==Bendamustine & Rituximab (BR)==
BR: Bendamustine, Rituximab
===Regimen===
Study 	Dates of enrollment 	Evidence
Berentsen et al. 2017 (CAD5)	2012-10-01 to 2015-12-31	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===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT02689986
==Eculizumab monotherapy==
===Regimen===
Study 	Dates of enrollment 	Evidence
Röth et al. 2018 (DECADE)	2011-01-06 to 2014-01-14	Phase 2, fewer than 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:
**Cycles 1 to 4: 600 mg IV once on day 1
**Cycles 5 to 15: 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
7-day cycle for 4 cycles, then 14-day cycle for 11 cycles (26 weeks total)
===References===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT01303952
==Fludarabine & Rituximab (FR)==
FR: Fludarabine & Rituximab
===Regimen===
Study 	Dates of enrollment 	Evidence	Efficacy
Berentsen et al. 2010	2005-02-01 to 2009-10-31	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===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00373594
==Rituximab monotherapy==
===Regimen===
Study 	Dates of enrollment 	Evidence	Efficacy
Berentsen et al. 2003 	2001-10-01 to 2003-05-01	Phase 2 	ORR: 54%
Schöllkopf et al. 2006	2002-10 to 2003-04 	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===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC
#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 dosing details in abstract have been reviewed by our editors EuroPMC
==Sutimlimab monotherapy==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator	Comparative Efficacy
Röth et al. 2021 (CARDINAL)	Not reported 	Phase 2 (RT) 	 	ORR: 54%
Röth et al. 2022 (CADENZA) 	2018-03-06 to 2020-09-29	Phase 3 (E-esc)	Placebo 	Higher composite primary endpointComposite primary endpoint: 73% vs 15%(OR 15.9, 95% CI 2.90-88.0)
====Immunosuppressive therapy====
*Sutimlimab (Enjaymo) by the following weight-based criteria: 
**Less than 75 kg: 6500 mg IV once on day 1
**75 kg or more: 7500 mg IV once on day 1
7-day course, then 14-day cycle for 12 cycles (26 weeks)
===References===
#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 EuroPMC NCT03347396
##Update: Röth A, Broome CM, Barcellini W, Tvedt THA, Miyakawa Y, D'Sa S, Cella D, Bozzi S, Jayawardene D, Yoo R, Shafer F, Wardęcki M, Weitz IC. Long-term sutimlimab improves quality of life for patients with cold agglutinin disease: CARDINAL 2-year follow-up. Blood Adv. 2023 Oct 10;7(19):5890-5897. Erratum in: Blood Adv. 2024 Jun 11;8(11):2650. link to original article link to PMC article EuroPMC
#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 link to PMC article EuroPMC NCT03347422
##PRO analysis: Röth A, Broome CM, Barcellini W, Jilma B, Hill QA, Cella D, Tvedt THA, Yamaguchi M, Lee M, Shafer F, Wardęcki M, Jiang X, Patel P, Joly F, Weitz IC. Sutimlimab provides clinically meaningful improvements in patient-reported outcomes in patients with cold agglutinin disease: Results from the randomised, placebo-controlled, Phase 3 CADENZA study. Eur J Haematol. 2023 Mar;110(3):280-288. Epub 2022 Dec 9. link to original article EuroPMC
Category:Cold agglutinin disease regimens
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Category:Complementopathies
Category:Hemolytic process