Cold agglutinin disease

Carboplatin & Paclitaxel (CP)

CP: Carboplatin & Paclitaxel

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Forde et al. 2022 (CheckMate 816)	2017-2019	Phase 3 (C)	1a. CP & Nivolumab 1b. CVb & Nivolumab 1c. DC & Nivolumab	Inferior EFS

Note: there were additional comparator options depending on histology; see the respective histology-specific pages for more details. This study was conducted in the United States. The reason for the study was that an unanswered question at the time was whether adding an immune checkpoint inhibitor would improve outcomes.

Biomarker eligibility criteria

• CheckMate 816: No sensitizing EGFR or ALK mutations

Chemotherapy

• Carboplatin (Paraplatin) AUC 5 or 6 IV once on day 1
• Paclitaxel (Taxol) 175 or 200 mg/m² IV once on day 1

21-day cycle for 3 cycles

Subsequent treatment

• Complete resection

References

1. CheckMate 816: Forde PM, Spicer J, Lu S, Provencio M, Mitsudomi T, Awad MM, Felip E, Broderick SR, Brahmer JR, Swanson SJ, Kerr K, Wang C, Ciuleanu TE, Saylors GB, Tanaka F, Ito H, Chen KN, Liberman M, Vokes EE, Taube JM, Dorange C, Cai J, Fiore J, Jarkowski A, Balli D, Sausen M, Pandya D, Calvet CY, Girard N; CheckMate 816 Investigators. Neoadjuvant Nivolumab plus Chemotherapy in Resectable Lung Cancer. N Engl J Med. 2022 May 26;386(21):1973-1985. Epub 2022 Apr 11. link to original article contains dosing details in manuscript PubMed NCT02998528

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Section editors
	Shruti Chaturvedi, MD, MSCI Baltimore, MD LinkedIn		Benjamin Tillman, MD Nashville, TN

4 regimens on this page 4 variants on this page

All lines of therapy

BR

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BR: Bendamustine, Rituximab

Regimen

Study	Evidence
Berentsen et al. 2017	Phase II

Chemotherapy

• Rituximab (Rituxan) 375 mg/m² IV once on day 1
• Bendamustine 90 mg/m² IV once per day on days 1 & 2

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

Eculizumab monotherapy

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Regimen

Study	Evidence
Röth et al. 2015 (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.

Therapy

• Eculizumab (Soliris) 600 mg IV once per week for 4 weeks, then 900 mg IV once on week 5, then 900 mg IV every 2 weeks

Supportive medications

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

26-week course

References

1. Abstract: Alexander Röth, MD, Martin Bommer, MD, Andreas Hüttmann, MD, Dörte Herich-Terhürne, Nils Kuklik, PhD, Lenz Veronika, Hubert Schrezenmeier, MD and Ulrich Dührsen, MD. Complement Inhibition with Eculizumab in Patients with Cold Agglutinin Disease (CAD): Results from a Prospective Phase II Trial (DECADE Trial). ASH Annual Meeting 2015 Abstract 274 link to abstract

Fludarabine & Rituximab

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Regimen

Study	Evidence
Berentsen et al. 2010	Phase II

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

• Fludarabine (Fludara) 40 mg/m² PO once per day on days 1 to 5, 29 to 34, 57 to 61, 85 to 89
• Rituximab (Rituxan) 375 mg/m² IV once per day on days 1, 29, 57, 85

One course

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

Rituximab monotherapy

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Regimen

Study	Evidence
Berentsen et al. 2003	Phase II
Schöllkopf et al. 2006	Phase II

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).

• Rituximab (Rituxan) 375 mg/m² IV once per week

4-week 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