Bendamustine and Rituximab Combination Therapy for Cold Agglutinin Disease

NCT02689986 | Completed Phase 2 DMC

• 1 other identifier: CAD5
• Study Type: interventional
• Target: 43
• Locations: 3 countries
• Sites: 8

Brief Summary

Prospective, non-randomized multicenter study on the safety and efficacy of combination therapy with bendamustine and rituximab for chronic cold agglutinin disease.

Conditions

Cold Agglutinin Disease; Autoimmune Hemolytic Anemia

Keywords

Cold agglutinin; Cold agglutinin disease; Anemia; Hemolytic; Autoimmune; Bendamustine; Rituximab

Outcome Measures

Primary Outcomes (1)

• Frequency of complete and partial responses (CR/PR)

  Responses will be assessed using the following, previously published definitions: Complete response (CR), Absence of anemia, no signs of hemolysis, no clinical symptoms of CAD, undetectable serum monoclonal protein, and no signs of clonal lymphoproliferation by bone marrow histology, immunohistochemistry and flow cytometry. Partial response (PR), Stable increase in hemoglobin levels by at least 2.0 g/dL or to the normal range, combined with a reduction of serum IgM concentrations by at least 50% or to the normal range, improvement of clinical symptoms, and transfusion independency. Non-response (NR), Patients not meeting the criteria for CR or PR.

  6 months

Secondary Outcomes (4)

• Time to response (TTR)

  6 months

• Time to best response (TTBR)

  1 year

• Response duration

  Through study completion; an average of 2 years

• Number of participants with treatment-related adverse events as assessed by current CTCAE criteria

  Through study completion; an average of 2 years

Study Arms (1)

Treatment arm

EXPERIMENTAL

Bendamustine, Rituximab

Drug: Bendamustine, Rituximab

Interventions

Bendamustine, Rituximab DRUG

Bendamustine, Rituximab

Also known as: Levact, MabThera

Treatment arm

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• CAD diagnosis defined by the combination of -
• Chronic hemolysis
• Cold agglutinin titer 64 or higher
• Positive direct antiglobulin test when performed with polyspecific antiserum, negative (or only weakly positive) with anti-IgG, and strongly positive with anti-C3d
• The presence of a clonal B-cell lymphoproliferative disorder defined by -
• Monoclonal band by serum electrophoresis with immunofixation, and/or
• CD20 positive lymphocyte population with cellular kappa/lamda-ratio higher than 3.5 or less than 0.9, using flowcytometric immunophenotyping of bone marrow aspirates
• Indication for therapy, i.e. significant anemia and/or considerable cold-induced circulatory symptoms
• Written informed consent

You may not qualify if:

• An aggressive lymphoma
• Known HIV infection
• Acute or chronic hepatitis B or C
• Pregnancy or breast-feeding
• Patients of childbearing age who are not willing to use safe contraception during the entire study period and 6 months following its cessation
• Age below 18 years
• Inability to cooperate

Sponsors & Collaborators

• Helse Fonna: lead

Study Sites (8)

Herlev University Hospital

Copenhagen, Denmark

Location

Turku University Hospital

Turku, Finland

Location

Haukeland University Hospital

Bergen, NO-5021, Norway

Location

Vestre Viken Hospital

Drammen, NO-3000, Norway

Location

Haugesund Hospital

Haugesund, NO-5504, Norway

Location

Akershus University Hospital

Nordbyhagen, Norway

Location

Oslo University Hospital

Oslo, NO-0027, Norway

Location

St Olav University Hospital

Trondheim, NO-7006, Norway

Location

Related Publications (18)

• Michel M. Classification and therapeutic approaches in autoimmune hemolytic anemia: an update. Expert Rev Hematol. 2011 Dec;4(6):607-18. doi: 10.1586/ehm.11.60.

  PMID: 22077525 BACKGROUND

• Randen U, Troen G, Tierens A, Steen C, Warsame A, Beiske K, Tjonnfjord GE, Berentsen S, Delabie J. Primary cold agglutinin-associated lymphoproliferative disease: a B-cell lymphoma of the bone marrow distinct from lymphoplasmacytic lymphoma. Haematologica. 2014 Mar;99(3):497-504. doi: 10.3324/haematol.2013.091702. Epub 2013 Oct 18.

  PMID: 24143001 BACKGROUND

• Berentsen S, Tjonnfjord GE. Diagnosis and treatment of cold agglutinin mediated autoimmune hemolytic anemia. Blood Rev. 2012 May;26(3):107-15. doi: 10.1016/j.blre.2012.01.002. Epub 2012 Feb 12.

  PMID: 22330255 BACKGROUND

• Berentsen S, Randen U, Vagan AM, Hjorth-Hansen H, Vik A, Dalgaard J, Jacobsen EM, Thoresen AS, Beiske K, Tjonnfjord 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. doi: 10.1182/blood-2010-06-288647. Epub 2010 Jul 15.

  PMID: 20634373 BACKGROUND

• Berentsen S, Beiske K, Tjonnfjord GE. Primary chronic cold agglutinin disease: an update on pathogenesis, clinical features and therapy. Hematology. 2007 Oct;12(5):361-70. doi: 10.1080/10245330701445392.

  PMID: 17891600 BACKGROUND

• Berentsen S, Ulvestad E, Langholm R, Beiske K, Hjorth-Hansen H, Ghanima W, Sorbo JH, Tjonnfjord GE. Primary chronic cold agglutinin disease: a population based clinical study of 86 patients. Haematologica. 2006 Apr;91(4):460-6.

  PMID: 16585012 BACKGROUND

• Berentsen S, Ulvestad E, Gjertsen BT, Hjorth-Hansen H, Langholm R, Knutsen H, Ghanima W, Shammas FV, Tjonnfjord 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. doi: 10.1182/blood-2003-10-3597. Epub 2003 Dec 30.

  PMID: 15070665 BACKGROUND

• Schollkopf 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. doi: 10.1080/10428190500286481.

  PMID: 16321854 BACKGROUND

• Gueli A, Gottardi D, Hu H, Ricca I, De Crescenzo A, Tarella C. Efficacy of rituximab-bendamustine in cold agglutinin haemolytic anaemia refractory to previous chemo-immunotherapy: a case report. Blood Transfus. 2013 Apr;11(2):311-4. doi: 10.2450/2012.0166-12. Epub 2013 Jan 22. No abstract available.

  PMID: 23399352 BACKGROUND

• Berentsen S, Ulvestad E, Tjonnfjord GE. B-lymphocytes as targets for therapy in chronic cold agglutinin disease. Cardiovasc Hematol Disord Drug Targets. 2007 Sep;7(3):219-27. doi: 10.2174/187152907781745279.

  PMID: 17896962 BACKGROUND

• Ulvestad E, Berentsen S, Bo K, Shammas FV. Clinical immunology of chronic cold agglutinin disease. Eur J Haematol. 1999 Oct;63(4):259-66. doi: 10.1111/j.1600-0609.1999.tb01887.x.

  PMID: 10530415 BACKGROUND

• Ulvestad E, Berentsen S, Mollnes TE. Acute phase haemolysis in chronic cold agglutinin disease. Scand J Immunol. 2001 Jul-Aug;54(1-2):239-42. doi: 10.1046/j.1365-3083.2001.00960.x.

  PMID: 11439172 BACKGROUND

• Berentsen S. How I manage cold agglutinin disease. Br J Haematol. 2011 May;153(3):309-17. doi: 10.1111/j.1365-2141.2011.08643.x. Epub 2011 Mar 8.

  PMID: 21385173 BACKGROUND

• Swiecicki PL, Hegerova LT, Gertz MA. Cold agglutinin disease. Blood. 2013 Aug 15;122(7):1114-21. doi: 10.1182/blood-2013-02-474437. Epub 2013 Jun 11.

  PMID: 23757733 BACKGROUND

• Stone MJ. Heating up cold agglutinins. Blood. 2010 Oct 28;116(17):3119-20. doi: 10.1182/blood-2010-07-297523.

  PMID: 21030565 BACKGROUND

• Berentsen S, Tjonnfjord GE, Shammas FV, Bergheim J, Hammerstrom J, Langholm R, Ulvestad E. No response to cladribine in five patients with chronic cold agglutinin disease. Eur J Haematol. 2000 Jul;65(1):88-90. doi: 10.1034/j.1600-0609.2000.9l201.x. No abstract available.

  PMID: 10914950 BACKGROUND

• Rummel M, Kaiser U, Balser C, Stauch M, Brugger W, Welslau M, Niederle N, Losem C, Boeck HP, Weidmann E, von Gruenhagen U, Mueller L, Sandherr M, Hahn L, Vereshchagina J, Kauff F, Blau W, Hinke A, Barth J; Study Group Indolent Lymphomas. Bendamustine plus rituximab versus fludarabine plus rituximab for patients with relapsed indolent and mantle-cell lymphomas: a multicentre, randomised, open-label, non-inferiority phase 3 trial. Lancet Oncol. 2016 Jan;17(1):57-66. doi: 10.1016/S1470-2045(15)00447-7. Epub 2015 Dec 5.

  PMID: 26655425 BACKGROUND

• Berentsen S, Randen U, Oksman M, Birgens H, Tvedt THA, Dalgaard J, Galteland E, Haukas E, Brudevold R, Sorbo JH, Naess IA, Malecka A, Tjonnfjord GE. Bendamustine plus rituximab for chronic cold agglutinin disease: results of a Nordic prospective multicenter trial. Blood. 2017 Jul 27;130(4):537-541. doi: 10.1182/blood-2017-04-778175. Epub 2017 May 22.

  PMID: 28533306 DERIVED

MeSH Terms

Conditions

Anemia, Hemolytic, Autoimmune; Anemia; Hemolysis

Interventions

Bendamustine Hydrochloride; Rituximab

Condition Hierarchy (Ancestors)

Anemia, Hemolytic; Hematologic Diseases; Hemic and Lymphatic Diseases; Autoimmune Diseases; Immune System Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Butyrates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Benzimidazoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Sigbjorn Berentsen, MD, PhD

  Department of Research and Innovation, Haugesund Hospital

  STUDY CHAIR

• Markku Oksman, MD

  Turku University Hospital, Turku, Finland

  PRINCIPAL INVESTIGATOR

• Henrik Birgens, MD, PhD

  Herlev University Hospital, Copenhagen, Denmark

  PRINCIPAL INVESTIGATOR

• Geir E Tjonnfjord, MD, PhD

  Oslo University Hospital, Oslo, Norway

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: MD, PhD

Study Record Dates

• First Submitted: February 16, 2016
• First Posted: February 24, 2016
• Study Start: January 1, 2013
• Primary Completion: December 1, 2016
• Study Completion: December 1, 2016
• Last Updated: January 9, 2017

Record last verified: 2017-01

Data Sharing

• IPD Sharing: Will share

Locations

NO (6); DK (1); FI (1)