Clinical Trial: Bendamustine and Rituximab Combination Therapy for Cold Agglutinin Disease

Study Status: Completed
Recruit Status: Completed
Study Type: Interventional

Official Title: The CAD5 Study::Therapy for Chronic Cold Agglutinin Disease: A Prospective, Non-randomized International Multicenter Trial on the Safety and Efficacy of Bendamustine and Rituximab Combination Therapy

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

Detailed Summary:

Background

Chronic cold agglutinin disease (CAD) is mediated by monoclonal cold-reactive autoantibodies that bind to erythrocyte surface antigens, causing hemagglutination and complement-mediated hemolysis. Anemia is severe in one-third of patients (hemoglobin level 8.0 g/dL or lower). Cold-induced circulatory symptoms are present in more than 90% of patients and may be disabling. CAD not associated with overt lymphoma or other disease has traditionally been classified as primary or idiopathic. A monoclonal lymphoproliferative bone marrow disorder can, however, be demonstrated by flow cytometry in 90% and by histology in approximately 75% of these patients, characterized by clonal proliferation of CD20+, kappa+ B-cells.

Approximately two-thirds of the patients experience exacerbation during febrile illnesses. During steady-state CAD, a majority of patients have low levels of complement proteins C3 and C4 because of a continuous consumption. These low levels, in particular low C4 availability, seem to be rate-limiting for hemolysis and prevent full-blown activation of the complement cascade with C5 cleavage and intravascular hemolysis. During acute phase reaction, C3 and C4 levels increase due to an enhanced production, resulting in exacerbation of hemolysis.

Counseling on cold avoidance has been recommended as the treatment of choice for most patients with primary CAD. A systematic review showed, however, that in more than 70% of cases, the physician and/or the patient did not perceive such measures as sufficient). Many standard therapies used in other autoimmune diseases or indolent lymphomas are inefficient, e.g. corticosteroids, alkylating agents, interferon-α and, probably, purine analogue single agent therapy. Treatment with the chimeric monoclonal anti-CD20 antib
Sponsor: Helse Fonna

Current Primary Outcome: Frequency of complete and partial responses (CR/PR) [ Time Frame: 6 months ]

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.



Original Primary Outcome: Same as current

Current Secondary Outcome:

  • Time to response (TTR) [ Time Frame: 6 months ]
    Time to response (TTR) is the time from start of therapy to the achievement of any degree of response.
  • Time to best response (TTBR) [ Time Frame: 1 year ]
    Time to best response (TTBR) is the time from start of therapy to the observation of the highest hemoglobin level achieved + 0.5 g/dL.
  • Response duration [ Time Frame: Through study completion; an average of 2 years ]
    Response duration is the time from achievement of any degree of response to relapse. Relapse is defined by one or more of the following events: A decline in hemoglobin level by at least 2.0 g/dL from the highest level achieved or to below 10.0 g/dL; transfusion requirement; or recurrence of significant cold-induced circulatory symptoms.
  • Number of participants with treatment-related adverse events as assessed by current CTCAE criteria [ Time Frame: Through study completion; an average of 2 years ]


Original Secondary Outcome: Same as current

Information By: Helse Fonna

Dates:
Date Received: February 16, 2016
Date Started: January 2013
Date Completion:
Last Updated: January 6, 2017
Last Verified: January 2017