Journal Club – CAD

Berentsen S, Ulvestad E, Gjertsen BT, et al. Rituximab for primary chronic cold agglutinin disease: a prospective study of 37 courses of therapy in 27 patients.

Clinical Question

Does rituximab induce clinically meaningful hematologic responses in patients with primary cold agglutinin disease (CAD)?

Background

Cold agglutinin disease (CAD) is a complement-mediated autoimmune hemolytic anemia caused by cold-reactive IgM antibodies that bind red cell carbohydrate antigens. Hemagglutination and complement activation (classically C3d-positive DAT) drive hemolysis.

Historically labeled “idiopathic,” CAD is now understood to represent an underlying clonal B-cell lymphoproliferative disorder, often resembling lymphoplasmacytic lymphoma in the marrow.

Conventional therapies (corticosteroids, alkylators, splenectomy, purine analogs) are largely ineffective in primary CAD. Early reports suggested activity of the anti-CD20 monoclonal antibody Rituximab, but prospective data were limited before this study, published in 2004.

Guidelines

Management of Cold agglutinin disease has evolved substantially since this 2004 study. Modern guidelines now incorporate both B-cell–directed therapy and complement inhibition, but rituximab remains a cornerstone of treatment.

Who Should Be Treated?

Current guidance emphasizes that not all CAD requires therapy. Treatment is recommended only for patients with:

• Symptomatic anemia
• Transfusion requirement
• Disabling cold-induced circulatory symptoms (acrocyanosis/Raynaud-like)

Modern guidelines consistently position rituximab-based therapy as first-line treatment for patients who need therapy.

• Rituximab +/- bendamustine is usually the recommended first line therapy (combination chemoimmunotherapy is preferred for fit patients with significant disease burden).
• Rituximab monotherapy remains appropriate for frail or elderly patients.
• Sutimlimab is a complement-directed therapy approved by the FDA in 2022 (more information can be found in this module)

Study Design

• Prospective, multicenter phase 2 trial
• Centers included: 10 Norwegian university and local hospitals
• Included 6 patients treated with rituximab in a previous trial (same inclusion and exclusion criteria)¹.
• Inclusion criteria:
  • Diagnosis of CAD defined as: chronic hemolysis and a cold agglutinin titer of 64 or higher.
  • Typical direct antiglobulin test (DAT) pattern: strong C3d, weak/negative IgG)
  • Serum and marrow exam had to confirm the presence of a clonal CD20 kappa phenotype.
  • Symptomatic disease
• Exclusion criteria:
  • Secondary CAD
  • Lymphocyte count > 50 x 109/L
  • Nonlymphatic malignant disease
  • Contraindications to rituximab
  • Severe disease other than CAD
• Follow-up: monthly assessment for 6 months and bone marrow reassessment at 3 and 6 months

Populations

• 27 patients
• 37 total courses of rituximab
• Baseline characteristics:
  • Mean age: 71 years
  • Mean hemoglobin: 8.5 g/dL
  • Median iIgM: 5.0 g/L

Interventions

• Rituximab 375 mg/m2 IV weekly for 4 doses
• Re-treatment was allowed for nonresponse at 3 months or relapse
• Patients were eligible for interferon (IFN) at relapse: new 4-week cycle of rituximab + IFN (subcutaneous, 5 million U, 3 times a week for 20 weeks)

Response Criteria

• Complete response (CR)
  • Resolution of anemia
  • Resolution of hemolysis
  • Disappearance of symptoms
  • Disappearance of monoclonal IgM
  • No signs of clonal lymphoproliferation in the marrow
• Partial response (PR)
  • Stable increase in hemoglobin of at least 2 g/dL or to normal range AND
  • Reduction of serum IgM by at least 50%
  • Improvement of symptoms
  • Transfusion independence
• No response (NR)
  • Failure to achieve CR or PR
• Relapse
  • Hemoglobin < 10 g/dL or decrease by at least 2 g/dL from highest level achieved OR
  • Need for re-treatment

Outcomes

• Overall response (CR + PR): 20 of 37 courses (54%), including 1 CR and 19 PR
  • First-line rituximab: 14/27 (52%) responded
  • Re-treatment: 6/10 (60%) responded
  • Responses were seen even after second relapse: 2/2 (100%) PR
• Only 5 patients treated with IFN: 3 PR and 2 NR
• Hemoglobin median increase: 4 g/dL among responders
• Time to response: 1.5 months (median)
• Duration of response: 11 months (median)
  • All but one responder relapsed if followed >12 months
  • Single CR lasted 42 months
• Safety:
  • No serious infusion reactions; one case of transient grade 4 neutropenia

Commentary

Rituximab is currently the cornerstone of B-cell directed therapy for cold agglutinin disease, but that has not always been the case. It was this prospective trial by Berentsen et al that paved the way for this anti-CD20 therapy to be widely used as first-line treatment for CAD.

Prior to 2004, CAD was ineffectively treated with corticosteroids, splenectomy and occasionally alkylating agents such as chlorambucil and cyclophosphamide. Many patients relied primarily on supportive care with thermal protection and transfusions.

This study published in Blood in 2004 changed the way we approached cold agglutinin disease. It demonstrated an overall response rate of 54% in 27 patients, with rapid hemoglobin improvement, feasible retreatment, and acceptable toxicity profile.

This was a phase 2, single-arm study with 27 patients. Without a comparator arm, it is difficult to quantify the magnitude of benefit relative to natural disease fluctuations, particularly in a condition known for seasonal variability. While response rates were encouraging, remissions were rarely durable beyond 1 year. Most responders eventually relapsed if followed long enough. The median duration of 11 months shows that rituximab monotherapy is rarely curative.

Nonetheless, this study was a phenomenal first step in changing the paradigm. After recognizing that CAD is a clonal B-cell disorder, investigators sought to improve response depth and durability.

The evolution continued with combination regimens. A prospective study published in 2010 evaluated fludarabine plus rituximab in CAD, demonstrating an improved overall response rate of approximately 76%, with deeper and more durable remissions compared with rituximab alone. Subsequently, a 2017 prospective trial studied bendamustine plus rituximab, demonstrating a 71% overall response rate, including a substantially higher proportion of complete responses.

This study attempted to explore rituximab plus IFN as a strategy to improve responses, based on the rationale that IFN may increase complement levels and up-regulate CD20 expression. However, only five patients received combination therapy, preventing any meaningful conclusions. In modern practice, IFN is no longer used in CAD, having been replaced by more effective and better-tolerated approaches.

Rituximab monotherapy may no longer be the most potent regimen available, but it was the catalyst that transformed CAD from a therapeutic dead end into a biologically targeted disease with multiple treatment strategies.

References

1. Berentsen S, Tjønnfjord GE, Brudevold R, Gjertsen BT, Langholm R, Løkkevik E, Sørbø JH, Ulvestad E. Favourable response to therapy with the anti-CD20 monoclonal antibody rituximab in primary chronic cold agglutinin disease. Br J Haematol. 2001 Oct;115(1):79-83. doi: 10.1046/j.1365-2141.2001.03078.x. PMID: 11722415. ↩︎

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