Management of Cold Agglutinin Disease

We posted a poll on twitter on 3/13/24 asking the following question:

• Most respondents chose Rituximab monotherapy.

Bottom line

• Not all patients with cold agglutinin disease (CAD) require therapy.
• Indications for therapy include:
  • Symptomatic anemia
  • Significant fatigue
  • Severe circulatory symptoms
• Treatment aims:
  • Minimizing symptoms
  • Maintaining an acceptable hemoglobin (Hb) level
• Therapy consists of:
  • General measures, including avoidance of exposure to cold
  • Directed treatment, including:
    • Removal of cold agglutinins (plasma exchange)
    • Eradication of B cell clone
    • Complement inhibition
• It is widely accepted that corticosteroids and splenectomy should not be used for treatment of CAD.
• Clinical practice guidelines recommend first-line therapy with rituximab with or without bendamustine.
• These guidelines were published prior to phase 3 clinical trials demonstrating efficacy of anti-complement therapy and FDA approval of  sutimlimab in February 2022 to decrease to decrease the need for red blood cell transfusion due to hemolysis (red blood cell destruction) in adults with CAD.
• Sutimlimab is currently the only approved treatment of hemolysis for CAD.

Overview of CAD

• Definitions:
  • Cold agglutinins are antibodies that recognize antigens on red blood cells (RBCs) at temperatures below normal core body temperature.
  • Cold agglutinin disease (CAD):
    • Also known as primary CAD or idiopathic CAD.
    • Refers to cold agglutinins that cause RBC agglutination and extravascular hemolysis in the absence of an underlying disorder. 
    • “An autoimmune hemolytic anemia (AIHA) with a monospecific direct antiglobulin test (DAT) strongly positive for C3d (and negative or weakly positive with IgG [immunoglobulin G]) and a cold agglutinin (CA) titer of 64 or greater at 4°C. We recognize that there may be occasional cases with CA titer < 64. Patients may have a B-cell clonal lymphoproliferative disorder (LPD) detectable in blood or marrow but no clinical or radiological evidence of malignancy.”¹
  • Cold agglutinin syndrome (CAS):
    • Also known as secondary CAD.
    • Refers to cold agglutinins that arise in the setting of an underlying clinical disease such as a specific infection, autoimmune disorder, or overt lymphoma.
    • “An AIHA, a monospecific DAT strongly positive for C3d (and negative or weakly positive with IgG) and a CA titer of 64 or greater at 4°C. Patients have an associated condition, for example infection, autoimmune disorder, overt evidence of a B-cell lymphoma (clinical or radiological), or other malignancy.”²
• Epidemiology:³
  • Prevalence of 5 to 20 cases per million.
  • Incidence of 0.5 to 1.9 cases per million per year.
  • Accounts for 15% to 30% of autoimmune hemolytic anemias.
• Pathophysiology:⁴
  • Indolent lymphoproliferative disorder (LPD) of the bone marrow in most cases.
  • Shares some common features with:
    • Lymphoplasmacytic lymphoma (LPL) and marginal zone lymphoma; however the MYD88 L265P somatic mutation, present in most cases of LPL, is usually not found in CAD.
    • Waldenstrom macroglobulinemia; however some differences have been demonstrated in immunoglobulin heavy and light chain gene use.
  • Cold agglutinins in CAD:
    • Monoclonal antibodies produced by clonal B cells, most often:
      • Of the IgMk class
      • With anti-I specificity
    • Bind to RBC surface (to the I surface antigen) resulting in:
      • RBC agglutination
      • Induction of complement-dependent hemolysis mediated by activation of the classical pathway:
        • Hemolysis is mainly extravascular mediated by opsonization with complement protein C3b and subsequent phagocytosis.
        • Intravascular hemolysis may also occur from terminal complement activation.
      • IgM-antigen complex binds to the C1 complement complex, resulting in the activation of C1s (a C1 complex serine protease), which splits C4 and C2; this action in turn generates the C3 convertase C4bC2a. C3 convertase catalyzes C3 proteolysis into C3a and C3b, which in turn triggers opsonization and extravascular hemolysis in the liver; intravascular hemolysis mediated by C5b–C9 occurs minimally because of intact CD55- and CD59-mediated regulation.⁵

• Clinical presentation:⁶
  • In a cohort of 232 patients with CAD:⁷
    • Anemia:
      • Severe (Hb < 8 g/dL) in 27%
      • moderate (Hb 8-10 g/dL) 37%
      • Mild (Hb 10 – lower limit of normal) 24%
    • Compensated hemolysis in 12%
  • Symptoms may include:
    • Cold induced ischemic symptoms such as:
      • Acrocyanosis
      • Raynaud-like phenomena
    • Fatigue attributed to:
      • Anemia
      • Complement activation
  • Exacerbations may occur with triggers such as:
    • Cold temperature
    • Infections
    • Vaccination
    • Surgery
    • Trauma
• Diagnosis:⁸⁹
  • Establishing the diagnosis of CAD:
    • Diagnosis of hemolytic anemia is based on:
      • Low Hb
      • Elevated absolute reticulocyte count
      • Serum markers of hemolysis including:
        • Increased:
          • LDH
          • Bilirubin
          • AST
        • Decreased haptoglobin
      • Urine:
        • Presence of urinary hemosiderin
        • Urinalysis/dipstick test positive for blood but urine microscopy negative for red cells, indicative of hemoglobinuria
    • Blood film – spherocytes, agglutination and/or polychromasia
    • Diagnosis of immune mechanism of hemolysis:
      • Positive direct antiglobulin test (DAT)
    • Diagnosis of cold antibody-mediated hemolysis:
      • Direct antiglobulin test:
        • Typically strongly positive for C3 only (usually C3d).
        • Can also be weakly positive for IgG in up in up to 20% of patients.
      • Cold agglutinin titer:
        • Defined as the inverse value of the highest dilution at which agglutination occurs.
        • Typically > 64
      • Determination of the thermal amplitude of the cold agglutinin:
        • Usually < 25 degrees C
        • Time consuming
        • May not be necessary in all patients
      • According to the British Society of Haematology:
        • CAD “can be diagnosed in patients with AIHA and a DAT positive to C3 +/- IgG, with a consistent clinical picture and a high titre cold reactive antibody. The thermal amplitude may be considered as a supportive serological investigation where diagnostic uncertainty exists”.¹⁰
    • Serum complement C3 and C4 may be low.
  • Establishing the presence of CA-associated lymphoproliferative disease (LPD):
    • Serum protein electrophoresis (SPEP), immune fixation, immunoglobulin class quantification:
      • Serum monoclonal IgMκ can be found by capillary or agarose electrophoresis and immunofixation in more than 90% of the patients.¹¹
    • Bone marrow biopsy:¹²¹³
      • May show a specific bone marrow histopathologic pattern, termed “primary CA-associated lymphoproliferative disorder (LPD)” and found to be distinct from lymphoplasmacytic lymphoma (LPL), marginal zone lymphoma (MZL)
      • MYD88 L265P mutation, present in almost all cases of LPL is absent or infrequent in CA-associated LPD.
    • Flow cytometry in a bone marrow aspirate should also be performed:
      • Usually shows clonal CD20+, κ+ lymphocytes
      • This examination is not sensitive enough if performed in peripheral blood.
    • International Consensus Meeting: A bone marrow biopsy and flow cytometry should be performed in all CAD cases prior to therapy.¹⁴

Management

• A note about clinical practice guidelines:
  • Clinical practice guidelines for treatment of cold agglutin disease were written prior to studies showing efficacy of complement inhibitors:
    • Clinical practice guidelines:
      • 2017 British Society for Haematology guideline¹⁵
      • 2020 recommendations from the First International Consensus Meeting.¹⁶
    • Phase 3 clinical trials with sutimlimab:
      • CARDINAL study 2021
      • CADENZA trial 2022
    • Based on data from the CARDINAL study, sutimlimab was first approved by the FDA in February 2022 to decrease the need for red blood cell transfusion due to hemolysis (red blood cell destruction) in adults with CAD. Sutimlimab-jome is currently the only approved treatment of hemolysis for CAD.
  • Current clinical practice guidelines currently recommend rituximab with or without bendamustine as first line therapy for CAD.
  • It remains to be seen how anticomplement therapy will be incorporated in future updated guideline recommendations.
• Not everyone with CAD needs treatment:
  • Patients with mild anemia or compensated hemolysis and no clinical symptoms have not been shown to benefit from treatment.
  • In unselected descriptive series, 70% to 80% of patients with CAD have received therapy.
• Treatment goals:¹⁷
  • Increase in Hb levels in patients with symptom-producing anemia including achievement of transfusion independency.
  • Improvement or resolution of disabling cold-induced circulatory symptoms.¹⁸
  • Improvement in quality of life.
• General strategies:¹⁹
  • Avoid cold exposure to reduce the risk of severe exacerbations:
    • According to the British Society of Haematology: “Patients should be advised to avoid cold exposure where possible (1C).”²⁰
  • Folic acid:
    • According to the British Society of Haematology: “Patients with AIHA should receive folic acid supplementation (1B).”²¹
  • Thromboprophylaxis:²²
    • Generally recommended in patients:
      • With acute exacerbations of hemolysis.
      • In high-risk situations (for example, immobilization and long-distance flights).
    • British Society of Haematology: “Thromboprophylaxis with low molecular weight heparin is recommended for in-patients with an acute exacerbation of haemolysis (1C) and should be considered in ambulatory patients during severe exacerbations (Hb<85 g/l) (2C).”²³
  • Blood transfusion:
    • In patients with a clinically significant cold type antibody, the use of a blood warmer and ensuring a warm environment for transfusion is rational although the evidence of benefit is limited.²⁴
• Therapeutic intervention should be considered for:
  • Symptomatic anaemia:
    • According to the British Society of Haematology, symptomatic anaemia is an indication for treatment (IC).²⁵
    • International Consensus Meeting: “Treatment would usually not be recommended for patients whose Hb is > 10 g/dL.”²⁶²⁷
  • Severe circulatory symptoms:
    • According to the British Society of Haematology, severe circulatory symptoms is an indication for treatment (IC).²⁸
    • International Consensus Meeting: “Although acrocyanosis is a common accompaniment of CAD, it is uncommon for this to be a driving indication for therapeutic intervention. In most patients, this can be managed with thermal protection only. Patients who have severe Raynaud’s phenomenon may require treatment if thermal protection fails.”²⁹
  • Transfusion dependence:
    • According to the British Society of Haematology, transfusion dependence is an indication for treatment (IC).³⁰
• In patients requiring treatment:
  • There is no generally no role for:
    • Corticosteroids:
      • Response rates of 14–69% in larger series.
      • Responses are often partial (remission in <20% of patients) and cannot be sustained without an unacceptably high steroid dose.
      • Adverse events include diabetes, skeletal events, and infection.
      • According to the International Consensus Meeting: “Treatment options such as those used in wAIHA (corticosteroids, azathioprine or cyclophosphamide) are not effective in CAD and should not be used.”³¹
      • According to to the British Society of Haematology, consider corticosteroids (prednisolone 1 mg/kg/day) if anemia is severe or life-threatening (2C).³²
      • Expert opinion:
        • Corticosteroids continue to be used at very high doses for long periods of time for the treatment of CAD, despite a lack of efficacy and recommendations by the international consensus group that they not be utilized.³³
        • CAD should not be treated with corticosteroid.³⁴
    • Splenectomy:
      • Not recommended because the extravascular hemolysis predominantly takes place in the liver.
    • Up-to-Date: “Glucocorticoids and splenectomy are not effective therapies in the majority of patients with CAD, in contrast to warm AIHA where these therapies are generally very effective”
  • Treatment options include:
    • Removal of antibodies (plasmapheresis):
      • Responses are often transient (since IgM production is ongoing).
      • May help to stabilize patients with severe disease in conjunction with alternative therapy.
      • Therapeutic apheresis for severe CAD is considered a category II indication by the American Society for Apheresis.
    • Eradication of monoclonal B cell clone in the bone marrow to reduce the production of monoclonal cold agglutinins (B cell–directed treatment):
      • Rituximab monotherapy (monoclonal anti-CD20 antibody):
        • Not FDA approved for CAD.
        • Has been used to treat CAD since the late 1990s.
        • Most well-documented therapy for CAD.
        • Can be used first-line in symptomatic CAD.
        • Dose: 375 mg/m2 for 4 weeks at 7-day intervals.
        • PR rate of about 50%.
        • Very few complete responses (CR).
        • Median increase in Hb level of 4.0 g/dL.
        • Time to response in CAD ranges from 1 to 8 months.³⁵
        • Median response duration of 6.5 to 11 months (relapses usually occur within 1 year).
        • Toxicity is low.
        • Retreatment may result in response in relapsed patients.
        • No published data on rituximab maintenance.
      • Rituximab and cytotoxic agents:³⁶
        • Rituximab and oral fludarabine³⁷
          • According to Up-to-Date, “Rituximab plus fludarabine is more toxic and should be reserved for third-line therapy in selected patients.”
        • Rituximab and bendamustine:
          • Can be used first-line in symptomatic CAD
          • In one study:³⁸
            • Rituximab 375 mg/m2 day 1 and bendamustine 90 mg/m2 day 1 and 2 for 4 cycles at 28 days interval
            • Seventy-one per cent responded; 40% achieved CR and 31% partial response (PR).
            • Hemoglobin levels increased by a median of 4.4 g/dL in the complete responders and 3.9 g/dL in those who had a PR.
            • Median time to response was 1.9 months
            • Grade 4 neutropenia occurred in 20% of the patients
        • Expert opinion: combination of rituximab with fludarabine or bendamustine increased efficacy in CAD compared with rituximab monotherapy but also presented greater side effects.³⁹
        • Up-to-Date:
          • “Rituximab plus bendamustine produces high response rates and often complete responses lasting for many years. However, toxicities may be greater than with rituximab monotherapy, limiting use of this combination in frail individuals.”
          • “We generally prefer rituximab plus bendamustine for individuals with chronic primary CAD, based on high, durable response rates demonstrated in observational studies.”
          • “It is useful to note that bendamustine plus rituximab is a highly effective combination for Waldenström macroglobulinemia (WM), which is one of the lymphoid malignancies most often associated with CAD.”
    • Complement inhibition:
      • Therapies that target the classical complement pathway can be used to reduce transfusion requirements and improve anemia and fatigue.
      • Complement-directed therapies:
        • Do not eliminate the cells producing the cold agglutinins
        • Are not expected to improve cold-induced symptoms related to RBC agglutination, as agglutination is mediated by the IgM molecules and is complement independent
      • Compared with B cell-directed therapies, which are temporary, complement-directed therapies will have to be continued indefinitely.
      • Eculizumab:⁴⁰
        • Monoclonal anti-C5 antibody.
        • Targets the terminal complement activation.
        • First complement inhibitor used for the treatment of severe CAD with primarily intravascular hemolysis.
        • May reduce the need for transfusion.
        • Shown to have benefit in reducing intravascular hemolysis but had no effect on extravascular hemolysis (C5 inhibition will not block the C3b-mediated, extravascular hemolysis).
        • Blockade of C5 results in only a small increase in Hb.
      • Sutimlimab (formerly BIVV009):
        • Humanized monoclonal antibody which selectively targets complement component C1s, inhibiting the formation of the C1 complex and classical complement pathway activation.
        • Results in increased mean hemoglobin levels within the first week.
        • Expert opinion: provides rapid clinical response when used in patients who have been refractory to treatment, in those who have lost response to prior therapy, or in emergency situations… Clinical data available to date support the positive benefit risk profile of sutimlimab in both transfusion-dependent and ‘milder’ forms of CAD, with rapid and sustained effects on hemolysis and meaningful improvements in fatigue and quality-of-life measures.⁴¹
        • Phase 1b study:⁴²
          • Sutimlimab rapidly suppressed activity in the classic complement pathway in healthy volunteers.
          • Repeat administration in patients with CAD inhibited hemolysis within 24 hours after administration, increased hemoglobin levels, and resulted in transfusion independence.
        • CARDINAL study:
          • 26-week multicenter, open-label, single-group phase 3 study
          • Study design:
            • 26-week treatment period:
              • Intravenous infusion on day 0 (the first day of treatment)
              • Intravenous infusion on day 7
              • Intravenous infusion every two weeks
            • Red-cell transfusions were performed if either:
              • Patient had a hemoglobin level of less than 9 g per deciliter and was symptomatic
              • Patient had a hemoglobin level of less than 7 g per deciliter with or without symptoms
            • After the 26-week treatment period, patients were eligible to continue to the open-label extension study.
          • Inclusion criteria included:
            • At least 18 years of age
            • Confirmed cold agglutinin disease
            • Recent history (within 6 months before enrollment) of red-cell transfusion
          • Exclusion criteria included:
            • Cold agglutinin syndrome
            • SLE
            • Treatment with rituximab monotherapy within 3 months before enrollment or treatment with rituximab combined with chemotherapy within 6 months before enrollment.
          • The composite primary end point was a normalization of the hemoglobin level to 12 g or more per deciliter or an increase in the hemoglobin level of 2 g or more per deciliter from baseline, without red-cell transfusion or medications prohibited by the protocol.
          • Results:
            • A total of 24 patients were enrolled.
            • Primary end point:
              • 13 of 24 patients (54%) met the prespecified criteria for the composite primary end point.
              • Among 11 patients who did not meet the prespecified criteria for the primary end point, 6 had evidence of a treatment response.
              • Evidence of a hematologic response was not observed in 3 patients.
            • Hb response:
              • Mean increase in Hb was 2.6 g per deciliter.
              • 20 patients (83%) had a mean hemoglobin change of 1 g or more per deciliter from baseline over the treatment period
            • Hemolytic markers (bilirubin level and LDH level) improved/normalized in most patients.
            • Patient-reported fatigue was reduced during sutimlimab treatment.
            • Activity in the classic complement pathway was rapidly inhibited, as assessed by a functional assay.
            • At least one adverse event occurred during the treatment period in 22 patients (92%).
            • Seven patients (29%) had at least one serious adverse event, none of which were determined by the investigators to be related to sutimlimab.
        • CADENZA trial:
          • 26-week, phase 3, randomized, placebo-controlled, double-blind trial
          • Inclusion criteria:
            • Confirmed CAD diagnosis
            • Hb < or equal to 10 g/dL
            • Bilirubin level above the normal reference range
            • Ferritin level above the lower limit of normal
            • symptomatic disease within 3 months of screening, defined as one or more of the following:
              • Symptomatic anemia
              • Acrocyanosis
              • Raynaud phenomenon
              • Hemoglobinuria
              • Disabling circulatory symptoms
              • Major adverse vascular event, including thrombosis.
          • Exclusion criteria included:
            • Cold agglutinin syndrome secondary to infection, rheumatologic disease, or active hematologic malignancy
            • History of blood transfusion within 6 months of screening or a history of > 1 blood transfusion within 12 months
            • Diagnosis of systemic lupus erythematosus or other autoimmune disorders
            • Recent rituximab
          • The primary efficacy endpoint was a composite of:
            • Hb increase from baseline of >1.5 g/dL at the treatment assessment time point (mean value from weeks 23, 25, and 26)
            • Absence of blood transfusions from week 5 to week 26
            • Avoidance of protocol-prohibited CAD medications from week 5 to week 26
          • Results:
            • 19 patients in the sutimlimab arm, 20 patients in the placebo arm
            • 16 (72.7%; 95% confidence interval [CI]: 49.8, 89.3) treated with sutimlimab vs 3 patients (15.0%; 95% CI: 3.2, 37.9) who received placebo met the prespecified criteria for the composite primary endpoint and achieved the protocol-defined responder criteria.
            • Sutimlimab, but not placebo, significantly increased mean hemoglobin and FACIT-Fatigue scores at treatment assessment timepoint.
            • Sutimlimab normalized mean bilirubin by week 1.
            • Improvements correlated with near-complete inhibition of the classical complement pathway and C4 normalization.
            • Twenty-one (96%) of sutimlimab patients and 20 (100%) placebo patients experienced 1 or more 1 treatment emergent adverse event.
          • Authors’ conclusions:
            • Sutimlimab has potential to be an important advancement in the treatment of CAD.

• Anticomplement therapy (cont’d):
  • Expert opinion:⁴³
    • Sutimlimab provides rapid clinical response when used in patients who have been refractory to treatment, in those who have lost response to prior therapy, or in emergency situations… Clinical data available to date support the positive benefit risk profile of sutimlimab in both transfusion-dependent and ‘milder’ forms of CAD, with rapid and sustained effects on hemolysis and meaningful improvements in fatigue and quality-of-life measures.
  • Expert opinion:⁴⁴
    • One would expect anti-complement therapies to be particularly helpful in severely anemic patient. The ischemic symptoms are not complement mediated and will not be relieved.
  • Expert opinion:⁴⁵
    • Clinical data available to date support the positive benefit risk profile of sutimlimab in both transfusion-dependent and ‘milder’ forms of CAD, with rapid and sustained effects on hemolysis and meaningful improvements in fatigue and quality-of-life measures.
    • In CAD, complement inhibition therapy with sutimlimab can:
      • Provide rapid clinical response when used in patients who have been refractory to treatment
      • In those who have lost response to prior therapy
      • In emergency situations
  • According to Up-to-Date, current as of 3/2024:
    • Complement-directed therapies are generally reserved for:
      • Individuals whose disease does not improve with immunosuppressive therapies such as rituximab, bortezomib, and/or fludarabine.
      • Those who cannot take these therapies.
      • Those who require a more rapidly acting or transient blockade of hemolysis.
• Other potential treatments:⁴⁶
  • Bortezomib, a reversible inhibitor against chymotrypsin-like activity of the 26S proteasome.⁴⁷
  • Pegcetacoplan (APL-2), a pegylated compstatin analog, approved for the treatment of paroxysmal nocturnal hemoglobinuria
  • Bruton’s tyrosine kinase inhibition using ibrutinib
• Tailored therapy according to clinical phenotype:
  • Expert opinion: “The clinical phenotypic variations seen in CAD may, in fact, inform the best algorithm for clinical management. For example, patients who have hemolysis, thrombosis, or other signs of chronic complement activation may be better managed with regimens that include classical complement pathway inhibition plus or minus B-cell-directed therapy. In contrast, patients who have mainly acrocyanotic symptoms, which are IgM-mediated, may benefit more from aggressive B-cell-directed therapy, as control of acrocyanosis may not be achieved with complement-based therapy.”⁴⁸