Cold agglutinin disease an ‘underappreciated’ anemia with promising new treatments
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Research presented at ASH Annual Meeting and Exposition provided an exciting update on many of the underappreciated clinical manifestations of cold agglutinin disease, as well as data on potential new therapeutic interventions.
Cold agglutinin disease (CAD), a rare hemolytic anemia, is mediated by auto IgM antibodies that generally have a thermal amplitude below core body temperature. The binding of these IgM antibodies to the ubiquitous I antigen on the surface of erythrocytes produces an Ag-Ab complex that very efficiently activates the classical pathway (CP) of complement via the C1 complex.
This CP activation leads to complement-mediated extra and/or intravascular hemolysis. In addition, the agglutination properties of the IgM can result in mild to severe circulatory symptoms.
Clinical manifestations
An evaluation of patient-reported disease burden among those with CAD informs us of the significant and ongoing burdens this disease places on patients.
According to results of a study by Su and colleagues presented at ASH, 68.8% of patients interviewed reported lifestyle or behavioral changes to help manage CAD. Patients reported a negative impact on daily activities, exercise, social/leisure activities, relationships, mood, ability to concentrate and emotions. The patients attributed this to fatigue/lack of energy and avoidance of cold environments.
In another study, Patel and colleagues demonstrated that patients with CAD were 60% more likely than a matched cohort to experience medically attended anxiety and/or depression. Further, patients with CAD were nearly twice as likely to be prescribed medication or psychotherapy for anxiety or depression. These findings are suggestive of possible extra-hematologic manifestations of CAD that can certainly impact quality of life.
Weitz and colleagues presented data evaluating the connection between inflammation and fatigue in patients with CAD. Researchers demonstrated that patients with CAD have elevations in both the proinflammatory cytokine IL-6 and the regulatory cytokine IL-10 at baseline.
As these patients were treated on a clinical trial evaluating sutimlimab (Sanofi), an anti-C1s monoclonal antibody that inhibits CP-mediated complement activation, the levels of both IL-6 and IL-10 decreased, highlighting the influence of complement inhibition on inflammation in CAD. In this study, researchers noted concurrent improvement in patients’ fatigue scores, suggesting a role for complement-mediated inflammation in the fatigue experienced by patients with CAD.
Wilson and colleagues presented data on the severity of anemia and health care resource utilization among patients with CAD, showing that more than 50% of patients experienced moderate to severe anemia within the first 6 months after diagnosis, which persisted in as many as 30% of patients up to 36 months after diagnosis despite off-label therapy.
Patients received a median four (interquartile range, 1-11) therapies and a mean 2.94 (standard deviation, 8.45) blood transfusions within the first 6 months. Outpatient and ER visits and hospitalizations also were high and did not diminish with time. These data indicate a real unmet therapeutic need in CAD as patients continue to require therapy, transfusions and hospitalizations.
Röth and colleagues presented the design of the CAD Real-World Evidence (CADENCE) Registry, which plans to enroll approximately 725 patients with CAD to better understand patient and clinical characteristics, patterns of CAD treatment, health care resource utilization, natural history of CAD, long-term clinical outcomes, and impact of the disease and therapy on quality of life. This is an important effort to help increase the fund of knowledge in the rare autoimmune hemolytic anemia.
New therapy
Several studies at ASH also included promising data on much-needed treatment options for CAD.
For instance, Jalink and colleagues presented a retrospective study evaluating the efficacy of the Bruton tyrosine kinase (BTK) inhibitor ibrutinib (Imbruvica; AbbVie/Pharmacyclics, Janssen) among 10 patients who were evaluated with a questionnaire.
Median follow-up was 20 months (range, 1-74). All patients showed an improvement in hemoglobin, resulting in one partial response and nine complete responses. Hemolysis improved in eight of the nine patients with complete response. Further, all seven patients with acrocyanotic symptoms reported improvement.
As CAD is now known to be a clonal B-cell disorder, further investigation into BTK inhibition is certainly warranted.
Two additional presentations by Röth and colleagues outlined the therapeutic benefits of complement inhibition with sutimlimab among patients with CAD.
One-year follow-up data from the phase 3 Cardinal trial — earlier results of which were presented as a late-breaking abstract at the 2019 ASH meeting — showed sutimlimab, a first-in-class classical pathway inhibitor, had a sustained treatment effect in CAD, with mean hemoglobin maintained at greater than 11g/dL at week 53.
Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) scores demonstrated a clinically meaningful increase from baseline within 1 week, which was maintained through week 51. Researchers identified no new safety concerns in longer follow-up.
Röth and colleagues also presented data from this trial looking at quality-of-life measures. Patients with CAD in this study had abnormal baseline quality-of-life measures that were consistent with those seen in patients with other autoimmune disorders and cancer.
Although FACIT-F results after treatment with sutimlimab have been discussed elsewhere looking at other measures of quality of life, researchers noted the greatest improvements in mobility and usual activity domains. After treatment with sutimlimab, patients demonstrated clinically meaningful improvement in all patient-reported outcomes. These improvements can be attributed to improvement in anemia but also may be related to complement inhibition and the role that plays in inflammation.
Future directions
The studies on anxiety and depression, inflammation, burden of disease and health care resource utilization among patients with CAD highlight many aspects of this disease that have been underappreciated.
New therapeutic interventions such at classical pathway inhibition with sutimlimab and BTK inhibition continue to show promise for patients with CAD.
As we look to the future, the CADENCE registry will help describe the natural history of CAD, as well as identify both hematologic and nonhematologic clinical manifestations. It also will guide our therapeutic decisions by providing long-term data on treatment outcomes.
References:
The following were presented at ASH Annual Meeting and Exposition (virtual meeting); Dec. 5-8, 2020:
Jalink M, et al. Abstract 1678.
- Patel P, et al. Abstract 1631.
Röth A, et al. Abstract 765.
- Röth A, et al. Abstract 1674.
Röth A, et al. Abstract 2537.
- Su J, et al. Abstract 2484.
Weitz IC, et al. Abstract 759.
- Wilson A, et al. Abstract 151.
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