Cold agglutinin disease (CAD) affects an estimated 5-20 individuals per million and comprises approximately 15%-30% of autoimmune hemolytic anemia cases.1 Hemolysis in CAD is mediated by the classical complement pathway.2 Despite significant progress in CAD treatment in recent decades, several limitations remain.
“The main challenge is a lack of approved therapies, and many patients are elderly and tolerate some therapies poorly,” explained Catherine M. Broome, MD, physician and associate professor in the department of medicine at MedStar Georgetown University Hospital’s Lombardi Comprehensive Cancer Center in Washington, DC.
Pharmacologic treatment is not indicated in all patients with CAD, such as those with mild anemia or compensated hemolysis (roughly one-half of patients) and no clinical symptoms.3 These individuals should be monitored for emerging symptoms, and all patients should receive advice regarding thermal protection.1
For those exhibiting bothersome symptoms such as symptomatic anemia, there are several possible treatment options supported by the literature. In contrast to therapies used in the treatment of warm autoimmune hemolytic anemia, experts emphasize that corticosteroids and splenectomy are generally ineffective in CAD, and unspecific immunosuppressants have been associated with low response rates in the limited data available.1
Read more about CAD patient education
Given the rarity of CAD and lack of comparative trials, treatment decisions are primarily based on findings from nonrandomized trials along with clinical experience.1
Pharmacologic Treatment Options
In the vast majority of CAD patients, complement fixation on the red cell membrane is mediated by an immunoglobulin M (IgM) protein.3 “Treatment options are limited to suppression of the IgM producing clone,” with rituximab, bendamustine, and bortezomib representing the most commonly used therapies, according to Morie A. Gertz, MD, MACP, consultant in the division of hematology and the Roland Seidler Jr. Professor of the Art of Medicine at the Mayo Clinic College of Medicine and Science in Rochester, Minnesota.
Rituximab monotherapy is the most commonly used therapy in CAD and represents the first-line treatment option for frail patients.1 Rituximab (375 mg/m2 for 4 cycles administered at 1-week intervals) has demonstrated response in roughly one-half of CAD patients, with increased hemoglobin (Hb) levels of 2-3 g/dL and IgM reductions exceeding 50% in many cases.2 However, findings suggest that the median duration of response to rituximab monotherapy is less than 1 year.3 Retreatment with rituximab has been successful in many patients with relapsed disease.1
Combined therapy with rituximab and bendamustine (rituximab 375 mg/m2 on day 1 and bendamustine 90 mg/m2 on days 1 and 2 for 4 cycles administered at 28-day intervals) showed high efficacy in a prospective multicenter trial reported in 2018 in Blood. In the sample of 45 patients, a complete or partial response was observed in 40% and 31% of participants, respectively.4
There was a longer time to response with this regimen compared to rituximab monotherapy, with some patients demonstrating a median response time of 1.9 months (range, 0.25-12 months). However, the response persisted in 90% of patients after 32 months.1 Follow-up data revealed that 53% of patients had achieved a complete response and the median duration of response was greater than 88 months.1
While one-third of patients developed grade 3 or 4 neutropenia, infection occurred in only 11% of the entire sample. This combination is “highly efficient, sufficiently safe, and may be considered in first line for patients with CAD requiring therapy,” the authors concluded.4
Read more about CAD treatment
In a prospective multicenter trial of 29 patients, the combination of oral fludarabine and rituximab led to a complete response rate in 21% of cases and a partial response in 55% of cases, with a median increase in Hb of 3.1 g/dL and a median response duration exceeding 66 months. Grade 3-4 neutropenia was reported in 41% of patients.5
Although this agent “can be quite myelosuppressive as well as immunosuppressive in this population, and its use needs to be carefully weighed against the risks,” fludarabine is a “consideration for long-term management of severely affected patients,” Dr. Gertz wrote in a paper published in 2019 in Clinical Advances in Hematology and Oncology.3
Bortezomib monotherapy represents a second- or third-line option for select cases. In a 2018 nonrandomized trial of 19 anemic patients with relapsed disease, 6 patients responded to a single cycle of therapy (1.3 mg/m2 on days 1, 4, 8, and 11), with 3 patients showing complete response and 3 patients showing partial response.6 Remission was maintained for at least 16 months in 4 of the 6 responders. Response rates could potentially increase if bortezomib is used for an extended duration or in combination with other therapies, although this requires further investigation.1
Complement Blockade and Beyond
“There have also been investigational trials looking at complement blockade as a strategy to resolve the hemolysis,” Dr. Gertz said. “Experimental use of agents that are capable of blocking early components of complement have shown the ability to raise the hemoglobin, lower the reticulocyte count, and lower the lactate dehydrogenase and bilirubin.”
To date, the most promising of these agents is sutimlimab, a monoclonal antibody targeting the C1s protein. Following favorable results in a phase 1B trial, Röth et al conducted a 26-week phase 3 open-label trial involving 24 transfusion-dependent patients with CAD. The results demonstrated rapid inhibition of activity in the classic complement pathway, with resulting increases in Hb levels, normalization of bilirubin levels, and clinically meaningful and persistent reductions in fatigue.7
In addition, 71% of patients remained transfusion-free from week 5 through week 26 of the study. At least 1 serious adverse event occurred in 29% of patients, none of which were linked to sutimlimab.7
“These studies also demonstrate a significant improvement in quality of life scores even before anemia has resolved, indicating the systemic inflammatory state in CAD patients that is treated with complement inhibition,” noted Dr. Broome, who coauthored the work.
Read about CAD experimental therapies
Researchers are investigating the efficacy and safety of sutimlimab in transfusion-independent CAD patients (estimated N=40) in a phase 3 randomized controlled trial.8 Other complement-directed therapies being investigated for potential use in CAD treatment include the anti-C1q monoclonal antibody ANX005 and the C3 inhibitor pegcetacoplan (APL-2).2
Preliminary data from an international case series also support the effectiveness of the BTK inhibitor ibrutinib in CAD.9
Among the remaining needs in CAD, the “biggest gap currently is educational, in that physicians are failing to recognize and make an accurate diagnosis in patients seen with anemia,” Dr. Gertz said. Clinicians should screen these individuals for hemolysis and, if detected, screening for cold agglutination should follow.
“We also need to continue to educate on the risk of venous thromboembolism (VTE) and the mortality associated with CAD,” Dr. Broome added. Studies have found that incidence rates of VTE were 2 times higher in CAD patients compared to controls, and 31% of CAD patients had a claim for thromboembolism in a study that analyzed medical records.3 Other findings have indicated mortality rates of 39% in CAD patients at 5 years post-diagnosis, compared to 18% in a comparison cohort.10
“Additional clinical trials evaluating therapy as well as the longitudinal patient registry will continue to provide insights into this rare disease,” she stated.
- Berentsen S. How I treat cold agglutinin disease. Blood. 2021;137(10):1295-1303. doi:10.1182/blood.2019003809
- Berentsen S. New insights in the pathogenesis and therapy of cold agglutinin-mediated autoimmune hemolytic anemia. Front Immunol. 2020;11:590. doi:10.3389/fimmu.2020.00590
- Gertz MA. How I treat cold agglutinin hemolytic anemia. Clin Adv Hematol Oncol. 2019;17(6):338-343.
- Berentsen S, Randen U, Oksman M, et al. Bendamustine plus rituximab for chronic cold agglutinin disease: results of a Nordic prospective multicenter trial. Blood. 2017;130(4):537-541. doi:10.1182/blood-2017-04-778175
- Berentsen S, Randen U, Vågan AM, et al. High response rate and durable remissions following fludarabine and rituximab combination therapy for chronic cold agglutinin disease. Blood. 2010;116(17):3180-3184. doi:10.1182/blood-2010-06-288647
- Rossi G, Gramegna D, Paoloni F, et al. Short course of bortezomib in anemic patients with relapsed cold agglutinin disease: a phase 2 prospective GIMEMA study. Blood. 2018;132(5):547-550. doi:10.1182/blood-2018-03-835413
- Röth A, Barcellini W, D’Sa S, et al. Sutimlimab in cold agglutinin disease. N Engl J Med. 2021;384(14):1323-1334. doi:10.1056/NEJMoa2027760
- ClinicalTrials.gov. A study to assess the efficacy and safety of BIVV009 (sutimlimab) in participants with primary cold agglutinin disease without a recent history of blood transfusion. NCT03347422. Accessed October 20, 2021.
- Bylsma LC, Gulbech Ording A, Rosenthal A, et al. Occurrence, thromboembolic risk, and mortality in Danish patients with cold agglutinin disease. Blood Adv. 2019;3(20):2980-2985. doi:10.1182/bloodadvances.2019000476
- Marit Jalink, Sigbjørn Berentsen, Jorge J. Castillo, et al. Effective treatment of cold agglutinin disease/cold agglutinin syndrome with ibrutinib: an international case series. Blood. 2020;136 (Supplement 1):29-30. doi:10.1182/blood-2020-139131