possible Treatment options

discuss all pros and cons with your medical professionals.

The following list describes treatments that are among the ones most regularly reported about Cold Agglutinin Disease and by the CAD patients who visit our website. This is not intended to be a comprehensive or all-inclusive list, and it may not be appropriate for your individual situation.  It is intended simply as a guide for reference and discussion.

Please be aware that all treatments, including blood transfusions, can have side effects, some known and others yet to be discovered. 

Rituximab (Rituxan® or Mabthera®) approved by the FDA in 1997. It is an anti-CD20 monoclonal antibody created to deplete B cells. The depletion interferes with the production of Cold Agglutinins and can result in a significant improvement in the hemoglobin levels for a number of CAD patients. Some will see no improvement. Following treatment, it may take weeks to months, even up to a year, to see a noticeable rise in the hemoglobin. In time, in most cases, the number of B-cells will again increase and it may be necessary to retreat with Rituxan, another single agent monoclonal antibody or a combination of drugs. Some patients remain treatment free for several years before requiring retreatment.

A course of treatment is normally four infusions that are given one per week for four weeks. Sometimes, a second course of four infusions is prescribed. There can be a risk with the initial dose due to the possibility of a serious allergic reaction. Medical facilities are well aware of this and take special precautions pretreating with an established protocol of Tylenol, Benadryl and sometimes Dexamethasone prior to the infusion. In July 2017, subcutaneous administration of rituximab was approved by the FDA to be used only after patients have received at least one treatment by IV.

Rituximab treatment is said to be an effective therapy leading to 45-60% partial responses (PRs). Complete responses (CRs) are rare. For the non-responders, it’s possible a second course may be beneficial. One can have side-effects, including fatigue, following Rituxan which will usually diminish after the course of treatment is completed.

For those concerned about an allergic reaction to Rituxan, which is a chimeric (mouse and human) single agent monoclonal antibody, there’s a test called HAMA (human anti-mouse antibody.) It can determine if patients have pre-existing human anti-mouse antibodies or have developed them due to recent treatments with a mAb (monoclonal antibody) drug such as Rituxan.

Rituxan should not be warmed prior to treatment but should be given at room temperature.

We consulted with Genentech, one of the manufacturers, and were advised that since Rituxan is a protein and heating degrades proteins, we should not warm the solution. Their literature regarding Rituxan says that once diluted for infusion, the product can be kept refrigerated for 24 hours and an additional 24 hours at room temperature (68-77 degrees). There should be no freezing or shaking!

According to our Medical Advisor, Dr. SigbjØrn Berentsen, “For drug safety reasons, we do not recommend prewarming of rituximab before infusion. The infusion solution should, however, definitely be room temperature and not be taken from the fridge. Even though this implies minor variations of the temperature between facilities and the infusion rate is often ‘rapid’ (which means 500 mL / 90 min.) from infusion #2 onwards, we do not think that this will cause sufficient cooling of the blood to induce significant hemolysis.”


Bendamustine and Rituximab. Bendamustine is an alkylating agent approved for the treatment of Indolent (progressing slowly) B-cell non-Hodgkin lymphoma and chronic lymphocytic leukemia. Rituximab is a monoclonal antibody against the B-cell protein CD20. Bendamustine-rituximab therapy results in high overall and CR (Complete

Response) rates with sustained remissions in CAD. Bendamustine plus rituximab for chronic cold agglutinin disease: results of a Nordic prospective multicenter trial  (Blood, 2017, vol. 130 (4): pp. 537-541).

Rituximab Plus Oral Fludaribine is another treatment option. High response rate and durable remission following fludarabine and rituximab combination therapy for chronic cold agglutinin disease. (Blood, 2010, vol.116 (17): pp. 3180-3184)

Eculizumab (Solaris) is used as a rapidly acting rescue therapy for severe CAD. Eculizumab in cold agglutinin disease (DECADE): an open-label, prospective, bicentric, nonrandomized phase 2 trial. Röth, A. 2018 Study Completed July 2017.
(Blood Adv., 2018 Oct 9; vol. 2(19): pp. 2543–2549). 

Ibrutinib (Imbruvica) is a BTK (Bruton tyrosine kinase), inhibitor for those with CAD and Waldenström’s Macroglobulinemia (WM).

Intravenous Immunoglobulin (IVIG) is an infusion of immunoglobulins to help fight infections for those who are not making enough antibodies on their own. IVIG may help raise red-blood cell counts in CAD. Treatment is typically every three to four weeks.
Blood transfusions of washed red cells are sometimes necessary as a temporary measure when the hemoglobin gets too low, seven to eight (US) and 70 to 80 Outside US), or below, and the antibody titer (antibody load) is high. The transfused blood should be warmed to prevent new red cells from being coated with antibodies.

Splenectomy Spleen removal is usually effective in helping warm agglutinins (wAIHA) but is an ineffective therapy for CAD.

Plasmapheresis (PP), which involves filtering blood to remove antibodies, is sometimes helpful for the short term when other treatments fail. In some cases, it has been useful prior to drug therapy and/or surgery to reduce the CA antibody load and resulting in a better outcome.

Black Box Warning for Procrit, Epogen, and Aranesp

These erythropoietins (EPO) are sometimes successful in raising hemoglobin levels in some with CAD. Aggressive use of erythropoiesis-stimulating agents to raise hemoglobin to a target of 11g/dL or greater increases the risk of death, serious cardiovascular and thromboembolic reactions. If prescribed by your medical professional, remind him/her of the above warning and ask to use the smallest possible dose and for the shortest time necessary to prevent the need for red blood cell transfusions.

Corticosteroids are not recommended to treat CAD. They are sometimes used for a short duration but are not an effective treatment for the long term. They are used to treat Warm Hemolytic Anemia.

Special Surgery requirements for CAD

For those with CAD requiring heart surgery or any type of invasive procedure, you need to be certain to be kept warm and any fluids infused must be warmed both during and following surgery. You may want to have your hematologist consult with your surgeon. Before surgery. remind all personnel and especially the doctors and nurses that you need to be kept warm.

New Treatments for B-Cell Diseases 

The current trend is away from chemotherapy and towards using monoclonal antibodies and immunotherapy to treat Blood Cancers and Autoimmune Diseases. In addition, there are several clinical trials in process.