Back Back
CAD Advances: FAQ
Advances in Cold Agglutinin Disease: Expert Answers to Your Most Pressing Questions

Released: December 22, 2023

Catherine M. Broome
Catherine M. Broome, MD
David Dingli
David Dingli, MD, PhD
Deva Sharma
Deva Sharma, MD, MS
Activity Information

Activity

Progress
1
Course Completed
Continue
Key Takeaways
  • Management of cold agglutinin disease with sutimlimab, an anti-complement C1 monoclonal antibody, is safe and effective and leads to resolution of hemolysis and hemoglobin recovery in both acute and chronic cases irrespective of previous history of transfusion or prior rituximab use.
  • Complement plays a limited role in IgM-mediated aggregation of red blood cells during an acrocyanosis event and thus treatment with sutimlimab may be supplemented with other therapies, including B cell depleting therapies, to address the underlying lymphoproliferative disorder leading up to IgM accumulation.
  • It is important to adhere to the every-2-week dosing interval with sutimlimab because failure to consistently do so may lead to breakthrough hemolysis that is recombinant erythropoietin-unresponsive and more challenging to manage; there are no data to support sutimlimab use off cycle (eg, less than every 2 weeks).

In this brief commentary, Catherine M. Broome, MD, David Dingli, MD, PhD, and Deva Sharma, MD, MS, answer frequently asked questions on the management of cold agglutinin disease (CAD) with available therapies that were submitted by an audience of healthcare professionals (HCPs) during a live CCO satellite symposium titled “Advances in Autoimmune Hemolytic Anemia: Targeting the Complement Cascade in Cold Agglutinin Disease” that was held during the 65th American Society of Hematology annual meeting in San Diego, California.


What would be your approach if you see an unexplained drop in hemoglobin with normal bilirubin while a patient is receiving sutimlimab? Would you recommend looking for internal bleeding in an elderly population? 

Catherine M. Broome, MD:
In a patient with normal bilirubin and a drop in hemoglobin, it is very difficult to explain this as hemolysis. In this scenario, I would investigate further what else might be causing the drop in hemoglobin. 

As we were treating patients in  the phase III CARDINAL trial of sutimlimab in patients with primary CAD with active hemolysis and recent history of blood transfusions, and the phase III CADENZA trial in patients with CAD with elevated bilirubin and no recent history of blood transfusions, we learned that some patients may have an inappropriately low erythropoietin (EPO) response related to other medical comorbidities, and that is something we may need to consider. If the patient is not achieving as good a hemoglobin response with a normalization in their bilirubin, you may also need to assess for deficiencies in iron, folic acid, or vitamin B12. In an older population, many of these things can occur. We must be vigilant and determine why they are becoming newly anemic.

Could you share your insights on patients with hemolytic crisis wherein you do not need to wait for failure with previous rituximab treatment?

Catherine M. Broome, MD:
These cases can be quite complex. For example, we had a patient with cold agglutinin syndrome who developed severe hemolysis following a liver transplant. This patient also had reactivation of an opportunistic infection with Epstein-Barr virus. When he presented back to the hospital, he had a hemoglobin of 3 g/dL, and lactate dehydrogenase >1000 U/L. It took us some time to detect that he had cold agglutinins, but he had a cold agglutinin titer that was greater than 1:2000, he had a positive direct antiglobulin test for C3, and was weakly positive for IgG. 

There were multiple concerns regarding a patient with a newly transplanted liver, particularly the risk of infection, other immunosuppressants that the patient was requiring, and the combination of those with sutimlimab to treat his cold agglutinin syndrome. We also were concerned about iron overload in this newly transplanted liver and about the potential risk of thrombosis.

Eventually, we were able to bring all the teams together and initiate sutimlimab therapy, which led to marked improvement in bilirubin and hemoglobin stabilization within 24 hours. After several days, the patient’s hemoglobin began to increase, bilirubin continued to decrease, and lactate dehydrogenase also decreased. He was also treated for his Epstein-Barr virus reactivation. After several months, the patient had a complete normalization of hemoglobin and we were able to discontinue sutimlimab therapy. So it was very fortunate that treatment with sutimlimab achieved what we needed in that acute setting. I do not know what would have happened to that patient if we had had to continue blood transfusions.

How do you treat acrocyanotic symptoms in patients who develop them while on sutimlimab?

David Dingli, MD, PhD: 
Sutimlimab is not particularly effective against acrocyanosis. As Dr Broome discussed in her presentation, the acrocyanosis component arises from the agglutination of red blood cells mediated by IgM, wherein the complement component activation is not something critical at that point in time. Again, sutimlimab monotherapy will not be particularly effective in that context. What will be effective will be thermal protection and sometimes, in this context, I have used alpha blockers to help improve the patient’s symptoms.

Catherine M. Broome, MD:
I agree. Sometimes thermal protection alone is not adequate. This is an area where I may look for available clinical trials exploring combinations of anti─B-cell therapy while patients are receiving sutimlimab. For a patient who has severe acrocyanotic symptoms and is on sutimlimab, you are controlling their hemolysis, and you may want to think about maybe using sutimlimab as a bridge to anti─B-cell directed therapy to reduce the titer of IgM auto antibody. 

David Dingli, MD, PhD: 
Absolutely. We must control the underlying lymphoproliferative disorder as a long-term approach to acrocyanosis. In the short term however, if there is a risk of digital gangrene, we may consider plasma exchange, which will rapidly bring IgM titer down and address the intravascular component. 

What are your thoughts in a scenario wherein acrocyanosis may increase upon receipt of sutimlimab? Do you think patients experience an increase in acrocyanosis because of the red blood cell mass increase, and would you consider bendamustine with rituximab to decrease a clone that is producing the IgM?

David Dingli, MD, PhD: 
So in principle, yes. Ideally, you can get the patient’s insurance to pay for all 3 very expensive therapies. I am assuming this question is about combining sutimlimab together with bendamustine and rituximab. It has not been my experience that acrocyanosis gets worse while the patient is on sutimlimab. In fact, I have yet to see a patient that complains about that. I live in Minnesota where it is quite cold most of the year, so if a patient’s acrocyanosis gets worse they will surely notice.

Are there any long-term adverse effects of using sutimlimab in younger patients?

David Dingli, MD, PhD: 
The follow-up with sutimlimab in either the phase III CARDINAL or CADENZA trial is not particularly long. It would be challenging to be definitive about this. What I can say is that quite some time ago, when I was still in medical school, we were educated on the notion that we must be very careful when dealing with the complement pathway because of its important role in controlling infections and that deficiencies in complement can lead to a high risk of infections. If we fast-forward to the year 2007, the first anti─complement C5 therapy―namely eculizumab― became available as a treatment for patients with paroxysmal nocturnal hemoglobinuria. Healthcare professionals were concerned that there would be a very high risk of infections with eculizumab, and thankfully that has not been the case. Can I say that there is no risk with long-term use of sutimlimab? Of course not, but it is also true that now we have much better vaccines and antibiotics to mitigate and manage infections. And it is safe to leave it at that.

Would you “space out” the dosing of sutimlimab longer than every 2 weeks after obtaining a good response?

Deva Sharma, MD, MS:
I personally do not have experience spacing them out. 

David Dingli, MD, PhD:
I have had situations where for logistic reasons the patient was not able to strictly follow the 14-day rule and I have not seen many issues to date. I obviously try to get them back on schedule as much as possible. 
I have also had a patient whose dose was delayed by a week, and we did not see a significant change in the hemoglobin. An audience member commented during the symposium that if you miss 1 sutimlimab dose during maintenance, you may not see a large effect, but if you miss doses regularly, the “track levels” will decrease and eventually lead to a breakthrough. Again, missing 1 dose is one thing but spacing out infusions may have potentially disastrous consequences (eg, severe hemolysis, free fall in hemoglobin without EPO response). Remember that the EPO response only kicks in when there is a very low hemoglobin level. So, most experts would advise against spacing the dose, but if a patient misses a dose you must watch for breakthrough hemolysis carefully. 

Catherine M. Broome, MD:
I agree. I am also not an advocate for changing the dosing interval of sutimlimab, knowing what we know about complement inhibition and the mechanism of sutimlimab. And as Dr Dingli said earlier, patients will miss a dose here and there sometimes because of travel or other life circumstances. I must say that in the clinical trial experience, during the washout period, patients did in fact have a resumption of hemolysis after missing their dose and this is something to be mindful of.

Your Thoughts?

What are your thoughts and questions on expert management of patients with CAD using novel anti-complement therapies? Answer the polling question and join the conversation by posting a comment in the discussion section below.

Continue

Poll

1.

Which of the following topics would you like to learn more about for patients with signs or symptoms of cold agglutinin disease?

Submit