Monday, 19 February 2018

Risk of haemolytic anaemia after alemtuzumab

Alemtuzumab use has been associated with the development of secondary autoimmunities.

Antibodies to Red blood cells can be one of these



di Ioia M, Farina D, di Tommaso V, Travaglini D, Pietrolongo E, Onofrj M, de Luca G. Simultaneous early-onset severe autoimmune haemolytic anemia and albuminuria during alemtuzumab treatment for multiple sclerosis. Mult Scler. 2018 Jan 1:1352458517743093. doi: 10.1177/1352458517743093. [Epub ahead of print]


BACKGROUNDAlemtuzumab, approved for multiple sclerosis (MS), can cause secondary autoimmune adverse events including thyroid disorders, immune thrombocytopenia (ITP), and glomerular nephropathies. Non-ITP autoimmune cytopenias are rarely reported.

OBJECTIVE:

To report a case of autoimmune hemolytic anemia (AIHA) and nephropathy in a MS patient treated with alemtuzumab.

CASE REPORT:

A 34-year-old man with MS developed albuminuria and AIHA after the first and only alemtuzumab treatment, with positive Coombs' direct and indirect tests and IgG autoantibodies. Both AIHA and nephropathy resolved 1 month after treatment with steroids and intravenous immunoglobulins.

CONCLUSION:

Our report adds to the literature on AIHA and nephropathy after alemtuzumab treatment and suggests to add Coombs' tests to the screening panel required for alemtuzumab treatment.

Meunier B, Rico A, Seguier J, Boutiere C, Ebbo M, Harle JR, Schleinitz N, Pelletier J. Life-threatening autoimmune warm haemolytic anemia following treatment for multiple sclerosis with alemtuzumab. Mult Scler. 2018 1352458517729766. doi: 10.1177/1352458517729766. [Epub ahead of print]

BACKGROUND: Alemtuzumab is a humanized monoclonal antibody directed at CD52 approved as a disease-modifying therapy for relapsing forms of multiple sclerosis (MS).


OBJECTIVE: To describe a case of a life-threatening autoimmune anemia occurring after a first course of alemtuzumab for relapsing-remitting MS in a 28-year-old male.


METHODS: Case report.


RESULTS: A 28-year-old male developed a life-threatening autoimmune anemia occurring 11 months after first alemtuzumab course.


CONCLUSION: We report the third case of autoimmune haemolytic anemia following treatment with alemtuzumab in a young MS patient. Due to the severity of this adverse event, neurologists using this treatment should be alert.

Haemolytic anemia or haemolytic anaemia is a form of anemia due to haemolysis, the abnormal breakdown of red blood cells (RBCs), either in the blood vessels (intravascular hemolysis) or elsewhere in the human body (extravascular, but usually in the spleen). It has numerous possible consequences, ranging from relatively harmless to life-threatening.

Symptoms of haemolytic anaemia are similar to other forms of anaemia (fatigue and shortness of breath), but in addition, the breakdown of red cells leads to jaundice.
Chronic haemolysis leads to an increased excretion of bilirubin into the biliary tract, which in turn may lead to gallstones. The continuous release of free haemoglobin has been linked with the development of pulmonary hypertension (increased pressure over the pulmonary artery); this, in turn, leads to episodes of syncope (fainting), chest pain, and progressive breathlessness. Pulmonary hypertension eventually causes right ventricular heart failure, the symptoms of which are peripheral oedema (fluid accumulation in the skin of the legs) and ascites (fluid accumulation in the abdominal cavity).
Coombs test (also known as antiglobulin test or AGT) The direct Coombs test is used to test for autoimmune hemolytic anemia; i.e., a condition of a low count of red blood cells (RBCs) caused by immune system lysis or breaking of RBC membranes causing RBC destruction. In certain diseases or conditions, an individual's blood may contain IgG antibodies that can specifically bind to antigens on the RBC surface membrane, and their circulating RBCs can become coated with IgG alloantibodies and/or IgG autoantibodies. Complement proteins may subsequently bind to the bound antibodies and cause RBC destruction. The direct Coombs test is used to detect the antibodies or complement proteins that are bound to the surface of red blood cells; a blood sample is taken and the RBCs are washed (removing the patient's own plasma) and then incubated with anti-human globulin (also known as "Coombs reagent"). If this produces agglutination of RBCs, the direct Coombs test is positive, a visual indication that antibodies (and/or complement proteins) are bound to the surface of red blood cells.

16 comments:

  1. What does the Barts MS clinic think of the suggestion of "adding Coombs' tests to the screening panel required for alemtuzumab treatment." Wouldn't the early signs of this condition be caught with the regular blood tests that are administered to persons receiving alumtuzumab? Or will the clinic add tests for Coombs' antibodies to the current regime of monthly blood tests?

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  2. Prof Larry Steinman's description of alemtuzumab use in MS as 'nuclear bombing the immune system' keeps becoming more and more accurate
    (In a talk to PwMS many years ago, when alemtuzumab was an exciting new drug in the pipeline)

    Which isn't too say that it isn't the best option at times

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    1. The Americans do not like Alemtuzumab, hence it is a third line there, it is a first line in Europe

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    2. Nuclear bombing as opposed to carpet bombing every month for ever.:-)

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  3. We keep being drip fed about the risks of Alemtuzumab without any balance. A high proportion of those with active disease go into long term remission (no relapses and no progression). My clinic who administered my infusions were excellent - they run through all the risks and what to do if I had any concerns. The monitoring picked up a thyroid issue a year or so after the second infusion. The issue was effectively addressed. I'm 14 years out from my second infusion and still no relapses or change in EDSS. I have yearly clinic appointments where they take bloods and give me an EDSS test. Also have an annual MRI. This drug comes with the risk of some side effects, but they can be picked up by monitoring and sorted out. The recipient must also be responsible for monitoring any changes in their health and reporting them to the clinician. I think Prof Steinman was involved in the development of Tysabri - pity he didn't spot the issue of PML (which can be a truly dreadful side-effect). Barts seem to have a downer on Alemtuzumab. Perhaps it's because it was developed at a rival centre or that their own Oral Cladribine was very slow out of the blocks and I suspect not as highly effective as Alemtuzumab. MS is a dreadful disease and I'm happy I took the nuclear option. It's not for everyone, but good clinics will know the risks, monitor for them, and treat as required.

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    1. Really glad Alemtuzumab is working out for you but the data from the Alemtuzumab trials has revealed very interesting potential mechanisms in the development of autoimmunity, as noted by Larry Steinman (who couldn't have foreseen the PML problem with Tysabri, no-one could until it was used widely a in a clinical setting). Some of the potential side-effects, though not as common as Grave's disease can be rather more serious. As to having a downer on Alemtuzumab, well not really, any highly effective MS treatment is to be rightly celebrated but we have been concerned that a lot of data concerning side-effects, lymphocyte re-population data and the development of neutralising antibodies which will limit efficacy have not been made clear and in my opinion in a deliberately obfuscatory manner. They now have thanks to the efforts of team G and FOI. Now we can truly appreciate how alemtuzumab (and other highly effective DMTs works, again thanks to FOI, revealing the central importance of hitting the memory b cell population) we can better target therapy to hit this population specifically, leaving more of the immune system intact, rather than the "glyphosate" option.
      Concerning Cladribine, I would remind you of the fable of the tortoise and the hare ;-)

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    2. You all know the potential for the long term benefits of alemtuzumab there is an ample literature on this. We have reported on the 5-7 yeat follow up also.

      "Barts have a downer"....not at all.....Barts was the largest recruiters for the trial outside of Cambridge and were involved in getting the drug through the regulatory hurdles when Cambridge went on sabbatical during this process. ProfG played a big part in Alemtuzumab getting a first line licence

      Likewise we were the ones asking about neutralizing antibodies, when we saw the drug failing in one of our patients which it does for some people. We were told more than once by different people that they did not occur....This was simply not true

      We have exposed the fact, as we should not have to ferret around the internet to find the information, that they do and you will get more studies on this.


      Indeed I now wonder whether neutralizing antibodies were at the heart of the dosing schedule used, knowing that it took a year for the titres of neutralizing antibodies to disapate and they would become more problematic after two treatment cycles....Is this a conspiracy theory. I am sorry I believe it should have been repoorted.

      I likewise believe that the neutralizing antibodies and the autoimmunities are a product of a similar process i.e. tolerance blockade and we are investigating this and we are reporting on this.


      Again I believe that we & you have been misled by the information reported. If we can understand how the autoimmunity develops maybe we may be able to limit it, making alemtuzumab a better drug.

      However if the other drugs work in a similar way, which they seem to, but lack the side effects we will have "natural selection"

      Anyway to your point, you monitor what you know what to look for, these case reports are examples warning people to be keep their eyes open.

      Oral cladribine may not be as effective...maybe... as one is limiting the amount of lymphopenia in the trials this was about 25% of cladribine verse over 80% severe lymphopenia for alemtuzumab. Hidden within the lymphopenia is the mechanism of action, but can you be more surgical on which cells to target.

      We will drip feed the risks of ocrelizumab and cladribine as they arrive.

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    3. One of my favourite bits of art work

      https://multiple-sclerosis-research.blogspot.com/2015/01/your-view-of-progress-on-progression.html

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    4. What happened with CAM-THY.
      Is this data being hidden?

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    5. I dont know

      However negative data is hard to publish it has been two years since the trial stopped according to website.

      We know that the trial was halted...this could be because it didn't work or made things worse.

      The ANN presentation didnt showsany data but the abstract suggests the methodology was wrong as the drug didn't do what it was supposed to do.

      We predicted the idea was wrong based on the suggestion that regulatory T cells are depleted not increased.

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    6. Yes the annual grant reports to the MRC:-)

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  4. Hi MD..have read this and other posts re Alemtuzumab you have written recently and trying to understand what it all means..I had Alemtuzumab in the summer and my lymphocyte count before treatment was 2.7, one month after treatment it was 0.4 and two months later 1.0. Does that mean it didn't work me? Did I repopulate to normal range levels too quickly? I'm still at about 1.0 six months later..I am not really told anything and am just trying to figure out until my next appointment in the summer.

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    1. Without differential cell counts it is hard to know what returned

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  5. CD20 cell: God, how I regret allowing them to infuse me with this s...t. Alemtuzumab should be off the market and pronto, there are better alternatives.

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