How ATG and ciclosporin treat aplastic anaemia

Why calming the immune system can help marrow recover

In acquired aplastic anaemia, the bone marrow stops making enough blood cells largely because the immune system attacks the stem cells that would make them. Treatments that suppress the immune system aim to stop that attack, so that whatever stem cells remain get the chance to recover and rebuild blood production.

This page covers three medicines that are often discussed together: antithymocyte globulin (ATG), ciclosporin and eltrombopag. It explains what each involves and what the trial evidence shows. The wider picture of options is in the treatment overview.

Antithymocyte globulin: a course given in hospital

ATG is a preparation of antibodies that suppress T cells, the immune cells thought to drive the attack on the marrow. Horse ATG is the standard first-line form in current UK guidance, and it is made by immunising horses with human lymphocytes. In a randomised trial, rabbit ATG was less effective than horse ATG, so horse ATG remains the usual choice.

Treatment is given in hospital, usually for up to three weeks, through a central line. Each daily dose runs as a slow infusion over 12 to 18 hours, and the first dose is preceded by a test dose given over an hour so that a serious allergy can be spotted early. Blood counts are checked before each day's dose, and transfusions may come first if levels are low, as explained in blood and platelet transfusions. The Aplastic Anaemia Trust fact sheet on ATG describes the stay in detail.

Reactions are common enough that they are planned for. Rashes, shivering, fevers, fluid retention and changes in blood pressure are the most frequent, so antihistamines and steroids are given before doses to reduce them. Serious allergic reactions are rare, at under 1% of people, and the team will stop the dose straight away if one starts.

Some people develop serum sickness, a delayed immune reaction, after the course has finished. Steroid treatment is started on the first day to reduce both the immediate reactions and the later risk, and the team may keep people in hospital for a while or manage them as outpatients. ATG can also lower platelet counts while it is given, so platelet transfusions are often needed in the weeks that follow.

Ciclosporin: a long course that needs regular checks

Ciclosporin is an immunosuppressant usually taken by mouth, and in aplastic anaemia it is normally given alongside ATG. It can also be given on its own, according to the same Aplastic Anaemia Trust fact sheet. Because it holds back the immune system for a long period, blood tests are repeated throughout treatment to check kidney and liver function.

Blood pressure is also monitored, because ciclosporin can make it rise. Some of the most common side effects are visible and can be surprising. The gums may become slightly enlarged or sore, and hair growth can increase. Headache, shaky hands, feeling sick and a reduced appetite are also commonly reported, according to North Bristol NHS Trust's ciclosporin leaflet.

That leaflet was written for people taking ciclosporin for ulcerative colitis, so its dosing and duration advice does not carry over to aplastic anaemia. The side effects it lists are general enough to be useful here, and your team will give you the details for your own treatment.

Adding eltrombopag to the standard combination

Eltrombopag is an oral medicine that acts on the thrombopoietin receptor. It was first studied in people whose aplastic anaemia had stopped responding to immunosuppression, and researchers then tested it as a first treatment. The thinking is that it helps the small number of stem and progenitor cells that remain to make blood.

The phase 3 RACE trial randomised people with previously untreated severe aplastic anaemia to horse ATG and ciclosporin, with or without eltrombopag. Adding eltrombopag improved the rate, speed and strength of blood count recovery, without additional toxic effects. It was started on day 14, partly to avoid cumulative toxicity from giving it alongside ATG.

The earlier single-group study, reported by Townsley and colleagues in the New England Journal of Medicine, found a complete response rate of 58% by six months in the group that started eltrombopag on day 1, compared with 10% in a historical comparison group. Because that comparison was with earlier patients rather than a randomised group, it is weaker evidence, and the randomised trial is the firmer guide.

Guidance has moved in the same direction. The 2024 British Society for Haematology guideline lists horse ATG and ciclosporin with eltrombopag, or a transplant from a matched sibling donor, as standard first-line treatment for newly diagnosed severe or very severe acquired aplastic anaemia. Some older patient information still describes eltrombopag as a later option, so it is worth asking your team what they recommend for you.

How long a response takes

Recovery is slow and is measured in months. According to The Aplastic Anaemia Trust, ATG usually takes three to six months to show an effect on blood counts, and around two in three people respond to it. Red cells, white cells and platelets can stay low during that time, which is why transfusions and infection precautions often continue at home.

Trial data suggest that eltrombopag may shorten the wait. In the randomised trial, the median time to first response was shorter in the eltrombopag group. In the earlier study, the average time to transfusion independence was about one month, and most partial and complete responses were present by three months. These are trial figures, so the timing for any one person can differ.

Relapse and clonal evolution, in plain terms

A relapse means blood counts fall again after an earlier response. Clonal evolution is a slower process. Over the years, some blood stem cells acquire changes that let one line expand, and in a minority of people this can develop into a myeloid condition such as myelodysplastic syndrome or acute myeloid leukaemia.

The risk is real, and it varies from person to person. The median time to clonal evolution after immunosuppressive therapy is four to six years, according to Townsley and colleagues. The RACE trial reports that myeloid malignant transformation usually appears in 10 to 15% of people five to 10 years after diagnosis. People who reach a strong blood count response have fewer complications, particularly relapse and clonal evolution, than those who do not.

Some people also have small blood cell clones that show up on testing. In RACE, eltrombopag did not select for growth of clones linked to paroxysmal nocturnal haemoglobinuria more than standard treatment did, and clones did not appear to hurt response or two-year outcomes. Anything unexpected on a blood test is worth discussing with your team, and the PNH page explains that condition in more detail.

Who these treatments suit

The choice depends on how severe the disease is, the person's age, and whether a well-matched donor is available. The BSH guideline also says that a transplant from an unrelated donor should be considered if immunosuppression fails, and sometimes straight away for younger adults with serious infections and a readily available unrelated donor. Older adults and people who are pregnant need special attention, and the guideline recommends discussion in specialist centres.

In the RACE trial, people with severe disease responded better than those with very severe disease, and people under 40 were more likely to respond. Those are patterns across a group, not predictions for one person. The stem cell transplant page covers the other route in more detail. Whether this combination suits you is a question for your haematology team, who know your counts and history.

Many people also find the months of treatment easier with support from the wider care team, and that team can point to what is available locally.

Immunosuppression buys marrow time, and that time is measured in months