As treatment options continue to improve and evolve, many haematologists are looking towards the use of combination therapies when treating Immune Thrombocytopenia (ITP).
What is combination therapy?
Combination therapy is the use of two or more drugs together from different drug classes in an effort to improve response. A response can include either an increase in platelet counts and/or reduce active bleeding.
Classes of drugs
Treatment for ITP broadly falls into three classes:
- Surgery – splenectomy is the oldest established treatment for ITP, and despite its decreasing use in modern times, due to more effective medical treatments, it remains a good option in certain circumstances.
- Drugs aimed at increasing platelet production – the thrombopoietin receptor agonists or TPORAs, which include eltrombopag, avatrombopag and romiplostim, are the drugs that have been best studied in treating ITP. Other lesser-used drugs also fall within this broad group, including danazol.
- Drugs aimed at decreasing platelet destruction – which are broadly immunosuppressive. These include steroids prednis(ol)one, dexamethasone, rituximab, mycophenolate (MMF), sirolimus and a host of other lesser-used drugs, in addition to a wide range of newer treatments currently under development in clinical trials. Immunosuppressive drugs generally dampen the immune system. In health, the immune system functions to fight off infections and develop memory to prevent repeated infections by the same bugs, but in autoimmune diseases such as ITP, the immune system has made an error in attacking “self” cells – platelets and their bone marrow parents, the megakaryocytes. Thus dampening the immune system can help.
What are the potential benefits of combination therapies?
Sometimes when drugs are used together, they have a “synergistic” effect. This means that the benefits are multiplied, rather than just being additive. An example of synergy is that drug X increases platelet count by 10 & drug Y increases platelet count by 10. An additive benefit of the two drugs would be an increase by 20, but a synergistic effect might be an increase by 100.
Generally speaking, the more drugs someone takes, the more “side effects” they might experience. However, with a synergistic effect it is often possible to use lower doses than might be used when the drugs are used individually, thus reducing potential side effects. Typically, a drug increasing platelet production will be combined with one or more drugs which decrease platelet destruction.
Clinical trials
The evidence base for treatment decisions in ITP is growing as the result of an increase in clinical trials over the past 20 years, with most clinical trials looking at the outcome of adding a single new treatment.
When reading reports on clinical trials, there is commonly a reference to previous “lines of therapy” used to treat people before starting the study drug. A line of therapy refers to particular treatment, typically a period of time spent on a drug, often with escalation to maximal dose, failure to respond, or loss of response, before moving on to another treatment (line).
In some reports, more than 10 lines of therapy have been used, suggesting that a person who has progressed through this treatment has very refractory (not responding to treatment) disease.
The problem with the approach of moving from one drug to the next is that drugs that have been tried previously are labelled as failures and may not be considered as useful in future treatment.
When combination therapy should be considered
As an ITP specialist, I see patients who have been treated without success despite multiple lines of therapy. The first consideration is to ensure that the diagnosis of ITP is correct. The next step is to check that any previous treatment has been given at a sufficient dose for long enough. Then the issue of combination therapy can come into play.
In my practice, I would add an immunosuppressive drug to a TPORA if escalation to maximum dose has not resulted in improved platelet counts. It is often possible to use low doses of immunosuppression (eg prednisolone 2.5 – 5mg daily) to convert a non-responder to a responder and the dose of TPORA can often be reduced. Drugs such as mycophenolate or sirolimus can be used instead of, or in addition to steroids, if necessary.
Another role for combination therapy
Another potential opportunity for combination therapy is in people on TPORAs who have big swings in the platelet count, even on a stable dose. While this isn’t always a problem, the addition of an immunosuppressive drug at low dose can sometimes iron out this variability in response.
In my experience, there are very few people with ITP who cannot be managed with readily available treatments, used in combination, if necessary. This has led to some difficulty in recruiting people with chronic ITP onto clinical trials, but trial enrolment is another possibility, for those who have responded poorly to previous treatments and can access trial centres.
There are specific issues with some immunosuppressive drugs used long term, which treating doctors and ITP patients taking the drugs should be aware of. There is too much detail to go into in this article, but I think ideally ITP patients on long term combination therapy should be treated by a haematologist who is willing to liaise closely with an an ITP specialist, or be managed directly by an ITP specialist.
The unmet need in ITP at present is to design better treatments for newly diagnosed ITP so that the disease is cured before progressing to the chronic stage. It seems most likely that some form of combination therapy might be the best approach. The UK FLIGHT study found that combining two immunosuppressive drugs (steroids and mycophenolate) resulted in less people progressing to chronic ITP on the combination arm than those treated with steroids alone. Other trials looking at promising experimental drugs in newly diagnosed ITP are currently underway.
In conclusion
As we continue to explore and understand the complexities of Immune Thrombocytopenia (ITP), the potential of combination therapy offers a promising avenue for treatment. By leveraging the synergistic effects of combining different drug classes, there is hope for achieving better patient outcomes with fewer side effects. While the current evidence base for combination therapies is limited, the positive results seen in clinical practice and early trials suggest that this approach could play a crucial role in managing ITP, especially for those with refractory disease.
Ongoing research and clinical trials will be essential in refining these strategies and developing more effective treatments. The goal is not only to manage ITP but to find ways to prevent its progression to the chronic stage, ultimately improving the quality of life for patients. Collaboration between haematologists and ITP specialists will be key in ensuring that patients receive the best possible care. As the landscape of ITP treatment evolves, combination therapy stands out as a beacon of hope for many patients and their healthcare providers.
Author: Dr Robert Bird, Haematologist and ITP Australia and New Zealand Medical Advisor