Q: How is refractory ITP treated in clinical practice?

If you say that a patient is treatment refractory, to me that is referring to a patient who did not go into remission when given a short course of steroids or a TPO-RA. If we consider refractory as meaning that he or she did not immediately go into a response or was not able to taper off steroids quickly, then TPO-RA really should be where you go. Again, splenectomy is now far down on the list. If we are going to talk about only people who did not have a good response from the TPO-RA or they are having problems with it, then we start getting into these other immunosuppressive agents (eg, mycophenolate, sirolimus, azathioprine, danazol, cyclophosphamide). In the International Consensus that was written, treatments were listed in alphabetical order because there are no head-to-head trials for any of these treatments. Therefore, treatment consists of going down the list and trying things until you happen to hit something that works. Unfortunately, there is no way to tell what is going to work with any of these treatment-refractory patients. I would love to say that I have figured out that “this patient needs this” and “this patient will respond to that,” but it basically becomes trial and error once you have gone through corticosteroids, intravenous immunoglobulin (IVIg), TPO-RA, and anti-CD20. If you are trying to avoid splenectomy, it is really trial and error to see what a treatment-refractory patient may respond to. Keep in mind that if patients donot respond to corticosteroids or IVIg, you have to completely rethink this diagnosis because you really have to have some kind of response to steroids or IVIg before you are willing to really call it ITP. In patients who have low platelet counts but not low enough to really treat them, you do not want to give them steroids just to prove the point, but, at the same time, you have to watch them really carefully because you may be dealing with something much different than ITP.

This is a very complex question because it just depends on how you are going to define refractory. The International Working Group defined refractory as failing splenectomy and other treatments, but refractory could mean that you cannot have a long-term unmaintained remission. Specifically, this could mean failing to induce an absolute remission or failing to respond adequately to medical therapy. There are disorders that are not ITP, but they respond to treatment with a TPO-RA. Failing splenectomy should not be the only criterion to define treatment-refractory ITP because there are a lot of patients who fail splenectomy, and it may be very determined by age and other factors. Since splenectomy is less commonly being used, we have to reassess what refractory actually is. I narrow refractory now to patients who do not respond to most of the well-established immune modulator agents such as steroids and IVIg, and even some agents such as azathioprine or mycophenolate. Treatment-refractory patients who are not responding to standard immune modulation make me consider that either there is another disease or there is a very strong T-cell–mediated disorder, meaning that there are some patients who appear to have a synthetic problem and it is predominately mediated by the T cell.  

I wrote an article with Cindy E. Neunert, MD, from Columbia University, on a tiered approach to treatment in patients with treatment-refractory ITP, and that is my practice. I really do not have much to add to what it says because it is what I do. The article, titled ͞How I Treat Refractory Immune Thrombocytopenia͟ and published in 2016 in Blood, provides a summary of my response to the management of children and adults with treatment-refractory ITP. It states that, in my practice, we do as follows:

“We begin with a critical reassessment of the diagnosis and a deliberate attempt to exclude nonautoimmune causes of thrombocytopenia and secondary ITP. For patients in whom the diagnosis is affirmed, we consider observation without treatment. Observation is appropriate for most asymptomatic patients with a platelet count of 20 to 30 × 10⁹/L or higher. We use a tiered approach to treat patients who require therapy to increase the platelet count. Tier 1 options (rituximab, thrombopoietin receptor agonists, low-dose corticosteroids) have a relatively favorable therapeutic index. We exhaust all Tier 1 options before proceeding to Tier 2, which comprises a host of immunosuppressive agents with relatively lower response rates and/or greater toxicity. We often prescribe Tier 2 drugs not alone but in combination with a Tier 1 or a second Tier 2 drug with a different mechanism of action. We reserve Tier 3 strategies, which are of uncertain benefit and/or high toxicity with little supporting evidence, for the rare patient with serious bleeding who does not respond to Tier 1 and Tier 2 therapies.”

TABLE