What Is the Optimal Treatment of ITP?

Cindy Neunert, MD
Department of Pediatrics, Division of Pediatric Hematology, Oncology, and Stem Cell Transplantation, Columbia University Herbert Irving Comprehensive Cancer Center
James B. Bussel, MD
Professor Emeritus of Pediatrics, Weill Cornell Medical College

In recent years, the number of treatment options available for patients with immune thrombocytopenia (ITP) has expanded. In addition to the classical trio of corticosteroids, intravenous immunoglobulin, and splenectomy, choices now include rituximab, thrombopoietin receptor agonists (TPO-RAs), and the tyrosine kinase inhibitor fostamatinib. However, a lack of randomized clinical trials evaluating the management of ITP has led to significant variation in practice patterns and lack of consensus regarding treatment options.

In 2019, the American Society of Hematology (ASH) updated its Clinical Practice Guidelines for ITP, in an effort led by Cindy Neunert, MD, of Columbia University Herbert Irving Comprehensive Cancer Center. Although the guidelines included 21 recommendations on the management of ITP in adults and children, the expert panel concluded that there was a “lack of evidence to support strong recommendations for various management approaches.”1

In this edition of Drawing First Blood, ASH Clinical News invited Dr. Neunert and James B. Bussel, MD, of Weill Cornell Medicine, to debate treatment options, with Dr. Neunert favoring novel treatment options like TPO-RAs and rituximab, and Dr. Bussel arguing on behalf of splenectomy. Drs. Neunert and Bussel also discuss some of the pros and cons of each option that should be weighed in shared decision-making with patients.

Cindy Neunert, MD: There is debate surrounding the optimal treatment for ITP and when to start treatment. Most guidelines for adult patients with ITP recommend initiating treatment when a platelet count is less than 20 to 30×109/L. However, this recommendation is based on limited, if any, evidence. There may be a subset of patients who would not require treatment even below this level.

James B. Bussel, MD: In my experience, most people are treated when levels are less than 30×109/L, but there are no real data either way to support a higher or lower threshold. The ASH guidelines also differentiate hospitalization in someone newly diagnosed with ITP and a patient with whom you are familiar. With a new ITP diagnosis, you do not yet know how he/she will respond to treatment or what his/her bleeding pattern will be.

Dr. Neunert: Yes, that distinction is important for the issue of hospitalization. We do not want patients to have to sit in the hospital until their platelet count recovers, but we do want to eliminate any concerns about follow-up and treatment adherence to ensure that they will not develop bleeding.

Dr. Bussel: It is also important that these patients are getting to see specialists who are familiar with ITP. A 2015 study, for example, found that about one-quarter of patients with ITP were receiving platelet transfusions, which is almost certainly unnecessary.2

Dr. Neunert: Yes, many newly diagnosed patients are managed by ER doctors and internal medicine hospitalists rather than hematologists. There are nuances to ITP treatments, which is why it is important for patients to follow up with clinicians who have experience with this condition.

Dr. Bussel: Before we debate the roles of splenectomy and newer agents, we should clarify that both the ASH Clinical Practice Guidelines for ITP and the International Consensus Report state that steroids in any form should be discontinued after 12 weeks.3 The toxicity definitely outweighs the benefits with longer use. This is especially true now that there are several good second-line treatments to consider.

Dr. Neunert: For patients with corticosteroid-dependent ITP or whose disease was unresponsive to corticosteroids, second-line options include splenectomy, rituximab, TPO-RAs, and, most recently, fostamatinib. At first, people were hopeful that rituximab would be a “magic bullet” for everyone with ITP; initially reported response rates were high, but, as we have seen, many patients do not respond or lose response over time.

However, rituximab has many benefits, including the fact that there is no need for ongoing therapy. A proportion of patients who receive rituximab will have a good and durable response. If the response isn’t indefinite, it may at least let them live ITP-free for a year or more. Rituximab is a good option for use in a patient who wants to avoid splenectomy. There also are data showing that certain groups of patients respond better to rituximab, such as young women.

Dr. Bussel: To my knowledge, the better responses in younger women has been established in three studies of women of child-bearing age.4,5,6

Dr. Neunert: Yes, those data have definitely influenced my practice and use of rituximab. It is important, however, to also look at the potential side effects of this treatment. In the pediatric realm, I know that persistent hypogammaglobulinemia is a concern.

Dr. Bussel: There is a long list of possible side effects associated with rituximab. Certainly, the first one that comes to mind is infusion reactions. In our sequential study of steroid premedication with rituximab, we showed these could largely be eliminated.7 Patients tended not to experience fever or chills if they were given a steroid with rituximab.

Hypogammaglobulinemia is a tricky topic. It would be better understood if, on every study, patients’ immunoglobulin levels were measured before and after treatment. In our 2004 study of rituximab, none of the participants became hypogammaglobulinemic; a 2006 study of children and adolescents treated with rituximab again showed that no child became significantly hypogammaglobulinemic.7,8

However, in a 2018 study, investigators found many cases of serious hypogammaglobulinemia with rituximab, contributing to the perception that hypogammaglobulinemia and infection is a big problem.9 It seems to occur more often in patients who are hypogammaglobulinemic to start with and in those receiving dexamethasone.10

Dr. Neunert: As long as hepatitis B serology is checked, I don’t think infection is a big concern with rituximab. I understand the hesitancy about rituximab in the pediatric world. In the adult setting, though, I cannot figure out why there seems to be a push to move away from rituximab and more toward the TPO-RAs.

TPO-RAs are an attractive option for some patients because their side effect profile is more palatable than rituximab or splenectomy. The downside that we all recognize is that once a patient discontinues the medicine, platelet counts tend to go back down. Some patients are able to come off TPOs and maintain a higher platelet count than what they had going into therapy, but that is not common; we don’t know if that count will be satisfactory enough to remain off drug and have a good quality of life. An “adequate” platelet count is different for every patient.

Dr. Bussel: We also have few long-term data for these agents. One study showed that some patients had a sustained response after discontinuing eltrombopag, but the median follow-up was just nine months.11

Dr. Neunert: Yes, we must be cautious when discussing what happens to patients when they come off TPO-RA treatment. Platelet counts can still fluctuate widely, even while taking a TPO-RA.

Dr. Bussel: There is a lot of mishandling of TPO-RAs. I believe people try to adhere too carefully to the package insert, which is wrong. I am referring here to the plan of holding the treatment if the count is greater than 400×109/L, which can then result in a rebound very low count a week later.

Dr. Neunert: The package insert should be revised. I also don’t always push the drug to hit a platelet count of 50×109/L.

The other elephant in the room is the lack of data on the overall costs of these different treatment pathways. Whether that should factor into our decision-making with an individual patient is a discussion for another time, but there is clearly a cost difference between chronic therapy with TPO-RA, short-term infusion of rituximab, and one-time surgery with splenectomy.

Dr. Bussel: The advantages of splenectomy are clear: It is the treatment option for ITP with the greatest curative potential. When I discuss splenectomy with patients, I hold up five fingers and say, “One person will not respond to splenectomy.” I lower one finger then continue, “One person will relapse,” and I take a second finger down. I leave the other three fingers up to illustrate the durable response rate of roughly 60%.

If you look at a systematic review of 135 case series between 1966 and 2004, the complete response rate to splenectomy was 66%.12 Of course, people were undergoing splenectomy relatively early in the disease course when that study was conducted, since rituximab and TPO-RAs were not options. If you wait one year to perform splenectomy, as is recommended in the ASH guidelines and the International Consensus Report, people might get better anyway, and the surgery becomes unnecessary. Either way, I don’t think the 60% number is that far off.

Dr. Neunert: Yes, approximately one in five patients will not respond to splenectomy and one in five will have a disease relapse, but the problem is getting longitudinal data on these patients. That is one of the biggest limitations we have in ITP management. We don’t know who ends up in remission and for how long. We don’t know who recovered or who had to continue on to a different treatment pathway. We tried to collect those data in a study of the Dallas ITP Cohort and even getting 6- and 12-month follow-up was difficult.13

I agree about some of the patients in those early cohorts in the systematic review study getting better on their own, and I would like to see what response rates look like in a modern cohort.

Dr. Bussel: I’d also note that, even when successful, there are risks to splenectomy. There are three agreed-upon risks: The first is what happens at surgery, which can include infection, bleeding, and thrombosis. While all of those are infrequent with splenectomy for ITP compared to splenectomy for some other indications such as myeloproliferative neoplasms, the risk is not zero. The second, and perhaps the most talked about, risk is developing sepsis after the spleen is removed. The risk is a little unclear, but is certainly very low – somewhere around 2%, with a mortality rate of 1%.

Dr. Neunert: But that is when we hear of it happening. We almost always learn about sepsis anecdotally because many adults never have follow-up for splenectomy status.

Dr. Bussel: The last risk is thrombosis. Studies have shown an approximately 1.5 times higher long-term risk for stroke in splenectomized patients, compared with disease-matched patients.14

Dr. Neunert: Yes, there are two time periods of concern for thrombosis: immediately postoperative and later on – a delayed risk. In one review of splenectomy, the thrombosis risk seemed lower in ITP than in other settings where splenectomy is done.15

Dr. Bussel: Without question, thrombosis risk is higher in settings such as hemolytic anemia than it is in ITP.

When thinking about the pros and cons of the ITP treatment pathways, the biggest challenge is that we still don’t have markers that objectively distinguish patient A from patient B. We don’t have studies that say, “This patient is going to develop chronic disease and this one isn’t. This patient is going to bleed and this one isn’t. This patient will respond to treatment ‘X’ and this one will not.” In leukemia, for example, cytogenetic and molecular genetic markers, histochemistry, and flow cytometry let clinicians divide patients into categories of disease. We aren’t at that point in ITP.

Dr. Neunert: I agree. It’s disappointing that we do not have many good biologic markers. We also lack cost-effectiveness data and comparative outcome studies. In ITP, we may not be able to compare treatments in a randomized trial, but we need to at least find a way to compare them appropriately. Right now, we don’t have that ability in any way, shape, or form.

Dr. Bussel: Let’s not be too negative, though. There are many good single-arm or placebo-controlled trials that indicate what will and won’t happen with certain treatments, which can be used as, at least, some basis for decisions about what to use in whom. Furthermore, there are newer approved (fostamatinib and avatrombopag) and investigational treatments, such as FcRn inhibitors and Bruton tyrosine kinase inhibitors, that may provide additional benefit in certain patients.

Still, there is absolutely no question that we need better comparative studies and better biomarkers. Hopefully, these will happen in the next few years.


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