 An important takeaway is that ITP is a heterogeneous disorder. There are different ways to treat it in the up-front and relapsed setting, so there’s no right way to do it. As we look at new and immersion therapies, we’re finding further evidence of the heterogeneity of this disease, seeing that there are subsets of patients who respond to complement inhibition, etc. We have our work cut out for us in the coming years as we figure out how to best treat our patients with ITP.

The most important takeaway message in ITP is that the disease is so heterogeneous that we need robust clinical trials. In my opinion, every patient who has the diagnosis of ITP should be placed into some prospective randomized controlled trial and a registry. This registry should look at biomarkers. It should be a biorepository so we can have a genetic as well as tissue examination. No patient in this country should be diagnosed and treated without being placed or considered to be placed into a clinical trial. We’re so far behind the Europeans and the Chinese in being able to gather data that we also have to convince the patients of the importance to participate in clinical trials. Our fellow hematologists in private practice have to appreciate that this ITP [immune thrombocytopenic purpura] is not the kind they learned about in medical school. This is a much more complicated disease, and patients deserve to be treated in a more innovative and creative manner.

One way we could do that is by better access of large databases and using existing records. If people could agree on standard things that would be evaluated in the way it was recorded, we could get there faster. Even 1 large randomized clinical trial of comparing second-line options would be amazing. I still think the biggest lesion, if you will, is our ability to define what’s in front of us. You talked about that, Craig, with what you said about the repository and genomic examination. It’s become pretty clear that it’s not as if 52% of the patients have a mutation in X and we just never saw that. It’s not impossible, but this is a multigenic disease with a number of contributing features. It will be hard to sort out, but the onus is on us to do that.

Dr Piatek, Dr Kessler, thank you very much for making this an enjoyable and fun discussion. I’ll look forward to seeing you all in the near future.

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Physicians share key takeaways from the discussion on diagnosis and treatment of immune thrombocytopenia.

Key Takeaways From Discussion

 Sutimlimab is a humanized monoclonal antibody that selectively inhibits activation of the complement pathway by binding to complement 1S. This drug, which is not approved, will be marketed by Sanofi. It was originally developed for cold agglutinin disease, for which there are very few successful approaches to treatment. Following the success in the cold agglutinin population, it was trialed in ITP [immune thrombocytopenic purpura]. The best study available with sutimlimab was reported by my colleague Dr Catherine Broome at ASH [American Society of Hematology Annual Meeting] 2020. This was a pilot phase 1 study. It included only 12 patients, but these patients were pretty beaten up. They had a median of over 4 prior failed therapies for their ITP. What was remarkable about this population is that with the treatment with sutimlimab, they had extremely rapid responses. It was much faster than what you saw even with avatrombopag, which is an even faster response than with eltrombopag. The first patient I gave to Dr Broome to treat had been refractory for years, with platelet counts running less than 10,000 per mm3. Within almost a day, her platelet count had tripled into a nondangerous area. We were so impressed.

The rest of the patients in this pilot trial also had very impressive responses, but not all developed complete responses. Eventually with some dose-response analysis, which they’re going to be doing in ongoing phase 2/3 clinical trials, we’ll be able to see some interesting responses. The importance of this study is not just the availability of a potential new agent. It also tells us about the heterogeneity of ITP and that not all ITPs are alike. Taking your point, Jim, ITP isn’t a single disease, and it has a single phenotype that we’ve relied on. Studies like this indicate that we have to be much more careful in stratifying how we use different agents for different patients.

 In the pilot study, there were very few SAEs [serious adverse events]. In fact, the patients in the study were stopped after 12 weeks and then went back to their baseline levels of very low platelet counts. If restarted on the sutimlimab, there were equally robust responses after rechallenging. Right now, this appears to be a relatively safe product. There doesn’t appear to be any increased risk of infection, which you would be concerned about by blocking any classical pathways of complement activation. I’d be very careful about making sure that these patients are adequately vaccinated prior to the initiation of this drug. Thus far, there have been no dangerous signals.

 BTK is involved in the innate and adaptive immune responses and is a signaling molecule in immune-mediated diseases. The BTK inhibitor that’s farthest along in clinical trials is rilzabrutinib. The most recent data was updated at ASH. This was a phase 1/2 study that included 45 patients treated with rilzabrutinib at 400 mg orally twice daily. These were heavily pretreated patients. The response rate was about 40%, and this was seen on the fast side, usually within 2 weeks. Of note, this BTK inhibitor doesn’t affect platelet aggregation, which has been an issue with other BTK inhibitors and would be, of course, important in consideration for patients with ITP. The most common adverse effects were diarrhea and nausea.

I’m gonna mention briefly FcRn inhibitors. There are at least 4 or 5 in trial. Some of them have had nice phase 2 studies in ITP and are in the midst of phase 3 studies with ITP. The thing that strikes me is that first, you lower the IgG levels substantially. This could be to 200 mg/dL with a lower limit of normal of a little over 600 mg/dL, yet there don’t seem to be infections. That’s explained by the fact that you’re not affecting IgA or IgM and presumably not affecting T-cell function, but all this remains to be clarified.

ITP experts discuss emerging ITP treatment landscape.

Experimental Agents for ITP

Let’s finish up talking about treatment sequencing. We talked about how rituximab might be particularly good in younger women, and it’s better earlier in the disease. Craig, if you use it later, you might still get responses, but it’s much less likely you’ll have a “curative” response. We all probably like TPO agents because, as you’ve mentioned, they have a high response rate and generally are safe. They often can be used for a long period of time. You highlighted appropriately the risk of thrombosis in that setting in anybody who’s on a TPO agent. In the EXTEND study of eltrombopag, most cases occurred within the first year, which suggested that if you had a predisposition, it would be brought out early. However, there are patients for whom it happens later. We talked about fostamatinib as another consideration. Do either of you use fostamatinib much? In what patient population? Dr Piatek, have you used fostamatinib? What’s your center’s view on that?

 Fostamatinib has a good response rate in the second-line setting, although that’s often used a little later. I use it in patients who aren’t good candidates for TPO-RAs [TPO receptor agonists]. For example, I have a patient with antiphosphate antibody syndrome with a history of PE [pulmonary embolism], so fostamatinib has been a good treatment. In practice, I’ve found that the GI [gastrointestinal] adverse effects seem to be less of an issue than have been reported. You use it in caution with somebody who has uncontrolled hypertension or wouldn’t use it in that setting. It’s a good option, particularly in patients for whom you can’t use TPO-RAs or you’re nervous about it.

Drs Piatek and Bussel discuss sequencing of therapies in ITP.

Sequencing in ITP

Craig, one of the things you’re highlighting is that we should do next-generation sequencing into marrow. Diagnosis of ITP [immune thrombocytopenia] is so primitive and pathetic. If you think of a leukemic who comes into the emergency department with thrombocytopenia, it turns out there are circulating blasts, you do this whole work-up, and divide them into 10 to 20 different types of leukemia. You have their treatment protocol all scripted out, including monitoring, and possibly things about what happens with relapse or nonresponse.

But if you take a patient with ITP who comes in, all we’ve agreed on is to do a complete CBC [complete blood count] and look at the smear. You could argue that in a younger woman there might be more autoimmunity. Craig, you were bringing up some of the issues in elderly patients. There is no consensus on which secondary ITP to look at. I think at the moment, that puts a tremendous amount of pressure on clinicians as to what subtle clues they could try teasing out, to then do a work-up for X, or Y, or Z. I think in the context of seeing patients with the clock ticking, with your next patient coming up, and if you’re late, Press Ganey [patient satisfaction surveys] will clobber you in the reviews, it’s really hard to integrate all that.

: Jim, I think you’re absolutely right that the diagnosis of ITP is often incorrect. We’ve seen and heard patients tell us about hereditary issues that turn out to be related to May-Hegglin anomaly. We’ve heard of issues where patients have had several problems, say with von Willebrand type 2B disease, as an example of misdiagnosis of ITP. You yourself have talked about many of the primitive immunologic abnormalities that are missed until they develop complications. You’re right, ITP is much more complicated than what we used to think of bread and butter hematology.

Dr Piatek, do you want to channel your inner Howard Liebman MD, hematologist here or not?

: Yes. I was going to say that another reason not to do a splenectomy would be that it might not be ITP.

Experts discuss lack of consensus in diagnosis of ITP and challenges physicians face.

Challenges With Diagnosis of ITP

We all know about steroids and IVIG [intravenous immunoglobulin] in ITP [immune thrombocytopenia] and pregnancy. With steroids, the general recommendations are to start with a lower dose and let a patient’s platelets be in the 20,000 per μL or anything over 30,000 per μL as long as they’re not having bleeding until it comes to the time of delivery. Recently, there have been 3 sets of studies on TPO [thrombopoietin] agents in pregnancy. One from China, published in 

 in 2017, looked at 33 pregnancies, 31 patients, using their TPO agent, which is not well licensed outside of China. Marc Michel, MD,’s study, published in 

 in September 2020, had about 7 patients with romiplostim and 7 with eltrombopag. Then I had the pleasure to present at ASH [American Society of Hematology annual meeting], and at least the abstract is published, on the general safety from looking at a registry of romiplostim use during pregnancy. Personally, I would go earlier to romiplostim in a pregnant patient, especially in the third trimester. Do either of you disagree with that or want to say more about it?

: I’m a little hesitant to do that yet, Jim. Since IVIG is so effective in the end of pregnancy prior to making a decision about the approach to delivery, my inclination right now is to remain with IVIG toward the end. Also, we know this will help with the child’s propensity to be thrombocytopenic. I know that the Michel study suggests that the newborn may have less of a chance of being thrombocytopenic. Nonetheless, I’m still a little nervous about using a TPO mimetic yet because the TPO mimetics also have stem cell stimulation properties. I’m a little nervous about that in newborns. I don’t think we have enough data yet, but I’m certainly interested in trying to see what the results would be with a TPO receptor agonist.

ITP experts share considerations in the treatment of pregnant patients with ITP.

ITP Treatment in Pregnancy

Craig, you promised to share your wisdom about how to manage the older patients with ITP [immune thrombocytopenic purpura] because there are changes in responses and especially adverse effects for some of the treatments we might use in someone younger. What do you think?

The treatment of older individuals with ITP has become a much more relevant topic these days because we know about the bimodal distribution of the onset of ITP. We realize now that the second wave above the young adult population is in the very old. We also know that this group is probably more heterogenous in their presentation. Although in several recent registry studies, there’s an increased incidence of thrombosis and an increased incidence of bleeding complications. Additionally, multiple medical comorbidities complicate the treatment of this population. We don’t have any good clinical trials in the older population. They’ve been excluded from many registration studies because of their medical comorbidities. There’s also a lot of patient selection bias by physicians who don’t want to put these patients in the clinical trials.

One thing about ITP in older patients is that we frequently call these patients primary ITP. As we learn more about the immune system, we’re going to learn that most of the ITP in older patients is probably secondary to other aging effects in the immune system. I call this immunosenescence of the immune system. We’re going to have to be very careful about this. When you take a look at the use of TPO mimetics up front in these populations, it seems to be very good, but you have to be very careful with the increased incidence of thrombotic complications.

What’s the best combination? We don’t know. Several registries, retrospective registries, suggest TPO [thrombopoietin] plus dexamethasone up front is probably a good way of approaching it. Some people think IVIG [Intravenous immune globulin] in this population is the best way to go with a TPO mimetic. We don’t know yet the best way of treating these patients. But there’s 1 thing that’s clear, and this is that older ITP is a heterogeneous group of individuals. Until we know more about the immune system to stratify risk, it’s going to be difficult to treat them.

 When would you do a bone marrow in a patient over 65 with ITP?

 The main reasons are if there were other cytopenias or there was dysplasia on peripheral smear. What about you?

 I mostly end up doing it based on response to treatment, meaning if you have somebody younger or older, if they’re difficult to treat, or if their count won’t go up at all. It makes me think, “I need to look at the marrow.” But I agree, there are many other considerations.

 Right, but if you’re using a TPO RA [receptor agonist], they’ll likely respond, right?

 Right. It depends on the response. Even though I like the idea of TPO RA—you may know I’ve been involved in the development of the 3 of them—that isn’t what I would use first. You can use steroids or IVIG to get the count up, but it’s a point well taken that TPO RAs are a game changer from the diagnostic point of view.

As a person who takes care of a lot of myelodysplasia in older individuals, I think the literature would suggest that 10% to 15% of myelodysplasia is associated with thrombocytopenia without organomegaly or peripheral blood changes. My feeling is that we should be doing bone marrows earlier in our patients. We should certainly be doing visualizations of the spleen, maybe with ultrasound, because many of these patients have splenomegaly that’s not appreciated on physical exam. The new approach to treating older patients is going to be doing next-generation sequencing on bone marrow specimens in order to stratify a patient risk.

Drs Bussel, Piatek and Kessler discuss treatment of older patients with ITP.

Treatment of Older Patients With ITP

 We had talked about changing to a different type of patient, so the use of rituximab up front, begging the questions about the COVID-19 era, would be less relevant. Let me mention that fostamatinib has been used as an anti-inflammatory agent for COVID-19 without the consideration of thrombocytopenia, which has been interesting. A preliminary pilot study from the NIH [National Institutes of Health] suggested it was effective. Additional studies are being pursued. Of the agents we’ve talked about for ITP [immune thrombocytopenic purpura], it probably has the more tolerability issues with causing high blood pressure and GI [gastrointestinal] adverse effects. But it can be very effective, even in TPO [thrombopoietin]–failure patients. It’s definitely been licensed since May 2018. It’s a very useful agent, especially if there’s a risk of thrombosis or if there’s a lot inflammation. But this needs to be fleshed out more.

Dr Bussel discusses the use of fostamatinib in patients who have progressed on TPO agents.

Fostamatinib in Immune Thrombocytopenia

For this patient, who might be a young woman, Caroline outlined specifically why dexamethasone and rituximab may be good. We’ve been talking about the risks of vaccination, and I thought you’d bring up flu vaccines. The other thing we talked about was TPO [thrombopoietin] agents. Caroline, how do you feel about splenectomy? Does your center do it anymore?

 I’m a millennial, so I don’t do splenectomies. Our institution [Keck School of Medicine] also doesn’t commonly do splenectomies. We have more options, and high response rates with the TPO agents, so you don’t have to go to splenectomy very often. It remains an effective treatment, however, because of the well-known risks and infection in thrombosis with splenectomy. It’s not used as often as it was some years ago.

 I use it very sparingly. In the last 5 years, I may have only had 2 patients who went to splenectomy. Typically, it’s patient resistance more than anything else, because there’s a role for splenectomy in individuals. You have to be very selective. The last time I did a splenectomy on an older individual, he had marginal zone lymphoma in the spleen, which was the actual cause of his ITP [immune thrombocytopenia]. So you have to be very careful. Looking at this patient in retrospect, they had a very small monoclonal spike that was intermittently present in the past—not when I saw him, but years before. Maybe that was a hint that there was another cause. You can use splenectomy sparingly and youthfully, but the resistance from the patient is what prevents us from using it more.

 One thing that’s embarrassing for us as a field is the way things used to be. If you had 100 patients with ITP and also presentation, how many would get better on their own within a year or more? I would have thought the answer was 5, 10, maybe nobody. It turns out to be at least 30%. One study we have from Austria for 3 years suggested 60%. Then there’s the conundrum of those patients not treated, which must have been milder or different from the ones we treat. You want to do the ones who need treatment. That’s a confounder. Back to the risk benefit, on any given day it always seems better to pick a TPO agent over a splenectomy. I’m not saying that’s right, but from the patient point of view, that’s a very strong force. The article from Shruti Chaturvedi, Donald Arnold, and Keith McCrae in 

 from 2018 explains how splenectomies are down but not out. It has a very nice discussion of why it should not be completely eliminated from the armamentarium.

ITP experts discuss use of splenectomy for treatment of ITP in their practices.

Role of Splenectomy in Immune Thrombocytopenia Treatment

 Caroline, why do you think the advent of COVID-19 and the pandemic has changed our approach to rituximab, given that it was controversial to begin with?

Rituximab is B-cell depleting, so for at least 6 months after receiving rituximab we could anticipate that our patients would have a decreased response to the COVID-19 vaccine. Because we don’t already have great long-term responses to rituximab, it seems to be falling even further out of favor in ITP [immune thrombocytopenia] in the COVID-19 era.

 That’s true, especially thinking about the third shot, the booster shot, is important for Omicron. It’s not like I got my 2 shots, and 2 to 4 weeks after that I received rituximab. It doesn’t matter as much anymore, especially with the questions surrounding how affective the monoclonals and oral agents are that aren’t available for regular use in patients who are infected. There’s been a tremendous decrease in the use of it, which seems quite appropriate.

 Jim, the other issue is not just the COVID-19 vaccine, which shows decreased responsiveness after rituximab, but also Pneumovax and other vaccines. There may be some differences between childhood ITP and adult ITP in this regard. It’s important to delay the use of rituximab for several weeks to get the patient adequately vaccinated for these various diseases.

Physicians share concerns with ITP medications and response to COVID-19 and other vaccinations.

Immune Thrombocytopenia Treatment, COVID, and Other Vaccinations

 Tell us about how you think rituximab should be used, up front or close to front?

 Rituximab has remained in the refractory setting for ITP for some time. It has also been studied in combination with other therapies such as high-dose dexamethasone in patients with newly diagnosed ITP who initially showed a strong overall response rate, sometimes up to 100%. When you go out to about a year, you’ll see that response rate drop to 60% or so, but we see still the good initial response. The problem we have with rituximab is the infectious risk, which I’ll come back to in a second. Certain sets of patients tend to respond better to rituximab, notably young women. So up-front steroids—dexamethasone and rituximab—remain an option for some patients in the up-front setting.

 If you measure immunoglobulin levels ahead of time and they’re normal—maybe I’m wrong, but I think there’s very little infectious risk with rituximab in the patients with ITP. We definitely need to discuss COVID-19 too because that’s incredibly important. In at least 1 of the studies, Nichola Cooper and I had 44 or 45 patients whose immunoglobulin remained normal. We have to worry about hepatitis B, but that’s become a much smaller issue lately because there are several treatments you can give if you need to.

PML [progressive multifocal leukoencephalopathy] is incredibly worrisome as well, but as far as I know, there was only 1 well-documented case of PML after rituximab and ITP. That case was very atypical. In the initial series in 

 in 2012 there were all kinds of malignant hematologic patients with the median time from rituximab to development of PML being about 6 months. The 1 case of ITP was over 3 years, and there were a number of intervening treatments. Lastly, in certain populations, even MMF has had risk of PML associated with it. In general, I don’t worry much about infections after rituximab, other than COVID-19, which we’ll come back to in a minute. What do you think Craig?

 I’m not a great fan of up-front rituximab. We’re all guided by our personal experiences, and I’ve had several patients who’ve received multiple cycles of rituximab because it didn’t work up front. I’ve seen several cases of individuals who developed severe immunodeficiency syndromes. This is something that needs to be brought up frequently when you consider placing patients in a complete response without rituximab. We have an 80% response rate with TPO plus dexamethasone up front with short cycles of dexamethasone. You can save the rituximab for the secondary ITP or the refractory ITPs rather than put it up front. My preference is not to use rituximab up front.

 There’s a lot of debate about this. If Terry Gernsheimer was on the call, she’d say that it was hard for her to see patients with ITP who hadn’t received rituximab already because it’s widely used. I agree with you about the multiple cycles, but I left out something important. In our experience, when you gave 3 cycles of dexamethasone with rituximab, you had about 20% of patients whose immunoglobulin levels did go down some and maybe 10% for whom they went down severely. We have used IVIG replacement in those patients for a very short period until their Ig-G recovered, but that’s debatable in certain settings as well.

ITP experts debate different strategies they use in upfront treatment of ITP.

Debate Regarding Upfront Treatment of Immune Thrombocytopenia

Good morning, everyone. It’s our pleasure to welcome you to an 

® discussion titled “Management of Patients with Immune Thrombocytopenia.” We have a distinguished panel that’s going to provide an interactive discussion of certain aspects of ITP [immune thrombocytopenia]. We can’t cover everything, but our distinguished panel has selected several cutting-edge items that will be interesting. Our panel consists of Craig Kessler, a professor at Georgetown University and a leading voice on ITP and hematology for years. He will help us with his wisdom and insights. Our other panelist is Caroline Piatek, a rising star at USC [the University of Southern California] by inheriting the mantle of Howard Liebman and Ilene Weitz as she develops her career.

My name is Jim Bussel. I’m a professor emeritus at Weill Cornell Medicine in New York. Because we can’t cover everything, we thought 1 of the features we would start with is treatment for early ITP. We’re not intending to discuss the use of IVIG [intravenous immune globulin] and steroids much, but Dr Kessler has promised us later a brief comparison of dexamethasone and prednisone. We’re going to take advantage of the ASH [American Society of Hematology] guidelines and international consensus reports. They both highlight the overuse of steroids in the early stages. Recently, at least 1 thrombopoietic agent has been licensed for us in newly diagnosed patients. We thought we’d start by discussing different frontline therapy strategies beyond IVIG and steroids, which can make it easier for practitioners to cut short the overuse of steroids. Craig, you were kind enough to volunteer to start. Tell us a little about the key points of TPO agents.

 Jim, the TPO agents have been a game changer in the treatment of ITP. As we see the successes of the TPO receptor agonist in the chronic phases of ITP, there’s a tendency to want to move the TPO agents closer to the acute management of ITP. This has been a very important move. There’s 1 TPO receptor agonist that’s been licensed for use in the persistent phase of ITP. One very interesting trial was published in the 

 last year, a randomized prospective study using TPO receptor agonists plus high-dose dexamethasone. This was compared with a high dose of dexamethasone alone. That study showed some very remarkable and encouraging results. The study indicated over 80% complete response rate in the TPO-plus-dexamethasone arm vs the high-dose dexamethasone arm alone. This information makes this combination possible, and it gives us feasibility to show that there’s safety and efficacy using that combo. In addition, there was an earlier trial looking at high-dose dexamethasone vs prednisone at the 1 mg/kg dose vs dexamethasone 40 mg orally daily for 4 days. There was statistically significant difference in that study with the immediate and complete response rate in the high-dose dexamethasone group vs prednisone. The attractiveness of the TPO study that I described is that we can probably limit the amount of corticosteroids in many of our patient populations because of the high degree of complications with continued high-dose corticosteroids.

 I’m going to comment briefly on the FLIGHT trial published in the 

 recently looking at MMF [mycophenolate mofetil] plus steroids vs steroids alone. In that study, a relatively small number of patients used dexamethasone.It appears that the combination was better in leading the cure in close to 80% vs steroids alone, which was surprisingly over 50%. There are a lot of flaws in that trial. It’s interesting that the quality of life was worse on the combination. We all thought it would be better because patients would use less steroids. There’s enough controversy that we can’t rely on it other than as an example.

Just to be a little controversial, that was an older population. Using high-dosage mycophenolate in an older population may not be the best way to handle ITP. Instead, maybe a younger population will be able to tolerate that dosing regimen better than the older population.

 That’s right: 27% or more were over 65 years old in that study, which is significant.

Drs Bussel and Kessler discuss treatment of early immune thrombocytopenia (ITP).

Caroline Piatek, MD

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