Presse Med. 2014; 43: e69–e78 ß 2014 Elsevier Masson SAS All rights reserved.

on line on www.em-consulte.com/revue/lpm www.sciencedirect.com

AUTOIMMUNE CYTOPENIAS

Quarterly Medical Review Thrombopoietic agents: There is still much to learn James B. Bussel, Madhavi Lakkaraja

Weill Cornell Medical College, Platelet Disorders Center, Departments of Pediatrics and Medicine, Division of Hematology, New York, NY 10065, United States

Correspondence:

In this issue Immune thrombocytopenic purpura: major progress in knowledge of the pathophysiology and the therapeutic strategy, but still a lot of issues Bertrand Godeau Pathogenesis of immune thrombocytopenia Douglas B Cines, Adam Cuker, John W Semple ITP and international guidelines, what do we know, what do we need? Francesco Rodeghiero, Marco Ruggeri Thrombopoietic agents: There is still much to learn James B. Bussel, Madhavi Lakkaraja Is B-cell depletion still a good strategy for treating immune thrombocytopenia? Bertrand Godeau, Roberto Stasi Novel treatments for immune thrombocytopenia Andrew Shih, Ishac Nazi, John G. Kelton, Donald M. Arnold Warm autoimmune hemolytic anemia: advances in pathophysiology and treatment Marc Michel Autoimmune neutropenia Aline Moignet, Thierry Lamy

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James B. Bussel, Weill Cornell Medical College, 525 East 68th Street, P695, New York, NY 10065, United States. [email protected]

Summary Thrombopoietic growth factors have had an interesting development path. Many studies were done with the first generation agents and this has defined the current way that the second generation agents are used. While the first generation agents were not surprisingly targeted at chemotherapy-induced thrombocytopenia, the second generation ones have been initially developed in ITP. Surprisingly, the thrombopoietic agents have not been as simple to work with as would have been anticipated in that the relationship of treatment to the platelet count, what to expect, in what patient, and with which underlying cause of thrombocytopenia has not nearly been as straight forward as it could be. Rather than being an ‘‘encyclopedic’’ review, this manuscript is intended to provide a state of the art description of what we do and do not know in regard to important questions about usage of these still novel agents.

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lready within five years of their licensure, thrombopoietic agents (TPO-A) have revolutionized the treatment of immune thrombocytopenia (ITP), the current management of hepatitis C, and seem potentially about to have major effects in other disease areas as well. The most obvious of these is treatment of aplastic anemia with TPO-A [1] but its use in non-immune inherited thrombocytopenias seems very promising as well [2]. The use of TPO-A in myelodysplastic syndrome (MDS) continues to be highly controversial and in non-myeloablative chemotherapyinduced thrombocytopenia remains to be developed as agents preserving chemotherapy doseintensity. Fortunately or unfortunately, these agents are not the be-all or the end-all in every condition, including ITP, but often have significant efficacy. Further studies about factors determining response and resistance to them and other issues connected with which patients respond and which patients do not, will have a major impact on their use in the future assuming that these parameters can be determined and easily identified. Both current agents are certainly expensive, as will be any novel ones in the future, and this could impact when they are used depending on whether there are other alternative treatments that are less expensive, that work as well or almost as well and that have as little in the way of toxicity.

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Available online: 27 March 2014

JB Bussel, M Lakkaraja

The TPO-A currently in use is so-called second generation and entered clinical trial in approximately 2002. In 1995, the first generation agents had been entered into clinical trial and continued in clinical trials until approximately 1999 or early 2000. There is considerable data with the first generation agents from many studies that were completed prior to their discontinuation from clinical use [3]. There is a tendency to think that issues with TPO-A are largely known based on many large randomized controlled clinical trials that have been performed (tables I and II). While certainly a large amount of critical information has been obtained, a number of important questions remain unanswered in different areas. As indicated, particularly important is who would respond and who would not. A parallel question would be which toxicities will be seen and in whom will these occur. Finally, a major area that remains not well understood is whether there is a direct effect on platelet production of TPO-A. In particular, it is known that TPO-A stimulate the production of megakaryocytes and cause them to proliferate so that the number of megakaryocytes in the marrow is increased [12]. It is not known whether such megakaryocyte stimulation by TPO-A directly increases platelet production or whether platelet production increases (as does the platelet count) as a by-product of having more megakaryocytes.

TPO-A perspectives

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Identifying lineage-specific growth factors has always been something of a holy grail. Technology had to improve for this to happen. Erythropoietin was initially identified in the 1980s and its clinical efficacy first demonstrated in cases of renal failure in which there was no or little erythropoietin production by diseased kidneys. At the same time, at the Walter and Eliza Hall Institute in Melbourne, scientists were working on identifying granulocyte colony stimulating factor (G-CSF) and granulocyte macrophage colony stimulating factor (GM-CSF). Soon thereafter, G-CSF was cloned at Memorial Sloan Kettering Centre and initial studies demonstrated important efficacy and proof of principle in the treatment of cases of severe congenital neutropenia. At this point, there was a delay until ingenious methods of identifying thrombopoietin were pursued and several groups cloned it simultaneously in 1994. Unlike the treatment of severe congenital neutropenia in which the G-CSF receptor was shown to be intact, it became known that the thrombopoietin receptor was defective in congenital amegakaryocytic thrombocytopenia (CAMT). In addition, there were fears that since both CAMT and TAR (thrombocytopenia and absent radii) were associated with a low but significant incidence of leukemia, these patients were not selected as initial targets for treatment. Instead, therefore chemotherapy-induced thrombocytopenia was the initial target of the first generation TPO-A. The results of the studies were able to demonstrate proof of principle but not to show clear

efficacy in leukemia in the setting of myeloablative chemotherapy during and following which many platelet transfusions are given. Therefore, when these agents proved that ‘‘thrombopoietin’’ had a major role in platelet production and reversing thrombocytopenia but that it would not be easy to license in chemotherapy-induced thrombocytopenia, ITP was chosen as the primary focus when the second generation agents became available for human use. Currently, there are two agents licensed in the United States and at least 80 other countries and these agents have been licensed primarily for ITP with eltrombopag also licensed for thrombocytopenia related to hepatitis C [13]. Once TPO-A was available for trial and proven effective in ITP, a number of additional studies took place for other indications. How did this come about and what do these agents do? First, it is of interest that thrombopoietin is considered to be the primary driver of all phases of thrombopoiesis. Other molecules contribute but it is not certain how much they contribute directly and how much they may contribute by altering the levels or the production of thrombopoietin. Other issues include in what way thrombopoietin acts on stem cells even though it stimulates generation of megakaryocyte precursors and progenitors all the way down to megakaryocytes.

Questions with some answers In dealing with TPO agents primarily regarding treatment of ITP, this manuscript will discuss frequently asked questions. The lack of or variability in information will be considered. Opinions may be expressed but they will be couched as such and there may be areas that are sufficiently unclear that no resolution has been arrived at.

What is the actual rate of response to TPO agents in ITP? If one looks at all of the studies done thus far that have large numbers of adults with ‘‘typical’’ persistent and chronic ITP, the response rate appears to range from 50–90% (depending upon whether one subtracts the placebo rate of response from the TPO-A rate of response or not). Probably, a realistic number for a typical patient who might be a little more difficult than average (which would be the reason why they are treated with a TPO-A) would be 60–70% or so in clinical practice. This again raises the question that it is often not clear who will respond and who will not and understanding the reason for this would be really helpful.

How long does it take to increase the platelet count? If one gives a dose of a TPO-A to which a patient will respond well, it would nonetheless take approximately one week to observe a response [4]. However, if one is starting at a lower dose, perhaps 1–3 mg/kg/injection/week (wk) of romiplostim and increases the dose by 1 mg/kg/wk, the patient might tome 43 > n84 > avril 2014

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Table I Findings from studies on romiplostim Name of study Bussel et al., 2006 [4]

Response to treatment/platelet count

Adverse events/complications

Phase 1: 4 weeks Platelet count (50,000 to 450,000/mm3) + at least twice baseline count: 4/12 (30%) Platelet count of  50,000: 7/12 (58.3%) Mean peak counts (apparent dose response): 3 mg – 163,000; 6 mg – 309,000; 10 mg – 746,000

No major complications

Phase 2: 6 weeks Targeted platelet count: 10/16 (62.5%) Mean platelet count: 1 mg – 135,000; 3 mg – 241,000; Placebo: 81,000 Kuter et al., 2008 [5]

26 weeks Durable platelet response: (26 weeks) Splenectomised patients: romiplostim 16/42 (38.1%) vs placebo 0/21 (0%) Non-splenectomised patients: romiplostim 25/41 (60.1%) vs placebo 1/21 (4.8%) Overall platelet response1: Splenectomised patients: 33/42 (79%), non-splenectomised: 36/41 (88%), placebo: 3/21 (14%). Time to achieve platelet count  50,000: splenectomised: 13.8 weeks, non-splenectomised: 15.2 weeks, placebo: 0.8 weeks Reduced or discontinued concurrent therapy: romiplostin: 20/23 (87%) [12/12 splenectomised and 8/11 non-splenectomised patients] pacebo: 6/16 (37.5%) [1/6 splenectomised and 5/10 nonsplenectomised patients]

Adverse events similar for romiplostin and placebo

Kuter et al., 2010 [6]

1 year Rate of platelet response: romiplostim = 2.3 times rtandard care group Treatment failure: romiplostim: 18/157 (11%) vs standard care: 23/77 (30%) Splenectomy: romiplostim: 14/157 (9%) vs standard care: 28/77 (36%) Romiplostim group: lower rate of bleeding events, fewer blood transfusions, and greater improvements in quality of life than standard-of-care

Serious adverse events: Romiplostim – 35/154 (23%) vs standard care – 28/75 (37%)

Kuter et al., 2013 [7]

Up to 6 years Median platelet count of 50–200 maintained at mean dose of 5–8 mg/Kg throughout the study. Platelet response achieved at least once by 95% patients with a platelet response maintained by all patients on a median 92% study visits

Thrombotic events: 65% patients not associated with platelet count Low rate of bleeding Infrequent need of rescue treatments

Overall = durable + transient.

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Table II Findings from studies on eltrombopag Name of study

Response to treatment/platelet count

Adverse events/complications

Bussel et al., 2007 [8]

6 weeks Platelet count  50,000 on day 43 of treatment: eltrombopag: 30 mg – 28%; 50 mg – 70% and 75 mg – 81% vs placebo – 11%. Median platelet count day 43: eltrombopag: 30 mg – 26,000, 50 mg – 128,000 and 75 mg – 183,000 vs placebo – 16,000. By day 15: > 80% patients on 50 or 75 mg of eltrombopag daily had increased platelet count

Incidence and severity of adverse events: similar in eltrombopag and placebo groups

Bussel et al., 2009 [9]

6 weeks Platelet Count  50,000 on day 43 of treatment: Eltrombopag: 43 (59%), Placebo: 6 (16%) Increased dose of Eltrombopag: 34 (10 responded)

Eltrombopag patients had less bleeding than placebo (OR: 0.49) Frequency of grade 3–4 adverse events: similar in both groups

Cheng et al., 2011 [10]

6 months Platelet count 50,000–400,000 weekly during the first 6 weeks and at least once every 4 weeks thereafter: Eltrombopag 106 (79%) vs. Placebo 17 (28%) Reduced concomitant treatment: eltrombopag: 37 (59%) vs placebo 10 (32%)

Thromboembolic agents: eltrombopag – 3 (2%), placebo – 0 (0%). Mild increase in alanine aminotransferase: eltrombopag – 9 (7%), placebo – 2 (3%). Increased total bilirubin: eltrombopag – 5 (4%). placebo – 0 (0%). Serious bleeding events: eltrombopag – 1 (< 1%) vs placebo – 4 (7%)

Saleh et al., 2013 [11]

Up to 5–6 years Interim analysis of EXTEND study. Platelet count  50,000 at least once: 254/299 (85%) [Splenectomized – 92/115 (80%), nonsplenectomized – 162/184 (88%)] Maintenance of platelet count (cumulative study weeks): Platelet count  50,000: 73/104 Platelet count 2 baseline: 109/156

Bleeding symptoms (% of patients) Baseline: 56 2 years: 20 3 years: 11 Reduction of concomitant treatments: 69/1001 Adverse events  1: 38 (13%) Thromboembolic events: 11 (4%) Increased liver enzymes: 5 (2%)

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100 (33%) were receiving concomitant treatments at study entry.

eventually respond but hypothetically would require a dose of 7 mg/kg/dose. In such a case, it might take 1–2 months before a response is observed. Similarly, with eltrombopag, it might take a month or more if a patient starts with 50 mg daily and takes that dose for 2–3 weeks before increasing to 75 mg if he would respond to 75 mg [9]. Furthermore, eltrombopag is very sensitive to food effects, especially calcium i.e. from dairy products or calcium fortified orange juice. If one is not aware of this and/or the patient does not reveal how he takes his medication, response might never occur until this is corrected [8–10].

Other questions focusing on the response

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A pertinent unanswered question here is: ‘‘Is there delayed response e.g. 1–3 months based on the time it takes to fully stimulate stem cells to increase megakaryocyte precursors and

really gear up to making more megakaryocytes and hence platelets?’’ As far as I know, there is no answer to this question. Another question involves patients whose counts increase but then cycle wildly up and down while on a constant dose of medication (or a fluctuating dose trying to keep up with the cycles). Why does this happen? One answer is that there appear to be a number of compensatory mechanisms that are intended to ‘‘correct’’ or ‘‘compensate’’ for too high a platelet count. When a TPO-A stimulates an increase in the platelet count, these mechanisms ‘‘kick in’’ and ‘‘over-react’’ to lower the platelet count too much. Then, the platelet count is overstimulated and the cycle starts again. This ‘‘answer’’ sounds plausible and may even be in line with the truth but conceals a vast amount of ignorance. Cyclic neutropenia, although rare, is well described, in the early days of G-CSF use, several cases of apparent severe congenital neutropenia (SCN) resembled cyclic

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Is there a major difference between the two agents eltrombopag and romiplostim? Certainly in the ITP studies to date [4,5,7–11,14], no major differences have emerged although there have been no direct comparisons. However, there are several differences in using these agents. First, in different countries, there may be different restrictions regarding for which conditions is one of them available or the other. While they are typically considered generically, increased medical regulation may limit usage of one or the other in certain conditions. Second, in the United States, the insurance that deals with this is different in different patients. Therefore, one patient may have better insurance with one agent and another patient may have better insurance with the other (although this seems to be less of an issue than it used to be). Given how expensive they are, a large copay could be prohibitive for many patients. Third, romiplostim is given subcutaneously weekly and eltrombopag is given orally daily. One basis for the insurance difference is that one comes out of the insurance for medications taken by mouth while the other comes from the ‘‘injectable’’ budget. Similarly, hematologists may prefer to increase their own reimbursement by giving an injection. It is also still true as of this writing that patients in the USA (unlike in Europe) cannot be taught to self-administer romiplostim and usually must come to the hematologist weekly to receive their injection of romiplostim as long as they continue the medication. In contrast, once the dose of eltrombopag is established, then, the patient can return monthly (if the liver tests have remained normal) and then twice monthly. While the ability to take eltrombopag orally and only once a day seems very good, as briefly discussed, eltrombopag has important dietary restrictions on how it can be taken. These restrictions tend to be absolute and can make it difficult to take eltrombopag because of having to avoid supplemental calcium like anything dairy as well as avoiding supplemental iron for 4 h on either side of ingesting eltrombopag and avoiding any food within 2 h. Usually the patient on eltrombopag has to plan their day’s eating and taking other medication around the decision when to take eltrombopag. The most common time is bedtime or the middle of the night mostly in elderly or diabetic patients who routinely get up in the middle of the night to urinate. As an aside, this brings up issues of how eltrombopag works since it seems that it requires its ‘‘chelation effect’’ to have a tome 43 > n84 > avril 2014

thrombocytotic impact and yet theoretically it is not clear how this is part of the mechanism of binding to and stimulating the thrombopoietin receptor. This in turn reminds us that eltrombopag (and other oral agents like EE501 aka avatrombopag which is in clinical trial) are dependent on whether one amino acid in the transmembrane portion of the TPO receptor is a lysine or a histidine [8]. Given the absence of specific evidence either way, this does not mean that the oral agents bind in the transmembrane domain since the single amino acid difference would likely have a conformational effect on the TPO receptor. Furthermore, binding to the transmembrane domain seems unlikely. This area of interest remains a black box.

If one of the licensed TPO agents does not work, is it worthwhile trying the other one? There is some data published suggesting that this may be the case e.g. that trying the other TPO-A may have value, but it remains completely unclear whether this is the exception or the rule or somewhere in between [15]. It would seem that the real answer to the question involves what other reasonably good options are available. If the patient and the physician both agree that it would be reasonable to try another therapy, then it would make sense to try the other agent. If on the other hand, both are clear that a TPO-A is optimal and other eligible treatments have been tried and did not work or had intolerable toxicity or are not acceptable for one reason or another (including personal preference), then, it would be appropriate to attempt the alternate TPO-A. This presumably should be in the setting of having given the highest dose of the first agent for at least 4 weeks before labelling it a failure and discontinuing it.

If you are using a TPO agent in treatment of ITP, can you use other treatment as well? It has been our experience that using a TPO-A with other treatments works very well. This is presumably because they likely work by two totally different mechanisms. If the thrombopoietic agent increases platelet production and another medication impedes platelet destruction than that should result in at least an additive effect if not synergy. Therefore, we believe that if you are using a medication and it alone is not working, instead of stopping it and going to something else, it usually makes more sense to continue it and add another medicine with a different mechanism of action (this expression of opinion comment applies to TPO-A but also is made more generally).

If a physician starts a patient on a TPO agent, is the patient going to be taking the TPO agent for life? The answer to this is complicated and also largely unknown. It would appear that within a ‘‘short’’ period of time (arbitrarily defined as 6 months to 2 years), a not insignificant fraction of

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neutropenia when stimulated enough to increase the neutrophil counts. There are a smaller number of cases of cyclic thrombocytopenia known. One ‘‘well-studied’’ case apparently is based on cyclic production of antiplatelet antibodies, this somehow seems unlikely but a better explanation is not evident at this time [14].

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patients, somewhere between 20 and 40%, would be able to discontinue treatment and nonetheless maintain an adequate count. However, it remains difficult to pick out those patients in advance and to know exactly who they are ahead of time. There are many ‘‘theoretical’’ possibilities as to why a patient could get better. One possibility is the passage of time. Certain patients appear to ‘‘redevelop’’ normal bone marrow platelet production and thus, achieve a better if not normal count. Alternatively, the induction of regulatory T-cells (Tregs) has been demonstrated in a small number of patients in association with an increased level of circulating TGF-beta [16]. It is not clear if these are an epiphenomenon or a functional mechanism of effect. Unpublished data in 35 patients has significantly related functional suppression to platelet response to TPO-A but this remains to be confirmed. Finally, as with IVIG, there could be many other possibilities, most of which remain to be discovered. Our impression is that it does seem that patients who are on TPO-A, even if they cannot discontinue them, seem to require less and less over time (years). An abstract presented at ASH identified 27 patients taken from multiple Amgen ITP studies using romiplostim in which these patients could discontinue romiplostim and not use any other ITP treatment for at least 6 months and maintain a count > 50,000/uL. These patients, compared to the others from the trial, tended to have had ITP for < 1 year and to be male. The median time of use of romiplostim before being able to discontinue it was 31 weeks but there were at least 2 patients who had had ITP for well over 10 years [17]. One could hypothesize for the latter two patients that these patients were ones in whom the ITP might have been close to burning out and the use of the TPO-A accelerated this process.

responders do not relapse more than 2 years after treatment whereas adults continue to relapse and eventually bring their response rate down to that of children. Therefore, a very tentative conclusion could be that platelet production is more of an issue in children with chronic ITP than it is in adults. Alternatively one could suggest that it is more possible to productively stimulate the bone marrow of children with chronic ITP than it is to do so in adults.

My patient is tired and complains of having no physical or mental energy. Is this part of ITP and will TPO agents improve this? First, it is now clear that fatigue and otherwise impaired health related quality of life (HRQoL) is common in ITP [20–22]. Numerous studies have documented this association. The etiology is uncertain and may involve underlying inflammation in some patients. Second studies have documented that TPO-A improve HRQoL in responders [10,20]. To the extent that this is true, there are at least two possible hypotheses. Either the higher rate of platelet turnover releases constituents from platelet granules that counteract fatigue or the induction of Tregs reduces the underlying inflammation. While in general, TPO-A seem to improve HRQoL, it nonetheless seems in my experience that there are a few patients who are more tired on TPO-A instead of less tired. With eltrombopag, one can wonder if it is a result of the chelating activity of the agent perhaps contributing to iron deficiency. In general, however, but not always TPO-A seem to help.

How do the use of TPO agents in patients with chronic ITP inform us (if they do at all) about the difference in pathophysiology between children and adults with chronic ITP?

My patient is pregnant again and had a hard time with her ITP in her last pregnancy. In the interim since the last pregnancy I have put her on eltrombopag/romiplostim and she has done very well with that. Can I continue it during the pregnancy?

It would appear from limited data obtained thus far that TPO-A is highly successful in young children with chronic ITP [18]. It would appear that they are even more successful in children than they are in adults. This is based on soft data. More solid comparisons will be possible after the results of three large in progress studies of children with ITP appear. These may confirm the two studies each with more than 20 patients that have appeared thus far (and demonstrated response rates of 70–80%) using all three different response criteria OR possibly ‘‘tone the expectations down’’ a little [19]. If this finding of children with chronic ITP appearing to have a higher response rate than adults is confirmed, it should not be considered as an expected finding because it is ‘‘children’’. For example, the use of rituximab in children is at best as good as that in adults which is only because children who are

Unfortunately, it does not appear to be safe to use the thrombopoietic agents during pregnancy. To extend the half-life of romiplostim (AMG531), the Fc piece of an IgG1 molecule was linked to the active thrombopoietic peptide, creating a peptibody [4]. This ‘‘peptibody’’ would be expected to cross the placenta into the fetus (as would any IgG molecule) by active transport via FcRn. Eltrombopag is a small molecule and for this reason, it would be expected to also cross the placenta into the fetus [8]. Therefore, based on the expectation that both of them would cross the placenta and potentially stimulate the fetus’ bone marrow, it would be far from ideal to use them during pregnancy. This physiology is beyond the ‘‘no data in pregnancy use at your own risk’’ category because we would actively expect worrisome things to happen.

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This problem could happen with any therapy. Even though there is no data, it is likely better if discontinuing treatment in a responder to taper off the TPO-A even if it is over 2–4 weeks rather than discontinuing it abruptly. The phenomenon of rebound thrombocytopenia presumably has to do with the regulation of TPO levels in the circulation. The presumption would be that the use of thrombopoietin would stimulate the number of TPO receptors in the circulation e.g. there would be more platelets and more megakaryocytes. Therefore, if the thrombopoietic agent is stopped abruptly, there would soon be the same amount of ‘‘endogenous thrombopoietin’’ but a larger number of receptors able to sop it up and there might be less TPO available to stimulate production of megakaryocytes. Since many of the patients treated with these agents have very low platelet counts to begin with, in many instances, the fall in the platelet count is merely back to baseline even though baseline may be a very low level. The platelet count usually does not fall until 1 to 3 weeks after stopping the TPO-A.

What is my risk of inducing leukemia or leukemic transformation with these agents? This is a complicated question and depends upon the underlying disease being treated. If a patient has MDS, then, there appears to be a clear risk of development of leukemia when treatment with TPO-A is used by itself [23]. If however one is treating ‘‘ITP’’, then, there appears to be no risk. To a small extent, there appears to be a tautology in that we know that certain patients with ITP, especially the refractory ones may have not just ITP but also an underlying MDS that is invisible using current techniques.

Do I have to worry about liver disease in patients on eltrombopag? Worry may be too strong but the possibility of transaminitis and/or hyperbilirubinemia requires monitoring [10]. In general, it appears that in the first month it is probably useful to check the LFTs every 2 weeks, then every 4 weeks and then every 2 months when/if values are consistently normal. In large studies like Raise and Extend, the rate of development of transaminitis is approximately 10% but only 3% of patients had to discontinue eltrombopag [10,11].

What is the biggest concern in using TPO agents? In my opinion, the biggest concern is development of thrombosis. The serious events like heart attacks and strokes were more likely to occur in elderly patients over the age of 60 and especially over 70 in one study [7,24]. The pathogenesis is confusing because the events are both arterial and venous and can occur at any time in the treatment. Studies of platelet tome 43 > n84 > avril 2014

activation with both eltrombopag and romiplostim show that the platelets are activated in ITP and move toward normal with treatment [25]. In addition, one small study suggested that Ddimer levels decrease slowly over one year of treatment [26,27]. It is possible that the younger platelets result in more thrombin being generated; thus far, no direct assays have explored this possibility although some may be in progress. Another possibility is that there is activated vascular endothelium. The easiest way to put all this together without invoking a more complicated explanation is to say that the platelet count often rises quickly and dramatically and the number of newly synthesized platelets (the number of platelet retics) increases as well [28]. Therefore, if a thrombosis were at risk of happening, it might be more likely with an increased number of young platelets around. This presumes that certain patients might be at risk of a thrombotic episode and were protected by their low platelet count. This contrasts with the prevailing clinical belief that in the event of thrombosis, it is better to maintain a sufficiently increased platelet count and pursue ‘‘normal’’ (full) anticoagulation. A further source of confusion is that thrombotic events are both arterial and venous rendering etiologic hypotheses either less clear or more complex [7,11]. Clinically, the thromboses are not linked to very high platelet counts [11] although a high platelet count could theoretically have been the nidus of the thrombosis, which took days to weeks to manifest clinically; this possibility has not been excluded. My reaction to this situation and its management is to be very liberal with administration of for example, baby aspirin if someone who might have been on baby aspirin e.g. a man of 65 years of age, suddenly dramatically increases his platelet count. This could even be to a level of over 50,000. A second point that is unequivocal is that if a thrombotic event occurs, the appropriate management is almost always to continue the TPOA and initiate appropriate anticoagulation. If anticoagulation is not initiated, the thrombus could propagate. If anticoagulation is initiated and the TPO-A is stopped, the patient would be at risk for life threatening bleeding in 1–2 weeks when the platelet count falls precipitously while they are still anticoagulated. The least clear situation is in the setting of a DVT in the leg re-deciding whether or not to place a filter. My bias is to be against a filter but this is in the absence of data and with improved filters that can be readily removed and may not cause as much lower limb thrombosis as older models. There was one study with eltrombopag in the hepatitis C area in which short-term treatment was given to allow procedures, such as liver biopsies. The study was stopped early after 239 of a projected 300 patients were enrolled because of 7 instances of thromboembolic events (TEE), primarily portal vein thrombi. For both eltrombopag and romiplostim, the rates of development of TEE were approximately 5–6% [7,11]. While that may

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How do I stop one or both of these agents if my patient is on them e.g. so-called rebound or discontinuation thrombocytopenia

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mirror the natural history of ITP, which is generally thought to be a mildly prothrombotic disease, it would appear that the 5– 6% with each agent occurred more quickly than would have been expected from ITP alone. In general, there has been no evidence that the patients with alternative hemostatic predispositions to thrombosis, e.g. factor V Leiden or anti-phospholipid antibodies, are the ones predisposed to thrombosis but family history, hyperlipidemia and other more general causes may contribute. This remains a thoroughly unresolved area, which would benefit from a clearer description of the background rate of thrombosis in ITP so that the effects of therapies could be compared to a baseline.

Does a patient on a TPO agent have an increased risk of marrow fibrosis? On the one hand, the studies from GSK of Eltrombopag [11] have suggested that this is a very minor issue and preliminary results of the Amgen romiplostim studies tend to confirm this. On the other hand, it would seem as if the results from our group including patients on both agents suggest that there may be an enhancement of fibrosis with considerable time on these agents [29]. If that time is hypothetically 3 or 4 or more years, then the studies that are prospectively looking for this may not identify it in their 2 (or at most 3)-year study period. Studies of mechanism have not greatly clarified this other than the supposition that the more TPO effect there is on megakaryocytes the more likely it is that there could be release of TGF-beta (and/or perhaps PDGF alpha) that would also contribute to fibrosis developing in the marrow. Overall, it certainly does not seem to be a major problem but it is not clear that 10–20% of patients would not develop MF-2 (scale MF-0 to MF-3) if not MF-3 marrows with time on treatment. The good news is that when treatment is stopped because of progressive fibrosis, in virtually all cases, the fibrosis has regressed. Similarly to the situation of induction of malignancy (next section), it appears that true myelofibrosis with collagen 1 and 3 (collagen and reticulin) only occurs if the marrow is not that of ITP but rather that of MDS.

Is a patient on a TPO agent at risk of developing a malignancy?

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The answer seems to be no. Studies, especially the long-term studies [7,11] have not shown a remarkable risk. However there are a small number of patients (1 or 2) who do develop malignancies e.g. lymphoma or leukemia. This seems within the realm for patients who are otherwise complex, followed for several years, and often elderly. Surprisingly, there may be no patients with Hodgkin disease which is associated with ITP and with which the ITP may precede the Hodgkin. In MDS, it seems that there is a clear risk of leukemogenesis with these agents, although it often resolves with discontinuation of TPO-A treat-

ment. As with marrow fibrosis, it may be possible that refractory ITP patients may have a component of MDS but it is highly speculative that this leads to malignancy.

If IVIG and TPO agents are both highly effective in ITP, both expensive and both have transient effects, why would one use TPO agents instead of IVIG in a patient requiring ongoing therapy? The benefit of the TPO-A compared to IVIG is that in most but not all patients they would keep the counts generally at a stable level as opposed to the use of IVIG or IV anti-D in which the counts go up and down like being on a roller coaster. With IVIG, the count is good some of the time but usually will rapidly approach the time to treat (whatever is used to determine this in a given patient) and the patient will have to deal with the uncertainty of not being sure about the count but knowing it is low. In addition, IVIG can take at least half of a day and can result in incapacitating headaches in many patients meaning that they miss at least 2 full days of ‘‘life’’ per treatment. Finally, with TPO-A, home care can be readily pursued [30].

Clinical use Given all these questions and possibilities, in which patients would one recommend or consider using a thrombopoietic agent [31]? The most obvious patient would be a 56-year-old patient who has failed steroids, then failed rituximab and then failed splenectomy. This patient would potentially benefit from the use of a TPO-A since the leading other therapies have been tried and were not effective. The next patient could be one who runs a platelet count of 20– 50,000/uL and has very little bleeding. However, she wants to participate in sports at a high enough level with enough contact risk that she would seriously consider using a treatment in order to be able to play. This has primarily come up for us in two patients who love skiing and wanted to be able to participate without worrying about what would happen if they fell badly or suffered a serious injury. A third patient could be one who runs a lower count, again perhaps 30–50,000/uL, however, he feels tired and draggy all the time and has an impaired quality of life. He can try treatment to see if it helps. Another patient could be like the first patient, except that they have only failed rituximab but refuse to proceed with splenectomy (or vice versa). Another patient might have additional bleeding despite a seemingly adequate count (30–50,000/uL). Finally, an elderly patient may not be a good candidate for splenectomy and may prefer a less intensive therapy than rituximab, especially since newer studies have paired it with 1–3 cycles of high dose dexamethasone. tome 43 > n84 > avril 2014

Thrombopoietic agents: There is still much to learn

AUTOIMMUNE CYTOPENIAS

Conclusion In summary, thrombopoietic agents have had a dramatic effect and changed the landscape of management of ITP. They resemble the advent of IVIG where all of the sudden there was an almost magical therapy that could increase the platelet count substantially on demand. While there were ‘‘downsides’’ to IVIG i.e. headache and to the thrombopoietic agents i.e. the possibility of thrombosis or marrow fibrosis, the primary restriction on both therapies is limited duration of effect combined with a high degree of expense. It may be easier to justify rituximab if there is hope it would provide a curative effect in the same way that splenectomy does but there are clear downsides to both of these treatments as well. Much of the choice depends upon beliefs and assumptions. For example, if one is concerned about the long-term outcome of splenectomy, one might be inclined to use TPO agents in younger patients, including children, with chronic disease thinking that even if they are on them for 5 years, if they

can discontinue treatment then, they will have come out ahead and avoided other potentially more toxic and not necessarily effective therapies. This puts together greater concerns about safety of other treatments than about TPO agents, and the thought that there would be improvement eventually. Much remains to be learned and clarified. Some studies are ongoing that will help to at least an extent answer the above issues. Other questions may persist for many years or even indefinitely. A better ability to distinguish individual patients as to what approach to take from the beginning would be very useful here (and in many other disease settings). The available information helps patients and physicians decide together what choices to make. The unanswered questions make the choices more difficult. Disclosure of interest: James B Bussels: my family has a limited amount of stock in GSK and Amgen, I get research support from them and from Eisai, I have given talks and received honoraria from GSK and Amgen.

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tome 43 > n84 > avril 2014

Thrombopoietic agents: there is still much to learn.

Thrombopoietic growth factors have had an interesting development path. Many studies were done with the first generation agents and this has defined t...
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