Platelet volume could predict the efficacy of thrombopoietin receptor agonists in the treatment of patients with primary immune thrombocytopenia

Immune thrombocytopenia (ITP) is an acquired autoimmune disorder characterized by isolated thrombocytopenia <100 × 109/L due to accelerated platelet destruction and/or impaired platelet production.1 Currently in the United States, there are three FDA-approved thrombopoietin receptor agonists (TPO-RA) for chronic ITP: eltrombopag, romiplostim and avatrombopag. All three have high response rates of 40%–90% depending upon the response definition and patient population.2 Previous studies demonstrated that sequential use of romiplostim or eltrombopag in either order resulted in a high response rate for the second agent. This is particularly true if there was a response to the first TPO-RA, for example, if the response was lost or if the patient was switched for a non-efficacy issue like toxicity. Lower response rates were observed in patients who did not respond to the first TPO-RA.3-5 Data comparing use of all three TPO-RAs during a patient's treatment course are limited. Between July 2019 (following FDA approval of avatrombopag) and September 2020, there were eight patients seen at New York Presbyterian Hospital – Weill Cornell (NYP-WC) with chronic ITP who had been treated with all three TPO-RAs. De-identified clinical data were collected from electronic medical records including demographics, duration of ITP, ITP treatment, response to and tolerance to TPO-RAs. The study was approved by the Institutional Review Board of NYP-WC with waiver of informed consent. Response was defined as platelet count ≥30 × 109/L and doubling of the baseline count with absence of bleeding without concomitant administration of a first line therapy. Statistical analysis was limited to descriptive measures. The eight patients (five females, three males), median age 64 (range 33–89) all had primary ITP with use of median four (range 2–13) ITP medications prior to starting a TPO-RA (Table 1). All eight had difficult to treat ITP with episodes of severe thrombocytopenia despite chronic treatment, periodically requiring rescue with intravenous immune globulin (IVIG) and/or corticosteroids. Three patients started their first TPO-RA at another institution (1, 2, 6). Initial TPO-RA choice was influenced by availability, insurance, patient preference, and financial limitations. Four patients received eltrombopag followed by romiplostim while four started with romiplostim followed by eltrombopag. All eight received avatrombopag last due to its being the most-recently licensed of the three agents. No patient went directly from one TPO-RA to another without intervening treatment and all received other treatments in conjunction with or in between TPO-RAs. Seven of eight patients responded to initial exposure to their first TPO-RA. Among the four patients who first received eltrombopag, three responded with median 12 months on treatment. The shortest was 1 week (allergic reaction) and the longest 8 years. One patient (7) was successfully tapered off eltrombopag until ITP relapse one year later (Table 1). Patient number eight did not respond as she received IVIg every 1–2 weeks during her initial 7 months on eltrombopag. However, this patient chose to re-initiate eltrombopag at the same dose (75 mg) after several weeks off and did not require IVIg for almost 3 months. The four patients who first received romiplostim all responded with a median 18 months on treatment (range 4–96 months). Two (1, 6) however, stopped treatment after 4 months due to unstable platelet responses and need for rescue therapy (Table 1). Six of eight patients (75%) responded to their second TPO-RA. For the four who initially received eltrombopag, all responded to romiplostim with median time on treatment 36.5 months (range 21–48 months). Reasons prompting the switch from eltrombopag to romiplostim included: no response/lost response (2), allergic reaction (1), and insurance/financial issues (1) (Table 1). Two of the four patients who received romiplostim first responded to eltrombopag with median time on treatment 6.5 months. Notably, one non-responder (patient 1) received only 1.5 weeks of eltrombopag without an increase to maximum dose; details are unclear as this occurred at an outside institution. Prior to availability of avatrombopag, six patients returned to a TPO-RA they had previously received. Five required higher doses on re-exposure, most without robust response (patients 1, 3, 5, 6, 7; Table 1). Four of eight patients underwent bone marrow biopsy prior to starting avatrombopag; None revealed evidence of an underlying hematologic malignancy and two had stable bone marrow fibrosis (MF-1). Six of eight (75%) patients responded to avatrombopag. Reasons prompting the switch to avatrombopag from the previous TPO-RA were patient preference (n = 4), lost response (n = 3), no response (n = 1). As of this report, five remain on avatrombopag with responses ranging from 8 to 16 months duration (Table 1). One patient (8) responded for 4 weeks. Two patients (2, 5) started prednisone, initially at a dose of 20–60 mg, concomitantly with the preceding TPO-RA a few weeks prior to starting avatrombopag; both required resumption of steroids for platelets <30 × 109/L after 8 and 9 months on avatrombopag, respectively (Table 1). The other three patients (7, 4, 6) remain on single agent avatrombopag. The two patients who did not respond to avatrombopag, also did not respond to eltrombopag. TPO-RAs represent an important treatment modality for patients with ITP. The high response rates and prolonged ability to safely use these agents has resulted in improved health and quality of life for many patients. While all three agents confer high response rates, no direct clinical comparisons exist. There are differences between the three agents in mechanism of action. Romiplostim binds to the TPO receptor at the endogenous TPO binding site, whereas eltrombopag and avatrombopag bind to a transmembrane portion of the receptor. The latter approach could yield improved responses through the additive effects of native TPO in combination with the TPO-RA.6 Furthermore, although eltrombopag and avatrombopag both bind to the transmembrane part of the TPO receptor, eltrombopag's effect is dependent upon its ability to chelate intracellular iron whereas avatrombopag is not a chelator.7 This difference explains their different dietary requirements – eltrombopag should be taken on an empty stomach while it is suggested that avatrombopag be taken with food. One study of endogenous TPO levels compared eltrombopag and romiplostim and suggested that romiplostim was effective in ITP patients at higher endogenous TPO levels than eltrombopag suggesting that romiplostim was a stronger agent.8 The TPO levels were not measured in this study. All eight of our difficult to treat ITP patients responded to at least one TPO-RA. Response rates of 75% were observed to a second, and subsequently third, TPO-RA. In this small sample, patients who did not initially respond to eltrombopag tended to lack response to avatrombopag. Among responders to each TPO-RA, there were patients who switched to a different TPO-RA due to lack of efficacy of a preceding TPO-RA as well as issues not related to efficacy (preference for an oral agent, intolerance, or insurance/financial). Re-exposure to a previously-used TPO-RA resulted in requirement of higher doses in five of six patients and also less robust response in three patients. Reasons for this lesser response are unclear but could represent evolution of clonal T cells.9 As an example, one patient on romiplostim had steadily tapered his dose down from 15 to 7 μg/kg/week. After trying eltrombopag without success, he no longer responded to romiplostim on re-initiation. Notwithstanding heterogeneity for interval of time between TPO-RAs, dose of TPO-RAs, and use concomitant ITP treatment in between and in conjunction with TPO-RAs, we believe that the described reflects" real-world" experience with ITP. There are several limitations in addition to small sample size. We did not assess TPO levels or TCR clonality. Not all patients received the maximum dose or adequate time on all TPO-RAs. Despite these limitations, these data support considering these three TPO-RAs as separate treatment options given good responses to sequential treatment. An exception might be that a lack of response to eltrombopag may predict a similar lack of response to avatrombopag. This would be consistent with both agents binding in the same transmembrane region of the TPO-R, distinct from that of endogenous TPO or romiplostim. Although combinations of TPO-RAs were not used in the current study, there are now preliminary results of a randomized controlled trial suggesting safety and efficacy of this approach.10 In conclusion, we would recommend, particularly for patients who have highly refractory ITP, to be cautious about switching from one TPO-RA to another unless due to toxicity or loss of response. Not only might the patient not respond to the other TPO-RA but there might be a diminished response on re-trial of the original agent. Similarly, initial lack of or loss of response to one TPO-RA should not preclude trying another but it appears better to switch between romiplostim and either eltrombopag or avatrombopag than to switch between eltrombopag and avatrombopag. These recommendations are preliminary and further investigation is encouraged. Eun-Ju Lee has served on the advisory board for Principia. Madhav Seshadri has no disclosures. James B. Bussel has served on advisory boards and/or consulted for Amgen, Novartis, Dova, Rigel, UCB, Argenx, Momenta, Regeneron, RallyBio, and CSL-Behring. Eun-Ju Lee, Madhav Seshadri and James B. Bussel contributed to the data acquisition and interpretation of data. Eun-Ju Lee and James B. Bussel wrote the manuscript. All authors provided input on the manuscript and approved the final version for submission. The data that support the findings of this study are available from the corresponding author upon reasonable request.

Real World Use of Thrombopoietin-Receptor Agonists in the Management of Immune Thrombocytopenia in the United Kingdom: Results from the TRAIT Study

Exposure to Corticoid-Sparing Treatments in Adult Primary Immune Thrombocytopenia before the Chronic Phase in the Era of Thrombopoietin Receptor Agonists in France. a Nationwide Population-Based Study

Safety and Efficacy of the Off-Label Use of Thrombopoietin Receptor Agonists for Immune Thrombocytopenia in Pregnancy: Results from a Multicentre Observational Study

Immune thrombocytopenia (ITP) patients have thrombocytopenia and increased bleeding risk, but, conversely, they also have increased thrombotic risk which appears to be exacerbated by thrombopoietin-receptor agonist (TPO-RA)-treatment. Microvesicles (MVs) released from activated/apoptotic cells are prothrombotic due to exposure of phosphatidylserine (PS) and tissue factor (TF). MVs are increased in ITP patients, but their prothrombotic effect, before and during treatment with TPO-RAs, is unclear.We studied the effect of TPO-RAs on the procoagulant activity of MVs in 11 ITP patients, before, and two and six weeks after initiation of treatment, and in 15 healthy controls. MV-associated PS-activity, TF-activity and the capacity of isolated MVs and plasma to generate thrombin in a phospholipid-dependent manner were measured.Before treatment with TPO-RAs, prothrombotic markers in ITP patients were comparable to levels found in healthy controls. After both two and six weeks of TPO-RA-treatment, ITP patients had higher MV-associated PS-activity and phospholipid-dependent thrombin generation in plasma than controls. In addition, ITP patients had increased phospholipid-dependent MV-associated thrombin generation two weeks after initiation of TPO-RA-treatment compared with controls and pre-treatment levels. MV-associated TF-activity was low in controls and in ITP patients before and after initiation of TPO-RA-treatment.In conclusion, TPO-RAs increase phospholipid-dependent MV-associated thrombin generation in ITP patients. This could contribute to or exacerbate a pre-existing hypercoagulable state. Phospholipid-dependent thrombin generation generated by isolated MVs, or measured directly in plasma, may be potential tools that could help in the risk-assessment of future thromboembolic events in ITP patients, both before and after initiation of TPO-RA-treatment.

Real-world study on thrombopoietin receptor agonists combined with rituximab in the treatment of Relapsed/Refractory primary immune thrombocytopenia

Potential Anti-Thrombotic Effect without Accompanying Hemorrhage with Fostamatinib Use in Patients with Immune Thrombocytopenia

Primary immune thrombocytopenia (ITP) is an acquired autoimmune hemorrhagic disease. Loss of immune tolerance plays a crucial role in the pathogenesis of ITP. Monocytes and macrophages play an indispensable role in the pathophysiology of hematopoietic malignancies and have been implicated as key players in platelet destruction. Approximately 80% of adult patients with ITP exhibit corticosteroid treatment failure or become dependent, requiring novel therapy. Thrombopoietin (TPO) receptor agonists (TPO-RAs) have been used clinically to manage ITP effectively, however, little is known about the effect of TPO-RAs on monocyte and macrophage modulation in adult ITP. In this study, we investigated the phenotypic evolution and potential immunomodulatory roles of monocytes/macrophages in ITP patients receiving eltrombopag therapy. Results showed that the peripheral monocyte count positively correlated with IFN-γ/IL-4 ratio in ITP patients. Moreover, numerous phenotype-associated genes in ITP macrophages exhibited diverse responses, and ITP macrophages exhibited more M1-related characteristics. After eltrombopag therapy, the peripheral monocyte count and IFN-γ/IL-4 ratio significantly decreased in ITP patients. M1-related characteristics of ITP macrophages were partially reversed by eltrombopag. Therefore, this study revealed eltrombopag restored the monocyte dynamics and the associated Th1/Th2 imbalance, and partially reversed the M1-related characteristics of the ITP macrophages, which suggest the potential vital roles of TPO-RAs in regulating the monocyte/macrophage plasticity in ITP.

Treatment of Primary Immune Thrombocytopenia with Thrombopoietin Receptor Agonists: Effect On Platelet Function and Plasma Thrombin Generation

Predictive Factors for Thrombopoietin Receptor Agonist Free Responses in Chronic ITP Patients: A Multicenter Retrospective Study with Long-Term Follow-up

Clinical Burden of Illness in Patients with Persistent or Chronic Primary Immune Thrombocytopenia Treated with Advanced Therapies in the United States

Switching from Eltrombopag to Hetrombopag in Patients with Primary Immune Thrombocytopenia (ITP): Post-Hoc Analysis of a Multicenter, Randomized Phase III Trial

Sustained Complete Remission Of Corticosteroid-Resistant Immune Thrombocytopenia With a Short Course Of Recombinant Human Thrombopoietin

Cytokine changes in response to TPO receptor agonist treatment in primary immune thrombocytopenia

Immune thrombocytopenia (ITP) is recognised as the most common autoimmune cytopenic disorder and has been defined as a process associated with accelerated platelet destruction and decreased platelet production. Demographically, ITP affects adults and children with a bimodal distribution, involving cohorts aged <18 and 75–84 years.1 The most consequential clinical manifestation of ITP is its increased risk of bleeding; however, sparse data exist to characterise this risk at the older extreme of the ageing spectrum. When diagnosed in adulthood, most patients will eventually develop chronic disease and require long-term treatment strategies. The prevalence of ITP in adults is estimated to be 12 per 100 000 adults in the United States and data from the French National Health Insurance System has cited a prevalence of chronic ITP up to nine per 100 000 person-years in men aged >75 years.2, 3 More recently, data from the Nordic Country Patient Registry for Romiplostim estimated the prevalence of chronic ITP as 10–10·7 per 100 000 adults in Denmark and Sweden;4 however, we believe these are likely underestimates. In their paper Sokal et al.5 present data from the Cytopénies Auto-immunes: Registre Midi-PyréneEN (CARMEN)-France registry that expand and our understanding of the real-world presentation, risk factors for bleeding, and management of primary ITP in elderly patients (EPs), defined as those aged 65–79 years, as compared with the very EPs (VEPs) aged ≥80 years. The results complement the findings from other large ITP registries that have focussed on EPs and VEPs6, 7 and confirm the expectation that VEPs have a greater number of comorbidities and experience more severe bleeding events and higher mortality compared to younger cohorts. Interestingly, findings were similar between VEP and EP groups as far as the need for and response to first-line treatment, receipt of second-line treatment modalities, development of persistent disease, and complications of ITP and its treatment, including any bleeding occurrence, infection, and thrombosis. First-line therapy in VEPs more frequently utilised a combination of corticosteroids and intravenous immunoglobulin (IVIg) as opposed to single-agent corticosteroids. Factors associated with bleeding in VEPs included female sex, platelet count of <20 × 109/l and exposure to anticoagulants. Despite the insights provided by the Sokal et al.5 study and other large ITP registries that have examined EPs and VEPs, significant gaps in our knowledge persist. We lack prospective randomised controlled treatment trials for these age cohorts and recognise that elderly adults were typically excluded from clinical registration trials, due to age-related entry criteria, medical comorbidities, and, most important, selection bias exercised by investigators. Thus, we are relegated to analyse and apply the results generated from robust observational, registry-based studies to track the natural history of ITP and treatment responses in various subcohorts. In the study by Sokal et al.,5 which purports to describe the prospective real-world experience of primary ITP in France between 2013 and 2018, 251 of the 541 patients enrolled in the CARMEN-France registry were EPs or VEPs. However, an additional selection occurred such that 67 patients were subsequently excluded from the study group. The size of this excluded group (26·6%) is significant when compared with 97 in the EP group and 87 in the VEP group. A further analysis of these patients might identify potential pitfalls in the diagnosis and management of primary versus secondary ITP in the elderly. Of particular interest is whether their exclusion was related to bone marrow pathology or cytogenetic/mutational abnormalities. If their ITP was deemed secondary rather than primary this would have implications for how we should approach the diagnosis and follow-up of EPs and VEPs. Guidelines for the evaluation of isolated thrombocytopenia and ruling out secondary causes of ITP are not standardised and, as a primary example, the routine performance of bone marrow aspiration and biopsy is controversial. In the Italian Hematology Centers Registry,6 bone marrow biopsy was performed in only half of the studied patients. Per the International Working Group guidelines, a bone marrow biopsy is not recommended when the thrombocytopenia is isolated and there are no abnormalities on physical examination or on the peripheral blood film.8 And yet, age is a risk factor for clonal cytopenias and neoplasms. Studies indicate that 12% of myelodysplastic syndrome (MDS) may present with isolated thrombocytopenia of <100 × 109/l,9 the most common cytogenetic profile being normal. Up to 80% of secondary MDS have abnormal karyotypes, while <50% of patients with de novo MDS will have an abnormal karyocyte.10 Thus, next-generation sequencing on bone marrow aspirates may become a useful tool in EPs and VEPs with suspected ITP. Published clinical trials have typically considered the diagnosis of primary ITP to represent a ‘single’ disease entity, characterised by a ‘common’ thrombocytopenic phenotype. On the other hand, it is increasingly apparent that ITP is actually a heterogeneous disorder with disparate underlying pathophysiology and immunological triggers, which change with normal ageing and become exaggerated with extreme ageing. We lack ITP clinical trials that examine baseline and post-treatment changes in immunological repertoires; however, given the increased number of medical co-morbidities and changes to the immune milieu with age, it would not be surprising if nearly all primary ITP in EPs and VEPs results from secondary immunological phenomena. As observed by Cines et al.,11 primary ITP will comprise an ever-decreasing proportion of patients as specific inciting events and immune defects are better identified. Currently, we lack specific assays to define immunological dysfunction and immunosenescence, validated predictive biomarkers, or knowledge of their prevalence in different patient subpopulations. Nor do we have a complete understanding of the coagulation profiles in EPs with ITP that give rise to bleeding or, more rarely, thrombosis. The propensity for haemorrhagic or thrombotic complications is further confounded by concurrent comorbidities and antiplatelet and systemic anticoagulation strategies prevalent in EP and VEP cohorts. This issue speaks directly to the safety of various treatment modalities and how treatment decisions will be made in the EP and VEP. The currently available clinical guidelines do not specifically address treatment of ITP in EPs or VEPs, suggesting that the recommendations can be extrapolated across all adult age cohorts.8, 12 The lack of high-quality, prospective efficacy and safety data specific to EPs remains a major challenge when making clinical treatment decisions and clinicians must balance risk of harm with the promise of response. For example, corticosteroids remain an important front-line ITP therapy. Sokal et al.5 report higher than expected response rates to corticosteroids ± IVIg in VEPs and EPs. Yet, corticosteroids can incite or exacerbate problems already associated with ageing, including hypertension, hyperglycaemia, mood disturbances and agitation, and gastrointestinal (GI) bleeding. VEPs were particularly vulnerable to GI bleeding in this study (five of nine of the most serious bleeding events). Another knowledge gap involves the safety and efficacy in VEPs and EPs of the thrombopoietin receptor agonists (TPO-RAs). As observed in the French registry, and consistent with evolving guidelines in the management of ITP, TPO-RAs were the preferred second-line agent. However, age >60 years was a risk factor for venous thromboembolism (VTE) and VTE-associated mortality. The TPO-RAs have been associated with excess arterial thromboses, which is an important consideration in VEPs and EPs with underlying atrial fibrillation and peripheral arterial disease. The Italian Registry for elderly ITP reported the incidence of thromboses during TPO-RA treatment to be 3·6 per 100 patient-years, with a significant incidence of progression or recurrence, even in patients with severe thrombocytopenia or receiving concurrent antiplatelet/anticoagulant therapy.13 Clinical registration drug trials with the various TPO-RAs have included very few EPs and even fewer if any VEPs. There are no comparative safety or efficacy trial data among the TPO-RAs for any age groups but there are provocative data suggesting that the TPO-RAs may influence immune modulation by increasing regulatory T-cell activity and by decreasing release of certain inflammatory cytokines.14 This may be pertinent in EPs and VEPs, in whom dysfunction of regulatory T cells and dysregulation of immune homeostasis are involved in the development of different autoimmune diseases in old age.15 As we move into the future of treating patients with ITP of all ages, the immunoheterogeneity of this disease entity will need to be considered, particularly in EPs and VEPs. Ideally, these different profiles could lead to immune stratification in adequately powered randomised controlled trials in EP- and VEP-related ITP and may provide predictive biomarkers for safety and efficacy of new therapies. The success of this approach will require international collaboration. In this spirit, the Sokal et al.5 paper can serve as a ‘call to action’ for the creation of a single longitudinal, international registry, employing standardised definitions of diagnosis and safety and efficacy, and this effort should be combined with a biorepository to study the immunoregulation of ITP in all age cohorts. This aspirational endeavour offers the potential to understand real-world primary ITP versus ‘masked’ secondary ITP in the elderly.