During the 65th ASH meeting that took place in San Diego in December 2023, many interesting abstracts concerning immune thrombocytopenia have been presented, covering different topics from the pathogenesis to treatments, from diagnosis to bleeding and thrombotic risk.
Here you can find a summary of the most relevant presentations; for the complete list of the abstracts, please visit the American Society of Hematology official website.
Particular scenarios.
Old and new treatment approaches may have an application in particular settings, such as pregnancy and secondary ITP which are often excluded from clinical trials and label indications. Data about thrombocytopenia secondary to immunotherapy have been presented, and about the use of TPO-mimetics in patients with anti-phospholipid syndrome, that are at an increased thrombotic risk. In fact, it is now well known that ITP is not a mere bleeding disorder, encompassing thrombotic and infectious risks, influenced by both the pathophysiology of the disease and the treatments received.
ITP in pregnancy and secondary ITP
The management of ITP may be challenging both for chronic patients who become pregnant as well as for patients newly diagnosed during pregnancy.
Guillet S et al. compared outcomes between these groups. The rate of new diagnosis was comparable between trimesters. 41.2% experienced a bleeding event, and 76.5% required treatment, more frequently in the “newly diagnosed” group. Neonatal ITP was observed in nearly 20% of newborns. For most women, de novo ITP remained active after delivery. He Y et al. investigated the efficacy and safety of the combination of low-dose rhTPO plus IVIg in 19 corticosteroid-resistant ITP patients during pregnancy, achieving a favorable response rate without safety concerns. Chen Y et al. confirmed the efficacy of adding IVIg to corticosteroid therapy to achieve a rapid platelet count increase during pregnancy.
In patients with secondary ITP, particularly those at increased thrombotic risk, such as patients with antiphospholipid syndrome, the use of TPO-RAs is debatable.
Cindy M et al. reported on the use of TPO-RAs in SLE or antiphospholipid syndrome patients, highlighting thrombotic events as a significant concern, especially in patients with a history of APS and other thrombotic risk factors.
With the widespread adoption of immunotherapy, particularly checkpoint inhibitors known for their autoimmune complications, the issue of ITP secondary to immunotherapy (IO-ITP) has become a non-negligible occurrence in everyday clinical practice.
Grinsztejn E et al. compared patients who developed ITP secondary to immunotherapy (IO-ITP) to patients with primary ITP. They identified 241 individuals who had received a checkpoint inhibitor for solid cancers and subsequently developed ITP, compared with a cohort of 14.171 patients with primary ITP. The IO-ITP group exhibited a higher median age, and a more frequent use of TPO-RAs as second-line treatment, with romiplostim being the most commonly prescribed agent.
ITP: risk of infections, thrombosis and bleeding
Immunosuppressive treatment has remained a milestone in the management of ITP and, except for TPO-mimetics, old and new therapeutic approaches aim to suppress the immune system. Frandsen A et al. showed that, compared to the general population, primary ITP patients are at higher risk of infections, which remains higher for several years after the diagnosis.
Despite being primarily hemorrhagic, ITP carries an increased risk of thrombosis. Rast JS et al. evaluated the occurrence and risk factors for venous and arterial thrombotic events (VTE and ATE) in 160 ITP patients in Vienna. The incidence was 6.8% for ATE and 8.7% for VTE. Patients who developed a thrombotic event were older, with more comorbidities, including APS, and had more frequently undergone splenectomy. Conversely, disease duration and treatment with corticosteroids or TPO-RAs were not associated with an increased thrombotic risk.
Monzon Manzano E et al. shed light on platelet dysfunction in ITP patients, finding that this is more common in the elderly, probably contributing to a higher bleeding risk in this population.
The unpredictable disease course and limited predictive factors for treatment response, coupled with the need for frequent treatment changes and associated side effects, may significantly impact the quality of life for both ITP patients and physicians. Bussel JB et al. underscored this perception of an unmet need for well-tolerated therapies capable of curing ITP, as evidenced by the I-WISh 2.0 survey results.
During the 65th ASH meeting that took place in San Diego in December 2023, many interesting abstracts concerning immune thrombocytopenia have been presented, covering different topics from the pathogenesis to treatments, from diagnosis to bleeding and thrombotic risk.
Here you can find a summary of the most relevant presentations; for the complete list of the abstracts, please visit the American Society of Hematology official website.
Treatment of primary ITP.
In the last years we have become accustomed to seeing many advances in the treatment of ITP, and the latest ASH meeting did not disappoint us. Besides TPO-mimetics, which are widely used as second-line therapy, advances in other treatment modalities have been highlighted. They include the BTK inhibitor rilzabrutinib, the FcRn inhibitor efgartigimod, an anti-CD38 antibody, a JAK 1/2 kinase inhibitor, and even the preclinical data of an anti-CD19 CAR-T cell and in vitro data of an anti-GPIbα chimeric auto-antibody receptor T cell.
The efficacy and safety of TPO-mimetics when used early in the course of the disease was explored by Virk Z et al., comparing the outcomes of patients treated with avatrombopag before (23) or during chronic phase (55). No differences were observed in terms of efficacy (considering both platelet response and bleeding events) and safety, with special focus on the occurrence of thrombocytosis and thromboembolic events with only one patient in the chronic group who developed a VTE.
TPO-mimetics are widely used as second-line therapy. Kuter D et al. reported on 375 patients with primary ITP lasting ≥3 months who were started with either TPO-RAs (51%) or rituximab (49%). A higher proportion of patients switched from rituximab to TPO-RAs (23.6%) than vice versa (9%). In both groups, the rate of bleeding events was 288 per 1000 person-years, thromboembolic events were 129 and infections 70 per 1000 person-years.
The use of high dose romiplostim (10mcg/kg) in patients with severe bleeding to rapidly increase platelet counts is quite common in clinical practice. However, King E et al. found that this practice significantly increased thrombotic events without affecting platelet response or time to response.
Yin J et al. and Fu H et al. explored the safety and efficacy of the combination of rhTPO plus either hetrombopag or eltrombopag. The first study enrolled 30 patients with severe ITP, mostly newly diagnosed. Platelet response was quick (a median of 4.5 days to reach a platelet count > 30×109/L), and no thrombotic events were reported. Similar results were reported by Fu H et al. with the combination of eltrombopag and rhTPO.
Beyond TPO-mimetics, promising results emerged from trials involving BTK inhibitors and efgartigimod. Cooper N et al. reported the results of part B phase 1/2 study with rilzabrutinib. 26 patients with relapsed/refractory ITP received rilzabrutinib 400 mg bid. The primary endpoint of durable platelet response was achieved by 9 patients (35%). Notably, 25% of patients achieved platelet counts ≥50×109/L by day 15 of treatment. Common AEs included diarrhea, headache and nausea. Tarantino M et al. reported on the effects of rilzabrutinib on bleeding and health-related quality of life (HRQoL).
Broome C et al. highlighted the rapid platelet count increase, within the first 7 days after treatment with efgartigimod in the phase 3 ADVANCE IV study.
New therapeutic approaches include cellular therapy, anti-CD38 antibodies and kinase inhibitors.
Wang Y et al. demonstrated the efficacy of CD19 CAR-T cells in a murine model of ITP, showing a significant increase in platelet count, and a decrease in the percentage of CD19+ B cells, CD138+ plasma cells, and antiplatelet antibodies.
Zhou J et al. developed anti-GPIbα chimeric auto-antibody receptor (CAAR) T cells that identify and eliminate autoreactive B cells, with promising results in vitro.
Chen Y et al. conducted a phase I study to explore the safety and efficacy of umbilical cord-derived mesenchymal stem cells (UC-MSCs) in 18 patients with R/R ITP, reporting a 44.4% response rate, with an acceptable safety profile.
Chen Y et al. reported encouraging results from a phase II trial with CM313, an anti-CD38 antibody administered weekly for 8 weeks: the primary endpoint of a platelet count ≥50×10 9/L within 8 weeks after the first dose was achieved by all seven evaluable patients.
Zhao P et al. evaluated the efficacy of baricitinib, a JAK 1/2 kinase inhibitor, in a randomized phase II trial, as first-line treatment in combination with high-dose dexamethasone, demonstrating a higher sustained response rate at 6 months, compared to dexamethasone alone.
During the 65th ASH meeting that took place in San Diego in December 2023, many interesting abstracts concerning immune thrombocytopenia have been presented, covering different topics from the pathogenesis to treatments, from diagnosis to bleeding and thrombotic risk.
Here you can find a summary of the most relevant presentations; for the complete list of the abstracts, please visit the American Society of Hematology official website.
Pathogenesis and diagnosis.
The pathogenesis of ITP is not fully understood, likely involving a complex interplay of multiple mechanisms that cooperate to increase platelet clearance and impair megakaryocyte activity. These mechanisms are probably initiated by antiplatelet antibodies and perpetuated by an abnormal activation of cytotoxic T cells, T helper cells, plasma cells and other immune effectors. Below you will read more about advances in understanding B and T-cell activity in ITP.
The occurrence of a moderate, isolated thrombocytopenia is rather frequent in everyday clinical practice, and it can be the manifestation of several diseases or conditions. The lack of a diagnostic test, or a diagnostic score for ITP complicates the diagnostic process, which frequently requires a panel of tests to rule out secondary causes or other diseases. Below you will read about a new diagnostic tool for differential diagnosis of primary versus secondary ITP. But clearly this issue is demanding further studies.
Pathogenesis
The role of antiplatelet antibodies in the pathogenesis of ITP is continuously under investigation. Han F et al. observed that patients with anti-GPIb antibodies respond less well to TPO-RA treatment, with impaired MK maturation in vitro. This finding was confirmed in animal model, where mice with GPIb alfa deficiency exhibited reduced responsiveness to TPO-RA treatment, inhibited MKpoiesis and platelet production, even in the presence of TPO.
Among cytokines, TGF-β1 seems to play a key role in ITP pathogenesis. Xu M et al. explored TGF-β1 in ITP patients treated with TPO-RAs, showing lower plasma activated TGF-β1 levels and regulatory T cells in non-responders and in those unable to achieve a sustained response. Lower levels of activated TGF-β1 in the bone marrow were associated with higher numbers of MKs, but impaired MKpoiesis. Knockout mice for TGF-β1 displayed reduced Treg cells, elevated M1 macrophages, and reduced response to TPO-RAs, which was restored by adding integrin αvβ8, which enhances TGF-β1 activation and promotes the formation of Tregs.
Iguratimod inhibits the production of several inflammatory cytokines by enhancing mitophagy, a process that eliminates damaged mitochondria. Chen Y et al. explored its effect in ITP. ITP patients’ CD4+ T cells exhibited compromised mitophagy and mitochondrial function, restored after Iguratimod treatment, along with rebalancing of Th1/Th2 lymphocytes, restoring Tregs and improving mitophagy and mitochondria function.
Diagnosis
The diagnosis of ITP may be challenging, and definite diagnostic criteria are still lacking. A new diagnostic tool proposed by the Japanese group (Kashiwagi H. et al.) integrates clinical features and laboratory markers into a scoring system designed to differentiate between hyporegenerative and consumption thrombocytopenia. Notably, this scoring system requires a normal or slightly increased plasma thrombopoietin (TPO) level and elevated percentage of immature platelets (IPF%) for the diagnosis of ITP. Validated on 112 thrombocytopenic patients, it showed a sensitivity of 53% and a specificity of 96%.
The occurrence of a mild-to-moderate isolated thrombocytopenia in asymptomatic patients is common in clinical practice. However, should this finding raise concern? Rudbeck Jule A. et al. explored whether such subjects carry a higher risk of hematological diseases and death. Their study, involving over 300.000 UK individuals aged 40-70 years and a validation cohort of over 100.000 Danish individuals, revealed an increased relative risk of hematologic disease and death, both from hematologic causes and overall, in individuals with thrombocytopenia with or without anemia. The 10-year absolute risk of death from hematologic disease remained below 5% for most combinations of sex, age, platelet count and hemoglobin, but was notably higher for men aged 60-70 years with mild anemia combined with moderate-severe thrombocytopenia, underscoring the need for special attention in this group.
ITP and other autoimmune cytopenias (AIC) can occur in the context of overt lymphoproliferative diseases requiring chemotherapy or be associated with indolent B-cell clones (IBC) that do not necessitate specific treatment. Zadro Y. et al. retrospectively reported on 187 adult patients with an AIC (ITP, AIHA or ES) associated with IBC, managed in France. Most of them (72%) were treated without chemotherapy, receiving corticosteroids, IVIg and rituximab, while the remaining (28%) received a chemotherapy-based treatment including cyclophosphamide, bendamustine and others. Interestingly, there was no difference in efficacy and safety between the two groups.
This is a multicenter, retrospective, European study to evaluate the standards of use of thrombopoietin receptor agonists (TPO-RA) in adult patients with primary ITP. Data will be collected through a retrospective chart review of patients with ITP who started TPO-RA treatment between January 2014 and December 2018.
Each of the 18 designated sites in the UK, Spain, Italy, Norway, France and Switzerland will collect data from patients with ITP who meet the inclusion criteria and agree to participate. The aim of the study is to provide a realistic and broad view of the use of TPO-RA in Europe at a time when so many new molecules are being tested in this disease, without being biased by the clinical practice of any particular center. The information to be analyzed will include patient or disease characteristics in the selection of TPO-RA, long-term efficacy and safety data of these agents, and treatment-free responses, among others.
This project was initiated in 2022 and will be completed in the middle of next year, when data from approximately 350 patients will have been collected. Currently, centers from the 6 European countries are actively recruiting and results of the study will be published by the end of 2024.
The project is coordinated by Maria Luisa Lozano, from the Hospital Universitario Morales Meseguer, Universidad de Murcia, Spain, and is conducted in collaboration with the Hematology Project Foundation, Vicenza, Italy.
After having described the registry sources (https://pubmed.ncbi.nlm.nih.gov/35303315/), ERCI launched a first feasibility study assessing the percentage of adult patients with primary ITP necessitating a 2nd (at least) line of treatment, and describing these lines. All European prospective registries gathering these data are participating: France, Germany, Italy, Norway, Switzerland and United Kingdom. The analyses will be performed in parallel in each country using the same protocol and statistical analysis plan. Aggregated results will be share for a common publication.
The next step will be to work on individual data linkage, with both regulatory and technical (data harmonization) tasks.
Among the abstracts presented on ITP biology at the last EHA 2023 annual meeting, the following are worth mentioning, concerning progresses which are being made in exploring ITP pathogenesis, and in particular megakaryocyte impairment, T cells abnormalities, mesenchymal stem cell disfunction, alterations of gut microbiota.
Yang P et al. evaluated CD4+ T cells in ITP pathogenesis, with particular focus on methylenetetrahydrofolate dehydrogenase 2 (MTHFD2), which was found to be upregulated in CD4+ T cells of ITP patients compared to healthy controls. The inhibition of MTHFD2 reduced the proliferation and activation of CD4+ T cells, reduced the proinflammatory cytokines and increased the percentage of T regulatory cells of ITP patients in vitro; same results could be obtained with Tacrolimus treatment in mice.
Megakaryocyte desyalilation is involved in impaired platelet production in ITP. MKs treated with IL-1beta exhibited increased neuraminidase-1 and consequently increased desyalilation. IL-1beta and IFN-beta were found to be upregulated in ITP patients. IL-1beta induces the STAT2-JAK pathway, which can be blocked by baricitinib, entailing a reduced desyalilation of MK in vitro and an in-vivo resolution of ITP in mice (Zhao P et al.).
Autophagy is a physiological process that allows normal cell growth; excessive autophagy leads to increased inflammation and cell death. Abnormalities in MK autophagy have already been described, and a study by Wu J et al. found defective activity of BM macrophages, resulting in impaired MK growth and platelet production. Chaperone-mediated autophagy (an autophagy which selectively degrades chaperone-labelled cargos in lysosomes) is also impaired in ITP and could be restored with specific treatment (Xu Y et al.).
Also mesenchymal stem cell deficiency is involved in ITP pathogenesis, and this may also be due to an abnormal complement activation (Zhu X et al.).
A report by Chen Q et al. suggested a role for progesterone in influencing the gut microbiota during pregnancy in ITP, which may interfere with mesenchymal stem cell functionality.
Among the abstracts presented at the 2023 EHA meeting, many focused on new drugs. In particular the FcRn inhibitor efgartigimod and the BTK inhibitors showed promising results, but also real-life experiences with fostamatinib, the TPO-mimetics and a meta-analysis on rituximab were presented.
Results of the ADVANCE+ study, a 52-week open-label extension (OLE) of the phase III, randomized, placebo-controlled trial with intravenous efgartigimod (the neonatal Fc receptor inhibitor) have been presented. 101 patients enrolled in the ADVANCE study entered the OLE and at the time of data analysis, 26.7% have completed the 52-week period, while 45.5% are still on treatment and 50% discontinued the study, 45% of them (23/51) due to lack of efficacy. Despite sustained reduction of 60% from baseline in total serum IgG levels, infections occurred in 33.7% of patients, mostly mild. The mean percentage of weeks with platelet count ≥50×109/L was 39.2% (Carpenedo M. et al.).
Orelabrutinib, an irreversible BTK inhibitor, is being tested as second-line therapy in a phase II trial in China, where patients are randomized to receive 50 mg/day (n=15 patients) or 30 mg/day (n=18 patients), with a permitted intra-patient dose-escalation in case of nonresponse. Overall, 12/33 patients (36.4%) experienced an increase in platelet count ≥50×109/L in the first 4 weeks of treatment. Responses were higher in the 50mg arm (40%) compared with the 30mg arm (22%), in which 12 patients needed to increase the dose. 27% achieved a durable response (platelet count ≥50×109/L for at least 4/6 visits). Adverse events were all grade 1-2 (Shi Y et al.).
Another BTK-inhibitor, zanubrutinib, has been administered in a phase I trial for a fixed-duration treatment of 6 weeks in 40 adult ITP patients resistant or relapsed after corticosteroid treatment. 22 patients (55%) achieved an overall response (platelet count ≥30×109/L). Notably, 6/22 were receiving a concomitant, non-corticosteroid treatment. The most common reported adverse events were infections, generally mild (Huang QS et al.).
The real-world use of fostamatinib has been explored by the French group within the CARMEN-ITP registry. 61 fostamatinib-treated patients from October 2021 to October 2022 were included, most of them with heavily pretreated, refractory ITP (5 median number of previous lines, median ITP duration 6.5 years). Response rate to fostamatinib was 30%, with a median duration of treatment of 2.2 months. 10 patients interrupted treatment due to inefficacy, 12 due to adverse drug reactions (Moulis G. et al.). The Spanish group has instead examined patients that, after having achieved a complete response, could taper and discontinue fostamatinib in the Spanish Fostasur observational, retrospective study. 44 patients were included, and the drug was successfully discontinued in 5 (11%). After a median follow-up of 11 weeks, only one patient relapsed, and responded again to fostamatinib resumption (Mingot-Castellano M.E. et al.).
The JAK1-2 kinase inhibitor baricitinib seems to inhibit IFN-induced antigen presentation: on these grounds a phase 2 trial with baricitinib fixed-duration (6 months) second-line therapy in adult patients with ITP is ongoing in China. 28 patients were treated, durable response (at 6 months) was achieved in 20 patients (71%), with a median time to response of 13 days. Nearly 50% of patients taking concomitant medications at baseline (steroids and TPO-mimetics) were able to discontinue the drugs (Zhao P. et al.).
A Chinese group also assessed the efficacy of a romiplostim biosimilar, QL0911 versus placebo in a randomized phase III trial of ITP adult patients who failed first-line therapy. Durable responses were achieved in 62% of patients treated with QL0911, significantly higher than the placebo group (as expected). No comparison with romiplostim was made (Zhou H. et al). A real-world study of hertrombopag, a TPO-mimetic made in China, showed that among 50 ITP patients with R/R ITP who started treatment, 46% responded at week 4, and 71% at week 12, with increasing rates of complete response. Treatment was more effective if administered as second-line option, and even in patients who previously failed eltrombopag (Feng Y et al.). An observational, retrospective study reported 14 years (2008 – 2022) of experience with TPO-mimetics in Barcelona, where 77 patients were treated, 57 with eltrombopag, 19 with romiplostim and 1 with avatrombopag. 89.6% of patients responded, treatment was successfully discontinued in 26% of them. 36% of patients switched the TPO-mimetic, and in 50% of cases switching was effective (Garcia-Pallarols F. et al.). Another single-center report from Spain retrospectively evaluated 96 patients treated with romiplostim or eltrombopag between 2010 and 2022. Response rates were similar to those previously reported, with a complete response rate of 86% with romiplostim and 70% with eltrombopag, and a discontinuation obtained in nearly 25% of patients (Martinez C. et al.).
A meta-analysis including five randomized controlled trials of rituximab + standard of care vs standard of care (463 patients in total) found that rituximab increased short-term (within 3 months) partial response and long-term (>6 months) partial and complete response, with a trend towards more infections in the rituximab arm. Data concerning follow-up longer than 12 months are scarce (Eshaghpour A et al.).
In the 28th European Hematology Association Congress, that took place in Frankfurt last June, interesting abstracts concerning different aspects of immune thrombocytopenia (ITP) were presented.
Here you can find a summary of the abstracts about ITP in pregnancy and others such as quality of life of ITP patients, and the search for factors predictive of response to splenectomy and rilzabrutinib.
For other topics, including the impact of COVID-19 and COVID-19 vaccination on ITP, the management of ITP in specific realities, such as Greece, Norway, Algeria, Tunisia and others see the 2023EHA abstract book.
General topics.
A large Danish population cohort study which enrolled 4.768 patients with newly diagnosed, primary ITP from 1980 to 2016, explored the incidence of solid and hematological cancers, compared to general population controls. Patients with ITP had a higher incidence of both hematological (leukemias and lymphomas) and solid cancers (more frequently upper gastrointestinal) (HR 7.43 and 1.29 respectively). Of note, the difference with the general population diminished over time, and equalized for solid cancers (Mannering N. et al.).
The results of the global I-WISH 2.0 survey, addressed to ITP patients and medical doctors, reported on the emotional burden of the disease and the impact on quality of life in terms of fatigue, concentration issues, financial burden, and treatment adherence (Cooper N et al).
A score predicting response to splenectomy was proposed by Zoletto S et al. that included age at diagnosis, autoimmune comorbidities, and dose of pre-splenectomy corticosteroids. It was tested on 25 patients and confirmed in 39, and it will need further validation.
Kuter D et al. explored baseline TPO levels in patients treated with rilzabrutinib, a BTK inhibitor, in the phase I/II trial: median baseline levels were in accordance with that expected (94 pg/mL), and decreased during treatment, concurrently with the increase of platelet counts. No association was observed between baseline platelet or TPO levels and platelets at week 12 or 24. Interestingly, rilzabrutinib was associated with stable B cell levels.
ITP in pregnancy.
Maternal and fetal outcomes in pregnancies of women with ITP in Italy were reported by Carpenedo M et al. Data of 95 pregnancies were retrospectively collected; in 68% of cases women had a prior diagnosis of ITP, but only one was already on treatment (cyclosporine). 65% were treated with first line during pregnancy, 21% received a second-line treatment and 8% a third line. In most cases, women were treated to reach a safe platelet count for delivery. TPO-mimetics were used in 7 cases. Thrombocytopenia was present in 17% of neonates, without life-threatening bleeding. Reports of TPO-mimetics in pregnancy are constantly increasing and their use in the third trimester seems safe for the mother and the baby, in cases of severe, refractory ITP with no other options (Sayed G et al.).
In 2007 an International Working Group (IWG) of ITP experts came together to propose a standardized terminology on ITP, with the aim of establishing a common language that would have benefit research, knowledge sharing and ultimately patients. This effort resulted in the publication in 2009 of the paper “Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children: report from an international working group”, which for the first time proposed the adoption of the term “Immune Thrombocytopenia” (ITP) and defined relevant outcomes and important aspects of the disease and its management.
The introduction of innovative drugs, in particular of TPO receptor agonists, and a better knowledge of ITP pathophysiology profoundly modified the clinical practice in ITP over the last 15 years and has made necessary an update of some of the previous definitions and terms, as well as the establishment of consensus on novel concepts.
The goal of this project is to produce a new standardization document, updated to the current knowledge and practice standards, using a modified Delphi method.
A Steering Committee (SC), composed by all ERCI founding members plus 5 major international ITP experts, has been formed and has started working on updated and novel definitions. The SC will soon produce a first draft of definitions and highlight areas of agreement and disagreement on different concepts.
Subsequently, a large international group of hematologists with expertise in ITP from North and South America, Europe, Asia, Africa and Australia, as well as patients advocates and representatives of EMA and FDA will be involved. The definitions drafted by the SC will finally be submitted to this large group of people in the form of a Delphi questionnaire to be further reviewed and improved with the aim of reaching a full consensus.
The project is coordinated by ERCI founding members and Co-chairs Prof. Francesco Rodeghiero (Hematology Project Foundation, Vicenza, Italy) and Prof. Cindy Neunert (Columbia University Medical Center, New York, US).
The 64th ASH annual meeting left us with a huge amount of news and food for thoughts, concerning several aspects of ITP, from diagnosis to treatment, from pathogenesis to predictive factors of response. For instance, can we confidently reassure a patient with an isolated, mild thrombocytopenia? May antiplatelet antibodies not just enhance platelet clearance, but also, by their binding, affect platelet function, thus explaining the different clinical phenotypes? Growing evidence supports the role of T cells in the pathogenesis of ITP, by participating to bone marrow dysfunction and mediating the lysis of circulating platelets. However, the role of antiplatelet antibodies remains unquestioned, as testified by the results of the phase III trial with Efgartigimod, a specific FcRn inhibitor. Efforts are being made in seeking factors predictive of response to treatment, both clinical and biologic. Is ITP just a matter of bleeding risk, or should we begin to consider it as a more “systemic” disease? You can find the answers to some of these questions in the next lines and if not, online at https://www.hematology.org/meetings/annual-meeting.
Epidemiology. A retrospective cohort study evaluated the long-term outcome of 91 patients with persistent isolated mild thrombocytopenia (PIMT), i.e. patients with a platelet count between 100 and 149×109/L. Compared to subjects with a normal platelet count, PIMT patients had a higher risk of developing after several years some hematological diseases (30.8% vs 1.9%): in most cases ITP, but also myelodysplastic syndrome (MDS), myeloproliferative neoplasms (MPN) and non-Hodgkin lymphoma, as well as systemic autoimmune diseases (Ayad et al. abs n° 19). These findings, if confirmed by prospective studies, may question the threshold of “low” platelet count which deserves further evaluation, and whether those subjects need a closer follow-up. For patients with a platelet count less then 100×10^9/L, the differential diagnosis is usually straightforward, however, in some cases of mild thrombocytopenia without a clear evidence of bone marrow dysplasia, the etiology may be tough. In such cases, the use of additional parameters may help, such as platelet indices and thrombopoietin (TPO) serum levels: compare to MDS, patients with ITP have usually higher immature platelet fraction and lower TPO serum levels. (Lucchini et al. abs n° 3765).
In the diagnostic work-up, it is important not to forget about the correlation of thrombocytopenia and Helicobacter pylori (HP) infection, especially in endemic areas. Platelet count of patients who tested positive for HP by urea breath test and serology do benefit from HP eradication (Siritham et al. abs n°917).
Biology. Bone marrow (BM) in ITP participates to the pathogenesis of the disease, probably as a target of the impaired immune system. BM of 40 ITP patients in 3 different stages of the disease (newly diagnosed treatment naïve, persistent-phase treatment-naïve, and relapsed patients) and 10 healthy controls was analyzed by Cytometry by Time of Flight (CyTOF). Compared with healthy controls, ITP patients had a higher proportion of monocytes and myeloid DCs. The proportion of CD4+ naïve and CD8+ naïve T cells was decreased in BM of ITP patients, while the proportion of CD8+ effector T cells was increased, with a reduced expression of the coinhibitory molecule CTLA-4, and an enhanced expression of the costimulatory molecules CD28 and ICOS (Liu et al. abs n° 914). These findings show that in the bone marrow of ITP patients, T-cells are active and armed, but against what? May they be armed against platelet antigens? In the peripheral blood of ITP patients, terminally differentiated effector memory CD8+ T cells (TEMRA) are oligoclonally expanded and functionally active. The clonally expanded TEMRA CD8+ T cells are not virus-driven, persist over the years and correlate with disease activity. When co-cultured with platelets, CD8+ T cells bind-to and directly cause platelet activation and death (Malik et al. abs n° 915).
So, would a treatment against T lymphocytes be effective? The mTOR inhibitor, Rapamycin, was tested both in vitro and in a mouse model of ITP, showing an inhibition of CD8+ T cell activity (reduced levels of granzyme B and perforin), and an increase in platelet counts. (Ni et al. abs n° 3764). The role of T cells in the pathogenesis of ITP can also be inferred from the response achieved to B-cell directed treatments. B cell activation markers (BAFF, APRIL) resulted higher in patients who responded to splenectomy, while patients who did not had higher T and NK cell functionality and cytotoxicity (Li at al. abs n° 916).
Has Eltrombopag an immunomodulatory effect on T cells? Eltrombopag in vitro suppresses the proliferation of T cells, probably due to its iron-chelating action. In fact, Deferoxamine induces the same cell cycle arrest to G1 phase, but in a less potent way. This effect is not seen with Romiplostim or rhTPO, that do not exhibit iron-chelating property. Furthermore, the addition of iron to Eltrombopag-treated T-cells restores cell proliferation. In vivo, patients who respond to Eltrombopag, display a reduction in the frequency of CD8+ TEMRA cells, suggesting an immunomodulatory effect of the drug (Tan et al. abs n° 2451).
Risk of bleeding and thrombosis in ITP.
ITP is mainly a bleeding disorder, but the thrombotic risk associated with the disease is not negligible, especially for some patients undergoing specific treatments. Venous Thromboembolism (VTE) is a non-negligible complication in patients with chronic ITP affecting 1.4 per 100 person-years. Low platelet count doesn’t seem to protect from VTE, but in the majority of cases patients had concurrent risk factors for thromboembolism. Arterial thromboembolism is also a non-infrequent complication (2 per 100 person-years), and often these patients are sub-optimally managed, likely due to the concern of the physician in treating them. The use of anticoagulation is therefore fundamental to prevent thrombosis in such patients: ITP management must aim to obtain the safest platelet count which allows the use of anticoagulation and/or antiplatelet agents (Wang et al. abs n° 22, 24). To support that, a French report showed that, in such patients, the use of one antiplatelet agent (acetylsalicylic acid) does not increase the risk of bleeding, compared to using two (Ollier et al. abs n° 23).
Bleeding symptoms are highly variable in ITP patients, and patients with the same platelet count may have different bleeding diathesis. Bleeding diathesis may be related to the epitope-specificity of the anti-platelet autoantibody: each epitope-specific antibody can differently alter platelet physiology and functionality. Anti-GPIIb/IIIa antibodies that bind to either the head or tail region of aIIb increased the expression of phosphatidylserine, the opposite effect is obtained with autoantibodies that bind to bIIIa. Anti-GPIIb/IIIa with other epitope specificity alter platelet spreading area and adhesion (Shaver et al. abs n°913). These findings show that, besides enhancing platelet clearance, anti-platelet antibodies may also impair platelet functionality. Bleeding can also manifest in a more subtle way, and also microbleeds may be dangerous and lead to clinical consequences, for example thinking about cerebral microbleeds (CMB) in children. Cerebral MRI found CMB in 5/38 children with ITP, all chronic; the presence of CMB correlated with higher bleeding score, while there was no correlation with disease duration, cognitive impairment, fatigue and health-related quality of life (Hart et al. abs n°21).
Is ITP just a matter of hemostasis?ITP doesn’t seem to only affect platelet count: fatigue, memory and concentration issues are symptoms patients often complain of. Is there a cognitive impairment in ITP? Episodic memory was the most damaged when evaluated with the CANTAB tool, and risk factors for such impairment were higher organ bleeding score, older age at diagnosis and at time of cognitive test, and a major number of ITP treatments received (Vladescu et al. abs n° 2447). Patients enrolled in the phase 1/2 Rilzabrutinib trial, who underwent the Cogstate Brief Battery test, showed a cognitive impairment both for psychomotor/attention, and for learning/memory skills (Kuter et al. abs n° 3773). Moreover, ITP patients are more likely to suffer from psychiatric conditions, such as depression, anxiety, obsessive-compulsive disorder and fatigue if compared to the general population (Mannering et al. abs n° 3768).
Treatment.
The efficacy and safety of intravenous Efgartigimod (a specific FcRn inhibitor) in adult patients with persistent or chronic ITP was evaluated in the phase III, placebo controlled ADVANCE trial. 131 heavily pretreated participants were randomized 2:1 to receive intravenously Efgartigimod or Placebo for 12 weeks. Efgartigimod showed superiority in terms of sustained response (platelet ≥50×10^9/L in ≥4 of 6 visits between weeks 19 and 24, without rescue therapy), which was achieved in 22% of patients (vs 5% in the placebo group), response rate according to IWG criteria (51% vs 20%), and onset of platelet response, without raising concerns in terms of toxicity (Broome et al. abs n°3, selected for Plenary Session presentation).
Is discontinuation of thrombopoietin receptor-agonists feasible in the real-life setting? A retrospective Spanish experience enrolled 133 patients, 75 treated with Eltrombopag and 13 with Romiplostim. 4/13 patients could discontinue Romiplostim, without need of further therapy, while 25/75 could discontinue Eltrombopag and maintain the remission. Globally, 33% of patients could successfully discontinue the TPO-RA. They also described a cohort of patients who switched from one TPO-RA to another, and treatment-free responses were observed also in this group (Ramirez Lopez et al. abs n°1127). A report from the German prospective study (RISA) of patients treated with Eltrombopag, confirmed the efficacy and safety of the drug. Notably, treatment was discontinued in 128/313 (42%) of patients, in most cases (43%) due to lack of efficacy, but 12% of patients discontinued the drug due to complete response (Meyer et al. abs n° 1130).
The efficacy of the combination of eltrombopag and rituximab over eltrombopag alone was reported in a single center, retrospective experience: 69 patients were treated in the combination arm and 53 in the eltrombopag group. Patients treated in the combination arm had higher rate of response at 12 and 24 weeks (72% vs 54% and 70% vs 50%) and also higher rates of treatment-free remission after eltrombopag discontinuation (25% vs 9%) (Yanmei et al. abs n° 2453). Eltrombopag may also be combined with other agents: an ongoing Chinese randomized phase II study is testing the efficacy of Eltrombopag plus Diacerein (which has shown to sensitize Megakaryocytes to TPO-RAs) versus Eltrombopag alone. Patients in the combination arm had a higher rate of initial responses, duration of response and less bleeding events (Sun et al. abs n° 3767).
Earlier use of Romiplostim was explored in a retrospective study, enrolling 78 patients with ITP diagnosis less than 12 months. Patients included in this study were treated either with Romiplostim or with immunosuppressive drugs (steroids, IVIg, Rituximab, Azathioprine, Cyclosporine, Danazol); those belonging to the first group reached a slightly higher median platelet count, had less bleeding events and could discontinue steroids earlier (McDonald et al. abs n° 1128). The growing availability of new drugs, targeting different mechanisms of ITP pathogenesis, and the exciting perspective of combining them, will deeply change ITP management in the next years. However, the issue of refractory ITP remains a challenging scenario, even though limited to a small proportion of patients. Data from the CARMEN-France registry, including all cases of incident ITP in adults since 2013, detected 32 (3%) patients refractory to both eltrombopag and romiplostim, and 24 (2.2%) refractory to both TPO-RAs and Rituximab. This group of patients is at high risk of bleeding (experienced by 100% of them), infection (25-29%), venous (8-9%) and arterial (3-4%) thrombosis, and hospitalization. Despite infrequent, multi-refractory ITP is a high-burden disease, with a non-negligible risk of infections (Moulis et al. abs n° 2449).
Factors predictive of response to treatment. A study of 275 patients with primary ITP explored the impact of body mass index (BMI) on ITP outcome. Patients were divided into 4 groups based on the degree of the overweight. Patients with higher BMI were more likely to require treatment, were more steroids dependent and needed more lines of therapy. No difference was found in terms of the level of response, time to response, refractoriness, bleeding and thrombotic complications (Xiao et al. abs n° 20). By evaluating lymphocyte subsets, cytokines, antiplatelet antibodies, lymphocytes subpopulations and some clinical parameters, a predictive scoring model of response to TPO-RAs versus corticosteroids, was proposed. Baseline levels of TGF-beta1 were positively correlated with the efficacy of TPO-RA, while baseline TPO levels were not. IP-10 (interferon-gamma induced protein 10) levels were good to predict corticosteroid efficacy. The predictive score attributed 1 point to each parameter, and based on the sum, the likelihood to respond to one treatment was determined (Xu et al. abs n° 1133).
ITP, vaccination and COVID-19. A retrospective study of 442 ITP patients found that 18/60 newly diagnosed had COVID-19-related-ITP: in 5 patients related to the infection and in 13 patients related to COVID-19 vaccine. Vax-ITP patients were older and responded less well to therapy. 69/382 patients had a relapse of ITP, in 52% related either to COVID-19 infection (1 case) or vaccination (35 cases) (Auteri et al. abs n° 3761). Another report did not find a higher ITP relapse rate following SARS-CoV-2 vaccination, compared to ITP relapse rate before COVID-19 pandemic (Stefani et al. abs n° 2444). The rate of ITP relapse during COVID-19 infection or vaccination appears low also in children and young adults, and usually the decrease in platelet counts is transient (MacWhirter et al. abs n° 1138).
DISCLAIMER: This selection of abstracts should not be intended as an appreciation of their relevance or as an encouragement to use their content to support clinical decisions.
