Prednisone vs high-dose dexamethasone in newly diagnosed adult primary immune thrombocytopenia: a randomized trial.

ABSTRACT: A debate exists regarding which type of corticosteroids (standard-dose prednisone [PDN] or high-dose dexamethasone [HD-DXM]) is the best first-line treatment for adult patients with newly diagnosed untreated primary immune thrombocytopenia (pITP). An ad hoc study compared PDN with HD-DXM in newly diagnosed untreated patients with pITP (aged ≥18 but ≤80 years, platelet count of ≤20 or >20 but <50 × 109/L, and bleeding score of ≥8). Patients were randomised to receive PDN 1 mg/kg per day from days 0 to 28 (Arm A) or HD-DXM 40 mg per day for 4 days, every 14 days, for 3 consecutive courses (Arm B). Fifty-nine of 113 patients (52.2%) were randomized to Arm A and 54 of 113 (47.8%) to Arm B. In evaluable patients, total initial responses (complete response [CR], partial response [PR], minimal response [MR]) were 44 of 56 (78.57%) in Arm A and 46 of 49 (93.88%) in Arm B at days 42 and 46, respectively (P = 0.0284). Total final responses (at day 180 from initial response) were 26 of 43 (60.47%) in Arm A and 23 of 39 (58.97%) in Arm B (P = 0.8907). Total persistent responses (at 12 months from initial response) were 25 of 31 (80.65%) in Arm A and 20 of 36 (55.56%) in Arm B (P = 0.0292). Seven relapses occurred. Median follow-up was 44.4 months. Overall survival was 100% at 48 months, overall disease-free survival was 81.11% at 48 months from day 180. PDN and pulsed HD-DXM were well tolerated; HD-DXM allows effective initial responses but less long lasting than PDN. This trial was registered at www.clinicaltrials.gov as #NCT00657410.

Efficacy and safety of the neonatal Fc receptor inhibitor efgartigimod in adults with primary immune thrombocytopenia (ADVANCE IV): a multicentre, randomised, placebo-controlled, phase 3 trial.

BACKGROUND: Primary immune thrombocytopenia is an autoimmune disorder mediated partly by platelet autoantibodies, resulting in thrombocytopenia, bleeding, and constitutional symptoms. Efgartigimod, a first-in-class novel human IgG1 Fc fragment, binds the neonatal Fc receptor with high affinity and thus reduces serum IgG concentrations, including autoantibodies. The objective of this study was to evaluate the efficacy and safety of efgartigimod in adults with persistent and chronic primary immune thrombocytopenia. METHODS: This phase 3, multicentre, randomised, double-blinded, placebo-controlled, 24-week study evaluated the efficacy and safety of intravenous efgartigimod in adults aged 18 years or older with chronic or persistent primary immune thrombocytopenia who had an average platelet count of less than 30 000, had responded to at least one previous immune thrombocytopenia therapy, and were on a concurrent therapy at baseline or had received at least a second previous immune thrombocytopenia therapy. The study took place in 71 participating sites from Asia, Europe, and North America. Patients were randomly assigned 2:1 to receive either efgartigimod (10 mg/kg) or placebo intravenously for the first 4 weeks, after which the dosing schedule could be altered to once per week or every other week depending on the patients' platelet count. The primary endpoint, evaluated in the chronic population, was sustained platelet count response (≥50 × 109 for at least 4 of the last 6 weeks). This study is registered with ClinicalTrials.gov (NCT04188379) and is completed. FINDINGS: A total of 205 patients were screened from Dec 9, 2019, to Feb 3, 2022, and 131 (86 in the efgartigimod group; 45 in the placebo group) were randomly assigned. These patients represented a population with long-term disease who had a mean time since diagnosis of 10·6 years and 67% (88/131) of whom had received at least three previous immune thrombocytopenia treatments. 22% (17/78) of patients with chronic immune thrombocytopenia receiving efgartigimod reached the primary endpoint compared with 5% (2/40) of those receiving placebo (p=0·032; adjusted difference in response, 16% [95% CI 2·6-26·4]). The median number of weeks of disease control in patients with chronic immune thrombocytopenia was 2·0 (IQR 0·0-11·0) for efgartigimod versus 0·0 (0·0-1·0) for placebo (p=0·0009). Efgartigimod was well tolerated; most adverse events were mild to moderate in severity. The most common adverse events of interest in both groups were headache (16% in efgartigimod and 13% in placebo), haematuria (16% in efgartigimod and 16% in placebo), and petechiae (15% in efgartigimod and 27% in placebo). INTERPRETATION: Efgartigimod significantly increased sustained platelet count responses compared with placebo in patients with chronic immune thrombocytopenia, including those who had received multiple previous immune thrombocytopenia therapies. Upon completion of the ADVANCE IV study, patients could enroll in the ongoing open-label extension. Subcutaneous efgartigimod is currently being evaluated in patients with immune thrombocytopenia in the ADVANCE SC+ trial. FUNDING: argenx.

Use and positioning of fostamatinib in the management of primary chronic immune thrombocytopenia: an Italian expert opinion.

Fostamatinib, a spleen tyrosine kinase (Syk) inhibitor, represents a new therapeutic opportunity for patients with immune thrombocytopenia (ITP) in Europe and Italy. However, the positioning of this drug in patient's therapeutic sequence is undefined within the most recent international guidelines. The conclusions from a consensus meeting between Italian experts, whose task was to outline the profile of the ideal candidate to receive fostamatinib, are reported here. A modified Delphi methodology was used to achieve shared statements, which were reported in a narrative form. In particular, the panelists examined the strengths and weaknesses of the registration studies in terms of clinical outcomes, the safety profile of fostamatinib, the drug's impact on the quality of life of patients with chronic ITP, and the potential benefits of its use in the pandemic era. Although the experience with thrombopoietin receptor agonists (TPO-RAs) and the amount of data from real-world studies suggest the preferential use of these drugs as a second-line treatment in most patients, the absence of an increased thrombotic risk in the clinical trials could make fostamatinib a reasonable choice in patients with an increased risk of vascular events. An unstable platelet count during TPO-RAs might also justify a switch to the Syk inhibitor, which is more likely to stabilize the platelet count in responders. Fostamatinib may be preferred to immunosuppressors during the SARS-CoV-2 pandemic, in patients at infectious risk, or in case of contraindication to splenectomy. Finally, the novel mechanism of action makes it an attractive drug in multi-refractory patient.

Nationwide Survey on the Use of Thrombopoietin Receptor Agonists (TPO-RA) for the Management of Immune Thrombocytopenia in Current Clinical Practice in Italy.

Background: Two thrombopoietin receptor agonists (TPO-RA), romiplostim and eltrombopag, are currently widely adopted as second-line ITP therapy even in the absence of robust evidence on their comparative advantages over rituximab or splenectomy or their preferential use in some specific clinical contexts. Methods: An online survey was distributed between May 2021 and June 2021 to collect standardized information on TPO-RA use in Italy. Results: Eighty-eight hematologists from 79 centers completed the survey. Eighty-four percent would use TPO-RA earlier than formally indicated, without a preference for young or elderly in 82% of respondents. No clear preference for either romiplostim or eltrombopag was indicated. Seventy-two percent would use TPO-RA in young patients aiming at a complete response followed by tapering, a strategy considered by only 16% in the elderly. Switching between the two agents was considered appropriate in case of insufficient response or intolerance. Tapering schedule by reducing the dosage and prolonging the intervals between administrations was preferred by 73% of respondents. TPO-RA was considered a risk factor for thrombosis by only 35%, and 94% would administer TPO-RA in elderly patients also in the presence of other thrombotic risk factors. Thirty-three percent of respondents would withdraw TPO-RA in case of thrombosis. The TPORA administration has been reported to be preferred over anti-CD20 or splenectomy by about half of the participants due to the ongoing COVID-19 pandemic. Conclusions: Significant discrepancies in TPO-RA use emerged from the survey, and participants would appreciate consensus-based specific guidance on the practical use of TPO-RA.

Recent progress in ITP treatment.

In this review, the recently approved drugs avatrombopag and fostamatinib, which were not extensively covered within 2019 international recommendations for ITP, will be discussed in some detail. Avatrombopag appears more convenient than eltrombopag as it does not require dietary restrictions or subcutaneous administration like romiplostim. However, data on quality of life (QoL) are lacking and the rate of thromboembolic events in exposed patients is not negligible. Efficacy of fostamatinib, an inhibitor of macrophagic activity, is supported by placebo-controlled trials in patients refractory to several therapies, including TPO-RA. While hypertension and diarrhea have been reported, only one minor thrombotic event occurred in 146 exposed patients. In addition, several new treatment combinations and new agents entered clinical investigation in recent years. In a UK trial, combining mycophenolate mofetil with corticosteroids as first line therapy was more effective than corticosteroids alone, but at the cost of worse QoL. No combination, including oseltamivir or all-trans retinoic acid or danazol, resulted in convincing evidence of superior efficacy and safety when used in first or later lines of treatment. Agents targeting specific mechanisms are also discussed: sutimlimab (complement inhibitor); rilzabrutinib (BTK inhibitor) and efgartigimod (modified Fc fragment inhibiting FcRn). Only efgartigimod has completed phase 3 investigation.

Acute promyelocytic leukaemia long-term survivors: higher fatigue and greater overall symptom burden.

OBJECTIVE: We aimed to investigate the association of fatigue with severity of other key cancer symptoms, as well as symptom interference with daily activities and outlook on life, in long-term survivors of acute promyelocytic leukaemia (APL). METHODS: The study sample consisted of APL survivors (n=244), with a median time from diagnosis of 14.3 years (IQR=11.1-16.9 years), previously enrolled in a long-term follow-up study. Symptom severity and symptom interference were assessed using the well-validated MD Anderson Symptom Inventory (MDASI). Fatigue was evaluated with the Functional Assessment of Chronic Illness Therapy-Fatigue questionnaire. RESULTS: Higher fatigue burden was associated with increased affective symptoms, memory problems, drowsiness, sleep disturbances, shortness of breath and pain. Higher levels of fatigue were also associated with higher scores across all interference items of the MDASI. Overall, symptoms interfered most with mood, but among APL survivors with high levels of fatigue, symptoms interfered most with enjoyment of life. Multivariable regression analysis confirmed the independent association between fatigue and all symptom severity items of the MDASI. CONCLUSIONS: The current findings show that long-term APL survivors who report higher fatigue also experience a greater overall symptom burden and a substantial impact on performance of daily activities. Further studies are needed to examine whether interventions aimed at reducing fatigue could also reduce overall symptom burden.

Association of Platelet Thromboxane Inhibition by Low-Dose Aspirin With Platelet Count and Cytoreductive Therapy in Essential Thrombocythemia.

Essential thrombocythemia (ET) is a myeloproliferative neoplasm characterized by enhanced platelet production and thrombotic complications. The inhibition of platelet cyclooxygenase (COX) activity by the standard once-daily aspirin is mostly incomplete due to accelerated thrombopoiesis. The phase II Aspirin Regimens in EsSential thrombocythemia (ARES) trial has recently compared the efficacy of once- vs. twice- or three-times daily low-dose aspirin in inhibiting platelet thromboxane (TX) A2 production, as reflected by serum (s) TXB2 measurements. The present substudy characterized the determinants of the highly variable response to the standard aspirin 100 mg once-daily regimen in fully compliant patients with ET and the effects of the experimental dosing regimens on response variability. By multivariable analysis, the platelet count (directly) and cytoreductive treatment (inversely) were significantly associated with sTXB2 values in 218 patients with ET. However, the platelet count positively correlated with sTXB2 in patients not being treated with cytoreductive drugs (ρ = 0.51, P < 0.01, n = 84), but not in patients on cytoreduction. Patients in the lowest sTXB2 quartile were older, more often on cytoreductive drugs, had lower platelet count and Janus-Associated Kinase2 (JAK2)-V617F allele frequency as compared with patients in the upper sTXB2 quartiles. After 2 weeks of a twice- or 3-times daily aspirin regimen, the association between the platelet count and sTXB2 became similar in cytoreduced and non-cytoreduced patients. In conclusion, the platelet count appears the strongest determinant of TXA2 inhibition by once-daily low-dose aspirin in ET, with different patterns depending of cytoreductive treatment. More frequent aspirin dosing restores adequate platelet inhibition and reduces interindividual variability, independently of cytoreduction.

Extensive variability in platelet, bleeding, and QOL outcome measures in adult and pediatric ITP: Communication from the ISTH SSC subcommittee on platelet immunology.

INTRODUCTION: Despite publication of standardization recommendations by the immune thrombocytopenia (ITP) International Working Group (IWG) in 2009, there remains inconsistent outcomes definitions across ITP studies. To understand current practices and inform future standardization efforts, we characterized how outcomes have been measured following publication of IWG recommendations. METHODS: PubMed/MEDLINE-indexed manuscripts published from January 2010 through December 2019 describing platelet, bleeding, and/or health-related quality of life (HRQoL) outcome measures in adult and pediatric ITP were comprehensively reviewed. This project was endorsed by the Platelet Immunology SSC of the ISTH. RESULTS: The PubMed/MEDLINE search revealed 1562 manuscripts; following review, 168 met inclusion criteria. Platelet response outcomes were reported in 141 studies, of which 57% did not use IWG definitions (using 21 distinct alternative platelet response schemes). Most randomized trials did not use IWG definitions, instead favoring platelet ≥50 × 109 /L to define response. Platelet ≥100 × 109 /L sustained for ≥6 months in the absence of therapy was the most common ITP remission definition. Bleeding outcomes were reported systematically in 41% of studies, which used 21 distinct reporting schemes. A plurality of adult studies used the World Health Organization Bleeding Scale and a plurality of pediatric studies used the Buchanan and Adix Score. HRQoL outcomes were reported in few studies (9%), which used a total of eight different HRQoL instruments. CONCLUSIONS: Despite prior attempts to standardize ITP outcome evaluation, wide variability in platelet, bleeding, and HRQoL outcomes remain. Most ITP studies did not systematically evaluate bleeding or HRQoL outcomes. Further standardization of outcome measurement in both pediatric and adult ITP is greatly needed.

Practical Recommendations for the Management of Patients with ITP During the COVID-19 Pandemic.

The current COVID-19 pandemic requires revisiting our current approach to major blood disorders, including ITP (Immune Thrombocytopenia), stirring up the production of several disease-specific practical guidelines. This report describes an updated version of consensus-based practical guidelines on the management of ITP, adapted to the Italian health system and social context. It highlights the role of the hematologist in offering guidance for choosing differentiated approaches in relation to specific circumstances and is intended to provide them with a useful tool for sharing the decision-making process with their patients. Probably, the greatest risk to avoid for a patient with suspected, ongoing or relapsed ITP - that is not severe enough to place him or her at risk for major bleeding - is to be infected in non-hospital and hospital healthcare settings. This risk must be carefully considered when adapting the diagnostic and therapeutic approach. More in detail, the document first addresses the appropriate management for COVID-19 negative patients with newly diagnosed ITP or who experience a relapse of previous ITP, according to first and second lines of treatment and then the management of COVID-19 positive patients according to their severity, from paucisymptomatic to those requiring admission to Intensive Cure Units (ICU). The pros and cons of the different treatments required to correct platelet count are discussed, as are some specific situations, including chronic ITP, splenectomy, thromboembolic complication and anti COVID-19 vaccination.

Real-world use of thrombopoietin receptor agonists in older patients with primary immune thrombocytopenia.

The efficacy and safety of thrombopoietin receptor agonists (TRAs) in older patients with primary immune thrombocytopenia (ITP) are unknown. We investigated TRA response and switch, thrombotic/hemorrhagic risk, and sustained responses off-treatment (SROTs) in 384 patients with ITP aged ≥60 years. After 3 months, 82.5% and 74.3% of eltrombopag- and romiplostim-treated patients, respectively, achieved a response; 66.7% maintained the response (median follow-up, 2.7 years). Eighty-five (22.2%) patients switched to the alternative TRA; although no cross-toxicity was observed, 83.3% of resistant patients had a response after the switch. Thirty-four major thromboses (3 fatal) and 14 major hemorrhages (none fatal) occurred in 18 and 10 patients, respectively, while on TRAs and were associated with thrombosis history (subdistribution hazard ratio, 2.04, P = .05) and platelet count <20 × 109/L (subdistribution hazard ratio, 1.69; P = .04), respectively, at TRA start. A recurrent event occurred in 15.6% of patients surviving thrombosis, in all cases but 1 during persisting TRA treatment (incidence rate, 7.7 per 100 patient-years). All recurrences occurred in the absence of adequate antithrombotic secondary prophylaxis. Sixty-two (16.5%) responding patients discontinued TRAs; 53 (13.8%) patients maintained SROTs, which were associated with TRA discontinuation in complete response (P < .001). Very old age (≥75 years; 41.1%) was associated with the more frequent start of TRAs in the persistent/acute phase but not with response or thrombotic/hemorrhagic risk. TRAs are effective in older patients with ITP, with no fatal hemorrhages and with SROTs in a significant portion of patients. Caution is warranted in patients with a history of thrombosis, and a careful risk/benefit balance should be considered.

Thrombosis in immune thrombocytopenia - current status and future perspectives.

Immune thrombocytopenia (ITP) is an autoimmune disorder in which a combination of defective platelet production and enhanced clearance leads to thrombocytopenia. The primary aim for therapy in patients with this condition is the prevention of bleeding. However, more recently, increased rates of venous and arterial thrombotic events have been reported in ITP, even in the context of marked thrombocytopenia. In this review we discuss the epidemiology, aetiology and management of thrombotic events in these patients. We consider the impact of ITP therapies on the increased thrombotic risk, in particular the use of thrombopoietin-receptor agonists (TPO-RAs), as well as factors inherent to ITP itself. We also discuss the limited evidence available to guide clinicians in the treatment of these complex cases.

Eltrombopag second-line therapy in adult patients with primary immune thrombocytopenia in an attempt to achieve sustained remission off-treatment: results of a phase II, multicentre, prospective study.

Up to 30% immune thrombocytopenia (ITP) patients achieve a sustained remission off-treatment (SROT) after discontinuation of thrombopoietin receptor agonists (TPO-RAs). Factors predictive of response are lacking. Patients aged ≥18 years with newly diagnosed or persistent ITP were treated with eltrombopag for 24 weeks. Primary end-point was SROT: the proportion of responders that were able to taper and discontinue eltrombopag maintaining the response during a period of observation (PO) of six months. Secondary end-points included the association between some immunological parameters (TPO serum levels, cytokines and lymphocyte subsets) and response. Fifty-one patients were evaluable. Primary end-point was achieved in 13/51 (25%) treated patients and 13/34 (38%) patients who started the tapering. Baseline TPO levels were not associated with response at week 24 nor with SROT. Higher baseline levels of IL-10, IL-4, TNF-α and osteopontin were negative factors predictive of response (P = 0·001, 0·008, 0·02 and 0·03 respectively). This study confirms that SROT is feasible for a proportion of ITP patients treated with eltrombopag. Some biological parameters were predictive of response.

International survey on Helicobacter pylori testing in patients with immune thrombocytopenia: Communication of the platelet immunology scientific and standardization committee.

Essentials When to test and treat H pylori among patients with ITP is controversial. We report the results of an international survey administered to physicians with experience treating ITP across 39 countries. The decision to test for H pylori was influenced by country, country of origin, and concomitant gastrointestinal symptoms. Testing and treating for H pylori among patients with ITP varied across geographic regions. ABSTRACT: Background Investigations for patients suspected of immune thrombocytopenia (ITP) lack standardization. A controversial issue is whether such patients should be tested for Helicobacter pylori, a known cause of secondary ITP. Objectives This Scientific and Standardization Committee Communication reports the results of an international survey to describe patterns of practice with respect to screening and treatment of H pylori among patients with ITP. Patients/Methods A 17-item scenario-based questionnaire was delivered to hematologists in countries across the world. The questionnaire was pilot tested before use. We used snowball sampling and a contact list of physicians from the Platelet Disorders Support Association to identify survey respondents. Data were analyzed descriptively. Results A total of 186 respondents from 39 countries completed the survey. Response rate from the snowball sample was 53.6%. Twenty-nine percent (n = 55) of respondents always tested ITP patients for H pylori, and 53% (n = 98) sometimes tested. Of the 37 respondents from Asia and the Middle East, 51.4% (n = 19) always tested for H pylori for the stated reasons of high local prevalence and perceived benefit of treatment on platelet count levels. Respondents were more likely to test patients who were from Asia (145/177, 80%) and who had concomitant gastrointestinal symptoms (133/183, 72%). For eradication therapy, 71 of 118 (60.2%) respondents used the combination of a proton pump inhibitor, clarithromycin, and amoxicillin for 14 days. Conclusions This international survey showed that testing for H pylori was most common in Asia and in patients from Asia. Testing and treating practices varied across geographic regions.