Therapeutic Advances in Hematology最新文献

Background: For more than 2 years medical practice has been dealing with the Covid-19 pandemic. Atypical symptoms, such as frostbites and acrosyndromes, have appeared, and autoimmune anemias (some of which with cold agglutinins) have been described.

Objectives: We planned to study the prevalence of positive direct Coombs tests (DCTs) and hemolytic autoimmune anemia in patients infected with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and its correlation with complications, and then investigate the impact of the infection on iron metabolism.

Design: This is an observational, cross-sectional, single-center, exploratory study.

Methods: We obtained Coombs tests in a population of 179 infected patients at the CHU of Liège. We then studied iron metabolism in some of these patients, by measuring serum ferritin, erythropoietin (EPO), erythroferrone and hepcidin.

Results: We did not identify any case of autoimmune hemolysis. However, there was a 20.3% prevalence of positive DCT, mainly with IgG (91.7%). These patients, compared to DCT-negative patients, were not only more anemic and transfused, but also required more transfers to intensive care units and had longer hospital stays and mechanical ventilation. The pattern of anemia was consistent with the anemia of inflammation, showing elevated hepcidin and ferritin levels, while EPO and erythroferrone values were lower than expected at this degree of anemia. Erythroferrone was higher and Hb was lower in DCT-positive patients. Finally, we identified a correlation between iron parameters and complicated forms of infection.

Conclusion: Covid-19 patients suffered from inflammatory anemia with more severe forms of infection correlated to positive DCT status. This could potentially be of interest for future clinical practice.

Background: Eltrombopag (ELT), a thrombopoietin receptor agonist (TPO-RA), has been approved for relapsed/refractory aplastic anemia (AA). However, data on avatrombopag (AVA), another TPO-RA, are limited, and the comparisons between the two TPO-RAs are lacking.

Objectives: We aimed to compare the efficacy and safety between ELT and AVA in relapsed/refractory AA patients.

Design: In this retrospective study, patients with relapsed/refractory AA who had been treated with ELT (N = 45) or AVA (N = 30) alone and had compatible baseline hematological parameters were compared.

Methods: Data from patients diagnosed with acquired AA were retrospectively collected. All patients were refractory/relapsed to standard immunosuppressive therapy (IST) for at least 6 months before ELT or AVA. Patients had to be treated with ELT or AVA alone for at least 6 months before evaluation if they did not respond. Baseline characteristics, overall response (OR), complete response (CR), relapse, adverse events, and factors that may affect efficacy were analyzed.

Results: Of the 75 patients enrolled, 45 received ELT and 30 received AVA. Patients with AVA had a higher percentage of abnormal liver or renal function than those with ELT (p = 0.036). No significant difference was found in the OR/CR rate in the first/second/third/sixth month between the two cohorts (p > 0.05). Patients treated with AVA had a shorter median time to response than those treated with ELT (p = 0.012) and had a higher platelet level in the second month (p = 0.041). AVA had fewer adverse events than ELT (p = 0.046). Under compatible follow-up time (p = 0.463), no difference was found between the ELT and AVA cohorts in relapse (p = 1.000) or clone evolution (p = 0.637). No predictive factors for OR and CR in the sixth month were found for either ELT or AVA.

Conclusion: With worse liver or renal function, AVA had a similar OR/CR rate but a shorter median time to response and fewer adverse events for patients with relapsed/refractory AA.

Patients with sickle cell disease (SCD) suffer from complications due to anemia, inflammation, and vaso-occlusion. Factors that trigger sickling and/or inflammation may initiate such complications, while treatment with hydroxyurea (HU) reduces their emergence and prolongs survival. On the contrary, inhibition of the BRAF-MEK-ERK pathway with BRAF and MEK inhibitors (BRAF/MEKi) has revolutionized treatment of melanoma but their use has been correlated with inflammatory adverse events. Thus, treatment of patients with SCD with BRAF/MEKi may be quite challenging and pyrexia in those patients should be managed as a medical emergency. In this article, intrigued by the case of a 36-year-old female patient with S/β-thal under HU who was treated with dabrafenib and trametinib for melanoma, we analyze the mechanisms underlying inflammation and vaso-occlusion in SCD, the mechanisms of pyrexia and inflammation induced by BRAF/MEKi, their potential interconnections, the shared role of the inflammasome in these two entities, and the protective effect of HU in SCD. Since SCD is the most common inheritable blood disorder, the administration of BRAF/MEKi for melanoma in patients with SCD may be a rather common challenge. Thus, proper treatment with HU may pave the way for an uneventful management of such patients.

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.

Gene-based therapy opens an entirely new paradigm in managing people with haemophilia (PWH), offering them the possibility of a functional cure by enabling continuous expression of factor VIII (FVIII) or factor IX (FIX) after transfer of a functional gene designed to replace the PWH's own defective gene. In recent years, significant advances in gene therapy have been made, resulting in clotting factor activity attaining near-normal levels, as reflected by 'zero bleeding rates' in previously severely inflicted patients following a single administration of adeno-associated viral (AAV) vectors. While this new approach represents a major advancement, there are still several issues that must be resolved before applying this technology in clinical practice. First, awareness, communication, and education about the therapeutic potential and modalities of gene therapy must be further strengthened. To this end, objective, unbiased, transparent, and regularly updated information must be shared, in an appropriate way and understandable language with the support of patients' organizations. Second, healthcare providers should adopt a patient-centred approach, as the 'one size fits all' approach is inappropriate when considering gene therapy. Instead, a holistic patient view taking into account their physical and mental dimensions, along with unexpressed expectations and preferences, is mandatory. Third, the consent procedure must be improved, ensuring that patients' interests are maximally protected. Finally, gene therapy is likely to be first delivered in a few centres, with the highest expertise and experience in this domain. Thus, patients should be managed based on a hub-and-spoke model, taking into account that the key to gene therapy's success lies in an optimal communication and collaboration both within and between haemophilia centres sharing their experiences in the frame of international registries. This review describes recent progress and explains outstanding hurdles that must be tackled to ease the implementation of this paradigm-changing new therapy.

Background: Patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) have limited treatment options. Ceralasertib, a selective ataxia telangiectasia and Rad-3-related protein (ATR) inhibitor, demonstrated synergistic preclinical activity with a Bruton tyrosine kinase (BTK) inhibitor in TP53- and ATM-defective CLL cells. Acalabrutinib is a selective BTK inhibitor approved for treatment of CLL.

Objectives: To evaluate ceralasertib ± acalabrutinib in R/R CLL.

Design: Nonrandomized, open-label phase I/II study.

Methods: In arm A, patients received ceralasertib monotherapy 160 mg twice daily (BID) continuously (cohort 1) or 2 weeks on/2 weeks off (cohort 2). In arm B, patients received acalabrutinib 100 mg BID continuously (cycle 1), followed by combination treatment with ceralasertib 160 mg BID 1 week on/3 weeks off from cycle 2. Co-primary objectives were safety and pharmacokinetics. Efficacy was a secondary objective.

Results: Eleven patients were treated [arm A, n = 8 (cohort 1, n = 5; cohort 2, n = 3); arm B, n = 3 (acalabrutinib plus ceralasertib, n = 2; acalabrutinib only, n = 1)]. Median duration of exposure was 3.5 and 7.2 months for ceralasertib in arms A and B, respectively, and 15.9 months for acalabrutinib in arm B. Most common grade ⩾3 treatment-emergent adverse events (TEAEs) in arm A were anemia (75%) and thrombocytopenia (63%), with four dose-limiting toxicities (DLTs) of grade 4 thrombocytopenia. No grade ⩾3 TEAEs or DLTs occurred in arm B. Ceralasertib plasma concentrations were similar when administered as monotherapy or in combination. At median follow-up of 15.1 months in arm A, no responses were observed, median progression-free survival (PFS) was 3.8 months, and median overall survival (OS) was 16.9 months. At median follow-up of 17.2 months in arm B, overall response rate was 100%, and median PFS and OS were not reached.

Conclusion: Ceralasertib alone showed limited clinical benefit. Acalabrutinib plus ceralasertib was tolerable with preliminary activity in patients with R/R CLL, though findings are inconclusive due to small sample size.

Registration: NCT03328273.

Background: Polycythemia vera (PV) patients often experience constitutional symptoms and are at risk of thromboembolism as well as disease progression to myelofibrosis or acute myeloid leukemia. Not only is PV often overlooked but treatment options are also limited, however.

Objectives: To explore the patient characteristics and treatment pattern of PV patients in Taiwan, and compare with other countries reported in the literature.

Design: This is a nationwide cross-sectional study.

Methods: The National Health Insurance Research Database in Taiwan, which covers 99% of the population, was utilized. Patients were identified during the cross-sectional period between 2016 and 2017, and their retrospective data were retrieved from 2001 to 2017.

Results: A total of 2647 PV patients were identified between 1 January 2016 and 31 December 2017. This study described the demographic information of these patients, including number of patients by risk stratification and by sex, age at diagnosis, age at cross-sectional period, rate of bone marrow aspiration/biopsy at diagnosis, comorbidities, number of postdiagnosis thrombosis, number of disease progression, and death. The mortality rate of PV patients (4.1%) over 60 of age was higher than the general population of the same age group (2.8%). This study also compared the different treatment patterns between sexes and risk groups. Hydroxyurea was deferred to an older age, but conversely was prescribed at higher dose to younger patients. Alarmingly, a high proportion of patients did not receive phlebotomy or hydroxyurea for at least 2 years. Furthermore, discrepancies in prevalence, age at diagnosis, sex ratio, incidence of thrombosis and mortality were also found when compared with data reported in other countries.

Conclusion: The clinical landscape of PV in Taiwan between 2016 and 2017 was examined. Distinctive patterns of phlebotomy and hydroxyurea were identified. Overall, these findings highlight the importance of understanding the patient characteristics and treatment patterns of PV in different regions to better inform clinical practice and improve patient outcomes.

Background: Patients with Philadelphia-negative chronic myeloproliferative neoplasms (MPN) typically incur high rates of infections and both drugs and comorbidities may modulate infection risk.

Objectives: The present study aims to assess the effect of immunosuppressive agents on clinical outcomes of MPN patients affected by the coronavirus disease 2019 (COVID-19).

Design: This is an observational study.

Methods: We specifically searched and analyzed MPN patients collected by EPICOVIDEHA online registry, which includes individuals with hematological malignancies diagnosed with COVID-19 since February 2020.

Results: Overall, 398 patients with MPN were observed for a median of 76 days [interquartile range (IQR): 19-197] after detection of SARS-CoV2 infection. Median age was 69 years (IQR: 58-77) and 183 individuals (46%) had myelofibrosis (MF). Overall, 121 patients (30%) of the whole cohort received immunosuppressive therapies including steroids, immunomodulatory drugs, or JAK inhibitors. Hospitalization and consecutive admission to intensive care unit was required in 216 (54%) and 53 patients (13%), respectively. Risk factors for hospital admission were identified by multivariable logistic regression and include exposure to immunosuppressive therapies [odds ratio (OR): 2.186; 95% confidence interval (CI): 1.357-3.519], age ⩾70 years, and comorbidities. The fatality rate was 22% overall and the risk of death was independently increased by age ⩾70 years [hazard ratio (HR): 2.191; 95% CI: 1.363-3.521], previous comorbidities, and exposure to immunosuppressive therapies before the infection (HR: 2.143; 95% CI: 1.363-3.521).

Conclusion: COVID-19 infection led to a particularly dismal outcome in MPN patients receiving immunosuppressive agents or reporting multiple comorbidities. Therefore, specific preventive strategies need to be tailored for such individuals.

Plain language summary: EPICOVIDEHA registry reports inferior outcomes of COVID-19 in patients with Philadelphia-negative chronic myeloproliferative neoplasms receiving immunosuppressive therapies. Patients with Philadelphia-negative chronic myeloproliferative neoplasms (MPN) incur high rates of infections during the course of their disease.The present study was aimed at assessing which patient characteristics predicted a worse outcome of SARS-COV-2 infection in individuals with MPN.To pursue this objective, the researchers analyzed the data collected by EPICOVIDEHA, an international online registry, which includes individuals with hematological malignancies diagnosed with COVID-19 since February 2020.The database provided clinical data of 398 patients with MPN incurring COVID-19:Patients were mostly elderly (median age was 69 years);Forty-six percent of them were affected by myelofibrosis, which is the most severe MPN;Moreover, 32%