Therapeutic Advances in Hematology最新文献

Janus kinase 2 (JAK2) inhibitors such as ruxolitinib have become standard-of-care therapy for patients with myeloproliferative neoplasms (MPNs); however, activation of alternate oncogenic pathways including nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) has limited durable response as single-agent therapy. With the rationale of targeting both pathways, we conducted a phase I dose escalation trial of pevonedistat in combination with ruxolitinib for the treatment of patients with myelofibrosis (NCT03386214). The primary objective was to assess the safety and tolerability of combination therapy with additional objectives of treatment efficacy and alterations of biomarkers. There were no dose-limiting toxicities observed with most adverse events being limited to grades 1/2. In secondary measures, anemia response was observed in two patients. Pro-inflammatory cytokines and iron parameters were longitudinally assessed, which revealed suppression of interleukin-6 and interferon-gamma in a dose-dependent manner across a subset of patients. These results suggest that combination therapy targeting both JAK2 and NFκB may hold clinical merit for MPN patients.

Interferons are cytokines with immunomodulatory properties and disease-modifying effects that have been used to treat myeloproliferative neoplasms (MPNs) for more than 35 years. The initial use of interferons was limited due to difficulties with administration and a significant toxicity profile. Many of these shortcomings were addressed by covalently binding polyethylene glycol to the interferon structure, which increases the stability, prolongs activity, and reduces immunogenicity of the molecule. In the current therapeutic landscape, pegylated interferons are recommended for use in the treatment of polycythemia vera, essential thrombocythemia, and primary myelofibrosis. We review recent efficacy, molecular response, and safety data for the two available pegylated interferons, peginterferon alfa-2a (Pegasys) and ropeginterferon alfa-2b-njft (BESREMi). The practical management of interferon-based therapies is discussed, along with our opinions on whether to and how to switch from hydroxyurea to one of these therapies. Key topics and questions related to use of interferons, such as their safety and tolerability, the significance of variant allele frequency, advantages of early treatment, and what the future of interferon therapy may look like, will be examined. Pegylated interferons represent an important therapeutic option for patients with MPNs; however, more research is still required to further refine interferon therapy.

Background: Real-world data assessing treatment outcomes in patients with hemophilia A in routine clinical practice are limited.

Objective: To evaluate the effectiveness and safety of octocog alfa in patients with moderate/severe hemophilia A receiving treatment in clinical practice.

Design: The international Antihemophilic Factor Hemophilia A Outcome Database study is an observational, noninterventional, prospective, multicenter study.

Methods: This planned interim data read-out was conducted following 7 years of observation of patients receiving octocog alfa (cut-off, 30 June 2020). The primary endpoint was joint health status, assessed by the Gilbert Score. Secondary endpoints included annualized bleeding rates (ABRs), Hemophilia Joint Health Score (HJHS), health-related quality of life, consumption, and safety. This post hoc analysis stratified data by hemophilia severity at baseline [moderate, factor VIII (FVIII) 1-5%; severe, FVIII <1%].

Results: Of the 711 patients in this analysis, 582 (82%) were receiving prophylaxis with octocog alfa at enrollment, and 498 (70%) had severe disease. Median Gilbert Scores were higher with on-demand therapy versus prophylaxis and scores were comparable in moderate and severe disease. In patients receiving prophylaxis, there was an improvement in HJHS Global Gait Score over 7 years of follow-up overall and in patients with severe disease. ABRs and annualized joint bleeding rates were low across all 7 years. An ABR of zero was reported in 34-56% of prophylaxis patients versus 20-40% in the on-demand group. ABRs were similar in severe and moderate disease. In total, 13/702 (1.9%) patients experienced 18 treatment-related adverse events.

Conclusion: These data demonstrate the long-term effectiveness and safety of octocog alfa in patients with moderate and severe hemophilia A, especially in those receiving prophylaxis. The high number of patients receiving on-demand treatment experiencing zero bleeds could be due to selection bias within the study, with patients with less severe disease more likely to be receiving on-demand treatment.

Trial registration: ClinicalTrials.gov: NCT02078427.

Idiopathic multicentric Castleman disease (iMCD) is a rare and cytokine storm-driven inflammatory disorder. The exact cause of iMCD is still unknown, although several hypotheses have been proposed. However, regardless of the underlying cause, the ultimate result is the activation of the inflammatory pathway, which can lead to damage in multiple organs. Currently, there have been several reports highlighting the intricate link between coronavirus disease 2019 (COVID-19) and iMCD. To better understand the impact of COVID-19-induced immune storm on iMCD, we conducted a multicenter retrospective study in three hospitals in China. A total of 28 patients with iMCD were included, among whom 25 had confirmed COVID-19 infection, and we presented 4 cases that showed different disease progression after the infection of COVID-19, including 2 who did not receive any treatment for Castleman disease before. Our findings underscore the necessity of carefully monitoring iMCD patients with COVID-19 and promptly intervening to address any changes in their condition. Besides, this study also summarized the shared cytokines between COVID-19 and iMCD. Recent studies have shown promising results in treating severe COVID-19 and iMCD using tocilizumab, an interleukin-6 receptor antagonist. Therefore, it suggests that other potential cytokine storm therapy targets that have been effective in COVID-19 may also be explored for the treatment of iMCD.

Over the last 20 years, breakthroughs in accessible therapies for the treatment of multiple myeloma (MM) have been made. Nevertheless, patients with MM resistant to immunomodulatory drugs, proteasome inhibitors, and anti-CD38 monoclonal antibodies have a very poor outcome. Therefore, it is necessary to explore new drugs for the treatment of MM. This review summarizes the mechanism of action of selinexor, relevant primary clinical trials, and recent developments in both patients with relapsed/refractory myeloma and patients with newly diagnosed myeloma. Selinexor may be useful for the treatment of refractory MM.

Background: Erythropoiesis stimulating agents (ESAs) are the first-line therapy in patients with lower-risk myelodysplastic syndromes (LR-MDS). Some predictive factors for ESAs response have been identified. Type and number of somatic mutations have been associated with prognosis and response to therapies in MDS patients.

Objectives: The objective was to evaluate the outcomes after ESAs in patients with LR-MDS and to address the potential predictive value of somatic mutations in ESAs-treated patients.

Design: Multi-center retrospective study of a cohort of 722 patients with LR-MDS included in the SPRESAS (Spanish Registry of Erythropoietic Stimulating Agents Study) study. Retrospective analysis of 65 patients with next generation sequencing (NGS) data from diagnosis.

Methods: ESAs' efficacy and safety were evaluated in patients receiving ESAs and best supportive care (BSC). To assess the potential prognostic value of somatic mutations in erythroid response (ER) rate and outcome, NGS was performed in responders and non-responders.

Results: ER rate for ESAs-treated patients was 65%. Serum erythropoietin (EPO) level <200 U/l was the only variable significantly associated with a higher ER rate (odds ratio, 2.45; p = 0.036). Median overall survival (OS) in patients treated with ESAs was 6.7 versus 3.1 years in patients receiving BSC (p < 0.001). From 65 patients with NGS data, 57 (87.7%) have at least one mutation. We observed a trend to a higher frequency of ER among patients with a lower number of mutated genes (40.4% in <3 mutated genes versus 22.2% in ⩾3; p = 0.170). The presence of ⩾3 mutated genes was also significantly associated with worse OS (hazard ratio, 2.8; p = 0.015), even in responders. A higher cumulative incidence of acute myeloid leukemia progression at 5 years was also observed in patients with ⩾3 mutated genes versus <3 (33.3% and 10.7%, respectively; p < 0.001).

Conclusion: This large study confirms the beneficial effect of ESAs and the adverse effect of somatic mutations in patients with LR-MDS.

The introduction of imatinib in 2000 opened the era of tyrosine kinase inhibitors (TKIs) for CML therapy and has revolutionized the life expectancy of CML patients, which is now quite like the one of the healthy aged population. Over the last 20 years, both the TKI therapy itself and the objectives have undergone evolutions highlighted and discussed in this review. The main objective of the CML therapy in the first 10 years after TKI introduction was to abolish the disease progression from the chronic to the blastic phase and guarantee the long-term survival of the great majority of patients. In the second 10 years (from 2010 to the present), the main objective of CML therapy moved from survival, considered achieved as a goal, to treatment-free remission (TFR). Two phenomena emerged: no more than 50-60% of CML patients could be candidates for discontinuation and over 50% of them molecularly relapse. The increased cumulative incidence of specific TKI off-target side effects was such relevant to compel to discontinue or reduce the TKI administration in a significant proportion of patients and to avoid a specific TKI in particular settings of patients. Therefore, the treatment strategy must be adapted to each category of patients. What about the patients who do not get or fail the TFR? Should they be compelled to continue the TKIs at the maximum tolerated dose? Alternative strategies based on the principle of minimal effective dose have been tested with success and they are now re-evaluated with more attention, since they guarantee survival and probably a better quality of life, too. Moving from treating the disease to treating the patient is an important change of paradigm. We can say that we are entering a personalized CML therapy, which considers the patients' age, their comorbidities, tolerability, and specific objectives. In this scenario, the new techniques supporting the monitoring of the patients, such as the digital PCR, must be considered. In the present review, we present in deep this evolution and comment on the future perspectives of CML therapy.

Background: ATP-competitive tyrosine kinase inhibitors (TKIs) are the current standard of care for patients with chronic phase-chronic myeloid leukemia (CP-CML) in the first-line and second-line (2 L) setting. Treatment after 2 L is not clearly established.

Objective: The objective of this study was to summarize the available evidence to compare the efficacy and safety of interventions in the treatment of CP-CML patients who had received ⩾2 prior TKIs.

Design: A systematic literature review was performed.

Data source and methods: A systematic literature review (SLR) of studies published until May 2021, reporting clinical outcomes in adult patients with CP-CML who had received ⩾ 2 prior TKIs was performed. Studies were identified through the database searches via Ovid platform (Embase, MEDLINE Epub Ahead of Print, In-Process and Other Non-Indexed Citations, and Cochrane Central Register of Controlled Trials), the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP), bibliographic search of relevant reviews, and proceedings from the previous 3 years of the key conferences in the field of oncology.

Results: Our search identified 38 relevant studies. Among the identified studies of the current third-line treatments, the major molecular response (MMR) rate for ponatinib was 19.0-66.7%, 23.3-25.5% for asciminib, 19.2% for omacetaxine, and 13.2% for bosutinib at 6 months. The complete cytogenetic response (CCyR) rate was 21.4-64.8% for ponatinib, 38.7-40.8% for asciminib, 18-24.2% for bosutinib, and 16.1% for omacetaxine at 6 months.

Conclusion: The findings from current SLR demonstrated the lack of data for patients with CML treated with ⩾2 TKIs. TKIs such as asciminib, ponatinib, and bosutinib are valid options for those patients. Further research is needed to identify the best treatment option for patients with CML receiving later lines of therapy.

Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired hematological disease. The development of complement inhibitors such as eculizumab, ravulizumab, and pegcetacoplan has revolutionized the management of PNH, leading to improvements in overall survival and quality of life for patients.

Objectives: This systematic review aims to provide comprehensive evidence of the efficacy of complement inhibitors in relation to treatment duration.

Design: This is a systematic review and meta-analysis.

Data sources and methods: A thorough literature search was conducted in MEDLINE, EMBASE, and the Cochrane Library up to 3 May 2022. We included all prospective interventional studies including single-arm trials. The primary outcomes of interest were lactate dehydrogenase (LDH) levels, hemoglobin (Hb) concentrations, transfusion avoidance, and Functional Assessment of Chronic Illness Therapy Fatigue (FACIT-F) scores.

Results: Our study included a total of 27 studies, comprising 5 randomized controlled trials and 11 single-arm trials, with a total of 912 patients with PNH. We stratified the studies according to treatment duration, based on the most frequently reported period of 26 weeks. Our analysis showed that treatment-naïve patients who received complement inhibitors had a pooled estimate of a decrease in LDH levels from baseline by -1462.0 U/L (95% CI: -1735.6 to -1188.5) for treatment ⩽26 weeks and -1696.5 U/L (95% CI: -2122.7 to -1270.2) for treatment >26 weeks. The mean Hb levels were increased by 1.4 g/dL (95% CI: 0.5-2.3) and 1.9 g/dL (95% CI: 0.7-3.1) in each group. Treatment with any complement inhibitor prevented the need for transfusion in at least 50% of patients with PNH in all treatment periods. Clinically meaningful improvements in FACIT-F were observed both before and after 26 weeks, with a pooled estimate of 6.8 (95% CI: 6.0-7.6) and 9.5 (95% CI: 7.0-12.0), respectively.

Conclusion: Our findings suggest that complement inhibitors can result in positive treatment outcomes and sustained benefits for patients with PNH.