Therapeutic Advances in Hematology最新文献

Background: Progress in improving risk stratification methods for patients with cytogenetically normal acute myeloid leukaemia (CN-AML) remains limited. This study investigates the prognostic significance and potential functional mechanism of malic enzyme 1 (ME1) in CN-AML.

Methods: Gene expression and clinical data of patients with CN-AML were obtained from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets, which were subjected to analysis. The prognostic significance of ME1 was assessed through Kaplan-Meier survival analysis, as well as univariate and multivariate Cox regression analyses. A novel risk model based on ME1 expression levels was developed using TCGA data for predicting CN-AML prognosis. Furthermore, the impact of ME1 silencing on AML cell lines was investigated using the Cell Counting Kit-8 assay and flow cytometry. Gene set enrichment analysis (GSEA) analysis and Western blotting were performed to explore the mechanism of ME1 in CN-AML.

Results: CN-AML patients expressing higher ME1 levels exhibited shorter event-free survival (EFS) and overall survival (OS) compared to those with lower ME1 expression in the TCGA and multiple GEO datasets (all p < 0.05). Univariate and multivariate Cox regression analyses indicated that ME1 expression served as an independent prognostic factor for the EFS (p = 0.024 in TCGA, p = 0.035 in GSE6891) and OS (p = 0.039 in TCGA, p = 0.008 in GSE6891) in patients with CN-AML. The developed risk model demonstrated that patients with CN-AML in the high-risk group had worse survival than those in the low-risk group (hazard ratio: 2.67, 95% confidence interval: 1.54-4.65, p < 0.001) and exhibited strong predictive accuracy for 1-, 3- and 5-year OS (area under the curve = 0.69, 0.75, 0.79, respectively). ME1 knockdown significantly inhibited proliferation and increased apoptosis in AML cells (all p < 0.05). GSEA and Western blotting demonstrated that ME1 regulates the IL-6/JAK2/STAT3 pathway in CN-AML.

Conclusion: Elevated ME1 expression serves as an indicator of poorer prognosis in patients with CN-AML, potentially facilitating leukaemogenesis through the IL-6/JAK2/STAT3 pathway. This suggests that ME1 could be a promising prognostic biomarker and therapeutic target for CN-AML.

Background: Multiple myeloma is a malignant haematological neoplasm characterised by clonal proliferation of plasma cells, with a complex clinical picture, and a significant impact on patient survival, in which the prognosis evaluation of patients is of great importance.

Objectives: In this single-centre retrospective analysis, performed in a group of newly diagnosed multiple myeloma patients, we examined several clinical and laboratory parameters in order to evaluate their trend according to survival of patients.

Design: We collected data from 190 newly diagnosed multiple myeloma evaluated at the Hematology Division of the 'Paolo Giaccone' University Hospital of Palermo from 1 January 2017 to 30 September 2022. Specifically, we performed our analysis in the entire cohort of patients and also in the specific disease isotype.

Methods: We evaluated simple and low-cost laboratory and haemorheological parameters, the latter obtained in a calculated way. The primary endpoint was to evaluate the trend and the differences of these parameters in the study population, divided into two specific groups, deceased and survivors after a specific observation period of almost 7 years.

Results: In the entire cohort of multiple myeloma patients, we observed a mortality rate of 40%, of whom 36.4% were men and 43.1% were women. Among the patients who died, in comparison with those who survived, it is significantly evident the increase in age, in red cell distribution width (RDW), RDW%/albumin ratio and in the RDW%/haemoglobin ratio; moreover, in the same patients subgroup, we observed a reduction in haematocrit, total serum protein, calculated whole blood viscosity (evaluated according to the de Simone formula), serum albumin, albumin/fibrinogen ratio and in haemoglobin levels.

Conclusion: The obtained data can represent a possible starting point for subsequent targeted analyses, aimed at studying the prognostic value of each individual parameter considered, favouring an increasingly complete and immediate prognostic evaluation of patients.

Background: Immune tolerance induction (ITI) is the gold standard for inhibitor eradication to restore the clinical efficacy of factor replacement therapy in haemophilia. However, as ITI often requires frequent administration over extended periods, it can be considered burdensome for patients and healthcare resources. Therefore, there is a need to optimise ITI treatment, particularly in patients who failed previous ITI attempts.

Objectives: The ReITIrate study aimed to prospectively evaluate rescue ITI with efmoroctocog alfa, an extended half-life recombinant FVIII Fc fusion protein (herein rFVIIIFc), within a limited 60-week timeframe in patients with severe haemophilia A and inhibitors who failed previous ITI attempts.

Design: ReITIrate was a phase IV, open-label, single-arm, interventional, multicentre study.

Methods: Primary endpoint was ITI success (negative titre, <0.6 BU/mL; incremental recovery >66%; elimination half-life ⩾7 hours) within 60 weeks. Exploratory immunophenotype analyses were performed to characterise anti-drug antibodies (ADA) and cellular immune responses.

Results: Nine of 16 enrolled subjects completed the ITI period during ReITIrate, of which one subject attained all 3 ITI success criteria after 46 weeks with no relapse. Two subjects achieved partial success (one subject met 2/3 success criteria; one met all criteria, but not simultaneously, with inhibitor recurrence). One additional subject (ITI failure) achieved negative inhibitor titre. Across these four subjects, median (range) time to negative titre was 19 (11-60) weeks. No new safety concerns were identified. IgG4 was the major contributor to the ADA IgG response. Subjects with partial/complete ITI success had fewer IgG subclasses involved than those who failed/withdrew. Immunophenotyping indicated an increase in regulatory T-cells (CD4⁺CD25⁺CD127^low), supporting the ability to perform sensitive blood sampling to identify immune tolerance markers.

Conclusion: This study demonstrates that ITI with rFVIIIFc given within a limited timeframe has potential benefit in a difficult-to-treat inhibitor haemophilia population who failed previous ITI attempts.

Trial registration: NCT03103542.

Background: Iron overload is considered an unfavorable prognosis in myelodysplastic syndrome (MDS) even in those undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). Although iron chelation therapy has improved the prognosis of these patients to some extent, the effect has not yet been satisfactory.

Objectives: This study aimed to investigate the impact of granulocyte colony-stimulating factor and decitabine (G-DAC)-containing conditioning in iron-overloaded MDS patients undergoing allo-HSCT.

Design: This was a retrospective study.

Methods: One hundred and ninety-seven patients were enrolled in this retrospective study. Based on the level of serum ferritin (SF) and conditioning regimen, all patients enrolled were divided into four groups: SF < 1000 µg/L with G-DAC conditioning (cohort 1), SF < 1000 µg/L with non-G-DAC conditioning (cohort 2), SF ⩾ 1000 µg/L with G-DAC conditioning (cohort 3), and SF ⩾ 1000 µg/L with non-G-DAC conditioning (cohort 4). The clinical features and prognosis of the four groups were analyzed.

Results: Significant differences in the 2-year overall survival (OS), disease-free survival (DFS), and the cumulative incidence of non-relapse mortality (NRM) were observed between the four groups. Multivariate analysis revealed that SF ⩾ 1000 µg/L was a risk factor for OS, DFS, and NRM while G-DAC-containing conditioning was a protective factor. Intriguingly, when cohort 1 to cohort 4 were included in the multivariate analysis, only cohort 4 was a risk factor for OS, DFS, and NRM, cohort 3 had no difference in prognosis compared with patients with SF < 1000 µg/L.

Conclusion: The poor prognosis of patients with iron overload may be overcome by G-DAC-containing conditioning partly.

Background: All-trans retinoic acid (ATRA) and arsenic trioxide (ATO) have revolutionized the treatment of acute promyelocytic leukemia (APL). However, the management of high-risk APL has not been conclusively established. The optimal dosage of anthracycline in the induction has long been debated when ATO is added.

Objectives: To explore the management of high-risk APL regarding the optimal dosage of anthracycline in the induction and the predicators of prognosis.

Design: This was a retrospective study in the real-world setting.

Methods: High-risk APL patients defined as white blood cell (WBC) greater than 10 × 10⁹/L who received ATO-based induction regimens were included. Data on clinical characteristics, treatment regimens, and prognosis including early death (ED) and overall survival (OS) were collected from medical records. Risk factors of ED and OS were analyzed.

Results: This research included a total of 130 participants. Fifty (38.5%) patients received ATO+ATRA dual induction plus standard-dose anthracycline (ATO + ATRA + stDNR). Fifty-nine (45.4%) patients received ATO + ATRA with consecutive low-dose anthracycline (ATO + ATRA + ldDNR). Twenty-one (16.2%) patients were treated with ATO and various chemotherapies (ATO + others). Compared with the other two groups, the ATO + ATRA + stDNR group had the lowest ED rate of 4.0% (10.2% and 52.4%, respectively; p < 0.001). Multivariate analysis revealed that age ⩾60 years (odds ratio (OR) = 8.888, 95% confidence interval (CI): 1.126-70.129), prothrombin time (PT) ⩾18 s (OR = 4.749, 95% CI: 1.252-18.007) and WBC ⩾100 × 10⁹/L (OR = 10.591, 95% CI: 1.995-56.232) were independent risk factors for ED. The 5-year OS rates of the three induction groups were 96%, 80%, and 31%, respectively. None of the 48 patients who underwent ATO + ATRA + stDNR induction relapsed, whereas 9.4% (5/53) patients in ATO + ATRA + ldDNR group relapsed, and the relapse rate was 30.0% (3/10) in ATO + others group (p = 0.003). The survival advantage of ATO + ATRA + stDNR was demonstrated by a Cox regression (hazard ratio (HR) = 5.079, 95% CI: 1.071-24.079). WBC ⩾100 × 10⁹/L was correlated with an inferior OS (HR = 3.402, 95% CI: 1.359-8.518).

Conclusion: Compared with low-dose anthracycline, standard-dose anthracycline combined with ATO and ATRA dual induction resulted in excellent outcome for high-risk APL patients.

Background: Carfilzomib is a second-generation proteasome inhibitor (PI) used for combination therapy with dexamethasone and/or lenalidomide in patients with relapsed or refractory multiple myeloma. Reports indicate that PIs have a unique toxicity profile that includes thrombocytopenia as a hematologic adverse event; however, its occurrence has not yet been quantified systematically.

Objectives: The main objective of our systematic review and meta-analysis is to investigate the incidence of thrombocytopenia in patients with multiple myeloma after treatment with carfilzomib.

Design: Selection of studies and meta-analysis of trials was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement.

Data sources and methods: Two investigators performed an independent literature search of PubMed, Web of Science, SciFinder, the Cochrane Central Register of Controlled Trials, as well as the US and EU clinical trials registries. The cumulative incidence and overall relative risk were calculated with the random effect model using RevMan and R statistical software.

Results: The analysis included a total of 9237 patients, 2516 patients in single-arm studies and 6721 patients in randomized controlled trials (RCTs). A total of 47 studies were included; among these, 14 were RCTs. Analysis of currently available data showed that treatment with carfilzomib may increase the incidence of all-grade thrombocytopenia, and this correlated with the dose used. With supportive therapy alone, the incidence is 26%. The addition of carfilzomib to the treatment results in a 37% increase in incidence, whereas with bortezomib, the increase is slightly lower at 34%. Surprisingly, when treatment with carfilzomib and bortezomib was compared, bortezomib was found to be more likely to exacerbate high-grade thrombocytopenia (7%) than carfilzomib (3%).

Conclusion: Clarification of these associations suggests that clinicians should be aware of the potential risk of high-grade thrombocytopenia occurring and monitor patients closely to take appropriate measures.

Trial registration: Registered in PROSPERO under the number CRD42022314378.

The incidence of pure red cell aplasia (PRCA) in chronic lymphocytic leukemia (CLL) is <1% and treatments include the use of steroids and therapeutic strategies including immunosuppressive therapies. Here we present a case of a CLL-associated PRCA successfully treated with acalabrutinib, a treatment never described before for this specific condition, obtaining a rapid response after failing two lines of therapy. Exploring the treatment rationale, both the immune modulation and the continuous control of the disease, could have played a role in the treatment efficacy. Covalent BTK inhibitors are an effective treatment option for autoimmune complications of CLL, including CLL-associated PRCA.

Background: Acalabrutinib is a highly selective, latest generation Bruton's tyrosine kinase inhibitors for the treatment of chronic lymphocytic leukemia (CLL). The ELEVATE-TN trial (NCT02475681) found significant benefits achieved by the acalabrutinib regimen compared to the chemoimmunotherapy regimen chlorambucil plus obinutuzumab in treatment-naïve CLL. The objective of this study was to explore the cost-effectiveness of acalabrutinib in the first-line treatment of CLL in the light of Chinese healthcare system.

Methods: We constructed a 4-week partitioned survival model and a 20-year lifetime horizon to estimate the cost and utility associated with CLL treatment. The survival data, direct medical costs, and utilities came from the ELEVATE-TN trial, YAOZHI database, and published literatures. The outputs of the model including total costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs) were calculated. One-way, probabilistic sensitivity, and scenario analyses were conducted to assess the robustness of the model.

Results: Over a 20-year lifetime horizon, treatment with acalabrutinib + obinutuzumab provided an additional 2.51 QALYs versus treatment with chlorambucil and obinutuzumab, while incurring incremental costs of $940,543 and an ICER of $374,449/QALY. Acalabrutinib had an incremental cost of $683,640 and provided an additional 2.24 QALYs, resulted an ICER of $305,562/QALY. One-way sensitivity analyses suggested that the model was most sensitive to utility of progression-free survival, progression disease, and the cost of acalabrutinib. Probabilistic sensitivity analyses showed that at the willingness-to-pay (WTP) threshold, the probabilities of the acalabrutinib regimens were at an absolute disadvantage. The scenario analyses showed altering the lifetime horizon or price of acalabrutinib did not reverse results of our model.

Conclusion: Acalabrutinib with or without obinutuzumab might not be a cost-effective option in recent China, when compared with chemoimmunotherapy for first-line patients with CLL at the commonly WTP threshold. It is therefore necessary to reduce the price of acalabrutinib.

Background: Crizanlizumab is a novel inhibitor of P-selectin, a key player in multicellular adhesion and inflammatory signaling, that leads to vaso-occlusion in sickle cell disease (SCD).

Objectives: The SOLACE-adults study evaluated the pharmacokinetics, pharmacodynamics (P-selectin inhibition), safety, and efficacy of crizanlizumab, with or without hydroxyurea/hydroxycarbamide, in patients with SCD.

Design: Phase II, single-arm, multicenter study.

Methods: Patients with SCD aged 16-70 years, with ⩾1 vaso-occlusive crisis (VOC) within 12 months before screening, received crizanlizumab 5.0 or 7.5 mg/kg intravenous infusion every 4 weeks; dose groups were enrolled sequentially.

Results: Of 57 patients enrolled, 45 received crizanlizumab 5.0 mg/kg and 12 received 7.5 mg/kg for a median duration of 206 and 170 weeks, respectively. Crizanlizumab concentrations reached maximum levels after a 30-min infusion and remained steady for 6 h, without significant accumulation. P-selectin inhibition was nearly complete for both doses. The median (interquartile range) absolute change in the annualized rate of VOCs leading to healthcare visit from baseline was -0.79 (-3.04, 2.01) in the 5.0 mg/kg group and -0.98 (-1.11, -0.41) in the 7.5 mg/kg group. All patients experienced at least one adverse event (AE), with no apparent differences between the two doses in the frequency and severity of AEs. Grade ⩾3 AEs occurred in 60% of the 5.0 mg/kg group and 58% of the 7.5 mg/kg group. Two patients in the 5.0 mg/kg group and one in the 7.5 mg/kg group had severe crizanlizumab-related infusion-related reactions, which resolved with treatment. No patients developed antibodies against crizanlizumab.

Conclusion: Crizanlizumab 5.0 and 7.5 mg/kg demonstrated a dose-proportional increase in exposure, sustained P-selectin inhibition, a tolerable safety profile, and a sustained reduction in VOCs leading to healthcare visit. This suggests that crizanlizumab is a useful treatment option for patients with SCD who have experienced VOCs.

Trial registration: NCT03264989.