Therapeutic Advances in Hematology最新文献

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.

Background: The myeloproliferative neoplasm (MPN) is a heterogeneous group of clonal hyperplasia hematopoietic stem cell disorders, predominantly affecting middle-aged and elderly individuals, with a slow disease progression. With advancements in disease-related research, the survival rates of MPN patients have significantly improved. This research primarily focuses on cardiovascular disease mortality (CVM) and prognostic factors in MPN patients, aiming to provide clinicians with more comprehensive references.

Methods: A total of 24,277 patients were included in the Surveillance, Epidemiology, and End Results (SEER) database. Cumulative mortality was assessed using a competing risk model, univariate and multivariate regression analysis of cardiovascular disease (CVD) mortality risk factors, and a comparison of standardized mortality ratio (SMR) and general population CVM.

Results: Among the 24,277 patients included in this study, a total of 8841 deaths occurred during the follow-up period, with 2429 attributed to CVD. Notably, the risk of CVM was found to be significantly higher in patients with MPNs compared to the general population. Furthermore, this risk increased over time. CVD emerged as the predominant cause of death among individuals aged over 80 years and younger patients exhibited a significantly elevated SMR. Additionally, age, race, marital status, and insurance status were identified as independent prognostic factors for CVM.

Conclusion: The incidence of cardiovascular events in patients with MPNs is significantly higher compared to the general population. Early screening and assessment of cardiac health should be implemented in MPN patients to prevent the occurrence of cardiovascular events and enhance their prognosis.

Background: Secondary myelofibrosis (SMF) is characterized by the excessive deposition of fibrous tissue on top of the primary disease, often causing clinical manifestations to be overshadowed by the primary disease. Unfortunately, current staging systems do not incorporate myelofibrosis, leading to potential treatment delays for SMF.

Objectives: To evaluate the prognosis of patients with multiple myeloma (MM) complicated with myelofibrosis.

Design: The study included the clinical data and treatment results of 208 newly diagnosed multiple myeloma (NDMM) patients who were treated in the Affiliated Hospital of Qingdao University from January 2014 to August 2020, and performed a retrospective analysis.

Methods: All patients underwent bone marrow biopsy, and MF severity was classified into grades 0-3 according to the 2016 WHO criteria. Treatment efficacy was evaluated based on the International Myeloma Working Group (IMWG) standard and SPSS was used for analysis.

Results: The MM patients without SMF exhibited better treatment response (p < 0.05). Importantly, increasing degrees of myelofibrosis were associated with a significant reduction in median progression-free survival (PFS; p < 0.05). MM-SMF patients exhibited significantly shorter median PFS and overall survival (OS; p < 0.05). In the MM-SMF group, neutrophil-lymphocyte ratio >2.39, monocyte-lymphocyte ratio ⩽0.18, and platelet-lymphocyte ratio ⩽61.6 were associated with significantly reduced median PFS and OS (p < 0.05). Notably, the use of bortezomib-based regimens did not significantly impact prognosis in MM-SMF patients, while lenalidomide-based regimens significantly extended median OS but did not significantly affect median PFS.

Conclusion: Myelofibrosis emerges as an important prognostic indicator for predicting the survival outcomes of NDMM patients. In the era of new therapeutics, there is a pressing need to explore novel treatment strategies in order to improve the prognosis of patients with multiple myeloma complicated by myelofibrosis.