Therapeutic Advances in Hematology最新文献

Background: Blinatumomab showed a higher complete remission (CR) rate and a safe bridging to allogeneic hematopoietic cell transplantation (allo-HCT) in adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (R/R BCP-ALL).

Objectives: We tried to analyze the outcome of blinatumomab compared with the real-world historical data. We expected superior outcome of blinatumomab compared with historical conventional chemotherapy.

Design: We conducted a retrospective study using real-world data in the Catholic Hematology Hospital.

Methods: Total 197 consecutive cases of R/R BCP-ALL were treated with conventional chemotherapy (n = 113) or blinatumomab, which was available since late 2016 (n = 84). Patients who achieved CR underwent allo-HCT if donor was available. We conducted a propensity score-matched cohort analysis using 5 criteria of age, CR duration, cytogenetics, previous allo-HCT, and salvage lines between historical group and blinatumomab.

Results: Each cohort consisted of 52 patients. In blinatumomab group, CR rate was higher (80.8% versus 53.8%, p = 0.006) and more patients proceeded to allo-HCT (80.8% versus 46.2%, p < 0.001). Among the CR patients with available minimal residual disease (MRD) results, 68.6% in blinatumomab group and 40.0% in conventional chemotherapy group were MRD-negative. Regimen-related mortality during the chemotherapy cycles was significantly higher in the conventional chemotherapy group (40.4% versus 1.9%, p < 0.001). Estimated 3-year overall survival (OS) was 33.2% (median, 26.3 months) after blinatumomab, and 15.4% (median, 8.2 months) after conventional chemotherapy (p < 0.001). Estimated 3-year non-relapse mortality were 30.3% and 51.9% (p = 0.004), respectively. In multivariate analysis, CR duration < 12 months showed more relapses and poor OS, and conventional chemotherapy showed higher non-relapse mortality and poor OS.

Conclusions: Matched cohort analysis showed superior outcomes of blinatumomab compared with conventional chemotherapy. However, large numbers of relapses and non-relapse mortalities continue to occur even after blinatumomab followed by allo-HCT. Novel therapeutic strategies are still needed for R/R BCP-ALL.

Background: Umbilical cord blood hematopoietic stem cells are commonly used for hematopoietic system reconstitution in recipients after umbilical cord blood transplantation (UCBT). However, the optimal conditioning regimen for UCBT remains a topic of debate. The exact impact of total body irradiation (TBI) as a part of conditioning regimens remains unknown.

Objectives: The aim of this study was to evaluate the impacts of TBI on UCBT outcomes.

Design: This was a multi-institution retrospective study.

Methods: A retrospective analysis was conducted on the outcomes of 136 patients receiving UCBT. Sixty-nine patients received myeloablative conditioning (MAC), in which 33 underwent TBI and 36 did not, and 67 patients received reduced-intensity conditioning (RIC), in which 43 underwent TBI and 24 did not. Univariate and multivariate analyses were conducted to compare the outcomes and the post-transplant complications between patients who did and did not undergo TBI in the MAC subgroup and RIC subgroup, respectively.

Results: In the RIC subgroup, patients who underwent TBI had superior overall survival (adjusted hazard ratio [aHR] = 0.25, 95% confidence interval [CI]: 0.09-0.66, p = 0.005) and progression-free survival (aHR = 0.26, 95% CI: 0.10-0.66, p = 0.005). However, in the MAC subgroup, there were no statistically significant differences between those receiving and not receiving TBI.

Conclusion: In the setting of RIC in UCBT, TBI utilization can improve overall survival and progression-free survival. However, TBI does not show superiority in the MAC setting.

Administration of abatacept following transplantation has been reported to inhibit graft rejection and graft-versus-host-disease (GvHD) in mouse models associated with allogeneic hematopoietic stem cell transplant (HSCT). This strategy has recently been adopted in clinical practice for GvHD prevention in human allogeneic HSCT and offers a unique approach to optimizing GvHD prophylaxis following alternative donor HSCTs. When combined with calcineurin inhibitors and methotrexate, abatacept had shown to be safe and effective in preventing moderate to severe acute GvHD in myeloablative HSCT using human leukocyte antigen (HLA) unrelated donors. Equivalent results are being reported in recent studies using alternative donors, in reduced-intensity conditioning HSCT and nonmalignant disorders. These observations have led to hypothesizing that even in the setting of increasing donor HLA disparity, abatacept when given with traditional GvHD prophylaxis does not worsen general outcomes. In addition, in limited studies, abatacept have being protective against the development of chronic GvHD through extended dosing and in the treatment of steroid-refractory chronic GvHD. This review summarized all the limited reports of this novels approach in the HSCT setting.

Non-Hodgkin's lymphomas (NHLs) comprise a diverse group of diseases, either of mature B-cell or of T-cell derivation, characterized by heterogeneous molecular features and clinical manifestations. While most of the patients are responsive to standard chemotherapy, immunotherapy, radiation and/or stem cell transplantation, relapsed and/or refractory cases still have a dismal outcome. Deep sequencing analysis have pointed out that epigenetic dysregulations, including mutations in epigenetic enzymes, such as chromatin modifiers and DNA methyltransferases (DNMTs), are prevalent in both B- cell and T-cell lymphomas. Accordingly, over the past decade, a large number of epigenetic-modifying agents have been developed and introduced into the clinical management of these entities, and a few specific inhibitors have already been approved for clinical use. Here we summarize the main epigenetic alterations described in B- and T-NHL, that further supported the clinical development of a selected set of epidrugs in determined diseases, including inhibitors of DNMTs, histone deacetylases (HDACs), and extra-terminal domain proteins (bromodomain and extra-terminal motif; BETs). Finally, we highlight the most promising future directions of research in this area, explaining how bioinformatics approaches can help to identify new epigenetic targets in B- and T-cell lymphoid neoplasms.

Background: Antihuman T lymphocyte porcine immunoglobulin (p-ATG) has been the most common ATG preparation in immunosuppressive therapy (IST) in Chinese patients with severe aplastic anemia (SAA) since 2009.

Objectives: This study aimed to evaluate the early hematologic response and long-term outcomes of a large cohort of patients with SAA who received p-ATG plus cyclosporine (CsA) as first-line therapy from 2010 to 2019.

Design: This is a single-center retrospective study of medical records.

Methods: We analyzed the data of 1023 consecutive patients with acquired aplastic anemia (AA) who underwent p-ATG combined with CsA as a first-line IST treatment from 2010 to 2019 at our department.

Results: The median age of the patients was 24 (4-75) years, and the median follow-up time was 57.2 months (3 days-137.5 months). There was an early mortality rate of 2.8% with a median death time of 0.9 months (3 days-2.9 months). The overall response rates were 40.6% and 56.1% at 3 and 6 months, respectively. The 5-year cumulative incidences of relapse and clonal evolution were 9.0% [95% confidence interval (CI) = 4.2-16.0%] and 4.5% (95% CI = 1.4-10.6%), respectively. The 5-year overall survival (OS) and event-free survival rates were 83.7% (95% CI = 81.1-86.0%) and 50.4% (95% CI = 47.1-53.5%), respectively.

Conclusion: p-ATG combined with CsA for the treatment of AA is effective and safe, and p-ATG can be used as an alternative ATG preparation for the standard IST regimen in areas in which h-ATG is not available.

Patients with β-thalassemia (β-TM) may have brain iron overload from long-term blood transfusions, ineffective erythropoiesis, and increased intestinal iron absorption, leading to cognitive impairment. Brain magnetic resonance imaging (MRI) methods such as the transverse relaxation rate, susceptibility-weighted imaging, and quantitative susceptibility mapping can provide quantitative, in vivo measurements of brain iron. This review assessed these MRI methods for brain iron quantification and the measurements for cognitive function in patients with β-TM. We aimed to identify the neural correlates of cognitive impairment, which should help to evaluate therapies for improving cognition and quality of life in patients with β-TM.

Platelets, derived from a certain subpopulation of megakaryocytes, are closely related to hemostasis, coagulation, metastasis, inflammation, and cancer progression. Thrombopoiesis is a dynamic process regulated by various signaling pathways in which thrombopoietin (THPO)-MPL is dominant. Thrombopoiesis-stimulating agents could promote platelet production, showing therapeutic effects in different kinds of thrombocytopenia. Some thrombopoiesis-stimulating agents are currently used in clinical practices to treat thrombocytopenia. The others are not in clinical investigations to deal with thrombocytopenia but have potential in thrombopoiesis. Their potential values in thrombocytopenia treatment should be highly regarded. Novel drug screening models and drug repurposing research have found many new agents and yielded promising outcomes in preclinical or clinical studies. This review will briefly introduce thrombopoiesis-stimulating agents currently or potentially valuable in thrombocytopenia treatment and summarize the possible mechanisms and therapeutic effects, which may enrich the pharmacological armamentarium for the medical treatment of thrombocytopenia.

Background: Thrombocytopenia is a common hematological manifestation in people living with human immunodeficiency virus (HIV) or acquired immune deficiency syndrome (AIDS; PLWHA). Data on the prognostic relationship and associated factors of thrombocytopenia and HIV infection in China are limited.

Objectives: We assessed the prevalence of thrombocytopenia, its association with prognosis, and analyzed the associated risk factors among demographic characteristics, comorbidities, hematological and bone marrow indicators.

Design: We collected patients identified as PLWHA in Zhongnan Hospital. The patients were divided into two groups: the thrombocytopenia group and the non-thrombocytopenia group. We analyzed and compared demographic characteristics, comorbidities, peripheral blood cells, lymphocyte subpopulations, infection indicators, bone marrow cytology, and bone marrow morphology of the two groups. Then we analyzed the risk factors for thrombocytopenia and the effect of platelet (PLT) values on the prognosis of patients.

Methods: Demographic characteristics and laboratory results were obtained from medical records. In contrast to other studies, we included bone marrow cytology and morphology in this study. Data were analyzed with multivariate logistic regression analysis. The Kaplan-Meier method was used to plot 60-month survival curves for the severe, mild, and non-thrombocytopenia groups. The value p < 0.05 was taken as statistically significant.

Results: Among 618 identified PLWHA, 510 (82.5%) were male. Overall, thrombocytopenia was found in 37.7% [95% confidence interval (CI): 33.9-41.5%]. Multivariable logistic regression analysis showed that age ⩾40 years [adjusted odds ratio (AOR) 1.869, 95% CI: 1.052-3.320], combined with hepatitis B (AOR 2.004, 95% CI: 1.049-3.826), high procalcitonin (PCT) count (AOR 1.038, 95% CI: 1.000-1.078) were risk factors of thrombocytopenia in PLWHA. An increased percentage of thrombocytogenic megakaryocytes was a protective factor, with an AOR 0.949 (95% CI: 0.930-0.967). Kaplan-Meier survival curve analysis showed that the prognosis was worse in the severe than in the mild (p = 0.002) and non-thrombocytopenia groups (p = 0.008).

Conclusion: We discovered a general high pervasiveness of thrombocytopenia in PLWHA in China. Age ⩾40 years, combined with hepatitis B virus infection, high PCT, and decreased percentage of thrombocytogenic megakaryocytes indicated a higher risk for developing thrombocytopenia. A PLT count ⩽50 × 10⁹/liter led to a worse prognosis. Therefore, early diagnosis and treatment of thrombocytopenia in these patients are useful.

Patients with relapsed and/or refractory (R/R) follicular lymphoma (FL) and mantle cell lymphoma (MCL) have a poor prognosis with anticipated short progression-free and overall survivals. Two CD19-directed chimeric antigen receptor T-cell (CAR T) therapies are approved in the United States for R/R FL, namely, axicabtagene ciloleucel (axi-cel) and tisagenlecleucel. The results of ZUMA-5 and ELARA studies led to the approval of axi-cel and tisagenlecleucel, respectively, after demonstrating high overall (ORR) and complete response (CR) rates in this high-risk population of FL patients who had received a median of 3 (range = 2-4) and 4 (range = 2-13) prior lines of therapies, respectively. For instance, the ORR for ZUMA-5 was 94% (CR = 79%), and for ELARA, it was 86% (CR = 69.1%). Pertaining to MCL, brexucabtagene autoleucel is approved for R/R MCL based on results of the ZUMA-2 study. In the latter study, despite the fact that all R/R MCL patients had been exposed to prior Bruton's tyrosine kinase inhibitors, the reported ORR was 91%, with 68% achieving a CR. These results undoubtedly demonstrate a strong efficacy of CAR T therapy in both R/R FL and MCL; yet, one must acknowledge the relatively short follow-up time of all aforementioned studies. Thus, longer follow-up showing durability of responses and long-term safety is definitely needed.

For approximately three decades, autologous hematopoietic cell transplantation (auto-HCT) has been the standard of care for patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) after frontline therapy. This approach is limited due to the intensity of chemotherapy and the proportion of patients who relapse after auto-HCT. Since the approval of anti-CD19 chimeric antigen receptor T-cell (CAR-T) therapy and novel agents, the treatment paradigm for DLBCL has changed remarkably. Anti-CD19 CAR-T therapy was first approved for relapsed DLBCL after two or more previous lines of therapy with long-lasting responses, with over 50% of patients still alive at 5-year follow-up. Here, we discuss recent randomized phase 3 clinical trials using axicabtagene ciloleucel, tisagenlecleucel, and lisocabtagene maraleucel in the second-line therapy setting compared with the standard of care in transplant-eligible patients who have DLBCL R/R within 12 months of completing chemo-immunotherapy, potentially changing the treatment algorithm for DLBCL.