Clinical Hematology International最新文献

Diffuse large B-cell lymphoma (DLBCL) is a biologically and clinically heterogeneous disease. Despite good responses to standard of care frontline chemoimmunotherapy, the prognosis of relapsed/refractory (R/R) patients remains obscured by the possible inadequate responses to salvage therapy, eligibility for autologous transplantation, age and comorbidities. Polatuzumab vedotin is an antibody-drug conjugate formed by a CD79b antibody conjugated to the highly cytotoxic agent monomethyl auristatin E by means of a cleavable linker. Following significant clinical efficacy in R/R DLBCL, polatuzumab vedotin was granted accelerated Food and Drug Administration (FDA) approval in combination with bendamustine plus rituximab for patients who have failed at least two prior therapies. Other clinical studies involving polatuzumab vedotin in combination with other therapy regimens are also under evaluation for previously untreated DLBCL patients. In this article, we review the different phases from the preclinical development of polatuzumab vedotin to studies leading to its first approval, and highlight the potential future roles of this molecule in the treatment landscape of DLBCL.

Background: Physical function prior to allogeneic hematopoietic cell transplant (HCT) is associated with survival and may be associated with patient physical activity (PA). Tools to evaluate PA prior to HCT are scarce. We aimed to evaluate the impact of easily obtained patient-report of PA prior to HCT on survival.

Methods: HCT recipients between January 1, 2011 and July 5, 2018 and who completed an International Physical Activity Questionnaire Short Form were included. This patient survey captures self-reported activities over the preceding week to determine PA level.

Results: We report a retrospective study of 587 adult (age ≥18) HCT recipients. The median age for the cohort was 57.9 years (range 19.9-76.1) with 149 patients (25.4%) age ≥65. Younger patients reported higher PA (low, median age 59.7 years; moderate, 56.1; high, 55.7; p < 0.001). High activity level was reported by males (66.7%; p < 0.001). Patients with low PA had HCT-comorbidity index (HCT-CI) ≥ 3 (68.1%, p = 0.002). When controlling for HCT-CI and disease risk index, higher PA was associated with improved overall survival (HR 0.954, 95% CI 0.921-0.988, p = 0.009). After adjusting for HCT-CI, higher PA was associated with reduced non-relapse mortality (NRM) (HR 0.931, 95% CI 0.891-0.972, p = 0.0013). Subgroup analysis in adults age ≥65 years also found that PA was lower in this population and associated with NRM mortality (HR 0.95, 95% CI 0.90-0.99, p = 0.041).

Conclusion: Patient-reported PA is a predictor of post-HCT survival. Future studies to validate incorporation of self-report tools to better predict patient-related adverse risk are warranted.

Isolated neutropenia without anemia or thrombocytopenia is a common clinical problem. The etiology of neutropenia may vary from transient bone marrow suppression, caused by self-limited viral illnesses, to previously undiagnosed congenital syndromes or serious systemic diseases. Consequently, determining the underlying cause of neutropenia and what treatment is required can be challenging. Acquired neutropenia is common and most of the times an etiologic factor can be found. Congenital neutropenia (CN) is rare, and we still have a lot to learn from mutational analysis as to the exact role of gene abnormalities in the pathogenesis of these complex diseases. This mini-review discusses a proposed approach to neutropenia in the adult patient.

When the bortezomib [PS341], adriamycin and dexamethasone (PAD) regimen was first evaluated, the response rate in untreated patients was much superior to that elicited by conventional chemotherapeutic agents. We demonstrated the efficacy of PAD in relapsed or refractory patients by comparing the response rate obtained in 53 patients who received vincristine, adriamycin and dexamethasone (VAD) or equivalent regimen as induction therapy, using a comparative design in which each patient acted as their own control. Whereas 25 patients had a positive response to VAD, 37 patients had a response to PAD ≤ partial remission (PR) (p = 0.023). Using the more stringent response level of very good PR (VGPR) the results favored the PAD regimen very significantly (p = 0.006) (McNemars test). Similar results were seen using paired M-protein levels from individual patient comparisons. As the PAD regimen was subsequently adopted as the re-induction therapy in the British Society for Blood and Marrow Transplantation/United Kingdom Myeloma Forum Myeloma X (Intensive) trial, now concluded, we have retrospectively analyzed the findings from both studies. Comparison of response rates and adverse effects of patients having had previous autologous transplantation (Cohort 1) with the corresponding data from Myeloma X showed close correlation. These findings provide evidence that rapid results may be obtained in the evaluation of newly introduced, and potentially highly effective, anti-tumour agents by direct comparison to the response to the immediately preceding standard regimen, particularly in relatively resistant tumours.

Cytokine release syndrome (CRS) has been increasingly recognized in various conditions including the coronavirus disease 2019 (COVID-19). It is not only associated with systemic inflammatory symptoms, but also hematological complications such as coagulopathy. CRS can affect various components of the coagulation pathway, including the endothelial cells, platelets, coagulation cascade, and fibrinolytic system. Different causes of CRS, such as primary hemophagocytic lymphohistocytosis (HLH), chimeric antigen receptor (CAR) T-cell therapy, and COVID-19, have different cytokine profiles and coagulopathy presentations, with microvascular thrombosis surfacing as a common pathology. HLH shares many features with severe CRS, and is characterized by severe consumptive coagulopathy, frequent disseminated intravascular coagulation and an increased bleeding risk. CAR T-cell therapy is characterized by frequent and mild consumptive coagulopathy, as well as an increased risk of thrombosis. While consumptive coagulopathy is rare in COVID-19, it is associated with an increased thrombotic risk. The differences can be explained by the severity of CRS and underlying conditions associated with coagulopathy. Various treatments, including cytokine inhibitors, plasma exchange, Janus kinases inhibitors, complement blockade, and corticosteroids are being studied to mitigate CRS-related coagulopathy.

The use of machine learning (ML) and deep learning (DL) methods in hematology includes diagnostic, prognostic, and therapeutic applications. This increase is due to the improved access to ML and DL tools and the expansion of medical data. The utilization of ML remains limited in clinical practice, with some disciplines further along in their adoption, such as radiology and histopathology. In this review, we discuss the current uses of ML in diagnosis in the field of hematology, including image-recognition, laboratory, and genomics-based diagnosis. Additionally, we provide an introduction to the fields of ML and DL, highlighting current trends, limitations, and possible areas of improvement.

T cells genetically engineered with chimeric antigen receptors (CART) have become a potent class of cancer immunotherapeutics. Numerous clinical trials of CART cells have revealed remarkable remission rates in patients with relapsed or refractory hematologic malignancies. Despite recent clinical success, CART cell therapy has also led to significant morbidity and occasional mortality from associated toxicities. Cytokine release syndrome (CRS) and Immune effector cell-associated neurotoxicity syndrome (ICANS) present barriers to the extensive use of CART cell therapy in the clinic. CRS can lead to fever, hypoxia, hypotension, coagulopathies, and multiorgan failure, and ICANS can result in cognitive dysfunction, seizures, and cerebral edema. The mechanisms of CRS and ICANS are becoming clearer, but many aspects remain unknown. Disease type and burden, peak serum CART cell levels, CART cell dose, CAR structure, elevated pro-inflammatory cytokines, and activated myeloid and endothelial cells all contribute to CART cell toxicity. Current guidelines for the management of toxicities associated with CART cell therapy vary between clinics, but are typically comprised of supportive care and treatment with corticosteroids or tocilizumab, depending on the severity of the symptoms. Acquiring a deeper understanding of CART cell toxicities and developing new management and prevention strategies are ongoing. In this review, we present findings in the mechanisms and management of CART cell toxicities.

Background: Monocytes are an essential cellular component of the innate immune system that support the host's effectiveness to combat a range of infectious pathogens. Hemopoietic cell transplantation (HCT) results in transient monocyte depletion, but the factors that regulate recovery of monocyte populations are not fully understood. In this study, we investigated whether the composition of the gastrointestinal microbiota is associated with the recovery of monocyte homeostasis after HCT.

Methods: We performed a single-center, prospective, pilot study of 18 recipients of either autologous or allogeneic HCT. Serial blood and stool samples were collected from each patient during their HCT hospitalization. Analysis of the gut microbiota was done using 16S rRNA gene sequencing, and flow cytometric analysis was used to characterize the phenotypic composition of monocyte populations.

Results: Dynamic fluctuations in monocyte reconstitution occurred after HCT, and large differences were observed in monocyte frequency among patients over time. Recovery of absolute monocyte counts and subsets showed significant variability across the heterogeneous transplant types and conditioning intensities; no relationship to the microbiota composition was observed in this small cohort.

Conclusion: In this pilot study, a relationship between the microbiota composition and monocyte homeostasis could not be firmly established. However, we identify multivariate associations between clinical factors and monocyte reconstitution post-HCT. Our findings encourage further longitudinal surveillance of the intestinal microbiome and its link to immune reconstitution.