Adoptive cellular therapies have revolutionized the management of hematologic malignancies, particularly lymphoma and multiple myeloma. These therapies targeting disease-specific antigens, such as CD19 in lymphoma and B...Adoptive cellular therapies have revolutionized the management of hematologic malignancies, particularly lymphoma and multiple myeloma. These therapies targeting disease-specific antigens, such as CD19 in lymphoma and B cell maturation antigen in multiple myeloma, are efficacious and well-tolerated compared with conventional chemotherapies. Unfortunately, their potential remains unrealized in acute myeloid leukemia (AML). This is because most targetable antigens on AML cells are also expressed on healthy myeloid hematopoietic stem cells (HSC). Therefore, targeting them results in severe myeloablative effects and pancytopenia. Several strategies have been devised to overcome this barrier, including identifying AML-specific antigens, limiting CAR-T cell persistence to prevent prolonged myeloablation, and creating AML-specific antigens through manipulating HSCs prior to allogenic transplant. In this review, we discuss these strategies and the ongoing clinical trials on adoptive cellular therapies in AML, limiting our focus to chimeric antigen receptor-T cells (CAR-T) and chimeric antigen receptor-natural killer cells (CAR-NK).
Chimeric antigen receptors (CARs) are synthetic engineered receptors with an antigen recognition domain derived from a high-specificity monoclonal antibody that can target surface molecules on tumor cells. T cells are ge...Chimeric antigen receptors (CARs) are synthetic engineered receptors with an antigen recognition domain derived from a high-specificity monoclonal antibody that can target surface molecules on tumor cells. T cells are genetically engineered to express CARs, thereby harnessing the antigen-recognition ability of antibodies and effector function of T cells. Target surface molecule selection is crucial for manufacturing CARs. Ideally, a target surface molecule should be restricted to tumor cells and minimally expressed or absent on normal tissues. Different CD19-targeted CAR-T cell therapies have been approved for the treatment of B-cell lymphoid malignancies that are refractory to other therapies, including indolent and aggressive B-cell non-Hodgkin lymphomas (NHL) and B-cell acute lymphoblastic leukemia (B-ALL). Despite impressive results, many patients with aggressive and refractory B-cell malignancies do not respond to or relapse after CD19 CAR-T cell therapies. Thus, several additional strategies are currently being evaluated to overcome these limitations. This review discusses studies on other promising CAR-T cell targets, including CD20, CD22, BAFF-R, ROR1, CD70, BCR complex, kappa/lambda light chains, multitargeted CAR-T cells, and combinations of CAR-T cell therapy with different drugs.
The U.S. Food and Drug Administration (FDA) approved 6 CAR T cell (CAR-T) products, including tisagenlecleucel (tisa-cel), axicabtagene ciloleucel (axi-cel), brexucabtagene autoleucel (brexu-cel), lisocabtagene maraleuce...The U.S. Food and Drug Administration (FDA) approved 6 CAR T cell (CAR-T) products, including tisagenlecleucel (tisa-cel), axicabtagene ciloleucel (axi-cel), brexucabtagene autoleucel (brexu-cel), lisocabtagene maraleucel (liso-cel), idecabtagene vicleucel (ide-cel), and ciltacabtagene autoleucel (cilta-cel) in the last 5 years. CAR T-cell therapy significantly improved outcomes for patients with B-cell non-Hodgkin lymphoma (NHL) and multiple myeloma (MM). However, recurrence and progression may occur after the initial response due to multiple mechanisms (Zeng and Zhang, 2022) [1]. Furthermore, CAR T-cell therapy is not broadly utilized in solid tumors due to various barriers. This review discusses the evolution of CAR T-cell therapies and how the "younger-generation" CAR T cells counteract these challenges to potentially broaden their applications in the future.
Increasing success of adaptive cell therapy (ACT), such as genetically engineered T cells to express chimeric antigen receptors (CARs) proven to be highly significant technological advancements and impressive clinical ou...Increasing success of adaptive cell therapy (ACT), such as genetically engineered T cells to express chimeric antigen receptors (CARs) proven to be highly significant technological advancements and impressive clinical outcomes in selected haematological malignancies, with promising efficacy. The evolution of CAR designs beyond the conventional structures is necessary to address some of the limitations of conventional CAR therapy and to expand the use of CAR T cells to a wider range of malignancies. There are various obstacles with a wide range of engineering strategies in order to improve the safety, efficacy and applicability of this therapeutic modality. Here we describe details of modular CAR structure with all the necessary domains and what is known about proximal CAR signalling in T cells. Furthermore, the global need for adoptive cell therapy is expanding very rapidly, and there is an urgent increasing demand for fully automated manufacturing methods that can produce large scale clinical grade high quality CAR engineered immune cells. Despite the advances in automation for the production of clinical grade CAR engineered cells, the manufacturing process is costly, consistent and involves multiple steps, including selection, activation, transduction, and Ex-Vivo expansion. Among these complex manufacturing phases, the choice of culture system to generate a high number of functional cells needs to be evaluated and optimized. Here we list the most advance fully automated to semi-automated bioreactor platforms can be used for the production of clinical grade CAR engineered cells for clinical trials but are far from being standardized. New processing options are available and a systematic effort seeking automation, standardization and the increase of production scale, would certainly help to bring the costs down and ultimately democratise this personalized therapy. In this review, we describe in detail different CAR engineered T cell platforms available and can be used in future for clinical-grade CAR engineered ATMP production.
Chimeric antigen receptor T cell (CAR-T) therapy is an immunotherapy, which represents a therapeutic breakthrough in the treatment of B-cell malignancies and multiple myeloma. Since the first CAR T-cell approval in 2017,...Chimeric antigen receptor T cell (CAR-T) therapy is an immunotherapy, which represents a therapeutic breakthrough in the treatment of B-cell malignancies and multiple myeloma. Since the first CAR T-cell approval in 2017, there have been five FDA approved CAR-T products, more approved disease indications for CAR-T therapy, and investigational trials launched for other cancers, including solid organ malignancies. CAR-T therapy possesses unique toxicities. Better understanding of these toxicities over time has helped in more efficient diagnosis, management, and treatment strategies. This review will focus on CAR-T-related toxicities including cytokine release syndrome, immune effector cell associated neurotoxicity syndrome (ICANS), cytokine release syndrome (CRS), and hemophagocytic lymphohistiocytosis (HLH)/ macrophage activation syndrome in terms of assessment, grading, and current management strategies. Additionally, this review will cover future directions and research on CAR-T-related toxicities.
Chimeric antigen receptor T-cell (CAR T) therapy has been proven effective in the third-line (and beyond) setting in patients with large B-cell lymphoma (LBCL). Until recently, high-dose chemotherapy followed by autologo...Chimeric antigen receptor T-cell (CAR T) therapy has been proven effective in the third-line (and beyond) setting in patients with large B-cell lymphoma (LBCL). Until recently, high-dose chemotherapy followed by autologous hematopoietic cell transplantation (auto-HCT) was considered the standard of care in the second-line setting in patients demonstrating an objective response before the procedure. The ZUMA-7 and TRANSFORM studies showed the benefit of axicabtagene ciloleucel and lisocabtagene maraleucel, respectively, in patients refractory to or relapsing within 12 months of first-line anthracycline-based chemoimmunotherapy. However, a third trial (BELINDA study) using tisagenlecleucel failed to show a benefit in the same setting compared to standard salvage chemoimmunotherapy followed by auto-HCT. Several differences exist between these trials, including trial designs, patient population, crossover permissibility, bridging therapy, and end-point definitions. In this review, we summarize the current evidence for the treatment of patients with LBCL in the third line and beyond and standard treatment in the second line before CAR T therapy approval and interpret outcomes of the three trials examining the role of CAR T therapy in the second line and their impact in reshaping future practice.
OBJECTIVE/BACKGROUND: Protein S (PS; encoded by the PROS1 gene), a key vitamin K-dependent anticoagulant protein, is emerging as a key structural and functional protein that is overexpressd in various malignancies, but h...OBJECTIVE/BACKGROUND: Protein S (PS; encoded by the PROS1 gene), a key vitamin K-dependent anticoagulant protein, is emerging as a key structural and functional protein that is overexpressd in various malignancies, but how PS signals to promote lung cancer progression is unclear. METHODS: We used immortalized, nontumorigenic human lung epithelial cell line NL-20, A549 cells as experimental cellular models for lung cancer, and human microvascular endothelial cells (HMEC-1) as a model system for angiogenesis. A loss- and gain-of-function approach was then used to analyze the role of tumor-derived PS and their natural TAM receptors Tyro3 and MerTK in regulating cell proliferation, migration, anchorage-independent growth, and capillary-like tube formation, all prominent attributes of the metastatic phenotype of tumor cells. RESULTS: Evidence is now provided that regulation of PROS1 gene expression using either stable cell lines expressing lentiviral-short hairpin RNA (shRNAs) or a replication-incompetent adenovirus alters the phosphorylation of several major signaling pathways, including Erk, PKB/Akt, p38, and focal adhesion kinase (FAK), and modulates PS-dependent Tyro3- and MerTK-mediated cell migration, proliferation, and anchorage-independent growth of lung cancer cells, and endothelial cell capillary-like tube formation. CONCLUSION: These finding suggest that the PS-Tyro3 and -MerTK axis mediates important signaling pathways to promote lung cancer progression. Genetic inhibition of endogenous PS may serve as a promising target for anticancer drug development.
BACKGROUND: Blood transfusion (BT) is essential in treating sickle cell disease (SCD); however, it leads to iron overload (IO) and oxidative stress. We studied the relationship between oxidative stress, iron status param...BACKGROUND: Blood transfusion (BT) is essential in treating sickle cell disease (SCD); however, it leads to iron overload (IO) and oxidative stress. We studied the relationship between oxidative stress, iron status parameters, hepcidin mRNA gene expression, and IO in SCD patients. METHODS: We classified all SCD patients (n = 90) into two groups: Group I, 45 children (s.ferritin ≥ 938 ng/mL) and Group II, 45 children (s.ferritin < 938 ng/mL). A total of 55 children, age and sex matched, participated as a control group. Malondialdehyde (MDA), nitrite, s.iron, s.total iron-binding capacity (sTIBC), transferrin saturation %, s.ferritin, s.hepcidin, and hepcidin mRNA gene expression were assessed. RESULTS: Among SCD BT-dependent patients (>3 times/year), 63% were from Group I and 37% from Group II, p < .01. The two patient groups had significantly lower s.hepcidin and hepcidin gene expression than controls ( p < .001). TIBC, s.iron, s.ferritin, transferrin saturation %, ferritin/hepcidin ratio, and MDA levels were higher among SCD patients than controls ( p < .001). Group I had higher mean level of ferritin/hepcidin ratio and MDA than Group II ( p < .01). The higher level of MDA and increased frequency of BT were the significant predicting risk factors for IO ( p < .05). A receiver-operating characteristic curve indicates that MDA is the outstanding significant biomarker for high level of s.ferritin with subsequent IO progression. CONCLUSION: MDA may serve as a biomarker of oxidative stress and IO in SCD patients. This result paid attention for urgent initiation of antioxidant and chelation therapy on detecting increased MDA level.
Linn SM, Nampoothiri RV, Chen C
… +11 more, Pasic I, Al-Shaibani Z, Lam W, Law AD, Michelis FV, Kim DDH, Gerbitz A, Lipton J, Kumar R, Mattsson J, Viswabandya A
BACKGROUND: Allogeneic hematopoietic stem cell transplantation (allo-HCT) is currently the only curative treatment for patients with chronic lymphocytic leukemia (CLL). METHODS: We analyzed the outcomes of 93 patients (m...BACKGROUND: Allogeneic hematopoietic stem cell transplantation (allo-HCT) is currently the only curative treatment for patients with chronic lymphocytic leukemia (CLL). METHODS: We analyzed the outcomes of 93 patients (median age: 52 years) who underwent allo-HCT at our center between 1989 and 2019. RESULTS: After a median follow-up of 35 months, relapse was observed in 15.1% (n = 14) patients. The estimated 2-year non-relapse mortality, relapse-free survival, and overall survival (OS) were 38.1%, 54.2%, and 58.7%, respectively. The ECOG performance status ≥ 2 (hazard ratio [HR]: 4.1; p = .001) and use of total body irradiation (in a myeloablative conditioning regimen; HR: 2.64; p = .005) were predictive of poor OS after multivariable analysis. The occurrence of sinusoidal obstruction syndrome/veno-occlusive disease post-transplant was associated with poor survival (p = .001). CONCLUSION: Although the use of kinase and bcl2 inhibitors may result in a decrease in the number and need of transplants, allo-HCT remains a viable option in selected patients with high-risk CLL and good performance status.
Some of the early complications of hematopoietic stem cell transplantation (HSCT) concerning the small vessels can be summarized as transplant-associated systemic vasculopathies (TASV). One enzyme known to play a major r...Some of the early complications of hematopoietic stem cell transplantation (HSCT) concerning the small vessels can be summarized as transplant-associated systemic vasculopathies (TASV). One enzyme known to play a major role in inflammation, tissue remodeling, and repair processes as well as tumor metastasis is heparanase (HPSE). HPSE genetic variants have recently been associated with significant influence on the risk of developing certain TASV such as a sinusoidal obstruction syndrome. This study aimed to validate the two known HPSE single nucleotide polymorphisms (SNPs)-rs4693608 and rs4364254-as a genetic predictor of TASV in a cohort of 494 patients and were correlated retrospectively with the clinical course post-HSCT. Significant association was revealed for rs4364254, showing that the incidence of TASV (38.0% vs. 57.8%, p = .009) and in particular of acute graft-versus-host disease (aGvHD) (36.3% vs. 54.0%, p = .0138) was lower in wildtype CC carriers than in TC/TT carriers. Moreover, compared with all other genotypes, the allelic combination GG-CC had the lowest incidence of TASV (34.9% vs. 57.4%, p = .0109) and aGvHD in particular (34.9% vs. 53.5%, p = .0315). A competing risk regression analysis confirmed a significantly reduced risk for a TASV in patients with GG (subhazard ratio [SHR] = 0.670, p = .043) and CC (SHR = 0.598, p = .041) compared with the corresponding homozygote SNP as well as for allelic combinations correlated with low HPSE gene expression (SHR = 0.630, p = .016) and in correlation with clinical risk factors. In summary, our study emphasizes an association of HPSE gene SNPs with TASV, in particular with aGvHD, which could be implementable as pre-transplant risk stratification if validated prospectively.
Sympathetic nervous system activation plays a role in the development of acute and chronic graft-versus-host disease (GVHD) following allogeneic hematopoietic cell transplantation (HCT). The primary objective was to comp...Sympathetic nervous system activation plays a role in the development of acute and chronic graft-versus-host disease (GVHD) following allogeneic hematopoietic cell transplantation (HCT). The primary objective was to compare the cause-specific hazard of grade II-IV and III-IV acute GVHD (aGVHD) and chronic GVHD (cGVHD) in the context of ß-blocker use and type (selective vs. non-selective). Secondary objectives included overall survival (OS), relapse-free survival (RFS), and cumulative incidence of relapse, non-relapse mortality (NRM), and grade II-IV and III-IV aGVHD and cGVHD. The current study included 151 patients ages 18 and older diagnosed with hematological malignancies who underwent reduced intensity conditioning allogeneic HCT from HLA matched related or unrelated donors between January 2014 and 2017. 31 patients were on a ß-blocker of which 71% were on a selective ß-blocker. The incidence of aGVHD was not different among groups. Results show a non-significant trend in the association between ß-blocker use and reduction in the risk of developing cGVHD (cause-specific hazard ratio 0.49, p = 0.060), with no negative impact on survival or relapse. The current data are supportive of a potential ß-adrenergic influence on the pathogenesis of GVHD, consistent with the inflammatory etiology of GVHD and the anti-inflammatory effects of ß-adrenergic antagonists.
BACKGROUND: Matched donor (MD) allogeneic hematopoietic stem cell transplantation (allo-HSCT) is currently the preferred choice of treatment for Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph ALL) pati...BACKGROUND: Matched donor (MD) allogeneic hematopoietic stem cell transplantation (allo-HSCT) is currently the preferred choice of treatment for Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph ALL) patients who have achieved complete remission. This systematic review and meta-analysis was conducted to investigate the effects of allo-HSCTs from different donor types for Ph ALL patients who received tyrosine kinase inhibitors (TKIs). METHODS: Studies in EMBASE and MEDLINE between inception and December 2020 were identified using search terms related to "Ph ALL" and "HSCT." Eligible studies were studies with Ph ALL patients who received a TKI and allo-HSCT. The primary outcomes of interest-the overall survival (OS) or relapse-free survival (RFS)-needed to be reported. The Mantel-Haenszel method was used to combine the effect estimates and associated 95% confidence intervals (CIs) of each donor type. RESULTS: Fourteen cohort studies were identified for the meta-analysis. Haploidentical (HID)-HSCT for Ph ALL patients resulted in a superior RFS to MD-HSCT, with a pooled odds ratio (OR) of 1.57 (95% CI, 1.05-2.32; I = 0%). However, HID-HSCT and MD-HSCT had comparable OS. Furthermore, HID-HSCT group had a significantly lower relapse rate than MD-HSCT group. On the other hand, the risks of graft-versus-host disease (GvHD) were higher for HID-HSCT and pooled OR of chronic GvHD rate. The OS and RFS of matched sibling-HSCT, matched unrelated-HSCT, and cord blood-HSCT were comparable with those of HID-HSCT. CONCLUSION: This systematic review and meta-analysis showed that HID-HSCT is as effective as MD-HSCT in Ph ALL patients.
Lisocabtagene maraleucel (liso-cel) is an autologous CD19-directed chimeric antigen receptor (CAR) T cell product, with a CD3ζ activatory domain connected to 4-1BB costimulatory domain. Liso-cel, unlike the other two app...Lisocabtagene maraleucel (liso-cel) is an autologous CD19-directed chimeric antigen receptor (CAR) T cell product, with a CD3ζ activatory domain connected to 4-1BB costimulatory domain. Liso-cel, unlike the other two approved products-axicabtagene ciloleucel and tisagenlecleucel-is manufactured separately from CD4 and CD8 T cells and then administered as a sequential infusion of the two components at equal target doses. The approval of liso-cel was based on the results of Transcend NHL 001, a single-arm, open-label, multicenter, seamless design trial that enrolled 344 patients, of whom 269 received conforming liso-cel. The most common histology was diffuse large B cell lymphoma, not otherwise specified (DLBCL NOS; n = 137, 51%) followed by DLBCL transformed from indolent lymphomas (n = 78, 29%). Encouraging results were reported, yielding an objective response rate across all dose levels of 73% [complete remission (CR) = 53%], with an estimated duration of response at 1 year of 55% for all patients and 65% for those achieving a CR. The estimated 12-month overall survival was 58% for all patients and 86% for those achieving a CR. Cytokine release syndrome and neurological adverse events were reported in 42% and 30%, respectively. This review summarizes the evidence on the safety and effectiveness of liso-cel, resulting in its addition to the current treatment armamentarium of relapsed or refractory large B cell lymphoma.
BACKGROUND: Immune checkpoint inhibitors (ICIs) are the newest class of anticancer drugs. Pneumonitis is increasingly being recognized as a potential complication of these agents. METHODS: We conducted a retrospective st...BACKGROUND: Immune checkpoint inhibitors (ICIs) are the newest class of anticancer drugs. Pneumonitis is increasingly being recognized as a potential complication of these agents. METHODS: We conducted a retrospective study of patients who received ICIs at a comprehensive cancer center. We collected data on demographics, type of malignancy, type of ICI agent, incidence of pneumonitis up to 6 weeks after receiving ICI agent, clinical characteristics, and risk factors for overall survival in patients who develop pneumonitis. RESULTS: A total of 654 patients received ICIs during the study period. The most common type of cancer for which ICI was given was adenocarcinoma of the lung (29%), followed by renal cell cancer (12%) and squamous cell lung cancer (12%). Among the study patients, 41% received nivolumab and 32% received pembrolizumab. Other patients in the study received combination of ICIs or ICI plus chemotherapeutic agent, or were part of clinical trial involving ICI. Overall 42 (6.4%) patients developed pneumonitis within 6 weeks after the last dose of treatment of any ICI agent. Of these, 81% of patients had Grade ≥ 2 pneumonitis and 45% of these required hospital admission for pneumonitis, with 10% of them requiring admission to intensive care unit. Overall, patients who received pembrolizumab-containing regimen, had prior chemotherapy, or who never had cancer-related surgery had increased risk of death. CONCLUSION: Our large retrospective study shows real-life data of incidence of pneumonitis in patients who are treated with ICIs for cancer treatment. Our data indicate that the incidence of pneumonitis is overall lower than that reported previously with relatively good outcomes.
Ahmed SO, El Fakih R, Elhaddad A
… +30 more, Hamidieh AA, Altbakhi A, Chaudhry QU, Bazarbachi A, Adil S, Al-Khabori M, Ben Othman T, Gaziev J, Khalaf M, Alshammeri S, Alotaibi S, Alshahrani M, Bekadja MA, Ibrahim A, Al-Wahadneh AM, Altarshi M, Alsaeed A, Madani A, Abboud M, Abujazar H, Bakr M, Abosoudah I, El Cheikh J, Almasari A, Alfraih F, Baldomero H, Elsolh H, Niederwieser D, Chaudhri N, Aljurf M
The World Health Organization-designated Eastern Mediterranean region (EMRO) consists of 22 countries in North Africa and Western Asia with a collective population of over 679 million. The area comprises some of the weal...The World Health Organization-designated Eastern Mediterranean region (EMRO) consists of 22 countries in North Africa and Western Asia with a collective population of over 679 million. The area comprises some of the wealthiest countries per capita income and some of the poorest. The population structure is also unique and contrasts with western countries, with a much younger population. The region sits in the heart of the thalassemia belt. Many countries have a significant prevalence of sickle cell disease, and cancer is on the rise in the region. Therefore, the strategic priorities for the growth and development of hematopoietic stem cell transplantation (HSCT) differ from country to country based on resources, healthcare challenges, and prevalent infrastructure. Thirty-one reporting teams to the Eastern Mediterranean Blood and Marrow Transplantation Group have active HSCT programs in 12 countries; allogeneic transplants outnumber autologous transplants, and the proportion of allotransplants for non-malignant conditions is higher in the EMRO region than in Western Europe and North America. The vast majority (99%) of allotransplants are from matched related donors. Matched unrelated donors and other alternate donor transplants are underutilized. The chance of finding a matched related donor for allografts is higher, with a significant chance of finding matched donors among non-sibling related donors. Reasons for relatively lower rates of transplants compared with other countries are multifactorial. Capacity building, development of newer centers, innovative funding, and better utilization of information technology are required to make transplantation as an accessible modality to more patients. Cost-effectiveness and cost-containment, regulation, and ensuring quality will all be priorities in planning HSCT development in the region.
The Internet of Things (IoT) has penetrated many aspects of everyday human life. The use of IoT in healthcare has been expanding over the past few years. In this review, we highlighted the current applications of IoT in...The Internet of Things (IoT) has penetrated many aspects of everyday human life. The use of IoT in healthcare has been expanding over the past few years. In this review, we highlighted the current applications of IoT in the medical literature, along with the challenges and opportunities. IoT use mainly involves sensors and wearables, with potential applications in improving the quality of life, personal health monitoring, and diagnosis of diseases. Our literature review highlights that the current main application studied in the literature is physical activity tracking. In addition, we discuss the current technologies that would help IoT-enabled devices achieve safe, quick, and meaningful data transfer. These technologies include machine learning/artificial intelligence, 5G, and blockchain. Data on current IoT-enabled devices are still limited, and future research should address these devices' effect on patients' outcomes and the methods by which their integration in healthcare will avoid increasing costs.
BACKGROUND: Hepatic veno-occlusive disease (VOD), also termed as sinusoidal obstruction syndrome (SOS), is a lethal complication after hematopoietic stem cell transplantation (HSCT). Various factors put patients undergoi...BACKGROUND: Hepatic veno-occlusive disease (VOD), also termed as sinusoidal obstruction syndrome (SOS), is a lethal complication after hematopoietic stem cell transplantation (HSCT). Various factors put patients undergoing allogeneic HSCT at an increased risk for VOD. Thrombomodulin (TM) is an important factor which has a wide range of effects, including anticoagulant, anti-inflammatory, angiogenic, and protective effect, on endothelial cells. It plays a role in preventing excessive coagulation and thrombosis by binding with thrombin and inhibiting the coagulation cascade. There are a limited number of options for the prevention of this fatal complication. Recombinant thrombomodulin (rTM), an endothelial anticoagulant co-factor, as prophylactic therapy might be able to prevent veno-occlusive complications after stem cell transplantation. METHODS: A literature search was performed on PubMed, Embase, and Web of Science. We used the following Mesh terms and Emtree terms, "Hepatic Veno-Occlusive Diseases" OR "Sinusoidal Obstruction" OR "Stem Cell Transplantations " AND "Thrombomodulin" from the inception of data up to April 1, 2021. The PICO (Patient/Population, Intervention, Comparison and Outcomes) framework was used for the literature search. RESULTS: For the VOD incidence after HSCTstem cell transplantation, the result was in favor of rTM with a risk ratio (RR) of 0.53 (I = 0%, 95% confidence interval [CI] = 0.32-0.89). The incidence of transplant-associated thrombotic microangiopathy (TA-TMA) after HSCT was reduced in rTM group. The RR for incidence of TA-TMA was 0.48 (I = 62%, 95% CI = 0.20-1.17) favoring rTM. The RR for incidence of graft-versus-host disease (GvHD) was also lower in rTM group, 0.48 (I = 64%, 95% CI = 0.32-0.72). CONCLUSION: In our meta-analysis, we evaluate the efficacy and safety of rTM in the prevention of SOS after HSCT. According to our results, rTM use led to a significant reduction in SOS episodes, TA-TMA, and GvHD after HSCT.
OBJECTIVE/BACKGROUND: Despite the success of chimeric antigen receptor (CAR) T-cell therapy in patients with aggressive non-Hodgkin lymphoma (aNHL), some patients still fail treatment, and their prognosis is dismal. METH...OBJECTIVE/BACKGROUND: Despite the success of chimeric antigen receptor (CAR) T-cell therapy in patients with aggressive non-Hodgkin lymphoma (aNHL), some patients still fail treatment, and their prognosis is dismal. METHODS: We performed a retrospective study of aNHL patients treated with axicabtagene ciloleucel (axi-cel) at two Mayo Clinic centers between 2018 and 2020. We evaluated predictive factors, toxicities, and responses to salvage regimens after CAR T-cell therapy. RESULTS: Thirty-four patients received axi-cel with a median length of hospitalization of 14 days. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome of any grade occurred in 91% and 41% of patients, respectively. Furthermore, 71% of patients responded to therapy, with 53% achieving a complete response (CR). The CRS grade and absolute lymphocyte count at leukapheresis (ALC) correlated with CR and overall survival (OS), respectively. After a median follow-up of 6.8 months (interquartile range [IQR] 4.6-14.9), 15 patients (44%) showed progressive disease (PD). Most patients (60%) progressed during the first 3 months and had persistent CD19 tumor expression. Elevated C-reactive protein at baseline increased the risk of PD, whereas elevated ferritin increased PD and mortality risk. Twelve patients received salvage therapy, but only three responded. Median OS of relapsed/refractory patients to axi-cel was 3 months (IQR 1.3-5.1). CONCLUSION: The grade of CRS and ALC correlated with better outcomes to axi-cel therapy. In addition, elevated inflammatory markers at baseline were associated with PD and shorter survival. Relapses after treatment frequently occur within months after axi-cel infusion; they confer a poor prognosis and create an urgent need for novel and effective treatment options in this patient population.
OBJECTIVE/BACKGROUND: Baseline neutrophil/lymphocyte ratio (NLR), a surrogate marker for systemic inflammation and immunosuppression, is a well-studied prognostic marker in non-small cell lung cancer (NSCLC). This study...OBJECTIVE/BACKGROUND: Baseline neutrophil/lymphocyte ratio (NLR), a surrogate marker for systemic inflammation and immunosuppression, is a well-studied prognostic marker in non-small cell lung cancer (NSCLC). This study tests if interim NLR is prognostic in NSCLC patients in remission. METHODS: This single-center, retrospective cohort study analyzed 131 NSCLC patients treated from 2010 to 2015 who achieved complete remission. NLR was calculated at baseline and from the first available blood sample during remission. Kaplan-Meier estimates of overall survival (OS) and time to recurrence were compared using the log-rank test for trend. Multivariable analysis was conducted using the Cox proportional hazards model. RESULTS: Of the 131 cases, 63 had subsequently recurred at the last follow-up. The mean age was 64 ± 10 years. Patients with stage I (35%), II (24%), and III (41%) were included. Histology were adenocarcinoma (60%), squamous cell (33%), and unspecified (7%). The majority of patients were smokers. For the univariate analysis interim NLR was binned into tertiles, NLR < 2, 2-4.08, and > 4.08. Of those with an interim NLR > 4.08, prognosis and recurrence risk were higher. In the multivariable analysis, remission NLR was strongly prognostic for OS ( p < .001) as did patient's age ( p = .002), but not stage, race, sex, and baseline NLR. CONCLUSIONS: Our study found that interim NLR, obtained in remission, was strongly prognostic for OS and recurrence.