Showing papers in "Hematological Oncology in 2021"
TL;DR: In this paper, the mechanism of circ_0009910 in acute myeloid leukemia (AML) cell-to-cell communication remained obscure. But, the role of circ9910-containing exosomes mediated proliferation, apoptosis and cell cycle progression of AML cells partially through miR-5195-3p/GRB10 axis.
Abstract: The exosomes are involved in intercellular communication via RNA trafficking in human diseases. Hsa_circ_0009910 (circ_0009910) is a novel leukemia-related circular RNA. However, the mechanism of circ_0009910 in acute myeloid leukemia (AML) cell-to-cell communication remained obscure. Expression of circ_0009910, miRNA (miR)-5195-3p and growth factor receptor-bound protein 10 (GRB10) was detected by quantitative real-time polymerase chain reaction and Western blotting. A stable cell coculture model was established and functional experiment was performed using Cell Counting Kit-8 assay, flow cytometry, and Western blotting. The interaction among circ_0009910, miR-5195-3p and GRB10 was confirmed by dual-luciferase reporter assay and RNA immunoprecipitation. As a result, circ_0009910 was upregulated in AML bone marrows and cells (HL-60 and MOLM-13), even higher in AML cells-derived exosomes. Functionally, blocking circ_0009910 via small interfering RNA (siRNA) suppressed cell proliferation and cell cycle progression, but facilitated apoptosis rate of HL-60 and MOLM-13 cells, accompanied with lower B-cell lymphoma 2 (Bcl-2) level and higher Bcl-2-associated X protein (Bax) level. circ_0009910 shuttled via exosomes negatively regulated miR-5195-3p expression by target binding. Furthermore, circ_0009910 knockdown via exosomes and miR-5195-3p overexpression via mimic resulted in similar results of circ_0009910 siRNA in proliferation, apoptosis and cell cycle progression of AML cells. Meanwhile, the role of circ_0009910 knockdown in AML cells was partially reversed by miR-5195-3p deletion, and restoring GRB10 could abrogate miR-5195-3p effect as well. Notably, GRB10 was a downstream target of miR-5195-3p. circ_0009910-containing exosomes mediated proliferation, apoptosis and cell cycle progression of AML cells partially through miR-5195-3p/GRB10 axis.
26 citations
TL;DR: In the recently revised WHO classification 2017 and the updated WHO-EORTC classification for CL 2018, primary cutaneous CD8+ acral T-cell lymphoma has been introduced as a new still provisional entity.
Abstract: Cutaneous T-cell lymphomas (CTCL) represent the majority of primary cutaneous lymphomas (CL). Mycosis fungoides (MF) and cutaneous CD30+ lymphoproliferative disorders account for 80% of all CTCL. CTCL show overlapping histological features. Thus clinical-pathological correlation is of importance to achieve final diagnosis. MF shows a characteristic evolution with patches, plaques, and in a subset of patients (10%-20%) with tumors. Therapy is stage-adapted with skin-directed therapies such as UV-light therapies and corticosteroids in early disease stage (i.e., patch and limited plaque stage) and systemic therapies (retinoids, interferon, mono chemotherapy, targeted therapy) and/or radiation therapy (local or total skin beam electron) in advanced stages. Novel therapies include targeted therapy such as mogamulizumab (anti-CCR4) or brentuximab vedotin (anti-CD30) and histone deacetylase inhibitors. Considering the impact of targeted therapies, biomarkers such as CD30 are not only crucial for the diagnosis and correct classification of an individual lymphoma case, but also for therapy as they may represent therapeutic targets. In the recently revised WHO classification 2017 and the updated WHO-EORTC classification for CL 2018, primary cutaneous CD8+ acral T-cell lymphoma has been introduced as a new still provisional entity. It displays characteristic clinical, histological, and phenotypic features and exhibits an excellent prognosis. Rare, but aggressive CTCL include cutaneous primary cutaneous aggressive epidermotropic CD8-positive T-cell lymphoma and cutaneous gamma/delta T-cell lymphoma, which present with rapid onset of necrotic or ulcerated plaques and tumors. As they have a poor prognosis, treatment includes multiagent chemotherapy and hematopoietic stem cell transplantation.
24 citations
TL;DR: The potential of bispecific antibodies to direct antigen-specific T cell-mediated cytotoxicity toward malignant cells bearing a target antigen was recognized over 35 years ago as discussed by the authors.
Abstract: The potential of bispecific antibodies to direct antigen-specific T cell-mediated cytotoxicity toward malignant cells bearing a target antigen was recognized over 35 years ago. Generally, this is accomplished by combining a T-cell receptor-specific monoclonal antibody or monoclonal antibody-derived fragment that is capable of activating and expanding resting T cells with a second monoclonal antibody or monoclonal antibody fragment directed against a tumor target antigen. Bispecific antibodies induce effector T cells that bind to tumor cells independently of their T-cell receptor specificity and without the requirement of MHC-mediated antigen presentation, focusing effector T-cell cytotoxicity on tumor cells bearing the target antigen. The therapeutic efficacy of this approach for treatment of relapsed or refractory B-cell lymphomas was first demonstrated with blinatumomab, a single molecule comprised of two linked single-chain variable fragments with binding specificities for CD19 and CD3. The recent demonstration that chimeric antigen receptor (CAR) modified T cells can achieve very durable remissions in some patients with relapsed or refractory B-cell lymphomas, as well as the potential efficacy of bispecific antibodies in CAR T cell failures, has rekindled interested in bispecific antibodies as a T cell-mediated therapeutic approach. We review the early results of phase 1 clinical trials of bispecific antibodies targeting CD20 on B cells and engaging T cells via CD3 in 1:1 or 2:1 CD20:CD3 Fab formats for treatment of relapsed or refractory B-cell lymphomas.
22 citations
TL;DR: KRd demonstrated to be effective in RRMM pts treated in real‐world setting, without new safety concerns, and better survival outcomes emerged for pts with ≤2 prior lines of therapy, achieving at least a VGPR, and without HRCA.
Abstract: Carfilzomib-lenalidomide-dexamethasone (KRd) has been approved for the treatment of relapsed/refractory multiple myeloma (RRMM). We conducted a retrospective analysis of 197 RRMM patients (pts) between January 2016 and March 2018 in six Italian hematologic centers, with the aim to evaluate efficacy and safety of KRd in real-life. At KRd initiation 27% carried high risk cytogenetic abnormalities (HRCA) [del17p and/or t(4;14) and/or t(14;16)], median number of prior lines of therapy was 2 (1-8), nearly all pts (96%) received prior bortezomib (18% refractory) while 45% were exposed to lenalidomide (R; 22% refractory). At the median of 12.5 months, 52% of the pts had discontinued treatment, mainly (66%) for progression. Main grade 3-4 adverse events were neutropenia (21%), infections (11%), and hypertension (6%). Overall, the response rate was 88%. The median progression-free survival (PFS) was 19.8 months and 1-year overall survival (OS) rate was 80.6%. By subgroup analysis, extended PFS and OS were observed for pts who received ≤2 prior lines of therapy (HR = 0.42, p < 0.001 and HR = 0.35, p = 0.001, respectively), not refractory to prior R (HR = 0.37, p < 0.001, and HR = 0.47, p = 0.024), without HRCA (HR = 0.33, p = 0.005 and HR = 0.26, p = 0.016) and achieving ≥ very good partial response (VGPR; HR = 0.17, p < 0.001 and HR = 0.18, p < 0.001). In conclusion, KRd demonstrated to be effective in RRMM pts treated in real-world setting, without new safety concerns. Better survival outcomes emerged for pts with ≤2 prior lines of therapy, achieving at least a VGPR, and without HRCA.
18 citations
TL;DR: Recently, activating somatic mutations in MAPK pathway genes, most notably BRAFV600E, have been discovered in almost all cases of LCH, and new insights into pathogenesis support reclassification of these conditions as a myeloid neoplastic disorders as mentioned in this paper.
Abstract: Children with Langerhnans cell histiocytosis (LCH) develop granulomatous lesions with characteristic clonal CD207+ dendritic cells that can arise as single lesions or life-threatening disseminated disease. Despite the wide range of clinical presentations, LCH lesions are histologically indistinguishable based on severity of disease, and uncertain classification as an immune versus neoplastic disorder has historically challenged the development of optimal clinical strategies for patients with LCH. Recently, activating somatic mutations in MAPK pathway genes, most notably BRAFV600E, have been discovered in almost all cases of LCH. Further, the stage of myeloid differentiation in which the mutation arises defines the extent of disease and risk of developing LCH-associated neurodegeneration. MAPK activation in LCH precursor cells drives myeloid differentiation, inhibits migration, and inhibits apoptosis, resulting in accumulation of resilient pathologic dendritic cells that recruit and activate T cells. Recurrent somatic mutations in MAPK pathway genes have also been identified in related histiocytic disorders: juvenile xanthogranuloma, Erdheim-Chester disease, and Rosai-Dorfman disease. New insights into pathogenesis support reclassification of these conditions as a myeloid neoplastic disorders. Continued research will uncover opportunities to identify novel targets and inform personalized therapeutic strategies based on cell of origin, somatic mutation, inherited risk factors, and residual disease.
18 citations
TL;DR: In this paper, the authors report the outcomes of 61 Greek patients, who received Pola-(B)R mainly within a compassionate use program, and confirm that Pola-BR is a promising treatment for rrDLBCL patients, inducing an adequate response rate with acceptable toxicity.
Abstract: Transplant-ineligible relapsed/refractory (rr) diffuse large B-cell lymphoma (DLBCL) patients represent an unmet medical need. Polatuzumab vedotin (Pola), an anti-CD79b antibody-drug-conjugate (ADG), with bendamustine- rituximab(BR) has recently gained approval for these patients, both in the USA and Europe, based on the GO29365 phase IIb trial. Real-life data with Pola are extremely limited. We report the outcomes of 61 Greek patients, who received Pola-(B)R mainly within a compassionate use program. Treatment was given for up to six 21-day cycles. Bendamustine was omitted in three cases due to previous short-lived responses. Fourty-nine rrDLBCL(efficacy cohort-EC) and 58 rr aggressive B-NHL (safety cohort-SC) patients received at least 1 Pola-BR cycle. Twenty-one (43%) patients of the EC responded with 12/49 (25%) CR and 9/49 (18%) PR as best response. Median progression-free survival, overall survival and duration of response were 4.0, 8.5, and 8.5 months respectively, while 55% of patients experienced a grade ≥3 adverse event, mainly hematologic. Treatment discontinuations and death during treatment were mainly due to disease progression. Twenty-two (41%) patients received further treatment; 11/22 are still alive, including one after CAR-T cells, and two after stem cell transplantation. Our data confirm that Pola-BR is a promising treatment for rrDLBCL patients, inducing an adequate response rate with acceptable toxicity. Pola-BR could be used as bridging therapy before further consolidative treatments.
17 citations
TL;DR: Hsa_circ_0002483 knockdown repressed AML cell proliferation and promoted cycle arrest and apoptosis via controlling miR‐758‐3p/MYC axis and circ_000 2483 could regulate MYC expression by miR•758‐ 3p.
Abstract: Circular RNAs are relevant to progression of acute myeloid leukemia (AML). Nevertheless, how and whether hsa_circ_0002483 (circ_0002483) participates in AML progression are largely uncertain. The bone marrow samples were harvested from 31 AML patients or 31 normal subjects. Circ_0002483, microRNA (miR)-758-3p and myelocytomatosis oncogene (MYC) abundances were examined via quantitative reverse transcription polymerase chain reaction and Western blot. Cell proliferation, cycle process and apoptosis were analyzed via Cell Counting Kit-8, flow cytometry, caspase 3 activity and related protein levels. Target relationship was investigated by dual-luciferase reporter assay and RNA immunoprecipitation. Circ_0002483 expression was elevated in AML patients and cells. Circ_0002483 silence constrained AML cell proliferation and facilitated cell cycle arrest and apoptosis. miR-758-3p was reduced in AML and decreased via circ_0002483. miR-758-3p down-regulation mitigated the inhibitive influence of circ_0002483 interference on AML progression. MYC was decreased by miR-758-3p, and circ_0002483 could regulate MYC expression by miR-758-3p. miR-758-3p overexpression restrained cell proliferation and promoted cycle arrest and apoptosis via decreasing MYC. Circ_0002483 knockdown repressed AML cell proliferation and promoted cycle arrest and apoptosis via controlling miR-758-3p/MYC axis.
17 citations
Kagoshima University1, Harvard University2, Memorial Sloan Kettering Cancer Center3, Nagoya City University4, Emory University5, Thomas Jefferson University6, Nagasaki University7, University of the Ryukyus8, University of Tokyo9, Yale University10, Kumamoto University11, Daiichi Sankyo12, Saitama Medical University13
15 citations
14 citations
14 citations
TL;DR: Doctors need to weigh the clinical benefits of this agent against higher toxicity, as all randomized controlled trials comparing obinutuzumab‐based regimens with rituximab‐ based regimens to better assess their toxicity profile are compiled.
Abstract: Rituximab, the first anti-CD20 monoclonal antibody, has dramatically improved outcomes for patients with B-cell lymphoproliferative disorders. Obinutuzumab was developed to potentiate activity and overcome resistance to rituximab. Clinical data suggest that obinutuzumab is superior to rituximab in follicular lymphoma (FL) and chronic lymphocytic leukemia (CLL). Yet, it has increased toxicity. This systematic review and meta-analysis compiled all randomized controlled trials (RCTs) comparing obinutuzumab-based regimens with rituximab-based regimens to better assess their toxicity profile. Primary outcome was grade 3-4 infections; secondary outcomes included any adverse events (AE), grade 3-4 AE, drug discontinuation rate, and 3-years mortality. Relative risks (RRs) were estimated and pooled using a fixed-effect model, unless there was significant heterogeneity, in which case a random-effects model was used. Our comprehensive search yielded five RCTs conducted between 2009 and 2014, including 4247 patients. The trials included FL patients, CLL and diffuse large B cell lymphoma. Monoclonal antibodies were given with different chemotherapy regimens (in four trials) or as monotherapy (in one trial). The point estimate favored increase in both grade 3-4 infections rate (RR 1.17 [95% CI, 1.0-1.36]) and any AE rate (RR 1.05 [95% 1-1.1]) with obinutuzumab, although this was not statistically significant. There was a significantly increased rate of grade 3-4 AE (RR 1.15 [95% CI, 1.09-1.2]), as well as grade 3-4 toxicities including thrombocytopenia (RR 2.8 [95% CI, 1.92-4.06]), infusion related reactions (RR 2.8 [95% CI, 2.16-3.64]) and cardiac events (RR 1.65 [95% CI, 1.11-2.46]). There was no significant difference in grade 3-4 anemia and neutropenia nor in the 3-year mortality rate. The point estimate favored increase in discontinuation rate due to AE with obinutuzumab, although without statistical significance (RR 1.24 [95% CI, 1.0-1.54]). In conclusion, physicians need to weigh the clinical benefits of this agent against higher toxicity.
TL;DR: The role of the tumor microenvironment (TME) for lymphoma cells looking at direct cell–cell interactions as well as cytokine‐related communications is introduced and a special attention will be given to the interactions of immune checkpoints.
Abstract: The tumor microenvironment (TME) - a term comprising non-neoplastic cells and extracellular matrix as well as various cytokines, chemokines, growth factors, and other substances in the vicinity of tumor cells - is an integrative part of most tumors including lymphomas. Interactions between lymphoma cells and the TME are vital for survival and proliferation of the former. In addition, lymphoma cells often reprogram the TME to protect them from defense mechanisms of the host's immune system. In this review, we will introduce the role of the tumor microenvironment (TME) for lymphoma cells looking at direct cell-cell interactions as well as cytokine-related communications. The immunomodulative/immunosuppressive role of the TME is more and more coming into the focus of potential new targeted therapies, and thus a special attention will be given to the interactions of immune checkpoints such as programed cell death protein 1 and L1 (PD-1/PD-L1), T-cell immunoglobulin and mucin-domain containing protein-3 (TIM-3), lymphocyte-activation gene 3 (LAG-3), and cytotoxic T-lymphocyte-associated protein-4 (CTLA4) with the TME, as well as their expression by both lymphoma cells and cells of the TME. Aspects of the TME will be discussed for indolent and aggressive B-cell lymphomas, Hodgkin lymphomas, and T-cell lymphomas. In addition, the potential influence of other immunomodulators such as lenalidomide will be briefly touched. The complex role of the TME is in the focus of new therapeutic options. In order to exploit its full therapeutic potential, however, a thorough understanding of TME biology and interaction between lymphoma cells and the TME, as well as the host's immune system and the TME is necessary.
Manchester Academic Health Science Centre1, Mayo Clinic2, University of Debrecen3, University of Barcelona4, Osaka University5, Harvard University6, University of Alberta7, University of Rochester Medical Center8, First Faculty of Medicine, Charles University in Prague9, Seattle Genetics10, Millennium Pharmaceuticals11
TL;DR: An updated analysis of the ECHELON‐1 study shows a favorable benefit‐risk balance in high‐risk patients, and patients in high-risk subgroups did not experience greater AE incidence or severity than patients in the total population.
Abstract: Approximately one-third of patients diagnosed with Hodgkin lymphoma presenting with Stage IV disease do not survive past 5 years. We present updated efficacy and safety analyses in high-risk patient subgroups, defined by Stage IV disease or International Prognostic Score (IPS) of 4-7, enrolled in the ECHELON-1 study that compared brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine (A + AVD) versus doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) as first-line therapy after a median follow-up of 37.1 months. Among patients treated with A + AVD (n = 664) or ABVD (n = 670), 64% had Stage IV disease and 26% had an IPS of 4-7. Patients with Stage IV disease treated with A + AVD showed consistent improvements in PFS at 3 years as assessed by investigator (hazard ratio [HR], 0.723; 95% confidence interval [CI], 0.537-0.973; p = 0.032). Similar improvements were seen in the subgroup of patients with IPS of 4-7 (HR, 0.588; 95% CI, 0.386-0.894; p = 0.012). The most common adverse events (AEs) in A + AVD-treated versus ABVD-treated patients with Stage IV disease were peripheral neuropathy (67% vs. 40%) and neutropenia (71% vs. 55%); in patients with IPS of 4-7, the most common AEs were peripheral neuropathy (69% vs. 45%), neutropenia (66% vs. 55%), and febrile neutropenia (23% vs. 9%), respectively. Patients in high-risk subgroups did not experience greater AE incidence or severity than patients in the total population. This updated analysis of ECHELON-1 shows a favorable benefit-risk balance in high-risk patients.
TL;DR: HCAR‐T therapy is safe and effective in DLBCL and ALL patients with chronic and resolved HBV infection under proper antiviral prophylaxis andHBV infection did not affect in vivo expansion of h CAR‐T cells or increase the risk of severe cytokine release syndrome.
Abstract: Chimeric antigen receptor-T (CAR-T) cell therapy is a promising treatment for CD19+ B-cell malignancies. However, elimination of B cells by anti-CD19 CAR-T cells may lead to the reactivation of hepatitis B virus (HBV) and related hepatitis in patients with HBV infection. This study aims to evaluate the safety and efficacy of humanized anti-CD19 CAR-T (hCAR-T) therapy in B-cell malignancies with HBV infection. Twenty relapsed/refractory (r/r) diffuse large B-cell lymphoma (DLBCL) and acute lymphoblastic leukemia (ALL) patients with HBV infection were treated with hCAR-T therapy. Among them, five hepatitis B antigen-positive patients who received antiviral prophylaxis did not develop HBV reactivation, including two patients who received both hCAR-T and allogeneic hematopoietic stem cell transplantation (allo-HSCT). Among 15 patients with resolved HBV infection, two received antiviral prophylaxis, and the other 13 did not experience HBV reactivation without antiviral prophylaxis. One patient with resolved HBV infection experienced HBV reactivation 6 months after hCAR-T therapy and sequential allo-HSCT. Moreover, HBV infection did not affect in vivo expansion of hCAR-T cells or increase the risk of severe cytokine release syndrome. In conclusion, hCAR-T therapy is safe and effective in DLBCL and ALL patients with chronic and resolved HBV infection under proper antiviral prophylaxis.
TL;DR: In this article, a digital droplet PCR (ddPCR) was successfully applied to several haematological malignancies to detect low levels of transcripts, with a high rate of reproducibility.
Abstract: In Ph+ acute lymphoblastic leukaemia (Ph+ ALL), minimal residual disease (MRD) is the most relevant prognostic factor. Currently, its evaluation is based on quantitative real-time polymerase chain reaction (Q-RT-PCR). Digital droplet PCR (ddPCR) was successfully applied to several haematological malignancies. We analyzed 98 samples from 40 Ph+ ALL cases, the majority enrolled in the GIMEMA LAL2116 trial: 10 diagnostic samples and 88 follow-up samples, mostly focusing on positive non-quantifiable (PNQ) or negative samples by Q-RT-PCR to investigate the value of ddPCR for MRD monitoring. DdPCR BCR/ABL1 assay showed good sensitivity and accuracy to detect low levels of transcripts, with a high rate of reproducibility. The analysis of PNQ or negative cases by Q-RT-PCR revealed that ddPCR increased the proportion of quantifiable samples (p < 0.0001). Indeed, 29/54 PNQ samples (53.7%) proved positive and quantifiable by ddPCR, whereas 13 (24.1%) were confirmed as PNQ by ddPCR and 12 (22.2%) proved negative. Among 24 Q-RT-PCR-negative samples, 13 (54.1%) were confirmed negative, four (16.7%) resulted PNQ and seven (29.2%) proved positive and quantifiable by ddPCR. Four of 5 patients, evaluated at different time points, who were negative by Q-RT-PCR and positive by ddPCR experienced a relapse. DdPCR appears useful for MRD monitoring in adult Ph+ ALL.
TL;DR: In this article, the authors investigated the prognostic value of PET radiomics in diffuse large B-cell lymphoma (DLBCL) patients treated with R-CHOP given either every 14 (testing set) or 21 days (validation set).
Abstract: Functional parameters from positron emission tomography (PET) seem promising biomarkers in various lymphoma subtypes. This study investigated the prognostic value of PET radiomics in diffuse large B-cell lymphoma (DLBCL) patients treated with R-CHOP given either every 14 (testing set) or 21 days (validation set). Using the PyRadiomics Python package, 107 radiomics features were extracted from baseline PET scans of 133 patients enrolled in the Swiss Group for Clinical Cancer Research 38/07 prospective clinical trial (SAKK 38/07) [ClinicalTrial.gov identifier: NCT00544219]. The international prognostic indices, the main clinical parameters and standard PET metrics, together with 52 radiomics uncorrelated features (selected using the Spearman correlation test) were included in a least absolute shrinkage and selection operator (LASSO) Cox regression to assess their impact on progression-free (PFS), cause-specific (CSS), and overall survival (OS). A linear combination of the resulting parameters generated a prognostic radiomics score (RS) whose area under the curve (AUC) was calculated by receiver operating characteristic analysis. The RS efficacy was validated in an independent cohort of 107 DLBCL patients. LASSO Cox regression identified four radiomics features predicting PFS in SAKK 38/07. The derived RS showed a significant capability to foresee PFS in both testing (AUC, 0.709; p < 0.001) and validation (AUC, 0.706; p < 0.001) sets. RS was significantly associated also with CSS and OS in testing (CSS: AUC, 0.721; p < 0.001; OS: AUC, 0.740; p < 0.001) and validation (CSS: AUC, 0.763; p < 0.0001; OS: AUC, 0.703; p = 0.004) sets. The RS allowed risk classification of patients with significantly different PFS, CSS, and OS in both cohorts showing better predictive accuracy respect to clinical international indices. PET-derived radiomics may improve the prediction of outcome in DLBCL patients.
TL;DR: In this paper, the influence of circRNAs on cell development in AML cells and the underlying regulatory mechanism was explored, and the expression of circ RNAs, microRNA-625-5p and sex-determining region Y-related high mobility group box 12 (SOX12) was detected by quantitative real-time polymerase chain reaction.
Abstract: Acute myeloid leukemia (AML) is a highly heterogeneous disease featured by a clonal proliferation derived from primitive hematopoietic stem/progenitor cells. Circular RNAs (circRNAs) have been identified as crucial regulators in the progression of various cancers, including AML. However, the molecular mechanism of AML is still not definite. This study aimed to explore the influences of circ_0012152 on cell development in AML cells and the underlying regulatory mechanism. The expression of circ_0012152, microRNA-625-5p (miR-625-5p) and sex-determining region Y-related high mobility group box 12 (SOX12) was detected by quantitative real-time polymerase chain reaction. The proliferation of AML cells was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay for cell viability, 5-ethynyl-2'-deoxyuridine incorporation assay for DNA biosynthesis and flow cytometry for cell cycle distribution, respectively. The death of AML cells was detected by flow cytometry. The protein expression was assessed by Western blot assay. Dual-luciferase reporter and RNA immunoprecipitation assays were carried out to examine the relationships among circ_0012152, miR-625-5p and SOX12. The expression of circ_0012152 was increased in AML tissues and cells and circ_0012152 knockdown suppressed proliferation and promoted death in AML cells. Further exploration revealed that circ_0012152 inhibited miR-625-5p expression and downregulation of miR-625-5p overturned the effects of circ_0012152 knockdown on proliferation and death in AML cells. Moreover, miR-625-5p targeted SOX12 and circ_0012152 facilitated the expression of SOX12 by relieving miR-625-5p-mediated inhibitory effect on SOX12 in AML cells. Circ_0012152 knockdown suppressed cell proliferation and promoted death by targeting SOX12 mediated by miR-625-5p in AML cells.
TL;DR: In this paper, the authors highlight some of the primary strategies and relevant studies aimed at improving the utility of CAR-T therapy in lymphoma and highlight the patients and disease subtypes that are most likely to benefit from CAR T.
Abstract: Chimeric antigen receptor (CAR) T cell therapy has significantly improved the outlook for patients with certain types of poor-risk lymphoma. Despite these advances, a majority of patients undergoing CAR T therapy will suffer progression or relapse of disease, and toxicity remains a concern. Additionally, the patients and disease subtypes that are most likely to benefit from CAR T have yet to be fully defined. Many ongoing trials are exploring novel CAR T approaches to address these concerns. In this review, we highlight some of the primary strategies and relevant studies aimed at improving the utility of CAR T therapy in lymphoma.
University of Ferrara1, Vita-Salute San Raffaele University2, Sapienza University of Rome3, University of Verona4, University of Padua5, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico6, University of Rome Tor Vergata7, University of Naples Federico II8, University of Modena and Reggio Emilia9, University of Pisa10, University of Siena11, European Institute of Oncology12
TL;DR: Oncologists enrolling patients in clinical trials can increase success rates by up to sevenfold by prioritizing participation in trials involving biomarker usage, while consideration of factors such as drug mechanism of action and line of therapy can further double the clinical trial success rate.
Abstract: This study analyzed the risk of clinical trial failure for leukemia drug development between January 1999 and January 2020. The specific leukemia subtypes of interest were acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), and chronic myeloid leukemia (CML). Drug development was investigated using data obtained from https://www.clinicaltrials.gov and other publicly available databases. Drug compounds were excluded if they began phase I testing for the indication of interest before January 1999, if they were not industry sponsored, or if they treated secondary complications of the disease. Further analysis was conducted on biomarker usage, drug mechanisms of action, and line of treatment. Drugs were identified following our inclusion criteria for ALL (72), CLL (106), AML (159), and CML (47). The likelihood (cumulative pass rate), a drug would pass all phases of clinical testing and obtain Food and Drug Administration approval, was 18% (ALL), 10% (CLL), 7% (AML), and 12% (CML). Biomarker targeted therapies improved the success rates by three- and sevenfold, for ALL and AML, respectively. Enzyme inhibitors doubled the cumulative success rate for AML. First-line therapy and kinase inhibitors both independently doubled the cumulative success rate for CLL. Oncologists enrolling patients in clinical trials can increase success rates by up to sevenfold by prioritizing participation in trials involving biomarker usage, while consideration of factors such as drug mechanism of action and line of therapy can further double the clinical trial success rate.
TL;DR: In this article, a modified version of the multi-agent therapy "VDT-PACE" incorporating new generation anti-MM agents daratumumab and carfilzomib (Dara-KDT-P(A)CE) was presented.
Abstract: The multi-agent therapy "VDT-PACE" represents an established regimen in RRMM. Here, we report on our experience with a "modified VDT-PACE" incorporating new generation anti-MM agents daratumumab and carfilzomib ("Dara-KDT-P(A)CE"). We retrospectively analyzed 38 patients with RRMM treated with "Dara-KDT-P(A)CE". The median age was 62 (rage 45-82) years, and the patients were heavily pretreated with a median of five (range 2-12) prior lines of therapy. Twenty-one (55%) patients suffered from penta-refractory MM. High-risk cytogenetics was present in 31 (81%) patients. The patients received a median of two (range 1-10) cycles of this therapy, and the ORR was 70%. Patients with penta-refractory MM and high-risk cytogenetics showed similar ORR of 65% and 79%, respectively. The median PFS and OS were 4.1 (95% CI 2.7-5.4) and 8.4 (95% CI 6.7-10.0) months, respectively. Patients with LDH>250 IU/l showed significantly shorter PFS in comparison with others patients (P=0.006). We used this regimen as bridging therapy prior to CAR T-cell infusion in four patients. In conclusion, "Dara-KDT-P(A)CE" is an effective salvage therapy for patients with heavily pretreated, multi-refractory, high-risk RRMM lacking alternative options. This article is protected by copyright. All rights reserved.
TL;DR: In this article, the authors focused on genomic variations (such as BTK and its downstream PCLG2 mutations as well as Del 8p, 2p+, Del 6q/8p, BIRC3, TRAF2, TRAf3, CARD11, and CCND1 mutations) and related pathways involved in cancer pathophysiology to discuss the mechanisms underlying resistance to BTKi.
Abstract: Bruton's tyrosine kinase inhibitors (BTKi) have revolutionized the treatment of B-cell lymphoma (BCL). These drugs interfere with the mechanisms underlying malignant B-cell pathophysiology, allowing better drug response as well as low toxicity. However, these multiple mechanisms also lead to drug resistance, which compromised the treatment outcome and needs to be solved urgently. This review focuses on genomic variations (such as BTK and its downstream PCLG2 mutations as well as Del 8p, 2p+, Del 6q/8p, BIRC3, TRAF2, TRAF3, CARD11, MYD88, and CCND1 mutations) and related pathways (such as PI3K/Akt/mTOR, NF-κB, MAPK signaling pathways, overexpression of B-cell lymphoma 6, platelet-derived growth factor, toll-like receptors, and microenvironment, cancer stem cells, and exosomes) involved in cancer pathophysiology to discuss the mechanisms underlying resistance to BTKi. We have also reviewed the newly reported drug resistance mechanisms and the proposed potential treatment strategies (the next-generation BTKi, proteolysis-targeting chimera-BTK, XMU-MP-3, PI3K-Akt-mTOR pathway, MYC or LYN kinase inhibitor, and other small-molecule targeted drugs) to overcome drug resistance. The findings presented in this review lay a strong foundation for further research in this field.
TL;DR: The role of lncRNAs in the expression and function of white blood cells and oncogenic transformation into four main types of leukemia is summarized.
Abstract: The study of long non-coding RNAs (lncRNA) is a newly established field and our knowledge about them is rapidly growing. These kinds of RNAs are unchanged parts of the genome throughout evolution, that modulate cell growth, differentiation, and apoptosis during diverse physiological and pathological processes including leukemia development. They have the capability to be useful biomarkers for the diagnosis, clinical typing, prognosis, as well as potential therapeutic targets. In this study, we summarized the role of lncRNAs in the expression and function of white blood cells and oncogenic transformation into four main types of leukemia.
TL;DR: Outcome of HL pts older than 71 years appeared to decrease substantially in comparison to the younger counterpart, and new, potentially less toxic strategies need to be investigated in prospective clinical trials in this particular frail population.
Abstract: Hodgkin lymphoma (HL) in older patients appears to be a different disease compared with younger patients with historically lower survival rates. This is related to a variety of factors, including increased treatment-related toxicity, the presence of comorbidities, and biologic differences. In order to better assess the clinical characteristics, treatment strategies, and outcome of this particular population, we conducted a population-based, retrospective analysis including 269 patients with HL older than 60 years (median age 71 years, range 60-94), treated between 2000 and 2017 in 15 referral centers across Switzerland. Primary endpoints were overall survival (OS), progression-free survival (PFS), and cause-specific survival (CSS). The vast majority of patients were treated with curative intent, either with a combined modality approach (chemotherapy followed by radiation therapy) or with systemic therapy. At a median follow-up of 6.6 years (95% confidence interval [CI], 6.0-7.6), 5-year PFS was 52.2% (95% CI, 46.0-59.2), 5-year OS was 62.5% (95% CI, 56.4-69.2), and 5-year CSS was 85.1.8% (95% CI, 80.3-90.1) for the entire cohort. A significant difference in terms of CSS was observed for patients older than 71 years in comparison to patients aged 60-70 years (hazard ratio 2.6, 1.3-5.0, p = 0.005). Bleomycin-induced lung toxicity (BLT) was documented in 26 patients (17.7%) out of the 147 patients exposed to this compound and was more frequent in patients older than 71 years (15/60, 25%). Outcome of HL pts older than 71 years appeared to decrease substantially in comparison to the younger counterpart. Treatment-related toxicities appeared to be relevant, in particular, BLT. New, potentially less toxic strategies need to be investigated in prospective clinical trials in this particular frail population.
TL;DR: In this article, the authors evaluated the relationship between baseline serum albumin levels on treatment-related complications, as well as short-term mortality and overall survival in 756 newly diagnosed acute myeloid leukemia (AML) patients.
Abstract: Older age and poor performance status lead to worse outcomes in acute myeloid leukemia (AML) patients. Hypoalbuminemia is a negative predictor of morbidity and mortality in several malignancies. We evaluated the relationship between baseline serum albumin levels on treatment-related complications, as well as short-term mortality and overall survival (OS) in 756 newly diagnosed AML patients. We conducted a retrospective multicenter study to examine treatment-related complications and OS according to pretreatment serum albumin levels: normal albumin ≥3.5 g/dl, marked hypoalbuminemia <2.5 g/dl, and hypoalbuminemia 2.5-3.4 g/dl. In an adjusted multivariate analysis, a lower baseline albumin was independently associated with a higher number of grade ≥3 complications when adjusting for age, secondary AML, sex and intensive treatment. When comparing normal to markedly low albumin levels, the estimated mean number of complications increases by a factor of 1.35. Patients who had a normal baseline albumin had a 30 day-mortality rate of 4.8%, which was significantly lower compared with patients with hypoalbuminemia (16.5%) and marked hypoalbuminemia (33.9%; p < 0.01). Similarly, 60-day mortality rate was significantly higher in the hypoalbuminemia group (24.0%) and marked hypoalbuminemia group (45%) compared with normal albumin group (8.3%; p < 0.01). Patients with lower baseline albumin levels have increased treatment-related morbidity and mortality, suggesting that pre-treatment serum albumin is an important independent prognostic marker.