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35,467,057 | PAX5 alterations in an infant case of KMT2A-rearranged leukemia with lineage switch. | Lineage switch is a rare event at leukemic relapse. While mostly known to occur in KMT2A-rearranged infant leukemia, the underlying mechanism is yet to be depicted. This case report describes a female infant who achieved remission of KMT2A-MLLT3-rearranged acute monocytic leukemia, but 6 months thereafter, relapsed as KMT2A-MLLT3-rearranged acute lymphocytic leukemia. Whole exome sequencing of the bone marrow obtained pre-post lineage switch revealed two somatic mutations of PAX5 in the relapse sample. These two PAX5 alterations were suggested to be loss of function, thus to have played the driver role in the lineage switch from acute monocytic leukemia to acute lymphocytic leukemia. |
35,465,834 | Traumatic lumbar punctures in diagnostic and intrathecal treatment punctures of pediatric hemato-oncology patients. | Successful first diagnostic lumbar puncture (LP) is crucial because intrathecal chemotherapy has not yet protected the central nervous system against cancer cells. If blood contaminates the cerebrospinal fluid (CSF) with blasts, they may enter the central neural system and compromise the patients health. We retrospectively determined the incidence of traumatic lumbar punctures (TLP) in 2,507 LPs of 250 pediatric hemato-oncology patients aged from one to 18 years, including both diagnostic and intrathecal treatment procedures, and 2,617 LPs of 1,525 other age-matched pediatric patients. We used ≥10 erythrocytesµL in the CSF sample as the criterion of TLP. TLPs were less frequent in hemato-oncology patients than in other patients (31.6% vs. 48.5%, |
35,464,442 | Genetic Engineering and Enrichment of Human NK Cells for CAR-Enhanced Immunotherapy of Hematological Malignancies. | The great clinical success of chimeric antigen receptor (CAR) T cells has unlocked new levels of immunotherapy for hematological malignancies. Genetically modifying natural killer (NK) cells as alternative CAR immune effector cells is also highly promising, as NK cells can be transplanted across HLA barriers without causing graft-versus-host disease. Therefore, |
35,464,394 | Design and Evaluation of TIM-3-CD28 Checkpoint Fusion Proteins to Improve Anti-CD19 CAR T-Cell Function. | Therapeutic targeting of inhibitory checkpoint molecules in combination with chimeric antigen receptor (CAR) T cells is currently investigated in a variety of clinical studies for treatment of hematologic and solid malignancies. However, the impact of co-inhibitory axes and their therapeutic implication remains understudied for the majority of acute leukemias due to their low immunogenicitymutational load. The inhibitory exhaustion molecule TIM-3 is an important marker for the interaction of T cells with leukemic cells. Moreover, inhibitory signals from malignant cells could be transformed into stimulatory signals by synthetic fusion molecules with extracellular inhibitory receptors fused to an intracellular stimulatory domain. Here, we designed a variety of different TIM-3-CD28 fusion proteins to turn inhibitory signals derived by TIM-3 engagement into T-cell activation through CD28. In the absence of anti-CD19 CAR, two TIM-3-CD28 fusion receptors with large parts of CD28 showed strongest responses in terms of cytokine secretion and proliferation upon stimulation with anti-CD3 antibodies compared to controls. We then combined these two novel TIM-3-CD28 fusion proteins with first- and second-generation anti-CD19 CAR T cells and found that the fusion receptor can increase proliferation, activation, and cytotoxic capacity of conventional anti-CD19 CAR T cells. These additionally armed CAR T cells showed excellent effector function. In terms of safety considerations, the fusion receptors showed exclusively increased cytokine release, when the CAR target CD19 was present. We conclude that combining checkpoint fusion proteins with anti-CD19 CARs has the potential to increase T-cell proliferation capacity with the intention to overcome inhibitory signals during the response against malignant cells. |
35,463,978 | Subcellular Proteome Analysis Reveals Apoptotic Vulnerability of T-Cell Acute Lymphoblastic Leukemia. | Targeting death receptor-mediated apoptosis in T-cell acute lymphoblastic leukemia (T-ALL), an aggressive disease with poor prognosis, is hindered by the inherent resistance of primary leukemia cells. Knowledge on therapeutic vulnerabilities in these malignant cells will provide opportunities for developing novel combinatory treatments for patients. Using label-free quantitative mass spectrometry and subcellular fractionation techniques, we systematically compared organelle-specific proteomes between Jurkat cells, an |
35,463,661 | Analysis of Multiple Vitamins Serum Levels and Disease-Related Factors in Children with Acute Leukemia. | To explore the relationship between vitamins levels and disease-related indicators in children with acute leukemia (AL). A total of 107 hospitalized children with AL were enrolled in this study and assigned to one group in each of the following categories infected group ( The vitamin D level was significantly higher in the noninfected group than in the infected group ( There are notable vitamins imbalances in children with AL. The imbalances influence disease-related factors and therefore provide some references for the prognosis and treatment of AL. |
35,462,726 | Lenalidomide induced secondary Acute Lymphoblastic Leukemia in a Multiple Myeloma patient A case-report. | Lenalidomide mechanism of action has been shown to modulate the different components of the immune system. A 68-year-old lady presented to us with severe backache and was then diagnosed with MM. Lenalidomide started as per protocol along with dexamethasone. Later, she presented with complaints of generalized weakness and her workup showed significant blast cells with Pan-B-cell markers consistent with secondary B-ALL. The reported incidence of secondary Acute Lymphocytic Leukemia is 2.3%. The development of more aggressive neoplasm in a patient with prior malignancy dictates a poor outcome and hence such patients should be enrolled in a clinical trial whenever available. |
35,462,434 | Production and optimization of l-asparaginase by Streptomyces koyangensis SK4 isolated from Arctic sediment. | Actinomycetes isolated from the Arctic sediment were evaluated for the production of the enzyme l-asparaginase, an enzyme used to treat acute lymphoblastic leukemia. The most potent strain Streptomyces koyangensis SK4 was selected for l-asparaginase enzyme production by submerged fermentation. The effect of various fermentation parameters on enzyme production was analyzed statistically using the Plackett-Burman design and response surface method. Effects of eight parameters including temperature, pH, incubation time, inoculum size, agitation speed, the concentration of starch, l-asparagine, and yeast extract were studied on l-asparaginase production by the Arctic isolate S. koyangensis SK4. Factors such as temperature, pH, incubation time, agitation speed, and l-asparagine concentration were found to be important factors influencing l-asparaginase production. Maximum enzyme activity of 136 IUml was obtained at 20°C on the seventh day of incubation in the asparagine dextrose broth maintained at pH 7.5, agitation speed 125 rpm, and l-asparagine concentration of 7.5 gL. The statistical optimization method described in this study proved effective for increasing the l-asparaginase production by Arctic actinomycetes. |
35,460,928 | A Clinically Applicable Prediction Model to Improve T Cell Collection in Chimeric Antigen Receptor T Cell Therapy. | As chimeric antigen receptor (CAR) T cell therapy targeting CD19 has shown favorable outcomes in patients with relapsed or refractory (rr) mature B cell lymphomas and B cell acute lymphoblastic leukemia (B-ALL), an increasing number of patients are waiting to receive these treatments. Optimized protocols for T cell collection by lymphapheresis for chimeric antigen receptor (CAR) T cell therapy are urgently needed to provide CAR T cell therapy for patients with refractory and progressive disease andor a low number of lymphocytes owing to prior chemotherapy. The predicted efficiency of CD3 |
35,459,909 | IRF4 deficiency vulnerates B-cell progeny for leukemogenesis via somatically acquired Jak3 mutations conferring IL-7 hypersensitivity. | The processes leading from disturbed B-cell development to adult B-cell progenitor acute lymphoblastic leukemia (BCP-ALL) remain poorly understood. Here, we describe Irf4 |
35,457,264 | Linear and Circular Long Non-Coding RNAs in Acute Lymphoblastic Leukemia From Pathogenesis to Classification and Treatment. | The coding regions account for only a small part of the human genome, and the remaining vast majority of the regions generate large amounts of non-coding RNAs. Although non-coding RNAs do not code for any protein, they are suggested to work as either tumor suppressers or oncogenes through modulating the expression of genes and functions of proteins at transcriptional, posttranscriptional and post-translational levels. Acute Lymphoblastic Leukemia (ALL) originates from malignant transformed BT-precursor-stage lymphoid progenitors in the bone marrow (BM). The pathogenesis of ALL is closely associated with aberrant genetic alterations that block lymphoid differentiation and drive abnormal cell proliferation as well as survival. While treatment of pediatric ALL represents a major success story in chemotherapy-based elimination of a malignancy, adult ALL remains a devastating disease with relatively poor prognosis. Thus, novel aspects in the pathogenesis and progression of ALL, especially in the adult population, need to be further explored. Accumulating evidence indicated that genetic changes alone are rarely sufficient for development of ALL. Recent advances in cytogenic and sequencing technologies revealed epigenetic alterations including that of non-coding RNAs as cooperating events in ALL etiology and progression. While the role of micro RNAs in ALL has been extensively reviewed, less attention, relatively, has been paid to other non-coding RNAs. Herein, we review the involvement of linear and circular long non-coding RNAs in the etiology, maintenance, and progression of ALL, highlighting the contribution of these non-coding RNAs in ALL classification and diagnosis, risk stratification as well as treatment. |
35,456,764 | A Gut Instinct on Leukaemia A New Mechanistic Hypothesis for Microbiota-Immune Crosstalk in Disease Progression and Relapse. | Despite significant advances in the treatment of Chronic Myeloid and Acute Lymphoblastic Leukaemia (CML and ALL, respectively), disease progression and relapse remain a major problem. Growing evidence indicates the loss of immune surveillance of residual leukaemic cells as one of the main contributors to disease recurrence and relapse. More recently, there was an appreciation for how the hosts gut microbiota predisposes to relapse given its potent immunomodulatory capacity. This is especially compelling in haematological malignancies where changes in the gut microbiota have been identified after treatment, persisting in some patients for years after the completion of treatment. In this hypothesis-generating review, we discuss the interaction between the gut microbiota and treatment responses, and its capacity to influence the risk of relapse in both CML and ALL We hypothesize that the gut microbiota contributes to the creation of an immunosuppressive microenvironment, which promotes tumour progression and relapse. |
35,456,416 | The Role of | In Brazil, Acute lymphoid leukemia (ALL) is the leading cause of cancer deaths in children and adolescents. Treatment toxicity is one of the reasons for stopping chemotherapy. Amerindian genomic ancestry is an important factor for this event due to fluctuations in frequencies of genetic variants, as in the |
35,456,315 | The Impact of ExosomesMicrovesicles Derived from Myeloid Dendritic Cells Cultured in the Presence of Calcitriol and Tacalcitol on Acute B-Cell Precursor Cell Lines with | Vitamin D analogs (VDAs) may directly inhibit the growth of normal and malignant (derived from acute lymphoblastic leukemia (ALL)) B cells, as both types of cells express vitamin D receptor (VDR). We performed anti-proliferative, morphology tests and phenotyping to evaluate the sensitivity of monocytes and iDCs (immature myeloid-derived dendritic cells) on calcitriol and tacalcitol treatment, phenotyping, morphology, and size distribution measurement to determine the characteristics of microvesicles (MVs) and exosomes (EXs) derived from them and, finally, phenotyping and Elisa test to determine the effects of VDAs on modulation of the phenotype of B cells through extracellular vesicles (EVs) released by iDCs. Our results confirmed that both SC cells and iDCs were sensitive to the VDAs and showed altered surface expression of markers associated with monocyte differentiation, which was resulting in the phenotypic changes in EVs derived from them. We also showed that obtained EVs could change the morphology and phenotype of ALL-B-derived precursor cells in a different way, depending on their origin. The differential effect of VDAs on ALL-B cells, which was associated with increased or decreased expression of CD27, CD24, CD38, and CD23 expression, was observed. Hence, further studies to explain the modulation in the composition of EVs by VDAs are required. |
35,455,869 | Interactive Video Games as a Method to Increase Physical Activity Levels in Children Treated for Leukemia. | Despite the beneficial effect of exercise, children treated for cancer do not engage in sufficient physical activity. It is necessary to search for attractive forms of physical activity, including interactive video games (IVGs). The aim of this study was to verify the effectiveness of the rehabilitation model developed by the authors based on the use of IVGs in children undergoing leukemia treatment. The study included a group of 21 children aged 7-13 years (12 boys, 9 girls) undergoing treatment for acute lymphoblastic leukemia (ALL) ( |
35,455,413 | Effect of ITPA Polymorphism on Adverse Drug Reactions of 6-Mercaptopurine in Pediatric Patients with Acute Lymphoblastic Leukemia A Systematic Review and Meta-Analysis. | 6-Mercaptopurine (6-MP) is a cornerstone of the maintenance regimen for pediatric acute lymphoblastic leukemia (ALL). Inosine triphosphate pyrophosphatase (ITPA) is considered a candidate pharmacogenetic marker that may affect metabolism and 6-MP-induced toxicities however, the findings are inconsistent. Therefore, we attempted to evaluate the effect of ITPA 94C>A polymorphism on 6-MP-induced hematological toxicity and hepatotoxicity through a systematic review and meta-analysis. A literature search for qualifying studies was conducted using the PubMed, Web of Science, and Embase databases until October 2021. Overall, 10 eligible studies with 1072 pediatric ALL patients were included in this meta-analysis. The results indicated that ITPA 94C>A was significantly associated with 6-MP-induced neutropenia (OR 2.38, 95% CI 1.56−3.62 p 0.005) and hepatotoxicity (OR 1.98, 95% CI 1.32−2.95 p 0.0009) however, no significant association was found between the ITPA 94C>A variant and 6-MP-induced leukopenia (OR 1.75, 95% CI 0.74−4.12 p 0.20). This meta-analysis demonstrated that ITPA 94C>A polymorphism could affect 6-MP-induced toxicities. Our findings suggested that ITPA genotyping might help predict 6-MP-induced myelosuppression and hepatotoxicity. |
35,454,927 | Recent Advances in Treatment Options for Childhood Acute Lymphoblastic Leukemia. | Acute lymphoblastic leukemia is the most common blood cancer in pediatric patients. There has been enormous progress in ALL treatment in recent years, which is reflected by the increase in the 5-year OS from 57% in the 1970s to up to 96% in the most recent studies. ALL treatment is based primarily on conventional methods, which include chemotherapy and radiotherapy. Their main weakness is severe toxicity, which prompts dose reduction, decreases the effectiveness of the treatment, and, in some cases, can lead to death. Currently, numerous modifications in treatment regimens are applied in order to limit toxicities emerging from conventional approaches and improve outcomes. Hematological treatment of pediatric patients is reaching for more novel treatment options, such as targeted treatment, CAR-T-cells therapy, and immunotherapy. These methods are currently used in conjunction with chemotherapy. Nevertheless, the swift progress in their development and increasing efficacity can lead to applying those novel therapies as standalone therapeutic options for pediatric ALL. |
35,454,892 | Next-Generation DNA Sequencing-Based Gene Panel for Diagnosis and Genetic Risk Stratification in Onco-Hematology. | A suitable diagnostic classification of myeloid neoplasms and acute leukemias requires testing for a large number of molecular biomarkers. Next-generation sequencing is a technology able to integrate identification of the vast majority of them in a single test. This manuscript includes the design, analytical validation and clinical feasibility evaluation of a molecular diagnostic kit for onco-hematological diseases. It is based on sequencing of the coding regions of 76 genes (seeking single-nucleotide variants, small insertions or deletions and CNVs), as well as the search for fusions in 27 target genes. The kit has also been designed to detect large CNVs throughout the genome by including specific probes and employing a custom bioinformatics approach. The analytical and clinical feasibility validation of the Haematology OncoKitDx panel has been carried out from the sequencing of 170 patient samples from 6 hospitals (in addition to the use of commercial reference samples). The analytical validation showed sensitivity and specificity close to 100% for all the parameters evaluated, with a detection limit of 2% for SNVs and SVs, and 20% for CNVs. Clinically relevant mutations were detected in 94% of all patients. An analysis of the correlation between the genetic risk classification of AML (according to ELN 2017) established by the hospitals and that obtained by the Haematology OncoKitDx panel showed an almost perfect correlation (K 0.94). Among the AML samples with a molecular diagnosis, established by the centers according to the WHO, the Haematology OncoKitDx analysis showed the same result in 97% of them. The panel was able to adequately differentiate between MPN subtypes and also detected alterations that modified the diagnosis ( |
35,454,781 | Early T-Cell Precursor ALL and Beyond Immature and Ambiguous Lineage T-ALL Subsets. | A wide range of immature acute leukemias (AL), ranging from acute myeloid leukemias with minimal differentiation to acute leukemias with an ambiguous lineage, i.e., acute undifferentiated leukemias and mixed phenotype acute leukemia with T- or B-plus myeloid markers, cannot be definitely assigned to a single cell lineage. This somewhat grey zone of AL expresses partly overlapping features with the most immature forms of T-cell acute lymphoblastic leukemia (T-ALL), i.e., early T-cell precursor ALL (ETP-ALL), near-ETP-ALL, and pro-T ALL. These are troublesome cases in terms of precise diagnosis because of their similarities and overlapping phenotypic features. Moreover, it has become evident that they share several genomic alterations, raising the question of how their phenotypes reflect distinct AL entities. The aim of this review was to provide a systematic overview of the genetic events associated with immature T-ALL and outline their relationship with treatment choices and outcomes, especially looking at the most recent preclinical and clinical studies. We wish to offer a basis for using the genetic information for new diagnostic algorithms, in order to better stratify patients and improve their management with more efficient and personalized therapeutic options. Understanding the genetic profile of this high-risk T-ALL subset is a prerequisite for changing the current clinical scenario. |
35,453,880 | Analysis of Argyrophilic Nucleolar Organizer Regions (AgNORs) in Acute Leukemia in Adults. | The evaluation of argyrophilic nucleolar organizer regions (AgNORs) uses a simple method used in research into neoplasm. Bone marrow aspirates from 70 patients with acute leukemia underwent morphological, immunophenotypic, and genetic assessment and were stained with silver nitrate. In leukemic cells, the mean AgNORs number, mean AgNORs area, and mean AgNOR-area-to-nucleus-area ratio were calculated in patients with acute myeloid leukemia (AML), patients with acute lymphoblastic leukemia (ALL), and selected risk groups. A higher value of all measured AgNOR parameters was observed in patients with AML compared to the ALL group. In AML patients, a higher mean AgNOR area was found in the ELN3 cytogenetic group compared to the ELN2 cytogenetic group. A higher value of the mean AgNOR count was observed in patients with white blood cells (WBCs) > 12 × 109L than in the group with WBCs ≤ 12 × 109L, as well as in patients with >20% blasts in peripheral blood (PB) than in patients with ≤20% blasts in PB. In the ALL group, a higher mean AgNOR-area-to-nucleus-area ratio was found in group with the presence of Philadelphia chromosome Ph() than without the Philadelphia chromosome Ph(−). AgNOR parameter analysis is a valuable method for differentiation of AML and ALL in adults. |
35,453,697 | Default-Mode Network Connectivity Changes Correlate with Attention Deficits in ALL Long-Term Survivors Treated with Radio- andor Chemotherapy. | Whether chemotherapy (ChT) and radiotherapy (RT) determine neurocognitive impairment in acute lymphoblastic leukemia long-term survivors (ALL LTSs) through similar mechanisms affecting the same brain regions is still unknown. We compared neurocognitive alterations, regional brain tissue volumes (by voxel-based morphometry), and functional connectivity of the main default-mode network hubs (by seed-based analysis of resting state functional MRI data), in 13 ALL LTSs treated with RT and ChT (Group A) and 13 treated with ChT only (Group B). Group A performed significantly worse than Group B at the digit span and digit symbol tests ( |
35,452,517 | Combining daratumumab with CD47 blockade prolongs survival in preclinical models of pediatric T-ALL. | Acute lymphoblastic leukemia (ALL) is the most common malignant disease affecting children. Although therapeutic strategies have improved, T-cell acute lymphoblastic leukemia (T-ALL) relapse is associated with chemoresistance and a poor prognosis. One strategy to overcome this obstacle is the application of monoclonal antibodies. Here, we show that leukemic cells from patients with T-ALL express surface CD38 and CD47, both attractive targets for antibody therapy. We therefore investigated the commercially available CD38 antibody daratumumab (Dara) in combination with a proprietary modified CD47 antibody (Hu5F9-IgG2σ) in vitro and in vivo. Compared with single treatments, this combination significantly increased in vitro antibody-dependent cellular phagocytosis in T-ALL cell lines as well as in random de novo and relapsedrefractory T-ALL patient-derived xenograft (PDX) samples. Similarly, enhanced antibody-dependent cellular phagocytosis was observed when combining Dara with pharmacologic inhibition of CD47 interactions using a glutaminyl cyclase inhibitor. Phase 2-like preclinical in vivo trials using T-ALL PDX samples in experimental minimal residual disease-like (MRD-like) and overt leukemia models revealed a high antileukemic efficacy of CD47 blockade alone. However, T-ALL xenograft mice subjected to chemotherapy first (postchemotherapy MRD) and subsequently cotreated with Dara and Hu5F9-IgG2σ displayed significantly reduced bone marrow infiltration compared with single treatments. In relapsed and highly refractory T-ALL PDX combined treatment with Dara and Hu5F9-IgG2σ was required to substantially prolong survival compared with single treatments. These findings suggest that combining CD47 blockade with Dara is a promising therapy for T-ALL, especially for relapsedrefractory disease harboring a dismal prognosis in patients. |
35,452,255 | Allogeneic double-negative CAR-T cells inhibit tumor growth without off-tumor toxicities. | The development of autologous chimeric antigen receptor T (CAR-T) cell therapies has revolutionized cancer treatment. Nevertheless, the delivery of CAR-T cell therapy faces challenges, including high costs, lengthy production times, and manufacturing failures. To overcome this, attempts have been made to develop allogeneic CAR-T cells using donor-derived conventional CD4 |
35,451,162 | Hypoalbuminemia and not undernutrition predicts high-dose methotrexate-induced nephrotoxicity in children with acute lymphoblastic leukemia in resource-constrained centers. | The standard practice to mitigate high-dose methotrexate (HD-MTX)-induced nephrotoxicity (HMN) in acute lymphoblastic leukemia (ALL) is to monitor levels until serum MTX falls below a predefined threshold. It is not feasible in most resource-constrained centers. Literature on the various factors affecting HMN in these centers is limited, retrospective, and heterogeneous. Though hypoalbuminemia has been postulated as a risk factor for HMN, the relationship of undernutrition with HMN has not been studied. This prospective observational study consecutively enrolled children < 12 years old with ALL receiving HD-MTX. Children with preexisting renal disease and exposed to nephrotoxic drugs two weeks preceding HD-MTX infusion were excluded. HD-MTX was administered over 24 hours (BFM-2009 protocol) with 12 hours of prehydration. Solitary MTX levels at 36 hours (MTX36) were outsourced, and 6-8 doses of leucovorin were given six-hourly. Hydration was continued till last dose of leucovorin. Various factors affecting HMN (rise in creatinine to 1.5 times baseline) were recorded age, sex, type of ALL, risk group of ALL, first dose of MTX, dose of MTX, undernourishment, serum protein, and albumin along with C-reactive protein and MTX36 levels. Forty-four children who received 150 HD-MTX cycles were analyzed. HMN was seen in 14% of cycles. On univariate analysis, undernourishment, MTX36 levels, hypoproteinemia, and hypoalbuminemia were significantly associated with HMN. On multivariate analysis, hypoalbuminemia and MTX36 levels significantly predicted the development of HMN with odds ratios of 4.71 and 1.45. Hypoalbuminemia and solitary serum MTX levels predict HMN in centers where serial MTX level monitoring is not feasible. |
35,449,729 | Co-Detection of VEGF-A and Its Regulator, microRNA-181a, May Indicate Central Nervous System Involvement in Pediatric Leukemia. | Central nervous system (CNS) involvement is a leading cause of therapy-refractory pediatric acute lymphoblastic leukemia (pALL), which is aggravated by underdiagnosing CNS disease with the currently used cell-based approach of cerebrospinal fluid (CSF) diagnostics. Our study focused on developing novel subcellular CNS leukemia indicators in the CSF and the bone marrow (BM) of patients with pALL. Serial liquid biopsy samples ( |
35,449,608 | An Unusual Presentation of Extramedullary Relapse Following Blinatumomab in Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia. | In adult patients, extramedullary relapse (EMR) in B-acute lymphoblastic leukemia (B-ALL) has a pejorative prognosis, especially after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Blinatumomab, a bispecific CD3CD19 antibody, is approved for relapsedrefractory acute lymphoblastic leukemia (ALL) and has proven its efficacy with good complete response (CR) rates and molecular responses in several trials. Unusual sites of relapse following treatment with blinatumomab for ALL are rarely reported. We describe the case of a 23-year-old male with B-ALL characterized as Philadelphia chromosome-positive without extramedullary lesions at diagnosis. He benefited from a matched-related donor allo-HSCT at first remission. A relapse in the bone marrow and central nervous system was diagnosed four months later. A treatment with blinatumomab was initiated with the obtention of CR after one cycle. During the third cycle of blinatumomab, multiple sites of EMR occurred initially with a painless swelling appearing in the areolas and the nipples, followed by bilateral testicular hypertrophy and moderate paraplegia. A diagnosis of leukemic infiltration on the areola-nipple complex was made by cytological analysis of the fine-needle aspiration of the left areola. The analysis of bone marrow was normal, but molecular BCR-ABL was positive. Systemic chemotherapy with hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) and cycles of blinatumomab with nilotinib was initiated in association with intrathecal chemotherapy and whole-brain radiation therapy. Clinical, molecular, and central nervous remissions were obtained. We report this case to describe multiple sites of EMR of B-ALL with atypical breast infiltration in an adult male patient following treatment with blinatumomab. |
35,448,507 | Probing Anti-Leukemic Metabolites from Marine-Derived | The unmet need for specific anti-leukemic agents for the treatment of acute lymphoblastic leukemia led us to screen a variety of marine-derived bacteria. The fermentation broth extract of |
35,447,374 | Updated Trends in Hematopoietic Cell Transplantation in the United States with an Additional Focus on Adolescent and Young Adult Transplantation Activity and Outcomes. | Hematopoietic cell transplantation (HCT) has been successfully used to treat many malignant and nonmalignant conditions. As supportive care, donor selection, and treatment modalities evolve, documenting HCT trends and outcomes is critical. This report from the Center for International Blood and Marrow Transplant Research (CIBMTR) provides an update on current transplantation activity and survival rates in the United States. Additional data on the use and outcomes of HCT in the adolescent and young adult (AYA) population are included. AYA patients more frequently receive peripheral blood stem cell grafts than pediatric patients, which may reflect differences in practice in pediatric versus adult treatment centers. The proportions of donor types also differ those in adult and pediatric populations. Outcomes for patients in the AYA age range are similar to those of pediatric patients for acute myelogenous leukemia but worse for acute lymphoblastic leukemia. Outcomes for both leukemias are better in AYA patients compared with older adults. Comparing the time periods 2000 to 2009 and 2010 to 2019 revealed significant improvement in overall survival across the age spectrum, but the greatest improvement in the AYA age group. |
35,446,934 | Preferential expansion of CD8 CD19-CAR T cells postinfusion and the role of disease burden on outcome in pediatric B-ALL. | T cells expressing CD19-specific chimeric antigen receptors (CD19-CARs) have potent antileukemia activity in pediatric and adult patients with relapsed andor refractory B-cell acute lymphoblastic leukemia (B-ALL). However, not all patients achieve a complete response (CR), and a significant percentage relapse after CD19-CAR T-cell therapy due to T-cell intrinsic andor extrinsic mechanisms. Thus, there is a need to evaluate new CD19-CAR T-cell products in patients to improve efficacy. We developed a phase 12 clinical study to evaluate an institutional autologous CD19-CAR T-cell product in pediatric patients with relapsedrefractory B-ALL. Here we report the outcome of the phase 1 study participants (n 12). Treatment was well tolerated, with a low incidence of both cytokine release syndrome (any grade, n 6) and neurotoxicity (any grade, n 3). Nine out of 12 patients (75%) achieved a minimal residual disease-negative CR in the bone marrow (BM). High disease burden (≥40% morphologic blasts) before CAR T-cell infusion correlated with increased side effects and lower response rate, but not with CD19-CAR T-cell expansion. After infusion, CD8 CAR T cells had a proliferative advantage over CD4 CAR T cells and at peak expansion, had an effector memory phenotype with evidence of antigen-driven differentiation. Patients that proceeded to allogeneic hematopoietic cell transplantation (AlloHCT) had sustained, durable responses. In summary, the initial evaluation of our institutional CD19-CAR T-cell product demonstrates safety and efficacy while highlighting the impact of pre-infusion disease burden on outcomes. This trial was registered at www.clinicaltrials.gov as NCT03573700. |
35,446,233 | Population pharmacokinetics of methotrexate in paediatric patients with acute lymphoblastic leukaemia and malignant lymphoma. | This study aimed to identify physiological and pharmacogenomic covariates and develop a population pharmacokinetic model of high-dose methotrexate (HD-MTX) in Chinese paediatric patients with acute lymphoblastic leukaemia (ALL) and malignant lymphoma.A total of 731 MTX courses and 1658 MTX plasm concentrations from 205 paediatric patients with ALL and malignant lymphoma were analysing using a non-linear mixed-effects model technique. 47 SNPs in 16 MTX-related genes were genotyped and screened as covariates. A PPK model was established to determine the influence of covariates, such as body surface area (BSA), age, laboratory test value, and SNPs on the pharmacokinetic process of HD-MTX.Two-compartmental model with allometric scaling using BSA could nicely characterise the |
35,445,848 | Global expression profiling of CD10 CD19 pre-B lymphoblasts from Hispanic B-ALL patients correlates with comparative TARGET database analysis. | Mexico City has one of the highest incidences of acute lymphoblastic leukemia (ALL) globally, with patients showing low survival, and high relapse rates. To gain more insight into the molecular features of B-ALL in Mexican children, we isolated CD10 CD19 precursor B lymphoblasts from four bone marrow and nine peripheral blood samples of B-ALL patients using a fluorescence-activated cell sorting protocol. The global gene expression profile (BM vs PB) revealed 136 differentially expressed genes 62 were upregulated (45.6%) and 74 were downregulated (54.4%). Pearsons correlation coefficient was calculated to determine the similarity between pre-B lymphoblast populations. We selected 26 highly significant genes and validated 21 by RT-qPCR (CNN3, STON2, CALN1, RUNX2, GADD45A, CDC45, CDC20, PLK1, AIDA, HCK, LY86, GPR65, PIK3CG, LILRB2, IL7R, TCL1A, DOCK1, HIST1H3G, PTPN14, CD72, and NT5E). The gene set enrichment analysis of the total expression matrix and the ingenuity pathway analysis of the 136 differentially expressed genes showed that the cell cycle was altered in the bone marrow with four overexpressed genes (PLK1, CDC20, CDC45, and GADD45A) and a low expression of IL7R and PIK3CG, which are involved in B cell differentiation. A comparative bioinformatics analysis of 15 bone marrow and 10 peripheral blood samples from Hispanic B-ALL patients collected by the TARGET program, corroborated the genes observed, except for PIK3CG. We conclude the Mexican and the Hispanic B-ALL patients studied present common driver alterations and histotype-specific mutations that could facilitate risk stratification and diagnostic accuracy and serve as potential therapeutic targets. |
35,445,593 | Prophylactic Central Nervous System Irradiation Is Not Indispensable in Adult Patients with Acute Lymphoblastic Leukemia A Multicenter Retrospective Cohort Study. | Studies comparing the efficacy and safety of prophylactic regimens for central nervous system (CNS) involvement in acute lymphoblastic leukemia (ALL) are scarce in adults. This multicenter retrospective study aimed to compare the efficacy of prophylactic regimens with and without CNS irradiation on the development of CNS relapse during follow-up. This was a multicenter comparative cohort study. A total of 203 patients were included from four tertiary care centers in Turkey. Patients were divided into two groups according to whether they received CNS irradiation or not. The groups were analyzed retrospectively regarding patient and disease characteristics, with the main focus being CNS relapse. While 105 patients received chemotherapy-based prophylaxis, 98 patients received additional CNS irradiation. These groups were statistically comparable in terms of demographic characteristics and risk factors for CNS involvement. In the irradiation group, patients were younger and had more stem cell transplants. In a median of 23.8 (11.1-62.4) months, there was no difference between the two groups regarding CNS relapse-free survival (log-rank p0.787). Craniospinal irradiation may not be indispensable for every adult patient with ALL, similarly to pediatric patients. It is crucial to avoid the long-term toxicities of radiation, especially in patients with long life expectancy. Craniospinal irradiation may be reserved for therapeutic use in cases of CNS relapse and prophylaxis for some high-risk patients. Erişkin akut lenfoblastik lösemi (ALL) hastalarında, santral sinir sistemi (SSS) tutulumuna karşı kullanılan profilaktik rejimlerin etkinlik ve güvenliğini karşılaştıran çalışma bulunmamaktadır. Bu çok merkezli retrospektif çalışmada, profilakside SSS ışınlamayı içeren ve içermeyen rejimlerin etkinliklerinin karşılaştırılması amaçlanmıştır. Bu çalışma, karşılaştırmalı retrospektif kohort çalışması olup Türkiye’de dört farklı üçüncü basamak merkeze başvuran 203 hastayla yapılmıştır. Hastalar, SSS ışınlaması alanlar ve almayanlar olarak iki gruba ayrılmıştır. Gruplar, takipte SSS tutulumu gelişimi temelinde hastaların ve ALL’nin özelliklerine göre karşılaştırılmıştır. Yüz beş hasta sadece kemoterapi bazlı profilaksi alırken, 98 hasta ek olarak SSS ışınlaması almıştır. SSS ışınlama grubundaki hastaların medyan yaşı daha küçüktür ve kök hücre nakli oranı daha yüksektir. Bunlar haricinde gruplar, demografik özellikler ve SSS tutulumu risk faktörleri açısından benzer dağılım göstermektedir. Medyan 23,8 (11,1-62,4) aylık takipte, SSS tutulumsuz sağkalım açısından iki grup arasında fark saptanmamıştır (log-rank p0,787). Pediatrik hastalarda kanıtlandığı gibi erişkin ALL hastalarında da SSS ışınlaması, çok yüksek riskli hastalar dışında profilakside yer almayabilir. Özellikle yüksek yaşam süresi beklenen hastalarda, ışınlamanın nörolojik toksisitesinden kaçınılması da günümüzde amaçlar arasında olmalıdır. Işınlamanın, SSS tutulumu gelişmiş hastalarda terapötik amaçla sınırlandırılması, çok yüksek riskli hastalar dışında iyi bir riskfayda oranına sahiptir. |
35,444,651 | Notch-Signaling Deregulation Induces Myeloid-Derived Suppressor Cells in T-Cell Acute Lymphoblastic Leukemia. | Notch receptors deeply influence T-cell development and differentiation, and their dysregulation represents a frequent causative event in T-cell acute lymphoblastic leukemia (T-ALL). Myeloid-derived suppressor cells (MDSCs) inhibit host immune responses in the tumor environment, favoring cancer progression, as reported in solid and hematologic tumors, with the notable exception of T-ALL. Here, we prove that Notch-signaling deregulation in immature T cells promotes CD11b |
35,443,604 | Programmed Death Ligand-1 is Frequently Expressed in Primary Acute Myeloid Leukemia and B-Acute Lymphoblastic Leukemia. | The introduction of checkpoint inhibitors in solid cancer therapy showed successful results. The role of Programmed Death-1Programmed Death-Ligand 1 (PD1PD-L1) in hematologic malignancies is currently being investigated and clinical trials are ongoing. Preliminary findings showed conflicting results. In this study, we examined the degree of PD-L1 and PD-L2 expression in primary acute leukemia patients. Flow cytometry expression of PD-L1 and PD-L2 was evaluated in de novo acute leukemia in the collaborating institutions between 2018 - 2020. One hundred forty patients were identified. PD-L1 was positive in 3470 (49%) of AML, 2550 (50%) of B-ALL, and none (020) of T-ALL patients. In contrast, PD-L2 was solely expressed in eight (19%) AML patients. The expression of PD-L1 showed statistically significant correlation with the type of acute leukemia (AML and B-ALL > T-ALL, p < 0.001) and with age group (adults > children, p 0.048), but not with blast count, immunophenotype or cytogenetic mutations. The positivity for PD-L1 was associated with worse overall survival in AML, but not in B-ALL. The expression of PD-L1 is common among newly diagnosed AML and B-ALL patients and is not restricted to relapsed cases as previously described. PD-L2 is less commonly expressed and is accompanied by PD-L1 expression. Positive PD-L1 patients may benefit from treatment with immune checkpoint inhibitors, especially in AML. Further studies are recommended. |
35,443,595 | Fatal Prototheca zopfii Algaemia in a Patient with Acute Lymphoblastic Leukemia a Case Report. | Prototheca algaemia is a rare but life-threatening disease that occurs primarily in immunocompromised patients. We report a fatal case of Prototheca zopfii bloodstream infection in a 54-year-old woman receiving chemotherapy for relapsed acute lymphoblastic leukemia. The isolate was identified using an automated biochemical identification system (VITEK 2 bioMerieux) and matrix-assisted laser desorptionionization time-of-flight mass spectrometry (VITEK MS bioMerieux). Partial 18S and 28S rDNA sequencing was performed for definitive identification and genotyping. The patient had persistent neutropenic fever, and isolates from blood culture were identified as P. zopfii. Sequencing was performed and the isolate was confirmed to be P. zopfii genotype 2, which was newly named as P. bovis. The patient was treated with liposomal amphotericin B but died of septic shock. Prototheca spp. should be considered an emerging pathogen, especially in immunocompromised patients, due to its ubiquitous nature. |
35,442,732 | Simultaneous monitoring of disease and microbe dynamics through plasma DNA sequencing in pediatric patients with acute lymphoblastic leukemia. | Treatment of acute lymphoblastic leukemia (ALL) necessitates continuous risk assessment of leukemic disease burden and infections that arise in the setting of immunosuppression. This study was performed to assess the feasibility of a hybrid capture next-generation sequencing panel to longitudinally measure molecular leukemic disease clearance and microbial species abundance in 20 pediatric patients with ALL throughout induction chemotherapy. This proof of concept helps establish a technical and conceptual framework that we anticipate will be expanded and applied to additional patients with leukemia, as well as extended to additional cancer types. Molecular monitoring can help accelerate the attainment of insights into the temporal biology of host-microbe-leukemia interactions, including how those changes correlate with and alter anticancer therapy efficacy. We also anticipate that fewer invasive bone marrow examinations will be required, as these methods improve with standardization and are validated for clinical use. |
35,442,720 | Acute Leukemia Classification Using Transcriptional Profiles From Low-Cost Nanopore mRNA Sequencing. | Most cases of pediatric acute leukemia occur in low- and middle-income countries, where health centers lack the tools required for accurate diagnosis and disease classification. Recent research shows the robustness of using unbiased short-read RNA sequencing to classify genomic subtypes of acute leukemia. Compared with short-read sequencing, nanopore sequencing has low capital and consumable costs, making it suitable for use in locations with limited health infrastructure. We show the feasibility of nanopore mRNA sequencing on 134 cryopreserved acute leukemia specimens (26 acute myeloid leukemia AML, 73 B-lineage acute lymphoblastic leukemia B-ALL, 34 T-lineage acute lymphoblastic leukemia, and one acute undifferentiated leukemia). Using multiple library preparation approaches, we generated long-read transcripts for each sample. We developed a novel composite classification approach to predict acute leukemia lineage and major B-ALL and AML molecular subtypes directly from gene expression profiles. We demonstrate accurate classification of acute leukemia samples into AML, B-ALL, or T-lineage acute lymphoblastic leukemia (96.2% of cases are classifiable with a probability of > 0.8, with 100% accuracy) and further classification into clinically actionable genomic subtypes using shallow RNA nanopore sequencing, with 96.2% accuracy for major AML subtypes and 94.1% accuracy for major B-lineage acute lymphoblastic leukemia subtypes. Transcriptional profiling of acute leukemia samples using nanopore technology for diagnostic classification is feasible and accurate, which has the potential to improve the accuracy of cancer diagnosis in low-resource settings. |
35,442,451 | Enrollment of Black Participants in Pivotal Clinical Trials Supporting US Food and Drug Administration Approval of Chimeric Antigen Receptor-T Cell Therapy for Hematological Malignant Neoplasms. | Disparities that affect Black persons with various hematological malignant neoplasms are substantial, yet little is known about disparities related to the use of US Food and Drug Administration (FDA)-approved chimeric antigen receptor-T cell (CAR-T) therapy. To examine the enrollment of Black participants in clinical trials that resulted in a subsequent FDA approval of CAR-T products in hematological malignant neoplasms. A cross-sectional study was performed using publicly available data on drug products and demographic subgroups from Drugsfda in the period of August 2017 to May 2021. Data analysis included patients with large B cell lymphoma, follicular lymphoma, mantle cell lymphoma, acute lymphoblastic leukemia, and multiple myeloma who were enrolled into 7 clinical trials that investigated various CAR-T products. The study was conducted from July 1, 2021, to November 30, 2021. Frequencies of participation of Black participants were calculated with adjustment for disease prevalence. Of the 1057 enrolled patients included in the study, CAR-T products were given to 746 patients (71%), and efficacy was reported for 729 enrolled patients (69%) across all the approved CAR-T products and indications. Most patients (1015 patients 96%) were enrolled in the US. Black participants were included in the racial category other in the study that supported tisagenlecleucel approval in acute lymphoblastic leukemia otherwise, their enrollment was specified either in the study publication andor the demographic subgroup information available under the FDA product labeling information. The number of Black participants who received the CAR-T product and had reported efficacy varied between studies (range, 1-12 participants 2%-5%). Adjusted prevalence measures showed the lowest participation to prevalence ratio of 0.2 for multiple myeloma and 0.6 for large B cell lymphoma. The findings of this study suggest that there are substantial disparities affecting Black patients across all approved CAR-T products used to treat hematological malignant neoplasms with otherwise limited effective treatment options. The study findings might aid policy discussions regarding the immediate need of regulations that enforce certain thresholds of Black patients enrollment before granting FDA approval. |
35,441,937 | Astaxanthin decreases the growth-inhibitory dose of cytarabine and inflammatory response in the acute lymphoblastic leukemia cell line NALM-6. | In spite of the great progress in acute lymphoblastic leukemia (ALL) treatment, a large number of patients still suffer from chemotherapy drug toxicity. As a routine medication for ALL treatment, cytarabine (Ara-C) has many side effects on the patients. Astaxanthin (ASX), on the other hand, is a carotenoid with antioxidant, anti-inflammatory and anti-cancer properties. The present study investigated the effects of ASX in combination with Ara-C on cell proliferation, apoptosis induction, and cell cycle arrest in NALM-6 cell line. NALM6 cells were treated with different concentrations of ASX, Ara-C, and their co-treatment. Cytotoxic effects were evaluated using MTT assay. After treating the cells with the IC50 dose of ASX, Ara-C and their co-treatment, we studied apoptosis induction, cell cycle arrest, and expression of apoptotic, anti-apoptotic, and inflammatory genes. MTT assay demonstrated that co-treatment of cytarabine and ASX had greater cytotoxicity effects compared with the IC50 dose of Ara-C alone. After 48 h of treatment of NALM-6 cells with the combination dose, expression levels of apoptotic genes (P53, caspase-8, 3), the anti-apoptotic gene (Bcl-xL) and inflammatory genes (IL-6, TNF-α) changed significantly compared to the untreated group (p < 0.05). Co-treatment of ASX and Ara-C has synergism effects on apoptosis pathways, cell proliferation inhibition, and decreased inflammation. |
35,441,457 | Dasatinib-therapy induced sustained remission in a child with refractory TCF7-SPI1 T-cell acute lymphoblastic leukemia. | The prognosis of patients with T-cell acute lymphoblastic leukemia (T-ALL) has been largely lacked behind than that of patients with B-cell ALL, especially in refractory or relapsed cases. Here, we describe a 4.7-year-old male child with TCF-SPI1-postitve T-ALL who developed refractoriness disease after a seven drugs-conventional therapy. Several studies have suggested the therapeutic potential of dasatinib in refractory T-ALL. Actually, dasatinib-included therapy dramatically reduces the leukemic burden and re-induces this patient into complete remission without systemic adverse events. Although this is a single exceptional case, the translational potential evidence of dasatinib in specific T-ALL subtype should not be under-estimated. |
35,438,901 | Childhood acute lymphoblastic leukemia in Mexico mortality trend analysis, 1998-2018. | To determine the magnitude of mortality due to acute lymphoblastic leukemia (ALL) nationally and by age group, sex, state of residence and insurance status, as well as to evaluate time trends during the period 1998-2018 Materials and methods. We obtained ALL mortality data and estimated age-standardized national, state-level and health insurance mortality rates. We conducted a joinpoint regression analysis to describe mortality trends across the study period and estimate the average annual percent change (AAPC). In a 20-year period, age-standardized ALL mortality rates increased from 1.6 per 100 000 in 1998 to 1.7 in 2018. Nationally, a constant annual increase in mortality was observed for both sexes (1998-2002 AAPC 0.6 in boys, and 1998-2002 AAPC 0.3 in girls). We observed heteroge-neity in childhood ALL at a state level. Our results reflect the social, economic, geographic diversity of the country. Monitoring and surveillance of this disease is crucial to assess quality of care. |
35,436,854 | An alternative CYB5A transcript is expressed in aneuploid ALL and enriched in relapse. | B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is a genetically heterogenous malignancy with poor prognosis in relapsed adult patients. The genetic basis for relapse in aneuploid subtypes such as near haploid (NH) and high hyperdiploid (HeH) BCP-ALL is only poorly understood. Pathogenic genetic alterations remain to be identified. To this end, we investigated the dynamics of genetic alterations in a matched initial diagnosis-relapse (ID-REL) BCP-ALL cohort. Here, we firstly report the identification of the novel genetic alteration CYB5Aalt, an alternative transcript of CYB5A, in two independent cohorts. We identified CYB5alt in the RNAseq-analysis of a matched ID-REL BCP-ALL cohort with 50 patients and quantified its expression in various molecular BCP-ALL subtypes. Findings were validated in an independent cohort of 140 first diagnosis samples from adult BCP-ALL patients. Derived from patient material, the alternative open reading frame of CYB5Aalt was cloned (pCYB5Aalt) and pCYB5Aalt or the empty vector were stably overexpressed in NALM-6 cells. RNA sequencing was performed of pCYB5Aalt clones and empty vector controls followed by differential expression analysis, gene set enrichment analysis and complementing cell death and viability assays to determine functional implications of CYB5Aalt. RNAseq data analysis revealed non-canonical exon usage of CYB5Aalt starting from a previously undescribed transcription start site. CYB5Aalt expression was increased in relapsed BCP-ALL and its occurrence was specific towards the shared gene expression cluster of NH and HeH BCP-ALL in independent cohorts. Overexpression of pCYB5Aalt in NALM-6 cells induced a distinct transcriptional program compared to empty vector controls with downregulation of pathways related to reported functions of CYB5A wildtype. Interestingly, CYB5A wildtype expression was decreased in CYB5Aalt samples in silico and in vitro. Additionally, pCYB5Aalt NALM-6 elicited a more resistant drug response. Across all age groups, CYB5Aalt was the most frequent secondary genetic event in relapsed NH and HeH BCP-ALL. In addition to its high subgroup specificity, CYB5Aalt is a novel candidate to be potentially implicated in therapy resistance in NH and HeH BCP-ALL. This is underlined by overexpressing CYB5Aalt providing first evidence for a functional role in BCL2-mediated apoptosis. |
35,436,564 | The tricks for fighting against cancer using CAR NK cells A review. | Natural killer (NK) cells seem to be the most common innate lymphocyte subtypes, and theyre known for their ability to guide anti-tumor and anti-viral responses, making them potentially therapeutic. Since NK cells lack polymorphic clonotypic receptors, they must rely on inhibitory receptors to develop, mature, and distinguish between self and non-self. In the clinic, genetically engineered immune cells expressing a chimeric antigen receptor (CAR) that consists of an extracellular antigen recognizing domain connected to an intracellular signaling domain have gained interest. The U.S. food and drug administration (FDA) approved two CAR-T cells, anti-CD19 CARs, for the treatment of relapsedrefractory B-cell acute lymphoblastic leukemia (B-ALL) and diffuse large B-cell lymphoma (DLBCL). Nevertheless, CAR-T cell therapy is linked to a series of negative side effects, including fatal cytokine release syndrome (CRS) and tumor lysis syndrome (TLS), as well as a lack of regulatory control. CAR-transduced NK cells (CAR-NK) are thought to have many benefits, including clinical safety, the mechanisms by which they identify cancerous cells, and their abundance in clinical specimens, according to a growing number of studies. In pre-clinical and clinical trials, human primary NK cells and the NK-92 cell line were effectively transduced to express CARs against hematological cancers and solid tumors. Here, it is tried to summarize the development of CAR-NK cells, challenges and coping strategies, as well as managing the challenges and obstacles related to its protection, which promises to eliminate the shortcomings of conventional CARs. |
35,436,470 | Primary acute lymphoblastic leukemia cells are susceptible to microtubule depolymerization in G1 and M phases through distinct cell death pathways. | Microtubule targeting agents (MTAs) are widely used cancer chemotherapeutics which conventionally exert their effects during mitosis, leading to mitotic or postmitotic death. However, accumulating evidence suggests that MTAs can also generate death signals during interphase, which may represent a key mechanism in the clinical setting. We reported previously that vincristine and other microtubule destabilizers induce death not only in M phase but also in G1 phase in primary acute lymphoblastic leukemia cells. Here, we sought to investigate and compare the pathways responsible for phase-specific cell death. Primary acute lymphoblastic leukemia cells were subjected to centrifugal elutriation, and cell populations enriched in G1 phase (97%) or G2M phases (80%) were obtained and treated with vincristine. We found death of M phase cells was associated with established features of mitochondrial-mediated apoptosis, including Bax activation, loss of mitochondrial transmembrane potential, caspase-3 activation, and nucleosomal DNA fragmentation. In contrast, death of G1 phase cells was not associated with pronounced Bax or caspase-3 activation but was associated with loss of mitochondrial transmembrane potential, parylation, nuclear translocation of apoptosis-inducing factor and endonuclease G, and supra-nucleosomal DNA fragmentation, which was enhanced by inhibition of autophagy. The results indicate that microtubule depolymerization induces distinct cell death pathways depending on during which phase of the cell cycle microtubule perturbation occurs. The observation that a specific type of drug can enter a single cell type and induce two different modes of death is novel and intriguing. These findings provide a basis for advancing knowledge of clinical mechanisms of MTAs. |
35,435,984 | Autologous Nanobody-Derived Fratricide-Resistant CD7-CAR T-cell Therapy for Patients with Relapsed and Refractory T-cell Acute Lymphoblastic LeukemiaLymphoma. | Since CD7 may represent a potent target for T-lymphoblastic leukemialymphoma (T-ALLLBL) immunotherapy, this study aimed to investigate safety and efficacy of autologous CD7-chimeric antigen receptor (CAR) T cells in patients with relapsed and refractory (RR) T-ALLLBL, as well as its manufacturing feasibility. Preclinical phase was conducted in NPG mice injected with Luc GFPCCRF-CEM cells. Open-label phase I clinical trial (NCT04004637) enrolled patients with RR CD7-positive T-ALLLBL who received autologous CD7-CAR T-cell infusion. Primary endpoint was safety secondary endpoints included efficacy and pharmacokinetic and pharmacodynamic parameters. CD7 blockade strategy was developed using tandem CD7 nanobody VHH6 coupled with an endoplasmic reticulumGolgi-retention motif peptide to intracellularly fasten CD7 molecules. In preclinical phase CD7 blockade CAR T cells prevented fratricide and exerted potent cytolytic activity, significantly relieving leukemia progression and prolonged the median survival of mice. In clinical phase, the complete remission (CR) rate was 87.5% (78) 3 months after CAR T-cell infusion 1 patient with leukemia achieved minimal residual disease-negative CR and 1 patient with lymphoma achieved CR for more than 12 months. Majority of patients (87.5%) only had grade 1 or 2 cytokine release syndrome with no T-cell hypoplasia or any neurologic toxicities observed. The median maximum concentration of CAR T cells was 857.2 cellsμL at approximately 12 days and remained detectable up to 270 days. Autologous nanobody-derived fratricide-resistant CD7-CAR T cells demonstrated a promising and durable antitumor response in RR T-ALLLBL with tolerable toxicity, warranting further studies in highly aggressive CD7-positive malignancies. |
35,435,398 | Budding yeast in a child with acute leukemia Nothing CRYPT(O)IC about it. | A 13-year-old girl child with B-cell precursor acute lymphoblastic leukemia presented with complaints of fever, fatigue and left-sided iliac mass of 20 days duration. Preliminary blood culture from the peripherally inserted central catheter (PICC) demonstrated the presence of budding yeast cells. This is a rare form of Disseminated cryptococcosis. Budding yeast cells emphasizes the significance of various differentials of yeast in positive blood cultures bottles, as identifying Cryptococcus from gram stain can be complicated. This manuscript also highlights the presence of crystalloid geometric appearance like Buckminsterfullerene, which is derived from the mucopolysaccharide capsule in Cryptococcus. These structures are rarely observed, and in this case, are exceptionally remarkable. |
35,434,830 | Analysis of the frequency distribution of five single-nucleotide polymorphisms of the MTRRgene in a Chinese pediatric population with acute lymphoblastic leukemia. | The objective of the present study was to examine the frequency distribution of five single-nucleotide polymorphisms (SNPs rs1801394 A>G, rs1532268 C>T, rs162036 A>G, rs10380 C>T, and rs9332 C>T) of the methionine synthase reductase (MTRR) gene, their effects on methotrexate (MTX) concentration, and the risk of relapse in a Chinese pediatric population with acute lymphoblastic leukemia (ALL). This was a retrospective single-center study, and all analyses were exploratory. Pediatric Department of Beijing Shijitan Hospital, Capital Medical University, Beijing, China. One hundred and forty pediatric patients with ALL. All patients were treated according to the Chinese Childrens Leukemia Group (CCLG)-ALL 2008 protocol. Serum MTX concentrations were measured using fluorescence polarization immunoassay. Genotyping of five SNPs was performed using the Sequenom MassARRAY iPLEX platform. Chinese children with ALL had a significantly lower frequency of rs1801394 G than European (EUR) and South Asian (SAS) populations significantly lower frequency of rs1532268 T than American (AMR), EUR, and SAS populations and significantly lower frequencies of rs162036 G, rs10380 T, and rs9332 T than African and AMR populations (p < 0.01). Seven haplotypes were observed, with the ACACC being the most common haplotype (49.9%) in our study. The median dose-normalized concentrations of MTX in serum at 24 h in children with rs1532268 CT and TT genotypes were significantly higher than those with CC genotype (p 0.04). Compared with children with AA-CC-AA-CC-CC diplotype, a significantly higher risk of relapse was observed in children with AG-CC-AA-CC-CC and AG-CC-AG-CC-CC diplotypes (p 0.03 and 0.003, respectively). The present study confirmed the ethnic differences in the distribution of MTRR rs1801394, rs1532268, rs162036, rs10380, and rs9332 polymorphisms. The rs1532268 polymorphism had greater effects on MTX disposition. The AG-CC-AA-CC-CC and AG-CC-AG-CC-CC diplotypes were significantly associated with higher risk of relapse of ALL. |
35,434,798 | Inhibition of the Sec61 translocon overcomes cytokine-induced glucocorticoid resistance in T-cell acute lymphoblastic leukaemia. | Glucocorticoid (GC) resistance is a poor prognostic factor in T-cell acute lymphoblastic leukaemia (T-ALL). Interleukin-7 (IL-7) mediates GC resistance via GC-induced upregulation of IL-7 receptor (IL-7R) expression, leading to increased pro-survival signalling. IL-7R reaches the cell surface via the secretory pathway, so we hypothesized that inhibiting the translocation of IL-7R into the secretory pathway would overcome GC resistance. Sec61 is an endoplasmic reticulum (ER) channel that is required for insertion of polypeptides into the ER. Here, we demonstrate that KZR-445, a novel inhibitor of Sec61, potently attenuates the dexamethasone (DEX)-induced increase in cell surface IL-7R and overcomes IL-7-induced DEX resistance. |
35,434,757 | Is hypoalbuminemia a risk factor for high-dose methotrexate toxicity in children with acute lymphoblastic leukemia | Repeated high-dose methotrexate (HDMTX) is a critical component of contemporary childhood acute lymphoblastic leukemia (ALL) treatment regimens. Serum albumin is considered a carrier of methotrexate (MTX) in the blood. Hypoalbuminemia is not a rare finding in children with leukemia. This study aimed to investigate the relationship between pre-infusion serum albumin and possible HDMTX toxicities. Thirty Egyptian children with ALL were consecutively enrolled in the study between May 2018 and July 2020. They were prospectively followed up while receiving HDMTX during the consolidation phase of the TOTAL study XV protocol. HDMTX was administered intravenously as a 24-h infusion every 2 weeks. Doses of 2.5 gm The patients age ranged from 2.3 to 13.3 years at diagnosis, and most of them had B cell ALL (86.7%). Overall, 120 HDMTX cycles were analyzed, equally distributed between low and standardhigh risk. Grade 3-4 anemia, grades 3-4 thrombocytopenia, febrile neutropenia, and oral mucositis were significantly more frequent in HDMTX cycles with pre-infusion hypoalbuminemia than those with normal pre-infusion albumin (p0.003, p0.007, p0.006, and p0.001, respectively). In addition, pre-infusion hypoalbuminemia was significantly associated with additional hospitalization due to HDMTX toxicity (p0.031). Most HDMTX toxicities were comparable irrespective of the MTX dose. Oral mucositis was more frequently encountered in the 2.5 gm Serum albumin levels should be checked before starting HDMTX cycles, especially in resource-limited settings where malnutrition is common, and serum MTX monitoring may not be available. Optimizing serum albumin levels before HDMTX may help decrease the possibility of HDMTX toxicities. |
35,432,537 | Comprehensive Analysis of Potential Biomarkers of Acute Lymphoblastic Leukemia in Children by Using a Competing Endogenous RNA Network. | Acute lymphoblastic leukemia (ALL) is the most serious hematological carcinoma in adolescents. The significance of long noncoding RNAs (lncRNAs) and their regulative role in the proliferation and differentiation of myeloid cells in cancer has been recently reported. Nevertheless, key RNAs and the regulatory mechanism of competitive endogenous RNA (ceRNA) network affected by pediatric ALL are not fully illustrated. In this study, phase 2 and 3 pediatric ALL RNA profiles were extracted from the TARGET database and used to identify lncRNAs, microRNAs, and messenger RNAs in high-risk ALL and reconstruct the sponge ceRNA regulatory network. Results indicated that 44 lncRNAs, 25 miRNAs, and 115 mRNA were updownregulated. Functional analysis with differentially expressed RNAs (DERNAs) showed enriched significant signaling pathways, including PI3K-Akt and p53 signaling cascades and other pathways associated with the tumor. Seventeen differential hub RNAs, including LINC00909, BZRAP1-AS1, C17orf76-AS1, HCG11, MIAT, SNHG5, SNHG15, and TP73-AS1, were identified. The Cox model of correlation indicated that 14 of these RNAs were associated with the progression of pediatric ALL. These findings would help clarify the regulatory role of several lncRNAs as well as provide insights into the leukemogenesis of pediatric ALL to further explore novel prognostic markerstherapeutic targets for ALL. |
35,431,864 | Epstein-Barr Virus Encephalitis and Disseminated Adenovirus Infection after Haploidentical Allogeneic Hematopoietic Stem Cell Transplantation for a Patient with Ph-Like Acute Lymphoblastic Leukemia. | Viral reactivation or infections are common complications after allogeneic hematopoietic stem cell transplantation, especially in haploidentical transplantation. Here, we presented a young patient with Ph-like acute lymphoblastic leukemia who suffered Epstein-Barr virus (EBV) encephalitis and disseminated adenovirus (ADV) infection after haploidentical peripheral blood (PB) stem cell transplantation. The patient was a 16-year-old boy and received PB stem cells from his HLA-haploidentical matched father. On day 44 after transplantation, he had viremia with cytomegalovirus, and EBV was diagnosed as EBV encephalitis after 2 weeks. On day 117, he had disseminated ADV infection and fulminant ADV hepatitis. It is very rare that successive EBV encephalitis and fulminant ADV hepatitis are present in the same patient. We summarized risk factors, clinical manifestations, diagnostic criteria, and effective treatments about EBV encephalitis and disseminated ADV infection. We try to enhance our understanding of the prevention, diagnosis, and potential treatment of EBV and ADV disease by reviewing the entire procedure. |
35,431,861 | Cervical Edema Extending to the Larynx as Local Cytokine Release Syndrome Following Chimeric Antigen Receptor T-Cell Therapy in a Boy with Refractory Acute Lymphoblastic Leukemia. | Cytokine release syndrome (CRS) is one of the major acute complications caused by massive cytokine release after chimeric antigen receptor (CAR) T-cell therapy. Patients with tumor masses were considered at high risk of local CRS induced by the expansion of CAR T cells in the tumor masses. However, even patients without any tumor burden around the neck are at risk of developing cervical edema as local CRS, which can lead to life-threatening airway obstruction. Here, we present the case of a 15-year-old boy who developed cervical edema as a local CRS after CAR T-cell therapy for refractory acute lymphoblastic leukemia. Despite administration of tocilizumab and methylprednisolone for persistent fever as a symptom of systemic CRS after CAR T-cell therapy, cervical edema occurred and extended to the larynx, resulting in dysphagia and hoarseness. Dexamethasone was remarkably effective, and the laryngeal symptoms resolved within a few hours. Local cytokine syndrome showed exacerbation with tocilizumab but exhibited considerable improvement with dexamethasone administration. |
35,431,360 | Susceptibility to thiopurine toxicity by | This study aimed to correlate the genetic profile of the This was an analytical, longitudinal, observational study in which the genotypes of the genes of interest were determined by PCR allelic discrimination with TaqMan® probes in patients receiving chemotherapy during the maintenance phase in the Pediatric Hematology and Oncology Unit in 2017. Sociodemographic and clinical data corresponding to the first six months of their maintenance chemotherapy were collected, and the correlation between the genotypes obtained and the development of side effects during the maintenance phase of chemotherapy in these patients was evaluated. Seventy pediatric patients were included in the study. Genetic analyses were carried out of these for Studies with a larger population size are needed and the evaluation of other genetic variants that may influence the development of side effects during maintenance chemotherapy. la finalidad de este estudio fue evaluar las asociaciones entre los perfiles de los genes Este fue un estudio observacional analítico, de corte longitudinal en el que los genotipos de los genes de interés fueron determinados mediante PCR de discriminación alélica con sondas TaqMan® en pacientes que estaban recibiendo quimioterapia de mantenimiento en la Unidad de Oncohematología Pediátrica durante el 2017. Los datos clínicos y sociodemográficos correspondientes a los primeros 6 meses de sus tratamientos de mantenimiento fueron colectados, y se evaluó la correlación entre los genotipos identificados y el desarrollo de efectos secundarios en estos pacientes. setenta pacientes fueron incluidos en el estudio, de estos, los análisis genéticos para Estos hallazgos resaltan la importancia de realizar estudios de este tipo con un mayor número de sujetos de estudio, así como plantean la necesidad de evaluar otras variantes genéticas que podrían tener algún impacto en el desarrollo de efectos secundarios durante la quimioterapia de mantenimiento. |
35,429,662 | Socioeconomic and Racial Disparity in Chimeric Antigen Receptor T Cell Therapy Access. | Chimeric antigen receptor (CAR) T cell therapy is changing the paradigm in hematologic malignancies, but disparities in access exist in the real-world setting. Efforts to address and eliminate these disparities will ensure availability of this life-saving therapy. This study aimed to determine patterns of racialethnic distribution, socioeconomic strata, insurance coverage, and travel time of CAR T cell recipients. We used the Vizient Clinical Database (CDB) to capture and analyze elective encounters for CAR T administration as well as encounters for any reason other than CAR T administration (non-CAR T) in patients with lymphoma, myeloma, and acute lymphoblastic leukemia. Travel time and median household income were calculated based on ZIP code of residence. We found that African Americans (AA) were less likely than other racialethnic groups to receive CAR T cell therapy. In addition, AA and Hispanic participants were underrepresented in clinical trials. Among the patients with myeloma, all of whom received CAR T cell therapy on a clinical trial, only 1% were African American and 5.4% were Hispanic, and only 7.3% of CAR T cell therapy-related admissions were of patients from neighborhoods with a mean income <$40,000. Almost one-third of the CAR T cell recipients lived >2 hours away from the center in which they were treated the majority of these patients were from the higher socioeconomic stratum (P < .001). There were fewer patients with Medicare and uninsured patients in the CAR T cell group. Our data indicate that socioeconomic stratum and insurance coverage are important underlying determinants of the identified disparities. Low clinical trial enrollment of minorities also feeds the inequity. Strategies to improve access need to be framed around addressing the causes for the observed disparities. |
35,427,182 | Physical Therapy Utilization Among Hospitalized Patients With Pediatric Acute Lymphoblastic Leukemia. | Patients with pediatric acute lymphoblastic leukemia (ALL) are at risk for impaired physical function from treatment. Early physical therapy (PT) may improve physical function and health in children with ALL, yet little is known about PT utilization in this population. Leveraging the Premier Healthcare Database, we conducted a cohort study including participants hospitalized with ALL at age 0-21 years from January 1, 2010, through March 31, 2017. A generalized mixed linear model assessed sociodemographic and clinical variables associated with receiving PT within 1 year of first hospitalization. Among 5,488 pediatric ALL patients from 330 hospitals (median age 7 years, interquartile range 4-14 years), only 27.2% overall and 58.9% with neuromuscular conditions received PT within a year of first ALL admission. In multivariable analysis, patients more likely to receive PT were age 10-14 years (odds ratio OR 1.46 95% CI, 1.20 to 1.76) or 15-21 years (OR 1.66 95% CI, 1.36 to 2.02) versus 0-4 years and Hispanic (OR 1.27 95% CI, 1.04 to 1.56) versus White. Patients less likely to receive PT were treated by a nonhematologyoncology pediatric (OR 0.56 95% CI, 0.46 to 0.70) or adult (OR 0.50 95% CI, 0.38 to 0.65) specialist versus a pediatric hematologistoncologist and treated at a nonteaching hospital (OR 0.53 95% CI, 0.36 to 0.79) versus a teaching hospital. Only 27.2% of pediatric ALL patients overall and 58.9% with neuromuscular conditions receive inpatient PT within a year of first ALL admission. Interventions to increase inpatient PT services to pediatric ALL patients and address disparities in PT utilization may improve the physical function and long-term health of survivors. |
35,427,125 | Novel Selective Galectin-3 Antagonists Are Cytotoxic to Acute Lymphoblastic Leukemia. | Galectin-3 is a β-galactoside-specific, carbohydrate-recognizing protein (lectin) that is strongly implicated in cancer development, metastasis, and drug resistance. Galectin-3 promotes migration and ability to withstand drug treatment of B-cell precursor acute lymphoblastic leukemia (BCP-ALL) cells. Due to high amino acid conservation among galectins and the shallow nature of their glycan-binding site, the design of selective potent antagonists targeting galectin-3 is challenging. Herein, we report the design and synthesis of novel taloside-based antagonists of galectin-3 with enhanced affinity and selectivity. The molecules were optimized by |
35,425,700 | A Nomogram for Predicting Event-Free Survival in Childhood Acute Lymphoblastic Leukemia A Multicenter Retrospective Study. | Even though childhood acute lymphoblastic leukemia (ALL) has an encouraging survival rate in recent years, some patients are still at risk of relapse or even death. Therefore, we aimed to construct a nomogram to predict event-free survival (EFS) in patients with ALL. Children with newly diagnosed ALL between October 2016 and July 2021 from 18 hospitals participating in the South China childrens leukemia Group (SCCLG) were recruited and randomly classified into two subsets in a 73 ratio (training set, n1187 validation set, n506). Least absolute shrinkage and selection operator (LASSO) and multivariate Cox regression analysis were adopted to screen independent prognostic factors. Then, a nomogram can be build based on these prognostic factors to predict 1-, 2-, and 3-year EFS. Concordance index (C-index), area under the curve (AUC), calibration curve, and decision curve analysis (DCA) were used to evaluate the performance and clinical utility of nomogram. The parameters that predicted EFS were age at diagnosis, white blood cell at diagnosis, immunophenotype, ETV6-RUNX1TEL-AML1 gene fusion, bone marrow remission at day 15, and minimal residual disease at day 15. The nomogram incorporated the six factors and provided C-index values of 0.811 95% confidence interval (CI) 0.792-0.830 and 0.797 (95% CI 0.769-0.825) in the training and validation set, respectively. The calibration curve and AUC revealed that the nomogram had good ability to predict 1-, 2-, and 3-year EFS. DCA also indicated that our nomogram had good clinical utility. Kaplan-Meier analysis showed that EFS in the different risk groups stratified by the nomogram scores was significant differentiated. The nomogram for predicting EFS of children with ALL has good performance and clinical utility. The model could help clinical decision-making. |
35,422,096 | Tisagenlecleucel in pediatric and young adult patients with Down syndrome-associated relapsedrefractory acute lymphoblastic leukemia. | Down syndrome-associated acute lymphoblastic leukemia (DS-ALL) patients suffer risk of chemotherapy-associated toxicities and poor outcomes. We evaluated tisagenlecleucel in 16 patients with DS-ALL in two phase 2 trials (ELIANA NCT02435849, ENSIGN NCT02228096) and a phase 3b, managed access protocol (B2001X NCT03123939). Patients were 5-22 years old, had a median of two prior lines of therapy (range, 1-4), and four (25%) had prior stem cell transplants. Fourteen of 16 patients (88%) achieved complete remission (CR) or CR with incomplete blood count recovery (CRi) 12 of 14 (86%) with CRCRi were minimal residual disease-negative. With a median follow-up of 13.2 months (range, 0.5-49.3 months), six patients (43%) relapsed after CR (three, CD19-negative three, unknown) between 80-721 days post-infusion. Ongoing remissions in nine patients ranged from 6-48 months. Any-grade and grade 34 AEs occurred in 16 and 14 patients, respectively 44% experienced grade 34 cytokine release syndrome and 13% experienced grade 34 neurological events. Grade 34 prolonged cytopenias occurred in 44% of patients. No grade 34 infections were observed. Tisagenlecleucel expansion and long-term persistence were consistent with previous reports. Comparable to ALL patients without DS, tisagenlecleucel produced high remission rates, manageable side-effects, and promising long-term outcomes in pediatricyoung adult patients with DS-ALL. Children with Down syndrome have a 20 times higher risk of developing a type of blood cancer called Down syndrome-associated acute lymphoblastic leukemia (ALL). Children who develop Down syndrome-associated ALL typically receive chemotherapy to treat their cancer however, they can experience severe toxicity or other consequences from these therapies, especially stem cell transplant, and have a poor prognosis if their disease returns after treatment. These children need an effective but less toxic treatment option. Tisagenlecleucel is a chimeric antigen receptor-T cell therapy that specially modifies the patient’s own T-cells to recognize and attack the cancer cells. Tisagenlecleucel is approved for use in children and young adults with ALL whose disease reappears after two or more treatments or whose disease doesn’t respond to treatment. Here we present data from 16 patients across three clinical studies showing that tisagenlecleucel is well-tolerated and an effective treatment option for children and young adults with Down syndrome-associated ALL, and was similar to what is observed in patients without Down syndrome. Taken together, patients with Down syndrome-associated ALL have unique medical needs, and tisagenlecleucel may help them live longer, avoid stem cell transplantation, and the toxicity from chemotherapy. |
35,422,065 | Validation of a small molecule inhibitor of PDE6D-RAS interaction with favorable anti-leukemic effects. | RAS mutations prevalent in high-risk leukemia have been linked to relapse and chemotherapy resistance. Efforts to directly target RAS proteins have been largely unsuccessful. However, since RAS-mediated transformation is dependent on signaling through the RAS-related C3 botulinum toxin substrate (RAC) small GTPase, we hypothesized that targeting RAC may be an effective therapeutic approach in RAS mutated tumors. Here we describe multiple small molecules capable of inhibiting RAC activation in acute lymphoblastic leukemia cell lines. One of these, DW0254, also demonstrates promising anti-leukemic activity in RAS-mutated cells. Using chemical proteomics and biophysical methods, we identified the hydrophobic pocket of phosphodiester 6 subunit delta (PDE6D), a known RAS chaperone, as a target for this compound. Inhibition of RAS localization to the plasma membrane upon DW0254 treatment is associated with RAC inhibition through a phosphatidylinositol-3-kinaseAKT-dependent mechanism. Our findings provide new insights into the importance of PDE6D-mediated transport for RAS-dependent RAC activation and leukemic cell survival. |
35,421,541 | Oncogenic isoform switch of tumor suppressor BCL11B in adult T-cell leukemialymphoma. | B-Cell leukemialymphoma 11B (BCL11B) is a transcription factor important for T-cell development and acts as a tumor suppressor gene in T-cell acute lymphoblastic leukemia. Here, we identified BCL11B as a candidate leukemia-associated gene in human T-cell leukemia virus type 1 (HTLV-1)-induced adult T-cell leukemialymphoma (ATLL). Interestingly, the short form lacking exon 3 (BCL11BS) protein was more highly expressed than the full-length BCL11B (BCL11BL) in leukemic cells from most of the ATLL patients, although expression ratios of BCL11BL to BCL11BS were almost equal in control CD4 |
35,421,218 | CD34CD19-CD22 B-cell progenitors may underlie phenotypic escape in patients treated with CD19-directed therapies. | CD19-directed immunotherapies have revolutionized the treatment of advanced B-cell acute lymphoblastic leukemia (B-ALL). Despite initial impressive rates of complete remission (CR) many patients ultimately relapse. Patients with B-ALL successfully treated with CD19-directed T cells eventually relapse, which, coupled with the early onset of CD22 expression during B-cell development, suggests that preexisting CD34CD22CD19- (pre)-leukemic cells represent an early progenitor origin-related mechanism underlying phenotypic escape to CD19-directed immunotherapies. We demonstrate that CD22 expression precedes CD19 expression during B-cell development. CD34CD19-CD22 cells are found in diagnostic and relapsed bone marrow samples of ∼70% of patients with B-ALL, and their frequency increases twofold in patients with B-ALL in CR after CD19 CAR T-cell therapy. The median of CD34CD19-CD22 cells before treatment was threefold higher in patients in whom B-ALL relapsed after CD19-directed immunotherapy (median follow-up, 24 months). Fluorescence in situ hybridization analysis in flow-sorted cell populations and xenograft modeling revealed that CD34CD19-CD22 cells harbor the genetic abnormalities present at diagnosis and initiate leukemogenesis in vivo. Our data suggest that preleukemic CD34CD19-CD22 progenitors underlie phenotypic escape after CD19-directed immunotherapies and reinforce ongoing clinical studies aimed at CD19CD22 dual targeting as a strategy for reducing CD19- relapses. The implementation of CD34CD19CD22 immunophenotyping in clinical laboratories for initial diagnosis and subsequent monitoring of patients with B-ALL during CD19-targeted therapy is encouraged. |
35,420,395 | CAR T-Cell Therapy in the Older Person Indications and Risks. | Validated metrics to optimize older adult patient selection for Chimeric Antigen Receptor T-cell therapy (CART) are lacking however, some preliminary data suggests that geriatric assessments and cumulative illness rating score may be useful tools. In addition, interventions capable of enhancing outcomes in older adults receiving CART have yet to be elucidated. The purpose of this review is to present data extrapolating from other diseases and therapeutic modalities, related to product selection, toxicity mitigation strategies, comprehensive coordinated models of care, and functional optimization of patients. The most robust data in older adults are among relapsed and refractory (rr) diffuse large B-cell lymphoma (DLBCL) patients where three products are available with the longest clinical follow up and the most abundant real-world evidence (RWE). Data for the approved CART products for follicular lymphoma (FL) and mantle cell lymphoma (MCL) are relatively new and RWE is lacking in general. Data for CART products in multiple myeloma (MM) and B-cell acute lymphoblastic leukemia (B-ALL) are even more recent, but preliminary data in older adults seem to follow the trend of excellent efficacy in this age group with age-stratified toxicity data limited. Landmark trials and RWE studies indicate that the high response rates of CART for older adult patients, age 65 years and older, are maintained, while toxicity may be amplified. Clinically important toxicities include grade 3 or higher cytokine release syndrome (CRS), neurotoxicity, and infections. |
35,420,152 | Meta-analysis effect of chemotherapy on intelligence of children treated for leukemia. | Leukemia is the most common pediatric malignancy. Acute lymphoblastic leukemia (ALL) is the most commonly observed subtype. To assess cognitive functioning in children and adolescents with ALL post-treatment chemotherapy-only (CT-only) or in combination with radiation therapy (CTRT). METHODS We searched in PubMed and PsycINFO (OvidSP). Relevant data were analyzed using statistical program Comprehensive Meta-Analysis (version 2). 44 studies were included in the overall meta-analysis with a total of 5059 patients. A weighted mean IQ of 100.1 (95% CI 99.1-101.0) was found overall after ALL treatment. In subanalyses, we found for CT-only a weighted mean IQ of 100.7 (95% CI 99.5-101.9) and for CTRT-treatment a weighted mean IQ of 98.2 (95%100.7 (95% CI 96.3-100.3). There was no significant difference from the normative control (mean 100.0 SD 15). No significant cognitive sequelae were shown in childhood survivors of leukemia who were exposed to either CT-only or CTRT therapy. Prospective studies are needed with inclusion of pre-and post-treatment IQ measurements, ideally compared to age and socio-economic status matched control groups. |
35,419,612 | lncRNA deregulation in childhood acute lymphoblastic leukemia A systematic review. | Childhood acute lymphoblastic leukemia (ALL), the most common pediatric cancer, is a heterogeneous disease comprised of multiple molecular subtypes with distinct somatic genetic alterations, which results in different outcomes for the patients. Accurate patient risk stratification through genetic markers could increase survival rates, but the identification of reliable biomarkers is needed, as 20‑30% of B‑ALL patients cannot be classified in the clinic with routine techniques and some patients classified as low‑risk and good‑responders to treatment will eventually relapse. Long non‑coding RNAs (lncRNAs) can represent novel candidates with diagnostic, classification, prognosis, and treatment response potential. However, regarding childhood ALL, there is inconsistency in the data reported due to the lack of a consensus nomenclature for lncRNA naming and the methodology and designing applied for their study. Therefore, the aim of the article is to clarify the potential of lncRNAs as biomarkers in childhood ALL through a systematic review. From a revision of 23 manuscripts, it was found that |
35,419,036 | Clinical and Genetic Characteristics of | Acute lymphoblastic leukemia (ALL) is a malignancy associated with altered lymphoid precursor hyperplasia and accompanied with different genetic mutations. Few studies have been reported on the association between gene mutations and clinical features of |
35,418,180 | Primary CD33-targeting CAR-NK cells for the treatment of acute myeloid leukemia. | Acute myeloid leukemia (AML) is a malignant disorder derived from neoplastic myeloid progenitor cells characterized by abnormal proliferation and differentiation. Although novel therapeutics have recently been introduced, AML remains a therapeutic challenge with insufficient cure rates. In the last years, immune-directed therapies such as chimeric antigen receptor (CAR)-T cells were introduced, which showed outstanding clinical activity against B-cell malignancies including acute lymphoblastic leukemia (ALL). However, the application of CAR-T cells appears to be challenging due to the enormous molecular heterogeneity of the disease and potential long-term suppression of hematopoiesis. Here we report on the generation of CD33-targeted CAR-modified natural killer (NK) cells by transduction of blood-derived primary NK cells using baboon envelope pseudotyped lentiviral vectors (BaEV-LVs). Transduced cells displayed stable CAR-expression, unimpeded proliferation, and increased cytotoxic activity against CD33-positive OCI-AML2 and primary AML cells in vitro. Furthermore, CD33-CAR-NK cells strongly reduced leukemic burden and prevented bone marrow engraftment of leukemic cells in OCI-AML2 xenograft mouse models without observable side effects. |
35,414,205 | Cytomegalovirus colitis in a child with leukemia a case report. | A 17-month-old boy with a known case of T-cell acute lymphoblastic leukemia was admitted to the authors hospital because of blood-streaked diarrhea a week after his last chemotherapy session. Initially, he was treated with supportive care and an empiric regimen for opportunistic causes of diarrhea however, this was not effective. Eventually, evaluation of his stool with PCR showed positivity for cytomegalovirus. Consequently, he responded dramatically to treatment with ganciclovir. Although cytomegalovirus colitis is rare, a few case reports suggest cytomegalovirus as a possible cause of colitis in children with leukemia, which can be fatal and should be considered as a differential diagnosis. |
35,414,137 | Acute lymphoblastic leukemia-derived extracellular vesicles affect quiescence of hematopoietic stem and progenitor cells. | Patient-derived xenografted (PDX) models were generated through the transplantation of primary acute lymphoblastic leukemia (ALL) cells into immunodeficient NSG mice. We observed that ALL cells from mouse bone marrow (BM) produced extracellular vesicles (EVs) with specific expression of inducible heat shock protein HSP70, which is commonly activated in cancer cells. Taking advantage of this specific expression, we designed a strategy to generate fluorescent HSP70-labeled ALL EVs and monitor the impact of these EVs on endogenous murine BM cells ex vivo and in vivo. We discovered that hematopoietic stem and progenitor cells (HSPC) were mainly targeted by ALL EVs, affecting their quiescence and maintenance in the murine BM environment. Investigations revealed that ALL EVs were enriched in cholesterol and other metabolites that contribute to promote the mitochondrial function in targeted HSPC. Furthermore, using CD34 |
35,413,962 | Meiotic drive in chronic lymphocytic leukemia compared with other malignant blood disorders. | The heredity of the malignant blood disorders, leukemias, lymphomas and myeloma, has so far been largely unknown. The present study comprises genealogical investigations of one hundred and twelve Scandinavian families with unrelated parents and two or more cases of malignant blood disease. For comparison, one large family with related family members and three hundred and forty-one cases of malignant blood disease from the Faroese population was included. The inheritance is non-Mendelian, a combination of genomic parental imprinting and feto-maternal microchimerism. There is significantly more segregation in maternal than in paternal lines, predominance of mother-daughter combinations in maternal lines, and father-son combinations in paternal lines. Chronic lymphocytic leukemia is the most frequent diagnosis in the family material, and chronic lymphocytic leukemia has a transgenerational segregation that is unique in that inheritance of susceptibility to chronic lymphocytic leukemia is predominant in males of paternal lines. Male offspring with chronic lymphocytic leukemia in paternal lines have a birth-order effect, which is manifest by the fact that there are significantly more male patients late in the sibling line. In addition, there is contravariation in chronic lymphocytic leukemia, i.e. lower occurrence than expected in relation to other diagnoses, interpreted in such a way that chronic lymphocytic leukemia remains isolated in the pedigree in relation to other diagnoses of malignant blood disease. Another non-Mendelian function appears in the form of anticipation, i.e. increased intensity of malignancy down through the generations and a lower age at onset of disease than otherwise seen in cases from the Cancer Registers, in acute lymphoblastic leukemia, for example. It is discussed that this non-Mendelian segregation seems to spread the susceptibility genes depending on the gender of the parents and not equally to all children in the sibling line, with some remaining unaffected by susceptibility i.e. healthy and unaffected, due to a birth order effect. In addition, anticipation is regarded as a non-Mendelian mechanism that can amplify, «preserve» these vital susceptibility genes in the family. Perhaps this segregation also results in a sorting of the susceptibility, as the percentage of follicular lymphoma and diffuse large B-cell lymphoma is lower in the family material than in an unselected material. Although leukemias, lymphomas and myelomas are potentially fatal diseases, this non-Mendelian distribution and amplification hardly play any quantitative role in the survival of Homo sapiens, because these diseases mostly occur after fertile age. |
35,411,280 | Prognostics and Clinical Outcomes in Patients Diagnosed With Acute Lymphoblastic Leukemia in King Abdulaziz University Hospital, Jeddah, Saudi Arabia. | Background Acute lymphoblastic leukemia (ALL) is a hematological cancer that causes an accumulation of immature cells in the bone marrow. The count of white blood cells (WBCs) is an independent predictor of survival. Integrating first-line treatment, such as intensive chemotherapy, with prognostic factors aids in developing critical therapeutic decisions and improving long-term outcomes. This study evaluated several prognostics such as age, WBCs, ALL cell subtypes, and absolute WBC counts. Methods This study involved a retrospective record review and was conducted by scanning the medical records of all individuals who developed ALL and were on chemotherapy at a teaching Hospital in Jeddah between 2012 and 2018. The data entry was done using Microsoft Excel, while the analysis was done using SPSS Version 21. To test any associations, frequency and measure of central tendencies, t-test, and chi-square test were used. Results A total of 98 of ALL patients were on chemotherapy, and 18 were excluded. Thus, 80 patients were analyzed. The mean age for all patients was 13.6 years (range 0.6-26.6 years), and the most frequent ages were less than 18 years (90%). More than half of them (62.5%) were males. The majority of the patients were Bangladeshi, Pakistani, Indian, Afghan, Indonesian, and Myanmar (37.7%), and the least were Saudi (3.8%). B subtype (75.9%) was more common than T subtype (24.1%). The first remission after treatment was in 66 patients, with a mean of 6.86 years. There was a significant adverse relationship between the ability of patients to reach the first remission and WBC count (p 0.032). There was strong significant negative correlation between absolute lymphocyte count (ALC) and survival duration after treatment (r -0.669 p 0.012). Conclusions The impact regarding age and WBC is almost like most previous studies. ALC shows a strong poor prognosis, while ALL cell subtypes demonstrate a contradictory prognosis effect. |
35,411,095 | JAK3 mutations and mitochondrial apoptosis resistance in T-cell acute lymphoblastic leukemia. | Resistance to mitochondrial apoptosis predicts inferior treatment outcomes in patients with diverse tumor types, including T-cell acute lymphoblastic leukemia (T-ALL). However, the genetic basis for variability in this mitochondrial apoptotic phenotype is poorly understood, preventing its rational therapeutic targeting. Using BH3 profiling and exon sequencing analysis of childhood T-ALL clinical specimens, we found that mitochondrial apoptosis resistance was most strongly associated with activating mutations of JAK3. Mutant JAK3 directly repressed apoptosis in leukemia cells, because its inhibition with mechanistically distinct pharmacologic inhibitors resulted in reversal of mitochondrial apoptotic blockade. Inhibition of JAK3 led to loss of MEK, ERK and BCL2 phosphorylation, and BH3 profiling revealed that JAK3-mutant primary T-ALL patient samples were characterized by a dependence on BCL2. Treatment of JAK3-mutant T-ALL cells with the JAK3 inhibitor tofacitinib in combination with a spectrum of conventional chemotherapeutics revealed synergy with glucocorticoids, in vitro and in vivo. These findings thus provide key insights into the molecular genetics of mitochondrial apoptosis resistance in childhood T-ALL, and a compelling rationale for a clinical trial of JAK3 inhibitors in combination with glucocorticoids for patients with JAK3-mutant T-ALL. |
35,410,925 | Impact of the COVID-19 pandemic on patients with paediatric cancer in low-income, middle-income and high-income countries a multicentre, international, observational cohort study. | Paediatric cancer is a leading cause of death for children. Children in low-income and middle-income countries (LMICs) were four times more likely to die than children in high-income countries (HICs). This study aimed to test the hypothesis that the COVID-19 pandemic had affected the delivery of healthcare services worldwide, and exacerbated the disparity in paediatric cancer outcomes between LMICs and HICs. A multicentre, international, collaborative cohort study. 91 hospitals and cancer centres in 39 countries providing cancer treatment to paediatric patients between March and December 2020. Patients were included if they were under the age of 18 years, and newly diagnosed with or undergoing active cancer treatment for Acute lymphoblastic leukaemia, non-Hodgkins lymphoma, Hodgkin lymphoma, Wilms tumour, sarcoma, retinoblastoma, gliomas, medulloblastomas or neuroblastomas, in keeping with the WHO Global Initiative for Childhood Cancer. All-cause mortality at 30 days and 90 days. 1660 patients were recruited. 219 children had changes to their treatment due to the pandemic. Patients in LMICs were primarily affected (n182219, 83.1%). Relative to patients with paediatric cancer in HICs, patients with paediatric cancer in LMICs had 12.1 (95% CI 2.93 to 50.3) and 7.9 (95% CI 3.2 to 19.7) times the odds of death at 30 days and 90 days, respectively, after presentation during the COVID-19 pandemic (p<0.001). After adjusting for confounders, patients with paediatric cancer in LMICs had 15.6 (95% CI 3.7 to 65.8) times the odds of death at 30 days (p<0.001). The COVID-19 pandemic has affected paediatric oncology service provision. It has disproportionately affected patients in LMICs, highlighting and compounding existing disparities in healthcare systems globally that need addressing urgently. However, many patients with paediatric cancer continued to receive their normal standard of care. This speaks to the adaptability and resilience of healthcare systems and healthcare workers globally. |
35,410,758 | Pretransplant Consolidation Therapies Improve the Outcome of Myeloablative Allogeneic Transplantation in Adults with Ph-negative Acute Lymphoblastic Leukemia. | The benefit of pre-transplant consolidation in patients with acute lymphoblastic leukemia (ALL) who achieved first complete remission (CR1) has not yet been clearly demonstrated. Here, we aimed to investigate the relationship between the treatments received before transplantation and transplant outcome in Ph-ALL patients who underwent myeloablative allo-HSCT in CR1. A total of 55, 32 (58.2%) men and 23 (41.8%) women, who underwent allo-HSCT with the diagnosis of Ph-ALL were evaluated retrospectively. All patients underwent to allo-HSCT with myeloablative conditioning regimen in the 1st CR from the available donor. In patients who received >2 consolidation, the 2-year and 3-year OS was 69% and 65%, respectively, while the 2-year and 3-year OS was 39% and 26%, respectively, in those who received < 2 consolidation (P .03). RFS was similar in both groups (P .8). One year- NRM was found 28% in patients who received ≥ 2 consolidations, and 37% in patients who received <2 consolidation (P .06). L-asparaginase, high dose methotrexate, and cranial treatments given before transplantation had no effect on transplant outcomes (P > .05). Contrary to the belief that pre-transplant consolidation is not beneficial in ALL patients who proceed with allo-HCST in CR1, our results showed that consolidation treatments reduce NRM and improve the survival. |
35,410,757 | SOHO State of the Art Updates and Next Questions Novel Transplant and Post-Transplant Options in Acute Lymphoblastic Leukemia. | Allogeneic hematopoietic cell transplantation (alloHCT) is a potentially curative treatment approach for patients with high-risk acute lymphoblastic leukemia (ALL). Despite development of several novel therapies targeting B-cell ALL, alloHCT continues to play an essential role in management, but the identification of patients who are most likely to benefit from alloHCT in first or subsequent remissions continues to evolve. Broader donor options, including haploidentical donors and umbilical cord blood, have enabled alloHCT for more patients, but improvements in front-line therapy and increasing use of high-sensitivity measurable residual disease (MRD) quantification continue to modify the calculus for selecting which patients require transplantation. MRD quantification has become increasingly important as a prognostic indicator, as well as a trigger for therapeutic intervention, since the achievement of MRD negative complete remission is well-established to be associated with improved transplant outcomes. ALL remains the only malignancy with approved therapy for MRD positivity after achievement of remission, and use of Blinatumomab in this setting currently appears to be most effective when used as a bridge-to-transplant, rather than a destination or purely consolidative therapy. Expanding options for those with relapsedrefractory disease, including chimeric antigen receptor (CAR)-T cells, also render more patient in suitably deep remissions to enable alloHCT with a high likelihood of success. It remains unclear whether CAR-T cell therapies may obviate the need for alloHCT in some patients, and currently available data suggest there remains a role for alloHCT after CAR-T. Together, these therapeutic advances appear to be improving post-transplant outcomes. Nevertheless, more remains to be studied regarding how to optimize use of available and emerging cellular and immune modulating therapies to maximize the likelihood of long-term post-alloHCT remission in high-risk ALL. |
35,410,148 | Humanized CD19 CAR-T cells in relapsedrefractory B-ALL patients who relapsed after or failed murine CD19 CAR-T therapy. | For CD19-positive relapsedrefractory B-cell acute lymphoblastic leukemia (rr B-ALL) after treatment with murine CD19 (mCD19) CAR-T, the reinfusion of mCD19 CAR-T cells may be ineffective due to anti-mouse single-chain variable fragment (scFv) antibody caused by mCD19 CAR. To overcome this immunogenicity, we applied humanized CD19 (hCD19) CAR-T cells to treat rr B-ALL patients with prior mCD19 CAR-T therapy. Nineteen pediatric and adult patients were included, 16 relapsed after and 3 were primarily resistant to mCD19 CAR-T. All patients presented with more than 5% blasts in bone marrow andor extramedullary disease, and still showed CD19 antigen expression. Humanized CD19-CARs were lentiviral vectors carrying a second generation CAR with 4-1-BB co-stimulatory and CD3ζ signaling domains. Patient-derived cells were collected for producing CAR-T cells, the median dose of infused hCD19 CAR-T cells was 2.4 × 10 hCD19 CAR-T resulted in a complete remission (CR) rate of 68% (1319). Among 13 remission patients, 11 underwent allogeneic hematopoietic cell transplantation (allo-HCT) (3 were second HCT) and 10 remained in CR the event-free survival rates at 12-18 months were 91% in 11 patients received following allo-HCT and 69% in all CR patients. Six cases had no response to hCD19 CAR-T, 3 died of disease progression another 3 received salvage second transplantation, of them, 2 relapsed again (one died). Cytokine release syndrome (CRS) occurred in 95% (1819) of patients, most CRS events were grade 1 and grade 2 (n 17), there was only one grade 4 CRS. Two cases experienced grade 1 neurotoxicity. Humanized CD19 CAR-T cell therapy could be a treatment option for CD19-positive B-ALL patients who relapsed after or resisted prior murine CD19 CAR-T, hCD19 CAR-T followed by allo-HCT provided a longer remission in CR patients. Nevertheless, the prognosis of non-responders to hCD19 CAR-T remained dismal. Chinese Clinical Trial RegistryWHO International Clinical Trial Registry ( ChiCTR1900024456 , URL www.chictr.org.cn ) registered on July 12, 2019. |
35,409,391 | Lineage Conversion in Pediatric B-Cell Precursor Acute Leukemia under Blinatumomab Therapy. | We report incidence and deep molecular characteristics of lineage switch in 182 pediatric patients affected by B-cell precursor acute lymphoblastic leukemia (BCP-ALL), who were treated with blinatumomab. We documented six cases of lineage switch that occurred after or during blinatumomab exposure. Therefore, lineage conversion was found in 17.4% of all resistance cases (427) and 3.2% of relapses (263). Half of patients switched completely from BCP-ALL to CD19-negative acute myeloid leukemia, others retained CD19-positive B-blasts and acquired an additional CD19-negative blast population myeloid or unclassifiable. Five patients had |
35,409,272 | Detection of Myosin 1g Overexpression in Pediatric Leukemia by Novel Monoclonal Antibodies. | Myosin 1g (Myo1g) is a mechanoenzyme associated with actin filaments, expressed exclusively in hematopoietic cells, and involved in various cellular functions, including cell migration, adhesion, and membrane trafficking. Despite the importance of Myo1g in distinct functions, there is currently no monoclonal antibody (mAb) against Myo1g. mAbs are helpful tools for the detection of specific antigens in tumor cells and other tissues. The development of mAbs against targeted dysregulated molecules in cancer cells remains a crucial tool for aiding in the diagnosis and the treatment of patients. Using hybridoma technology, we generated a panel of hybridomas specific for Myo1g. ELISA, immunofluorescence, and Western blot assay results revealed the recognition of Myo1g by these novel monoclonal antibodies in normal and transformed T and B cells. Here, we report the development and application of new monoclonal antibodies against Myo1g for their potential use to detect its overexpression in acute lymphoblastic leukemia (ALL) patients. |
35,409,154 | Overcoming Steroid Resistance in Pediatric Acute Lymphoblastic Leukemia-The State-of-the-Art Knowledge and Future Prospects. | Acute lymphoblastic leukemia (ALL) is the most common malignancy among children. Despite the enormous progress in ALL therapy, resulting in achieving a 5-year survival rate of up to 90%, the ambitious goal of reaching a 100% survival rate is still being pursued. A typical ALL treatment includes three phases remission induction and consolidation and maintenance, preceded by a prednisone prephase. Poor prednisone response (PPR) is defined as the presence of ≥1.0 × 10 |
35,409,072 | Biomarkers of Glucose Metabolism Alterations and the Onset of Metabolic Syndrome in Survivors of Childhood Acute Lymphoblastic Leukemia. | Owing to advances in treatment modalities and supportive care, overall survival rates have reached up to 90% among children with acute lymphoblastic leukemia (ALL). However, due to the underlying illness and therapy, they are at a greater risk of developing lifestyle diseases. Hence, special attention is paid to early detection of the components of metabolic syndrome (MetS). This study aimed at investigating the association of plasma levels of nine diabetes markers with being overweight and components of MetS in ALL survivors. The study included 56 subjects with mean age of 12.36 ± 5.15 years. The commercially available Bio-Plex Pro Human Diabetes 10-Plex Panel kit was used to evaluate levels of diabetes biomarkers. ALL survivors presented statistically higher concentrations of GIP (p 0.026), glucagon (p 0.001), leptin (p 0.022), and PAI-1 (p 0.047), whereas the concentration of ghrelin was lower (p < 0.001) compared to the control group. Moreover, subjects within normal BMI range showed higher GIP (p 0.005) and lower ghrelin concentration (p < 0.001) compared to healthy peers. At least one risk factor of MetS was present in 58.9% of participants, who showed significantly higher levels of C-peptide (p 0.028), leptin (p 0.003), and PAI-1 (p 0.034) than survivors who did not meet any MetS criteria. In conclusion, ALL survivors are at greater risk of disturbances in carbohydrate metabolism. Understanding the pathogenesis and applicability of diabetes markers is crucial for developing strategies to prevent metabolic syndrome in ALL survivors. |
35,407,383 | In | Hypofibrinogenemia (HF) in adult acute lymphoblastic leukemia (ALL) of B lineage is uncommon and mostly associated with asparaginase (ASP) delivery. Since we noticed a significant reduction in fibrinogen (FBG) plasma levels even before the first ASP dose, we aim to assess the levels of FBG during induction treatment and explore if the FBG fall correlated with therapies other than asparaginase andor specific leukemia biological features. We retrospectively analyzed FBG levels in 115 patients with B-ALL. In 74 (64%) out of 115 patients FBG decline occurred during the steroid prephase. In univariate analysis, such a steroid-related HF was significantly associated with |
35,406,576 | Treatment of Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia in Adults. | Philadelphia-chromosome positive acute lymphoblastic leukemia (Ph ALL) is the most common subtype of B-ALL in adults and its incidence increases with age. It is characterized by the presence of BCR-ABL oncoprotein that plays a central role in the leukemogenesis of Ph ALL. Ph ALL patients traditionally had dismal prognosis and long-term survivors were only observed among patients who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) in first complete remission (CR1). However, feasibility of allo-HSCT is limited in this elderly population. Fortunately, development of increasingly powerful tyrosine kinase inhibitors (TKIs) from the beginning of the 2000s dramatically improved the prognosis of Ph ALL patients with complete response rates above 90%, deep molecular responses and prolonged survival, altogether with good tolerance. TKIs became the keystone of Ph ALL management and their great efficacy led to develop reduced-intensity chemotherapy backbones. Subsequent introduction of blinatumomab allowed going further with development of chemo free strategies. This review will focus on these amazing recent advances as well as novel therapeutic strategies in adult Ph ALL. |
35,405,782 | Prognostic significance of IKZF1 gene deletions in patients with B-cell acute lymphoblastic leukemia. | null |
35,405,780 | A retrospective comparative study of haplotype hematopoietic stem cell transplantation and human leukocyte antigen-matched sibling donor hematopoietic stem cell transplantation in the treatment of acute B-lymphocyte leukemia. | null |
35,404,534 | How essential are in-person clinic visits during maintenance treatment of children with acute lymphoblastic leukemia | Acute lymphoblastic leukemia (ALL) is the most common cancer in children. Treatment consists of an initial intensive phase of chemotherapy, followed by a prolonged period of maintenance chemotherapy intended to reduce the risk of relapse. During the COVID-19 pandemic, the need arose to identify and reduce non-essential hospital visits. We aimed to determine which proportion of in-person clinic visits during ALL maintenance therapy was associated with a change of management based on the results of the physical examination. Medical records of children receiving maintenance chemotherapy for B-precursor ALL between September 2019 and February 2020 were reviewed. Visits with a new finding on physical examination were divided into those where an in-person assessment was deemed essential versus not essential. Finally, we determined the proportion of essential in-person visits that resulted in a change of management. A total of 240 maintenance visits by 75 children were analyzed. An abnormal finding on physical examination was noted during 20 visits (8.3%). Of those, 14 (5.8%) uncovered a new finding, six (2.5%) were classified as in-person visit essential, and among those six visits, three (1.2%) resulted in a change of patient management (one for acute otitis media, one for wheezing, and one for limp). Our findings support the evaluation of care delivery models other than in-person visits during ALL maintenance therapy. A prospective study is required to delineate criteria, benefitsrisks, and families perspectives associated with virtual care delivery and the optimal frequency of in-person visits. |
35,403,825 | Identification of 4-Anilinoquin(az)oline as a Cell-Active Protein Kinase Novel 3 (PKN3) Inhibitor Chemotype. | Deep annotation of a library of 4-anilinoquin(az)olines led to the identification of 7-iodo-N-(3,4,5-trimethoxyphenyl)quinolin-4-amine 16 as a potent inhibitor (IC |
35,403,813 | Neurocognitive outcomes in survivors of childhood acute lymphoblastic leukemia Experience from a tertiary care center in India. | Data of neurocognitive deficits in survivors of acute lymphoblastic leukemia (ALL) is scarce from low middle-income countries (LMICs), and is influenced by biological and cultural variations. The objective of this study was to assess the prevalence and spectrum of neurocognitive deficits in a cohort of survivors from India. Seventy survivors of childhood ALL were evaluated for neurocognitive deficits by the Indian adaptation of Wechsler Intelligence Scale for Children - Fourth Edition (WISC-IV The mean (SD) current age and time since diagnosis was 10.5 (±3.2) years and 5 (±2.8) years, respectively. The mean FSIQ was 86.1 ± 20.5, with significant neurocognitive deficit (FSIQ <90) being prevalent in 50% (95% CI 38%-62%) of the cohort. The proportion of survivors with deficits in individual domains of verbal comprehension, perceptual reasoning, working memory, and processing speed were 49%, 50%, 47%, and 44%, respectively. The odds of having neurocognitive deficits were higher when a child belonged to lower socioeconomic strata (OR 5.7, p .004), parents with lower education attainment (OR 4.3, p .041), and whose birth order was higher (OR 20.1, p .005). Age at diagnosisassessment, chemotherapy received, or dose of radiotherapy did not have a direct impact on neurocognition. Rates of neurocognitive deficits are higher in survivors in LMICs, with socioeconomic variables contributing more than the direct neurotoxic effects of treatment. |
35,403,603 | Dexamethasone-Induced Sarcopenia and Physical Frailty in Children With Acute Lymphoblastic Leukemia Protocol for a Prospective Cohort Study. | During treatment for pediatric acute lymphoblastic leukemia (ALL), children receive high doses of dexamethasone for its apoptotic effect on leukemia cells however, muscle atrophy is a well-known serious side effect. Muscle atrophy (loss of muscle mass) accompanied by a decreased muscle strength may lead to a generalized impaired skeletal muscle state called sarcopenia. Loss of muscle mass is also an indicator of physical frailty, which is defined as a state of increased vulnerability that is characterized by co-occurrence of low muscle mass, muscle weakness, fatigue, slow walking speed, and low physical activity. Both sarcopenia and physical frailty are related to an increased risk of infections, hospitalizations, and decreased survival in children with chronic diseases. This study aims to (1) estimate the occurrence of sarcopenia and physical frailty in children during ALL maintenance therapy, (2) evaluate the effect of administering dexamethasone, and (3) explore determinants associated with these outcomes. This prospective study is being pursued within the framework of the DexaDays-2 study a randomized controlled trial on neurobehavioral side effects in pediatric patients with ALL. A total of 105 children (3-18 years) undergoing ALL maintenance treatment at the Princess Máxima Center for Pediatric Oncology are included in this study. Sarcopeniafrailty assessments are performed before and just after a 5-day dexamethasone course. A subset of 50 children participating in the DexaDays-2 trial because of severe dexamethasone-induced neurobehavioral problems were assessed at 3 additional timepoints. The sarcopeniafrailty assessment consists of bioimpedance analysis (skeletal muscle mass SMM), handheld dynamometry (handgrip strength), Pediatric Quality of Life Inventory Multidimensional Fatigue Scale (fatigue), Timed Up and Go Test (TUG walking speed), and physical activity questionnaires. To evaluate potential change in sarcopeniafrailty components after a 5-day dexamethasone administration, a paired Student t test or Mann-Whitney U test will be used. Because of the presence of repeated measurements, generalized linear mixed models will be used to estimate the effect of dexamethasone on sarcopenia and frailty outcomes. Multivariable regression models will be estimated to investigate associations between the assessment scores and patient and treatment-related factors. Patient accrual started in 2018 and was finalized in spring 2021. From autumn 2021 onward final data analyses will be performed. This first study combining parameters of sarcopenia and physical frailty is of importance because these conditions can seriously complicate continuation of ALL therapy, independence in physical functioning, reaching motor milestones, and participating in daily life activities. The results will provide knowledge about these complications, the association between dexamethasone treatment and muscle loss and other components of frailty, and therefore insights into the severity of this side effect. By exploring potential determinants that may be associated with sarcopenia and physical frailty, we may be able to identify children at risk at an earlier stage and provide timely interventions. DERR1-10.219633517. |
35,402,840 | MYC in T-cell acute lymphoblastic leukemia functional implications and targeted strategies. | T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological cancer that frequently occurs in children and adolescents, which results from the transformation of immature T-cell progenitors. Aberrant cell growth and proliferation of T-ALL lymphoblasts are sustained by activation of strong oncogenic drivers. Mounting evidence highlights the critical role of the NOTCH1-MYC highway toward the initiation and progression of T-ALL. MYC has been emphasized as a primary NOTCH1 transcriptional target impinging in leukemia-initiating cell activity particularly responsible for disease onset and relapse. These findings lay a foundation of T-ALL as an ideal disease model for studying MYC-mediated cancer. The biology of MYC deregulation in T-ALL supports innovative strategies for therapeutic targeting of MYC. To summarize the relevant literature and data in recent years, we here provide a comprehensive overview of the functional importance of MYC in T-ALL development, and the molecular mechanisms underlying MYC deregulation in T-ALL. Finally, we illustrate the innovative MYC-targeted approaches that have been evaluated in pre-clinical models and shown significant efficacy. Given the complexity of T-ALL molecular pathogenesis, we propose that a combination of anti-MYC strategies with conventional chemotherapies or other targetedimmunotherapies may provide the most durable response, especially for those patients with relapsed and refractory T-ALL. |
35,402,839 | Colony-stimulating factor 3 receptor (CSF3R) M696T mutation does not impact on clinical outcomes of a Ph acute lymphoblastic leukemia patient. | Colony-stimulating factor 3 receptor (CSF3R) mutations have been identified in a variety of myeloid disorders. Although CSF3R point mutations (eg, T618I) are emerging as key players in chronic neutrophilic leukemiaatypical chronic myelogenous leukemia , the significance of rarer CSF3R mutations is unknown. Here, we report a 32-year-old female who was diagnosed as Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph |
35,402,834 | Abnormal bone marrow microenvironment the harbor of acute lymphoblastic leukemia cells. | Bone marrow (BM) microenvironment regulates and supports the production of blood cells which are necessary to maintain homeostasis. In analogy to normal hematopoiesis, leukemogenesis is originated from leukemic stem cells (LSCs) which gives rise to more differentiated malignant cells. Leukemia cells occupy BM niches and reconstruct them to support leukemogenesis. The abnormal BM niches are the main sanctuary of LSCs where they can evade chemotherapy-induced death and acquire drug resistance. In this review, we focus on the protective effects of BM niche cells on acute lymphoblastic leukemia cells. |
35,402,448 | A Study Protocol for Validation and Implementation of Whole-Genome and -Transcriptome Sequencing as a Comprehensive Precision Diagnostic Test in Acute Leukemias. | Whole-genome sequencing (WGS) and whole-transcriptome sequencing (WTS), with the ability to provide comprehensive genomic information, have become the focal point of research interest as novel techniques that can support precision diagnostics in routine clinical care of patients with various cancer types, including hematological malignancies. This national multi-center study, led by Genomic Medicine Sweden, aims to evaluate whether combined application of WGS and WTS (WGTS) is technically feasible and can be implemented as an efficient diagnostic tool in patients with acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). In addition to clinical impact assessment, a health-economic evaluation of such strategy will be performed. The study comprises four phases (i.e., retrospective, prospective, real-time validation, and follow-up) including approximately 700 adult and pediatric Swedish AML and ALL patients. Results of WGS for tumor (90×) and normalgermline (30×) samples as well as WTS for tumors only will be compared to current standard of care diagnostics. Primary study endpoints are diagnostic efficiency and improved diagnostic yield. Secondary endpoints are technical and clinical feasibility for routine implementation, clinical utility, and health-economic impact. Data from this national multi-center study will be used to evaluate clinical performance of the integrated WGTS diagnostic workflow compared with standard of care. The study will also elucidate clinical and health-economic impacts of a combined WGTS strategy when implemented in routine clinical care. httpsdoi.org10.1186ISRCTN66987142, identifier ISRCTN66987142. |
35,402,356 | Is It Possible to Separate the Graft-Versus-Leukemia (GVL) Effect Against B Cell Acute Lymphoblastic Leukemia From Graft-Versus-Host Disease (GVHD) After Hematopoietic Cell Transplant | Hematopoietic cell transplant is a curative therapy for many pediatric patients with high risk acute lymphoblastic leukemia. Its therapeutic mechanism is primarily based on the generation of an alloreactive graft-versus-leukemia effect that can eliminate residual leukemia cells thus preventing relapse. However its efficacy is diminished by the concurrent emergence of harmful graft-versus-host disease disease which affects healthly tissue leading to significant morbidity and mortality. The purpose of this review is to describe the interventions that have been trialed in order to augment the beneficial graft-versus leukemia effect post-hematopoietic cell transplant while limiting the harmful consequences of graft-versus-host disease. This includes many emerging and promising strategies such as |
35,402,256 | Repeated Lineage Switches in an Elderly Case of Refractory B-Cell Acute Lymphoblastic Leukemia With | Lineage switches in acute leukemia occur rarely, and the underlying mechanisms are poorly understood. Herein, we report the case of an elderly patient with leukemia in which the leukemia started as B-cell acute lymphoblastic leukemia (B-ALL) and later changed to B- and T-cell mixed phenotype acute leukemia (MPAL) and acute myeloid leukemia (AML) during consecutive induction chemotherapy treatments. A 65-year-old woman was initially diagnosed with Philadelphia chromosome-negative B-ALL primarily expressing TdTCD34HLA-DR more than 20% of the blasts were positive for CD19CD20cytoplasmic CD79acytoplasmic CD22CD13CD71.The blasts were negative for T-lineage markers and myeloperoxidase (MPO). Induction chemotherapy with the standard regimen for B-ALL resulted in primary induction failure. After the second induction chemotherapy regimen, the blasts were found to be BT bi-phenotypic with additional expression of cytoplasmic CD3. A single course of clofarabine (the fourth induction chemotherapy regimen) dramatically reduced lymphoid marker levels. However, the myeloid markers (e.g., MPO) eventually showed positivity and the leukemia completely changed its lineage to AML. Despite subsequent intensive chemotherapy regimens designed for AML, the patients leukemia was uncontrollable and a new monoblastic population emerged. The patient died approximately 8 months after the initial diagnosis without experiencing stable remission. Several cytogenetic and genetic features were commonly identified in the initial diagnostic B-ALL and in the following AML, suggesting that this case should be classified as lineage switching leukemia rather than multiple simultaneous cancers (i.e., |
35,402,186 | High cystic fibrosis transmembrane conductance regulator expression in childhood B-cell acute lymphoblastic leukemia acts as a potential therapeutic target. | The role of cystic fibrosis transmembrane conductance regulator We continued to collect the peripheral blood and bone marrows of human childhood patients diagnosed with primary B-ALL as well as non-leukemia controls and isolated lymphocytes for analysis using western blotting and quantitative real-time polymerase chain reaction (qPCR) assay. Then, we used immunofluorescence, co-immunoprecipitation, western blotting, luciferase, 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di-phenytetrazoliumromide (MTT) assays to identify the interaction of CFTR with Wnt signaling in B-ALL. Finally, we established B-ALL xenograft model in non-obese diabeticsevere combined immunodeficiency (NODSCID) mice using SUP-B15 cells, and examined whether the CFTR inhibitor CFTR-inh172 could active against SUP-B15-Dependent B-ALL Highly expressed CFTR protein and mRNA are associated with primary childhood B-ALL patients. Aberrantly upregulated CFTR and Wnt signaling, our previously reported CFTR-Dvl2-β-catenin pathway, is found in human childhood B-ALL patients. Interference with CFTR in B-ALL cell lines induces the downregulation of DVL2β-catenin and Wnt downstream target accompanied by a reduction of cell proliferation. Furthermore, B-ALL cell lines SUP-B15 cell-transplanted NODSCID mice treated with CFTR inhibitor CFTRinh-172 had significantly longer survival and slower leukemia progression compared with mice treated with vehicle dimethyl sulfoxide (DMSO). These findings demonstrate that highly expressed CFTR is associated with human childhood B-ALL and the potential of CFTR inhibitor CFTR-inh172 for the treatment of human B-ALL. |
35,401,878 | Soluble Sema4D Level Is Positively Correlated with Sema4D Expression in PBMCs and Peripheral Blast Number in Acute Leukemia. | Semaphorin 4D (Sema4D) is highly expressed in various cancers and leukemia. It is involved in the development of acute leukemia. A high level of soluble Sema4D is also present in the plasma of acute leukemia patients. However, it remains unknown whether Sema4D is associated with the clinical characteristics of acute leukemia. In this study, Sema4D expression was examined in peripheral blood mononuclear cells (PBMCs) and bone marrow mononuclear cells (BMMCs) of patients with acute leukemia, and it was highly expressed in the PBMCs of B-acute lymphoblastic leukemia (ALL), T-ALL, and acute myeloid leukemia (AML) patients and in the BMMCs of B-ALL and AML patients but not in the BMMCs of T-ALL patients. Sema4D expression was higher in the PBMCs of T-ALL patients than in the PBMCs of B-ALL or AML patients. In addition, Sema4D expression in BMMCs was reduced in B-ALL patients during the chemotherapy process. It was lower in remission patients than in newly diagnosed and patients without remission. In acute leukemia, soluble Sema4D level in serum is positively correlated with Sema4D expression in PBMCs, leukocyte number, and peripheral blast number. Those results suggest that the levels of Sema4D and its soluble form are associated with acute leukemia development and may be regarded as a potential biomarker in pediatric acute leukemia. |
35,401,837 | Endothelial PERK-ATF4-JAG1 axis activated by T-ALL remodels bone marrow vascular niche. | The endoplasmic reticulum unfolded protein response (UPR) is a conserved adaptive signaling in ER homeostasis and has emerged as critical in highly proliferating cells and potential treatment target for acute T-cell lymphoblastic leukemia (T-ALL). |
35,401,501 | Monoallelic | Early T-cell development is precisely controlled by E proteins, that indistinguishably include HEBTCF12 and E2ATCF3 transcription factors, together with NOTCH1 and pre-T cell receptor (TCR) signalling. Importantly, perturbations of early T-cell regulatory networks are implicated in leukemogenesis. NOTCH1 gain of function mutations invariably lead to T-cell acute lymphoblastic leukemia (T-ALL), whereas inhibition of E proteins accelerates leukemogenesis. Thus, NOTCH1, pre-TCR, E2A and HEB functions are intertwined, but how these pathways contribute individually or synergistically to leukemogenesis remain to be documented. To directly address these questions, we leveraged |
35,400,665 | Survival and prognostic analysis of T-cell lymphoblastic lymphoma patients treated with dose-adjusted BFM-90 regimen. | We aimed to investigate the long-term prognosis and prognostic factors of T-cell lymphoblastic lymphoma (T-LBL) patients who received dose-adjusted Berlin-Frankfurt-Münster (BFM)-90 regimen as first-line therapy in our center. A total of 145 T-LBL patients who underwent first-line dose-adjusted BFM-90 was retrospectively reviewed. Conditional survival analysis was used to evaluate the long-term prognosis of patients. Receiver operating characteristic (ROC) curve was applied to determine the optimal cut-off value for neutrophil-to-lymphocyte ratio (NLR). Estimated 3-year overall survival (OS) and progression-free survival (PFS) rates for overall were 66.8% and 58.4%, respectively. Conditional survival analysis showed that for patients having survived 3 and 5 years or more after the completion of the treatment, the estimated subsequent 3-year OS thereafter increased to 85.7% and 94.3, respectively. Patients receiving consolidation APBSCT (Autologous peripheral blood stem cell transplantation) after BFM-90 regimen had superior 3-year OS than those with non-APBSCT (79.1% |
35,400,363 | Prognostic Value of Average Daily Platelet Increase in Childhood B-cell Acute Lymphoblastic Leukemia Patients. | To evaluate the prognosis value of average daily platelet amount increase in children with B-cell acute lymphoblastic leukemia(B-ALL) treated by CCCG-ALL-2015 regimen. 106 children with primary B-ALL were retrospective analyzed, standardized MRD test protocol was used to detect the MRD level (19 d and 46 d) after chemotherapy. The platelet count was measured by Sysmex XE-2100. Kaplan-Meier survival curve statistics was used to analyze the event free survival(EFS) rate of the children. The trend of negative correlation existed between PPC and TPR (r Ap can reflect the effect of B-ALL chemotherapy and can be used to monitor the curative effect and prognosis of B-ALL children. 定量检测平均每日血小板增长量在B细胞急性淋巴细胞白血病患儿中的预后价值. 评价平均每日血小板增长量(average daily platelet amount increase, Ap)在 CCCG-ALL-2015 方案治疗的B细胞急性淋巴细胞白血病（B-ALL）患儿预后中的价值. 回顾性分析106例初发B-ALL患儿，标准化MRD检测方案检测化疗后d 19与d 46 MRD水平，Sysmex XE-2100检测血小板计数，Kaplan-Meier生存曲线分析患儿的无事件生存(EFS）率. 相关性分析显示PPC和TPR呈负相关（r Ap增生可反映B-ALL化疗效果，可用于B-ALL患儿疗效及预后的监测. |
35,400,361 | Effect of Hypoxia Inducible Factor-1α on Chemosensitivity of B-ALL Cells to Vincristine and Its Mechanism. | To explore the effect of hypoxia on the chemosensitivity of B-acute lymphoblastic leukemia （B-ALL） cells to Vincristine (VCR) and the mechanisms. B-ALL cells SUP-B15, Nalm-6 and RS411 were selected as the research objects. The cells were divided into the control group and the hypoxia mimic group (CoCl CoCl Under hypoxic conditions, HIF-1α may mediate VCR resistance in B-ALL cells by downregulating the pro-apoptotic protein BAX. 低氧诱导因子-1α对B-ALL细胞长春新碱敏感性的影响及机制研究. 研究低氧条件下急性B淋巴细胞白血病（B-ALL）细胞对长春新碱（VCR）敏感性的影响及可能的作用机制. 以B-ALL细胞SUP-B15、Nalm-6及RS411为研究对象，将细胞分为对照和低氧模拟组（CoCl CoCl 低氧条件下HIF-1α可能通过下调促凋亡蛋白BAX表达导致B-ALL细胞对VCR耐药. |
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