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36,897,378 | Significance of CEBPE Gene Promoter Polymorphism (Rs2239630 G > A) Assessment in Childhood B-cell Acute Lymphoblastic Leukemia. | A significant association has been reported between CEBPE gene promoter polymorphisms (rs2239630 G > A) and the incidence of B-cell acute lymphoblastic leukemia (B-ALL). However, no previous study on this issue has been included among the Egyptian cohort of pediatric patients with B-ALL. Therefore, this study was designed to address the associations between CEBPE polymorphisms and susceptibility to B-ALL, as well as its impact on the outcome of B-ALL Egyptian patients with B-ALL. In the current study, we evaluated the rs2239630 polymorphism in 225 pediatric patients and 228 controls to assess the association of different rs2239630 genotypes with childhood susceptibility to B-ALL and the impact on the outcome of the patients. The frequency of the A allele was significantly higher in the cases of B-ALL compared with the control group (P 0.004). By analyzing different genotypes for the predictive value of disease development, the GA and AA genotypes have been identified to be the highest among multivariate factors with an odds ratio of 3.330 (95% CI 1.105-10.035). Likewise, the A allele was significantly associated with the shortest overall survival. CEBPE gene promoter polymorphism (rs2239630 G > A) AA is frequently associated with B-ALL and has the worst overall survival among the 3 genotypes, followed by the GA and GG genotypes (P < 0.001). |
36,897,339 | Polo-like kinase 1 Decrease During Induction Therapy Could Indicate Good Treatment Response, Favorable Risk Stratification, and Prolonged Survival in Pediatric Acute Lymphoblastic Leukemia. | Polo-like kinase 1 (PLK1) modulates leukemia cell apoptosis, proliferation, and cell cycle arrest in the progression of acute lymphoblastic leukemia (ALL). This study intended to investigate the dysregulation of PLK1 and its association with induction therapy response and prognosis in pediatric ALL patients. Bone marrow mononuclear cell samples were collected from 90 pediatric ALL patients at baseline and on the 15th day of induction therapy (D15), as well as from 20 controls after enrollment, for the detection of PLK1 by reverse transcription-quantitative polymerase chain reaction. PLK1 was increased in pediatric ALL patients compared with controls (P<0.001). In pediatric ALL patients, PLK1 decreased from baseline to D15 (P<0.001). Lower PLK1 at baseline was associated with a good prednisone response (P0.002), while decreased PLK1 at D15 was related to good prednisone response (P0.001), better bone marrow response (P0.025), and favorable risk stratification (P0.014). In addition, reduced PLK1 at baseline was linked with better event-free survival (EFS) (P0.046), and decreased PLK1 at D15 was related to prolonged EFS (P0.027) and overall survival (OS) (P0.047). Moreover, PLK1 decline ≥25% was linked to favorable EFS (P0.015) and OS (P0.008). Further multivariate Cox proportional regression analysis revealed that PLK1 decline ≥25% was independently linked with prolonged EFS (hazard ratio (HR)0.324, P0.024) and OS (HR0.211, P0.019). The reduction of PLK1 after induction therapy reflects a good treatment response and correlates with a favorable survival profile in pediatric ALL patients. |
36,897,251 | Anti-CD19 CAR T-Cell consolidation therapy combined with CD19 feeding T cells and TKI for Ph acute lymphoblastic leukemia. | We conducted a single-arm, open-label, single-center phase I study (Clinicaltrials.gov NCT03984968) to assess the safety and efficacy of multicycle-sequential anti-CD19 CAR T-cell therapy in combination with autologous CD19 feeding T cells (FTCs) and TKI as consolidation therapy in patients under the age of 65 years with de novo Ph-positive CD19 B-ALL who are not eligible for allo-HSCT. Participants were given induction chemotherapy as well as systemic chemotherapy with TKI. Afterward, they received a single cycle of CD19 CAR T-cell infusion and another three cycles of CD19 CAR T-cell and CD19 FTC infusions, followed by TKI as consolidation therapy. CD19 FTCs were given at three different doses (2×106kg, 3.25×106kg, and 5×106kg). The phase I results of the first 15 patients, including 2 withdrawals, are presented. Phase II research is still ongoing. The most common adverse events were cytopenia (1313) and hypogammaglobinemia (1213). There were no CRS above grade 2 or ICANS, or grade 4 nonhematologic toxicities. All 13 patients achieved CR, including 12 patients with CMR at the data cutoff on Mar 31, 2022. The RFS was 84% (95% CI, 66%-100%), and the OS was 83% (95% CI, 58%-100%) with a median follow-up of 27 months (7-57 months). The total number of CD19-expressing cells decreased with an increasing CMR rate. CD19 CAR T cells survived for up to 40 months, whereas CD19 FTCs vanished in 8 patients 3 months after the last infusion. These findings merit further evaluation and could form the basis for the development of an allo-HSCT-free consolidation paradigm. |
36,897,249 | Opposing Effects of KDM6A and JDP2 on Glucocorticoid Sensitivity in T-ALL. | Glucocorticoids (GCs) are a cornerstone of acute lymphoblastic leukemia (ALL) therapy. While mutations in NR3C1, which encodes the GC receptor (GR), and other genes involved in GC signaling occur at relapse, additional mechanisms of adaptive GC resistance are uncertain. We transplanted and treated ten primary mouse T-lineage acute lymphoblastic leukemias (T-ALLs) initiated by retroviral insertional mutagenesis with the GC dexamethasone (DEX). Multiple, distinct relapsed clones from one such leukemia (T-ALL 8633) exhibited discrete retroviral integrations that up-regulated Jdp2 expression. This leukemia harbored a Kdm6a mutation. In the human T-ALL cell line CCRF-CEM, enforced JDP2 over-expression conferred GC resistance, while KDM6A inactivation unexpectedly enhanced GC sensitivity. In the context of KDM6A knock-out, JDP2 over-expression induced profound GC resistance, counteracting the sensitization conferred by KDM6A loss. These resistant double mutant cells with combined KDM6A loss and JDP2 over-expression exhibited decreased NR3C1 mRNA and GR protein up-regulation upon DEX exposure. Analysis of paired samples from two KDM6A-mutant T-ALL patients in a relapsed pediatric ALL cohort revealed a somatic NR3C1 mutation at relapse in one and markedly elevated JDP2 expression in another. Together, these data implicate JDP2 over-expression as a mechanism of adaptive GC resistance in T-ALL that functionally interacts with KDM6A inactivation. |
36,895,914 | Superior survival outcome of blinatumomab compared with conventional chemotherapy for adult patients with relapsed or refractory B-cell precursor acute lymphoblastic leukemia a propensity score-matched cohort analysis. | Blinatumomab showed a higher complete remission (CR) rate and a safe bridging to allogeneic hematopoietic cell transplantation (allo-HCT) in adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (RR BCP-ALL). We tried to analyze the outcome of blinatumomab compared with the real-world historical data. We expected superior outcome of blinatumomab compared with historical conventional chemotherapy. We conducted a retrospective study using real-world data in the Catholic Hematology Hospital. Total 197 consecutive cases of RR BCP-ALL were treated with conventional chemotherapy ( Each cohort consisted of 52 patients. In blinatumomab group, CR rate was higher (80.8% Matched cohort analysis showed superior outcomes of blinatumomab compared with conventional chemotherapy. However, large numbers of relapses and non-relapse mortalities continue to occur even after blinatumomab followed by allo-HCT. Novel therapeutic strategies are still needed for RR BCP-ALL. |
36,895,789 | Requirement for ER-mitochondria Ca | Acute lymphoblastic leukemia (aLL) is a malignant cancer in the blood and bone marrow characterized by rapid expansion of lymphoblasts. It is a common pediatric cancer and the principal basis of cancer death in children. Previously, we reported that L-asparaginase, a key component of acute lymphoblastic leukemia chemotherapy, causes IP3R-mediated ER Ca |
36,895,294 | Clofarabine in Pediatric Acute Relapsed or Refractory Leukemia Where Do We Stand on the Bridge to Hematopoietic Stem Cell Transplantation | Despite pronounced improvement in overall survival (OS) in pediatric leukemia, a proportion of patients continue to suffer from lack of response or relapse, and the management of such patients is exceedingly difficult. Immunotherapy and engineered chimeric antigen receptor (CAR) T-cell therapy have shown promising results in the course of relapsed or refractory acute lymphoblastic leukemia (ALL). However, conventional chemotherapy continues to be utilized for re-induction purposes whether independently or in combination with immunotherapy. Forty-three pediatric leukemia patients (age < 14 years at diagnosis) consecutively diagnosed at our institution and got treated with clofarabine based regimen at a single tertiary care hospital between January 2005 and December 2019 were enrolled in this study. ALL comprised of 30 (69.8%) patients of the cohort while the remaining 13 (30.2%) were with acute myeloid leukemia (AML). Post-clofarabine bone marrow (BM) was negative in 18 (45.0%) cases. Overall clofarabine failure rate was 58.1% (n 25) with 60.0% (n 18) in ALL and 53.8% (n 7) in AML (P 0.747). Eighteen (41.9%) patients eventually underwent hematopoietic stem cell transplantation (HSCT) 11 (61.1%) were from ALL group and remaining seven (38.9%) were AML (P 0.332). Three- and 5-year OS of our patients was 37.7±7.6% and 32.7±7.3%. There was a trend of better OS for ALL patients compared to AML (40.9±9.3% vs. 15.4±10.0%, P 0.492). Cumulative probability of 5-year OS was significantly better in transplanted patients (48.1±12.1% vs. 21.4±8.4%, P 0.024). Though almost 90% of our patients proceeded to HSCT with complete response post-clofarabine treatment, yet clofarabine-based regimens are associated with the significant burden of infectious complications and sepsis-related deaths. |
36,895,126 | A hospital-based oral health education program impacts in pediatric cancer patients-A pilot study. | To assess the impact of an oral health education and preventive program (OHEPP) for pediatric cancer patients. This was a single-arm study with 27 children and adolescents undergoing antineoplastic treatments. Patients were followed up for 10 weeks, and their oral health conditions were evaluated using the Modified Gingival Index (MGI), Visible Plaque Index (VPI), and the modified Oral Assessment Guide (OAG). Audiovisual resources, storytelling, and ludic instruments were used to provide oral health education to patients and parentscaregivers. The patients mean age was 9.41 (±4.49) years, and acute lymphoblastic leukemia was the most prevalent diagnosis (22.2%). Mean MGI and VPI values were 0.82 (±0.59) and 54.11% (±19.92%) at baseline and 0.33 (±0.29) and 19.83% (± 11.47%) after 10 weeks, respectively (p < .05). The mean OAG score was 9.51 (±2.54) and 36 cases (19.8%) of severe oral mucositis (SOM) were documented. Patients with higher MGI were more likely to develop SOM. The OHEPP had a positive impact on pediatric patients undergoing cancer therapy by improving their periodontal health, reducing biofilm accumulation, and preventing the development of OM lesions. |
36,894,417 | Secondary acute lymphoblasticlymphocytic leukemia - done playing second fiddle | Acute lymphoblasticlymphocytic leukemia (ALL) occurring post-cancer diagnosis (secondary ALL - sALL) is increasingly recognized as a discrete entity, constituting up to as much as 5-10% of all new ALL diagnoses, and carrying its own biologic, prognostic and therapeutic significance. In this review, we will outline the history and current state of research into sALL. We will explore the evidence for differences underlining its existence as a distinct subgroup, as well as examining what might be driving such differences etiologically, including prior chemotherapy. We will examine these distinctions on population-, chromosomal-, and molecular-levels, and we will consider whether they translate to differences in clinical outcome, and whether they do - or should - warrant differences in treatment selection. |
36,892,593 | PH negative acute lymphoblastic leukemia in adolescents and young adults treated according a MRD adapted BFM ALL IC 2009 protocol Argentine real-world data on 171 patients. | Intensified pediatric chemotherapy regimens to treat adolescents and young adults (AYA) patients with Philadelphia negative acute lymphoblastic leukemia (ALL) have been associated with better outcomes. The local BFM 2009-based scheme complements the risk stratification assessing the measurable residual disease (MRD) along the induction phase with increasing levels of sensitivity. The present retrospective multicenter analysis included 171 AYA (15-40 years) patients treated accordingly between 2013 and 2019. Ninety-one percent obtained morphological complete remission, 67% a negative (<0.1%) MRD at day 33 (TP1), and 78% a negative (<0.01%) MRD at day 78 (TP2). The overall survival (OS) and the event-free survival (EFS) at 2 years were 62%±4.1 and 55%±4.1, respectively. The OS and EFS were significant better for prednisone responders, who achieved <10% BM blast at day 15, a negative MRD at TP1 or at TP2, and for low-risk patients. Age ≤30 years and WBC <30×10 |
36,892,134 | Comparison of flowcytometry-based scoring system for the diagnosis of early T precursor-acute lymphoblastic leukemia. | Early T cell precursor-acute lymphoblastic leukemia (ETP-ALL) is a hematolymphoid malignancy where the blasts demonstrate T cell differentiation markers along with stem cell and myeloid antigen expression. The differential diagnosis of ETP-ALL from non-ETP ALL and mixed phenotype acute leukemia is often challenging due to its overlapping immunophenotypic picture with co-expression of myeloid antigens. In this study, we endeavored to describe the immune-phenotype profile of ETP-ALL in our patients and compared the utility of four different scoring systems for better discrimination of these entities. This retrospective analysis included 31 ETP-ALL out of 860 acute leukemia cases consecutively diagnosed at the two tertiary care centers. Flowcytometry-based immunophenotype was reviewed for all the cases, and the utility of four flow-based objective scorings was assessed for the diagnosis of ETP-ALL. Receiver operating curves were drawn to compare the different flow-based scoring systems. The prevalence of ETP-ALL was 40% (n 3177 T-ALL) in our study group, comprised mainly of adults with a median age of 20 years. The five-marker scoring system had the maximum area under the curve, followed by the seven-marker scoring system. A cut-off of ≥2.5 was more specific (sensitivity 91% specificity 100%), while a score of ≥1.5 was more sensitive but slightly less specific (sensitivity 94%, specificity 96%). The WHO criteria for the diagnosis of ETP-ALL should be followed across all laboratories to avoid confusion and for better treatment stratification. Flow-based scoring systems can be objectively employed for better detection of cases. |
36,891,758 | Impact of asparaginase discontinuation on outcomes of children with acute lymphoblastic leukaemia receiving the Japan Association of Childhood Leukaemia Study ALL-02 protocol. | Asparaginase is an essential drug for acute lymphoblastic leukaemia (ALL) treatment, but has several side effects, and its discontinuation often compromises patient outcomes. In the prospective Japan Association of Childhood Leukaemia Study ALL-02 protocol, two major changes were made (1) additional chemotherapies to compensate for the reduction of treatment intensity when asparaginase was discontinued and (2) more intensive concomitant corticosteroid administration, relative to our previous ALL-97 protocol. In ALL-02 study, 1192 patients were included and L-asparaginase was discontinued for 88 (7.4%). Discontinuation due to allergy was markedly decreased relative to the ALL-97 protocol (2.3% vs 15.4%). Event-free survival (EFS) among patients with T-ALL was compromised when L-asparaginase was discontinued, as well as among patients with high-risk B-cell ALL, especially when discontinued before maintenance therapy. Moreover, multivariate analysis identified discontinuation of L-asparaginase as an independent poor prognostic factor for EFS. In the current study, additional chemotherapies failed to fully compensate for L-asparaginase discontinuation, illustrating the difficulty of replacing asparaginase with other classes of drugs, although this study was not designed to evaluate the effect of these modifications. Concomitant intensive corticosteroid treatment may help to reduce allergy to asparaginase. These results will assist in further optimization of asparaginase use. |
36,891,751 | Impact of central nervous system involvement in adult patients with Philadelphia-negative acute lymphoblastic leukemia a GRAALL-2005 study. | Whereas the prognosis of adult patients with Philadelphia-negative acute lymphoblastic leukemia (ALL) has greatly improved since the advent of pediatric-inspired regimens, the impact of initial central nervous system (CNS) involvement has not been formerly reevaluated. We report herein the outcome of patients with initial CNS involvement included in the pediatric-inspired prospective randomized GRAALL-2005 study. Between 2006 and 2014, 784 adult patients (18-59 years old) with newly diagnosed Philadelphia-negative ALL were included of whom 55 (7%) had CNS involvement. In CNS-positive patients, overall survival was shorter (median 1.9 years vs. not reached, HR1.8 1.3-2.6, P. |
36,891,734 | The oncogenetic landscape and clinical impact of | Not available. |
36,891,576 | Management of adverse events in young adults and children with acute B-cell lymphoblastic leukemia receiving anti-CD19 chimeric antigen receptor (CAR) T-cell therapy. | With impressive clinical advancements in immune effector cell therapies targeting CD19, chimeric antigen receptor (CAR) T-cell therapy has emerged as a new paradigm for treating relapsedrefractory B-cell malignancies. Currently, three second-generation CAR T-cell therapies have been approved, of which only tisagenlecleucel (tisa-cel) is approved for treating children and young adults with B-cell acute lymphoblastic leukemia (ALL) with durable remission rates of approximately 60-90%. Although CAR T-cell therapies are considered to treat refractory B-ALL, they are associated with unique toxicities such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). The severity of CAR T-cell therapy toxicities can vary according to several clinical factors. In rare cases, severe CRS can progress to a fulminant hyperinflammatory syndrome known as hemophagocytic lymphohistiocytosis, which has a poor prognosis. The first-line treatments for CRSICANS include tocilizumab and corticosteroids. When severe CAR T-cell toxicity is resistant to first-line treatment, an additional approach is required to manage the persistent inflammation. In addition to CRSICANS, CAR T-cell therapy can cause early and delayed hematological toxicity, which can predispose patients to severe infections. The use of growth factors and anti-infective prophylaxis should follow institutional guidelines according to patient-specific risk factors. This review provides a thorough summary of updated practical recommendations for managing acute and delayed adverse effects following anti-CD19 CAR T-cell therapy in adults and children. |
36,891,042 | Effect of serum albumin level on high-dose methotrexate induced toxicities in acute lymphoblastic leukemia patients. | Methotrexate (MTX) is a key therapeutic agent for leukemias. When given in high doses, leucovorin rescue is added to reduce its toxicity. It has been postulated that low albumin levels are associated with delayed clearance and increased toxicity of MTX. Hence, this prospective cohort study was proposed to evaluate the correlation between serum albumin level and HDMTX toxicity in acute lymphocytic leukemia (ALL) patients and to compare the MTX toxicity in hypo and normoalbuminemic patients. Forty-six ALL patients of either gender aged 2-40 years receiving HDMTX for 1 There was a negligible correlation between cumulative albumin levels of all four cycles and cumulative toxic events. The median toxic events were 19 (16-23). The Spearmen correlation coefficient ρ was 0.055 ( There was negligible correlation between albumin levels and MTX toxicity despite delayed clearance supporting the safety of MTX in mildly hypoabuminemic patients. |
36,890,697 | Melatonin protects against methotrexate hepatotoxicity in young rats Impact of PI3KAktmTOR signaling. | With the improvement in childrens acute lymphoblastic leukemia (ALL) care, the survival rate in children ALL has improved much. Methotrexate (MTX) plays an essential role in the success of childrens ALL treatment. Since hepatotoxicity is commonly reported in individuals treated with intravenous or oral MTX, our study further examined the hepatic effect following intrathecal MTX treatment, which is an essential treatment for leukemia patients. Specifically, we examined the pathogenesis of MTX hepatotoxicity in young rats and explored the impact of melatonin treatment in protection against MTX hepatotoxicity. Successfully, we found that melatonin was able to protect against MTX hepatotoxicity. |
36,882,724 | A case of SARS-CoV-2 Omicron reinfection resulting in a significant immunity boost in a paediatric patient affected by B-cell acute lymphoblastic leukemia. | Since its emergence in November 2021, SARS-CoV-2 Omicron clade has quickly become dominant, due to its increased transmissibility and immune evasion. Different sublineages are currently circulating, which differ in mutations and deletions in regions of the SARS-CoV-2 genome implicated in the immune response. In May 2022, BA.1 and BA.2 were the most prevalent sublineages in Europe, both characterized by ability of evading natural acquired and vaccine-induced immunity and of escaping monoclonal antibodies neutralization. A 5-years old male affected by B-cell acute lymphoblastic leukemia in reinduction was tested positive for SARS-CoV-2 by RT-PCR at the Bambino Gesù Children Hospital in Rome in December 2021. He experienced a mild COVID-19 manifestation, and a peak of nasopharyngeal viral load corresponding to 15.5 Ct. Whole genome sequencing identified the clade 21 K (Omicron), sublineage BA.1.1. The patient was monitored over time and tested negative for SARS-CoV-2 after 30 days. Anti-S antibodies were detected positive with modest titre (3.86 BAUmL), while anti-N antibodies were negative. 74 days after the onset of the first infection and 23 days after the last negative test, the patient was readmitted to hospital with fever, and tested positive for SARS-CoV-2 by RT-PCR (peak of viral load corresponding to 23.3 Ct). Again, he experienced a mild COVID-19. Whole genome sequencing revealed an infection with the Omicron lineage BA.2 (21L clade). Sotrovimab administration was started at the fifth day of positivity, and RT-PCR negativity occurred 10 days later. Surveillance SARS-CoV-2 RT-PCR were persistently negative, and in May 2022, anti-N antibodies were found positive and anti-S antibodies reached titres > 5000 BAUmL. By this clinical case, we showed that SARS-CoV-2 reinfection within the Omicron clade can occur and can be correlated to inadequate immune responses to primary infection. We also showed that the infections length was shorter in the second respect to first episode, suggesting that pre-existing T cell-mediated immunity, though not preventing re-infection, might have limited the SARS-CoV-2 replication capacity. Lastly, Sotrovimab treatment retained activity against BA.2, probably accelerating the viral clearance in the second infectious episode, after which seroconversion and increase of anti-S antibodies titres were observed. |
36,882,529 | Glymphatic system dysfunction in pediatric acute lymphoblastic leukemia without clinically diagnosed central nervous system infiltration a novel DTI-ALPS method. | Central nervous system (CNS) infiltration commonly occurs in children with acute lymphoblastic leukemia (ALL). Nevertheless, CNS infiltration is rarely detected at the initial diagnosis. The glymphatic system, which regulates cerebrospinal fluid (CSF) and interstitial fluid transport, is considered one of the possible routes of CNS infiltration by leukemia cells. In this study, we used diffusion tensor image analysis along the perivascular space (DTI-ALPS) method to investigate glymphatic system function and obtained CSF volume using synthetic magnetic resonance imaging (SyMRI) in pediatric ALL without clinically diagnosed CNS infiltration. Twenty-nine ALL and 29 typically developing (TD) children were prospectively recruited (age 4-16 years) in the present study. Group differences in brain volumetric parameters, brain water diffusivities, and the ALPS index were evaluated after controlling for age, gender, and handedness. Furthermore, significant group-different parameters were correlated with clinical information using partial correlations analysis. Lower Dxassoc and ALPS index, and increased CSF volume were found in pediatric ALL (all p Dysfunction of the glymphatic system and accumulation of CSF were presented in pediatric ALL without clinically diagnosed CNS infiltration. These novel findings suggested that the glymphatic system might be essential in the early-stage process of ALL CNS infiltration, which provides a new direction for exploring underlying mechanisms and early detection of pediatric ALL CNS infiltration. • Lower Dxassoc and ALPS index, and increased CSF volume were found in pediatric ALL (all p |
36,882,308 | Chemotherapy with the use of next-generation TKIs based on MRD has the potential to avoid hematopoietic stem cell transplantation in treatment for adults with Philadelphia chromosome-positive acute lymphoblastic leukemia. | Allogeneic hematopoietic stem cell transplantation (allo-HSCT) as postremission treatment is recommended for Philadelphia-positive acute lymphoblastic leukemia (Ph ALL) in current guidelines. However, comparisons of later generation tyrosine kinase inhibitors (TKIs) plus chemotherapy with allo-HSCT have yielded similar outcomes. This meta-analysis was performed to evaluate allo-HSCT in first complete remission (CR1) versus chemotherapy for adult Ph ALL in the TKI era. Pooled assessment of the hematologic and molecular complete response rates was performed after 3-month TKI treatment. Hazard ratios (HRs) were determined for disease-free survival (DFS) and overall survival (OS) benefit with allo-HSCT. The effect of measurable residual disease status on survival benefit was also analyzed. Thirty-nine retrospective and prospective single-arm cohort studies involving 5054 patients were included. Combined HRs indicated that in the general population, allo-HSCT favorably influenced DFS and OS. Achieving complete molecular remission (CMR) within 3 months after starting induction was a favorable survival prognostic factor regardless of whether the patient had undergone allo-HSCT. Among the patients with CMR, survival rates in the nontransplant subgroup were comparable with those in the transplant subgroup, with the estimated 5-year OS of 64% versus 58% and 5-year DFS of 58% versus 51%, respectively. The use of next-generation TKIs results in a higher proportion of patients achieving CMR (ponatinib 82% vs. imatinib 53%), while improving survival in nontransplant patients. Our novel findings suggest that combination chemotherapy plus TKIs leads to a comparable survival benefit as with allo-HSCT for MRD-negative (CMR) patients. This study provides novel evidence for allo-HSCT indications for Ph ALL in CR1 in the TKI era. |
36,880,203 | High Response Rates and Transition to Transplant after Novel Targeted and Cellular Therapies in Adults with RelapsedRefractory Acute Lymphoblastic Leukemia with Philadelphia-Like Fusions. | Philadelphia (Ph)-like acute lymphoblastic leukemia (ALL) is associated with poor response to standard chemotherapy. However, outcomes with novel antibody and cellular therapies in relapsedrefractory (rr) Ph-like ALL are largely unknown. We conducted a single-center retrospective analysis of adult patients (n 96) with rr B-ALL with fusions associated with Ph-like who received novel salvage therapies. Patients were treated with 149 individual novel regimens blinatumomab 83, inotuzumab ozogamicin (InO) 36 and CD19CAR T cells 30. The median age at first novel salvage therapy was 36 years (range 18-71). Ph-like fusions were IGHCRLF2 (n 48), P2RY8CRLF2 (n 26), JAK2 (n 9), ABL-class (n 8), EPORIGH (n 4) and ETV6NTRK2 (n 1). CD19CAR T cells were administered later in the course of therapy compared to blinatumomab and InO (P<0.001) and more frequently in recipients who relapsed after allogeneic hematopoietic cell transplantation (alloHCT) (P0.002). Blinatumomab was administered at older age compared to InO and CAR T-cells (P0.004). The complete remission (CR)CR with incomplete hematologic recovery (CRi) rates were 63%, 72%, and 90% following blinatumomab, InO and CD19CAR, respectively, among which 50%, 50%, and 44% of responders underwent consolidation with alloHCT, respectively. In multivariable analysis, the type of novel therapy (P 0.044) and pretreatment marrow blasts (P0.006) predicted CRCRi rate, while Ph-like fusion subtype (P 0.016), pretreatment marrow blasts (P0.022) and post response consolidation with alloHCT (P< 0.001) influenced event-free survival. In conclusion, novel therapies are effective in inducing high remission rates in patients with rr Ph-like ALL and successfully transitioning the responders to alloHCT. This article is protected by copyright. All rights reserved. |
36,879,893 | Multilineage Lymphoblastic Lymphoma as an Initial Presentation of Mixed Phenotype Acute Leukemia. | Mixed phenotype acute leukemia (MPAL) is characterized by leukemic blasts that express markers of multiple lineages. Compared with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL), MPAL is considered to have a poor treatment outcome. We report a case of MPAL Tmyeloid not otherwise specified that was initially presented as multilineage lymphoblastic lymphoma and subsequently developed into leukemic MPAL. An acute lymphoblastic leukemia-based treatment regimen was ineffective, but azacitidine and venetoclax therapy resulted in hematological complete remission. Our case suggests that multilineage lymphoblastic lymphoma should be considered to be the same disease as MPAL, albeit with different clinical presentations. Optimal treatment for MPAL has not been established yet, but azacitidine and venetoclax therapy may be a potential approach. |
36,879,459 | Donor Hematopoietic Stem CellLymphocyte Maintenance Treatment After CAR T-Cell Therapy in Patients With B-Cell Acute Lymphoblastic Leukemia Relapse Following Stem Cell Transplant. | Maintaining the efficacy of anti-CD19 chimeric antigen receptor modified (CAR) T-cell therapy in patients with B-cell acute lymphoblastic leukemia (B-ALL) relapse after allogeneic hematopoietic stem cell transplant (allo-HSCT) is an urgent problem. In this study, we aimed to compare the efficacy of donor hematopoietic stem cell infusion (DSI) therapy and donor lymphocyte infusion (DLI) therapy as a maintenance therapy after RR B-ALL patients achieved CR in anti-CD19-CAR T-cell therapy but relapsed after allo-HSCT. In total, 22 B-ALL patients who relapsed after allo-HSCT received anti-CD19-CAR T-cell therapy. Patients who responded to CAR T-cell therapy received DSI or DLI as maintenance therapy. We compared the clinical responses, acute graft versus host disease (aGVHD), expansion of CAR-T-cells, and adverse events between the two groups. In our study, 19 patients received DSIDLI as maintenance therapy. After DSIDLI therapy, progression-free survival and overall survival were higher in the DSI group than in the DLI group at 365 days. The grades I and II of aGVHD was observed in four patients (36.4%) in the DSI group. Only one patient developed grade II aGVHD in the DLI group. The peaks of CAR T-cells in the DSI group were higher than those in the DLI group. IL-6 and TNF-α levels increased again in nine of 11 patients after DSI but not in the DLI group. Our findings indicate that for B-ALL patients who relapse after allo-HSCT, DSI is a feasible maintenance therapy if CR is obtained with CAR-T-cell therapy. |
36,878,730 | Long term outcomes of corticosteroid graft versus host disease prophylaxis in peripheral blood allogeneic hematopoietic stem cell transplant A comparative cohort analysis. | Corticosteroids (CS) have previously been incorporated into graft versus host disease (GVHD) prophylaxis regimens for bone marrow (BM) haemopoietic stem cell transplant (HSCT). To assess the impact of prophylactic CS in HSCT using peripheral blood (PB) stem cells. Patients were identified from three HSCT centres receiving a first PB-HSCT between January 2011 and December 2015 from a fully HLA-matched sibling or unrelated donor for acute myeloid leukemia or acute lymphoblastic leukemia. To enable meaningful comparison, patients were divided into two cohorts. Cohort 1 included only myeloablative matched sibling HSCT, where the only variation in GVHD prophylaxis was the addition of CS. In these 48 patients, there were no differences in GVHD, relapse, non-relapse mortality, overall survival or GVHD-relapse-free-survival (GRFS) at four years post-transplant. Cohort 2 included the remaining HSCT recipients, where one group received CS-prophylaxis, and the non-CS group received an antimetabolite, ciclosporin and ATLG. In these 147 patients, those receiving CS-prophylaxis experienced higher rates of chronic GVHD (71% vs 18.1%, p < 0.001) and lower rates of relapse (14.9% vs 33.9%, p 0.02). Those receiving CS-prophylaxis had a lower 4-year GRFS (15.7% vs 40.3%, p 0.002). There does not appear to be a role for adding CS to standard GVHD prophylaxis regimens in PB-HSCT. This article is protected by copyright. All rights reserved. |
36,877,527 | Vincristine and Dexamethasone Pulses in Addition to Maintenance Therapy Among Pediatric Acute Lymphoblastic Leukemia(GD-ALL-2008) an Open-label, Multicentre, Randomized, Phase III Clinical Trial. | The efficacy and safety on the addition of vincristine (VCR) and dexamethasone (DEX) pulses to maintenance therapy among childhood acute lymphoblastic leukemia (ALL) remain uncertain. Herein, we perform an open-label, multicentre, randomized, phase III clinical trial, which was conducted at nine major medical centers in Guangdong province, China. Patients were randomly assigned either the conventional maintenance therapy (control group, n 384) or the VCRDEX pulse (treatment group, n 375). When limited to the SR cohort, 10-year EFS was 82.6% (95%CI 75.9-89.9) in the control group and 80.7% (95%CI74-88.1) in the treatment group (P |
36,877,337 | Approach to the Treatment of Philadelphia Chromosome-Negative B-cell ALL in Older Adults Is Age Becoming just a Number | Despite progress in the treatment of pediatric B-cell acute lymphoblastic leukemia (ALL) and PH ALL, fewer advancements have been for older adults with PH-negative B-cell ALL. Treatment of this population is mired by higher incidence of poor risk biologic features, increased incidence of medical comorbidities, and higher rates of treatment-related mortality (TRM). Here, we review the difficulties in managing elderly patients with PH-negative ALL. The development of novel agents has brought additional tools to the armamentarium of drugs and has changed the landscape of treatment. More recent clinical trials and future clinical trials focus on blinatumomab, inotuzomab ozogamicin (IO), andor chimeric antigen receptor T-cell (CAR-T) either alone or integrated with dose-reduced chemotherapy regimens. The introduction of novel agentstherapies and incorporation into our current treatment paradigms may finally offer an avenue to improve the dismal outcomes seen in this population. |
36,877,306 | Identification of Hub Genes Associated with Resistance to Prednisolone in Acute Lymphoblastic Leukemia Based on Weighted Gene Co-expression Network Analysis. | Resistance against glucocorticoids which are used to reduce inflammation and treatment of a number of diseases, including leukemia, is known as the first stage of treatment failure in acute lymphoblastic leukemia. Since these drugs are the essential components of chemotherapy regimens for ALL and play an important role in stop of cell growth and induction of apoptosis, it is important to identify genes and the molecular mechanism that may affect glucocorticoid resistance. In this study, we used the GSE66705 dataset and weighted gene co-expression network analysis (WGCNA) to identify modules that correlated more strongly with prednisolone resistance in type B lymphoblastic leukemia patients. The PPI network was built using the DEGs key modules and the STRING database. Finally, we used the overlapping data to identify hub genes. out of a total of 12 identified modules by WGCNA, the blue module was find to have the most statistically significant correlation with prednisolone resistance and Nine genes including SOD1, CD82, FLT3, GART, HPRT1, ITSN1, TIAM1, MRPS6, MYC were recognized as hub genes Whose expression changes can be associated with prednisolone resistance. Enrichment analysis based on the MsigDB repository showed that the altered expressed genes of the blue module were mainly enriched in IL2STAT5, KRAS, MTORC1, and IL6-JAK-STAT3 pathways, and their expression changes can be related to cell proliferation and survival. The analysis performed by the WGCNA method introduced new genes. The role of some of these genes was previously reported in the resistance to chemotherapy in other diseases. This can be used as clues to detect treatment-resistant (drug-resistant) cases in the early stages of diseases. |
36,876,249 | Pseudoclitoromegaly from acute T-cell lymphoblastic leukemia. | A 7-year-old girl presented with painful genital enlargement, which was first believed to be clitoromegaly of hormonal origin. However, on the physical exam the clitoris was not visible and the prepuce and labia minora were enlarged and tender. Magnetic resonance imaging demonstrated an infiltrative abnormal signal with restricted diffusion involving the enlarged clitoris and adjacent soft tissues of the prepuce and labia minora, confirming a nonhormonal infiltrative malignancy. The same abnormal signal was present in enlarged inguinal lymph nodes, the kidneys, and an anterior mediastinal mass. The pathologic diagnosis was T-cell acute lymphoblastic leukemia. |
36,874,377 | Improved survival of adolescents and young adults patients with T-cell acute lymphoblastic leukemia. | The outcome of T-cell acute lymphoblastic leukemia (T-ALL) has improved with the use of pediatric-inspired protocols in the adolescents and young adults (AYA) population. There is limited literature regarding the outcome of T-ALLlymphoblastic lymphoma (LBL) AYA patients treated with pediatric protocols. A total of 35 T-ALLLBL-AYA patients ages between 14 and 55 years were treated with AYA-15 protocol. At a median follow-up of 5 years the overall survival, disease-free survival and event-free survival are 71%, 62% and 49.6% respectively. Toxicities were within the expected range. Our single-center experience real-world data in treating T-ALLLBL-AYA patients with pediatric-inspired protocol demonstrates encouraging results of high survival rate and excellent tolerability for patients aged 18-55 years. |
36,873,995 | Chemo-free maintenance therapy in adult T-cell acute lymphoblastic leukemia A case report and literature review. | Maintenance therapy in adult T-cell acute lymphoblastic leukemia (T-ALL) is the longest phase but with limited option. The classic drugs used in the maintenance phase such as 6-mercaptopurine, methotrexate, corticosteroid and vincristine have potentially serious toxicities. Optimizing therapy in the modern age, chemo-free maintenance therapy regimens for patients with T-ALL may dramatically improve the maintenance therapeutic landscape. We report here the combination of Anti-programmed cell death protein 1 antibody and histone deacetylase inhibitor as chemo-free maintenance treatment in a T-ALL patient with literature review, thus providing a unique perspective in addition to valuable information which may inform novel therapeutic approaches. |
36,873,581 | Neuropsychiatric disorders in adults undergoing chimeric antigen receptor T cells therapy for aggressive lymphomas and acute lymphoblastic leukemia. | To evaluate risk factors for neuropsychiatric disorders (NPD) in recipients of CART therapy. Patients ≥ 18 years with acute lymphoblastic leukemia (ALL), and aggressive B-cell lymphomas who received CART in 2018 were evaluated. Patients with and without NPD were compared. NPD was diagnosed in 31.2% of patients. Compared to patients without NPD, patients with NPD were likely to be females ( Female gender and ALL were risk factors for NPD. |
36,873,097 | The influence of | 6-Mercaptopurine (6-MP) serves as the backbone of maintenance therapy in acute lymphoblastic leukemia. The nucleoside diphosphate-linked moiety X-type motif 15 genes ( |
36,872,903 | Infections and Acute Lymphoblastic Leukemia Is the Sum Worth More than the Parts Evidence from Birth Characteristics. | The etiology of childhood acute lymphoblastic leukemia (ALL) has long been studied piecemeal with investigations leading to a lengthy list of putative risk factors including several with immune modulatory effects. The ubiquity of many of these factors (e.g., daycare attendance, low parity, breastfeeding, normal vaccinations) belies the rarity of ALL as an outcome. In this commentary, Pombo-de-Oliveira and colleagues show that a key feature may be the combination of particular risk factors, as the birth characteristics cesarean section and birth order when combined interact to impart higher risk of ALL than would be suggested by the additive risk of both factors. This statistical interaction would be predicted by the delayed infection hypothesis wherein infant immune isolation promotes developmental vulnerability to ALL upon infection exposure later in childhood. Pombo-de-Oliveira and colleagues show further that lack of breastfeeding, a postnatal factor leading to further immune isolation, induces additional risk. In sum, the data reveal a combination of factors that together could impart a healthy trained immune system allowing for moderated responses to later exposures with microbial and viral antigens. Such priming of the immune system avoids maladaptive immunologic consequences of delayed antigenic stimulation leading to ALL and other diseases. Further research utilizing biomarkers of specific exposures (in addition to the proxy measures used here) will be helpful to realize the full potential for immune modification for ALL prevention. See related article by Pombo-de-Oliveira et al., p. 371. |
36,872,149 | SOHO State of the Art Updates and Next Questions Hyper-CVAD in 2022 Lessons Learned and New Approaches. | Combination chemotherapy is the mainstay of treatment for acute lymphoblastic leukemia (ALL). The Hyper-CVAD regimen was developed in 1992 at MD Anderson Cancer Center and has since become a standard of care option for adult patients with ALL. Since its conception, a number of modifications have been implemented to customize the regimen for different patient populations and safely incorporate novel therapies without compromising tolerability. We aim to review the evolution of the Hyper-CVAD regimen over the past 3 decades, focusing on clinical pearls, as well as future directions. |
36,871,952 | Flow cell sorting followed by PCR-based clonality testing may assist in questionable diagnosis and monitoring of acute lymphoblastic leukemia. | Multicolor flow cytometry (MFC) has highly reliable and flexible algorithms for diagnosis and monitoring of acute lymphoblastic leukemia (ALL). However, MFC analysis can be affected by poor sample quality or novel therapeutic options (e.g., targeted therapies and immunotherapy). Therefore, an additional confirmation of MFC data may be needed. We propose a simple approach for validation of MFC findings in ALL by sorting questionable cells and analyzing immunoglobulinT-cell receptor (IGTR) gene rearrangements via EuroClonality-based multiplex PCR. We obtained questionable MFC results for 38 biological samples from 37 patients. In total, 42 cell populations were isolated by flow cell sorting for downstream multiplex PCR. Most of the patients (n 29) had B-cell precursor ALL and were investigated for measurable residual disease (MRD) 79% of them received CD19-directed therapy (blinatumomab or CAR-T). We established the clonal nature of 40 cell populations (95.2%). By using this technique, we confirmed very low MRD levels (<0.01% MFC-MRD). We also applied it to several ambiguous findings for diagnostic samples, including those with mixed-phenotype acute leukemia, and the results obtained impacted the final diagnosis. We have demonstrated possibilities of a combined approach (cell sorting and PCR-based clonality assessment) to validate MFC findings in ALL. The technique is easy to implement in diagnostic and monitoring workflows, as it does not require isolation of a large number of cells and knowledge of individual clonal rearrangements. We believe it provides important information for further treatment. |
36,870,963 | Molecular characterization of the circadian clock in paediatric leukaemia patients a prospective study protocol. | In many organisms, including humans, the timing of cellular processes is regulated by the circadian clock. At the molecular level the core-clock consists of transcriptional-translational-feedback loops including several genes such as BMAL1, CLOCK, PERs and CRYs generating circa 24-h rhythms in the expression of about 40% of our genes across all tissues. Previously these core-clock genes have been shown to be differentially expressed in various cancers. Albeit a significant effect in treatment optimization of chemotherapy timing in paediatric acute lymphoblastic leukaemia has previously been reported, the mechanistic role played by the molecular circadian clock in acute paediatric leukaemia remains elusive. To characterize the circadian clock, we will recruit patients with newly diagnosed leukaemia and collect time course saliva and blood samples, as well as a single bone marrow sample. From the blood and bone marrow samples nucleated cells will be isolated and further undergo separation into CD19 To the best of our knowledge this is the first study aiming to characterize the circadian clock in a cohort of paediatric patients with acute leukaemia. In the future we hope to contribute to uncovering further vulnerabilities of cancers associated with the molecular circadian clock and in particular adjust chemotherapy accordingly, leading to more targeted toxicity, and hence decreased systemic toxicities. |
36,869,895 | MIP3α as an early prognostic predictor for patients with B-cell malignancies receiving CD19CD22-redirected CAR-T cell cocktail therapy. | Identifying the temporal pattern of recurrence and prognostic biomarkers would further help improve the efficacy of chimeric antigen receptor (CAR) -T therapy. We examined the prognoses of 119 patients after sequential infusion of anti-CD19 and anti-CD22, a cocktail of 2 single-target CAR (CAR1922) T cells in an open-label, single-center clinical trial (ChiCTR-OPN-16008526). And we, from a 70-biomarker panel, identified candidate cytokines that might predict the treatment failure, including primary non-response (NR) and early relapse (ER). In our study, 3 (11.5%) patients with B-cell acute lymphoblastic leukemia (B-ALL) and 9 (12.2%) cases of B-cell non-Hodgkin lymphoma (NHL) failed to respond to sequential CAR1922 T-cell infusion (NR). A total of 11 (42.3%) B-ALL patients and 30 (52.7%) B-NHL patients had relapses during follow-up. Most recurrence events (67.5%) occurred within six months of sequential CAR T-cell infusion (ER). We found that macrophage inflammatory protein (MIP)-3α was a highly sensitive and specific prognostic predictor for patients with NRER and those attaining over-6-month remission. Patients who had higher MIP3α levels after sequential CAR1922 T-cell infusion had significantly favorable progression-free survival (PFS) than their counterparts with relatively lower MIP3α expression. Our experiments demonstrated that MIP3α could enhance the therapeutic effect of CAR-T cells by promoting T-cell infiltration into and enriching memory-phenotype T cells in the tumor environment. This study showed that relapse occurred mainly within six months after sequential CAR1922 T-cell infusion. Moreover, MIP3α could act as a valuable post-infusion biomarker for identifying patients with NRER. |
36,868,895 | Clinical use of CAR T-cells in treating acute lymphoblastic leukemia. | Chimeric antigen receptor (CAR) T-cell therapy has transformed the treatment landscape for adult patients with relapsed or refractory B-cell acute lymphoblastic leukemia (RR B-ALL). However CAR T-cell therapy of RR T-ALL has unique challenges, such as the lack of specific tumor antigens, cell fratricide and T cell aplasia, in comparison with that of RR B-ALL. Despite promising therapeutic outcomes in RR B-ALL, application of this therapy is limited by high relapse rates and immunological toxicities. Recent studies suggest patients who underwent allogeneic hematopoietic stem cell transplantation post-CAR T-cell therapy would achieve durable remission and better survival, but this remains controversial. Herein, I briefly review published data on the clinical use of CAR T-cells in treating ALL. |
36,867,854 | JAK2 in Ph-like B-Acute Lymphoblastic Leukemia. | The Janus Kinase 2 gene (JAK2) provides instructions for generating a protein that promotes the division and growth, or what is referred to as the proliferation, of cells. This generated protein relays signals in cells in order to promote cell growth, as well as help manage the count of white blood cells, red blood cells, and platelets that are generated within the bone marrow. Mutations and rearrangements of JAK2 are found in 3.5% of B-acute lymphoblastic leukemia (B-ALL) cases and in 18.9% of Down syndrome B-ALL patients, and are associated with a Ph-like ALL and a poor prognosis. However, there have been great challenges in understanding their role in this pathogenesis. In this review, we will discuss the most recent literature and trends associated with JAK2 mutations in patients with B-ALL. |
36,867,579 | Diagnostic utility of whole genome sequencing in adults with B-other acute lymphoblastic leukemia. | Genomic profiling at diagnosis of B-cell precursor Acute Lymphoblastic Leukemia (BCP-ALL) in adults is used to guide disease classification, risk stratification and treatment decisions. Patients for which diagnostic screening fails to identify disease defining or risk stratifying lesions are classified as B-other ALL. We screened a cohort of 652 BCP-ALL cases enrolled in UKALL14 to identify and perform whole genome sequencing (WGS) on paired tumor-normal samples. For 52 B-other patients we compared WGS findings to data from clinical and research cytogenetics. WGS identifies a cancer associated event in 5152 cases, this includes an established subtype defining genetic alteration in 552 that were previously missed by standard-of-care genetics. Of the 47 true B-other ALL we identified a recurrent driver in 87% (41). Complex karyotype by cytogenetics emerges as a heterogeneous group, including distinct genetic alterations associated with either favorable (DUX4-r) or poor outcomes (MEF2D-r, IGKBCL2). For a subset of 31 cases, we integrate findings from RNA-sequencing (RNA-seq) analysis to include fusion gene detection, and classification by gene expression. Compared to RNA-seq, WGS was sufficient to detect and resolve recurrent genetic subtypes, however RNA-seq can provide orthogonal validation of findings. In conclusion, we demonstrate that WGS can identify clinically relevant genetic abnormalities missed by standard-of-care testing and identify leukemia driver events in virtually all cases of B-other ALL. |
36,867,356 | Minimal residual disease detection by mutation-specific droplet digital PCR for leukemialymphoma. | Minimal residual disease (MRD) is usually defined as the small number of cancer cells that remain in the body after treatment. The clinical significance of MRD kinetics is well recognized in treatment of hematologic malignancies, particularly acute lymphoblastic leukemia (ALL). Real time quantitative PCR targeting immunoglobulin (Ig) or T-cell receptor (TCR) rearrangement (PCR-MRD), as well as multiparametric flow cytometric analysis targeting antigen expression, are widely used in MRD detection. In this study, we devised an alternative method to detect MRD using droplet digital PCR (ddPCR), targeting somatic single nucleotide variants (SNVs). This ddPCR-based method (ddPCR-MRD) had sensitivity up to 1E-4. We assessed ddPCR-MRD at 26 time points from eight T-ALL patients, and compared it to the results of PCR-MRD. Almost all results were concordant between the two methods, but ddPCR-MRD detected micro-residual disease that was missed by PCR-MRD in one patient. We also measured MRD in stored ovarian tissue of four pediatric cancer patients, and detected 1E-2 of submicroscopic infiltration. Considering the universality of ddPCR-MRD, the methods can be used as a complement for not only ALL, but also other malignant diseases regardless of tumor-specific IgTCR or surface antigen patterns. |
36,865,272 | Bayesian modelling of response to therapy and drug-sensitivity in acute lymphoblastic leukemia. | Acute lymphoblastic leukemia (ALL) is a heterogeneous haematologic malignancy involving the abnormal proliferation of immature lymphocytes and accounts for most paediatric cancer cases. The management of ALL in children has seen great improvement in the last decades thanks to greater understanding of the disease leading to improved treatment strategies evidenced through clinical trials. Common therapy regimens involve a first course of chemotherapy (induction phase), followed by treatment with a combination of anti-leukemia drugs. A measure of the efficacy early in the course of therapy is the presence of minimal residual disease (MRD). MRD quantifies residual tumor cells and indicates the effectiveness of the treatment over the course of therapy. MRD positivity is defined for values of MRD greater than 0.01%, yielding left-censored MRD observations. We propose a Bayesian model to study the relationship between patient features (leukemia subtype, baseline characteristics, and drug sensitivity profile) and MRD observed at two time points during the induction phase. Specifically, we model the observed MRD values via an auto-regressive model, accounting for left-censoring of the data and for the fact that some patients are already in remission after the first stage of induction therapy. Patient characteristics are included in the model via linear regression terms. In particular, patient-specific drug sensitivity based on ex vivo assays of patient samples is exploited to identify groups of subjects with similar profiles. We include this information as a covariate in the model for MRD. We adopt horseshoe priors for the regression coefficients to perform variable selection to identify important covariates. We fit the proposed approach to data from three prospective paediatric ALL clinical trials carried out at the St. Jude Children’s Research Hospital. Our results highlight that drug sensitivity profiles and leukemic subtypes play an important role in the response to induction therapy as measured by serial MRD measures. |
36,863,616 | The anticancer effect of PASylated calreticulin-targeting L-ASNase in solid tumor bearing mice with immunogenic cell death-inducing chemotherapy. | L-Asparaginase (L-ASNase), a bacterial enzyme that degrades asparagine, has been commonly used in combination with several chemical drugs to treat malignant hematopoietic cancers such as acute lymphoblastic leukemia (ALL). In contrast, the enzyme was known to inhibit the growth of solid tumor cells in vitro, but not to be effective in vivo. We previously reported that two novel monobodies (CRT3 and CRT4) bound specifically with calreticulin (CRT) exposed on tumor cells and tissues during immunogenic cell death (ICD). Here, we engineered L-ASNases conjugated with monobodies at the N-termini and PAS200 tags at the C-termini (CRT3LP and CRT4LP). These proteins were expected to possess four monobody and PAS200 tag moieties, which did not disrupt the L-ASNase conformation. These proteins were expressed 3.8-fold more highly in E. coli than those without PASylation. The purified proteins were highly soluble, with much greater apparent molecular weights than expected ones. Their affinity (Kd) against CRT was about 2 nM, 4-fold higher than that of monobodies. Their enzyme activity (∼6.5 IUnmol) was similar to that of L-ASNase (∼7.2 IUnmol), and their thermal stability was significantly increased at 55 °C. Their half-life times were > 9 h in mouse sera, about 5-fold longer than that of L-ASNase (∼1.8 h). Moreover, CRT3LP and CRT4LP bound specifically with CRT exposed on tumor cells in vitro, and additively suppressed the tumor growth in CT-26 and MC-38 tumor-bearing mice treated with ICD-inducing drugs (doxorubicin and mitoxantrone) but not with a non-ICD-inducing drug (gemcitabine). All data indicated that PASylated CRT-targeted L-ASNases enhanced the anticancer efficacy of ICD-inducing chemotherapy. Taken together, L-ASNase would be a potential anticancer drug for treating solid tumors. |
36,861,936 | PPARG, GNG12, and CD19 are potential independent predictors of central nerve recurrence in childhood acute lymphoblastic leukemia. | To identify biomarkers that can predict the recurrence of the central nervous system (CNS) in children with acute lymphoblastic leukemia (ALL). The transcriptome and clinical data of ALL in children were downloaded from the TARGET database. Transcriptome data were analyzed by bioinformatics method to identify core (hub) genes and establish a risk assessment model. Univariate Cox analysis was performed on each clinical data, and multivariate Cox regression analysis was performed on the obtained results and risk score. The children ALL phase I samples from TARGET database were used for validation. Univariate multivariate Cox analysis of 10 hub genes identified showed that |
36,861,687 | Assessment of metabolic syndrome parameters in pediatric acute lymphoblastic leukemia survivors. | This study aims to demonstrate the prevalence of metabolic syndrome parameters and to investigate their relationship with body mass index in pediatric acute lymphoblastic leukemia survivors. The cross-sectional study was conducted between January and October 2019 at the Department of Pediatric Hematology and comprised acute lymphoblastic leukemia survivors who had been treated between 1995 and 2016 and had been off treatment for at least 2 years. The control group included 40 healthy participants who were matched for age and gender. The two groups were compared in terms of various parameters (BMI body mass index, waist circumference, fasting plasma glucose, HOMA-IR Homeostatic Model Assessment-Insulin Resistance, etc.). Data were analyzed using Statistical Package for the Social Sciences (SPSS) 21. Of the 96 participants, 56 (58.3%) were survivors and 40 (41.6%) were controls. Among the survivors, there were 36 (64.3%) men, whereas the control group had 23 (57.5%) men. The mean age of the survivors was 16.67 ± 3.41 years, whereas the mean age of the controls was 15.51 ± 4.2 years (P > 0.05). Multinomial logistic regression analysis showed that cranial radiation therapy and female gender were associated with overweight and obesity (P < 0.05). A significant positive correlation was found between BMI and fasting insulin, in survivors (P < 0.05). Disorders of the metabolic parameter were found to be more common among acute lymphoblastic leukemia survivors than among healthy controls. |
36,861,439 | 2022 Chinese expert consensus and guidelines on clinical management of toxicity in anti-CD19 chimeric antigen receptor T-cell therapy for B-cell non-Hodgkin lymphoma. | Adoptive cellular immunotherapy with chimeric antigen receptor (CAR) T cells has emerged as a novel modality for treating relapsed andor refractory B-cell non-Hodgkin lymphoma (B-NHL). With increasing approval of CAR T-cell products and advances in CAR T cell therapy, CAR T cells are expected to be used in a growing number of cases. However, CAR T-cell-associated toxicities can be severe or even fatal, thus compromising the survival benefit from this therapy. Standardizing and studying the clinical management of these toxicities are imperative. In contrast to other hematological malignancies, such as acute lymphoblastic leukemia and multiple myeloma, anti-CD19 CAR T-cell-associated toxicities in B-NHL have several distinctive features, most notably local cytokine-release syndrome (CRS). However, previously published guidelines have provided few specific recommendations for the grading and management of toxicities associated with CAR T-cell treatment for B-NHL. Consequently, we developed this consensus for the prevention, recognition, and management of these toxicities, on the basis of published literature regarding the management of anti-CD19 CAR T-cell-associated toxicities and the clinical experience of multiple Chinese institutions. This consensus refines a grading system and classification of CRS in B-NHL and corresponding measures for CRS management, and delineates comprehensive principles and exploratory recommendations for managing anti-CD19 CAR T-cell-associated toxicities in addition to CRS. |
36,861,414 | RNA helicase DHX15 exemplifies a unique dependency in acute leukemia. | RNA-binding proteins (RBPs) have emerged as essential regulators to control gene expression and modulate multiple cancer traits. T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy derived from transformation of T-cell progenitors that normally undergo discrete steps of differentiation in the thymus. Yet implications of essential RBPs during T-cell neoplastic transformation remain largely unclear. Systematic evaluation of RBPs identifies RNA helicase DHX15, which facilitates the disassembly of spliceosome and release of lariat introns, as a T-ALL dependency factor. Functional analysis using multiple murine T-ALL models demonstrates the essential importance of DHX15 in tumor cell survival and leukemogenesis. Moreover, single-cell transcriptomics reveals that DHX15 depletion in T-cell progenitors hinders burst proliferation during CD4-CD8-(DN)-to-CD4CD8(DP) transition. Mechanistically, abrogation of DHX15 perturbs RNA splicing and leads to diminished levels of SLC7A6 and SLC38A5 transcripts due to intron retention, thereby suppressing glutamine import and mTORC1 activity. We further propose a DHX15 signature modulator drug ciclopirox and demonstrate prominent anti-T-ALL efficacy. Collectively, we here highlight the functional contribution of DHX15 to leukemogenesis through regulation of established oncogenic pathways. These findings also suggest a promising therapeutic approach that splicing perturbation by targeting spliceosome disassembly may achieve considerable anti-tumor efficacy. |
36,861,410 | null | Not available. |
36,861,396 | B-lineage acute lymphoblastic leukemia causes cell autonomous defects in long-term hematopoietic stem cell function. | Not available. |
36,860,237 | Immersive Virtual Reality to Distract From Pain in Children Treated With L-asparaginase by Intramuscular Injection. | Background Treatment-related pain and discomfort are two of the most common manifestations in children with acute lymphoblastic leukemia (ALL). Patients with ALL are usually treated with L-asparaginase (L-ASP) by intramuscular injection. Children receiving L-ASP chemotherapy must bear adverse reactions such as pain caused by intramuscular injections. The use of virtual reality (VR) distraction technology could be a non-pharmacological intervention to bolster patients comfort and decrease anxiety and procedure-related pain within hospital settings. Methodology The study explored the potential benefits of VR as a psychological intervention to induce positive emotions and reduce pain levels in participants receiving L-ASP injections. Participants in the study had the opportunity to select a nature theme of their choosing during their treatment session. The study provided a noninvasive solution that promoted relaxation to reduce anxiety by shifting an individuals mood positively during treatment. The objective was met by measuring participants mood and pain levels before and after the VR experience and participant satisfaction with the use of the technology. This mixed-methods study of children aged six to 18 received L-ASP between April 2021 and March 2022, using a Numerical Rating Scale (NRS) with sheer numbers ranging from 0 (no pain) to 10 (extreme or most pain possible). Semi-structured interviews were conducted to collect new data and explore participants thoughts and beliefs about a particular topic. A total of 14 patients participated. Descriptive statistics and content analysis are used to describe the data analyzed. VR is an enjoyable distraction intervention for managing treatment-related pain in ALL with intramuscular chemotherapy. Results Eight of 14 patients found a reduction in perceived pain after wearing VR. During the intervention implementation, the primary caregivers felt that the patients pain perception was more positive when using the virtual reality device, and there was less resistance and less crying. Conclusions This study describes changes and experiences associated with pain and physical discomfort in children with ALL receiving intramuscular chemotherapy. This teaching model is applied to developing medical personnel, providing information about the disease and daily care, and educating the participants family members. This study may expand the usage of VR applications so that more patients can benefit from them. |
36,858,620 | Establishment and Characterization of an Acute Lymphocytic Leukemia Cell Line Expressing CD13 and CD33 with a Complex Philadelphia Translocation. | Objective To investigate the pathogenesis of Philadelphia (Ph)-positive acute lymphocytic leukemia (ALL), we established a lymphoblastoid cell line. Methods Bone marrow cells from a patient with Ph-positive ALL were enriched by Ficoll-Hypaque centrifugation and cultured in medium with fetal calf serum. Materials The mononuclear cells of bone marrow aspirate were obtained from an adult man with ALL after he experienced relapse following induction therapy including imatinib mesylate. Results The cell line termed TNA-M was established, carrying a three-way Ph translocation involving two chromosome 9s and one chromosome 22 as a sole karyotypic abnormality. Furthermore, the cells were positive for CD13 and CD33 in addition to CD19, CD22 and CD79a antigens. Conclusion This unique cell line is expected to be a valuable tool for understanding the pathogenesis of Ph-positive ALL. |
36,857,419 | HLH-like toxicities predict poor survival following use of tisagenlecleucel in children and young adults with B-ALL. | Chimeric antigen-receptor (CAR)-associated hemophagocytic lymphohistiocytosis (HLH)-like toxicities involving hyperferritinemia, multi-organ dysfunction, coagulopathy, andor hemophagocytosis are described as occurring in a subset of patients with cytokine release syndrome (CRS). Case series report poor outcomes for those with B-acute lymphoblastic leukemia (B-ALL) who develop HLH-like toxicities, although larger outcomes analyses of children and young adults (CAYA) with B-ALL who develop these toxicities following commercial tisagenlecleucel are not described. Using a multi-institutional database of 185 CAYA with B-ALL, we conducted a retrospective cohort study including groups that developed HLH-like toxicities, high grade CRS without HLH-like toxicities, or no to low grade CRS without HLH-like toxicities. Primary objectives included characterizing the incidence, outcomes, and pre-infusion factors associated with HLH-like toxicities. Among 185 CAYA infused with tisagenlecleucel, 26 (14.1%) met criteria for HLH-like toxicities. One-year overall survival and relapse-free survival were 25.7% and 4.7% in those with HLH-like toxicities, compared with 80.1% and 57.6% in those without. In multivariable analysis for death, meeting criteria for HLH-like toxicities carried a hazard ratio of 4.61 (95% confidence interval 2.41-8.83), controlling for disease burden, age, and sex. Patients who developed HLH-like toxicities had higher pre-tisagenlecleucel disease burden, ferritin, C-reactive protein levels, and lower platelet and absolute neutrophil counts than patients with high grade or nolow grade CRS without HLH-like toxicities. Overall, CAYA with B-ALL who developed HLH-like toxicities following tisagenlecleucel experienced high rates of relapse and non-relapse mortality, indicating the urgent need for further investigations into prevention and optimal management of patients who develop HLH-like toxicities following tisagenlecleucel. |
36,856,803 | Real-world outcomes of adult patients with acute lymphoblastic leukemia treated with a modified CALGB 10102 regimen. | Acute lymphoblastic leukemia (ALL) is an aggressive bone marrow cancer with disparate outcomes. Data on patient outcomes in real world settings outside of clinical trials is limited. The current study reports on outcomes for 137 ALL patients who received an adult induction and consolidation regimen derived from the CALGB 10102 trial modified without alemtuzumab. Of the 137 patients, 32 were < 40 years old, 52 were between 40 and 59, and 53 were ≥ 60 years old. Overall, 109 (79.6%) patients achieved a complete remission (< 40 96.1%, 40-59 86.5%, and 62.3% ≥ 60 (p 0.0002)). Progression free survival for the entire cohort was 13.5 months and by age was 19.8 months for less than 40, 23.4 months for 40 to 59 and 6.7 months for ≥ 60 p 0.0002. Median survival was 22.1 months for the entire cohort (32.9 months for ages < 40, 26.6 months ages 40-59, 7.8 months ≥ 60, p < 0.001). |
36,856,175 | Anlotinib inhibits proliferation and induces apoptosis in B-cell acute lymphoblastic leukemia by targeting the BTK and AKTmTOR pathway. | Acute lymphoblastic leukemia (ALL) is the second most common acute leukemia in adults, whose known drug treatments are limited and expensive. This investigation aimed to investigate the therapeutic potential of anlotinib in B-cell acute lymphoblastic leukemia (B-ALL). The B-ALL cell lines Nalm-6 and BALL-1 were used to verify the therapeutic potential of anlotinib in B-ALL. The cell activity was measured by Cell Counting Kit-8. Apoptosis was detected by Annexin V-FITCPI double staining combined with flow cytometry. Afterward, the binding capacity of anlotinib to the critical protein was predicted by molecular docking, and the protein changes in the related pathways downstream of the target proteins were verified by western blot. Finally, the effect of anlotinib on the survival rate was verified in B-ALL nude mice. Anlotinib inhibited the proliferation of the B-ALL cell lines, Nalm-6, and BALL-1, and promoted apoptosis. Molecular docking results showed that it had the potential binding ability to BTK. Western blot revealed that anlotinib was able to inhibit the phosphorylation of BTK, AKT, and mTOR, thereby inhibiting the proliferation of B-ALL cells. In addition, anlotinib suppressed weight loss and prolonged the survival time of mice. To summarize, anlotinib can inhibit the proliferation of B-ALL and promotes apoptosis by inhibiting the phosphorylation of BTK and AKT, and mTOR. |
36,854,700 | Recent research on chimeric antigen receptor T cells in children with refractoryrelapsed acute lymphoblastic leukemia. | At present, the treatment of refractoryrelapsed acute lymphoblastic leukemia is still in a difficult situation, and even if the intensity of chemotherapy is increased or it is combined with hematopoietic stem cell transplantation, some children may have a poor prognosis and a short survival time. Chimeric antigen receptor T-cell (CAR-T) immunotherapy uses genetically engineered T cells and does not rely on the human leukocyte antigen pathway to recognize tumor-specific antigens, and then CAR-T cells bind to target antigen cells to trigger immune response, thereby exerting a sustained anti-leukemia effect. As the most rapidly developed tumor immunotherapy, major breakthroughs have been made for CAR-T cells in the treatment of various hematological tumors, but there still lacks a comprehensive system for the research, development, and production of CAR-T cells and standardized diagnosis and treatment protocols in China. This article reviews the recent research on CAR-T cells in children with refractoryrelapsed acute lymphoblastic leukemia. 目前儿童复发难治性急性淋巴细胞白血病的治疗仍处于困境，即使提高化疗强度或联合造血干细胞移植，仍有部分患儿预后差，生存期短。嵌合抗原受体T细胞（chimeric antigen receptor T-cell，CAR-T）免疫疗法通过基因工程修饰T细胞，并利用不依赖于人类白细胞抗原途径识别肿瘤特异性抗原，靶向结合目标抗原细胞，触发免疫反应，从而发挥持续的抗白血病效应。作为发展最为迅速的肿瘤免疫疗法，CAR-T细胞在多种血液肿瘤的治疗中取得了突破性的进展，但目前国内尚未建立全面的CAR-T细胞研发生产体系和规范的临床诊治方案。该文就CAR-T细胞在儿童复发难治性急性淋巴细胞白血病中的研究进展作一综述。. |
36,853,312 | The Relationship between Gene Polymorphisms od the XRCC1 and TP53 with the Gender of Children with Acute Leukemia. | The relevance of the study lies in the fact that although the role of polymorphism of some genes that are responsible for cell apoptosis and deoxyribonucleic acid repair in the development of acute leukemia has already been established, its relationship with the gender of patients has not been studied enough. This study was aimed at studying the relationship between the Arg399Gln polymorphism in the XRCC1 deoxyribonucleic acid repair gene and the Arg72Pro polymorphism in the TP53 tumor suppressor gene encoding the p53 protein with the gender of children with acute leukemia. The study included 100 newly diagnosed pediatric patients of Kyrgyz nationality (69 boys and 31 girls), among which there were 77 patients with acute lymphoblastic leukemia, 22 patients with acute myeloblastic leukemia and 1 patient with a biphenotypic variant. Determination of polymorphisms was carried out by PCR-RFLP analysis or polymerase chain reaction followed by an analysis of restriction fragment length polymorphism. The interrelation of the results obtained with the patients gender was assessed using statistical methods. The study showed that there were no gender differences for all three genotypes of the Arg72Pro polymorphic marker of the tumor suppressor p53 (ТР53). Three Arg399Gln genotypes of the XRCC1 gene also did not depend on gender. However, with a separate analysis of each polymorphism, there was a tendency for a greater proportion of the ArgGln genotype in the group of boys compared to girls. The GlnGln polymorphism relationship requires further study due to insufficient data for analysis. The study has expanded the understanding of genetic changes and their relationship with gender, which have diagnostic, prognostic and therapeutic implications in acute leukemia. The conducted research of the relationship between individual phenotypes of acute lymphoblastic leukemia with risky polymorphisms in some genes contributes to the study of AL. |
36,849,202 | Role of peripheral blood MRD and 18F-FDG PET in the post-CAR relapse setting a case study of discordant peripheral blood and bone marrow MRD. | Chimeric antigen receptor (CAR) T cell therapy is an effective salvage therapy for pediatric relapsed B-cell acute lymphoblastic leukemia (B-ALL), yet is challenged by high rates of post-CAR relapse. Literature describing specific relapse patterns and extramedullary (EM) sites of involvement in the post-CAR setting remains limited, and a clinical standard for post-CAR disease surveillance has yet to be established. We highlight the importance of integrating peripheral blood minimal residual disease (MRD) testing and radiologic imaging into surveillance strategies, to effectively characterize and capture post-CAR relapse. Here, we describe the case of a child with multiply relapsed B-ALL who relapsed in the post-CAR setting with gross non-contiguous medullary and EM disease. Interestingly, her relapse was identified first from peripheral blood flow cytometry MRD surveillance, in context of a negative bone marrow aspirate (MRD <0.01%). Positron emission tomography with 18F-fluorodeoxyglucose revealed diffuse leukemia with innumerable bone and lymph node lesions, interestingly sparing her sacrum, the site of her bone marrow aspirate sampling. We highlight this case as both peripheral blood MRD and 18F-fluorodeoxyglucose positron emission tomography imaging were more sensitive than standard bone marrow aspirate testing in detecting this patients post-CAR relapse. ClinicalBiologic Insight In the multiply relapsed B-ALL setting, where relapse patterns may include patchy medullary andor EM disease, peripheral blood MRD andor whole body imaging, may carry increased sensitivity at detecting relapse in patient subsets, as compared with standard bone marrow sampling. |
36,848,637 | Classification and genetics of pediatric B-other Acute Lymphoblastic Leukemia by targeted RNA-sequencing. | Acute lymphoblastic leukemia (ALL) can be classified into different subgroups based on recurrent genetic alterations. Here, targeted RNA-sequencing was used to identify the novel subgroups of ALL in 144 B-other and 40 classical ALL samples. The classical TCF3-PBX1, ETV6-RUNX1, KMT2A-rearranged, BCR-ABL1, and novel P2RY8-CRLF2, ABL-, JAK2-, ZNF384-, MEF2D-, and NUTM1-fusions were easily identified by fusion transcript analysis. IGH-CRLF2 and IGH-EPOR were found by abnormally high levels of expression of CRLF2 or EPOR. DUX4-rearranged were identified by the unusual expression of DUX4 genes and an alternative exon of ERG, or by clustering analysis of gene expression. PAX5-driven ALL, including fusions, intragenic amplifications and mutations were identified by SNV analysis and manual inspection using the IGV software. Exon junction analysis allowed detection of some intragenic ERG and IKZF1 deletions. CRLF2-high associated with initial white blood cell (WBC) ≥50,000L and GATA3 risk alleles (rs3781093 and rs3824662), while ABLJAK2EPOR-fusions associated with high WBC, NCI high risk and IKZF1del. ZNF384-fusions associated with CALLA-negativity and NUTM1-fusions with infants. In conclusion, Targeted RNA-sequencing further classified 96144 (66.7%) B-other cases. All novel ALL subgroups, except for iAMP21, hyper- and hypodiploid cases were identified. Curiously, we observed higher frequencies of girls within B-rest ALLs and boys in PAX5-driven cases. |
36,847,405 | Assessment of Chimeric Antigen Receptor T Cell-Associated Toxicities Using an Acute Lymphoblastic Leukemia Patient-derived Xenograft Mouse Model. | Chimeric antigen receptor T (CART) cell therapy has emerged as a powerful tool for the treatment of multiple types of CD19 |
36,845,621 | Optimizing Management of the Central Nervous System in Patients with Acute Lymphoblastic Leukemia Undergoing Allogeneic Stem Cell Transplantation. | To evaluate clinical outcomes and patterns of failure, specifically in regards to the central nervous system (CNS), in patients with acute lymphoblastic leukemia (ALL) undergoing allogeneic hematopoietic stem cell transplantation (HSCT) using total body irradiation (TBI)-based conditioning regimens. All adult patients (aged ≥18 years) with ALL undergoing allogeneic HSCT using TBI-based conditioning regimens treated from 1995 to 2020 at Duke University Medical Center were evaluated. Various patient, disease, and treatment-related factors were collected, including CNS prophylaxis and treatment interventions. Clinical outcomes, including freedom from CNS relapse, were calculated using the Kaplan-Meier method for patients with and without CNS disease at presentation. One hundred and fifteen patients with ALL were included the analysis (myeloablative, 110 nonmyeloablative, 5). Of the 110 patients undergoing a myeloablative regimen, most (n 100) did not have CNS disease before transplant. For this subgroup, peritransplant intrathecal chemotherapy was administered in 76% (median of 4 cycles) and 10 received a radiation boost to the CNS (cranial irradiation, 5 craniospinal, 5). Only 4 failed in the CNS after transplant, none of whom received a CNS boost, with freedom from CNS relapse at 5 years of 95% (95% confidence interval (CI), 84-98%). Freedom from CNS relapse was not improved with a radiation therapy boost to the CNS (100% vs 94%, A CNS boost may not be necessary in patients with high-risk ALL without CNS disease undergoing a myeloablative HSCT using a TBI-based regimen. Favorable outcomes were observed with a low-dose craniospinal boost in patients with CNS disease. |
36,844,179 | Prediction of Nonrelapse Mortality in Patients With Acute Myeloid Leukemia and Acute Lymphoblastic Leukemia Receiving Allogeneic Stem Cell Transplantation With Posttransplantation Cyclophosphamide-based Graft Versus Host Disease Prophylaxis. | Graft versus host disease (GVHD) prophylaxis with posttransplantation cyclophosphamide (PTCY) has been established to reduce severe GVHD, and thereby potentially reducing nonrelapse mortality (NRM) after allogeneic stem cell transplantation (alloSCT). We evaluated the predictive capacity of established NRM-risk scores in patients receiving PTCY-based GVHD prophylaxis, and subsequently developed and validated a novel PTCY-specific NRM-risk model. Adult patients (n 1861) with AML or ALL in first complete remission who received alloSCT with PTCY-based GVHD prophylaxis were included. The PTCY-risk score was developed using multivariable Fine and Gray regression, selecting parameters from the hematopoietic cell transplantation-comorbidity index (HCT-CI) and European Group for Blood and Marrow Transplantation (EBMT) score with a subdistribution hazard ratio (SHR) of ≥1.2 for 2-year NRM in the training set (70% split), which was validated in the test set (30%). The performance of the EBMT score, HCT-CI, and integrated EBMT score was relatively poor for discriminating 2-year NRM (c-statistic 51.7%, 56.6%, and 59.2%, respectively). The PTCY-risk score included 10 variables which were collapsed in 3 risk groups estimating 2-year NRM of 11% ± 2%, 19% ± 2%, and 36% ± 3% (training set, c-statistic 64%), and 11% ± 2%, 18% ± 3%, and 31% ± 5% (test set, c-statistic 63%), which also translated into different overall survival. Collectively, we developed an NRM-risk score for acute leukemia patients receiving PTCY that better predicted 2-year NRM compared with existing models, which might be applicable to the specific toxicities of high-dose cyclophosphamide. |
36,843,105 | Secondary involvement of gallbladder by acute lymphoblastic leukemia presenting clinically as cholecystitis in a young patient a case report. | Primary lymphoma of the liver, gallbladder, and extrahepatic bile ducts or secondary involvement of these organs by leukemia is exceedingly rare. Patients with primary lymphoma or leukemic involvement of the biliary tract and liver often present with symptoms and signs of biliary tract obstruction or inflammation. We present a case of a 24-year-old male with biliary tract symptoms who underwent laparoscopic cholecystectomy. His precholecystectomy complete blood count performed on the same morning showed 72% lymphocytes while peripheral blood smears showed approximately 15% blasts. Surgeon went ahead with the procedure. Imaging done prior to surgery showed thickened gallbladder, while the liver, biliary tract, and pancreas did not show any thickening or mass lesion. However, the liver was enlarged. Grossly, the gallbladder wall did not show any stones or discrete mass involving the wall. Instead, there was subtle thickening of the gallbladder wall due to diffuse infiltration by the leukemic infiltrate. This lymphoid population reacted with PAX-5 and TdT immunohistochemical antibodies in a diffuse manner confirming precursor B-cell origin. This patient was found to have B-lymphoblastic leukemia involving his bone marrow on further clinical and diagnostic workup. Patient responded well to chemotherapy and is currently on maintenance treatment. He is well 1.5 years after his diagnosis. This case highlights a unique and rare scenario where a previously undiagnosed and unsuspected hematologic malignancy initially presented with clinical features of a chronic inflammatory condition involving an abdominal organ owing to secondary involvement by the malignant infiltrate. |
36,842,323 | l-Asparaginase regulates mTORC1 activity via a TSC2-dependent pathway in pancreatic beta cells. | Eif2ak4, a susceptibility gene for type 2 diabetes, encodes GCN2, a molecule activated by amino acid deficiency. Mutations or deletions in GCN2 in pancreatic β-cells increase mTORC1 activity by decreasing Sestrin2 expression in a TSC2-independent manner. In this study, we searched for molecules downstream of GCN2 that suppress mTORC1 activity in a TSC2-dependent manner. To do so, we used a pull-down assay to identify molecules that competitively inhibit the binding of the T1462 phosphorylation site of TSC2 to 14-3-3. l-asparaginase was identified. Although l-asparaginase is frequently used as an anticancer drug for acute lymphoblastic leukemia, little is known about endogenous l-asparaginase. l-Asparaginase, which is expressed downstream of GCN2, was found to bind 14-3-3 and thereby to inhibit its binding to the T1462 phosphorylation site of TSC2 and contribute to TSC2 activation and mTORC1 inactivation upon TSC2 dephosphorylation. Further investigation of the regulation of mTORC1 activity in pancreatic β-cells by l-asparaginase should help to elucidate the mechanism of diabetes and insulin secretion failure during anticancer drug use. |
36,841,758 | A novel Menin-MLL1 inhibitor, DS-1594a, prevents the progression of acute leukemia with rearranged MLL1 or mutated NPM1. | Mixed lineage leukemia 1-rearranged (MLL1-r) acute leukemia patients respond poorly to currently available treatments and there is a need to develop more effective therapies directly disrupting the Menin‒MLL1 complex. Small-molecule-mediated inhibition of the protein‒protein interaction between Menin and MLL1 fusion proteins is a potential therapeutic strategy for patients with MLL1-r or mutated-nucleophosmin 1 (NPM1c) acute leukemia. In this study, we preclinically evaluated the new compound DS-1594a and its salts. We evaluated the preclinical efficacy of DS-1594a as well as DS-1594a·HCl (the HCl salt of DS-1594a) and DS-1594a·succinate (the succinic acid salt of DS-1594a, DS-1594b) in vitro and in vivo using acute myeloid leukemia (AML)acute lymphoblastic leukemia (ALL) models. Our results showed that MLL1-r or NPM1c human leukemic cell lines were selectively and highly sensitive to DS-1594a·HCl, with 50% growth inhibition values < 30 nM. Compared with cytrabine, the standard chemotherapy drug as AML therapy, both DS-1594a·HCl and DS-1594a·succinate mediated the eradication of potential leukemia-initiating cells by enhancing differentiation and reducing serial colony-forming potential in MLL1-r AML cells in vitro. The results were confirmed by flow cytometry, RNA sequencing, RT‒qPCR and chromatin immunoprecipitation sequencing analyses. DS-1594a·HCl and DS-1594a·succinate exhibited significant antitumor efficacy and survival benefit in MOLM-13 cell and patient-derived xenograft models of MLL1-r or NPM1c acute leukemia in vivo. We have generated a novel, potent, orally available small-molecule inhibitor of the Menin-MLL1 interaction, DS-1594a. Our results suggest that DS-1594a has medicinal properties distinct from those of cytarabine and that DS-1594a has the potential to be a new anticancer therapy and support oral dosing regimen for clinical studies (NCT04752163). |
36,840,454 | Minimal Residual Disease Detection Using Gene Scanning Analysis, Fluorescent Fragment Analysis, and Capillary Electrophoresis for IgH Rearrangement in Adult B-Lineage Acute Lymphoblastic Leukemia A Cross-Sectional Study. | Minimal residual disease (MRD) is considered the greatest prognostic factor in acute lymphoblastic leukemia (ALL). MRD is a valuable tool for anticipating impending relapse and treatment response assessment. The objective of the present study was to investigate whether the detection of IgH gene rearrangement using polymerase chain reaction (PCR)-based GeneScan analysis could be a complementary method to monitor MRD along with the quantitative realtime PCR (qPCR). In this cross-sectional study, we valued the MRD levels, based on the GeneScanning analysis (GSA), and then compared the data with quantitative real-time polymerase chain reaction at different time points in peripheral blood (PB) samples of adult B-lineage ALL patients (n35). The specific polymerase chain reaction (PCR) primers for IGH gene FR-1 and fluorescence-labeled J-primer were used and analyzed by capillary gel electrophoresis on a sequencer. The results of this study were compared with the previously reported MRD results obtained by the IGH rearrangements allele-specific oligonucleotide (ASO) -qPCR methods. The total concordance rate was 86.7%, with a P<0.001. MRD results obtained by GSA and ASO-qPCR methods were concordant in all diagnostic samples and samples on the 14th and 28th days of induction therapy. The results of these 2.5 years follow-ups demonstrated a significant correlation between the two techniques (r0.892, P<0.001). It seems that the PCR-based GeneScan analysis of IGH gene rearrangement detection may be a valuable molecular technique to distinguish monoclonality from polyclonality. And also, it may be a precise tool to detect the residual leukemic DNA in the PB follow-up samples of patients. |
36,836,703 | Gaussian Blurring Technique for Detecting and Classifying Acute Lymphoblastic Leukemia Cancer Cells from Microscopic Biopsy Images. | Visual inspection of peripheral blood samples is a critical step in the leukemia diagnostic process. Automated solutions based on artificial vision approaches can accelerate this procedure, while also improving accuracy and uniformity of response in telemedicine applications. In this study, we propose a novel GBHSV-Leuk method to segment and classify Acute Lymphoblastic Leukemia (ALL) cancer cells. GBHSV-Leuk is a two staged process. The first stage involves pre-processing, which uses the Gaussian Blurring (GB) technique to blur the noise and reflections in the image. The second stage involves segmentation using the Hue Saturation Value (HSV) technique and morphological operations to differentiate between the foreground and background colors, which improve the accuracy of prediction. The proposed method attains 96.30% accuracy when applied on the private dataset, and 95.41% accuracy when applied on the ALL-IDB1 public dataset. This work would facilitate early detection of ALL cancer. |
36,835,986 | The Significance of CD20 Intensity Variance in Pediatric Patients with B-Cell Precursor Acute Lymphoblastic Leukemia. | B-cell precursor acute lyphoblastic leukemia (ALL) is a common pediatric malignancy and patients may have significant benefits from monoclonal antibodies therapy with increased survival rates. Positive CD20 expression is identified in about half of these patients and its presence may serve as a prognostic factor in disease evolution. We performed a retrospective study including 114 patients diagnosed with B-ALL and evaluated the expression of CD20 through flow cytometry at diagnosis and on day 15. Additional immunophenotypic analyses as well as cytogenetic and molecular genetic analyses were also performed. We observed an increase in the mean fluorescence intensity (MFI) of CD20 between diagnosis-1.9 (1.2-3.26) and day 15 6.17 (2.14-27.4), ( |
36,835,271 | Differential Expression of LLT1, SLAM Receptors CS1 and 2B4 and NCR Receptors NKp46 and NKp30 in Pediatric Acute Lymphoblastic Leukemia (ALL). | Acute lymphoblastic leukemia (ALL) represents the most common pediatric cancer. Most patients (85%) develop B-cell ALL however, T-cell ALL tends to be more aggressive. We have previously identified 2B4 (SLAMF4), CS1 (SLAMF7) and LLT1 (CLEC2D) that can activate or inhibit NK cells upon the interaction with their ligands. In this study, the expression of 2B4, CS1, LLT1, NKp30 and NKp46 was determined. The expression profiles of these immune receptors were analyzed in the peripheral blood mononuclear cells of B-ALL and T-ALL subjects by single-cell RNA sequencing data obtained from the St. Jude PeCan data portal that showed increased expression of LLT1 in B-ALL and T-ALL subjects. Whole blood was collected from 42 pediatric ALL subjects at diagnosis and post-induction chemotherapy and 20 healthy subjects, and expression was determined at the mRNA and cell surface protein level. A significant increase in cell surface LLT1 expression in T cells, monocytes and NK cells was observed. Increased expression of CS1 and NKp46 was observed on monocytes of ALL subjects at diagnosis. A decrease of LLT1, 2B4, CS1 and NKp46 on T cells of ALL subjects was also observed post-induction chemotherapy. Furthermore, mRNA data showed altered expression of receptors in ALL subjects pre- and post-induction chemotherapy treatment. The results indicate that the differential expression of the receptorsligand may play a role in the T-cell- and NK-cell-mediated immune surveillance of pediatric ALL. |
36,834,787 | Targeting Glutaminolysis Shows Efficacy in Both Prednisolone-Sensitive and in Metabolically Rewired Prednisolone-Resistant B-Cell Childhood Acute Lymphoblastic Leukaemia Cells. | The prognosis for patients with relapsed childhood acute lymphoblastic leukaemia (cALL) remains poor. The main reason for treatment failure is drug resistance, most commonly to glucocorticoids (GCs). The molecular differences between prednisolone-sensitive and -resistant lymphoblasts are not well-studied, thereby precluding the development of novel and targeted therapies. Therefore, the aim of this work was to elucidate at least some aspects of the molecular differences between matched pairs of GC-sensitive and -resistant cell lines. To address this, we carried out an integrated transcriptomic and metabolomic analysis, which revealed that lack of response to prednisolone may be underpinned by alterations in oxidative phosphorylation, glycolysis, amino acid, pyruvate and nucleotide biosynthesis, as well as activation of mTORC1 and MYC signalling, which are also known to control cell metabolism. In an attempt to explore the potential therapeutic effect of inhibiting one of the hits from our analysis, we targeted the glutamine-glutamate-α-ketoglutarate axis by three different strategies, all of which impaired mitochondrial respiration and ATP production and induced apoptosis. Thereby, we report that prednisolone resistance may be accompanied by considerable rewiring of transcriptional and biosynthesis programs. Among other druggable targets that were identified in this study, inhibition of glutamine metabolism presents a potential therapeutic approach in GC-sensitive, but more importantly, in GC-resistant cALL cells. Lastly, these findings may be clinically relevant in the context of relapse-in publicly available datasets, we found gene expression patterns suggesting that in vivo drug resistance is characterised by similar metabolic dysregulation to what we found in our in vitro model. |
36,834,692 | IKAROS in Acute Leukemia A Positive Influencer or a Mean Hater | One key process that controls leukemogenesis is the regulation of oncogenic gene expression by transcription factors acting as tumor suppressors. Understanding this intricate mechanism is crucial to elucidating leukemia pathophysiology and discovering new targeted treatments. In this review, we make a brief overview of the physiological role of IKAROS and the molecular pathway that contributes to acute leukemia pathogenesis through |
36,833,225 | The Role of IRX Homeobox Genes in Hematopoietic Progenitors and Leukemia. | IRX genes are members of the TALE homeobox gene class and encode six related transcription factors (IRX1-IRX6) controlling development and cell differentiation of several tissues in humans. Classification of TALE homeobox gene expression patterns for the hematopoietic compartment, termed TALE-code, has revealed exclusive IRX1 activity in pro-B-cells and megakaryocyte erythroid progenitors (MEPs), highlighting its specific contribution to developmental processes at these early stages of hematopoietic lineage differentiation. Moreover, aberrant expression of IRX homeobox genes IRX1, IRX2, IRX3 and IRX5 has been detected in hematopoietic malignancies, including B-cell precursor acute lymphoblastic leukemia (BCP-ALL), T-cell ALL, and some subtypes of acute myeloid leukemia (AML). Expression analyses of patient samples and experimental studies using cell lines and mouse models have revealed oncogenic functions in cell differentiation arrest and upstream and downstream genes, thus, revealing normal and aberrant regulatory networks. These studies have shown how IRX genes play key roles in the development of both normal blood and immune cells, and hematopoietic malignancies. Understanding their biology serves to illuminate developmental gene regulation in the hematopoietic compartment, and may improve diagnostic classification of leukemias in the clinic and reveal new therapeutic targets and strategies. |
36,833,191 | Case Report Rare | Chromosomal rearrangements involving the |
36,832,353 | Childhood Acute Lymphoblastic Leukemia Showing Unilateral Motor Dysfunction Prior to Chemotherapy A Diffusion Tensor Tractography Study. | This study aimed to evaluate children with lymphoblastic leukemia and examine the potential correlation between corticospinal tract (CST) injury and motor dysfunction prior to chemotherapy using diffusion tensor tractography (DTT). Nineteen consecutive patients with childhood leukemia (mean age 7.483 ± 3.1 years, range 4-12 years) with unilateral motor dysfunction who underwent DTT prior to chemotherapy and twenty healthy individuals (mean age 7.478 ± 1.2 years range 4-12 years) were enrolled. Motor functions were evaluated by two independent investigators. The cause of neurological dysfunction was identified based on the CST state using mean fractional anisotropy (FA), mean fiber volume (FV), and CST integrity using DTT. All patients showed disrupted integrity and significantly decreased FA and FV in the affected CST compared to the unaffected CST and the control group ( |
36,831,690 | Optimal Use of Novel Immunotherapeutics in B-Cell Precursor ALL. | Novel immune therapies are currently being used for patients with RR ALL based on their ability to induce not only hematologic but also molecular remission. Despite promising results, specific clinical conditions, such as high tumor burden or extra medullary relapse, are still associated with a remarkably poor clinical outcome. Therefore, how to optimize the choice and the timing of such new treatments within different clinical settings remains a matter of debate. In addition, with the aim of increasing the rate and depth of molecular remission, clinical studies are currently evaluating the combination of these immunotherapies with chemotherapy in the contest of frontline treatment. The preliminary data suggest that this approach may increase the cure rate and perhaps reduce the use of allogeneic stem cell transplantation (alloHSCT) in first remission. In Ph-positive ALL, reproducible results are showing that frontline treatment programs, based on the combination of tyrosine kinase inhibitors and immunotherapy, can achieve unprecedented rates of hematologic and molecular remission as well as a long-term cure, even in the absence of chemotherapy and alloHSCT. The results from these studies have led to the development of potentially curative treatment modalities, even for older ALL patients who cannot be treated with conventional intensive chemotherapy. The present review examined the evidence for an appropriate use of the new immunotherapies in ALL patients and provided some appraisal of the current and future possible uses of these drugs for achieving further therapeutic improvement in the treatment of this disease. |
36,831,391 | Multi-Omic Approaches to Classify, Predict, and Treat Acute Leukemias. | Acute lymphoblastic leukemia (ALL) is the most common childhood cancer, in which nearly 5% of the cases are diagnosed before the first year of age .... |
36,831,356 | One-Carbon (Folate) Metabolism Pathway at Birth and Risk of Childhood Acute Lymphoblastic Leukemia A Biomarker Study in Newborns. | Leukemia is the most common cancer in children in industrialized countries, and its initiation often occurs prenatally. Folic acid is a key vitamin in the production and modification of DNA, and prenatal folic acid intake is known to reduce the risk of childhood leukemia. We characterized the one-carbon (folate) metabolism nutrients that may influence risk of childhood acute lymphoblastic leukemia (ALL) among 122 cases diagnosed at age 0-14 years during 1988-2011 and 122 controls matched on sex, age, and raceethnicity. Using hydrophilic interaction chromatography (HILIC) applied to neonatal dried blood spots, we evaluated 11 folate pathway metabolites, overall and by sex, raceethnicity, and age at diagnosis. To conduct the prediction analyses, the 244 samples were separated into learning (75%) and test (25%) sets, maintaining the matched pairings. The learning set was used to train classification methods which were evaluated on the test set. High classification error rates indicate that the folate pathway metabolites measured have little predictive capacity for pediatric ALL. In conclusion, the one-carbon metabolism nutrients measured at birth were unable to predict subsequent leukemia in children. These negative findings are reflective of the last weeks of pregnancy and our study does not address the impact of these nutrients at the time of conception or during the first trimester of pregnancy that are critical for the embryos DNA methylation programming. |
36,830,882 | Two Ways of Targeting a CD19 Positive Relapse of Acute Lymphoblastic Leukaemia after Anti-CD19 CAR-T Cells. | Therapeutic options for CD19 Cells from successive B-ALL relapses from one patient were collected. A broad immunophenotype analysis was performed. Previously targeted antigen expression, even if maintained, decreased in relapses, and new targetable antigens appeared. Cytotoxic assays showed that ALL relapses remained sensitive to lysis mediated either by ADCC, CAR-T, or TCR, even if the lysis kinetics were different depending on the effector used. We also identified an immunosuppressive monocytic population in the last relapse sample that may have led to low persistence of CAR-T. CD19 |
36,829,303 | Low leukemia burden improves blinatumomab efficacy in patients with relapsedrefractory B-cell acute lymphoblastic leukemia. | A lower baseline bone marrow blast percentage (bBMB%) is associated with better outcomes in patients with B-cell acute lymphoblastic leukemia (B-ALL) receiving blinatumomab. The objective of this analysis was to investigate the association between bBMB% and treatment outcomes in relapsedrefractory (RR) B-ALL. Data from five trials of blinatumomab for RR B-ALL were pooled for analyses. Patients were placed in one of three groups group 1, ≥50% bBMBs group 2, ≥25% to <50% bBMBs group 3, ≥5% to <25% bBMBs. Response and survival outcomes were compared between groups. Data from 683 patients (166 pediatric, 517 adult) were analyzed. Collectively, patients in groups 2 and 3 had significantly higher odds of achieving a complete remission (CR) (odds ratio OR, 3.50 95% confidence interval (CI), 2.23-5.48 and 3.93 95% CI, 2.50-6.18, respectively p < .001) and minimalmeasurable residual disease response (OR, 2.61 and 3.37, respectively p < .001) when compared with group 1 (reference). Groups 2 and 3 had a 37% and 46% reduction in the risk of death (hazard ratio HR, 0.63 and 0.54, respectively p < .001) and a 41% and 43% reduction in the risk of an event (relapse or death) (HR, 0.59 and 0.57, respectively p < .001) compared with group 1. No significant differences in response or survival outcomes were observed between groups 2 and 3. Seven of nine patients whose bBMB% was lowered to <50% with dexamethasone achieved CR with blinatumomab. Any bBMB% <50% was associated with improved efficacy following blinatumomab treatment for RR B-ALL. |
36,828,987 | Biochemical characterization of extremozyme L-asparaginase from Pseudomonas sp. PCH199 for therapeutics. | L-asparaginase (L-ASNase) from microbial sources is a commercially vital enzyme to treat acute lymphoblastic leukemia. However, the side effects associated with the commercial formulations of L-ASNases intrigued to explore for efficient and desired pharmacological enzymatic features. Here, we report the biochemical and cytotoxic evaluation of periplasmic L-ASNase of Pseudomonas sp. PCH199 isolated from the soil of Betula utilis, the Himalayan birch. L-ASNase production from wild-type PCH199 was enhanced by 2.2-fold using the Response Surface Methodology (RSM). Increased production of periplasmic L-ASNase was obtained using an optimized osmotic shock method followed by its purification. The purified L-ASNase was a monomer of 37.0 kDa with optimum activity at pH 8.5 and 60 ℃. It also showed thermostability retaining 100.0% (200 min) and 90.0% (70 min) of the activity at 37 and 50 ℃, respectively. The K |
36,828,586 | Characterization of network hierarchy reflects cell state specificity in genome organization. | Dynamic chromatin structure acts as the regulator of transcription program in crucial processes including cancer and cell development, but a unified framework for characterizing chromatin structural evolution remains to be established. Here, we performed graph inferences on Hi-C data sets and derived the chromatin contact networks. We discovered significant decreases in information transmission efficiencies in chromatin of colorectal cancer (CRC) and T-cell acute lymphoblastic leukemia (T-ALL) compared to corresponding normal controls through graph statistics. Using network embedding in the Poincaré disk, the hierarchy depths of chromatin from CRC and T-ALL patients were found to be significantly shallower compared to their normal controls. A reverse trend of change in chromatin structure was observed during early embryo development. We found tissue-specific conservation of hierarchy order in chromatin contact networks. Our findings reveal the top-down hierarchy of chromatin organization, which is significantly attenuated in cancer. |
36,827,680 | Lenalidomide-associated B-cell ALL clinical and pathologic correlates and sensitivity to lenalidomide withdrawal. | Lenalidomide is an effective component of induction and maintenance therapy for multiple myeloma, though with risk of secondary malignancies, including acute lymphoblastic leukemia (ALL). In contrast to therapy-related myeloid neoplasia, lenalidomide-associated lymphoblastic neoplasia remains poorly characterized. We conducted a dual institution retrospective study of 32 ALL cases that arose following lenalidomide maintenance (all B-lineage, 3132 BCRABL-negative). B-ALL was diagnosed at median 54 months (range 5-119) following first exposure to lenalidomide and following median 42 months of cumulative lenalidomide exposure (range 2-114). High incidence of TP53 mutations (919 evaluable cases) and low hypodiploidy (826) were identified. Despite older age of many patients and poor-risk features of B-ALL cases observed, rates of complete response (CR) or CR with incomplete hematologic recovery were high following B-ALL therapy (2528 patients receiving treatment). Median event-free survival was 35.4 months among treated patients (not reached among those undergoing allogeneic hematopoietic cell transplantation HCT), and 16 patients remain alive without evidence of B-ALL following HCT or extended maintenance therapy. Additionally, we describe regression of B-ALL or immature B-cell populations with B-ALL immunophenotype following discontinuation of lenalidomide in 5 patients, suggesting that lenalidomide may drive leukemic progression even after initiation of lymphoblastic neoplasia and that lenalidomide withdrawal alone may be an appropriate first-line intervention in selected patients. Monitoring for early B-ALL-like proliferations may offer opportunities for lenalidomide withdrawal to prevent progression. Established combination chemotherapy regimens, newer surface antigen-targeted approaches, and allogeneic HCT are effective in many patients with lenalidomide-associated B-ALL and should be offered to medically fit patients. |
36,825,099 | Dosimetric Evaluation of the Uterus in Patients Receiving Total Body Irradiation with Ovarian Shielding. | Infertility is a well-known late complication in patients receiving hematopoietic stem cell transplantation (HSCT). We previously reported that total body irradiation (TBI) with ovarian shielding reduces the radiation dose to the ovaries to 2.4 Gy - one-fifth of the dose compared to conventional TBI - and preserves fertility without increasing the risk of relapse. Exposure to the uterus and ovaries can reportedly affect pregnancy and childbirth. However, the dose constraint of the uterus that causes infertility remains unknown. Herein, we report the pregnancy and birth outcomes of 2 patients who gave birth following TBI with ovarian shielding and evaluated the dose to the uterus using a dose-volume histogram. Case 1 involved a 30-year-old woman with acute myeloid leukemia who underwent HSCT at 21 years of age with a uterus mean dose ( |
36,824,825 | Epigenomic mapping in B-cell acute lymphoblastic leukemia identifies transcriptional regulators and noncoding variants promoting distinct chromatin architectures. | B-cell lineage acute lymphoblastic leukemia (B-ALL) is comprised of diverse molecular subtypes and while transcriptional and DNA methylation profiling of B-ALL subtypes has been extensively examined, the accompanying chromatin landscape is not well characterized for many subtypes. We therefore mapped chromatin accessibility using ATAC-seq for 10 B-ALL molecular subtypes in primary ALL cells from 154 patients. Comparisons with B-cell progenitors identified candidate B-ALL cell-of-origin and AP-1-associated Pro-B progenitor cells as the most common cell-of-origin for B-ALL AP-1 TF-associated |
36,824,131 | Comparison of diagnostic and treatment processes among pediatric and adolescents and young adults populations suffering from acute lymphoblastic leukemia and lymphomas. | Acute lymphoblastic leukemia (ALL) and lymphomas affect both pediatric and adult populations, therefore, they might be treated by pediatric or adult centers.It has been proven that the prognosis among adolescents and young adults (AYA) is poorer than among children, which remains a subject of research. Many factors are suspected to affect the diagnostic and treatment processes in adolescents and young adults, one of them being the organization of the healthcare system.The aimof the studywas to compare the time intervals between different events on disease trajectory in pediatric and AYA groups suffering from ALL and lymphomas. We collected data on 81 patients diagnosed with ALL (50 children and 31 AYAs) and 100 patients diagnosed with lymphomas (50 children and 50 AYAs). Statistical analysis was performed in order to compare the groups. The results confirmed the hypothesis that the duration of the diagnostic process differs significantly between groups. For patients with ALL, the analyzed time intervals were significantly shorter in the pediatric group than in the AYA group first contact with a GP - admission to Hematology Department (2 vs. 5 days pvalue 0.004), first contact with a GP - treatment (6 vs. 12 days, p-value0.001), diagnosis - treatment (1 vs. 3 days, p-value0.003). In the case of patients suffering from lymphomas, the results were similar. The analyzed time intervals were significantly shorter in the pediatric group than in the AYA group first contact with a GP- diagnosis (21 vs. 40.5 days, p-value<0.0001), first contact with a GP - treatment (27 vs. 65 days, p-value<0.0001). Trend analysis showed that the longer patients had presented symptoms before contacting the primary care physician, the longer they waited for the beginning of treatment both in ALL and lymphomas groups (p-values0.0129 and 0.0038 respectively). As the diagnostic and treatment processes are longer for AYA patients, actions must be undertaken in order to ensure equality and improve the healthcare system in Poland and possibly other countries. |
36,822,174 | LncRNA15691 promotes T-ALL infiltration by upregulating CCR9 via increased MATR3 stability. | Our previous studies demonstrated that CCR9 plays an important role in several aspects of T-cell acute lymphoblastic leukemia progression and that CCR9 is a potential therapeutic target. However, the underlying mechanism that regulates CCR9 expression remains incompletely understood. In this study, bioinformatics analysis and validation in clinical samples revealed the lncRNA15691 to be positively correlated with CCR9 mRNA expression and significantly upregulated in T-cell acute lymphoblastic leukemia samples and CCR9high T-cell acute lymphoblastic leukemia cell lines. LncRNA15691, a previously uncharacterized lncRNA, was found to be located in both the cytoplasm and the nucleus via fluorescence in situ hybridization assay. In addition, lncRNA15691 upregulated the expression of CCR9 and was involved in T-cell acute lymphoblastic leukemia cell invasion. In vivo experiments showed that lncRNA15691 promoted leukemia cell hominginfiltration into the bone marrow, blood, and spleen, whereas the CCR9 ligand, CCL25, augmented the extramedullary infiltration of CCR9low leukemia cells overexpressing lncRNA15691 into blood, spleen, and liver. Subsequently, RNA protein pull-down assays, coupled with liquid chromatography-tandem mass spectrometry, were used to uncover potential lncRNA15691-interacting proteins, which were then validated by RNA immunoprecipitation. These mechanistic studies revealed that lncRNA15691 upregulated CCR9 expression via directly binding to and stabilizing MATR3 by inhibiting its nuclear degradation mediated by PKA. Collectively, our study revealed a novel mechanism of regulating CCR9 expression and implicated lncRNA15691 as a potential novel biomarker for T-cell acute lymphoblastic leukemia infiltration. |
36,821,772 | Impact of Vincristine-Steroid Pulses in Maintenance for B-Cell Pediatric ALL A Systematic Review and Meta-Analysis. | The benefit associated with the incorporation of vincristine-corticosteroid pulses into maintenance therapy for pediatric acute lymphoblastic leukemia (ALL) is unclear, particularly in the context of modern intensive therapy. This systematic review and meta-analysis examined the impact of reducing frequency of vincristine-steroid pulses during maintenance for newly diagnosed pediatric patients with B-cell ALL. Two authors reviewed all eligible studies identified through a comprehensive search, extracted data from the 25 included publications (12 513 patients), and assessed risk of bias. We created historical and contemporary subgroups the latter included trials providing a version of Protocol III from early Berlin-Frankfurt-Munster trials and eliminating routine prophylactic cranial radiation. Meta-analysis of event-free survival data suggested no benefit between more frequent or less frequent pulses in contemporary trials (HR 0.96, 95%CI 0.85-1.09) which differs significantly from historical trials (HR 0.79, 95%CI 0.68-0.91, p0.04). We found no significant impact of reduced pulse frequency on overall survival or relapse risk. There was however an increased odds of Grade 3 non-hepatic toxicity in the high pulse frequency group (OR 1.31, 95%CI 1.12-1.52). This systematic review suggests that the previous benefit conferred by frequent pulses of vincristine-steroids in maintenance therapy for pediatric B-cell ALL in historical trials no longer applies in contemporary trials but is associated with toxicity. These results will help guide development of the next phase of clinical trials in the field of pediatric ALL and question the continued use of pulses in maintenance for patients not on clinical trials, particularly those experiencing toxicity. |
36,820,588 | Allogeneic stem cell transplantation without preconditioning in a child with therapy-related myelodysplastic syndrome A case report. | Infants with mixed-lineage leukemia (MLL)-rearranged leukemia are usually refractory to standard induction therapy and are not immediate candidates for allogeneic hematopoietic stem cell transplantation (allo-HSCT). Chromosome 11q23 translocations, resulting in MLL rearrangement, have been well characterized in infant acute lymphoblastic leukemia (ALL). While t(411) ALL continues to have carry a bleak prognosis, patients with therapy-related myelodysplastic syndrome (t-MDS) have a shorter median overall survival than those compared with de novo MDS. We describe a child with t-MDS who evolved from MLL-rearranged ALL and was successfully treated with HSCT without toxic preconditioning. MDS diagnosis was based on morphological characteristics of bone marrow dysplasia in patients with clinical manifestations evidence of hematopoiesis impairments by different combinations of anemia, leukopenia, neutropenia, and thrombocytopenia. Although the best donor for allo-HSCT is generally considered an human leukocyte antigen-matched sibling, only 30% of patients have a suitable sibling. HSCT from an unrelated donor is a suitable option for patients with t-MDS who do not have matched sibling donors. Allo-HSCT without recipient preconditioning could be a promising treatment option for t-MDS, especially for patients with recurrent or persistent infections. Cytogenetics, prognosis, and treatment of t-MDS are briefly discussed. Preconditioning before allo-HSCT seriously damages immune function. This work reviews our experience with a patient with t-MDS following ALL complicated by recurrent infections, and highlights our choice to omit preconditioning from allo-HSCT. |
36,819,185 | Malignant DFFB isoform switching promotes leukemia survival in relapse pediatric T-cell acute lymphoblastic leukemia. | With modern treatment most children with acute lymphoblastic leukemia (ALL) survive without relapse. However, for children who relapse the prognosis is still poor, especially in children with T-cell phenotype (T-ALL) and remains the major cause of death. The exact mechanism of relapse is currently not known. While contribution of RNA processing alteration has been linked to other hematological malignancies, its contribution in pediatric T-ALL may provide new insights. Almost all human genes express more than one alternative splice isoform. Thus, gene modulation producing a diverse repertoire of the transcriptome and proteome have become a significant molecular marker of cancer and a potential therapeutic vulnerability. To study this, we performed RNA-sequencing analysis on patient-derived samples followed by splice isoform-specific PCR. We uncovered a distinct RNA splice isoform expression pattern characteristic for relapse samples compared to the leukemia samples from the time of diagnosis. We also identified deregulated splicing and apoptosis pathways specific for relapse T-ALL. Moreover, patients with T-ALL displayed pro-survival splice isoform switching favoring pro-survival isoforms compared to normal healthy stem cells. Cumulatively, pro-survival isoform switching and DFFB isoform regulation of SOX2 and MYCN may play a role in T-ALL proliferation and survival, thus serving as a potential therapeutic option. |
36,819,173 | Germline | Familial platelet disorder with associated myeloid malignancy (FPD-MM OMIM 601399) is related to germline |
36,819,167 | Safety of re-challenging adults with acute lymphoblastic leukemia with PEG-asparaginase-induced severe hypertriglyceridemia when treated with a pediatric-inspired regimen. | PEG-asparaginase is used as a treatment for Philadelphia-negative acute lymphoblastic leukemia. In pediatric studies, triglycerides (TGs) were affected more by PEG-asparaginase than by native L-asparaginase (10.0% vs. 5.5%). We conducted a retrospective study to determine the safety of re-challenging adult patients with PEG-asparaginase after experiencing an episode of severe hypertriglyceridemia (>1000 mgdl or 11.4 mmolL). The incidence of hypertriglyceridemia associated with PEG-asparaginase in adult patients was high (67.5%). Therefore, checking TGs at baseline and monitoring levels while receiving PEG-asparaginase need to be considered and studied in prospective studies. However, in patients with hypertriglyceridemia not complicated by acute pancreatitis, re-challenging is safe once TG levels normalize. |
36,817,761 | Chidamide as maintenance after chemotherapy or hematopoietic stem cell transplantation in 27 children with T-cell lymphoblastic leukemia A real-world prospective study. | The long-term overall survival of children with T-cell acute lymphoblastic leukemia (T-ALL) is limited to approximately 80-85% because of a high incidence of relapse after achieving remission with intensive chemotherapy and hematopoietic stem cell transplantation (HSCT). Novel treatment strategies inducing long-term remission are needed to improve the outcome. Histone deacetylase inhibitors (HDACis) have been reported to be effective in a series of T-ALL cases. Preclinical studies suggested that T-ALL cells are sensitive to Chidamide, which is a selective HDACi. This preliminary clinical study evaluated the efficacy and safety of Chidamide in combination with chemotherapy or post-HSCT for children with T-ALL at a dose of 0.5 mgkg weight of patient twice per week for at least 6 months. In total, 27 children with a mean age of 7.88 years were included. The high-risk proportion was 66.7%. After a median follow-up period of 37.8 months (9.5-67.9 months), the overall survival and event-free survival in the patients treated with Chidamide were 94.1 and 95.2%, respectively. All patients except two maintained persistent remission with <0.01% blast cells in minimal residual disease. The combination therapy with Chidamide in a case series of T-ALL shows the promising clinical efficacy and good safety in children. httpswww.chictr.org.cn, identifier ChiCTR2000030357. |
36,817,394 | AgNOR patterns and configurations in adult acute leukemia patients. | The number of argyrophilic nucleolus organizer regions (AgNOR) is related to the proliferative activity of cells and the degree of neoplastic transformation. The surface area of AgNOR depending on nuclear structure may be a predictor of tumor recurrence, while research into acute leukemias is scarce. The aim of the study was to determine whether the assessment of AgNOR parameters is useful in the differentiation of acute leukemias and, together with cytogenetic changes, would allow for a quick evaluation of the risk group. The AgNOR structures were analyzed in terms of the shape, surface area and distribution in bone marrow blast cells in patients with acute leukemias. We observed significant differences in the AgNOR structures, simple, compound and complex patterns between acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Complex structures were more numerous in ALL than in AML patients. There were significant differences in the distribution of AgNOR configuration among various cytogenetic AML risk groups. We observed a significant difference in the mean number of AgNOR between ALL-T and ALL-B. We detected diversity in the AgNOR structures and pattern map in AML and ALL. Thus, presentation of a variety of AgNOR configurations is innovative and can be a useful method of differentiating patients with acute leukemia types and cytogenetic risk. |
36,816,964 | Possible mechanism of metabolic and drug resistance with L-asparaginase therapy in childhood leukaemia. | L-asparaginase, which hydrolyzes asparagine into aspartic acid and ammonia, is frequently used to treat acute lymphoblastic leukaemia in children. When combined with other chemotherapy drugs, the event-free survival rate is 90%. Due to immunogenicity and drug resistance, however, not all patients benefit from it, restricting the use of L-asparaginase therapy in other haematological cancers. To solve the problem of immunogenicity, several L-ASNase variants have emerged, such as |
36,816,392 | Monitoring of treatment with L-asparaginase in children with acute lymphoblastic leukaemia, with a focus on silent inactivation and its influence on the treatment outcome. | The aim of the study was to analyse the frequency of silent inactivation and allergic reaction to asparaginase (ASP) and its impact on treatment results in patients with lymphoblastic leukaemia. Seventy patients with acute lymphoblastic leukaemia treated with ASP were enrolled in the study. Asparaginase activity was monitored. The patients were switched to another ASP formulation after allergy or inactivation. The treatment results were analysed. Silent inactivation of native Monitoring of ASP activity is crucial to recognize silent inactivation and to guarantee treatment effectiveness by switching to other ASP preparations. |
36,815,626 | Total body irradiation-free haploidentical peripheral blood stem cell transplantation compared to related and unrelated donor transplantation in pediatrics with acute lymphoblastic leukemia. | Acute lymphoblastic leukemia (ALL) is the most prevalent childhood cancer under the age of 15 years. Despite the recent advances in therapeutic regimens, relapse occurs in 15%-20% of pediatric patients after chemotherapy, and hematopoietic stem cell transplantation (HSCT) is the best treatment option. However, donor availability is one of the major challenges. Over the last decade, haploidentical donor (HID) transplantation has evolved as an alternative option. Herein, we aimed to compare the transplant outcomes in pediatric patients receiving total body irradiation (TBI)-free myeloablative regimens, between non-HID and HID transplant. The study included 60 pediatric ALL patients who had undergone HSCT from October 2016 until September 2020. Forty-three patients received non-HID HSCT, while 17 patients received HID. The sources of stem cells (SC) were peripheral blood stem cells (PBSC) for all the patients. The conditioning regimen was based on busulfan and cyclophosphamide. For graft-versus-host disease (GvHD) prophylaxis, patients received cyclosporine and methotrexate in the setting of non-HID transplantation, where HIDs received post-transplant cyclosporine and cyclophosphamide. The cumulative incidences of 3-year overall survival (OS) were 73.1%, 66.6%, and 69.5%, for matched sibling donor-matched related donor (MSD-MRD), matched unrelated donor-mismatched unrelated donor (MUD-MMUD), and HID groups, respectively (p .85). The cumulative incidences of grade II-IV acute GvHD for the MRD, MUD-MMUD, and HID groups were 29%, 41%, and 49%, respectively (p .47). Furthermore, the 3-year cumulative incidence of chronic GvHD was MSD-MRD 70% versus MUD-MMUD 42% versus HID 45% (p .64). The 3-year cumulative incidence of relapse post transplantation was 45%, 18%, and 45%, respectively, for the MSD-MRD, MUD-MMUD, and HID groups, and the differences were not statistically significant (p .55). There was a higher risk for cytomegalovirus (CMV) infection in patients receiving HID transplants compared to those of non-HIDs (p < .01). Our results indicate that PBSC-HID transplant outcomes in the setting of non-TBI conditioning are comparable to those of non-HIDs in pediatric ALL patients. |
36,815,611 | Subsequent cancers within 5 years from initial diagnosis of childhood cancer. Patterns and risks in the population of Great Britain. | Patterns and risks of subsequent primary tumours (SPTs) among long-term survivors of childhood cancer have been extensively described, but much less is known about early SPTs (ESPTs) occurring within 5 years after initial diagnosis. We carried out a population-based study of ESPTs following childhood cancer throughout Britain, using the National Registry of Childhood Tumours. The full study series comprised all ESPTs occurring among 56,620 children whose initial cancer diagnosis was in the period 1971-2010. Frequencies of ESPT were calculated for the entire cohort. For analyses of risk, follow-up began 92 days after initial diagnosis. ESPT developed in 0.4% of children overall, 0.52% of those initially diagnosed at age less than 1 year and 0.38% of those diagnosed at age 1-14 years. Standardised incidence ratio (SIR) was 7.7 (95% confidence interval CI 6.7-8.9), overall 9.5 (95% CI 7.1-12.5) for children initially diagnosed in 1981-1990 and 6.5-7.5 for those from earlier and later decades. SIR by type of first cancer ranged from 4.4 (95% CI 1.8-9.1) for Wilms tumour to 13.1 (95% CI 7.7-21.0) for non-Hodgkin lymphoma. SIR by type of ESPT ranged from 2.0 (95% CI 1.0-3.4) for acute lymphoblastic leukaemia to 66.6 (95% CI 52.3-83.6) for acute myeloid leukaemia. Predisposition syndromes were known to be implicated in 21% of children with ESPT and suspected in another 5%. This study provides an overview of the patterns and risks of ESPTs in a large population where many children received therapy that is still in widespread use. Further research will be needed to monitor and understand changes in risk as childhood cancer treatment continues to evolve. |
36,814,093 | Clinical, biological, and outcome features of P2RY8-CRLF2 and CRLF2 over-expression in pediatric B-cell precursor acute lymphoblastic leukemia according to the CCLG-ALL 2008 and 2018 protocol. | CRLF2 alterations are associated with B-cell precursor acute lymphoblastic leukemia (BCP-ALL). This study aimed to explore the clinical, biological, and outcome features of pediatric BCP-ALL with CRLF2 abnormalities. This study enrolled 630 childhood BCP-ALLs treated on CCLG-ALL 2008 or 2018 protocol. P2RY8-CRLF2 was determined by Sanger sequencing and CRLF2 expression was evaluated by qRT-PCR. The correlation between clinical, biological features and outcomes with P2RY8-CRLF2 or CRLF2 over-expression were analyzed. P2RY8-CRLF2 and CRLF2 over-expression were found in 3.33% and 5.71% respectively. P2RY8-CRLF2 was associated with male, higher frequency of CD7 expression, high WBC and MRD before consolidation. CRLF2 over-expression showed ETV6-RUNX1 These findings indicate P2RY8-CRLF2 identifies a subset of patients with specific features and adverse outcomes that could be improved by risk-directed treatment. |
36,813,736 | Prognosis of patients with acute lymphoblastic leukaemia relapsing after allogeneic stem cell transplantation. | The outcomes of patients with acute lymphoblastic leukaemia (ALL) presenting relapse after allogeneic stem cell transplant (Allo-SCT) are poor, with few data available in this setting. To evaluate the outcomes of patients with ALL presenting relapsed after allo-SCT, we performed a retrospective study including 132 from 11 centers in Spain. Therapeutic strategies consisted of palliative treatment (n22), chemotherapy (n82), tyrosine kinase inhibitors (n26), immunotherapy with inotuzumab andor blinatumumab (n19), donor lymphocyte infusions (n29 pts), second allo-SCT (n37) and CAR T therapy (n14). The probability of overall survival (OS) at 1 and 5 years after relapse was 44% (95%CI 36% 52%) and 19% (95% CI 11% 27%). In the 37 patients undergoing a second allo-SCT, the 5-year estimated OS probability was 40% 22% 58%. Younger age, recent allo-SCT, late relapse, 1st complete remission at 1st allo-SCT and chronic graft-versus-host disease confirmed their positive impact on survival in the multivariable analysis. Despite the poor prognosis of patients with ALL presenting relapse after a first allo-SCT, some can be satisfactorily rescued and a second allo-SCT still remains a valid option for selected patients. Moreover, emerging therapies really might improve ALL patients outcome when relapsing after an allo-SCT . |
36,812,801 | Reliable cell preparation protocol for Raman imaging to effectively differentiate normal leukocytes and leukemic blasts. | Leukemias are a remarkably diverse group of malignancies originating from abnormal progenitor cells in the bone marrow. Leukemia subtypes are classified according to the cell type that has undergone neoplastic transformation using demanding and time-consuming methods. Alternative is Raman imaging that can be used both for living and fixed cells. However, considering the diversity of leukemic cell types and normal leukocytes, and the availability of different sample preparation protocols, the main objective of this work was to verify them for leukemia and normal blood cell samples for Raman imaging. The effect of glutaraldehyde (GA) fixation in a concentration gradient (0.1 %, 0.5 %, and 2.5 % GA) on the molecular structure of T-cell acute lymphoblastic leukemia (T-ALL) and peripheral blood mononuclear cells (PBMCs) was verified. Changes in the secondary structure of proteins within cells were indicated as the main effect of fixation, as shown by an increase in band intensity at 1041 cm |
36,812,120 | Comparative treatment costs of risk-stratified therapy for childhood acute lymphoblastic leukemia in India. | To evaluate the treatment cost and cost effectiveness of a risk-stratified therapy to treat pediatric acute lymphoblastic leukemia (ALL) in India. The cost of total treatment duration was calculated for a retrospective cohort of ALL children treated at a tertiary care facility. Children were risk stratified into standard (SR), intermediate (IR) and high (HR) for B-cell precursor ALL, and T-ALL. Cost of therapy was obtained from the hospital electronic billing systems and details of outpatient (OP) and inpatient (IP) from electronic medical records. Cost effectiveness was calculated in disability-adjusted life years. One hundred and forty five patients, SR (50), IR (36), HR (39), and T-ALL (20) were analyzed. Median cost of the entire treatment for SR, IR, HR, and T-ALL was found to be $3900, $5500, $7400, and $8700, respectively, with chemotherapy contributing to 25%-35% of total cost. Out-patient costs were significantly lower for SR (p < 0.0001). OP costs were higher than in-patient costs for SR and IR, while in-patient costs were higher in T-ALL. Costs for non-therapy admissions were significantly higher in HR and T-ALL (p < 0.0001), representing over 50% of costs of in-patient therapy. HR and T-ALL also had longer durations of non-therapy admissions. Based on WHO-CHOICE guidelines, the risk-stratified approach was very cost effective for all categories of patients. Risk-stratified approach to treat childhood ALL is very cost-effective for all categories in our setting. The cost for SR and IR patients is significantly reduced through decreased IP admissions for both, chemotherapy and non-chemotherapy reasons. |
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