Acute Lymphoblastic Leukemia Patients Research Articles

Bacterial heat shock protein genes during induction chemotherapy in pediatric patients with acute lymphoblastic leukemia.

Background: Heat shock proteins (HSP) protect cancer cells. Gastrointestinal bacteria contain HSP genes and can release extracellular vesicles which act as biological shuttles. Stress from treatment may result in a microbial community with more HSP genes, which could contribute to circulating HSP levels. Methods: The authors examined the abundance of five bacterial HSP genes pre-treatment and during induction in stool sequences from 30 pediatric acute lymphoblastic leukemia patients. Results: Decreased mean HTPG counts (p=0.0024) pre-treatment versus induction were observed. During induction, HTPG, Shannon diversity and Bacteroidetes decreased (p=7.5e-4; 1.1e-3; 8.6e-4), while DNAK and Firmicutes increased (p=6.9e-3; 9.2e-4). Conclusion: Understanding microbial HSP gene community changes with treatment is the first step in determining if bacterial HSPs are important to the tumor microenvironment and leukemia treatment.

Single-cell multi-omics reveal stage of differentiation and trajectory-dependent immunity-related gene expression patterns in human erythroid cells.

The role of Erythroid cells in immune regulation and immunosuppression is one of the emerging topics in modern immunology that still requires further clarification as Erythroid cells from different tissues and different species express different immunoregulatory molecules. In this study, we performed a thorough investigation of human bone marrow Erythroid cells from adult healthy donors and adult acute lymphoblastic leukemia patients using the state-of-the-art single-cell targeted proteomics and transcriptomics via BD Rhapsody and cancer-related gene copy number variation analysis via NanoString Sprint Profiler. We found that human bone marrow Erythroid cells express the ARG1, LGALS1, LGALS3, LGALS9, and C10orf54 (VISTA) immunosuppressive genes, CXCL5, CXCL8, and VEGFA cytokine genes, as well as the genes involved in antimicrobial immunity and MHC Class II antigen presentation. We also found that ARG1 gene expression was restricted to the single erythroid cell cluster that we termed ARG1-positive Orthochromatic erythroblasts and that late Erythroid cells lose S100A9 and gain MZB1 gene expression in case of acute lymphoblastic leukemia. These findings show that steady-state erythropoiesis bone marrow Erythroid cells express myeloid signature genes even without any transdifferentiating stimulus like cancer.

Incidence and Survivability of Acute Lymphocytic Leukemia Patients in the United States: Analysis of SEER Data Set from 2000-2019

Incidence and Survivability of Acute Lymphocytic Leukemia Patients in the United States: Analysis of SEER Data Set from 2000-2019

Detection of Bk Polyomavirus Antigen in Patients with Acute Lymphoblastic Leukemia

Background: BK polyomavirus that is acquired in early childhood as BKPyV is near ubiquitous in adults with a seroprevalence of >80%, it has been found as the main cause of hemorrhagic cystitis in hematopoietic stem cell transplantation patients, due to immunosuppression regimen that lead to the activation of the virus from the latency status and lead to increased viral shedding in urine (viuria).
 Objective: To investigate the frequency of BK Polyomavirus antigen excretion in urine of children with acute lymphoblastic leukemia with and without chemotherapy and compare it with normal controls. 
 Patients and Methods: A case-control study conducted from December 2021 to May 2022 in Baghdad, Iraq on leukemia patients of Central Pediatrics Hospital (Al-Eskan ). Urine samples and urine sediment smears were collected from 60 acute lymphoblastic leukemia patients. And compared with 60 apparently healthy age and sex-matched children, BK polyomavirus antigen in urine was detected using Enzyme-linked Immunosorbent Assay and urine cytology were Pap stained for the detection of decoy cells (DCs).
 Results: Positive BKPyV antigen in urine was seen in 55 (91.7%) of Acute lymphoblastic leukemia patients and 39 (65.0%) in controls (p=<0.001) and all the patients were decoy negative. There was no significant effect of the positivity of antigenuria on neither leukocytes level nor on the occurance of relapse in leukemia patients. 
 Conclusion: The very high frequency of BKPyV in the urine signifies the importance of reactivation of this virus in ALL patients with and without chemotherapy.

Detection of Bk Polyomavirus Antigen in Patients with Acute Lymphoblastic Leukemia

Background: BK polyomavirus that is acquired in early childhood as BKPyV is near ubiquitous in adults with a seroprevalence of >80%, it has been found as the main cause of hemorrhagic cystitis in hematopoietic stem cell transplantation patients, due to immunosuppression regimen that lead to the activation of the virus from the latency status and lead to increased viral shedding in urine (viuria). Objective: To investigate the frequency of BK Polyomavirus antigen excretion in urine of children with acute lymphoblastic leukemia with and without chemotherapy and compare it with normal controls. Patients and Methods: A case-control study conducted from December 2021 to May 2022 in Baghdad, Iraq on leukemia patients of Central Pediatrics Hospital (Al-Eskan ). Urine samples and urine sediment smears were collected from 60 acute lymphoblastic leukemia patients. And compared with 60 apparently healthy age and sex-matched children, BK polyomavirus antigen in urine was detected using Enzyme-linked Immunosorbent Assay and urine cytology were Pap stained for the detection of decoy cells (DCs). Results: Positive BKPyV antigen in urine was seen in 55 (91.7%) of Acute lymphoblastic leukemia patients and 39 (65.0%) in controls (p=<0.001) and all the patients were decoy negative. There was no significant effect of the positivity of antigenuria on neither leukocytes level nor on the occurance of relapse in leukemia patients. Conclusion: The very high frequency of BKPyV in the urine signifies the importance of reactivation of this virus in ALL patients with and without chemotherapy. Keywords: Acute lymphoblastic leukemia, BK Polyomavirus, Antigenuria

Targeted treatment options for paediatric B-cell precursor acute lymphoblastic leukaemia patients with constitutional or somatic chromosome 21 alterations

BackgroundChromosome 21 is affected in ∼60% of paediatric B-cell precursor acute lymphoblastic leukaemia (BCP-ALL) patients and includes somatic and constitutional gains, intrachromosomal amplification of chromosome 21 (iAMP21), and the translocation t(12;21) resulting in the ETV6::RUNX1 gene fusion. MethodsSince these numeric and structural chromosome 21 alterations are not targetable, we studied the type and frequency of yet-proven targetable events co-occurring with chromosome 21 alterations. ResultsAmong 307 primary paediatric BCP-ALL cases, JAK/STAT pathway lesions were most frequent in patients with constitutional gain of chromosome 21 (Down syndrome ALL; 35/71, 49%) and iAMP21 (9/22, 41%). RAS pathway lesions were most frequent in high hyperdiploidy (62/108, 57%) and FLT3 lesions were most frequent in iAMP21 (7/22, 32%). Virtually all cases expressed CD19 and CD22 at the cell surface. Positivity for CD20 surface expression ranged from 67% in iAMP21 (8/12) to 20% in ETV6::RUNX1 (26/129). ConclusionActivated JAK/STAT, RAS or FLT3 signalling, and CD marker surface expression may provide targetable treatment options for the majority of chromosome 21-altered BCP-ALL cases.

Risk factors and mortality associated with venous thromboembolism in the elderly US population with acute lymphocytic leukemia

ObjectiveThe purpose of our study was to examine risk factors for venous thromboembolism (VTE) and VTE associated mortality in elderly acute lymphocytic leukemia (ALL) patients receiving different treatment options. MethodsWe analyzed data from the United States SEER-Medicare database (2007–2015) for patients ≥65 years diagnosed with ALL. Data were stratified by treatment options into three groups as chemotherapy: the use of antimetabolites, anthracyclines, alkylating agents or vinca alkaloids; other treatment: the use of corticosteroids/tyrosine kinase inhibitors without chemotherapy; and no treatment. Logistic regression was used to examine risk factors for VTE and Cox proportional regression was used to evaluate Hazard Ratios (HRs) for the effect of VTE on mortality in ALL patients. ResultsIn a cohort of 1088 elderly ALL patients, 17.4 % patients had a diagnosis of VTE. VTE was diagnosed in 27.7 % of 159 patients who received chemotherapy, 16.2 % of 328 patients who received other treatment, and 15.3 % of 601 patients who did not receive any treatment (p < 0.001). Adjusted odds of VTE were 1.59 (95 % CI, 1.02–2.48) in patients who received chemotherapy, and ORa = 0.88 (95 % CI, 0.60–1.30) in those who received other treatment, compared to those who did not receive any treatment. VTE was not associated with the risk of death in ALL patients (HRa = 0.85, 95 % CI, 0.70–1.02). ConclusionOur study identified VTE risk factors and the effect of VTE on mortality in elderly ALL patients with and without treatment.

Hybrid Email and Outpatient Clinics to Optimize Maintenance Therapy in Acute Lymphoblastic Leukemia.

Acute lymphoblastic leukemia treatment includes an outpatient (OP)-based 2-year maintenance therapy (MT). Over an 8-year period, patients were transited from only OP to a hybrid e-clinic/OP-clinic model. Electronic and patient-held medical records of acute lymphoblastic leukemia patients 1 to 18 years old during MT were used to analyze demographics, drug doses, treatment response and cost. A survey evaluated family satisfaction with the hybrid service. Four hundred and seventy-eight children, all with at least 1 year of MT from March 13, 2014 to March 24, 2022 were grouped into 4 treatment eras, representing the transition from all OP (era 1) to the current hybrid MT practice (era 4). Cohort demographics were similar across all eras. With transition to era 4, OP visits decreased to a third (16 to 18/48 visits). Practice optimization in era 2 resulted in higher MT dose intensity in subsequent eras (era 1: median 82% [interquartile range, 63 to 97]; era 2: 93% [73 to 108]; era 3: 88% [68 to 106]; era 4: 90% [74 to 114], P <0·0001), with no differences in absolute neutrophil count or neutropenia-related toxicity ( P =0.8). The hybrid service reduced MT expenses by ~50% and families (133/156, 85%) reported being very satisfied. Our experience indicates that a hybrid model is feasible, effective and less burdensome for patients and families.

T(1;4) translocation in a child with acute lymphoblastic leukemia: a case report

BackgroundAcute lymphoblastic leukemia is the most common childhood cancer, with an 80% frequency in children between 1 and 10 years old. The outcome and prognosis of acute lymphoblastic leukemia in children depends on various factors, such as age, clinical and biological features, and cytogenetic factors.Case presentationWe report the case of a pediatric patient, a 4-year-old Moroccan female who was referred to the Hematology and Oncology Department of 20 August 1953 Hospital in Casablanca and diagnosed with B-cell acute lymphoblastic leukemia associated with a rare genetic chromosomal abnormality.ConclusionTranslocation (1;4)(p21;p15) is a relatively rare chromosomal abnormality found in human leukemia and was never described isolated in pediatric B-cell acute lymphoblastic leukemia patients. It showed a good evolution by complete remission and recovery of this patient after receiving all chemotherapy and after 8 years of follow-up.

Epidemiological and clinical characteristics of adult acute lymphoblastic leukemia patients in Chile: A single-center analysis

BackgroundAcute lymphoblastic leukemia represents 20% of acute leukemias in adults. Currently, there is limited data in Chile regarding the clinical, cytogenetic, and prognostic characteristics of this condition. MethodsThis is a retrospective, observational, and descriptive study of 67 patients treated for acute lymphoblastic leukemia at the Arturo Lopez Perez Foundation between 2018 and 2021. The main objective is to evaluate epidemiological and clinical characteristics, as well as identifying factors associated with improved overall survival and/or progression-free survival. Results88% of the cases were B-lineage, mainly the common B phenotype. Cytogenetic analysis was performed in less than 50% of the patients, with lower yield than expected according to the literature. Molecular testing was performed in 86.5% of the patients, with the most frequent alteration being BCR-ABL. No study was performed to search for Ph-like abnormalities. The rate of complete response after induction was 83.3%, the majority of patients having negative minimal residual disease. Only 12% of the patients received consolidation with allogenic bone marrow transplant. At 2 years, the overall survival was 69% and the progression-free survival was 59%. ConclusionThe results in terms of overall survival and progression-free survival are similar to those reported in the literature. Important diagnostic gaps prevent adequate prognostic characterization. Allogeneic consolidation transplantation was performed in a lower percentage than expected, highlighting the national deficit in access to this treatment.

Management of adult acute lymphoblastic leukemia in the Gulf Cooperation Council (GCC) countries: A consensus report from the GCC Adult ALL Working Group.

Leukemia burden is growing in the Gulf Council Cooperation (GCC) countries. Nonetheless, there is no unified protocol for managing adult acute lymphoblastic leukemia (ALL) patients in the GCC-countries. Therefore, the GCC Adult-ALL Treaters working group developed this consensus to address the adult-ALL treatment protocols in the GCC-countries and related toxicities' management. Besides, the consensus aimed to highlight the current unmet needs and treatment gaps and provide recommendations to optimize adult-ALL care and patient-centered communication. A three-step modified Delphi method to develop evidence-based recommendations through two-voting rounds and in-between virtual meetings are used in the manuscript development. A 12 experts' panel from five GCC-countries and two international experts were invited to participate in this consensus. This consensus consisted of 35-statements that highlighted the experts' recommendations to optimize ALL adults' care in the first line setting and manage pediatric or pediatric-inspired regimens-related toxicities. Besides, guidance was provided for future research direction and improve patient-centered communication. In conclusion, the adult-ALL management landscape is evolving, and the current evidence highlights better response and survival outcomes with pediatric or pediatric-inspired regiments. Therefore, protocols are needed to optimize the adult-ALL management in the GCC and tailored clinical-trials findings according to the GCC patients' characteristics and local-healthcare infrastructure.

Leveraging health care technology to improve health outcomes and reduce outcome disparities in AYA leukemia.

Significant improvements have occurred for adolescent and young adult (AYA) B-cell acute lymphoblastic leukemia (B-ALL) patients following the widespread adoption of "pediatric-inspired" treatment regimens for AYA patients cared for in adult oncology settings. However, for AYA patients, aged 15 to 39, an outcomes gap remains in B-ALL, necessitating the incorporation of novel therapies into up-front treatment regimens. As a result, clinical trial enrollment remains the current standard of care for AYA B-ALL across disease subtypes when available and accessible. Currently, several up-front trials are looking to incorporate the use of inotuzumab, blinatumomab, and chimeric antigen receptor T-cell therapy into existing chemotherapy backbones for AYA patients, as well as tyrosine kinase inhibitors for both Philadelphia-positive (Ph+) and Ph-like B-ALL. In addition to ongoing attempts to improve up-front treatments by incorporating immunotherapy and targeted approaches, the increased use of next generation sequencing for measurable residual disease evaluation has led to superior risk-stratification and a decreased need to pursue consolidative hematopoietic stem cell transplantation during the first complete remission for many patients.

Impact of inotuzumab ozogamicin on outcome in relapsed or refractory acute B-cell lymphoblastic leukemia patients prior to allogeneic hematopoietic stem cell transplantation and risk of sinusoidal obstruction syndrome/venous occlusive disease.

We evaluated 58 patients with relapsed or refractory (r/r) acute B-lymphoblastic leukemia (B-ALL; median age 42.5 years; range, 16-69 years), treated with inotuzumab ozogamicin (INO) between 2016-2022 and who received an allogeneic hematopoietic stem cell transplantation (allo-HCT) consecutively. Forty-seven (81%) of the 58 patients were heavily pretreated receiving intensive chemotherapy +/- tyrosine kinase inhibitor, blinatumomab in 24 (41%) and allo-HCT at first-line in 11 (19%) patients. Complete remission rate prior to allo-HCT was 84%. Median follow-up was 30.5 months and median overall survival (OS) measured from start of INO was 11.2 months. One- and 2-year OS rates were 50% (95% confidence interval [CI]: 38.4-56.1) and 36.7% (95% CI: 25.5-52.9), respectively. Sinusoidal obstruction syndrome/venous occlusive disease (SOS/ VOD) after allo-HCT occurred in 17 (29%) patients. Of those, nine (53%) patients died due to SOS/VOD and multi-organ failure. Two had received >2 INO cycles (3 cycles, 5 cycles, N=1, each), all others ≤2 INO cycles prior to allo-HCT. Logistic regression analysis revealed conditioning with double alkylators (P=0.038) and allo-HCT during first-line therapy (P=0.050) as significant risk factors for SOS/VOD and in trend allo-HCT ≤60 days from last INO application (P=0.07), whereas number of INO cycles before allo-HCT and time between last INO application and allo-HCT were not significant. Relapse/progressive disease occurred in 20 (34%) patients. Of those, five (25%) patients are still alive, whereas 15 succumbed of their disease. Treatment with INO seems to be an effective approach with successful bridge-to-transplant. However, risk of SOS/VOD is high, necessitating continuous monitoring and recognition of SOS/VOD risk factors.

Characterisation of FLT3 alterations in childhood acute lymphoblastic leukaemia

BackgroundAlterations of FLT3 are among the most common driver events in acute leukaemia with important clinical implications, since it allows patient classification into prognostic groups and the possibility of personalising therapy thanks to the availability of FLT3 inhibitors. Most of the knowledge on FLT3 implications comes from the study of acute myeloid leukaemia and so far, few studies have been performed in other leukaemias.MethodsA comprehensive genomic (DNA-seq in 267 patients) and transcriptomic (RNA-seq in 160 patients) analysis of FLT3 in 342 childhood acute lymphoblastic leukaemia (ALL) patients was performed. Mutations were functionally characterised by in vitro experiments.ResultsPoint mutations (PM) and internal tandem duplications (ITD) were detected in 4.3% and 2.7% of the patients, respectively. A new activating mutation of the TKD, G846D, conferred oncogenic properties and sorafenib resistance. Moreover, a novel alteration involving the circularisation of read-through transcripts (rt-circRNAs) was observed in 10% of the cases. Patients presenting FLT3 alterations exhibited higher levels of the receptor. In addition, patients with ZNF384- and MLL/KMT2A-rearranged ALL, as well as hyperdiploid subtype, overexpressed FLT3.DiscussionOur results suggest that specific ALL subgroups may also benefit from a deeper understanding of the biology of FLT3 alterations and their clinical implications.

The effectiveness of blinatumomab in clearing measurable residual disease in pediatric B-cell acute lymphoblastic leukemia patients detected by next-generation sequencing.

Blinatumomab improved survival outcomes in B-cell acute lymphoblastic leukemia (B-ALL) patients with measurable residual disease (MRD) <10-4 . However, data on blinatumomab clearing MRD with high sensitivity of 10-6 remain scarce. This study evaluates the effectiveness of blinatumomab in eradicating extremely low level (up to <10-6 ) of MRD, as detected by next-generation sequencing (NGS), in children with B-ALL. Patients (n = 19) whose MRD was undetectable by multiparameter flow cytometry (MFC) (sensitivity of 10-4 ) but detectable by NGS after chemotherapy and followed by blinatumomab consolidation were included retrospectively. After one course of blinatumomab, 13/19 patients (68%) successfully achieved NGS-MRD clearance (undetectable). With a median follow-up of 13.3 months, three of patients who were NGS-MRD positive relapsed within 1.8 months, while another three remained complete remission. Our study was the first to demonstrate that blinatumomab could further eradicate MRD after patients achieve MFC-MRD undetectable in B-ALL patients.

Abstract B110: Race/ethnicity, socioeconomic status, and early death among children enrolled in clinical trials for acute lymphoblastic leukemia

Abstract Introduction: Prior work indicates that Hispanic and Black children diagnosed with leukemia may experience a higher risk of death in the period shortly after diagnosis, but no work has examined these disparities taking into account leukemia subtypes and the role socioeconomic status (SES) may play. We investigated reported race/ethnicity (RRE), health insurance status, neighborhood SES, and early death among pediatric acute lymphoblastic leukemia (ALL) patients enrolled on clinical trials. Methods: Using data from the Childhood Cancer Research Network as well as Children’s Oncology Group therapeutic trials, we estimated the associations between RRE (Non-Hispanic [NH] White, NH Black, NH Asian/Pacific Islander [PI], or Hispanic/Native American), health insurance status, neighborhood SES using the Yost Index, and death within 60 days of diagnosis using multivariable logistic regression. All analyses were adjusted for age at diagnosis, sex, and ALL subtype (Standard Risk B-Cell, High Risk B-Cell, Infant ALL, T-Cell). We also estimated associations among non-infant patients diagnosed with B-Cell ALL, additionally adjusting for standard or high-risk disease. All associations were estimated as odds ratios (OR) with 95% confidence intervals (CI). Results: Overall, we analyzed data from 8,634 pediatric ALL cases (7,559 B-Cell; 122 Infant ALL; 953 T-Cell) enrolled across 7 clinical trials (AALL0232, AALL0331, AALL0434, AALL0631, AALL0932, AALL1131, AALL1231). In total, there were 29 deaths within 60 days of diagnosis, including 22 among B-Cell, 4 among infant ALL, and 3 among T-Cell patients. In the full analysis, infant ALL subtype was very strongly associated with early death compared to Standard Risk B-Cell patients (OR: 37.8 [95% CI: 9.22, 137]). We also observed a suggestive association between NH Asian/PI RRE and higher odds of early death compared to NH Whites (OR: 3.10 [95% CI: 0.71, 9.63]), which remained after limiting the analysis to B-Cell patients (OR: 5.63 [95% CI: 1.24, 18.7]). No association was apparent between NH Black or Hispanic/Native American RRE and odds of early death. Neighborhood SES was not significantly associated with early death, though point estimates suggested a potential protective effect of increasing SES. Lack of health insurance was also suggestively associated with greater odds of early death (OR: 2.78 [95% CI: 0.60, 9.47]). Conclusion: Unlike prior work, we observed increased odds of death soon after diagnosis for NH Asian/PI children. Future work incorporating more detailed treatment and cytogenetic subtype information is needed to identify the factors contributing to this disparity. Citation Format: Sarah Lucht, Jeannette M. Sample, Logan Spector, Jenny N. Poynter, Lucie Turcotte, Erin L. Marcotte. Race/ethnicity, socioeconomic status, and early death among children enrolled in clinical trials for acute lymphoblastic leukemia [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr B110.

N-acetyl cysteine turns EPAC activators into potent killers of acute lymphoblastic leukemia cells

Today, the majority of pediatric B cell precursor acute lymphoblastic leukemia (BCP-ALL, hereafter ALL) patients survive their disease, but many of the survivors suffer from life-limiting late effects of the treatment. ALL develops in the bone marrow, where the cells are exposed to cAMP-generating prostaglandin E2. We have previously identified the cAMP signaling pathway as a putative target for improved efficacy of ALL treatment, based on the ability of cAMP signaling to reduce apoptosis induced by DNA damaging agents. In the present study, we have identified the antioxidant N-acetyl cysteine (NAC) as a powerful modifier of critical events downstream of the cell permeable cAMP analogue 8-(4-chlorophenylthio) adenosine-3', 5'- cyclic monophosphate (8-CPT). Accordingly, we found NAC to turn 8-CPT into a potent killer of ALL cells in vitro both in the presence and absence of DNA damaging treatment. Furthermore, we revealed that NAC in combination with 8-CPT is able to delay the progression of ALL in a xenograft model in NOD-scid IL2Rγnull mice. NAC was shown to rely on the ability of 8-CPT to activate the guanine-nucleotide exchange factor EPAC, and we demonstrated that the ALL cells are killed by apoptosis involving sustained elevated levels of calcium imposed by the combination of the two drugs.. Taken together, we propose that 8-CPT in the presence of NAC might be utilized as a novel strategy for treating pediatric ALL patients, and that this powerful combination might be exploited to enhance the therapeutic index of current ALL targeting therapies.

Transcription factor 12-mediated self-feedback regulatory mechanism is required in DUX4 fusion leukaemia.

IGH::DUX4 is frequently observed in 4% B-cell acute lymphoblastic leukaemia patients. Regarding the IGH::DUX4-driven transactivation and alternative splicing, which are the main reasons behind this acute leukaemia outbreak, it remains unclear how transcriptional cofactors contribute to this oncogenic process. Further investigation is required to elucidate their specific role in leukaemogenesis. In order to investigate the cofactors of IGH::DUX4, integrated mining of Chromatin immunoprecipitation (ChIP)-sequencing and RNA-sequencing of leukaemia cells and patient samples were conducted. Furthermore, to elucidate the synergistic interaction between transcription factor 12 (TCF12) and IGH::DUX4, knockdown and knockout experiment, mammalian two-hybridisation assay, co-immunoprecipitation and in situ proximity ligation assays were carried out. Additionally, to further investigate the direct interaction between TCF12 and IGH::DUX4, AI-based structural simulations were utilised. Finally, to validate the synergistic role of TCF12 in promoting IGH::DUX4 leukaemia, cell proliferation, apoptosis and drug sensitivity experiments were performed. In this study, we observed that the IGH::DUX4 target gene TCF12 might be an important cofactor/helper for this oncogenic driver. The co-expression of IGH::DUX4 and TCF12 resulted in enhanced DUX4-driven transactivation. Supportively, knockdown and knockout of TCF12 significantly reduced expression of IGH::DUX4-driven target genes in leukaemia REH (a precursor B-cell leukaemia cell line) and NALM-6 cells (a precursor B-cell leukaemia cell line). Consistently, in TCF12 knockout cells, the expression of structure-based TCF12 mutant, but not wild-type TCF12, failed to restore the TCF12-IGH::DUX4 crosstalk and the synergistic transactivation. More importantly, the breakdown in TCF12-IGH::DUX4 cooperation impaired IGH::DUX4-driven leukaemia cell survival, caused sensitivity to the chemotherapy. Altogether, these results helped to define a previously unrecognised TCF12-mediated positive self-feedback regulatory mechanism in IGH::DUX4 leukaemia, which holds the potential to function as a pivotal drug target for the management of this particular form of leukaemia. Transcription factor 12 (TCF12) is a new novel cofactor in IGH::DUX4 transcriptional complexes/machinery. TCF12 mediates a positive self-feedback regulatory mechanism in IGH::DUX4-driven oncogenic transaction. IGH::DUX4-TCF12 structure/cooperation might represent a potent target/direction in future drug design against B-cell acute lymphoblastic leukaemia.

Clinical Significance of Serum CD155 Levels in Acute Lymphoblastic Leukemia Patients

Background: Acute lymphoblastic leukemia (ALL) is a hematologic malignancy characterized by poor outcomes in adults. Traditional diagnostic and prognostic markers take into account clinical data but also rely heavily on expensive and invasive tests such as bone marrow studies with cytogenetics. CD155 is an adhesion molecule that also modulates immune response in malignancy. Previous studies have shown that serum CD155 (sCD155) levels are higher in patients with malignancies, and have demonstrated a correlation between higher levels of sCD155 and poor outcomes. This study investigated the diagnostic and prognostic value of sCD155 in adult patients with acute lymphoblastic leukemia. Methodology: 32 adult patients with acute lymphoblastic leukemia and 15 control patients were enrolled in this study. Clinical and outcome data were collected from patients and a blood sample from patients and controls was collected with ELISA testing for sCD155 levels. Results: sCD155 was found to be significantly higher in patients than controls (p&amp;lt;0.05) and was significantly associated with bone marrow aspirate blast count. It was not associated with other clinical parameters including gender, age, initial CBC parameter counts, presence of lymphadenopathy, presence of CNS infiltration, presence of Philadelphia chromosome, type of ALL, or risk stratification of ALL besides being associated with hepatosplenomegaly. ROC curve showed high sensitivity and specificity of sCD155 and Kaplan Meir curve showed a trend towards worse outcomes in patients with high sCD155 but it was not statistically significant. Conclusion: sCD155 remains a promising marker for diagnosis of ALL but further studies are needed to confirm its prognostic value.

Multicenter Campus ALL Study on Infectious Complications in Ph- Acute Lymphoblastic Leukemia Patients Treated in the Real Life with the Gimema LAL1913 Protocol

Background The Italian national program of pediatric-inspired chemotherapy GIMEMA LAL1913 trial for adult Ph- acute lymphoblastic leukemia (Ph- ALL) has reported favorable results particularly in the younger subgroup of patients (pts) aged 18-40 years (Bassan et al, Blood Adv 2023). After the closure of the trial, this treatment scheme was adopted in the clinical practice by many Italian hematology centers for the treatment of newly diagnosed adult Ph- ALL. The safety of this intensive treatment in terms of infectious complications deserves to be investigated in the real life. Aims To evaluate in the context of the real life the incidence of infectious complications in Ph- ALL pts treated off protocol according to the GIMEMA LAL1913 chemotherapy scheme and to assess the impact of the prophylactic measures adopted. Methods We retrospectively collected data on 178 Ph- ALL pts treated in 13 Italian hematology centers participating to the Campus ALL network in Italy. Pts were homogeneously treated following the GIMEMA LAL1913 scheme, but the use of anti-infective prophylaxis differed among centers and among cycles. We analyzed data with regard to the type and site of the infections, the cycles of treatment during which the infections occurred. Finally, we correlated the incidence of the infections with the presence or absence of anti-infective prophylaxis. Results A total of 301 infectious events were diagnosed during the treatment of 134 of the 178 Ph- ALL pts (75%), including 98 episodes of fever of unknown origin (FUO) reported in 58 pts (33%). The distribution of the different types of documented infections for a total of 195 is reported in Table 1. The severity grading of infections (CTCAE.5) was available in 137 events and was ≥3 in 101. SARS COV2 infection accounted for 22% of the viral infections (8/36 cases). We diagnosed 24 pulmonary infections (in 21 pts): 15 mycotic (13 probable and 2 possible), 6 bacterial and 3 viral infections. The number of pts undergoing an infection/cycle is shown in Table 2: 69 patients had at least one infection during cycle 1 (39% of treated pts); infections were mainly bacterial and occurred in prevalence during cycle 1. Two patients died of sepsis by Pseudomonas aeruginosa during cycle 1 (mortality rate: 1.1%). Pts receiving antibacterial prophylaxis were 94/178 (53%). Bacterial infections were reported in 47 pts receiving prophylaxis and in 41 pts who did not undergo prophylaxis; the difference between the two groups was not significant (p: 0.8). Patients receiving antifungal prophylaxis were 119/178 (67%). Mycotic infections were reported in 14 pts, and in 10 pts who did not receive prophylaxis; again, no significant difference was recorded between the two groups (p: 0.3). Patients receiving antiviral prophylaxis were 151/178 (85%). Viral infections were reported in 30 pts and in 4 pts not receiving prophylaxis; no statistical difference was observed (p: 0.4). Summary/Conclusion The intensive GIMEMA LAL1913 treatment applied in the real life to newly diagnosed adult Ph- ALL pts is associated with a non-negligible rate of infections; &amp;gt;75% of treated pts suffered from at least one infection. Moreover, the large majority of these infections were severe with a CTCAE.5 grading ≥3. However, the infection-related mortality was very low (1.%); the anti-infective treatment together with the achievement of a complete hematologic recovery were able to control and resolve the infectious complications. Bacterial infections were prevalent and bacteremias/sepsis represented 70% of events. Cycle 1 was most affected by infectious complications of all types; mycotic and viral infections were mostly reported during cycle 1, while they decreased markedly during the following cycles. Also incidence of bacterial events decreased during treatment, though they continued to occur also in the late phases of the management suggesting that a high level of attention should be maintained up to the end of treatment. Anti-infective prophylaxis was heterogeneously applied, but it remains unclear if it is necessary. The first analysis of this survey does not show an advantage of prophylaxis in reducing infections; however, particularly for fungal complications, the numbers are too limited to consider these results as conclusive. Data collection is still ongoing, and a larger sample size will allow more robust conclusions.