RARE DISEASE
Precursor B-cell acute lymphoblastic leukemia
Precursor B-cell acute lymphoblastic leukemia
Precursor B-cell acute lymphoblastic leukemia
Synonyms: B-ALL, Precursor B-cell acute lymphoblastic leukemia/lymphoma, Precursor B-cell acute lymphocytic leukemia, Precursor B-cell acute lymphocytic leukemia/lymphoma
Synonyms: B-ALL, Precursor B-cell acute lymphoblastic leukemia/lymphoma, Precursor B-cell acute lymphocytic leukemia, Precursor B-cell acute lymphocytic leukemia/lymphoma
Synonyms: B-ALL, Precursor B-cell acute lymphoblastic leukemia/lymphoma, Precursor B-cell acute lymphocytic leukemia, Precursor B-cell acute lymphocytic leukemia/lymphoma
Drug discovery
30
drugs
With orphan designations
Overview
Precursor B-cell acute lymphoblastic leukemia (B-ALL) is an aggressive hematologic malignancy characterized by uncontrolled proliferation of immature B-cell lymphoblasts in bone marrow and blood. It accounts for 75–80% of pediatric ALL cases and 75% of adult ALL cases [1][6]. Prognosis depends on age, cytogenetics (e.g., BCR-ABL1, ETV6-RUNX1), and treatment response, with 5-year survival rates exceeding 90% in children but ≤60% in adults [12][16]. Modern protocols combine chemotherapy, targeted therapies (e.g., blinatumomab, TKIs), and allogeneic hematopoietic cell transplantation (allo-HCT) for high-risk or relapsed cases [3][8].
Therapies
First-line: Pediatric/adolescent regimens (BFM-based protocols) yield 85–95% complete remission [3][12]
Relapsed/refractory: Immunotherapy (blinatumomab/inotuzumab) followed by allo-HCT doubles survival vs standard chemotherapy [3][14]
Emerging approaches: CAR-T cell therapy for multi-relapsed cases and MRD-directed therapies [13][18]
Categories: rare hematological diseases, rare neoplastic diseases, rare transplant-related disorders
Research Papers
3,177 drug discovery papers about Precursor B-cell acute lymphoblastic leukemia, with 4 first-in-class and 19 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
3,177 drug discovery papers about Precursor B-cell acute lymphoblastic leukemia, with 4 first-in-class and 19 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-09-30 | Bortezomib-based chemotherapy in Chinese pediatric patients with relapsed/refractory acute lymphoblastic leukemia: A single-center retrospective study.
Relapsed/refractory acute lymphoblastic leukemia (R/R ALL) remains a major challenge in pediatric hematologic malignancies, with poor outcomes following standard salvage therapy. Real-world data regarding the use of bortezomib-based regimens in Chinese children are limited. To evaluate the effectiveness and safety of bortezomib-based chemotherapy in Chinese pediatric patients with R/R ALL. We retrospectively reviewed 12 pediatric patients with R/R ALL who received bortezomib-based chemotherapy at our center between January 2019 and January 2026. Clinical characteristics, responses, survival, and adverse events were evaluated. Complete remission (CR), CR with incomplete recovery (CRi), persistent disease (PD), and minimal residual disease (MRD) were assessed per standard criteria. Survival probabilities were estimated using the Kaplan-Meier analysis. Nine patients had B-cell ALL (B-ALL) and three had T-cell ALL (T-ALL). Among those with B-ALL, the CR/CRi rate was 88.9% (8/9), and 62.5% (5/8) of responders bridged to hematopoietic stem cell transplantation (HSCT). Notably, five of eight responders with B-ALL achieved MRD <0.01%, including all three refractory patients. In contrast, none of the three patients with T-ALL achieved remission; all experienced PD, with a median survival of 3 months. The 3-year overall survival and event-free survival rates for the entire cohort were 48.6% (95% confidence interval [CI], 19.2%-73.0%) and 36.4% (95% CI, 5.8%-69.8%), respectively. Treatment-related toxicities were manageable, with the most common being hematologic suppression and infections. Bortezomib-based chemotherapy showed promising salvage activity in pediatric patients with R/R B-ALL, enabling remission and HSCT bridging. However, its activity against T-ALL appears limited in this small cohort, warranting further investigation.
2026-09-26 | CREB1 and GSK3 Isoforms as Potential Adaptive Signaling Nodes in PI3K/Akt/mTOR Inhibitor Treated Philadelphia Chromosome-Positive B-ALL.
Philadelphia chromosome-positive (Ph+) B-cell acute lymphoblastic leukemia (ALL), driven by the BCR-ABL1 fusion, remains highly aggressive, with poor prognosis despite tyrosine kinase inhibitor (TKI) therapy. Aberrant PI3K/Akt/mTOR pathway activation contributes to resistance, warranting identification of predictive kinase biomarkers. To identify and validate critical phospho-kinase markers within the PI3K/Akt/mTOR axis as candidate adaptive signaling nodes and exploratory prognostic markers in Ph+ B-ALL. Network pharmacology using STRING and Cytoscape mapped the protein-protein interactions, identifying high-centrality nodes. Functional enrichment analyses (GO/KEGG) were then performed via ShinyGO. Experimentally, phospho-kinase arrays profiled 39 kinase phosphorylation sites in Ph+ B-ALL cells (SUPB-15) treated with PI3K/Akt/mTOR inhibitors (Rapamycin, GDC-0941, GSK690693, Perifosine). Gene expression was validated by RT-qPCR in 100 Ph+ B-ALL patients and protein validation employed Western blot in 50 patient samples with 15 and five healthy controls, respectively. Network analysis identified CREB1 and GSK3 isoforms as central hub regulators. Phospho-kinase profiling revealed p-CREB (Ser133) phosphorylation upregulation following Perifosine, GDC-0941, and Rapamycin treatment, with no statistically significant change after GSK690693. p-GSK3α/β (Ser21/9) phosphorylation showed a statistically significant increase after Perifosine, with non-significant trends after GDC-0941, and a significant reduction following Rapamycin. Hierarchical clustering then divided proteins into four distinct clusters positioning CREB1 in cluster 3 and GSK3α/β in cluster 2 as candidate adaptive response markers based on their phosphorylation profiles. RT-qPCR demonstrated marked downregulation of GSK3α (approximately 71%), GSK3β (63%), and CREB1 (65%) transcripts in patients versus controls, with even greater suppression seen in cell lines. Conversely, Western blot revealed a significant 2.49 fold elevated p-CREB (Ser133) (β = 1.317, p = 0.000347) and a phospho-GSK3α/β (Ser21/9) level that did not differ significantly between patients and controls (β = 0.467, p = 0.466), revealing mRNA-protein discordance indicative of compensatory post-transcriptional and post-translational regulation. These findings represent treatment-associated and disease-state associations between altered phosphorylation states and the Ph+ B-ALL context; functional validation remains an essential next step. mRNA-protein discordance with transcriptional downregulation (63-71%) contrasting with elevated p-CREB levels (2.49-fold, p = 0.000347) suggests post-translational compensatory mechanisms under therapeutic pressure. CREB1 and GSK3 isoforms emerge as central network nodes that might potentially mediate adaptive resistance, although functional validation is required. It should be noted that the evidence presented is associative rather than causal and a direct link between the observed phosphorylation changes and clinical drug resistance has not been established in this study. Sustained CREB phosphorylation despite PI3K/Akt/mTOR inhibition implicates alternative kinase pathways (MAPK/ERK, CaMK), supporting rational combination therapy strategies. These findings position p-CREB and p-GSK-3α/β as candidate biomarkers, highlighting the value of phospho-proteomics over transcriptomics alone in capturing pathway activation. Multi-omics integration may prove essential for overcoming adaptive resistance in ALL patients.
2026-09-24 | Outcome after first relapse post-immunochemotherapy in older adults with Philadelphia-negative B-cell acute lymphoblastic leukemia: A GRAALL study.
Inotuzumab (InO)-based frontline regimens have significantly improved the survival of older patients with Philadelphia-negative (Ph-) B-cell acute lymphoblastic leukemia (B-ALL). Yet, outcome after relapse is not reported for this population. The retrospective RELAPSINO study describes post-relapse outcome of 48 older patients treated front-line with a combination of InO and low-dose chemotherapy in the EWALL-INO trial (NCT03249870). At relapse (91% medullary), median age was 70 years and median duration of first complete remission (CR1) 15.2 months. CD19 or CD22 expression loss was observed in respectively 13% and 23% of evaluable cases. Most patients (85%) received salvage therapy (blinatumomab, low dose or intensive chemotherapy, in combination or not). There was no InO re-treatment. Overall, CR2 was reached by 51% of the patients. Median event-free survivals (EFS, 3.2 months) and overall survivals (OS, 4.5 months) were dismal. For patients achieving CR2, 2-year OS was 46% and leukemia-free survival (LFS) was 36%. By multivariable analysis, not receiving intensive chemotherapy was associated with significantly lower EFS (hazard ratio [HR], 3.28; 95% confidence interval [CI], 1.43-7.53, p = .005), LFS (HR, 13.2; 95% CI, 2.46-70.88, p = .003), and OS (HR, 3.25; 95% CI, 1.39-7.59, p = .006). CR1 duration ≥12 months was significantly associated with better EFS (HR, 0.31; 95% CI, 0.14-0.67, p = .003), LFS (HR, 0.16; 95% CI, 0.04-0.72, p = .01), and OS (HR, 0.42; 95% CI, 0.20-0.89, p = .023). Not achieving CR2 was associated with lower OS (HR, 8.0; 95% CI, 3.25-20.1, p < .001). Receiving blinatumomab had no impact. These results indicate that salvage regimen should be proposed in this context, allowing 50% of patients to achieve CR2 and have better survival.
2026-09-24 | Beyond CAR-T: Preventing and Treating Relapse in B-Cell Haematological Malignancies.
Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment landscape of relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL), non-Hodgkin lymphoma (NHL), and multiple myeloma (MM); however, a substantial proportion of patients eventually experience disease relapse despite an initial response. This review provides a brief overview of CAR-T cell therapy, including its manufacturing process and associated toxicities, before examining the biological mechanisms underlying post-CAR-T relapse in B-ALL, NHL-particularly large B-cell lymphoma (LBCL)-and MM. We critically review current and emerging strategies to prevent and manage relapse. Strategies for relapse prevention primarily include consolidation approaches, such as allogeneic hematopoietic stem cell transplantation (allo-HSCT), maintenance with targeted agents (e.g., tyrosine kinase inhibitors in Philadelphia chromosome-positive B-ALL), and CAR-T cell reinfusion, whereas relapse management is disease-specific and increasingly incorporates novel therapeutic agents, including bispecific antibodies (BsAbs) and other targeted therapies. However, current evidence remains largely preliminary and is limited by the paucity of randomized prospective trials.
2026-09-08 | Pathway incompatibility between NF-κB and RAS signaling constrains oncogenicity in B-cell leukemia.
Oncogenic pathways do not always cooperate; in some contexts, their co-activation is antagonistic and suppresses tumorigenesis, a phenomenon we termed pathway incompatibility. However, the mechanisms underlying this antagonism and the role of receptor context in shaping these interactions remain unclear. During normal B-cell development, precursor B-cell receptor (pre-BCR) signaling supports survival and proliferation of early B-cell precursors before transition to expression of the mature B-cell receptor (BCR). B-cell acute lymphoblastic leukemia (B-ALL), the most common childhood cancer, is characterized by developmental arrest prior to BCR expression, and approximately 35% of cases harbor activating RAS-ERK mutations that mimic pre-BCR-dependent survival signaling. NF-κB plays context-dependent roles in B-cell malignancies, but whether it influences the compatibility between oncogenic RAS signaling and BCR expression remains poorly understood. Activation of canonical NF-κB induced apoptotic depletion of RAS-driven B-ALL cells. Mechanistically, NF-κB suppressed pre-BCR-dependent survival signaling while promoting expression of BCR components. Consistent with this shift, oncogenic RAS signaling was poorly tolerated in BCR-positive cells unless BCR expression was disrupted. Pharmacologic activation of NF-κB reduced ERK signaling and selectively impaired viability of RAS-driven B-ALL cells, with enhanced effects in combination with ERK inhibition. Together, these findings show that canonical NF-κB signaling promotes BCR expression, which constrains oncogenic RAS activity, and establish pathway incompatibility as a mechanism through which receptor context can limit oncogenic potential.
antibodies
2026-09-29 | The Clinical Impact of End-of-Consolidation Measurable Residual Disease in High-Risk Pediatric B-Cell Acute Lymphoblastic Leukemia.
IntroductionBlinatumomab (BLINA) has improved event-free survival (EFS) and overall survival (OS) in pediatric patients with high-risk B-cell acute lymphoblastic leukemia (ALL) and has become an effective bridging therapy to hematopoietic cell transplantation. However, the prognostic significance of end-of-consolidation (EoC) measurable residual disease (MRD) in the current BLINA-incorporated treatment era remains unclear.MethodsWe retrospectively enrolled pediatric patients diagnosed with high-risk B-cell ALL between February 2022 and December 2024 at Chang Gung Memorial Hospital. Patients were categorized into EoC MRD-negative and EoC MRD-positive groups. EoC MRD was assessed by multiparameter flow cytometry, with real-time quantitative polymerase chain reaction used as a complementary molecular method when applicable. Outcomes of interest included EFS, OS, and BLINA-related adverse events (AEs).ResultsThe cohort consisted of 15 patients. With a median follow-up of 24 months, the observed 2-year EFS and OS rates were 71.5% and 86.7%, respectively. The EoC MRD-positive group demonstrated significantly higher relapse rates (57.1% vs. 0%, P = 0.0256) and numerically higher mortality rates (28.6% vs. 0%, P = 0.2). The 2-year EFS was significantly higher in the EoC MRD-negative group (100% vs. 42.9%, P = 0.02). Although the EoC MRD-negative group demonstrated a numerically higher 2-year OS (100% vs. 71.9%, P = 0.12), the difference did not reach statistical significance. Regarding safety, no high-grade short-term or long-term BLINA-related AEs were observed in either group.ConclusionIn this preliminary retrospective study, EoC MRD negativity was associated with sustained disease control during short-term follow-up and favorable survival outcomes in pediatric patients with high-risk B-cell ALL treated with BLINA-based therapy. These findings suggest that EoC MRD assessment might provide additional prognostic information in the contemporary BLINA treatment era. Further prospective studies with larger cohorts are warranted to validate these observations.
2026-09-15 | High-risk features in adult patients with B-cell acute lymphoblastic leukemia: redefining risk in the era of targeted immunotherapy.
The treatment landscape of adult B-cell acute lymphoblastic leukemia (B-ALL) has changed substantially with the introduction of targeted immunotherapeutic agents. Historically, high-risk disease was defined by clinical and cytogenetic features such as older age, elevated leukocyte count, and Philadelphia chromosome (Ph)-positive status. Advances in genomic profiling, together with the use of next-generation tyrosine kinase inhibitors, bispecific T-cell engagers, antibody-drug conjugates, and chimeric antigen receptor T-cell therapies, have altered both treatment outcomes and risk stratification. Outcomes for patients with Ph-positive B-ALL have improved markedly, particularly with ponatinib- and blinatumomab-based regimens, but several molecularly defined subgroups continue to have poor prognoses. These include IKZF1plus Ph-positive B-ALL, TP53-mutated and hypodiploid B-ALL, Ph-like B-ALL, and KMT2A-rearranged B-ALL. Emerging evidence indicates that introducing immunotherapeutic agents early in treatment can improve response quality and rates of measurable residual disease negativity, including in patients with high-risk disease. Relapse nevertheless remains a major challenge, and the optimal integration of novel agents, allogeneic hematopoietic cell transplantation, and cellular immunotherapy remains uncertain. This review summarizes the biological and clinical features of the major high-risk molecular subgroups of adult B-ALL and discusses how recent therapeutic advances are redefining risk assessment and treatment strategies in the era of targeted immunotherapy.
2026-09-07 | [Effect of inorganic pyrophosphatase PPA1 on proliferation and apoptosis of abnormal naive cells in acute B-lymphocytic leukemia].
Objective: To investigate the role of inorganic pyrophosphatase (PPA1) in the proliferation of abnormal naive lymphocytes in B-cell acute lymphoblastic leukemia (B-ALL) and evaluate its potential as a tumor marker. Methods: Bioinformatics analysis predicted the characteristics of the PPA1 gene. Bone marrow specimens were collected from patients with B-ALL, and abnormal immature B lymphocytes were isolated by CD19 and CD10 immunomagnetic beads, with normal cells as controls. PPA1 expression was detected with quantitative polymerase chain reaction (qPCR) and Western blot. B-ALL cell lines NALM-6 and HAL-01 were cultured in vitro, and recombinant PPA1 protein (rPPA1) or PPA1 monoclonal antibody was added to assess changes in cell proliferation, apoptosis, mitochondrial membrane potential, and cell cycle. The GV492-PPA1 overexpression plasmid was constructed and transfected into cells to assess the effect of PPA1 overexpression. shRNA was designed to construct the GV644-shPPA1 recombinant plasmid, and lentiviral transduction was performed to inhibit PPA1 expression. The impact on tumor cells was observed, and the expression levels of key proteins in the PI3K/AKT pathway and apoptosis-related factors were detected. Results: In abnormal immature B lymphocytes from patients with B-ALL, the transcription and expression levels of PPA1 were 3.75 - 14.89 times and 1.25 - 3.79 times those of normal cells, respectively. rPPA1 promoted NALM-6 and HAL-01 cell proliferation, with increased proliferation rates of 29.97% and 20.96% after treatment with 10 μg/ml for 72 h and 48.40% and 58.08% at 20 μg/ml, respectively. PPA1 monoclonal antibody (1:2 000, 1:1 000, 1:500) significantly inhibited proliferation at 19.53%, 46.90%, and 49.42% for NALM-6 cells and 22.29%, 52.41%, and 58.35% for HAL-01 cells, respectively. PPA1 monoclonal antibody (1:2 000, 1:1 000) induced apoptosis, increasing the apoptosis rate of NALM-6 cells from 10.01% to 20.17% and 29.11%, and that of HAL-01 cells from 12.65% to 18.53% and 31.80%. After treatment with the same PPA1 monoclonal antibody dilutions, the proportion of JC-1 monomers significantly increased, reaching 4.08- and 6.49-fold of the control in NALM-6 cells, and 3.99- and 6.42-fold in HAL-01 cells, indicating a decrease in mitochondrial membrane potential, whereas the cell cycle was arrested at the G(0)/G(1) phase. Overexpression of PPA1 for 48 and 72 h increased the proliferation rate of NALM-6 cells by 25.05% and 26.14%, and that of HAL-01 cells by 26.14% and 29.25%, respectively. PPA1 expression inhibition suppressed proliferation, with inhibition rates of 19.77% (48 h) and 28.99% (72 h) for NALM-6 cells, and 20.90% (72 h) for HAL-01 cells. qPCR and Western blot results revealed that PPA1 inhibition reduced the phosphorylation level of the PI3K/AKT pathway and regulated the expression of MDM2, P53, and apoptosis-related factors. Conclusion: PPA1 is closely associated with the proliferation and development of abnormal immature lymphocytes in B-ALL. PPA1 expression inhibition suppresses abnormal cell proliferation and promotes apoptosis, indicating that PPA1 has potential as a new target for tumor prevention and treatment.
2026-09-04 | Pre-treatment T cell features and immune-milieu characteristics shape treatment-induced exhaustion and resistance to Blinatumomab in B-cell acute lymphoblastic leukemia.
Blinatumomab (Blina), a CD19×CD3 bispecific T cell engager, is approved for the treatment of B-cell precursor acute lymphoblastic leukemia (BCP-ALL), yet resistance remains a major challenge and the mechanisms driving treatment failure remain poorly understood. To define the immunological determinants of resistance, we performed longitudinal profiling of peripheral blood T cells and the immune milieu of 34 patients receiving Blina using flow cytometry (n=19), single-cell CITE-seq (n=13), ex vivo Blina-induced cytotoxicity (n=26) and serum proteomics (n=17). At baseline, Responders (R) were enriched for CD8+ effector memory T cells (TEM) expressing higher levels of cytotoxic genes and their transcriptional regulator ZNF683. Conversely, CD8+ TEM from Non-Responders (NR) displayed transcriptional features of activation without proportionate cytotoxic commitment. Over the course of the first treatment cycle, NR exhibited a progressive expansion of TIM3+CD8+ T cells that correlated with a rapid loss of ex vivo cytotoxic function. Linking baseline state to post-treatment T-cell exhaustion, the magnitude of TIM3+CD8+ expansion correlated inversely with baseline ZNF683 expression in CD8+TEM. Beyond T-cell-intrinsic features, NR harbored an immunosuppressive milieu characterized by higher circulating levels of M2-polarizing factors (CSF-1, HGF) and the TIM-3 ligand Galectin-9, which correlated positively with the magnitude of TIM3+CD8+ T-cell expansion. These findings indicate that post-Blina CD8+ T-cell exhaustion is associated with resistance and it is shaped by both reduced ZNF683-dependent cytotoxic programming in CD8+ TEM and an immunosuppressive milieu. This provides a rationale for risk stratification based on baseline transcriptional profiling of CD8+ TEM and for combinatorial strategies targeting the suppressive microenvironment.
2026-09-01 | EARLY RESPONSE AND GENETICS DEFINE RELAPSE RISK AFTER FRONTLINE BLINATUMOMAB IN CHILDHOOD B-ALL: A COHORT STUDY.
Blinatumomab is increasingly incorporated into frontline therapy for B-cell acute lymphoblastic leukaemia (B-ALL), yet risk stratification remains based on chemotherapy-era factors that may not apply in the immunotherapy setting. We analysed a national cohort to define determinants of relapse following frontline blinatumomab. Children and young people (1-24 years) in the UK and Ireland diagnosed with B-ALL between 2018 and 2025 who were chemotherapy-intolerant or resistant received blinatumomab in place of selected components of the frontline chemotherapy backbone. Outcomes were analysed according to conventional prognostic variables, genetic features, and response to blinatumomab. Among 225 patients, 195 received chemotherapy following blinatumomab (Blin-CT) and 30 underwent first-remission HSCT. In the Blin-CT cohort, traditional risk factors, including age, white cell count, high-risk genetics, and pre-blinatumomab end-of-induction measurable residual disease (MRD) did not predict relapse. On univariable analysis, relapse risk was increased with detectable MRD after blinatumomab cycle 1 (C1-END; hazard ratio HZR 6.61, p<0.001), IKZF1plus (HZR 3.64, p=0.04), JAK-STAT abnormalities (HR 3.56, p=0.05), and DUX4 rearrangements (HZR 4.24, p=0.03). In multivariable modelling, C1-END MRD and IKZF1plus remained independently associated with relapse, whereas DUX4-rearranged cases were strongly associated with persistent MRD at C1-END. An integrated model incorporating C1-END MRD, IKZF1plus, and DUX4-r defined a high-risk subgroup (33%) with an 18% 2-year relapse rate versus 0% in remaining patients (bootstrapped HZR 12.82, p=0.001, C-index=0.81). Relapse following frontline blinatumomab is determined by early treatment response and genetic subtype rather than conventional chemotherapy-derived risk factors. These findings support immunotherapy-specific risk stratification to guide treatment intensity.
oligonucleotides
2026-06-15 | Delivery of Monomethyl Auristatin E Using Ionizable Lipid Nanoparticles for B‑Cell Acute Lymphoblastic Leukemia Treatment.
Ionizable lipid nanoparticles (LNPs) are the leading method for clinically delivering nucleic acid cargoes such as messenger or small interfering RNAs. The capacity of LNPs to encapsulate and deliver small molecule therapeutics alongside traditional nucleic acid cargo remains largely unexplored. Beginning the development of a dual delivery approach using LNPs holds significant potential for treating malignancies prone to therapeutic resistance. B-cell acute lymphoblastic leukemia (B-ALL) is a hematologic malignancy with a poor prognosis in patients who experience relapse or are refractory to standard-of-care treatments. Here, we encapsulated the antimitotic agent, monomethyl auristatin E (MMAE), within prefabricated LNPs containing nonfunctional negative control small interfering RNA (siRNA) and evaluated the resulting antileukemic activity in B-ALL preclinical models. We optimized a postfabrication loading technique to encapsulate MMAE within LNPs while maintaining their superior siRNA retention and favorable physicochemical characteristics. Flow cytometry and confocal microscopy studies confirmed that the LNP uptake by B-ALL cells occurred through clathrin-mediated endocytosis and macropinocytosis. MMAE loaded within LNPs demonstrated potent antileukemic efficacy against B-ALL cells in vitro compared to the standard-of-care chemotherapeutic vincristine. Furthermore, within a B-ALL human xenograft murine model, MMAE-loaded LNPs exhibited over a 2-fold reduction of leukemic burden in the spleen and the peripheral blood as compared to LNPs without MMAE. Taken together, this study provides the groundwork for developing LNPs as a clinically translatable codelivery platform for chemotherapy and siRNA to improve the treatment of challenging malignancies, such as B-ALL.
2026-05-13 | Defibrotide-Responsive Cutaneous Endothelial Injury Following Allogeneic Hematopoietic Stem Cell Transplant: A Case Report.
A 57 -year -old woman with relapsed Philadelphia chromosome -negative B -cell acute lymphoblastic leukemia developed diffuse non -blanching erythematous skin lesions following allogeneic hematopoietic stem cell transplant. The lesions appeared concomitantly with hepatic sinusoidal obstruction syndrome and persisted despite engraftment and supportive therapy. Skin biopsy excluded graft -versus -host disease. Upon initiation of defibrotide for moderate hepatic sinusoidal obstruction syndrome, both hepatic and cutaneous findings resolved completely. This case underscores the systemic endothelial -protective potential of defibrotide, extending beyond the hepatic microvasculature, and highlights cutaneous endotheliopathy as a possible manifestation of transplant -associated endothelial injury.
2025-11-10 | surviBALL: exploring lncRNA expression at diagnosis for 5-year EFS risk stratification in pediatric B-ALL-a proof of concept.
B-cell Acute Lymphoblastic Leukemia (B-ALL) remains an important cause of cancer-related death in children. Therefore, accurate identification at diagnosis of patients at high risk of relapse is crucial. In this context, long non-coding RNAs (lncRNAs) could be novel candidates with great potential. Hence, the aim of this study was to identify new prognostic biomarkers in pediatric B-ALL through an RNA sequencing (RNA-seq) approach that allows the detailed exploration of a wide range of lncRNAs. Total RNA from two cohorts of B-ALL patients (C1 with 50 Spanish patients, and C2 with 72 Canadian patients) was sequenced with a depth of approximately 150 million paired-reads using Illumina technology. All protein coding and non-coding genes included in lncRNAKB annotation were studied to develop a gene expression-based 5-year Event Free Survival (EFS) prediction model. First, univariate Cox proportional hazards analyses identified 48 genes significantly associated with higher EFS risk in both cohorts. From these, ALASSO regression selected five genes, all of which are lncRNAs, as the most informative to develop the prediction model, which we have called surviBALL. Stratification of patients into three risk groups according to the surviBALL model revealed significantly poorer EFS in high-risk patients across C1, C2, and the integrated C1 + C2 cohort (P < 0.001). Validation in an independent cohort of 177 publicly available B-ALL samples confirmed surviBALL's prediction capacity (P = 2.80 × 10- 4) and its independence of both subtype and MRD. These findings suggest that surviBALL has the potential to complement current risk stratification approaches, particularly by identifying patients at high risk of relapse at diagnosis. As a hypothesis-generating proof of concept, this study highlights the promise of more personalized treatment strategies and warrants further validation in independent cohorts.
2025-10-13 | Long non-coding RNAs in B-cell acute lymphoblastic leukemia: Disease implication, challenges and therapeutic opportunities.
B-cell acute lymphoblastic leukemia (B-ALL) manifests as an abnormal proliferation of neoplastic B-cell lymphocytes, adversely affecting both children and adults. Despite the advancements in cancer research, B-ALL cure remains challenging due to the complexity of the disease and immense subtype heterogeneity. Better understanding of the molecular mechanisms driving B-ALL pathogenesis is imperative to identify the novel therapeutic markers that can impede disease progression. Genomic and transcriptomic studies involving patient samples have underscored the emerging role of long non-coding RNAs (lncRNAs) in the diverse B-ALL landscape. Their dysregulation has been linked to malignant proliferation, metastasis, and varying patient survival outcomes. Gaining detailed mechanistic insights into the role of lncRNAs in B-ALL pathophysiology is pivotal for understanding their contributions to disease progression and developing new therapeutics. Herein, we have comprehensively discussed B-ALL and its diverse subtypes, focusing on the pivotal role played by various lncRNAs in fine-tuning signaling pathways, disease heterogeneity and progression. We have also explored recent advances in our understanding of the diverse classes of lncRNA inhibitors, evaluating their potential as B-ALL therapeutics and challenges associated with their development.
2025-06-01 | Integrative Genetic and Transcriptomic Subtyping Improves Prognosis Prediction in B-Lineage Acute Lymphoblastic Leukemia.
Whole-transcriptomic sequencing (WTS) has remarkably advanced our understanding of B-lineage acute lymphoblastic leukemia (B-ALL), allowing for detailed gene expression profiling and discovery of novel therapeutically relevant subtypes. The aim of this study was to evaluate the diagnostic and prognostic relevance of combining WTS with traditional genetic methods in risk-stratifying B-ALL. In a cohort of 394 patients (301 children and 93 adults), conventional techniques such as fluorescence in situ hybridization, cytogenetics, and reverse-transcription PCR identified sentinel chromosomal abnormalities like BCR::ABL1, TCF3::PBX1, ETV6::RUNX1, and KMT2A-R (rearranged), and ploidy status. WTS was performed on selected 257 patients to identify subtypes such as Ph-like, DUX4-R, PAX5-altered (PAX5-ALT), MEF2D-R, BCL2-R, UBTF-R, PAX5 P80R, NUTM1-R, ZNF384-R, ZNF384-like, ETV6::RUNX1-like, IKZF1 N159Y, and HLF-R. We used a multipronged strategy to identify the borderline subtypes such as Ph-like, PAX5-ALT, and CRLF2 (non-Ph-like), by integrating gene expression signatures using t-distributed stochastic neighbor embedding, subtype-defining mutations, gene fusions, and copy number assessments. Our integrated approach not only identifies prognostically relevant sentinel molecular subtypes but also increases subtype assignment in upto ∼95% of B-ALL patients. The pro-B immunophenotype was found to be more frequent in UBTF-R and MEF2D-R ALL. Ph-like ALL was associated with poor remission rates and higher minimal residual disease positivity, while DUX4-R showed favorable prognosis. We further categorized pediatric patients into 3 risk groups: favorable (hyperdiploid, ETV6::RUNX1, and DUX4-R), poor (BCR::ABL1, Ph-like, KMT2A-R, TCF3::PBX1, iAMP21, and hypodiploid), and intermediate (PAX5-ALT, PAX5 P80R, NUTM1-R, MEF2D-R, CRLF2 [non-Ph-like], UBTF-R, ZNF384-R, ZNF384-like, BCL2-R, IKZF1 N159Y, ETV6::RUNX1-like, and B-rest). Event-free survival and overall survival were significantly associated with this risk stratification. In adults, Ph-like ALL showed worse prognosis, particularly, in BCR::ABL1-negative ALL patients. Among the DUX4-R B-ALL, those with IKZF1 deletion had worse event-free survival and overall survival. We also identified several novel gene rearrangements in different subtypes of B-ALL. Our study demonstrated that integrating WTS with traditional methods provides a comprehensive, accurate, and cost-effective strategy for risk assessment and treatment planning for B-ALL.
cell therapies
2026-09-03 | Tumour immunotherapy in solid and hematologic malignancies: Progress, challenges, and a practical framework.
Tumour immunotherapy has reshaped the landscape of oncology by translating fundamental insights from immunosurveillance, immunoediting, and checkpoint biology into effective clinical strategies. This review traces the historical trajectory of tumour immunotherapy, from the early observations of William Coley to the development of modern immune checkpoint inhibitors (ICIs) targeting cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death protein 1/ligand 1 (PD-1/PD-L1). Moreover, a comprehensive analysis of the progress of immunotherapy across different tumour types is provided. In solid tumours, significant benefits have been achieved in ``inflamed'' or ``hot'' cancers like melanoma, non-small-cell lung cancer, and renal cell carcinoma. However, formidable hurdles remain in ``non-inflamed'' or ``cold'' tumours such as pancreatic ductal adenocarcinoma, glioblastoma, and microsatellite-stable colorectal cancer. In hematologic malignancies, living drugs and redirecting immunotherapies have demonstrated profound efficacy: CAR-T therapy has achieved durable remissions in B-cell acute lymphoblastic leukemia (B-ALL) and diffuse large B-cell lymphoma (DLBCL), while T-cell engagers offer a rapid, ``off-the-shelf'' option for multiple myeloma. Collectively, this review synthesizes these developments into a practical framework based on tumour immune context, offering a guide for optimizing current treatments and directing future research to overcome resistance and benefit more patients.
2026-08-18 | Mathematical modelling of immune persistence and relapse pathways in CAR T-cell therapy for B-ALL
Chimeric antigen receptor (CAR) T-cell therapy has transformed the treatment of B-cell acute lymphoblastic leukaemia (B-ALL). Despite high initial response rates, a substantial fraction of patients relapse, often due to loss of CAR T-cell persistence, antigen escape, or immune-privileged sites that shield tumour cells. Prolonged CAR T-cell persistence is clinically associated with durable remission, but why it is required remains poorly understood. To address this, we develop and analyse the BEAM (Blast, Effector, Activated, Memory) model of CAR T-cell dynamics in B-ALL. BEAM extends predator--prey models with three CAR T-cell states (memory, activated, effector) coupled to a logistic growth equation for the blasts, calibrated against the FELIX trial of obecabtagene autoleucel in adult B-ALL. We find that both memory and effector persistence prevent relapse, but for distinct reasons: memory persistence sustains surveillance against low-burden or slowly proliferating residual disease, while effector persistence clears isolated blasts emerging from immune-privileged sites. The model further predicts a trade-off between immediate cytotoxicity and durable surveillance, and identifies initial tumour burden as a key modifiable factor for reducing antigen-negative relapse. Together, these results offer a framework for designing more durable, individually tailored CAR T-cell therapies.
2026-08-10 | Laboratory Concordance and Prognostic Impact of 10-Color Flow Cytometry and Next-Generation Sequencing-Based Immunoglobulin Gene Assay for Measurable Residual Disease Monitoring in Adult B-Cell Acute Lymphoblastic Leukemia: A Multicenter Study From Thai Acute Leukemia Working Group (TALWG).
Measurable residual disease (MRD) is a key prognostic marker for patient survival. This study evaluated concordance between 10-color flow cytometry and next-generation sequencing (NGS)-based immunoglobulin heavy chain (IGH) gene assays for MRD detection and to assess prognostic significance in adult B-cell acute lymphoblastic leukemia (B-ALL). This multicenter prospective study enrolled 51 patients with newly diagnosed B-ALL. Bone marrow samples were obtained at diagnosis, post-induction (1 month), and post-early consolidation (3 months). Flow cytometry and NGS-IGH were performed at three timepoints to assess MRD B-ALL. Patients were classified as high risk according to white blood cell count and cytogenetic features in 37.3% and 64.7% of patients, respectively. Treatment protocols included pediatric-inspired regimens (41.2%), adult-ALL protocols (52.9%), and low-intensity chemotherapy. All 16 Philadelphia chromosome-positive patients received tyrosine kinase inhibitors. Twenty patients underwent allogeneic hematopoietic cell transplantation (HCT) in first complete remission (CR). Median relapse-free survival (RFS) and overall survival were 19 and 39 months, respectively. MRD negativity at 3 months by either method correlated with significantly superior RFS. Allogeneic HCT also conferred RFS benefit. MRD positive patients without HCT had the worst RFS. Flow cytometry MRD positivity at 3 months independently predicted inferior RFS (HR 3.81; 95% CI 1.01-14.43). The overall concordance between flow cytometry and NGS was 80.7%. MRD positivity at 3 months post-treatment strongly predicted relapse, supporting its use to guide therapeutic modifications of B-ALL. Apart from NGS-based IGH clonality assays, 10-color flow cytometry offers an alternative in resource-limited settings.
2026-08-04 | CAR-T versus allogeneic transplantation as consolidation for B-cell acute lymphoblastic leukemia in remission: a propensity-score matched study.
Despite being a standard consolidation treatment, allogeneic hematopoietic stem cell transplantation (allo-HSCT) for B-cell acute lymphoblastic leukemia (B-ALL) in remission is still hampered by relapse and complications. While CAR-T therapy is revolutionizing later-line treatment, its role as a consolidation strategy in remission, particularly for patients ineligible for transplantation, remains unexplored. This study compared the efficacy of CAR-T therapy with that of allo-HSCT as consolidation for B-ALL patients in complete remission (CR). A retrospective, propensity-score matched study was performed from September 1, 2012 to December 31, 2024, including 75 B-ALL patients treated with CAR-T or allo-HSCT as consolidation therapy. Firth penalized likelihood Cox models and restricted mean survival time (RMST) models were built for time-to-event outcomes. The 2-year progression-free survival (PFS) and 2-year overall survival (OS) rates showed no significant differences between the CAR-T and HSCT cohorts (CR1: 2-year PFS rate: 65.8% vs. 88.9%, P = 0.146, 2-year OS rate: 83.6% vs. 91.3%, P = 0.512; CR2: 2-year PFS rate: 42.2% vs. 64.3%, P = 0.360). The RMSTs of PFS and OS also have no significant differences (CR1: RMST of PFS difference = -7.738, P = 0.496, RMST of OS difference = -2.257, P = 0.788; CR2: RMST of PFS difference = -6.176, P = 0.700, RMST of OS difference = -8.391, P = 0.477) truncated at the minimum of the largest follow-up times in each cohort (CR1, 74.6 months; CR2, 75.0 months). In multivariate analysis, patients treated with allo-HSCT had better PFS in CR1 group (HR = 4.579, 95%CI, 1.020-20.563, P = 0.038). High risk stratification was an independent factor associated with worse OS for B-ALL patients in CR (CR1: HR = 8.010; 95%CI, 1.744-36.781, P = 0.048; CR2 HR = 5.110, 95%CI, 1.167-22.378, P = 0.004). The results indicated that CAR-T consolidation regimen showed comparable survival to that of allo-HSCT in matched B-ALL patients, which might support its potential as a consolidation alternative for B-ALL patients ineligible for allo-HSCT.
2026-07-24 | B-cell activating factor receptor expression in B-lymphoblastic leukaemia: Flow cytometric analysis and implications for targeted therapy.
Cluster of differrentiation 19 (CD19)-directed therapies have significantly improved outcomes in B-cell malignancies; however, relapse driven by antigen escape remains a major clinical challenge, underscoring the need for alternative therapeutic targets. The B-cell activating factor receptor (BAFF-R), a key regulator of B-cell survival, is highly expressed in mature B-cell neoplasms, but its relevance in B-lymphoblastic leukaemia (B-ALL) remains unclear. We assessed BAFF-R expression in diagnostic and relapsed fresh B-ALL samples using multi-parameter flow cytometry. BAFF-R was consistently expressed in most cases, albeit at lower levels than in mature B cells, and expression was retained in the majority of CD19-negative relapses following CD19-directed therapy. Notably, tumor protein p53 (TP53) alterations were significantly enriched in CD19-negative immune escape disease (68.8% vs. 21.7%; p = 0.0006; OR = 7.9), yet BAFF-R expression remained preserved in this high-risk group. These findings establish BAFF-R as a stable immunotherapeutic target in B-ALL, including in CD19-negative and TP53-altered relapsed disease, and underscore its relevance amid ongoing early-phase clinical trials of BAFF-R-directed chimeric antigen receptor (CAR) T-cell therapy.
other
2026-08-06 | IKAROS isoforms differentially control gene expression and differentiation of a B-cell acute lymphoblastic leukemia cell line.
B-cell acute lymphoblastic leukemia (B-ALL) is the most common malignancy occurring in children and a leading cause of cancer-related mortality, thus there is an urgent need for development of novel therapeutic strategies for high risk B-ALL patients. The significance of IKZF1 gene alterations in B-ALL cases is controversial, as some studies have shown those to be associated with poor prognosis, while others have reported that deletion of exons 4-7 of the IKZF1 gene, which results in generation of IKAROS isoform 6, is related favorable prognosis. For the present study, clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 was employed for knockout of the IKZF1 gene and various IKAROS knockout lines were established, which allowed for investigation of precise functions of the gene by comparing four lines with different IKAROS isoform 1 and 6 statuses. The results clearly showed induction of significant differentiation and cell cycle progression in IKAROS isoform 6 knockout clones. Furthermore, knockout of IKAROS isoform 6 resulted in significant upregulation of the expression of IKAROS isoform 1 as well as signal transducer and activator of transcription 5 (STAT5) activity, which are considered to be related to the observed features. Further investigations are warranted to provide greater mechanistic insight regarding IKAROS-mediating pathways, which will lead to development of novel therapy for human B-ALL.
2026-06-20 | Differential cytokine architecture in patients treated with CART19 versus CART22.
Cytokine release syndrome (CRS) is a life-threatening toxicity of chimeric antigen receptor T-cell therapy (CART) for B-cell acute lymphoblastic leukemia (B-ALL). Lower rates of severe CRS have been reported in patients treated with CD22-directed CART (CART22) compared with those treated with CD19-directed CART (CART19). More than 1,000 serum proteins were measured using a proximity extension assay on 40 patients treated with CART19 or CART22 and cytokines were compared. Single-cell (single-cell RNA-sequencing (scRNAseq)) was used to identify cellular and transcriptional differences between patients treated with CART19 and CART22. CART19-blast and CART22-blast interactions at the immune synapse (IS) were modeled in vitro. We identified interleukin-10 (IL-10) as a critical endogenous modulator of CRS and demonstrated that previous treatment with CART is associated with increased serum IL-10 in the setting of subsequent relapse. Mechanistically, IL-10 induced higher interferon gamma expression and SOCS3 upregulation in both CART19 and CART22 cells. IL-10 differentially impacted the CART IS, prolonging the CART19 but shortening the CART22 IS. Using scRNAseq we demonstrated upregulation of SOCS3 in CART22 patient CD4 T-cells, potentially suppressing trans-IL-6 signaling. These findings reveal IL-10 as a potent CRS-mitigating factor and support IL-10 enhancement strategies to improve the safety of CART.
2026-05-11 | CRISPR Genome Editing and the Future of Leukaemia Immunotherapy.
Leukaemia presents ongoing therapeutic challenges due to relapse and toxicity associated with standard treatments. By enabling more targeted and safer therapies, CRISPR genome editing is emerging as a powerful tool to address these issues. We review current literature on CRISPR technologies in leukaemia immunotherapy, focussing on studies involving four key antigens commonly targeted in leukaemia: CD33, CD7, CD45 and CD19. We trace the evolution of CRISPR technologies from conventional CRISPR-Cas9 to base editing, highlighting how CRISPR platforms are being repurposed to enhance efficacy and clinical safety. Key studies targeting CD33 demonstrate how editing strategies can enable safer acute myeloid leukaemia (AML) therapies by reducing off-tumour toxicity; those addressing CD7 show how base editing prevents T-cell fratricide in T-cell acute lymphoblastic leukaemia (T-ALL) immunotherapy; studies focusing on CD45 illustrate how targeted editing facilitates universal CAR T-cell therapy; and clinical trials on CD19 support the feasibility of "off-the-shelf" treatments against paediatric B-cell acute lymphoblastic leukaemia (B-ALL). While base editing excels in precision and functional preservation, CRISPR-Cas9 remains preferred when complete gene knockout is desired. As off-tumour toxicity and fratricide are addressed, the future clinical impact of these technologies is poised to expand.
2026-04-04 | Interleukin-27 remodels the bone marrow niche to suppress B-cell development and leukaemia progression in mouse models.
Interleukin-27 (IL-27) is an immunoregulatory cytokine, but its role in B-cell haematopoiesis and B-cell acute lymphoblastic leukaemia (B-ALL) within the bone marrow (BM) niche remains unclear. IL-27 was delivered in vivo using adeno-associated virus. B-cell reconstitution, mixed BM chimeras, and an N-myc-driven B-ALL model were analysed by flow cytometry, transcriptional profiling, and survival studies. Group comparisons were assessed using Student's t-test, and survival was evaluated by Kaplan-Meier analysis with log-rank tests. Sustained IL-27 expression selectively impaired B-cell reconstitution while preserving overall haematopoietic recovery, with marked reductions in CLPs and early B-cell subsets. IL-27 directly inhibited early B-lineage differentiation and concurrently remodelled the BM microenvironment by downregulating VCAM-1, ICAM-2, CXCL12, and IGF-1. These niche alterations were associated with reduced BM-resident B-ALL burden, enhanced chemotherapy efficacy, and improved survival in B-ALL-bearing mice. IL-27 showed no direct cytotoxicity toward B-ALL cells, supporting an indirect, niche-mediated mechanism. IL-27 constrains B-cell haematopoiesis and B-ALL progression through coordinated progenitor inhibition and BM niche remodelling, revealing a cytokine-driven strategy with the potential to enhance leukaemia therapy. This work was supported by the National Key R&D Program of China (Grant No. 2021YFA1100800 to A.-B.L.) and the National Natural Science Foundation of China (Grant No. 82100180).
2026-03-31 | Chimeric antigen receptor T-cell therapies related to immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome: Diagnosis, high-risk factors, and management.
Immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS) is a life-threatening complication of chimeric antigen receptor T cell (CAR-T) therapy. Despite its high mortality rate, IEC-HS remains underrecognized due to overlapping clinical and laboratory features with severe cytokine release syndrome (CRS), leading to delayed diagnosis and suboptimal management. This review systematically analyzes key strategies to distinguish IEC-HS from severe CRS in the literature. The analysis focuses on temporal patterns, such as the delayed onset of IEC-HS after CAR-T infusion. It also examines dynamic laboratory trends, including persistently elevated ferritin and lactate dehydrogenase levels and a slower decline in C-reactive protein (CRP). In addition, distinct cytokine profiles are discussed, such as prolonged interferon-gamma (IFN-γ) elevation and surges in chemokines and growth factors. We further identify high-risk factors for IEC-HS, including patient-specific factors (baseline inflammation, low natural killer [NK] cell counts), disease-related factors (high B-cell acute lymphoblastic leukemia [B-ALL] burden and prior high-grade CRS), and CAR-T-related factors (CD22 target, CD28 costimulation, T-cell selection, high CAR-T cell dose, excessive CAR-T cell expansion, and TET2 gene mutation). For management, we evaluate conventional therapies (corticosteroids, etoposide) and emerging immunomodulatory agents (anakinra, ruxolitinib, emapalumab), emphasizing the 2023 treatment regimen by the American Society of Transplantation and Cellular Therapy (ASTCT). By integrating risk stratification, early diagnostic criteria, and tailored therapeutic approaches, this review aims to improve clinical outcomes for IEC-HS patients.
small molecules
2026-09-30 | Bortezomib-based chemotherapy in Chinese pediatric patients with relapsed/refractory acute lymphoblastic leukemia: A single-center retrospective study.
Relapsed/refractory acute lymphoblastic leukemia (R/R ALL) remains a major challenge in pediatric hematologic malignancies, with poor outcomes following standard salvage therapy. Real-world data regarding the use of bortezomib-based regimens in Chinese children are limited. To evaluate the effectiveness and safety of bortezomib-based chemotherapy in Chinese pediatric patients with R/R ALL. We retrospectively reviewed 12 pediatric patients with R/R ALL who received bortezomib-based chemotherapy at our center between January 2019 and January 2026. Clinical characteristics, responses, survival, and adverse events were evaluated. Complete remission (CR), CR with incomplete recovery (CRi), persistent disease (PD), and minimal residual disease (MRD) were assessed per standard criteria. Survival probabilities were estimated using the Kaplan-Meier analysis. Nine patients had B-cell ALL (B-ALL) and three had T-cell ALL (T-ALL). Among those with B-ALL, the CR/CRi rate was 88.9% (8/9), and 62.5% (5/8) of responders bridged to hematopoietic stem cell transplantation (HSCT). Notably, five of eight responders with B-ALL achieved MRD <0.01%, including all three refractory patients. In contrast, none of the three patients with T-ALL achieved remission; all experienced PD, with a median survival of 3 months. The 3-year overall survival and event-free survival rates for the entire cohort were 48.6% (95% confidence interval [CI], 19.2%-73.0%) and 36.4% (95% CI, 5.8%-69.8%), respectively. Treatment-related toxicities were manageable, with the most common being hematologic suppression and infections. Bortezomib-based chemotherapy showed promising salvage activity in pediatric patients with R/R B-ALL, enabling remission and HSCT bridging. However, its activity against T-ALL appears limited in this small cohort, warranting further investigation.
2026-09-26 | CREB1 and GSK3 Isoforms as Potential Adaptive Signaling Nodes in PI3K/Akt/mTOR Inhibitor Treated Philadelphia Chromosome-Positive B-ALL.
Philadelphia chromosome-positive (Ph+) B-cell acute lymphoblastic leukemia (ALL), driven by the BCR-ABL1 fusion, remains highly aggressive, with poor prognosis despite tyrosine kinase inhibitor (TKI) therapy. Aberrant PI3K/Akt/mTOR pathway activation contributes to resistance, warranting identification of predictive kinase biomarkers. To identify and validate critical phospho-kinase markers within the PI3K/Akt/mTOR axis as candidate adaptive signaling nodes and exploratory prognostic markers in Ph+ B-ALL. Network pharmacology using STRING and Cytoscape mapped the protein-protein interactions, identifying high-centrality nodes. Functional enrichment analyses (GO/KEGG) were then performed via ShinyGO. Experimentally, phospho-kinase arrays profiled 39 kinase phosphorylation sites in Ph+ B-ALL cells (SUPB-15) treated with PI3K/Akt/mTOR inhibitors (Rapamycin, GDC-0941, GSK690693, Perifosine). Gene expression was validated by RT-qPCR in 100 Ph+ B-ALL patients and protein validation employed Western blot in 50 patient samples with 15 and five healthy controls, respectively. Network analysis identified CREB1 and GSK3 isoforms as central hub regulators. Phospho-kinase profiling revealed p-CREB (Ser133) phosphorylation upregulation following Perifosine, GDC-0941, and Rapamycin treatment, with no statistically significant change after GSK690693. p-GSK3α/β (Ser21/9) phosphorylation showed a statistically significant increase after Perifosine, with non-significant trends after GDC-0941, and a significant reduction following Rapamycin. Hierarchical clustering then divided proteins into four distinct clusters positioning CREB1 in cluster 3 and GSK3α/β in cluster 2 as candidate adaptive response markers based on their phosphorylation profiles. RT-qPCR demonstrated marked downregulation of GSK3α (approximately 71%), GSK3β (63%), and CREB1 (65%) transcripts in patients versus controls, with even greater suppression seen in cell lines. Conversely, Western blot revealed a significant 2.49 fold elevated p-CREB (Ser133) (β = 1.317, p = 0.000347) and a phospho-GSK3α/β (Ser21/9) level that did not differ significantly between patients and controls (β = 0.467, p = 0.466), revealing mRNA-protein discordance indicative of compensatory post-transcriptional and post-translational regulation. These findings represent treatment-associated and disease-state associations between altered phosphorylation states and the Ph+ B-ALL context; functional validation remains an essential next step. mRNA-protein discordance with transcriptional downregulation (63-71%) contrasting with elevated p-CREB levels (2.49-fold, p = 0.000347) suggests post-translational compensatory mechanisms under therapeutic pressure. CREB1 and GSK3 isoforms emerge as central network nodes that might potentially mediate adaptive resistance, although functional validation is required. It should be noted that the evidence presented is associative rather than causal and a direct link between the observed phosphorylation changes and clinical drug resistance has not been established in this study. Sustained CREB phosphorylation despite PI3K/Akt/mTOR inhibition implicates alternative kinase pathways (MAPK/ERK, CaMK), supporting rational combination therapy strategies. These findings position p-CREB and p-GSK-3α/β as candidate biomarkers, highlighting the value of phospho-proteomics over transcriptomics alone in capturing pathway activation. Multi-omics integration may prove essential for overcoming adaptive resistance in ALL patients.
2026-09-24 | Outcome after first relapse post-immunochemotherapy in older adults with Philadelphia-negative B-cell acute lymphoblastic leukemia: A GRAALL study.
Inotuzumab (InO)-based frontline regimens have significantly improved the survival of older patients with Philadelphia-negative (Ph-) B-cell acute lymphoblastic leukemia (B-ALL). Yet, outcome after relapse is not reported for this population. The retrospective RELAPSINO study describes post-relapse outcome of 48 older patients treated front-line with a combination of InO and low-dose chemotherapy in the EWALL-INO trial (NCT03249870). At relapse (91% medullary), median age was 70 years and median duration of first complete remission (CR1) 15.2 months. CD19 or CD22 expression loss was observed in respectively 13% and 23% of evaluable cases. Most patients (85%) received salvage therapy (blinatumomab, low dose or intensive chemotherapy, in combination or not). There was no InO re-treatment. Overall, CR2 was reached by 51% of the patients. Median event-free survivals (EFS, 3.2 months) and overall survivals (OS, 4.5 months) were dismal. For patients achieving CR2, 2-year OS was 46% and leukemia-free survival (LFS) was 36%. By multivariable analysis, not receiving intensive chemotherapy was associated with significantly lower EFS (hazard ratio [HR], 3.28; 95% confidence interval [CI], 1.43-7.53, p = .005), LFS (HR, 13.2; 95% CI, 2.46-70.88, p = .003), and OS (HR, 3.25; 95% CI, 1.39-7.59, p = .006). CR1 duration ≥12 months was significantly associated with better EFS (HR, 0.31; 95% CI, 0.14-0.67, p = .003), LFS (HR, 0.16; 95% CI, 0.04-0.72, p = .01), and OS (HR, 0.42; 95% CI, 0.20-0.89, p = .023). Not achieving CR2 was associated with lower OS (HR, 8.0; 95% CI, 3.25-20.1, p < .001). Receiving blinatumomab had no impact. These results indicate that salvage regimen should be proposed in this context, allowing 50% of patients to achieve CR2 and have better survival.
2026-09-24 | Beyond CAR-T: Preventing and Treating Relapse in B-Cell Haematological Malignancies.
Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment landscape of relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL), non-Hodgkin lymphoma (NHL), and multiple myeloma (MM); however, a substantial proportion of patients eventually experience disease relapse despite an initial response. This review provides a brief overview of CAR-T cell therapy, including its manufacturing process and associated toxicities, before examining the biological mechanisms underlying post-CAR-T relapse in B-ALL, NHL-particularly large B-cell lymphoma (LBCL)-and MM. We critically review current and emerging strategies to prevent and manage relapse. Strategies for relapse prevention primarily include consolidation approaches, such as allogeneic hematopoietic stem cell transplantation (allo-HSCT), maintenance with targeted agents (e.g., tyrosine kinase inhibitors in Philadelphia chromosome-positive B-ALL), and CAR-T cell reinfusion, whereas relapse management is disease-specific and increasingly incorporates novel therapeutic agents, including bispecific antibodies (BsAbs) and other targeted therapies. However, current evidence remains largely preliminary and is limited by the paucity of randomized prospective trials.
2026-09-08 | Pathway incompatibility between NF-κB and RAS signaling constrains oncogenicity in B-cell leukemia.
Oncogenic pathways do not always cooperate; in some contexts, their co-activation is antagonistic and suppresses tumorigenesis, a phenomenon we termed pathway incompatibility. However, the mechanisms underlying this antagonism and the role of receptor context in shaping these interactions remain unclear. During normal B-cell development, precursor B-cell receptor (pre-BCR) signaling supports survival and proliferation of early B-cell precursors before transition to expression of the mature B-cell receptor (BCR). B-cell acute lymphoblastic leukemia (B-ALL), the most common childhood cancer, is characterized by developmental arrest prior to BCR expression, and approximately 35% of cases harbor activating RAS-ERK mutations that mimic pre-BCR-dependent survival signaling. NF-κB plays context-dependent roles in B-cell malignancies, but whether it influences the compatibility between oncogenic RAS signaling and BCR expression remains poorly understood. Activation of canonical NF-κB induced apoptotic depletion of RAS-driven B-ALL cells. Mechanistically, NF-κB suppressed pre-BCR-dependent survival signaling while promoting expression of BCR components. Consistent with this shift, oncogenic RAS signaling was poorly tolerated in BCR-positive cells unless BCR expression was disrupted. Pharmacologic activation of NF-κB reduced ERK signaling and selectively impaired viability of RAS-driven B-ALL cells, with enhanced effects in combination with ERK inhibition. Together, these findings show that canonical NF-κB signaling promotes BCR expression, which constrains oncogenic RAS activity, and establish pathway incompatibility as a mechanism through which receptor context can limit oncogenic potential.
antibodies
2026-09-29 | The Clinical Impact of End-of-Consolidation Measurable Residual Disease in High-Risk Pediatric B-Cell Acute Lymphoblastic Leukemia.
IntroductionBlinatumomab (BLINA) has improved event-free survival (EFS) and overall survival (OS) in pediatric patients with high-risk B-cell acute lymphoblastic leukemia (ALL) and has become an effective bridging therapy to hematopoietic cell transplantation. However, the prognostic significance of end-of-consolidation (EoC) measurable residual disease (MRD) in the current BLINA-incorporated treatment era remains unclear.MethodsWe retrospectively enrolled pediatric patients diagnosed with high-risk B-cell ALL between February 2022 and December 2024 at Chang Gung Memorial Hospital. Patients were categorized into EoC MRD-negative and EoC MRD-positive groups. EoC MRD was assessed by multiparameter flow cytometry, with real-time quantitative polymerase chain reaction used as a complementary molecular method when applicable. Outcomes of interest included EFS, OS, and BLINA-related adverse events (AEs).ResultsThe cohort consisted of 15 patients. With a median follow-up of 24 months, the observed 2-year EFS and OS rates were 71.5% and 86.7%, respectively. The EoC MRD-positive group demonstrated significantly higher relapse rates (57.1% vs. 0%, P = 0.0256) and numerically higher mortality rates (28.6% vs. 0%, P = 0.2). The 2-year EFS was significantly higher in the EoC MRD-negative group (100% vs. 42.9%, P = 0.02). Although the EoC MRD-negative group demonstrated a numerically higher 2-year OS (100% vs. 71.9%, P = 0.12), the difference did not reach statistical significance. Regarding safety, no high-grade short-term or long-term BLINA-related AEs were observed in either group.ConclusionIn this preliminary retrospective study, EoC MRD negativity was associated with sustained disease control during short-term follow-up and favorable survival outcomes in pediatric patients with high-risk B-cell ALL treated with BLINA-based therapy. These findings suggest that EoC MRD assessment might provide additional prognostic information in the contemporary BLINA treatment era. Further prospective studies with larger cohorts are warranted to validate these observations.
2026-09-15 | High-risk features in adult patients with B-cell acute lymphoblastic leukemia: redefining risk in the era of targeted immunotherapy.
The treatment landscape of adult B-cell acute lymphoblastic leukemia (B-ALL) has changed substantially with the introduction of targeted immunotherapeutic agents. Historically, high-risk disease was defined by clinical and cytogenetic features such as older age, elevated leukocyte count, and Philadelphia chromosome (Ph)-positive status. Advances in genomic profiling, together with the use of next-generation tyrosine kinase inhibitors, bispecific T-cell engagers, antibody-drug conjugates, and chimeric antigen receptor T-cell therapies, have altered both treatment outcomes and risk stratification. Outcomes for patients with Ph-positive B-ALL have improved markedly, particularly with ponatinib- and blinatumomab-based regimens, but several molecularly defined subgroups continue to have poor prognoses. These include IKZF1plus Ph-positive B-ALL, TP53-mutated and hypodiploid B-ALL, Ph-like B-ALL, and KMT2A-rearranged B-ALL. Emerging evidence indicates that introducing immunotherapeutic agents early in treatment can improve response quality and rates of measurable residual disease negativity, including in patients with high-risk disease. Relapse nevertheless remains a major challenge, and the optimal integration of novel agents, allogeneic hematopoietic cell transplantation, and cellular immunotherapy remains uncertain. This review summarizes the biological and clinical features of the major high-risk molecular subgroups of adult B-ALL and discusses how recent therapeutic advances are redefining risk assessment and treatment strategies in the era of targeted immunotherapy.
2026-09-07 | [Effect of inorganic pyrophosphatase PPA1 on proliferation and apoptosis of abnormal naive cells in acute B-lymphocytic leukemia].
Objective: To investigate the role of inorganic pyrophosphatase (PPA1) in the proliferation of abnormal naive lymphocytes in B-cell acute lymphoblastic leukemia (B-ALL) and evaluate its potential as a tumor marker. Methods: Bioinformatics analysis predicted the characteristics of the PPA1 gene. Bone marrow specimens were collected from patients with B-ALL, and abnormal immature B lymphocytes were isolated by CD19 and CD10 immunomagnetic beads, with normal cells as controls. PPA1 expression was detected with quantitative polymerase chain reaction (qPCR) and Western blot. B-ALL cell lines NALM-6 and HAL-01 were cultured in vitro, and recombinant PPA1 protein (rPPA1) or PPA1 monoclonal antibody was added to assess changes in cell proliferation, apoptosis, mitochondrial membrane potential, and cell cycle. The GV492-PPA1 overexpression plasmid was constructed and transfected into cells to assess the effect of PPA1 overexpression. shRNA was designed to construct the GV644-shPPA1 recombinant plasmid, and lentiviral transduction was performed to inhibit PPA1 expression. The impact on tumor cells was observed, and the expression levels of key proteins in the PI3K/AKT pathway and apoptosis-related factors were detected. Results: In abnormal immature B lymphocytes from patients with B-ALL, the transcription and expression levels of PPA1 were 3.75 - 14.89 times and 1.25 - 3.79 times those of normal cells, respectively. rPPA1 promoted NALM-6 and HAL-01 cell proliferation, with increased proliferation rates of 29.97% and 20.96% after treatment with 10 μg/ml for 72 h and 48.40% and 58.08% at 20 μg/ml, respectively. PPA1 monoclonal antibody (1:2 000, 1:1 000, 1:500) significantly inhibited proliferation at 19.53%, 46.90%, and 49.42% for NALM-6 cells and 22.29%, 52.41%, and 58.35% for HAL-01 cells, respectively. PPA1 monoclonal antibody (1:2 000, 1:1 000) induced apoptosis, increasing the apoptosis rate of NALM-6 cells from 10.01% to 20.17% and 29.11%, and that of HAL-01 cells from 12.65% to 18.53% and 31.80%. After treatment with the same PPA1 monoclonal antibody dilutions, the proportion of JC-1 monomers significantly increased, reaching 4.08- and 6.49-fold of the control in NALM-6 cells, and 3.99- and 6.42-fold in HAL-01 cells, indicating a decrease in mitochondrial membrane potential, whereas the cell cycle was arrested at the G(0)/G(1) phase. Overexpression of PPA1 for 48 and 72 h increased the proliferation rate of NALM-6 cells by 25.05% and 26.14%, and that of HAL-01 cells by 26.14% and 29.25%, respectively. PPA1 expression inhibition suppressed proliferation, with inhibition rates of 19.77% (48 h) and 28.99% (72 h) for NALM-6 cells, and 20.90% (72 h) for HAL-01 cells. qPCR and Western blot results revealed that PPA1 inhibition reduced the phosphorylation level of the PI3K/AKT pathway and regulated the expression of MDM2, P53, and apoptosis-related factors. Conclusion: PPA1 is closely associated with the proliferation and development of abnormal immature lymphocytes in B-ALL. PPA1 expression inhibition suppresses abnormal cell proliferation and promotes apoptosis, indicating that PPA1 has potential as a new target for tumor prevention and treatment.
2026-09-04 | Pre-treatment T cell features and immune-milieu characteristics shape treatment-induced exhaustion and resistance to Blinatumomab in B-cell acute lymphoblastic leukemia.
Blinatumomab (Blina), a CD19×CD3 bispecific T cell engager, is approved for the treatment of B-cell precursor acute lymphoblastic leukemia (BCP-ALL), yet resistance remains a major challenge and the mechanisms driving treatment failure remain poorly understood. To define the immunological determinants of resistance, we performed longitudinal profiling of peripheral blood T cells and the immune milieu of 34 patients receiving Blina using flow cytometry (n=19), single-cell CITE-seq (n=13), ex vivo Blina-induced cytotoxicity (n=26) and serum proteomics (n=17). At baseline, Responders (R) were enriched for CD8+ effector memory T cells (TEM) expressing higher levels of cytotoxic genes and their transcriptional regulator ZNF683. Conversely, CD8+ TEM from Non-Responders (NR) displayed transcriptional features of activation without proportionate cytotoxic commitment. Over the course of the first treatment cycle, NR exhibited a progressive expansion of TIM3+CD8+ T cells that correlated with a rapid loss of ex vivo cytotoxic function. Linking baseline state to post-treatment T-cell exhaustion, the magnitude of TIM3+CD8+ expansion correlated inversely with baseline ZNF683 expression in CD8+TEM. Beyond T-cell-intrinsic features, NR harbored an immunosuppressive milieu characterized by higher circulating levels of M2-polarizing factors (CSF-1, HGF) and the TIM-3 ligand Galectin-9, which correlated positively with the magnitude of TIM3+CD8+ T-cell expansion. These findings indicate that post-Blina CD8+ T-cell exhaustion is associated with resistance and it is shaped by both reduced ZNF683-dependent cytotoxic programming in CD8+ TEM and an immunosuppressive milieu. This provides a rationale for risk stratification based on baseline transcriptional profiling of CD8+ TEM and for combinatorial strategies targeting the suppressive microenvironment.
2026-09-01 | EARLY RESPONSE AND GENETICS DEFINE RELAPSE RISK AFTER FRONTLINE BLINATUMOMAB IN CHILDHOOD B-ALL: A COHORT STUDY.
Blinatumomab is increasingly incorporated into frontline therapy for B-cell acute lymphoblastic leukaemia (B-ALL), yet risk stratification remains based on chemotherapy-era factors that may not apply in the immunotherapy setting. We analysed a national cohort to define determinants of relapse following frontline blinatumomab. Children and young people (1-24 years) in the UK and Ireland diagnosed with B-ALL between 2018 and 2025 who were chemotherapy-intolerant or resistant received blinatumomab in place of selected components of the frontline chemotherapy backbone. Outcomes were analysed according to conventional prognostic variables, genetic features, and response to blinatumomab. Among 225 patients, 195 received chemotherapy following blinatumomab (Blin-CT) and 30 underwent first-remission HSCT. In the Blin-CT cohort, traditional risk factors, including age, white cell count, high-risk genetics, and pre-blinatumomab end-of-induction measurable residual disease (MRD) did not predict relapse. On univariable analysis, relapse risk was increased with detectable MRD after blinatumomab cycle 1 (C1-END; hazard ratio HZR 6.61, p<0.001), IKZF1plus (HZR 3.64, p=0.04), JAK-STAT abnormalities (HR 3.56, p=0.05), and DUX4 rearrangements (HZR 4.24, p=0.03). In multivariable modelling, C1-END MRD and IKZF1plus remained independently associated with relapse, whereas DUX4-rearranged cases were strongly associated with persistent MRD at C1-END. An integrated model incorporating C1-END MRD, IKZF1plus, and DUX4-r defined a high-risk subgroup (33%) with an 18% 2-year relapse rate versus 0% in remaining patients (bootstrapped HZR 12.82, p=0.001, C-index=0.81). Relapse following frontline blinatumomab is determined by early treatment response and genetic subtype rather than conventional chemotherapy-derived risk factors. These findings support immunotherapy-specific risk stratification to guide treatment intensity.
oligonucleotides
2026-06-15 | Delivery of Monomethyl Auristatin E Using Ionizable Lipid Nanoparticles for B‑Cell Acute Lymphoblastic Leukemia Treatment.
Ionizable lipid nanoparticles (LNPs) are the leading method for clinically delivering nucleic acid cargoes such as messenger or small interfering RNAs. The capacity of LNPs to encapsulate and deliver small molecule therapeutics alongside traditional nucleic acid cargo remains largely unexplored. Beginning the development of a dual delivery approach using LNPs holds significant potential for treating malignancies prone to therapeutic resistance. B-cell acute lymphoblastic leukemia (B-ALL) is a hematologic malignancy with a poor prognosis in patients who experience relapse or are refractory to standard-of-care treatments. Here, we encapsulated the antimitotic agent, monomethyl auristatin E (MMAE), within prefabricated LNPs containing nonfunctional negative control small interfering RNA (siRNA) and evaluated the resulting antileukemic activity in B-ALL preclinical models. We optimized a postfabrication loading technique to encapsulate MMAE within LNPs while maintaining their superior siRNA retention and favorable physicochemical characteristics. Flow cytometry and confocal microscopy studies confirmed that the LNP uptake by B-ALL cells occurred through clathrin-mediated endocytosis and macropinocytosis. MMAE loaded within LNPs demonstrated potent antileukemic efficacy against B-ALL cells in vitro compared to the standard-of-care chemotherapeutic vincristine. Furthermore, within a B-ALL human xenograft murine model, MMAE-loaded LNPs exhibited over a 2-fold reduction of leukemic burden in the spleen and the peripheral blood as compared to LNPs without MMAE. Taken together, this study provides the groundwork for developing LNPs as a clinically translatable codelivery platform for chemotherapy and siRNA to improve the treatment of challenging malignancies, such as B-ALL.
2026-05-13 | Defibrotide-Responsive Cutaneous Endothelial Injury Following Allogeneic Hematopoietic Stem Cell Transplant: A Case Report.
A 57 -year -old woman with relapsed Philadelphia chromosome -negative B -cell acute lymphoblastic leukemia developed diffuse non -blanching erythematous skin lesions following allogeneic hematopoietic stem cell transplant. The lesions appeared concomitantly with hepatic sinusoidal obstruction syndrome and persisted despite engraftment and supportive therapy. Skin biopsy excluded graft -versus -host disease. Upon initiation of defibrotide for moderate hepatic sinusoidal obstruction syndrome, both hepatic and cutaneous findings resolved completely. This case underscores the systemic endothelial -protective potential of defibrotide, extending beyond the hepatic microvasculature, and highlights cutaneous endotheliopathy as a possible manifestation of transplant -associated endothelial injury.
2025-11-10 | surviBALL: exploring lncRNA expression at diagnosis for 5-year EFS risk stratification in pediatric B-ALL-a proof of concept.
B-cell Acute Lymphoblastic Leukemia (B-ALL) remains an important cause of cancer-related death in children. Therefore, accurate identification at diagnosis of patients at high risk of relapse is crucial. In this context, long non-coding RNAs (lncRNAs) could be novel candidates with great potential. Hence, the aim of this study was to identify new prognostic biomarkers in pediatric B-ALL through an RNA sequencing (RNA-seq) approach that allows the detailed exploration of a wide range of lncRNAs. Total RNA from two cohorts of B-ALL patients (C1 with 50 Spanish patients, and C2 with 72 Canadian patients) was sequenced with a depth of approximately 150 million paired-reads using Illumina technology. All protein coding and non-coding genes included in lncRNAKB annotation were studied to develop a gene expression-based 5-year Event Free Survival (EFS) prediction model. First, univariate Cox proportional hazards analyses identified 48 genes significantly associated with higher EFS risk in both cohorts. From these, ALASSO regression selected five genes, all of which are lncRNAs, as the most informative to develop the prediction model, which we have called surviBALL. Stratification of patients into three risk groups according to the surviBALL model revealed significantly poorer EFS in high-risk patients across C1, C2, and the integrated C1 + C2 cohort (P < 0.001). Validation in an independent cohort of 177 publicly available B-ALL samples confirmed surviBALL's prediction capacity (P = 2.80 × 10- 4) and its independence of both subtype and MRD. These findings suggest that surviBALL has the potential to complement current risk stratification approaches, particularly by identifying patients at high risk of relapse at diagnosis. As a hypothesis-generating proof of concept, this study highlights the promise of more personalized treatment strategies and warrants further validation in independent cohorts.
2025-10-13 | Long non-coding RNAs in B-cell acute lymphoblastic leukemia: Disease implication, challenges and therapeutic opportunities.
B-cell acute lymphoblastic leukemia (B-ALL) manifests as an abnormal proliferation of neoplastic B-cell lymphocytes, adversely affecting both children and adults. Despite the advancements in cancer research, B-ALL cure remains challenging due to the complexity of the disease and immense subtype heterogeneity. Better understanding of the molecular mechanisms driving B-ALL pathogenesis is imperative to identify the novel therapeutic markers that can impede disease progression. Genomic and transcriptomic studies involving patient samples have underscored the emerging role of long non-coding RNAs (lncRNAs) in the diverse B-ALL landscape. Their dysregulation has been linked to malignant proliferation, metastasis, and varying patient survival outcomes. Gaining detailed mechanistic insights into the role of lncRNAs in B-ALL pathophysiology is pivotal for understanding their contributions to disease progression and developing new therapeutics. Herein, we have comprehensively discussed B-ALL and its diverse subtypes, focusing on the pivotal role played by various lncRNAs in fine-tuning signaling pathways, disease heterogeneity and progression. We have also explored recent advances in our understanding of the diverse classes of lncRNA inhibitors, evaluating their potential as B-ALL therapeutics and challenges associated with their development.
2025-06-01 | Integrative Genetic and Transcriptomic Subtyping Improves Prognosis Prediction in B-Lineage Acute Lymphoblastic Leukemia.
Whole-transcriptomic sequencing (WTS) has remarkably advanced our understanding of B-lineage acute lymphoblastic leukemia (B-ALL), allowing for detailed gene expression profiling and discovery of novel therapeutically relevant subtypes. The aim of this study was to evaluate the diagnostic and prognostic relevance of combining WTS with traditional genetic methods in risk-stratifying B-ALL. In a cohort of 394 patients (301 children and 93 adults), conventional techniques such as fluorescence in situ hybridization, cytogenetics, and reverse-transcription PCR identified sentinel chromosomal abnormalities like BCR::ABL1, TCF3::PBX1, ETV6::RUNX1, and KMT2A-R (rearranged), and ploidy status. WTS was performed on selected 257 patients to identify subtypes such as Ph-like, DUX4-R, PAX5-altered (PAX5-ALT), MEF2D-R, BCL2-R, UBTF-R, PAX5 P80R, NUTM1-R, ZNF384-R, ZNF384-like, ETV6::RUNX1-like, IKZF1 N159Y, and HLF-R. We used a multipronged strategy to identify the borderline subtypes such as Ph-like, PAX5-ALT, and CRLF2 (non-Ph-like), by integrating gene expression signatures using t-distributed stochastic neighbor embedding, subtype-defining mutations, gene fusions, and copy number assessments. Our integrated approach not only identifies prognostically relevant sentinel molecular subtypes but also increases subtype assignment in upto ∼95% of B-ALL patients. The pro-B immunophenotype was found to be more frequent in UBTF-R and MEF2D-R ALL. Ph-like ALL was associated with poor remission rates and higher minimal residual disease positivity, while DUX4-R showed favorable prognosis. We further categorized pediatric patients into 3 risk groups: favorable (hyperdiploid, ETV6::RUNX1, and DUX4-R), poor (BCR::ABL1, Ph-like, KMT2A-R, TCF3::PBX1, iAMP21, and hypodiploid), and intermediate (PAX5-ALT, PAX5 P80R, NUTM1-R, MEF2D-R, CRLF2 [non-Ph-like], UBTF-R, ZNF384-R, ZNF384-like, BCL2-R, IKZF1 N159Y, ETV6::RUNX1-like, and B-rest). Event-free survival and overall survival were significantly associated with this risk stratification. In adults, Ph-like ALL showed worse prognosis, particularly, in BCR::ABL1-negative ALL patients. Among the DUX4-R B-ALL, those with IKZF1 deletion had worse event-free survival and overall survival. We also identified several novel gene rearrangements in different subtypes of B-ALL. Our study demonstrated that integrating WTS with traditional methods provides a comprehensive, accurate, and cost-effective strategy for risk assessment and treatment planning for B-ALL.
cell therapies
2026-09-03 | Tumour immunotherapy in solid and hematologic malignancies: Progress, challenges, and a practical framework.
Tumour immunotherapy has reshaped the landscape of oncology by translating fundamental insights from immunosurveillance, immunoediting, and checkpoint biology into effective clinical strategies. This review traces the historical trajectory of tumour immunotherapy, from the early observations of William Coley to the development of modern immune checkpoint inhibitors (ICIs) targeting cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death protein 1/ligand 1 (PD-1/PD-L1). Moreover, a comprehensive analysis of the progress of immunotherapy across different tumour types is provided. In solid tumours, significant benefits have been achieved in ``inflamed'' or ``hot'' cancers like melanoma, non-small-cell lung cancer, and renal cell carcinoma. However, formidable hurdles remain in ``non-inflamed'' or ``cold'' tumours such as pancreatic ductal adenocarcinoma, glioblastoma, and microsatellite-stable colorectal cancer. In hematologic malignancies, living drugs and redirecting immunotherapies have demonstrated profound efficacy: CAR-T therapy has achieved durable remissions in B-cell acute lymphoblastic leukemia (B-ALL) and diffuse large B-cell lymphoma (DLBCL), while T-cell engagers offer a rapid, ``off-the-shelf'' option for multiple myeloma. Collectively, this review synthesizes these developments into a practical framework based on tumour immune context, offering a guide for optimizing current treatments and directing future research to overcome resistance and benefit more patients.
2026-08-18 | Mathematical modelling of immune persistence and relapse pathways in CAR T-cell therapy for B-ALL
Chimeric antigen receptor (CAR) T-cell therapy has transformed the treatment of B-cell acute lymphoblastic leukaemia (B-ALL). Despite high initial response rates, a substantial fraction of patients relapse, often due to loss of CAR T-cell persistence, antigen escape, or immune-privileged sites that shield tumour cells. Prolonged CAR T-cell persistence is clinically associated with durable remission, but why it is required remains poorly understood. To address this, we develop and analyse the BEAM (Blast, Effector, Activated, Memory) model of CAR T-cell dynamics in B-ALL. BEAM extends predator--prey models with three CAR T-cell states (memory, activated, effector) coupled to a logistic growth equation for the blasts, calibrated against the FELIX trial of obecabtagene autoleucel in adult B-ALL. We find that both memory and effector persistence prevent relapse, but for distinct reasons: memory persistence sustains surveillance against low-burden or slowly proliferating residual disease, while effector persistence clears isolated blasts emerging from immune-privileged sites. The model further predicts a trade-off between immediate cytotoxicity and durable surveillance, and identifies initial tumour burden as a key modifiable factor for reducing antigen-negative relapse. Together, these results offer a framework for designing more durable, individually tailored CAR T-cell therapies.
2026-08-10 | Laboratory Concordance and Prognostic Impact of 10-Color Flow Cytometry and Next-Generation Sequencing-Based Immunoglobulin Gene Assay for Measurable Residual Disease Monitoring in Adult B-Cell Acute Lymphoblastic Leukemia: A Multicenter Study From Thai Acute Leukemia Working Group (TALWG).
Measurable residual disease (MRD) is a key prognostic marker for patient survival. This study evaluated concordance between 10-color flow cytometry and next-generation sequencing (NGS)-based immunoglobulin heavy chain (IGH) gene assays for MRD detection and to assess prognostic significance in adult B-cell acute lymphoblastic leukemia (B-ALL). This multicenter prospective study enrolled 51 patients with newly diagnosed B-ALL. Bone marrow samples were obtained at diagnosis, post-induction (1 month), and post-early consolidation (3 months). Flow cytometry and NGS-IGH were performed at three timepoints to assess MRD B-ALL. Patients were classified as high risk according to white blood cell count and cytogenetic features in 37.3% and 64.7% of patients, respectively. Treatment protocols included pediatric-inspired regimens (41.2%), adult-ALL protocols (52.9%), and low-intensity chemotherapy. All 16 Philadelphia chromosome-positive patients received tyrosine kinase inhibitors. Twenty patients underwent allogeneic hematopoietic cell transplantation (HCT) in first complete remission (CR). Median relapse-free survival (RFS) and overall survival were 19 and 39 months, respectively. MRD negativity at 3 months by either method correlated with significantly superior RFS. Allogeneic HCT also conferred RFS benefit. MRD positive patients without HCT had the worst RFS. Flow cytometry MRD positivity at 3 months independently predicted inferior RFS (HR 3.81; 95% CI 1.01-14.43). The overall concordance between flow cytometry and NGS was 80.7%. MRD positivity at 3 months post-treatment strongly predicted relapse, supporting its use to guide therapeutic modifications of B-ALL. Apart from NGS-based IGH clonality assays, 10-color flow cytometry offers an alternative in resource-limited settings.
2026-08-04 | CAR-T versus allogeneic transplantation as consolidation for B-cell acute lymphoblastic leukemia in remission: a propensity-score matched study.
Despite being a standard consolidation treatment, allogeneic hematopoietic stem cell transplantation (allo-HSCT) for B-cell acute lymphoblastic leukemia (B-ALL) in remission is still hampered by relapse and complications. While CAR-T therapy is revolutionizing later-line treatment, its role as a consolidation strategy in remission, particularly for patients ineligible for transplantation, remains unexplored. This study compared the efficacy of CAR-T therapy with that of allo-HSCT as consolidation for B-ALL patients in complete remission (CR). A retrospective, propensity-score matched study was performed from September 1, 2012 to December 31, 2024, including 75 B-ALL patients treated with CAR-T or allo-HSCT as consolidation therapy. Firth penalized likelihood Cox models and restricted mean survival time (RMST) models were built for time-to-event outcomes. The 2-year progression-free survival (PFS) and 2-year overall survival (OS) rates showed no significant differences between the CAR-T and HSCT cohorts (CR1: 2-year PFS rate: 65.8% vs. 88.9%, P = 0.146, 2-year OS rate: 83.6% vs. 91.3%, P = 0.512; CR2: 2-year PFS rate: 42.2% vs. 64.3%, P = 0.360). The RMSTs of PFS and OS also have no significant differences (CR1: RMST of PFS difference = -7.738, P = 0.496, RMST of OS difference = -2.257, P = 0.788; CR2: RMST of PFS difference = -6.176, P = 0.700, RMST of OS difference = -8.391, P = 0.477) truncated at the minimum of the largest follow-up times in each cohort (CR1, 74.6 months; CR2, 75.0 months). In multivariate analysis, patients treated with allo-HSCT had better PFS in CR1 group (HR = 4.579, 95%CI, 1.020-20.563, P = 0.038). High risk stratification was an independent factor associated with worse OS for B-ALL patients in CR (CR1: HR = 8.010; 95%CI, 1.744-36.781, P = 0.048; CR2 HR = 5.110, 95%CI, 1.167-22.378, P = 0.004). The results indicated that CAR-T consolidation regimen showed comparable survival to that of allo-HSCT in matched B-ALL patients, which might support its potential as a consolidation alternative for B-ALL patients ineligible for allo-HSCT.
2026-07-24 | B-cell activating factor receptor expression in B-lymphoblastic leukaemia: Flow cytometric analysis and implications for targeted therapy.
Cluster of differrentiation 19 (CD19)-directed therapies have significantly improved outcomes in B-cell malignancies; however, relapse driven by antigen escape remains a major clinical challenge, underscoring the need for alternative therapeutic targets. The B-cell activating factor receptor (BAFF-R), a key regulator of B-cell survival, is highly expressed in mature B-cell neoplasms, but its relevance in B-lymphoblastic leukaemia (B-ALL) remains unclear. We assessed BAFF-R expression in diagnostic and relapsed fresh B-ALL samples using multi-parameter flow cytometry. BAFF-R was consistently expressed in most cases, albeit at lower levels than in mature B cells, and expression was retained in the majority of CD19-negative relapses following CD19-directed therapy. Notably, tumor protein p53 (TP53) alterations were significantly enriched in CD19-negative immune escape disease (68.8% vs. 21.7%; p = 0.0006; OR = 7.9), yet BAFF-R expression remained preserved in this high-risk group. These findings establish BAFF-R as a stable immunotherapeutic target in B-ALL, including in CD19-negative and TP53-altered relapsed disease, and underscore its relevance amid ongoing early-phase clinical trials of BAFF-R-directed chimeric antigen receptor (CAR) T-cell therapy.
other
2026-08-06 | IKAROS isoforms differentially control gene expression and differentiation of a B-cell acute lymphoblastic leukemia cell line.
B-cell acute lymphoblastic leukemia (B-ALL) is the most common malignancy occurring in children and a leading cause of cancer-related mortality, thus there is an urgent need for development of novel therapeutic strategies for high risk B-ALL patients. The significance of IKZF1 gene alterations in B-ALL cases is controversial, as some studies have shown those to be associated with poor prognosis, while others have reported that deletion of exons 4-7 of the IKZF1 gene, which results in generation of IKAROS isoform 6, is related favorable prognosis. For the present study, clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 was employed for knockout of the IKZF1 gene and various IKAROS knockout lines were established, which allowed for investigation of precise functions of the gene by comparing four lines with different IKAROS isoform 1 and 6 statuses. The results clearly showed induction of significant differentiation and cell cycle progression in IKAROS isoform 6 knockout clones. Furthermore, knockout of IKAROS isoform 6 resulted in significant upregulation of the expression of IKAROS isoform 1 as well as signal transducer and activator of transcription 5 (STAT5) activity, which are considered to be related to the observed features. Further investigations are warranted to provide greater mechanistic insight regarding IKAROS-mediating pathways, which will lead to development of novel therapy for human B-ALL.
2026-06-20 | Differential cytokine architecture in patients treated with CART19 versus CART22.
Cytokine release syndrome (CRS) is a life-threatening toxicity of chimeric antigen receptor T-cell therapy (CART) for B-cell acute lymphoblastic leukemia (B-ALL). Lower rates of severe CRS have been reported in patients treated with CD22-directed CART (CART22) compared with those treated with CD19-directed CART (CART19). More than 1,000 serum proteins were measured using a proximity extension assay on 40 patients treated with CART19 or CART22 and cytokines were compared. Single-cell (single-cell RNA-sequencing (scRNAseq)) was used to identify cellular and transcriptional differences between patients treated with CART19 and CART22. CART19-blast and CART22-blast interactions at the immune synapse (IS) were modeled in vitro. We identified interleukin-10 (IL-10) as a critical endogenous modulator of CRS and demonstrated that previous treatment with CART is associated with increased serum IL-10 in the setting of subsequent relapse. Mechanistically, IL-10 induced higher interferon gamma expression and SOCS3 upregulation in both CART19 and CART22 cells. IL-10 differentially impacted the CART IS, prolonging the CART19 but shortening the CART22 IS. Using scRNAseq we demonstrated upregulation of SOCS3 in CART22 patient CD4 T-cells, potentially suppressing trans-IL-6 signaling. These findings reveal IL-10 as a potent CRS-mitigating factor and support IL-10 enhancement strategies to improve the safety of CART.
2026-05-11 | CRISPR Genome Editing and the Future of Leukaemia Immunotherapy.
Leukaemia presents ongoing therapeutic challenges due to relapse and toxicity associated with standard treatments. By enabling more targeted and safer therapies, CRISPR genome editing is emerging as a powerful tool to address these issues. We review current literature on CRISPR technologies in leukaemia immunotherapy, focussing on studies involving four key antigens commonly targeted in leukaemia: CD33, CD7, CD45 and CD19. We trace the evolution of CRISPR technologies from conventional CRISPR-Cas9 to base editing, highlighting how CRISPR platforms are being repurposed to enhance efficacy and clinical safety. Key studies targeting CD33 demonstrate how editing strategies can enable safer acute myeloid leukaemia (AML) therapies by reducing off-tumour toxicity; those addressing CD7 show how base editing prevents T-cell fratricide in T-cell acute lymphoblastic leukaemia (T-ALL) immunotherapy; studies focusing on CD45 illustrate how targeted editing facilitates universal CAR T-cell therapy; and clinical trials on CD19 support the feasibility of "off-the-shelf" treatments against paediatric B-cell acute lymphoblastic leukaemia (B-ALL). While base editing excels in precision and functional preservation, CRISPR-Cas9 remains preferred when complete gene knockout is desired. As off-tumour toxicity and fratricide are addressed, the future clinical impact of these technologies is poised to expand.
2026-04-04 | Interleukin-27 remodels the bone marrow niche to suppress B-cell development and leukaemia progression in mouse models.
Interleukin-27 (IL-27) is an immunoregulatory cytokine, but its role in B-cell haematopoiesis and B-cell acute lymphoblastic leukaemia (B-ALL) within the bone marrow (BM) niche remains unclear. IL-27 was delivered in vivo using adeno-associated virus. B-cell reconstitution, mixed BM chimeras, and an N-myc-driven B-ALL model were analysed by flow cytometry, transcriptional profiling, and survival studies. Group comparisons were assessed using Student's t-test, and survival was evaluated by Kaplan-Meier analysis with log-rank tests. Sustained IL-27 expression selectively impaired B-cell reconstitution while preserving overall haematopoietic recovery, with marked reductions in CLPs and early B-cell subsets. IL-27 directly inhibited early B-lineage differentiation and concurrently remodelled the BM microenvironment by downregulating VCAM-1, ICAM-2, CXCL12, and IGF-1. These niche alterations were associated with reduced BM-resident B-ALL burden, enhanced chemotherapy efficacy, and improved survival in B-ALL-bearing mice. IL-27 showed no direct cytotoxicity toward B-ALL cells, supporting an indirect, niche-mediated mechanism. IL-27 constrains B-cell haematopoiesis and B-ALL progression through coordinated progenitor inhibition and BM niche remodelling, revealing a cytokine-driven strategy with the potential to enhance leukaemia therapy. This work was supported by the National Key R&D Program of China (Grant No. 2021YFA1100800 to A.-B.L.) and the National Natural Science Foundation of China (Grant No. 82100180).
2026-03-31 | Chimeric antigen receptor T-cell therapies related to immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome: Diagnosis, high-risk factors, and management.
Immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS) is a life-threatening complication of chimeric antigen receptor T cell (CAR-T) therapy. Despite its high mortality rate, IEC-HS remains underrecognized due to overlapping clinical and laboratory features with severe cytokine release syndrome (CRS), leading to delayed diagnosis and suboptimal management. This review systematically analyzes key strategies to distinguish IEC-HS from severe CRS in the literature. The analysis focuses on temporal patterns, such as the delayed onset of IEC-HS after CAR-T infusion. It also examines dynamic laboratory trends, including persistently elevated ferritin and lactate dehydrogenase levels and a slower decline in C-reactive protein (CRP). In addition, distinct cytokine profiles are discussed, such as prolonged interferon-gamma (IFN-γ) elevation and surges in chemokines and growth factors. We further identify high-risk factors for IEC-HS, including patient-specific factors (baseline inflammation, low natural killer [NK] cell counts), disease-related factors (high B-cell acute lymphoblastic leukemia [B-ALL] burden and prior high-grade CRS), and CAR-T-related factors (CD22 target, CD28 costimulation, T-cell selection, high CAR-T cell dose, excessive CAR-T cell expansion, and TET2 gene mutation). For management, we evaluate conventional therapies (corticosteroids, etoposide) and emerging immunomodulatory agents (anakinra, ruxolitinib, emapalumab), emphasizing the 2023 treatment regimen by the American Society of Transplantation and Cellular Therapy (ASTCT). By integrating risk stratification, early diagnostic criteria, and tailored therapeutic approaches, this review aims to improve clinical outcomes for IEC-HS patients.
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Drug Discovery Landscape
30 orphan drug designations for Precursor B-cell acute lymphoblastic leukemia, including 4 approved therapies.
30 orphan drug designations for Precursor B-cell acute lymphoblastic leukemia, including 4 approved therapies.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
enzomenib | small molecules | FDA | Sumitomo Pharma America, Inc. | |
cell therapy product derived from an allogeneic hematopoietic stem cell donor and expressed anti-CD19 chimeric antigen receptor, T cell receptor of invariant natural killer T cells, and interleukin-15 | cell therapies | FDA | — | Shanghai Allovanta Biotechnology Co., Ltd. |
blinatumomab | antibodies | FDA | Amgen Inc. | |
surovatamig | antibodies | FDA | AstraZeneca Pharmaceuticals LP | |
universal chimeric antigen receptor T cells (UCAR-T) targeting CD7 | cell therapies | FDA | Bioheng Therapeutics US LLC | |
chimeric antigen receptor T cells targeting CD19 & CD22 | cell therapies | FDA | Shenzhen Pregene Biopharma Co., Ltd. | |
Allogeneic peripheral blood-derived T-cells, fratricide-resistant, transduced with a lentivirus vector expressing a chimeric antigen receptor against CD7 | cell therapies | EMA | — | Yes Pharmaceutical Development Services GmbH |
small molecule cytidine triphosphate synthase 1 (CTPS1) inhibitor | small molecules | FDA | — | Step Pharma |
adeno-associated viral serotype rh74 vector encoding an anti-CD19-anti-CD3 bispecific protein | gene therapies | FDA | Vironexis Biotherapeutics, Inc. | |
Anti-CD19 Chimeric Antigen Receptor T-Cell Injection | cell therapies | FDA | Juventas Cell Therapy Ltd. | |
Axicabtagene ciloleucel | cell therapies | EMA | Kite Pharma EU B.V. | |
Allogeneic umbilical cord blood cells treated ex vivo with 16,16-dimethyl prostaglandin E2 | cell therapies | EMA | Fate Therapeutics Limited | |
Spanlecortemlocel | cell therapies | EMA | Novartis Europharm Limited | |
Pinometostat | small molecules | EMA | Voisin Consulting Life Sciences | |
Moxetumomab pasudotox | proteins | EMA | AstraZeneca AB | |
Inotuzumab ozogamicin [Besponsa] | antibodies | EMA | Approved | Pfizer Europe MA EEIG |
inotuzumab ozogamicin [Besponsa] | antibodies | FDA | Approved | Wyeth Pharmaceuticals, LLC |
inotuzumab ozogamicin | antibodies | FDA | Approved | Wyeth Pharmaceuticals, LLC |
inotuzumab ozogamicin [Besponsa] | antibodies | FDA | Approved | Wyeth Pharmaceuticals, LLC |
Ponatinib hydrochloride [Iclusig] | small molecules | EMA | Incyte Biosciences Distribution B.V. | |
Mercaptopurine [Xaluprine] | small molecules | EMA | Nova Laboratories Ireland Limited | |
Allogeneic umbilical cord blood cells-derived CD133+ cells ex vivo expanded | cell therapies | EMA | Regulatory Resources Group Limited | |
Vincristine sulfate | small molecules | EMA | Pharma Gateway AB | |
Dasatinib [Sprycel] | small molecules | EMA | [INACTIVE] Bristol-Myers Squibb Pharma EEIG | |
Imatinib mesilate [Glivec] | small molecules | EMA | Novartis Europharm Limited | |
Nelarabine [Atriance] | small molecules | EMA | Novartis Europharm Limited | |
Asparaginase [Spectrila] | proteins | EMA | [INACTIVE] Medac Gesellschaft fuer klinische Spezialpraeparate mbH | |
Plitidepsin [Aplidin] | small molecules | EMA | — | Pharma Mar S.A. |
Clofarabine [Evoltra] | small molecules | EMA | [INACTIVE] Sanofi B.V. | |
Ricin (blocked) conjugated murine mca (anti-b4) | antibodies | FDA | — | ImmunoGen, Inc. |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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