Blinatumomab, a bispecific T-cell engager (BiTE), has shown substantial efficacy in treating both relapsed/refractory (R/R) Philadelphia chromosome (Ph)-positive and Ph-negative acute lymphoblastic leukemia (ALL). With its targeted mechanism of action, favorable safety profile, and ability to induce deep molecular remissions, blinatumomab is increasingly incorporated into frontline treatment regimens for B-ALL. Recently, the Food and Drug Administration (FDA) has approved its use in the frontline setting for Ph-negative ALL. In Ph-negative ALL, combining blinatumomab with intensive chemotherapy has resulted in superior measurable residual disease (MRD) clearance and improved long-term outcomes. In Ph-positive ALL, combination therapies involving tyrosine kinase inhibitors (TKIs), particularly ponatinib and blinatumomab, are challenging the traditional approach of allogeneic hematopoietic stem cell transplantation (allo-SCT). This review explores the current evidence supporting the frontline use of blinatumomab in newly diagnosed adults with B-ALL, its impact on treatment paradigms, and potential future directions, including novel combination therapies and the role of emerging immunotherapeutic approaches.

Background: Philadelphia-like acute lymphoblastic leukemia (Ph-like ALL) is a high-risk subtype of B-cell ALL characterized by a gene expression profile similar to BCR::ABL1-positive leukemia, but lacking the BCR::ABL1 fusion gene. It is frequently associated with kinase-activating alterations, such as CRLF2 rearrangements, JAK-STAT pathway mutations, and ABL-class fusions. Patients with Ph-like ALL typically experience poor outcomes with conventional chemotherapy, underscoring the need for intensified and targeted therapeutic approaches. Methods: This review summarizes current evidence regarding the role of hematopoietic stem cell transplantation (HSCT) in patients with Ph-like ALL. We analyzed retrospective cohort studies, registry data, and ongoing clinical trials, focusing on transplant indications, molecular risk stratification, measurable residual disease (MRD) status, timing of transplant, and post-transplant strategies. Results: Retrospective data suggest that HSCT in first complete remission (CR1) may improve survival in patients with high-risk molecular lesions or MRD positivity at the end of induction. However, the lack of prospective data specific to Ph-like ALL limits definitive conclusions. Post-transplant relapse remains a challenge, and novel strategies, including the use of tyrosine kinase inhibitors or JAK inhibitors as post-HSCT maintenance therapy, are being explored. Emerging immunotherapies, such as chimeric antigen receptor (CAR) T cells, may reshape the therapeutic landscape and potentially alter the indications for transplantation. Conclusions: HSCT remains a crucial therapeutic option for selected patients with Ph-like ALL, particularly those with poor molecular risk features or persistent MRD. However, further prospective studies are needed to evaluate the indication for HSCT in CR1 and the potential integration of transplantation with targeted and immunotherapeutic strategies. Personalized treatment approaches based on genomic profiling and MRD assessment are essential to improve outcomes in this high-risk subset.

Background: Acute lymphoblastic leukemia (ALL) is a genetically heterogeneous malignancy driven by structural variants (SVs) that impact diagnosis, prognosis, and treatment. Traditional methods such as karyotyping, FISH, and PCR often fail to detect cryptic or complex rearrangements, which are critical for accurate risk stratification. Methods: Optical Genome Mapping (OGM) is a technology that directly analyzes ultra-high-molecular-weight DNA, enabling the identification of balanced and unbalanced SVs, copy number variations (CNVs), and gene fusions with high resolution. This review compares the advantages and limitations of OGM versus standard techniques in ALL. Results: OGM improves ALL diagnosis by detecting clinically relevant alterations such as IKZF1 deletions, cryptic KMT2A rearrangements, and kinase fusions, especially in cases with normal or uninformative karyotypes. It reduces artifacts by eliminating cell culture and shortens reporting times. OGM resolves complex events like intrachromosomal amplifications and chromothripsis, enhancing classification and therapy decisions. Limitations include reduced sensitivity in repetitive regions, challenges in detecting Robertsonian translocations, difficulties with complex ploidies, and lower sensitivity for low-frequency subclones. Conclusions: Integrating OGM with next-generation sequencing (NGS) allows comprehensive genomic profiling, improving diagnosis, prognosis, and personalized treatment in ALL. Future advancements promise to further enhance the clinical utility of OGM.

Background: In younger, fit patients with acute myeloid leukemia (AML), intensive chemotherapy (IC) followed by consolidation or allogeneic hematopoietic stem cell transplantation (HSCT) is the standard approach. The authors performed a systematic review and meta‐analysis to evaluate younger patients with AML treated with hypomethylating agents (HMA) plus venetoclax. Methods: This systematic review and meta‐analysis was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta‐Analyses guidelines. MEDLINE and the Cochrane Library were systematically searched through February 2026. Studies included AML patients with a median age <70 years treated with HMA/venetoclax. Primary outcomes were complete remission (CR/CRi) rate, measurable residual disease (MRD) negativity, 1‐year overall‐survival (OS), 1‐year event‐free survival (EFS), and rates of HSCT. Results: Eight studies (two randomized controlled trials, two phase 2 trials, and four real‐world studies), comprising 429 patients with a mean age of 54 years, were included. The pooled CR/CRi rate was 66% (95% confidence interval [CI], 48%–85%), with an MRD‐negative rate of 69% (95% CI, 49%–90%). The pooled 1‐year OS was 75% (95% CI, 63%–86%), exceeding Surveillance, Epidemiology, and End Results database cohorts (62%). The 1‐year EFS was 59% (95% CI, 53%–65%), with low between‐study heterogeneity. Overall, 66% of patients successfully proceeded to HSCT. Meta‐regression analyses suggested a trend toward improved EFS and OS in studies using decitabine than azacitidine. Conclusions: In younger patients with AML, HMA plus venetoclax yielded high response rates, MRD negativity, and a substantial proportion of patients proceeding to HSCT. These findings support HMA/venetoclax as an effective induction strategy in selected younger patients and provide a rationale for prospective randomized trials comparing this approach with IC‐based regimens.

Adult acute lymphoblastic leukemia (ALL) is a highly heterogeneous hematologic malignancy where treatment response and relapse risk do not exclusively rely on the identification of genetic lesions but also on dynamic biological states sustained by specific transcriptional and epigenetic programs. Although the integrated application of multi-omics approaches has significantly expanded our knowledge of oncogenic dependencies, cellular plasticity, and mechanisms of therapeutic resistance, its systematic translation into the clinical practice of adult ALL is yet to become a reality. The aim of this review is to provide a critical and focused synthesis on how the integration of genomics, transcriptomics, and epigenetics enables the interpretation of disease biological behaviors and may guide personalized therapeutic strategies while simultaneously addressing the major limitations that hinder clinical implementation. Genomics allows for the identification of driver events and pharmacologically actionable vulnerabilities, whereas transcriptomics, including single-cell analyses, reveals functional states associated with clonal persistence, glucocorticoid resistance, and therapeutic adaptation, even in the absence of new mutations. In parallel, epigenetic signatures emerge as key elements in stabilizing oncogenic programs and resistant phenotypes, contributing to the biological plasticity of leukemic cells and representing potentially reversible therapeutic targets. Taken together, multi-omics signatures provide an integrated functional readout of adult ALL and support a dynamic precision-medicine model. However, adaptive therapeutic decisions aimed at relapse prevention require the full integration of these approaches through standardized strategies, longitudinal studies, and a sustainable implementation of molecular profiling and minimal residual disease monitoring.

Daratumumab combined with bortezomib, thalidomide, and dexamethasone (Dara-VTD) is a highly effective induction therapy for newly diagnosed multiple myeloma (NDMM) patients eligible for autologous stem cell transplantation (ASCT). However, its impact on stem cell mobilization requires a critical evaluation. This study examines the effects of Dara-VTD on stem cell mobilization and collection outcomes. A multicenter retrospective study included 81 consecutive NDMM patients treated with Dara-VTD (from November 2021 to June 2023). Data on stem cell mobilization and collection were compared with 93 historical VTD patients. Mobilization regimens included cyclophosphamide (CTX), vinorelbine + CTX, and chemotherapy-free approaches, with plerixafor used as rescue therapy. Mobilization success was evaluated by CD34 + cell yield, additional agent use, and leukapheresis sessions required. The median CD34 + yield in the Dara-VTD group was 5.1 million cells/kg, with 96.3% of patients achieving > 2 × 10^6 cells/kg of body weight. Plerixafor use was significantly higher in the Dara-VTD group (56.2%) compared to VTD (4.3%), and CTX-based regimens showed superior mobilization efficacy ( p = 0.01). Engraftment was faster in the Dara-VTD group, with median neutrophil and platelet recovery at 11 and 13 days, compared to 12 and 17 days in the VTD group ( p < 0.05). Dara-VTD maintains the feasibility of ASCT, with comparable stem cell mobilization and collection outcomes to VTD. Mobilization success is influenced by individualized strategies, with CTX and plerixafor playing key roles in optimizing stem cell yield. Despite the challenges posed by daratumumab, stem cell mobilization remains effective, and Dara-VTD does not compromise the transplant process.