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PubMed2026

Consolidation Therapy Based on Mutation Clearance in Acute Myeloid Leukemia.

BACKGROUND: Optimal consolidation therapy for patients with intermediate-risk acute myeloid leukemia (AML) in first complete remission (CR1) is controversial. Retrospective studies have suggested that the clearance of leukemia-associated mutations (LAMs) in CR1 may predict lower relapse risk and better outcomes with high-dose cytarabine (HiDAC) consolidation. We tested this hypothesis prospectively. METHODS: We performed a phase II, multicenter study of intermediate-risk, transplant-eligible, de novo AML in patients 18-60 years of age who achieved a complete remission (CR) or CR with incomplete count recovery (CRi) after induction therapy. Tumor and normal whole-exome sequencing was performed at presentation to identify somatic LAMs (median ∼30 LAMs/patient). In remission marrow samples, LAM variant allele frequencies (VAFs) were then remeasured using a VAF cutoff of less than 2.5% to define clearance. Patients who met this LAM clearance threshold received HiDAC consolidation, whereas those with persistent LAMs (VAF ≥2.5%) were recommended to undergo allogeneic hematopoietic cell transplantation. The primary endpoint compared relapse-free survival (RFS) of intermediate-risk patients with complete LAM clearance to historical cohorts with intermediate-risk AML who received HiDAC-based regimens in CR1. To account for an unplanned interim assessment, the significance threshold for the primary analysis was 0.01. RESULTS: Among 100 patients who were evaluated, intermediate-risk patients who cleared all LAMs in CR1 (n=33) had a median RFS of 33.1 months (95% confidence interval, 11.7-NA) compared to a median RFS of 11.7 months in the historical cohort (n=239; 95% confidence interval, 9.9-15.6, P=0.015). CONCLUSIONS: Among patients with intermediate-risk AML, clearance of LAMs after induction, followed by HiDAC consolidation in CR1, was associated with longer RFS compared with similarly treated historical controls. Although this result did not meet the prespecified threshold for statistical significance, the reported association sets the stage for a randomized trial to further evaluate this strategy. (ClinicalTrials.gov number, NCT02756962.).

Humans↗

PubMed2026

Blinatumomab for Replacing Chemotherapy in Pediatric Acute Lymphoblastic Leukemia.

BACKGROUND: Blinatumomab, a bispecific T-cell engager targeting the CD19 antigen on B cells, may offer an option to safely replace cycles of traditional chemotherapy in pediatric patients with newly diagnosed high-risk B-cell acute lymphoblastic leukemia (ALL). METHODS: We randomly assigned, in a 1:1 ratio, children with high-risk B-cell ALL to receive two cycles of blinatumomab (blinatumomab group) or two cycles of chemotherapy (control group) after consolidation. The primary end point was event-free survival as evaluated in a time-to-event analysis; the duration of event-free survival was defined as the time from randomization to the first event among resistance to protocol treatment, relapse, second cancer, or death from any cause. Our primary objective was to evaluate whether the 4-year event-free survival would be 10 percentage points higher in the blinatumomab group than in the control group. RESULTS: Overall, 709 of 768 eligible patients (92.3%) underwent randomization; 358 were assigned to the blinatumomab group and 351 to the control group. A planned interim analysis at a median follow-up of 2.9 years showed an estimated 4-year event-free survival of 83.0% (95% confidence interval [CI], 77.4 to 87.4) in the blinatumomab group and 70.3% (95% CI, 63.8 to 75.9) in the control group (P = 0.0002 in an intention-to-treat analysis). The estimated hazard ratio for a primary end-point event (blinatumomab vs. control) was 0.51 (95% CI, 0.35 to 0.73) as assessed with a Cox model. Infection related to the trial treatment occurred in 23.9% of patients in the blinatumomab group and in 69.4% of those in the control group (P<0.001). Life-threatening adverse events occurred in 2 patients (0.5%) in the blinatumomab group, including one (in 0.3%) that was fatal, and in 16 patients (4.7%) in the control group. Neurotoxic events were reported in 12.0% and 3.2%, respectively (P<0.001). Cytokine release syndrome of grade 2 or higher occurred in 1.1% of patients in the blinatumomab group. CONCLUSIONS: In children with newly diagnosed high-risk B-cell ALL, replacement of two cycles of highly toxic conventional chemotherapy with blinatumomab resulted in a significantly greater percentage of patients with event-free survival at 4 years. (Funded by Deutsche Krebshilfe and others; AIEOP-BFM ALL 2017 EudraCT number, 2016-001935-12; EU Clinical Trials number, 2023-509856-32-00; and ClinicalTrials.gov number, NCT03643276.).

Adolescent↗

PubMed2026

Frontline therapies for adult patients with newly diagnosed Philadelphia chromosome-negative B-cell acute lymphoblastic leukemia: a systematic literature review.

OBJECTIVES: Philadelphia (Ph) chromosome-negative B-cell acute lymphoblastic leukemia (B-ALL) is the most common ALL in adults. Overall survival (OS) with frontline chemotherapy remains poor. Blinatumomab is currently the only targeted agent approved for frontline treatment. METHODS: We systematically reviewed 96 studies (43 interventional, 53 observational) between 2012-2026 evaluating frontline pharmacologic therapy in adults with Ph- B-ALL. RESULTS: Across chemotherapy studies, nearly half of patients relapsed within 3 years, and only 49%-69% survived beyond 3 years. Blinatumomab demonstrated robust and consistent efficacy in first complete response (CR1), supported by 2 randomized controlled trials (RCT) and 16 single-arm trials (SAT). In one RCT, blinatumomab reduced the risk of death by 59% versus chemotherapy alone (HR 0.41) when added to frontline consolidation in minimal residual disease (MRD) negative patients. Median OS reached 41.2 months in a SAT where blinatumomab monotherapy was administered to patients in MRD-positive CR1. SATs showed consistent efficacy outcomes regardless of age, MRD status, or chemotherapy backbone. DISCUSSION: Additional targeted therapies still under investigation have shown mixed results. CONCLUSION: Frontline inotuzumab (±blinatumomab) plus chemotherapy showed promise in older populations, while the efficacy benefit of rituximab was inconclusive. No new safety signals were identified in the frontline setting for targeted therapies.

Humans↗

PubMed2026

The Addition of Concurrent Immune Checkpoint Inhibitors for Chemoradiotherapy With Consolidative Immune Checkpoint Inhibitors in Unresectable Cancers: A Systematic Review and Meta-Analysis.

Following the success of chemoradiotherapy (CRT) combined with consolidative immune checkpoint inhibitors (ICIs) in locally advanced tumors, over 30 ongoing randomized controlled trials (RCTs) are investigating the potential benefits of adding concurrent ICIs. To investigate the differences in efficacy and safety between adding and not adding concurrent ICIs to CRT followed by consolidative ICIs, a literature search was conducted in PubMed, Embase, and the Cochrane Library, incorporating RCTs comparing CRT combined with consolidative ICIs versus CRT alone, or CRT with both concurrent and consolidative ICIs versus CRT alone. The primary outcomes were overall survival (OS) and progression-free survival (PFS). To reduce potential bias, an additional mirror-design analysis was performed through network meta-analysis. A total of 13 RCTs comprising 6868 patients and 14 cohort studies comprising 4724 patients were included. While patients treated with CRT and consolidative ICIs demonstrated significantly superior OS and PFS to patients treated with CRT alone in RCTs (HR of OS, 0.743, 95% CI, 0.654-0.843; HR of PFS, 0.674, 95% CI, 0.577-0.786), CRT and concurrent-plus-consolidative ICIs did not improve OS and PFS compared with CRT alone (HR of OS, 0.942, 95% CI, 0.782-1.134; HR of PFS, 0.880, 95% CI, 0.752-1.030). Significant differences were detected in OS (p = 0.038) and PFS (p = 0.017) between CRT combined with consolidative ICIs treatment versus CRT combined with concurrent and consolidative ICIs treatment from RCTs. In conclusion, adding concurrent ICIs may dampen the survival benefits of CRT combined with consolidative ICIs. This evidence informs future RCT design strategies.

Humans↗

PubMed2026

Resurrection biology: Melatonin as a modulator of anastasis (Review).

Although apoptosis is regarded as an irreversible and terminal process, recent research has identified anastasis as a cellular mechanism that enables cell recovery even after the activation of executioner caspases. While important in supporting tissue homeostasis following mild or transient injury, anastasis presents significant challenges in oncology, as cancer cells may exploit this phenomenon to evade chemotherapy, subsequently acquiring aggressive traits such as genomic instability, stem‑like properties, and increased metastatic capacity. N‑acetyl‑5‑methoxytryptamine (melatonin), recognized for its antioxidant activity and role as a mitochondrial regulator, has been associated with several biological processes that overlap with pathways involved in anastasis, including mitochondrial bioenergetics, redox homeostasis, and DNA repair mechanisms. However, direct evidence supporting a role for melatonin in regulating anastasis remains limited. The present review consolidated current insights into the molecular regulation of anastasis, examining its biphasic transcriptional profile and oncogenic consequences, while exploring the mechanistic links between melatonin biology and pathways relevant to apoptotic recovery and evaluating the therapeutic prospects of melatonin in targeting anastasis as a strategy to mitigate tumor recurrence and improve clinical outcomes.

Melatonin↗

PubMed2026

Quizartinib for patients with newly diagnosed FLT3-ITD-positive AML who received maintenance therapy in QuANTUM-First.

QuANTUM-First demonstrated improved overall survival (OS) in patients with newly diagnosed acute myeloid leukemia with FMS-like receptor tyrosine kinase 3-internal tandem duplication (FLT3-ITD) treated with quizartinib + standard chemotherapy. Herein, we evaluated the impact of postconsolidation/posttransplant single-agent maintenance therapy on clinical outcomes in patients receiving maintenance, focusing on measurable residual disease (MRD) status at maintenance onset. OS, event-free survival, and relapse-free survival were prespecified exploratory analyses. Cumulative incidence of relapse, analyses by allogeneic hematopoietic cell transplant (allo-HCT), and analyses by MRD status were post hoc and not powered for statistical significance. Samples for FLT3-ITD MRD analysis were collected from patients with composite complete remission ≤30 days before receiving maintenance and assessed using an ultrasensitive amplicon-based assay. More patients who had received an allo-HCT and quizartinib treatment received maintenance (71%) vs placebo (55%); OS benefit was not demonstrated among these patients. In patients who did not undergo allo-HCT, quizartinib maintenance was associated with a significant OS benefit (hazard ratio [HR], 0.401; 95% confidence interval [CI], 0.192-0.838), including a benefit in patients who were MRD negative at the start of maintenance (OS HR, 0.194; 95% CI, 0.056-0.676). Patients who were MRD negative at the completion of consolidation achieved 89.1% (95% CI, 70.0-96.4) survival at 3 years with quizartinib maintenance in the absence of allo-HCT. These data suggest that for patients who achieve FLT3-ITD MRD negativity after induction and consolidation with quizartinib, maintenance with quizartinib provides a significant survival benefit and, in some patients, may eliminate the need for allo-HCT. This trial was registered at www.clinicaltrials.gov as NCT02668653.

Humans↗