The trial is registered as NCT05853965 and is planned to enroll as many as 49 patients at German hospitals. Phase I will evaluate four dose levels of belantamab mafodotin plus venetoclax, with or without dexamethasone, to determine the maximum tolerated dose and recommended phase 2 dose. A subsequent phase IIa expansion will treat 25 additional patients at the dose selected through phase I, based on safety, tolerability and preliminary efficacy. The first patient was enrolled in April 2024, and the total planned trial duration is 44 months, with survival follow-up continuing through the last patient’s final study visit.

Eligible patients must have relapsed or refractory multiple myeloma with documented t(11;14) translocation, progressive disease during or after the most recent treatment line, and sufficient organ function. The protocol was amended from its original requirement for at least four prior treatment lines. Under the revised criteria, enrollment can begin at first relapse after at least one treatment line, provided patients have previously received a proteasome inhibitor, an immunomodulatory drug and an anti-CD38 monoclonal antibody. The selected population therefore has exposure to three major classes of myeloma therapy, although the protocol does not require all participants to be refractory to each class.

Phase I uses a traditional 3+3 dose-escalation design. Cohorts of three patients will receive successively assessed dose combinations, and an additional three patients may be enrolled at the same dose level if a dose-limiting toxicity occurs. The design anticipates 12 patients if 12 can be allocated across the four cohorts, but phase I may include between 12 and 24 patients depending on dose-limiting toxicities and the need to expand a cohort. Dexamethasone is included in the third and fourth cohorts to assess a triplet regimen. An independent data and safety monitoring board, comprising two multiple myeloma experts and a biostatistician, will review the accumulated safety data and recommend the dose for phase IIa.

Belantamab mafodotin is planned at 1.9 mg/kg intravenously every six weeks. The schedule was selected to reduce the potential burden and severity of corneal toxicity while preserving antitumour activity, and it differs from the more frequent schedules used in earlier and ongoing combination studies. Venetoclax will be tested orally at 400 mg or 800 mg once daily, beginning with 400 mg in the initial belantamab mafodotin combination cohort. The final phase I cohort is designed to assess belantamab mafodotin at 1.9 mg/kg every six weeks, venetoclax at 800 mg daily and dexamethasone at 40 mg weekly, with the steroid dose reduced to 20 mg weekly for patients aged 75 or older. These are investigational trial regimens rather than established approaches to treatment.

The phase I primary objectives are to establish the maximum tolerated and recommended phase 2 doses and to characterize the safety profile of the combination. Dose-limiting toxicities include specified prolonged grade 4 neutropenia or thrombocytopenia, any grade 4 nonhematological toxicity, and selected grade 3 nonhematological events judged possibly related to the study drugs by the monitoring board. Adverse events and changes in clinical signs and laboratory parameters will also be assessed using Common Terminology Criteria for Adverse Events version 5.0. The phase IIa primary objective is to assess safety and efficacy at the dose established in phase I.

Secondary efficacy endpoints include overall response rate, International Myeloma Working Group response categories, progression-free survival, duration of response, health-related quality of life and the proportion of patients achieving minimal residual disease negativity at a sensitivity of 10−5. Bone marrow testing is planned every four cycles, approximately every six months, and at progression, with minimal residual disease status assessed by a central laboratory. Quality-of-life questionnaires—EQ-5D, QLQ-C30 and QLQ-MY20—will be collected at baseline and additional follow-up points. Exploratory analyses will examine circulating tumor cells, mitochondrial activity and single-cell immunophenotyping to investigate possible response and resistance patterns.

Because corneal toxicity is a known concern with belantamab mafodotin, the protocol requires a baseline ophthalmologic examination and examinations before dosing during the first six cycles, followed by assessments every three months when no significant findings are present. Participants receive preservative-free artificial tears, are offered cooling eye masks during infusion, and may not wear contact lenses during treatment. Dose holds or reductions follow a scale integrating ophthalmologic findings, best-corrected visual acuity and patient-reported symptoms. The protocol also recommends anti-infective prophylaxis and follow-up for toxicity, remission status and subsequent antimyeloma treatment.

The principal limitation is that this is a protocol paper without efficacy, safety or tolerability results for BELI(E)VE, and no datasets were generated or analysed for the publication. The open-label, single-country design is intended primarily to establish a dose and provide preliminary evidence on safety and activity rather than a definitive comparison with another regimen. The planned analyses are descriptive and exploratory. Whether simultaneous targeting of BCMA and BCL-2 can benefit patients with t(11;14)-positive disease therefore remains unestablished and will require completion of both study phases and peer-reviewed reporting of the observed data.

Subject of Research: A phase I/IIa protocol testing dual BCMA and BCL-2 targeting in t(11;14)-positive relapsed or refractory multiple myeloma

Article Title: Belantamab mafodotin plus venetoclax in t(11;14)-positive relapsed or refractory multiple myeloma – the BELI(E)VE trial

Article References: Schaefers, C., Khandanpour, C., Hänel, M., Kull, M., Alsdorf, W., Kamili, A., Kosch, R., Krüger, W., Bohl, S., Mai, E. K., Scheid, C., Einsele, H., Brüggemann, M., Suling, A., Zapf, A., Bokemeyer, C., Weisel, K., & Leypoldt, L. (2026). Belantamab mafodotin plus venetoclax in t(11;14)-positive relapsed or refractory multiple myeloma – the BELI(E)VE trial. BMC Cancer, 26(1), Article 1141. https://doi.org/10.1186/s12885-026-16905-3

Image Credits: AI Generated

DOI: 10.1186/s12885-026-16905-3

Keywords: BELI(E)VE trial, multiple myeloma, t(11;14) translocation, belantamab mafodotin, venetoclax, phase I/IIa, dose escalation, clinical trial protocol, BCMA, BCL-2, Belantamab, mafodotin

The intellectual backbone of the review is a distinction that the authors insist has been too often blurred in the literature. Bulk acute myeloid leukemia blasts and leukemic stem cells are not interchangeable entities. The stem cell concept traces back to landmark xenotransplantation studies from the 1990s showing that only a minor fraction of primary leukemia cells could initiate and serially propagate the disease in mice. Because surface markers alone do not prove stemness, the authors reserve the term leukemic stem cell only for studies that directly demonstrated functional self-renewal or serial repopulation. This matters therapeutically, because bulk blasts and stem cells remodel the marrow through partly overlapping but non-identical programs, and a drug validated against one population may fail against the other.

To appreciate what leukemia destroys, one must first understand what the healthy niche does. The normal bone marrow contains interconnected endosteal and perivascular niches where mesenchymal stromal cells, endothelial cells, osteolineage cells, macrophages, adipocytes, and sympathetic nerves deliver spatially and temporally orchestrated signals. Stem cell factor and the chemokine CXCL12, produced by stromal and vascular populations, keep hematopoietic stem cells retained, quiescent, and ready for regeneration. Metabolically, quiescent stem cells favor glycolysis in low-oxygen, low-reactive-oxygen-species environments, while activation pushes them toward mitochondrial oxidative phosphorylation. Even sympathetic neural signaling contributes, driving circadian stem cell mobilization through regulation of stromal CXCL12. It is precisely this finely tuned machinery that leukemia dismantles.

The review catalogs how bulk leukemia cells vandalize these compartments. Classical models demonstrate leukemia-induced sympathetic neuropathy, endosteal vascular remodeling, and disruption of the adipocytic niche, all of which impair normal blood production. At the stromal level, acute myeloid leukemia cells can hijack bioelectric signaling through CaV1.2-dependent mechanisms and induce p16INK4a-driven senescence in mesenchymal stromal cells, converting them into senescent factories that secrete pro-leukemic inflammatory factors such as IL-6 and CCL2. AML-derived BMP6 induces the transcription factor ID1 in stromal cells, which stabilizes SP1 and boosts production of ANGPTL7, further supporting leukemia progression. Meanwhile, TWIST1-high clonal cells redirect stromal differentiation toward an adipogenic, leukemia-supportive state, and TGF-beta1 functionally disables the stromal support of healthy hematopoiesis.

The leukemic stem cell evidence is narrower but mechanistically striking. In one key study, TET2-mediated mRNA demethylation regulated expression of TSPAN13 and thereby tuned the CXCR4/CXCL12 axis that governs stem cell homing to protected marrow regions and their self-renewal. Another investigation defined an ALDH2-PKCdelta-SHMT2 axis that sustains metabolic plasticity and allows stem-enriched populations to evade chemotherapy. ALDH3A2 has been shown to protect AML cells from oxidative death and ferroptosis-inducing stress, although the authors note that this study did not formally define the protected cells as leukemic stem cells. In the KG-1a cell-line model, CX43-mediated mitochondrial transfer from stromal cells preserved stem-like properties, while primary patient studies documented chemotherapy-associated mitochondrial transfer to bulk leukemic cells, a form of cellular altruism that literally donates energy machinery to surviving tumor cells.

Drug resistance emerges repeatedly as a niche-driven phenomenon. CD44 engagement on leukemia cells increases the avidity of the integrin VLA-4, strengthening VCAM-1-dependent adhesion and pro-survival signaling within the marrow. Stromal cells express CYP3A4, a drug-metabolizing enzyme that can chemically inactivate FLT3 inhibitors, effectively turning healthy tissue into a shield against targeted therapy. In FLT3-mutant AML, longitudinal profiling revealed a stepwise, niche-catalyzed evolution toward resistance to gilteritinib, including early dependence on AURKB, and BTK-dependent autophagy contributes to FLT3-inhibitor failure. TGF-beta receptor-SMAD3 signaling enhances DNA double-strand break repair and confers PARP-inhibitor resistance in marrow-based models, though the authors classify this as a leukemia-cell rather than stem-cell mechanism. Even venetoclax, the flagship BCL-2 inhibitor that preferentially eradicates quiescent leukemic stem cells by disrupting oxidative phosphorylation in combination with azacitidine, can be undermined by stromal signaling that raises alternative anti-apoptotic proteins and metabolic flexibility.

The review also surveys how immune and metabolic warfare unfold in the leukemic marrow. T cells from AML patients’ bone marrow show reversible functional suppression, elevated checkpoint expression, and defective immune-synapse formation, while AML-cell IDO1 expression shifts the B-cell compartment toward regulatory populations. Metabolic competition compounds the damage: the voracious glycolysis and oxygen consumption of leukemic cells starve effector immune cells of substrate, and accumulating lactate drives GPR81-dependent polarization of macrophages toward an immunosuppressive phenotype. Loss of ANXA5 in leukemia cells amplifies inflammatory conditioning through the COX2/PGE2 axis. On the defensive side, activating the NLRP3 inflammasome in marrow dendritic cells increased IL-1beta and Th1/IFN-gamma responses with antileukemic activity in preclinical models, hinting that reawakening local immunity is feasible.

To contextualize AML biology, the authors carefully compare other marrow-resident malignancies while insisting their findings not be transplanted wholesale. In B-cell acute lymphoblastic leukemia, stromal cells convert to cancer-associated fibroblast-like states and adipogenic progenitors support residual disease through SDF-1/CXCR4 and IL-7/VCAM1 pathways; in T-ALL, dexamethasone-induced adipocytes protect cells via a CXCL13-associated program. In chronic myeloid leukemia, TNF-alpha expands stromal precursors that promote leukemic stem cell growth through CXCL1/CXCR2, and stromal transfer of metabolic proteins drives imatinib resistance. Multiple myeloma remodels adipocytes into senescent, metabolically dysfunctional cells that support steroid resistance. These parallels reveal conserved principles, such as chemokine-mediated retention and bidirectional metabolic exchange, but the authors treat the specific pathways as comparative hypotheses rather than established AML targets.

On the therapeutic frontier, the review summarizes an array of niche-directed strategies, most still preclinical. Bone-marrow-targeted yolk-shell nanoparticles loaded with a LOXL2 inhibitor disrupt the collagen scaffold that anchors leukemia cells, detaching them from matrix protection and sensitizing them to chemotherapy. A marrow-responsive polymeric system co-delivering a drug and siRNA against CXCR4 and mitophagy reduced stem cell homing, stemness, and relapse-related phenotypes. Bisphosphonate-modified nanocomposites targeting the C-Myb/Survivin axis and CD123-targeted aptamer nanoparticles delivering EZH2 siRNA demonstrated activity against MLL-AF9-rearranged AML in cell, animal, and patient-derived xenograft models. The BET protein degrader ARV-825 simultaneously attacked leukemic stem and progenitor cells and eroded stromal protection, while arsenic trioxide has been reported to reprogram the microenvironment while directly killing blasts. VLA-4 blockade sensitized leukemic and myeloma cells to CD3-redirection therapy in cross-disease preclinical models, and a phase 3 transplantation trial showed that prophylactic N-acetyl-L-cysteine improved endothelial function and hematopoietic reconstitution after haploidentical stem cell transplantation, underscoring that rebuilding the niche matters as much as attacking it.

The authors close with a sober assessment of what stands between promising preclinical results and clinical reality: model dependence and the cellular and spatial heterogeneity of the human marrow. They propose five research priorities, including spatially resolved mapping of leukemia cell and stem cell states across marrow subniches, functional validation of putative stem-cell-specific mechanisms, humanized organoid and organ-on-chip platforms, rational scheduling of niche-directed agents with chemotherapy or immunotherapy, and strategies that restore normal vascular and stromal function after remission. Recent work showing that venetoclax and azacitidine can themselves damage sinusoidal endothelium and alter immune subsets is a pointed reminder that even our best drugs reshape the battlefield. If the marrow niche can be mapped, decoded, and selectively disarmed, the sanctuary that has long shielded acute myeloid leukemia from cure may finally become its Achilles’ heel.

Subject of Research: How the bone marrow microenvironment is remodeled in acute myeloid leukemia and how niche-directed therapies may overcome treatment resistance

Article Title: Malignant remodeling of the bone marrow microenvironment in acute myeloid leukemia: mechanisms and therapeutic implications

Article References: Xu, W., Han, Q., Sun, C., & Li, D. (2026). Malignant remodeling of the bone marrow microenvironment in acute myeloid leukemia: mechanisms and therapeutic implications. Frontiers in Oncology, 16, Article 1903019. https://doi.org/10.3389/fonc.2026.1903019

Image Credits: AI Generated

DOI: 10.3389/fonc.2026.1903019

Keywords: acute myeloid leukemia, bone marrow microenvironment, leukemic stem cells, treatment resistance, mesenchymal stromal cells, CXCL12-CXCR4 axis, venetoclax, immunosuppression, metabolic reprogramming, nanomedicine, drug resistance, hematopoiesis

The authors argue that MPAL is not merely a diagnostic curiosity but a window into the fundamental biology of hematopoietic lineage commitment. The fifth edition of the World Health Organization classification (WHO-HEM5) and the International Consensus Classification (ICC) have refined lineage assignment criteria and genetic exclusions, yet uncertainty persists in cases with borderline myeloperoxidase expression, bilineal architecture, and treatment-associated lineage change. These borderline scenarios expose the limitations of phenotype-based classification systems that were never designed to accommodate cells straddling two developmental programs simultaneously.

Genomic and single-cell studies have revealed that similar immunophenotypes can arise from distinct clonal trajectories. Lesions such as BCR::ABL1 fusion, KMT2A rearrangements, BCL11B deregulation, and TP53 alterations shape developmental potential, prognosis, and therapeutic vulnerability in ways that immunophenotyping alone cannot capture. Two patients with identical blast surface markers may harbor fundamentally different founding clones, explaining why treatment responses can diverge so dramatically even among individuals who appear clinically comparable at diagnosis.

This clonal heterogeneity has direct therapeutic consequences. Retrospective evidence supports acute lymphoblastic leukemia-like induction for many children and fit younger adults with MPAL, whereas treatment in adults requires closer integration of age, fitness, adverse genetics, and early measurable residual disease response. The review emphasizes that MPAL management cannot rely on a single protocol; it must be adaptive, tracking the founding clone across phenotypic states through rapid genomic profiling, broad flow and molecular MRD assessment, and systematic reassessment at relapse.

The therapeutic landscape for MPAL has broadened considerably in recent years. Tyrosine kinase inhibitors targeting BCR::ABL1, venetoclax, menin inhibitors, bispecific antibodies, antibody-drug conjugates, and cellular therapies now offer multiple angles of attack. Yet these agents can also impose selective pressures that promote antigen loss or lineage switch, the very phenomena that make MPAL so difficult to eradicate. A therapy that clears blasts expressing one surface marker may simply enrich a subclone that has shed that marker or committed to the opposite lineage.

Measurable residual disease monitoring emerges as the critical connective tissue in the authors’ proposed framework. Rather than relying on a single flow cytometry gate or a single fusion transcript, MPAL management should employ broad flow and molecular MRD assessment capable of detecting the founding clone regardless of its current phenotypic costume. Early MRD response, the review argues, should inform treatment intensity decisions in adults, where the balance between aggressive induction and tolerability is most delicate.

The review also addresses treatment-associated lineage change, a phenomenon in which therapy itself drives leukemic cells to abandon their original identity. This plasticity is not random; it reflects the underlying developmental potential encoded in the founding clone’s genomic lesions. BCL11B deregulation, for instance, is associated with T-lymphoid identity, while KMT2A rearrangements can sustain both myeloid and lymphoid programs. Understanding which lesions confer which developmental potentials allows clinicians to anticipate where a clone might flee under therapeutic pressure.

The authors call for prospective international studies linking lineage architecture, genomic drivers, target distribution, and MRD kinetics to define durable treatment strategies for MPAL. Without such studies, the field remains dependent on retrospective evidence and extrapolation from ALL and AML trials, populations from which MPAL patients were often excluded precisely because of their ambiguous phenotype. The rarity of MPAL makes single-center prospective trials impractical, underscoring the need for coordinated international collaboration.

What makes this review particularly timely is the convergence of several technological advances: single-cell multiomics, broad molecular MRD platforms, and a growing arsenal of targeted agents. Together, these tools make it feasible, for the first time, to manage MPAL as a dynamic clonal disease rather than a static diagnostic category. The founding clone can be identified at diagnosis, tracked through treatment, and reassessed at relapse, with therapy adjusted in response to its evolutionary behavior.

The Tongji Hospital team’s synthesis, published open access under a Creative Commons license and funded by the National Natural Science Foundation of China, arrives as hematologists worldwide grapple with how to integrate these advances into clinical practice. For a disease that sits at the boundary of two classical categories, MPAL may ultimately prove to be the proving ground for a new paradigm in hematology: one in which lineage is not a fixed label but a moving target, and in which the founding clone, not the blast phenotype, is the true unit of disease.

Subject of Research: Mixed phenotype acute leukemia: classification, clonal biology, and precision therapy

Article Title: Mixed phenotype acute leukemia across lineage boundaries: from classification to clonal biology and precision therapy

Article References: Wang, Y., Su, S., & Xiao, Y. (2026). Mixed phenotype acute leukemia across lineage boundaries: from classification to clonal biology and precision therapy. Cancer Cell International. https://doi.org/10.1186/s12935-026-04486-x

Image Credits: AI Generated

DOI: 10.1186/s12935-026-04486-x

Keywords: mixed phenotype acute leukemia, MPAL, acute leukemia, lineage plasticity, measurable residual disease, precision medicine, hematology, WHO-HEM5, International Consensus Classification, BCR::ABL1, KMT2A, venetoclax

The study, published in the journal Pharmacia, is notable for what it did not use: the polished, idealized data of randomized clinical trials. Instead, researchers built their model on local real-world evidence drawn from 69 Bulgarian patients treated at the Specialized Hospital for Active Treatment of Hematological Diseases. Forty-nine patients received venetoclax plus azacitidine in a prospective cohort followed from 2022 to 2024, after venetoclax entered the national reimbursement lists, while 20 patients treated with azacitidine alone between 2018 and 2022 served as the comparator. By anchoring the azacitidine cohort in the pre-venetoclax era, the investigators deliberately avoided calendar-related bias, ensuring that both groups were treated within comparable modern clinical contexts.

All patients had newly diagnosed acute myeloid leukemia and were deemed ineligible for intensive chemotherapy for concrete clinical reasons: age of 75 or older, significant pulmonary or cardiac disease, liver cirrhosis, active resistant infection, poor functional status, kidney failure, or similar conditions. This is precisely the population in which treatment decisions carry the highest stakes and the least margin for error, and in which the balance between extending life and preserving its quality becomes most delicate.

Methodologically, the team constructed a one-year state-occupancy model with monthly cycles, dividing each patient’s trajectory into three mutually exclusive states: event-free survival, progressed or relapsed disease, and death. Rather than a full Markov transition model, which would have demanded stronger assumptions than the sparse progression data could justify, the researchers used a partitioned-survival-style approach in which monthly state proportions were derived directly from observed overall survival and reconstructed event-free survival. Progressed disease occupancy was calculated as the difference between the two survival curves, and death as one minus overall survival, with internal consistency checks ensuring that event-free survival never exceeded overall survival and that no state ever turned negative.

Quality of life entered the model through monthly patient responses to the EORTC quality-of-life questionnaire, mapped onto utility values using a published regression algorithm. Event-free patients carried a mean utility of 0.75, while those in progressed or relapsed disease averaged 0.63. Costs were tallied from the perspective of the Bulgarian National Health Insurance Fund and included drug acquisition, hospitalization, monitoring, diagnostic investigations, and supportive and palliative care, all priced at 2024 list prices and converted to euros at the fixed national exchange rate. Venetoclax acquisition alone cost roughly €9,760 per month, while azacitidine monotherapy ran about €2,802 monthly.

The base-case results were stark. Total yearly costs reached €99,532.86 per patient on the combination versus €44,344.09 on azacitidine alone, an incremental cost of €55,188.77. Against that expenditure, the combination delivered 0.51 quality-adjusted life-years versus 0.32, and 0.68 life-years versus 0.45, yielding incremental gains of 0.19 QALYs and 0.23 life-years. The resulting cost-effectiveness ratios were €289,309.59 per QALY gained and €235,736.28 per life-year gained, both far above Bulgaria’s accepted threshold of roughly €54,815, which corresponds to three times gross domestic product per capita.

Probabilistic sensitivity analysis using Monte Carlo simulation underscored how fragile the value proposition is at current prices. Only 4.4 percent of simulated cost-per-QALY estimates fell below the national threshold, and for cost per life-year gained the figure was 6.7 percent. The analysis suggested that the combination would only become acceptably cost-effective at a willingness-to-pay threshold of around €300,000, equivalent to more than twelve times GDP per capita, with results plateauing near €400,000. The model also faithfully captured the darker side of the therapy: some patients experienced severe adverse events during induction, and in certain simulations the combination produced negative quality-adjusted or even negative life-year gains, reflecting early treatment-related mortality.

One-way sensitivity analyses revealed that the results were most sensitive to the effectiveness of the combination itself. If venetoclax plus azacitidine delivered 30 percent lower QALYs or life-years than assumed, the cost per QALY soared past €1.5 million and the cost per life-year beyond €1.9 million. Yet the dispersion of probabilistic results clustered tightly around the base case for survival outcomes, suggesting that the survival benefit itself was relatively consistent, even as quality-of-life impacts varied more widely across patients.

Perhaps the most intriguing finding is how closely the Bulgarian real-world result mirrors trial-based economics from wealthier countries. The exploratory cost-utility ratio of roughly €289,000 per QALY aligns remarkably well with a United States estimate of $260,343 per QALY, lending incidental validation to the quality-of-life mapping algorithm the Bulgarian team employed. Meanwhile, first-year survival in the local cohort was numerically higher on the combination, and event-free survival was significantly better, indicating improved disease control even within a single year of follow-up. The authors contrast this with a real-world study in older, frailer patients where the combination was poorly tolerated, noting that their cohort’s median age of 71, close to Bulgarian life expectancy, may partly explain the difference.

The researchers are careful to frame their work as hypothesis-generating rather than reimbursement-grade. The sample of 69 patients is small, progression ascertainment was incomplete, the one-year horizon misses longer-term survival and late costs, and no external validation against larger multicenter datasets was yet possible. Longer time horizons in other analyses have pushed cost-effectiveness ratios down dramatically, to figures as low as $74,141 per life-year gained, suggesting that the true value of the combination may be substantially better than a one-year snapshot can capture. Still, the study delivers something Bulgaria has lacked: a transparent, locally grounded account of what this breakthrough therapy actually costs and delivers within its own health system. As venetoclax and similar targeted agents spread across Central and Eastern Europe, models like this one will become essential instruments for deciding which medical miracles a national payer can realistically afford, and at what price the arithmetic of hope must ultimately be settled.

Subject of Research: Cost-effectiveness of venetoclax plus azacitidine versus azacitidine monotherapy in Bulgarian patients with acute myeloid leukemia ineligible for intensive chemotherapy

Article Title: Exploratory cost-utility and cost-effectiveness analysis of venetoclax plus azacitidine vs. azacitidine monotherapy in Bulgarian patients with AML ineligible for intensive chemotherapy: a real-world-data-influenced state-occupancy model

Article References: Donchev, M., Davidkova, Y., Tachkov, K., & Petrova, G. (2026). Exploratory cost-utility and cost-effectiveness analysis of venetoclax plus azacitidine vs. azacitidine monotherapy in Bulgarian patients with AML ineligible for intensive chemotherapy: a real-world-data-influenced state-occupancy model. Pharmacia, 73, Article e197277. https://doi.org/10.3897/pharmacia.73.e197277

Image Credits: AI Generated

DOI: 10.3897/pharmacia.73.e197277

Keywords: acute myeloid leukemia, venetoclax, azacitidine, cost-effectiveness, cost-utility analysis, QALY, real-world data, state-occupancy model, Bulgaria, health economics, pharmacoeconomics, National Health Insurance Fund

The review’s central provocation is that the famous Warburg effect, the observation that cancer cells preferentially ferment glucose into lactate even in the presence of oxygen, is an incomplete map of tumor metabolism. Tumors, the authors emphasize, are far more metabolically diverse than the Warburg model suggests. Cancer cells possess a dual capacity: many can oxidize glucose through fully functional mitochondria via oxidative phosphorylation, or OXPHOS, while simultaneously running glycolysis. Strikingly, some cells occupy hybrid states in which both pathways operate concurrently, feeding energy production and biomass synthesis at the same time. Systems-level modeling and gene-signature approaches, such as quantifying downstream targets of AMPK and HIF-1, now provide tools to measure where a given tumor sits on this glycolytic-to-oxidative spectrum.

This plasticity is not a biochemical curiosity; it is clinically consequential. Hybrid glycolysis/OXPHOS phenotypes are specifically associated with metastasis and therapy resistance, and coexisting cell populations within a single tumor can reverse their energetic control, switching between sugar fermentation and oxygen-based respiration in response to environmental cues or drug pressure. The mechanistic wiring involves oncogenic and stress-responsive pathways converging on shared glycolytic effectors. The enzymes HK2, PKM2 and LDHA are targets of both c-Myc and hypoxia-inducible factors, while PI3K–AKT–mTOR signaling drives nutrient uptake and anabolic growth and AMPK guards the energy balance. Because these circuits interact, a single tumor can harbor genuinely different metabolic states in its oxygen-starved core versus its well-perfused margin, complicating any therapy that blocks just one pathway.

Within that heterogeneity, some tumors are strikingly dependent on mitochondrial respiration. Preclinical development of complex I inhibitors has flagged acute myeloid leukemia, subsets of lymphoma, glioblastoma, triple-negative breast cancer, melanoma and pancreatic ductal adenocarcinoma as OXPHOS-reliant contexts. Melanoma is the canonical example: PGC-1α-driven mitochondrial oxidative metabolism is described as essential for the growth and survival of a defined subset of human melanomas, a biologically grounded metabolic subtype that could, in principle, be identified in surgical specimens and used to stratify patients. The review argues that this phenotype-aware view, rather than an assumption of uniform glycolytic dependence, should anchor future translational studies.

Mitochondrial DNA adds another layer of vulnerability and opportunity. Unlike nuclear DNA, mtDNA is not protected by histones, making it exceptionally susceptible to oxidative damage generated inside the mitochondrial matrix. Mutations in genes encoding respiratory chain complexes I, III and IV appear across cancers and can reshape metabolism in ways that enhance tumorigenesis and adaptation. Crucially, the functional impact of any mutation depends on heteroplasmy, the proportion of mutant to wild-type genomes in each cell, so a mutation list alone cannot predict metabolic behavior. Yet mtDNA features may soon guide treatment: in a 2024 study of 308 patients with mismatch repair–deficient colorectal cancer, higher tumor mitochondrial DNA copy number correlated with better disease-free and overall survival, and those patients appeared to derive greater benefit from adjuvant chemotherapy. Because mtDNA copy number can be measured in resected tissue, it is an attractive perioperative biomarker, though the authors stress it still requires prospective validation.

The therapeutic record is humbling, and the review does not soften it. Metformin, the widely repurposed respiratory inhibitor, failed in the phase III MA.32 trial: adding it to standard therapy did not improve invasive disease–free survival in unselected early breast cancer, and it produced more grade 3 nonhematological toxicities and poorer adherence. Intriguingly, metformin did measurably lower CA 15-3 and estradiol levels, proof that biomarker modulation does not guarantee survival benefit without proper patient selection. More dramatic still is the story of IACS-010759, a potent, selective complex I inhibitor that entered phase I trials in relapsed or refractory acute myeloid leukemia and advanced solid tumors. Dose-limiting lactate elevation and neurotoxicity produced a narrow therapeutic index, no recommended phase 2 dose could be established, target inhibition was modest, and the trials were discontinued. Meanwhile, devimistat, a lipoate analog targeting two TCA cycle enzyme complexes, failed to improve survival when added to modified FOLFIRINOX in metastatic pancreatic cancer in the phase III AVENGER 500 trial.

Apoptosis targeting tells a sharper two-sided tale. Venetoclax, a BH3 mimetic that selectively neutralizes the anti-apoptotic protein BCL-2, transformed outcomes in acute myeloid leukemia: in the phase 3 VIALE-A trial, azacitidine plus venetoclax extended overall survival in previously untreated patients ineligible for intensive chemotherapy. That is clinical proof of principle that manipulating mitochondrial apoptotic priming can work. But translation to solid tumors has faltered, exemplified by the randomized phase II VERONICA trial, in which venetoclax plus fulvestrant did not significantly improve clinical benefit rate or progression-free survival in ER-positive, HER2-negative metastatic breast cancer. Broader BCL-2 family inhibition carries its own liabilities, with navitoclax’s thrombocytopenia a recurring dose-limiting concern, and venetoclax-associated events such as tumor lysis syndrome would complicate perioperative timing.

What elevates this review beyond a standard mechanism summary is its surgical framing. The authors propose that resected tumors become maps rather than samples: mass spectrometry imaging could chart metabolites across anatomically defined regions such as tumor core, invasive margin, hypoxic zones and adjacent healthy tissue, while matched single-cell sequencing and spatial transcriptomics would link those metabolic landscapes to specific malignant, stromal and immune cell populations. Integrating such data with histopathology, treatment exposure and outcomes could identify glycolytic, OXPHOS-dependent and metabolically plastic subpopulations associated with response, resistance or recurrence, and reveal cells that switch fuel sources after therapy and thereby seed relapse. Timing matters too: because postoperative recovery demands a metabolic shift from catabolism to repair, broad mitochondrial inhibition around surgery could interfere with healing and would need careful scheduling alongside nutritional status and wound recovery.

The immune dimension adds a final twist. Mitochondrial fitness is essential for antitumor T cells: OXPHOS and complex III-derived reactive oxygen species support NFAT signaling, IL-2 production and antigen-specific expansion, while the tumor microenvironment’s hypoxia and nutrient deprivation suppress PGC-1α-driven mitochondrial biogenesis in CD8-positive T cells, pushing them toward terminal exhaustion. Restoring mitochondrial fitness can reinvigorate these cells, so any therapy intended to cripple tumor mitochondria must spare those of infiltrating lymphocytes. Meanwhile, mtDNA released into the cytosol or extracellular space activates cGAS–STING, TLR9 and inflammasome pathways, linking mitochondrial injury to innate immunity, and mitochondria-targeted sensitizers that release damage-associated molecular patterns are being explored for immunogenic cell death. Early clinical signals include a phase I dose-escalation trial of an engineered mitochondrial vaccine in advanced solid tumors, registered with objective response rate endpoints but no outcomes yet reported, and preclinical work showing that the mitochondria-targeted antioxidant MitoQ radiosensitizes MDA-MB-231 but not MCF7 breast tumors, prevented recurrence and metastasis in mouse models at nanomolar concentrations that spared nonmalignant cells, and has a defined response signature for bulk biopsies.

The synthesis that emerges is deliberately unsentimental: mitochondrial vulnerabilities are a context-dependent opportunity, not a universal off switch. The authors call for metabolic phenotype classification, biomarker-guided patient selection and rational combinations, with pharmacodynamic readouts such as the rise in mitochondrial-to-genomic DNA ratio observed during complex I inhibition, and continued development of increasingly precise mitochondrial genome editors whose off-target edits have been reduced by more than 99 percent in preclinical systems. The near-term payoff is unlikely to be a single metabolic drug; it will more likely be a workflow in which a surgical specimen is spatially profiled, a tumor’s hybrid metabolic state is quantified, and a mitochondria-directed intervention is timed and combined accordingly. If that vision holds, the organelle once dismissed as an evolutionary passenger in cancer may become the anatomical and therapeutic reference point of multimodal oncology.

Subject of Research: Mitochondrial metabolic plasticity, hybrid glycolysis/OXPHOS states, and biomarker-guided therapeutic targeting in surgical oncology

Article Title: Mitochondrial metabolic plasticity in cancer: hybrid bioenergetic states and translational targeting in surgical oncology

Article References: Chattopadhyay, D., Rajendran, R. L., Mubin, N., Tendulkar, D., Singh, T. D., Ghosh, S., Jha, S. K., Gangadaran, P., & Ahn, B.-C. (2026). Mitochondrial metabolic plasticity in cancer: hybrid bioenergetic states and translational targeting in surgical oncology. Experimental Biology and Medicine, 251, Article 11244. https://doi.org/10.3389/ebm.2026.11244

Image Credits: AI Generated

DOI: 10.3389/ebm.2026.11244

Keywords: mitochondria, cancer metabolism, OXPHOS, glycolysis, Warburg effect, metabolic plasticity, mitochondrial DNA, surgical oncology, OXPHOS inhibitors, venetoclax, tumor microenvironment, biomarkers

The research team, led by Joan Montero and Carles Rentero, set out to understand how membrane-associated proteins influence the intrinsic pathway of apoptosis, the controlled self-destruction programme that healthy cells and many cancer therapies rely on. At the centre of this pathway lies the mitochondrial outer membrane, where members of the BCL-2 protein family engage in a delicate tug-of-war. Pro-apoptotic effectors such as BAK and BAX, when unleashed, punch holes in the mitochondrial membrane and trigger cell death, while pro-survival guardians such as BCL-2 and BCL-xL keep them in check. The balance between these opposing forces determines what researchers call apoptotic priming, a measure of how readily a cell will commit to mitochondrial apoptosis when stressed.

To quantify this balance, the investigators employed BH3 profiling, a functional precision medicine technique that uses synthetic peptides derived from BH3 domains, the interaction motifs of BCL-2 family proteins, to probe the mitochondrial priming state of living cells. When the researchers depleted ANXA6 in HeLa cells, a widely used laboratory model, they observed a striking reduction in apoptotic priming. In other words, cells lacking ANXA6 became more resistant to mitochondrial apoptosis, effectively raising their threshold for self-destruction. This finding positioned ANXA6, for the first time, as a regulator of the apoptotic machinery rather than merely a structural component of cellular membranes.

Digging deeper into the molecular consequences of ANXA6 loss, the team found that the reduced priming was accompanied by two key changes in the BCL-2 family landscape: an increase in BCL-2 expression, the canonical anti-apoptotic guardian, and a decrease in BAK, one of the essential executioner proteins that directly mediates mitochondrial membrane permeabilisation. Importantly, these changes occurred independently of any alterations in mitochondrial mass or morphology, indicating that ANXA6 does not simply reshape the organelle but instead rewires the signalling networks that govern the BCL-2 family. The phenotype therefore reflects a genuine shift in the regulatory circuitry of apoptosis rather than a passive consequence of altered mitochondrial biology.

The mechanistic clue emerged when the researchers examined pro-survival signalling pathways upstream of the BCL-2 family. ANXA6-deficient cells displayed enhanced activation of AKT, a well-characterised kinase that promotes cell survival and is known to modulate the activity and abundance of BCL-2 family members through phosphorylation-dependent mechanisms. This observation supports a model in which ANXA6 functions as a negative regulator of pro-survival signalling: when ANXA6 is present, AKT activity is held in check, the BCL-2 family balance tilts toward apoptosis, and cells remain primed for death. When ANXA6 is lost, the brakes come off pro-survival pathways, BCL-2 accumulates, BAK dwindles, and the cell becomes fortressed against mitochondrial apoptosis.

Having established this mechanism in a cellular model, the team turned to acute lymphoblastic leukaemia, a disease where the BCL-2 family has direct clinical relevance. Across a panel of ALL cell lines and patient samples, the researchers uncovered a consistent correlation pattern: ANXA6 expression inversely correlated with BCL-2 levels and positively correlated with the pro-apoptotic proteins BAK and BAD. This inverse relationship mirrors the mechanism defined in HeLa cells and suggests that ANXA6 abundance may serve as a biomarker of the apoptotic wiring state in leukaemia cells, potentially distinguishing primed, drug-sensitive tumours from resistant ones.

The functional consequences of this correlation were tested directly in selected ALL cell models. When ANXA6 was depleted, apoptotic priming dropped, confirming that the mechanism operates in leukaemia cells and is not an artefact of the HeLa system. More strikingly, ANXA6 depletion increased sensitivity to pharmacological inhibition of both BCL-2 and BCL-xL, the two major pro-survival proteins targeted by BH3 mimetics, a class of drugs that includes venetoclax, an agent already approved for certain blood cancers. This result carries a paradoxical but clinically meaningful implication: although ANXA6 loss lowers apoptotic priming and makes cells more resistant to intrinsic death signals, it simultaneously renders them more dependent on BCL-2 family pro-survival proteins for their survival, creating a therapeutic vulnerability that BH3 mimetics can exploit.

This apparent paradox resolves once the BCL-2 family balance is viewed as a system. By reducing BAK and increasing BCL-2, ANXA6 depletion shifts the survival of leukaemia cells from a state where death effectors are readily activated to one where survival hinges almost entirely on the anti-apoptotic shield. In such a state, blocking the shield with a BH3 mimetic leaves the cell with few remaining defences, and apoptosis proceeds efficiently. The finding suggests that ANXA6 expression levels could help stratify ALL patients by their likely dependency on BCL-2 family proteins, guiding the selection of those most likely to benefit from venetoclax or related agents, an approach consistent with the broader movement toward functional precision medicine in haematological malignancies.

The study also fills a conceptual gap in cancer biology by connecting membrane dynamics to apoptotic regulation. ANXA6 is a calcium-dependent phospholipid-binding protein involved in endocytosis, membrane repair, and signalling platform organisation, processes that have been implicated in cancer progression but rarely linked directly to the mitochondrial apoptosis machinery. The new data indicate that these membrane-oriented functions may feed into survival signalling cascades such as the AKT pathway, which in turn sculpt the BCL-2 family. If confirmed in further models, this positions annexins and other membrane-associated proteins as upstream nodes in the network that determines whether a cancer cell lives or dies in response to therapy.

For patients with acute lymphoblastic leukaemia, particularly those with relapsed or refractory disease where treatment options remain limited, the findings offer a potential path toward more rational drug selection. Rather than relying solely on genetic mutations to guide therapy, clinicians may one day incorporate measurements of apoptotic priming and ANXA6 expression to identify tumours primed for BCL-2 dependency. The Barcelona team, working alongside collaborators at Charité-Universitätsmedizin Berlin, the German Cancer Consortium, Prinses Máxima Centrum in Utrecht, the University of Heidelberg, and the University of Sydney, emphasises that their results position ANXA6 as a modulator of the apoptotic threshold and a potential determinant of BCL-2 dependency and response to BH3 mimetics in ALL. Further studies will be needed to validate ANXA6 as a predictive biomarker in prospective clinical cohorts and to explore whether pharmacologically targeting ANXA6 or its downstream signalling partners can sensitise resistant leukaemias to existing apoptotic therapies.

Subject of Research: The role of Annexin A6 in regulating apoptotic priming and BCL-2 family protein balance in acute lymphoblastic leukaemia

Article Title: Annexin A6 modulates apoptotic priming and BCL-2 dependency in acute lymphoblastic leukaemia

Article References: Bernaus-Esqué, M., Alcon, C., Manzano-Muñoz, A., Liu, Y., Lazaro-Navarro, J., Alasfar, L., Eckert, C., Lissat, A., Garrabou, G., Lu, A., Tebar, F., Grewal, T., Enrich, C., Montero, J., & Rentero, C. (2026). Annexin A6 modulates apoptotic priming and BCL-2 dependency in acute lymphoblastic leukaemia. Cell Death Discovery. https://doi.org/10.1038/s41420-026-03336-z

Image Credits: AI Generated

DOI: 10.1038/s41420-026-03336-z

Keywords: Annexin A6, apoptotic priming, BCL-2, acute lymphoblastic leukaemia, BH3 mimetics, AKT signalling, BAK, BAD, mitochondrial apoptosis, functional precision medicine, venetoclax, haematological malignancies

Acute myeloid leukemia is an aggressive cancer of the blood and bone marrow in which abnormal myeloid cells proliferate uncontrollably, crowding out healthy blood-forming tissue. For decades, the backbone of treatment was intensive chemotherapy, which many patients, particularly older adults, could not tolerate. The arrival of venetoclax changed that calculus. Venetoclax is a selective inhibitor of BCL-2, a protein that leukemia cells exploit to evade programmed cell death. By binding BCL-2, venetoclax restores the apoptotic pathway, priming malignant cells to self-destruct. When combined with hypomethylating agents such as azacitidine or with low-dose cytarabine, it has produced remission rates in clinical trials that were unthinkable for unfit or elderly patients a decade ago.

The Lanzhou study captured how this class of drugs performs outside the tightly controlled environment of a randomized trial. Among the 165 patients in the cohort with newly diagnosed acute myeloid leukemia, 74.5 percent achieved what clinicians call composite complete remission, a measure that includes complete remission itself as well as complete remission with incomplete blood count recovery. That figure aligns closely with results from pivotal registration trials, suggesting that the drug combination retains its efficacy when delivered in routine clinical practice, where patients are often older, carry more comorbidities, and present with more heterogeneous disease biology than trial enrollees.

The picture was markedly different for the 51 patients with relapsed or refractory disease, whose leukemia had either returned after prior treatment or had never responded to it. In this group, only 39.2 percent achieved composite complete remission. That gap is clinically meaningful and underscores a central challenge in modern hematology: while venetoclax has transformed first-line therapy, salvage treatment for patients whose disease has escaped earlier regimens remains one of the most difficult problems in the field. Leukemia cells that survive initial therapy often carry mutations and survival adaptations that blunt the effectiveness of BCL-2 inhibition, and the study’s numbers quantify that resistance in a real-world setting.

Survival analysis revealed which factors determined long-term outcomes in each group. Among patients with newly diagnosed disease, three variables emerged as independent predictors of shorter overall survival: failure to achieve composite complete remission, older age, and the presence of an NF1 mutation. The NF1 gene encodes neurofibromin, a negative regulator of the RAS signaling pathway, and mutations in it are associated with dysregulated cell growth and, in some contexts, with resistance to certain targeted therapies. Its identification here as an adverse marker adds to a growing body of evidence that the mutational landscape of a patient’s leukemia shapes how much benefit venetoclax-based regimens can deliver.

In the relapsed or refractory group, the determinants of response were different. A lower pretreatment white blood cell count and a higher bone marrow blast percentage were associated with achieving composite complete remission, an apparently counterintuitive pairing that the authors report as an observational finding from multivariable analysis. Meanwhile, failure to achieve remission in this group was strongly linked to higher mortality, reinforcing the point that for relapsed patients, the first salvage attempt is often the best chance to regain disease control. Together, these findings suggest that clinicians managing relapsed disease should weigh disease burden and inflammatory parameters carefully when selecting and timing venetoclax-based salvage therapy.

The most technically ambitious component of the study was the construction of a predictive model for early remission. The researchers assembled a multivariable model using six predictors: AML status, meaning whether disease was newly diagnosed or relapsed or refractory; age; bone marrow blast percentage; platelet count; Eastern Cooperative Oncology Group performance status, a standard measure of a patient’s functional fitness; and TET2 mutation status. TET2 is an epigenetic regulator frequently mutated in myeloid malignancies, and prior research has suggested that TET2-mutant leukemia cells may be particularly sensitive to BCL-2 inhibition, making its inclusion in the model biologically coherent rather than merely statistical.

The model’s performance was quantified using the area under the receiver operating characteristic curve, a metric that expresses how well a model discriminates between patients who respond and those who do not, with 0.5 representing chance and 1.0 representing perfect prediction. The apparent AUC was 0.841, with a 95 percent confidence interval of 0.785 to 0.897, indicating good discriminative ability. Crucially, the team did not rely on a single fit of the data. They internally validated the model using 1,000 bootstrap resamples, a resampling technique that repeatedly refits the model on random subsets of the data to estimate how much its performance is inflated by overfitting. This kind of validation is considered best practice in clinical prediction modeling and lends credibility to the reported statistics.

The model’s predictive reach extended beyond remission itself. When the researchers applied a fixed CRc score to survival outcomes, it yielded time-dependent AUCs of 0.788 at six months and 0.695 at twelve months for overall survival. In practical terms, this means the score captured early treatment trajectory well, with its discriminatory power gradually attenuating over the first year, as would be expected for a model built around baseline and early-treatment variables. The authors are appropriately cautious about these results, noting that the model may be useful for estimating early treatment response but that external validation in independent cohorts is needed before it can be applied routinely in clinical decision-making.

The significance of this work lies less in any single number than in its demonstration of how precision oncology is maturing. Venetoclax-based therapy is now a global standard for many patients with acute myeloid leukemia, yet response remains unpredictable at the individual level, and the drug carries costs, both financial and toxicological, including the risk of tumor lysis syndrome and severe cytopenias. A validated tool that integrates disease status, age, blast burden, platelet count, performance status, and clonal genetics could help oncologists identify patients unlikely to benefit from a first cycle, prompting earlier consideration of alternative strategies or clinical trial enrollment. For now, the Lanzhou cohort offers clinicians a rigorous real-world benchmark: roughly three in four newly diagnosed patients and two in five relapsed patients can expect a remission with venetoclax-based regimens, and a growing statistical toolkit is making those odds calculable before the first dose is even given.

Subject of Research: Venetoclax-based therapy outcomes and remission prediction modeling in acute myeloid leukemia

Article Title: Retrospective evaluation of venetoclax-based regimen in newly diagnosed and relapsed/refractory acute myeloid leukemia: Efficacy determinants, survival outcomes, and model validation

Article References: Wang, A., Liang, H., Ren, C., Wang, Y., Guo, J., Li, J., Yu, X., & Liu, B. (2026). Retrospective evaluation of venetoclax-based regimen in newly diagnosed and relapsed/refractory acute myeloid leukemia: Efficacy determinants, survival outcomes, and model validation. Annals of Hematology. https://doi.org/10.1007/s00277-026-07258-9

Image Credits: AI Generated

DOI: 10.1007/s00277-026-07258-9

Keywords: acute myeloid leukemia, venetoclax, composite complete remission, BCL-2 inhibitor, prediction model, overall survival, NF1 mutation, TET2 mutation, relapsed refractory AML, retrospective study, hematology, bootstrap validation

The argument builds on a striking real-world study that has recently energized the field. A retrospective, two-stage cohort analysis by Chen and colleagues examined early bone-marrow-guided venetoclax management in patients with newly diagnosed acute myeloid leukemia who were considered unsuitable for intensive chemotherapy. Among 371 evaluable patients, the investigators found that using early marrow assessments to guide treatment was associated with significantly reduced early venetoclax exposure and a marked drop in day-56 infection-related hospitalization, which fell from 37.4 percent to 24.0 percent, corresponding to an adjusted odds ratio of 0.46 with a p-value of 0.005. In other words, simply looking at the marrow earlier allowed clinicians to pull back on the drug before the most dangerous toxicities took hold.

The second stage of the Chen study sharpened the finding further. Among 237 patients who responded to initial therapy, shortening venetoclax to fourteen days or fewer per cycle reduced prolonged grade-4 neutropenia from 61.0 percent to 41.6 percent, an adjusted odds ratio of 0.41 with a p-value of 0.003. Infection-related hospitalization also fell, with an adjusted odds ratio of 0.43 and a p-value of 0.014. Critically, these toxicity reductions came without any significant change in measurable residual disease negativity, overall survival, or relapse-free survival. For a drug whose most feared side effect is profound, prolonged neutropenia that opens the door to life-threatening infections, the implication is provocative: some patients may be receiving more venetoclax than they need, and the excess exposure may be pure harm.

Yet the editorial is careful to frame these results as a beginning rather than an endpoint. Because the Chen study was retrospective, its findings are vulnerable to selection bias; clinicians may have shortened therapy preferentially in patients who already looked healthier, which could inflate the apparent safety benefit. The absence of randomization means the two compared groups may have differed in ways the statistical adjustments could not fully capture. Adnan also notes that the study showed no significant difference in overall survival or progression-free survival, which supports the idea that shortening was not harmful but does not prove that shortened venetoclax is truly equivalent in efficacy. Prospective, ideally randomized validation remains the essential next step before practice changes on a wide scale.

There is a deeper conceptual problem as well, and it sits at the heart of the proposed framework. Bone marrow morphology, the century-old practice of examining stained marrow smears under a microscope, is functional and widely available, but it is a blunt instrument. It can miss small populations of leukemic cells that persist below the threshold of visual detection, and its interpretation varies between observers. The editorial contends that early marrow morphology is useful but insufficient on its own, and that relying on a single marker to decide whether to curtail a backbone therapy in a disease as heterogeneous as acute myeloid leukemia is inherently risky.

This is where measurable residual disease enters the picture. A consensus document from the European LeukemiaNet MRD Working Party, authored by Heuser and colleagues, established MRD as a central biomarker in acute myeloid leukemia, serving prognostic, predictive, monitoring, and efficacy-response functions. A positive or negative MRD result indicates whether quantifiable disease is detected above specific thresholds, but those thresholds differ depending on the assay and the laboratory performing it. Flow cytometry, polymerase chain reaction-based assays for mutations such as NPM1, and other techniques each carry distinct sensitivities and limitations, which means an MRD result must always be interpreted in context rather than treated as an absolute verdict.

Recognizing these limitations, recent work by Bancos and colleagues has advocated a multimodal approach to residual disease assessment, tracing the evolution from cytogenetics and molecular biology to emerging technologies such as methylation pattern analysis and surface-enhanced Raman scattering. Each molecular marker, whether marrow morphology, conventional MRD, or molecular MRD via next-generation sequencing, may contribute to diagnosis and monitoring, but none is individually sufficient to guide every treatment decision. The editorial takes this logic one step further and applies it specifically to the question of venetoclax duration, proposing that the integration of multiple markers could provide a more precise and personalized basis for deciding when to stop or shorten therapy.

The framework also draws inspiration from the broader multi-omics movement in hematology. A review by Soleimani Samarkhazan highlighted how integrating complementary molecular and transcriptomic indicators can enable more accurate response-adapted approaches in acute myeloid leukemia, potentially allowing venetoclax duration to be customized according to both morphological and biological measures of disease response. Under such a model, a patient whose marrow clears rapidly, whose MRD assays turn negative early, whose leukemic clone shows molecular responses on sequencing, and whose blood counts recover promptly might safely de-escalate to shorter venetoclax cycles. Conversely, a patient with persistent molecular evidence of disease might continue full-dose therapy or be considered for escalation, even if the microscope looks reassuringly empty.

The stakes of getting this right are considerable. Acute myeloid leukemia is a progressively increasing form of leukemia with consistently high incidence and mortality, imposing a growing strain on health systems worldwide. Projections based on the Global Burden of Disease Study 2021 estimate that by 2040 the number of cases will rise significantly, with predicted figures reaching approximately 184,287.88 for incidence and 165,537.59 for mortality. The economic toll is equally sobering: a United States analysis by Hagiwara and colleagues of 9,455 newly diagnosed patients found that the average healthcare cost per patient was 386,077 dollars. Every day of unnecessary venetoclax exposure adds hospitalizations, growth factor use, transfusions, and infection management to that bill, while every day of insufficient exposure risks relapse, which is far more expensive and far more deadly.

What makes the editorial’s proposal compelling is that it reframes a question the field has been circling for years. Venetoclax-based regimens have delivered unprecedented response rates in unfit patients, but the drug’s hallmark toxicity, myelosuppression, has remained a stubborn constraint, and clinicians have lacked a principled way to know when enough is enough. By proposing a multi-marker panel that unites marrow morphology, MRD, molecular MRD via next-generation sequencing, and hematologic recovery, the editorial sketches a route toward treating venetoclax duration the way modern oncology treats nearly everything else: as a variable to be tuned by data rather than fixed by tradition. The author acknowledges the constraints of the underlying evidence, including the retrospective design of the pivotal real-world study and the possibility that no single marker can capture the full complexity of the disease. But the direction of travel is clear, and the call for prospective research into a multi-marker response-adapted framework gives the field a concrete hypothesis to test. If randomized studies confirm that response-guided shortening preserves survival while stripping away toxicity, the fixed ten-plus-month venetoclax paradigm could give way to something smarter, safer, and genuinely personal, and the editorial argues that the tools to build that future are already on the laboratory bench.

Subject of Research: Response-adapted venetoclax dosing guided by multi-marker disease assessment in acute myeloid leukemia

Article Title: Presenting a multi-marker response-adapted framework for venetoclax duration in acute myeloid leukemia

Article References: Adnan, N. (2026). Presenting a multi-marker response-adapted framework for venetoclax duration in acute myeloid leukemia. Annals of Hematology, 105(10), Article 414. https://doi.org/10.1007/s00277-026-07280-x

Image Credits: AI Generated

DOI: 10.1007/s00277-026-07280-x

Keywords: acute myeloid leukemia, venetoclax, measurable residual disease, bone marrow morphology, next-generation sequencing, BCL-2 inhibitor, neutropenia, response-adapted therapy, multi-omics, hematology, treatment de-escalation, European LeukemiaNet

Waldenström macroglobulinemia is a rare and indolent B-cell lymphoma characterized by the accumulation of malignant lymphoplasmacytic cells in the bone marrow and, crucially, by the overproduction of monoclonal immunoglobulin M, an antibody protein that thickens the blood and can cause hyperviscosity, neuropathy, and organ damage. Because the disease is uncommon, most treatment evidence comes from small trials and single-arm studies, leaving clinicians with genuine uncertainty when patients relapse after frontline therapy. This rarity is precisely why the French group’s multicenter approach matters: by pooling patients from 17 centers, the investigators assembled one of the larger cohorts ever reported for this specific treatment strategy.

The drug at the center of the study, venetoclax, belongs to a class of agents known as BH3 mimetics. These small molecules bind to BCL-2, an anti-apoptotic protein that many B-cell cancers exploit to evade programmed cell death. By occupying the BCL-2 binding groove, venetoclax releases the cellular brakes on apoptosis, allowing malignant lymphocytes to self-destruct. The drug has already transformed the treatment landscape for chronic lymphocytic leukemia, and earlier monotherapy studies suggested promising activity in relapsed or refractory Waldenström macroglobulinemia, a population with significant unmet medical need. What remained unclear was whether venetoclax should be given alone or in combination with other agents in this disease.

The WAVE investigators turned to real-world clinical practice to answer that question. The 46 patients included in the analysis had received a median of three prior lines of treatment before starting venetoclax, and 89 percent had already been exposed to a Bruton tyrosine kinase inhibitor, the class of drugs that has become a cornerstone of Waldenström macroglobulinemia therapy. This detail is important: these were heavily pretreated patients whose disease had already evaded the most effective modern targeted therapies, meaning that any meaningful response signal carries real clinical weight. Among the cohort, 25 patients, or 54 percent, received venetoclax combined with an anti-CD20 antibody, typically rituximab or a related monoclonal antibody that targets the CD20 surface protein found on B cells and recruits the immune system to destroy antibody-coated tumor cells.

The headline finding concerns response depth. At the time of best response, patients treated with the combination achieved a deep response rate, defined as very good partial response plus uncertain complete response, of 56 percent, compared with just 24 percent among those treated with venetoclax monotherapy, a difference that reached statistical significance with a p value of 0.03. In lymphoma care, depth of response is not an academic nicety. Deeper remissions, particularly those in which the monoclonal IgM protein falls to very low or undetectable levels, are consistently associated with longer periods of disease control before relapse. For a disease in which the abnormal protein itself drives many of the symptoms, pushing IgM down as far as possible translates directly into clinical benefit.

Perhaps more striking was the result of the multivariate analysis. When the investigators adjusted for other clinical variables, anti-CD20 combination therapy emerged as the only factor independently associated with achieving a deep response, with a hazard ratio of 4.07 and a p value of 0.03. In other words, the antibody combination quadrupled the odds of a deep remission regardless of other patient characteristics. This kind of signal, emerging from a retrospective dataset where treatment assignment was not randomized, cannot prove causation on its own, but it provides a strong rationale for the prospective trials that the authors say are needed to confirm the strategy.

The progression-free survival data reinforced the same direction of benefit, though with more statistical uncertainty. At two years, 78 percent of patients treated with venetoclax plus anti-CD20 had not experienced disease progression or death, compared with 54 percent of those on monotherapy. The confidence intervals were wide, spanning 54 to 90 percent for the combination arm and 27 to 74 percent for monotherapy, and the difference did not reach statistical significance with a p value of 0.25. That lack of formal significance is unsurprising given the modest sample size, but the magnitude of the gap, nearly 25 percentage points at two years, is the kind of signal that clinicians and trial designers take seriously.

Safety, as always in combination therapy, is the counterweight to efficacy, and here the picture was more nuanced. Grade 3 or higher adverse events occurred in 17 patients, or 68 percent, of those receiving the combination, versus 7 patients, or 33 percent, of those on venetoclax alone, a difference that was statistically significant with a p value of 0.02. Three cases of febrile aplasia, episodes of fever accompanied by severe suppression of blood cell production, were reported, though these did not differ significantly between the two groups. The increased toxicity of the combination is consistent with what is known about adding antibody therapy to targeted agents: the pairing amplifies immune-mediated tumor killing but also increases the burden on the bone marrow and the immune system. For a largely elderly patient population, this trade-off between deeper remissions and higher rates of serious side effects will need careful weighing in future prospective studies.

The WAVE study also illustrates a broader shift in how rare-cancer evidence is generated. Randomized trials in diseases with incidence rates as low as Waldenström macroglobulinemia’s can take years to accrue even modest numbers of patients, and many relapsed patients cannot wait. Retrospective multicenter cohorts like this one, harmonized across 17 institutions and analyzed with multivariate statistics, offer a pragmatic middle path: they capture the messy reality of clinical practice, including heterogeneous prior treatments and variable dosing schedules, and they generate hypothesis-driving signals that can justify the prospective studies that ultimately change guidelines. The French FILO network has been particularly productive in this regard, leveraging the centralized structure of French hematology care to assemble cohorts that individual centers never could.

For patients and their physicians, the practical message is cautiously encouraging. Venetoclax, with or without an anti-CD20 antibody, is an oral, targeted, chemotherapy-free approach for a disease that has historically been treated with rituximab-based chemoimmunotherapy, proteasome inhibitors, or BTK inhibitors. The WAVE data suggest that in the relapsed or refractory setting, particularly after BTK inhibitor exposure, the combination strategy offers the best chance of a deep and durable response, at the cost of more frequent severe side effects. The authors themselves frame the findings as warranting further evaluation in prospective studies, and that is the appropriate note of restraint. Until randomized data arrive, the study gives hematologists a real-world benchmark and gives patients with few remaining options a reason for measured optimism that the next generation of trials will refine exactly who benefits most from this two-pronged attack on their cancer.

Subject of Research: Venetoclax with or without anti-CD20 antibody therapy for relapsed or refractory Waldenström macroglobulinemia

Article Title: Relapsed/refractory WAldenström macroglobulinemia patients treated by VEnetoclax with or without anti-CD20 antibody: WAVE a retrospective study of the French CLL/WM group (FILO)

Article References: Vonfeld, M., Systchenko, T., Debureaux, P.-E., Dupuis, J., Roos-Weil, D., Ysebaert, L., Dilhuydy, M.-S., Malphettes, M., Croizier, C., Aurran, T., Inchiappa, L., Willems, L., Hivert, B., Lévy, V., Bussot, L., Bouclet, F., Laribi, K., Clavert, A., Durand, A., & Tomowiak, C. (2026). Relapsed/refractory WAldenström macroglobulinemia patients treated by VEnetoclax with or without anti-CD20 antibody: WAVE a retrospective study of the French CLL/WM group (FILO). Annals of Hematology. https://doi.org/10.1007/s00277-026-07293-6

Image Credits: AI Generated

DOI: 10.1007/s00277-026-07293-6

Keywords: Waldenström macroglobulinemia, venetoclax, anti-CD20 antibody, BTK inhibitor, relapsed refractory lymphoma, BCL-2, targeted therapy, retrospective study, hematology, monoclonal antibody, progression-free survival, FILO

The historical record explains why skepticism took root. Studies conducted in the 1980s and 1990s reported in-hospital mortality approaching 90 percent among patients with acute myeloid leukemia who required invasive mechanical ventilation. Against such figures, many clinicians questioned whether intensive care offered anything more than a prolonged and painful death. Yet the evidence landscape has steadily transformed. Refinements in patient selection, combined with sweeping advances in supportive care, have progressively improved outcomes, and more recent studies report in-ICU mortality rates of approximately 45 percent for critically ill patients with acute leukemia. That trajectory, from near-certain fatality to a coin-flip chance of survival, represents one of the quiet revolutions in hematology and intensive care.

A major new analysis has now brought unprecedented statistical weight to this transformation. An individual participant data meta-analysis by Chean and colleagues, published in Intensive Care Medicine, examines the outcomes of critically ill adults with acute leukemia using data from 2,003 patients treated in 55 intensive care units across 19 countries, with an inclusion period spanning more than two decades, from January 2000 to July 2023. The scale and duration of the study fill a long-standing knowledge gap created by earlier single-center investigations and limited sample-size analyses that focused mainly on patients younger than 60 years, a group that no longer reflects the real-world demographics of the disease.

What distinguishes this meta-analysis methodologically is its use of the individual participant data approach. Unlike conventional meta-analyses that rely on aggregated results extracted from published papers, an IPD meta-analysis goes back to the raw data of each contributing study and reanalyzes them. This allows researchers to improve both the quantity and quality of the evidence, to include information that was never reported in the original publications, and to standardize analyses and outcome definitions across studies. The method demands that investigators contact the corresponding author of every included trial or cohort, an arduous process that explains why such analyses remain relatively rare but carry exceptional authority when completed.

The findings confirm what many specialists hoped but could not previously prove with such rigor: ICU mortality has decreased over time among patients requiring mechanical ventilation. The authors of the accompanying editorial, Guillaume Berton and Norbert Vey of Aix-Marseille University and Institut Paoli-Calmettes in Marseille, attribute this trend to improvements on two fronts simultaneously. On the hematology side, new chemotherapy regimens have emerged, while supportive care has advanced dramatically through antimicrobial prophylaxis and improved management of febrile neutropenia, the dangerous fever that strikes patients whose infection-fighting white cells have been wiped out by both disease and treatment.

Perhaps the most striking demographic shift documented in the analysis is the changing age profile of patients reaching the ICU. The proportion of patients older than 65 years admitted to intensive care nearly doubled over the study period, rising from 18 percent before 2010 to 33 percent after 2010. This is not a coincidence of referral patterns but a direct consequence of therapeutic innovation. For decades, elderly patients with acute leukemia were often offered palliative care because intensive cytotoxic chemotherapy, the gold standard for younger patients, was considered too toxic for bodies with diminished functional reserves. That paradigm has been upended by non-intensive approaches, most notably the combination of hypomethylating agents with the BCL-2 inhibitor venetoclax, which has demonstrated a median overall survival of 14.7 months and has become the standard of care for AML patients ineligible for intensive chemotherapy.

The therapeutic revolution extends further. Although the Chean meta-analysis excluded post-transplant ICU admissions, advances in allogeneic stem-cell transplantation now allow this potentially curative procedure to be offered to increasingly older patients, with evidence supporting matched sibling, unrelated, and haploidentical donor options in those over 60. Together, these developments signal that treatment for older AML patients has moved decisively from palliative approaches to strategies with curative intent, and the resulting lengthening of survival will only reinforce the role of intensive care in this population. But with more therapeutic possibilities come new dilemmas, above all patient selection, which must rest on a careful evaluation of frailty and is tightly interwoven with the triage decisions made before ICU admission is even offered.

The meta-analysis also delivered a finding that unsettles prior assumptions: older age, defined as above 65 years, emerged as an adverse predictor of in-ICU mortality. This contrasts with earlier studies that had reported in-ICU mortality rates for elderly patients similar to those of younger cohorts. The editorial authors suggest the discrepancy may reflect variable levels of expertise among the participating centers, illustrated by differences in outcomes according to the national economic level of the countries involved. Such disparities may influence not only the quality of intensive care management but also which patients are selected for admission in the first place, raising uncomfortable questions about equity of access to critical care for older patients with leukemia.

The stakes of that triage question are amplified by what happens after patients leave the unit. A recent report highlighted in the editorial found that a significant proportion of AML patients require modifications to their antileukemic treatment following ICU discharge, altering their long-term prognosis, with older age increasing this risk. In other words, the ICU episode does not exist in isolation; it can derail the optimal cancer therapy on which survival ultimately depends. Conversely, one important limitation of the Chean analysis is that treatment response was not considered, even though response is a major determinant of survival and of the success of organ failure management. Future studies, the editorial argues, should incorporate modern response criteria, including the residual disease assessments now routinely used in hematology practice.

Finally, the editorial closes with a human dimension that data alone cannot capture: patients’ own wishes. Goals-of-care discussions are key to determining the most appropriate management strategy for critically ill patients with cancer, yet they remain relatively infrequent in practice, a gap that demands further research. Meanwhile, the treatment landscape continues to accelerate. More potent antileukemic agents are inducing deeper and longer responses, but each advance carries novel toxicities: venetoclax can trigger tumor lysis syndrome, targeted molecular therapies against FLT3, IDH, and menin can provoke differentiation syndrome causing respiratory, hemodynamic, and renal failure, and the spread of immunotherapy brings risks exemplified by cytokine release syndrome and immune cell-associated neurotoxicity seen with T-cell engagers and CAR T cells in acute lymphoblastic leukemia. As these therapies expand, the editorial concludes, more than ever a continuous close collaboration between intensivists and hematologists is paramount to ensure proper management of these increasingly complex, increasingly survivable patients.

Subject of Research: Intensive care unit access and outcomes for critically ill adults with acute leukemia

Article Title: Beyond classical boundaries: rethinking ICU access in acute leukemia

Article References: Berton, G., & Vey, N. (2026). Beyond classical boundaries: rethinking ICU access in acute leukemia. Intensive Care Medicine. https://doi.org/10.1007/s00134-026-08623-y

Image Credits: AI Generated

DOI: 10.1007/s00134-026-08623-y

Keywords: acute leukemia, intensive care unit, acute myeloid leukemia, ICU mortality, mechanical ventilation, venetoclax, hypomethylating agents, allogeneic stem-cell transplantation, tumor lysis syndrome, individual participant data meta-analysis, elderly patients, goals of care