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 study was co-led by Kasiani Myers of the Division of Bone Marrow Transplantation and Immune Deficiency at Cincinnati Children’s Hospital Medical Center, working alongside 26 fellow researchers from the International SDS Research Consortium. Their central conclusion is stark: performing transplants in patients aged 14 and younger, shortly after detecting warning signs such as clones of mutated bone marrow cells or progressive dysplastic changes, appears to dramatically improve two-year survival compared with delaying intervention until myelodysplastic syndrome or acute myeloid leukemia has already taken hold. For patients with this rare condition, the researchers argue, waiting until malignancies are diagnosed may simply be too late.

Shwachman-Diamond syndrome is caused by mutations in the SBDS gene, inherited in an autosomal recessive pattern, meaning both parents must pass on a mutated copy for a child to be affected. The disorder disrupts normal development of the pancreas, skeletal system, liver, and central nervous system, but its most lethal consequence is the transformation of bone marrow into myelodysplastic syndrome or acute myeloid leukemia. The condition was first described in 1964 by Harry Shwachman and Louis Diamond, two physicians who recognized a distinctive pattern of pancreatic insufficiency and bone marrow failure in young patients. Because standard prenatal and newborn screening panels do not test for the syndrome, diagnosis typically occurs during infancy through physical examinations and blood counts that reveal abnormally low levels of circulating cells.

The clinical picture in early childhood is often dominated by digestive and growth problems rather than malignancy. Infants and toddlers with the syndrome frequently struggle with feeding difficulties, failure to thrive, and recurrent infections driven by neutropenia, a shortage of infection-fighting white blood cells. Many lack the pancreatic enzymes needed to digest food properly, requiring lifelong enzyme replacement therapy. Skeletal abnormalities such as scoliosis and delayed tooth development are common, and specialty dental care becomes a recurring part of medical management. Over time, however, the marrow itself becomes increasingly unstable, and the risk of leukemic transformation climbs steadily with age.

To quantify that risk with unprecedented precision, the international team pooled data from 847 cases spanning patients from infancy to beyond age 50, creating the largest known collection of Shwachman-Diamond syndrome outcomes in existence. The numbers they uncovered are sobering. While the incidence of potentially lethal malignancies was as low as 2 percent among 5-year-olds, the cumulative risks of myelodysplastic syndrome, acute myeloid leukemia, and bone marrow failure approached 78 percent by age 50. In other words, nearly four out of five people born with the syndrome will face a life-threatening hematologic crisis by midlife if current surveillance and treatment patterns remain unchanged.

The survival data surrounding early transplantation are the study’s most practice-changing finding. Among 24 high-risk patients who underwent hematopoietic cell transplantation before a malignancy was diagnosed, nearly 82 percent were alive two years after the procedure. By contrast, two-year survival dropped to 55 percent when the transplant was performed after myelodysplastic syndrome had already been identified, and fell further to 36 percent once acute myeloid leukemia had emerged. The gradient is unambiguous: the earlier the intervention relative to malignant transformation, the better the outcome. The co-authors state that these data support surveillance and early transplantation for patients who develop high-risk features, preempting malignancy rather than reacting to it.

The concept of clonal evolution is central to understanding why timing matters so much. In Shwachman-Diamond syndrome, the bone marrow gradually accumulates genetically distinct populations of cells, some of which carry mutations that confer a growth advantage and predispose toward leukemia. When clinicians detect these mutated clones or observe progressive dysplastic changes under the microscope, they are essentially witnessing the earliest molecular steps of a trajectory toward cancer. The new study suggests that this window, before frank malignancy appears, represents the optimal moment for replacing the compromised marrow with healthy donor stem cells through transplantation.

Current clinical practice has generally taken a more conservative approach, with physicians tending to defer transplantation until patients develop myelodysplastic syndrome or acute myeloid leukemia, conditions that are far more dangerous and harder to treat. The reasoning behind that caution has been understandable, since stem cell transplants carry significant risks of their own, including graft-versus-host disease, infection, and organ toxicity. But the new survival figures suggest that this conservatism may be misplaced for patients with clear high-risk biomarkers. The rising global use of genetic screening tests may help reveal more children born with the syndrome, potentially allowing earlier-stage treatment and wider awareness of the testing needed to detect high-risk biomarkers before transformation occurs.

Significant barriers remain, however, and the researchers are careful not to overstate what the data can support. Stem cell transplants are expensive procedures that pose real risks of complications, potentially limiting access for young people in low-resource regions where the syndrome may be underdiagnosed or misdiagnosed. Advocates believe the true number of affected individuals in the United States could be as high as 3,000, far exceeding the roughly 400 patients currently identified, because many cases go unrecognized. More research is needed to determine the ideal age and risk factors for moving forward with transplantation, and whether alternative therapies can be developed that would spare patients the risks of the procedure itself.

Funding for the project came from multiple sources, including the National Institutes of Health, a Cancer Research UK Discovery Award, the UK Medical Research Council, the Rosetrees Trust, and a European Cooperation in Science and Technology Action grant. The study’s conflict-of-interest disclosures note that several co-authors serve as consultants for Athernal Bio and that Myers has received research support from Elixirgen Therapeutics and Incyte. The publication arrives at a moment when the International SDS Research Consortium hopes its findings will prompt clinicians worldwide to reconsider when to intervene, replacing a reactive posture toward malignancy with a proactive one grounded in molecular surveillance. For families navigating a condition that has offered few decisive treatment options, the study provides something rare and valuable: a clear, evidence-based signal that acting early, before cancer develops, may be the single most important choice available.

Subject of Research: Timing of hematopoietic cell transplantation for improving survival in Shwachman-Diamond syndrome

Article Title: Earlier HCT improves survival for youth with Shwachman-Diamond Syndrome

Article References: Earlier HCT improves survival for youth with Shwachman-Diamond Syndrome. Original publication (Bibliographic details unavailable.)

Image Credits: AI Generated

DOI: Not provided

Keywords: Shwachman-Diamond syndrome, hematopoietic cell transplantation, bone marrow failure, myelodysplastic syndrome, acute myeloid leukemia, SBDS gene, clonal evolution, Cincinnati Children's Hospital, New England Journal of Medicine, rare genetic disorder, stem cell transplant, leukemia risk

The study, published in iScience, followed four AML patients through two critical stages: before transplantation, when their disease had failed to reach remission, and after transplantation, when their leukemia had relapsed with donor-derived immune cells now patrolling the bone marrow. The researchers profiled 95,426 individual cells from these patients alongside four healthy donors, capturing the complete transcriptomic landscape of the bone marrow microenvironment at both time points. What they found was a bone marrow ecosystem fundamentally reshaped by malignancy, with T cell frequencies dramatically lower than in healthy donors and leukemia-like cells dominating the cellular terrain.

Using an integrated computational strategy combining reference-based annotation, copy number variation analysis, and differentiation-state prediction, the team classified the leukemia-like cells into eight distinct subtypes, including hematopoietic stem cell-like blasts, progenitor-like blasts, granulocyte-monocyte progenitor-like blasts, and actively cycling blasts. Pseudotime analysis revealed a developmental trajectory flowing from stem cell-like blasts toward more differentiated subtypes, confirming that the leukemia maintained a cellular hierarchy mirroring normal hematopoiesis. Critically, the stem cell-like blasts carried the highest leukemic stem cell 17-gene score, a validated measure of stemness and treatment resistance, and their proportion increased after transplantation.

These stem cell-like blasts were not merely more primitive — they were more immunosuppressive. Compared with their non-stem counterparts, they upregulated the expression of macrophage migration inhibitory factor (MIF), transforming growth factor beta 1 (TGFB1), galectin-9 (LGALS9), and HLA-E, while simultaneously downregulating HLA class II molecules. This molecular cocktail is a known inducer of T cell and natural killer cell dysfunction. The researchers also noted that antigen-presentation changes after transplantation were molecule-specific rather than uniformly suppressed, with HLA-DR upregulated while HLA-DP and HLA-DQ were downregulated, suggesting a nuanced immune escape strategy rather than blanket silencing.

Turning to the T cell compartment, the team identified three clusters characterized by high expression of inhibitory receptors such as PD-1, LAG-3, and TIGIT, which they defined as IR-high T cells. Clonal expansion analysis showed that highly expanded T cell subsets concentrated mainly in the CD8-positive effector and IR-high clusters in AML patients, while limited expansion was focused in naive and memory populations in healthy donors. A pairwise transition index revealed that CD8-positive IR-high T cells had the highest transition likelihood from effector cells, confirming that these exhausted populations emerged directly from the cytotoxic effector pool. Compared with effector cells, IR-high T cells expressed lower levels of the cytotoxic molecules granzyme B and perforin but higher levels of inhibitory receptors and the transcription factors TOX and NR4A2.

The most striking discovery came when the researchers compared the transcriptional programs of self-derived exhausted T cells before transplantation with donor-derived exhausted T cells after relapse. Self-derived exhausted T cells were characterized by enrichment of NFATC1 and NFATC3 transcriptional programs together with increased TOX and EOMES expression, whereas donor-derived exhausted T cells exhibited enrichment of NFATC2-associated signatures accompanied by elevated NR4A2 expression. Gene regulatory network analysis showed that in self-derived exhausted cells, NFATC1 primarily regulated TOX, EOMES, and multiple inhibitory receptors, while in donor-derived cells, NFATC2 primarily regulated NR4A2 and various inhibitory receptors. This fundamental divergence in regulatory architecture means that the two forms of T cell exhaustion, though phenotypically similar, run on entirely different molecular engines.

Further subclustering revealed four major exhausted T cell populations: a progenitor population, an effector population, a terminally exhausted population, and an actively dividing population. Slingshot trajectory inference showed transitions flowing from the progenitor exhausted subtype toward the other three states. Each exhausted subtype carried higher TOX and EOMES expression before transplantation but higher NR4A2 after relapse. In the progenitor exhausted cells, NFATC3 mainly regulated HAVCR2, EOMES, SELL, and TCF7; in the effector exhausted cells, NFATC2 regulated effector-related genes such as TBX21, ZEB2, and GZMB; and in the terminally exhausted cells, NFATC1 regulated TOX, EOMES, CTLA4, HAVCR2, and PDCD1. These findings suggest that the progenitor exhausted population can differentiate into other exhausted subtypes through activation of different transcription factors whose downstream effects differ dramatically.

The bone marrow microenvironment itself was profoundly immunosuppressive at both disease stages. Monocytes expressed high levels of PD-L1 and interleukin-10 but low levels of the costimulatory ligand ICOSLG compared with healthy donors. Dendritic cells similarly upregulated PD-L1, PD-L2, interleukin-10, and HLA-E while downregulating HLA class II molecules. Regulatory T cells expressed elevated levels of PD-1, CTLA-4, LAG-3, TIM-3, TIGIT, TGFB1, granzyme B, perforin, and the key transcription factors FOXP3, STAT5, and NFKB1, with most of these molecules more prominently expressed after transplantation. Hematopoietic stem cell-like blasts upregulated CD274, CD48, FGL1, interleukin-10, CD47, TGFB1, LGALS9, and HLA class I molecules while downregulating the costimulatory ligand TNFSF4. Together, these cellular components constituted an immunosuppressive bone marrow niche that persisted across both pre- and post-transplantation settings.

Cell-cell communication analysis using CellChat and scMLnet revealed that leukemia-like cells interacted most strongly with CD8-positive effector and exhausted T cells among all T cell subtypes. In the pre-transplant setting, ligand-receptor pairs including HLA-E:CD8A/B, MIF:(CD74+CD44), LGALS9:PTPRC, and TGFB1:TGFBR1/2 were enriched in these interactions, and computational modeling predicted that these signaling pathways further regulated the activation of NFAT family transcription factors in the exhausted T cells. In the post-transplant setting, similar interactions were detected except that the TGFB1:TGFBR1/2 pathway was absent. Leukemia cells also communicated indirectly with exhausted T cells through intermediary populations — regulatory T cells, monocytes, and dendritic cells — modulating their immunosuppressive transcriptional programs and downstream target genes such as LCK, CD86, TNFSF13, and GRN, which in turn participated in signaling interactions associated with NFAT-related transcriptional activity in the exhausted T cells.

Among all leukemia cell subtypes, hematopoietic stem cell-like blasts had the most comprehensive ligand-receptor pairs interacting with exhausted T cells, regulatory T cells, monocytes, and dendritic cells, and their communication probabilities were relatively high at both disease stages. Survival analysis using The Cancer Genome Atlas AML dataset revealed that a gene set consisting of only three ligands — MIF, LGALS9, and TGFB1 — had the best prognostic value for overall survival, outperforming TGFB1 alone and gene sets including HLA class I molecules. The researchers conclude that targeting TOX in self-derived exhausted T cells, NR4A2 in donor-derived exhausted T cells, and the signaling molecules MIF, galectin-9, and TGF-β1 could represent a strategy for reversing T cell exhaustion and improving outcomes in AML patients, though they acknowledge that the findings are primarily computational and will require experimental validation in larger cohorts.

Subject of Research: Single-cell dissection of T cell exhaustion niches in acute myeloid leukemia

Article Title: Single-cell dissection of self-derived versus donor-derived T cell exhaustion niches in patients with acute myeloid leukemia

Article References: Yu, C.-Z., Chen, Y.-L., Zhang, X.-H., Xu, L.-P., Wang, Y., Chen, H., Chen, Y.-H., Wang, F.-R., Sun, Y.-Q., Zhang, Y.-Y., Lv, M., Mo, X.-D., Cheng, Y.-F., Liu, K.-Y., Zhao, X.-S., Sun, X.-Q., Zhao, X.-Y., Huang, X.-J., & Chang, Y.-J. (2026). Single-cell dissection of self-derived versus donor-derived T cell exhaustion niches in patients with acute myeloid leukemia. iScience, 29(11), Article 117918. https://doi.org/10.1016/j.isci.2026.117918

Image Credits: AI Generated

DOI: 10.1016/j.isci.2026.117918

Keywords: acute myeloid leukemia, T cell exhaustion, single-cell sequencing, stem cell transplantation, immunotherapy, tumor microenvironment, Single-cell, dissection, self-derived, versus, donor-derived, cell

The research, led by Kristina Warolén and Martin Jädersten of Karolinska University Hospital together with colleagues at Sahlgrenska University Hospital in Gothenburg, compared two cohorts of intensively treated AML patients diagnosed between January 2020 and October 2023. The Stockholm cohort, comprising 116 patients, had access to the Stockholm Region’s hospital-at-home (HaH) service, an infrastructure of 11 healthcare companies operating 38 units across 8 geographic areas. The Gothenburg cohort, 49 patients, received conventional inpatient care without such support. Because both hospitals sit in major urban centers and care is delivered free of charge through Sweden’s universal healthcare system, the researchers hypothesized that the two populations would be broadly comparable, and indeed the cohorts were well matched for age, comorbidity as measured by the Charlson Comorbidity Index, and disease risk according to the European Leukemia Net 2022 classification.

The Stockholm HaH model is remarkable for its scope. At home, patients can receive advanced supportive care that most health systems would consider strictly inpatient territory: intravenous fluids, parenteral nutrition, intravenous medications, and blood and platelet transfusions, the latter sometimes administered at local HaH hubs. Each unit is staffed by physicians, nurses, and other healthcare professionals capable of telephone support and emergency house calls around the clock. Although HaH staff receive no formal additional training in hematology, they manage a wide range of advanced medical conditions in oncology and beyond. Laboratory results are reviewed simultaneously by HaH teams and by junior physicians on the hematology ward through a shared electronic health record, and a joint management plan for transfusions and neutropenic complications is documented for every patient. The maximum distance from a patient’s home to Karolinska University Hospital in Huddinge is around 150 kilometers, and in the Stockholm archipelago, helicopter service is available for emergencies.

The primary endpoint of the study was a composite of death or requirement of a higher level of care, defined as the need for vasopressors, high-flow oxygen or non-invasive ventilation, or intensive care admission, during the first two treatment cycles. The results were striking in their equivalence. After the first cycle, 12 of 116 Stockholm patients (10 percent) met the primary endpoint, compared with 4 of 49 Gothenburg patients (8 percent), a difference that was statistically indistinguishable. Crucially, ten of the twelve Stockholm events occurred in patients who had never been discharged to HaH at all, and five of those patients died during the first cycle. Only two patients discharged to home care were later readmitted requiring a higher level of care, one needing vasopressors for a single day and one needing high-flow oxygen for a single day. No deaths occurred after discharge to HaH.

The efficiency gains, by contrast, were dramatic. During the first cycle, 94 percent of Stockholm patients were discharged, versus just 2 percent in Gothenburg, where 48 of 49 patients remained hospitalized for the entirety of the neutropenic phase. Median inpatient stay after the first cycle was 16 days in Stockholm versus 28 days in Gothenburg, and after the second cycle 9 versus 18 days. Over the first two cycles, Stockholm patients spent on average three additional weeks at home, roughly a third of the entire treatment period. Readmissions were common, with 50 of 109 discharged patients returning to hospital during the first cycle, but the reasons were revealing: clinical deterioration with fever, other symptoms, adherence to older protocols, patients not yet enrolled in the HaH program, persistent fever without deterioration, and in only two cases, patient preference.

Perhaps the most technically interesting finding concerns febrile neutropenia, the fever that signals possible infection during the neutropenic nadir. Among 150 neutropenic episodes in discharged Stockholm patients across the first two cycles, fever developed in 130 cases, or 86.7 percent. Of these, 38 episodes, 29 percent, were resolved entirely with intravenous antibiotics administered at home, while the majority of admitted patients received their first antibiotic dose at home before transfer, minimizing the time from fever onset to treatment. Early administration of antibiotics in febrile neutropenia is known to reduce morbidity and mortality, and the HaH model’s ability to deliver piperacillin-tazobactam, increasingly as a continuous infusion, often within an hour of fever onset may have favorably influenced outcomes even for patients ultimately admitted. Notably, patients treated entirely at home had significantly fewer positive blood cultures, 11 percent versus 39 percent among admitted patients, likely reflecting less severe illness.

The study also generated data relevant to evolving international guidelines. In 42 cases, Stockholm clinicians discontinued intravenous antibiotics while patients were still neutropenic, a practice that the older ECIL-4 guidelines from 2011 discouraged, recommending an additional 24 to 48 hours of hospitalization. In practice, 76 percent of these patients did not need to restart antibiotics within 72 hours, and although ten did restart, none required a higher level of care or died. The updated ECIL-10 guidelines from 2024 now permit close monitoring of neutropenic patients discontinuing antibiotics in either inpatient or outpatient settings, bringing official recommendations into line with what the Stockholm team had been doing for years.

There were also unexpected signals suggesting that home care may do more than merely relocate treatment. Stockholm patients required 40 percent fewer days of intravenous antibiotics than their Gothenburg counterparts across the first two cycles, a difference the authors attribute partly to more liberal use of G-CSF, which can shorten neutropenia by up to five days, but possibly also to faster recovery driven by better nutrition, greater physical activity, and a lower risk of acquiring multidrug-resistant bacteria outside the hospital environment. Intriguingly, while three-month and twelve-month survival were comparable between cohorts, there was a trend toward better long-term survival in Stockholm beyond the first year, with a hazard ratio of 0.62 that did not reach statistical significance but raises the possibility that home-based care supports immune function and tolerance of subsequent therapies, including stem cell transplantation.

The authors are careful about limitations. The retrospective design, modest sample sizes, and reduced statistical power to detect rare but severe adverse events all temper the conclusions, and differences in local practice between the two centers, particularly G-CSF use, complicate direct comparison. Factors such as having a relative at home, distance from hospital, compliance, and language skills likely influenced who could be managed at home but were not systematically evaluated, and there was no structured assessment of patient experience, though routine questionnaires suggested near-universal gratitude for the program, with patients valuing home-cooked meals, emotional support, and time with family. Still, out of nearly 200 episodes of outpatient care of neutropenic AML patients, only 2 percent of readmissions required a higher level of care, no worse than expected for this heavily treated population.

The implications extend well beyond Sweden. As hospital-at-home services expand internationally, driven in part by lessons from the COVID-19 pandemic, which originally pushed the Stockholm program to keep febrile patients home to reduce SARS-CoV-2 exposure and relieve bed shortages, this study offers a practical blueprint for extending home care to one of the most vulnerable populations in oncology. It required no additional on-call staffing or dedicated resources, leveraging existing HaH infrastructure alongside AML-specific protocols. Karolinska has already moved further, offering selected patients consolidation chemotherapy at home via electronic infusion pumps since November 2022, and a prospective study of quality of life, depression, nutrition, and muscle mass is underway. If confirmed in prospective trials, the message is simple and potentially transformative: for many patients with acute myeloid leukemia, the safest place to endure the hardest weeks of treatment may be home.

Subject of Research: Outpatient management of intensively treated acute myeloid leukemia through a hospital-at-home program

Article Title: Hospital at home enables safe and efficient outpatient management of intensively treated acute myeloid leukemia

Article References: Warolén, K., Blennow, O., Ravn Landtblom, A., Nilsson, C., Kullänger Schalling, L., Andersson, C., Lind, C., Hållander, S., Westerberg, S., Stjernfeldt, A.-S., Sporre, E., Leskinen, H., Söderholm, L., Wennström, L., Broliden, P. A., Deneberg, S., Espman, E., von Bahr, L., & Jädersten, M. (2026). Hospital at home enables safe and efficient outpatient management of intensively treated acute myeloid leukemia. Supportive Care in Cancer, 34(10), Article 954. https://doi.org/10.1007/s00520-026-11171-2

Image Credits: AI Generated

DOI: 10.1007/s00520-026-11171-2

Keywords: acute myeloid leukemia, hospital at home, febrile neutropenia, intensive chemotherapy, outpatient care, Karolinska University Hospital, supportive care, intravenous antibiotics, neutropenia, home care, hematology, patient safety

The researchers focused on RNA rather than DNA for several reasons. RNA is generally more indicative of recent microbial activity, since it is transcribed from active genes and degrades more quickly than DNA. In addition, a much larger portion of microbial genomes is transcribed into RNA, making it a richer analyte for detecting microbial presence. The team reasoned that these properties could make RNA a more sensitive and informative marker of circulating microbes than DNA, which had been the focus of earlier studies.

To conduct the analysis, the researchers used a large whole-transcriptome dataset from hundreds of patients with acute myeloid leukemia. The samples included blood and bone marrow specimens collected at diagnosis. The team applied stringent quality control measures to distinguish true microbial signals from artifacts, filtering out low-confidence classifications and removing taxa that were unlikely to be members of the human microbiome. They also compared their findings against healthy controls to ensure that the microbial signals were specific to leukemia patients.

The analysis revealed that bacterial RNA far outnumbered viral RNA in the samples, with bacterial reads dominating the circulating metatranscriptome. The researchers found that the overall microbial load varied considerably from patient to patient, and that this variation was not explained by differences in sample collection or processing. When they compared patients with high versus low microbial loads, they observed differences in the composition of the immune cell populations in the samples, suggesting a link between circulating microbes and the immune environment of the disease.

One of the most striking findings involved the relationship between microbial load and treatment response. The researchers found that patients with higher microbial loads tended to show differences in the expression of genes involved in immune pathways, including the complement cascade and the antibacterial response. They also observed that the abundance of specific microbial taxa correlated with the expression of genes involved in butyrate metabolism, a pathway that has been implicated in immune regulation and cancer progression.

The team also explored whether the microbial signals could predict response to specific therapies. They found that the abundance of certain taxa was associated with differences in the sensitivity of leukemia cells to a range of drugs, including agents that target the BCL-2 protein and other survival pathways. While the study did not establish a causal relationship between circulating microbes and drug response, the findings suggest that the circulating metatranscriptome may carry information relevant to therapeutic decision-making.

The researchers applied several statistical models to account for potential confounders, including differences in sequencing batch, age, and sample type. They also used permutation testing to assess the significance of their findings, ensuring that the observed associations were unlikely to arise by chance. The team emphasized that the study was exploratory in nature and that further work would be needed to validate the findings in independent cohorts.

The study has important implications for the field of cancer microbiome research. Earlier studies have reported microbial DNA in tumors and blood samples from cancer patients, but the field has been plagued by concerns about contamination and artifacts. The new study addresses these concerns by applying rigorous quality control measures and by focusing on RNA, which is less susceptible to contamination from environmental sources. The findings suggest that the circulating metatranscriptome may be a valuable and underexplored source of clinical information in leukemia.

The researchers also noted that their findings may have relevance beyond acute myeloid leukemia. The pathways implicated in the study, including immune regulation and butyrate metabolism, are involved in a range of cancers and inflammatory diseases. The team suggested that the circulating metatranscriptome may be a useful analyte in other cancers as well, and that further work should explore its potential in these settings.

The study represents an important step forward in the effort to understand the role of microbes in cancer. By focusing on RNA and by applying rigorous quality control measures, the researchers have provided a valuable resource for the field and have opened a new avenue for clinical investigation. The findings suggest that the circulating metatranscriptome may carry information relevant to treatment response and immune regulation, and that further work should explore its potential as a clinical tool in leukemia and beyond.

Subject of Research: Circulating microbial RNA in acute myeloid leukemia patients

Article Title: The circulating metatranscriptome in acute myeloid leukemia patients: an RNA-seq reanalysis

Article References: Nguyen, A. D. D., Kern, R., Dombrovski, T., & LaFramboise, T. (2026). The circulating metatranscriptome in acute myeloid leukemia patients: an RNA-seq reanalysis. Frontiers in Microbiomes, 5, Article 1903806. https://doi.org/10.3389/frmbi.2026.1903806

Image Credits: AI Generated

DOI: 10.3389/frmbi.2026.1903806

Keywords: acute myeloid leukemia, microbiome, metatranscriptome, RNA, treatment response, immune regulation, butyrate metabolism, cancer, blood, bone marrow, circulating, acute

The research team, led by Alexander C. Angleitner and colleagues, analyzed 85 adults with acute leukemia or MDS who relapsed after a first allogeneic hematopoietic cell transplantation between 2010 and 2022. Sixty patients received therapeutic donor lymphocyte infusions (DLI), while 25 underwent a second allogeneic transplant. Unlike many prior comparisons, the researchers anchored their analysis at the moment of relapse rather than the date of treatment, a methodological choice designed to eliminate so-called immortal time bias, in which patients who survive long enough to receive a delayed intervention artificially inflate that intervention’s apparent benefit.

The central finding was stark in its symmetry. Median overall survival from relapse was 0.92 years for patients who received a second transplant and 0.61 years for those treated with DLI, a difference that failed to reach statistical significance (p = 0.295). Even after propensity score matching, which paired patients on performance status and time to relapse to reduce confounding, the matched cohort of 36 patients showed a numerically longer median survival after second transplantation (1.01 years versus 0.49 years), but the difference remained statistically indistinguishable from chance.

Beneath the surface of equivalent survival, however, the two strategies revealed opposing risk profiles. Using Fine-Gray competing risks regression, the researchers found that patients treated with DLI faced a higher cumulative incidence of relapse-related mortality, reaching 50 percent at two years compared with 38 percent after second transplantation. Conversely, non-relapse mortality, deaths from treatment complications rather than the disease itself, trended higher after second transplantation, reaching 40 percent at two years versus 24 percent after DLI. Neither contrast achieved statistical significance, but the pattern is clinically meaningful: the second transplant appears to control disease more effectively while exacting a heavier toll from toxicity.

The biology behind these divergent risks reflects the fundamental nature of each intervention. DLI works by harnessing the graft-versus-leukemia effect, in which donor T cells recognize and attack malignant cells. But its efficacy drops sharply when disease burden is high. Prior studies have shown that DLI administered at the molecular relapse stage or for minimal residual disease positivity can yield two-year survival rates approaching 56 percent, whereas DLI given during overt hematologic relapse produces survival around 21 percent at two years. The Göttingen study deliberately focused on therapeutic DLI, meaning infusions given only after documented hematologic or clinical relapse, excluding preemptive use for falling donor chimerism or isolated MRD positivity.

DLI protocols in the study followed a stepwise dose-escalation scheme, beginning at 0.5 million CD3-positive T cells per kilogram of body weight and escalating up to 10 million cells per kilogram across as many as five monthly infusions. Infusions were halted in cases of disease progression, unacceptable toxicity, or graft-versus-host disease exceeding grade I. The median patient received three infusions. The authors note that cumulative dose exposure may have been constrained by early disease progression and by variable donor lymphocyte availability, potentially limiting the therapy’s efficacy in this overt-relapse setting.

Second transplantation, by contrast, offered more aggressive disease control at the cost of intensity. Ninety-two percent of second transplants used reduced-intensity conditioning regimens, and 96 percent involved a different donor than the first transplant, though prior evidence suggests donor change itself confers no clear survival advantage. Notably, patients heading toward a second transplant waited longer from relapse to treatment, a median of 74 days versus 42.5 days for DLI, largely because many underwent intensive cytoreductive chemotherapy first, including FLAG, HAM, ICE, or fludarabine-cytarabine protocols. DLI recipients more often received lower-intensity bridging such as hypomethylating agents with or without venetoclax, or no salvage therapy at all.

Prognostic factors emerged clearly from the analysis. Performance status at intervention was the strongest predictor of survival, with each increment in ECOG score associated with a 51 percent increase in the hazard of death in univariate analysis. Myeloablative conditioning during the first transplant and longer time from transplant to relapse were also associated with better outcomes, both well-established markers of more indolent disease biology. Restricted mean survival time analysis, which captures average survival over a fixed horizon and is less sensitive to long-term survivor outliers, showed 0.95 years of expected survival over two years for DLI patients versus 1.04 years for second transplant recipients, again with overlapping confidence intervals.

The study’s limitations are substantial and acknowledged candidly by the authors. The single-center, retrospective design introduces selection bias: patients chosen for second transplantation generally had better functional status, no uncontrolled graft-versus-host disease, and longer remissions, while DLI was more often deployed in advanced relapse or when transplantation was deemed infeasible. The matched cohort of 36 patients was too small to detect modest survival differences, molecular and cytogenetic data were missing in nearly half the cohort, and MDS patients appeared exclusively in the DLI group, creating baseline imbalance. Crossover was also common, with 15 percent of DLI patients eventually receiving a second transplant and 24 percent of second-transplant patients later receiving DLI.

Despite these caveats, the study carries a clear message for clinicians and patients navigating relapse after transplant. With two-year survival after post-transplant relapse typically below 15 percent in historical series, and no survival advantage demonstrated for either strategy in this matched comparison, treatment selection should remain individualized, driven by performance status, remission duration, patient preferences, and feasibility rather than by any expectation of a survival gain. The authors call for larger, prospective multicenter studies with prespecified handling of salvage therapy and crossover to determine whether defined patient subsets might benefit preferentially from one approach. Until such data exist, the choice between a second transplant and therapeutic DLI remains a judgment call, made at the bedside rather than dictated by the evidence.

Subject of Research: Comparing therapeutic donor lymphocyte infusion and second allogeneic transplantation for relapse after allogeneic stem cell transplantation in acute leukemia and MDS

Article Title: Matched comparison of therapeutic DLI and second allogeneic transplantation after relapse of acute leukemia or MDS

Article References: Angleitner, A. C., Maulhardt, M., Hasenkamp, J., Büntzel, J., & Wulf, G. (2026). Matched comparison of therapeutic DLI and second allogeneic transplantation after relapse of acute leukemia or MDS. Frontiers in Hematology, 5, Article 1826416. https://doi.org/10.3389/frhem.2026.1826416

Image Credits: AI Generated

DOI: 10.3389/frhem.2026.1826416

Keywords: donor lymphocyte infusion, second allogeneic transplantation, acute myeloid leukemia, myelodysplastic syndrome, post-transplant relapse, graft-versus-leukemia, overall survival, non-relapse mortality, relapse-related mortality, propensity score matching, hematopoietic cell transplantation, competing risks analysis

The work, led by Alexandre Coudray, Romain Forey, and colleagues at EPFL and collaborating institutions, introduces two linked algorithms named CLIMB and CLIFF. CLIMB addresses the classical problem of deconvolution: given a bulk RNA-sequencing profile that represents the summed expression of thousands of cells, estimate both the proportions of each cell type present and the expression programs those cell types are running. CLIFF then builds on that decomposition to do something more ambitious: it resolves bulk drug sensitivity measurements, which normally report only an averaged response across an entire sample, into cell-subtype-specific and single-cell-specific estimates of how sensitive each cellular component is to a given compound.

The conceptual foundation of the approach rests on a mapping between two data worlds that rarely meet. Single-cell RNA sequencing provides exquisitely detailed snapshots of individual cells, but it is expensive, technically demanding, and difficult to pair with functional readouts such as drug screening. Bulk RNA sequencing is cheap, abundant, and routinely paired with drug-response data in large clinical cohorts, but it lacks cellular resolution. CLIMB and CLIFF act as a bridge between these worlds: they use single-cell reference data to teach a model what the expression signatures of specific cell types look like, and then apply that learned mapping to interpret bulk profiles. The authors describe this as single-cell-to-bulk transcriptome mapping, and it is this transfer of resolution from the single-cell domain to the bulk domain that gives the framework its power.

Validation began in a controlled setting. The team mixed leukemic cell lines together in the laboratory in known proportions and generated bulk profiles of these artificial mixtures. Because the true cellular composition was experimentally established, the researchers could measure exactly how well CLIMB recovered the ground truth. The algorithm performed accurately, and the same mixtures, which had also been profiled for their responses to drugs, allowed the team to verify that CLIFF could correctly attribute drug sensitivity to the constituent cell lines.

Real-world applications, however, are messier than laboratory mixtures. In clinical practice, the single-cell reference data used to train a deconvolution model rarely comes from the same patients, the same sequencing platforms, or even the same disease context as the bulk samples being analyzed. To test whether CLIMB could withstand these so-called reference-to-target mismatches, the researchers constructed large-scale pseudo-bulk analyses: they aggregated single-cell RNA-sequencing data from independent references across two disease contexts and five cancer types, deliberately introducing the kinds of discrepancies that arise in real studies. Even under these challenging conditions, CLIMB accurately inferred cellular composition and outperformed state-of-the-art bulk deconvolution methods, suggesting that the framework is robust to the imperfections of real reference data.

One of the most striking demonstrations of the method comes from acute myeloid leukemia, or AML, an aggressive blood cancer in which a rare population of leukemic stem cells is thought to sustain the disease and drive relapse after treatment. These cells are notoriously difficult to study because they are scarce and hard to isolate, yet they are believed to be a critical target for curative therapy. CLIMB proved capable of estimating leukemic stem cell fractions with high accuracy across three test datasets and three independent patient cohorts, offering researchers a computational window into a cell population that has long evaded routine measurement in bulk clinical samples.

With the deconvolution engine validated, the team turned to the question that motivates much of precision oncology: which drugs actually kill which cells? To answer it at scale, they applied their framework to the beatAML cohort, currently the most extensive database of ex-vivo drug screening data, in which primary AML samples from patients have been tested against hundreds of compounds while their molecular profiles were simultaneously recorded. Running CLIFF on this resource generated a cell-subtype-resolved drug sensitivity landscape covering 121 compounds, effectively transforming a database of averaged responses into a map of which drugs act on which cellular populations within the leukemia.

The analysis surfaced several compounds that appear putatively active against leukemic stem cells, a finding with direct therapeutic implications. Among the candidates identified were midostaurin, a multikinase inhibitor already approved for use in AML; A-674563, an AKT inhibitor; SNS-032, an inhibitor of cyclin-dependent kinases; and foretinib, another multikinase inhibitor. Because leukemic stem cells are implicated in treatment resistance and relapse, compounds that preferentially target them could inform new therapeutic strategies, particularly for patients whose disease persists after standard induction chemotherapy. The authors emphasize that these are computational predictions that would require experimental and clinical validation, but the framework provides a systematic way to prioritize candidates that would otherwise be hidden inside bulk averages.

Beyond the specific findings in leukemia, the study articulates a broader methodological vision. Bulk functional measurements, whether drug screens, CRISPR perturbation screens, or other phenotypic assays, are abundant in biomedicine precisely because they are scalable and inexpensive. The CLIMB-CLIFF framework offers a general recipe for endowing such measurements with cellular resolution by leveraging the growing library of single-cell atlases. The authors position the approach as an attractive new computational tool for drug development and precision medicine, one that could in principle be extended beyond oncology to any context where heterogeneous cell mixtures obscure the signals that matter, from autoimmune disease to neurodegeneration.

The work also arrives at a moment of intense interest in computational deconvolution, as the field grapples with how to reconcile the explosion of single-cell data with the continued dominance of bulk assays in clinical and pharmaceutical settings. By demonstrating accuracy across controlled mixtures, cross-dataset pseudo-bulk benchmarks, multiple cancer types, and a large clinical drug-screening cohort, the EPFL-led team has provided one of the more comprehensive validations of the deconvolution concept to date. If the predictions hold up in laboratory follow-up, the ability to computationally resolve which cells in a tumor respond to which drugs could reshape how drug screens are interpreted, how patient stratification is performed, and ultimately how therapies are matched to the specific cellular vulnerabilities hidden within each patient’s disease.

Subject of Research: Computational deconvolution of bulk transcriptomic and drug sensitivity data to single-cell resolution

Article Title: Computational deconvolution of drug sensitivity via single-cell–to–bulk transcriptome mapping

Article References: Coudray, A., Forey, R., Bejar Haro, B., Martins, F., Carlevaro-Fita, J., Sheppard, S., Offner, S. E., La Manno, G., Obozinski, G., & Trono, D. (2026). Computational deconvolution of drug sensitivity via single-cell–to–bulk transcriptome mapping. PLOS Computational Biology, 22(10), e1014862. https://doi.org/10.1371/journal.pcbi.1014862

Image Credits: AI Generated

DOI: 10.1371/journal.pcbi.1014862

Keywords: computational biology, deconvolution, single-cell RNA sequencing, bulk RNA-seq, drug sensitivity, acute myeloid leukemia, leukemic stem cells, machine learning, beatAML, precision medicine, drug development, bioinformatics

The retrospective analysis, led by Aneta Nowicka and Lidia Gil at Poznan University of Medical Sciences together with statisticians Anna Sowińska and Barbara Więckowska, followed 219 adults receiving their first induction therapy for acute myeloid leukemia between 2012 and 2025. Rather than simply counting infections, the team set out to map how the entire infectious ecology of the ward shifted over time, in parallel with rising antimicrobial resistance, the arrival of the SARS-CoV-2 pandemic, changes in prophylaxis protocols, and the steady improvement of diagnostic methods. The result is one of the most detailed longitudinal portraits to date of what actually threatens patients during the most vulnerable phase of leukemia treatment.

The central finding concerns the 2018 decision to halt universal fluoroquinolone prophylaxis, a policy change many centers feared would backfire. Using an interrupted time series approach, the researchers compared the pre-2018 era, when every patient received the preventive antibiotic, with the post-2018 era, when it was discontinued. Proportional bloodstream infections fell from 40.6 percent to 34.7 percent, and the share of infections caused by multidrug-resistant organisms dropped from 77.2 percent to 68.6 percent. Crucially, there was no compensatory surge of Gram-negative bacteria, the feared consequence of removing antibiotic pressure. Meanwhile, 30-day mortality declined from 11.9 percent to 5.1 percent.

These numbers carry a technical message that goes beyond a single drug. Fluoroquinolones exert strong selective pressure on gut and environmental bacteria, and prolonged use is a well-known driver of resistance in organisms such as Escherichia coli and Pseudomonas aeruginosa. The Polish data suggest that withdrawing this pressure allowed the local microbial ecology to rebalance, with resistant strains becoming proportionally less dominant without any increase in overall infectious burden. The authors conclude that the evolving infectious etiology in acute myeloid leukemia is driven by temporal, diagnostic, and ecological transitions rather than by any novel pathogen, and that halting fluoroquinolone prophylaxis was clinically safe.

The study also tackled a question that has divided the hematology community since the arrival of targeted therapies: do the newer induction regimens, built around agents such as FLT3 and IDH inhibitors, change the infection profile compared with conventional intensive chemotherapy? The team compared 189 patients on standard induction therapy with 30 patients on novel targeted induction. The answer, at least in this cohort, was reassuringly mundane. Rates of microbiologically documented infections were nearly identical, at 53.3 percent versus 51.3 percent, bloodstream infections were comparable at 33.3 percent versus 38.1 percent, and invasive fungal disease was actually less frequent in the targeted group, at 6.7 percent versus 13.2 percent.

Two apparent differences did emerge in the targeted therapy group, but the authors are careful to disentangle them from confounding. VIM-producing Pseudomonas aeruginosa, a carbapenem-resistant Gram-negative organism carrying the VIM metallo-beta-lactamase gene, appeared in 30.8 percent of relevant infections in the targeted cohort versus 3.3 percent in the standard cohort, a statistically significant difference. SARS-CoV-2 infection likewise affected 53.3 percent of targeted therapy patients versus 33.3 percent. Yet both targeted therapy and the pandemic era, along with more sensitive molecular diagnostics, overlapped almost completely in time. The elevated rates therefore reflect when those patients were treated and how thoroughly they were tested, not the drugs themselves.

This distinction matters for how centers design supportive care. If the infection risks of targeted induction are essentially those of the era rather than of the agent, then prophylaxis and monitoring protocols should be calibrated to local epidemiology and resistance patterns rather than to the specific drug combination. The authors frame this as a call for continuously adapting supportive frameworks, an argument reinforced by the observation that diagnostic methodology itself changed over the study period, with molecular panels detecting organisms and resistance genes that earlier cultures would have missed entirely.

The overall mortality figures provide context for the stakes. Across the full 13-year cohort, 30-day mortality during induction was 8.2 percent, a figure that reflects both the inherent toxicity of myeloablative therapy and the infectious complications that follow. The halving of that rate between eras cannot be attributed to prophylaxis policy alone, since supportive care, antifungal strategies, and general hematology practice all evolved simultaneously. But the direction of change is consistent with a growing body of evidence that indiscriminate antibacterial prophylaxis buys less protection than once believed, while fueling the resistance crisis that complicates every subsequent infection.

As an exploratory, single-center retrospective study, the analysis has limits the authors acknowledge. The targeted induction cohort is small, the pandemic confounds any comparison spanning 2020 onward, and observational time series cannot prove causation. Still, the study offers rare real-world evidence on a question that trials rarely address: what happens to the microbial landscape of a hematology ward when a long-standing prophylaxis policy is reversed. For clinicians weighing antibiotic stewardship against infection fear, the Polish experience suggests that the fear may be the more outdated of the two.

Subject of Research: Evolving infectious epidemiology in acute myeloid leukemia in the contemporary era: a 13-year retrospective, single-center analysis of induction therapies

Article Title: Evolving infectious epidemiology in acute myeloid leukemia in the contemporary era: a 13-year retrospective, single-center analysis of induction therapies

Article References: Nowicka, A., Sowińska, A., Więckowska, B., & Gil, L. (2026). Evolving infectious epidemiology in acute myeloid leukemia in the contemporary era: a 13-year retrospective, single-center analysis of induction therapies. Annals of Hematology. https://doi.org/10.1007/s00277-026-07323-3

Image Credits: AI Generated

DOI: 10.1007/s00277-026-07323-3

Keywords: acute myeloid leukemia, fluoroquinolone prophylaxis, antimicrobial resistance, bloodstream infections, induction chemotherapy, targeted therapy, SARS-CoV-2, multidrug-resistant organisms, hematology, infection epidemiology, Evolving, infectious

Under normal physiological conditions, the bone marrow niche maintains hematopoietic stem and progenitor cells in a delicate balance of quiescence, self-renewal, and differentiation. This balance is orchestrated through tightly regulated interactions among cytokines, chemokines, adhesion molecules, and metabolic cues. In AML, however, leukemic cells disrupt this equilibrium by secreting their own signals and by directly reprogramming stromal, vascular, immune, and metabolic components of the niche. The result is a microenvironment that no longer supports healthy blood production but instead favors malignant persistence. The review emphasizes that this reprogramming is not a passive consequence of tumor growth but an active, bidirectional crosstalk driven by soluble factors, cell-to-cell contact, extracellular vesicles, and metabolic exchange.

At the heart of this crosstalk lies the CXCL12–CXCR4 chemokine signaling axis, described by the authors as the dominant regulatory pathway governing leukemic cell homing and retention. CXCL12, also known as stromal-derived factor-1, is continuously secreted by mesenchymal stromal cells, osteoblasts, and endothelial cells within the bone marrow. AML blasts frequently overexpress CXCR4, the receptor for CXCL12, allowing them to respond strongly to this gradient and anchor themselves within protective niches. Upon activation, CXCR4 triggers intracellular cascades including PI3K/AKT, ERK/MAPK, and NF-κB, which collectively promote survival, proliferation, and resistance to apoptosis. Clinically, high CXCR4 expression correlates with poor prognosis and increased relapse risk, underscoring the pathway’s central role in disease progression.

Beyond chemokines, the review details how cytokines and growth factors shape the leukemic niche. Transforming growth factor-beta (TGF-β), produced by stromal cells, immune cells, and sometimes by leukemic blasts themselves, activates SMAD-dependent transcriptional programs that suppress immune cell function and drive leukemic cells toward a quiescent state less vulnerable to cell cycle–dependent chemotherapy. Vascular endothelial growth factor (VEGF) promotes angiogenesis and vascular remodeling, creating specialized microenvironments rich in growth factors and oxygen gradients that sustain leukemic stem cells. Inflammatory cytokines such as TNF-α and interleukin-6 activate NF-κB and JAK/STAT signaling respectively, reinforcing anti-apoptotic gene expression and creating a feed-forward loop that sustains both niche remodeling and leukemic persistence.

The review also highlights the emerging role of extracellular vesicles, particularly exosomes ranging from 30 to 150 nanometers, as key mediators of intercellular communication in AML. Leukemic cells release large numbers of these membrane-bound vesicles, which are taken up by stromal, endothelial, and immune cells through endocytosis or membrane fusion. The cargo—proteins, lipids, and microRNAs such as miR-155 and miR-150—alters gene expression in recipient cells, converting healthy mesenchymal stromal cells into leukemia-supportive elements that secrete increased amounts of IL-6, IL-8, and CCL2. This bidirectional reprogramming establishes a self-reinforcing inflammatory loop that enhances leukemic retention, survival, and chemoresistance. Extracellular vesicles also suppress T-cell proliferation and natural killer cell cytotoxicity, extending the immunosuppressive reach of the leukemic niche beyond the bone marrow itself.

Adhesion-mediated signaling represents another critical layer of chemoprotection. Integrins such as VLA-4 on leukemic cells bind to VCAM-1 on stromal cells, triggering PI3K/AKT signaling that enhances anti-apoptotic responses and reduces chemotherapy sensitivity. β2-integrins activate a Syk–STAT signaling axis that further boosts leukemic survival and proliferation. This phenomenon, termed cell adhesion–mediated drug resistance (CAM-DR), allows AML cells to physically anchor themselves within niches that shield them from cytotoxic agents while simultaneously activating intracellular survival pathways. The review notes that stromal niches can also provide a physical barrier, allowing residual leukemic stem cells to survive treatment and eventually seed relapse.

Metabolic crosstalk between leukemic cells and the bone marrow microenvironment adds yet another dimension to niche-mediated chemoprotection. Bone marrow adipocytes supply fatty acids that leukemic cells utilize through fatty acid oxidation, enhancing mitochondrial function and providing an alternative energy source under nutrient stress. Stromal cells contribute amino acids and lipids that sustain biosynthetic activity. Hypoxic regions within the leukemic marrow stabilize hypoxia-inducible factors HIF-1α and HIF-2α, driving metabolic reprogramming toward glycolysis and upregulating angiogenic factors such as VEGF. Cells in these hypoxic niches often show reduced sensitivity to chemotherapy, partly due to slower growth and activation of HIF-dependent anti-apoptotic pathways. The authors emphasize that these metabolic adaptations are not isolated events but converge on shared intracellular hubs including PI3K/AKT and mTOR signaling.

The immune microenvironment within the AML bone marrow undergoes profound functional impairment. T cells exhibit signs of exhaustion marked by reduced proliferation and impaired cytokine production, driven in part by activation of the PD-1/PD-L1 immune checkpoint axis. Regulatory T cells are often expanded, further suppressing anti-leukemic responses through TGF-β–mediated mechanisms. Natural killer cells, which normally target and destroy malignant cells, are inhibited by TGF-β signaling that reduces expression of activating receptors and cytotoxic mediators. Macrophages within the leukemic niche acquire tumor-associated phenotypes, secreting IL-6, TNF-α, and IL-10 to reinforce survival signaling and immune suppression. Myeloid-derived suppressor cells further block T-cell activation through reactive oxygen species and immunosuppressive cytokines. Galectins, particularly galectin-1, galectin-3, and galectin-9, contribute additional layers of immune modulation and drug resistance.

A particularly important insight from the review concerns the spatial organization of leukemic stem cells within distinct bone marrow niches. The endosteal niche, composed of mesenchymal stromal cells, osteoblastic cells, and extracellular matrix components, maintains leukemic stem cells in a quiescent G0 state through signals that limit cell cycle entry. This

Subject of Research: Bone marrow niche-mediated chemoprotection and chemoresistance mechanisms in acute myeloid leukemia

Article Title: Crosstalk of factors underlying bone marrow niche-mediated chemoprotection in acute myeloid leukemia

Article References: Shah, A., Trivedi, A. K., & Chaturvedi, C. P. (2026). Crosstalk of factors underlying bone marrow niche-mediated chemoprotection in acute myeloid leukemia. Frontiers in Hematology, 5, Article 1850831. https://doi.org/10.3389/frhem.2026.1850831

Image Credits: AI Generated

DOI: 10.3389/frhem.2026.1850831

Keywords: acute myeloid leukemia, bone marrow niche, chemoresistance, CXCL12-CXCR4, leukemic stem cells, tumor microenvironment, extracellular vesicles, Frontiers in Hematology, Crosstalk, factors, underlying, bone

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