The researchers randomly assigned 65 piglets, 28 days old and weighing 7.59 ± 1.11 kilograms, to five treatments with 13 animals per group. The groups received a basal control diet, a diet supplemented with 1% L-glutamate, a diet supplemented with 1% L-aspartate, a diet containing 1% of each amino acid, or basal diet supplemented with 50 mg/kg carbadox. All pigs were orally inoculated with F18 ETEC for three consecutive days, beginning on day 7.

Blood was collected before inoculation and on days 9, 11, 21 and 28. The small intestine was sampled on day 12, near peak infection, and day 28, during recovery. The protocol was reviewed and approved by the UC Davis Institutional Animal Care and Use Committee under protocol 23529.

The challenge was followed by changes in blood-cell profiles and circulating markers of inflammation, although the response to dietary treatment was selective rather than uniform. White blood cell, neutrophil, lymphocyte, monocyte, eosinophil and basophil counts increased after inoculation and peaked on day 21, with no treatment differences in these populations at the individual sampling points. Red blood cell count, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, platelet count and total protein concentration also increased on days 9 and 11 relative to pre-inoculation values, while hematocrit, mean corpuscular volume, red cell distribution width and mean platelet volume decreased.

Serum tumor necrosis factor-alpha rose on days 11, 21 and 28, serum interleukin-8 increased on day 11, and C-reactive protein and haptoglobin rose during the early post-challenge period. These infection-associated shifts occurred across the experiment, whereas the amino-acid groups differed from controls or the carbadox group in selected outcomes at particular times. Differences in red blood cell indices were most evident during recovery.

On day 21, piglets receiving L-glutamate or L-aspartate had higher hemoglobin concentration, hematocrit and mean corpuscular hemoglobin than controls. Mean corpuscular volume was also greater in the L-glutamate, L-aspartate and combined-supplement groups than in controls. At that point, L-glutamate and the combination had higher red cell distribution width than controls, while L-aspartate did not show the same elevation.

By day 28, L-glutamate and L-aspartate had lower red cell distribution width than controls, and L-aspartate also showed a tendency toward a greater mean corpuscular volume. These measurements document differences in red blood cell size, hemoglobin content and population uniformity. Systemic inflammatory markers showed a similarly time-dependent pattern.

On day 9, L-aspartate and the combined treatment had lower serum interleukin-8 concentrations than controls, while L-glutamate and L-aspartate had lower C-reactive protein than pigs receiving carbadox. On day 11, all three amino-acid treatments had lower C-reactive protein than controls and the antibiotic group, although pigs receiving the combined supplement had the highest serum tumor necrosis factor-alpha among the groups. By days 21 and 28, haptoglobin was substantially higher in controls than in each amino-acid group and in the carbadox group.

No treatment differences were detected for tumor necrosis factor-alpha, interleukin-8 or C-reactive protein on those later dates. The results therefore show modulation of selected inflammatory markers rather than broad or consistent suppression of every inflammatory signal. Mucosal gene-expression measurements revealed additional differences by intestinal segment and stage of infection.

On day 12, L-aspartate reduced ileal interleukin-8 expression compared with controls, the combined treatment and carbadox. In contrast, pigs receiving both amino acids had higher ileal interleukin-1 beta and interleukin-17A expression than pigs receiving L-aspartate or carbadox, as well as higher jejunal interleukin-1 beta expression. L-glutamate tended to have lower jejunal Toll-like receptor 4 expression, and the combination tended to have lower ileal tumor necrosis factor-alpha expression.

These results came from messenger RNA analysis of intestinal tissue. They establish differences in transcriptional responses, not direct evidence of altered cytokine protein abundance, bioactivity, epithelial integrity or clinical disease severity. By day 28, the intestinal expression profile included several genes associated with immune regulation and tissue repair.

In the jejunum, L-glutamate, L-aspartate and the combination tended to increase interleukin-4 expression relative to controls, while L-glutamate, L-aspartate and carbadox significantly increased interleukin-13 expression. In the ileum, the combined treatment had the greatest interleukin-4 expression, and L-glutamate had greater transforming growth factor beta 1 expression than the other treatments. Untargeted metabolomics offered an exploratory view of biochemical differences among the groups.

The researchers detected 414 features in day-12 jejunal mucosa, including 170 identified metabolites, and 393 features, including 161 identified metabolites, in day-12 ileal mucosa. Day-11 serum contained 402 detected features, of which 142 were identified. Higher jejunal aspartate abundance in pigs receiving L-glutamate or the combination met the predefined exploratory criteria, as did higher ileal glutaric acid in the combined group.

Large fold changes included increased serum palmitoleic and oleic acids with all three amino-acid treatments, increased jejunal maltose, lactose and sucrose, and increased ileal sucrose and cellobiose in L-glutamate-fed pigs. These are treatment-associated differences, not direct evidence that the metabolic changes were beneficial. Pathway enrichment identified recurring associations with alanine, aspartate and glutamate metabolism, the citrate cycle, arginine biosynthesis and carbohydrate-related pathways across serum and intestinal samples.

Glutathione metabolism and taurine and hypotaurine metabolism also appeared in intestinal comparisons, while metabolites including glucose-6-phosphate and fructose-6-phosphate were associated with pentose-phosphate-related changes. The analysis used an exploratory false-discovery-rate threshold below 0.2, together with nominal significance, pathway impact above 0.1 and, for selected metabolites, a variable-importance score above 1. The findings are therefore hypothesis-generating: they cannot identify which metabolic route produced an immune difference or show that greater abundance of a metabolite represented improved health.

Several limitations constrain how the results can be interpreted. L-glutamate and L-aspartate were added as crystalline ingredients in place of corn, so the diets differed not only in the presence of these amino acids but also in total amino acid and nitrogen supply. The combined group received twice the supplemental amino-acid amount of either single-ingredient group, making additive, synergistic and greater-substrate effects impossible to separate.

Only six or seven pigs per group were assessed at the terminal tissue-sampling points, limiting precision for segment-specific immune results. The artificial challenge also does not reproduce the full conditions of commercial production. Taken together, the experiment shows that L-glutamate and L-aspartate can modulate selected hematological, inflammatory and metabolic responses during experimental ETEC challenge in weaned piglets, but it does not demonstrate reduced antibiotic need, improved growth or superiority of the combined treatment.

Subject of Research: Effects of L-glutamate and L-aspartate supplementation on hematological, immune and metabolic responses in ETEC-challenged weaned piglets

Article Title: Dietary L-glutamate, L-aspartate, and their combination supplementation modulated hematological, immune, and metabolic responses in weaned piglets challenged with enterotoxigenic Escherichia coli

Article References: Wongchanla, S., Park, Y., Park, S., Sun, S., & Liu, Y. (2026). Dietary L-glutamate, L-aspartate, and their combination supplementation modulated hematological, immune, and metabolic responses in weaned piglets challenged with enterotoxigenic Escherichia coli. Frontiers in Veterinary Science, 13, 1938098. https://doi.org/10.3389/fvets.2026.1938098

Image Credits: AI Generated

DOI: 10.3389/fvets.2026.1938098

Keywords: ETEC, weaned piglets, L-glutamate, L-aspartate, amino acid nutrition, intestinal immunity, hematology, inflammation, metabolomics, piglet nutrition, Dietary, combination

The study is important because measuring a contaminant in fish tissue alone does not reveal its full biological effect. A metal can accumulate in an organ without producing an obvious external sign, while changes in blood chemistry and microscopic tissue injury can reveal physiological stress before populations or entire food webs are visibly affected. By examining all three levels at once, the researchers assessed not only how much material had entered the fish, but also whether the animals showed signs of injury, impaired function or a disturbed internal balance.

Wild and farm-reared C. mrigala were collected from the River Jhelum and local fish farms, respectively. The investigators analyzed the liver, gills and muscles for toxic metals and essential elements. The liver recorded the highest metal accumulation, followed by the gills and then the muscles. This pattern is consistent with the liver’s central role in metabolism and detoxification, while the gills provide a large interface between the fish and contaminated water. Muscle is the principal edible tissue in the assessment, making its concentration particularly relevant to questions about dietary exposure.

Calcium and magnesium were the most abundant essential elements in the analyzed tissues. Such elements are not contaminants in the same sense as toxic metals: they are normal constituents of the body and can perform essential biological functions when present in appropriate amounts. Their presence alongside potentially harmful elements illustrates why evaluating pollution requires more than identifying every chemical substance in tissue. The assessment also found that nickel, chromium and arsenic were the predominant toxic metals, pointing to a mixture of potentially harmful elements rather than contamination by a single substance.

The clearest difference between the two groups appeared in their physiological condition. Wild fish showed marked changes in hematological and biochemical indicators, which the researchers used to evaluate fish health alongside direct tissue analysis. Blood measurements can reflect changes in oxygen transport, metabolism and cellular regulation, while serum biochemical measurements can reveal disturbances in organ function and metabolism. Although the accessible summary does not report individual values for each marker, it identifies the combined pattern as evidence of a stronger stress response in river fish. The approach shows why a multi-biomarker strategy is more informative than relying on a single laboratory measurement.

Microscopic examination produced an equally concerning picture. The wild fish displayed severe histopathological damage in the gills, liver and muscles, whereas the farmed specimens showed lower overall contamination and less marked physiological disturbance. Gills are especially important in freshwater fish because their filaments and lamellae provide the principal surface for water exchange and oxygen uptake. Injury in this tissue can therefore impair respiration, while liver damage may interfere with metabolism and detoxification. Damage to muscle adds another dimension, affecting the structure and function of tissue commonly consumed by people.

The study’s human health risk assessment found a minimal risk from consuming farm-reared fish but warned that wild C. mrigala from the River Jhelum may pose significant health concerns. This contrast is not evidence that farmed fish are entirely free of contaminants, because metals can also enter controlled aquaculture systems through feed, water or other inputs. Rather, the results show substantially lower risk in the farmed specimens examined. For people who depend on the river as a source of food, the findings are more immediate: regularly eating wild fish from a contaminated environment may increase exposure to metals that accumulate in edible muscle and in organs that may also be consumed.

From an environmental perspective, the findings suggest that C. mrigala may serve as a useful indicator of metal pressure in freshwater systems. The species is widely consumed and can occupy waters affected by human activity, allowing researchers to connect water quality with body burdens and biological effects. The study does not identify a single source of the contamination, but the combination of arsenic, chromium and nickel is consistent with the need to examine multiple potential pathways rather than assume that every metal has the same origin. The River Jhelum results also reinforce the need for routine, geographically representative monitoring across seasons and sites.

The authors call for improved waste management, continuous environmental monitoring and regular limnological assessments to protect aquatic ecosystems and public health. Those recommendations are closely linked: pollution control reduces the input of metals, monitoring identifies whether interventions are working, and repeated biological assessments reveal effects that chemical measurements alone may miss. The comparison with farmed fish provides a practical signal that controlled production conditions can produce markedly different outcomes. The larger challenge is to determine whether the conditions allowing metal accumulation in the Jhelum can be reduced rapidly enough to protect wild fish, the food web and the communities that rely on the river.

Subject of Research: Assessment of metal accumulation, physiological stress and human health risks in wild and farmed Cirrhinus mrigala

Article Title: Physiological assessment of metal accumulation and multi-biomarker stress responses in wild and farmed Cirrhinus mrigala

Article References: Ijaz, S., Ullah, S., Impellitteri, F., & Faggio, C. (2026). Physiological assessment of metal accumulation and multi-biomarker stress responses in wild and farmed Cirrhinus mrigala. Environmental Monitoring and Assessment, 198(11), Article 1224. https://doi.org/10.1007/s10661-026-16076-5

Image Credits: AI Generated

DOI: 10.1007/s10661-026-16076-5

Keywords: River Jhelum, Cirrhinus mrigala, metal bioaccumulation, toxic metals, fish health, histopathology, hematology, aquatic pollution, human health risk, environmental monitoring, Physiological, assessment

The study, published in the Annals of Hematology, drew on the National Inpatient Sample, the largest publicly available all-payer hospital database in the United States. The researchers, led by co-first authors May AlMoshary of Princess Nourah bint Abdulrahman University in Riyadh and Ahmed Elbataa of Al-Azhar University in Cairo, examined seven years of admissions data spanning 2016 through 2022. They identified 191,640 weighted hospitalizations of adults admitted with a principal diagnosis of acute leukemia, using standardized ICD-10-CM diagnostic codes to ensure consistent case identification across hundreds of hospitals nationwide.

Within that enormous cohort, 8,880 hospitalizations, or 4.6 percent, involved venous thromboembolism. That figure may sound modest, but in the context of a disease whose treatment already involves profound disruptions of the blood system, it represents a substantial clinical burden. More troubling is the trajectory: after adjusting for patient and hospital characteristics, the prevalence of venous thromboembolism climbed significantly between 2016 and 2022, a trend the authors describe as statistically robust with a p-value of 0.032. The burden peaked at 5.3 percent in 2021, suggesting that the pressures of the pandemic era, or evolving treatment patterns, may have intensified the thrombotic risk faced by leukemia patients.

Acute leukemia occupies a peculiar and dangerous position in hematology. Unlike solid tumors, which promote clotting through local inflammation and vessel compression, leukemia floods the bone marrow and bloodstream with malignant white blood cells that actively subvert the coagulation system. Patients simultaneously face thrombocytopenia, a dangerous shortage of platelets that predisposes them to catastrophic bleeding, and a hypercoagulable state driven by tumor cell procoagulants, inflammatory cytokines, and chemotherapy itself. The result is a clinical tightrope: the same patient may need transfusions to survive a hemorrhage and anticoagulants to survive a clot, often within the same hospital week.

This competing thrombohemorrhagic dynamic is precisely why the research team chose blood product transfusion as the primary outcome of their analysis. Transfusion requirements, they argue, serve as a clinically meaningful proxy for the overall balance between clotting and bleeding that defines acute leukemia care. What they found was unexpected. After multivariable adjustment, patients with venous thromboembolism actually had lower odds of receiving a blood product transfusion, with an adjusted odds ratio of 0.842. The authors are careful about interpretation, noting that this paradoxical inverse association may reflect unmeasured disease severity rather than a genuine protective effect, and that clinicians may withhold transfusions or anticoagulation in ways that confound simple associations.

The other outcomes were far less ambiguous. Venous thromboembolism was independently associated with a 47.8 percent increase in the odds of dying in the hospital, an adjusted odds ratio of 1.478 with a p-value below 0.001. Patients with clots stayed in the hospital dramatically longer, an average of 8.41 additional days, and generated substantially higher costs, with inflation-adjusted hospital charges exceeding those of clot-free admissions by an average of $127,633. For a disease already among the most expensive to treat in medicine, the economic toll of thrombotic complications alone is staggering.

Methodological rigor is a strength of the analysis. Because the National Inpatient Sample uses a complex survey design with weighting to represent the full national population of hospitalizations, the researchers employed multivariable regression models that accounted for that design, ensuring their estimates reflect national patterns rather than the quirks of any hospital subset. To test the durability of their findings, they ran propensity-score weighted sensitivity analyses using average treatment effect on the treated weights, a technique that statistically balances the clot and no-clot groups on observed characteristics. Every major association, from the mortality signal to the transfusion paradox, remained stable under this scrutiny.

The rising trend in clot prevalence deserves particular attention. Several forces could be driving it. Treatment landscapes for acute leukemia have shifted over the study window, with wider adoption of intensive induction regimens, novel targeted agents, and supportive care advances that keep patients alive longer and thus exposed to thrombotic risk for greater spans of time. Improved imaging, particularly more routine use of computed tomography pulmonary angiography, may also be detecting clots that previously went undiagnosed. And the 2021 peak coincides with the COVID-19 pandemic, a period when viral infection itself became a potent prothrombotic force and hospital systems were strained to their limits.

For clinicians, the message is that venous thromboembolism should be treated as a first-order complication of acute leukemia rather than an afterthought. Prophylaxis decisions in this population are genuinely difficult, because standard anticoagulation carries hemorrhagic risk in patients whose platelet counts can plummet without warning. Yet the mortality association documented here suggests that under-recognition or undertreatment of thrombosis carries its own lethal price. The authors suggest that their nationally representative figures can help calibrate risk-benefit calculations, identifying which hospitalized leukemia patients might merit closer surveillance, earlier imaging, or tailored prophylactic strategies.

The study also carries implications for health systems and researchers. The added length of stay and cost burden quantified here, more than eight extra bed-days and over $127,000 in additional charges per complicated admission, translate into enormous aggregate expenditure when multiplied across the tens of thousands of leukemia admissions each year. Future work, the team notes, should probe the mechanisms behind the transfusion paradox and the drivers of the rising trend, ideally with granular clinical data that the administrative coding of the National Inpatient Sample cannot provide. For now, the analysis stands as one of the clearest national portraits to date of a quiet killer complicating one of medicine’s most aggressive cancers, and a reminder that in acute leukemia, the battle between clotting and bleeding is fought on every hospital ward, every day.

Subject of Research: Venous thromboembolism prevalence and inpatient outcomes in hospitalized adults with acute leukemia in the United States, 2016–2022

Article Title: National trends and inpatient outcomes of venous thromboembolism in hospitalized acute leukemia: a propensity-score weighted analysis, 2016–2022

Article References: AlMoshary, M., Elbataa, A., Mansour, A., Murad, M. R., Alabed, A., ALSubhi, S. A., Alzarea, E. A., Halawani, S. H., Bajuaifer, N. A., Basonbul, A. A., Abdelbary, L., & Bakhsh, E. (2026). National trends and inpatient outcomes of venous thromboembolism in hospitalized acute leukemia: a propensity-score weighted analysis, 2016–2022. Annals of Hematology. https://doi.org/10.1007/s00277-026-07312-6

Image Credits: AI Generated

DOI: 10.1007/s00277-026-07312-6

Keywords: venous thromboembolism, acute leukemia, National Inpatient Sample, in-hospital mortality, blood transfusion, hospital length of stay, propensity-score weighting, hematology, thrombosis, hospitalization costs, ICD-10-CM, retrospective cohort

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 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

Myelofibrosis belongs to a group of chronic blood cancers known as myeloproliferative neoplasms, in which the bone marrow overproduces different types of blood cells. In myelofibrosis specifically, the spongy interior of the bone that manufactures blood cells develops fibrotic scar tissue, progressively impairing its ability to produce enough healthy blood cells. The disease is rare, with estimates suggesting that up to six people per 100,000 are living with it. Despite its low prevalence, myelofibrosis carries serious consequences: individuals face an elevated risk of transformation to acute myeloid leukemia, as well as disease-related complications including enlargement of the spleen, the organ that helps fight infection and filter blood, and the development of blood clots.

For much of the modern treatment era, clinicians have relied on a relatively limited therapeutic arsenal. JAK inhibitors, a class of drugs that modulate signaling pathways driving the disease, can reduce spleen enlargement and ease other symptoms, and they remain the mainstay of pharmacologic management. The only potentially curative option, however, is allogeneic stem cell transplant, a procedure in which a patient’s faulty blood-forming cells are replaced with healthy stem cells from a donor. Because myelofibrosis is rare and its course can be unpredictable, approaches to treatment have historically varied substantially among clinicians, a problem the new guidelines were designed to address by synthesizing available evidence into practical, actionable recommendations.

Among the most consequential recommendations is extended molecular testing at diagnosis. Genetic profiling helps identify high-risk mutations that can inform prognosis and guide treatment selection, allowing clinicians to stratify patients more precisely than clinical criteria alone. The guidelines also call for early transplant consultation for higher-risk individuals who are receiving and responding to JAK inhibitors, a recommendation that reflects the delicate timing calculus of transplantation: referring too late can mean losing the window in which a patient is well enough to undergo the procedure, while referring patients who will never need it exposes them to unnecessary risk.

The guidance takes a nuanced position on JAK inhibitor use depending on disease risk. For lower-risk individuals with disease-related symptoms, the guidelines support the use of these agents to improve quality of life. Conversely, for higher-risk individuals without disease-related symptoms, the recommendations advise avoiding JAK inhibitors, a stance that underscores a central tension in myelofibrosis care: symptom relief must be weighed against disease control and the pursuit of curative intent in patients whose biology portends aggressive disease. This risk-adapted framework is one of the clearest signals the panel has sent about how personalized the management of this cancer should become.

Anemia receives dedicated attention in the guidelines, covering strategies for managing low blood counts that arise either from myelofibrosis itself or from JAK inhibitor therapy. Anemia is among the most burdensome manifestations of the disease, contributing to fatigue, transfusion dependence, and diminished survival, yet evidence for its optimal management has remained fragmented. By consolidating guidance in this area, the panel aims to give clinicians a more consistent framework for a problem that routinely complicates long-term treatment.

Another notable recommendation concerns low-dose aspirin for patients carrying the JAK2 V617F mutation, the most common genetic alteration in myelofibrosis. Because these patients face an elevated risk of blood clots, the guidelines address whether aspirin therapy can meaningfully reduce thrombotic complications in this specific molecular subgroup. The inclusion of a mutation-specific recommendation illustrates how deeply genetic testing now permeates the management of myeloproliferative neoplasms, extending beyond diagnosis and prognosis into preventive care.

Guideline panel chair Brady Stein, MD, professor of medicine at Northwestern University’s Feinberg School of Medicine, emphasized the practical intent behind the effort. According to Stein, the recommendations address questions that routinely come up for clinicians and patients managing myelofibrosis, and the hope is that they will enable hematologists to more confidently deliver better care to their patients. He also acknowledged that important gaps in evidence remain, expressing hope that the questions the panel asked can help set a future research agenda to further improve care for patients with this disease.

Indeed, the guidance explicitly identifies several areas where more research is needed. These include enhancing the prediction of which patients will benefit from specific treatments, establishing better approaches to myelofibrosis-related anemia, and clarifying the optimal timing for transplant. Each of these gaps reflects a broader challenge in rare-disease medicine: with limited patient populations, randomized trials are difficult to mount, and evidence often accrues slowly. By articulating a research agenda alongside its clinical recommendations, the panel has effectively mapped the frontier for the next generation of myelofibrosis studies.

For patients, the practical message is that the guidance clinicians use for treating myelofibrosis has changed. The new ASH guidelines emphasize individualized care based on a patient’s symptoms, spleen enlargement, anemia, genetic testing results, transplant eligibility, and personal preferences. Patients may want to ask their care team whether extended molecular testing is appropriate for them, whether a JAK inhibitor may help with symptoms or spleen enlargement, how anemia should be managed, and whether they should be referred for a stem cell transplant consultation. For those with the JAK2 V617F mutation, the guidelines also address the use of low-dose aspirin to help prevent blood clots. Additional resources, including snapshots, visual summaries, and teaching slides, are available through the Society’s website, offering patients and clinicians alike a shared foundation for navigating a disease that has long demanded more certainty than the evidence could provide.

Subject of Research: Clinical practice guidelines for the management of myelofibrosis, a rare bone marrow cancer

Article Title: ASH issues new recommendations to improve myelofibrosis care

Article References: ASH issues new recommendations to improve myelofibrosis care. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: myelofibrosis, American Society of Hematology, Blood Advances, JAK inhibitors, stem cell transplant, molecular testing, JAK2 V617F, anemia, aspirin, myeloproliferative neoplasm, clinical guidelines, hematology

The patient’s story began insidiously. For six months, the 79-year-old man experienced mild fatigue and generalized weakness that remained stable before worsening dramatically in the final month. He described episodes of his legs giving out, new-onset muscle cramping, dizziness, unintentional weight loss, night sweats, early satiety, anorexia, and nocturia. He denied any recent fever. Two weeks before admission, his primary care physician detected anemia and marked leukocytosis, an abnormally high white blood cell count, prompting referral for specialist evaluation. The patient had no significant past medical history, which made the laboratory findings that followed all the more alarming.

On admission, the numbers were staggering. His white blood cell count reached 292.74 × 10³/μL, roughly thirty times the upper limit of the normal range of 4 to 10 × 10³/μL. The differential count revealed a chaotic mixture: 42% neutrophils, 24% lymphocytes, 12% myelocytes, 8% band cells, 5% metamyelocytes, 1% promyelocytes, and 4% blasts, immature cells that should rarely appear in circulating blood. He was also profoundly anemic, with hemoglobin of 8.5 g/dL against a reference range of 12.3 to 15.3 g/dL, and an elevated red cell distribution width of 18.2% indicating marked variation in red cell size. His platelet count remained deceptively normal at 343 × 10³/μL. Lactate dehydrogenase, an enzyme released when cells die rapidly, was elevated at 890 U/L, signaling the intense cellular turnover characteristic of proliferative hematologic malignancies.

A peripheral blood smear provided the first major clue. The slide showed a full spectrum of myeloid precursors, including myelocytes, metamyelocytes, promyelocytes, and occasional blasts, a picture highly suggestive of chronic myeloid leukemia. Yet the lymphocyte percentage of 24% appeared deceptively normal on its face. The absolute lymphocyte count told a different story: with total leukocytosis of 292.74 × 10³/μL, the 24% fraction corresponded to an absolute lymphocyte count of 70.26 × 10³/μL, a figure dramatically above normal. This distinction between relative and absolute counts proved pivotal, as it flagged the presence of a second proliferative disorder hiding behind the dominant myeloid picture. Recognizing the myeloproliferative emergency, clinicians started the patient on hydroxyurea from the first day, and over an 18-day course his leukocyte count fell significantly to 11.8 × 10³/μL.

Molecular testing then confirmed the myeloid diagnosis. The patient expressed strong levels of the BCR::ABL1 p210 transcript, the hallmark fusion gene generated by the t(9;22)(q34;q11) chromosomal translocation, along with weak expression of the p190 variant. This translocation fuses the ABL1 gene on chromosome 9 with the BCR gene on chromosome 22, creating the infamous Philadelphia chromosome. The resulting fusion protein exhibits constitutive tyrosine kinase activity, driving uncontrolled proliferation of myeloid cells. Based on these findings, the patient began imatinib, a targeted tyrosine kinase inhibitor, on day 10 of admission at 400 mg daily.

But the diagnostic workup was not finished. Flow cytometry of the peripheral blood, performed to assess blast percentage, revealed a clonal B-cell population expressing CD5, CD19, and CD20, an immunophenotype classic for chronic lymphocytic leukemia. The test was repeated for confirmation and yielded identical results. CLL is defined by the clonal expansion and progressive accumulation of mature B lymphocytes, most of which express the CD5 antigen, infiltrating the peripheral blood, bone marrow, lymphatic tissues, and spleen. Imaging studies added further evidence: abdominal and pelvic ultrasonography identified multiple pathologic lymph nodes, including portacaval nodes up to 15 mm and left mesenteric nodes up to 12 mm in short-axis diameter, all round, lacking the central echogenic hilum of healthy nodes. Splenomegaly was also noted, with a cranio-caudal diameter of 205 mm.

By discharge, the white cell count had normalized to 10.7 × 10³/μL and lactate dehydrogenase had fallen to 363 U/L, indicating reduced cellular turnover. However, anemia had worsened to 7.5 g/dL and thrombocytopenia had developed, with platelets dropping to 69 × 10³/μL, possibly reflecting disease burden or cytotoxic effects of therapy. The lymphocyte percentage was markedly elevated at 82.2%, supporting the concurrent lymphoproliferative diagnosis. After two months of continuous imatinib treatment, the patient showed significant clinical and hematological response, with marked reduction in white cell count and notable improvement in performance status, though persistent lymphocytosis remained. Tragically, approximately two months after treatment initiation, he developed severe community-acquired pneumonia and died of respiratory failure, cutting follow-up short.

The simultaneous occurrence of CML and CLL presents a fascinating biological puzzle. CLL is the most prevalent leukemia in adults across Western countries, with an estimated incidence of 4 to 6 cases per 100,000 individuals annually, and over 70% of patients diagnosed at 65 years or older. CML is the most common myeloproliferative disorder characterized by the BCR::ABL1 fusion gene. Despite both conditions preferentially affecting elderly populations, their coexistence is exceedingly uncommon. Documented presentations include sequential diagnoses, where one malignancy follows the other, and synchronous onset, in which both are identified at the same time. In over half of reported cases, CLL preceded CML, and many of those patients had received chemoimmunotherapy with agents such as fludarabine or chlorambucil, raising the possibility that DNA damage or selection pressures from CLL therapy might contribute to subsequent CML. Notably, the present patient had no history of cytotoxic therapy, making his simultaneous presentation even more enigmatic.

Several hypotheses attempt to explain this biclonal leukemic phenomenon. Cytogenetic studies in some cases show that the two malignancies arise from separate hematopoietic clones: researchers have demonstrated BCR::ABL1 fusion confined exclusively to the myeloid fraction, while monoclonal immunoglobulin gene rearrangement was found only in the lymphoid CLL cells, supporting two distinct malignant clones coexisting rather than a single clone transforming along two lineages. Conversely, other authors speculate that both neoplasms may originate from a single pluripotent hematopoietic stem cell that acquires mutations enabling both myeloid and lymphoid transformation. If BCR::ABL1 occurred in an early progenitor, it could theoretically give rise to both myeloid and lymphoid clones, though direct proof remains lacking. A third mechanism involves microenvironmental effects: BCR::ABL1-positive cells produce cytokines such as interleukin-3, which can stimulate CD34⁺ progenitors and B-lymphoid cells, meaning a CML clone could in theory secrete factors that drive expansion of a B-lymphoid clone, or vice versa.

This case underscores the critical importance of comprehensive diagnostic evaluation when patients present with atypical hematological findings. The peripheral blood smear, flow cytometry, and molecular studies were all pivotal in unraveling the dual diagnosis, and the distinction between relative and absolute lymphocyte counts proved essential to recognizing the second malignancy. The pathogenesis of such rare co-occurrence remains under active debate, with the consensus being that it is heterogeneous: some patients demonstrably arise from separate clones, while others are best explained by a shared stem-cell origin. Genetic instability, environmental triggers, or stochastic events may all contribute to this rare dual leukemogenesis. As the population ages and diagnostic techniques grow more sensitive, clinicians may encounter such dual malignancies more frequently, making awareness of this phenomenon increasingly relevant for hematologists managing elderly patients with complex blood disorders.

Subject of Research: Rare co-occurrence of chronic myeloid leukemia and chronic lymphocytic leukemia in a single patient

Article Title: A Rare Case of Chronic Lymphocytic Leukemia and Chronic Myeloid Leukemia in an Elderly Patient: A Case Report

Article References: Kamandi, M., & Alvandi Fard, M. M. (2026). A Rare Case of Chronic Lymphocytic Leukemia and Chronic Myeloid Leukemia in an Elderly Patient: A Case Report. Clinical Case Reports, 14(10), Article e73136. https://doi.org/10.1002/ccr3.73136

Image Credits: AI Generated

DOI: 10.1002/ccr3.73136

Keywords: chronic myeloid leukemia, chronic lymphocytic leukemia, BCR::ABL1, flow cytometry, hematology, case report, Rare, Case, Chronic, Lymphocytic, Leukemia, Myeloid

The review, led by Julia Yescas and colleagues at Northwestern University Feinberg School of Medicine, together with collaborators at Yale, Case Western Reserve, and MD Anderson Cancer Center, examines how aggressive cutaneous T-cell lymphomas become addicted to dysregulated kinase signaling and how that addiction becomes both a therapeutic vulnerability and an escape route. The authors argue that understanding the molecular architecture of resistance is essential for designing next-generation inhibitors and rational combination strategies that could finally deliver durable remissions in these devastating diseases.

Primary cutaneous aggressive epidermotropic cytotoxic T-cell lymphoma, first recognized as a distinct entity in 1999, is characterized by epidermotropic CD8-positive cytotoxic T cells expressing granzyme B, perforin, and TIA-1. Despite its rarity, the disease carries a median overall survival of just 32 months and a five-year survival of only 31 percent. Recent high-throughput genomic studies have revealed that this lymphoma harbors recurrent and targetable kinase fusions at striking frequency. In one study, fusion genes involving JAK2 were detected in three of twelve patients, while another reported kinase gene fusions in six of six samples, with five harboring a JAK2 fusion and one carrying a novel ABL1 fusion. A separate report described a fusion joining SATB1 to FGFR1, a receptor tyrosine kinase for fibroblast growth factors. In all cases, the tyrosine kinase domains are conserved at the C-terminus and fused to a diverse set of partner genes including STAT3, KHDRBS1, PICALM, CAPRIN1, PCM1, and TFG. The biological basis for the recurrent involvement of JAK2, rather than the JAK1 and JAK3 family members typically utilized by CD8-positive T cells, remains unknown, though the authors speculate it may reflect lineage infidelity, with transformed cells deviating from canonical cytokine signaling to exploit JAK2-mediated proliferative pathways.

Primary cutaneous gamma delta T-cell lymphoma presents a different genomic landscape. This rare and highly aggressive subset, with a median overall survival of approximately 31 months and a five-year disease-specific survival of only 19.9 percent, is characterized by marked genomic instability, with a median of 166.5 somatic copy number variants per sample. Rather than kinase fusions, PCGDTL harbors recurrent point mutations in key oncogenic signaling pathways, including the MAPK pathway (KRAS, NRAS, MAPK1), the MYC pathway (MYC, MYCN, FBXW7), and the JAK/STAT pathway (STAT3, STAT5B, JAK3, SOCS1). Among these, KRAS mutations were most common, while approximately 21 percent of samples carried JAK/STAT point mutations. Notably, clinical and histopathologic features correlate with TCR delta-chain usage—epidermal and dermal cases typically express TRVδ1, while subcutaneous cases express TRδV2—yet next-generation sequencing has not identified major mutational differences between these subsets.

The clinical experience with targeted inhibitors in both subtypes tells a consistent story of initial sensitivity followed by adaptive escape. In the first reported clinical use of a tyrosine kinase inhibitor in PCAETL, a patient harboring the SATB1-FGFR1 fusion was treated with the FGFR inhibitor pemigatinib. The response was remarkable: approximately 90 percent regression of ulcerated lesions within two weeks, with partial remission maintained for around four months. However, adverse events including hyperphosphatemia, nail changes, and ocular irritation necessitated a dose reduction. The patient’s lesions relapsed within one month, and sequencing revealed secondary point mutations within the FGFR1 kinase domain. The patient expired two months later. In PCGDTL, a patient with SOCS1 loss treated with the JAK1/2 inhibitor ruxolitinib achieved near-complete regression after four weeks, but disease progression occurred after eight weeks, accompanied by newly acquired lesions. Sequencing of the relapse sample revealed a STAT5B p.N642H mutation, a well-characterized gain-of-function driver associated with T-cell neoplasms and drug-resistant leukemias. Another PCGDTL patient harboring a JAK3 p.A573V mutation was enrolled in a phase II trial of the dual SYK/JAK inhibitor cerdulatinib, achieving an 86 percent reduction in skin disease burden after seven weeks. But therapy was discontinued due to grade 3 adverse events, and shortly after, relapse occurred with sequencing revealing acquired JAK3 p.M511I, JAK1 p.L783F, and JAK1 p.T901A mutations in circulating tumor cells.

The structural basis of these resistance mutations reveals elegant molecular logic. In the FGFR1 case, two secondary mutations were detected following pemigatinib treatment: E462V in the juxtamembrane region and V561L in the kinase domain. The E462V substitution, despite its location in a critical signaling hub, did not confer resistance—structural modeling showed no clashes or modulation of the drug-binding state. In contrast, V561L represents a canonical gatekeeper mutation that sterically impedes inhibitor binding and enhances ATP affinity, thereby reducing drug potency. Structural modeling of the analogous V561M substitution revealed that replacement with a bulky methionine side chain induces steric clashes within the inhibitor-binding pocket, accounting for observed resistance. This mutation has been previously described in FGFR1-driven myeloproliferative neoplasms, where it confers broad resistance to multiple FGFR inhibitors.

In the JAK pathway, the resistance architecture is equally instructive. The STAT5B p.N642H mutation occurs in the Src homology 2 domain and stabilizes STAT5B dimers, increases phosphorylation, and renders the protein constitutively active. Structural studies indicate that this substitution alters the hydrogen-bonding network within the phosphotyrosine pocket, favoring inter-protein interactions in the STAT5B dimer. The JAK3 mutations follow a different logic: M511 lies within the SH2-pseudokinase linker, which typically interacts with the kinase domain active site, and the M511I substitution destabilizes this linker, promoting kinase domain activation. A573 is located within the alphaC helix of the pseudokinase domain, a structural element that toggles between active and inactive conformations. Through structural modeling with cerdulatinib, the combination of M511I and A573V causes steric hindrance, suggesting these variants confer resistance through inter- or intramolecular interaction alterations. Remarkably, the JAK1 p.L783F mutation, which also causes steric hindrance with cerdulatinib, occurs in a different JAK family member than JAK3, raising important questions about how cross-kinase cooperation contributes to drug resistance. The combined presence of JAK3 p.A573V and JAK1 p.L783F conferred greater resistance to cerdulatinib compared to single mutants, indicating cooperative resistance across paralogous kinases.

Toxicity emerges as an indirect but powerful facilitator of resistance. Pemigatinib’s most common adverse events include hyperphosphatemia, nail toxicity, alopecia, diarrhea, anemia, dry eyes, and serous retinal detachment—manifestations that reflect the broad physiological role of FGFR signaling in the corneal epithelium, photoreceptors, iris, and hair follicles. Ruxolitinib, evaluated in a phase II trial of 53 patients with CTCL, produced anemia in 15 patients, diarrhea in 7, thrombocytopenia in 9, and neutropenia in 10, reflecting the critical role of JAK2 signaling in erythropoietin and thrombopoietin receptor function. Cerdulatinib, targeting both SYK and JAK families, produced frequent grade 3 or higher adverse events in a phase II trial of relapsed or refractory peripheral T-cell lymphoma and CTCL, including increased lipase in 29.2 percent, increased amylase in 43.1 percent, diarrhea in 43.1 percent, and anemia in 32.3 percent. Serious adverse events occurred in 64.6 percent of patients, and tragically, two deaths not related to disease progression were attributed to the drug. When dose reductions or discontinuations become necessary, resistant subclones may gain a selective advantage under reduced drug exposure.

The review argues that durable responses will require moving beyond single-agent therapy toward rational combination regimens. Preclinical and clinical evidence across malignancies supports combining kinase inhibitors with immune checkpoint blockade. In non-small cell lung cancer, the JAK1 inhibitor itacitinib combined with pembrolizumab achieved a 12-week overall response rate of 62 percent with a median progression-free survival of 23.8 months. In Hodgkin lymphoma, ruxolitinib combined with nivolumab yielded an overall response rate of 53 percent, with ruxolitinib appearing to rescue exhausted T cells and synergize with checkpoint blockade in reshaping the myeloid compartment. Although no clinical trials have yet evaluated such combinations in aggressive T-cell lymphomas, the authors suggest these approaches warrant investigation given the immune-evasive nature of these tumors. Topical application of inhibitors might also circumvent systemic toxicity and provide a window for prolonged therapeutic efficacy.

Aggressive cutaneous T-cell lymphoma thus presents both a challenge and an opportunity for precision dermato-oncology. The discovery of recurrent kinase alterations reveals that subsets of these lymphomas are mechanistically dependent on constitutive kinase activity for survival and proliferation, making them vulnerable to targeted inhibition. Yet the predictable emergence of adaptive resistance—through gatekeeper mutations, cooperative cross-kinase substitutions, and toxicity-driven dose reductions—underscores that single-agent approaches are insufficient. Future progress, the authors conclude, relies on molecular stratification based on kinase dependency, longitudinal genomic monitoring to detect resistance as it emerges, rational combination therapy, and the development of mutation-selective next-generation inhibitors capable of overcoming the adaptive mechanisms that currently limit treatment durability.

Subject of Research: Kinase inhibitor resistance in cutaneous T-cell lymphomas

Article Title: Mechanisms of kinase inhibitor resistance in subtypes of cutaneous T-cell lymphomas

Article References: Yescas, J. A., Bunick, C. G., Grada, A., Guitart, J., Torres-Cabala, C. A., Le Poole, I. C., & Zhou, X. A. (2026). Mechanisms of kinase inhibitor resistance in subtypes of cutaneous T-cell lymphomas. Frontiers in Hematology, 5, Article 1812908. https://doi.org/10.3389/frhem.2026.1812908

Image Credits: AI Generated

DOI: 10.3389/frhem.2026.1812908

Keywords: cutaneous T-cell lymphoma, kinase inhibitors, drug resistance, JAK/STAT pathway, FGFR1, precision oncology, hematology, Mechanisms, kinase, inhibitor, resistance, subtypes

APL is a strikingly curable leukemia when treated correctly, driven by a fusion protein called PML/RARA that makes the malignant promyelocytes exquisitely sensitive to two targeted agents: all-trans retinoic acid (ATRA), which forces the leukemic cells to mature, and arsenic trioxide (ATO), which degrades the fusion protein itself. In standard-risk patients, the combination cures more than 90 percent. But high-risk disease, defined by the Sanz classification as a white blood cell count above 10 × 10⁹ per liter, carries early mortality of 15 to 25 percent, compared with 5 to 10 percent in standard-risk patients. Most of those early deaths come from catastrophic bleeding, differentiation syndrome, and infection, not from uncontrolled leukemia.

The landmark APL0406 and AML17 trials established ATRA plus ATO as the standard of care for standard and intermediate-risk APL, but they excluded high-risk patients or included too few for separate analysis. Concerned that the targeted agents alone could not adequately reduce the enormous tumor burden of high leukocytosis, many centers continued to treat high-risk patients with intensive anthracycline-based induction, typically three or more doses of idarubicin or daunorubicin equivalents. Recent prospective studies, including the APOLLO trial and the chemotherapy-free APL15 trial, have begun to question whether that extra chemotherapy actually helps.

To settle the question, a team led by Mohamed M. Khamis of Mercy Hospital and Saint Louis University School of Medicine conducted a PRISMA-compliant systematic review registered with PROSPERO, searching PubMed and the Cochrane Library from 2000 through 2025. They defined reduced-intensity regimens as ATRA plus ATO with cytoreduction limited to a single dose of gemtuzumab ozogamicin (GO) at 6 to 9 mg/m², one or two doses of low-dose idarubicin at 12 mg/m² each, or hydroxyurea alone. Intensive regimens were defined as ATRA-based therapy with three or more anthracycline doses. The search identified 325 unique records, of which 17 studies providing 25 treatment arms met the inclusion criteria, yielding 449 patients on reduced-intensity arms and 874 on intensive arms.

The pooled complete remission rate was 92.3 percent for reduced-intensity induction versus 89.3 percent for intensive chemotherapy, a 3.0 percentage point difference that was not statistically significant. Heterogeneity was strikingly low in the reduced-intensity group, with an I² of 0 percent, indicating remarkably consistent results across studies, while the intensive group showed moderate heterogeneity at 56.1 percent. Early mortality, defined as death within 30 days, was 8.8 percent versus 10.4 percent, again not statistically different. Relapse rates were 3.9 percent versus 5.5 percent, favoring the gentler approach but not reaching significance.

The most compelling finding came from the two randomized controlled trials with documented event definitions. The AML17 trial randomized 57 high-risk patients to ATRA plus ATO plus GO versus ATRA plus idarubicin, reporting 5-year recurrence-free survival of 100 percent versus 83 percent. The APOLLO trial randomized 133 high-risk patients to ATRA plus ATO with limited idarubicin versus standard AIDA chemotherapy, reporting 2-year event-free survival of 88 percent versus 71 percent, with relapse rates of 1.8 percent versus 17 percent and serious adverse events in 32 percent versus 68 percent. Pooling the hazard ratios from these two trials yielded an event-free survival hazard ratio of 0.23, representing a 77 percent reduction in events favoring reduced-intensity induction.

An exploratory white blood cell-stratified analysis revealed perhaps the most mechanistically revealing pattern. When the researchers examined complete remission by median white blood cell count below or above 30 × 10⁹ per liter, the reduced-intensity complete remission rate remained stable, shifting by only 0.9 percentage points across strata. The intensive chemotherapy complete remission rate, by contrast, declined from 96.0 percent to 86.6 percent, a drop of 9.4 percentage points, at the highest white blood cell levels. This pattern suggests that ATRA plus ATO maintains efficacy even at extreme disease burden, where conventional chemotherapy shows diminishing returns due to treatment-related complications.

The mechanistic explanation lies in the unique biology of APL. Unlike de novo acute myeloid leukemia, where chemotherapy intensity correlates with disease control, PML/RARA-positive promyelocytes are uniquely vulnerable to targeted therapy regardless of presenting leukocytosis. ATRA induces differentiation of the malignant cells, while ATO degrades the fusion protein that drives the leukemia. This molecular susceptibility explains why reduced-intensity regimens maintain efficacy even at white blood cell counts of 30 × 10⁹ per liter or higher, where the included studies enrolled patients with counts reaching 339 × 10⁹ per liter. The authors note that a dedicated subgroup for white blood cell counts above 50 × 10⁹ per liter was not feasible because no included arm had a median count that high, but the white blood cell count of 30 × 10⁹ per liter stratum encompassed arms with ranges extending to extreme leukocytosis.

Real-world validation studies strengthen the meta-analytic conclusions. The HARMONY registry, encompassing 1,438 patients across diverse practice settings, demonstrated 7-year overall survival of 91 percent and relapse rates of only 3 percent with ATRA plus ATO, with outcomes independent of the Sanz risk score. A French multicenter cohort found 5-year overall survival of 89.9 percent versus 72.7 percent favoring ATRA plus ATO over chemotherapy in high-risk patients. These data, spanning different supportive care infrastructures and geographic regions, suggest that the meta-analytic findings generalize beyond controlled trial populations.

For cytoreduction, the authors recommend gemtuzumab ozogamicin as a single dose of 6 or 9 mg/m², which provides targeted promyelocyte reduction without prolonged myelosuppression. For centers without access to GO, low-dose idarubicin at one or two doses of 12 mg/m² each provides effective cytoreduction with substantially lower toxicity. Hydroxyurea represents an alternative strategy, particularly in resource-limited settings, and has demonstrated efficacy in the APL15 chemotherapy-free approach. The choice of agent should be individualized based on institutional access, patient comorbidities, and degree of leukocytosis. The authors acknowledge limitations, including the predominance of observational data with potential confounding by indication, treatment heterogeneity within the reduced-intensity group, and geographic variations in supportive care practices. However, sensitivity analyses restricted to the two randomized trials showed consistent and even stronger results, and leave-one-out analysis demonstrated that no single study disproportionately influenced the pooled estimates. The convergent evidence from randomized trials, observational studies, and real-world registries supports reduced-intensity ATRA plus ATO-based regimens using GO or low-dose anthracycline as the preferred first-line therapy for high-risk APL.

Subject of Research: Hematology

Article Title: Reduced-intensity versus intensive induction in high-risk acute promyelocytic leukemia: a systematic review and meta-analysis

Article References: Khamis, M. M., Guevara Rodriguez, N. A., & Kunwor, R. (2026). Reduced-intensity versus intensive induction in high-risk acute promyelocytic leukemia: a systematic review and meta-analysis. Frontiers in Hematology, 5, Article 1851998. https://doi.org/10.3389/frhem.2026.1851998

Image Credits: AI Generated

DOI: 10.3389/frhem.2026.1851998

Keywords: acute promyelocytic leukemia, ATRA, arsenic trioxide, meta-analysis, high-risk APL, event-free survival, hematology, Reduced-intensity, versus, intensive, induction, high-risk

The research team, led by endocrinologists at Basaksehir Cam and Sakura City Hospital affiliated with the University of Health Sciences, analyzed records from 252 patients. The cohort comprised 132 patients with overt Cushing syndrome, subdivided into 75 with Cushing disease, where a pituitary tumor drives excess adrenocorticotropic hormone, and 57 with adrenal Cushing syndrome, where the adrenal gland itself overproduces cortisol. A further 68 patients had mild autonomous cortisol secretion, often abbreviated MACS, a subtle biochemical abnormality frequently detected in adrenal incidentalomas, and 52 patients had nonfunctioning adrenal tumors, or NFAT, which secrete no excess hormone. The investigators compared standard complete blood count parameters across these groups, including total white blood cell count and the individual counts of neutrophils, monocytes, lymphocytes, eosinophils, and basophils, together with two widely used derived indices, the neutrophil-to-lymphocyte ratio and the monocyte-to-lymphocyte ratio.

Cortisol is a potent immunomodulatory hormone, and its chronic excess has long been known to reshape circulating leukocyte populations. Glucocorticoids promote the release of mature neutrophils from the bone marrow, delay their apoptosis, and simultaneously drive the redistribution and death of lymphocytes, producing the classic picture of neutrophilia with relative lymphopenia seen in states of glucocorticoid excess. What has remained uncertain is whether the low-grade, often subclinical cortisol elevation of MACS produces hematological changes that are detectable and comparable to those of overt disease. Resolving this question matters clinically, because MACS is increasingly diagnosed as adrenal imaging becomes more common, yet its systemic consequences remain debated.

The results were clear-cut at the extremes. Total white blood cell count, neutrophil count, monocyte count, and the monocyte-to-lymphocyte ratio were all significantly higher in patients with overt Cushing syndrome than in either the MACS group or the NFAT group, with p values at or below 0.002. The neutrophil-to-lymphocyte ratio, a marker frequently studied in inflammatory and endocrine disease, was significantly elevated in overt Cushing syndrome only in comparison with MACS once the analysis was corrected for multiple comparisons using the Bonferroni method. This pattern indicates that the myeloid expansion characteristic of glucocorticoid excess, with more neutrophils and monocytes relative to lymphocytes, is a feature of overt disease rather than of the milder biochemical state.

In striking contrast, no significant differences emerged between the MACS and NFAT groups on any individual parameter, with all p values exceeding 0.05. The effect sizes separating these two groups were uniformly small, with Cohen’s d values ranging from 0.02 to 0.17, a range conventionally interpreted as negligible. The authors note that any true difference between mild autonomous cortisol secretion and nonfunctioning tumors is likely to be small, although they caution that subtle effects cannot be entirely excluded by a study of this size. In practical terms, a routine blood count cannot currently distinguish a patient with mild cortisol autonomy from one with a hormone-silent adrenal mass.

Beyond group comparisons, the study examined how leukocyte parameters track with biochemical measures of cortisol burden. Neutrophil count, monocyte count, the neutrophil-to-lymphocyte ratio, and the monocyte-to-lymphocyte ratio each correlated positively with multiple cortisol markers, which in this clinical context typically include urinary free cortisol, late-night salivary cortisol, and the dexamethasone suppression test. This dose-response relationship strengthens the biological plausibility of the findings: the more cortisol circulating, the more pronounced the shift toward myeloid cells in the peripheral blood. It also suggests that these inexpensive, routinely measured indices could serve as accessible proxies for the immunological impact of cortisol excess.

To move beyond univariate comparisons, the researchers performed an exploratory linear discriminant analysis, a multivariate statistical technique that seeks linear combinations of variables best separating predefined groups. The analysis aimed to characterize the overall leukocyte profiles of Cushing disease, adrenal Cushing syndrome, MACS, and NFAT. On the primary discriminant axis, basophil count emerged as the parameter with the highest normalized loading. However, the authors themselves flag an important statistical caveat: because basophil counts are small in absolute magnitude, their loadings can be inflated by scale-related artifacts rather than reflecting a genuine biological signal. This transparency is a notable feature of the paper, which consistently frames its multivariate results as exploratory.

Indeed, the authors are explicit that the classification performance of the discriminant model was modest and not validated in an independent cohort. They emphasize that these findings are hypothesis-generating and should not be interpreted as evidence of a validated diagnostic tool or of a pathophysiological continuum linking mild and overt cortisol excess. This restraint matters in a field where machine-learning-style analyses of routine laboratory data are increasingly promoted as diagnostic shortcuts. The study instead delivers a more measured message: overt hypercortisolism leaves a clear myeloid signature in the blood, but mild autonomous cortisol secretion, at least as captured by standard hematological parameters, does not.

The clinical implications cut in two directions. For patients with overt Cushing syndrome, the correlation between myeloid indices and cortisol burden adds to the evidence that chronic glucocorticoid excess produces measurable systemic inflammation-like changes, which may be relevant to the elevated cardiovascular and infectious risk seen in these patients. For the growing population of patients found to have adrenal incidentalomas, the absence of hematological differences between MACS and NFAT suggests that routine blood counts offer no added diagnostic value in characterizing the functional status of such tumors, and that established endocrine testing remains essential.

As a single-center retrospective cross-sectional study, the work has inherent limitations, including the possibility of selection bias and the inability to establish causality or track changes over time within individual patients. Nevertheless, by systematically comparing four clinically distinct adrenal and pituitary states within a single cohort, the study provides one of the clearest pictures to date of where, on the spectrum of cortisol excess, the immune system begins to visibly shift. The answer, apparently, is not at the mild end. Future prospective studies with larger MACS cohorts and longitudinal sampling will be needed to determine whether subtle immune changes emerge over time, and whether any leukocyte signature could eventually complement, rather than replace, the biochemical tests that currently define this enigmatic condition.

Subject of Research: Peripheral leukocyte profiles across clinical forms of hypercortisolism and nonfunctioning adrenal tumors

Article Title: Peripheral leukocyte profiles in different clinical forms of hypercortisolism and nonfunctioning adrenal tumors: a retrospective cross-sectional study

Article References: Burhan, S., Ozkahraman, A. U., Korkmaz Yilmaz, M., Akbulut, S., Cicek, M. Z., Niyazoglu, M., & Hatipoglu, E. (2026). Peripheral leukocyte profiles in different clinical forms of hypercortisolism and nonfunctioning adrenal tumors: a retrospective cross-sectional study. BMC Endocrine Disorders. https://doi.org/10.1186/s12902-026-02668-2

Image Credits: AI Generated

DOI: 10.1186/s12902-026-02668-2

Keywords: Cushing syndrome, mild autonomous cortisol secretion, adrenal incidentaloma, leukocytes, neutrophil-to-lymphocyte ratio, monocyte-to-lymphocyte ratio, cortisol, endocrinology, hematology, linear discriminant analysis, biomarkers, nonfunctioning adrenal tumor