Treatment-free remission as a new goal in the management of chronic myeloid leukemia: Clinical and biological aspects.

The therapeutic armamentarium of chronic myeloid leukemia (CML) has dramatically improved after small molecule tyrosine kinase inhibitors (TKIs) targeting BCR::ABL1 became available, with a life expectancy now close to that of the general population. Although highly effective, these drugs also have a toxicity profile that is often mild to moderate, but sometimes severe. Indeed, long-term treatment with TKIs can lead to chronic adverse events that can negatively affect patients' quality of life and can promote significant morbidity and mortality, particularly in the case of second- or third-generation TKIs. Treatment discontinuation has therefore become an emerging goal for CML patients and numerous studies have evaluated in off-TKI subjects what requirements are appropriate for an attempt at treatment-free remission (TFR). TFR eligibility is currently limited to a small population of subjects with both deep and sustained molecular responses to TKIs. For those attempting TFR, average success rates are promising, with 25%-30% of patients experiencing prolonged TFR. In case of failure to maintain sustained TFR, safety results to date are reassuring, with almost all patients responding successfully to resumption of TKIs, and advanced-phase disease progression representing a very rare event. The purpose of this review is to discuss guidelines for TKI discontinuation, clinical advances from clinical trials and real-life experiences, and describe areas of research, particularly regarding the biological factors capable of predicting the success of TFR.

Chromosome 9p trisomy increases stem cells clonogenic potential and fosters T-cell exhaustion in JAK2-mutant myeloproliferative neoplasms.

JAK2V617F is the most recurrent genetic mutation in Philadelphia-negative chronic Myeloproliferative Neoplasms (MPNs). Since the JAK2 locus is located on Chromosome 9, we hypothesized that Chromosome 9 copy number abnormalities may be a disease modifier in JAK2V617F-mutant MPN patients. In this study, we identified a subset of MPN patients with partial or complete Chromosome 9 trisomy (+9p patients), who differ from JAK2V617F-homozygous MPN patients as they carry three JAK2 alleles as well as three copies of all neighboring gene loci, including CD274, encoding immunosuppressive Programmed death-ligand 1 (PD-L1) protein. Investigation of the clonal hierarchy revealed that the JAK2V617F occurs first, followed by +9p. Functionally, CD34+ cells from +9p MPN patients demonstrated increased clonogenicity, generating a greater number of primitive colonies, due to high OCT4 and NANOG expression, with knock-down of these genes leading to a genotype-specific decrease in colony numbers. Moreover, our analysis revealed increased PD-L1 surface expression in malignant monocytes from +9p patients, while analysis of the T cell compartment unveiled elevated levels of exhausted cytotoxic T cells. Overall, here we identify a distinct novel subgroup of MPN patients, who feature a synergistic interplay between +9p and JAK2V617F that shapes immune escape characteristics and increased stemness in CD34+ cells.

Prognostic and Predictive Models in Myelofibrosis.

PURPOSE OF REVIEW: Myelofibrosis (MF) includes prefibrotic primary MF (pre-PMF), overt-PMF and secondary MF (SMF). Median overall survival (OS) of pre-PMF, overt-PMF and SMF patients is around 14 years, seven and nine years, respectively. Main causes of mortality are non-clonal progression and transformation into blast phase. RECENT FINDINGS: Discoveries on the impact of the biological architecture on OS have led to the design of integrated scores to predict survival in PMF. For SMF, OS estimates should be calculated by the specific MYSEC-PM (MYelofibrosis SECondary-prognostic model). Information on the prognostic role of the molecular landscape in SMF is accumulating. Crucial treatment decisions for MF patients could be now supported by multivariable predictive algorithms. OS should become a relevant endpoint of clinical trials. Prognostic models guide prediction of OS and treatment planning in MF, therefore, their timely application is critical in the personalized approach of MF patients.

Proposals for revised International Working Group-European LeukemiaNet criteria for anemia response in myelofibrosis.

ABSTRACT: With emerging new drugs in myelofibrosis (MF), a robust and harmonized framework for defining the severity of anemia and response to treatment will enhance clinical investigation and facilitate interstudy comparisons. Accordingly, the lead authors on the 2013 edition of the International Working Group-European LeukemiaNet (IWG-ELN) response criteria in MF were summoned to revise their document with the intent to (1) account for gender-specific differences in determining hemoglobin levels for eligibility criteria; (2) revise the definition of transfusion-dependent anemia (TDA) based on current restrictive transfusion practices; and (3) provide a structurally simple and easy to apply response criteria that are sensitive enough to detect efficacy signals (minor response) and also account for major responses. The initial draft of the 2024 IWG-ELN proposed criteria was subsequently circulated around a wider group of international experts and their feedback incorporated. The proposed articles include new definitions for TDA (≥3 units in the 12 weeks before study enrollment) and hemoglobin thresholds for eligibility criteria (<10 g/dL for women and <11 g/dL for men). The revised document also provides separate (TDA vs non-TDA) and graded (major vs minor response) response criteria while preserving the requirement for a 12-week period of screening and observation on treatment.

Targeting exhausted cytotoxic T cells through CTLA-4 inhibition promotes elimination of neoplastic cells in human myelofibrosis xenografts.

Myeloproliferative neoplasms represent a group of clonal hematopoietic disorders of which myelofibrosis (MF) is the most aggressive. In the context of myeloid neoplasms, there is a growing recognition of the dysregulation of immune response and T-cell function as significant contributors to disease progression and immune evasion. We investigated cytotoxic T-cell exhaustion in MF to restore immune response against malignant cells. Increased expression of inhibitory receptors like CTLA-4 was observed on cytotoxic T cells from MF patients together with a reduced secretion of IFNɣ and TNFɑ. CTLA-4 ligands CD80 and CD86 were increased on MF granulocytes and monocytes highlighting a possible role for myeloid cells in suppressing T-cell activation in MF patients. Unlike healthy donors, the activation of cytotoxic T cells from MF patients was attenuated in the presence of myeloid cells and restored when T cells were cultured alone or treated with anti-CTLA-4. Moreover, anti-CTLA-4 treatment promoted elimination of neoplastic monocytes and granulocytes in a co-culture system with cytotoxic T cells. To test CTLA-4 inhibition in vivo, patient-derived xenografts were generated by transplanting MF CD34+ cells and by infusing homologous T cells in NSGS mice. CTLA-4 blockade reduced human myeloid chimerism and led to T-cell expansion in spleen and bone marrow. Overall, these findings shed light on T-cell dysfunction in MF and suggest that CTLA-4 blockade can boost the cytotoxic T cell-mediated immune response against tumor cells.

Clinical impact of mutated JAK2 allele burden reduction in polycythemia vera and essential thrombocythemia.

The variant allele frequency (VAF) of driver mutations (JAK2, CALR) in myeloproliferative neoplasms is associated with features of advanced disease and complications. Ruxolitinib and interferon were reported to variably reduce the mutant VAF, but the long-term impact of molecular responses (MR) remains debated. We prospectively measured changes in JAK2 and CALR VAF in 77 patients with polycythemia vera and essential thrombocythemia, treated with ruxolitinib for a median of 8 years, and assessed correlation with complete clinical and hematological response (CCHR) and outcomes. At last observation time, JAK2 VAF reduced overall from a median of 68% (range, 20%-99%) to 3.5% (0%-98%). A profound and durable MR (DMR; defined as a VAF stably ≤2%), including complete MR in 8%, was achieved in 20% of the patients, a partial MR (PMR; VAF reduction >50% of the baseline level) in 25%, and 56% had no molecular response (NMR). A CCHR was reached by 69% overall, independently of any degree of MR achieved; conversely, a DMR correlated with longer duration of CCHR and, most importantly, with reduced rate of progression to myelofibrosis and with longer myelofibrosis-free, event-free and progression-free survival. Achievement of PMR also had some favorable impact on outcomes, compared to NMR. A baseline JAK2 VAF <50%, and a VAF reduction of ≥35% after 2 years of treatment, predicted for the achievement of DMR and reduced progression to myelofibrosis. Overall, these findings support the clinical value of achieving profound, durable MR and its consideration as surrogate endpoint in future clinical trials.

Molecular characterization of diffuse large B-cell lymphomas associated with hepatitis C virus infection.

Hepatitis C virus (HCV)-associated diffuse large B-cell lymphoma (DLBCL) displays peculiar clinicopathological characteristics, but its molecular landscape is not fully elucidated. In this study, we investigated the clinicopathological and molecular features of 54 patients with HCV-associated DLBCL. The median age was 71 years. An underlying marginal zone lymphoma component was detected in 14.8% of cases. FISH analysis showed rearrangements involving BCL6 in 50.9% of cases, MYC in 11.3% and BCL2 in 3.7%. Lymph2Cx-based assay was successful in 38 cases, recognizing 16 cases (42.1%) as ABC and 16 cases as GCB subtypes, while six resulted unclassified. ABC cases exhibited a higher lymphoma-related mortality (LRM). Next-generation sequencing analysis showed mutations in 158/184 evaluated genes. The most frequently mutated genes were KMT2D (42.6%), SETD1B (33.3%), RERE (29.4%), FAS and PIM1 (27.8%) and TBL1XR1 (25.9%). A mutation in the NOTCH pathway was detected in 25.9% of cases and was associated with worst LRM. Cluster analysis by LymphGen classified 29/54 cases within definite groups, including BN2 in 14 (48.2%), ST2 in seven (24.2%) and MCD and EZB in four each (13.8%). Overall, these results indicate a preferential marginal zone origin for a consistent subgroup of HCV-associated DLBCL cases and suggest potential implications for molecularly targeted therapies.

Using real-world evidence in haematology.

Most new drug approvals are based on data from large randomized clinical trials (RCTs). However, there are sometimes contradictory conclusions from seemingly similar trials and generalizability of conclusions from these trials is limited. These considerations explain, in part, the gap between conclusions from data of RCTs and those from registries termed real world data (RWD). Recently, real-world evidence (RWE) from RWD processed by artificial intelligence has received increasing attention. We describe the potential of using RWD in haematology concluding RWE from RWD may complement data from RCTs to support regulatory decisions.

Investigation of Serum Albumin as a Dynamic Treatment-Specific Surrogate for Outcomes in Patients With Myelofibrosis Treated With Ruxolitinib.

PURPOSE: Ruxolitinib improves splenomegaly and disease-related symptoms in most patients with myelofibrosis (MF), and it has been associated with a survival benefit in higher-risk patients with splenomegaly. Spleen volume reduction has been associated with a survival benefit in ruxolitinib-treated patients; however, its use as a surrogate is limited. We hypothesized that an anti-inflammatory response to ruxolitinib would correlate with improved patient outcomes. METHODS: We interrogated serum albumin, an acute phase reactant and marker of nutritional status in 590 patients with MF and analyzed differential trajectories of albumin on the basis of ruxolitinib treatment. Additionally, we assessed the prognostic role of baseline albumin and change in albumin. RESULTS: We found that serum albumin levels tend to decrease in patients with MF; however, this tendency is abrogated by ruxolitinib treatment. To that end, baseline serum albumin level correlates with overall survival (OS) in patients with MF, independent of the variables that comprise the dynamic international prognostic scoring system; however, this correlation is limited to ruxolitinib-naïve patients. In ruxolitinib-treated patients, the change in serum albumin after ruxolitinib treatment, rather than the baseline value, is associated with improved OS, a finding not seen in ruxolitinib-naïve patients. CONCLUSION: These findings suggest that serum albumin, a ubiquitously available laboratory value, has specific relevance in patients with MF and reflects therapeutic response to ruxolitinib.

Two-Pole Nature of the Λ(1405) Resonance from Lattice QCD.

This Letter presents the first lattice QCD computation of the coupled channel πΣ-K[over ¯]N scattering amplitudes at energies near 1405 MeV. These amplitudes contain the resonance Λ(1405) with strangeness S=-1 and isospin, spin, and parity quantum numbers I(J^{P})=0(1/2^{-}). However, whether there is a single resonance or two nearby resonance poles in this region is controversial theoretically and experimentally. Using single-baryon and meson-baryon operators to extract the finite-volume stationary-state energies to obtain the scattering amplitudes at slightly unphysical quark masses corresponding to m_{π}≈200 MeV and m_{K}≈487 MeV, this study finds the amplitudes exhibit a virtual bound state below the πΣ threshold in addition to the established resonance pole just below the K[over ¯]N threshold. Several parametrizations of the two-channel K matrix are employed to fit the lattice QCD results, all of which support the two-pole picture suggested by SU(3) chiral symmetry and unitarity.

Ropeginterferon phase 2 randomized study in low-risk polycythemia vera: 5-year drug survival and efficacy outcomes.

In patients with low-risk polycythemia vera, exposure to low-dose Ropeginterferon alfa-2b (Ropeg) 100 µg every 2 weeks for 2 years was more effective than the standard treatment of therapeutic phlebotomy in maintaining target hematocrit (HCT) (< 45%) with a reduction in the need for phlebotomy without disease progression. In the present paper, we analyzed drug survival, defined as a surrogate measure of the efficacy, safety, adherence, and tolerability of Ropeg in patients followed up to 5 years. During the first 2 years, Ropeg and phlebotomy-only (Phl-O) were discontinued in 33% and 70% of patients, respectively, for lack of response (12 in the Ropeg arm vs. 34 in the Phl-O arm) or adverse events (6 vs. 0) and withdrawal of consent in (3 vs. 10). Thirty-six Ropeg responders continued the drug for up to 3 years, and the probability of drug survival after a median of 3.15 years was 59%. Notably, the primary composite endpoint was maintained in 97%, 94%, and 94% of patients still on drug at 3, 4, and 5 years, respectively, and 60% of cases were phlebotomy-free. Twenty-three of 63 Phl-O patients (37%) failed the primary endpoint and were crossed over to Ropeg; among the risk factors for this failure, the need for more than three bloodletting procedures in the first 6 months emerged as the most important determinant. In conclusion, to improve the effectiveness of Ropeg, we suggest increasing the dose and using it earlier driven by high phlebotomy need in the first 6 months post-diagnosis.

An enigmatic presentation of Escherichia coli endocarditis: Emphasizing the role of brain magnetic resonance imaging.

Key Clinical Message: Infective endocarditis should be considered in any febrile individual with acute onset neurological symptoms. If suspicion is high, a negative brain computed tomography does not virtually exclude embolism, and magnetic resonance imaging is warranted. Abstract: A diagnosis of infective endocarditis (IE) is often delayed, particularly in those infected with unusual organisms. Hereby, we report a case of a female patient presented with dysarthria, confusion, and altered mental status after being treated for Escherichia coli bacteremia. Computed tomography of the brain was unrevealing; however, scattered embolic phenomena were visualized on magnetic resonance imaging (MRI). The case underscores the importance of clinical awareness, particularly in the setting of unusual microorganisms, and the role of brain MRI in the diagnosis of IE.

Incidence of blast phase in myelofibrosis according to anemia severity.

Myelofibrosis (MF) is a clonal malignancy frequently characterized by anemia and in 10%-20% of cases it can evolve into blast phase (BP). Anemia in MF is associated with reduced survival and -in primary MF- also with an increased probability of BP. Conventional treatments for anemia have limited effectiveness in MF. Within a dataset of 1752 MF subjects largely unexposed to ruxolitinib (RUX), BP incidence was 2.5% patients per year (p-y). This rate reached respectively 4.3% and 4.5% p-y in case of patients with common terminology criteria for adverse events (CTCAE) grade 3/4 and grade 2 anemia, respectively, that represented together 32% of the cohort. Among 273 MF cases treated with RUX, BP incidence was 2.89% p-y and it reached 4.86% p-y in subjects who started RUX with CTCAE grade 2 anemia (one third of total). Within patients with red blood cell transfusion-dependency at 6 months of RUX (21% of the exposed), BP rate was 4.2% p-y. Our study highlights a relevant incidence of BP in anemic MF patients, with a similar rate whether treated with or without RUX. These findings will help treating physicians to make decisions on the safety profile of innovative anemia treatments.

Genome Sequence of Clinical Acinetobacter baumannii Strain V15.

Acinetobacter baumannii is recognized as a critical human pathogen by the World Health Organization, and therefore there is increasing interest in studying its biology and pathophysiology. Among other strains, A. baumannii V15 has been extensively used for these purposes. Here, the genome sequence of A. baumannii V15 is presented.

Light regulation in critical human pathogens of clinical relevance such as Acinetobacter baumannii, Staphylococcus aureus and Pseudomonas aeruginosa.

It is now clearly recognized that light modulates the physiology of many bacterial chemotrophs, either directly or indirectly. An interesting case are bacterial pathogens of clinical relevance. This work summarizes, discusses, and provides novel complementary information to what is currently known about light sensing and responses in critical human pathogens such as Acinetobacter baumannii, Pseudomonas aeruginosa and Staphylococcus aureus. These pathogens are associated with severe hospital and community infections difficult to treat due to resistance to multiple drugs. Moreover, light responses in Brucella abortus, an important animal and human pathogen, are also compiled. Evidence recovered so far indicates that light modulates aspects related to pathogenesis, persistence, and antibiotic susceptibility in these pathogens; such as motility, biofilm formation, iron uptake, tolerance to antibiotics, hemolysis and virulence. The pathogens elicit differential responses to light depending likely on their pathophysiology, ability to cause disease and characteristics of the host. The response to light is not restricted to discrete physiological traits but is global. In higher organisms, light provides spatial and temporal information. Then, it is crucial to understand what information light is providing in these bacterial pathogens. Our current hypothesis postulates that light serves as a signal that allows these pathogens to synchronize their behavior to the circadian rhythm of the host, to optimize infection. Advances on the molecular mechanism of light signal transduction and physiological responses to light, as well as in the relation between light and bacterial infection, would not only enlarge our understanding of bacterial pathogenesis but also could potentially provide alternative treatment options for infectious illnesses.

Ocular syphilis mimicking Vogt-Koyanagi-Harada syndrome: a diagnostic dilemma.

This case demonstrates the dilemma in the diagnosis of ocular syphilis, as it can mimic many other ocular conditions where initial steroid therapy might complicate the disease course and can worsen the infection. Also, it represents an example of anchoring bias, where a provisional diagnosis resulted in unnecessary treatment that would have worsened her clinical outcomes.

CARDIOGENIC SHOCK ASSOCIATED WITH ACUTE NOROVIRUS GASTROENTERITIS: WHAT IS NEEDED TO PROVE CAUSALITY?

Acute myocarditis is a well-recognized condition attributable to a variety of viral illnesses. Common viral aetiologies include enteroviruses including coxsackie, adenovirus, influenza, echovirus, parvovirus B19 and herpesvirus. A high index of suspicion, early diagnosis, and prompt management with supportive anti-failure measures, and in selected cases immunosuppressive therapies including high-dose steroids, might be considered for better outcomes. The authors report a case of sudden onset of acute heart failure complicated by cardiogenic shock caused by viral myocarditis in a patient who initially presented with norovirus gastroenteritis. She had no previous cardiac history or significant cardiovascular risk factors. Prompt medical management for cardiogenic shock for norovirus-induced myocarditis was started, her symptoms gradually improved, and she was discharged safely on regular follow-up. LEARNING POINTS: Viral myocarditis exhibits a wide spectrum of symptoms ranging from non-specific prodromes such as fatigue and myalgia to chest pain, life-threatening arrhythmias, fulminant heart failure, or even sudden cardiac death.Common viral aetiologies for myocarditis include enteroviruses including coxsackie, adenovirus, influenza, echovirus, parvovirus B19 and herpesvirus.A high index of suspicion, early diagnosis, and prompt management with supportive anti-failure measures, and in selected cases immunosuppressive therapies including high-dose steroids, might be considered for better outcomes in cases of acute myocarditis.

BfmRS encodes a regulatory system involved in light signal transduction modulating motility and desiccation tolerance in the human pathogen Acinetobacter baumannii.

We have previously shown that Acinetobacter baumannii as well as other relevant clinical bacterial pathogens such as Staphylococcus aureus and Pseudomonas aeruginosa, perceive and respond to light at 37 °C, the normal temperature in mammal hosts. In this work, we present evidence indicating that the two-component system BfmRS transduces a light signal in A. baumannii at this temperature, showing selective involvement of the BfmR and BfmS components depending on the specific cellular process. In fact, both BfmR and BfmS participate in modulation of motility by light, while only BfmR is involved in light regulation of desiccation tolerance in this microorganism. Neither BfmR nor BfmS contain a photoreceptor domain and then most likely, the system is sensing light indirectly. Intriguingly, this system inhibits blsA expression at 37 °C, suggesting antagonistic functioning of both signaling systems. Furthermore, we present evidence indicating that the phosphorylatable form of BfmR represses motility. Overall, we provide experimental evidence on a new biological function of this multifaceted system that broadens our understanding of A. baumannii's physiology and responses to light.