Myelofibrosis.

The clinical phenotype of primary and post-polycythemia vera and postessential thrombocythemia myelofibrosis (MF) is dominated by splenomegaly, symptomatology, a variety of blood cell alterations, and a tendency to develop vascular complications and blast phase. Diagnosis requires assessing complete cell blood counts, bone marrow morphology, deep genetic evaluations, and disease history. Driver molecular events consist of JAK2V617F, CALR, and MPL mutations, whereas about 8% to 10% of MF are "triple-negative." Additional myeloid-gene variants are described in roughly 80% of patients. Currently available clinical-based and integrated clinical/molecular-based scoring systems predict the survival of patients with MF and are applied for conventional treatment decision-making, indication to stem cell transplant (SCT) and allocation in clinical trials. Standard treatment consists of anemia-oriented therapies, hydroxyurea, and JAK inhibitors such as ruxolitinib, fedratinib, and pacritinib. Overall, spleen volume reduction of 35% or greater at week 24 can be achieved by 42% of ruxolitinib-, 47% of fedratinib-, 19% of pacritinib-, and 27% of momelotinib-treated patients. Now, it is time to move towards new paradigms for evaluating efficacy like disease modification, that we intend as a robust and unequivocal effect on disease biology and/or on patient survival. The growing number of clinical trials potentially pave the way for new strategies in patients with MF. Translational studies of some molecules showed an early effect on bone marrow fibrosis and on variant allele frequencies of myeloid genes. SCT is still the only curative option, however, it is associated with relevant challenges. This review focuses on the diagnosis, prognostication, and treatment of MF.

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.

Validation and molecular integration of the RR6 model to predict survival after 6 months of therapy with ruxolitinib.

Not available.

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.

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.

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.

Antibody response after vaccination against SARS-CoV-2 in adults with hematological malignancies: a systematic review and meta-analysis.

Vaccines against SARS-CoV-2 have shown remarkable efficacy and thus constitute an important preventive option against coronavirus disease 2019 (COVID-19), especially in fragile patients. We aimed to systematically analyze the outcomes of patients with hematological malignancies who received vaccination and to identify specific groups with differences in outcomes. The primary end point was antibody response after full vaccination (2 doses of mRNA or one dose of vectorbased vaccines). We identified 49 studies comprising 11,086 individuals. Overall risk of bias was low. The pooled response for hematological malignancies was 64% (95% confidence interval [CI]: 59-69; I²=93%) versus 96% (95% CI: 92-97; I²=44%) for solid cancer and 98% (95% CI: 96-99; I²=55%) for healthy controls (P<0.001). Outcome was different across hematological malignancies (P<0.001). The pooled response was 50% (95% CI: 43-57; I²=84%) for chronic lymphocytic leukemia, 76% (95% CI: 67-83; I²=92%) for multiple myeloma, 83% (95% CI: 69-91; I²=85%) for myeloproliferative neoplasms, 91% (95% CI: 82-96; I²=12%) for Hodgkin lymphoma, and 58% (95% CI: 44-70; I²=84%) for aggressive and 61% (95% CI: 48-72; I²=85%) for indolent non-Hodgkin lymphoma. The pooled response for allogeneic and autologous hematopoietic cell transplantation was 82% and 83%, respectively. Being in remission and prior COVID-19 showed significantly higher responses. Low pooled response was identified for active treatment (35%), anti-CD20 therapy ≤1 year (15%), Bruton kinase inhibition (23%), venetoclax (26%), ruxolitinib (42%), and chimeric antigen receptor T-cell therapy (42%). Studies on timing, value of boosters, and long-term efficacy are needed. This study is registered with PROSPERO (clinicaltrials gov. Identifier: CRD42021279051).

Is there a gender effect in polycythemia vera?

In recent times, there has been a growing interest in understanding the impact of gender on disease biology and clinical outcomes in Philadelphia-negative chronic myeloproliferative neoplasms. Among those, polycythemia vera (PV) is characterized by increased thrombotic risk, systemic symptoms, and overall reduced survival. Here, we aim to summarize data on whether and to what extent female sex can affect PV biology and outcome. To this end, we will discuss the latest acquisitions in terms of pathogenesis, diagnosis, epidemiology, clinical presentation and symptoms burden, thrombotic risk and related treatment strategies, and prognosis in female patients affected by PV.

Chikungunya in solid organ transplant recipients, a case series and literature review.

Chikungunya virus is a recent emerging arbovirus in Latin America, and the clinical manifestations can vary from fever and rash to severe chronic inflammatory arthritis. Few reports have been published regarding this infection in immunocompromised patients, including solid organ transplant recipients. We report a case series of solid organ transplant recipients with confirmed Chikungunya infection by positive reverse transcription polymerase chain reaction (RT-PCR), identified between January 2014 and December 2016. In addition, we conducted a literature review searching PubMed, EMBASE, and LILACS databases on Chikungunya infection in solid organ transplant recipients. Ten solid organ transplant recipients were included, consisting of 5 kidney, 4 liver, and 1 liver/kidney transplant recipient. Mean age of the transplant recipients was 47 years, and the most frequent symptoms of Chikungunya infection were arthralgia and fever. None of the patients required treatment in the intensive care unit, no deaths or graft rejection occurred. None of our patients had recurrent arthritis during 3-month follow-up period after the infection. Twenty-one cases of Chikungunya virus were identified in the literature review. Most cases had a benign clinical course with no severe complications, death, or chronic inflammatory arthritis. In conclusion, Chikungunya infection in solid organ transplant recipients has a benign course and has no chronic recurrent arthritis. It is possible that the immunosuppression regimen could decrease the risk of severe or chronic inflammatory manifestations in solid organ transplant recipients infected with Chikungunya.

Polycythemia vera: from new, modified diagnostic criteria to new therapeutic approaches.

Polycythemia vera (PV) is a Philadelphia chromosome-negative chronic myeloproliferative neoplasm that is associated with a Janus kinase 2 (JAK2) mutation in most cases. The most recent update to the World Health Organization diagnostic criteria for PV was published in 2016. These were the modifications with the greatest effect: (1) lowering the hemoglobin threshold, allowing a diagnosis of PV at 16.5 g/dL in males and at 16.0 g/dL in females and (2) introducing a hematocrit cutoff (49% in males and 48% in females). Patients with PV who are older than 60 years or have had a previous thrombotic event are considered at high risk for thrombosis. Leukocytosis and a high allele burden are additional risk factors for thrombosis and myelofibrosis, respectively. After disease has progressed to post-polycythemia vera myelofibrosis (PPV-MF), survival must be assessed according to the recently developed Myelofibrosis Secondary to PV and ET-Prognostic Model (MYSEC-PM). This model is based on age at diagnosis, a hemoglobin level below 11 g/dL, a platelet count lower than 150 × 109/L, a percentage of circulating blasts of 3% or higher, a CALR-unmutated genotype, and the presence of constitutional symptoms. Therapy is based on phlebotomy to maintain the hematocrit below 45% and (if not contraindicated) aspirin. When a cytoreductive drug is necessary, hydroxyurea or interferon can be used as first-line therapy, although the demonstration of an advantage of interferon over hydroxyurea is still pending. In patients whose disease fails to respond to hydroxyurea, ruxolitinib is a safe and effective choice.

New molecular genetics in the diagnosis and treatment of myeloproliferative neoplasms.

PURPOSE OF REVIEW: Myeloproliferative neoplasms (MPN) are conditions of great interest because of the identification of their molecular basis and of the entering of new small molecules into clinical practice. The aim of this review is to report the role of mutations in the diagnosis, prognosis, and in the prediction of response to JAK inhibitors in MPN. RECENT FINDINGS: New mutations of the CALR gene have been discovered in patients without JAK2 or MPL mutations and are now included in the World Health Organization classification system. The role of ASXL1 and SRSF2 together with the driver mutations is emerging in the prognostication of myelofibrosis. SUMMARY: A wide mutational analysis of MPN helps to define diagnosis and prognosis. In the future, clinical trials based on a robust valuation of mutations will guide treatment decision-making towards precision medicine.

Impact of ruxolitinib on the natural history of primary myelofibrosis: a comparison of the DIPSS and the COMFORT-2 cohorts.

The international prognostic scoring system (IPSS) provides reliable risk assessment in patients with primary myelofibrosis (PMF). Recent clinical trials in PMF patients with intermediate-2 or high IPSS risk have shown a survival advantage of ruxolitinib over placebo (COMFORT-1) or best available therapy (COMFORT-2). Because crossover was allowed in these studies, we analyzed the cohort of ruxolitinib-naive patients used for developing the dynamic IPSS (DIPSS). By adopting ad hoc statistical analyses, we compared survival from diagnosis of 100 PMF patients receiving ruxolitinib within COMFORT-2 with that of 350 patients of the DIPSS study. Subjects were properly matched, and both left-truncation and right-censoring were accounted in order to compare higher IPSS risks exclusively. Patients receiving ruxolitinib had longer survival (5 years, 95% confidence interval [CI]: 2.9-7.8 vs 3.5 years, 95% CI: 3.0-3.9) with a hazard ratio of 0.61 (95% CI: 0.41-0.91; P = .0148). This observation suggests that ruxolitinib may modify the natural history of PMF.

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.