Phosphatidylinositol-3-kinase (PI3K) inhibitors have shown activity in relapsed or refractory (R/R) indolent non-Hodgkin lymphoma (iNHL). PI3K inhibitors have been hampered by poor long-term ...tolerability and toxicity, which interfere with continuous use. Umbralisib, a dual inhibitor of PI3Kδ/casein kinase-1ε, exhibits improved selectivity for PI3Kδ compared with other PI3K inhibitors. This phase IIb trial was designed to evaluate the efficacy and safety of umbralisib in patients with R/R iNHL.
In this multicohort, open-label, phase IIb study, 208 patients with R/R marginal zone, follicular, or small lymphocytic lymphoma (MZL, FL, or SLL) unresponsive to prior treatments (≥ 1 MZL; ≥ 2 FL/SLL), including ≥ 1 anti-CD20-based therapy, were administered umbralisib 800 mg orally once daily until disease progression, unacceptable toxicity, or study withdrawal. Primary end point is overall response rate; secondary end points include time to response, duration of response, progression-free survival, and safety.
The median follow-up is 27.7 months (efficacy) and 21.4 months (safety). The overall response rate was 47.1%, and tumor reduction occurred in 86.4% of patients. The median time to response was 2.7-4.6 months. The median duration of response was not reached for MZL, 11.1 months for FL, and 18.3 months for SLL. Median progression-free survival was not reached for MZL, 10.6 months for FL, and 20.9 months for SLL. At least one grade ≥ 3 treatment-emergent adverse event (TEAE) was reported in 53.4% of patients. TEAEs led to umbralisib discontinuation in 32 patients (15.4%). A total of 31 patients (14.9%) discontinued because of a treatment-related adverse event. Grade ≥ 3 TEAEs reported in ≥ 10% of patients: neutropenia (11.5%) and diarrhea (10.1%). Increased ALT/AST (grade ≥ 3) occurred in 6.7%/7.2% of patients.
Umbralisib achieved meaningful clinical activity in heavily pretreated patients with iNHL. The safety profile was manageable, with a relatively low incidence of immune-mediated toxicities and adverse event-related discontinuations.
Immunotherapy has revolutionized the treatment of cancers. There are several approaches, including naked monoclonal antibodies, antibody–drug conjugates, immune-checkpoint inhibitors and chimeric ...antigen receptor T cell therapies with important success. Bispecific antibodies represent a novel immunotherapeutic approach for the treatment of several malignancies, in particular non-Hodgkin’s lymphoma (NHL) and multiple myeloma (MM). Early-phase studies have shown encouraging clinical activity in poor-risk B cell NHL and MM. Several constructs are currently available and in clinical development for the treatment of these malignancies. Here, we present a narrative review of the most current data on bispecific antibodies in B cell NHL and MM.
Survival following melanoma and chronic lymphocytic leukemia (CLL) have both been individually associated with previous history of non-melanoma skin cancers (specifically keratinocyte carcinomas KC). ...Furthermore, melanoma and CLL have been reported to occur within the same patients. The survival experience of patients with both cancers is understudied, and the role of history of KC is unknown. Additional research is needed to tease apart the independent associations between KC and CLL survival, KC and melanoma survival, and the co-occurrence of all three cancers.
A retrospective cohort study was conducted among patients who were diagnosed with melanoma and/or CLL at a comprehensive cancer center between 2008 and 2020. Multivariable Cox regression models were used to examine the association between history of KC and survival following melanoma and/or CLL with careful consideration of calendar year of diagnosis, treatment regimens and other risk factors. A nested case-control study comparing patients with both CLL and melanoma to those with only CLL or only melanoma was conducted to compare blood parameters across the three groups.
A time-dependent association was observed between history of KC and favorable melanoma survival within 4 years following diagnosis and poorer survival post 7 years after melanoma diagnosis. History of KC was not significantly associated with survival following the diagnosis of CLL, after adjustment for clinical factors including historical/concurrent melanoma. Patients with co-occurring melanoma and CLL tended to be diagnosed with melanoma first and had elevated blood parameters including white blood cell and lymphocyte counts as compared with patients who were diagnosed with only melanoma.
History of KC was an independent predictor of survival following melanoma but not of CLL. Additional studies are needed to determine if blood parameters obtained at the time of melanoma diagnosis could be used as a cost-effective way to identify those at high risk of asymptomatic CLL for the promotion of earlier CLL diagnosis.
Patients with follicular lymphoma, an indolent form of non-Hodgkin lymphoma, typically experience multiple relapses over their disease course. Periods of remission become progressively shorter with ...worse clinical outcomes after each subsequent line of therapy. Currently, no clear standard of care/preferred treatment approach exists for patients with relapsed or refractory follicular lymphoma. As novel agents continue to emerge for treatment in the third-line setting, guidance is needed for selecting the most appropriate therapy for each patient. Several classes of targeted therapeutic agents, including monoclonal antibodies, phosphoinositide 3-kinase inhibitors, enhancer of zeste homolog 2 inhibitors, chimeric antigen receptor (CAR) T-cell therapies, and bispecific antibodies, have been approved by regulatory authorities based on clinical benefit in patients with relapsed or refractory follicular lymphoma. Additionally, antibody-drug conjugates and other immunocellular therapies are being evaluated in this setting. Effective integration of CAR-T cell therapy into the treatment paradigm after two or more prior therapies requires appropriate patient selection based on transformation status following a rebiopsy; a risk evaluation based on age, fitness, and remission length; and eligibility for CAR-T cell therapy. Consideration of important logistical factors (e.g., proximity to the treatment center and caregiver support during key periods of CAR-T cell therapy) is also critical. Overall, an individualized treatment plan that considers patient-related factors (e.g., age, disease status, tumor burden, comorbidities) and prior treatment types is recommended for patients with relapsed or refractory follicular lymphoma. Future analyses of real-world data and a better understanding of mechanisms of relapse are needed to further refine patient selection and identify optimal sequencing of therapies in this setting.
Unlike most cells of the body which function in an ionic environment controlled within narrow limits, spermatozoa must function in a less controlled external environment. In order to better ...understand how sperm control their membrane potential in different ionic conditions, we measured mouse sperm membrane potentials under a variety of conditions and at different external K(+) concentrations, both before and after capacitation. Experiments were undertaken using both wild-type, and mutant mouse sperm from the knock-out strain of the sperm-specific, pH-sensitive, SLO3 K(+) channel. Membrane voltage data were fit to the Goldman-Hodgkin-Katz equation. Our study revealed a significant membrane permeability to both K(+) and Cl(-) before capacitation, as well as Na(+). The permeability to both K(+) and Cl(-) has the effect of preventing large changes in membrane potential when the extracellular concentration of either ion is changed. Such a mechanism may protect against undesired shifts in membrane potential in changing ionic environments. We found that a significant portion of resting membrane potassium permeability in wild-type sperm was contributed by SLO3 K(+) channels. We also found that further activation of SLO3 channels was the essential mechanism producing membrane hyperpolarization under two separate conditions, 1) elevation of external pH prior to capacitation and 2) capacitating conditions. Both conditions produced a significant membrane hyperpolarization in wild-type which was absent in SLO3 mutant sperm. Hyperpolarization in both conditions may result from activation of SLO3 channels by raising intracellular pH; however, demonstrating that SLO3-dependent hyperpolarization is achieved by an alkaline environment alone shows that SLO3 channel activation might occur independently of other events associated with capacitation. For example sperm may undergo stages of membrane hyperpolarization when reaching alkaline regions of the female genital tract. Significantly, other events associated with sperm capacitation, occur in SLO3 mutant sperm and thus proceed independently of hyperpolarization.
Airway pressure release ventilation is a ventilatory mode characterized by a mandatory inverse inspiratory:expiratory ratio with a very short expiratory phase, aimed to avoid derecruitment and allow ...spontaneous breathing. Recent basic and clinical evidence suggests that this mode could be associated with improved outcomes in patients with acute respiratory distress syndrome. The aim of this study was to compare the outcomes between airway pressure release ventilation and traditional ventilation targeting low tidal volume, in patients with severe coronavirus disease 2019.
Single-center randomized controlled trial.
ICU of a Mexican referral center dedicated to care of patients with confirmed diagnosis of coronavirus disease 2019.
Ninety adult intubated patients with acute respiratory distress syndrome associated with severe coronavirus disease 2019.
Within 48 hours after intubation, patients were randomized to either receive ventilatory management with airway pressure release ventilation or continue low tidal volume ventilation.
Forty-five patients in airway pressure release ventilation group and 45 in the low tidal volume group were included. Ventilator-free days were 3.7 (0-15) and 5.2 (0-19) in the airway pressure release ventilation and low tidal volume groups, respectively (p = 0.28). During the first 7 days, patients in airway pressure release ventilation had a higher Pao2/Fio2 (mean difference, 26 95%CI, 13-38; p < 0.001) and static compliance (mean difference, 3.7 mL/cm H2O 95% CI, 0.2-7.2; p = 0.03), higher mean airway pressure (mean difference, 3.1 cm H2O 95% CI, 2.1-4.1; p < 0.001), and higher tidal volume (mean difference, 0.76 mL/kg/predicted body weight 95% CI, 0.5-1.0; p < 0.001). More patients in airway pressure release ventilation had transient severe hypercapnia, defined as an elevation of Pco2 at greater than or equal to 55 along with a pH less than 7.15 (42% vs 15%; p = 0.009); other outcomes were similar. Overall mortality was 69%, with no difference between the groups (78% in airway pressure release ventilation vs 60% in low tidal volume; p = 0.07).
In conclusion, when compared with low tidal volume, airway pressure release ventilation was not associated with more ventilator-free days or improvement in other relevant outcomes in patients with severe coronavirus disease 2019.
Opinion statement
Post CAR-T failures represent a new unmet need in R/R LBCL. The prognosis is usually very poor and standard treatment options that can guide clinicians are, unfortunately, not ...available. While polatuzumab, tafasitamab, selinexor, and loncastuximab tesirine are available as SOC since they are FDA approved, data is lacking in the post CAR-T setting. However, they could be used in the absence of other treatment options (clinical trials). A selected group of patients may be treated with checkpoint inhibitors, likely low tumor burden or low proliferative lymphomas or those with PD-L1 expression. For localized relapses, radiation therapy could be considered. A main consideration should be given to clinical trials. So far, it appears that bi-specific antibodies have the best encouraging data (high response rates) with manageable toxicities and logistics; thus, we recommend clinicians to enroll patients in clinical trials utilizing these agents. Other cell therapies (such as dual CAR-T or allogeneic products) should also be considered; however, challenges with logistics and further immunosuppression (especially if patients had prolonged cytopenias from prior CAR-T therapy) may affect its applicability right after CAR-T relapse. It is unclear whether these options will lead to long-term remissions; thus, consolidation with stem cell transplantation (either auto or allogeneic SCT) could be considered in eligible patients.
Disease overview
Epstein Barr virus‐positive (EBV+) diffuse large B‐cell lymphoma (DLBCL), not otherwise specified (NOS) is an entity included in the 2016 WHO classification of lymphoid neoplasms. ...EBV+ DLBCL, NOS, is an aggressive B‐cell lymphoma associated with chronic EBV infection, and a poor prognosis with standard chemotherapeutic approaches.
Diagnosis
The diagnosis is made through a careful pathological evaluation. Detection of EBV‐encoded RNA is considered standard for diagnosis; however, a clear cutoff for positivity has not been defined. The differential diagnosis includes plasmablastic lymphoma, DLBCL associated with chronic inflammation, primary effusion lymphoma, HHV8+ DLBCL, NOS, and EBV+ mucocutaneuos ulcer.
Risk‐stratification
The International prognostic index (IPI) and the Oyama score can be used for risk‐stratification. The Oyama score includes age >70 years and presence of B symptoms. The expression of CD30 is emerging as a potential adverse, and targetable, prognostic factor.
Management
Patients with EBV+ DLBCL, NOS, should be staged and managed following similar guidelines than patients with EBV‐negative DLBCL. EBV+ DLBCL, NOS, however, has a worse prognosis than EBV‐negative DLBCL in the era of chemoimmunotherapy. There is an opportunity to study and develop targeted therapy in the management of patients with EBV+ DLBCL, NOS.
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