Ohad Shimshon Bentur

PURPOSE: Peripheral T-cell lymphomas (PTCLs) are rare, heterogeneous, aggressive lymphomas. Five-year overall survival (OS) remains approximately 30%-40%, and most patients will develop relapsed or refractory (R/R) disease. Duvelisib is an oral dual inhibitor of phosphatidylinositol 3-kinase (PI3K)-δ and PI3K-γ isoforms. Here, we report on the final analysis of the phase II PRIMO trial (ClinicalTrials.gov identifier: NCT03372057 ; Secura Bio, Inc) evaluating duvelisib monotherapy in R/R PTCL. METHODS: PRIMO was conducted in two phases (dose optimization and dose expansion [PRIMO-EP]) at 45 centers globally. Eligible patients were age 18 years and older, had histologically confirmed diagnosis of PTCL, and had received ≥2 cycles of one standard regimen for PTCL. Based on dose optimization results, the selected regimen for PRIMO-EP was 75 mg twice a day for two cycles (to maximize disease control) followed by 25 mg twice a day (to reduce late toxicities), continued until progressive disease or unacceptable toxicity. RESULTS: PRIMO-EP (N = 123) outcomes included independent review committee–assessed objective response rate (ORR): 48.0%, complete response rate (CRR): 33.3%, median progression-free survival (mPFS): 3.4 months, median OS (mOS): 12.4 months, and median duration of response (mDOR): 7.9 months. In the angioimmunoblastic T-cell lymphoma (AITL) subgroup, outcomes were ORR: 62.2%, CRR: 51.4%, mPFS: 8.3 months, mOS: 18.1 months, and mDOR: 11.3 months. Treatment-emergent adverse events (TEAEs; any grade) occurred in 120 patients (97.6%), and TEAEs grade ≥3 occurred in 91 patients (74.0%). TEAEs resulting in dose hold or dose reduction occurred in 44.7% and 9.8% of patients, respectively. CONCLUSION: The PRIMO study demonstrates significant activity and tolerability of duvelisib in patients with R/R PTCL, most notably in the AITL subgroup. This provides strong rationale for further development in PTCL, and more specifically in the subgroup of nodal T-follicular helper cell lymphoma.

Based on early reports of the efficacy of hydroxychloroquine sulfate (HCQS) to inhibit SARS-CoV-2 viral replication in vitro, and since severe pulmonary involvement is the major cause of COVID-19 mortality, we assessed the safety and efficacy of aerosolized HCQS (aHCQS) therapy in animals and humans. In a Phase 1 study of aHCQS in healthy volunteers, doses up to 50 mg were well tolerated and estimated epithelial lining fluid concentrations immediately after inhalation (>2,000 μM) exceeded the in vitro concentrations needed for suppression of viral replication (≥119 μM). A study in rats comparing HCQS solution administered orally (13.3 mg/kg) and by intratracheal installation (IT 0.18 mg/kg, <5% of oral dose) demonstrated that at 2 minutes, IT administration was associated with 5X higher mean hydroxychloroquine (HCQ) concentrations in the lung (IT: 49.5 ± 6.5 µg HCQ/g tissue, oral: 9.9 ± 3.4; p<0.01). A subsequent study of IT and intranasal HCQS in the Syrian hamster model of SARS-CoV-2 infection, however, failed to show clinical benefit. We conclude that aHCQS alone is unlikely to be effective for COVID-19, but based on our aHCQS pharmacokinetics and current viral entry data, adding oral HCQS to aHCQS, along with a transmembrane protease inhibitor, may improve efficacy.

Introduction: Obesity is more prevalent among African American individuals, increasing the risk for cardiorenal morbidity. We explored interactions between race, BMI, and the risk of hyperfiltration associated with obesity-related glomerulopathy (ORG). Methods: We created a cohort of female adolescents from electronic health records. Glomerular filtration rate (GFR) was estimated in two ways: (A) using standard age recommended formulae and (B) absolute eGFR – adjusted to individual body surface area (BSA). Multivariate logistic regression was used to analyze the contribution of risk factors for ORG-associated hyperfiltration defined as 135 mL/min/1.73 m² or 135 mL/min, according to BMI group. Pearson’s coefficient was used to assess correlation with creatinine clearance (CrCl). Results: The final cohort included 7,315 African American and 15,102 non-African American adolescent females, with CrCl available for internal validation in 207 non-African American and 107 African American individuals. Compared with non-African American ethnicity, African American ethnicity was independently associated with a lower risk of hyperfiltration with standard eGFR calculations (odds ratio [OR] = 0.57, 95% confidence intervals [CIs] 0.45–0.71), associations were enhanced for absolute eGFR (OR = 0.81, 95% CI 0.69–0.95). Absolute eGFR values agreed better with CrCl (r = 0.63), compared to standard indexed eGFR formulae. Proportions classified as hyperfiltration changed with standard versus absolute eGFR; they were similar across BMI groups with the first and reflected obesity with the later. Conclusion: Adjusting to individual BSA improves estimation of GFR and identification of obesity-related hyperfiltration. More accurate and earlier ascertainment of obesity-related hyperfiltration may have important consequences for preservation of kidney function.

The molecular basis of platelet-fibrin interactions remains poorly understood despite the predominance of fibrin in thrombi. We have studied the interaction of platelets with polymerizing fibrin by adding thrombin to washed platelets in the presence of the peptide RGDW, which inhibits the initial platelet aggregation mediated by fibrinogen binding to αIIbβ3 but leaves intact a delayed increase in light transmission (delayed wave; DW) as platelets interact with the polymerizing fibrin. The DW was absent in platelets from a patient with Glanzmann thrombasthenia, indicating a requirement for αIIbβ3. The DW required αIIbb3 activation and it was inhibited by the αIIbβ3 antagonists eptifibatide and the monoclonal antibody (mAb) 7E3, but only at much higher concentrations than needed to inhibit platelet aggregation initiated by a thrombin receptor activating peptide (T6). Surface plasmon resonance and scanning electron microscopy studies both supported fibrin having greater avidity for αIIbβ3 than fibrinogen rather than greater affinity, consistent with fibrin’s multivalency. mAb 10E5, a potent inhibitor of T6-induced platelet aggregation, did not inhibit the DW, suggesting that fibrin differs from fibrinogen in its mechanism of binding. Inhibition of factor XIII–mediated fibrin cross-linking by >95% reduced the DW by only 32%. Clot retraction showed a pattern of inhibition similar to that of the DW. We conclude that activated αIIbβ3 is the primary mediator of platelet-fibrin interactions leading to clot retraction, and that the interaction is avidity driven, does not require fibrin cross-linking, and is mediated by a mechanism that differs subtly from that of the interaction of αIIbβ3 with fibrinogen.

Introduction Prehospital therapy of ST-elevation myocardial infarction (STEMI) with αIIbβ3 antagonists improves clinical outcomes, but they are difficult to use in prehospital settings. RUC-4 is a novel αIIbβ3 antagonist being developed for prehospital therapy of STEMI that rapidly achieves high-grade platelet inhibition after subcutaneous administration. Standard light transmission aggregometry (LTA) is difficult to perform during STEMI, so we applied VerifyNow (VN) assays to assess the pharmacodynamics of RUC-4 relative to aspirin and ticagrelor. Methods Blood from healthy volunteers was anticoagulated with phenylalanyl-prolyl-arginyl chloromethyl ketone (PPACK) or sodium citrate, treated in vitro with RUC-4, aspirin, and/or ticagrelor, and tested with the VN ADP + PGE₁, iso-TRAP, and base channel (high concentration iso-TRAP + PAR-4 agonist) assays. The results were correlated with both ADP (20 µM)-induced LTA and flow cytometry measurement of receptor occupancy and data from individuals treated in vivo with RUC-4. Results RUC-4 inhibited all three VN assays, aspirin did not affect the assays, and ticagrelor markedly inhibited the ADP + PGE₁ assay, slightly inhibited the iso-TRAP assay, and did not inhibit the base channel assay. RUC-4's antiplatelet effects were potentiated in citrate compared with PPACK. Cut-off values were determined to correlate the results of the VN iso-TRAP and base channel assays with 80% inhibition of LTA. Conclusion The VN assays can differentiate the early potent anti-αIIbβ3 effects of RUC-4 from delayed effects of P2Y12 antagonists in the presence of aspirin. These pharmacodynamic assays can help guide the clinical development of RUC-4 and potentially be used to monitor RUC-4's effects in clinical practice. O. S. Bentur contributed concept/design, designed, and conducted the in vitro experiments, analyzed the data, drafted the article, and critically revised the article. J. Li designed and provided training on the PAC1 binding assay. C. S. Jiang analyzed and interpreted the data. L. H. Martin participated in the planning and carrying out of the phase I study. D. J. Kereiakes was the principal investigator of the RUC-4 phase I study and critically reviewed the article. B. S. Coller conceived and oversaw the project, drafted the article, critically revised the article, and approved the article. Received: 28 January 2021 Accepted: 16 June 2021 Article published online: 28 September 2021 © 2021. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/) Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany

Introduction: RUC-4 is a novel platelet integrin αIIbβ3 antagonist specifically designed for first point-of-medical contact (ambulance or ER) treatment of patients with ST segment elevation myocardial infarction in combination with aspirin. Ongoing Phase 1 studies indicate that RUC-4 at a dose of 0.075 mg/kg administered subcutaneously can inhibit ADP-induced platelet aggregation by ~80% within 15 minutes, with a return toward baseline within 60-90 minutes. It may be advantageous to monitor the antiplatelet effects of RUC-4 on admission to the hospital, but optical aggregometry (OA) takes too long to guide immediate therapeutic decisions. The automated VerifyNow (VN) assays provide rapid point-of-care assessment of the effect of antiplatelet agents. The VN IIb/IIIa assay uses a thrombin receptor activating peptide (isoTRAP) to activate the platelets and the VN Aspirin assay uses arachidonic acid, whereas the PRU (P2Y12) assay uses isoTRAP in one channel and a mixture of ADP and PGE1 in another. We recently reported that: 1. Aspirin does not affect the IC50 for RUC-4 when measured by OA of platelet-rich plasma (PRP) in response to ADP, and 2. The IC50 is lower in PRP that is prepared from blood anticoagulated with citrate rather than PPACK, consistent with RUC-4's mechanism of action in displacing the Mg2+ ion from the MIDAS domain (Vootukuri et al., J Clin Transl Sci; in press). We now have explored the sensitivity of the VN assays to RUC-4 and the effects of aspirin and different anticoagulants. Methods: Whole blood anticoagulated with either sodium citrate (0.32%) or PPACK (100 µM) from healthy volunteers who were either taking or not taking daily aspirin was treated in vitro with RUC-4 to achieve final whole blood concentrations between 30 and 900 nM. Blood was incubated for 10 minutes at room temperature and then tested with either the IIb/IIIa or PRU cartridge. Results: Whole blood samples were obtained from 13 healthy volunteers who provided consent, of whom 7 were taking aspirin. The antiplatelet effect of aspirin in the latter 7 participants was confirmed with the VN Aspirin assay. 1. PPACK vs citrate anticoagulation in blood from individuals who were not treated with aspirin. The percent inhibition values produced by different concentrations of RUC-4 in whole blood anticoagulated with either PPACK or citrate and activated with isoTRAP were highly correlated (R2=0.95; p<0.01) despite differences in absolute values (IC50s of 141 ± 5 vs 88 ± 7 nM, respectively, p=0.01; n=6). The comparable values using ADP+PGE1 as the activator were also highly correlated (R2=0.95; p<0.01) despite differences in absolute values (IC50s of 128 ± 5 vs 69 ± 8 nM, p=0.01; n=6). Based on these results, we selected citrate-anticoagulated blood for additional studies because vacuum blood collection tubes containing citrate, but not PPACK, are available commercially. 2. Effect of RUC-4 on VN assays: a) Impact of aspirin on results in the PRU cartridge. The IC50s in the isoTRAP channel were similar using blood from individuals who were not taking aspirin (88 ± 7 nM) or taking aspirin (97 ± 20 nM; p=0.35; n=9). Similar results were obtained using the ADP+ PGE1 channel (69 ± 8 vs 70 ± 8 nM; p=0.84; n=9). b) Comparison of the 2 different isoTRAP channels with blood from people on aspirin. RUC-4 showed similar dose-responses in both isoTRAP channels, with an IC50 of 79 ± 26 nM in the IIb/IIIa cartridge vs 97 ± 20 nM in the PRU cartridge (p=0.12; n=5). c) Comparison of the isoTRAP vs ADP+PGE1 channel using blood from people on aspirin. The ADP+PGE1 channel was more sensitive to the lower concentrations of RUC-4 than the isoTRAP channel, showing, for example, ~40% inhibition at 30 nM compared to ~20%, respectively (Figure; p<0.02 based on comparison of IC50s ). Discussion: We conclude that RUC-4 produces dose-dependent inhibition of the VN isoTRAP channels in both the IIb/IIIa and PRU cartridges, as well as the ADP+PGE1 channel in the PRU cartridge. The PRU cartridge ADP+PGE1 channel is more sensitive than the isoTRAP channel to low concentrations of RUC-4. Since P2Y12 antagonists inhibit the ADP+PGE1 channel, but not the isoTRAP channels, the effect of RUC-4 on patients who are not treated with a P2Y12 antagonist may be monitored with the PRU ADP+PGE1 channel or the isoTRAP channel in either the PRU or IIb/IIIa cartridge. The RUC-4 effects in patients treated with a P2Y12 antagonist may be monitored with the isoTRAP channel in either cartridge. Figure Disclosures: Coller: Accumetrics/Instrumentation Laboratory: Patents & Royalties: VerifyNow assay; Scholar Rock: Consultancy, Equity Ownership; CeleCor: Consultancy, Equity Ownership, Research Funding; Centocor/Janssen: Patents & Royalties: abxicimab.

Hodgkin lymphoma (HL), a disease of mostly young patients, also peaks in the elderly. Despite the profound improvement in the outcome of young patients, in the elderly, 5-year progression-free survival (PFS) rates are under 70%. Interim PET-CT (iPET) is known to be highly predictive for PFS in young HL patients, but it has not been sufficiently validated in the elderly patient population. In this multi-center collaboration, all consecutive elderly patients (age ≥ 60) diagnosed with HL between 1998 and 2016 were retrospectively reviewed. Baseline characteristics, outcome measures, and iPET results, classified according to the Deauville score, were recorded and analyzed. We identified 78 elderly HL patients (median age 69) who underwent iPET. ABVD was the treatment regimen in 52 (67%) patients. Eighty-three percent of patients had iPET scores of 1–3 while 17% had scores of 4–5. Patients with iPET scores of 1–3 had 5-year PFS and OS rates of 72% and 82% compared with 25% and 45%, respectively, in patients with scores of 4–5 (p < 0.001). Our findings show that iPET is highly predictive of outcome in elderly HL patients and provide evidence that iPET-guided therapy in this patient population may be key to achieving superior treatment outcome.

Stress, the nonspecific response to any demand for change, is an adaptive response of the human body to various stimulants. As such, stress-induced hypercoagulation may represent an adaptive response to bleeding. Numerous epidemiological studies have revealed that a correlation exists between stress and thrombotic risk and biochemically, links of the relationship between psychological stress and coagulation pathways have been made. The stress reaction is coupled with neurohormonal changes mediated mainly by the sympathetic neural system and the hypothalamic–pituitary–adrenal axis. Singling out the specific pathways affecting coagulation in this complex response is hampered by many confounders. The mediators of the stress reaction (neurotransmitters and hormones) can directly affect platelets and the coagulation cascade and indirectly affect hemostasis via changes in hemodynamics. In this review, the authors will delineate the distinct neurobiological mechanisms that govern the effects of stress on coagulation, and report their recent findings.

Hodgkin lymphoma is the most common hematological malignancy in pregnancy. Its management presents several unique challenges, as decisions have to take both maternal and fetal risks into consideration. Using three hypothetical cases, we review current evidence and guidelines and suggest our recommendations for managing pregnant Hodgkin lymphoma patients. The opportunity for a prompt and accurate diagnosis should not be missed; this may be achieved by vigilance to suggestive symptoms, performance of biopsy which is not contraindicated during pregnancy and use of MRI for staging. Most patients should receive treatment with doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD) after completion of the first trimester. Bridging therapy with corticosteroids or vinblastine should be considered during the first trimester. In most cases of early disease, the addition of chemotherapy cycles to the treatment plan seems preferable to radiation therapy. Diagnosis at relapse raises unique dilemmas regarding second‐line chemotherapeutic regimens and timing of consolidation with high‐dose therapy and autologous stem cell transplantation, an approach which is contraindicated during pregnancy. Considering the excellent outcomes of Hodgkin lymphoma outside pregnancy, every effort should be made to strive toward a curative treatment plan while balancing the multiple issues and dilemmas which arise when treating this malignancy in a pregnant patient.

Follicular lymphoma (FL) is the most common subtype of indolent non-Hodgkin lymphoma. Patients with stage I disease are usually treated with radiotherapy (RT). In previous studies, mostly from the pre positron emission tomography–computed tomography (PET-CT) era, the 5 year progression-free survival (PFS) and overall survival (OS) rates of stage I disease were 60–80% and 80–93%, respectively. This study retrospectively evaluated the outcome of stage I FL which was treated with involved field RT in the PET-CT era between 2002 and 2015. Ninety-one patients were enrolled. Five year PFS and OS rates were 73% and 97%, respectively. Relapse occurred in 19 (21%) patients, 74% occurring outside the radiation field. In conclusion, PET-CT staging of clinical stage I FL may contribute to the improved prognosis in patients treated with RT compared to historical cohorts, possibly due to better identification of “genuine” stage I disease.