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Deletion of chromosome 17p (del[17p]) in patients with chronic lymphocytic leukaemia confers very poor prognosis when treated with standard chemo-immunotherapy. Venetoclax is an oral small-molecule BCL2 inhibitor that induces chronic lymphocytic leukaemia cell apoptosis. In a previous first-in-human study of venetoclax, 77% of patients with relapsed or refractory chronic lymphocytic leukaemia achieved an overall response. Here we aimed to assess the activity and safety of venetoclax monotherapy in patients with relapsed or refractory del(17p) chronic lymphocytic leukaemia. In this phase 2, single-arm, multicentre study, we recruited patients aged 18 years and older with del(17p) relapsed or refractory chronic lymphocytic leukaemia (as defined by 2008 Modified International Workshop on Chronic Lymphocytic Leukemia guidelines) from 31 centres in the USA, Canada, UK, Germany, Poland, and Australia. Patients started once daily venetoclax with a weekly dose ramp-up schedule (20, 50, 100, 200, 400 mg) over 4–5 weeks. Patients were then given daily 400 mg continuous dosing until disease progression or discontinuation for another reason. The primary endpoint was the proportion of patients achieving an overall response, assessed by an independent review committee. Activity and safety analyses included all patients who received at least one dose of study drug (per protocol). This study is registered with ClinicalTrials.gov, number NCT01889186. Follow-up is ongoing, and patients are still receiving treatment. Between May 27, 2013, and June 27, 2014, 107 patients were enrolled into the study. At a median follow-up of 12·1 months (IQR 10·1–14·2), an overall response by independent review was achieved in 85 (79·4%; 95% CI 70·5–86·6) of 107 patients. The most common grade 3–4 adverse events were neutropenia (43 [40%]), infection (21 [20%]), anaemia (19 [18%]), and thrombocytopenia (16 [15%]). Serious adverse events occurred in 59 (55%) patients, irrespective of their relationship to treatment, with the most common (≥5% of patients) being pyrexia and autoimmune haemolytic anaemia (seven [7%] each), pneumonia (six [6%]), and febrile neutropenia (five [5%]). 11 patients died in the study within 30 days of the last dose of venetoclax; seven due to disease progression and four from an adverse event (none assessed as treatment related). Results of this trial show that venetoclax monotherapy is active and well tolerated in patients with relapsed or refractory del(17p) chronic lymphocytic leukaemia, providing a new therapeutic option for this very poor prognosis population. Additionally, in view of the distinct mechanism-of-action of venetoclax, combinations or sequencing with other novel targeted agents should be investigated to further advance treatment of del(17p) chronic lymphocytic leukaemia. AbbVie and Genentech.

BackgroundCD73 is present on subsets of B and T cells and is involved in lymphocyte activation. CPI-006 is a humanized IgG1, Fcγ receptor deficient anti-CD73 that has agonistic properties. In vitro studies and ongoing cancer clinical trials show that CPI-006 binds to B cells leading to expression of CD69, trafficking to lymph nodes, immunoglobulin class switching, transformation to plasmablasts and generation of memory B cells.1 Recently, a patient in the cancer trial with asymptomatic COVID-19 developed high titers of neutralizing anti-SARS-CoV-2 antibodies following administration of CPI-006. A phase 1 trial in COVID-19 was initiated to evaluate the use of CPI-006 to enhance anti-viral immune response (NCT04464395).MethodsSingle intravenous dose escalation with N=5 per cohort of 0.3, 1.0, 3.0 and 5.0 mg/kg. Pt eligibility included PCR positive nasal swab for COVID-19; hospitalized with O2 saturation of ≥92% on <5 l/min of O2. Pts received standard care for COVID-19. Pts were monitored for safety, COVID-19 symptoms, inflammatory markers and anti-SARS-CoV-2 antibodies by ELISA. Immunophenotyping of blood by flow cytometry was performed.Results10 pts have been treated in the first 2 cohorts; median age 64 (range 28–76) and all had comorbidities: diabetes (4), hypertension (2), obesity (7) and/or cancer (2). Median duration of symptoms prior to CPI-006 was 8 days (range 1–21 days). No treatment-related adverse events were reported. There was no correlation between duration of symptoms and baseline anti-viral titers. Kinetics of anti-SARS-CoV-2 response to spike protein are shown for 7 pts with follow-up ≥ 7 days post CPI-006 (figure 1). One pt with lymphopenia (600/mm3) had delayed response to CPI-006; all other pts generated antibody response by Day 7 post-CPI-006 to both spike and RBD. Increasing titers of IgG and IgM antibodies were observed out to 28 days post treatment. In one pt examined, memory B cells increased from 1.81% to 4.83% of B cells 28 days after treatment with serum IgG titers to spike and to RBD of >1:50,000. 2 of 2 pts had increase in both CD4 and CD8 T effector memory cells at day 28. All pts were discharged (median 4 days) with clinical improvement.Abstract 325 Figure 1Antibody responses to SARS-CoV-2 spike protein in patients treated with CPI-006ConclusionsCPI-006 is well tolerated in COVID-19 pts. Low baseline titers of antibodies to virus were increased following CPI-006 in all treated pts. Immunomodulation with CPI-006 represents a novel therapy for COVID-19 aimed at stimulating more robust and prolonged anti-SARS-CoV-2 immunity potentially after infection or with vaccination.Trial RegistrationNCT04464395Ethics ApprovalThe study was approved by Temple University Hospital’s Ethics Board, Western IRB, approval number 1-1317457-1.ReferenceLuke J, Powderly J, Merchan J, Barve M, Hotson A, Mobasher M, Kwei L, Luciano G, Buggy J, Piccione E, Miller R. Immunobiology, preliminary safety, and efficacy of CPI-006, an anti-CD73 antibody with immune modulating activity, in a phase 1 trial in advanced cancers. J Clin Oncol 2019; 37:15 suppl, 2505.

BackgroundMupadolimab (mupa) is a humanized FcγR binding-deficient IgG1 anti-CD73 antibody that has agonistic properties.1 CD73 is involved in production of adenosine and in cellular trafficking. Mupa reacts with the majority of circulating B cells leading to activation and expression of differentiation markers CD69, CD138 and CD38, and transformation into plasmablasts with secretion of IgM and IgG. B cell activation provided the rationale to develop mupa for immunotherapy of cancer and Covid-19. Intratumor HPV specific B cells have been reported in HNSCC.2 This report describes properties of mupa and the early signs of clinical activity in HPV+ HNSCC.MethodsELISA and flow cytometry were used to measure binding of anti-CD73. Humanized NSG-SGM3 mice were used to evaluate effects of Mupa on human anti-SARS CoV2 spike protein (SP) response. CD73 expression in biopsies was measured by immunohistochemistry. Mupa (IV q 3 weeks) with or without pembrolizumab is being evaluated in an ongoing phase 1 trial in patients with refractory cancers.ResultsMupa binding to CD73 was blocked by APCP, an analog of adenosine diphosphate that locks CD73 in the closed conformation, indicating mupa binding to the open conformation. Cross blocking and cellular internalization studies showed that mupa is distinct from other anti-CD73 antibodies such as MEDI9447 and AD2. NSG-SGM3 mice were immunized with 50 µg SP subcutaneously and treated with mupa 10mg/kg or control IgG IP. Mupa treated animals mounted an antigen specific human anti-SP response; no antibody responses were seen in controls (P=0.02). In the dose-escalation portion of the phase 1 trial, mupa doses of ≥12 mg/kg saturated CD73 sites on circulating B cells. High stromal CD73 expression was observed in HPV+ HNSCC biopsies from 5 evaluable patients with chemotherapy and anti-PD1 refractory disease, and tumor regression was seen in 2 of these patients receiving 7 and 16 cycles of ≥12 mg/kg mupa without pembrolizumab. Safety of mupa+pembrolizumab was evaluated in 16 patients with no MTD reached and no changes in serum immunoglobulins. Transient reductions in circulating CD73 B cells were observed consistent with redistribution to lymphoid tissues.ConclusionsCD73 plays a role in B cell activation and differentiation. Mupa is an antibody with agonistic activity that stimulates B cells and enhances antigen specific antibody production. This activity supports a strategy to combine mupa with pembrolizumab to enhance both humoral and cellular immunity in the treatment of viral associated cancers such as HPV+HNSCC, and viral infections.Trial RegistrationNCT03454451ReferencesWillingham S, Criner G, Hill C, Hu S, Rudnick J, Daine-Matsuoka B, Hsieh J, Mashhedi H, Hotson A, Brody J, Marron T, Piccione E, Buggy J, Mahabhashyam S, Jones W, Mobasher M, Miller R. Characterization and Phase 1 trial of a B cell activating anti-CD73 antibody for the immunotherapy of COVID-19. medRxiv, 2020; https://doi.org/10.1101/2020.09.10.20191486.Wieland A, Patel M, Cardenas M, Eberhardt C, Hudson W, Obeng R, Griffith C, Wang X, Chen Z, Kissick H, Saba N, Ahmed R. Defining HPV-specific B cell responses in patients with head and neck cancer. Nature 2020; https://doi.org/10.1038/s41586-020-2931-3.Ethics ApprovalThe study was approved by Western IRB, approval number 1-1066703-1. Participants gave informed consent before taking part.

The combination of the BCL2 inhibitor venetoclax plus obinutuzumab was more effective in the treatment of older medically ill patients with untreated chronic lymphocytic leukemia than was chlorambucil plus obinutuzumab. Progression-free survival at 2 years was 88% with venetoclax and 64% with chlorambucil.

In a trial involving patients with relapsed or refractory chronic lymphocytic leukemia, the BCL2 inhibitor venetoclax in combination with rituximab resulted in a higher 2-year rate of progression-free survival than bendamustine in combination with rituximab (85% vs. 36%).

To the Editor: In the phase 3 MURANO trial, Seymour et al. (March 22 issue) 1 compared the efficacy of venetoclax plus rituximab with that of bendamustine plus rituximab in patients with relapsed or refractory chronic lymphocytic leukemia. Patients were stratified according to the presence or absence of chromosome 17p deletion, which was present in 46 of 173 patients (26.6%) in the venetoclax–rituximab group and 46 of 169 patients (27.2%) in the bendamustine–rituximab group. In the multicenter phase 2 trial of the German Chronic Lymphocytic Leukemia Study Group, chromosome 17p deletion was the only established risk factor that negatively affected the . . .

The COVID-19 pandemic has become the leading societal concern. The pandemic has shown that the public health concern is not only a medical problem, but also affects society as a whole; so, it has also become the leading scientific concern. We discuss in this treatise the importance of bringing the world’s scientists together to find effective solutions for controlling the pandemic. By applying novel research frameworks, interdisciplinary collaboration promises to manage the pandemic’s consequences and prevent recurrences of similar pandemics.

Physicians’ knowledge of therapy and counseling stands among the most important issues in the viewpoints of clients who refer to psychiatric centers. Transsexual patients are very important in this regard. The goal of this research is to study their attitude toward doctors’ empathy. A group of transsexual patients who referred to the Tehran Institute of Psychiatry, Iran, answered the Jefferson Scale of Empathy. The relationship of the patients’ age, gender, education level, and lifestyle with their attitude was measured. This study was conducted on 40 patients, including 16 women (40%) and 24 men (60%). In terms of education, 8 patients had a degree below high school diploma (20%), 9 had high school diploma (22.5%), and 23 patients were university students or of higher education level (57.5%). Among these patients, 6 were unemployed (15%), 10 were students (25%), and the rest were employed. Moreover, 8 participants lived alone (20%), 5 lived with their friends (12.5%), and 27 lived with their family (67.5%). Gender had no influence on the average score of the questionnaires, yet level of education had some influence. Lifestyle also had a significant influence on the patients’ attitude. On the other hand, patients whose problems began before the age of 12 had lower score than others. Experienced psychologists in referential centers can express greater levels of empathy to specific diseases and this trend is very effective on the patients’ cooperation level. In order to create an effective relationship between physicians and patients, the efficiency of the health system and increasing satisfaction of specific patients should be considered.

Physicians' knowledge of therapy and counseling stands among the most important issues in the viewpoints of clients who refer to psychiatric centers. Transsexual patients are very important in this regard. The goal of this research is to study their attitude toward doctors' empathy. A group of transsexual patients who referred to the Tehran Institute of Psychiatry, Iran, answered the Jefferson Scale of Empathy. The relationship of the patients' age, gender, education level, and lifestyle with their attitude was measured. This study was conducted on 40 patients, including 16 women (40%) and 24 men (60%). In terms of education, 8 patients had a degree below high school diploma (20%), 9 had high school diploma (22.5%), and 23 patients were university students or of higher education level (57.5%). Among these patients, 6 were unemployed (15%), 10 were students (25%), and the rest were employed. Moreover, 8 participants lived alone (20%), 5 lived with their friends (12.5%), and 27 lived with their family (67.5%). Gender had no influence on the average score of the questionnaires, yet level of education had some influence. Lifestyle also had a significant influence on the patients' attitude. On the other hand, patients whose problems began before the age of 12 had lower score than others. Experienced psychologists in referential centers can express greater levels of empathy to specific diseases and this trend is very effective on the patients' cooperation level. In order to create an effective relationship between physicians and patients, the efficiency of the health system and increasing satisfaction of specific patients should be considered.

Personality's characteristics of managers play a major role in the performance of directors in that organization. Recent research approaches conducted in this field have insisted on the influence factors: extroversion, temperamental personality, openness, adaptability and conscientiousness on directors' yield. The present study aiming to examine the relationship between personality's characteristics and directors' efficiency were designed and implemented in 2009 in Lorestan University of Basic Medical Sciences. This descriptive study was done by correlation way on 80 directors employed in the Medical Sciences University. There was a positive (direct) relationship between personality's characteristics and managers' efficiency in University of Basic Medical Science, also relation of extroversion factor, openness factor, adjustment factor, conscience factor with efficiency is direct and significant. But there was a significant and inverse relationship between neuroticism factor and efficiency. An effective and efficient management must possess features such as accountability, flexibility, connectivity and amiability and avoid also temperamental personality factors (neuroticism).