Background. Patients with cancer and health care workers (HCW) are at higher risk for SARS-CoV-2 infection. There are limited data regarding the rate of symptomatic versus asymptomatic infection and ...subsequent seropositivity in both populations. Methods. We performed a prospective study of patients and HCW across two institutions during the first wave of the pandemic to analyze the prevalence of SARS-CoV-2 antibodies, the extent of associated symptoms, and durability of serologic response. Results. In 1,953 persons (733 patients and 1,220 HCW), overall seropositivity rates for 3.1% patients (95% CI 2.0–4.7) and 3.7% HCW (95% CI 2.7–4.9, p=0.520), were similar. Each institutions’ seropositivity rates were numerically higher in HCW than patients. Non-Hispanic Whites and Asians had lower antibody rates (2.8%, 95% CI 2.0–3.8 and 3.3%, 95% CI 1.2–7.0) compared to Hispanics (6.9%, 95% CI 3.4–12.4) and non-Hispanic Blacks (5.9%, 95% CI 3.3–9.7), p<0.001. Among persons with a positive SARS-CoV-2 antibody, 87% of patients and 56% of HCW did not recall having had a fever. Among HCW, administrative and technical personnel were most likely to be seropositive. The rate of persistent seropositivity at 3 months was similar between patients and HCW and was not influenced by the reporting of fever, cancer type, or therapy. Conclusion. These data suggest that patients are not at higher risk for febrile SARS-CoV-2 infections or more transient immunity than HCWs. Furthermore, racial differences and lack of association with the extent of HCW contact with COVID-19 patients suggest that community rather than hospital virus exposure was a source of many infections.
A cross-sectional study was carried out among 39 current smokers (CS) and 60 noncurrent smokers (NCS) to evaluate the effects of cigarette smoking on folate and vitamin B-12 concentrations in the ...circulation and in tissues directly exposed to cigarette smoke. Univariate analysis showed significantly lower plasma, red blood cell (RBC), and buccal mucosa (BM) folate and BM vitamin B-12 concentrations in CS compared with NCS. The association between smoking and folate and vitamin B-12 concentrations in plasma, RBCs, and BM cells was reduced after other variables were controlled for. Total folate intake and plasma vitamin C concentrations were significant predictors of plasma and RBC folate concentrations. The plasma and RBC concentrations of folate were significantly lower in subjects who had last smoked < 1 h before the blood sample was drawn than in subjects who had smoked earlier. At the current recommended dietary allowance (RDA) for folate, CS had 42% lower plasma folate concentrations than NCS, whereas at an intake three times the RDA, the plasma folate concentration was the same for CS and NCS. The results also suggested that CS have BM folate and vitamin B-12 concentrations that are lower than those of NCS.
Introduction:
In spite of improvement seen in frontline therapies in MCL, a majority of pts still relapse and have then short remissions while developing frequently chemoresistance. A number of novel ...therapies have been developed in r/r MCL showing activity even in chemorefractory pts, including BTK inhibitor ibrutinib (Ib) and immunomodulator lenalidomide (Len), both approved in that setting. Though ibrutinib had been shown to partially antagonize the activity of rituximab particularly ADCC, by suppression of NK cell activity (ITK inhibition), lenalidomide, on the opposite, has been shown to improve rituximab-induced ADCC, providing a rationale for the combination R2-Ib, also supported by higher efficacy seen when combining rituximab with either ibrutinib or lenalidomide with rituximab.
Methods:
Pts with r/r MCL and measurable disease received ibrutinib orally daily at 560 mg and lenalidomide using a 3/3 design dose escalation schedule beginning at 15mg of Len escalated to 20mg on Days 1-21 of each 28-day cycle together with rituximab IV at 375mg/m2 weekly x 4 doses during cycle 1 and on day 1 of cycles 2 to 6 and only on even cycles from cycles 6 to 24. Both Len and Ib were continued until POD or toxicity. Endpoints included maximum tolerated dose (MTD) and RP2D based on safety/toxicity assessment as well as response rate (Cheson criteria (2007). Restaging was performed every 2 cycles for the first 6 cycles and then every 3 cycles afterwards until POD or toxicity or removal for study.
Results:
Among the 16 patients enrolled 14 were treated (one declined after signing consent, the other one was a screening failure (EF drop)). There were 3 females and 11 males, with a median age of 67.5y (range 47-81) and median number of prior lines of therapy of 1 (range 1-4); 10 patients received prior intensive therapy w/ or w/o autologous stem cell transplant, there were 2 blastoid variants and 50% pts had interm/high risk by the sMIPI model. Four pts were treated in the 15 mg lenalidomide cohort (one patient was replaced for DLT) and 10 pts enrolled in the 20 mg cohort.
Results:
A total of 14 pts received treatment, three are too early to evaluate (1 currently in cycle 1 and 2 cycle 2) and 10 are still on therapy. Treatment was overall well tolerated with a total of 75 cycles delivered. Regarding non-hematological toxicities, there was no grade 4 while grade 3 was observed in 57% pts including abdominal pain, ALT/AST increase, diarrhea, erythematous rash, fatigue, hypokalemia, or hyponatremia. Grade 3 rash, fatigue, or diarrhea required dose interruptions of Len and/or Ib in 9 instances with all pts able to resume at full dose after recovery. There was one DLT - hyponatremia during cycle 1 (which led to a 7 day medication hold by his local oncologist and patient declined to continue afterwards). There were 5 Grade 4 related hematological toxicities (neutropenia).There were three SAEs: one fever neutropenia (negative cultures / no sepsis), one grade 3 abdominal pain and diarrhea w/ E. Coli positivity via GI pathogen panel, which resolved quickly and was felt to be unrelated to study treatment. One patient had a grade 5 toxicity w/ cardiac arrest deemed unrelated during cycle 10 (while in CR).
Out of the 10 evaluable pts, 6 pts (60%) responded all CR (Cheson 2007) yielding an ORR=60% (95% CI 35.0% - 85.0%). There were also three SD: one with 45% decrease, one w/ 31% reduction and one w/37% reduction in target lesions and one had POD (blastoid variant) after 2 cycles. One patient retracted from study after 2 cycles and achieving a CR before progressing 8 months later. The median DOR was 7.5 months (range 5.0 - 16 months). With a median follow-up for the entire cohort of 8 months (range 2.0 - 18 months) the progression-free survival (PFS) at 6-months was 91%(95% CI, 65.0% - 100.0%) and at 9-months was 54.6% (95% CI 16.6% - 88.8%). The 6 months overall survival was 100% and 66.7% (95% CI 16.8% - 88.8%) at 9 months.
Conclusion:
The R2-Ib regimen was well tolerated as also observed in the MCL6 (PHILEMON) trial and led to a high CR rate (60%) in r/r MCL c/w results with durable responses, offering a salvage platform in a population who failed several lines of chemotherapy including intensive therapy in most cases.
PFS
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The use of ASCT is highly established as consolidation or salvage for multiple myeloma (MM) and post salvage therapy in non-Hodgkin Lymphomas (NHL), particularly diffuse large B-cell lymphoma (DLBCL) ...with chemosensitive disease, as well as upfront consolidation in PTCL given poor outcomes after standard therapy (Philip et al., NEJM 1995, Kewalramani et al., Br J Haematol 2006, Gisselbrecht et al., J Clin Oncol 2010, Kumar et al., Leukemia 2012). Although a significant number of pts experience long-term disease-free survival following ASCT, those with high-risk disease (i.e.high-risk cytogenetics in MM, primary refractory DLBCL) are likely to present early relapses, particularly in the first 18 months post-ASCT, illustrating the need for better disease control strategies following ASCT. The rapidly rising impact of checkpoint inhibitors in oncology provides an opportunity for its usage as post-ASCT consolidation, especially given the favorable immunologic milieu found in the immediate post-ASCT setting (i.e. decreased T-regs, increased effector T-cells) and minimal expected tumor burden at that time. Here, we report preliminary safety and efficacy data of a Phase I trial evaluating I and N as post-ASCT consolidation.
Pts with the following malignancies were eligible, if they presented at least stable disease after most recent line of therapy: DLBCL: primary refractory or relapsed, PTCL: de novo stage III/IV or relapsed, MM: transplant-naïve with high-risk cytogenetics or relapse within 3 years of upfront ASCT.
Pts were enrolled prior to ASCT, starting in July 2016. Total accrual goal is 42 patients. All pts with DLBCL/PTCL received BEAM (carmustine 300 mg/m2 day -6, etoposide 200 mg/m2 and cytarabine 200 mg/m2 days -5 to -2, melphalan 140 mg/m2 day -1) as conditioning regimen for ASCT, all pts with MM received melphalan 200 mg/m2 on day -1.
For pts who achieved appropriate hematologic recovery (ANC >800/mm3 and platelets > 20,000/mm3), I/N were started between days 14 and 28 post ASCT. The infusion schedule was:
• I: 1 mg/kg; 6 doses Weeks 1, 4, 7, 10, 16, 22
• N: 3 mg/kg; 12 doses Weeks 1, 4, 7, 10, 12, 14, 16, 18, 20, 22, 24, 26
At this time, 25 patients have been enrolled and received at least one dose of I/N. Additional pts are in screening and results will be updated.
Median follow-up from time of first I/N infusion is 24 weeks (range 2-49). Adverse events (AEs) were documented starting week 1, day 1 of I/N infusion. AEs deemed at least possibly related to I and/or N were termed immune-related (irAEs) with 80% of pts developing irAEs of any grade (table 1). Treatment-related AEs of any grade that led to discontinuation of I/N occurred in 6 pts (24% total: colitis 12%, pneumonitis 4%, adrenal crisis 4% and hepatotoxicity 4%). One death attributable to I/N occurred (due to recurrent pneumonitis complicated by parainfluenza). Therapy with systemic steroids for management of irAEs was required for 19 pts (76%). 70% of irAEs improved within one week and 65% resolved within 2 weeks of initiation of steroids. Median time on treatment with I/N for development of irAEs was 9 weeks (range 2-25). For pts who discontinued treatment due to toxicity, the median time on I/N was 5 weeks (range 3-14). Incidence of irAEs was similar across disease groups.
With a median follow-up of 24 weeks, OS is 92% and PFS is 88% for the entire cohort. 100% of the pts with relapsed MM after first ASCT (50% of whom had less than CR to 1st ASCT) are now in stringent complete remission (sCR). 100% of pts with primary refractory DLBCL are in CR (table 2).
The toxicity profile of consolidation with I/N following ASCT was within expectations. Although there has been a significant number of irAEs (80%) given the mechanism of action of these drugs, this rate is not higher than what has been previously reported with I/N combination in other disease settings (Larkin et al., NEJM 2015, Postow et al., NEJM 2015) and all patients except 1 had resolution of irAEs with the use of systemic steroids . With a median follow-up of 6 months, 84% of pts across disease groups are in complete remission. Interestingly, 5 of 6 patients who had early discontinuation due to AEs, presented sustained remission. Correlative studies evaluating blood immunophenotype are being reported in a separate abstract.
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Here, we report on a phase IIa study to determine the intubation rate, survival, viral clearance, and development of endogenous Abs in patients with COVID-19 pneumonia treated with convalescent ...plasma (CCP) containing high levels of neutralizing anti-SARS-CoV-2 Abs. Radiographic and laboratory evaluation confirmed all 51 treated patients had COVID-19 pneumonia. Fresh or frozen CCP from donors with high titers of neutralizing Abs was administered. The nonmechanically ventilated patients (n = 36) had an intubation rate of 13.9% and a 30-day survival rate of 88.9%, and the overall survival rate for a comparative group based on network data was 72.5% (1625/2241). Patients had negative nasopharyngeal swab rates of 43.8% and 73.0% on days 10 and 30, respectively. Patients mechanically ventilated had a day-30 mortality rate of 46.7%; the mortality rate for a comparative group based on network data was 71.0% (369/520). All evaluable patients were found to have neutralizing Abs on day 3 (n = 47), and all but 1 patient had Abs on days 30 and 60. The only adverse event was a mild rash. In this study on patients with COVID-19 disease, we show therapeutic use of CCP was safe and conferred transfer of Abs, while preserving endogenous immune response.
Paul Behaving Badly Richards, E. Randolph; O'Brien, Brandon J
2016, 2016-11-13
eBook
Randolph Richards and Brandon O'Brien explore the complicated persona and teachings of the apostle Paul. Unpacking his personal history and cultural context, they show how Paul both offended Roman ...perspectives and scandalized Jewish sensibilities, revealing a vision of Christian faith that was deeply disturbing to others in his day and remains so in ours.
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