Key findings from the UKCCMP cohort of 877 patients with haematological malignancy and COVID-19: disease control as an important factor relative to recent chemotherapy or anti-CD20 therapy.

Patients with haematological malignancies have a high risk of severe infection and death from SARS-CoV-2. In this prospective observational study, we investigated the impact of cancer type, disease activity, and treatment in 877 unvaccinated UK patients with SARS-CoV-2 infection and active haematological cancer. The primary end-point was all-cause mortality. In a multivariate analysis adjusted for age, sex and comorbidities, the highest mortality was in patients with acute leukaemia [odds ratio (OR) = 1·73, 95% confidence interval (CI) 1·1-2·72, P = 0·017] and myeloma (OR 1·3, 95% CI 0·96-1·76, P = 0·08). Having uncontrolled cancer (newly diagnosed awaiting treatment as well as relapsed or progressive disease) was associated with increased mortality risk (OR = 2·45, 95% CI 1·09-5·5, P = 0·03), as was receiving second or beyond line of treatment (OR = 1·7, 95% CI 1·08-2·67, P = 0·023). We found no association between recent cytotoxic chemotherapy or anti-CD19/anti-CD20 treatment and increased risk of death within the limitations of the cohort size. Therefore, disease control is an important factor predicting mortality in the context of SARS-CoV-2 infection alongside the possible risks of therapies such as cytotoxic treatment or anti-CD19/anti-CD20 treatments.

Integrated safety analysis of umbralisib, a dual PI3Kδ/CK1ε inhibitor, in relapsed/refractory lymphoid malignancies.

Phosphoinositide 3-kinase-δ (PI3Kδ) inhibitors are active in lymphoid malignancies, although associated toxicities can limit their use. Umbralisib is a dual inhibitor of PI3Kδ and casein kinase-1ε (CK1ε). This study analyzed integrated comprehensive toxicity data from 4 open-label, phase 1 and 2 studies that included 371 adult patients (median age, 67 years) with relapsed/refractory non-Hodgkin lymphoma (follicular lymphoma [n = 147]; marginal zone lymphoma [n = 82]; diffuse large B-cell lymphoma/mantle cell lymphoma [n = 74]; chronic lymphocytic leukemia [n = 43]; and other tumor types [n = 25]) who were treated with the recommended phase 2 dose of umbralisib 800 mg or higher once daily. At data cutoff, median duration of umbralisib treatment was 5.9 months (range, 0.1-75.1 months), and 107 patients (28.8%) received umbralisib for ≥12 months. Any-grade treatment-emergent adverse events (AEs) occurred in 366 (98.7%) of 371 patients, with the most frequent being diarrhea (52.3%), nausea (41.5%), and fatigue (31.8%). Grade 3 or higher treatment-emergent AEs occurred in 189 (50.9%) of 371 patients and included neutropenia (11.3%), diarrhea (7.3%), and increased aminotransferase levels (5.7%). Treatment-emergent serious AEs occurred in 95 (25.6%) of 371 patients. AEs of special interest were limited and included pneumonia (29 of 371 [7.8%]), noninfectious colitis (9 of 371 [2.4%]), and pneumonitis (4 of 371 [1.1%]). AEs led to discontinuation of umbralisib in 51 patients (13.7%). Four patients (1.1%) died of AEs, none of which was deemed related to umbralisib. No cumulative toxicities were reported. The favorable long-term tolerability profile and low rates of immune-mediated toxicities support the potential use of umbralisib for the benefit of a broad population of patients with lymphoid malignancies.

Pooled-analysis of Lipegfilgrastim Effectiveness and Safety Among Patients With Blood Malignancies in the Real-world Setting.

BACKGROUND/AIM: The aim of this report was to summarize the real-world experience with lipegfilgrastim as a neutropenia prophylaxis in a large cohort of lymphoma patients receiving immuno-, chemo-therapy. PATIENTS AND METHODS: Observational clinical data were derived from two phase IV studies (NADIR and LEOS) with similar protocols conducted in eight European countries for 677 patients. RESULTS: Categories for risk of febrile neutropenia were predominantly high (54.5%) or intermediate (38.8%). The most frequent patient-associated risk factors were age >65 years (54.4%), female sex (43.9%), hemoglobin <12 g/dL (25.3%), and prior febrile neutropenia (14.5%). The incidence of febrile neutropenia and Grade 3/4 neutropenia was 5.9% and 14.6%, respectively over all cycles of immuno-, chemo-therapy (n=3018). Adverse drug reactions occurred in 74 patients (10.9%), with bone pain (2.2%), myalgia (1.8%), and pyrexia (1.0%) occurring in ≥1% of patients. CONCLUSION: Lipegfilgrastim prophylaxis against chemotherapy-induced neutropenia was effective and well tolerated in lymphoma patients in real-world clinical practice.

COVID-19 mortality in patients with cancer on chemotherapy or other anticancer treatments: a prospective cohort study.

BACKGROUND: Individuals with cancer, particularly those who are receiving systemic anticancer treatments, have been postulated to be at increased risk of mortality from COVID-19. This conjecture has considerable effect on the treatment of patients with cancer and data from large, multicentre studies to support this assumption are scarce because of the contingencies of the pandemic. We aimed to describe the clinical and demographic characteristics and COVID-19 outcomes in patients with cancer. METHODS: In this prospective observational study, all patients with active cancer and presenting to our network of cancer centres were eligible for enrolment into the UK Coronavirus Cancer Monitoring Project (UKCCMP). The UKCCMP is the first COVID-19 clinical registry that enables near real-time reports to frontline doctors about the effects of COVID-19 on patients with cancer. Eligible patients tested positive for severe acute respiratory syndrome coronavirus 2 on RT-PCR assay from a nose or throat swab. We excluded patients with a radiological or clinical diagnosis of COVID-19, without a positive RT-PCR test. The primary endpoint was all-cause mortality, or discharge from hospital, as assessed by the reporting sites during the patient hospital admission. FINDINGS: From March 18, to April 26, 2020, we analysed 800 patients with a diagnosis of cancer and symptomatic COVID-19. 412 (52%) patients had a mild COVID-19 disease course. 226 (28%) patients died and risk of death was significantly associated with advancing patient age (odds ratio 9·42 [95% CI 6·56-10·02]; p<0·0001), being male (1·67 [1·19-2·34]; p=0·003), and the presence of other comorbidities such as hypertension (1·95 [1·36-2·80]; p<0·001) and cardiovascular disease (2·32 [1·47-3·64]). 281 (35%) patients had received cytotoxic chemotherapy within 4 weeks before testing positive for COVID-19. After adjusting for age, gender, and comorbidities, chemotherapy in the past 4 weeks had no significant effect on mortality from COVID-19 disease, when compared with patients with cancer who had not received recent chemotherapy (1·18 [0·81-1·72]; p=0·380). We found no significant effect on mortality for patients with immunotherapy, hormonal therapy, targeted therapy, radiotherapy use within the past 4 weeks. INTERPRETATION: Mortality from COVID-19 in cancer patients appears to be principally driven by age, gender, and comorbidities. We are not able to identify evidence that cancer patients on cytotoxic chemotherapy or other anticancer treatment are at an increased risk of mortality from COVID-19 disease compared with those not on active treatment. FUNDING: University of Birmingham, University of Oxford.

Construction of the secondary care administrative records frailty (SCARF) index and validation on older women with operable invasive breast cancer in England and Wales: a cohort study.

OBJECTIVES: Studies that use national datasets to evaluate the management of older women with breast cancer are often constrained by a lack of information on patient fitness. This study constructed a frailty index for use with secondary care administrative records and evaluated its ability to improve models of treatment patterns and overall survival in women with breast cancer. DESIGN: Retrospective cohort study. PARTICIPANTS: Women aged ≥50 years with oestrogen receptor (ER) positive early invasive breast cancer diagnosed between 2014 and 2017 in England. METHODS: The secondary care administrative records frailty (SCARF) index was based on the cumulative deficit model of frailty, using International Statistical Classification of Diseases, Injuries and Causes of Death, 10th revision codes to define a set of deficits. The index was applied to administrative records that were linked to national cancer registry datasets. The ability of the SCARF index to improve the performance of regression models to explain observed variation in the rate of surgery and overall survival was evaluated using Harrell's c-statistic and decision curve analysis. External validation was performed on a dataset of similar women diagnosed in Wales. RESULTS: The SCARF index captured 32 deficits that cover functional impairment, geriatric syndromes, problems with nutrition, cognition and mood, and medical comorbidities. In the English dataset (n=67 925), the prevalence of frailty in women aged 50-69, 70-79 and ≥80 years was 15%, 28% and 47%, respectively. Adding a frailty measure to regression models containing age, tumour characteristics and comorbidity improved their ability to: (1) discriminate between whether a woman was likely to have surgery and (2) predict overall survival. Similar results were obtained when the models were applied to the Welsh cohort (n=4 230). CONCLUSION: The SCARF index provides a simple and consistent method to identify frailty in population level data and could help describe differences in breast cancer treatments and outcomes.

Health-related quality of life in the phase III GALLIUM study of obinutuzumab- or rituximab-based chemotherapy in patients with previously untreated advanced follicular lymphoma.

Health-related quality of life was a secondary endpoint in the phase III GALLIUM study in previously untreated patients with follicular lymphoma who were treated with rituximab- or obinutuzumab-chemotherapy. Patients were randomized 1:1 to receive induction therapy with obinutuzumab- or rituximab-chemotherapy and maintenance in responders. Health-related quality of life was assessed using the Functional Assessment of Cancer Treatment-Lymphoma questionnaire, incorporating well-being and lymphoma-specific subscales. Assessments were performed at baseline, and during induction, maintenance, and follow-up (maximum 84 months). Clinically meaningful responses were defined by minimally important difference values. Of 1202 randomized patients (median follow-up 57.4 months), 557/601 (92.7%; obinutuzumab-chemotherapy) and 548/601 (91.2%; rituximab-chemotherapy) completed all Functional Assessment of Cancer Treatment-Lymphoma scales at baseline. Mean baseline health-related quality of life scores were similar between both arms, with all patients having some functional impairment and lymphoma symptoms. Over the course of treatment, mean health-related quality of life remained similar in both arms. Equal proportions of patients in both arms achieved minimally important difference by the Functional Assessment of Cancer Treatment-Lymphoma lymphoma-specific subscale and summary scales throughout induction, maintenance, and follow-up. On each summary scale, ~ 50% of patients in each arm achieved minimally important difference by maintenance month 2. In GALLIUM, similar improvements in health-related quality of life were seen with obinutuzumab- and rituximab-chemotherapy, suggesting that both treatments reduced lymphoma-related symptoms, and treatment-related side effects did not abrogate these improvements in well-being. ClinicalTrials.gov identifier: NCT01332968.

Favourable outcomes for high-risk Burkitt lymphoma patients (IPI 3-5) treated with rituximab plus CODOX-M/IVAC: Results of a phase 2 UK NCRI trial.

Introduction: Outcomes after frontline treatment of Burkitt lymphoma (BL) have improved with the introduction of dose-intense chemotherapy regimens, such as CODOX-M/IVAC. While rituximab has increased survival rates for most forms of high-grade B-cell lymphoma, there has previously been hesitancy about incorporating it into BL treatment, partly due to concerns about increased toxicity. Prospective data using the standard dose CODOX-M/IVAC regimen in combination with rituximab are lacking. We conducted a single-arm phase 2 trial to assess the efficacy and toxicity of R-CODOX-M/R-IVAC. Methods: Eligible patients were aged 18-65 years, with newly diagnosed BL with MYC rearrangement as the sole cytogenetic abnormality, and high-risk disease, defined by an International Prognostic Index (IPI) score of 3-5. Patients received two cycles of R-CODOX-M chemotherapy alternating with two cycles of R-IVAC, followed by two further cycles of rituximab alone. The primary endpoint was 2-year progression-free survival. Results: Thirty-eight patients were registered but after central pathology review, 27 patients had confirmed BL and commenced study treatment. Median age was 35 years, 14.8% patients had central nervous system involvement and 18.5% were HIV positive. Twenty-two (81.4%) patients completed four cycles of chemotherapy. There were two treatment-related deaths (7.4%). Two-year progression-free and overall survival rates were 77.2% (90% confidence interval [CI]: 56.0-89.0) and 80.7% (90% CI: 59.6-91.5), respectively. Conclusions: This prospective trial demonstrates excellent survival rates with R-CODOX-M/R-IVAC in a high-risk BL cohort. It provides reassuring evidence regarding the feasibility of this regimen and also provides a benchmark for future studies.

Pixantrone plus rituximab versus gemcitabine plus rituximab in patients with relapsed aggressive B-cell non-Hodgkin lymphoma not eligible for stem cell transplantation: a phase 3, randomized, multicentre trial (PIX306).

PIX306 was a phase 3, randomised, single-blind, multicentre trial conducted in adult patients with diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma (FL) grade 3 who relapsed after ≥1 rituximab-containing regimen and were not eligible for a stem cell transplant. Patients were randomised 1:1 to pixantrone 50 mg/m2 or gemcitabine 1000 mg/m2 on days 1, 8 and 15 of a 28-day cycle, combined with rituximab 375 mg/m2 on day 1, for up to six cycles. Patients were followed for up to 96 weeks. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), complete response (CR) rate, overall response rate (ORR) and safety. Overall, 312 patients were randomised (median age 73·0 years). The study did not meet its primary endpoint. Median PFS [95% confidence interval (CI)] was 7·3 months (5·2-8·4) with pixantrone + rituximab (PIX + R) and 6·3 months (4·4-8·1) with gemcitabine + rituximab [GEM + R; hazard ratio (HR): 0·85; 95% CI 0·64-1·14; P = 0·28]. Median OS was 13·3 (10·1-19·8) months with PIX + R and 19·6 (12·4-31·9) months with GEM + R (HR: 1·13; 95% CI 0·83-1·53). ORR was 61·9% and 43·9% respectively and CR rate 35·5% and 21·7%. The incidence of adverse events, including cardiac events, was not statistically significant different between PIX + R and GEM + R.

Addressing frailty in patients with breast cancer: A review of the literature.

Various studies have documented variation in the management of older patients with breast cancer, and some of this variation stems from different approaches to balancing the expected benefit of different treatments, with the ability of patients to tolerate them. Frailty is an emerging concept that can help to make clinical decisions for older patients more consistent, not least by providing a measure of 'biological' ageing. This would reduce reliance on 'chronological' age, which is not a reliable guide for decisions on the appropriate breast cancer care for older patients. This article examines the potential of frailty assessment to inform on breast cancer treatments. Overall, the current evidence highlights various benefits from implementing comprehensive geriatric assessment and screening for frailty in breast cancer patients. This includes a role in supporting the selection of appropriate therapies and improving physical fitness prior to treatment. However, there are challenges in implementing routine frailty assessments in a breast cancer service. Studies have used a diverse array of frailty assessment instruments, which hampers the generalisability of research findings. Consequently, a number of issues need to be addressed to clearly establish the optimal timing of frailty assessment and the role of geriatric medicine specialists in the breast cancer care pathway.

Relaxation and exercise in lymphoma survivors (REIL study): a randomised clinical trial protocol.

BACKGROUND: Lymphoma survivors commonly report ongoing complaints including fatigue, pain, depression and decreased quality of life (QoL) following treatment. Although evidence suggests that both relaxation and exercise can significantly improve such symptoms, there is no consensus on which intervention is more effective. This paper presents the REIL (Relaxation and Exercise In Lymphoma) Study protocol. The REIL study aims to compare the effect of two home-based interventions - relaxation and exercise - on QoL in lymphoma survivors. METHODS: Eligible participants (n = 36) will be randomised to a relaxation or exercise programme to perform at least three times per week. The primary outcome measure is QoL, assessed by the European Organisation for Research and Treatment of Cancer QoL Questionnaire Core 30 (EORTC QLQ-C30). Secondary outcome measures include body composition, cardiovascular status, pulmonary function, grip strength, functional exercise capacity (six minute walk test), well-being assessed by the FACT-Lym questionnaire, and psychological status assessed by the Hospital Anxiety and Depression Scale. Total duration of the study will be twelve weeks and outcome measures will be assessed at baseline, six weeks and at the end of the study. DISCUSSION: It is anticipated that results from this preliminary study will begin to highlight effective pathways to improve QoL following chemotherapy for this population. This will better inform healthcare professionals to optimise QoL of lymphoma patients, and enable a smooth transition from being a cancer patient to survivor. TRIAL REGISTRATION: The REIL study has been registered on a publicly accessible database, ClinicalTrials.gov, Registration Number: NCT02272751, October 2014.

Positron Emission Tomography Score Has Greater Prognostic Significance Than Pretreatment Risk Stratification in Early-Stage Hodgkin Lymphoma in the UK RAPID Study.

PURPOSE: Accurate stratification of patients is an important goal in Hodgkin lymphoma (HL), but the role of pretreatment clinical risk stratification in the context of positron emission tomography (PET) -adapted treatment is unclear. We performed a subsidiary analysis of the RAPID trial to assess the prognostic value of pretreatment risk factors and PET score in determining outcomes. PATIENTS AND METHODS: Patients with stage IA to IIA HL and no mediastinal bulk underwent PET assessment after three cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine; 143 PET-positive patients (PET score, 3 to 5) received a fourth doxorubicin, bleomycin, vinblastine, and dacarbazine cycle and involved-field radiotherapy, and 419 patients in complete metabolic remission were randomly assigned to receive involved-field radiotherapy (n = 208) or no additional treatment (n = 211). Cox regression was used to investigate the association between PET score and pretreatment risk factors with HL-specific event-free survival (EFS). RESULTS: High PET score was associated with inferior EFS, before (P < .001) and after adjustment (P = .01) for baseline risk stratification. Only patients with a postchemotherapy PET score of 5 (uptake ≥ three times maximum liver uptake) had an increased risk of progression or HL-related death (hazard ratio, 9.4 v score of 3; 95% CI, 2.8 to 31.3 and hazard ratio, 6.7 v score of 4; 95% CI, 1.4 to 31.7). Patients with a PET score of 5 also had inferior progression-free and overall survival. There was no association between European Organisation for Research and Treatment of Cancer or German Hodgkin Study Group risk group and EFS, before or after adjusting for PET score (all P > .4). CONCLUSION: In RAPID, a positive PET scan did not carry uniform prognostic weight; only a PET score of 5 was associated with inferior outcomes. This suggests that in future trials involving patients without B symptoms or mediastinal bulk, a score of 5 rather than a positive PET result should be used to guide treatment escalation in early-stage HL.

Surgery and adjuvant radiotherapy for unilateral ductal carcinoma in situ (DCIS) in women aged over 70 years: A population based cohort study.

BACKGROUND: There is little clinical evidence to guide treatment decisions for ductal carcinoma in situ (DCIS) in older women. This study evaluated how the management of DCIS in women aged 70 or more compared with women aged 50-69 in England and Wales. METHOD: The study identified women aged ≥50 years with new unilateral DCIS diagnosed between 2014 and 2016 from linked cancer registration and routine hospital datasets for England and Wales. Rates of surgery and adjuvant radiotherapy were examined by age, deprivation, fitness measures (comorbidity and frailty), method of presentation and tumour grade using multilevel logistic regression. RESULTS: 12,716 women were diagnosed with unilateral DCIS between 2014 and 2016, of whom 2,754 (22%) were aged ≥70 years and 74% were screen detected. High grade DCIS was common, irrespective of age and method of presentation. Fewer women aged ≥70 had surgery compared to women aged 50-69 (81% vs. 94%), which was only partly explained by poor fitness. Use of radiotherapy following breast conserving surgery was strongly associated with grade, and was received by less than 16% of all patients with low grade tumours. Over 70% of women aged 50-69 with high grade DCIS received radiotherapy, but this fell to 35% among women aged ≥80. Use of radiotherapy was not associated with patient fitness. CONCLUSION: Treatment decisions for women with DCIS varied by age at diagnosis. Lower rates of surgery and adjuvant radiotherapy in older women were only partly explained by patient fitness. Better evidence is needed to aid treatment selection for older women with DCIS.

Treatment of aggressive B-cell non-Hodgkin lymphoma beyond frontline therapy in patients not eligible for stem cell transplantation: a structured review.

Aggressive B-cell non-Hodgkin lymphoma (aNHL) accounts for ∼50% of all NHL cases. The only potentially curative, broadly available treatment for patients with relapse, failing frontline treatment, is high-dose therapy followed by autologous stem cell transplantation (ASCT); patients ineligible for/who have failed ASCT have limited standard-of-care options. We conducted a structured review of treatments for relapsed/refractory patients with aNHL based on literature published between 2006 and 2017. Of the 22 publications identified for inclusion, most described phase II, single-arm trials (N = 25-217), and only three were randomized studies (phase II [N = 96], phase II/III [N = 111] and phase III [N = 338]). The majority of treatments evaluated resulted in only modest efficacy (median progression-free survival, 2.1-20.0 months) and ultimately poor health outcomes (median overall survival, 25 weeks-15.5 months). In conclusion, there is an unmet need for novel, effective, and tolerable treatments for patients with relapsed/refractory aNHL who are ineligible for/have failed ASCT.

Real-world safety experience of tevagrastim/ratiograstim/biograstim and tbo-filgrastim, short-acting recombinant human granulocyte colony-stimulating factors.

PURPOSE: Recombinant granulocyte colony-stimulating factors (rG-CSFs), such as filgrastim, are administered to prevent complications in patients receiving chemotherapy. In Europe, a biosimilar to filgrastim, tevagrastim/ratiograstim/biograstim, was approved in 2008. In the USA, the same product was approved as tbo-filgrastim under a 351(a) biologic license application in 2012 with the brand name Granix®. Postmarket surveillance remains a priority for monitoring the safety of biologics and biosimilars to identify rare and immunogenicity-related events. We report the global and US pharmacovigilance data for tevagrastim/ratiograstim/biograstim and tbo-filgrastim, respectively. METHODS: Cumulative exposure and adverse event data from initial approval in Europe to December 31, 2016, were collected globally from spontaneous reports submitted by healthcare professionals and consumers, scientific literature, competent authorities, and solicited case reports from non-interventional studies. A separate search was conducted on the global data set to identify reports originating from the USA and Puerto Rico to describe the US experience. RESULTS: Overall, the global safety profile of tevagrastim/ratiograstim/biograstim in the postmarket, real-world setting was comparable to clinical trial experience. Postmarket safety experience of tbo-filgrastim in the USA was consistent with global data. The most common SAEs were febrile neutropenia and decreased white blood cell count. The most common non-serious event was bone pain. There was no evidence of immunogenicity. CONCLUSIONS: This pharmacovigilance analysis indicates that postmarket experience of tevagrastim/ratiograstim/biograstim and tbo-filgrastim is consistent with clinical trials. Adverse reactions associated with the originator rG-CSF (capillary leak syndrome and glomerulonephritis) have not been observed with tevagrastim/ratiograstim/biograstim or tbo-filgrastim during the postmarket period.

Long-Term Response and Remission with Pixantrone in Patients with Relapsed or Refractory Aggressive Non-Hodgkin Lymphoma: Post-Hoc Analysis of the Multicenter, Open-Label, Randomized PIX301 Trial.

BACKGROUND: Pixantrone is recommended in relapsed and refractory non-Hodgkin lymphoma (NHL) or heavily pretreated NHL patients. Its conditional approval in Europe was based on results from the open-label, randomized, phase 3 PIX301 study, comparing pixantrone monotherapy with physician's choice of treatment in 140 patients with relapsed or refractory aggressive NHL. METHODS: This post-hoc analysis of the PIX301 study investigated possible correlations between patient characteristics and clinical response in 17 patients (24%) treated with pixantrone who achieved a complete response (CR) or an unconfirmed complete response (CRu) at study end. RESULTS: These patients (10 male and 7 female) had a median age of 61 (range 41-75) years, and the most common diagnoses were diffuse large B-cell lymphoma (n = 10) and transformed indolent lymphoma (n = 4). Most had received two prior lines of therapy (n = 12). There was wide variation in the time from diagnosis to study entry (219-4777 days). Among the 17 patients who achieved a CR/CRu with pixantrone, 6 had stable or progressive disease as a response to their last regimen, 7 had a partial response, and 4 had a CR/CRu. Four patients from the pixantrone group survived without progression for more than 400 days. Prior response to previous therapies did not appear to affect long-term response to pixantrone. CONCLUSIONS: These observations suggest that pixantrone monotherapy in patients with multiply relapsed or refractory aggressive NHL who had received at least two prior therapies can be associated with durable responses and long-term remission, and this may be unrelated to the clinical response to the last therapy.

Immunoglobulin G; structure and functional implications of different subclass modifications in initiation and resolution of allergy.

IgE and not IgG is usually associated with allergy. IgE lodged on mast cells in skin or gut and basophils in the blood allows for the prolonged duration of allergy through the persistent expression of high affinity IgE receptors. However, many allergic reactions are not dependent on IgE and are generated in the absence of allergen specific and even total IgE. Instead, IgG plasma cells are involved in induction of, and for much of the pathogenesis of, allergic diseases. The pattern of IgG producing plasma cells in atopic children and the tendency for direct or further class switching to IgE are the principle factors responsible for long-lasting sensitization of mast cells in allergic children. Indirect class switching from IgG producing plasma cells has been shown to be the predominant pathway for production of IgE while a Th2 microenvironment, genetic predisposition, and the concentration and nature of allergens together act on IgG plasma cells in the atopic tendency to undergo further immunoglobulin gene recombination. The seminal involvement of IgG in allergy is further indicated by the principal role of IgG4 in the natural resolution of allergy and as the favourable immunological response to immunotherapy. This paper will look at allergy through the role of different antibodies than IgE and give current knowledge of the nature and role of IgG antibodies in the start, maintenance and resolution of allergy.

Inhibition of HOX/PBX dimer formation leads to necroptosis in acute myeloid leukemia cells.

The HOX genes encode a family of transcription factors that have key roles in both development and malignancy. Disrupting the interaction between HOX proteins and their binding partner, PBX, has been shown to cause apoptotic cell death in a range of solid tumors. However, despite HOX proteins playing a particularly significant role in acute myeloid leukemia (AML), the relationship between HOX gene expression and patient survival has not been evaluated (with the exception of HOXA9), and the mechanism by which HOX/PBX inhibition induces cell death in this malignancy is not well understood. In this study, we show that the expression of HOXA5, HOXB2, HOXB4, HOXB9, and HOXC9, but not HOXA9, in primary AML samples is significantly related to survival. Furthermore, the previously described inhibitor of HOX/PBX dimerization, HXR9, is cytotoxic to both AML-derived cell lines and primary AML cells from patients. The mechanism of cell death is not dependent on apoptosis but instead involves a regulated form of necrosis referred to as necroptosis. HXR9-induced necroptosis is enhanced by inhibitors of protein kinase C (PKC) signaling, and HXR9 combined with the PKC inhibitor Ro31 causes a significantly greater reduction in tumor growth compared to either reagent alone.