For patients with peripheral T-cell lymphoma (PTCL), outcomes using frontline treatment with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or CHOP-like therapy are typically poor. ...The ECHELON-2 study demonstrated that brentuximab vedotin plus cyclophosphamide, doxorubicin, and prednisone (A+CHP) exhibited statistically superior progression-free survival (PFS) per independent central review and improvements in overall survival versus CHOP for the frontline treatment of patients with systemic anaplastic large cell lymphoma or other CD30-positive PTCL.
ECHELON-2 is a double-blind, double-dummy, randomized, placebo-controlled, active-comparator phase III study. We present an exploratory update of the ECHELON-2 study, including an analysis of 5-year PFS per investigator in the intent-to-treat analysis group.
A total of 452 patients were randomized (1 : 1) to six or eight cycles of A+CHP (N = 226) or CHOP (N = 226). At median follow-up of 47.6 months, 5-year PFS rates were 51.4% 95% confidence interval (CI): 42.8% to 59.4% with A+CHP versus 43.0% (95% CI: 35.8% to 50.0%) with CHOP (hazard ratio = 0.70; 95% CI: 0.53-0.91), and 5-year overall survival (OS) rates were 70.1% (95% CI: 63.3% to 75.9%) with A+CHP versus 61.0% (95% CI: 54.0% to 67.3%) with CHOP (hazard ratio = 0.72; 95% CI: 0.53-0.99). Both PFS and OS were generally consistent across key subgroups. Peripheral neuropathy was resolved or improved in 72% (84/117) of patients in the A+CHP arm and 78% (97/124) in the CHOP arm. Among patients who relapsed and subsequently received brentuximab vedotin, the objective response rate was 59% with brentuximab vedotin retreatment after A+CHP and 50% with subsequent brentuximab vedotin after CHOP.
In this 5-year update of ECHELON-2, frontline treatment of patients with PTCL with A+CHP continues to provide clinically meaningful improvement in PFS and OS versus CHOP, with a manageable safety profile, including continued resolution or improvement of peripheral neuropathy.
•A total of 452 patients with previously untreated PTCL were randomized (1 : 1) to six or eight cycles of A+CHP or CHOP.•The 5-year PFS rates were 51.4% with A+CHP versus 43.0% with CHOP (hazard ratio = 0.70; 95% CI: 0.53-0.91).•The 5-year OS rates were 70.1% with A+CHP versus 61.0% with CHOP (hazard ratio = 0.72; 95% CI: 0.53-0.99).•Peripheral neuropathy was resolved or improved in 72% of patients in the A+CHP arm and 78% in the CHOP arm.•The ORR was 59% with brentuximab vedotin retreatment after A+CHP and 50% with subsequent brentuximab vedotin after CHOP.
Safety and efficacy data on pegylated asparaginase (PEG-ASP) in adult acute lymphoblastic leukaemia (ALL) induction regimens are limited. The UK National Cancer Research Institute UKALL14 trial ...NCT01085617 prospectively evaluated the tolerability of 1000 IU/m
PEG-ASP administered on days 4 and 18 as part of a five-drug induction regimen in adults aged 25-65 years with de novo ALL. Median age was 46.5 years. Sixteen of the 90 patients (median age 56 years) suffered treatment-related mortality during initial induction therapy. Eight of the 16 died of sepsis in combination with hepatotoxicity. Age and Philadelphia (Ph) status were independent variables predicting induction death >40 versus ⩽40 years, odds ratio (OR) 18.5 (2.02-169.0), P=0.01; Ph- versus Ph+ disease, OR 13.60 (3.52-52.36), P<0.001. Of the 74 patients who did not die, 37 (50.0%) experienced at least one grade 3/4 PEG-ASP-related adverse event, most commonly hepatotoxicity (36.5%, n=27). A single dose of PEG-ASP achieved trough therapeutic enzyme levels in 42/49 (86%) of the patients tested. Although PEG-ASP delivered prolonged asparaginase activity in adults, it was difficult to administer safely as part of the UKALL14 intensive multiagent regimen to those aged >40 years. It proved extremely toxic in patients with Ph+ ALL, possibly owing to interaction with imatinib.
Summary
Large B‐cell lymphoma (LBCL) patients with comorbidities and/or advanced age are increasingly considered for treatment with CD19 CAR T, but data on the clinical benefit of CAR T in the less ...fit patient population are still limited. We analysed outcomes of consecutive patients approved for treatment with axicabtagene ciloleucel (axi‐cel) or tisagenlecleucel (tisa‐cel) by the UK National CAR T Clinical Panel, according to fitness for autologous stem cell transplant (ASCT). 81/404 (20%) of approved patients were deemed unfit for ASCT. Unfit patients were more likely to receive tisa‐cel versus axi‐cel (52% vs. 48%) compared to 20% versus 80% in ASCT‐fit patients; p < 0.0001. The drop‐out rate from approval to infusion was significantly higher in the ASCT‐unfit group (34.6% vs. 23.5%; p = 0.042). Among infused patients, response rate, progression‐free and overall survival were similar in both cohorts. CAR T was well‐tolerated in ASCT‐unfit patients with an incidence of grade ≥3 cytokine release syndrome and neurotoxicity of 2% and 11%, respectively. Results from this multicentre real‐world cohort demonstrate that CD19 CAR T can be safely delivered in carefully selected older patients and patients with comorbidities who are not deemed suitable for transplant.
Summary
Background
Loss‐of‐function mutations in the filaggrin gene (FLG) could have opposing effects on cancer risk, as mutations are associated with both 10% higher serum vitamin D levels, which ...may protect against cancer, and with impaired skin barrier function, which may lead to higher cancer susceptibility.
Objectives
To investigate the association of the FLG genotype and cancer types in four population‐based cohorts.
Methods
A total of 13 376 individuals were genotyped for FLG mutations. Information on cancer was obtained from the Danish Cancer Registry. Persons with a history of cancer at baseline were excluded from prospective analyses.
Results
There were 1339 incident cancers (median follow‐up 11·4 years). The hazard ratios (HRs) and 95% confidence intervals (CIs) for FLG mutation carriers vs. wild types were: for any cancer (HR 0·95, 95% CI 0·78–1·16), any cancer excluding nonmelanoma skin cancer (NMSC) (HR 1·05, 95% CI 0·84–1·31), head and neck cancer (HR 1·72, 95% CI 0·71–4·15), colorectal cancer (HR 0·82, 95% CI 0·44–1·52), bronchus and lung cancer (HR 1·34, 95% CI 0·77–2·33), breast cancer (HR 0·58, 95% CI 0·30–1·14), uterine cancer (HR 0·42, 95% CI 0·06–3·10), prostate cancer (HR 1·09, 95% CI 0·61–1·94), urinary cancer (HR 1·30, 95% CI 0·51–3·29), malignant melanoma (HR 1·03, 95% CI 0·41–2·58) and NMSC (HR 0·70, 95% CI 0·47–1·05). Among participants aged over 60 years at baseline, we found statistically significant lower risks of all cancers and NMSC among FLG mutation carriers.
Conclusions
The only significant associations between FLG loss‐of‐function mutations and cancer were in subgroup analyses.
What's already known about this topic?
Loss‐of‐function mutations in the filaggrin gene (FLG) affect 8–10% of Northern Europeans and result in ichthyosis vulgaris and high risk of atopic dermatitis.
The impaired skin barrier in FLG mutation carriers is associated with 10% higher serum vitamin D levels.
What does this study add?
Apart from a borderline‐significant lower risk of nonmelanoma skin cancer among filaggrin mutation carriers, the filaggrin genotype was not associated with cancer incidence except in subgroup analyses.
Summary
The success of CD19 Chimeric antigen receptor (CAR) T‐cell therapy in large B‐cell lymphoma (LBCL) has been partially offset by toxicity and logistical challenges, which off‐the‐shelf agents ...like CD20xCD3 bispecific antibodies might potentially overcome. However, when using CAR T outcomes as the ʽstandard‐of‐care comparator̕ for relapsed/refractory (r/r) LBCL, a potential learning curve with implementing a novel, complex therapy like CAR T needs to be considered. To address this, we analysed 726 UK patients intended to be treated with CD19 CAR T for r/r LBCL and compared outcomes between the first year of the national CAR T programme (Era 1; 2019) and the more recent treatment era (Era 2; 2020–2022). We identified significant improvements for Era 2 versus Era 1 in dropout rate (17% vs. 27%, p = 0.001), progression‐free survival (1‐year PFS 50% vs. 32%, p < 0.001) and overall survival (1‐year OS 60% vs. 40%, p < 0.001). We also observed increased use of bridging therapy, improvement in bridging outcomes, more tocilizumab/corticosteroid use, reduced high‐grade cytokine release syndrome (4% vs. 9%, p = 0.01) and intensive care unit admissions (20% vs. 32%, p = 0.001). Our results demonstrate significant improvement in CAR T outcomes over time, highlighting the importance of using up‐to‐date clinical data when comparing CAR T against new treatment options for r/r LBCL.
CAR T outcomes in the UK over time.
Summary
In the early 2000s the preservative methylisothiazolinone (MI) was released as an individual preservative for industrial products and, in 2005, it was permitted for use in cosmetic products. ...Up until then MI had been used only in combination with methylchloroisothiazolinone (MCI). MCI/MI is one of the most frequent causes of preservative contact allergy and early studies showed that both MI and MCI are sensitizers. The prevalence of MI contact allergy is already around 1·5% and sources of exposure are associated with occupation, cosmetic products or household products. Use of MI in industrial products is not restricted and cases of occupational contact allergy to MI, e.g. in painters, are reported. The frequency of use of MI in cosmetics is low, around 1%, while up to 16·5% of household products were preserved with MI. We found 19 (1·5%) out of 1272 cosmetic products labelled with MI, primarily rinse‐off products, and analysed the concentration of MI by high‐performance‐liquid‐chromatography the ultraviolet and mass spectrometry detection. The use concentration ranged between 2 and 100 ppm. Repeated exposure to MI showed that many patients allergic to MI reacted to 50 ppm which is half the maximum permitted concentration of MI in cosmetics. The recent cases and prevalence studies on MI contact allergy could be the first sign of an epidemic of MI contact allergy. The development in prevalence of MI contact allergy should be closely monitored by including MI in the European Baseline Series at 2000 ppm.
Background Psoriasis vulgaris could be associated with the filaggrin null genotype since certain known susceptibility loci for psoriasis are shared with susceptibility loci for atopic dermatitis. ...Furthermore, filaggrin expression is lowered in psoriatic skin lesions but normally expressed in uninvolved skin. So far five relatively small patient‐based case‐control studies have rejected a possible association between psoriasis and the two most prevalent filaggrin null mutations, 2282del4 and R501X.
Objectives To reinvestigate a possible association between psoriasis and filaggrin null mutation status by using cross‐sectional general population questionnaire data. Also, to perform a meta‐analysis including published studies that investigated the relation between filaggrin gene mutations R501X and 2282del4, respectively, and psoriasis vulgaris.
Methods Between June 2006 and May 2008, a cross‐sectional study was performed in the general population in Copenhagen. A random sample of 7931 subjects aged 18–69 years was invited to participate in a general health examination including a questionnaire and 3471 (43.7%) participated. A total of 3335 (96.1%) individuals were filaggrin genotyped for the 2282del4 and R501X mutations. A meta‐analysis was undertaken to investigate the relation between filaggrin gene mutations and psoriasis vulgaris.
Results The prevalence of self‐reported psoriasis was 6.7% among the 3240 respondents. The prevalence of the R501X and 2282del4 filaggrin null genotypes was 9.3% in subjects who reported psoriasis and 8.0% in subjects who did not report psoriasis (OR = 1.28; 95% CI = 0.74–1.89; P = 0.78). The meta‐analysis found no association between the filaggrin null genotypes R501X and 2282del4 and psoriasis (OR = 1.04; 95% CI = 0.81–1.35).
Conclusions Psoriasis was not associated with the R501X and 2282del4 filaggrin null genotypes in a general population study and in a meta‐analysis on published studies.
PDF
