Improved outcomes of large B-cell lymphoma patients treated with CD19 CAR T in the UK over time.

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 'standard-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 in patients with large B-cell lymphoma not fit for autologous transplant.

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.

The ECHELON-2 Trial: 5-year results of a randomized, phase III study of brentuximab vedotin with chemotherapy for CD30-positive peripheral T-cell lymphoma.

BACKGROUND: 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. PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Short contact with nickel causes allergic contact dermatitis: an experimental study.

BACKGROUND: Knowledge about the required duration of exposure for elicitation of allergic nickel dermatitis in nickel-allergic individuals is limited. However, it often has been proposed that short skin contact is safe. OBJECTIVES: To examine whether repeated skin contact with nickel over short time periods (3 × 10 min) can elicit allergic nickel dermatitis. METHODS: Sixteen nickel-allergic adults and 10 controls were exposed to, respectively, nickel- and aluminium-containing discs on each volar forearm and on each earlobe for 3 × 10 min. One arm was pretreated for 24 h with sodium lauryl sulfate (SLS) 0·5% under occlusion before exposure. One aluminium and one nickel exposure site were clinically evaluated, and blood flow was measured with laser Doppler flowmetry at day 2 and day 4. RESULTS: Ten of 16 (63%) nickel-allergic participants developed allergic nickel dermatitis on SLS-pretreated arm skin and three of 16 (19%) developed it on normal skin on the earlobe. On the SLS-pretreated arms of nickel-allergic participants, blood flow increased significantly more on the nickel-exposed skin than on the aluminium-exposed skin on days 2 and 4. No change in clinical reactivity or blood flow was found on normal forearm skin in nickel-allergic participants or on any skin in controls. CONCLUSIONS: This experimental study showed that relatively short repeated skin contact (3 × 10 min) with metallic nickel elicits allergic nickel dermatitis in irritated skin and at sites with previous dermatitis. The results support the restrictions in current nickel regulation.

Pegylated-asparaginase during induction therapy for adult acute lymphoblastic leukaemia: toxicity data from the UKALL14 trial.

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/m2 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.

Filaggrin loss-of-function mutations and incident cancer: a population-based study.

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.

Nickel allergy following European Union regulation in Denmark, Germany, Italy and the U.K.

BACKGROUND: Nickel allergy is common worldwide. It is associated with hand dermatitis, and sensitization is often induced by nickel-releasing jewellery. The European Union (EU) introduced legislation to control nickel content and release from jewellery and other consumer items through the EU Nickel Directive 1994, which came into force in 2001 and is now part of the REACH regulation. OBJECTIVES: To examine the effects of the EU nickel regulations on the prevalence of nickel allergy in four European countries. METHODS: Nickel patch-test data from 180,390 patients were collected from national databases in Denmark, Germany, Italy and the U.K. from between 1985 and 2002 to 2010. Patients with suspected allergic contact dermatitis who had been patch tested with nickel sulfate 5% in petrolatum were included in the analysis. The main outcomes studied were the percentage of positive results to nickel patch tests, and changes in trends with time in an age- and sex-stratified analysis. RESULTS: A statistically significant decrease in nickel allergy was observed in Danish, German and Italian women aged below 30 years. In female patients in the U.K. this was observed between 2004 and 2010. In young men, a statistically significant decrease in nickel allergy was observed in Germany and the U.K., whereas a nonsignificant increase was observed in Italy. CONCLUSIONS: There has been a reduction in the prevalence of nickel allergy in young women, contemporaneous with the introduction of the nickel regulation. A reduction is also suggested in men in Germany and the U.K. A causative effect of the regulatory intervention is the most likely explanation.

Impaired hapten sensitization in patients with autoimmune disease.

An inverse relation between contact allergy and autoimmune diseases is suggested from epidemiological studies. The aim of this study was to investigate susceptibility and reactivity in patients with psoriasis, patients with diabetes and healthy controls in an experimental sensitization study. We sensitized 68 adult individuals (23 patients with psoriasis, 22 patients with diabetes and 23 healthy controls) with diphenylcyclopropenone (DPCP) and assessed challenge responses with visual scoring and ultrasound. Skin biopsies from challenged skin were investigated for differences in down-regulatory mechanisms with immunohistochemistry and gene-expression profiles using microarray technology. The sensitization ratios were 26%, 36% and 65% for the psoriatic, diabetic and healthy groups, respectively. Logistic regression analysis gave an odds ratio (OR) for a patient with psoriasis or diabetes type I of being sensitized to 0·18 [95% confidence interval (CI): 0·039-0·85], P = 0·031 and 0·74 (95% CI: 0·548-1·008), P = 0·056, respectively. A high degree of forkhead box P3-positive (FoxP3(+) ) cells were found in biopsies of positively challenged reactions, but only limited numbers in negatively challenged reactions, with no difference among the groups. No specific mRNA expression was found in the challenged skin of negative elicitation reactions, also indicating no sign of active down-regulation. The study contibutes strongly to the evidence of a decreased susceptibility to develop contact allergy in individuals with autoimmune diseases such as psoriasis.

Pragmatic approach to the clinical work-up of patients with putative allergic disease to metallic orthopaedic implants before and after surgery.

Allergic complications following insertion of metallic orthopaedic implants include allergic dermatitis reactions but also extracutaneous complications. As metal-allergic patients and/or surgeons may ask dermatologists and allergologists for advice prior to planned orthopaedic implant surgery, and as surgeons may refer patients with complications following total joint arthroplasty for diagnostic work-up, there is a continuous need for updated guidelines. This review presents published evidence for patch testing prior to surgery and proposes tentative diagnostic criteria which clinicians can rely on in the work-up of patients with putative allergic complications following surgery. Few studies have investigated whether subjects with metal contact allergy have increased risk of developing complications following orthopaedic implant insertion. Metal allergy might in a minority increase the risk of complications caused by a delayed-type hypersensitivity reaction. At present, we do not know how to identify the subgroups of metal contact allergic patients with a potentially increased risk of complications following insertion of a metal implant. We recommend that clinicians should refrain from routine patch testing prior to surgery unless the patient has already had implant surgery with complications suspected to be allergic or has a history of clinical metal intolerance of sufficient magnitude to be of concern to the patient or a health provider. The clinical work-up of a patient suspected of having an allergic reaction to a metal implant should include patch testing and possibly in vitro testing. We propose diagnostic criteria for allergic dermatitis reactions as well as noneczematous complications caused by metal implants.

Excessive nickel release from earrings purchased from independent shops and street markets--a field study from Warsaw and London.

BACKGROUND: Nickel allergy is frequent and cause morbidity and increased health care costs. OBJECTIVE: The aim of this study was to determine the proportion of inexpensive earrings randomly purchased from stores and street markets in two capitals that gave positive dimethylglyoxime (DMG) test reactions and to determine whether the degree of nickel release was related to shop category. METHODS: Random inexpensive metallic earrings were purchased from stores and vendors in London and Warsaw. A qualitative investigation of nickel release by using the DMG test was performed. RESULTS: DMG testing revealed that respectively 15.1% (n=205) and 18.4% (n=206) of earrings purchased in London and Warsaw released nickel as indicated by positive test outcomes. Stratification by store category showed that DMG test-positive jewellery were mainly purchased from street markets and from stores that were not part of national or international chains. CONCLUSIONS: Despite the EU Nickel Directive having resulted in decreasing prevalence of nickel allergy, a large proportion of inexpensive earrings still release nickel in concentrations that may result in nickel allergy and dermatitis. Authorities should prioritize information campaigns and random inspections as a legislation that is not followed is of limited value.

The association between null mutations in the filaggrin gene and contact sensitization to nickel and other chemicals in the general population.

BACKGROUND: It was recently shown that filaggrin gene (FLG) null mutations are positively associated with nickel sensitization. We have hypothesized that histidine-rich filaggrin proteins in the epidermis chelate nickel ions and prevent their skin penetration and exposure to Langerhans cells. Furthermore, we have proposed that the low degree of genetic predisposition to nickel sensitization found by a Danish twin study was explained by a high prevalence of ear piercing among participants resulting in 'bypassing' of the filaggrin proteins. OBJECTIVES: To investigate the association between FLG null mutations and (nickel) contact sensitization. METHODS: A random sample of 3335 adults from the general population in Denmark was patch tested and genotyped for R501X and 2282del4 in the FLG gene. RESULTS: The combined carrier frequency of FLG null mutations was 8·1%. Nickel, fragrance and contact sensitization to at least one allergen were not associated with FLG null mutations. A crude analysis on women who did not have ear piercings revealed a positive association between FLG null mutations and nickel sensitization [8·3% vs. 2·4%; odds ratio (OR) 3·71, 95% confidence interval (CI) 0·73-18·96] as well as between FLG null mutations and allergic nickel dermatitis (8·3% vs. 1·3%; OR 6·75, 95% CI 1·17-38·91). FLG mutation status and atopic dermatitis were positively associated with neomycin or ethylenediamine sensitization. CONCLUSIONS: This study suggests that FLG null mutations may be a risk factor for the development of nickel sensitization. However, ear piercing was a much stronger risk factor in our general population and we could therefore identify a positive association only in women without ear piercings. Contact sensitization to specific chemicals is related to treatment exposure.

The effect of tobacco smoking and alcohol consumption on the prevalence of self-reported hand eczema: a cross-sectional population-based study.

BACKGROUND: Hand eczema is a prevalent disorder that leads to high health care costs as well as a decreased quality of life. Important risk factors include atopic dermatitis, contact allergy and wet work whereas the role of null mutations in the filaggrin gene complex remains to be clarified. It has been debated whether life-style factors such as tobacco smoking and alcohol consumption are associated with hand eczema. OBJECTIVES: The current study aimed to investigate whether self-reported hand eczema was associated with smoking and alcohol consumption in the general population. METHODS: Between June 2006 and May 2008, a cross-sectional study was performed in the general population in Copenhagen, the capital of Denmark. A random sample of 7931 subjects aged 18-69 years old was invited to participate in a general health examination including a questionnaire; 3471 (44%) participated. Data were analysed with logistic regression analyses and associations were expressed as odds ratios (ORs) with 95% confidence intervals (CI). RESULTS: The prevalence of hand eczema was higher among previous smokers (OR = 1.13; CI = 0.90-1.40), current light smokers (OR = 1.51; CI = 1.14-2.02) and current heavy smokers (OR = 1.38; CI = 0.99-1.92) compared with never-smokers. CONCLUSIONS: Tobacco smoking was positively associated with hand eczema among adults from the general population in Denmark. Apparently, current light smokers (< 15 g daily) had a higher prevalence of hand eczema than current heavy smokers (> 15 g daily) but this needs to be reconfirmed. Alcohol consumption was not associated with hand eczema.

Consumer available permanent hair dye products cause major allergic immune activation in an animal model.

Background p-Phenylenediamine (PPD) and related substances are ingredients of more than two-thirds of oxidative (permanent) hair dyes currently used. Although PPD is a potent skin sensitizer in predictive assays, the extent to which permanent hair dyes sensitize humans has been questioned due to the in-use conditions, e.g. the presence of couplers in the hair dye gel and rapid oxidation using a developer. Objectives To study the skin sensitizing potential of permanent hair dyes in mice. Methods Two different permanent hair dye products containing PPD were studied in CBA mice using a modified version of the local lymph node assay. The colour gel and developer (oxidant) were tested separately and in combination. Response was measured by ear swelling and cytokine production in ear tissue and serum by enzyme-linked immunosorbent assay. The immune cellular response in the draining lymph nodes was analysed by flow cytometry. Results Application of the colour gel both alone and mixed with the developer induced skin production of interleukin (IL)-1beta, tumour necrosis factor-alpha and IL-6 as well as systemic IL-6 release. Both treatments induced B- and T-cell infiltration as well as T-cell proliferation within the draining lymph nodes. Treatment with the mixture induced at least 20% more skin inflammation, cytokine production and CD4+ T-cell activation compared with the colour gel alone. Conclusions Consumer available PPD-containing permanent hair dyes can be potent and rapid immune activators. Mixing the colour gel and developer (oxidant) increased the induction of skin inflammation compared with application of the colour gel alone.

No association between nickel allergy and reporting cosmetic dermatitis from mascara or eye shadow: a cross-sectional general population study.

BACKGROUND: In theory, all pigmented make-up products may contain metal allergens including nickel. Eyelid dermatitis has previously been observed among nickel allergic dermatitis patients following exposure to nickel containing mascara and eye shadow. However, an association between nickel eyelid dermatitis and nickel in make-up products remains controversial. OBJECTIVE: This cross-sectional patch test study investigated whether the frequency of self-reported cosmetic dermatitis from mascara or eye shadow use was higher among nickel allergic Danish women than women without nickel allergy. METHODS: In 2006, a total of 1843 18-69 year old women completed a postal questionnaire including questions on cosmetic dermatitis and were patch tested with nickel sulphate. Data were analysed by logistic regression analyses and associations were expressed as odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS: The prevalence of nickel allergy was similar among women who reported cosmetic dermatitis from eye shadow or mascara and among women who did not report such symptoms. Cosmetic dermatitis was positively associated with self-reported atopic dermatitis and age. CONCLUSION: Overall, no association between having nickel allergy and reporting cosmetic dermatitis from mascara or eye shadow use was found in the general population. This does not exclude a causal relationship in selected cases.

Nickel allergy: relationship between patch test and repeated open application test thresholds.

BACKGROUND: The frequency of nickel allergy varies between different population groups. Exposure regulation has proven effective in decreasing the frequency. Experimental studies with other allergens have shown a significant relation between patch test reactivity and repeated open application test (ROAT) reactivity. OBJECTIVES: This study was aimed at determining the elicitation threshold in nickel-allergic individuals in a patch test and a ROAT, and comparing the threshold from these two test methods. METHODS: Twenty nickel-allergic persons were tested with a dilution series of 19 concentrations in a patch test and a dilution series of three concentrations in a ROAT, with duration of up to 21 days. Eighteen persons with no nickel allergy were included as control group for the ROAT. RESULTS: The predicted dose which will elicit a reaction in 10% of allergic individuals was calculated to be 0.78 microg nickel cm(-2) in the patch test. The threshold for the ROAT (in microg nickel cm(-2) per application) was significantly lower than the threshold for the patch test, while the dose-response for the accumulated ROAT dose at 1 week, 2 weeks and 3 weeks was very similar to the patch test dose-response; indeed, there was no statistically significant difference. CONCLUSIONS: For elicitation of nickel allergy the elicitation threshold for the patch test is higher than the elicitation threshold (per application) for the ROAT, but is approximately the same as the accumulated elicitation threshold for the ROAT. This may be important for risk assessment based on dose-response results from allergic patients.

Incidence of hand eczema in a population-based twin cohort: genetic and environmental risk factors.

BACKGROUND: Population-based studies on the incidence of hand eczema are sparse. OBJECTIVES: The aim of this prospective follow-up study was to determine the incidence rate of hand eczema in a population-based twin cohort. Secondly, the role of genetic factors and other potential risk factors for hand eczema was investigated. METHODS: A questionnaire on self-reported hand eczema was answered by 5610 and 4128 twin individuals in 1996 and 2005, respectively. Data were analysed in a Poisson regression analysis. RESULTS: The crude incidence rate was 8.8 cases per 1000 person-years (95% confidence interval, [CI] 7.7-9.9). Incidence rate ratios (IRRs) dependent on the co-twin's hand eczema status revealed a significant, doubled risk for monozygotic twin individuals with a co-twin affected by hand eczema, compared with dizygotic twin individuals with a co-twin affected by hand eczema (IRR 2.4, 95% CI 1.4-4.1). Also, significantly increased IRRs were found for positive patch test, atopic dermatitis, and wet work. CONCLUSIONS: Hand eczema is still a frequent disease and genetic factors are confirmed important risk factors. Positive patch test, atopic dermatitis and wet work were associated with an increased risk, whereas no association with age, sex, smoking or alcohol was found.

Chromium allergy: significance of both Cr(III) and Cr(VI).

Most studies investigating chromium allergy have been performed with Cr(VI). However, real exposure to chromium from leather products includes both Cr(III) and Cr(VI). We have determined and compared the minimum elicitation threshold (MET) concentration for Cr(III) and Cr(VI) in Cr(VI)-sensitive patients. In addition, reactions to combinations of Cr(III) and Cr(VI) were compared to reactions elicited by Cr(III) and Cr(VI) alone. Dilution series of Cr(III) and Cr(VI) were applied in Finn Chambers on the back of 18 patients. The patches were left for 2 days and readings were done on days 2, 3 and 7. The MET10% for Cr(III) and Cr(VI) was calculated from the dose-response curves to be 0.18 microg/cm2/48 h (6 p.p.m.) and 0.03 microg/cm2/48 h (1 p.p.m.), respectively. No significant differences in the response to combined Cr(III) and Cr(VI) solutions versus single solutions were found. Cr(III) was concluded to play an important role in chromium allergy, because Cr(III) and Cr(VI) were both capable of eliciting eczema at low concentrations. Rather than regarding chromium dermatitis as a result of Cr(VI) allergy alone, it may be more correct to consider it as a result of a combined Cr(III) and Cr(VI) allergy.