Efficacy of venetoclax monotherapy in patients with relapsed chronic lymphocytic leukaemia in the post-BCR inhibitor setting: a UK wide analysis.

Venetoclax is a BCL2 inhibitor with activity in relapsed/refractory (R/R) chronic lymphocytic leukaemia (CLL). We conducted a multi-centre retrospective analysis of 105 R/R CLL patients who received venetoclax pre-National Health Service commissioning. The median age was 67 years and median prior lines was 3 (range: 1-15). 48% had TP53 disruption. At ≥2 lines, 60% received a Bruton Tyrosine Kinase inhibitor (BTKi) and no prior phosphoinositide 3-kinase inhibitor (Pi3Ki), 25% received a Pi3Ki and no prior BTKi, and 10% received both. Patients discontinued B cell receptor inhibitor (BCRi) because of toxicity in 44% and progression in 54%. Tumour lysis syndrome risk was low, intermediate or high in 27%, 25%, and 48% respectively. Overall response was 88% (30% complete response [CR]). The overall response rate was 85% (CR 23%) in BTKi-exposed patients, 92% (CR 38%) in Pi3Ki-exposed patients and 80% (CR 20%) in both (P = 0·59). With a median follow-up of 15·6 months, 1-year progression-free survival was 65·0% and 1-year overall survival was 75·1%. Dose reduction or temporary interruption did not result in an inferior progression-free or discontinuation-free survival. Risk of progression or death after stopping a prior BCRi for progression was double compared to those stopping for other reasons (predominantly toxicity) (Hazard Ratio 2·01 P = 0·05). Venetoclax is active and well tolerated in R/R CLL post ≥1 BCRi. Reason(s) for stopping BCRi influences venetoclax outcomes.

CHOP versus GEM-P in previously untreated patients with peripheral T-cell lymphoma (CHEMO-T): a phase 2, multicentre, randomised, open-label trial.

BACKGROUND: Outcomes with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) or CHOP-like chemotherapy in peripheral T-cell lymphoma are poor. We investigated whether the regimen of gemcitabine, cisplatin, and methylprednisolone (GEM-P) was superior to CHOP as front-line therapy in previously untreated patients. METHODS: We did a phase 2, parallel-group, multicentre, open-label randomised trial in 47 hospitals: 46 in the UK and one in Australia. Participants were patients aged 18 years and older with bulky (tumour mass diameter >10 cm) stage I to stage IV disease (WHO performance status 0-3), previously untreated peripheral T-cell lymphoma not otherwise specified, angioimmunoblastic T-cell lymphoma, anaplastic lymphoma kinase-negative anaplastic large cell lymphoma, enteropathy-associated T-cell lymphoma, or hepatosplenic γδ T-cell lymphoma. We randomly assigned patients (1:1) stratified by subtype of peripheral T-cell lymphoma and international prognostic index to either CHOP (intravenous cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1·4 mg/m2 [maximum 2 mg] on day 1, and oral prednisolone 100 mg on days 1-5) every 21 days for six cycles; or GEM-P (intravenous gemcitabine 1000 mg/m2 on days 1, 8, and 15, cisplatin 100 mg/m2 on day 15, and oral or intravenous methylprednisolone 1000 mg on days 1-5) every 28 days for four cycles. The primary endpoint was the proportion of patients with a CT-based complete response or unconfirmed complete response on completion of study chemotherapy, to detect a 20% superiority of GEM-P compared with CHOP, assessed in all patients who received at least one cycle of treatment and had an end-of-treatment CT scan or reported clinical progression as the reason for stopping trial treatment. Safety was assessed in all patients who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov (NCT01719835) and the European Clinical Trials Database (EudraCT 2011-004146-18). FINDINGS: Between June 18, 2012, and Nov 16, 2016, we randomly assigned 87 patients to treatment, 43 to CHOP and 44 to GEM-P. A planned unmasked review of efficacy data by the independent data monitoring committee in November, 2016, showed that the number of patients with a confirmed or unconfirmed complete response with GEM-P was non-significantly inferior compared with CHOP and the trial was closed early. At a median follow-up of 27·4 months (IQR 16·6-38·4), 23 patients (62%) of 37 assessable patients assigned to CHOP had achieved a complete response or unconfirmed complete response compared with 17 (46%) of 37 assigned to GEM-P (odds ratio 0·52, 95% CI 0·21-1·31; p=0·164). The most common adverse events of grade 3 or worse in both groups were neutropenia (17 [40%] with CHOP and nine [20%] with GEM-P), thrombocytopenia (4 [10%] with CHOP and 13 [30%] with GEM-P, and febrile neutropenia (12 [29%] with CHOP and 3 [7%] with GEM-P). Two patients (5%) died during the study, both in the GEM-P group, from lung infections. INTERPRETATION: The number of patients with a complete response or unconfirmed complete response did not differ between the groups, indicating that GEM-P was not superior for this outcome. CHOP should therefore remain the reference regimen for previously untreated peripheral T-cell lymphoma. FUNDING: Bloodwise and the UK National Institute of Health Research.

Subsoil drain sumps are a key container for Aedes aegypti in Cairns, Australia.

The contribution of subterranean drain sumps to pupal and adult populations of Aedes aegypti is reported for the 1st time in Cairns, Australia. Pupal surveys were used to quantify the relative contribution of drain sumps to the total population of Ae. aegypti by concurrent survey of sump and water-bearing containers in yards of inner-city premises. A total of 854 mosquito pupae were collected, predominantly Ae. aegypti and Culex quinquefasciatus (26.3 and 69.8%, respectively). Drain sumps provided a relatively uncommon (n = 4) but productive source for pupal Ae. aegypti, producing 14.7% of the combined yard and drain sump population. Drain sumps in inner-city Cairns most commonly occurred in parking lots (52.6%). Subsequently, a sticky emergent adult trap (SEAT) was developed to provide a pragmatic method to assess production of Ae. aegypti by drain sumps. A total of 866 adult mosquitoes were trapped from 162 drain sumps over a 48-h exposure period, comprising Ae. aegypti and Cx. quinquefasciatus (21 and 79%, respectively). Advantages of the SEAT are an ability to rapidly count, identify, and sex mosquitoes and to provide specimens for molecular analysis where necessary. The treatment of water-bearing drain sumps is a critical element of control campaigns against Ae. aegypti.

An adulticidal sticky ovitrap for sampling container-breeding mosquitoes.

The efficacy of a standard ovitrap and an ovitrap featuring an internal wall covered by a polybutylene adhesive was compared in field studies in Cairns, Australia. The sticky ovitrap was as effective as the standard ovitrap in detecting Aedes aegypti, with 67.5% and 64% of traps positive for Ae. aegypti, respectively. Significantly higher numbers of Ae. aegypti were collected by traps set outside rather than inside premises. Sticky ovitraps also readily collected Ochlerotatus notoscriptus and, especially, Culex quinquefasciatus. With a 10X hand lens, mosquitoes of these species could readily be identified in traps set for 3 and 7 days. The sticky ovitraps were comparable in cost and as time efficient as standard ovitraps. The greatest advantage of the sticky ovitrap is the collection of adult female mosquitoes, negating the need to rear larvae for identification and providing a faster, more direct measure of the effectiveness of ovipositional attractants than egg counts. Finally, we demonstrated that sticky ovitraps, being adulticidal, have potential as a supplementary control measure, especially for quarantine programs designed to prevent the import and export of container-breeding vector mosquitoes at sea- and airports.