Influence of personalized extended interval dosing on the natalizumab wearing-off effect - a sub-study of the NEXT-MS trial

Background and objectives: Wearing-off symptoms during natalizumab treatment in multiple sclerosis are characterized by an increase of MS-related symptoms prior to natalizumab administration. The influence of extended interval dosing (EID) on wearing-off symptoms are important to consider, as this might cause hesitancy in initiating or continuing EID. Methods: Participants of the NEXT-MS trial, in which treatment intervals are adjusted based on drug concentrations, were divided into two groups: an extended group containing participants with at least one week of additional interval extension, and a group with a fixed interval during the trial (range 4–7 weeks). Changes in the occurrence, frequency, onset, and severity of wearing-off symptoms were evaluated. Results: 255 participants were included (extended group n = 171, fixed group n = 84). The odds on occurrence of wearing-off symptoms in the extended group did not increase after extending the treatment interval. Additional analyses for frequency, onset, and severity of wearing-off symptoms showed no changes over time. Mean decrease in natalizumab drug concentration did not influence the frequency of wearing-off symptoms. Discussion: Wearing-off symptoms were not reinforced by further extending the natalizumab interval. Wearing-off symptoms might increase in a minority of patients after EID, although our data support the view that wearing-off symptoms appear to be unrelated to the decrease in natalizumab trough drug concentrations.</p

Molecular characteristics of carbapenemase-producing Enterobacterales in the Netherlands; results of the 2014–2018 national laboratory surveillance

Objectives: Carbapenem resistance mediated by mobile genetic elements has emerged worldwide and has become a major public health threat. To gain insight into the molecular epidemiology of carbapenem resistance in The Netherlands, Dutch medical microbiology laboratories are requested to submit suspected carbapenemase-producing Enterobacterales (CPE) to the National Institute for Public Health and the Environment as part of a national surveillance system. Methods: Meropenem MICs and species identification were confirmed by E-test and MALDI-TOF and carbapenemase production was assessed by the Carbapenem Inactivation Method. Of all submitted CPE, one species/carbapenemase gene combination per person per year was subjected to next-generation sequencing (NGS). Results: In total, 1838 unique isolates were received between 2014 and 2018, of which 892 were unique CPE isolates with NGS data available. The predominant CPE species were Klebsiella pneumoniae (n = 388, 43%), Escherichia coli (n = 264, 30%) and Enterobacter cloacae complex (n = 116, 13%). Various carbapenemase alleles of the same carbapenemase gene resulted in different susceptibilities to meropenem and this effect varied between species. Analyses of NGS data showed variation of prevalence of carbapenemase alleles over time with blaOXA-48 being predominant (38%, 336/892), followed by blaNDM-1 (16%, 145/892). For the first time in the Netherlands, blaOXA-181, blaOXA-232 and blaVIM-4 were detected. The genetic background of K. pneumoniae and E. coli isolates was highly diverse. Conclusions: The CPE population in the Netherlands is diverse, suggesting multiple introductions. The predominant carbapenemase alleles are blaOXA-48 and blaNDM-1. There was a clear association between species, carbapenemase allele and susceptibility to meropenem

Decrease of natalizumab drug levels after switching from intravenous to subcutaneous administration in patients with multiple sclerosis

Background Natalizumab is effective in the treatment of multiple sclerosis (MS). In 2021, the European Medicines Agency approved the subcutaneous (SC) variant of natalizumab which can be used instead of intravenous administration. However, the course of drug levels varies between administration routes, and the Food and Drug Administration rejected the request for approval of natalizumab SC for reasons that were not disclosed. Our objective was to evaluate the course of natalizumab trough drug levels in patients who switched from natalizumab intravenous to SC on various treatment intervals. Methods The NEXT-MS trial (N=382) investigates personalised treatment of natalizumab, in which infusion intervals are prolonged based on individual natalizumab trough drug levels. In 2021, an amendment was approved allowing participants to switch from intravenous to SC administration with frequent measurements of natalizumab drug levels and antidrug antibodies (ADAs). Results were compared with linear mixed model analyses. Results Until December 2022, 15 participants switched to SC natalizumab. Natalizumab drug levels with SC administration were on average 55% lower compared with intravenous administration (Exp (estimate) 0.45, 95% CI 0.39 to 0.53, p<0.001), leading to very low trough drug levels in three patients on extended treatment intervals. No natalizumab ADAs were detected during intravenous or SC treatment. None of the participants on natalizumab SC showed evidence of MS disease activity. Conclusions Natalizumab trough drug levels can decrease after switching from natalizumab intravenous to SC administration. We advise to monitor trough drug levels in patients with low natalizumab drug levels during intravenous treatment, patients with higher body mass index or patients on extended treatment intervals who switch to SC administration of natalizumab

Sequential versus combination chemotherapy with capecitabine, irinotecan, and oxaliplatin in advanced colorectal cancer (CAIRO): a phase III randomised controlled trial

The optimum use of cytotoxic drugs for advanced colorectal cancer has not been defined. Our aim was to investigate whether combination treatment is better than sequential administration of the same drugs in patients with advanced colorectal cancer. We randomly assigned 820 patients with advanced colorectal cancer to receive either first-line treatment with capecitabine, second-line irinotecan, and third-line capecitabine plus oxaliplatin (sequential treatment; n=410) or first-line treatment capecitabine plus irinotecan and second-line capecitabine plus oxaliplatin (combination treatment; n=410). The primary endpoint was overall survival. Analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov with the number NCT00312000. 17 patients (nine in the sequential treatment group, eight in the combination group) were found to be ineligible and were excluded from the analysis. 675 (84%) patients died during the study: 336 in the sequential group and 339 in the combination group. Median overall survival was 16.3 (95% CI 14.3-18.1) months for sequential treatment and 17.4 (15.2-19.2) months for combination treatment (p=0.3281). The hazard ratio for combination versus sequential treatment was 0.92 (95% CI 0.79-1.08; p=0.3281). The frequency of grade 3-4 toxicity over all lines of treatment did not differ significantly between the two groups, except for grade 3 hand-foot syndrome, which occurred more often with sequential treatment than with combination treatment (13%vs 7%; p=0.004). Combination treatment does not significantly improve overall survival compared with the sequential use of cytotoxic drugs in advanced colorectal cancer. Thus sequential treatment remains a valid option for patients with advanced colorectal cance

Addition of the nuclear export inhibitor selinexor to standard intensive treatment for elderly patients with acute myeloid leukemia and high risk myelodysplastic syndrome

Treatment results of AML in elderly patients are unsatisfactory. In an open label randomized phase II study, we investigated whether addition of the XPO1 inhibitor selinexor to intensive chemotherapy would improve outcome in this population. 102 AML patients > 65 years of age (median 69 (65–80)) were randomly assigned to standard chemotherapy (3 + 7) with or without oral selinexor 60 mg twice weekly (both arms n = 51), days 1–24. In the second cycle, cytarabine 1000 mg/m2 twice daily, days 1–6 with or without selinexor was given. CR/CRi rates were significantly higher in the control arm than in the investigational arm (80% (95% C.I. 69–91%) vs. 59% (45–72%; p = 0.018), respectively). At 18 months, event-free survival was 45% for the control arm versus 26% for the investigational arm (Cox-p = 0.012) and overall survival 58% vs. 33%, respectively (p = 0.009). AML and infectious complications accounted for an increased death rate in the investigational arm. Irrespective of treatment, MRD status after two cycles appeared to be correlated with survival. We conclude that the addition of selinexor to standard chemotherapy does negatively affect the therapeutic outcome of elderly AML patients. (Netherlands Trial Registry number NL5748 (NTR5902), www.trialregister.nl)

Melphalan, prednisone, and lenalidomide versus melphalan, prednisone, and thalidomide in untreated multiple myeloma

The combination of melphalan, prednisone and thalidomide (MPT) is considered standard therapy for newly diagnosed patients with multiple myeloma (NDMM) who are ineligible for stem-cell transplantation. Long term treatment with thalidomide is hampered by neurotoxicity. Melphalan, prednisone and lenalidomide, followed by lenalidomide maintenance therapy showed promising results, without severe neuropathy emerging. We randomly assigned 668 NDMM patients, ineligible for stem-cell transplantation, between nine 4-weekly cycles of MPT followed by thalidomide maintenance until disease progression or unacceptable toxicity (MPT-T) and the same MP regimen with thalidomide being replaced by lenalidomide (MPR-R). This multicenter, open-label, randomised phase 3 trial was undertaken by HOVON and the NMSG. The primary endpoint was progression-free survival (PFS). The accrual for the study was completed in October 19, 2012. 318 patients were randomly assigned to receive MPT-T and 319 MPR-R. After a median follow up of 36 months PFS with MPT-T was 20 months (95% CI 18-23 months) versus 23 months (95% CI 19-27 months) with MPR-R (HR 0.87 [0.72-1.04], p=0.12). Response rates were similar, with ≥VGPR 47% and 45% respectively. Hematological toxicity was more pronounced with MPR-R, especially grade 3 and 4 neutropenia: 64 versus 27%. Neuropathy ≥ grade 3 was significantly higher in the MPT-T arm; 16% versus 2% in MPR-R, resulting in a significant shorter duration of maintenance therapy (5 versus 17 months in MPR-R), irrespective of age. MPR-R has no advantage over MPT-T concerning efficacy. The toxicity profile differed with clinically significant neuropathy during thalidomide maintenance versus myelosuppression with MPR