Maintenance Chemotherapy

High risk neuroblastoma (HRNB) accounts for 15% of all pediatric cancer deaths. Despite aggressive therapy approximately half of patients will relapse, typically with only transient responses to second-line therapy. This study evaluated the ornithine decarboxylase inhibitor difluoromethylornithine (DFMO) as maintenance therapy to prevent relapse following completion of standard therapy (Stratum 1) or after salvage therapy for relapsed/refractory disease (Stratum 2). This Phase II single agent, single arm multicenter study enrolled from June 2012 to February 2016. Subjects received 2 years of oral DFMO (750 ± 250 mg/m2 twice daily). Event free survival (EFS) and overall survival (OS) were determined on an intention-to-treat (ITT) basis. 101 subjects enrolled on Stratum 1 and 100 were eligible for ITT analysis; two-year EFS was 84% (±4%) and OS 97% (±2%). 39 subjects enrolled on Stratum 2, with a two-year EFS of 54% (±8%) and OS 84% (±6%). DFMO was well tolerated. The median survival time is not yet defined for either stratum. DFMO maintenance therapy for HRNB in remission is safe and associated with high EFS and OS. Targeting ODC represents a novel therapeutic mechanism that may provide a new strategy for preventing relapse in children with HRNB.

The evolving paradigm of continuous therapy and maintenance treatment approaches in multiple myeloma (MM) offers prolonged disease control and improved outcomes compared to traditional fixed-duration approaches. Potential benefits of long-term strategies include sustained control of disease symptoms, as well as continued cytoreduction and clonal control, leading to unmeasurable residual disease and the possibility of transforming MM into a chronic or functionally curable condition. "Continuous therapy" commonly refers to administering a doublet or triplet regimen until disease progression, whereas maintenance approaches typically involve single-agent or doublet treatment following more intensive prior therapy with autologous stem cell transplant (ASCT) or doublet, triplet, or even quadruplet induction therapy. However, the requirements for agents and regimens within these contexts are similar: treatments must be tolerable for a prolonged period of time, should not be associated with cumulative or chronic toxicity, should not adversely affect patients' quality of life, should ideally be convenient with a minimal treatment burden for patients, and should not impact the feasibility or efficacy of subsequent treatment at relapse. Multiple agents have been and are being investigated as long-term options in the treatment of newly diagnosed MM (NDMM), including the immunomodulatory drugs lenalidomide and thalidomide, the proteasome inhibitors bortezomib, carfilzomib, and ixazomib, and the monoclonal antibodies daratumumab, elotuzumab, and isatuximab. Here we review the latest results with long-term therapy approaches in three different settings in NDMM: (1) maintenance treatment post ASCT; (2) continuous frontline therapy in nontransplant patients; (3) maintenance treatment post-frontline therapy in the nontransplant setting. We also discuss evidence from key phase 3 trials. Our review demonstrates how the paradigm of long-term treatment is increasingly well-established across NDMM treatment settings, potentially resulting in further improvements in patient outcomes, and highlights key clinical issues that will need to be addressed in order to provide optimal benefit.

BackgroundStandard-of-care antiretroviral therapy (ART) uses a combination of drugs deemed essential to minimise treatment failure and drug resistance. Protease inhibitors are potent, with a high genetic barrier to resistance, and have potential use as monotherapy after viral load suppression is achieved with combination treatment. We aimed to assess clinical risks and benefits of protease inhibitor monotherapy in long-term clinical use: in particular, the effect on drug resistance and future treatment options.MethodsIn this pragmatic, parallel-group, randomised, controlled, open-label, non-inferiority trial, we enrolled adults (≥18 years of age) positive for HIV attending 43 public sector treatment centres in the UK who had suppressed viral load (FindingsBetween Nov 4, 2008, and July 28, 2010, we randomly allocated 587 participants to OT (291) or PI-mono (296). At 3 years, one or more future drug options had been lost in two participants (Kaplan-Meier estimate 0·7%) in the OT group and six (2·1%) in the PI-mono group: difference 1·4% (-0·4 to 3·4); non-inferiority shown. 49 (16·8%) participants in the OT group and 65 (22·0%) in the PI-mono group had grade 3 or 4 clinical adverse events (difference 5·1% [95% CI -1·3 to 11·5]; p=0·12); 45 (six treatment related) and 56 (three treatment related) had serious adverse events.InterpretationProtease inhibitor monotherapy, with regular viral load monitoring and prompt reintroduction of combination treatment for rebound, preserved future treatment options and did not change overall clinical outcomes or frequency of toxic effects. Protease inhibitor monotherapy is an acceptable alternative for long-term clinical management of HIV infection.FundingNational Institute for Health Research.

Upadacitinib (UPA) is a selective Janus kinase 1 inhibitor that improves moderate-to-severe atopic dermatitis, but real-world strategies to maintain remission after response remain unclear. We conducted a multicenter retrospective study in Japan of 219 patients aged ≥ 12 years who achieved protocol-defined remission, defined as Investigator's Global Assessment (IGA) 0/1 at two visits ≥ 4 weeks apart during UPA treatment. Patients were classified as on-label (continuous daily 15 or 30 mg), spacing/reduction (extension of the dosing interval and/or dose-reduction after remission), or discontinuation (stopping UPA after remission). The primary endpoint was maintenance of remission over 48 weeks; secondary endpoints were time to relapse, outcomes after treatment modification, remission at 72 weeks after ≥ 24 weeks of sustained remission, and safety. Because the analysis was restricted to responders who achieved remission, generalizability to all UPA-treated patients is limited. Seventy-five percent of patients achieved IGA 0/1 within about 4 months of starting UPA. Over the subsequent 48 weeks, 127/200 (63.5%, 95% CI 56.6-69.9) maintained IGA 0/1. When stratified by post-remission dosing strategy (n = 193; excluding 7 who switched to other systemic therapy), remission at 48 weeks was maintained in 93/145 (64.1%, 95% CI 55.8-71.9) in the on-label group, 24/32 (75.0%, 95% CI 56.6-88.5) in the spacing/reduction group, and 6/16 (37.5%, 95% CI 15.2-64.6) in the discontinuation group. Among patients with ≥ 24 weeks of sustained remission, week-72 IGA 0/1 maintenance rates were 70.7% (95% CI 60.7-79.1; n = 107), 100% (95% CI 63.1-100.0; n = 8), and 60.0% (95% CI 20.0-90.0; n = 5) in the on-label, spacing/reduction, and discontinuation groups, respectively; estimates for spacing/reduction and discontinuation were imprecise due to small sample sizes. Longer on-label treatment before tapering or discontinuation tended to be associated with a lower relapse risk. UPA showed a safety profile consistent with previous studies. Acne, herpes simplex, herpes zoster, and folliculitis were the most frequent adverse events, and most were mild and manageable, although one herpes zoster case required temporary interruption. In this responder-enriched real-world Japanese cohort, UPA induced remission in most patients within 4 months and allowed approximately two-thirds to maintain remission over 48 weeks. Observed outcomes suggest that maintaining on-label dosing and cautious spacing/reduction after sustained remission may help preserve disease control, whereas discontinuation may be associated with a higher risk of relapse; however, comparisons between dosing strategies are descriptive and hypothesis-generating. Prospective studies are needed to confirm these findings.