In-class transition (iCT) of proteasome inhibitor-based therapy: a community approach to multiple myeloma management

Abstract Long-term proteasome inhibitor (PI) treatment can improve multiple myeloma (MM) outcomes, but this can be difficult to achieve in clinical practice due to toxicity, comorbidities, and the burden of repeated parenteral administration. US MM-6 (NCT03173092) enrolled transplant-ineligible patients with newly diagnosed MM to receive all-oral ixazomib-lenalidomide-dexamethasone (IRd; ≤39 cycles or until progression or toxicity) following three cycles of bortezomib-based induction. Primary endpoint: 2-year progression-free survival (PFS). Key secondary/exploratory endpoints included overall response rate (ORR), overall survival (OS), safety, quality of life (QoL), treatment satisfaction, and actigraphy. At datacut, in the fully accrued cohort of 140 patients, median age was 73 years with 42% aged ≥75 and 61% deemed frail; 10% of patients were ongoing on treatment. After a median follow-up of 27 months, the 2-year PFS rate was 71% (95% confidence interval: 61–78). ORR increased from 62% at the end of induction to 80% following in-class transition (iCT) to IRd for a median of 11 months. The 2-year OS rate was 86%. The overall safety profile/actigraphy levels were consistent with previous reports; QoL/treatment satisfaction scores were stable with ongoing therapy. iCT to IRd may allow prolonged PI-based therapy with promising efficacy and a tolerable safety profile, while maintaining QoL

Outcomes of Treatment with the Chimeric Antigen Receptor (CAR) T Cell Therapy Lisocabtagene Maraleucel (liso-cel) in the Nonuniversity Setting: Initial Results from the Outreach Study

Background: Currently approved CAR T cell therapies are generally administered as inpatient treatment at university medical centers due to concerns about the frequency, onset, severity, and management of AEs, including cytokine release syndrome (CRS) and neurological events (NEs). Infusion and monitoring of patients who receive CAR T cell therapy at nonuniversity medical centers and in outpatient settings have not been specifically studied. Liso-cel is an investigational, CD19-directed, defined composition, 4-1BB CAR T cell product administered at equal target doses of CD8+ and CD4+ CAR+ T cells. The liso-cel clinical program allows outpatient treatment per investigator discretion, with standardized guidelines for safety monitoring and AE management. Here we present preliminary safety and efficacy outcomes of liso-cel in relapsed/refractory (R/R) aggressive large B-cell lymphoma (LBCL) across inpatient and outpatient settings at nonuniversity medical centers in the OUTREACH study (NCT03744676). Methods: This open-label, multicenter, phase 2 study enrolled adult patients with R/R LBCL at nonuniversity medical centers, including those with university affiliations and centers naïve to CAR T cell therapy. Inclusion criteria included ECOG PS of 0-1, PET-positive disease, adequate organ function, and R/R disease after ≥2 lines of prior systemic therapy including chemoimmunotherapy. Prior autologous HSCT was permitted, but prior allogeneic HSCT was prohibited. After leukapheresis and 3 days of lymphodepleting chemotherapy, patients received liso-cel infusion at a dose of 100 × 106 CAR+ T cells. The primary endpoint was incidence of grade ≥3 CRS, NEs, prolonged cytopenias through day 29, and infections. Secondary endpoints included safety and overall response rate (ORR). All study sites had a multidisciplinary CAR T cell therapy team and standard operating procedures for toxicity monitoring/management of patients treated and/or monitored as outpatients. CRS was graded as per 2014 Lee criteria; NEs were defined as liso-cel-related investigator-assessed events and graded as per NCI CTCAE v4.03. Results: At data cutoff, 34 patients were treated with liso-cel (inpatients, n = 12; outpatients, n = 22); 5 patients were treated at non-Foundation for the Accreditation of Cellular Therapy (FACT)-accredited sites. Demographics and baseline disease characteristics were similar between inpatients and outpatients (Table); overall, median age was 66 years (range, 34-83), 68% had diffuse LBCL not otherwise specified, and 88% were refractory to last therapy. CRS was reported in 4 inpatients (33%) and 9 outpatients (41%), with no grade ≥3 events. NEs were reported in 3 inpatients (25%) and 6 outpatients (27%), with 1 grade 3 event in the outpatient group. Median (range) time to onset of CRS and NEs, respectively, was 2.5 (1-3) and 10 (5-16) days for inpatients and 6 (2-9) and 8.5 (6-13) days for outpatients. Tocilizumab and/or corticosteroid use for CRS and/or NE management was generally low (inpatients, n = 2 [17%]; outpatients, n = 5 [23%]). Overall, the most common (≥45%) treatment-emergent AEs (TEAEs) were neutropenia (76%), leukopenia (50%), and anemia (47%). Prolonged cytopenias (grade ≥3 lab values at Day 29) were reported for 7 (21%) patients. No grade 5 TEAEs were reported. Early (≤ study Day 4) and overall hospitalization in outpatients was 18% and 50%, respectively; median time to hospitalization was 5 (2-9) days and median length of stay was 6 (1-18) days. Among efficacy-evaluable patients (n = 31), ORR was 75% for inpatients and 84% for outpatients; CR rate was 50% and 68%, respectively. Of the 5 patients treated at non-FACT-accredited sites (inpatients, n = 1; outpatients, n = 4), 2 had CRS and/or NEs, but none were grade ≥3 events; none of these patients received tocilizumab or corticosteroids. Of these 5 patients, 1 achieved CR and 1 achieved PR; 2 had stable disease and 1 had progressive disease. Conclusions: Patients with R/R aggressive LBCL were successfully treated with liso-cel and monitored for CAR T cell therapy-related toxicities at nonuniversity medical centers in inpatient and outpatient settings using standard operating procedures and multidisciplinary teams. Incidences of severe CRS and NEs were low, as was tocilizumab and/or corticosteroid use. Liso-cel showed encouraging preliminary efficacy in both inpatients and outpatients. This trial is ongoing and actively recruiting

Rivaroxaban for Thromboprophylaxis in High-Risk Ambulatory Patients with Cancer

BACKGROUND: Ambulatory patients receiving systemic cancer therapy are at varying risk for venous thromboembolism. However, the benefit of thromboprophylaxis in these patients is uncertain. METHODS: In this double-blind, randomized trial involving high-risk ambulatory patients with cancer (Khorana score of ≥2, on a scale from 0 to 6, with higher scores indicating a higher risk of venous thromboembolism), we randomly assigned patients without deep-vein thrombosis at screening to receive rivaroxaban (at a dose of 10 mg) or placebo daily for up to 180 days, with screening every 8 weeks. The primary efficacy end point was a composite of objectively confirmed proximal deep-vein thrombosis in a lower limb, pulmonary embolism, symptomatic deep-vein thrombosis in an upper limb or distal deep-vein thrombosis in a lower limb, and death from venous thromboembolism and was assessed up to day 180. In a prespecified supportive analysis involving the same population, the same end point was assessed during the intervention period (first receipt of trial agent to last dose plus 2 days). The primary safety end point was major bleeding. RESULTS: Of 1080 enrolled patients, 49 (4.5%) had thrombosis at screening and did not undergo randomization. Of the 841 patients who underwent randomization, the primary end point occurred in 25 of 420 patients (6.0%) in the rivaroxaban group and in 37 of 421 (8.8%) in the placebo group (hazard ratio, 0.66; 95% confidence interval [CI], 0.40 to 1.09; P = 0.10) in the period up to day 180. In the prespecified intervention-period analysis, the primary end point occurred in 11 patients (2.6%) in the rivaroxaban group and in 27 (6.4%) in the placebo group (hazard ratio, 0.40; 95% CI, 0.20 to 0.80). Major bleeding occurred in 8 of 405 patients (2.0%) in the rivaroxaban group and in 4 of 404 (1.0%) in the placebo group (hazard ratio, 1.96; 95% CI, 0.59 to 6.49). CONCLUSIONS: In high-risk ambulatory patients with cancer, treatment with rivaroxaban did not result in a significantly lower incidence of venous thromboembolism or death due to venous thromboembolism in the 180-day trial period. During the intervention period, rivaroxaban led to a substantially lower incidence of such events, with a low incidence of major bleeding. (Funded by Janssen and others; CASSINI ClinicalTrials.gov number, NCT02555878.)

Phase 1b dose-escalation study of the selective, noncovalent, reversible Bruton\u27s tyrosine kinase inhibitor vecabrutinib in B-cell malignancies.

Not available