Process, resource and success factors associated with chimeric antigen receptor T-cell therapy for multiple myeloma.

Background: Chimeric antigen receptor T-cell (CAR-T) therapy represents a new frontier in multiple myeloma. It is important to understand critical success factors (CSFs) that may optimize its use in this therapeutic area. Methods: We estimated the CAR-T process using time-driven activity-based costing. Information was obtained through interviews at four US oncology centers and with payer representatives, and through publicly available data. Results: The CAR-T process comprises 13 steps which take 177 days; it was estimated to include 46 professionals and ten care settings. CSFs included proactive collaboration, streamlined reimbursement and CAR-T administration in alternative settings when possible. Implementing CSFs may reduce episode time and costs by 14.4 and 13.2%, respectively. Conclusion: Our research provides a blueprint for improving efficiencies in CAR-T therapy, thereby increasing its sustainability for multiple myeloma.

Patients with multiple myeloma can now be treated with chimeric antigen receptor T-cell (CAR-T) therapy. We studied how CAR-T therapy is used for multiple myeloma. We also studied things that could help make this therapy easier for doctors to use. The CAR-T process takes 13 steps and 177 days. It begins with the choice to use the therapy and ends about 100 days after it is used. The process uses 46 different healthcare professionals and ten different locations. We found several possible changes that can improve this process. Of these changes, three stand out. First, improved teamwork between members of the care team can help them prepare for and resolve possible problems. Second, reducing insurance red tape will make it easier to provide CAR-T therapy to patients. Third, allowing use of CAR-T therapy in places other than hospitals can help more patients receive this therapy. If applied, these three things may lower the time needed to treat patients by 14.4% and may reduce costs by 13.2%.

Monotherapy with pixantrone in histologically confirmed relapsed or refractory aggressive B-cell non-Hodgkin lymphoma: post-hoc analyses from a phase III trial.

This post hoc analysis of a phase 3 trial explored the effect of pixantrone in patients (50 pixantrone, 47 comparator) with relapsed or refractory aggressive B-cell non-Hodgkin lymphoma (NHL) confirmed by centralized histological review. Patients received 28-d cycles of 85 mg/m(2) pixantrone dimaleate (equivalent to 50 mg/m(2) in the approved formulation) on days 1, 8 and 15, or comparator. The population was subdivided according to previous rituximab use and whether they received the study treatment as 3rd or 4th line. Median number of cycles was 4 (range, 2-6) with pixantrone and 3 (2-6) with comparator. In 3rd or 4th line, pixantrone was associated with higher complete response (CR) (23·1% vs. 5·1% comparator, P = 0·047) and overall response rate (ORR, 43·6% vs. 12·8%, P = 0·005). In 3rd or 4th line with previous rituximab (20 pixantrone, 18 comparator), pixantrone produced better ORR (45·0% vs. 11·1%, P = 0·033), CR (30·0% vs. 5·6%, P = 0·093) and progression-free survival (median 5·4 vs. 2·8 months, hazard ratio 0·52, 95% confidence interval 0·26-1·04) than the comparator. Similar results were found in patients without previous rituximab. There were no unexpected safety issues. Pixantrone monotherapy is more effective than comparator in relapsed or refractory aggressive B-cell NHL in the 3rd or 4th line setting, independently of previous rituximab.

Prespecified candidate biomarkers identify follicular lymphoma patients who achieved longer progression-free survival with bortezomib-rituximab versus rituximab.

PURPOSE: Identify subgroups of patients with relapsed/refractory follicular lymphoma deriving substantial progression-free survival (PFS) benefit with bortezomib-rituximab versus rituximab in the phase III LYM-3001 study. EXPERIMENTAL DESIGN: A total of 676 patients were randomized to five 5-week cycles of bortezomib-rituximab or rituximab. The primary end point was PFS; this prespecified analysis of candidate protein biomarkers and genes was an exploratory objective. Archived tumor tissue and whole blood samples were collected at baseline. Immunohistochemistry and genetic analyses were completed for 4 proteins and 8 genes. RESULTS: In initial pairwise analyses, using individual single-nucleotide polymorphism genotypes, one biomarker pair (PSMB1 P11A C/G heterozygote, low CD68 expression) was associated with a significant PFS benefit with bortezomib-rituximab versus rituximab, controlling for multiple comparison corrections. The pair was analyzed under dominant, recessive, and additive genetic models, with significant association with PFS seen under the dominant model (G/G+C/G). In patients carrying this biomarker pair [PSMB1 P11A G allele, low CD68 expression (≤50 CD68-positive cells), population frequency: 43.6%], median PFS was 14.2 months with bortezomib-rituximab versus 9.1 months with rituximab (HR 0.47, P < 0.0001), and there was a significant overall survival benefit (HR 0.49, P = 0.0461). Response rates were higher and time to next antilymphoma therapy was longer in the bortezomib-rituximab group. In biomarker-negative patients, no significant efficacy differences were seen between treatment groups. Similar proportions of patients had high-risk features in the biomarker-positive and biomarker-negative subsets. CONCLUSIONS: Patients with PSMB1 P11A (G allele) and low CD68 expression seemed to have significantly longer PFS and greater clinical benefit with bortezomib-rituximab versus rituximab.

Bortezomib plus rituximab versus rituximab in patients with high-risk, relapsed, rituximab-naïve or rituximab-sensitive follicular lymphoma: subgroup analysis of a randomized phase 3 trial.

BACKGROUND: The randomized phase 3 LYM3001 trial in relapsed follicular lymphoma (FL) demonstrated higher overall (ORR) and complete response (CR) rates and prolonged progression-free survival (PFS) with bortezomib-rituximab versus rituximab. We report findings in high-risk patients (FL International Prognostic Index [FLIPI] score ≥3, and high tumor burden by modified Groupe d'Etude des Lymphomas Folliculaires [GELF] criteria). METHODS: Patients aged ≥18 years with grade 1/2 FL, ≥1 measurable lesion, and documented relapse or progression following prior therapy, rituximab-naïve or rituximab-sensitive, were enrolled at 164 centers in 29 countries across Europe, the Americas, and Asia-Pacific. Patients were randomized (1:1) to five 5-week cycles of bortezomib-rituximab (bortezomib 1.6 mg/m2, days 1, 8, 15, and 22, all cycles; rituximab 375 mg/m2, days 1, 8, 15, and 22, cycle 1, and day 1, cycles 2-5; N=336) or rituximab alone (N=340). Randomization was stratified by FLIPI score, prior rituximab, time since last dose of anti-lymphoma therapy, and geographical region. The primary endpoint of the study was PFS. RESULTS: 103 bortezomib-rituximab and 98 rituximab patients had high-risk FL. The ORR was 59% versus 37% (p=0.002), the CR/CRu rate was 13% versus 6% (p=0.145), and the durable response rate was 45% versus 26% (p=0.008) with bortezomib-rituximab versus rituximab. Median PFS was 9.5 versus 6.7 months (hazard ratio [HR] 0.667, p=0.012) with bortezomib-rituximab versus rituximab; median time to progression was 10.9 versus 6.8 months (HR 0.656, p=0.009); median time to next anti-lymphoma treatment was 14.8 versus 9.1 months (HR 0.762, p=0.103); and the 1-year Overall Survival rate was 83.1% versus 76.6%. Overall, 51% of bortezomib-rituximab and 32% of rituximab patients reported grade ≥3 adverse events, including neutropenia (18%, 6%), anemia (4%, 5%), diarrhea (8%, 0%), thrombocytopenia (5%, 2%), and sensory neuropathy (1%, 0%). CONCLUSIONS: High-risk FL patients treated with bortezomib-rituximab had significantly higher ORR and longer PFS than patients receiving rituximab alone, with greater clinical benefit than in the overall study population; additional toxicity was acceptable and did not affect treatment feasibility. TRIAL REGISTRATION: The phase 3 LYM3001 trial is registered with ClinicalTrials.gov, with the identifier NCT00312845.

Bortezomib plus rituximab versus rituximab alone in patients with relapsed, rituximab-naive or rituximab-sensitive, follicular lymphoma: a randomised phase 3 trial.

BACKGROUND: Bortezomib and rituximab have shown additive activity in preclinical models of lymphoma, and have been shown to be active and generally well tolerated in a randomised phase 2 study in patients with follicular and marginal zone lymphoma. We compared the efficacy and safety of rituximab alone or combined with bortezomib in patients with relapsed or refractory follicular lymphoma in a phase 3 setting. METHODS: In this multicentre phase 3 trial, rituximab-naive or rituximab-sensitive patients aged 18 years or older with relapsed grade 1 or 2 follicular lymphoma were randomly assigned (1:1) to receive five 35-day cycles consisting of intravenous infusions of rituximab 375 mg/m(2) on days 1, 8, 15, and 22 of cycle 1, and on day 1 of cycles 2-5, either alone or with bortezomib 1·6 mg/m(2), administered by intravenous injection on days 1, 8, 15, and 22 of all cycles. Randomisation was stratified by FLIPI score, previous use of rituximab, time since last therapy, and region. Treatment assignment was based on a computer-generated randomisation schedule prepared by the sponsor. Patients and treating physicians were not masked to treatment allocation. The primary endpoint was progression-free survival analysed by intention to treat. This trial has been completed and is registered with ClinicalTrials.gov, number NCT00312845. FINDINGS: Between April 10, 2006, and Aug 12, 2008, 676 patients were randomised to receive rituximab (n=340) or bortezomib plus rituximab (n=336). After a median follow-up of 33·9 months (IQR 26·4-39·7), median progression-free survival was 11·0 months (95% CI 9·1-12·0) in the rituximab group and 12·8 months (11·5-15·0) in the bortezomib plus rituximab group (hazard ratio 0·82, 95% CI 0·68-0·99; p=0·039). The magnitude of clinical benefit was not as large as the anticipated prespecified improvement of 33% in progression-free survival. Patients in both groups received a median of five treatment cycles (range 1-5); 245 of 339 (72%) and 237 of 334 (71%) patients in the rituximab and bortezomib plus rituximab groups, respectively, completed five cycles. Of patients who did not complete five cycles, most discontinued early because of disease progression (77 [23%] patients in the rituximab group, and 56 [17%] patients in the bortezomib plus rituximab group). Rates of adverse events of grade 3 or higher (70 [21%] of 339 rituximab-treated patients vs 152 [46%] of 334 bortezomib plus rituximab treated patients), and serious adverse events (37 [11%] patients vs 59 [18%] patients) were lower in the rituximab group than in the combination group. The most common adverse events of grade 3 or higher were neutropenia (15 [4%] patients in the rituximab group and 37 [11%] patients in the bortezomib plus rituximab group), infection (15 [4%] patients and 36 [11%] patients, respectively), diarrhoea (no patients and 25 [7%] patients, respectively), herpes zoster (one [<1%] patient and 12 [4%] patients, respectively), nausea or vomiting (two [<1%] patients and 10 [3%] patients, respectively) and thrombocytopenia (two [<1%] patients and 10 [3%] patients, respectively). No individual serious adverse event was reported by more than three patients in the rituximab group; in the bortezomib plus rituximab group, only pneumonia (seven patients [2%]) and pyrexia (six patients [2%]) were reported in more than five patients. In the bortezomib plus rituximab group 57 (17%) of 334 patients had peripheral neuropathy (including sensory, motor, and sensorimotor neuropathy), including nine (3%) with grade 3 or higher, compared with three (1%) of 339 patients in the rituximab group (no events of grade ≥3). No patients in the rituximab group but three (1%) patients in the bortezomib plus rituximab group died of adverse events considered at least possibly related to treatment. INTERPRETATION: Although a regimen of bortezomib plus rituximab is feasible, the improvement in progression-free survival provided by this regimen versus rituximab alone was not as great as expected. The regimen might represent a useful addition to the armamentarium, particularly for some subgroups of patients. FUNDING: Johnson & Johnson Pharmaceutical Research & Development and Millennium Pharmaceuticals, Inc.