Matching-Adjusted Indirect Comparison of Brexucabtagene Autoleucel (ZUMA-2) and Pirtobrutinib (BRUIN) in Patients with Relapsed/Refractory Mantle Cell Lymphoma Previously Treated with a Covalent Bruton Tyrosine Kinase Inhibitor.

INTRODUCTION: Patients with relapsed/refractory (R/R) mantle cell lymphoma (MCL) often require multiple lines of treatment and have a poor prognosis, particularly after failing covalent Bruton tyrosine kinase inhibitor (cBTKi) therapy. Newer treatments such as brexucabtagene autoleucel (brexu-cel, chimeric antigen receptor T cell therapy) and pirtobrutinib (non-covalent BTKi) show promise in improving outcomes. METHODS: Without direct comparative evidence, an unanchored matching-adjusted indirect comparison was conducted to estimate the relative treatment effects of brexu-cel and pirtobrutinib for post-cBTKi R/R MCL. Using logistic propensity score models, individual patient-level data from ZUMA-2 brexu-cel-infused population (N = 68) were weighted to match pre-specified clinically relevant prognostic factors based on study-level data from the BRUIN cBTKi pre-treated cohort (N = 90). The base-case model incorporated the five most pertinent factors reported in ≥ 50% of both trial populations: morphology, MCL International Prognostic Index, number of prior lines of therapy, disease stage, and prior autologous stem cell transplant. A sensitivity analysis additionally incorporated TP53 mutation and Ki-67 proliferation. Relative treatment effects were expressed as odds ratios (ORs) or hazard ratios (HRs) with 95% confidence intervals (CIs). RESULTS: In the base-case model, brexu-cel was associated with higher rates of objective response (OR 10.39 [95% CI 2.81-38.46]) and complete response (OR 10.11 [95% CI 4.26-24.00]), and improved progression-free survival (HR 0.44 [95% CI 0.25-0.75]), compared to pirtobrutinib. Overall survival and duration of response favored brexu-cel over pirtobrutinib but the differences crossed the bounds for statistical significance. Findings were consistent across the adjusted and unadjusted analyses. CONCLUSIONS: Findings suggest that brexu-cel may offer clinically and statistically significant benefits regarding objective response, complete response, and progression-free survival compared to pirtobrutinib among patients with R/R MCL after prior cBTKi therapy. Given the short follow-up and high degree of censoring in BRUIN, an analysis incorporating updated BRUIN data may provide more definitive overall survival results.

Health Care Resource Utilization and Total Costs of Care for Adult Patients With Relapsed or Refractory Acute Lymphoblastic Leukemia in the United States: A Retrospective Claims Analysis.

PURPOSE: Although immunotherapies such as blinatumomab and inotuzumab have led to improved outcomes, financial burden and health resource utilization (HRU) have increased for adult patients with relapsed or refractory B-cell acute lymphoblastic leukemia (R/R B-ALL). This study assessed real-world HRU and costs of care among adult patients with R/R B-ALL by line of therapy (LoT) in the United States. METHODS: We selected patients from the MarketScanⓇ Database (January 1, 2016 through December 31, 2020) as follows: ≥1 claims of ALL-indicated first-line (1L) therapies, ≥1 diagnosis of ALL before the index date (1L initiation date), 6-month continuous enrollment before the index date, second-line (2L) therapy initiation, ≥18 years old at 2L, no clinical trial enrollment, no diagnosis of other forms of non-Hodgkin's lymphoma, and no claim for daratumumab or nelarabine during the study period. Outcome measures included claim-based time to next treatment (TTNT), all-cause and adverse event (AE)-related HRU, and all-cause and AE-related costs. FINDINGS: The R/R B-ALL cohort (N = 203) was 60% male, median age of 41 years, and median Charlson Comorbidity Index score of 3.0. Mean (SD) follow-up was 17.8 (11.8) months. Of those who received 2L, 55.7% (113/203) required 3L, and 15% (30/203) initiated 4L+. Patients relapsed quickly, with a median TTNT of 170 days, 169 days, and 205 days for 2L, 3L, and 4L+, respectively. Hospitalization rates were high across each LoT (2L, 88%; 3L, 73%; 4L+, 73%), and the mean (SD) inpatient length of stay increased by LoT as follows: 8.6 (6.8) days for 2L, 10.6 (13.3) for 3L, and 11.6 (13.6) for 4L+. Mean (SD) overall costs were substantial within each LoT at $513,279 ($599,209), $340,419 ($333,555), and $390,327 ($332,068) for 2L, 3L, and 4L+, respectively. The mean (SD) overall/per-patient-per-month AE-related costs were $358,676 ($497,998) for 2L, $202,621 ($272,788) for 3L, and $210,539 ($267,814) for 4L+. Among those receiving blinatumomab or inotuzumab within each LoT, the mean (SD) total costs were $566,373 ($621,179), $498,070 ($376,260), and $512,908 ($159,525) for 2L, 3L, and 4L+, respectively. IMPLICATIONS: These findings suggest that adult patients with R/R B-ALL relapse frequently with standard of care and incur a substantial HRU and cost burden with each LoT. Those treated with blinatumomab or inotuzumab incurred higher total costs within each LoT compared with the overall R/R B-ALL cohort. Alternative therapies with longer duration of remission are urgently needed, and HRU should be considered for future studies examining the optimal sequencing of therapy.

Chimeric antigen receptor T-cell treatment patterns in relapsed or refractory large B-cell lymphoma.

Aim: To investigate real-world chimeric antigen receptor (CAR) T-cell therapy treatment patterns. Patient & methods: Relapsed/refractory large B-cell lymphoma patients who received CAR T-cell therapy were identified. Patient characteristics, setting of CAR T-cell infusion, incidence of CAR T-cell therapy-associated adverse events and healthcare resource utilization were assessed. Results: Of 1175 patients, 83% were infused inpatient. Within three days postinfusion, inpatient-infused patients had a significantly higher risk of CAR T-associated adverse events (hazard ratio: 2.67; 95% CI: 2.09-3.42) compared with outpatient-infused patients. By day 30, 67% of outpatient-infused patients were hospitalized at least once. Conclusion: These findings suggest that physicians were able to select lower-risk patients for outpatient infusion, but postinfusion hospitalizations still occur.

This study tracks outcomes in patients with relapsed/refractory large B-cell lymphoma who received chimeric antigen receptor (CAR) T-cell therapy between 2017 and 2020. The authors used the Anlitiks All-Payor Claims (AAPC) database, which includes insurance claims of patients covered through Medicare, Medicaid or commercial insurance plans. AAPC includes over 80% of insured patients in the USA healthcare system. The study describes where patients received CAR T-cell therapy (inpatient/outpatient), rates of adverse events potentially related to CAR T-cell treatment and how much healthcare the patients received. In the 3 days after receiving CAR T-cell therapy, rates of CAR T-associated adverse events were significantly higher in patients who received CAR T-cell therapy in the inpatient setting, compared with outpatients. The findings suggest that lower-risk patients may receive CAR T-cell therapy as outpatients, but that most outpatient-infused patients will still require inpatient care.

Health resource utilization and costs of care for adult patients with relapsed or refractory mantle cell lymphoma in the United States: a retrospective claims analysis.

OBJECTIVES: We assessed real-world healthcare resource utilization (HRU) and costs among US patients with relapsed or refractory mantle cell lymphoma (R/R MCL) by line of therapy (LoT). METHODS: We selected patients from MarketScan® (1/1/2016-12/31/2020): ≥1 claims of MCL-indicated first line (1L) therapies, ≥1 diagnoses of MCL pre-index date (1L initiation date), ≥6-month continuous enrollment pre-index date, second line (2L) therapy initiation, ≥18 years old at 2L, and no clinical trial enrollment. Outcomes included time to next treatment (TTNT), all-cause HRU, and costs. RESULTS: The cohort (N = 142) was 77.5% male, aged 62 years (median). Sixty-six percent and 23% advanced to 3L and 4L+, respectively. Mean (median) TTNT was 9.7 (5.9), 9.3 (5.0), and 6.3 (4.2) months for 2L, 3L, and 4L+, respectively. Mean (median) per patient per month (PPPM) costs were $29,999 ($21,313), $29,352 ($20,033), and $30,633 ($23,662) for 2L, 3L, and 4L+, respectively. Among those who received Bruton tyrosine kinase inhibitors, mean (median) PPPM costs were $24,702 ($17,203), $31,801 ($20,363), and $36,710 ($25,899) for 2L, 3L, and 4L+, respectively. CONCLUSIONS: During the period ending in 2020, patients relapsed frequently, incurring high HRU and costs across LoTs. More effective treatments with long-lasting remissions in R/R MCL may reduce healthcare burden.

Mantle cell lymphoma is a rare blood cancer of white blood cells. This type of cancer can be hard to treat, even with new treatments. In about 15% to 20% of people, the cancer will not get better or will come back within 2 years of starting treatment. When this happens, there are few good options for treatments that work. Using medical claims data, we looked at healthcare use and costs among US patients with mantle cell lymphoma that came back after treatment or did not respond to treatment. We found 142 patients who met the study criteria. Of these, 77.5% were men with a median age of 62 years. Sixty-six percent got a third of the treatment and 23% got a fourth treatment or more. The time until the next treatment was about 9­10 months for patients who got a second and third treatments.. It was about 6 months for people who got a fourth or more treatment. The average monthly cost of treatment was about $30,000 for those receiving a second or fourth or more treatment. It was slightly less for those who got a third treatment. For those who got Bruton's tyrosine kinase inhibitors, the monthly costs went up with each treatment they needed. Overall, we found that during the study period, patients with mantle cell lymphoma worsened quickly, received multiple treatments, and had high costs of care. Better treatments that work longer are needed.

Safety and Efficacy of Axicabtagene Ciloleucel versus Standard of Care in Patients 65 Years of Age or Older with Relapsed/Refractory Large B-Cell Lymphoma.

PURPOSE: Older patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL) may be considered ineligible for curative-intent therapy including high-dose chemotherapy with autologous stem-cell transplantation (HDT-ASCT). Here, we report outcomes of a preplanned subgroup analysis of patients ≥65 years in ZUMA-7. PATIENTS AND METHODS: Patients with LBCL refractory to or relapsed ≤12 months after first-line chemoimmunotherapy were randomized 1:1 to axicabtagene ciloleucel [axi-cel; autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy] or standard of care (SOC; 2-3 cycles of chemoimmunotherapy followed by HDT-ASCT). The primary endpoint was event-free survival (EFS). Secondary endpoints included safety and patient-reported outcomes (PROs). RESULTS: Fifty-one and 58 patients aged ≥65 years were randomized to axi-cel and SOC, respectively. Median EFS was greater with axi-cel versus SOC (21.5 vs. 2.5 months; median follow-up: 24.3 months; HR, 0.276; descriptive P < 0.0001). Objective response rate was higher with axi-cel versus SOC (88% vs. 52%; OR, 8.81; descriptive P < 0.0001; complete response rate: 75% vs. 33%). Grade ≥3 adverse events occurred in 94% of axi-cel and 82% of SOC patients. No grade 5 cytokine release syndrome or neurologic events occurred. In the quality-of-life analysis, the mean change in PRO scores from baseline at days 100 and 150 favored axi-cel for EORTC QLQ-C30 Global Health, Physical Functioning, and EQ-5D-5L visual analog scale (descriptive P < 0.05). CAR T-cell expansion and baseline serum inflammatory profile were comparable in patients ≥65 and <65 years. CONCLUSIONS: Axi-cel is an effective second-line curative-intent therapy with a manageable safety profile and improved PROs for patients ≥65 years with R/R LBCL.

Matching-adjusted indirect comparison of axi-cel and liso-cel in relapsed or refractory large B-cell lymphoma.

In the absence of a randomized head-to-head trial, an unanchored matching-adjusted indirect comparison was performed to estimate the relative treatment effects of axicabtagene ciloleucel (axi-cel; ZUMA-1) versus lisocabtagene maraleucel (liso-cel; TRANSCEND-NHL-001) for treatment of relapsed/refractory (R/R) large B-cell lymphoma (LBCL) after at least two lines of therapy. After matching, axi-cel and liso-cel had comparable objective response rates and duration. Compared to liso-cel, axi-cel was associated with improvements in overall survival (hazard ratio [HR]: 0.53 [95% CI: 0.34-0.82]) and progression-free survival (HR: 0.61 [95% CI: 0.40-0.92]). Axi-cel was associated with a higher rate of grade ≥3 cytokine release syndrome (odds ratio [OR]: 3.64 [95% CI: 1.04-12.76]) and neurological events (OR: 3.45 [95% CI: 1.65-7.19]), with smaller differences estimated in scenario analyses including ZUMA-1 safety management cohorts. Results suggest axi-cel improved survival compared to liso-cel but with increased odds of specific adverse events.

Patient preferences for treatment in relapsed/refractory diffuse large B-cell lymphoma: a discrete choice experiment.

Aim: We quantified patient preferences for second-line diffuse large B-cell lymphoma therapies, including attributes of chimeric antigen receptor (CAR) T-cell therapy. Materials & methods: Using a discrete choice experiment, we surveyed 224 diffuse large B-cell lymphoma patients from the USA and Europe. Patients chose between two treatment options defined by six attributes with predefined levels for overall survival, adverse events (severe cytokine-release syndrome, severe neurological toxicities, severe infection) and time to return to pre-treatment functioning. Results: Increasing the probability of 1-year survival was most important to patients, followed by avoiding risks of cytokine-release syndrome and neurological toxicities. Respondents required a 13-14 percentage point increased 1-year survival probability to accept risks of treatment-associated adverse events. Conclusion: Patients prioritize survival and will accept certain adverse event risks to gain survival improvements.

Chimeric antigen receptor (CAR) T-cell therapy is a new treatment for patients with diffuse large B-cell lymphoma. CAR T-cell therapies are made from a patient's own cells, modified in a laboratory and used to attack cancer cells. While CAR T-cell therapies may increase long-term survival, they can also cause temporary but serious side effects, including neurological issues (e.g., headache, confusion, brain swelling) and cytokine-release syndrome (CRS), an inflammatory condition that can cause fever, breathing difficulties and organ dysfunction. To understand how patients' perspectives of CAR T-cell therapy compared with their perspectives on other treatments for diffuse large B-cell lymphoma, we surveyed 224 patients in the USA and Europe. They were asked to choose between two treatments in a series of choice sets, each displaying varying levels of aspects of cancer therapies, including survival and risks of serious side effects. Their choices allowed us to measure which factors were most important to patients when making decisions about treatment. We found that increasing the probability of survival was most important, followed by avoiding risks of neurological complications and CRS. Patients were willing to accept increased risks of neurological toxicities and CRS if they could obtain a 13­14 percentage point increase in the probability of surviving for at least 1 year after treatment.

Burden of illness and outcomes in second-line large B-cell lymphoma treatment: real-world analysis of Medicare beneficiaries.

Aims: To characterize elderly large B-cell lymphoma patients who progress to second-line treatment to identify potential unmet treatment needs. Patients & methods: Retrospective USA cohort study, patients receiving second-line autologous stem cell transplant (SCT) preparative regimen ('ASCT-intended') versus those who did not; stratified further into those who received a stem cell transplant and those who did not. Primary outcomes were: healthcare resource utilization, costs and adverse events. Results: 1045 patients (22.0%) were included in the ASCT-intended group, 23.3% of whom received SCT (5.1% of entire second-line population). Non-SCT patients were older and had more comorbidities and generally higher rates of healthcare resource utilization and costs. Conclusion: Elderly second-line large B-cell lymphoma patients incurred substantial costs and a minority received potentially curative SCT, suggesting significant unmet need.

Lay abstract Large B-cell lymphoma (LBCL) is an aggressive form of cancer. Although chemotherapy is often initially successful, LBCL recurs in about 50% of patients. For many years, the standard of care for recurrent LBCL has been a course of strong chemotherapy followed by stem cell transplant (SCT). However, many older patients cannot tolerate or do not respond well to chemotherapy and therefore cannot proceed to SCT. In this real-world study of Medicare patients, we found that only 5.1% of patients with recurrent LBCL ever received potentially curative SCT. They also had higher healthcare costs than similar patients who did receive SCT. This shows a significant unmet need in elderly LBCL patients that may potentially be addressed with recent treatment innovations.