Outpatient Administration of CAR T-cell Therapies Using a Strategy of No Remote Monitoring and Early CRS Intervention.

Recent studies demonstrating the feasibility of outpatient chimeric antigen receptor modified (CAR) T-cell therapy administration are either restricted to CARs with 41BB costimulatory domains or employ intensive at-home monitoring. We report outcomes of outpatient administration of all commercially available CD19- and BCMA-directed CAR-T therapy using a strategy of no remote at-home monitoring and an early cytokine release syndrome (CRS) intervention strategy. Patients with hematologic malignancies who received CAR T-cell therapy in the outpatient setting during 2022-23 were included. Patients were seen daily in the cancer center day hospital for the first 7-10 days and then twice weekly through day 30. The primary endpoint was to determine 3-, 7- and 30-day post CAR T-cell infusion hospitalizations. Early CRS intervention involved administering tocilizumab as an outpatient for grade ≥1 CRS. 58 patients received outpatient CAR T-cell infusion (33 myeloma, 24 lymphoma and 1 acute lymphoblastic leukemia). Of these, 17 (41%), 16 (38%), and 9 (21%) patients were admitted between days 0-3, 4-7 and 8-30 post-CAR T-cell infusion, respectively. The most common reason for admission was CAR T-cell-related toxicities (33/42). Hospitalization was prevented in 15 out of 35 patients who received tocilizumab for CRS as an outpatient. The non-relapse mortality rates were 1.7% at 1 month and 3.4% at 6 months. In conclusion, we demonstrate that the administration of commercial CAR T-cell therapies in an outpatient setting is safe and feasible without intensive remote monitoring employing an early CRS intervention strategy.

Charting the Course: Sequencing Immunotherapy for Multiple Myeloma.

Multiple chimeric antigen receptor (CAR) T-cell and bispecific antibody (bsAb) therapies have been approved, demonstrating impressive clinical efficacy in relapsed/refractory multiple myeloma (MM). Currently, these treatment share overlapping approval indications in the relapsed/refractory space, highlighting the importance of optimal selection and sequencing to maximize clinical efficacy. For patients previously unexposed to T-cell-directed therapies, several factors should be weighed when both options are available. These factors include access and logistical challenges associated with CAR T-cell therapy, disease-specific factors such as tempo of disease relapse, in addition to patient-specific factors such as frailty, and distinct toxicity profiles across these agents. Sequential therapy, whether it involves CAR T-cell therapy followed by bsAb or vice versa, has demonstrated clinical efficacy. When sequencing these agents, it is crucial to consider various factors that contribute to treatment resistance with careful selection of treatments for subsequent therapy in order to achieve favorable long-term patient outcomes.

Current trends and outcomes in cellular therapy activity in the United States, including prospective Patient Reported Outcomes data collection within the CIBMTR registry.

BACKGROUND: Center for International Blood and Marrow Transplant Research (CIBMTR) prepares an annual set of summary slides to detail the trends in transplantation and cellular therapies. For the first time in the 2023 summary slides, CIBMTR incorporates data for patients receiving chimeric antigen receptor T-cell (CAR-T) infusions. In addition, the data on patient-reported outcomes (PROs) is also included. OBJECTIVES: This report aims to update the annual trends in US HCT activity and incorporate data on the use of CAR-T therapies. Here we also aim to present and describe the development, implementation, and current status of the PRO data collection. STUDY DESIGN: In August 2020, CIBMTR launched the Protocol for Collection of Patient Reported Outcomes Data (CIBMTR PRO Protocol). The CIBMTR PRO Protocol operates under a centralized infrastructure to reduce burden to centers. Specifically, PRO data is collected from a prospective convenience sample of adult HCT and CAR-T patients who received treatment at contributing centers and consented for research. Data are merged and stored with the clinical data and used under the governance of the CIBMTR Research Database Protocol. Participants answer a series of surveys developed by the Patient Reported Outcomes Measurement Information System© (PROMIS) focusing on physical, social and emotional, and others measures assessing financial well-being, occupational functioning, and social determinants of health. To complement traditionally measured clinical outcomes, the surveys are administered at the same timepoints that clinical data is routinely collected. RESULTS: As of September 2023, PRO data from 993 patients across 25 different centers has been collected. With the goal of incorporating these important patient perspectives into standard clinical care, CIBMTR has added the PRO data to Data Back to Centers (DBtC). Through expanding the data types represented in the registry, CIBMTR aims to support holistic research accounting for the patient perspective in improving patient outcomes. CONCLUSION: PRO data at CIBMTR aims to provide the foundation for future large scale, population-level evaluations to determine areas for improvement, emerging disparities in access and health outcomes (eg, by age, race, and ethnicity), and new therapies that may impact current treatment guidelines. Continuing to collect and grow the PRO data is critical for understanding these changes and identifying methods for improving patient quality of life.

Safety and efficacy of anti-BCMA CAR-T cell therapy in older adults with multiple myeloma: A systematic review and meta-analysis.

INTRODUCTION: Anti-B-cell maturation antigen (BCMA) chimeric antigen receptor T-cell (CAR-T) therapy is transforming the care of patients with relapsed/refractory multiple myeloma (MM). Unfortunately, despite being a disease of older adults these patients remain under-represented in most pivotal clinical trials. We performed a systematic review and proportion meta-analysis of prospective clinical trials and observational studies of anti-BCMA CAR-T therapy in patients with MM with the aim to determine the efficacy and safety of this therapy in older adults (≥65 years). MATERIALS AND METHODS: We searched the Pubmed, Scopus, Web of Science (WOS), Ovid, Embase, CENTRAL, and CINAHL databases through September 9, 2022 and abstracts from the American Society of Hematology (ASH) Annual Meeting 2022. Primary outcome measures included overall response rate (ORR), rates of cytokine release syndrome (CRS), and immune cell-effector-associated neurotoxicity syndrome (ICANS). study was registered with PROSPERO (study number: CRD42022334287). RESULTS: After screening 2218 references, 14 studies were included for data extraction, with a total of 558 patients, 26.2% (n = 146) of whom were older adults. The pooled ORR amongst this population was 93%, which was comparable to the ORR of 86% amongst younger patients. In older adults, the rates of CRS (any grade) and grade ≥ 3 were 95% and 21%, respectively. For younger patients, the pooled rate of CRS (any grade) and grade ≥ 3 CRS was 91% and 20%, respectively. The rate of ICANS (any grade) in older adults was 15%, which was higher than that observed in those <65 years. CONCLUSION: Older adults experience comparable outcomes to younger patients with anti-BCMA CAR-T therapy, albeit with numerically higher rates of neurotoxicity.

Simple Score of Albumin and CRP Predicts High-Grade Toxicity in Patients with Multiple Myeloma Receiving CAR-T Therapy.

Administration of chimeric-antigen receptor T-cell (CAR-T) therapy is complex and associated with unique toxicities. Identifying patients at risk for inferior outcomes is important for individualized management. The Glasgow-prognostic score (GPS) is a simple score shown to be highly prognostic of outcomes in the setting of traditional chemotherapy or checkpoint inhibitor administration. We sought to evaluate the value of the GPS to predict outcomes of patients with relapse refractory multiple myeloma (RRMM) receiving anti-BCMA CAR-T therapy. We included all patients treated with commercial CAR-T therapy for RRMM between 5/1/2021 and 2/1/2023 at the Moffitt Cancer Center. The GPS (CRP >1 mg/dL, 1 point; albumin <3.5, 1 point) was calculated for all patients at lymphodepletion (day -6) and patients were grouped as high-risk GPS (score = 2) or low-risk GPS (0 or 1). The primary endpoint was overall survival (OS) at day 100. A total of 139 pts were included, with a median follow-up of 6.7 months (95% CI, 6.2 to 8.9 months). Pts were treated with either idecabtagene vicleucel (83%) or ciltacabtagene autoleucel (17%). In total, 14% were classified with high-risk GPS, with significantly increased risk for grade 3 cytokine release syndrome (P = .003) and ICANS of any grade (P < .001). Patients in the high-risk GPS group had significantly lower day-100 OS (68.4% versus 97.3%, P < .001), OS at 6 months (56% versus 91.8% P = .0019) and PFS at 6 months (38.3% versus 72.3%, P = .03). The association of GPS with day-100 OS remained significant in a multivariable model. In conclusion, the GPS identifies a group of high-risk patients with RRMM receiving CAR-T therapy who experience increased rates of immune-mediated toxicity and are at higher risk for early mortality.

A multicenter analysis of the outcomes with venetoclax in patients with relapsed mantle cell lymphoma.

To report the activity of venetoclax in patients with relapsed mantle cell lymphoma (MCL), we identified 81 patients treated with venetoclax monotherapy (n = 50, 62%) or in combination with a Bruton tyrosine kinase inhibitor (BTKi) (n = 16, 20%), an anti-CD20 monoclonal antibody (n = 11, 14%), or other active agents at 12 US academic medical centers. Patients had high-risk disease features including Ki67 >30% (61%), blastoid/pleomorphic histology (29%), complex karyotype (34%), and TP53 alterations (49%), and received a median of 3 prior treatments including BTKis in 91%. Venetoclax alone or in combination resulted in an overall response rate (ORR) of 40% and median progression-free (PFS) and overall survival (OS) of 3.7 and 12.5 months, respectively. The receipt of ≤3 prior treatments was associated with higher odds of response to venetoclax in a univariable analysis. In a multivariable analysis, having a high-risk Mantle Cell Lymphoma International Prognostic Index score before receiving venetoclax and disease relapse or progression within 24 months of diagnosis were associated with inferior OS whereas the use of venetoclax in combination was associated with superior OS. Although most patients (61%) had low risk for tumor lysis syndrome (TLS), 12.3% of patients developed TLS despite the implementation of several mitigation strategies. In conclusion, venetoclax resulted in good ORR but short PFS in patients with MCL who are at high risk, and may have a better role in earlier lines of treatment and/or in conation with other active agents. TLS remains an important risk in patients with MCL who initiate treatment with venetoclax.

Geriatric assessment in older adults with non-Hodgkin lymphoma: A Young International Society of Geriatric Oncology (YSIOG) review paper.

Non-Hodgkin lymphoma (NHL) is a disease of older adults, with a median age at diagnosis of 67 years. Treatment in older adults with NHL is challenging. The aging process is associated with a decline in functional reserve that varies among individuals, and results in an increasing risk of treatment-related toxicity and mortality. Chronological age and performance status fail to capture the multidimensional and heterogeneous nature of the aging process. A geriatric assessment (GA) screens multiple geriatric domains and provides a more accurate assessment of functional reserve. Several abbreviated GA tools have been developed for use in oncology clinics and help identify patients at high risk for chemotherapy-related toxicity and mortality. In this review, we explore GA tools validated for use in patients with NHL. We discuss the evidence behind GA-guided treatment in NHL and present a suggested approach to assessing frailty in this patient population.

Ofatumumab plus HyperCVAD/HD-MA induction leads to high rates of minimal residual disease negativity in patients with newly diagnosed mantle cell lymphoma: Results of a phase 2 study.

BACKGROUND: Ofatumumab is a humanized type 1 anti-CD20 monoclonal antibody. Preclinical studies show improved complement-mediated cytotoxicity (CMC) compared to rituximab in mantle cell lymphoma (MCL). This study evaluates the safety and efficacy of combining ofatumumab with HyperCVAD/MA (O-HyperCVAD) in newly diagnosed MCL. METHODS: In this single-arm phase 2 study, 37 patients were treated with the combination of O-HyperCVAD for 4 or 6 cycles, followed by high dose chemotherapy and autologous stem cell transplant. Primary objectives were overall response rate (ORR) and complete response (CR) rate at the end of therapy. Secondary objectives included minimal residual disease (MRD) negativity, progression-free survival (PFS), and overall survival (OS). RESULTS: Median age was 60 years; ORR was 86% and 73% achieved a CR by modified Cheson criteria. The MRD negativity rate was 78% after 2 cycles of therapy, increasing to 96% at the end of induction; median PFS and OS were 45.5 months and 56 months, respectively. Achieving a post-induction CR by both imaging and flow cytometry was associated with improved PFS and OS. Early MRD negativity (post-2 cycles) was also associated with an improved PFS but not OS. There were 3 deaths while on therapy, and grades 3 and 4 adverse events (AEs) were observed in 22% and 68% of the patients. CONCLUSION: The addition of ofatumumab to HyperCVAD/HD-MA led to high rates of MRD negativity by flow cytometry in patients with newly diagnosed MCL. Achieving a CR post-induction by both imaging and flow cytometry is associated with improved overall survival.

Frequency and timing of other primary cancers in patients with chronic lymphocytic leukemia (CLL): a 17-year longitudinal study.

Patients with chronic lymphocytic leukemia (CLL) are known to be at a higher risk of developing other primary cancers (OPC). Identifying latency and risk factors associated with OPCs in CLL is of interest as select patients may potentially benefit from early treatment of CLL with targeted therapies to improve immune surveillance. In this single-center retrospective study, 16.9% of 969 patients with CLL were diagnosed with an OPC. Interestingly, 44% of OPCs were diagnosed prior to the CLL diagnosis, including 30% that were diagnosed >1 year prior. This included a majority of genitourinary cancers and melanoma skin cancers. Patients with CLL and an OPC were older than pts with no OPCs but no other risk factors for developing OPCs were identified. Our data suggest that not only are patients with CLL at higher risk of developing OPCs and warrant appropriate cancer surveillance, but the risk also precedes CLL diagnosis by several years.

Assessment of the Efficacy of Therapies Following Venetoclax Discontinuation in CLL Reveals BTK Inhibition as an Effective Strategy.

PURPOSE: Venetoclax-based therapy is a standard-of-care option in first-line and relapsed/refractory chronic lymphocytic leukemia (CLL). Patient management following venetoclax discontinuation remains nonstandard and poorly understood. EXPERIMENTAL DESIGN: To address this, we conducted a large international study to identify a cohort of 326 patients who discontinued venetoclax and have been subsequently treated. Coprimary endpoints were overall response rate (ORR) and progression-free survival for the post-venetoclax treatments stratified by treatment type [Bruton's tyrosine kinase inhibitor (BTKi), PI3K inhibitor (PI3Ki), and cellular therapies]. RESULTS: We identified patients with CLL who discontinued venetoclax in the first-line (4%) and relapsed/refractory settings (96%). Patients received a median of three therapies prior to venetoclax; 40% were BTKi naïve (n = 130), and 81% were idelalisib naïve (n = 263). ORR to BTKi was 84% (n = 44) in BTKi-naïve patients versus 54% (n = 30) in BTKi-exposed patients. We demonstrate therapy selection following venetoclax requires prior novel agent exposure consideration and discontinuation reasons. CONCLUSIONS: For BTKi-naïve patients, selection of covalently binding BTKis results in high ORR and durable remissions. For BTKi-exposed patients, covalent BTK inhibition is not effective in the setting of BTKi resistance. PI3Kis following venetoclax do not appear to result in durable remissions. We conclude that BTKi in naïve or previously responsive patients and cellular therapies following venetoclax may be the most effective strategies.See related commentary by Rogers, p. 3501.

Dose reductions in ibrutinib therapy are not associated with inferior outcomes in patients with chronic lymphocytic leukemia (CLL).

Ibrutinib is a first-in-class small molecule inhibitor that has shown remarkable efficacy in the treatment of CLL. Current guidelines recommend lifelong administration at a fixed daily dose of 420 mg. Data from real-world studies indicate up to 17.5% of patients discontinue ibrutinib due to toxicity. Hypothetically, judicious dose reductions could result in improved tolerance. Our objective was to study the impact of dose reductions on outcomes in CLL patients treated with ibrutinib in a real-world setting. We identified 70 CLL patients treated with ibrutinib at Roswell Park Comprehensive Cancer Center between January 2014 and June 2017. Twenty-three (31.3%) patients required dose reductions. There was no statistically significant difference in overall response rate (ORR), clinical benefit rate (CBR), median progression-free survival, and overall survival (OS) between the dose-reduced and standard-dose groups (SDGs). These results extended to all patients, irrespective of whether the modification was made within three months of treatment initiation, or later.

Contemporary Trends and Comparative Outcomes With Adjunctive Inferior Vena Cava Filter Placement in Patients Undergoing Catheter-Directed Thrombolysis for Deep Vein Thrombosis in the United States: Insights From the National Inpatient Sample.

OBJECTIVES: The aim of this study was to investigate the contemporary trends and comparative effectiveness of adjunctive inferior vena cava filter (IVCF) placement in patients undergoing catheter-directed thrombolysis (CDT) for treatment of proximal lower extremity or caval deep vein thrombosis. BACKGROUND: CDT is being increasingly used in the management of proximal deep vein thrombosis. Although a significant number of patients treated with CDT undergo adjunctive IVCF placement, the benefit of this practice remains unknown. METHODS: The National Inpatient Sample database was used to identify all patients with proximal or caval deep vein thrombosis who underwent CDT (with and without adjunctive IVCF placement) in the United States between January 2005 and December 2013. A propensity score-matching algorithm was then used to derive 2 matched groups of patients (IVCF and no IVCF) for comparative outcomes (mortality and major and minor bleeding) and resource use analysis. RESULTS: Of the 7,119 patients treated with CDT, 2,421 (34%) received IVCFs. There was no significant difference in in-hospital mortality (0.7% vs 1.0%; p = 0.20), procedure-related hemorrhage (1.4% vs. 1.0%; p = 0.23), or intracranial hemorrhage (0.7% vs. 0.6%; p = 0.70) between the IVCF (n = 2,259) and no-IVCF (n = 2,259) groups, respectively. Patients undergoing IVCF placement had higher rates of hematoma (3.4% vs 2.1%; p = 0.009), higher in-hospital charges ($104,049 ± 75,572 vs. $92,881 ± 80,194; p < 0.001) and increased length of stay (7.3 ± 5.6 days vs. 6.9 ± 6.9 days; p = 0.046) compared with the no-IVCF group. CONCLUSIONS: This nationwide observational study suggests that one-third of all patients undergoing CDT receive IVCFs. IVCF use was not associated with a decrease in in-hospital mortality but was associated with higher inpatient charges and longer length of stay.

Acute lymphoblastic leukemia presenting as a breast lump: A report of two cases.

Extra-medullary leukemic infiltration of the breast by acute lymphoblastic leukemia (ALL) is very rare. We report two cases of ALL presenting as breast masses and diagnosed on fine-needle aspiration (FNA). Our first patient, a post-partum 30-year-old female, developed bilateral breast lumps in her last trimester of pregnancy and complained of easy fatigability. Our second patient, a 14-year-old girl, presented with a right-breast lump of 1-week duration. She had received treatment for ALL 1 year back and had been in complete remission for the last 1 year. FNA of the breast nodules done in both the cases revealed diffuse infiltration by lymphoblasts. Subsequent hematological investigations confirmed bone marrow involvement by ALL in the first case and extra-medullary relapse in the second case. Fine-needle aspiration cytology (FNAC) is an easy and cost effective method for the early diagnosis of metastatic leukemic infiltration, avoiding unnecessary excisional biopsies in such cases.