Lisocabtagene Maraleucel Research Articles

Lisocabtagene maraleucel in the treatment of relapsed/refractory large B-cell lymphoma.

Lisocabtagene maraleucel (liso-cel) is one of the three US FDA-approved chimeric antigen receptor T-cell therapies for the treatment of relapsed/refractory (R/R) large B-cell lymphoma (LBCL). TRANSCEND is the landmark trial that led to the approval of liso-cel in the third-line setting for R/R diffuse LBCL, primary mediastinal B-cell lymphoma, follicular lymphoma grade 3B and transformed lymphoma. The TRANSFORM and PILOT studies evaluated the use of liso-cel in the second-line treatment of R/R LBCL. This review details the structure and manufacturing process of liso-cel that make it distinct from other approved chimeric antigen receptor constructs, outlines results from landmark trials of liso-cel in LBCL and discusses liso-cel toxicity.

Management Considerations for Patients With Primary Refractory and Early Relapsed Diffuse Large B-Cell Lymphoma.

Most patients with diffuse large B-cell lymphoma (DLBCL) will be cured with up-front chemoimmunotherapy, but 30%-40% of patients will experience relapsed disease. Historically, salvage chemotherapy followed by autologous stem-cell transplant (ASCT) was the mainstay of treatment for these patients. However, research has demonstrated that patients with primary refractory or early relapsed (R/R; high-risk) DLBCL do not benefit from ASCT, prompting investigation into other options. With the advent of chimeric antigen receptor (CAR) T-cell therapy, treatment of R/R DLBCL has changed dramatically. With positive outcomes in the TRANSFORM and ZUMA-7 trials with manageable toxicity profiles, approval was obtained for lisocabtagene maraleucel (liso-cel) and axicabtagene ciloleucel (axi-cel) as second-line therapies for high-risk R/R DLBCL. However, these trials required patients to be medically fit for ASCT. In PILOT, liso-cel was deemed a reasonable treatment option for R/R transplant-ineligible patients. We recommend either axi-cel or liso-cel for fit patients with high-risk R/R DLBCL or liso-cel for unfit R/R patients as a second-line therapy. If CAR T-cell therapy is not an option, we recommend consideration of either ASCT if the patient has chemosensitive disease and is fit or clinical trial if the patient is unfit or has chemoresistant disease. If trials are not an option, alternative treatments are available. With the advent of additional therapies such as bispecific T-cell-engaging antibodies, the treatment landscape of R/R DLBCL may be upended. There continue to be many unanswered questions in the management of patients with R/R DLBCL, but given the promise of cellular therapies, outcomes are more optimistic in this group with historically dismal survival.

Chimeric Antigen Receptor T-Cell (CAR T-Cell) Therapy for Primary and Secondary Central Nervous System Lymphoma: A Systematic Review of Literature.

Relapsed/refractory central nervous system (CNS) lymphoma, whether primary or secondary, is associated with poor prognosis with currently available treatment modalities, including high-dose chemotherapy-autologous stem cell transplantation. The pivotal ZUMA-1 and JULIET trials that led to FDA approval of Axicabtagene ciloleucel and Tisagenlecleucel for relapsed refractory large cell lymphoma excluded patients with CNS involvement due to concerns of increased toxicity. However, TRANSCEND study for Lisocabtagene maraleucel in relapsed refractory large cell lymphoma allowed patients with CNS involvement and reported manageable CNS toxicities in these patients. In the real-world experience, chimeric antigen receptor T-cell (CAR T) therapy has been deemed safe and effective for these patients with poor prognosis. In this systematic review, we analyzed available literature to evaluate the role of CAR T-cell therapy in both primary and secondary CNS lymphoma using Embase, Cochrane, and PubMed databases. A total of 14 studies, including 8 retrospective analyses and 6 prospective studies/clinical trials, were included in the qualitative synthesis to study the safety and efficacy of CAR T. Based on our analysis, CAR T-cell therapy appears to be associated with reasonable efficacy and a manageable safety for primary and secondary CNS lymphoma.

Lisocabtagene maraleucel as second-line therapy for large B-cell lymphoma: primary analysis of the phase 3 TRANSFORM study

AbstractThis global phase 3 study compared lisocabtagene maraleucel (liso-cel) with a standard of care (SOC) as second-line therapy for primary refractory or early relapsed (≤12 months) large B-cell lymphoma (LBCL). Adults eligible for autologous stem cell transplantation (ASCT; N = 184) were randomly assigned in a 1:1 ratio to liso-cel (100 × 106 chimeric antigen receptor–positive T cells) or SOC (3 cycles of platinum-based immunochemotherapy followed by high-dose chemotherapy and ASCT in responders). The primary end point was event-free survival (EFS). In this primary analysis with a 17.5-month median follow-up, median EFS was not reached (NR) for liso-cel vs 2.4 months for SOC. Complete response (CR) rate was 74% for liso-cel vs 43% for SOC (P < .0001) and median progression-free survival (PFS) was NR for liso-cel vs 6.2 months for SOC (hazard ratio [HR] = 0.400; P < .0001). Median overall survival (OS) was NR for liso-cel vs 29.9 months for SOC (HR = 0.724; P = .0987). When adjusted for crossover from SOC to liso-cel, 18-month OS rates were 73% for liso-cel and 54% for SOC (HR = 0.415). Grade 3 cytokine release syndrome and neurological events occurred in 1% and 4% of patients in the liso-cel arm, respectively (no grade 4 or 5 events). These data show significant improvements in EFS, CR rate, and PFS for liso-cel compared with SOC and support liso-cel as a preferred second-line treatment compared with SOC in patients with primary refractory or early relapsed LBCL. This trial was registered at www.clinicaltrials.gov as #NCT03575351.

Early Cytopenias and Infections Following Chimeric Antigen Receptor T-Cell Therapy: A Single Center Experience

Background: Chimeric antigen receptor (CAR) T-cell therapy has shown promising responses in various hematologic malignancies. Cytopenias including anemia, neutropenia, and thrombocytopenia are common and manageable toxicities in the first 90 days after CAR T-cell therapy. Factors contributing to hematopoietic recovery following CAR T-cell therapy have not been well studied. Objective: Characterize the cytopenias, potential associated risk factors, incidence and management of infections, utilization of granulocyte-colony stimulating factor (G-CSF), thrombopoietin receptor (TPO) agonists, stem cell boosts, and immunoglobulin (IVIG) in the first 90 days after CAR T-cell infusion. Methods: This retrospective, single center chart review included 49 patients with various hematologic malignancies (non-Hodgkin lymphoma, acute lymphoblastic leukemia, multiple myeloma) treated with CAR T-cell therapy between March 2019 and July 2022. White blood cell count, absolute lymphocyte count, absolute neutrophil count, hemoglobin, platelet counts, and inflammatory markers were recorded at apheresis, lymphodepletion (day -5), day 0, +7, +14, +21, +30, +60, and +90. Cytopenias were documented using CTCAE grading system. Hypogammaglobulinemia (IgG<400 mg/dL) and infections by day +30 and day +90 were evaluated. Administration of GCSF, TPO-agonist, and IVIG up to day +90 were recorded. Recovery of immune repertoire using bone marrow biopsy and immunodeficiency panel results were included when available. Responses to CAR T were documented using disease specific disease response criteria. Cytokine release syndrome (CRS) and immune effector cell associated neurologic syndrome (ICANS) were graded using the ASTCT consensus criteria. The data was censored at date of progression, death or day +90 post CAR T-cell infusion. Results: Forty-nine patients received CAR T-cell therapy including axicabtagene ciloleucel (n = 6), tisagenlecleucel (n = 13), brexucabtagene autoleucel (n = 9), lisocabtagene maraleucel (n = 11), idecabtagene vicleucel (n = 10) from March 2019 to March 2022. Patient characteristics for all patients and those with and without grade 3-4 cytopenias at day +90 are seen in Table 1. The incidences of grade 3-4 lymphopenia, neutropenia, anemia, and thrombocytopenia at day 0 were 96%, 35%, 18%, and 20%; at day 30 the incidences were 38%, 40%, 19%, and 33%; at day +90 the incidences were 21%, 18%, 4%, and 11%, respectively with further characterization in Figure 1. Day +90 overall response rate and complete response rates were 49% and 43%, respectively with no significant differences between patients with and without cytopenias on day+90. Any grade CRS and ICANS were seen in 76% and 33% of the patients with grade 3+ CRS and ICANS seen in 2% and 10% of the patients, respectively. No significant differences were observed in the incidence of cytopenias in patients with any grades or grade 3+ CRS and ICANS. Infections occurred in 39% of patients and were severe, requiring hospitalization and intravenous treatment in 14%. The median time to infection was 8 days post infusion with 63% of infections having a bacterial source and 52% a viral source. None of the patients with cytopenias developed underlying myelodysplastic syndrome post CAR T. No cytopenia or infection related deaths were noted. Per physician discretion, GCSF was administered to 21 patients with median time to initiation of 23 days (range 14-140 days) and median duration of use of 33 days, with four patients having ongoing use at the time of last follow up. TPO-agonists were administered to nine patients. Eighteen patients received IVIG. Six patients received a stem cell boost due to prolonged cytopenia at a median of 54 days post CAR T-cell infusion and led to successful recovery of cytopenias. Further statistical analysis is under consideration to assess patient and disease related factors that may contribute to delayed hematopoietic recovery and associated complications of infections, bleeding and transfusions and will be available for the meeting. Conclusion: Cytopenias commonly persist through day +90 days post CAR T-cell therapy. Infections are common but manageable. The use of GCSF, TPO agonists, and IVIG appeared safe and did not worsen CRS or ICANS. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

PIT565, a First-in-Class Anti-CD19, Anti-CD3, Anti-CD2 Trispecific Antibody for the Treatment of B Cell Malignancies

The robust expression of the CD19 antigen in ALL and NHL has resulted in the development of highly effective therapeutics targeting CD19 by leveraging redirected T cells, which include the bispecific T-cell engager blinatumomab and CD19-directed CAR-T therapies axicabtagene ciloleucel, tisagenlecleucel, and lisocabtagene maraleucel. However, T cell exhaustion contributes to treatment failure following anti-CD19 bispecific T-cell engager and CAR-T therapies. To circumvent this issue, we have developed a first-in-class anti-CD19, anti-CD3, anti-CD2 IgG-like trispecific antibody, PIT565, that simultaneously engages CD19+ on tumor cells, CD3 (TCR signaling component) and CD2 (a costimulatory receptor) on T cells, which leads to redirected T-cell cytotoxicity towards CD19-positive malignant B cells. CD2 signaling has been associated with non-exhausted T cell phenotype. The interaction between CD2 and its ligand, CD58, has been shown to be important for tumor cell killing by CD19 CAR-T cells, while the loss of CD58 expression on lymphoma cells correlates with resistance and relapse in patients treated with CD19 CAR-T therapy. Therefore, CD2 co-stimulation via PIT565 may overcome T cell exhaustion and increase the depth and duration of response in patients compared to CD3 bispecifics. A redirected T cell cytotoxicity (RTCC) in vitro assay, employing co-cultures of CD19+ tumor cells and primary T-cells, demonstrated dose-dependent T-cell proliferation, cytokine production, and tumor cell lysis, which was more potent than the bispecific counterpart. Furthermore, in repeat-challenge RTCC assays, PIT565 mediated more sustained T cell activity in tumor cell killing and proliferation compared to control bispecifics. In addition, PIT565 demonstrated a more robust anti-tumor response than a control bispecific against an established diffuse large B cell lymphoma tumor in the human peripheral blood mononuclear cell adoptive transfer model. In safety and pharmacology studies, PIT565 showed IgG-like pharmacokinetics and an expected pharmacology and tolerability profile similar to CD3 bispecifics in cynomolgus monkey. Taken together, the findings from the preclinical studies suggest that PIT565 may achieve deeper and more durable responses compared to competitor CD3 bispecifics. First-in-human trial of PIT565 (NCT05397496) has been initiated and will be conducted in patients who are diagnosed with relapsed and/or refractory adult NHL after receiving two or more lines of chemotherapy and patients with relapsed and/or refractory B-ALL.

Correlative Biomarkers for CART19 Response in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma

Introduction: CD19 CAR T cell (CART19) therapy has changed the paradigms for managing relapsed diffuse large B cell lymphoma (DLBCL) however there remain challenges to achieving long term durable responses for majority of patients. Studies of lymphoma microenvironment (LME) hypothesize LME may affect CART19 response (Kotlov et al, Cancer Discov, 2021). In this study, we assessed the somatic mutation and LME profile through whole exome (WES) and RNA-sequencing (RNA-Seq) of patients treated with CART19 therapy to identify biomarkers of response. Methods: Patients from our center treated with commercial CART19 cells and biospecimen consents were identified for tumor biopsy samples pre and post-CART19 therapy. Matched normal were collected when available. WES and RNA-Seq were performed on tumor samples. Cell of origin (COO), double hit gene signatures (DHITs), and lymphoma microenvironment (LME) subtypes were calculated as described in Kotlov et al (Cancer Discov, 2021). The primary outcome endpoint was persistent response 6 months (mo) post CART19 infusion. Progression free (PFS) and overall survival (OS) was assessed by Kaplan Meier method and curves compared using log rank test. Results: WES and RNA-Seq were performed on 54 tumor samples from 49 patients with R/R DLBCL receiving CART19, either axicabtagene ciloleucel (n = 30), tisagenlecleucel (n = 18), or lisocabtagene maraleucel (n = 1). Samples were collected before (n=41) and after (n=13) CART19 therapy, and of these there are 5 patients with paired pre and post-CART samples. WES was successful in 49 samples from 44 patients, while RNA-Seq was successful in 51 samples from 47 patients. In 49 patients, overall response at 3 mo was 77.6%, (38/49) (59.2% CR, 18.4% PR), and PFS at 6 mo was 49% (24/49). Transformed DLBCL comprised 37% (18/49) of patients with overall response at 3 mo 89% (16/18) (61% CR, 28% PR), and PFS at 6 mo was 61% (11/18). We confirmed prognostic biomarkers to CAR-T therapy, such as increased lactate dehydrogenase (LDH, p = 0.01), standard uptake values (SUV, p = 0.02), and metabolic tumor volume (MTV, p = 0.02). Genomic features added further nuance into the understanding of CART19 outcomes (Figure 1). Single feature analysis revealed PIK3CA amplification was associated with improved PFS (p = 0.03), and MHCII RNA expression correlated with response to CART19 at 6 mo in GCB DLBCL (p = 0.03). Upregulation of MHCII is likely associated with the centrocyte-like phenotype, which was confirmed by a higher centrocyte B-cell associated gene signature in GCB in responders versus non-responders (p = 0.01) (Dybkær et al, JCO, 2015). Differential gene expression (DEG) analysis also revealed higher expression of MHCII genes in GCB-like responders and patients with transformed FL. In DLBCL, TGF-β pathway is inactivated via SMAD1 whose methylation suppress gene expression and inhibit chemo-sensitization. SMAD1 suppression is also associated with a depleted LME (Clozel et al, Cancer Discov, 2013; Stelling et al, Blood, 2018). High expression of SMAD1 was associated with being progression free at 6 mo in both activated B cell-like (ABC) (p = 0.003) and GCB (p = 0.06) DLBCL. The cohort was classified into favorable (germinal center-like and mesenchymal) and unfavorable (inflamed and depleted) LME subtypes (Figure 2). Favorable LME subtypes demonstrated superior OS relative to unfavorable subtypes (p = 0.02). Longitudinal analysis of one patient with paired pre- and post- CART19 tumor samples detected a potential mechanism of CAR-T relapse through B2M loss of function mutations in ABC DLBCL. Interestingly, the LME also switched from mesenchymal to depleted between the pre- and post-CART19 samples. Other paired samples will be further analyzed. Conclusion: Integrated molecular analysis of the LME and genomic alterations provides valuable information about correlative biomarkers for response to CART19 immunotherapy in DLBCL patients. With this cohort, PIK3CA amplification corresponded to improved PFS in DLBCL. We observed increased MHCII expression and centrocyte-like cells in GCB DLBCL CART19 responders, while SMAD1 was higher in ABC responders. Germinal center-like and mesenchymal LME exhibited increased OS, while inflamed and depleted LME subtypes had decreased OS. These genomic biomarkers for CART19 treatment response may help guide clinical treatment plans, minimize adverse events, or develop new therapeutic approaches. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Successful Outpatient Treatment and Monitoring Following Administration of Various Anti-CD19 Chimeric Antigen Receptor Therapies in B-Cell Lymphomas

Background: Chimeric Antigen Receptor (CAR) T-cell therapy is available as a salvage option for patients with relapsed/refractory B-cell lymphomas (DLBCL, FL, and MCL). Historically, most CAR T-cell therapy has been administered in the inpatient setting due to the potential need to closely monitor or treat cytokine release syndrome (CRS) and neurologic toxicity (NT). However, the introduction of rigorous outpatient monitoring programs incorporating nurse-driven education, patient/caregiver-driven after-hours reporting, and prophylactic corticosteroids may enable outpatient administration and monitoring of CAR T-cell in a large proportion of patients. Outpatient monitoring can improve quality of life for the patient as well as reduce healthcare costs. Objective: Describe clinical outcomes in a cohort of patients who received a variety of commercial CAR T-cell therapies and were subsequently monitored in the outpatient setting. Study Design: This is a retrospective analysis of 20 patients treated with outpatient CAR T-cell therapy between February 2021 and March 2022 with all patients having at least 100 days of post-infusion follow up. Additional data points included progression free survival, overall survival, HCT-CI score, prior lines of treatment, ECOG scores (before and after treatment), and incidence of cytokine release syndrome and neurological toxicity. Responses to treatment were determined based on radiographic tumor evaluation by metabolic response with PET-CT. Patients were monitored with daily RN triage visits and in the absence of complications, were seen twice weekly by an advanced practice provider (APP) or MD. Patients did not use remote monitoring devices and both patients and caregivers were encouraged to self-report any symptoms of CRS or NT to a 24 hour on-call APP/MD. Results: Of the 20 patients in the cohort, 2, 3, 14, and 1 patients received tisagenlecleucel, axicabtagene ciloleucel, lisocabtagene maraleucel, and brexucabtagene autoleucel, respectively. The median age was 69.5 (range 46-81). 60% of patients were male. 65% (13/20) of patients were treated with prophylactic dexamethasone. 55% of patients had an IPI score of 3-4. 25% (5/20) of patents had an ECOG score of 2 or greater. Median HCT-CI score was 1 and ≥2 in 9/20 (45%) patients (range 0-5). Overall, 10/20 (50%) patients were admitted in the first month of therapy (all initially for management of CRS), and no patients were admitted within the first 72 hours after infusion. The incidence of CRS was 11/20 (55%) with grade 3+ CRS of 5%. The incidence of NT was 9/20 (45%), with grade 3+ NT of 20%. Progression free survival in the cohort was 65% at 6 months and 60% at 1 year, and overall survival was 85% and 75%, respectively. 2 (10%) patients died prior to day 30 of treatment, one due to MRSA bacteremia (which developed >1 week into hospital admission), one due to progressive disease. No patients were admitted directly to the ICU. Conclusions: In a single-center cohort of patients who received CAR T-cell therapy and were subsequently monitored in the outpatient setting without remote monitoring devices, only half of the patients were admitted in the 1st month of therapy and no patients were admitted within the first 72 hours after infusion. 2 patients died in the first month of treatment for reasons unlikely to be related to outpatient monitoring. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Trial in Progress: Acalabrutinib Maintenance Following Cellular Therapy for Large B-Cell Lymphoma Patients at High Risk for Relapse

Background Large B-cell lymphoma has been shown to be driven by B-cell receptor signaling, which can be disrupted using Bruton tyrosine kinase (BTK) inhibition. Acalabrutinib has been studied in large B-cell lymphoma in combination with intensive therapies with encouraging results (Davies et al., Blood 2020). Preclinical studies have shown BTK inhibition could improve the effectiveness of anti-CD19 chimeric antigen receptor (CAR) T-cell therapy by improving the tumor microenvironment and delaying T-cell exhaustion (Qin et al., J Immunother 2020). BTK inhibition also has the potential to enhance the T-cell directed graft-versus-malignancy effect of allogeneic stem cell transplantation (alloHCT). This trial seeks to develop an effective therapeutic strategy to prevent relapse following cellular therapy in a specific group of large B-cell lymphoma patients that is high risk for relapse. Design This is a single-arm, open-label, multi-center phase Ib/II clinical trial to evaluate the safety and effectiveness of acalabrutinib as maintenance therapy in a subpopulation of patients with large B-cell lymphoma who are at high risk for relapse after cellular therapy. Inclusion criteria includes 1) patients undergoing autologous stem cell transplant (autoHCT) or any FDA-approved CAR T-cell therapy product for high grade B-cell lymphoma, large B-cell lymphoma with a history of secondary central nervous system (CNS) involvement, histologic transformation of indolent lymphoma to large B-cell lymphoma, or large B-cell lymphoma with high-risk international prognostic index score of 4 or 5 and 2) patients undergoing alloHCT for large B-cell lymphoma. The sample size for this study is 24 patients total, including 12-15 patients treated post-CAR T-cell therapy and 12-15 patients treated post-transplant. Patients will be started on maintenance with acalabrutinib on day +90 following alloHCT, day +60 following autoHCT, or between days +28 and +104 following CAR T-cell therapy. This trial will open at University of California Los Angeles and University of California Davis (two constituent sites of the University of California Hematologic Malignancies Consortium). Objectives The primary objective is to determine the safety and tolerability of maintenance acalabrutinib following cellular therapy in patients with large B-cell lymphoma at high risk for relapse. Secondary objectives include to estimate the effectiveness of maintenance acalabrutinib and to estimate the rates of dose reductions, dose pauses, and permanent discontinuations of acalabrutinib that occur post-cellular therapy. Exploratory objectives include to evaluate CAR T-cell persistence with acalabrutinib maintenance, to determine if there are signs of CNS penetration of acalabrutinib, and to evaluate changes before and after initiation of acalabrutinib in intracellular cytokine and phospho-protein profiling of peripheral blood mononuclear cells. Main Outcomes The primary endpoint is tolerability, determined by permanent discontinuation of acalabrutinib within 12 months from cellular therapy due to intolerance, defined as grade >3 non-hematologic toxicity or grade 4 hematologic toxicity considered related to acalabrutinib that occurs for the third time after previously holding and resuming acalabrutinib. Secondary endpoints include PFS and OS following cellular therapy and the incidence of dose changes and stopping of acalabrutinib. Conclusions This trial will use acalabrutinib as maintenance therapy for large B-cell lymphoma patients at high risk for relapse in the hopes of improving outcomes post-cellular therapy. If there is a PFS benefit in all three groups combined (CAR T-cell therapy, alloHCT, autoHCT), there will be rationale to expand each individual group into a separate larger trial. This study is registered with clinicaltrials.gov: NCT05256641. References Davies A, Caddy J, Mercer K, et al. Acalabrutinib in Combination with Rituximab, Cyclophosphamide, Doxorubicin, Vincristine and Prednisolone (R-CHOP) As First Line Therapy for Patients with Diffuse Large B-Cell Lymphoma (DLBCL): The Accept Phase Ib/II Single Arm Study. Blood. 2020;136(Supplement_1):38-39. Qin JS, Johnstone TG, Baturevych A, et al. Antitumor potency of an anti-CD19 chimeric antigen receptor T-cell therapy, lisocabtagene maraleucel in combination with ibrutinib or acalabrutinib. J Immunother. 2020;43(4):107-120. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Predictors and Implications of Renal Injury in Large Cell Lymphoma Patients Receiving CD19 CAR T Cell Therapy

Background: Chimeric Antigen Receptor (CAR) T cells directed against CD19 induce durable remissions in patients with relapsed or refractory large cell lymphoma (LBCL), but many patients experience treatment-related toxicity. Cytokine release syndrome (CRS), immune effector cell-associated neurologic syndrome (ICANS), and hematologic toxicity are extensively characterized. However, limited data exist on the burden, predictors, and implications of acute kidney injury (AKI) after CAR T cell therapy. Methods: In this single-center real-world retrospective study, we analyzed baseline (pre-lymphodepletion) and dynamic changes in renal function in adult patients with relapsed or refractory LBCL treated with CD19 CAR T cells. Estimated glomerular filtration rate (eGFR) was calculated via the 2021 CKD-EPI Creatinine Equation. Chronic kidney disease grading was tiered by the Kidney Disease Improving Global Outcomes (KDIGO) definitions. Serum creatinine values from day -5 through day 180 were used to assess AKI, which was defined by KDIGO criteria. Outcomes were measured from the first day of lymphodepletion. For AKI assessment, disease relapse or progression, anticancer treatment after CAR T cells, and death were considered competing events. Results: We included 200 LBCL patients with a median age of 66 (IQR 20-86) that were treated with CD19 CAR T cells (50% axicabtagene ciloleucel, 32% tisagenlecleucel, 18% lisocabtagene maraleucel) between 2016 and 2022. At baseline, most patients (54%) had a normal eGFR (eGFR ≥90 mL/min) followed by grade 2 CKD (eGFR 60-89 mL/min) in 34% and grade 3 CKD (eGFR 30-59 mL/min) in 12%. Patients with decreased renal function were more likely to be older (p < 0.001) and received CAR T cells with a 41BB costimulatory domain (p=0.028). In a cause-specific Cox model, baseline renal dysfunction was associated with an increased risk for severe neutropenia after CAR-T cell infusion (eGFR 60-89 vs. eGFR ≥90 mL/min; HR 1.53 [95% CI, 1.08-2.17]; p = 0.018). Pre-lymphodepletion eGFR was however not associated with overall survival (OS; p = 0.25), progression-free survival (PFS; p = 0.62), CRS grade 2+ (p = 0.34), or ICANS grade 2+ (p = 0.59). The cumulative incidence of day 180 AKI at any grade and grade 2+ AKI was 14% [95% CI 9.3 - 19%] and 4.5% [95% CI 2.2 - 8%], respectively (Figure 1A). At day 180, 14 of 83 (17%) evaluable patients had an eGFR <60. In a univariable cause-specific Cox regression model, baseline lower hemoglobin (p = 0.01) and albumin levels (p < 0.001) and higher ferritin (p = 0.005) and LDH levels (p = 0.05) were associated of AKI; no association was detected with baseline renal function (p = 0.47). Serum albumin remained significant in a multivariable model for AKI (HR 0.17 [95%CI 0.08 - 0.37], p < 0.001; Figure 1B). In a subset of patients with extensive cytokine profiling (n=50), pre-lymphodepletion log transformed IL6 was strongly associated with AKI (HR 3.59 [95% CI 1.19 - 10.8]). Finally, patients who developed any AKI through day 180 had significantly lower PFS (HR 2.13 [95% CI 1.35-3.37]; P=0.001) and OS (HR 2.01 [95% CI 1.22-3.31]; P=0.006). Conclusions: In this largest study to date on renal injury in CAR T patients, we find acute kidney injury as a common complication of CAR-T cell therapy, exceeding 10%. The association between renal injury and subsequent mortality suggests that AKI is a clinically and prognostically significant complication. The discovery that readily available biomarkers reflecting physiological reserve, disease burden, and systemic inflammation inform on renal injury risk may support personalized stratification for risk mitigation. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A Phase Ib Open-Label Study Evaluating the Safety and Efficacy of NKTR-255 in Combination with CD19-Directed CAR-T Cell Therapy in Patients with Relapsed/Refractory (R/R) Large B-Cell Lymphoma (LBCL)

Background: Lisocabtagene maraleucel (liso-cel), an autologous CD19-directed 4-1BB-costimulated chimeric antigen receptor (CAR) T-cell therapy, has demonstrated high overall response rates in patients with relapsed or refractory (R/R) large B-cell lymphoma (LBCL). However, approximately half of the treated patients will fail to achieve remission or will relapse. Thus, strategies to further improve the efficacy of CD19 CAR-T cell products are needed. NKTR-255 is a novel clinical grade polymer-conjugated interleukin-15 (IL-15) agonist, which engages the entire IL-15 receptor complex with improved pharmacokinetic properties compared with native IL-15, further promoting the proliferation and survival of T cells. In patients treated with CD19 CAR-T cells, peak serum IL-15 concentration after CAR-T cell infusion was associated with CAR-T cell counts in blood and antitumor response. Furthermore, preclinical data in immunodeficient mice bearing Raji lymphoma have shown that NKTR-255 enhanced expansion, survival, and anti-tumor activity of CD19 CAR-T cells. These results suggest that IL-15 supplementation may enhance efficacy of CD19-directed CAR-T cell therapy. Methods: NKTR-255 is being evaluated in combination with the CD19 CAR-T cell product, liso-cel, in an open-label, single center non-randomized study (phase 1b) in patients with R/R LBCL who are eligible for commercial liso-cel treatment. Subjects will receive lymphodepletion chemotherapy with cyclophosphamide and fludarabine followed by liso-cel infusion per Breyanzi® package insert, and NKTR-255 at 1.5 µg/kg intravenously every 3 weeks starting at approximately 10 to 14 days after CAR-T cell infusion. We considered that the earliest suitable time after CAR-T cell infusion to start NKTR-255 in this initial clinical trial would be around day 7 to 14, to allow deferral of patients with severe CAR-T cell related toxicities, namely cytokine release syndrome and immune effector cell neurotoxicity syndrome, early after CAR-T cell infusion and decrease potential toxicities from IL-15 supplementation. Approximately 12 subjects will be enrolled during dose escalation to determine the optimal biological dose. The study will start at Cohort A (NKTR-255 starting on day 14 at 1.5 µg/kg), then escalate to Cohort B (NKTR-255 starting on day 10 at 1.5 µg/kg) if not toxicities are observed. In the event of DLTs, the dose of NKTR-255 may be de-escalated to Cohort C (0.75 µg/kg starting on day 14). After NKTR-255 administration is deemed safe in Cohorts A and B, the expansion cohort may commence where up to 24 subjects may be enrolled in total. The proposed recommended dose was based on the starting dose of the first-in-human phase 1 study of single agent NKTR-255 in patients with R/R hematologic malignancies (NCT04136756). The dose limiting toxicity (DLT) period is 21 days after the first NKTR-255 dose. The primary objectives include safety and tolerability of NKTR-255 in combination with liso-cel, optimal biological dose (OBD) determination, and complete response (CR) rate at 3 months. Secondary endpoints include CR rate and objective response rate (ORR) at 6 months, duration of response (DOR), progression free survival (PFS), and overall survival (OS). Up to 24 patients will be enrolled during cohort allocation to determine the OBD. Clinical trial information is available at CT.gov: NCT05359211. Conclusions: This clinical trial will evaluate the safety and efficacy of NKTR-255 in combination with liso-cel aiming to increase the response rates and durability of response compared with CD19 CAR-T cells alone. Based on the biological rationale of IL-15 supplementation, correlative data from CD19 CAR-T cell studies, and results from preclinical studies with xenogeneic mouse models, NKTR-255 has the potential to augment currently approved cellular therapies. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Chimeric Antigen Receptor T-Cell Therapy Setting of Care: A Retrospective Cohort Analysis of MCL and FL Patients in the US

Introduction The United States (US) Food and Drug Administration has recently approved chimeric antigen receptor (CAR) T-cell therapy for patients with relapsed/refractory mantle cell lymphoma (MCL) and follicular lymphoma (FL). Although CAR T-cell therapy is commonly administered in inpatient settings, as clinicians gain experience, there is growing interest in providing infusions and follow-up care in the outpatient setting. This study describes patient characteristics, treatment setting, CAR T-cell therapy-associated adverse events (CAR T-AEs), and health resource utilization (HRU) for real-world CAR T-cell therapy use for MCL and FL. Methods A retrospective analysis of the Anlitiks All-Payor Claims (AAPC) data for services rendered from April 2017 to March 2022 was conducted. The database includes open-source fully adjudicated pharmacy and medical claims of patients who are insured through Medicare, Medicaid, or commercial plans, representing over 80% of the US population. MCL (ICD-9/10-CMs: 200.x, C83.1x) and FL patients (ICD-9/10-CMs: 202.xx, C82.xx) with a first claim (index date) for CAR T-cell therapy (MCL: brexucabtagene autoleucel [brexu-cel] or unspecified CAR T-cell agent; FL: lisocabtagene maraleucel [liso-cel], tisagenlecleucel [tisa-cel], axicabtagene ciloleucel [axi-cel] or unspecified agent) between October 2017 and December 2021, with ≥ 180 days of pre-index and ≥ 90 days of post-index follow-up were identified. Demographics, clinical characteristics, and treatment (infusion) setting (inpatient/outpatient Authorized Treatment Centers [ATCs]) were examined. Incidence of observed CAR T-AEs and HRU were analyzed overall and stratified by infusion setting. Descriptive statistics were reported as frequencies and percentages for categorical variables; mean, median, and range for continuous variables. Chi-square tests (categorical measures), t-tests, and Wilcoxon-rank sum tests (continuous measures) were used to assess group differences, where appropriate. Time from leukapheresis to CAR T-cell infusion was assessed with adjusted Cox proportional hazards models. Results The final sample consisted of a total of 151 MCL and 267 FL patients treated with CAR T-cell therapy. Among MCL patients, 75% were male, mean age was 63.8 (±8.6) years, and 58.3% (n=88) were commercially insured while 30.5% (n=46), 8.6% (n=13) and 2.6% (n=4) had Medicare, Medicaid and unknown/other insurance types, respectively. Among FL patients, 65% were male, mean age was 61.4 (±10.3) years, and 70.0% (n=187) were commercially insured while 19.9% (n=53), 7.1% (n=19) and 3.0% (n=8) had Medicare, Medicaid and unknown/other insurance types, respectively. Overall, 71.5% and 80.9% of MCL and FL patients were infused inpatient, respectively. Among FL patients with a specified CAR T-cell therapy, axi-cel accounted for the majority of patients. Median time from leukapheresis to infusion was similar for inpatient (MCL/FL: 27 days) and outpatient (MCL: 25 days; FL: 27 days) settings. Both MCL brexu-cel and FL axi-cel patients had similar median time from leukapheresis to infusion compared to their respective unspecified CAR T patient cohorts (MCL: both 26 days; FL 25 and 27 days). A total of 113 (74.8%) and 182 (68.2%) MCL and FL patients had an observed CAR T-associated AE within 90 days post-infusion, respectively. HRU analysis is underway. Conclusions In this analysis, nearly 3 in 4 MCL patients and more than 4 in 5 FL patients received CAR T-cell therapy infusions in inpatient settings. Median time from leukapheresis to CAR T-cell infusion was similar for MCL and FL in both infusion settings. Approximately three-fourths of MCL patients and two-thirds of FL patients experienced at least one observed CAR T-associated AE within 90 days post-infusion. Recent data on real-world treatment patterns enhance understanding of CAR T-cell therapy use in the evolving MCL and FL treatment landscape. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Longitudinal Patient-Reported Outcomes in Patients Receiving Chimeric Antigen Receptor (CAR) T-Cell Therapy

Background: CAR T-cell therapy is a novel treatment for patients with hematologic malignancies that carries risk of unique toxicities such as cytokine release syndrome (CRS) and immune effector cell-associated neurologic toxicity (ICANS). Patients are at risk for quality of life (QOL) deterioration and immense physical and psychological symptom burden given these toxicities, their illness, and the need for a prolonged hospitalization. Yet, data that comprehensively depict the longitudinal patient-reported outcomes (PROs) of patients receiving CAR T-cell therapy are limited. Methods: We conducted a longitudinal cohort study of 100 consecutive adult patients with hematologic malignancies receiving CAR T-cell therapy at Massachusetts General Hospital (MGH) between 4/2019 and 11/2021. Patients completed baseline questionnaires prior to receipt of CAR T-cell therapy about sociodemographic data, QOL (Functional Assessment of Cancer Therapy-General), physical symptoms (Edmonton Symptom Assessment Survey-revised [ESAS-r]), and psychological distress (Hospital Anxiety and Depression Scale and Post-Traumatic Stress Checklist) and completed PRO questionnaires at 1 week, 1 month, 3 months, and 6 months after CAR T-cell infusion. We used descriptive statistics to summarize patient characteristics and PROs at each timepoint and rates of clinically significant depression, anxiety, and post-traumatic stress disorder (PTSD) based on establish cutoffs. We conducted paired t-tests analyzing changes in QOL, physical, and psychological symptoms from baseline to 1 week, 3 months, and 6 months. We used multivariable linear regression models to examine factors associated with QOL at three months after CAR T-cell infusion. Results: We enrolled 71.4% (100/140) of eligible patients (median age 66 years; 63% male sex; 77% married/living with partner). The most common diagnosis was lymphoma (71%) followed by multiple myeloma (28%); A plurality (34%) received tisagenlecleucel, followed by lisocabtagene maraleucel (16%), axicabtagene ciloleucel (13%), and idecabtagene vicleucel (12%). The overall response rate was 80%, and with a median follow up of 14 months after CAR T-cell infusion, 38% died. CRS and ICANS occurred in 76% and 33% of patients, respectively. At baseline, median QOL score was 77.9 (range: 34-107), and was 70.0 (35-107) at 1 week, 76.0 (46-106) at 1 month, 83.5 (29-108) at 3 months, and 83.7 (34-107) at 6 months. Severe physical symptoms (ESAS-r score >=7) were reported by 47%, 52%, 35%, 28%, and 28% of patients at baseline, 1 week, 1 month, 3 months, and 6 months, respectively. The rates of clinically significant anxiety, depression, and PTSD symptoms at each time point are depicted in figure 1. Patient's QOL decreased at 1 week (mean difference [md]=5.1, p=0.04), but increased at 3 months (md -5.2, p=0.04) and 6 months (md=-5.3, p=0.07) compared to baseline. Patient's physical symptoms increased at 1 week, but decreased at 3 months (md 5.1, p=0.03) and 6 months (md=4.5, p=0.07), compared to baseline. There was no significant difference in anxiety symptoms from baseline to 1 week, 1 month, or 3 months. Anxiety symptoms improved at 6 months compared to baseline. There was no significant difference in depression or PTSD symptoms across all time points compared to baseline. In univariate linear regression, older age (β=0.4; p=0.01) and undergraduate or graduate degree (β=7.53, p=0.04) were associated with better QOL, whereas baseline anxiety symptoms (β=-14.3, p<0.01), baseline depression symptoms (β=-16.6, p<0.01), and baseline PTSD symptoms (β=-18.8, p<0.01) were associated with worse QOL at 3 months. In separate multivariable models including age, sex, education, marital status, and Eastern Cooperative Oncology Group performance status given collinearity among baseline PROs, anxiety (β=-10.6, p<0.01), depression (β=-12.6, p<0.01), and PTSD symptoms (β=-16.2, p<0.01) were the only factors associated with QOL at 3 months. Conclusion: Patients receiving CAR T-cell therapy experience significant QOL impairment and physical and psychological symptom burden, which peaks 1 week after cell infusion and improves by 6 months post-infusion. Given high rates of persistent severe symptoms and clinically significant psychological distress, interventions to improve the QOL of these patients are warranted. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Network Meta-Analysis (NMA) of Chimeric Antigen Receptor (CAR) T-Cell Therapy for the Treatment of Relapsed/Refractory Diffuse Large B-Cell Lymphoma (DLBCL) after 2 Prior Treatments Using Published Comparative Studies

INTRODUCTION Historically, the clinical prognosis for patients with relapsed/refractory (r/r) diffuse large B-cell lymphoma (DLBCL) has been poor, with limited curative treatment options. However, the introduction of chimeric antigen receptor CAR T-cell (CAR-T) therapy is changing how r/r DLBCL patients are treated. Regulatory approvals of axicabtagene ciloleucel (axi-cel), lisocabtagene maraleucel (liso-cel) and tisagenlecleucel (tisa-cel) in patients with DLBCL with two or more prior lines of treatment were based on their respective non-comparative trials: ZUMA-1, JULIET, and TRANSCEND NHL 001 (TRANSCEND). To understand the comparative efficacy of these CAR-T therapies, treatment comparisons across trials are necessary. In the absence of direct evidence, several matching-adjusted indirect comparisons (MAICs) have been conducted, but have led to conflicting results. This may be, in part, due to the lack of a common comparator. In parallel, to characterize the efficacy of CAR-T compared to other available treatment options, comparisons of these single-arm studies to external historical standard-of-care (SoC) cohorts have been published. Use of this evidence base allows the construction of a network to with a common comparator, which may reduce bias in between treatment estimates. We leveraged this available evidence to conduct an adjusted indirect comparison of axi-cel, liso-cel, and tisa-cel using published comparative studies of CAR-T products to historical SoC cohorts. METHODS On 17th September 2021, we systematically searched EMBASE and MEDLINE databases. Three additional conferences were searched. Eligible studies enrolled patients with r/r DLBCL and compared approved CAR-T therapies to SoC. Outcomes of interest were response and time-to-event outcomes. Safety outcomes were not reported in SCHOLAR-1 and published comparisons to SCHOLAR-1 so safety could not be explored in this analysis. The systematic search followed the Preferred Reporting Item for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. All study selection and data extraction steps were conducted in dual and independently. For indirect treatment comparisons, network meta-analyses (NMA) were conducted using a Bayesian framework. For dichotomous outcomes, we used logistic regression with binomial link function. A linear regression on log-transformed hazard ratios (HR) were used for available time-to-event outcomes. The NMA used an anchored network with the historical SoC serving as the common comparator. RESULTS The search identified 467 publications, of which 3 were included in the evidence base (Figure 1). In the first study, axi-cel individual patient data (IPD) was compared to SCHOLAR-1 (a historical SoC cohort) IPD using propensity score methods. For the second, a matching adjusted indirect comparison (MAIC) was used to compare liso-cel IPD to SCHOLAR-1 summary data. For the third, tisa-cel IPD was compared to CORAL IPD, a historical SoC cohort (and a sub-cohort of SCHOLAR-1). The results from the ITT population of JULIET were used in this analysis. Available outcomes across all three studies included overall survival (OS) and overall response rate (ORR). Complete response (CR) was analyzed where possible. All three treatments were superior to SoC across all outcomes (Table 1). For OS, axi-cel had a significantly lower hazard ratio for death relative to liso-cel and tisa-cel. Both axi-cel and liso-cel had improved ORR relative to tisa-cel, but were not statistically different from one another. CONCLUSIONS Results of the analyses suggest that axi-cel leads to improved OS in r/r DLBCL relative to liso-cel and tisa-cel. Axi-cel and liso-cel were comparable with respect to response outcomes, showing favorable ORR relative to tisa-cel. These results are in line with MAIC results, where efficacy between CAR-T treatments have been directly compared, but offer the advantage of being able to include a common comparator in the absence of placebo controlled RCTs. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Real-World Bridging Therapy (BT) of Patients with Relapsed or Refractory (r/r) Large B-Cell Lymphoma (LBCL) Treated with Chimeric Antigen Receptor (CAR) T-Cell Therapy: A Systematic Literature Review (SLR) and Meta-Analysis

Objectives: Using BT with commercially available CAR T-cell therapy for treatment of r/r LBCL is at the discretion of treating physicians. With emerging real-world data on CAR T-cell therapy, we conducted an SLR to understand the patterns of BT use in real-world settings and to investigate its association with effectiveness and safety outcomes. Methods: We systematically searched EMBASE, MEDLINE, and 15 conferences through April 1, 2022 for real-world observational studies describing patterns of BT use among adult patients receiving CAR T-cell therapy for r/r LBCL. In addition to data on the use of BT, the estimated effects of BT on clinical outcomes were also extracted. Weighted means were calculated using both fixed- and random-effects meta-analyses for use and type of BT, study location, and CAR T-cell product. The associations between use of BT and post-infusion overall and complete response rate (ORR and CR rate), progression-free survival (PFS), overall survival (OS), cytokine release syndrome (CRS), and neurotoxicity (NT) were assessed by meta-analyses of the reported effects of BT, with adjusted and unadjusted treatment effects analyzed separately. Results: The search identified 4,242 citations; 65 publications on 42 studies reporting on real-world use of BT were included in the evidence base, of which 32 publications on 25 studies reported on the associations between BT and clinical outcomes. No real-world study on lisocabtagene maraleucel was found at the time of the search. At baseline (apheresis or infusion), patients receiving axicabtagene ciloleucel (axi-cel) were younger compared with patients receiving tisagenlecleucel (tisa-cel) (weighted average of median age 59.5 years for axi-cel vs 62.6 years for tisa-cel), while more likely to have an International Prognostic Index (IPI) of ≥ 3 (51% for axi-cel vs 41% for tisa-cel), and more likely to have bulky disease (24% for axi-cel vs 16% for tisa-cel); sex, disease stage, double/triple hit, number of prior lines of therapy, prior history of autologous stem cell transplant, and refractory status were comparable between the two products. A shorter median time from leukapheresis to infusion (vein-to-vein time) for axi-cel was observed in both US- (weighted average 27.7 d for axi-cel vs 44.0 d for tisa-cel) and European-based studies (40.0 d for axi-cel vs 49.3 d for tisa-cel). On weighted average, 63% (95% confidence interval [CI] 53%-72%) of axi-cel recipients received BT compared with 80% (95% CI 72%-86%) of tisa-cel recipients (Table 1). Overall, use of BT was also more common in Europe (83%) than in the US (51%). Among patients who received BT, the most common type was chemo/chemoimmunotherapy (70% overall; 62% for axi-cel; 88% for tisa-cel) followed by steroids in the US (21% vs 12% in Europe) or radiation therapy in Europe (17% vs 17% in the US). Response to BT was seldomly reported and heterogeneous. Meta-analyses based on 7 available real-world cohorts (6 studies) that reported adjusted results on OS did not provide sufficient evidence to indicate an association between use of BT and OS (hazard ratio [HR] 1.20; 95% CI 0.76-1.89; Figure 1). Use of BT was also not associated with PFS based on adjusted results of 4 available cohorts (HR 1.28; 95% CI 0.91-1.80). Limited to unadjusted results only, no significant associations were found between use of BT and ORR (odds ratio [OR] 0.91; 95% CI 0.60-1.38), CR rate (OR 0.40; 95% CI 0.10-1.71), CRS of grade ≥ 3 (OR 0.98; 95% CI 0.54-1.76) or NE of grade ≥ 3 (OR 1.36; 95% CI 0.94-1.97). Conclusions: These findings provide a comprehensive picture of patterns of BT use in real-world settings, notably its more frequent use in Europe and among patients receiving tisa-cel. Despite the more frequent use of BT with tisa-cel, patients receiving tisa-cel did not appear to have more severe disease at baseline, suggesting that the shorter vein-to-vein time for axi-cel may have contributed to the reduced use of BT among its recipients. Given the use of BT could be heavily confounded by unknown factors that affect physicians’ decisions, the lack of adjusted analyses limit the conclusions that can be drawn on its association with clinical outcomes. Prospective studies evaluating the value of integrating BT with CAR T-cell therapy are warranted. JM and ZHH contributed equally. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Inflammatory Biomarker Clusters Are Predictive of Response and Toxicity in Large B-Cell Lymphoma Treated with CD19 CAR-T Cell Therapy

Disease recurrence and toxicity are common sequelae of CD19-directed chimeric antigen T-cell (CAR-T) cell therapy in large B-cell lymphoma (LBCL). We have developed a machine learning approach that is informative of adverse CAR-T outcomes and can support personalized treatment approaches. In a single-center cohort of 198 LBCL patients treated with CD19-CAR-T cells (axicabtagene ciloleucel [axi-cel] 50%, tisagenlecleucel [tisa-cel] 32%, lisocabtagene maraleucel [liso-cel] 18%), we applied unsupervised k-means clustering on standard laboratory and cytokine measurements collected within the day prior to CAR-T infusion. Three distinct biomarker clusters emerged (Fig. A) - inflammatory (n=27, 14%), neutral (n=121, 61%), and favorable (n=50, 25%). The inflammatory subgroup was enriched for patients with high levels of inflammatory markers such as IL-6, TNFa, and ferritin, while the favorable cluster tended to have higher complete blood counts and albumin; intermediate values were characteristic of the neutral subgroup. To determine the clinical implications of these subgroups, we studied their association with day 100 best response to CAR-T, significant toxicity by day 30 (defined as life-threatening complications such as immune toxicities requiring intervention, bloodstream infections, or early death), and overall survival (OS) after multivariate adjustment for CAR-T costimulatory domain (CD28 vs 41BB), patient age, primary refractory disease, and pre-lymphodepletion LDH. Compared to those in the favorable biomarker cluster, patients in the inflammatory cluster (Fig. A) had increased odds of not achieving CR by day 100 (odds ratio [OR] 4.23, 95% confidence interval [CI] 1.37-14.4, p < 0.05) and a high toxicity profile (OR 12.5, 95% CI 3.66-49.5, p < 0.001). OS was also reduced with the inflammatory subgroup in univariable analysis (Fig. B) and a multivariable Cox regression model (hazard ratio [HR] 4.03, 95% CI 1.99-8.16, p < 0.001). Patients in the neutral subgroup, compared to those in the favorable group, had reduced overall survival (HR 1.80, 95% CI 1.00-3.24, p < 0.05) and increased odds of high toxicity (OR 3.40, 95% CI 1.56-7.79, p <0.01). Serial assessment of the uncommon biomarkers and cytokines in our day 0 panel may not be readily available to many centers. We developed a random forest prediction model for cluster type based on patient, disease, and widely available pre-lymphodepletion laboratory features. Our random forest model outperformed gradient boosting and logistic regression model alternatives and achieved a high discrimination (AUC 0.81) for cluster prediction. Next, we applied the random forest model to pre-lymphodepletion data from an independent LBCL cohort (n=155) from a different center (Fig. B). Most patients were assigned to the neutral subgroup (n=108, 70%) followed by the inflammatory (21%) and favorable (9%) subgroup. Assignment to the inflammatory cluster was strongly associated with inferior OS compared to the favorable subgroup (HR 2.89, 95% CI 1.12-7.48, p < 0.05) after multivariate adjustment for CAR-T costimulatory domain (CD28 vs 41BB), patient age, primary refractory disease, and pre-lymphodepletion LDH. In conclusion, we identified three pre-infusion (day 0) biomarker clusters, which are tightly associated with CAR-T outcomes. These clusters could guide decision-making regarding hospitalization after CAR-T infusion and to preempt early inflammation and disease relapse in high-risk subgroups. Finally, to improve accessibility to cluster assignment, we developed a prediction model for cluster type based on readily available pre-lymphodepletion data and applied it towards an external center cohort as a proof-of-principle. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

The Financial Toxicity of FDA-Drugs Approved for Malignant Hematology

Background: Many Food and Drug Administration (FDA) drugs (FDADs) are available now for patients with malignant hematology (MH). Still,the high prices of FDADs for MH affect the care of these patients and our health care system. Here, we estimated one monthly supply price (OMSP) for FDADs for MH approved between 2011 and 2021. Also, we reported the total cost (TC) of FDADs by multiplying OMSP times the assumed duration of therapy based on the available overall survival (OS) (OMSP x OS (months)). Methods: We performed a retrospective review of clinical trials (CTs) published from January 2011 to May 2021 that led to FDA approval of hematological malignancy drugs (Leukemias, lymphomas, Multiple Myeloma (MM), Myelodysplastic Syndrome (MDS), and Myeloproliferative Neoplasm (MPN)). The drugs investigated were selected using FDA Databases, 'Oncology (Cancer) / Hematologic Malignancies Approval Notifications' and 'Novel Drug Approvals'. CTs were also reviewed for demographic data on ClinicalTrials.gov (CT.gov) and Primary Literature on drug approval. FDADs were divided into disease groups: acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), MDS+MPN, MM, and lymphoma. We compared prices between drug.com and UpToDate using the lowest price for each drug (the percentage change was low 0.18). We calculated the median of OMSP for each group, compared the median of OMSP between oral (PO), subcutaneous (SQ), and intravenous (IV) FDADs, and calculated TC for each group. For non-reached OS, we used 60 months to calculate TC. Results: Sixty-one FDADs were identified; 9,4,4,7 and 4 for AML, CML, ALL, CLL, and MDS+MPN, respectively. For MM and lymphoma, we identified 11 and 22, FDADs, respectively. The median of PO, SQ, and IV FDADs were 29, 4, and 30, respectively (some drugs were approved for more than one group). The median of OMSP for AML, CML, ALL, CLL, and MDS+MPN were $30,923 [range, $5,989-36,099], $19,343 [range, $20,834-22,570], $75,839 [range, $48,917-93,660] (excluding chimeric antigen receptor-T cell (CAR-T) therapy), $15,263 [range, $3,532- 23,091], and $15,284 [range, $8,060- 24,157], respectively. The median of OMSP for MM and lymphoma excluding CAR-T were $20,514 [range, $2,090-35,276 ] and $18,434 [range, $6,834-34,351], respectively. The median of OMSP for PO, SQ, and IV FDADs were $18,291 [range, $2,628-31,686], $18,370 [range, $6,934-22,583] and $24,691 [range, $2,090-93,660] (excluding CAR-T cell therapy), respectively. All FDADs for ALL patients were IV. The median OMSP for FDADs approved from (2011 to 2016) and (2016 to 2021) were $22,233 (range, $8,300-23,091) and $24,517 (range, $2,352-86,253), respectively. The median TC for AML, CML, ALL, CLL, and MDS+MPN were $351,327 (range, $196,380-791,041), $1,160,597 (range, $1,097,482-1,354,993), $547,091 (range, $244,587-$985,915), $971,160 (range, $564,720-3,456,000), and $1,114,038 (range, $255,502-1,449,447), respectively. OS was not reached for all CML drugs, in 5/7 (71%) of CLL drugs and 12/61 (34%) of all FDADs. The median TC for MM and lymphoma were $607,031 [range, $18,813-1,743,706 ] and $884,900 [range, $183,817-9,116,360], respectively. Excluding CAR-T drugs, The highest OMSP was for ALL but not TC due to the short median OS (10 months) (Figure 1). There were 5 CAR-T products approved between August 2017 and March 2021 (tisagenlecleucel, axicabtagene ciloleucel, lisocabtagene maraleucel, brexucabtagene autoleucel and idecabtagene vicleucel). The median cost was $432,055 (range, $373,000-475,000), and the estimated OMSP was $21,635 (range,$6,216-39,583). The median household monthly income was $6,558 in 2020 in the United States (US). In 2020, 8.6% of US population (28 million) did not have helath insurance at any point during the year. There are currently no generic drug products of these FDADs available in the US. Conclusion: The cost-effectiveness of CAR-T products is relatively similar to other FDADs. Patients with malignant hematologic disorders are affected by treatment-related financial harm. Although the costs used for this analyses may be modulated by many factors where the actual cost may not be what is reported in the sources used, the financial impact is still significant for many patients. There is a need for strategies to lower the costs. The value of drugs should be considered in formulating treatment guidelines. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Lisocabtagene Maraleucel (Liso-cel) in Patients with Relapsed or Refractory (R/R) Large B-Cell Lymphoma (LBCL) Treated As Outpatients or Inpatients in the Community/Nonuniversity Setting: Patient-Reported Outcomes/Health-Related Quality of Life from the Outreach Study

Background: Liso-cel is an autologous, CD19-directed, defined composition, 4-1BB CAR T cell product administered at equal target doses of CD8+ and CD4+ CAR+ T cells that has shown clinical efficacy in patients with R/R LBCL. In TRANSCEND NHL 001 (NCT02631044), patients with third-line or later LBCL treated with liso-cel at academic centers had early, sustained, and clinically meaningful improvements in health-related quality of life (HRQOL) and symptoms that correlated with antitumor activity (Patrick et al. Blood Adv 2021). Here we present patient-reported outcome (PRO)/HRQOL results from the OUTREACH study (NCT03744676), which enrolled patients with R/R LBCL across outpatient and inpatient settings at community sites in the United States. We aimed to assess whether HRQOL among patients treated with liso-cel would, at a minimum, be maintained over the course of the study. Methods: Adults with R/R PET-positive LBCL after ≥ 2 lines of therapy and ECOG PS ≤ 1 were enrolled at community (nontertiary care) sites. Patients with mild to moderate organ function (LVEF ≥ 40%; serum CrCl > 30 mL/min), secondary CNS lymphoma, and prior autologous HSCT were eligible. After leukapheresis and lymphodepleting chemotherapy, patients received liso-cel at a target dose of 100 × 106 CAR+ T cells. Patients completed European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire-Core 30 (EORTC QLQ-C30) and EQ-5D-5L (health utility index [HUI] and visual analog scale [VAS]) before treatment (≤ 7 days before lymphodepletion; baseline); before infusion on day of liso-cel infusion (Day 1); and on Days 29, 60, 90, 180, 270, 365, 545, and 730/end of study; and at disease progression. The primary HRQOL domains of interest were the EORTC QLQ-C30 global health status/QOL, physical functioning, role functioning, cognitive functioning, fatigue, and pain. A linear mixed model for repeated measures analysis was performed to assess the least squares (LS) mean change from baseline for visits with ≥ 10 patients. Within-patient meaningful change from baseline was calculated using responder definitions (in points): 5-30 for EORTC QLQ-C30 (based on thresholds set by Cocks and Buchanan [ISOQOL 2015]), 0.08 for EQ-5D-5L HUI, and 7 for EQ-5D-5L VAS. Within-group meaningful change from baseline was defined by the minimally important differences set by Cocks et al (Eur J Cancer 2012). Results: Among the 79 liso-cel‒treated patients, completion rates for the HRQOL assessment were high (≥ 70%) across most visits for all measures. For EORTC QLQ-C30, mean baseline scores were meaningfully worse than in a general noncancer population (difference of ≥ 10 points) for role functioning and fatigue. The overall LS mean change from baseline showed significant and meaningful improvement for the primary domains of EORTC QLQ-C30 global health status/QOL, fatigue, and pain, as well as the EQ-5D-5L VAS (Table). Cognitive functioning and HUI were comparable with the general population at baseline and were maintained over time after liso-cel infusion. In individual assessments across visits, most patients (57%‒100%) experienced either meaningful improvement or no meaningful improvement or deterioration for all domains, and more than half achieved meaningful improvement in global health status/QOL (32.9%‒59.5%), fatigue (27.1%‒65.5%), pain (38.6%‒66.7%), and EQ-5D-5L VAS (27.8%‒71.4%) at most time points, with lowest percentages observed on Day 1. Results comparing PRO/HRQOL data for patients treated in an outpatient versus inpatient setting will be reported in the presentation. Conclusions: In the OUTREACH study, patients had impaired HRQOL at baseline compared with the general noncancer population. HRQOL was either improved or maintained from baseline in most patients with R/R LBCL who received liso-cel as third-line or later treatment in OUTREACH, with the greatest improvements observed in the Global health status/QOL, fatigue, and pain domains. These findings show the importance of PRO/HRQOL assessments as supportive measurements of treatment outcome in patients with R/R LBCL, and they lend support to the use of liso-cel in treating patients with R/R LBCL at community centers and in the outpatient setting. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Real-World Impact of Time from Leukapheresis to Infusion (Vein-to-Vein Time) in Patients with Relapsed or Refractory (r/r) Large B-Cell Lymphoma (LBCL) Treated with Axicabtagene Ciloleucel

Background: Compared with other CAR T-cell products, axicabtagene ciloleucel (axi-cel) had a shorter median wait time from leukapheresis to infusion, referred to as vein-to-vein time (real-world: axi-cel, 28 d vs tisagenlecleucel, 45 d; clinical trial: lisocabtagene maraleucel, 37 d; Riedell et al. Transplant Cell Ther 2022; Abramson et al. Lancet 2020). A study based on the JULIET trial suggested that reduced wait time is associated with increased efficacy (Chen et al.Value Health 2022). Here, we assessed the real-world impact of vein-to-vein time on outcomes of axi-cel in r/r LBCL. Methods: A total of 1383 patients from 78 US centers treated with commercial axi-cel for r/r LBCL between October 2017 and August 2020 were identified from a non-interventional post-authorization safety study using the Center for International Blood and Marrow Transplant Research (CIBMTR) registry. Patients with the following were excluded: primary central nervous system lymphoma or lymphoma other than LBCL, prior non-transplant cellular therapy, missing data on comorbidity (Sorror et al. Blood 2005), unknown or outlying date of leukapheresis (≤2 d before lymphodepleting [LD] chemotherapy or ≥144 d before infusion), or no follow-up. Effectiveness outcomes were overall and complete response rates (ORR and CR rates), duration of response (DOR), and progression-free and overall survival (PFS and OS). Adverse events of interest included cytokine release syndrome (CRS, Lee 2014 criteria), immune effector cell-associated neurotoxicity syndrome (ICANS, ASTCT criteria), and prolonged neutropenia and thrombocytopenia. Odds ratios (ORs) and hazard ratios (HRs) were estimated using logistic and Cox regressions after adjustment of key prognostic factors such as age, comorbidities, ECOG performance status, disease characteristics at diagnosis, and bridging therapy (Table 1). Adjusted curves were generated based on the direct adjusted survival function (Makuch J Chronic Dis 1982). Results: Overall, median vein-to-vein time (from leukapheresis to infusion) for axi-cel was 27 d (interquartile range [IQR], 26-32 d), including a median of 5 d (IQR, 5-5 d) from start of LD chemotherapy to infusion. Vein-to-vein times were consistent regardless of the following baseline characteristics: disease histology, sex, race, ethnicity, ECOG performance status before infusion, or chemo-sensitivity. Patients with shorter vein-to-vein times appeared to be younger and less likely to have comorbidities (Table 1). Patients with vein-to-vein time of ≥40 d were more heavily pretreated and more likely to receive bridging therapy. At a median follow-up of 24.2 months, better outcomes were observed in patients with shorter vein-to-vein times. CR rates were 60%, 61%, and 50% (ORR 77%, 77%, and 70%) for patients with vein-to-vein time of <28 d, ≥28 to <40 d, and ≥40 d, respectively. OS at 24 months was 53% for patients with vein-to-vein time of both <28 d and ≥28 to <40 d, vs 38% for those with ≥40 d wait time. After other key prognostic factors were adjusted, patients with vein-to-vein time of ≥ 40 d had significantly lower CR rate and OS compared with patients with <28 d (OR 0.61 [95% CI 0.42-0.90] for CR; HR 1.33 [95% CI 1.05-1.70] for OS) and ≥28 to <40 d wait time (OR 0.66 [95% CI 0.45-0.97] for CR; HR 1.36 [95% CI 1.06-1.74] for OS). CRS of any grade or Grade ≥3 and prolonged neutropenia were consistent regardless of vein-to-vein time. Patients with vein-to-vein time of <28 d had more ICANS of any grade compared with those with ≥28 to <40 d wait time (OR 1.34 [95% CI 1.06-1.71]), while ICANS of Grade ≥3 was not significantly different between the two groups (Table 1). Among patients alive at Day 30, those with vein-to-vein time of ≥28 to <40 d and ≥40 d had higher rates of prolonged thrombocytopenia compared with those with <28 d wait time (OR 1.44 [95% CI 1.07-1.92] and 1.95 [95% CI 1.29-2.95], respectively). Conclusions: In this real-world analysis, most patients with r/r LBCL received axi-cel infusion within 5 weeks after apheresis. Shorter vein-to-vein time was associated with a favorable CR rate, OS, and reduced risk of prolonged thrombocytopenia even after adjustment of key prognostic factors; however, ICANS of any grade may be higher. Overall, these findings highlight the importance of shortening vein-to-vein time in patients treated with axi-cel. FLL and Z-HH contributed equally. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Clonal Myeloid Disorders Following CAR T-Cell Therapy

Background: Long-term complications of chimeric antigen receptor (CAR) T-cell therapy are not well-defined. Data on secondary malignancies after CAR T-cell therapy are emerging, and chemotherapy-related myeloid malignancies are of concern in these patients. We aimed to determine the incidence of myeloid neoplasms, including myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), following CAR T-cell therapy. We also aimed to determine the prevalence of somatic mutations associated with clonal myeloid disorders such as clonal hematopoiesis of indeterminate potential (CHIP) or clonal cytopenia of undetermined significance (CCUS) in these patients. Methods: This was a single-center retrospective cohort study that evaluated consecutive adult patients with an underlying hematologic malignancy treated with CAR T-cell therapy at our institution. We reviewed bone marrow biopsies, including cytogenetics, as well as hematologic sequencing panels following CAR T-cell therapy. Primary outcome was the cumulative incidence of myeloid neoplasms at one year. We calculated cumulative incidence with 95% confidence intervals (CI) with death as a competing event using statistical software XLSTAT. Results: A total of 78 consecutive patients who received CAR T-cell therapy between 2016 and 2022 at our institution were included. Of these, 61.5% were male and median age at time of therapy was 65.9 years (range 21.3-85.0). Patients had received a median of 3 (IQR, 2-4.1) lines of chemotherapy prior to CAR T-cell therapy, and 30.7% had undergone a prior autologous stem cell transplant. Most common indications for CAR T-cell therapy included diffuse large B-cell lymphoma (DLBCL, 57.7%) and multiple myeloma (24.4%), with the remainder split between mantle cell lymphoma (7.7%), chronic lymphocytic lymphoma (3.8%), high-grade B-cell lymphoma (2.6%), and one patient each with follicular lymphoma, follicular lymphoma transformed to DLBCL, and primary mediastinal B-cell lymphoma. Most common CAR T-cell therapies administered were lisocabtagene maraleucel (39.7%), axicabtagene ciloleucel (24.4%), and idecabtagene vicleucel (7.7%). At 30 days post-CAR T-cell therapy, 44.9% had complete response, 29.5% had partial response, 10.3% had stable disease, and 15.4% had progressive disease. A total of 37.1% died during the follow-up period; among patients who died, overall survival was a median 161 days (IQR, 104-259). Following CAR T-cell therapy, 73.1 % of patients had a bone marrow biopsy, 10.2% had a myeloid sequencing panel, and 10.3% had a lymphoid sequencing panel from peripheral blood or bone marrow. Median time of total follow-up was 14.8 months (IQR, 6.5-28.8). Two patients developed MDS and one developed AML; characteristics of patients diagnosed with a myeloid neoplasm are shown in table 1. Cumulative incidence of subsequent myeloid neoplasms at one year was 4.2% (95% CI 1.4-12.7) as shown in Figure 1. The incidence rate for development of a myeloid neoplasm was 2.3 cases per 100 person-years (95% CI, 0.60-.7.1). Additionally, four patients, including one who developed MDS, were found to have mutations associated with myeloid disorders on hematologic sequencing; this represents 5.1% of total patients and 25.0% of those with sequencing data available. Mutations are outlined in Table 1. Conclusion: A significant proportion of patients developed myeloid malignancies following CAR T-cell therapy, including two patients who had only received two lines of prior chemotherapy each. Mutations associated with myeloid neoplasms were found in one-quarter of the patients who had next generation sequencing performed. These findings suggest that further study is warranted to better define the causative role of CAR T-cell therapy in the development of myeloid disorders. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal