Refractory B-cell Lymphoma Research Articles

Use of locally produced anti-CD19 CAR-T cells in the treatment of relapsed/refractory B-cell lymphomas in adults

Background. Patients with B-cell lymphoma have an extremely unfavorable prognosis after relapse or in case of refractoriness to the first and consecutive lines of immunochemotherapy with the anti-CD19 CAR-T cells being the only therapeutic option to such patients. the manual preparation of anti-CD19 CAR-T lymphocytes was reproduced in the N. N. Alexandrov republican research and practical center for oncology and medical radiology (Minsk). Their safety was demonstrated. Aim. To estimate safety, tolerability and efficacy of the in-house CAR-T cells, including objective response rate, progression-free and overall survival. Materials and methods. The second generation anti-CD19 chimeric antigen receptor contained an anti-CD19 antibody scFv fragment, CD28 transmembrane domain, 4-1BB and CD3z signaling domains. the coding sequence was cloned into the lentiviral vector S4. The cell product was obtained by expansion of CD4- and CD8-positive lymphocytes populations with IL-7 and IL-15 after initial activation and lentiviral transduction with vector S4. CAR-T cells were infused into 8 patients with refractory forms of B-cell lymphoma after the preliminary lymphodepleting chemotherapy. Persistence of CAR-T cells was assessed by flow cytometry. therapeutic efficiency was assessed by positron emission tomography-computed tomography with 18F-fluorodeoxyglucose. Results. Expansion of CAR-T cells with resulting b-cell aplasia was observed in all patients. the median of observation was 113 days (range 22–529 days). objective response rate was 100 %, complete remission was observed in 6 patients, partial response – in 1 patient. One patient died because of complications before the clinical response. Overall survival was 88 ± 12 %. cytokine release syndrome and neurotoxicity were not observed in 6 out of 8 patients despite a high tumor burden. Conclusion. Our study demonstrated efficiency and safety of the in-house CAR-T cells for the treatment of patients with refractory B-cell lymphomas.

POSTER: ABCL-612 Real-World Outcomes in Patients With Relapsed or Refractory (r/r) Aggressive Large B-Cell Lymphoma (LBCL) Treated With Chemo-Immunotherapy

POSTER: ABCL-612 Real-World Outcomes in Patients With Relapsed or Refractory (r/r) Aggressive Large B-Cell Lymphoma (LBCL) Treated With Chemo-Immunotherapy

ABCL-612 Real-World Outcomes in Patients With Relapsed or Refractory (r/r) Aggressive Large B-Cell Lymphoma (LBCL) Treated With Chemo-Immunotherapy

ABCL-612 Real-World Outcomes in Patients With Relapsed or Refractory (r/r) Aggressive Large B-Cell Lymphoma (LBCL) Treated With Chemo-Immunotherapy

The nutritional impact of CD19-targeted CAR-T therapy versus BEAM chemotherapy for adult patients with lymphoma.

Chimeric antigen receptor T (CAR-T) cell therapy is a novel therapy demonstrating durable remissions in patients with refractory or relapsing non-Hodgkin's B-cell lymphoma. Maintaining a patient's nutritional status has been demonstrated to improve outcomes in cancer treatment. However, no studies have investigated how CAR-T therapy affects nutritional status, nor compared its impact with other cancer treatments for this patient group. The primary aim of the present study was to investigate the effect of CAR-T therapy on the prevalence of nutrition impact symptoms (NIS) and nutritional status within 30 days post-treatment of patients with lymphoma compared to a conditioning regimen for autologous haematopoetic stem cell transplant (carmustine/BCNU, Etoposide, cytarabine/Ara-C, Melphalan [BEAM] auto-haematopoetic stem cell transplant [HSCT]). Clinical notes of patients with lymphoma who underwent either CAR-T therapy or BEAM auto-HSCT between 2018 and 2021 were reviewed. Data extracted included body weight measurements and NIS, including decreased appetite, nausea, vomiting, diarrhoea, constipation, mucositis, cytokine release syndrome (CRS) and neurotoxicity at baseline and 30 ± 7 days post-treatment. In total, 129 adults with lymphoma (n = 88 CAR-T vs. n = 41 BEAM) were included. Nutritional status was assessed in both groups at baseline prior to treatment. Mean absolute weight change was significantly different between groups (3.05 kg in CAR-T, -5.9 kg in BEAM, p ≤ 0.001). This was also significant when weight loss was categorised into percentage weight loss (p = 0.01). CAR-T patients experienced a significantly lower prevalence of decreased appetite (52.3% vs. 97.6%) nausea (25% vs. 78%,) vomiting (10.2% vs. 53.7%), diarrhoea (43.2% vs. 96.7%) and mucositis (5.7% vs. 75.6%) combined across all levels of severity compared to BEAM chemotherapy (all p ≤ 0.01). CRS and neurotoxicity, which are specific side effects of CAR-T therapy, were moderately positively associated with weight loss. Weight loss, percentage weight loss and NIS were significantly reduced in CAR-T compared to BEAM treatment. However, patients who experienced neurotoxicity during treatment did have significant weight loss.

Negative Prognostic Impact of High-Dose or Long-Term Corticosteroid Use in Patients with Relapsed or Refractory B-Cell Lymphoma Who Received Tisagenlecleucel

The prognostic impact of corticosteroid therapy in patients receiving tisagenlecleucel (tisa-cel) treatment who are more likely to develop cytokine release syndrome (CRS) remains unclear. This study aimed to evaluate the clinical impact and lymphocyte kinetics of corticosteroid administration for CRS in 45 patients with relapsed and/or refractory B cell lymphoma treated with tisa-cel. This was a retrospective evaluation of all consecutive patients diagnosed with relapsed and/or refractory diffuse large B cell lymphoma, follicular lymphoma with histologic transformation to large B cell lymphoma, or follicular lymphoma who received commercial-based tisa-cel treatment. The best overall response rate, complete response rate, median progression-free survival (PFS), and median overall survival (OS) were 72.7%, 45.5%, 6.6 months, and 15.3 months, respectively. CRS (predominantly grade 1/2) occurred in 40 patients (88.9%), and immune effector cell-associated neurotoxicity syndrome (ICANS) of all grades occurred in 3 patients (6.7%). No grade ≥3 ICANS occurred. Patients with high-dose (≥524 mg, methylprednisolone equivalent; n = 12) or long-term (≥8 days; n = 9) corticosteroid use had inferior PFS and OS to patients with low-dose or no corticosteroid use (both P < .05). The prognostic impact remained even in 23 patients with stable disease (SD) or progressive disease (PD) before tisa-cel infusion (P = .015). but not in patients with better disease status (P = .71). The timing of corticosteroid initiation did not have a prognostic impact. Multivariate analysis identified high-dose corticosteroid use and long-term corticosteroid use as independent prognostic factors for PFS and OS, respectively, after adjusting for elevated lactate dehydrogenase level before lymphodepletion chemotherapy and disease status (SD or PD). Lymphocyte kinetics analysis demonstrated that after methylprednisolone administration, the proportions of regulatory T cells (Tregs), CD4+ central memory T (TCM) cells, and natural killer (NK) cells were decreased, whereas the proportion of CD4+ effector memory T (TEM) cells was increased. Patients with a higher proportion of Tregs at day 7 had a lower incidence of CRS, but this did not affect prognosis, indicating that early elevation of Tregs may serve as a biomarker for CRS development. Furthermore, patients with higher numbers of CD4+ TCM cells and NK cells at various time points had significantly better PFS and OS, whereas the number of CD4+ TEM cells did not impact prognostic outcomes. This study suggests that high-dose or long-term corticosteroid use attenuates the efficacy of tisa-cel, especially in patients with SD or PD. Additionally, patients with high levels of CD4+ TCM cells and NK cells after tisa-cel infusion had longer PFS and OS.

Durable responses with ALK inhibitors for primary refractory anaplastic lymphoma Kinase-positive large B-cell lymphoma.

Durable responses with ALK inhibitors for primary refractory anaplastic lymphoma Kinase-positive large B-cell lymphoma.

PHASE 1/2A CLINICAL TRIAL OF BI‐1206, A MONOCLONAL ANTIBODY TO CD32B (FCGRIIB), IN COMBINATION WITH RITUXIMAB IN SUBJECTS WITH INDOLENT B‐CELL LYMPHOMA

Introduction: Anti-CD20 antibodies, such as rituximab, are an essential therapy resource in patients with B-cell lymphomas. However, approximately 15% of patients are refractory to treatment, and 25% relapse within 3 years following treatment. Non-clinical and retrospective clinical data indicate that the inhibitory Fc receptor CD32b promotes resistance through mechanisms acting on tumor and immune effector cells. Expressed on tumor B cells, CD32b triggers rituximab internalization, and tumor CD32b expression correlates inversely with response to rituximab or rituximab-containing therapy in MCL, FL, and DLBCL. BI-1206 is a human recombinant anti-CD32b (FcγRIIB) antagonistic IgG1 antibody that blocks rituximab internalization and, in non-clinical experimental models, enhances efficacy and overcomes rituximab resistance. During early clinical development of BI-1206, frequent infusion-related reactions were observed after intravenous (IV) administration. The development of a novel pre-medication regimen using two doses (16–24 h and 1 h) of corticosteroids prior to IV administration, as well as of a subcutaneous (SC) administration, have been shown to improve the tolerability of BI-1206 significantly, and both methods of administration are evaluated in the current trial. Methods: The current phase 1/2a multicenter clinical trial includes relapsed or refractory B-cell lymphoma, including FL (except FL grade 3B), MZL, and MCL. This trial will evaluate the safety and tolerability of IV and SC BI-1206 administered in combination with rituximab. The ivRP2D has been established, and enrollment of patients to SC BI-1206 to establish scRP2D has started. Ph2a of the trial will consist of cohorts of at minimum 6 and maximum 12 subjects each, receiving ivRP2D, scRP2D, and potential additional dose levels of interest. During induction therapy, patients receive one dose of single-agent rituximab (375 mg/m2) followed by dosing of BI-1206 with subsequent rituximab on weeks 2, 3, and 4. Patients showing clinical benefit (complete response [CR], partial response [PR], or stable disease [SD]) at week 6 are eligible for continued maintenance therapy with dosing of BI-1206 and rituximab every 8 weeks for up to 7 cycles. The research was funded by: BioInvent Keywords: Combination Therapies, Immunotherapy, Ongoing Trials Conflicts of interests pertinent to the abstract. M. Jerkeman Honoraria: Gilead, Janssen, Roche, AstraZeneca, Abbvie, BMS Research funding: Gilead, Janssen, Roche, AstraZeneca, Abbvie, BMS P. Abrisqueta Costa Consultant or advisory role Janssen, Roche, Abbvie, BMS, Astrazeneca, Gilead, Beigene Honoraria: Janssen, Roche, Abbvie, BMS, Astrazeneca, Gilead Educational grants: Janssen, Abbvie J. M. Sancho Cia Consultant or advisory role Roche, Janssen, Novartis, BMS-Celgene, Kite-Gilead, Beigene, Lilly, Incyte, Miltenyi Biomedicine Honoraria: Roche, Janssen, Novartis, BMS-Celgene, Kite-Gilead, Takeda, Incyte M. Bastos-Oreiro Consultant or advisory role Roche, Kite, Novartis, Takeda, Janssen, Incyte Honoraria: Roche, Kite, Novartis, Takeda, Janssen, Incyte Research funding: Roche Educational grants: Roche, Kite, Novartis, Takeda, Janssen, Incyte J. B. Cohen Consultant or advisory role Janssen, Astra Zeneca, BeiGene, Loxo/Lilly, Gilead, ADCT Research funding: Genentech, Takeda, Novartis, Celgene, BioInvent, LAM Therapeutics, Loxo/Lilly, Astra Zeneca R. Cordoba Mascunano Consultant or advisory role Roche, Abbvie, Janssen, Astra Zeneca, Beigene, Lilly, Kite, Incyte, Takeda, Kiowa-Kirin E. Domingo Domenech Consultant or advisory role TAKEDA Honoraria: TAKEDA Educational grants: TAKEDA, BMS S. Novelli Canales Honoraria: Mundipharma Research funding: Novartis M. Borggren Employment or leadership position: BioInvent Stock ownership: BioInvent B. Frendeus Employment or leadership position: BioInvent Stock ownership: BioInvent I. Karlsson Employment or leadership position: BioInvent Stock ownership: BioInvent L. Mårtensson Employment or leadership position: BioInvent Stock ownership: BioInvent S. Patel Employment or leadership position: BioInvent Stock ownership: BioInvent I. Teige Employment or leadership position: BioInvent Stock ownership: BioInvent J. E. Wallin Employment or leadership position: BioInvent, Lilly Keywords: combination therapies, immunotherapy, ongoing trials Stock ownership: BioInvent, Lilly A. Mc Allister Employment or leadership position: BioInvent Stock ownership: BioInvent

Real-world use of tisagenlecleucel in children and young adults with relapsed or refractory B-cell lymphomas.

10031 Background: Survival for pediatric B-cell lymphomas (BCL) exceeds 90% with modern regimens, however outcomes remain poor for patients with relapsed or refractory (R/R) disease. Tisagenlecleucel is a CD19-directed CAR T-cell therapy (CART) that is FDA approved for adults with R/R BCL. No data exists for use of tisagenlecleucel in R/R pediatric BCL. Methods: We surveyed 48 sites in the Pediatric Real-World CAR Consortium to retrospectively describe use and outcomes of tisagenlecleucel for pediatric patients with R/R BCL. This cohort included 10 patients from 7 centers aged ≤25 years who were infused between 2019-2022 and were ≥3 months from CART. We aimed to describe response rates, as determined by each institution based on positron emission tomography, bone marrow evaluation, and/or cerebrospinal fluid (CSF) studies, along with toxicity and outcomes in this population. Results: Ten patients received CART with a median age at infusion of 19 (range, 7-24) years. Five patients had B-lymphoblastic lymphoma (B-LLy), 2 had primary mediastinal BCL, and 1 each had Burkitt lymphoma, diffuse large B-cell lymphoma (DLBCL), and post-transplant lymphoproliferative disorder related DLBCL. Five patients had primary refractory disease, and 5 were in ≥2nd relapse. Three had received prior hematopoietic stem cell transplant (HSCT). Two had CSF involvement, and 1 had central nervous system parenchymal disease at time of infusion. CART was well tolerated with 1 patient experiencing grade 3 cytokine release syndrome and 2 patients experiencing neurotoxicity (grade 2 n = 1, grade 3 n = 1), both of whom had CSF involvement at time of CART infusion. Best overall response was complete response (CR) for 6, partial response (PR) for 2, and refractory disease for 2. Two patients, both with B-LLy, underwent allogeneic HSCT while in CART-mediated CR with B-cell aplasia. Both patients with PR (1 DLBCL, 1 Burkitt) subsequently relapsed with CD19-negative disease; the patient with DLBCL subsequently achieved CR with salvage immuno-chemotherapy and HSCT. All 6 CR patients remain in remission at a median time to follow-up of 31 (range, 14-47) months. Conclusions: This multicenter case series of CD19-directed CART for R/R pediatric BCL suggests that tisagenlecleucel may be safe and active in this population with all CR patients currently in sustained remission. Larger studies are needed to understand how best to incorporate CART into treatment for R/R pediatric BCL. [Table: see text]

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Introduction: Central nervous system (CNS) involvement in patients with refractory or relapsed large B-cell lymphoma (LBCL) is associated with an extremely poor prognosis. Autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy is an approved treatment for patients with refractory or relapsed (R/R) LBCL that has changed the prognosis of patients with chemoresistant LBCL. However, data regarding efficacy and safety of CART cell treatment in patients with active CNS involvement are limited since they are excluded from most of clinical trials. Methods: We retrospectively collected data from 75 patients with LBCL, treated with CART cells from January 2020 to January 2023 in Henri Mondor Hospital. We identified 13 patients with active CNS involvement at the time of CAR-T cell treatment decision: 12/13 had abnormal neurological examination, 8/11 had head and/or medullar MRI abnormalities consistent with lymphoma and 9/10 had detectable lymphoma cells in the cerebrospinal fluid. We compared the characteristics of the 13 patients with CNS involvement (CNS+) with 62 patients without evidence of active CNS disease (CNS-). Median age was 69 and 59 years, respectively (p = 0.05). CNS+ patients received a median of 2 previous lines of treatment versus 3 for CNS- patients (p = 0.34). Performance status prior to CART-cell injection was 2 or more in 9/13 (69%) and 11/62 (18%) p < 0.001, respectively. 5/13 (38%) CNS+ patients had high grade B-cell lymphomas versus 11/62 (18%) CNS- (p = 0.13). CAR-T-cell was axi-cel in 10/13 (77%) CNS+ patients versus 42/62 (68%) CNS– (p = 0.74). It is noteworthy that 7/13 (54%) CNS+ patients had pre-existing low-grade B-cell lymphomas versus 15/62 (24%) CNS- (p = 0.046). Results: The best overall response rate was identical in both groups: 12/13 (92%) in CNS+ patients versus 51/61 (92%) in CNS-, including 11/13 (85%) and 44/61(72%) complete metabolic response. As shown in the figure, median progression free survival and overall survival was 5.5 and 8.4 months, respectively in CNS+ patients versus 11.5 and 21 months in CNS- patients (not significant). Regarding safety, 13/13 (100%) CNS+ patients had a cytokine release syndrome (10 grade 1–2 and 3 grade 3) versus 54/62 (87%) CNS- (49 grade 1–2 and 5 grade 3–4) and 10/13 (77%) experienced ICANS (6 grade 1–2 and 4 grade 3–4) versus 28/62 (45%) CNS- (27 grade 1–2 and 1 grade 3–4) (p = 0.06 and 0.02 for grade 3–4). Transfer into an intensive care unit occurred in 4/13 (31%) CNS+ patients versus 9/62 (15%) CNS- (p = 022). Median time of hospitalization was 37 days for CNS+ patients versus 20 days for CNS- patients (p = 0.007). Six CNS+ patients died from which 5 died of progression and 1 of infection. Keywords: Aggressive B-cell non-Hodgkin lymphoma, Cellular therapies, Immunotherapy Conflicts of interests pertinent to the abstract. F. Lemonnier Consultant or advisory role: BMS, Kiowa, Miltenyi Educational grants: Gilead, Janssen, Roche L. Roulin Educational grants: Kite gilead, Novartis, Bristol myers squibb

Six-year safety and efficacy results from the CHRONOS-1 study of the PI3K inhibitor copanlisib in patients with relapsed or refractory follicular lymphoma.

7555 Background: The efficacy of copanlisib, an intravenous pan-class I phosphatidylinositol 3-kinase (PI3K) inhibitor, was demonstrated in the Phase II CHRONOS-1 study in patients with relapsed or refractory indolent B-cell lymphoma (Dreyling et al. J Clin Oncol 2017). Copanlisib was approved by the US Food and Drug Administration in 2017 for the treatment of patients with follicular lymphoma (FL) who have received ≥2 therapies. Here, we describe updated efficacy and safety data from patients with FL at the 6-year follow-up of CHRONOS-1. Methods: CHRONOS-1 included patients with relapsed or refractory indolent FL (grades 1-3a) who had received ≥2 lines of therapy. Copanlisib 60 mg was administered via intravenous infusion on days 1, 8, and 15 of a 28-day cycle. Objective tumor response rate (ORR) was assessed by independent radiologic review (Cheson et al. J Clin Oncol 2007) as the primary efficacy endpoint. Safety analysis included adverse events graded using CTCAE v4.03. Results: 104 patients with FL were treated in CHRONOS-1, of whom 99.0% ( n= 103) discontinued treatment at the time of database cut-off on June 30, 2022. 72% of patients ( n= 75) received ≥1 line of subsequent systemic anti-cancer therapy during follow-up, with 40% receiving a rituximab-based regimen. At the cut-off, ORR (primary endpoint) was 57.7% ( n= 60), with 19.2% ( n= 20) of patients achieving a complete response. Median duration of response was 12.2 months (range 1.1-48.1). Median progression-free survival (PFS) was 11.2 months (range 0.2-51.5) with a median follow-up of 20.7 months (95% confidence interval [CI] 11.5, 31.5); PFS rate was 32% at 2 years. Median overall survival was 46.3 months (range 0.7-82.9) with a total of 56 events and a median follow-up of 82.4 months (95% CI 79.3, 84.9); survival rate was 43% at 6 years. Median duration of treatment was 6.0 months (range 0.23-80.9). No patients experienced transformation to aggressive lymphoma (diffuse large B-cell lymphoma). The primary reasons for stopping treatment included radiologic disease progression (42.3%; n= 44) and adverse events not associated with clinical disease progression (29.8%; n= 31). The safety profile was consistent with the reported 2-year follow-up data (Dreyling et al. Am J Hematol 2020). The most common treatment-emergent adverse events (all grades/grades 3-4) were infusion-related hyperglycemia (50.0%/39.5%), diarrhea (36.5%/8.7%), hypertension (28.8%/23.1%), pyrexia (27.9%/4.8%), and neutropenia (26.0%/23.0%). Conclusions: Copanlisib continued to induce robust response and durable survival in patients with relapsed or refractory indolent FL at 6 years of follow-up. Copanlisib was well tolerated, with no new safety signals and no evidence of malignant transformation. These results further support the long-term use of copanlisib in this patient population. Clinical trial information: NCT01660451 .

Subgroup analyses of primary refractory (refr) vs early relapsed (rel) large B-cell lymphoma (LBCL) from the TRANSFORM study of lisocabtagene maraleucel (liso-cel) vs standard of care (SOC) as second-line (2L) therapy.

7526 Background: The TRANSFORM primary analysis (PA; NCT03575351) confirmed the superior efficacy of liso-cel vs SOC as 2L therapy in patients (pts) with primary refr or early rel LBCL (Abramson et al. Blood 2022). Response to first-line (1L) therapy (refr vs rel), which was a study randomization stratification factor, may influence future treatment response. Here, we present results for refr and rel LBCL subgroups from the TRANSFORM PA. Methods: TRANSFORM is a randomized phase 3 study of liso-cel vs SOC (salvage chemotherapy [CT] followed by high-dose CT [HDCT]/autologous SCT [ASCT]) in adults ≤ 75 y with LBCL primary refr to or rel ≤ 12 mo after 1L therapy and eligible for HDCT/ASCT. The primary endpoint was event-free survival (EFS); key secondary endpoints were CR rate, PFS, and OS. In this predefined subgroup analysis, refr was SD, PD, PR, or CR with rel &lt; 3 mo after 1L therapy; rel was CR with rel ≥ 3 mo and ≤ 12 mo after 1L therapy. Results: 92 pts were randomized to each arm. Most pts in the liso-cel and SOC arms had refr disease (73% and 76%, respectively; rel disease, 27% and 24%). Baseline characteristics in the refr and rel subgroups, respectively, were generally balanced: median LDH (U/L; liso-cel, 228.5 and 225; SOC, 259 and 259); median SPD (cm2; liso-cel, 11 and 12; SOC, 15.5 and 18); high-grade B-cell lymphoma (liso-cel, 27% and 16%; SOC, 27% and 9%); diffuse LBCL not otherwise specified (liso-cel, 58% and 56%; SOC, 49% and 73%). Consistent with the overall study population, EFS, CR rate, and PFS favored liso-cel vs SOC in both subgroups (Table). Safety was also consistent. Grade ≥ 3 cytokine release syndrome (CRS) and neurological events (NE) were low in refr (1% and 4%) and rel (0 and 4%) subgroups, respectively, with no grade 4/5 CRS or NEs. Conclusions: In TRANSFORM, liso-cel showed benefits in EFS, PFS, and CR rate vs SOC irrespective of prior response to 1L therapy. As refr LBCL is historically difficult to treat, outcomes for liso-cel in this subgroup are encouraging. Clinical trial information: NCT03575351 . [Table: see text]

Patients’ experience with chimeric antigen receptor T-cell therapy for DLBCL in China: a qualitative study

PurposeThe experiences of patients with diffuse large B-cell lymphoma (DLBCL) treated with chimeric antigen receptor (CAR) T-cell therapy have received little attention. This study aimed to explore the treatment experiences of patients with relapsed or refractory (R/R) B-cell lymphoma during CAR T-cell therapy in China.MethodsThis descriptive qualitative study was conducted using face-to-face semi-structured interviews with 21 DLBCL patients 0–2 years after CAR-T infusion. Two researchers independently coded the interviews in MAXQDA 2022, and the original data were analyzed by conventional content analysis.ResultsFour themes emerged from the transcripts: (1) physiological distress, (2) functional impacts, (3) psychological experience, and (4) support requirement. Participants expressed 29 short-term or long-term symptoms related to their disease and treatment, influencing their daily life and function in a social setting. The participants expressed different negative emotions, polarized expectations about efficacy, and over-reliance on authoritative medical care. Their major concerns and hopes were achieving life goals, being treated with respect, obtaining more information about CAR T-cell therapy, and receiving government financial sponsorship.ConclusionsThe patients experienced short-term and long-term symptoms of physical distress. Patients who have experienced failure in CAR T-cell therapy also experience strong negative emotions, such as dependency and guilt. They also require authentic spiritual and financial information that is authentic. Our study may guide the development of standardized and comprehensive nursing care for R/R DLBCL patients undergoing CAR T-cell therapy in China.

Characterization of the input material quality for the production of tisagenlecleucel by multiparameter flow cytometry and its relation to the clinical outcome.

Tisagenlecleucel (tisa-cel) is a CD19-specific CAR-T cell product approved for the treatment of relapsed/refractory (r/r) DLBCL or B-ALL. We have followed a group of patients diagnosed with childhood B-ALL (n = 5), adult B-ALL (n = 2), and DLBCL (n = 25) who were treated with tisa-cel under non-clinical trial conditions. The goal was to determine how the intensive pretreatment of patients affects the produced CAR-T cells, their in vivo expansion, and the outcome of the therapy. Multiparametric flow cytometry was used to analyze the material used for manufacturing CAR-T cells (apheresis), the CAR-T cell product itself, and blood samples obtained at three timepoints after administration. We present the analysis of memory phenotype of CD4/CD8 CAR-T lymphocytes (CD45RA, CD62L, CD27, CD28) and the expression of inhibitory receptors (PD-1, TIGIT). In addition, we show its relation to the patients' clinical characteristics, such as tumor burden and sensitivity to prior therapies. Patients who responded to therapy had a higher percentage of CD8+CD45RA+CD27+ T cells in the apheresis, although not in the produced CAR-Ts. Patients with primary refractory aggressive B-cell lymphomas had the poorest outcomes which was characterized by undetectable CAR-T cell expansion in vivo. No clear correlation of the outcome with the immunophenotypes of CAR-Ts was observed. Our results suggest that an important parameter predicting therapy efficacy is CAR-Ts' level of expansion in vivo but not the immunophenotype. After CAR-T cells' administration, measurements at several timepoints accurately detect their proliferation intensity in vivo. The outcome of CAR-T cell therapy largely depends on biological characteristics of the tumors rather than on the immunophenotype of produced CAR-Ts.

Safety and efficacy of tisagenlecleucel in patients with relapsed or refractory B-cell lymphoma: the first real-world evidence in Japan.

Tisagenlecleucel, an autologous CD19-directed T-cell immunotherapy, can induce a durable response in adult patients with relapsed/refractory (r/r) B-cell lymphoma. To elucidate the outcome of chimeric antigen receptor (CAR) T-cell therapy in Japanese, we retrospectively analyzed the outcomes of 89 patients who received tisagenlecleucel for r/r diffuse large B-cell lymphoma (n = 71) or transformed follicular lymphoma (n = 18). With a median follow-up of 6.6-months, 65 (73.0%) patients achieved a clinical response. The overall survival (OS) and event-free survival (EFS) rates at 12months were 67.0% and 46.3%, respectively. Overall, 80 patients (89.9%) had cytokine release syndrome (CRS), and 6 patients (6.7%) had a grade ≥ 3 event. ICANS occurred in 5 patients (5.6%); only 1 patient had grade 4 ICANS. Representative infectious events of any grade were cytomegalovirus viremia, bacteremia and sepsis. The most common other adverse events were ALT elevation, AST elevation, diarrhea, edema, and creatinine elevation. No treatment-related mortality was observed. A Sub-analysis showed that a high metabolic tumor volume (MTV; ≥ 80ml) and stable disease /progressive disease before tisagenlecleucel infusion were both significantly associated with a poor EFS and OS in a multivariate analysis (P < 0.05). Notably, the combination of these 2 factors efficiently stratified the prognosis of these patients (HR 6.87 [95% CI 2.4-19.65; P < 0.05] into a high-risk group). We report the first real-world data on tisagenlecleucel for r/r B-cell lymphoma in Japan. Tisagenlecleucel is feasible and effective, even in late line treatment. In addition, our results support a new algorithm for predicting the outcomes of tisagenlecleucel.

Prognostic value of baseline and early response FDG-PET/CT in patients with refractory and relapsed aggressive B-cell lymphoma undergoing CAR-T cell therapy

PurposeChimeric antigen receptor (CAR)-T cells are a viable treatment option for patients with relapsed or refractory (r/r) aggressive B-cell lymphomas. The prognosis of patients who relapse after CAR-T cell treatment is dismal and factors predicting outcomes need to be identified. Our aim was to assess the value of FDG-PET/CT in terms of predicting patient outcomes.MethodsTwenty-two patients with r/r B-cell lymphoma who received CAR-T cell treatment with tisagenlecleucel (n = 17) or axicabtagene ciloleucel (n = 5) underwent quantitative FDG-PET/CT before (PET-0) and 1 month after infusion of CAR-T cells (PET-1). PET-1 was classified as complete metabolic response (CMR, Deauville score 1–3) or non-CMR (Deauville score 4–5).ResultsAt the time of PET-1, 12/22 (55%) patients showed CMR, ten (45%) patients non-CMR. 7/12 (58%) CMR patients relapsed after a median of 223 days, three of them (25%) died. 9/10 (90%) non-CMR patients developed relapse or progressive disease after a median of 91 days, eight of them (80%) died. CMR patients demonstrated a significantly lower median total metabolic tumor volume (TMTV) in PET-0 (1 ml) than non-CMR patients (225 ml).ConclusionOur results confirm the prognostic value of PET-1. 42% of all CMR patients are still in remission 1 year after CAR T-cell treatment. 90% of the non-CMR patients relapsed, indicating the need for early intervention. Higher TMTV before CAR-T cell infusion was associated with lower chances of CMR.

Retracted: Parallel CD19/CD20 CAR-Activated T-Cells Are More Effective for Refractory B-Cell Lymphoma In Vitro and In Vivo.

[This retracts the article DOI: 10.1155/2022/1227308.].

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.

CO126 Axicabtagene Ciloleucel for the Treatment of B-Cell Lymphoma- Gaps, Opportunities and Future Perspectives

Axicabtagene ciloleucel (axi-cel; KTE-C19) is an engineered autologous anti-CD19 chimeric antigen receptor T cell therapy (CAR T-cell therapy) being used for the treatment of relapsed or refractory B-cell lymphomas (BCLs). Axi-cel therapy has proven to be better compared to the standard of care (SOC) therapy, like a high dose of platinum-containing salvage regimens or autologous stem cell transplantation. To improve potency and reduce toxicity with axi-cel therapy, cell product composition can be tweaked.

Frailty in Patients Undergoing Chimeric Antigen Receptor T-Cell (CAR T) Therapy at Princess Margaret Cancer Centre: A Prospective Pilot Study

Introduction Princess Margaret Cancer Centre is 1 of 3 adult centres in Ontario, Canada providing Chimeric Antigen Receptor T-Cell (CAR T) therapy as a standard of care treatment for patients with relapsed and refractory B-cell lymphoma, with the first patient treated in June 2020. There is no upper age limit for treatment referral, and frailty is an important consideration in assessing fitness for treatment. However, there is limited published research in this area. One study found that fit patients had improved response rates, progression-free survival (PFS), and overall survival (OS), than patients who were unfit/frail (Zhang. Leuk Lymph. 2022). This data supports the need for further characterization of frailty in patients undergoing CAR-T. This study aims to determine if frailty assessments pre-CAR T can predict those at higher risk for acute toxicities, PFS, and OS. Additionally, changes in frailty in the 12 months following treatment compared to baseline will be described. Understanding how CAR T therapy affects a patient's frailty over time will facilitate planning appropriate interventions. Methods We performed a cohort study of consecutive patients with lymphoma undergoing CAR T-cell therapy at our institution, from April 2021 to present. Information regarding clinical presentation, histological subtype, prognostic factors, bridging treatment, and acute toxicity, such immune effector cell-associated neurotoxicity syndrome (ICANS) and CRS, were collected. Frailty was evaluated using the Clinical Frailty Scale (CFS), Grip Strength, Gait Speed, Mini-Cog, Edmonton Symptom Assessment System (ESAS) and Patient Health Questionnaire (PHQ-2 and PHQ-9) at 5 time points: baseline (clearance visit), and 1, 3, 6 and 12 months post-CAR T. We discontinued assessments upon progression. At baseline, additional assessments were completed to further characterize frailty including the Vulnerable Elders Survey (VES-13), Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI) and Cumulative Illness Rating Scale (CIRS). Results Thirty patients have been enrolled to date. Mean age was 59 ± 13.5 years and patients were primarily male (58.6%). All 30 patients were diagnosed with non-Hodgkin lymphoma; 46.4% had de novo diffuse large B-cell lymphoma, and 21% had transformation from follicular lymphoma. Median follow-up is 2.9 months (Q1 1.2, Q3 9.4). All 30 patients completed assessments at baseline, 21 completed 1 month, 11 completed 3 month, 5 completed 6 month, and 4 completed 12 month assessments. Median scores on the HCT-CI, CIRS and VES-13 at baseline were 1.0 (Q1 0.0, Q3 3.0), 2.0 (Q1 1.0, Q3 6.0) and 1.0 (Q1 0.0, Q3 5.0), respectively. There were clinically significant changes observed in CFS over time (p=0.043), with mean scores of 3.60 (0.25) at baseline and 2.00 (0.67) at 12 months (Table 1). There were no significant changes (p=0.969; p=0.582) between timepoints for either of the physical assessments of grip strength or gait speed. Compared to other assessments, PHQ total score had a larger difference between timepoints with mean scores of 2.33 (0.93) at baseline and 0.00 (0.00) at 12 months, however, this was not significant (p=0.052), likely related to limited sample size (N=4). When analyzing specific acute toxicities, 7 patients experienced ICANS (Grade 3 7.1%, Grade 2 3.6%, Grade 1 (14.3%)). Twenty-five patients (89.3%) experienced CRS (Grade 2 50.0%, Grade 1 39.3%) during the 30 days following cell re-infusion. There have been 8 progression events (2 patients with progression remain alive), and 7 deaths with 1 occurring without disease progression. There was a 76.9% probability of PFS at 3 months and 64.5% at 6 months, with 3 month and 6 month OS 80.2% and 74.5%. Conclusions The only repeated measurement of frailty that found to have clinically significant changes between timepoints was the CFS, suggesting an element of reversible functional impairment related to patients’ lymphoma. Overall patients appear to be impaired at baseline, worsen through the first 1-3 months, and improve by 12 month if in remission. However, the number of patients who completed the 12 month visit to date is small and more data is needed from ongoing follow-up and accrual. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A Phase 1 Study of ADI-001: Anti-CD20 CAR-Engineered Allogeneic Gamma Delta1 (γδ) T Cells in Adults with B-Cell Malignancies

Introduction: ADI-001 is a first-in-class allogeneic gamma delta (γδ) CAR T cell therapy targeting the B-cell antigen CD20. ADI-001 has both adaptive and innate cytotoxic effector functions to complement CAR targeting, potentially enhancing efficacy and reducing the possibility of tumor escape due to antigen loss. ADI-001 expresses MHC-independent γδ T cell receptors, thus lowering the risk of graft-versus-host disease (GvHD) without the need for gene editing. Methods: This multicenter phase 1 clinical trial is evaluating ADI-001 in adults with relapsed / refractory B-cell lymphoma. Eligibility criteria included the presence of measurable lesions, expression of CD20 on tumor cells and ≥ 2 prior systemic therapies. All patients received conditioning therapy with fludarabine and cyclophosphamide. ADI-001 can be administered at four dose levels (DL) (DL1:3E7, DL2:1E8, DL3:3E8 and DL4:1E9 CAR+ cells) in a 3+3 dose-escalation scheme. Patients who completed the 28-day DLT period were considered evaluable. In DL3, patients could receive a second course of conditioning therapy and be re-dosed with ADI-001 if there was no DLT during the first 28 days, no progressive disease on PET/CT assessment on Day 28, and have recovered from cytopenias. Treatment-emergent adverse events were graded by CTCAE v5.0, and Immune Effector Cell Associated Neurologic Syndrome (ICANS) and Cytokine Release Syndrome (CRS) assessments were performed per ASTCT criteria. Objective response rates (ORR) were evaluated by independent radiographic review per Lugano 2014 criteria. Results: As of 15 July 2022, 11 patients were enrolled and nine were evaluable. Of these nine patients, six (67%) were male and the median age was 62 years (range 45-75). Eight patients had large B-cell lymphoma (LBCL) and one had mantle cell lymphoma (MCL). Of the eight patients with LBCL, five had diffuse-large B-cell lymphoma (DLBCL), two had high-grade B-cell lymphoma (HGBCL) with double/triple hit, and one had HGBCL not otherwise specified. At baseline, the median IPI score was four (range 2-4); the median tumor burden was 2,974 (150-7,919) mm2, and 89% (8/9) had stage III/IV disease. The median number of prior therapies was four (range 2-5). Four patients had prior anti-CD19 CAR T cell therapy (two Liso-cel and two Axi-cel). Among nine evaluable patients, three patients were treated at each of DL1, DL2, and DL3. Two patients at DL3 were re-dosed with a second course of ADI-001. Two patients developed CRS: one Grade 1 and one Grade 2. One patient developed a Grade 1 ICANS which resolved within 24 hours. There were no ≥ Grade 3 CRS or ICANS. The only related SAEs were Grade 2 CRS, Grade 1 ICANS and Grade 3 adenoviraemia. There was no reported GvHD or protocol-defined DLT events. The best ORR was 78% (7/9), and the complete response (CR) rate was 78% (7/9). For the four patients who had prior CD19 CAR T therapies, the ORR was 100% (4/4) and CR rate was also 100%. As of the data cut-off date, of the seven patients who had achieved CR, two patients progressed, one died while in complete remission and four were still in CR and in active follow-up, with a range of follow-up time between 1.2 and 8.8 months. CAR+ γδ T cell kinetics improved in a dose-dependent manner with peak cell expansion occurring between Days 7 and 10 at DL3 based on flow cytometry. Conclusions: ADI-001 γδ CAR T cells maintained a favorable safety profile. Preliminary efficacy showed encouraging CR rate and sustained durability in patients, including those previously exposed to CAR T therapy. Additional data will be presented at the meeting. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal