Refractory non-Hodgkin Lymphoma Research Articles

Enrichment of CD4+ and CD8+ T lymphocytes with a column-free flow-based device for clinical cell manufacturing.

In recent years, adoptive T cell-based immunotherapies have been developed to treat a wide range of hematologic malignancies, including relapsed or refractory non-Hodgkin lymphoma, B-cell leukemia, and multiple myeloma. Most of the commercially approved adoptive T cell therapies are composed of chimeric antigen receptor (CAR)-based T cells, which are a patient's own T cells engineered for recognition of a specific surface antigen, such as CD19 or CD20. Unselected peripheral blood mononuclear cells (PBMCs) have recently been used in several manufacturing protocols, but the vast majority of protocols still use CD4/CD8-selected T cells. The first step in manufacture of these CAR-T products involves simultaneous selection/purification of CD4+ and CD8+ (or CD4/CD8 positive) T cells. The typical approach for selection of CD4/CD8 subsets for clinical manufacturing involves immunomagnetic labeling followed by selection of positively labeled cells using static column-based approaches that are prone to cell clogging events and typically take approximately 2 to 3 hours in a closed system. Here, we used a new column-free, flow-based, fully closed system suitable for clinical cell manufacturing for isolation of CD4/CD8 cells with high purity in a rapid fashion that could accommodate varying capacities without compromising cell recovery. This new approach allows markedly faster cell selection, preserving the quality of the cells that are used for downstream CAR-T cell manufacture. We report the results of our successful validation runs using the new MARS Bar enrichment platform using human apheresis-derived leukocytes for CD4/CD8 isolation in a selection buffer or directly in T-cell culture media for subsequent CAR-T cell production. Our data show a rapid and robust CD4/CD8 enrichment with an enrichment time shortened to 1 hour or less. Overall purity (based on CD3+ expression) of the cells was 95.51 ± 1.23% and 93.13 ± 0.30% for fresh and thawed T cells, respectively. Cell recoveries were 64.68 ± 14.05% and 57.06 ± 6.28% for fresh and thawed cells, respectively. We then further tested the MARS Bar enrichment platform after cell wash/volume reduction using the LOVO Automated Cell Processing System, leading to a higher consistency in CD3+ purity and increased cell recovery of 73.0 ± 4.73%. Enriched cells were characterized by high viability, ie, 90.5 ± 0.05% for fresh leukopaks when used together with the LOVO device. Altogether, the new approach using the MARS Bar platform allows one to customize and standardize the selection process by using a stand-alone instrument in a clinical manufacturing setting together with cGMP grade reagents and buffers.

Valemetostat monotherapy in patients with relapsed or refractory non-Hodgkin lymphoma: a first-in-human, multicentre, open-label, single-arm, phase 1 study.

Few treatment options exist for patients with non-Hodgkin lymphoma, and outcomes remain poor for relapsed or refractory disease. We evaluated the safety and preliminary clinical activity of valemetostat, a novel inhibitor of EZH2 and EZH1, in patients with relapsed or refractory non-Hodgkin lymphomas. This first-in-human, multicentre, open-label, single-arm, phase 1, dose-escalation and dose-expansion trial was done in 19 hospitals across Japan and the USA. Patients were included if they were aged 18 years or older in the USA or 20 years or older in Japan with a primary diagnosis of relapsed or refractory non-Hodgkin lymphoma and an Eastern Cooperative Oncology Group performance status of 0 or 1. In the dose-escalation part, patients received oral valemetostat at doses of 150 mg per day, 200 mg per day, 250 mg per day, and 300 mg per day continuously in 28-day cycles until progressive disease or unacceptable toxicities. All patients received 200 mg per day in the dose-expansion part. The primary endpoints were safety, pharmacokinetics, and the recommended phase 2 dose; the secondary endpoints were the maximum tolerated dose and the antitumour activity of valemetostat. Responses were assessed in patients who received at least one dose, with measurable lesions at baseline according to the International Working Group 2007 revised criteria for malignant lymphoma (peripheral T-cell lymphoma and B-cell non-Hodgkin lymphoma) and the modified 2009 criteria for adult T-cell leukaemia/lymphoma. The trial is registered with ClinicalTrials.gov, NCT02732275, and is currently active, but not recruiting. Between April 7, 2016, and June 10, 2021, 90 patients (53 [59%] males and 37 [41%] females; 49 [54%] Asian, 33 [37%] White, and eight [9%] Black) were enrolled and treated with valemetostat and included in the safety analysis set. 57 (63%) patients had peripheral T-cell lymphoma, 14 (16%) had adult T-cell leukaemia/lymphoma, and 19 (21%) had B-cell non-Hodgkin lymphoma. Seven (8%) patients received valemetostat 150 mg per day, 74 (82%) received 200 mg per day, seven received 250 mg per day, and two received 300 mg per day. Median follow-up was 7·4 months (IQR 3·4-17·6). All patients had at least one treatment-emergent adverse event; the most common treatment-emergent adverse events of any grade were decreased platelet count (52 [58%] of 90 patients), dysgeusia (45 [50%]), and anaemia (38 [42%]). The most common grade 3-4 adverse events were decreased neutrophil count (21 [23%]), decreased platelet count (18 [20%]), and decreased lymphocyte count (17 [19%]). The most common serious adverse event of any grade was Pneumocystis jirovecii pneumonia (four [4%]). No treatment-related deaths occurred. The overall response rate was 54·5% (48 of 88; 95% CI 43·6-65·2) for patients in the efficacy analysis set. The maximum tolerated dose was not reached; the recommended phase 2 dose of 200 mg per day was determined. Valemetostat exposure was variable between patients and was overlapped over the dose range of 150-250 mg per day. The safety profile of valemetostat monotherapy was acceptable in these patients with relapsed or refractory non-Hodgkin lymphoma. Favourable clinical activity was observed. These findings support a new indication for valemetostat in this setting. Daiichi Sankyo.

Predictors and implications of renal injury after CD19 chimeric antigen receptor T-cell therapy.

Chimeric Antigen Receptor (CAR) T cells targeting CD19 induce durable remissions in patients with relapsed or refractory non-Hodgkin lymphoma (NHL), but many patients experience treatmentrelated toxicity. Cytokine release syndrome and immune effector cell-associated neurologic syndrome are extensively characterized. However, limited data exist on the burden, predictors, and implications of acute kidney injury (AKI) after CAR T cell therapy. On initial screening of the FDA adverse event reporting system, we identified a disproportionately high rate of renal adverse events among nearly 6,000 CAR T adverse event reports, suggesting it is clinically important in this patient population. In a subsequent single-center analysis of 399 NHL patients treated with CD19 CAR T cells, we found a substantial burden of AKI after CAR T infusion (10% and 5% of any grade and grade ≥2 AKI) with pre-renal causes being predominant (72%). Evolution to chronic kidney disease was rare, however, 3 patients required hemodialysis. Importantly, patients experiencing cytokine release syndrome and/or neurotoxicity as well as those with low serum albumin and high inflammatory cytokines, including IL-6 and TNF-alpha, were more likely to develop AKI. While pre-CAR T renal dysfunction was not associated with adverse outcomes, patients developing post-CAR T AKI had lower overall survival compared to their counterparts. Our findings indicate that renal dysfunction is a common toxicity of CAR T cell therapy with meaningful prognostic impact. Notably, the link between systemic inflammation and renal dysfunction, suggests that readily available biomarkers may inform on renal injury risk after CAR T cell therapy.

Steroid Prophylaxis in Patients Receiving CAR T-Cell Therapy for Relapsed and Refractory Non-Hodgkin Lymphoma

Steroid Prophylaxis in Patients Receiving CAR T-Cell Therapy for Relapsed and Refractory Non-Hodgkin Lymphoma

Real-World Efficacy and Safety of the Combination of Rituximab, Lenalidomide, and Ibrutinib in Patients with Relapsed and/or Refractory Non-Hodgkin Lymphoma

Real-World Efficacy and Safety of the Combination of Rituximab, Lenalidomide, and Ibrutinib in Patients with Relapsed and/or Refractory Non-Hodgkin Lymphoma

Haploidentical transplantation with post-transplant cyclophosphamide versus single cord blood transplantation in adults with relapsed/refractory non-Hodgkin lymphoma.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative treatment for relapsed or refractory non-Hodgkin lymphoma (R/R NHL). Allo-HSCT using post-transplant cyclophosphamide (PTCY-haplo) and umbilical cord blood transplantation (uCBT) are important donor options in the absence of matched related siblings. However, the data comparing these two donor sources in R/R NHL are limited. Using the Japanese nationwide transplantation registry data, we identified 857 patients with R/R NHL, including 169 patients who received PTCY-haplo and 688 who received uCBT for their first allo-HSCT between January 2013 and December 2021; 514 patients (60%) had B-cell lymphoma. More PTCY-haplo recipients received allo-HSCT using a reduced-intensity conditioning regimen in recent years. The 3-year overall survival (OS), progression-free survival (PFS), and graft-versus-host disease (GVHD)-free/relapse-free survival (GRFS) rates in the PTCY-haplo and uCBT groups were 44% versus 39% (P = 0.326), 34% versus 33% (P = 0.660), and 19% versus 23% (P = 0.910), respectively; the adjusted hazard ratios for OS, PFS, and GRFS were 0.89 (95% confidence interval: 0.69-1.15, P = 0.373), 0.98 (0.78-1.22, P = 0.852), and 0.92 (0.83-1.21, P = 0.920), respectively. The PTCY-haplo group showed faster neutrophil and platelet engraftment and a lower incidence of grade III-IV acute GVHD. Thus, PTCY-haplo and uCBT could serve as alternative donor sources in patients with R/R NHL.

800MO First report of BCL-2 inhibitor TQB3909 in pts with relapsed or refractory non-Hodgkin lymphoma (NHL) and acute myeloid leukemia (AML): Data from a phase I study

800MO First report of BCL-2 inhibitor TQB3909 in pts with relapsed or refractory non-Hodgkin lymphoma (NHL) and acute myeloid leukemia (AML): Data from a phase I study

A phase I, first-in-human study of ONO-7018 in patients with relapsed/refractory non-Hodgkin lymphoma or chronic lymphocytic leukemia.

TPS7083 Background: Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is a key component of the caspase recruitment domain-containing protein 11 (CARD 11)-B-cell lymphoma/leukemia 10 (BCL 10)-MALT1 signalosome complex, which activates nuclear factor-kappaB (NF-κB) signaling in response to B-cell–receptor or T-cell–receptor stimulation. Activation of NF-κB signaling promotes survival and proliferation of B-cell lymphoma and T-cell lymphoma. ONO-7018 is an oral, potent, and selective MALT1 inhibitor that has demonstrated preclinical efficacy in several lymphoma models (Morishita D, et al. Blood. 2020). Therefore, ONO-7018 has therapeutic potential for non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL). This study aims to determine the maximum tolerated dose (MTD) and to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy of ONO-7018 as monotherapy in patients with relapsed or refractory NHL or CLL. Methods: This Phase I, first-in-human, open-label, multicenter study will be done in two parts, a dose-escalation phase (part 1) and a dose-expansion phase (part 2). An estimated 54 eligible patients will be enrolled. Patients must be adults with relapsed/refractory NHL or CLL with measurable disease; all acute toxic effects of prior antitumor therapy should be grade ≤1; have Eastern Cooperative Oncology Group performance status 0 to 2; and have adequate bone marrow, renal, and hepatic function. Exclusion criteria include history of other lymphoid malignancy, central nervous system involvement, active autoimmune disease, systemic and active infection, serious or uncontrolled medical disorder, and patient inability to swallow tablets. ONO-7018 will be administered orally. In part 1, patients will be assigned to a dose level cohort (≤4 dose levels: DL1-DL4) using a 3+3 dose-escalation design. In part 2, patients will be given the recommended dose level from part 1, following safety review. The primary endpoints include dose-limiting toxicity, MTD, and treatment-emergent adverse events. Secondary endpoints include pharmacokinetics, objective response rate, duration of response, progression-free survival, and overall survival. The study began February 13, 2023, and is currently recruiting; part 1 is ongoing. Clinical trial information: NCT05515406 .

Glofitamab monotherapy retreatment in patients with heavily pre-treated relapsed or refractory (R/R) non-Hodgkin lymphoma (NHL): Results from a phase I/II study.

7020 Background: Fixed-duration glofitamab, a CD20xCD3 T-cell engaging bispecific antibody with a novel 2:1 configuration, has demonstrated efficacy and manageable safety in a Phase I/II study (NCT03075696) in heavily pre-treated patients (pts) with R/R NHL (Dickinson. N Engl J Med 2022). We report efficacy and safety data for pts with R/R NHL retreated with glofitamab monotherapy after response to initial glofitamab treatment. Methods: Pts who completed initial treatment and achieved complete response (CR), partial response (PR), or stable disease were eligible for retreatment after documented progression. Initial treatment included obinutuzumab pre-treatment (Gpt) 7 days before the first glofitamab dose, then glofitamab intravenously at either a fixed dose of 0.015–25mg (14- or 21-day cycles) or step-up dosing (2.5mg, then 10mg in Cycle [C] 1, followed by a target dose of 16 or 30mg [C2 onward, 21- day cycles]) for up to 12 cycles. Retreatment was administered at the escalation dose received or at the highest glofitamab dose cleared in the study at time of retreatment, with Gpt 7 days before the first glofitamab dose. As with initial treatment, retreatment was permitted for 12 cycles or until progression or unacceptable toxicity, whichever occurred first. Results: As of Sept 4, 2023, 13 pts (diffuse large B-cell lymphoma [DLBCL], n=4; follicular lymphoma [FL], n=4; mantle cell lymphoma [MCL], n=2; transformed FL [trFL], n=2; high grade B-cell lymphoma, n=1) had received glofitamab retreatment (retreatment dose: 10mg, n=1; 10/16mg, n=1; 2.5/10/30mg, n=11). Median age was 63.0 years (range: 44–81). With initial treatment, 9 pts had CR and 4 pts had PR (best response by investigator). Median time from end of initial treatment to initiation of retreatment was 13.0 months (range: 4.1–27.4). Median number of retreatment cycles received was 5 (range: 2–12). During retreatment, 9 pts (69.2%) responded: CR, 38.5% (FL, n=2; trFL, n=1; MCL, n=2); PR, 30.8% (FL, n=1; trFL, n=1; DLBCL, n=2). Of the 5 pts with CR at retreatment, 3 pts had CR and 2 pts had PR with initial treatment. Of the 4 pts with PR at retreatment, 3 pts had CR and 1 pt had PR with initial treatment. Median retreatment follow-up time was 25.9 months and 5 pts had responses ongoing at data cut-off (FL, n=2; MCL, n=2; trFL, n=1). The safety profile for glofitamab retreatment was consistent with prior reports of glofitamab monotherapy in R/R NHL (Hutchings. J Clin Oncol 2021). Cytokine release syndrome occurred in 7 pts (53.8%; all Grade 1/2). Exploratory data on B-cell pharmacodynamics, CD20 expression, and T-cell status before retreatment will be presented. Conclusions: Glofitamab monotherapy retreatment was efficacious in heavily pre-treated pts with R/R NHL who responded to initial glofitamab treatment before subsequent progression. The safety profile was consistent with that of initial treatment. Clinical trial information: NCT03075696 .

Long term follow-up results of BRL-201 phase I study, a CRISPR-based non-viral PD-1 locus specific integrated anti-CD19 CAR-T cells in treating relapsed or refractory non-Hodgkin's lymphoma.

Long term follow-up results of BRL-201 phase I study, a CRISPR-based non-viral PD-1 locus specific integrated anti-CD19 CAR-T cells in treating relapsed or refractory non-Hodgkin's lymphoma.

Immunotherapy of Hematological Malignancies of Human B-Cell Origin with CD19 CAR T Lymphocytes.

Acute lymphoblastic leukemia (ALL) and non-Hodgkin's lymphoma (NHL) are hematological malignancies with high incidence rates that respond relatively well to conventional therapies. However, a major issue is the clinical emergence of patients with relapsed or refractory (r/r) NHL or ALL. In such circumstances, opportunities for complete remission significantly decline and mortality rates increase. The recent FDA approval of multiple cell-based therapies, Kymriah (tisagenlecleucel), Yescarta (axicabtagene ciloleucel), Tecartus (Brexucabtagene autoleucel KTE-X19), and Breyanzi (Lisocabtagene Maraleucel), has provided hope for those with r/r NHL and ALL. These new cell-based immunotherapies use genetically engineered chimeric antigen receptor (CAR) T-cells, whose success can be attributed to CAR's high specificity in recognizing B-cell-specific CD19 surface markers present on various B-cell malignancies and the subsequent initiation of anti-tumor activity. The efficacy of these treatments has led to promising results in many clinical trials, but relapses and adverse reactions such as cytokine release syndrome (CRS) and neurotoxicity (NT) remain pervasive, leaving areas for improvement in current and subsequent trials. In this review, we highlight the current information on traditional treatments of NHL and ALL, the design and manufacturing of various generations of CAR T-cells, the FDA approval of Kymriah, Yescarta Tecartus, and Breyanzi, and a summary of prominent clinical trials and the notable disadvantages of treatments. We further discuss approaches to potentially enhance CAR T-cell therapy for these malignancies, such as the inclusion of a suicide gene and use of FDA-approved drugs.

457 A Phase I Trial of Tazemetostat and Venetoclax in Relapsed and Refractory non-Hodgkin Lymphoma

OBJECTIVES/GOALS: Primary Objective: To evaluate the safety of venetoclax plus tazemetostat in patients with relapsed and refractory (R/R) Follicular lymphoma (FL) or Diffuse large B-cell lymphoma (DLBCL) Secondary Objectives: 1. To evaluate the tolerability of the combination of T+V using patient reported outcomes (PROs) 2. To evaluate the efficacy of T+V METHODS/STUDY POPULATION: Study design: A phase I trial in two parts: Part 1: a single-arm, open-label sequential dose escalation (3+3) of venetoclax in combination with tazemetostat, given at its recommended phase II dose (RP2D) of 800mg BID, to determine the maximum tolerated dose (MTD) of venetoclax. Part 2: two expansion cohorts (R/R DLBCL and R/R FL) to further characterize the safety and tolerability of the combination, and to estimate the preliminary efficacy. We will perform additional exploratory studies to determine if there are biologic features that correlate with responses. Eligibility: up to 38 patients aged >/=18 years old with histologically confirmed diagnosis of FL or DLBCL who have received at least 2 prior lines of therapy for lymphoma with evidence of disease progression and meet inclusion criteria RESULTS/ANTICIPATED RESULTS: Primary Endpoints: 1. Incidence and severity of adverse events as per CTCAEv5 2. Dose-limiting toxicity (DLT) of T+V, and to establish the maximum tolerated dose (MTD) of V plus fixed dose T Secondary Endpoints: 1. Incidence and Severity of toxicity and quality of life as per PRO-CTCAE and FACT-Lym 2. Overall response rate (ORR), complete response (CR) rate, partial response (PR) rate, as per Lugano criteria 3. Duration of response (DOR), progression-free survival (PFS), overall survival (OS)Exploratory Endpoints: 1. Characterization of tumor cells pre-treatment (including EZH2 mutations and BCL2 translocations) 2. Phenotypic analysis (including BCL2 expression) and quantification of the tumor microenvironment in pre-treatment samples (using image mass cytometry)Explorato DISCUSSION/SIGNIFICANCE: There is a need for novel therapeutic approaches to improve the prognosis for patients with R/R NHL. Preclinical data suggests synergism between the pair.5 Importantly, this represents a chemotherapy-free, oral regimen. If well tolerated, this could present an alternative therapeutic option for patients ineligible for more intensive therapies.

Primary vs. pre-emptive anti-seizure medication prophylaxis in anti-CD19 CAR T-cell therapy

IntroductionSeizures may occur in up to 30% of non-Hodgkin lymphoma patients who received anti-CD19 CAR T-cell therapy, yet the optimal anti-seizure medication (ASM) prevention strategy has not been thoroughly investigated.MethodsConsecutive patients affected by refractory non-Hodgkin lymphoma who received anti-CD19 CAR T-cells were included. Patients were selected and assessed using similar internal protocols. ASM was started either as a primary prophylaxis (PP-group) before CAR T-cells infusion or as a pre-emptive therapy (PET-group) only upon the onset of neurotoxicity development.ResultsOne hundred fifty-six patients were included (PP-group = 88, PET-group = 66). Overall, neurotoxicity and severe neurotoxicity occurred in 45 (29%) and 20 (13%) patients, respectively, equally distributed between the two groups. Five patients experienced epileptic events (PET-group = 3 [4%]; PP-group = 2 [2%]). For all the PET-group patients, seizure/status epilepticus occurred in the absence of overt CAR-T-related neurotoxicity, whereas patients in the PP-group experienced brief seizures only in the context of critical neurotoxicity with progressive severe encephalopathy. ASMs were well-tolerated by all patients, even without titration. No patients developed epilepsy or required long-term ASMs.ConclusionOur data suggest that both primary and pre-emptive anti-seizure prophylaxis are safe and effective in anti-CD19 CAR T-cell recipients. Clinical rationale suggests a possible more favourable profile of primary prophylaxis, yet no definitive conclusion of superiority between the two ASM strategies can be drawn from our study.

Evaluation of the cardiac safety of parsaclisib, a selective PI3Kδ inhibitor, in patients with previously treated B-cell malignancies: Results from the CITADEL-101 study.

Parsaclisib, a potent and selective phosphatidylinositol 3 kinase δ inhibitor, has been investigated for the treatment of B-cell malignancies and studied in patients with autoimmune diseases and myelofibrosis. The CITADEL-101 study (NCT02018861) assessed safety, tolerability, and preliminary efficacy of parsaclisib in patients with relapsed or refractory non-Hodgkin lymphoma. This study evaluated the cardiac safety of parsaclisib as monotherapy based on data from 72 patients enrolled in the CITADEL-101 study. Time-matched pharmacokinetic and ECG measurements were collected at specified times for 69 patients receiving monotherapy in doses of 5, 10, 15, 20, 30, and 45 mg once daily. Based on the categorical outlier analysis, no dose-dependent effect was observed on the incidence of outliers in QT interval corrected for heart rate (HR) by Fridericia's method (QTcF), HR, or cardiac conduction. Based on central tendency analysis, the least square means (LSMs) (90% confidence interval [CI]) of ΔQTcF from the central tendency analysis ranged from -6.83 (-18.8 to 5.19) to 4.75 ms (0.410-9.09) across dose groups (below 20 ms, the threshold of large QT effects) and was not considered dose dependent. Moreover, the LSMs of ΔHR, ΔPR interval, and ΔQRS interval were minor. From the concentration-ΔQTcF analyses, the predicted ΔQTcF (90% CI) for all dose levels was between 0.365 (-1.75 to 2.48) and 7.87 ms (0.921-14.8), with the highest upper limit of CIs well below 20 ms, and therefore, a large QT/QTc effect was ruled out up to the highest dose level (45 mg) investigated. Overall, parsaclisib at the dose ranges studied did not reveal concentration-dependent effects on change in QTcF and did not have a significant effect on HR or cardiac conduction.

Prevalence of non-Hodgkin lymphoma patients at high-risk of failure after CAR T-cell therapy eligible for bridging radiation therapy.

The aim of this study was to determine the prevalence of patients with relapsed or refractory (R/R) non-Hodgkin lymphoma (NHL) meeting high-risk criteria for early relapse after CD19 CAR T-cell therapy (CART) who have disease encompassable in a standard radiation therapy (RT) plan (defined as <5 malignant lesions) and may benefit from bridging RT prior to CD19 CART. This is a single-center, retrospective study of patients with R/R NHL who received CD19 CART from 2018 to 2022. Eligible patients had pre-apheresis radiologic studies available. All patients were classified by number of lesions and history of high-risk disease criteria: bulky disease ≥10 cm, ≥1 extranodal (EN) sites, LDH ≥normal, or ≥1 lesion with SUVmax ≥10. A total of 81 patients with R/R NHL were evaluated. Based on our definition, 40 (49%) patients would have been eligible for bridging RT, including 38 patients who met high-risk criteria: 31 with ≥1 EN site, 19 had ≥1 lesion with SUVmax ≥10, 16 with bulky disease, and 3 with elevated LDH. At 3 months after CART, ORRs in high-risk patients with <5 lesions, ≥5 lesions, and no lesions on pre-apheresis studies were 76% (CR 69%, PR 7%), 70% (CR 60%, PR 10%), and 80% (CR 80%), respectively. Approximately 47% (38/81) of patients were classified as at high risk of relapse after CART with disease encompassable in a standard radiation plan and eligible for bridging RT studies.

Peripheral blood stem cells mobilization in patients with relapsed or refractory lymphomas: A single-center experience.

High-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (AHSCT) is an established treatment for chemosensitive patients with relapsed or refractory (R/R) non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL). We present the results of using different salvage chemotherapy plus granulocyte colony stimulating factor (G-CSF) for mobilization of peripheral blood stem cells in R/R lymphoma patients. For salvage chemotherapy, 93 patients received platinum-containing regimens, 4 patients received cytarabine-containing regimens, and 5 patients received other regimens. Patient distributions were HL (n = 35) and NHL (n = 67). In 87.2% of patients, first mobilization trial was successful (>2 × 10 6 CD34+ cells/kg). In 58.8% of patients, first apheresis season >5 × 10 6 CD34+ cells/kg collections was achieved. All 12.7% of patients were poorly mobilized at the first mobilization. There was no statistical difference between the previous chemotherapy numbers and failed mobilization ( P > 0.05). Five patients who were poorly mobilized and 4 patients who were successfully mobilized underwent a previous radiotherapy ( P < 0.05). Thirteen patients who were poorly mobilized in the first mobilization underwent a platinum-containing salvage regimen. At the time of the first mobilization, the average peripheral CD 34 counts in the successfully mobilized group were statistically higher than that in the poorly mobilized group ( P < 0.01). We demonstrated that peripheral CD 34 cell count in the peripheral blood on the first apheresis day was a significant factor for more stem cell mobilization, fewer apheresis sessions, less volume, and earlier neutrophil engraftment for patients with R/R lymphoma and eligible for AHSCT. The history of the previous radiotherapy was a significant factor for poor mobilization.

Loss of CD20 expression as a mechanism of resistance to mosunetuzumab in relapsed/refractory B-cell lymphomas

AbstractCD20 is an established therapeutic target in B-cell malignancies. The CD20 × CD3 bispecific antibody mosunetuzumab has significant efficacy in B-cell non-Hodgkin lymphomas (NHLs). Because target antigen loss is a recognized mechanism of resistance, we evaluated CD20 expression relative to clinical response in patients with relapsed and/or refractory NHL in the phase 1/2 GO29781 trial investigating mosunetuzumab monotherapy. CD20 was studied using immunohistochemistry (IHC), RNA sequencing, and whole-exome sequencing performed centrally in biopsy specimens collected before treatment at predose, during treatment, or upon progression. Before treatment, most patients exhibited a high proportion of tumor cells expressing CD20; however, in 16 of 293 patients (5.5%) the proportion was <10%. Analyses of paired biopsy specimens from patients on treatment revealed that CD20 levels were maintained in 29 of 30 patients (97%) vs at progression, where CD20 loss was observed in 11 of 32 patients (34%). Reduced transcription or acquisition of truncating mutations explained most but not all cases of CD20 loss. In vitro modeling confirmed the effects of CD20 variants identified in clinical samples on reduction of CD20 expression and missense mutations in the extracellular domain that could block mosunetuzumab binding. This study expands the knowledge about the occurrence of target antigen loss after anti-CD20 therapeutics to include CD20-targeting bispecific antibodies and elucidates mechanisms of reduced CD20 expression at disease progression that may be generalizable to other anti-CD20 targeting agents. These results also confirm the utility of readily available IHC staining for CD20 as a tool to inform clinical decisions. This trial was registered at www.ClinicalTrials.gov as #NCT02500407.

Real-World Efficacy and Safety of Rituximab, Lenalidomide and İbrutinib Combination in Patients with Relapsed and/or Refractory Non-Hodgkin Lymphoma

Background: Relapsed or refractory (R/R) Non-Hodgkin Lymphoma (NHL) is associated with poor outcomes and the therapic options are limited. Recently, the combination of rituximab, lenalidomide, and ibrutinib (RLI) suggest promising efficacy in some clinical studies. Consequently, we report outcome of patients with R/R HL treated with RLI in this retrospective study aiming at evaluating efficacy and safety of RLI in a real-life setting. Methods: This retrospective, single-center study analyzed the outcomes of RLI as an off label salvage theraphy in patients with R/R NHL between June 2020 and April 2022. All patients received Lenalidomide 10-25 mg po daily on days 1-21 every 28 days and Ibrutinib 560 mg po daily on days 1-28. Patients with diffuse large B-cell lymphoma (DLBCL), primary central nervous system lymphoma (PCNSL), marginal zone lymphoma (MZL) received Rituximab at a dose of 375 mg/m2 iv on day 1 of cycles 1-6 every 28 days, patients with mantle cell lymphoma (MCL) received the same dose of Rituximab once a week for 4 weeks during cycle 1, then on day 1 of cycles 2-12 every 8 weeks. Ibrutinib and/or lenalidomide was administered until progression or unacceptable toxicity. The response was assessed with according to the Lugano criteria. The primary end point was overall response rate (ORR). Secondary endpoints were complete response (CR), partial response (PR), time to response (TTR), duration of response (DoR), overall survival (OS), progression free survival (PFS) and safety. Results: We analyzed 21 patients including DLBCL (n = 16), PCNSL (n = 2), MCL (n = 2), MZL (n = 1). The median age was 60 years (range, 24-84). The majority of patients had advanced disease stage (53%) and were refractory to their last therapy (57%). The non-GCB type was more common (67%) in patients with DLBCL and PCNSL. Nine patients (56%) with DLBCL had MYC and BCL2 and/or BCL6 rearrangements. Median number of prior therapies was 3 (range, 2-6). Eleven patients had prior auto and/or allo stem cell transplantation. Median follow-up time was 6.6 months (range, 0.4-22.3). Eleven patients (52%), 6 patients (29%) and 2 patients (10%) received RLI for ≥ 3, 6 and 12 months respectively. Patients had received a median of 3 (range, 1-19) cycles of RLI. Progressive disease (PD) was the most common reason for treatment discontinuation (53%). All of the patients were evaluable for response. The median TTR was 2 months (range, 1.7-3.8). The ORR was 38% (95% CI 15%-61%) with 29% CR and 9% PR. At the time of the analysis, the median DoR was 12.8 monts (range, 4.4-19.5+). Deaths were reported for 13 (62%) patients [n = 10 PD, n = 3 adverse events (AEs)]. The median OS was 7.9 months (95% CI 2.2-13.5) and median PFS was 3.5 months (95% CI 0.0- 8.3). The most common non-hematologic AEs were fatigue (48%), infection (38%), diarrhea (29%). AEs were frequently reported at the 25 mg lenalidomise dose, but the majority (77%) of patients experienced a grade 1-2 AE. The hematologic AEs were neutropenia (48%) [grade 3-4 (100%)], thrombocytopenia (19%) and anaemia (19%). AEs led to discontinuation in 5% (n = 1) of patients (sepsis). Conclusions: Our results suggest that RLI is a viable therapeutic option with promising activity and favorable toxicity profile in patients with R/R NHL patients.

The Outcome of Tisagenlecleucel (Tisa-Cel) Vs Axicabtagene Ciloleucel (Axi-Cel) CD-19 CAR-T Cell Therapy in Relapsed/Refractory NHL, Real World Data, Single Institution Experience

ABSTRACT Background: In the Kingdom of Saudi Arabia, non-Hodgkin lymphoma (NHL) reported as 6.1%. The estimated age adjusted incidence is 6/100,000. The more advanced disease stage at presentation reaches up to 40% stage IV. The cure rate with first line of therapy (R-CHOP) reaches up to 70%. The CD 19 chimeric antigen receptor (CAR) T-cell therapy targets CD19-expressing B cells and shows efficacy against B-cell lymphomas. Objective: The registration of CAR-T therapy products at KSA was in 2020 for Tisa-Cel and 2022 for Axi-Cel. The objective is to describe the outcome of the more available CAR-T therapy products in relapsed or refractory NHL. Methods: Retrospective analysis of CAR-T therapy outcome in NHL and compare the outcome of the two products for the same patient's population, using patients' chart electronic file assessment in the tertiary institution treating over 500 new lymphoma per year. Patients: Between November 2020 and May 2023, 44 patients with relapsed or refractory NHL to ≥2 lines of therapy, Follicular lymphoma (FL) relapsed after three lines of therapy counted for four patients treated with Axi-Cel. All patients received an infusion were included in the analysis. Of the 44 patients, 54.5% were male (n=24), the median age was 51 (20-75), and ECOG was 0-3. NHL subtype includes germinal center B-cell (GCB) 52% (n=23) and activated B-cell (ABC) 38.6% (n=17); the disease stage by PET/CT scan was III (47.7%, n=21) and IV (47.7%, n=21). In Axi-Cel group, 9.1% (n=4) received CAR-T as second line for relapse refractory disease or relapse within 12 months of complete remission (CR) after 1 st line therapy. Other patients received at least two lines of therapy prior to CAR-T infusion; 65.9% received ≥ 3 lines of therapy. Seven patients (16%) relapsed after autologous stem cell transplantation (ASCT) have received CAR-T therapy Tica-Cel product (n=6). Four patients (9.1%) have controlled CNS involvement at the infusion time. All patients received lymphodepletion (LD) therapy with fludarabine and cyclophosphamide (Flu/Cy). 25% (n=11) needed bridging chemotherapy therapy before LD, radiation therapy (XRT) bridging was counted for 13 patients (29.5%). The patients' characteristics and disease in Table-1. Results: Overall response rate (ORR), complete responses (CR), partial responses (PR). The respective toxicities include cytokine release syndrome (CRS) and neurologic events namely ICANS. The best ORR was 68.2%; 43.2% of the patients had CR and 25% had PR. The disease progression (DP) was 29.5%. In Axi-Cel group, ORR, CR, PR, and DP was 84.2%, 52.6%, 31.6% and 10.5, respectively. In Tica-Cel group; ORR, CR, PR, and DP was 56%, 36%, 20% and 44%, respectively. The estimated 2 years overall survival was 75% in all patients; 89.5% and 64% in Axi-Cel and Tica-Cel, respectively (p=0.47), Figure1. The estimated overall progressive free survival (PFS) was 61.4% with 73.7% in Axi-Cel group and 52% in Tica-Cel group (p=0.2), Figure2, the best PFS was seen in GCB subtype 65.2% vs 47.1% in ABC, (p= 0.05), Figure4. In FL, PFS was 100%, the patient number is small. PFS was 62.5% in-patient with CRS compared with 50% on non-CRS patient, not statistically significant (p= 0.7), Figure3. The main toxicities post CAR-T cell infusion including cytokines release syndrome (CRS) was 90.9% with 9% grade ≥ 3. In Tica-Cel, grade CRS-IV was 9% while 0% in Axi-Cel. Neurotoxicity (NT)-ICANS was 27% with grade ≥ 3 of 13.6% in both groups (20% in Tica-Cel and 5.6% in Axi-Cel). Tocilizumab was used in 72.7% in all cohorts with higher number of patients in Axi-Cel 17/19 (98.5%). Dexamethasone (Dexa) was used in CRS in 36.4%, in Axi-Cel; 42% of patients received Dexa while 32% in Tica-Cel group. In addition, for treatment of ICANS; Dexa was needed in 31.6% of Axi-Cel patients and 20% in Tica-Cel group. Upon the latest patient's follow-up, two patients (10.5%) in Axi-Cel group and 36% (n=9) in Tica-Cel group died from DP. The outcome of both products is summarized in Table-2. Conclusions: In this single-center retrospective analysis of CAR T-cell therapy in relapsed or refractory NHL or FL in adults, the rates of durable responses were like the real-world data. The best response rate was higher in Axi-Cel group; however, the follow-up duration of disease response is shorter in Axi-Cel group. The toxicity profile is similar in both groups with a bit higher of Grade-III-IV ICANS in Tica-Cel group. Keywords NHL, FL, CAR-T, CRS, ICANS

Updated Follow-up of a Phase 1 Trial of Bispecific CART19/20 Cells for Relapsed or Refractory Non-Hodgkin Lymphoma

CART19/20 was developed by engineering autologous naïve/memory T (T N/MEM) cells with a bispecific anti-CD19/CD20 chimeric antigen receptor (CAR) with the goal of mitigating antigen escape and lack of CAR T-cell persistence. We report an update of an ongoing first-in-human phase 1 clinical trial of CART19/20 for patients with relapsed/refractory non-Hodgkin lymphoma (R/R NHL) (NCT04007029). Eligible patients were ≥18 years old with R/R diffuse large B-cell lymphoma (DLBCL) or primary mediastinal B-cell lymphoma (PMBCL) after ≥2 prior lines of therapy, or with mantle-cell lymphoma (MCL), follicular lymphoma (FL), or CLL/SLL after ≥3 prior lines of therapy. Autologous leukocytes were obtained by leukapheresis and sorted for CD14-/CD25-/CD62L+ T N/MEM cells, followed by lentiviral transduction of the bispecific CD19/CD20 CAR. Lymphodepletion chemotherapy with fludarabine 30 mg/m 2/day and cyclophosphamide 500 mg/m 2/day was administered on Days −5 to −3 prior to CAR T-cell infusion. The primary endpoint was assessment of safety. Secondary endpoints were overall response rate (ORR), progression free survival (PFS), overall survival (OS), and CART19/20 transgene persistence. As of data cutoff on July 21, 2023, 11 patients had received CART19/20 cells (6 DLBCL, including 4 transformed FL; 3 primary FL; 1 PMBCL; 1 MCL). Patients were treated at two dose levels, either 50 x 10 6 ± 30% CAR+ cells (8 patients) or 200 x 10 6 ± 30% CAR+ cells (3 patients). The median age was 58 (range: 34 to 70). Patients had received a median of 3 prior lines of therapy (range: 2 - 4). None of the treated patients had received prior CAR-T cell therapy; one patient had received a prior CD19-directed therapy. All patients had stage IV disease and 9 of 11 patients received bridging therapy. The engineered CART19/20 cells were enriched with central-memory T cells (T CM: CD45RA-/CD45RO+/CD62L+) which composed a median of 30.8% (range: 5.3 - 80.1%) of the CAR+ T-cells in the infused products. There were no occurrences of CRS grade ≥ 2 or neurotoxicity of any grade. Six patients had grade 1 cytokine release syndrome (CRS) with a median onset of 8 days from infusion (range: 5 - 11 days). One patient met criteria for dose-limiting toxicity with persistent thrombocytopenia after Day+120. Ten of the 11 patients achieved an objective response (91% ORR), with 8 patients (73%) achieving complete response (CR). One patient with FL, who progressed 18 months after receiving CART19/20, received a second infusion of CART19/20 cells and achieved a second CR for 14.9 months. With a median follow-up of 32.3 months (range: 5.1 - 44.0 months), the median PFS (95% CI 2.6 months - not estimable) and median OS (95% CI 5.7 months - not estimable) have not been reached. Overall, CART19/20 demonstrated a favorable safety profile with no severe CRS or neurotoxicity of any grade. Moreover, CART19/20 showed robust activity in patients with R/R NHL with durable responses seen. By utilizing a bispecific CAR and enriching for T N/MEM cells, this phase 1 trial of CART19/20 demonstrates the possibility of improving outcomes through targeting common mechanisms of CAR-T cell resistance.