Refractory Aggressive B-cell Lymphoma Research Articles

New therapies for relapsed or refractory aggressive B-cell lymphoma increase survival: Analysis from the RELINF registry of the GELTAMO group.

New therapies for relapsed or refractory aggressive B-cell lymphoma increase survival: Analysis from the RELINF registry of the GELTAMO group.

A Compilation of Experiences in Utilizing CAR-T Cell Therapy for Richter's Transformation

Objective:Even with Bruton tyrosine kinase inhibitors (BTKis) and BCL2 inhibitors, the prognosis for Richter's Transformation (RT) remains dismal, with a median overall survival (OS) of only 9-12 months from initial diagnosis. Although there are reports on CAR-T therapy for RT, the sample size is small and the conclusions vary greatly. Methods: We conducted a retrospective investigation of the efficacy of CAR-T cell therapy in treating RT at our center. Each participant provided their informed consent to partake in the “Phase II Clinical Trial of Sequential CAR-T Cell Therapy Targeting Different B-Cell Epitopes for Recurrent, Refractory Aggressive B-Cell Lymphoma”(Protocol number: BR-XG-CART-II, ChiCTR2100055062, Ethical Approval Number 20191225-PJ-003). Before lymphocyte collection, chemotherapy regimen without fludarabine/ Bendamustine is first used to reduce peripheral blood tumor load if peripheral blood tumor cells are higher than 10%. Patients with extramedullary tumor loads of 5cm or larger were treated with tumor reduction chemotherapy between lymphocyte collection and CART cell transfusion. The pretreatment scheme based on Bendamustine or FC scheme was adopted before CAR-T cells were infused. The efficacy and safety of CART cells were observed. Results: Between Feb 1, 2020 and Feb 28, 2023, our center administered CAR-T cell therapy to 16 patients diagnosed with RT, all of whom developed into diffuse large B-cell lymphoma. The patient population had a median age of 59 years (range: 42-69 years), consisting of 62.5% (10/16) males and 37.5% (6/16) females. The ECOG scores varied between 0 and 3. The median number of prior treatment lines was 5 (2-7). 93.8% failed previous BTKis treatment and 75% failed BCL2 inhibitor treatment; 93.8% had undergone chemotherapy (median 6 courses). 1 patient had previously failed universal CAR-T cell therapy, and another relapsed after autologous transplantation. 90% had at least one TP53 abnormality detected by either FISH or second-generation gene sequencing. Extramedullary masses were found in 87.5% (14/16) of patients, with a median maximum diameter of 42.5mm (18-144mm). Masses larger than 5cm were found in 25% (4/16) of cases, marrow involvement was noted in 62.5% (10/16), and cerebrospinal fluid was affected in 18.75% (3/16). None of the patients had central masses observed in their MRIs. During lymphocyte collection, 58.3% of patients showed positivity for peripheral blood tumor cells, with a maximum tumor cell proportion of 5.69%. The median infused CAR-T cell dose was 1.37×10 6/kg. 12 of them were injected with mouse CD19CAR-T, 2 with human CD20CART, and 2 with human CD19CART. CRS occurred in 81.3%of patients, of which, 68.8%were grade 1-2 and 12.5%were grade 3. Central CRS occurred in 6.3% (1/16) of patients. The complete response (CR) rate at the 3-month mark stood at 56.3% (9/16), with an overall response rate (ORR) of 68.8% (11/16). As of July 6, 2023, the median follow-up time was 10.6 months (4.4-33.6m), the 1-year OS was 73.4%, and the 1-year PFS was 68.8%. Median OS and PFS were not reached. One of the five patients who did not respond later underwent allogeneic hematopoietic stem cell transplantation and is still alive. The other four, despite attempts at salvage treatment including second CAR-T cell therapy, all died, with a median OS of only 5.6 months (4.4-8.9m). None of the four patients with extramedullary masses larger than 5cm achieved ORR despite tumor-reducing chemotherapy prior to CAR-T infusion. Only 1 of 3 patients with central involvement achieved CR and experienced grade 3 CRS along the way, while the other 2 did not respond to CAR-T therapy. Among all patients, only one experienced central CRS, and his cerebrospinal fluid showed no signs of tumor cells prior to the administration of CAR-T treatment. A patient who was in CR succumbed to an acute coronary event 19 months following infusion, despite remaining in CR. Conclusion: Even in the presence of TP53 gene abnormalities, resistance to BTK/BCL2 inhibitors, and unsuccessful previous chemotherapy regiments, A single CAR T cell therapy can result in CR in more than half of RT patients. Nonetheless, the prognosis remains bleak for patients presenting with large tumor masses and central nervous system involvement, despite having received chemotherapy aimed at reducing tumor size. The outlook is particularly dismal for those patients who fail to respond to CAR-T cell therapy.

Evaluation of the T-Cell Metabolic State of Starting Material and Manufactured CAR T Cell Products and Clinical Outcome of CAR T-Cell Therapy for Large B Cell Lymphoma

Background Although chimeric antigen receptor (CAR)-T cells are a viable treatment option for patients with relapsed or refractory (r/r) aggressive B-cell lymphomas, more than half of patients experience relapse within the first two years after product infusion. Successful autologous cell-based anti-cancer therapies require persistence of effector cells, features that highly depend on complex metabolic processes. We earlier demonstrated in chronic lymphocytic leukemia, that expansion and persistence of CD19-CAR T-cell infusion in vivo was correlated with increased mitochondrial mass and enhanced biogenesis(van Bruggen et al, Blood 2019). Metabolic features might therefore serve as early biomarker tools to predict efficacy and outcome of CAR T-cell therapy and might allow therapeutic targeting but did was never studied in a prospective clinical trial. Aims Perform extensive phenotyping and state-of-the-art metabolic state analyses of T cells prior and post CAR T cell production and investigate correlations with clinical outcomes and patient characteristics. Methods Samples were obtained from large B cell lymphoma (LBCL) patients that were part of the TRANSCEND-NHL-001 trial (NCT02631044, Abramson et al, Lancet 2020).Thirty-two patients with r/r B-cell lymphoma who received CAR-T cell treatment lisocabtagene maraleucel (16 responders (R) and 16 non-responders (NR)) were included in our analyses and (metabolically) analyzed by flow cytometry and extracellular flux analysis. Metabolic phenotyping was performed on 53 samples at baseline and 44 samples after an in vitro stimulation. Extracellular flux analysis was done on 14 DP samples. The cohort was split evenly between Responders and Non-responders, and balanced for a score calculated taking key clinical baseline characteristics that were found to be associated with response into account (NCT02631044, Abramson et al, Lancet 2020). Both T cells obtained at time of leukopheresis (starting material (SMAT)) and CAR-T drug products (DP), (following transduction of a CD19-targeted CAR T cell product with a defined CD4 and CD8 composition bearing a 4-1BB costimulatory domain and expansion) were analyzed directly after thawing and after stimulation with anti-CAR-antibody in case of CDP, or αCD3/αCD28 antibodies for SMAT samples. Patients consented to these studies and researchers were blinded for clinical outcomes at time of analysis. Results We found that the baseline clinical factors that associate with clinical response are related to specific metabolic cellular phenotypes, both in SMAT and DP, and with and without T cell stimulation. SMAT samples from patients with higher baseline scores show signs of an increased exhausted phenotype with regards to cellular ROS and exhaustion marker expression, whilst a more plentiful memory-like phenotype was seen in patients with a lower baseline score. When clustering by clinical response status, analysis of glucose and fatty-acid uptake, neutral lipid content, cellular ROS, mitochondrial mass and potential and flux data showed that responders, in both SMAT and DP samples, have an all-round increased metabolic activity upon αCD3/αCD28 or CAR T-receptor triggering, respectively, when compared to non-responders (Figure 1A). Furthermore, responding patients show enrichment of CD27 expression in the SMAT material, indicating a more abundant memory phenotype. Summary/Conclusions This is the first evidence of an association between a specific immune-metabolic phenotype of (CAR-) T cells and outcome of CAR-T cell therapy in patients with relapsed/refractory LBCL. More specifically, a higher abundance of memory phenotypes, metabolic activity and mitochondrial biogenesis of both harvested T cells and CAR-T product associates with improved clinical response. Combining metabolic, phenotypical and clinical characteristics and biomarkers of patient T cells (both pre- or post-production) shows the importance of the metabolic phenotype and fitness of T cell starting material, underlying the importance of early line CAR T therapy following diagnosis.

Clinical Utility of Circulating Tumor (ct)DNA Quantity and Kinetics in Patients Undergoing CAR T-Cell Therapy for Relapsed/Refractory Aggressive B-Cell Lymphoma

Background: CD19-targeted CAR T-cells are approved for relapsed and/or refractory (RR) aggressive B-cell lymphomas. While some patients experience durable remissions, others do not respond or relapse. Improved patient selection and early identification of patients who may need additional therapies are thus necessary. ctDNA is a promising biomarker for prognostication in DLBCL and has the potential to guide therapeutic decisions. We aimed to explore the possible clinical utility of ctDNA quantitation in patients with aggressive B-cell lymphomas undergoing CAR T-cell therapy. Methods: Twenty-eight patients undergoing CAR T-cell therapy as part of standard of care pathways for RR aggressive B-cell lymphoma were included. Pre- and post-CAR T-cell infusion ctDNA samples were retrospectively analyzed with a panel of over 400 genes relevant to B-NHL using a modified version of the AVENIO ctDNA analysis workflow (Roche; Research Use Only) based on the previously described CAPP-Seq workflow (Kurtz, J Clin Oncol 2018). Peripheral blood was used as a source of germline DNA to allow selection of tumor-specific variants in the ctDNA. ctDNA levels were expressed as mean mutant molecules per mL (MMPM) and ctDNA clearance was determined using a detection cutoff of p = 0.005. ctDNA results were correlated with clinical findings and outcomes including response rate, PFS and OS. Results: Eighteen male and 10 female patients were included in the analysis (median age 63). Sixteen (57%) patients had a diagnosis of DLBCL while the remainder had transformed FL or MZL (n=6), HGBL (n=4) and PMBL (n=2). Seventeen patients were treated with tisagenlecleucel and 11 with axicabtagene ciloleucel. Twenty-five (89%) patients had stage III or IV disease and 15 (54%) patients had ≥3 lines of prior therapy. The median number of tumor-specific variants in baseline ctDNA samples was 31 (range 1-252). ctDNA levels correlated with metabolic tumor volumes across all time points (Spearman r=0.69, p<0.0001). There was a greater reduction in ctDNA quantity observed in those who achieved CR/PR (n=21) at day 28 vs those who progressed (n=7) (median MMPM log-fold reduction 1.3 vs -0.9). Baseline ctDNA quantity was significantly higher in those with an elevated LDH pre-lymphodepletion compared to those with a normal LDH (median MMPM 228.5 vs 7.6, p = 0.0003). Survival also correlated with baseline ctDNA measurement with patients with a ctDNA quantity above the median of the cohort having a significantly shorter OS compared to those below the median (median OS 6.7 mo vs not reached, p=0.0012). Four patients had no detectable ctDNA at day 28 post CAR T-cell infusion including 1 patient with pseudoprogression on imaging (SUVMax 10) who had no evidence of lymphoma on biopsy and remained in CR. Of the 4 patients who were ctDNA negative at day 28, 3 remained in long-term remission. In summary, measurement of ctDNA quantity and kinetics shows promising clinical utility in the context of CAR T-cell treatment for aggressive B-cell lymphoma including prediction of outcome and resolving radiological pseudoprogression. Larger prospective cohorts and standardized methodological approaches are required to optimize predictive thresholds for clinical outcomes.

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

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.

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.

Abatacept As Salvage Therapy for Graft-Versus-Host Disease in Allogenic Hematopoietic Stem Cell Transplantation : A Systematic Review

Introduction Graft vs host disease (GVHD) is one of the major complications after allogenic - Hematopoietic stem cell transplantation (allo-HSCT). It has been reported in around 70 % of patients after allo-HSCT and leads to increased non-relapse mortality (NRM)/transplant-related mortality (TRM) and also contributes to impaired quality of life. Cytotoxic T-lymphocyte-associated protein 4 (CTLA4), expressed on the surface of regulatory T cells and activated conventional T cells play a role in inhibiting T cell activation by modulating the costimulatory CD28 signal. The CTLA4-Fc fusion proteins abatacept and belatacept lead to immunosuppression induced by blocking CD28-costimulation. CTLA4Ig (Abatacept) has recently been approved by US Food and Drug Administration for prophylaxis of acute GVHD following mismatched unrelated donor (URD) HSCT. Methods We performed a comprehensive literature search on PubMed and ClinicalTrials.gov. We used the MeSH terms for Abatacept and Stem Cell Transplantation and their associated keywords. The search yielded 153 articles. Screening and data extraction were done according to PRISMA guidelines. After excluding case reports, review articles, 4 clinical studies (n=236) were included. Results: The total number of patients tested in the Abatacept group was 193. (Table 1.) In a retrospective trial by Wertheimer T et al., patients with severe cGVHD receiving abataceptdid not need new immunosuppressive treatments (80%) within 3 months of starting abatacept therapy. Patients with lung involvement (n = 9) showed significant benefit with an overall response rate of 89% based on lung severity score (n = 6), and lung function as measured by FEV1. In the phase II trial by Watkins et al addition of T-cell co-stimulation blockade with abatacept to calcineurin inhibitor (CNI)/methotrexate (MTX)-based GVHD prophylaxis, lead to reduced aGVHD, and improved day +180 severe-aGVHD-free-survival. Incidence of grade 3-4 aGVHD in 8/8-HLA-matched URD, was 6.8% (abatacept) versus 14.8% (placebo) (P = .13, hazard ratio = 0.45). Severe-aGVHD-free-survival (SGFS) was 93.2% (CNI/MTX + abatacept) versus 82% (CNI/MTX + placebo, P = .05). In the smaller 7/8-HLA-mismatched URD cohort, grade 3-4 aGVHD was 2.3% (CNI/MTX + abatacept), which compared favorably with a nonrandomized matched cohort of CNI/MTX (30.2%, P < .001), with improved SGFS (97.7% v 58.7%, P < .001). In retrospective study by Khandelwal, P, et al, addition of Abatacept to post-transplantation cyclophosphamide (PTCy) based haploidentical transplantation for patients with thalassemia major (TM, n=5) and sickle cell disease (SCD, n=5), showed that none of the patients in the abatacept group, had grades III-IV aGVHD by day +100 compared with 50% in the group with standard aGVHD prophylaxis (P = 0.001). Thalassemia-free survival after HSCT was 100% in the patients who received abatacept compared to 62.5% in the cohort with standard aGVHD prophylaxis at follow-up (P = 0.007) .In another study by Jaiswal, et al, patients with refractory aggressive B-cell lymphoma (R-ABCL) following autologous HSCT received CTLA4Ig-based reduced-intensity conditioning and sequential CTLA4Ig-primed donor lymphocyte infusions (DLIs) on days +7, +21, and +35. aGVHD was not seen in any patient and cGVHD was seen in 2 patients. 3 patients had disease-progression at 100 days, progression-free and GVHD-free survival at 2 years was 75%. Conclusion: This systematic review shows that abatacept could be a promising treatment option for GvHD after HSCT. Abatacept is a novel treatment modality to markedly reduce GVHD and infections and yet augment NK cell-mediated cytotoxicity following HSCT. The addition of abatacept to routine GVHD prophylaxis reduced the incidence of GVHD without impacting engraftment or survival. Additional randomized clinical trials are needed to establish the efficacy and safety of to prevent GVHD after HSCT with a larger number of patients to confirm these results.

Polatuzumab vedotin in relapsed / refractory aggressive B-cell lymphoma

ABSTRACT Introduction Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive lymphoma histology. Outcomes for patients with relapsed or refractory (R/R) disease remain suboptimal. Polatuzumab vedotin (polatuzumab) is a recently approved antibody drug conjugate that targets CD79b, with a tubulin toxin payload, that has demonstrated significant clinical activity and an acceptable toxicity profile when administered with both anti-CD20 monoclonal antibodies and chemotherapy in clinical trials. Areas covered In this article, we discuss the early-phase trials supporting the accelerated FDA approval of polatuzumab for patients with R/R DLBCL and review the status of and data from ongoing trials combining polatuzumab with other agents. Expert Opinion Polatuzumab is an important new tool for the management of patients with R/R DLBCL who are ineligible for or who relapse following standard second-line therapies. Combinations of polatuzumab with other agents may represent an opportunity to improve outcomes for this difficult to treat population. The recent publication of the POLARIX trial (NCT03274492) incorporating polatuzumab in the frontline treatment of DLBCL may impact the future role of this agent in the R/R setting.

All-Oral Low-Dose Chemotherapy TEPIP is Effective and Well-Tolerated in Relapsed/Refractory Patients With Aggressive B-Cell Lymphoma.

PurposeTreatment options in patients (pts.) with advanced relapsed and refractory aggressive B-cell lymphoma are limited. Palliative all-oral chemotherapy regimens reduce in-patient visits and contribute to quality of life. The all-oral low-dose chemotherapy regimen TEPIP comprises the conventional chemotherapy agents trofosfamide, etoposide, procarbazine, idarubicin and prednisolone.MethodsSafety and efficacy of TEPIP was evaluated in an observational retrospective, single-center study at the University Medical Center Regensburg between 2010 and 2020. Treatment with TEPIP was applied for 7 or 10 days during a 28-days period. In a subgroup of fit and therapy-motivated pts. rituximab was added. End points were overall survival (OS) and progression free survival (PFS). Adverse events ≥ CTCAE grade III were reported.Results35 highly pre-treated pts. with aggressive B-cell lymphoma were enrolled. Median age at TEPIP start was 67 years and 85% of pts. received TEPIP as ≥ third treatment line. Overall response rate (ORR) was 23% (CR 17%). Pts. benefited from additional rituximab administration (ORR 67%) and a lower number of pre-treatments (ORR 41%). The OS was 3.3 months (m) with a 1y-OS of 25.7% and the PFS amounted to 1.3 m with a 1y-PFS of 8.8%. OS and PFS were significantly prolonged in pts. that responded to treatment or additionally received rituximab. Adverse events were mainly hematological and occurred in 49% of pts.ConclusionTEPIP was well-tolerated and induced respectable response in a difficult-to-treat patient cohort. In particular, the all-oral administration enables out-patient use with palliative intent.

Matching-adjusted indirect treatment comparison of chimeric antigen receptor T-cell therapies for third-line or later treatment of relapsed or refractory large B-cell lymphoma: lisocabtagene maraleucel versus tisagenlecleucel

BackgroundThere are no head-to-head clinical studies comparing chimeric antigen receptor (CAR) T-cell therapies for the treatment of relapsed or refractory aggressive large B-cell lymphomas. Naive, indirect comparisons may be inappropriate, as the study designs and patient populations could differ substantially. Matching-adjusted indirect comparisons (MAIC) can reduce many biases associated with indirect comparisons between studies. To determine the comparative efficacy and safety of lisocabtagene maraleucel (liso-cel) to tisagenlecleucel, we describe an unanchored MAIC of the pivotal studies TRANSCEND NHL 001 (TRANSCEND; NCT02631044; liso-cel) and JULIET (NCT02445248; tisagenlecleucel).MethodsIndividual patient data (IPD) from TRANSCEND were available to the authors; for the JULIET pivotal study, summary-level data from the published study were used. To balance the populations between two studies, IPD from TRANSCEND were adjusted to match the marginal distribution (e.g., mean, variance) of clinical factors among patients from JULIET.ResultsResults from the primary MAIC showed liso-cel had statistically significant greater efficacy than tisagenlecleucel (objective response rate: odds ratio [OR] = 2.78, 95% confidence interval [CI]: 1.63‒4.74; complete response rate: OR = 2.01, 95% CI: 1.22‒3.30; progression-free survival: hazard ratio [HR] = 0.65, 95% CI: 0.47‒0.91; overall survival: HR = 0.67, 95% CI: 0.47‒0.95). MAIC of safety outcomes showed lower ORs for all-grade and grade ≥ 3 cytokine release syndrome, and grade ≥ 3 prolonged cytopenia for liso-cel when compared with tisagenlecleucel; there were no statistically significant differences detected for other safety outcomes.ConclusionsOverall, this MAIC of two CAR T-cell therapies indicates liso-cel had favorable efficacy and a comparable or better safety profile relative to tisagenlecleucel.Clinical trial registration: ClinicalTrials.gov identifiers: NCT02631044 and NCT02445248.

Point-of-care anti-CD19 CAR T-cells for treatment of relapsed and refractory aggressive B-cell lymphoma

Anti CD19 chimeric antigen receptor (CAR) T-cell therapy has transformed the care of relapsed and refractory aggressive B-cell lymphoma. However, financial toxicity and manufacturing time represent barriers to its widespread implementation. Study applicability, toxicity, and efficacy of a locally produced autologous CD19-directed CAR T-cell product were studied. We performed a phase 1b/2 clinical trial with a point-of-care (POC) CAR T-cell product that contains a CD28 costimulatory domain. Adult patients with aggressive B-cell lymphoma or transformed low-grade lymphoma who received at least 2 prior regimens were eligible. A total of 73 patients, with a median age of 49 years, met inclusion criteria. CAR T-cell production time from apheresis was 10 days (interquartile range 10-11), negating the need for bridging chemotherapy. Overall and complete response rates were 62.5% and 37.5%. Median progression-free and overall survival were 3.7 and 12.1 months, respectively. Overall and progression-free survival at 12 months were 52.1% (confidence interval [CI]: 40.8%-66.5%) and 40% (CI: 30%-53.7%), respectively. Patients who achieved response had longer progression-free and overall survival. Grade 3-4 cytokine release syndrome was observed in 9.5% of the patients, and immune effector cell-associated neurotoxicity syndrome grade 3-4 in 21.9%. No deaths occurred due to CAR T-cell toxicity. Fifteen patients (20%) underwent allogeneic stem cell transplantation at a median time of 60 days after CAR T-cell therapy; 8 were alive at last follow-up. Of the 6 patients who underwent the transplantation in complete response 2 deceased because of toxicity. POC CAR T-cells are a feasible therapeutic option in aggressive B-cell lymphoma. They provide good efficacy while minimizing production time and the need for bridging therapy.

Salvage High-dose Melphalan With Autologous Stem cell Transplantation as Bridge to Consolidation Therapy for Chemoresistant Aggressive B-cell Lymphoma

BackgroundPatients suffering from refractory aggressive B-cell lymphoma not responding to salvage chemotherapy have a dismal prognosis. CAR T-cells or allogeneic stem cell transplantation (SCT) are potentially curative approaches. However, obtaining a remission, and lowering tumor burden before consolidation seems crucial for long-term efficacy of both treatment modalities. Materials and MethodsIn this retrospective analysis, we reviewed patients with chemoresistant aggressive B-cell lymphoma, defined as being refractory or progressive to at least second line salvage chemotherapy including the regimen immediately preceding autologous stem cell transplantation (ASCT), treated at 2 tertiary centers, who were eligible for intensive treatment using single agent high-dose (HD) melphalan to obtain a remission before consolidating therapy. ResultsWe identified 36 patients that received single agent HD melphalan and ASCT as remission induction followed by CAR T-cells or allogeneic stem cell transplantation (SCT). Thirteen of the evaluable patients (39.4%) achieved a partial remission and 9 patients (27.73%) a complete remission, resulting in an overall response rate (ORR) of 66.7%. High remission rates were seen across all subgroups including patients with primary refractory lymphoma (ORR 58.3%), uncontrolled disease and high tumor burden as indicated by increased LDH levels (ORR 66.7% for patients with elevated LDH above 2 times upper limit of norm). 22 patients proceeded to allogeneic SCT and 5 to CAR T-cell therapy. Treatment related mortality of ASCT was 5.5% (2 patients, both due to infections). Two-year overall survival of all patients was 15.8%, primarily due to a high non–relapse mortality (45.5%) of allogeneic SCT patients treated with myeloablative conditioning chemotherapy. ConclusionSingle agent HD melphalan produces high remission rates in patients with chemoresistant, uncontrolled aggressive B-cell lymphoma and provides a window of opportunity for consolidation therapy. MicroabstractPatient with refractory/relapsed aggressive B-cell lymphoma after salvage therapy are an unmet medical need because of their very poor prognosis. In our retrospective analysis of 36 patients we showed that single agent high-dose melphalan can achieve high response rates (ORR 66.7%) even in uncontrolled disease enabling consolidation therapy e.g. with allogeneic stem cell transplantation or CAR T-cell therapy.

CAR T cells for the long run in aggressive B-cell lymphoma.

Since first being reported in 2010, 1 Kochenderfer JN Wilson WH Janik JE et al. Eradication of B-lineage cells and regression of lymphoma in a patient treated with autologous T cells genetically engineered to recognize CD19. Blood. 2010; 116: 4099-4102 Crossref PubMed Scopus (912) Google Scholar CD19-directed chimeric antigen receptor (CAR) T cells have led a revolution in the treatment of B-cell non-Hodgkin lymphomas. The US Food and Drug Administration have approved three CAR T-cell products for the treatment of relapsed or refractory aggressive B-cell lymphomas: tisagenlecleucel, axicabtagene ciloleucel, and lisocabtagene maraleucel. All three showed high rates of complete responses in patients with refractory disease in pivotal trials (37 [40%] of 93, 2 Schuster SJ Bishop MR Tam CS et al. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med. 2019; 380: 45-56 Crossref PubMed Scopus (1179) Google Scholar 59 [58%] of 101, 3 Locke FL Ghobadi A Jacobson CA et al. Long-term safety and efficacy of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1–2 trial. Lancet Oncol. 2019; 20: 31-42 Summary Full Text Full Text PDF PubMed Scopus (693) Google Scholar and 136 [53%] of 256, 4 Abramson JS Palomba ML Gordon LI et al. Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study. Lancet. 2020; 396: 839-852 Summary Full Text Full Text PDF PubMed Scopus (271) Google Scholar respectively), taking into account different patient selection and trial designs in each study. In parallel, real-world data have emerged for these products, showing similar overall responses of 61·8% (95% CI 53·6–69·6) for tisagenlecleucel and 70% (61–78) for axicabtagene ciloleucel, and complete responses in 60 (39%) of 152 patients for tisagenlecleucel and 61 (50%) of 122 patients for axicabtagene ciloleucel. 5 Pasquini MC Hu ZH Curran K et al. Real-world evidence of tisagenlecleucel for pediatric acute lymphoblastic leukemia and non-Hodgkin lymphoma. Blood Adv. 2020; 4: 5414-5424 Crossref PubMed Scopus (71) Google Scholar , 6 Jacobson CA Hunter BD Redd R et al. Axicabtagene ciloleucel in the non-trial setting: outcomes and correlates of response, resistance, and toxicity. J Clin Oncol. 2020; 38: 3095-3106 Crossref PubMed Scopus (72) Google Scholar Real-world studies have supported the efficacy and safety of CD19-directed CAR T-cell therapies, including in many patients who would not have been eligible for the pivotal clinical trials. Among patients treated with axicabtagene ciloleucel in the ZUMA-1 study 7 Jacobson C Locke FL Ghobadi A et al. Long-term survival and gradual recovery of B cells in patients with refractory large B cell lymphoma treated with axicabtagene ciloleucel (axi-cel). Blood. 2020; 136: 40-42 Google Scholar with at least 4 years of follow-up (median follow-up 51·1 months), the median overall survival was 25·8 months, and the 4-year estimated overall survival was 44%. The reported duration of follow-up in the JULIET study was relatively short until now. Long-term clinical outcomes of tisagenlecleucel in patients with relapsed or refractory aggressive B-cell lymphomas (JULIET): a multicentre, open-label, single-arm, phase 2 studyTisagenlecleucel shows durable activity and manageable safety profiles in adult patients with relapsed or refractory aggressive B-cell lymphomas. For patients with large B-cell lymphomas that are refractory to chemoimmunotherapy or relapsing after second-line therapies, tisagenlecleucel compares favourably with respect to risk–benefit relative to conventional therapeutic approaches (eg, salvage chemotherapy). Full-Text PDF

CAR T-cell therapy for secondary CNS DLBCL

AbstractManagement of secondary central nervous system (SCNS) involvement in relapsed or refractory aggressive B-cell lymphomas remains an area of unmet medical need. We report a single-center retrospective analysis of 7 adult patients with SCNS lymphoma (SCNSL) who underwent chimeric antigen receptor (CAR) T-cell therapy for their refractory disease, and we describe the safety of whole brain radiation therapy (WBRT) as a bridging therapy. Six patients (85.7%) achieved a complete response at day 28, and 1 patient had progressive disease. The median progression-free survival was 83 days (range, 28-219 days), and median overall survival was 129 days (range, 32-219 days). Three patients died as a result of disease progression. Of the 5 patients who received WBRT as bridging therapy, 3 had no immune effector cell–associated neurotoxicity syndrome (ICANS), but 2 patients had grade 1 or grade 3 ICANS. No grade 4 ICANS was reported in this subset of patients. We conclude that SCNSL should not preclude patients from receiving CAR T-cell therapy as a treatment option because of concerns regarding ICANS, and bridging with WBRT is not associated with increased ICANS.

A Phase 1 Trial of Alisertib and Romidepsin for Relapsed/Refractory Aggressive B-Cell and T-Cell Lymphomas

Introduction. The histone deacetylase inhibitor (HDACi) romidepsin and the aurora A kinase inhibitor (AURKA) have both shown activity as monotherapies in patients with relapsed peripheral T-cell lymphoma (PTCL) and aggressive B-cell lymphomas (BCL), but most responses are partial and relapses often occur. In preclinical studies, AURKAs have shown to enhance lymphoma cell death to HDACis through repression of C-Myc and C-Myc-responsive micro RNAs, exhibiting highly synergistic effects in lymphoma cell lines through cytokine modulation. Therefore, we initiated a phase I trial (NCT01897012) combining alisertib with romidepsin in patients with multiple lymphoma subtypes.Methods. Patients with PTCL, Hodgkin lymphoma (HL) or aggressive BCL, relapsed or refractory to at least 1 line of therapy, were eligible for the study. Six dose levels were defined (Table) and a standard 3+3 design used for dose escalation; cycles were repeated every 21 days for levels 1-4, amended to every 28 days for levels 5-8, for a maximum of 8 cycles. Dose limiting toxicity (DLT) was assessed during cycle 1 and defined as grade 4 neutropenia or thrombocytopenia lasting longer than 14 days and/or uncontrollable grade 3 or 4 non-hematological toxicity.Results. Nineteen patients have been enrolled in the study between 08/2013 and 03/2017. Median time from first diagnosis to enrollment was 11 months (range, 1-281 months); median age was 56 (range, 23-77 years) and 16 (84%) were male; 11 (58%) patients had aggressive diffuse large B-cell lymphoma (DLBCL), 3 (16%) PTCL, 3 (16%) HL and 2 (10%) Burkitt lymphoma (BL); median number or previous regimens was 3 (range, 1-8), 5 (26%) patients had received autologous stem cell transplant (SCT) and 3 (16%) allogeneic SCT; overall response rate (ORR) to latest regimen was 26% and 17 (89%) patients had relapsed within 6 months. Three patients have been enrolled at dose level 1-5, and 4 at dose level 6 (1 patient withdraw consent before completion of DLT evaluation, so cohort was expanded).Median number of cycles delivered was 1 (range, 1-8) and 18 (95%) patients have discontinued treatment to date; reasons for study discontinuation were: progression in 14 (78%) patients, completion of treatment in 2 (12%), indication for SCT in 1 (5%), and patient's choice in 1 (5%). No DLTs have been observed to date. The most common (> 10%) grade 3-4 toxicities were thrombocytopenia (47%), anemia (32%), neutropenia (32%), infections (26%) and fatigue (16%). Fifteen patients were evaluable for response by PET/CT, and 4 patients stopped treatment after 1 cycle, before restaging: 3 because of clinical progression and 1 because of patient's choice; among 7 patients who had a decrease in tumor burden, median reduction was 44% (range, 11-89%), and among 8 patients who had an increase in tumor burden, median increase was 51% (range, 4-300%). Two patients (10%) achieved complete remission (1 patient with HL, 1 with PTCL), 1 (5%) partial remission (1 patient with HL), and 4 (21%) stable disease, and ORR rate was 15%. Only 1 (5%) patient proceeded to SCT (allogeneic) after 3 months of treatment. After a median follow-up of 4 months (range, 1-46 months), median progression-free survival (PFS) was 1 month (range, 1-14 months), and the longest PFS (> 6 months) was observed in 1 patient with heavily pretreated HL (lymphocyte depleted) and 3 patients with PTCL (Figure). At most recent follow-up, 17 patients have progressed, 1 after SCT.After a median follow-up of 4 months (range, 1-46 months), median OS was 7 months (range, 1-46 months). At most recent follow-up, 11 (58%) patients have died, all of disease progression.Discussion. The combination of romidepsin and alisertib can be safely used as salvage therapy in patients with relapsed or refractory aggressive B-cell lymphomas and PTCL, however the majority of patients have developed disease progression during follow-up suggesting rationale for potential maintenance therapy, improved methods to select patients who would have the highest likelihood of benefit, and evaluation of other targeted therapy doublets or triplets for these diagnoses. Initial gene expression profiling (GEP) results have shown that upregulation of genes associated with anti-tumor immune response correlates with response. Enrollment to the higher dose level (7 and 8) is ongoing. [Display omitted] DisclosuresNastoupil:Janssen: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; TG Therapeutics: Honoraria, Research Funding; Gilead: Honoraria; Karus Therapeutics: Research Funding; Abbvie: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Kwak:InnoLifes: Consultancy, Equity Ownership; Celltrion, Inc: Consultancy; Pepromene Bio: Consultancy, Equity Ownership. Lee:KITE PHARMA: Consultancy. Wang:BeiGene: Research Funding; Celgene: Honoraria, Research Funding; Dava Oncology: Honoraria; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; June Therapeutics: Research Funding; Kite Pharma: Research Funding; Onyx: Research Funding; Pharmacyclics: Research Funding; Proteolix: Honoraria, Research Funding; Acerta Pharma: Consultancy, Research Funding; Asana Biosciences: Research Funding. Westin:Apotex: Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees. Wesson:seattle genetics: Honoraria. Fanale:BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CELGENE: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ONYX: Research Funding; MERCK: Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC THERAPEUTICS: Research Funding; AMGEN: Membership on an entity's Board of Directors or advisory committees; MOLECULAR TEMPLATES: Research Funding; SEATTLE GENETICS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; TAKEDA: Honoraria, Research Funding; GENENTECH: Research Funding.

CAR-T TREK through the lymphoma universe, to boldly go where no other therapy has gone before.

Chimeric antigen receptor (CAR) T cells (CART) therapies have changed and continue to change the treatment paradigms for B-cell malignancies because they can achieve durable complete remission in patients in whom multiple lines of treatment have failed. These unprecedented results have led to the widespread use of anti-CD19 CART therapy for patients with relapsed and refractory aggressive large B-cell lymphomas. While long-term follow-up data show that about one-third of patients achieve prolonged complete remission and are potentially cured, the majority of patients either do not respond to CD19 CART therapy or eventually relapse after CD19 CART therapy. These results are, on the one hand, driving intense research into identifying mechanisms of relapse and, on the other hand, inspiring the development of novel strategies to overcome resistance. This review summarizes current clinical outcomes of CART immunotherapy in B-cell non-Hodgkin lymphomas, describes the most up-to-date understanding of mechanisms of relapse and discusses novel strategies to address resistance to CART therapy. We are indeed at the beginning of a scientific trek to explore the mechanisms of resistance, seek out new, more effective treatment approaches based on these discoveries and to boldly go where no other therapy has gone before!

CAR T-Cell Therapy for B-Cell non-Hodgkin Lymphoma and Chronic Lymphocytic Leukemia: Clinical Trials and Real-World Experiences.

Chimeric antigen receptor-modified (CAR) T cells targeting CD19 have revolutionized the treatment of relapsed or refractory aggressive B-cell lymphomas, and their use has increased the cure rate for these cancers from 10 to 40%. Two second-generation anti-CD19 CAR T-cell products, axicabtagene ciloleucel and tisagenlecleucel, have been approved for use in patients, and the approval of a third product, lisocabtagene maraleucel, is expected in 2020. The commercial availability of the first two products has facilitated the development of real-world experience in treating relapsed or refractory aggressive B-cell lymphomas, shed light on anti-CD19 CAR T-cell products' feasibility in trial-ineligible patients, and raised the need for strategies to mitigate the adverse effects associated with anti-CD19 CAR T-cell therapy, such as cytokine release syndrome, neurotoxicity, and cytopenia. In addition, promising clinical data supporting the use of anti-CD19 CAR T-cell therapy in patients with indolent B-cell lymphomas or chronic lymphocytic leukemia have recently become available, breaking the paradigm that these conditions are not curable. Multiple clinical CAR T-cell therapy-based trials are ongoing. These include studies comparing CAR T-cell therapy to autologous stem cell transplantation or investigating their use at earlier stages of disease, novel combinations, and novel constructs. Here we provide a thorough review on the use of the anti-CD19 CAR T-cell products axicabtagene ciloleucel, tisagenlecleucel and lisocabtagene maraleucel in patients with indolent or aggressive B-cell lymphoma or with chronic lymphocytic leukemia, and present novel CAR T cell-based approaches currently under investigation in these disease settings.

Efficacy and safety of pixantrone for the treatment of multiply relapsed or refractory aggressive non-Hodgkin B-cell lymphomas.

Few treatment options exist for patients with relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (NHL) who fail first- and second-line therapies. Pixantrone is a novel aza-anthracenedione agent with reduced potential for cardiotoxicity but maintained anti-tumour activity relative to anthracyclines. The current retrospective, observational, real-life study was undertaken in 79 patients who received pixantrone monotherapy for multiply R/R aggressive B-cell NHL in Spain and Italy. Before pixantrone, patients had received a median of 3 prior therapies and 84.6% of them were refractory to the last regimen. Median progression-free survival (mPFS) was 2.8months (95% confidence interval [CI] 2.1-3.6) and median overall survival (mOS) was 4.0months (95%CI 5.6-7.9), with an objective response rate (ORR) of 29% (complete remission [CR]: 13.2%, partial remission [PR]: 15.2%). Patients receiving ≥2 cycles of pixantrone showed mPFS and mOS of 3.1 and 6.0months, respectively, and an ORR of 36.8% (CR: 17.5%, PR: 19.3%). Overall, 63.3% of patients reported ≥1 adverse event (AE), most commonly haematological AEs. One patient developed grade 2 sinus tachycardia. Pixantrone was effective and well tolerated in a real-world population of multiply R/R patients with aggressive B-cell NHL, many of whom had very poor prognostic factors.