scholarly journals EBV Positive DLBCL Is Effectively Treated with Commercial CAR T Cell Therapy but Is Associated with Higher Rates of Severe Immune Effector Cell Associated Neurologic Syndrome (ICANS): A Single Institution Experience

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3862-3862
Author(s):  
Liana Nikolaenko ◽  
Alex F. Herrera ◽  
Elizabeth Budde ◽  
Joo Y. Song ◽  
Geoffrey Shouse
Keyword(s):  
T Cell ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Immune Effector Cell ◽  
T Cell Therapy ◽  
Immune Effector ◽  
Car T Cell Therapy ◽  
Car T ◽  
Grade 3

Abstract Introduction: CAR T-cell therapy (CART) has revolutionized the treatment landscape of aggressive B cell lymphoma (aBCL) in the relapsed/refractory (r/r) setting, including high-risk groups such as high grade B cell lymphoma (HGBCL), primary refractory disease, and chemo-resistant relapses. To date, however, there has been no data reported, on the outcomes of patients with Epstein-Barr virus positive (EBV+) DLBCL, NOS. EBV+ DLBCL, NOS is a high-risk group of aBCL characterized by the incorporation of EBV into the malignant cells, with the chronic inflammation associated with EBV infection being thought to contribute to DLBCL pathogenesis. It has been shown to be less responsive to standard chemotherapy with high relapse rates and overall poor prognosis. In the present study, we analyze outcomes and toxicities of patients with EBV+ DLBCL, NOS treated with CD19CART. Methods: We retrospectively analyzed charts of patients treated with commercially available CD19CAR T-cell products for the treatment of aBCL at City of Hope (COH) between April 2018 and March 2021. EBV status was determined by immunohistochemical stains from EBER in situ hybridization on paraffin embedded tissues. Patients were included in the analysis if they had positive or negative EBER staining, referred as EBV+ or EBV-, respectively. The investigation was approved by the COH IRB. Cytokine release syndrome (CRS) and immune effector cell associated neurologic syndrome (ICANS) were graded using ASTCT criteria (Lee et al. BBMT 2019). Demographics were analyzed with descriptive statistics. Univariate analysis was performed by Chi Square test. Results: Seventy-three patients had tumor samples that were evaluable for analysis, 92% (n=67) were negative for EBER and 8% (n=6) were positive for EBER. In the entire cohort, the median age was 62 years (range, 21-90), and included 18% (n=13) transformed follicular lymphoma, 73% (n=53) DLBCL, NOS, and 10%(n=7) DH. The median number of prior lines of therapy was 2 (range, 2-6) and 15% (n=11) patients had prior autologous stem cell transplant. Comparing the EBV+ patients to the EBV-, the CR rate was 67% (n=4) vs 58% (n=34), with 16% (n=1) PR vs 27% (n=15) (ORR 83% vs 74%). With a median follow up of 17.0 months (range, 3.6-38.3), 33% (n=2) of EBV+ patients had progressed vs 42% (n=28). In the EBV+ DLBCL, NOS group, 3 CR patients had absence of detectable EBV PCR in the peripheral blood at the time of CART; 1 CR patient did not have clinical indication for EBV viral load (VL) evaluation (EBV PCR not measured); 1 PR and 1 PD patients had detectable viremia. At the time of analysis, 31% (n=21) of EBV- patients died vs 33% (n=2) of EBV+ patients, both with non-CR response to CAR T and persistent EBV VL during therapy. In terms of toxicity, overall CRS rates were similar with 83% (n=5) in the EBV+ patients and 86% (n=58) in EBV- patients. Although overall incidences of ICANS were similar between the two groups (50% [n=3] vs 45% [n=30]), grade 3 ICANS was higher in EBV+ patients (50% [n=3]) than in EBV- patients( 7.5% [n=5]; p = 0.02). EBV VL did not correlate with CRS or neurotoxicity. Conclusion: We present a retrospective analysis of EBV+ DLBCL, NOS patients treated with CART at our institution. Based on our analysis, despite the limited number of cases, the CART is an effective therapy for EBV+ DLBCL,NOS with response rates similar to what has been reported in the literature for other aBCL groups. Responses appear to be improved if EBV VL is undetectable at the time of CART. Interestingly, we demonstrate a statistically significant higher rates of grade 3 ICANS in patients with EBV+ DLBCL,NOS. Our data suggests that close monitoring for ICANS during CART should be considered in EBV+ DLBCL patients with early therapeutic intervention to prevent severe toxicity. Further investigation of a larger cohort of EBV+ DLBCL patients, as well as a deeper analysis of inflammatory markers and EBV viremia in these patients undergoing CART may provide further insight to response and toxicity profile. Disclosures Nikolaenko: Rafael Pharmaceuticals: Research Funding; Pfizer: Research Funding. Herrera: Seagen: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Takeda: Consultancy; ADC Therapeutics: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Tubulis: Consultancy; Kite, a Gilead Company: Research Funding; Karyopharm: Consultancy; Gilead Sciences: Research Funding. Budde: Mustang Bio, Inc: Research Funding; Gilead: Consultancy; Merck, Inc: Research Funding; AstraZeneca: Research Funding; Amgen: Research Funding; IGM Biosciences: Research Funding; Roche: Consultancy; BeiGene: Consultancy; Novartis: Consultancy. Shouse: Kite Pharma: Speakers Bureau; Beigene: Honoraria.

scholarly journals Axicabtagene Ciloleucel: Clinical Data for the Use of CAR T-cell Therapy in Relapsed and Refractory Large B-cell Lymphoma

2020 ◽  
pp. 106002802094423
Author(s):  
Zachery Halford ◽  
Mary Kate Anderson ◽  
Lunawati L. Bennett
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Large B Cell Lymphoma ◽  
Car T Cell Therapy ◽  
Car T ◽  
Grade 3

Objective: To evaluate the literature for axicabtagene ciloleucel (axi-cel), a first-in-class chimeric antigen receptor (CAR) T-cell therapy, in the treatment of relapsed/refractory (r/r) large B-cell lymphoma (LBCL). Data Sources: We conducted a PubMed (inception to June 22, 2020) and ClinicalTrials.gov search using the following terms: CD19, chimeric antigen receptor, and lymphoma. Study Selection and Data Extraction: All retrospective and prospective studies evaluating the use of axi-cel in LBCL were reviewed. Data Synthesis: In the pivotal ZUMA-1 trial, axi-cel exhibited unprecedented overall and complete response rates of 83% and 58%, respectively. With a median follow-up of 27.1 months, 39% of patients had ongoing responses. Furthermore, postmarketing retrospective analyses found similar response rates in a more clinically diverse LBCL patient population. Novel CAR T-cell therapy elicits unique and potentially life-threatening toxicities that include cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS). Studies reported grade ≥3 CRS in 7% to 14% of patients and grade ≥3 ICANS in 31% to 55% of patients. Relevance to Patient Care and Clinical Practice: Axi-cel was the first US Food and Drug Administration–approved genetically engineered autologous CAR T-cell agent in r/r LBCL, representing an important milestone and paradigm shift in cancer treatment. Adoptive T-cell immunotherapy is a breakthrough treatment modality requiring careful patient selection, multidisciplinary collaboration, comprehensive patient counseling, and expert training to ensure optimal treatment. Conclusions: The initial and ongoing results with axi-cel are encouraging, but long-term safety and efficacy data are lacking. Additional studies are required to identify axi-cel’s ideal place in LBCL therapy.

scholarly journals Unbiased Metabolomic Screening Reveals Pre-Existing Plasma Signatures in Large B-Cell Lymphoma Patients Treated with Anti-CD19 Chimeric Antigen Receptor (CAR) T-Cells: Association with Cytokine Release Syndrome (CRS) and Neurotoxicity (ICANS)

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 42-43
Author(s):  
Akansha Jalota ◽  
Courtney E. Hershberger ◽  
Manishkumar S. Patel ◽  
Agrima Mian ◽  
Daniel M. Rotroff ◽  
...  
Keyword(s):  
T Cell ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Large B Cell Lymphoma ◽  
Car T Cell Therapy ◽  
Car T

Background: CAR T-cells that target CD19 have been approved by the FDA for treatment of relapsed/refractory large B cell lymphoma (r/r LBCL). Despite clinical efficacy in chemo-refractory patients, the benefit of this approach is often complicated by potentially severe toxicities such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). The physiological basis of these limitations remains poorly understood, and represents an unmet clinical need. Metabolomics is a global approach that can be used to identify diverse low molecular weight biochemical entities with a wide range of functions. In this study we have employed an untargeted metabolomics approach to identify novel metabolites present in the plasma of patients treated with CAR T-cell therapy that associate with clinical outcomes and toxicities of treatment. Methods: Peripheral blood specimens were collected at the time of apheresis from 41 r/r LBCL patients treated with Axicabtagene Ciloleucel (Axi-cel; n=31) and Tisagenlecleucel (Tisa-cel; n=10). Baseline clinical characteristics and details of prior treatment were captured for all patients. Response outcomes and toxicity grading as measured by ASTCT consensus criteria for CRS and ICANS were recorded. Plasma was isolated from blood and analyzed for metabolites using a commercial Ultrahigh Performance Liquid Chromatography-Tandem Mass Spectrometry platform. Association analysis was performed using ordinal logistic regression to identify the metabolites whose plasma abundance at the time of apheresis correlated with ICANS and CRS grade (FDR ≤0.2). In addition, significant metabolites were utilized to identify perturbations of biologically relevant pathways associated with CRS/ICANS grade. Results: The median age of patients studied was 61 (range 25 - 77), with 25 (61%) males. All patients were previously treated with R-CHOP or R-EPOCH. Twenty (48.8%) patients had high or high-intermediate IPI at baseline. The patients had received a median of 3 (range, 2-6) lines of therapy prior to CAR T-cell therapy, with 21 (51.22%) having received prior autologous stem cell transplantation. At the 3-month time point, response evaluation was available for 28 Axi-cel and 10 Tisa-cel recipients. An objective response was seen in 16 (57%) and 2 (20%) patients, and death was documented in 3 (11%) and 2 (20%) patients, in the Axi-cel and Tisa-cel groups, respectively. Untargeted metabolomics revealed a total of 1,241 metabolites, detected in positive, negative and polar modes, of which 1,011 were named. These include lipids, amino acids, xenobiotics, nucleotides, partially characterized compounds, cofactors and vitamins. In examining toxicities of CAR-T cell treatment, we identified three metabolites whose abundance was negatively associated with ICANS grade (FDR ≤0.2), indicating that high abundance of these metabolites at the time of apheresis was associated with a decreased risk of (i.e. protection from) ICANS. Plasma metabolites were also found to be associated with CRS, with 23 associated with an increased risk (i.e. predisposing to) of CRS, and 204 associated with decreased risk (i.e. protection from) of CRS. Using a hypergeometric test for over-represented metabolites in the KEGG metabolic pathways (FDR ≤0.2), caffeine metabolism, glycine, serine, and threonine metabolism, arginine biosynthesis, and aminoacyl-tRNA biosynthesis were identified as the most significantly represented pathways. Conclusion: Pre-existing biochemical signatures present in the plasma at the time of apheresis are strongly associated with toxicities observed in response to commercial CD19 CAR T-cell therapies. These endogenous metabolites may serve as biomarkers for monitoring risk of toxicity associated with CD19 CAR T cell treatment and provide insight into rational clinical interventions to mitigate such risks. Disclosures Rotroff: Interpares Biomedicine LLC.: Current equity holder in publicly-traded company; CAR-T Response: Patents & Royalties. Hill:Takeda: Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; AstraZenica: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Beigene: Consultancy, Honoraria, Research Funding.

Retreatment (reTx) of patients (pts) with refractory large B-cell lymphoma with axicabtagene ciloleucel (axi-cel) in ZUMA-1.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 8012-8012
Author(s):  
Frederick Lundry Locke ◽  
Nancy L. Bartlett ◽  
Caron A. Jacobson ◽  
Olalekan O. Oluwole ◽  
Javier Munoz ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Expansion ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Large B Cell Lymphoma ◽  
Car T Cell Therapy ◽  
Car T ◽  
Grade 3

8012 Background: Axi-cel, an autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy, is approved in the US and EU for pts with relapsed/refractory large B cell lymphoma after ≥ 2 prior therapies. In the ZUMA-1 pivotal study (NCT02348216), the objective response rate (ORR) was 83% (58% complete response [CR] rate; Locke et al. Lancet Oncol. 2019). While axi-cel has demonstrated durable responses in a subset of pts, approximately half of all responders relapsed, and little is known on the viability of reTx with CAR T cell therapy. Here we report outcomes of pts retreated with axi-cel in ZUMA-1. Methods: Pts with progressive disease (PD) were eligible for reTx if there was no evidence of CD19 loss by local review, and if during 1st Tx they did not experience any dose-limiting toxicities, as defined in Phase 1, or comparable toxicities in Phase 2. Pts received the same regimen at reTx as at 1st Tx: 2 × 106 CAR T cells/kg after conditioning chemotherapy. Results: Thirteen pts in Cohorts 1 – 4 received axi-cel reTx. Prior to 1st Tx, most pts (69%) had an IPI score 3-4, 85% had disease stage 3-4, and the median number of prior regimens was 3 (range, 2 – 6). At first Tx, 6 pts achieved a CR, 6 achieved partial response (PR), and 1 pt had stable disease (SD) prior to PD. Median duration of first response was 96 days (range, 56 – 274). There was no Grade ≥ 3 cytokine release syndrome (CRS; 6 pts each had Grade 1 and 2). There were no Grade 4 or 5 neurologic events (NEs; 2 pts had Grade 1, 1 had Grade 2, and 7 had Grade 3). Upon reTx, 54% of pts achieved response (4 CR, 3 PR). Response to reTx was more common among pts who achieved CR at 1st Tx (83%; 4/6 CR, 1 PR, 1 SD) than in pts who achieved PR at 1st Tx (33%; 2/6 PR, 1 SD, 3 PD), and no response was observed in the pt with SD at 1st Tx. Median duration of response at reTx was 81 days (range, 1 – 225+). Response with reTx was longer than that with 1st Tx for 2 pts. One pt remains in response 255 days post-reTx. Comparable rates of CRS were observed with reTx as with 1st Tx. Compared with 1st Tx, fewer pts experienced NEs with reTx, and those that did occur were of lower grade: 23% (3 of 13 pts) had Grade 3; 23% (3 of 13 pts) had Grade 1, and 8% (1 of 13 pts) had Grade 2. Peak CAR T cell expansion was lower upon reTx vs 1st Tx (median, 4.3 vs 66.1 CAR gene-marked cells/µL blood). Conclusions: Based on this limited sample size, reTx with axi-cel may have clinical efficacy, although transient, in some pts, especially those who achieve CR with 1st Tx. CAR T cell expansion and severe CRS and NEs may be attenuated at reTx. Further studies with additional pts are needed to confirm these results. Clinical trial information: NCT02348216 .

scholarly journals Influence of TP53 Mutation on Survival of Diffuse Large B-Cell Lymphoma in the CAR T-Cell Era

Cancers ◽  
2021 ◽  
Vol 13 (22) ◽  
pp. 5592
Author(s):  
Edit Porpaczy ◽  
Philipp Wohlfarth ◽  
Oliver Königsbrügge ◽  
Werner Rabitsch ◽  
Cathrin Skrabs ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
B Cell ◽  
Tp53 Mutation ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

Refractory/relapsed diffuse large B-cell lymphoma (DLBCL) is associated with poor outcome. The clinical behavior and genetic landscape of DLBCL is heterogeneous and still not fully understood. TP53 mutations in DLBCL have been identified as markers of poor prognosis and are often associated with therapeutic resistance. Chimeric antigen receptor T-cell therapy is an innovative therapeutic concept and represents a game-changing therapeutic option by supporting the patient’s own immune system to kill the tumor cells. We investigated the impact of TP53 mutations on the overall survival of refractory/relapsed DLBCL patients treated with comparable numbers of therapy lines. The minimum number of therapy lines was 2 (median 4), including either anti-CD19 CAR T-cell therapy or conventional salvage therapy. A total of 170 patients with DLBCL and high-grade B-cell lymphoma with MYC, BCL2, and/or BCL6 rearrangements (DHL/THL), diagnosed and treated in our hospital between 2000 and 2021, were included. Twenty-nine of them received CAR T-cell therapy. TP53 mutations were found in 10/29 (35%) and 31/141 (22%) of patients in the CAR T-cell and conventional groups, respectively. Among the 141 patients not treated with CAR T cells, TP53 mutation was an independent prognostic factor for overall survival (OS) (median 12 months with TP53 vs. not reached without TP53 mutation, p < 0.005), but in the CAR T cell treated group, this significance could not be shown (median OS 30 vs. 120 months, p = 0.263). The findings from this monocentric retrospective study indicate that TP53 mutation status does not seem to affect outcomes in DLBCL patients treated with CAR T-cell therapy. Detailed evaluation in large cohorts is warranted.

scholarly journals DLBCL patients treated with CD19 CAR T cells experience a high burden of organ toxicities but low nonrelapse mortality

2020 ◽  
Vol 4 (13) ◽  
pp. 3024-3033 ◽  
Author(s):  
Kitsada Wudhikarn ◽  
Martina Pennisi ◽  
Marta Garcia-Recio ◽  
Jessica R. Flynn ◽  
Aishat Afuye ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
B Cell Lymphoma ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T ◽  
Grade 3

Abstract Cytokine release syndrome (CRS) immune effector cell–associated neurotoxicity syndrome are the most notable toxicities of CD19 chimeric antigen receptor (CAR) T-cell therapy. In addition, CAR T-cell–mediated toxicities can involve any organ system, with varied impacts on outcomes, depending on patient factors and involved organs. We performed detailed analysis of organ-specific toxicities and their association with outcomes in 60 patients with diffuse large B-cell lymphoma (DLBCL) treated with CD19 CAR T cells by assessing all toxicities in organ-based groups during the first year posttreatment. We observed 539 grade ≥2 and 289 grade ≥3 toxicities. Common grade ≥3 toxicities included hematological, metabolic, infectious, and neurological complications, with corresponding 1-year cumulative incidence of 57.7%, 54.8%, 35.4%, and 18.3%, respectively. Patients with impaired performance status had a higher risk of grade ≥3 metabolic complications, whereas elevated lactate dehydrogenase was associated with higher risks of grade ≥3 neurological and pulmonary toxicities. CRS was associated with higher incidence of grade ≥3 metabolic, pulmonary, and neurologic complications. The 1-year nonrelapse mortality and overall survival were 1.7% and 69%, respectively. Only grade ≥3 pulmonary toxicities were associated with an increased mortality risk. In summary, toxicity burdens after CD19 CAR T-cell therapy were high and varied by organ systems. Most toxicities were manageable and were rarely associated with mortality. Our study emphasizes the importance of toxicity assessment, which could serve as a benchmark for further research to reduce symptom burdens and improve tolerability in patients treated with CAR T cells.

scholarly journals Tumor burden, inflammation, and product attributes determine outcomes of axicabtagene ciloleucel in large B-cell lymphoma

2020 ◽  
Vol 4 (19) ◽  
pp. 4898-4911 ◽  
Author(s):  
Frederick L. Locke ◽  
John M. Rossi ◽  
Sattva S. Neelapu ◽  
Caron A. Jacobson ◽  
David B. Miklos ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Tumor Burden ◽  
Durable Response ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Large B Cell Lymphoma ◽  
Car T Cell Therapy ◽  
Car T

Abstract ZUMA-1 demonstrated a high rate of durable response and a manageable safety profile with axicabtagene ciloleucel (axi-cel), an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, in patients with refractory large B-cell lymphoma. As previously reported, prespecified clinical covariates for secondary end point analysis were not clearly predictive of efficacy; these included Eastern Cooperative Oncology Group performance status (0 vs 1), age, disease subtype, disease stage, and International Prognostic Index score. We interrogated covariates included in the statistical analysis plan and an extensive panel of biomarkers according to an expanded translational biomarker plan. Univariable and multivariable analyses indicated that rapid CAR T-cell expansion commensurate with pretreatment tumor burden (influenced by product T-cell fitness), the number of CD8 and CCR7+CD45RA+ T cells infused, and host systemic inflammation, were the most significant determining factors for durable response. Key parameters differentially associated with clinical efficacy and toxicities, with both theoretical and practical implications for optimizing CAR T-cell therapy. This trial was registered at www.clinicaltrials.gov as #NCT02348216.

CD22-Directed CAR T-Cell Therapy Induces Complete Remissions in CD19-Directed CAR-Refractory Large B-Cell Lymphoma

Blood ◽  
2020 ◽  
Author(s):  
John H Baird ◽  
Matthew Joshua Frank ◽  
Juliana Craig ◽  
Shabnum Patel ◽  
Jay Y Spiegel ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Dose Escalation Study ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Large B Cell Lymphoma ◽  
Car T Cell Therapy ◽  
Car T ◽  
Large B Cell

The prognosis for patients with large B-cell lymphoma (LBCL) progressing after treatment with chimeric antigen receptor (CAR) T-cell therapy targeting CD19 (CAR19) is poor. We report on the first three consecutive patients with autologous CAR19-refractory LBCL treated with a single infusion of autologous 1×106 CAR+ T-cells/kg targeting CD22 (CAR22) as part of a phase I dose escalation study. CAR22 therapy was relatively well tolerated, without any observed non-hematologic adverse events higher than grade 2. Following infusion, all three patients achieved complete remission, with all responses ongoing at the time of last follow up (mean 7.8 months, range 6-9.3). Circulating CAR22 cells demonstrated robust expansion (peak range 85.4-350 cells/µL), and persisted beyond three months in all patients with continued radiographic responses and corresponding decreases in circulating tumor DNA (ctDNA) beyond six months post-infusion. Further accrual at a higher dose level in this phase 1 dose-escalation study is ongoing and will explore the role of this therapy in patients who have failed prior CAR T-cell therapies. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT04088890)

Single-Center Experience with Axicabtagene-Ciloleucel (Axi-cel) and Tisagenlecleucel (Tisa-cel) for Relapsed/Refractory Diffuse Large B-Cell Lymphoma: Comparable Response Rates and Manageable Toxicity

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 34-35
Author(s):  
Veit Buecklein ◽  
Viktoria Blumenberg ◽  
Josephine Ackermann ◽  
Christian Schmidt ◽  
Kai Rejeski ◽  
...  
Keyword(s):  
T Cell ◽  
Research Funding ◽  
B Cell Lymphoma ◽  
Time Interval ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Single Center Experience ◽  
Car T Cell Therapy ◽  
Car T

The CD19 CAR T-cell products Axi-cel and Tisa-cel induce complete responses (CR) in 40-58% of patients (pts) with relapsed/refractory (r/r) Diffuse Large B-Cell Lymphoma (DLBCL). However, treatment can be associated with significant toxicity, with Cytokine release syndrome (CRS) and Immune effector cell-associated neurotoxicity syndrome (ICANS) as the most prominent and specific adverse events of CAR T-cell therapy. Toxicity profiles differ between both commercially available products, mainly due to their divergent co-stimulatory domain (4-1BB in Tisa-cel vs. CD28 in Axi-cel). Here, we report our single-center experience of DLBCL patients treated with Axi-cel or Tisa-cel at the LMU Munich University Hospital between January 2019 and June 2020. Toxicities, response rates and survival of DLBCL patients were retrospectively assessed. As of June 2020, 48 patients were enrolled for CD19-CAR T-cell therapies at our centre, and 37 DLBCL patients (pts) were apheresed. Median time interval between apheresis and CAR T-cell treatment was 39 days. So far, 31 DLBCL pts were transfused (Axi-cel: 18, Tisa-cel: 13). Median age of transfused pts was 60 years (range 19-74, Axi-cel: 60 years, Tisa-cel: 60 years). ECOG was 0-1 in 19 and 2-3 in 12 pts at time of CAR T-cell transfusion (Axi-cel: 0-1 in 13 and 2-3 in 5 pts, Tisa-cel: 0-1 in 6 and 2-3 in 7 pts). 13 pts had undergone prior stem cell transplant (9 autologous, 3 allogeneic, Axi-cel: 4 auto, 2 allo; Tisa-cel: 5 auto, 1 allo). Median number of prior DLBCL therapy lines was four (range 2-9, Axi-cel: 4, Tisa-cel: 4). Only 9/31 pts (29%) met the inclusion criteria of the pivotal clinical trials (due to e.g. infection, CNS disease, thrombocytopenia) at time of enrolment into our CAR T-cell treatment program. 23 pts (74%) received bridging chemotherapy (Axi-cel: 13/18 pts [72%]; Tisa-cel: 10/13 [77%]). Further details on radiographic response and the incidence of toxicities for all treated pts are summarized in the accompanying table. Response assessment after three months using PET/CT was available for 28 pts. Objective response rate (ORR) was 46%, with CR in eight (28%) and partial remission (PR) in five pts (18%). CRS occurred in 29/31 pts (84% CRS °1-2, 10% °3). Tocilizumab was applied in all CRS pts, with a median of four total infusions (range 1-4). 16 pts (52%) developed ICANS (33% °1-2, 16% °3-4, and 3% °5), which was managed with steroids in 9/16 pts. With a median follow-up of seven months, median progression-free survival (PFS) was 2.4 months for all pts. PFS was significantly longer for pts with normal vs. elevated LDH at time of apheresis (not reached vs. 1.5 mo, p=0.031). PFS of patients with two prior lines of therapy (n=7) was comparable with pts with three (n=5) or more (n=15) lines (2 lines: 3.1 mo, ≥3 lines: 1.9 mo, p=0.520). The time interval of ≤ 12 months (n=8 pts) from initial diagnosis of DLBCL to CAR T-cell transfusion was not prognostic and did not identify patients with worse PFS (≤12 mo: 1.7 months, &gt;12 mo: 2.8 mo, p=0.569). In summary, in our cohort of heavily pretreated patients with a median of four prior DLBCL therapy lines, we observed an ORR of 46% (28% CR) at 3 months after CAR T-cell therapy, with no significant differences between patients treated with Axi-cel and Tisa-cel. In line with results of the pivotal clinical trials, treatment with Axi-cel was associated with a moderately higher incidence of ICANS. Overall, CAR T-cell toxicities were well manageable. Normal LDH levels at time of apheresis identified patients with high probability of sustained remission. In contrast, the number of prior therapy lines or the time interval from initial diagnosis of DLBCL to CAR T-cell transfusion had no impact on PFS. These hypothesis-generating findings might be helpful for future clinical decision-making, but need to be confirmed in a larger cohort. Therefore, we have set up a comprehensive patient monitoring program to identify predictive clinical and immunological markers of response and survival in CAR T-cell treated DLBCL patients. We will present updated results with longer follow-up at the annual meeting. Figure Disclosures Buecklein: Celgene: Research Funding; Pfizer: Consultancy; Gilead: Consultancy, Research Funding; Novartis: Research Funding; Amgen: Consultancy. Blumenberg:Novartis: Research Funding; Celgene: Research Funding; Gilead: Consultancy, Research Funding. Subklewe:Seattle Genetics: Research Funding; Morphosys: Research Funding; Celgene: Consultancy, Honoraria; Novartis: Consultancy, Research Funding; Janssen: Consultancy; Pfizer: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria, Research Funding; Roche AG: Consultancy, Research Funding; AMGEN: Consultancy, Honoraria, Research Funding.

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