Refractory non-Hodgkin Lymphoma Research Articles

Circulating Tumor DNA Correlation with Lymphoma Response and Survival Outcomes at Multiple Time Points of Anti - CD19 CAR T Cell Therapy

Background Chimeric antigen receptor T (CAR T) cells targeting CD19 have clinical activity against relapsed or refractory (r/r) non-Hodgkin lymphoma (NHL), with high response rates. However, approximately a third of patients fail to respond to CAR T cells and more than half will present disease progression within one year. Circulating tumor DNA (ctDNA) is emerging as a powerful tool for prediction of response in hematologic malignancies. Here, we present the results of ctDNA analysis of 28 patients participating in a phase I clinical trial of point of care manufactured antiCD19 CAR T cells with TNFRSF19 transmembrane domain using CliniMACS Prodigy device (Caimi PF, et al. Blood 2021; 138(S1):3833) (NCT03434769). Methods Twenty-eight relapsed or refractory NHL patients treated with CAR T cells were included in the ctDNA analysis. Blood samples were collected at baseline (prior to lymphodepletion), on the day of infusion (T = 0) and 30 days after CAR T cell infusion and profiled using the CAPP-Seq strategy (Rossi, 2017). A targeted resequencing panel optimized to include the coding exons and splice sites of 154 genes (370 Kb) recurrently mutated in B cell NHL were used on cfDNA from plasma and on paired germline DNA isolated from paired peripheral blood mononuclear cells. Sequencing was performed using the Nextseq 550 platform (Illumina) to obtain a depth of coverage >2000x in >80% of the target region in all samples. A stringent and completely automated bioinformatic pipeline was applied to call non-synonymous somatic mutations, using the somatic function of VarScan2. Disease response was measured on day 30 and 90 with PET/CT scan. Progression free survival (PFS) and overall survival (OS) were measured from the time of CAR T cell infusion and estimated using Kaplan-Meier analysis. Statistical analyses were done using R and its packages. Comparisons between groups were done using Fisher exact test between categorical variables, optimal ctDNA cutpoints for categorical endpoints were done using the cutpointr R package, and using the maximally selected rank statistics for time to event endpoints. Results 75 plasma samples were available for analysis (T-6, n = 26; T0, n = 22; T30, n = 27). The median ctDNA load reported as haploid genome equivalents per ml (hGE/mL) was 75.81 at T-6 (range: 0-8373). There was a statistically significant decrease in ctDNA load on T0 (0,33 hGE/mL [range: 0-48126], p = 0.02) and T+30 (0,38 hGE/ml [range: 0-2855], p < 0.001)(Figure 1). Six patients (23%) had undetectable ctDNA on T-6, despite having measurable disease. The optimal cutoff value for T-6 ctDNA was determined at 250 hGE/mL, patients with lower values (20/26) had higher rates of complete response (CR) (95% vs. 33%, p < 0.01) as well as longer median PFS (26 vs. 2 months, p < 0.001) and OS (NR vs. 20 months, p <0.01). We did not find an association between higher T-6 ctDNA levels and CRS or ICANS. Genes recurrently affected by non-synonymous somatic variants in 26 patients at T-6 were BCL2 and KMT2D (27%), IGLL5 (23%), BCL6 and CARD11 (19%), MYC and TP53 (15%). Lymphodepletive chemotherapy resulted in a decrease in ctDNA in 17/20 patients with paired samples, 13 patients decreased ≥1 log and 8 by ≥ 2 log. Sixteen patients had undetectable ctDNA levels at T0, which includes 9 patients with previous measurable ctDNA. Patients with ctDNA under 10 hGE/ml had higher CR rates (88% vs. 33%, p = 0.03) as well as longer median PFS (26 vs. 1 month, p = 0.03) and OS (NR vs. 13 months, p = 0.005). On day T30, 21/26 patients with paired preCAR T samples had decreased ctDNA by >1 log, 19 (70%) had undetectable levels. Among patients with undetectable ctDNA on day 30, best response was CR for 18 (94%), 4 of whom had PR on PET/CT on day 30 and went on to convert to CR. Patients with undetectable ctDNA had longer median PFS (37 vs. 2 months, p = 0.002) (Figure 2) and OS (NR vs. 13 months, p < 0.001). Conclusions Detection of ctDNA in r/r NHL patients treated with CAR T cells has predictive value at different timepoints. Lower ctDNA burden prior to lymphodepletion is associated with improved outcomes, likely a reflection of lower disease burden. In addition, ctDNA concentration decreases both after lymphodepletive chemotherapy and after CAR T cells correlate with disease response, PFS and OS. Mutational profiling of ctDNA can provide information regarding recurrent mutations in cases with and without disease response to CAR T cells. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

High Safety and Efficacy of CRISPR-Based Non-Viral PD-1 Locus Specific Integrated Anti-CD19 CAR-T Cells (BRL-201) in Treating Relapsed or Refractory Non-Hodgkin's Lymphoma: First-in-Human Phase I Study

High Safety and Efficacy of CRISPR-Based Non-Viral PD-1 Locus Specific Integrated Anti-CD19 CAR-T Cells (BRL-201) in Treating Relapsed or Refractory Non-Hodgkin's Lymphoma: First-in-Human Phase I Study

Risk of Cytokine Release Syndrome with Glofitamab Is Predicted By an Updated Model with a Potential Clinical Application

Background: Cytokine release syndrome (CRS) is a potentially life-threatening toxicity caused by immune activation. CRS can be triggered non-specifically by T-cell engaging therapies. Komanduri et al. (ASH 2021) outlined a model based on eight baseline factors (CRS-risk score; CRS-RS) which allowed accurate classification of risk for Grade ≥2 CRS upon treatment with glofitamab. Glofitamab is a CD20xCD3 T-cell-engaging bispecific monoclonal antibody with a novel 2:1 (CD20:CD3) configuration that has shown promising efficacy with a manageable safety profile in NP30179 (NCT03075696), an ongoing Phase I/II dose-finding study of glofitamab in pts with relapsed or refractory (R/R) non-Hodgkin lymphoma (NHL; Dickinson et al. ASCO 2022). While CRS is observed with glofitamab, cases typically occur with Grade 1/2 severity (per ASTCT grading; Lee et al. Biol Blood Marrow Transplant 2019) mostly in the first cycle (C). Here, we introduce a streamlined model based on five baseline factors (CRS-RS.5p) derived from the original CRS-RS, an ongoing non-interventional study (GO43921) to assess the performance of CRS-RS.5p, and the potential application of the risk score in a clinical setting. Methods: In both models, using a weighted sum of baseline clinical, laboratory and imaging parameters, pts are assigned a risk score as a continuous measure for developing CRS after the first dose of glofitamab. Using a defined cut-off, pts are classified as low or high risk of CRS. The original CRS-RS model parameters were: age >64 years at study entry, lactate dehydrogenase pre-anti-CD20 treatment >280 U/L, white blood cell count pre-anti-CD20 treatment >4.5x109 cells/L, Ann Arbor Stage III/IV at study entry, sum of the product of the perpendicular diameters at study entry ≥3000mm2, cardiac comorbidity, bone marrow infiltration, and atypical or leukemic cells in peripheral blood at study entry. The simplified CRS-RS.5p concentrates on the first five parameters utilizing the same weighting scheme as in CRS-RS. The primary objective of the GO43921 study is to determine if a five-baseline-parameter model can predict Grade ≥2 CRS events after the first dose of glofitamab. Seven studies were identified in which pts with aggressive NHL (first line and R/R, excluding mantle cell lymphoma) were treated with glofitamab step-up dosing as either monotherapy or part of combination therapy. In most studies, pts are pretreated with 1000mg obinutuzumab, with intravenous glofitamab being administered on Days (D) 1 (2.5mg) and 8 (10mg) of C1, then at the target dose (30mg) from C2D1 onwards. Several combination studies started glofitamab step-up dosing after multiple cycles of R-CHOP (glofitamab D8 [2.5mg], D15 [10mg], target dose D8 [30mg] in the following cycle). Prospective data has been collected since December 2021, and retrospective data from included studies were analyzed to increase the sample of Grade ≥2 CRS events. Here, CRS-RS.5p is compared with CRS-RS for the NP30179 dataset, and CRS-RS.5p performance in the ongoing GO43921 study is analyzed. Results: In NP30179, data acquired since the introduction of CRS-RS (n=44) showed that CRS-RS and CRS-RS.5p identified as high risk the same pts who experienced Grade ≥2 events (Figure A; four Grade 2, one Grade 3). In the whole NP30179 validation cohort, both CRS-RS and CRS-RS.5p achieved negative predictive values of 0.97 (n=148, Standard error=0.02). For GO43921, at the clinical cut-off date (June 6, 2022), the CRS-RS.5p model had predicted all 11 of the Grade ≥2 CRS events in the second-line or later setting for pts with aggressive NHL (n=123, with data collected retrospectively for 82 pts; Figure B). The association of the CRS-RS.5p score with the ASTCT CRS Grade after the first dose of glofitamab was similar across all available data sets from NP30179 and GO43921 (logistic regression; p<0.001 for NP30179, p=0.004 for GO43921). No influence of steroid premedication class on CRS-RS performance was observed. A low-risk group (CRS-RS.5p <4.0) comprised 48% of pts in NP30179 and 46% in GO43921. Conclusions: Data from the CRS-RS.5p model showed identical performance with the previous 8-parameter CRS-RS model in predicting which pts with aggressive NHL are most at risk of Grade ≥2 CRS after the first dose of glofitamab. With reduced complexity, the CRS-RS.5p has a potential application as a practical, clinical decision tool to guide hospitalization for pts at high risk of Grade ≥2 CRS. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Evaluation of Epcoritamab and Rituximab Combination in Preclinical Models of B-Cell Non-Hodgkin's Lymphoma (NHL)

Background: Epcoritamab (Epco) is a CD3 bispecific antibody that induces selective, potent T-cell-mediated killing of CD20-positive malignant B-cells. In the phase 1/2 monotherapy study, subcutaneous administered Epco showed a favorable safety profile and promising efficacy, including complete responses in heavily pretreated patients with relapsed / refractory non-Hodgkin's lymphoma (Hutchings et al, Lancet 2021; Thieblemont et al, EHA 2022, LB2364; EPCORE NHL-1). Ongoing clinical studies combining Epco with standard-of-care therapies including combinations with Rituximab show promising preliminary anti-tumor activity in diffuse large B-cell lymphoma and follicular lymphoma (Falchi et al, ASCO 2022 abstracts 7523 and 7524; EPCORE NHL-2 arm 1 and 2; NCT04663347). Here we evaluated the competition for CD20 binding and functional interactions between these agents and modeled its impact on Epco, T-cell, and tumor cell trimer formation that drives Epco clinical activity. Aims: Investigate the preclinical binding and functional interaction between Epco and Rituximab to establish the potential for the combination of these agents in the treatment of B-cell NHL. Methods: Competition between Epco and Rituximab for binding to CD20 cells was assessed by Flow Cytometry after incubating the single labeled agent in the presence of increasing concentrations of the competitor and vice-versa (across 0.1 - 300 ug/ml evaluated for each agent), on a range of CD20 expressing lymphoma cell lines. Epco-induced-T cell activation and redirected T cell cytotoxicity was determined by co-culturing T cells with lymphoma cells with varying expression of CD20. Rituximab antibody-dependent cellular cytotoxicity (ADCC) activity was assessed by incubating fresh peripheral blood mononuclear cells with lymphoma cells in the presence of a CD3 control Epco antibody (DuoBody-ctrlxCD20). Data from binding and cytotoxicity was used to quantify the degree of binding curve shifts at different Rituximab:Epco concentrations as well as the impact on predicted trimer formation and cytotoxicity, based on modeling. Results: In binding assays, the addition of Rituximab resulted in a dose-dependent reduction of Epco binding to CD20 expressing lymphoma cell lines, with a significant reduction of Epco binding observed at clinically relevant Epco concentrations in cells with high CD20 expression levels (Figure 1). Similar binding interference interactions were observed for binding of Epco to cell lines with low and intermediate CD20 expression levels. Binding of Rituximab to cell lines expressing high CD20 levels was not significantly reduced by clinically relevant concentrations of Epco. In Epco functional studies, the addition of increasing concentrations of Rituximab did not affect Epco cytotoxic activity at clinically relevant range of Rituximab doses tested (Figure 2). Similarly, no effect of Rituximab on Epco-mediated T cell activation was observed at clinically relevant concentrations of Rituximab and Epco. ADCC activity at clinically relevant concentrations of Rituximab (10-250 ug/ml) was not impacted by incubation with the CD3 control Epco antibody (DuoBody-ctrlxCD20), even at concentrations exceeding the Epco clinical concentrations. Modeling and simulation of in vitro data showed that at clinically relevant concentration of Epco, the presence of clinically relevant concentration of Rituximab does not meaningfully impact Epco trimer formation, and the predicted trimer formation remains above EC90 relative to that needed for 50% cell kill. Conclusions: Our studies showed that while Rituximab exerts significant interference on Epco binding to CD20-expressing cells, tumor-cell cytotoxicity by Epco is minimally affected by clinically relevant concentrations of Rituximab. This conclusion is supported by preclinical modeling and simulations showing that Epco activity driven by trimer formation is not meaningfully impacted by clinical concentrations of Rituximab. Furthermore, we found a limited effect of Epco on Rituximab binding to CD20 and no impact on ADCC activity by Rituximab, thereby supporting potential synergy in the combination between these agents. Results from this study confirm the ability to combine Epco with CD20 antibodies, specifically with Rituximab, and the potential for synergistic activity of this combination. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

The Duration of Coronavirus Disease 2019 (COVID-19) Clearance in Patients with Hematological Malignancies Can be Stratified By the Number of Chemotherapy Treatment and Severity of COVID-19

Patients with hematological malignancies (HM) have an increased risk of severe coronavirus disease 2019 (COVID-19) and subsequent mortality. Moreover, patients with HM have prolonged viral shedding and long-term infectivity. However, the infectious period varies depending on the degree of immunosuppression caused by the disease itself and intensity of chemotherapy. The infectivity of the virus can be evaluated by the cycle threshold (Ct) value obtained from reverse transcription quantitative polymerase chain reaction (RT-qPCR), which is inversely proportional to the viral load. Viral cultures are less likely to be positive when Ct values exceed 30-35, which suggests that patients with Ct values above the threshold may be less infectious. Our study evaluated the trajectories of serial Ct values of patients with HM indicated for the test-based strategy and examined the relationship between patients' characteristics and the duration of viral shedding. Seventeen patients with HM that were treated for COVID-19 at our hospital from January to April 2022 were included. We excluded three patients to whom the test-based strategy was not applied. In our test-based de-isolation strategy, RT-qPCR testing using nasopharyngeal swabs was performed twice a week in patients. We de-isolated patients when their Ct values were ≥ 30 after their symptoms resolved. The patients were categorized according to the duration needed to achieve a Ct value of >30: cluster 1 (< 20 days), cluster 2 (21-40 days), and cluster 3 (>40 days). The similarities in patients' characteristics in each cluster and the differences between the clusters were examined. A total of 14 patients were analyzed, and the median age of the patients was 71 years old (range: 28-82 years old). Eight patients had non-Hodgkin lymphoma (NHL), four had acute leukemia (AL), and two had multiple myeloma (MM). Of the patients with NHL, four were treatment-naive or on first-line chemotherapy, while the other four had relapsed or refractory (r/r) NHL. Among r/r NHL patients, two received salvage chemotherapy, and the remaining two had opted for best supportive care. Three of the four patients with AL achieved complete remission (CR) after allogeneic hematopoietic stem cell transplantation (HSCT), while the other had a relapse after receiving salvage chemotherapy. One of the patients with MM achieved CR with maintenance therapy after autologous HSCT, while the other received sixth-line chemotherapy for refractory disease. The severity of COVID-19, which was defined by the National Institutes of Health guideline, was asymptomatic in two patients, mild in eight, moderate in one, severe in three, and critical in one. A total of 117 PCR tests were performed, and Ct values were available for 114 of them. The median time for Ct value to reach >30 was 23 days (range: 14-84 days). Five patients were categorized into cluster 1, six into cluster 2, and three into cluster 3. In cluster 1, patients were untreated or received less than three courses of chemotherapy within the past year and had mild or moderate COVID-19 infection. Patients in cluster 2 received three or more courses of chemotherapy or HSCT in the past year and had severe COVID-19 infection. Cluster 3 consisted of three patients who were treated with high-dose immunosuppressant for active graft-versus-host disease, had a history of long-term chemotherapy, and were critically ill from COVID-19 infection. The duration of viral shedding in patients with HM was generally prolonged and stratified by treatment history and severity of COVID-19. The number of chemotherapy treatment and severity of COVID-19 may serve as useful indicators to determine whether a test-based de-isolation strategy should be followed in patients with HM. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

High Grade B Cell NHL Outcomes: Real World Experience from the UK

Incidence of non-Hodgkin lymphoma (NHL) is increasing; it is already the sixth most common malignancy in UK (Cancer Research UK NHL incidence statistics 2022). It can present in aggressive or indolent form. Whilst for those with chemo-sensitive disease prognosis is good, with 5 year overall survival (OS) >50%, those with relapsing/refractory (R/R) forms have consistently poor outlook. Historically only 30-40% of these tolerate/respond to salvage therapy with <30% of those who respond able to proceed to consolidation with autologous stem cell transplant (ASCT). Despite this ~50% will relapse (Crump et al, Blood 2017 doi: 10.1182/blood-2017-03-769620). Recent treatment advances seek to address this area of unmet need. CAR-T cell therapy is presented as a highly effective solution for this cohort of patients. The pivotal studies leading to licensing and widespread adoption of these therapies drew comparison from SCHOLAR-1 which pooled data from 2 phase 3 clinical trials and 2 observational cohorts enabling data on 636 patients with refractory NHL to be analysed. There are challenges with this dataset and notably it does not include UK patients. We analysed patient level data for a UK NHL cohort and compare these to other, more historical data sets. 165 patients were identified. Diagnoses included primary DLBCL, DLBCL-transformed follicular lymphoma and PMBCL. Demographics: 92 male, 73 female; median age 64 (24-86yrs). Stage at diagnosis: I 10.3%, II 13.3%, III 21.2%, IV 54.5%, unknown <1%. IPI: 0- 2.4%, 1 - 13.3%, 2 - 27.3%, 3 - 26.7%, 4 - 18.8%, 5 - 3.6%, unknown 7.8%. C-MYC present in 20.7% of those where evaluated (24/116); of those 41.7% (10) double hit, 12.5% (3) triple hit. Cell of origin available for 54.5% (ACB 36.7%, GCB 63.3%). >90% considered suitable for intensive therapy; PS: 0 - 43%, 1 - 33.9%, 2 - 12.7%, 3 - 9.1%, 4 - <1%, unknown 4.2%. Nearly 2 thirds required >1 line treatment: 1 - 37%, 2 - 33.3%, 3 - 20.6%, 4 - 6.1%, 5 or greater - 3%. First line: 57.6% (95/165) 6-8 cycles R-CHOP (22% also received CNS prophylaxis - HD or intrathecal methotrexate, 16.8% additional radiotherapy (IFRT)); 10.3% abbreviated R-CHOP +/- IFRT; 9.7% dose attenuated R-CHOP, 16.4% R-CODOX-M/R-IVAC, 4.8% R-mini-CHOP, 1.8% non-intensive regimes and <1% IFRT alone. Best response was CR 52.7%, PR 11.5%, SD 13.3%, PD 11.5%, not available 10.9%. 63% (104/165) required second line treatment; time to treatment ranged from <6 months (27.9%), 6-12 months (32.7%), >12 months (37.5%), unknown in 2 cases. PS at first relapse: PS 0 - 36.6%, 1 - 45.5%, 2 - 7.1%, 3 - 7.1%, 4 - <1%. 35.6% with refractory disease had improvement in PS with treatment despite suboptimal response. 7.1% were considered too frail for further treatment. Second line therapy was primarily platinum based +/- IFRT +/- HD Mtx 71.2%; other intensive regimes included R-IVE, R-DHAP, R-ESHAP, R-CHOP and MATRIX (11.5%), less intensive regimes included R-lenalidomide, R-BP, R-miniCHOP, R-CVP, IFRT and R-CEPP (17.3%). Best response was CR 24.0%, PR 18.3%, SD 7.7%, PD 44.2%, not evaluated 5.8%. 31.7% proceeded to ASCT, 6 required >1 line of salvage therapy prior to ASCT. Exclusion basis: refractory disease 26.3%, declining PS and suboptimal response 7.5%, age only (>72years) 8.75%, frailty (PS > 2 - treatment induced/ comorbidities) 16.25%, age and frailty 13.75%, failed harvest 6.25%, patient choice 6.3%. 22 (66.6%) achieved CR after ASCT. 45 had suboptimal response to ≥2 lines intensive therapy but maintained fitness and would have been eligible for CAR-T. 47% (49/104) of those requiring salvage therapy proceeded to third line, 38.8% had refractory disease requiring treatment within 12months of first salvage treatment. 14.3% (7/49) had received ASCT. 57.1% (28/49) received intensive therapy, 18.4% (9/49) proceeded to ASCT. 42.9% were treated non-intensively. This UK dataset, analysing real world experience, highlights the challenge of high grade NHL. Whilst OS is: 2 year 63%, 5 year 29.1% with an additional 4.2% and 27.9% alive but <2 and <5 years from diagnosis respectively, for those with R/R disease OS is significantly reduced: 2 year 35.8%, 5 year 21.8%. CR rate after first line is 53.9%. However, 63% of patients required second line treatment; 4.8% relapsed >12months, 33.3% refractory; objective response rate (ORR) 42.3% (CR 24.0%), 35.8% alive at 2 years, 21.8% at 5 years. This is comparable to results from the referenced SCHOLAR-1 study supporting it as a reference point for new therapies.

PET-CT Findings may Guide Patient Selection for Accelerated Radiotherapy in Salvage Chemotherapy Refractory NHL

<h3>Purpose/Objective(s)</h3> The management of patients with aggressive Non-Hodgkin Lymphoma (NHL) who are refractory to salvage chemotherapy is unclear as these patients respond poorly to an autologous stem cell transplant (ASCT) or chimeric antigen receptor (CAR) T-cell therapy. Accelerated radiotherapy (twice daily fractions) is associated with high response rates enabling patients to proceed with aggressive consolidative management including an ASCT or CAR T-cell therapy. Patient selection for this aggressive management remains problematic. <h3>Materials/Methods</h3> We retrospectively reviewed patients identified to have salvage chemotherapy refractory NHL who underwent accelerated radiotherapy (twice daily fractions) guided by a pre-radiotherapy PET-CT. Clinicopathologic factors associated with a max SUV ≥10 within the target volume were assessed by chi-squared analysis. A cox regression analysis identified factors that were independently associated with survival outcomes. <h3>Results</h3> From 2004-2020, 41 patients met inclusion criteria having progressed on salvage chemotherapy and subsequently underwent salvage accelerated radiotherapy to a median dose of 36 Gy in 20 twice daily fractions. Patients who were medically fit with treatment response underwent an ASCT (n=19) or CAR T-cell therapy (n=4) within 100 days (median: 19 days) of salvage radiotherapy completion. The two-year progression-free survival (PFS) and overall survival (OS) rates following salvage radiotherapy were 49.8% and 46.0% respectively. On the PET-CT immediately prior to radiotherapy, the max SUV within the target volume was ≥10 in 23 patients. A max SUV ≥10 was not associated with any clinicopathologic factor, however bulky disease (≥7.5 cm) prior to radiotherapy (30.4% vs 11.1%, <i>p</i>=0.058) had a non-statistically significant trend of association. Patients with a max SUV ≥10 compared to those with a max SUV <10 had a worse CR rate within the salvage radiotherapy field (26.1% vs 66.7%, <i>p</i>=0.009). A max SUV ≥10 was independently associated with worse PFS (HR: 5.92, 95% CI: 2.15-16.29, <i>p</i><0.001) and OS (HR: 5.23, 95% CI: 1.68-16.30, <i>p</i>=0.004) in the cox regression analysis. <h3>Conclusion</h3> Patients with salvage chemotherapy refractory NHL have a poor prognosis, yet they can still achieve a high response rate and favorable survival outcomes with radiotherapy accelerated (twice daily fractions) enabling them to successfully undergo an ASCT or CAR T-cell therapy. This data suggests that PET-CT findings (max SUV <10 within the target volume) may further delineate patients who maximally benefit from such aggressive management.

ABCL-012 Salvage Chemotherapy in Refractory/Relapsed Non-Hodgkin Lymphoma Treatment From the Perspective of Developing Country Management

One hundred relapsed or refractory NHL patients were randomly divided into 2 groups receiving either GDP or DHAP for 4 to 6 cycles. The primary endpoints were overall survival and progression-free survival. The secondary endpoints were response to treatment, toxicity profile of each regimen, and quality of life. The overall response rate was 70% in the GDP group and 64% in the DHAP group with no statistically significant difference between them (P = 0.5). There was no significant difference between the groups regarding toxicity profile, except that febrile neutropenia episodes were much less frequent in the GDP group (P = 0.04). Quality of life was significantly better in the GDP group than in the DHAP group (P = 0.04). GDP is as effective as DHAP for relapsed or refractory lymphoma with less toxicity and better quality of life.

Clinical significance of clonal hematopoiesis in the setting of autologous stem cell transplantation for lymphoma.

Autologous stem cell transplantation (ASCT) remains a key therapeutic strategy for treating patients with relapsed or refractory non-Hodgkin and Hodgkin lymphoma. Clonal hematopoiesis (CH) has been proposed as a major contributor not only to the development of therapy-related myeloid neoplasms but also to inferior overall survival (OS) in patients who had undergone ASCT. Herein, we aimed to investigate the prognostic implications of CH after ASCT in a cohort of 420 lymphoma patients using ultra-deep, highly sensitive error-correction sequencing. CH was identified in the stem cell product samples of 181 patients (43.1%) and was most common in those with T-cell lymphoma (72.2%). The presence of CH was associated with a longer time to neutrophil and platelet recovery. Moreover, patients with evidence of CH had inferior 5-year OS from the time of first relapse (39.4% vs. 45.8%, p= .043) and from the time of ASCT (51.8% vs. 59.3%, p= .018). The adverse prognostic impact of CH was not due to therapy-related myeloid neoplasms, the incidence of which was low in our cohort (10-year cumulative incidence of 3.3% vs. 3.0% in those with and without CH, p= .445). In terms of specific-gene mutations, adverse OS was mostly associated with PPM1D mutations (hazard ratio (HR) 1.74, 95% confidence interval (CI) 1.13-2.67, p= .011). In summary, we found that CH is associated with an increased risk of non-lymphoma-related death after ASCT, which suggests that lymphoma survivors with CH may need intensified surveillance strategies to prevent and treat late complications.

649TiP A phase I/Ib study evaluating the safety, pharmacokinetics, and preliminary efficacy of LP-118 in subjects with relapsed or refractory haematological malignancies

Newave Pharmaceutical is developing an investigational compound LP-118, a next generation selective B-cell lymphoma 2 (BCL-2) inhibitor with tuned B-cell lymphoma extra-large (BCL-XL) activity to improve antitumor efficacy and reduce risk for thrombocytopenia. Clinical development of LP-118 includes targeting of relapsed or refractory hematological malignancies. BCL-2 and BCL-XL are important anti-apoptotic proteins in the intrinsic apoptotic pathway and are involved in the pathophysiology of many hematologic malignancies, including Non-Hodgkin’s Lymphoma (NHL), Richter transformation (RT), multiple myeloma (MM), acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), etc. (Valentin, Grabow et al. 2018). Considering that concern about acquired resistance to venetoclax (the first FDA-approved BCL-2 selective inhibitor indicated for the treatment of AML has been an obstacle in the treatment of AML patients, a promising strategy for overcoming BCL-2 acquired resistance mutation is urgently needed (Tahir, Smith et al. 2017) The inhibitory effect of LP-118 on the targets BCL-2 and BCL-XL is carefully adjusted to be between that of navitoclax and venetoclax with the aim of minimizing BCL-XL on-target platelet toxicity while retaining and improving antitumor efficacy. Newave Pharmaceutical, Inc. intends to conduct the first in human study of LP-118 in hematologic malignancies with a primary focus on relapsed or refractory NHL, RT, MM, T-PLL, AML, ALL, MDS, MDS/MPN, and MF. Phase Ia dose-escalation will begin with Group 1 until DLT is observed and MTD is established, or until an RP2D or OBD is established. Once the MTD, RP2D, or OBD is established for Group 1, the phase Ia dose escalation can proceed for Group 2 (hight risk). Group 1 relapsed/refractory: low risk tumor lysis CLL/SLL; MF, MDS/MPN, CMML-2, MPN-BP, MDS, AML; NHL, RT, MM, T-PLL; ALL A classic “3+3” design will be used in this study. The safe starting dose of LP-118 calculated from non-clinical toxicity studies is 50 mg/d. To mitigate risk of TLS, an accelerated step-up dosing schedule of LP-118 will be used to reach the target dose for each cohort. NCT04771572. Newave Pharmaceutical Inc.

Response to Brentuximab Vedotin by CD30 Expression in Non-Hodgkin Lymphoma.

BackgroundThe safety and efficacy of brentuximab vedotin (BV), an antibody-drug conjugate directed to the CD30 antigen, has been assessed in several trials in patients with peripheral T-cell lymphoma (PTCL), cutaneous T-cell lymphoma (CTCL), or B-cell non-Hodgkin lymphoma (NHL). The objective of this research was to examine the relationship between CD30 expression level and clinical response to BV.Patients and MethodsWe analyzed response in patients treated with BV monotherapy in 5 prospective clinical studies in relapsed or refractory PTCL, CTCL, or B-cell NHL. CD30 expression was assessed by immunohistochemistry (IHC) using the Ber H2 antibody for 275 patients.ResultsAcross all 5 studies, 140 (50.9%) patients had tumors with CD30 expression <10%, including 60 (21.8%) with undetectable CD30 by IHC. No significant differences were observed for any study in overall response rates between patients with CD30 expression ≥10% or <10%. Median duration of response was also similar in the CD30 ≥10% and <10% groups for all studies.ConclusionsIn this analysis of studies across a range of CD30-expressing lymphomas, CD30 expression alone, as measured by standard IHC, does not predict clinical benefit from BV, making the determination of a threshold level of expression uncertain.

Abstract CT127: Trial in progress: A phase II, open-label, multicenter study of capivasertib, a potent, oral pan-AKT inhibitor in patients with relapsed or refractory B-cell non-hodgkin lymphoma (CAPITAL)

Abstract Background: The PI3K/AKT/mTOR pathway is an established therapeutic target in indolent B-cell non-Hodgkin lymphoma (B-NHL). Several PI3K inhibitors are approved to treat relapsed/refractory (R/R) follicular lymphoma (FL) and, more recently, marginal zone lymphoma (MZL). Nonetheless, potential class-specific and PI3K-isoform-related toxicities may limit their clinical utility. Capivasertib is an oral, potent, selective inhibitor of the 3 AKT isoforms that demonstrated a manageable safety profile (n&amp;gt;1500) and survival benefit in combination with other agents in patients (pts) with solid tumors. Unlike PI3K inhibitors, colitis or pneumonitis have not been a concern with monotherapy. Preclinically, capivasertib was active both in vitro in a large panel of B-NHL cell lines and in vivo in PTEN-null GCB-DLBCL PDX models, where it downregulated the oncogenic factor MYC. In the JVM2 mantle cell lymphoma (MCL) cell line, capivasertib showed superior activity vs PI3Ka/d (AZD8835) and PI3Kb/d (AZD8186) inhibitors. Of note, AKT activation following dysregulation of PTEN has been frequently described in FL (where &amp;gt;85% of tFL or FL/DLBCL exhibited a GCB phenotype). Therefore, capivasertib may represent an effective treatment option for pts with R/R B-NHL. Trial Design: This modular phase II study will enroll pts in 3 cohorts according to B-NHL type. Core inclusion criteria include: age ≥18 years and ECOG PS ≤2. Module-specific criteria include: cohort 1A: R/R FL after ≥2 prior systemic lines (max 5), including an anti-CD20 monoclonal antibody (mAb) and an alkylating agent; cohort 1B: R/R MZL of splenic, nodal, and extranodal subtypes after ≥2 prior systemic lines (max 5) including ≥1 anti-CD20 mAb; cohort 1C: R/R MCL after ≥2 prior systemic lines (max 4), previously exposed to anti-CD20 mAb and a BTK inhibitor. Pts with FL grade 3B, transformed disease, blastoid or TP53 mutation MCL, active CNS disease, diabetes requiring insulin, or being &amp;lt;3 months post-CD19-directed CAR-T therapy will be excluded.Capivasertib will be administered orally at 480 mg BID with an intermittent schedule (4 days on/3 days off; 28-day cycles) until disease progression or unacceptable toxicity. The primary efficacy endpoint in AACR 2022_Capivasertib TiP Abstracteach cohort is objective response rate based on 2014 Lugano criteria per blinded independent central review. Secondary endpoints include duration of response, progression-free survival, overall survival, patient-reported outcomes, safety, and pharmacokinetics. An interim analysis of safety will occur when approximately 30 pts across all cohorts have been treated for 8 weeks. An interim analysis of efficacy will occur after 28 pts (cohorts 1A+1B) or 24 pts (cohort 1C) have been treated for 4 months. A total of 272 pts are planned across 28 sites in 7 countries globally (US, Europe, and Asia). Recruitment began in October 2021. Funding: AstraZeneca Clinical Trial Registration: NCT050080552 Citation Format: Michael Wang, Ho-Jin Shin, Alex F. Herrera, Moshe Levy, Wong Seog Kim, Tae Min Kim, Jin Seok Kim, Dok Hyun Yoon, Vincent Ribrag, Miguel Canales, John Radford, Dima El-Sharkawi, Brandy Hemmer, Richa Manwani, Veerendra Munugalavadla, Robert Chen, Andrew Mortlock, Alessandra Forcina, Franck Morschhauser. Trial in progress: A phase II, open-label, multicenter study of capivasertib, a potent, oral pan-AKT inhibitor in patients with relapsed or refractory B-cell non-hodgkin lymphoma (CAPITAL) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT127.

Abstract 2639: KB-0742 is active in preclinical MYC high models of TNBC, ovarian, and DLBCL cancers

Abstract MYC is an early-response gene downstream of many receptor complexes, and a component that promotes several pro-growth signal transduction pathways. As a result, MYC expression is highly regulated, but once dysregulated in cancer, MYC promotes tumorigenesis via activation of cell growth, proliferation, and angiogenesis. CDK9 is both an upstream and downstream cofactor of MYC. CDK9 promotes MYC expression through its recruitment to super enhancers at the MYC amplicon and acts as a cofactor to drive gene expression programs. Previously, we profiled pan-cancer sensitivity to KB-0742, a potent, selective, and orally bioavailable small-molecule inhibitor of CDK9, and identified MYC-amplified cancers as being especially sensitive to KB-0742. To better understand the connection between MYC and KB-0742 sensitivity, 11 different tumor types were evaluated preclinically using immortalized cell lines, patient-derived cell lines (PDCs), patient-derived organoids (PDOs), and patient-derived xenografts (PDXs). The 11 indications included head and neck, esophageal, gastric, liver, non-small cell lung cancer (NSCLC), pancreatic, ovarian, triple-negative breast cancer (TNBC), prostate, colon, and lymphoma. For 5 of the indications (head and neck, esophageal, gastric, liver, and colon), little activity was observed in cell lines and in vivo with weak correlations to MYC amplification. TNBC, ovarian cancer, and lymphoma showed good responses to KB-0742 treatment. For TNBC and ovarian, immortalized and patient-derived cell lines indicated lower IC50 values with increased MYC amplification or expression, but the results were not statistically significant. However, in vivo assessments using 15 PDX models showed good correlation of tumor growth inhibition (TGI) and MYC amplification/expression, with some tumor regressions observed in several ovarian models. Two PDO models of TNBC with different treatment histories were also treated with KB-0742 and compared to 4 standard-of-care (SOC) compounds. KB-0742 showed much greater activity in the models, with maximal inhibition rates of 100% and 89%. Cell-line screens of blood cancer-derived cell lines showed that lymphocyte-derived cell lines were the most sensitive to KB-0742 as compared to all other cancer types. We tested several PDX models for response to our compound. Treatment with KB-0742 resulted in TGIs of over 50% in several lymphoma models, including a TGI of 56% in 1 model of double-hit diffuse large B-cell lymphoma. These data support the continual development of KB-0742, which is currently being tested in a phase 1/2 clinical trial (NCT04718675). The dose-escalation phase is opened to relapsed or refractory solid tumors or non-Hodgkin lymphoma. Once a recommend phase 2 dose is determined, we plan to open dedicated expansion arms enrolling patients with MYC over-expression/amplification within the tumor types supported by these studies. Citation Format: Melinda A. Day, Douglas C. Saffran, Tressa Hood, Nikolaus Obholzer, Akanksha Pandey, Charles Y. Lin, Pavan Kumar, Jorge DiMartino. KB-0742 is active in preclinical MYC high models of TNBC, ovarian, and DLBCL cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2639.

CD20 and CD19 expression loss in relapsed or refractory b-cell non-Hodgkin lymphoma: A retrospective cohort.

e19537 Background: CD20-targeted therapies such as rituximab are widely used in the management of B-cell non-Hodgkin lymphoma (NHL). Re-treatment with anti-CD20 agents is common, however previous research has demonstrated loss of CD20 expression at time of relapse or refractory disease in a subset of patients. There is also amplified interest in alternative targets, specifically CD19, in the relapsed or refractory setting. Incidence of CD19 loss has been explored in post-CAR T cell therapy patients but not described elsewhere. We hypothesized that CD marker loss may be higher than previous reports due to expanded use of CD20- and CD19-targeted therapy. Methods: The present study is a retrospective cohort analysis of 229 patients with B-cell NHL from Harbor-UCLA Medical Center in Los Angeles, CA from 2006 to 2022. Charts were retrospectively reviewed for cases of B-cell NHL, and data was collected about demographics, diagnosis, treatment, and relapses. CD20 and CD19 expression analysis was performed by immunohistochemistry and / or flow cytometry at diagnosis and at each relapse whenever possible. The primary endpoint of the study was the rate of CD marker expression loss at time of relapse. Results: The cohort of 229 patients was composed of 54.1% diffuse large B-cell lymphoma (DLBCL), 14.4% follicular lymphoma (FL), 8.3% high-grade B-cell lymphoma (HGBCL), 7.0% marginal zone lymphoma (MZL), 4.8% mantle cell lymphoma (MCL), and 11.2% other. Overall, 28.8% (66/229) patients had relapsed or refractory disease. The rate of CD20 expression loss was 7.9% (5/63) across all relapses with two patients converting at first relapse (1 FL relapsing as HGBCL, 1 MZL), two patients at 2nd relapse (1 FL relapsing as DLBCL, 1 MZL relapsing as DLBCL), and one patient at 5th relapse (1 MZL). All five patients with CD20 phenotypic conversion received rituximab, and three patients received two or more rounds of anti-CD20 therapy. The median OS after CD20 expression loss was 4 months (95% CI 3.3 – 4.7 months). All patients (14/14) who had CD19 testing performed at relapse maintained CD19 positivity. Conclusions: This retrospective study demonstrates a rate of CD20 expression loss at relapse of 7.9%, which is less than previously reported rates ranging between 11-60%. CD20 expression loss seems to be associated with transformation to high-grade lymphoma, poor overall survival, and marginal zone histology. The conservation of CD19 expression across relapses supports the use of novel anti-CD19 targeted therapy in the relapsed or refractory setting. Whenever possible, repeat biopsy should be done at time of relapse prior to treatment with CD-targeted therapy. This study is of notable clinical relevance with expanded use of anti-CD20 agents and novel CD19-targeted therapies in the management of B-cell NHL.

Relma-cel (JWCAR029) in relapsed and refractory B-cell non-Hodgkin lymphoma: A two-year survival update of a phase I study.

e19555 Background: B-cell non-Hodgkin lymphoma (B-NHL) has a very poor prognosis. Relma-cel (JWCAR029) is a CD19-targeted chimeric antigen receptor T (CAR-T) cell suspension. In a phase I trial performed in November 2017 in Beijing Cancer Hospital, China, JWCAR029 was used to treat relapsed/refractory B-NHL (R/R B-NHL) in adult patients, showing a high response rate and persistent response. This report aimed to update 2-year survival data generated in the above trial. Methods: This was an open-label, dose-escalating phase I study (JWCAR029-001, NCT03344367) involving patients with R/R B-NHL. The patients received a 3-day treatment with the conditioning chemotherapy regimen, consisting of fludarabine (25 mg/m2/day) and cyclophosphamide (250 mg/m2/day). Then, they received a single dose of intravenous JWCAR029 (25×106, 50×106, 100×106, or 150×106 CAR T cells). Two-year PFS and OS after JWCAR029 treatment were evaluated. The data were updated till the cut-off date of January 18, 2021. Results: A total of 23 patients with R/R B-NHL were enrolled, of whom 22 completed single-dose JWCAR029 cell infusion. All patients completed the 2-year follow-up, with a median time of 24.2 (95%CI 24.0-24.3) months. Based on the efficacy analysis set comprising 20 patients, the best ORR and CRR were 85.00% and 70.00%, respectively. In subgroup analysis, 1-year ORR and CRR in patients administered 100×106 cells were both 3/5 (60%); they were both 5/8 (62.5%) in those administered 150×106 cells. The 1-year and 2-year PFS rates (11 patients censored) were both 55.0%. Median PFS was not reached (95%CI 3.0 months-NA). The 1-year and 2-year PFS rates in patients administered 100×106 cells were both 60.0%; these values were both 62.5% in individuals treated with 150×106 cells. The 1-year and 2-year OS rates (3 patients censored) were both 68.6%. Median OS was not reached (95%CI 10.4 months-NA). The 1-year and 2-year OS rates in patients administered 100×106 cells were both 60.0%; these values were both 75.0% in those treated with 150×106 cells. A total of 6 patients (30%) died. No grade 3 and above CRS or NT were found. Conclusions: JWCAR029 was approved in China in September 2021 after the RELIANCE study (NCT04089215) reported its excellent efficacy and tolerable toxicity in the treatment of relapsed/refractory B-cell lymphoma. This report indicated that R/R B-NHL cases could benefit from JWCAR029. R/R B-NHL cases administered JWCAR029 at 100×106 or 150×106 cells had a promising response rate, with durable PFS and sustained OS benefits after 12 months. The effectiveness and safety of JWCAR029 need to be confirmed in the real-world setting. Clinical trial information: NCT03344367.

CRC-403: A phase 1/2 study of bbT369, a dual targeting CAR T-cell drug product with a gene edit, in relapsed and/or refractory B-cell non-Hodgkin lymphoma (NHL).

TPS7580 Background: Although CD19 directed CAR T cell therapies have improved outcomes for non-Hodgkin's lymphoma (NHL) patients, only about 30-40% of 3L+ patients obtain long term remission after this treatment (Neelapu et al. 2017; Schuster et al. 2019). bbT369, a next generation, dual targeted (CD79a/CD20), gene edited (CBLB gene knock out) autologous CAR T cell therapy was devised to overcome hypothesized mechanisms of CD19 CAR T cell treatment failure including loss/downregulation of target antigen, loss of co-stimulation pathways on tumor cells, exhaustion of CAR T cells, and CAR T cell dysfunction due to an immunosuppressive microenvironment (Shah and Fry 2019). bbT369 uses an OR gated design to limit antigen escape and contains split costimulatory domains (CD28 and 41BB) to enhance T cell activation. Methods: CRC-403 (NCT05169489) is a non-randomized, open label, multi-site phase 1/2 study enrolling relapsed and/or refractory B cell non-Hodgkin’s lymphoma (NHL), including diffuse large B cell lymphoma (DLBCL), high-grade B cell lymphoma (HGBCL), primary mediastinal (thymic) large B cell lymphoma (PMBCL), follicular lymphoma (FL) 3b, and DLBCL transformed from FL (tFL). Patients must have relapsed after ASCT or at least 2 prior lines of therapy. Patients with tFL must be relapsed after receipt of ASCT or at least 2 prior therapies after documentation of transformation. Patients with previous exposure to non-investigational CD19 directed CAR T cell therapy who did not experience disease progression within 6 weeks of initial CAR T cell infusion are eligible for enrollment. Approximately 50 patients will be enrolled in the phase 1 portion. The primary endpoints of the phase 1 portion are determination of the MTD, determination of recommended phase 2 dose (RP2D) and safety. Secondary endpoints include overall response rate, complete response rate, time to response and time to next anti-lymphoma treatment. Exploratory endpoints include DOR, PFS, OS, CAR+ T cell expansion and correlations between clinical response and T cell phenotype or antigen expression on tumor cells. The starting dose of bbT369 will be 50x106 CAR+ T cells and a BOIN design will be used for dose escalation/de-escalation decisions during the study. Upon establishment of the RP2D, the phase 2 portion will begin enrollment. Clinical trial information: NCT05169489.

Outcomes of Tisagenlecleucel in Lymphoma Patients With Predominant Management in an Ambulatory Setting

IntroductionChimeric antigen receptor T-cell therapy (CAR T) is a revolutionary adoptive immunotherapy approach in lymphoma; however, substantial resources are necessary for administration and care of these patients. Our institution has administered tisagenlecleucel primarily in an outpatient setting, and here we report our clinical outcomes. Patients and MethodsWe conducted a single institution, retrospective study investigating outcomes of adult lymphoma patients treated with commercial tisagenlecleucel between 10/2017 and 12/2020. We analyzed patient characteristics and outcomes of efficacy and safety including overall response rate, progression-free survival, overall survival and cytokine-release syndrome, neurotoxicity, and hospitalizations. ResultsSeventy-two patients with relapsed or refractory non-Hodgkin lymphoma (NHL) who received commercial tisagenlecleucel were identified; 68 (94.4%) patients received outpatient tisagenlecleucel. The overall response rate was 43% with a complete response observed in 25 patients (34.7%). At a median follow-up of 9.1 months, the median progression-free survival was 3.3 months. Grade 3-4 cytokine release syndrome was not observed in the study group and two patients had grade 3-4 neurotoxicity. Twenty-six patients (36.1%) were admitted within 30 days after infusion with a median length of stay of 5 days. Fourteen patients (19.4%) were admitted within 72 hours of infusion. No patient died of CAR T cell-related toxicity. ConclusionOur experience affirms treatment with tisagenlecleucel in the outpatient setting is safe and feasible with close supervision and adequate institutional experience. After infusion, adverse events were manageable and the majority of patients did not require hospitalization.

Odronextamab, a human CD20×CD3 bispecific antibody in patients with CD20-positive B-cell malignancies (ELM-1): results from the relapsed or refractory non-Hodgkin lymphoma cohort in a single-arm, multicentre, phase 1 trial

Odronextamab is a hinge-stabilised, fully human IgG4-based CD20 × CD3 bispecific antibody that binds CD3 on T cells and CD20 on B cells. We aimed to evaluate the safety and antitumour activity of odronextamab in patients with relapsed or refractory B-cell non-Hodgkin lymphoma. This single-arm, multicentre, phase 1, dose-escalation and dose-expansion (ELM-1) trial was conducted at ten academic sites across the USA and Germany. Patients aged 18 years or older with CD20-positive relapsed or refractory B-cell malignancies who previously received CD20-directed antibody therapy and who had at least one measurable lesion, and an ECOG performance status of 0 or 1 were included. Patients received intravenous odronextamab, according to a step-up dosing schedule in cycle 1, followed by treatment once per week at target doses ranging from 0·1 mg to 320 mg during cycles 2-4 (each cycle was 21 days). After cycle 4, maintenance treatment occurred every 2 weeks until disease progression or unacceptable toxicity. The primary endpoint of safety was assessed by the incidence of adverse events and dose-limiting toxicities to determine the maximum tolerated dose or phase 2 dose of odronextamab, or both. Preliminary antitumour activity, as measured by objective response rate, was a secondary endpoint. This study is registered with ClinicalTrials.gov, NCT02290951. From Feb 4, 2015, to Sept 25, 2021, 145 heavily pretreated patients (median of 3 (IQR 2-5] previous therapies) were enrolled (94 to the dose-escalation and 51 to the dose-expansion part of the study). The median age of patients was 67·0 years (IQR 57·0-73·0); 101 (70%) were male and 44 (30%) were female; most participants were White (119 [82%]) and not Hispanic or Latino (132 [91%]). 42 (29%) patients received previous CAR T therapy and 119 (82%) were refractory to the last line of therapy. Median duration of follow-up was 4·2 months (IQR 1·5-11·5). During dose escalation, odronextamab was administered up to the maximum dose of 320 mg once per week and no dose-limiting toxicities were observed. The recommended dose for expansion in patients with follicular lymphoma grade 1-3a was 80 mg and was 160 mg for patients with diffuse large B-cell lymphoma. Cytokine release syndrome and neurological treatment-emergent adverse events were predominantly low grade and did not result in treatment discontinuation. The most common grade 3 or worse treatment-emergent adverse events were anaemia (36 [25%]), lymphopenia (28 [19%]), hypophosphataemia (27 [19%]), neutropenia (27 [19%]), and thrombocytopenia (20 [14%]). Serious treatment-emergent adverse events occurred in 89 (61%) of 145 patients; the most frequent were cytokine release syndrome (41 [28%]), pyrexia (11 [8%]), pneumonia (nine [6%]), and infusion-related reaction (six [4%]). Four deaths were considered related to treatment (gastric perforation in a patient with gastric involvement by lymphoma, lung infection, pneumonia, and tumour-lysis syndrome). Objective response rate was 51% (95% CI 42-59; 72 of 142). In patients with follicular lymphoma who received odronextamab doses of 5 mg or higher, the objective response rate was 91% (95% CI 75-98; 29 of 32) and the complete response rate was 72% (95% CI 53-86; 23 of 32). In patients with diffuse large B-cell lymphoma without previous CAR T-cell therapy who received doses of 80 mg or higher, the objective response rate was 53% (eight of 15) and all responses were complete responses. In patients with diffuse large B-cell lymphoma who had previous CAR T-cell therapy and received doses of 80 mg or higher, the objective response rate was 33% (ten of 30) and complete response rate was 27% (eight of 30). Odronextamab monotherapy showed a manageable safety profile and encouraging preliminary activity, including durable responses in heavily pretreated patients with B-cell non-Hodgkin lymphoma, supporting further clinical investigation in phase 2 and 3 trials. Regeneron Pharmaceuticals.

Cytopenia after CAR-T Cell Therapy-A Brief Review of a Complex Problem.

Simple SummaryChimeric Antigen Receptor T-cell (CAR-T) immunotherapy has emerged as a new life-saving treatment modality in patients with relapsed or refractory B-cell malignancies and multiple-myeloma. In this form of therapy, patient’s T-cells are modified by various genetic techniques to express a new receptor that identifies and kills the cancer cells. With increasing use, they present with distinct immune mediated side effects such as cytokine release syndrome (CRS), neurotoxicity, and prolonged cytopenia. While our understanding of CRS and other immune side-effects has increased, prolonged cytopenia post CAR-T infusion remains under-recognized and under-reported. With the focus on prolonged cytopenia in this review, we aim to summarize findings of various clinical trials, postulated mechanisms, and clinical interventions to risk-stratify and manage this clinical entity.Chimeric Antigen Receptor T-cell (CAR-T) immunotherapy has emerged as an efficacious and life extending treatment modality with high response rates and durable remissions in patients with relapsed and refractory non-Hodgkin lymphoma (NHL), follicular lymphoma, and B-cell acute lymphoblastic leukemia (B-ALL) as well as in other diseases. Prolonged or recurrent cytopenias after CAR-T therapy have increasingly been reported at varying rates, and the pathogenesis of this complication is not yet well-understood but is likely contributed to by multiple factors. Current studies reported are primarily retrospective, heterogeneous in terms of CAR-Ts used and diseases treated, non-uniform in definitions of cytopenias and durations for end points, and vary in terms of recommended management. Prospective studies and correlative laboratory studies investigating the pathophysiology of prolonged cytopenias will enhance our understanding of this phenomenon. This review summarizes knowledge of these cytopenias to date.

Renal outcomes after chimeric antigen receptor T-cell therapy: a single-center perspective

Chimeric antigen receptor (CAR) T-cell therapy represents a major advancement in the treatment of patients with acute lymphoblastic leukemia (ALL) and refractory non-Hodgkin lymphoma [1]. CAR T-cells are genetically engineered T-cells that express a surface receptor that contains a single-chain variable fragment (scFv) that can recognize tumor antigens and target tumor cells. The intracellular portion of the CAR includes T-cell receptor and costimulatory domains that result in T-cell activation and proliferation upon antigen binding. CAR T-cell activation is essential for their antineoplastic function, but involves the release of cytokines and chemokines, which in turn recruit other effector cells of the immune system, such as macrophages. A well-described complication of CAR T-cell therapy is cytokine release syndrome (CRS), an immunoinflammatory event associated with uncontrolled release of cytokines. The release of cytokines can lead to vasodilation, decreased cardiac output and intravascular volume depletion, which may potentiate renal injury. Kidney injury remains a less-recognized side effect of CRS and CAR T-cells. There are limited data regarding renal outcomes of patients treated with CAR T-cells [2, 3] but there is no information about outcomes after CAR T-cell therapy in patients with underlying chronic kidney disease (CKD). We aim to further elucidate outcomes in patients with CKD treated with CAR T-cell therapy at our institution.