B-cell non-Hodgkin Lymphoma Patients Research Articles

Pediatric B-cell Non-Hodgkin Lymphoma: The Impact of Therapy Response and Relapse on Outcome. A Single-center Analysis.

Pediatric patients with primary refractory or relapsed B-cell non-Hodgkin lymphoma (B-NHL) have highly unfavorable prognosis. In this study, we retrospectively analyzed outcomes in pediatric B-NHL patients treated in a single center in Poland from 1995 to 2022, with emphasis on therapy results in patients with progression or relapse. The primary objectives were a 5-year probability of overall survival (pOS) and a 5-year probability of event-free survival (pEFS). The secondary objectives involved the assessment of prognostic factors. A total of 76 children were eligible for the analysis. The 5-year pOS was 76.7%, and the 5-year pEFS was 72.9%. At diagnosis, elevated lactate dehydrogenase activity, the presence of B symptoms, bone marrow, skeletal or mediastinal involvement, and stage IV disease were associated with inferior outcomes. Nine children experienced progression and four relapse. The 5-year pOS for patients with progression was 38.1%. Two patients treated with hematopoietic stem cell transplantation (HSCT) as part of salvage therapy survived. However, only one out of seven patients who were treated without HSCT survived. The 5-year pOS was 0.0% in patients with relapsed disease. The most significant factor related to outcomes in pediatric B-NHL is therapy response, with a high mortality rate in children with refractory disease and relapse. There is no consensus on the salvage therapy approach; however, HSCT appears to be the optimal choice.

Gene expression profiling in B-cell non-Hodgkin lymphomas

Abstract BACKGROUND: Gene expression profiling has become a fundamental tool in cancer diagnosis and management. B-cell non-Hodgkin lymphoma (B-NHL) is a group of malignant neoplasms originating from the lymphoid tissues, mainly the lymph nodes and the gene expression technique was used to unravel its complexity and aid in clinical decision-making. OBJECTIVES: The aims of this study were to find the significance of gene expression profiling focusing on colony-stimulating factor 1 receptor (CSF1R), myeloid differentiation factor 88 (MyD88), and tumor necrosis factor-α (TNF-α) as a promising approach in B-NHL diagnosis and their comparison with healthy controls. PATIENTS, MATERIALS AND METHODS: The current clinical prospective study was mediated from June 1, 2021, to December 30, 2022, of NHL patients in Kurdistan, Iraq. Seventy-three patients were recruited from Nanakali Hospital for Blood Diseases and Cancer, Erbil. The integration of gene expression biomarkers uses quantitative real-time polymerase chain reaction technique to diagnose B-NHL. Specifically, we focused on three key genes MyD88, TNF, and CSF1R whose expression profiles were analyzed in B-NHL patients and controls. We leveraged a dataset to explore gene expression patterns in B-NHL and applied classification algorithms to distinguish between B-NHL patients and controls. RESULTS: The initial results show the overall lower CSF1R expression in B-NHL as compared to the controls and a significant reduction in CSF1R expression in females (≤50 years and >50 years). The result considers lower CSF1R expression in B-NHL males (≤50 years) and higher but not significant in males (>50 years). CONCLUSIONS: These B-NHL-expressed genes may be considered potential diagnostic markers with their meaningful comparisons to control groups, and they could be proposed to guide the management of patients and facilitate their stratification into clinical trials.

A study of the relationship between circulating cytokines (interleukin-2 receptor and tumor necrosis factor receptor 2) and risk of B-cell non-hodgkin lymphoma.

Mature B-cell non-Hodgkin lymphoma (B-NHL) occurs due to uncontrolled B-lymphocyte clonal expansion. Cytokines can directly stimulate B-cell proliferation and prevent B-cell apoptosis. Dysregulation of cytokines may play an important role in the development of B-NHL by enhancing chromosomal translocation, which is the hallmark of B-NHL. Both interleukin 2 and tumor necrosis factor-α are proinflammatory cytokines and play important roles in the growth, differentiation, and apoptosis of B cells.We conducted a prospective case-control study applied to 50 patients with B-NHL at Kasr Al Aini Hospital, Cairo University, and 50 age- and sex-matched controls. Clinical, laboratory and imaging data were collected. In all patients and controls, sIL-2R and sTNF-R2 levels were measured by enzyme-linked immunosorbent assay (ELISA). The Spearman correlation test was used to evaluate the correlation between the studied cytokines and clinical, laboratory and imaging findings. Sensitivity analysis was conducted to detect the cutoff values of the studied cytokines.Serum levels of sIL-2R and sTNF-R2 were significantly higher in patients than in controls. Additionally, their levels were significantly higher in aggressive types and advanced stages of lymphoma. Also, the studied cytokines were significantly correlated with different clinical and laboratory parameters of lymphoma. The level of sIL-2R and sTNF-R2 were closely related to the type of lymphoma (P value ˂ 0.001 and 0.012, respectively), further it was also associated with the natural history of lymphoma (aggressive vs. indolent) (P value ˂0.001 and 0.04 respectively).We concluded that Pretreatment levels of sIL-2R and sTNF-R2 may play a role in the natural history and prognosis of lymphoma. They may be used as a prognostic factor for B-NHL patients and may also help with treatment decisions.

Elevated serum cathepsin S is associated with HDL3a and HDL3b subclasses in non-Hodgkin lymphoma patients

Background: Recent findings point to the key role of cathepsin S (CTSS) in the survival of malignant cells, as well as the significance of the anti-apoptotic properties of high-density lipoprotein (HDL) that contribute to enhanced cell survival. The purpose of this study is to analyze CTSS as a potential biomarker in lymphoma. Also, in order to better understand the role of CTSS in the origin and development of lymphoma, its association with cystatin C (Cys C), lipids, and inflammatory markers was analyzed. Methods: The study included 90 subjects: 11 Hodgkin (HL) and 44 B-cell non-Hodgkin lymphoma (NHL) patients, and 35 healthy subjects. CTSS was determined using the Invitrogen ELISA kit (Thermo Fisher Scientific, Inc., Waltham, MA, USA). Results: The level of CTSS was significantly higher in NHL patients than in control subjects: 12.20 (9.75-14.57) vs 9.97 (8.44-10.99), P<0.001. In NHL patients, there was a positive correlation between CTSS and the proportions of HDL3a, HDL3b, and the sum of the HDL3 subclasses (r=0.506, P<0.001; r=0.411, P=0.006, r=0.335, P=0.026, respectively). In addition, the area under the receiver operating characteristic curve (AUC curve) of CTSS was 0.766 (CI: 0.655-0.856). Conclusions CTSS is significantly elevated in patients with NHL and has the potential to be a new diagnostic biomarker. Moreover, demonstrating a correlation between CTSS levels and the proportion of anti-apoptotic HDL3a and HDL3b subclasses improves understanding of NHL, as well as contributes to the development of new therapeutic strategies for this cancer.

Preclinical assessment of IPH6501, a first-in-class IL2v-armed tetraspecific NK cell engager directed against CD20 for R/R B-NHL, in comparison with a CD20-targeting T cell engager.

7030 Background: The therapeutic landscape for relapsed or refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL) is evolving to include targeted T-cell based immunotherapies, including CD19-targeted CAR-T and CD3xCD20 T-cell engaging (TCE) bispecific antibodies. Yet, there remains an unmet medical need for patients who are refractory to, or ineligible for these treatments. Leveraging natural killer (NK) cells emerges as a promising strategy in hematological malignancies, as shown in a Phase 1 study with IPH6101/SAR’579 in R/R AML (Stein, ASCO 2023; Bajel, ASH 2023). Methods: We developed IPH6501, a tetraspecific antibody-based NK cell engager that simultaneously targets on NK cells the CD16a and NKp46 receptors, the IL-2 receptor with an engineered IL-2 variant (IL2v) and on B-NHL cells the CD20 antigen. This approach boosts NK cell activation and proliferation, cytotoxicity against tumor cells, and cytokine production. The IL-2 variant is designed with mutations that prevent binding to CD25 (IL-2Rα), limiting Treg activation and potential IL-2-related side effects. IPH6501 has been evaluated in mouse, non-human primate, and human-derived models, including cells from R/R B-NHL patients. Results: In vivo studies in non-human primates and tumor mouse models revealed that IPH6501, at well-tolerated doses, significantly boosted peripheral NK cell proliferation, drove their accumulation at tumor locations, and effectively eradicated CD20+ cells in blood and tissues. In human derived-models, IPH6501 significantly induced NK cell proliferation and cytotoxicity. Notably, IPH6501 showed potent activity against a range of B-NHL cell lines, including those with low CD20 expression. In addition, IPH6501 upregulated the expression of activating receptors on NK cells, such as NKG2D, essential for the recognition and killing of malignant cells, thereby introducing another mode of action enabling the elimination of CD20-negative tumor cells. In a comparative analysis with a CD3xCD20 TCE, IPH6501 induced lower cytokine secretion, suggesting a potentially safer profile. Additionally, IPH6501 showed higher killing efficacy compared to the TCE in samples from healthy individuals as well as R/R B-NHL patients, underscoring its therapeutic potential. Conclusions: The preclinical demonstrations of IPH6501 activities across various in vivo models and its effectiveness in ex vivo assays using cells from R/R B-NHL patients provide compelling evidence of its therapeutic potential and tolerability. IPH6501 is emerging as a promising new candidate within the treatment landscape for R/R B-NHL and is currently being investigated in a global, first-in-human phase 1/2 study (NCT 06088654).

A phase IIA clinical trial to evaluate a reversible Bruton’s tyrosine kinase inhibitor (BTKi) HBW-3220 capsules in patients with relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL).

e19042 Background: This clinical study is to evaluate HBW-3220, a novel BTKi with an improved in vitro profile than the existing non-covalent drugs pirtobrutinib (approved) and nemtabrutinib (Phase III). HBW-3220 shows superior inhibition against BTK wild-type and several common mutants, such as C481S, C481R, T474I, T316A, and L528W (enriched in pirtobrutinib resistance), and hematopoietic cell kinase (HCK, a key contributor to BTKi resistance due to kinase-defective BTK). Methods: This phase IIA clinical study is conducted in R/R B-NHL patients who had received two or more prior lines of treatment. The dose escalation study adopts accelerated titration and a "3+3" design, with a daily single dose of 15, 30, 60, 90, 120, or 150 mg. During the dose escalation phase, the sponsor and investigators determine whether to expand the cohort of the previous dose based on the existing data. Adverse events (AEs) are assigned according to NCI Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Response assessment is based on iwCLL 2018 guidelines for chronic lymphocytic leukemia (CLL), IWWM-7 consensus for Waldenstrom macroglobulinemia (WM), and Lugano 2014 guidelines for all other lymphomas, including small lymphocytic lymphoma (SLL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), and follicular lymphoma (FL). Results: 29 patients have been enrolled, and the dose escalation study has been completed. No dose-limiting toxicity (DLT) occurred in any patient, implicating good tolerability. Adverse events (AEs), similar to other BTKis, were mostly Grade 1 or 2, including fever (36%), diarrhea (32%), headache (18%), anemia (39%), infectious pneumonia (18%), decreased neutrophils count (39%), decreased platelet count (29%), increased alanine aminotransferase (21%), etc. Drug-related Grade 3 AEs included decreased neutrophil count (n=3, 11%), increased lymphocyte count (n=2, 7%), and infectious pneumonia (n=2, 7%). 23 patients underwent at least 1 response assessment. The overall response rate (ORR) in CLL/SLL (all with prior irreversible BTKi treatment, and 4 of them with additional BCL2 inhibitor treatment), MZL, MCL, and DLBCL patients were 83% (5/6), 50% (2/4), 40% (2/5) and 33% (1/3), respectively. Among the ORR, 90% (9/10) were in the 90 mg and above dose group, regardless of previous BTKi treatment history or mutation status of p53 and BTK. After oral administration, the drug exposures showed dose-dependent increases. The time to maximum plasma concentration (Tmax) was 2 hours, and the elimination half-life (T1/2) was 19 hours. Conclusions: The current data show that HBW-3220 is well tolerated with no DLT occurred at daily doses up to 150 mg, displaying most promising efficacy in patients with CLL/SLL, MZL, and MCL. Clinical trial information: ChiCTR2200062537.

A phase 1/2, open-label, multicenter trial investigating the safety, tolerability, and preliminary antineoplastic activity of IPH6501, a first-in-class NK cell engager, in patients with relapsed and/or refractory CD20-expressing non-Hodgkin lymphoma.

TPS7095 Background: The therapeutic landscape for relapsed and/or refractory B-cell non-Hodgkin lymphoma (B-NHL) is evolving to include targeted T-cell based immunotherapies. However, there remains an unmet medical need for patients who are refractory to, relapsing from, or are ineligible for these therapies. Leveraging natural killer (NK) cells emerges as a promising strategy, as demonstrated in a Phase 1 study with IPH6101/SAR’579 in R/R AML (Stein, ASCO 2023; Bajel, ASH 2023), and offers a novel approach that could complement or provide an alternative to T-cell therapies. IPH6501 is a first-in-class tetraspecific antibody-based NK cell engager that simultaneously targets the CD16a and NKp46 receptors on NK cells and CD20 on B-NHL cells. It also includes an engineered IL-2 variant designed with mutations to avoid binding to CD25 (IL-2Rα), limiting Treg activation and potential IL-2 related side effects, whilst inducing NK proliferation. In preclinical animal models, IPH6501 boosted NK cell proliferation and activation, and CD20+ target cell elimination in peripheral blood and tissues, at well-tolerated doses. In samples obtained from R/R B-NHL patients, IPH6501 demonstrated greater killing efficacy compared to a CD3xCD20 T-cell engager, and yet lower cytokine secretion, suggesting a potentially safer profile. Methods: This is a global first-in-human, multicenter, open-label Phase 1/2 study to evaluate the safety profile (DLTs and MTD), tolerability according to NCI-CTCAE v5.0 and to determine the RP2D of IPH6501 for patients with B-NHL (NCT06088654). Secondary objectives are to characterize the pharmacokinetic profile and evaluate the immunogenicity of IPH6501. Eligible subjects are aged ≥18 years with advanced, histologically confirmed, CD20+ B-NHL with an ECOG PS ≤2, and without established alternative therapy. Subjects must have received ≥2 prior systemic therapies which may have included astem cell transplant or CAR-T cell therapy. The Phase 1 part of the study will consist of a dose escalation part which will follow a3+3 design to determine the MTD or the highest dose to be tested as defined in protocol if the MTD has not been reached, and a dose assessment part to randomize ≥2 dose levels to determine the RP2D. The Phase 2 part will enroll one or more cohorts of selected B-cell NHL subtypes to be determined at a later stage. Up to 184 subjects will be enrolled, and the study is open in the United States, Australia and Europe. Clinical trial information: NCT06088654 .

Abstract CT147: Phase I clinical study of Bruton’s tyrosine kinase inhibitor (BTKi) HBW-3220 capsules in patients with relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL)

Abstract Purpose: This clinical study is to evaluate HBW-3220, a novel reversible BTK inhibitor (BTKi) with an improved in vitro profile than the existing non-covalent drugs pirtobrutinib (LOXO-305, approved) and MK-1026 (Phase III). HBW-3220 shows superior inhibition against BTK wild-type and several common mutants, such as C481S, C481R, T474I, T316A, and L528W (the one predominantly enriched in patients resistant to the newer-generation BTKis), and hematopoietic cell kinase (HCK), a key contributor to the development of ibrutinib resistance associated with kinase-defective BTK. Methods: This phase I clinical study was conducted in R/R B-NHL patients who had received two or more prior lines of treatments. The dose escalation study adopts accelerated titration and a "3+3" design, with a daily single dose of 15, 30, 60, 90, 120, or 150 mg. During the dose escalation phase, the sponsor and investigators determined whether to expand the cohort of the previous dose based on the existing data. Adverse events (AEs) were assigned according to NCI Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Response assessment was based on the iwCLL 2018 guidelines, the IWWM-7 consensus, or the Lugano 2014 guidelines, according to the respective disease type. Results: 28 patients have been enrolled so far, and the dose escalation study has been completed. No dose-limiting toxicity (DLT) occurred in any patient, implicating good tolerability. Adverse events (AEs), similar to other BTKis, were mostly Grade 1 or 2, including fever (38%), diarrhea (35%), headache (19%), anemia (42%), infectious pneumonia (23%), decreased neutrophils (42%), decreased platelet count (27%), increased alanine aminotransferase (23%), etc. Drug-related Grade 3 AEs included neutrophil count decreased (n=3, 11%), increased lymphocyte count (n=2, 7%), and infectious pneumonia (n=2, 7%). 21 patients underwent at least 1 response assessment (4 chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL); 4 marginal zone lymphoma (MZL); 5 mantle cell lymphoma (MCL); 3 diffuse large B-cell lymphoma (DLBCL); 5 other B-NHL), and the results are 1 complete response (CR), 6 partial response (PR), and 1 partial response with lymphocytosis (PR-L). The overall response rate (ORR) in CLL/SLL (all with prior irreversible BTKi treatment, and 2 of them with additional BCL2 inhibitor treatment), MZL, MCL, and DLBCL patients were 75% (3/4, including 1 PR-L), 50% (2/4), 40% (2/5) and 33% (1/3), respectively. Among the ORR (including CR, PR, and PR-L), 88% (7/8) were in the 90 mg and above dose group, regardless of previous BTKi treatment history or mutation status of p53 and BTK C481S. In the 90 mg and above dose group, the ORR is 47%. After oral administration, the drug exposures showed dose-dependent increases. The time to maximum plasma concentration (Tmax) was 2 hours, and the elimination half-life (T1/2) was 19 hours. Conclusions: The current data show that HBW-3220 is well tolerated, showing no DLT occurred at daily doses up to 150 mg, and has good efficacy in patients with CLL/SLL, MZL, and MCL. Citation Format: Ning Lee, Yingfu Li, Yong Mao, Guanfeng Liu, Jiang Li, Qingchun Liu. Phase I clinical study of Bruton’s tyrosine kinase inhibitor (BTKi) HBW-3220 capsules in patients with relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT147.

Efficacy of programmed cell death 1 inhibitor maintenance after chimeric antigen receptor T cells in patients with relapsed/refractory B-cell non-Hodgkin-lymphoma.

Chimeric antigen receptor (CAR)-T cells obtained long-term durability in about 30% to 40% of relapsed/refractory (r/r) B-cell non-Hodgkin lymphoma (B-NHL). Maintenance therapy after CAR-T is necessary, and PD1 inhibitor is one of the important maintenance therapy options. A total of 173 r/r B-NHL patients treated with PD1 inhibitor maintenance following CD19/22 CAR-T therapy alone or combined with autologous hematopoietic stem cell transplantation (ASCT) from March 2019 to July 2022 were assessed for eligibility for two trials. There were 81 patients on PD1 inhibitor maintenance therapy. In the CD19/22 CAR-T therapy trial, the PD1 inhibitor maintenance group indicated superior objective response rate (ORR) (82.9% vs 60%; P = 0.04) and 2-year progression-free survival (PFS) (59.8% vs 21.3%; P = 0.001) than the non-maintenance group. The estimated 2-year overall survival (OS) was comparable in the two groups (60.1% vs 45.1%; P = 0.112). No difference was observed in the peak expansion levels of CD19 CAR-T and CD22 CAR-T between the two groups. The persistence time of CD19 and CD22 CAR-T in the PD1 inhibitor maintenance group was longer than that in the non-maintenance group. In the CD19/22 CAR-T therapy combined with ASCT trial, no significant differences in ORR (81.4% vs 84.8%; P = 0.67), 2-year PFS (72.3% vs 74.9%; P = 0.73), and 2-year OS (84.1% vs 80.7%; P = 0.79) were observed between non-maintenance and PD1 inhibitor maintenance therapy groups. The peak expansion levels and duration of CD19 and CD22 CAR-T were not statistically different between the two groups. During maintenance treatment with PD1 inhibitor, all adverse events were manageable. In the multivariable analyses, type and R3m were independent predictive factors influencing the OS of r/r B-NHL with PD1 inhibitor maintenance after CAR-T therapy. PD1 inhibitor maintenance following CD19/22 CAR-T therapy obtained superior response and survival in r/r B-NHL, but not in the trial of CD19/22 CAR-T cell therapy combined with ASCT.

Abstract 1344: Improvement of the anti-tumor activity of NK cells and the efficacy of anti-CD20 monoclonal antibodies in the therapy of B cell-derived malignancies

Abstract Resistance of tumor cells to immunotherapy with monoclonal antibodies (mAbs) often relies on the reduced level of the antigen targeted by the particular mAb. We have therefore screened for the compounds able to upregulate selected antigens on the surface of lymphoma/leukemia cells, to minimize the possibility of resistance acquired by the tumor cells. We have found that members of a specific class of antibiotics, known as cation carriers, namely salinomycin (SAL), monensin (MON), narasin, and nigericin exhibit great CD20 antigen-upregulating abilities. A variety of Burkitt’s lymphoma and diffuse large B-cell lymphoma (DLBCL) cell lines as well as patients-derived primary malignant cells, such as DLBCL and chronic lymphocytic leukemia (CLL) cells exhibited upregulation of surface CD20 upon the treatment with SAL and MON at concentrations as low as 250nM and 50 nM, respectively. As a consequence, these compounds appeared to be beneficial for the therapy of lymphoma/leukemia with anti-CD20 mAbs, both in vitro and in animal models.Moreover, the proteomics analysis revealed that besides CD20, cation carriers upregulated a number of different proteins on the surface of tumor cells, including proteins implicated in the interaction with immune cells. These included ICAM1, HLA-A/B/C, CD155, CD80, CD86 and ULBP2/5/6. Particularly important appears to be the upregulation of antigens interacting with the activating receptors on NK cells, helping them to overcome the inhibitory signals and stimulate the lysis of tumor cells. Thus, the results of proteomics analysis explained why SAL- or MON-pretreated tumor cells were efficiently eliminated by NK cells, even in the absence of therapeutic mAb. In light of our discoveries, it seems reasonable to consider the cation carriers as promising drug candidates for the improvement of NK cell anti-tumor activity and potential treatment of B-cell non-Hodgkin lymphoma patients, in combination with anti-CD20 mAbs.Funding: National Science Centre (NCN, Poland), grants 2019/35/B/NZ5/01445 and 2020/39/B/NZ6/03513. Citation Format: Abdessamad Zerrouqi, Aleksandra Zdanowicz, Anna Torun, Andrzej Ciechanowicz, Bhaskar Pradhan, Grzegorz Rymkiewicz, Dimitar Efremov, Beata Pyrzynska. Improvement of the anti-tumor activity of NK cells and the efficacy of anti-CD20 monoclonal antibodies in the therapy of B cell-derived malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1344.

Interstitial pneumonia development after chemotherapy in B-cell non-hodgkin's lymphoma patients: clinical profiles and risk factors.

Interstitial pneumonia (IP) is a significant adverse effect of chemotherapy in B-cell non-Hodgkin's lymphoma (NHL) patients. This study aimed to identify the clinical characteristics, risk factors, and treatment outcomes associated with IP in these patients. A retrospective review of 615 NHL patients treated at the Fourth Hospital of Hebei Medical University from 2016 to 2021 identified 50 patients with IP post-chemotherapy as the case group. A propensity score matched control group of 55 patients without pneumonia was established. Clinical profiles, risk factors, and treatment outcomes were evaluated. The IP incidence was 8.13% (50/615) in B-cell NHL patients. Multivariate analysis revealed liposomes, elevated lactate dehydrogenase (LDH), and erythrocyte sedimentation rate (ESR) as independent risk factors for IP. Receiver Operating Characteristic (ROC) curve analyses suggested that alterations in LDH and ESR could predict IP risk. The conclusion suggests that IP is associated with liposomal doxorubicin-induced lung injury and other cytotoxic chemotherapy, possibly due to Rituximab (RTX)-induced immune imbalance. Given the potential of IP with pulmonary infections, high-risk patients may need prophylactic antibiotics and appropriate corticosteroid therapy.

Safety and Efficacy of a-319 (a CD3xCD19 T cell engager) in Patients with Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma

Background: A-319 is a CD19 x CD3 bispecific T cell engager to treat B-cell non-Hodgkin Lymphoma (B-NHL). A-319 contains a scFV domain derived from SP34 CD3 antibody and a CD19 binding domain in a Fab format without Fc. A-319 has the same mechanism of action as that of blinatumomab, and may benefit B-NHL patients. We report the phase I study results of A-319 in patients with relapsed/refractory B-NHL. Methods: The current study is a multi-center, open-label, dose-escalation phase I clinical study. The primary endpoint was to determine the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of A-319. The secondary endpoints were to evaluate the pharmacokinetics (PK) and efficacy. During dose escalation stage, one treatment cycle contains one week of A-319 priming doses and three weeks of treatment doses. During priming doses, A-319 was administered three times per week (day 1, day 3 and day 5) at dose level of 0.05 ug/kg/day by 24 hr IV infusion. Dose escalation started at week two at dose level of 0.05, 0.15, 0.3, 0.6, 1.2, 1.8 and 2.4 ug/kg/day, respectively, by 6 hr IV infusion three times per week. The study was registered at ClinicalTrials.gov (NCT04056975). Results: A total of 21 B-NHL patients (CD19+) were treated with A-319 for at least 1 cycle. Eighteen (85.7%) patients experienced adverse events and 12 (57.1%) patients experienced treatment-related adverse events (TRAEs). The most common TRAE was cytokine release syndrome (CRS, 23.8%, n=5), followed by fever (66.7%, n=14) and decreased immunoglobulin (23.8%, n=5). Most of the reported adverse events were CTCAE Grade I-II. Five patients experienced CRS (Grade I-II, n=5；≥Grade III, n=0). Six patients experienced immune effector cell-associated neurotoxicity syndrome (Grade I-II, n=6；Grade III, n=2). The serious adverse events were reported in 3 patients, which included lung infection (Grade III, n=1), interstitial pneumonia (Grade I, n=1), and pulmonary embolism (Grade III, n=1). There was no reported DLT. No fatal cases were reported during treatment. The preliminary pharmacokinetic (PK) results showed that A-319 has linear PK properties with an estimated T 1/2 of 6-10 hrs. Preliminary responses were reported that one patient achieved complete remission (CR), 3 achieved partial remission (PR), and 7 achieved stable disease (SD) after one cycle of treatment. In the 5 th cohort (at the dose level of 1.2 ug/kg/day), one patient with diffuse large B cell lymphoma (DLBCL) achieved CR, one with follicular lymphoma (FL) achieved PR and on with DLBCL achieved SD. Conclusions: A-319 was well tolerated in relapsed/refractory B-NHL. A-319 at the dose level of 1.2 ug/kg/day showed encouraging disease control and warranted further clinical investigation.

First Report of Phase 1 Studies of DZD8586, a BBB Penetrant LYN/BTK Dual Inhibitor, in Patients with B-Cell Non-Hodgkin Lymphoma (B-NHL)

Introduction Resistance to covalent (ibrutinib, acalabrutinib and zanubrutinib) and non-covalent BTK inhibitors (pirtobrutinib) is an emerging clinical challenge. DZD8586 was designed as a full blood-brain barrier (BBB) penetrable LYN/BTK dual inhibitor. Preclinical study suggested DZD8586 has a good selectivity against other TEC family kinases (TEC, ITK, TXK, BMX). DZD8586 inhibits BTK-dependent and BTK-independent BCR signaling pathways by targeting LYN and BTK, which could potentially overcome resistance to both covalent and non-covalent BTK inhibitors for the treatment of CLL and MCL, as well as DLBCL. Two phase 1 clinical studies are ongoing in patients with relapsed or refractory (r/r) B-NHL to assess safety, pharmacokinetics (PK), pharmacodynamics (PD) and anti-tumor efficacy of DZD8586. Methods TAI-SHAN1 (NCT05844956; CTR20220558) and TAI-SHAN5 (NCT05824585) are phase 1 dose escalation and expansion studies in patients with r/r B-NHL. Both studies have similar dose escalation strategies. Patients who progressed following or intolerant of prior systemic therapy were enrolled. Pooled safety and efficacy analysis was performed. In addition, modulation of PD biomarkers was also evaluated. Tumor responses were investigator assessed according to Lugano 2014, IPCG 2005, or iwCLL 2018, as appropriate. Results As of June 15, 2023, 17 patients with r/r B-NHL have been enrolled and received DZD8586 at doses ranging from 10 to 100 mg once daily (QD) (10 mg， n=1；25 mg， n=4；50 mg， n=7；100 mg， n=5). The median age was 61 years, 71% were male, and 53% had an ECOG PS of 1. Histological subtypes included CLL, SCNSL, DLBCL, MCL, FL and MZL. The median number of prior therapies was 3 (range 2 - 8). All patients received prior chemotherapy and anti-CD20 therapy. Six patients, including 1 CLL, 2 MCL, 1 MZL, 1 SCNSL and 1 DLBCL had received prior treatment with covalent BTK inhibitors. DZD8586 was well tolerated across the doses investigated. Drug-related treatment emergent adverse events (TEAEs) reported in > 2 patients included thrombocytopenia (10/17), neutropenia (5/17), and upper respiratory tract infection (3/17). The most common ≥ grade 3 TEAE was thrombocytopenia (3/17, all at 100 mg). Other ≥ grade 3 TEAEs, including neutropenia, drug eruption and upper respiratory tract infection, were each reported by one patient. Bleeding, atrial fibrillation, and arthralgia were not reported. Grade 1 diarrhoea was reported in one patient. The maximum tolerated dose was defined as 100 mg QD. All these TEAEs were reversible after dose interruption and/or with supportive care. The longest duration on treatment was 10+ months. Among 13 patients treated at doses ≥ 25 mg QD with at least one tumor assessment, the objective response rate (ORR) was 9/13 (69.2%). Responses were observed across different histological subtypes (1/2 in SCNSL; 4/5 in DLBCL; 1/2 in FL; 1/1 in MCL, 1/2 in MZL and 1/1 CLL carrying C481S mutation). Among the 5 evaluable BTKi treated patients, tumor responses were observed in 3 patients. The longest duration of response (DoR) was 6.4+ months, and the patient was still ongoing with DZD8586 treatment and responding. PK was generally dose-proportional across the dose ranges of 10 to 100 mg. DZD8586 was absorbed with median t max 1.5 hours, and eliminated with mean terminal half-life of ~18 hours. Accumulation of about two folds in AUC was noted at steady state following once daily dosing. Dose dependent pBTK modulation in whole blood cells was detected, and at the doses ≥ 25 mg, sustained pBTK inhibition was observed. The unbound CSF-to-plasma concentration ratio (K puu,CSF) was 1.2 from one CNSL patient with available CSF samples, suggesting excellent CNS penetration of DZD8586 in humans. Conclusion In the preliminary pooled analysis of two ongoing phase 1 trials, DZD8586 has encouraging anti-tumor activity and safety in heavily pre-treated B-NHL patients. The combination of BBB penetration, dual inhibition of LYN/BTK and potential to overcome C481S mutant CLL and other covalent BTKi resistant lymphomas suggest this may be a useful agent. Updated data will be presented at the meeting.

GB261, an Fc-Function Enabled and CD3 Affinity De-Tuned CD20/CD3 Bispecific Antibody, Demonstrated a Highly Advantageous Safety/Efficacy Balance in an Ongoing First-in-Human Dose-Escalation Study in Patients with Relapsed/Refractory Non-Hodgkin Lymphoma

Introduction: GB261 is a novel and highly differentiated CD20/CD3 bispecific T cell engager antibody computationally designed to maintain Fc effector function, i.e., antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and complement-dependent cytotoxicity (CDC) to broaden the mechanisms of action (MOA) for tumor cell killing. Furthermore, the “imbalanced” design of GB261 integrates de-tuned CD3 binding to reduce CRS incidence and improve safety features of the Fc effector function. Extensive pre-clinical studies have shown that GB261 has a highly advantageous safety/efficacy balance.Here, we present the preliminary clinical safety and efficacy results of an ongoing phase I/II study for GB261 (NCT04923048). Methods: This is an open-label, multicenter (China and Australia), dose-escalation/expansion phase 1/2 study of GB261 to evaluate the safety, tolerability and efficacy in patients with Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma(B-NHL) and Chronic Lymphocytic Leukemia (CLL). Adult patients were eligible when they have CD20+ r/r B-NHL or CLL with no available standard of care treatments, adequate organ function, and no CNS involvement or other CNS disease, infections or other active/serious medical issues that may affect compliance or interpretation of results. GB261 was administered in 21-day cycles, weekly (QW) for the first 6 doses followed by every 3 weeks (Q3W) until disease progression, or other situation defined in protocol. Response assessment was based on Lugano 2014 and LYRIC 2016 criteria. Results: As of June 17, 2023, 47 r/r B-NHL patients (DLBCL:76.6%; FL:23.4%) were enrolled at flat or step-up doses of GB261 ranging from 1mg to 300 mg. Median age was 60.0 years (range: 28, 81), 55.3% of patients were male. Median prior lines of therapy were 3 (range: 1, 10). 78.7% of patients were refractory to any anti-CD20 therapy, 70.2% refractory to their last systemic therapy. Median time since last prior therapy to first study treatment was 1.9 months. In efficacy evaluable patients (n=22) from 3mg to 100mg, with at least 75% dose exposure before the first radiographic assessment, the median duration of study follow-up was 4.5 months (95%CI: 4.0, 7.4). The overall response rate (ORR) was 73% (16/22), and complete response rate (CRR) was 45.5% (10/22). ORR and CRR were 100% and 100% in 3mg, 56% and 22% in 10mg, 67% and 33% in 30mg. At 100mg dose, there were 5 evaluable patients, with ORR 100% (5/5), CRR 80% (4/5) and PR (20%, 1/5; mosunetuzumab-refractory rrDLBCL patient). Median time to response (TTR) was 1.3 months (95%CI: 1.2, 1.5), the same as median time to CR. Median duration of response (DOR) was not reached. In safety evaluable patients (n=47), the median duration of study follow-up was 4.1 months (95%CI: 2.9, 5.3). Treatment-emergent adverse events (TEAEs) were 95.7%, treatment-related adverse events were 85.1%. The most common TEAEs were COVID-19 infection (40.4%; grade 1 or 2: 27.6%; grade >=3: 12.8%) and neutropenia (31.9%; grade 1or 2: 14.9%; grade >=3: 17.0%). AE related treatment discontinuation and death were reported in 2 patients, which were all due to COVID-19 pneumonia. CRS occurred in 12.8% (6/47) patients, was mild and transient. CRS in 100mg were 14.3% (2/14). All cases of CRS were grade 1 (8.5%, 4/47) or 2 (4.3%, 2/47), no grade 3 (Lee et al., ASTCT criteria), no interruptions of treatment, and no administration of Tocilizumab. The median duration of CRS was 7 hours. No ICANS were reported. The PK profile of GB261 appeared to be linear across dose ranges tested (1mg-100mg). Effective half-life appeared to be 2-3 weeks which supports every 3-4 weeks dosing. Conclusion: GB261, a novel and highly differentiated CD20/CD3 bispecific antibody, is the first clinical stage Fc+ CD20/CD3 T cell engager. In heavily pretreated B-NHL patients, GB261 showed a highly advantageous safety/efficacy balance, consistent with the MOA. The safety profile is excellent especially for the CRS which is very mild, transient and less frequent compare with other CD20/CD3 bispecific antibodies. The response after GB261 treatment was early, deep and durable. At the 100mg dose level, 80% of patients achieved CR and with favorable safety. Additionally, clinical benefit seen in other CD20/CD3 bispecific antibody failed patients provides clinical support to the unique and differentiated MOA of GB261.

Comparison of Bendamustine Versus Fludarabine/ Cyclophosphamide Lymphodepletion in Adult Patients Receiving CD19 CAR-T Cell Therapy

INTRODUCTION: Lymphodepleting chemotherapy (LDC) prior to CAR-T infusion is required for more effective expansion and persistence of infused T cells. Most commonly, fludarabine and cyclophosphamide (flu/cy) has been used. Given recent drug shortages, alternative chemotherapeutic agents such as bendamustine have been used, although limited data exists to evaluate its safety and efficacy. Our study aimed to investigate the outcomes and toxicity profile associated with the use of bendamustine compared to flu/cy LDC in patients receiving CD19 CAR T cells for B-cell non-Hodgkin lymphoma (B-NHL). METHODS: In this retrospective analysis we included patients with relapse/ refractory B-NHL (follicular lymphoma (FL), mantle cell lymphoma (MCL), and large B cell lymphoma (LBCL)) treated with commercial CD19 CAR-T from Memorial Sloan Kettering Cancer Center (MSKCC) and Hackensack Meridian Health (HMH) between January 2020 to December 2022. We compared the outcomes and toxicity of those patients who received bendamustine LDC to historical controls treated with flu/cy. Response and toxicities including CRS and ICANS were assessed using the Lugano 2014 and ASTCT criteria, respectively. RESULTS: Two hundred and forty-two B-NHL (21 FL, 25 MCL, 196 LBCL) patients underwent CAR-T infusion, with 179 receiving flu/cy and 63 receiving bendamustine LDC. Baseline characteristics were comparable in each group except for number of lines of prior therapy, with the bendamustine group having received a median of 2 lines of prior therapy compared to 3 lines in the flu/cy group (p = 0.005). Patients with LBCL receiving bendamustine LDC had overall lower rates of all grade CRS (58% vs. 83%, p < 0.001), and all grade ICANS (6% vs. 31%, p < 0.001), as well as grade 3+ CRS (0% vs. 28%, p = 0.6) and grade 3+ ICANS (0% vs. 12%, p = 0.004). Additionally, LBCL patients receiving bendamustine had lower rates of D+30 neutropenia (absolute neutrophil counts 2.05 versus 1.40, p = 0.02), and a lower cumulative incidence of febrile neutropenia at D+30 (6.2% (95% CI 1.6 - 16) versus 38% (95% CI 30-46%)). The median follow-up for patients with LBCL who received bendamustine LDC was 4.3 months (95% CI 3.8 - 6) and 13 months (95% CI 12-17) in those receiving flu/cy LDC. Analysis of the best overall response rate (ORR) by day 100 of the LBCL cohort did not reveal any significant difference based on the type of LDC received (70% versus 77%, respectively, p = 0.4). Within the LBCL group, there was no significant difference in the bendamustine versus flu/cy groups with the estimated 1-year progression free survival at 40% (95% CI 25-64) versus 42% (95% CI 33-52) (Figure 1), and 1-year overall survival of 76% (95% CI 61-93) versus 68% (95% CI 59-77), respectively. CONCLUSIONS: Bendamustine LDC appears to be a satisfactory LDC agent with a more favorable toxicity profile compared to flu/cy in patients receiving CD19 CAR T cells for B-NHL. While we noted comparable outcomes between the two groups, the short follow-up time in the bendamustine group currently limits a clearer assessment of potential differences in survival between the two groups. Longer follow up is necessary to ensure responses are sustained in those receiving bendamustine.

Clinical and laboratory features in B-cell non-Hodgkin lymphoma patients with positive hepatitis B surface antigen

Clinical and laboratory features in B-cell non-Hodgkin lymphoma patients with positive hepatitis B surface antigen

CT radiomics can predict disease progression within 6 months after chimeric antigen receptor-modified T-cell therapy in relapsed/refractory B-cell non-Hodgkin's lymphoma patients

To predict progression within 6 months after chimeric antigen receptor-modified (CAR) T-cell therapy for relapsed/refractory (R/R) B-cell non-Hodgkin's lymphoma (B-NHL) patients by radiomic indexes derived from contrast-enhanced computed tomography (CECT) examinations. Seventy R/R B-NHL patients who underwent CECT before treatment with CAR T-cells were examined retrospectively. In total, 297 volumes of interest for lesions were segmented from CECT images. Patients without and with disease progression were assigned to groups 1 and 2, respectively. Radiomic and combined predictive models were constructed by three machine-learning algorithms using features from the training set, respectively. Furthermore, predictive models were constructed based on multi-lesion-based and largest-lesion-based radiomic features, respectively. In the test set, no marked differences were observed between the areas under the curves (AUCs) of the combined and radiomic models for all three machine-learning algorithms (all p>0.05). Differences in machine-learning algorithms did not significantly affect the predictive performances of the models. Radiomics and combined models constructed with multi-lesion-based radiomic features showed better predictive performances than those applying largest-lesion-based radiomic features (all p<0.05 for comparisons between combined models). CECT-based radiomic features may be applied to predict disease progression in R/R B-NHL patients within 6 months after CAR T-cell treatment, and radiomic features from multiple lesions may have better predictive efficacy. Different machine-learning algorithms may not show significant differences in prediction performance.

A phase 1 study of AT101, a novel anti-CD19 CAR-T cell therapy targeting a membrane-proximal epitope of CD19, in patients with relapsed or refractory B cell non-Hodgkin lymphoma.

7522 Background: All the FDA-approved CD19 CAR-T products are based on FMC63 scFv, which binds to the membrane-distal region of CD19. We developed a novel anti-CD19 antibody clone (1218) that binds to a membrane-proximal epitope of CD19, thereby not competing with FMC63. AT101 is an autologous CAR T cell transduced with a lentiviral vector, including the CD19-CAR with a humanized scFv of 1218, 4-1BB costimulatory, and CD3zeta domain. Methods: In this phase 1 trial, patients (n = 3 per dose level; up to n = 18 in total) are treated with AT101 in 3 dose-escalation cohorts based on a standard 3 + 3 design. Each patient received a single intravenous dose of AT101 at dose level (DL) 1 (0.2 x 106 cells/kg), DL2 (1.0 x 106 cells/kg), or DL3 (5.0 x 106 cells/kg). The primary objective is to determine the safety, the maximum tolerated dose (MTD), and the recommended phase 2 dose (RP2D) of AT101. The secondary objective is to evaluate the pharmacokinetics of AT101 and the preliminary efficacy, such as overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), event-free survival (EFS), and overall survival (OS). Key eligibility criteria include patients aged ≥19 with histologically confirmed relapsed or refractory B-cell non-Hodgkin lymphoma (NHL). Results: Fourteen patients were enrolled from March 2022 to December 2022, and nine were treated. The median age of treated patients was 61.6 years (ranged from 39 to 84) after a median of 4 prior lines of therapy (range 2-10). Their subtypes of NHL were as follows: diffuse large B cell lymphoma (n = 4), follicular lymphoma (n = 3), mantle cell lymphoma (n = 1), or marginal zone lymphoma (n = 1). The dosing of AT101 at DL1 and DL2 was completed. The dosing at DL3 is ongoing. Across cohorts 1 and 2, no grade 3 or higher cytokine release syndrome (CRS) was reported. Among the first three patients at DL1, one dose-limiting toxicity (DLT) of grade 4 neurotoxicity was observed but resolved in a week without sequelae. No other DLTs were observed in the additional three patients at the DL1 and three at the DL2 cohort. Another one at DL2 experienced grade 1 CRS with grade 1 neurotoxicity. Five patients experienced Grade ≥3 hematologic toxicities. An ORR is 66.7% (4/6) in cohort 1 and 100% (3/3) in cohort 2, including six complete responses (CR, 50.0% [3/6] in cohort 1 and 100% [3/3] in cohort 2). As of February 13, 2023, all six CRs are ongoing, including two patents exceeding six months after the treatments. Updated results will be presented at the meeting, including the cohort of DL3. Conclusions: In this phase I study, AT101 was well tolerated at the first two dose levels and showed promising efficacy in relapsed or refractory B-cell NHL patients. The majority of adverse effects were transient and manageable. The administrations of DL3 are currently ongoing, and updated results will be presented at the meeting. Clinical trial information: NCT05338931 .

G protein-coupled receptor 183 mediates the sensitization of Burkitt lymphoma tumors to CD47 immune checkpoint blockade by anti-CD20/PI3Kδi dual therapy.

Immunotherapy-based regimens have considerably improved the survival rate of B-cell non-Hodgkin lymphoma (B-NHL) patients in the last decades; however, most disease subtypes remain almost incurable. TG-1801, a bispecific antibody that targets CD47 selectively on CD19+ B-cells, is under clinical evaluation in relapsed/refractory (R/R) B-NHL patients either as a single-agent or in combination with ublituximab, a new generation CD20 antibody. A set of eight B-NHL cell lines and primary samples were cultured in vitro in the presence of bone marrow-derived stromal cells, M2-polarized primary macrophages, and primary circulating PBMCs as a source of effector cells. Cell response to TG-1801 alone or combined with the U2 regimen associating ublituximab to the PI3Kδ inhibitor umbralisib, was analyzed by proliferation assay, western blot, transcriptomic analysis (qPCR array and RNA sequencing followed by gene set enrichment analysis) and/or quantification of antibody-dependent cell death (ADCC) and antibody-dependent cell phagocytosis (ADCP). CRISPR-Cas9 gene edition was used to selectively abrogate GPR183 gene expression in B-NHL cells. In vivo, drug efficacy was determined in immunodeficient (NSG mice) or immune-competent (chicken embryo chorioallantoic membrane (CAM)) B-NHL xenograft models. Using a panel of B-NHL co-cultures, we show that TG-1801, by disrupting the CD47-SIRPα axis, potentiates anti-CD20-mediated ADCC and ADCP. This led to a remarkable and durable antitumor effect of the triplet therapy composed by TG-1801 and U2 regimen, in vitro, as well as in mice and CAM xenograft models of B-NHL. Transcriptomic analysis also uncovered the upregulation of the G protein-coupled and inflammatory receptor, GPR183, as a crucial event associated with the efficacy of the triplet combination. Genetic depletion and pharmacological inhibition of GPR183 impaired ADCP initiation, cytoskeleton remodeling and cell migration in 2D and 3D spheroid B-NHL co-cultures, and disrupted macrophage-mediated control of tumor growth in B-NHL CAM xenografts. Altogether, our results support a crucial role for GPR183 in the recognition and elimination of malignant B cells upon concomitant targeting of CD20, CD47 and PI3Kδ, and warrant further clinical evaluation of this triplet regimen in B-NHL.

Anti-CD20 antibodies and bendamustine attenuate humoral immunity to COVID-19 vaccination in patients with B-cell non-Hodgkin lymphoma

Serologic responses of COVID-19 vaccine are impaired in patients with B-cell lymphoma, especially those who had recently been treated with anti-CD20 monoclonal antibodies. However, it is still unclear whether those patients develop an immune response following vaccination. We investigated the efficacy of vaccination against SARS-CoV-2 in 171 patients with B-cell non-Hodgkin lymphoma (B-NHL) who received two doses of an mRNA-based COVID-19 vaccine and we compared the efficacy of vaccination to that in 166 healthy controls. Antibody titers were measured 3 months after administration of the second vaccine dose. Patients with B-NHL showed a significantly lower seroconversion rate and a lower median antibody titer than those in healthy controls. The antibody titers showed correlations with the period from the last anti-CD20 antibody treatment to vaccination, the period from the last bendamustine treatment to vaccination and serum IgM level. The serologic response rates and median antibody titers were significantly different between diffuse large B-cell lymphoma (DLBCL) patients in whom anti-CD20 antibody treatment was completed within 9 months before vaccination and follicular lymphoma (FL) patients in whom anti-CD20 antibody treatment was completed within 15 months before vaccination. Moreover, the serologic response rates and median antibody titers were significantly different among FL patients in whom bendamustine treatment was completed within 33 months before vaccination. We demonstrated that B-NHL patients who were recently treated with anti-CD20 antibodies and bendamustine had a diminished humoral response to COVID-19 vaccination. UMIN 000,045,267.