Refractory B-cell Lymphoma Research Articles

Eleven cases of laryngeal edema after tisagenlecleucel infusion: a 3-year single center retrospective study of CD19-directed chimeric antigen receptor T-cell therapy for relapsed and refractory B-cell lymphomas.

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CAR-T cell therapy in evolving therapeutic landscape of relapsed or refractory primary mediastinal b-cell lymphoma (PMBCL): challenges and aspirations — two case reports

CAR-T cell therapy in evolving therapeutic landscape of relapsed or refractory primary mediastinal b-cell lymphoma (PMBCL): challenges and aspirations — two case reports

Pembrolizumab in Japanese patients with primary mediastinal large B-cell lymphoma: results from the KEYNOTE-A33 study.

KEYNOTE-A33 (NCT04317066) is an open-label, single-arm, phase 1 trial designed to evaluate the safety and efficacy of pembrolizumab in Japanese patients with relapsed or refractory (R/R) primary mediastinal large B-cell lymphoma (PMBCL). Patients received pembrolizumab 200mg every 3weeks for up to 35 cycles. The primary endpoints were safety and objective response rate (ORR) per International Working Group 2007 criteria by independent central review. The secondary endpoint was disease control rate (DCR). Duration of response (DOR), progression-free survival (PFS), and overall survival (OS) were exploratory. Seven patients were enrolled and treated; the median age was 32years (range 26-43) and 86% were female. The median time from the first dose to data cutoff (April 12, 2022) was 5.6months (range 2.4-21.2). Grade 3-5 treatment-related adverse events (AEs) occurred in 2 patients (29%; 2 grade 4 neutropenia, 1 grade 3 febrile neutropenia); however, no patient discontinued pembrolizumab or died because of treatment-related AEs. The ORR was 43% [95% confidence interval (CI) 10-82]. DCR was 57% (95% CI 18-90). Median DOR was not reached (NR). Four (57%) patients had a reduction in target lesion size of ≥ 50%. The median PFS was 2.9months (95% CI 2.6-NR). The median OS was 17.5months (95% CI NE-NE), and the 12months OS rate was 100%. Overall, pembrolizumab had manageable safety and clinically meaningful antitumor activity in Japanese patients with R/R PMBCL, results that were consistent with those observed in prior global studies. Registry and the Registration No. of the study/trial: Clinicaltrials.gov: NCT04317066.

ABCL-185 Mosunetuzumab wWth Polatuzumab Vedotin: Subgroup Analyses in Patients (pts) With Primary Refractory or Early Relapsed Large B-Cell Lymphoma (LBCL)

ABCL-185 Mosunetuzumab wWth Polatuzumab Vedotin: Subgroup Analyses in Patients (pts) With Primary Refractory or Early Relapsed Large B-Cell Lymphoma (LBCL)

Nivolumab for CNS relapsed refractory primary mediastinal B-cell lymphoma: case report and review of the literature

Nivolumab for CNS relapsed refractory primary mediastinal B-cell lymphoma: case report and review of the literature

Mosunetuzumab With Polatuzumab Vedotin: Subgroup Analyses in Patients (pts) With Primary Refractory or Early Relapsed Large B-Cell Lymphoma (LBCL)

Mosunetuzumab With Polatuzumab Vedotin: Subgroup Analyses in Patients (pts) With Primary Refractory or Early Relapsed Large B-Cell Lymphoma (LBCL)

Bendamustine is a safe and effective lymphodepletion agent for axicabtagene ciloleucel in patients with refractory or relapsed large B-cell lymphoma

BackgroundFludarabine in combination with cyclophosphamide (FC) is the standard lymphodepletion regimen for CAR T-cell therapy (CAR T). A national fludarabine shortage in 2022 necessitated the exploration of alternative regimens with...

Real-world use of tisagenlecleucel in children and young adults with relapsed or refractory B-cell lymphomas

Real-world use of tisagenlecleucel in children and young adults with relapsed or refractory B-cell lymphomas

Salvage CD20-SD-CART therapy in aggressive B-cell lymphoma after CD19 CART treatment failure.

Patients with relapsed/refractory aggressive B-cell lymphoma(r/r aBCL)who progressed after CD19-specific chimeric antigen receptor T-cell therapy (CD19CART) had a poor prognosis. Application of CAR T-cells targeting a second different antigen (CD20) expressed on the surface of B-cell lymphoma as subsequent anti-cancer salvage therapy (CD20-SD-CART) is also an option. This study aimed to evaluate the survival outcome of CD20-SD-CART as a salvage therapy for CD19 CART treatment failure. This retrospective cohort study enrolled patients with aBCL after the failure of CD19 CART treatment at Beijing Gobroad Boren Hospital from December 2019 to May 2022. Patients were subsequently treated with CD20CART therapy or non-CART therapy (polatuzumab or non-polatuzumab). A total of 93 patients were included in the study, with 54 patients receiving CD20-SD-CART therapy. After a median follow-up of 18.54 months, the CD20-SD-CART group demonstrated significantly longer median progression-free survival (4.04 months vs. 2.27 months, p=0.0032) and median overall survival (8.15 months vs. 3.02 months, p<0.0001) compared to the non-CART group. The complete response rate in the CD20-SD-CART group (15/54, 27.8%) was also significantly higher than the non-CART group (3/38, 7.9%, p=0.03). Multivariate analysis further confirmed that CD20CART treatment was independently associated with improved overall survival (HR, 0.28; 95% CI, 0.16-0.51; p<0.0001) and progression-free survival (HR, 0.46; 95% CI, 0.27-0.8; p=0.005). CD20-SD-CART could serve as an effective therapeutic option for patients with relapsed or refractory aggressive B-cell lymphoma after CD19CART treatment failure.

Mosunetuzumab with polatuzumab vedotin: Subgroup analyses in patients (pts) with primary refractory or early relapsed large B-cell lymphoma (LBCL).

7021 Background: The primary analysis of mosunetuzumab with polatuzumab vedotin (mosun-pola) in the Phase Ib/II study (NCT03671018) demonstrated durable responses and manageable safety in pts with relapsed or refractory (R/R), transplant-ineligible LBCL (Budde et al. Nat Med 2023). Here, we present results for primary refractory (refr) or early relapse (rel) subgroups from this study after a median follow-up of 23.9 months. Methods: Pts with R/R LBCL (diffuse LBCL not otherwise specified [NOS], high-grade B-cell lymphoma [HGBCL], transformed follicular lymphoma (FL), and FL grade 3b) and who received ≥1 prior line of therapy (including an anti-CD20 antibody) were treated with mosun-pola. Refr was defined as SD, PD, PR, or CR with relapse &lt;3 months after first-line (1L) therapy. Rel was defined as CR with relapse ≥3 and ≤12 months after 1L therapy. The primary endpoint was best overall response rate (ORR) by IRC using Lugano 2014 response criteria. Key secondary endpoints included CR rate, duration of response (DOR), duration of CR (DOCR), progression-free survival (PFS), overall survival (OS), and safety. Results: As of July 6, 2023, of the 98 pts in the overall population, 45 (46%) and 27 (28%) pts had refr or rel LBCL, respectively. At baseline, the median age in the refr and rel subgroups was 68 and 70 years respectively; 23/45 pts (51%) and 6/27 pts (22%) were treated with mosun-pola as second-line, respectively. The majority of refr/rel pts had DLBCL NOS (71%; 78%) or HGBCL (24%; 19%), Ann Arbor stage III/IV (80%; 89%), elevated LDH (55%; 48%), and extranodal involvement (67%; 59%). In refr pts, the ORR was 49%, which was generally consistent with the overall population (59%); although the sample size was limited, higher responses (ORR: 74%) were observed in rel pts. Additional clinical outcomes are reported (Table). The safety profile was consistent with the overall population. Grade 3 CRS occurred in one pt in each subgroup. Treatment-related ICANS-like events occurred in 2/45 pts (4%; refr) and 3/27 pts (11%; rel). Conclusions: Mosun-pola demonstrated durable benefits in ORR and CR rates irrespective of a poor response to 1L treatment. Outcomes for pts with refr or rel LBCL are encouraging. Clinical trial information: NCT03671018 . [Table: see text]

Abstract CT194: N-myristoylation inhibitor zelenirstat: New mechanistic insights and efficacy signals from a first in human phase I study

Abstract Introduction. Zelenirstat (PCLX-001) is a small molecule inhibitor of N-myristoylation, a process that involves addition of the fatty acid myristate to over 200 proteins by two N-myristoyltransferases (NMT1 and 2). These include Src family kinases and c-Abl. Inhibition of N-myristoylation by zelenirstat leads to the degradation of non-myristoylated proteins and cancer cell death. We conducted a phase I trial to evaluate the safety, tolerability, and maximally tolerated dose (MTD) of zelenirstat in patients with refractory cancer. Methods. Differential mass spectrometry was performed in NMT1 and NMT2 CRISPR/Cas9 KOs or zelenirstat-treated HAP1 cells to identify N-myristoylation-regulated proteins. Fully consented patients with advanced solid malignancies or refractory B-cell lymphomas were administered escalating doses of zelenirstat in 28-day cycles until progression or dose-limiting toxicity (DLT). Results. Proteomic analysis of cells with genetic or pharmacological NMT inhibition was performed to gain insights into NMT substrates and function. In addition to the rapid degradation of SFKs, which disrupts the pro-survival signaling of RTKs, we identified multiple respiratory complex I proteins as the most degraded, including NDUFAF4. NMT1 KO and zelenirstat treatment disrupted complex I leading to oxidative phosphorylation (OXPHOS) inhibition, which is essential for both cancer stem cell survival and metastasis. Continuous once-daily zelenirstat at 20 mg to 210 mg was well tolerated, with no dose-limiting toxicities in 24 patients up to and including 210 mg. Gastrointestinal DLTs were observed in the 280 mg cohort, establishing 210 mg as the MTD. Oral absorption was rapid, and pharmacokinetics were suitable for once daily dosing. Seven patients had stable disease as best response, including pancreatic, ovarian and colon cancer patients; one colon cancer patient with 5 prior lines of therapy continues 210 mg beyond 11 cycles with reduction in carcinoembryonic antigen (CEA) and tumor dimensions. Kaplan-Meier analysis revealed longer progression-free survival (log-rank p=0.033) and overall survival (p=0.026) in the patients treated at 210 mg (n=7) when compared with patients treated in lower dose cohorts (n=17). Conclusion. Zelenirstat has a unique dual impact on growth signaling and OXPHOS. Having previously demonstrated pre-clinical efficacy in hematologic cancers in vitro and in vivo, we now demonstrate the therapeutic potential of zelenirstat in patients with refractory advanced solid malignancies, warranting further clinical evaluation in these indications. Citation Format: Luc Gerard Berthiaume, Erwan Beauchamp, Jay Gamma, Rony Pain, Morris A. Kostiuk, Christopher R. Cromwell, Eman W. Moussa, Olivier Julien, Basil P. Hubbard, John Kuruvilla, Laurie H. Sehn, Jennifer Spratlin, Rahima Jamal, Randeep Sangha, John R. Mackey. N-myristoylation inhibitor zelenirstat: New mechanistic insights and efficacy signals from a first in human phase I study [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 CT194.

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

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

Using Oncolytic Virus to Retask CD19-Chimeric Antigen Receptor T Cells for Treatment of Pancreatic Cancer: Toward a Universal Chimeric Antigen Receptor T-Cell Strategy for Solid Tumor.

Chimeric antigen receptor (CAR) T cells targeting the B-cell antigen CD19 are standard therapy for relapsed or refractory B-cell lymphoma and leukemia. CAR T cell therapy in solid tumors is limited due to an immunosuppressive tumor microenvironment and a lack of tumor-restricted antigens. We recently engineered an oncolytic virus (CF33) with high solid tumor affinity and specificity to deliver a nonsignaling truncated CD19 antigen (CD19t), allowing targeting by CD19-CAR T cells. Here, we tested this combination against pancreatic cancer. We engineered CF33 to express a CD19t (CF33-CD19t) target. Flow cytometry and ELISA were performed to quantify CD19t expression, immune activation, and killing by virus and CD19-CAR T cells against various pancreatic tumor cells. Subcutaneous pancreatic human xenograft tumor models were treated with virus, CAR T cells, or virus+CAR T cells. In vitro, CF33-CD19t infection of tumor cells resulted in >90% CD19t cell-surface expression. Coculturing CD19-CAR T cells with infected cells resulted in interleukin-2 and interferon gamma secretion, upregulation of T-cell activation markers, and synergistic cell killing. Combination therapy of virus+CAR T cells caused significant tumor regression (day 13): control (n = 16, 485 ± 20 mm 3 ), virus alone (n = 20, 254 ± 23 mm 3 , p = 0.0001), CAR T cells alone (n = 18, 466 ± 25 mm 3 , p = NS), and virus+CAR T cells (n = 16, 128 ± 14 mm 3 , p < 0.0001 vs control; p = 0.0003 vs virus). Engineered CF33-CD19t effectively infects and expresses CD19t in pancreatic tumors, triggering cell killing and increased immunogenic response by CD19-CAR T cells. Notably, CF33-CD19t can turn cold immunologic tumors hot, enabling solid tumors to be targetable by agents designed against liquid tumor antigens.

Chimeric antigen receptor T-cell therapy after COVID-19 in refractory high-grade B-cell lymphoma

Although chimeric antigen receptor T-cell (CAR-T) therapies have dramatically improved the outcomes of relapsed/refractory B-cell malignancies, recipients suffer from severe humoral immunodeficiencies. Furthermore, patients with coronavirus disease 2019 (COVID-19) have a poor prognosis, as noted in several case reports of recipients who had COVID-19 before the infusion. We report the case of a 70-year-old woman who developed COVID-19 immediately before CAR-T therapy for high-grade B-cell lymphoma. She received Tixagevimab−Cilgavimab chemotherapy and radiation therapy but never achieved remission. She was transferred to our hospital for CAR-T therapy, but developed COVID-19. Her symptoms were mild and she was treated with long-term molnupiravir. On day 28 post-infection, lymphodepleting chemotherapy was restarted after a negative polymerase chain reaction (PCR) test was confirmed. The patient did not experience recurrence of COVID-19 symptoms or severe cytokine release syndrome. Based on the analysis and comparison of the previous reports with this case, we believe that CAR-T therapy should be postponed until a negative PCR test is confirmed. In addition, Tixagevimab−Cilgavimab and long term direct-acting antiviral agent treatment can be effective prophylaxis for severe COVID-19 and shortening the duration of infection.

ADCT-602, a Novel PBD Dimer-containing Antibody-Drug Conjugate for Treating CD22-positive Hematologic Malignancies.

Relapsed or refractory B-cell acute lymphoblastic leukemia (R/R B-ALL) and lymphomas have poor patient outcomes; novel therapies are needed. CD22 is an attractive target for antibody-drug conjugates (ADCs), being highly expressed in R/R B-ALL with rapid internalization kinetics. ADCT-602 is a novel CD22-targeting ADC, consisting of humanized mAb hLL2-C220, site specifically conjugated to the pyrrolobenzodiazepine dimer-based payload tesirine. In preclinical studies, ADCT-602 demonstrated potent, specific cytotoxicity in CD22-positive lymphomas and leukemias. ADCT-602 was specifically bound, internalized, and trafficked to lysosomes in CD22-positive tumor cells; after cytotoxin release, DNA interstrand crosslink formation persisted for 48 hours. In the presence of CD22-positive tumor cells, ADCT-602 caused bystander killing of CD22-negative tumor cells. A single ADCT-602 dose led to potent, dose-dependent, in vivo antitumor activity in subcutaneous and disseminated human lymphoma/leukemia models. Pharmacokinetic analyses (rat and cynomolgus monkey) showed excellent stability and tolerability of ADCT-602. Cynomolgus monkey B cells were efficiently depleted from circulation after one dose. Gene signature association analysis revealed IRAK1 as a potential marker for ADCT-602 resistance. Combining ADCT-602 + pacritinib was beneficial in ADCT-602-resistant cells. Chidamide increased CD22 expression on B-cell tumor surfaces, increasing ADCT-602 activity. These data support clinical testing of ADCT-602 in R/R B-ALL (NCT03698552) and CD22-positive hematologic cancers.

Hypofractionated radiotherapy for refractory or relapsed aggressive B-cell lymphoma in the rituximab era

BackgroundRadiotherapy (RT) is an effective and available local treatment for patients with refractory or relapsed (R/R) aggressive B-cell lymphomas. However, the value of hypofractionated RT in this setting has not been confirmed.MethodsWe retrospectively analyzed patients with R/R aggressive B-cell lymphoma who received hypofractionated RT between January 2020 and August 2022 at a single institution. The objective response rate (ORR), overall survival (OS), progression-free survival (PFS) and acute side effects were analyzed.ResultsA total of 30 patients were included. The median dose for residual disease was 36 Gy, at a dose per fraction of 2.3–5 Gy. After RT, the ORR and complete response (CR) rates were 90% and 80%, respectively. With a median follow-up of 10 months (range, 2–27 months), 10 patients (33.3%) experienced disease progression and three died. The 1-year OS and PFS rates for all patients were 81.8% and 66.3%, respectively. The majority (8/10) of post-RT progressions involved out-of-field relapses. Patients with relapsed diseases, no response to systemic therapy, multiple lesions at the time of RT, and no response to RT were associated with out-of-field relapses. PFS was associated with response to RT (P = 0.001) and numbers of residual sites (P < 0.001). No serious non-hematological adverse effects (≥ grade 3) associated with RT were reported.ConclusionThese data suggest that hypofractionated RT was effective and tolerable for patients with R/R aggressive B-cell lymphoma, especially for those that exhibited localized residual disease.

Improving the safety of CAR-T-cell therapy: The risk and prevention of viral infection for patients with relapsed or refractory B-cell lymphoma undergoing CAR-T-cell therapy.

Chimeric antigen receptor (CAR) T-cell therapy, an innovative immunotherapeutic against relapsed/refractory B-cell lymphoma, faces challenges due to frequent viral infections. Despite this, a comprehensive review addressing risk assessment, surveillance, and treatment management is notably absent. This review elucidates immune response compromises during viral infections in CAR-T recipients, collates susceptibility risk factors, and deliberates on preventive strategies. In the post-pandemic era, marked by the Omicron variant, new and severe threats to CAR-T therapy emerge, necessitating exploration of preventive and treatment measures for COVID-19. Overall, the review provides recommendations for viral infection prophylaxis and management, enhancing CAR-T product safety and recipient survival.

Early failure is still a poor prognostic factor in patients with relapsed or refractory large B-cell lymphoma in the era of CAR T-cell therapy.

Patients with refractory or relapsed (R/R) large B-cell lymphoma (LBCL) refractory to first-line chemotherapy or with early relapse have poor outcomes. While chimeric antigen receptor (CAR) T-cell therapy has impressive efficacy after two or more lines of chemotherapy, it's still uncertain if these outcomes remain consistent in the context of third-line CAR T-cell therapy. We conducted a retrospective study of 107 R/R LBCL patients. Patients with relapse 12 months or more after their first-line chemoimmunotherapy (late failure: n = 25) had significantly longer overall survival (OS) than patients with refractory disease or relapse within 12 months (early failure: n = 82) (median OS: not achieved vs. 18.4 months; P < 0.001). Among patients who proceeded to autologous hematopoietic stem-cell transplantation (auto-HSCT), those with late failure had significantly longer event-free survival (EFS) than those with early failure (median EFS: 26.9 vs. 3.1 months; P = 0.012). However, no significant difference in EFS was detected among patients who underwent CAR T-cell therapy (median EFS: not reached vs. 11.8; P = 0.091). Cox regression with restricted cubic spline demonstrated that timing of relapse had significant impact on EFS in patients with auto-HSCT but not in patients with CAR T-cell therapy. Of patients who were scheduled for CAR T-cell therapy, those with late failure were significantly more likely to receive CAR T-cell therapy than those with early failure (90% vs. 57%; P = 0.008). In conclusion, patients with early failure still experienced poor outcomes after the approval of third-line CAR T-cell therapy.

CAR T-cell therapy for malignant lymphoma

Advances in understanding of the pathogenesis of B-cell lymphoma have led to development of various novel targeted therapies. Among them, CD19-targeted chimeric antigen receptor (CAR) T-cell therapies for relapsed and refractory B-cell lymphomas have shown remarkable efficacy in clinical trials, and three CAR T-cell products are now available in Japan. Real-world evidence (RWE) has shown that these products can provide comparable efficacy to clinical trials in clinical practice, where CAR T-cells were administered in patients with wider range of backgrounds. This finding will certainly broaden the role of CAR T-cell therapies in the treatment of B-cell lymphoma. However, since about half of the patients treated with CAR T-cell therapy progress thereafter, there is an urgent need for risk stratification and optimized management of refractory cases. Here, we review the results of clinical trials and RWE of CAR T-cell therapy in B-cell lymphoma.

Mosunetuzumab-a newly emerged hope in relapse or refractory B-cell lymphomas

Mosunetuzumab-a newly emerged hope in relapse or refractory B-cell lymphomas