Combination of acalabrutinib with lenalidomide and rituximab in relapsed/refractory aggressive B-cell non-Hodgkin lymphoma: a single-arm phase II trial

Rituximab: a review of its use in non-Hodgkin's lymphoma and chronic lymphocytic leukaemia.

T.M. AnoopBackground The role of serum free light chain (FLC) as a prognostic biomarker in lymphoproliferative diseases is being increasingly studied. In this study we present the 5-year survival outcome for patients with aggressive B-cell non-Hodgkin's lymphoma (NHL) and their relation to FLC and other known prognostic markers. Materials and Methods This is a prospective study conducted in patients diagnosed with aggressive B-cell NHL. Serum FLC level and ratio were estimated prior to initiation of treatment. Results A total of 100 patients were included in the study from December 2013 to December 2015 with a median age of 53 years. Thirty-eight patients (38%) had elevated FLC level of which 26% were polyclonal and 12% were monoclonal elevations. Abnormal FLC ratio was noted in 12% patients. Median follow-up duration of the study was 75 months. Five-year relapse-free survival (RFS) for the study population was 54.4%. Five-year RFS was 64.1% for early stage and 48.2% for advanced stage diseases ( p = 0.05). The RFS was significantly better in age less than 60 years (59.5% vs 43.8%, p < 0.001). Five-year overall survival (OS) was 61.3%. OS was significantly better in younger patients (73.6% vs 33.4%, p < 0.001), with International Prognosis Index score of 0 to 2 (87.4% vs 26.7%, p < 0.001). Patients with elevated FLC had inferior RFS (50% vs 71.4%, p = 0.04). Abnormal FLC ratio also strongly corresponded to inferior RFS (54.5% vs 66.2%, p = 0.001). OS was also significantly inferior in patients with abnormal FLC ratio (72.6% vs 63.6%, p = 0.001). Conclusion In patients with newly diagnosed aggressive B-cell NHL, elevated FLC levels and abnormal FLC ratio were significantly associated with inferior survival.

Background: Many patients with relapsed/refractory (R/R) aggressive B-cell non-Hodgkin lymphoma (B-NHL) are unable to tolerate, access, or benefit from intensive chemo-therapeutic approaches or cellular therapies and will invariably relapse; therefore, novel approaches are urgently required. Odronextamab (REGN1979) is a hinge-stabilized, human CD20 × CD3 IgG4-based bispecific antibody that elicits T-cell-mediated cytotoxicity of malignant B cells. In a Phase 1 study, odronextamab monotherapy showed a manageable safety profile with encouraging preliminary activity in heavily pre-treated patients with R/R B-NHL (Bannerji R, et al. Lancet Haematol. 2022;9(5):e327-39). REGN5837 is a hinge-stabilized, human CD28 × CD22 IgG4-based bispecific antibody that provides a co-stimulatory signal (signal 2). When combined with odronextamab (signal 1), REGN5837 improved anti-tumor efficacy and survival in in vivo diffuse large B-cell lymphoma tumor models via enhanced T-cell expansion. We hypothesize that combining REGN5837 with odronextamab may deepen and extend anti-tumor activity in patients with aggressive lymphoma. Methods: ATHENA-1 (NCT05685173) is a Phase 1, open-label, first-in-human study of REGN5837 in combination with odronextamab in patients with R/R aggressive B-NHL. During induction, odronextamab and REGN5837 will be administered weekly over 21-day cycles. To mitigate potential CRS events, odronextamab will be introduced with step-up dosing as a monotherapy, followed by introduction of REGN5837 on C2 D15 with step-up dosing. Maintenance will consist of 28-day cycles (odronextamab and REGN5837 administration on D1, 15). Patients who achieve a sustained complete response (≥9 months) will have study drug(s) administration changed to once every 4 weeks. Patients must be aged ≥18 years, have Eastern Cooperative Oncology Group performance status ≤1, with adequate organ function, and have CD20+ aggressive B-NHL that progressed after ≥2 lines of systemic therapy containing at least an anti-CD20 antibody and an alkylating agent, with or without prior chimeric antigen receptor T-cell therapy. Exclusion criteria include prior allogeneic stem cell transplant, organ transplant, or CD20xCD3 bispecific antibodies, or mantle cell lymphoma or central nervous system lymphoma. Primary endpoints are incidence of dose-limiting toxicities and the incidence and severity of treatment-emergent adverse events. Secondary endpoints include pharmacokinetics of odronextamab and REGN5837, anti-drug antibody incidence, objective response rate, complete response rate, duration of response, progression-free survival, and overall survival. Enrolment is planned to open in early 2023. Citation Format: John Baird, Pim G. Mutsaers, Jeremy S. Abramson, Manjusha Namuduri, Jingjin Li, Nickolas A. Sophos, Min Zhu, Jurriaan Brouwer-Visser, Hesham Mohamed, Aafia Chaudhry, Andrew J. Davies. Trial in progress: ATHENA-1 - a phase 1, open-label, first-in-human study to assess safety and tolerability of REGN5837 in combination with odronextamab in patients with relapsed/refractory aggressive B-cell non-Hodgkin lymphomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT129.

Optimising outcomes for patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) remains one of the greatest challenges still facing haemato-oncologists today. The SCHOLAR-1 analysis pooled trial and retrospective data (n = 636) and served to outline the bleak outcomes [median overall survival (OS) 6·3 months] for many of our patients who fail to respond to initial treatment. Poor outcomes included patients refractory to front-line potentially curative treatment (median OS 7·1 months) or relapsing within 12 months of autologous stem cell transplantation (autoSCT) (median OS 6·2 months) (Crump et al., 2017). Clear progress has been made over recent years in the field of cellular therapy, and recently for relapsed, refractory DLBCL patients. Chimeric antigen receptor (CAR) T-cell therapy harnesses patients’ own T-cell-mediated immunity to induce a CD19-directed DLBCL tumour assault. High initial efficacy and durable responses in a significant minority of patients have been demonstrated in phase-II single-arm trials of patients with relapsed or refractory aggressive B-cell non-Hodgkin lymphoma (NHL) (predominantly DLBCL) (Neelapu et al., 2017; Schuster et al., 2018). However, as the authors of the accompanying manuscript highlight, CAR-T therapy is associated with significant toxicities (Neelapu et al., 2018), the challenge of equitable, timely administration across populations, and a substantial financial burden to health-care systems (Hernandez et al., 2018). Whilst maximising cure in the front-line setting is clearly still the preferred goal, the quest remains to find highly efficacious, non-toxic, and widely applicable therapies in patients failing front-line anthracycline-based immunochemotherapy who have otherwise failed or are unsuitable for autoSCT. Pixantrone is a novel aza-anthracenedione which is structurally similar to anthracyclines and is licenced in relapsed or refractory DLBCL and National Institute for Health and Care Excellence (NICE)-approved in the UK following the PIX301 trial (Pettengell et al., 2012). PIX301 compared 85 mg/m2 of pixantrone on days 1, 8 and 15 of a 28-day cycle for up to six cycles, with the control arm of ‘best available monotherapy’ for patients with aggressive B-cell NHL (primarily DLBCL). Seventy patients were randomized in each arm, including single-agent vinorelbine (16%), oxaliplatin (46%), ifosfamide (18%), etoposide (13%), mitoxantrone (6%) and gemcitabine (1%) in the non-pixantrone arm. End of treatment complete response (CR) and overall response rates (ORR) were superior in the pixantrone arm [ORR 37·1% (CR 20·0%) vs. ORR 14·3% (CR 5·7%); CR P = 0·021; ORR P = 0·003]. This resulted in a modest progression-free survival (PFS) advantage in favour of pixantrone (median PFS by intention-to-treat 5·3 vs. 2·6 months; hazard ratio (HR) 0·60, P = 0·005) but no OS benefit was seen. Patients were eligible for this trial if they were initially anthracycline-sensitive. Eligible patients had a documented response to prior anthracycline-based therapy of at least 24 weeks, introducing a key potential source of bias within the study design. Subsequently, a UK-wide retrospective non-trial cohort series (n = 92) demonstrated more limited efficacy (ORR 24%, CR 10%) of pixantrone monotherapy in a heavily-pretreated [median prior lines 3 (range: 2–9)], high-risk patient group (Eyre et al., 2016). Eighty-five percent had refractory DLBCL and 72% had an international prognostic index of 3–5. The median PFS in this UK cohort following NICE approval was a disappointing 2·0 months [95% confidence interval (CI) 1·5–2·4] and the median OS was 3·4 months. Unsurprisingly, patients with anthracycline-sensitive disease (relapsed >12 months from front-line treatment) had a significantly improved PFS on multivariable analysis (HR: 0·43; 95% CI 0·22–0·82;P = 0·011). In light of these data, we eagerly awaited the results of the PIX306, published in this edition of the British Journal of Haematology (Pettengell et al., 2019). Pixantrone combined with rituximab (PIX-R) was randomised 1:1 against gemcitabine plus rituximab (GEM-R) as the standard-of-care arm in this phase-III multicentre trial of 312 patients with relapsed aggressive B-cell NHL deemed ineligible for autoSCT. Briefly, there were no significant differences in median PFS [7·3 (95% CI 5·2–8·4) months with PIX-R vs. 6·3 (95% CI 4·4–8·1) months with GEM-R (HR: 0·85; 95% CI 0·64–1·14; P = 0·28)] or indeed median OS [13·3 (95% CI 10·1–19·8) months with PIX-R vs. 19·6 (95% CI 12·4–31·9) months with GEM-R (HR: 1·13; 95% CI 0·83–1·53)] between the treatment arms. No patient subgroups could be identified for whom PIX-R was statistically more beneficial in terms of survival. The PFS was longer in the control arm than the investigators expected; the initial statistical calculations assumed a median PFS of 2·8 months with GEM-R. The improved PFS was likely due to the exclusion of patients with refractory DLBCL from an otherwise ‘trial-fit’ population. Ultimately this is a negative trial and showed that PIX-R is broadly equivalent in terms of efficacy and survival to GEM-R in patients with aggressive B-cell NHL enriched for DLBCL. Despite this, the authors are to be strongly congratulated for conducting this large international collaborative effort; one of the very few randomised controlled trials in relapsed, refractory aggressive B-cell NHL and the only published phase-III trial to date in exclusively autoSCT-ineligible aggressive B-cell NHL patients. Despite the disappointing outcome of the PIX306 trial, hope remains elsewhere for our patients. The antibody–drug conjugate polatuzumab vedotin targeting the CD79b component of the B-cell receptor, in combination with bendamustine and rituximab (BR), has recently received Food and Drug Administration (FDA) approval for the treatment of adult patients with relapsed or refractory DLBCL for whom autoSCT is not suitable. Approval was based on a small randomised phase-II trial where this combination showed an improved ORR (PET CR: 40% vs. 18%; P = 0.026), PFS (HR: 0.34; P < 0.0001) and OS (HR: 0.42; P = 0.0023) compared to BR (Sehn et al., 2018). This combination seems to represent a step forward in this setting, although no randomised phase-III trial is planned. We do, however, eagerly await the results of the randomised phase-III POLARIX trial (NCT03274492) comparing front-line polatuzumab vedotin plus R-CHP versus R-CHOP. Ongoing clinical trials in the field of relapsed, refractory DLBCL continue to investigate targeted agents of promise. CD19 monoclonal antibodies such as the Fc-engineered tafasitamab in combination with lenalidomide are undergoing active investigation (Salles et al., 2019). This combination has shown interesting efficacy in a phase-II trial (L-MIND; NCT02399085) of relapsed (not refractory) DLBCL. The antibody is currently being tested in a randomised phase-III clinical trial in combination with bendamustine (B-MIND; NCT02763319) and the final results of both studies are awaited with interest. Bi-specific T-cell engagers such as mosunetuzumab or CD20-TCB (RG6026) engage T cells by co-targeting CD3 and a B-cell surface marker (typically CD19 or CD20) and are a drug class of great potential, with impressive efficacy in early phase-I–II trials (Budde et al., 2018; Dickinson et al., 2019). Antibody–drug conjugates such as loncastuximab tesirine (Lonca), which comprises a humanized anti-CD19 antibody conjugated to a potent pyrrolobenzodiazepine dimer toxin, have displayed early efficacy signals. Lonca at ≥120 μg/kg has substantial anti-tumour activity in relapsed, refractory DLBCL (ORR 43.3%) displaying equivalent efficacy in refractory patients compared to those with relapsed disease (Radford et al., 2019). Finally, the novel combination of rituximab, lenalidomide and ibrutinib has shown encouraging activity (ORR 65%) in relapsed or refractory non-germinal centre type DLBCL in response-evaluable patients (Goy et al., 2019). Despite the genuine interest in these newer agents with novel mechanisms of action, continuing to demand the testing of agents demonstrating efficacy in early-phase single-arm trials in large, well-designed randomised clinical phase-III trials such as PIX306 must remain the focus of the international treating community. Only then will we truly understand the value of novel agents of promise in relapsed or refractory DLBCL.

Odronextamab (REGN1979), a Human CD20 x CD3 Bispecific Antibody, Induces Durable, Complete Responses in Patients with Highly Refractory B-Cell Non-Hodgkin Lymphoma, Including Patients Refractory to CAR T Therapy

Molecular genetics of aggressive B-cell lymphoma.

Here, we evaluate the sensitivity and specificity of a new 11-parameter flow cytometry (FCM) approach versus conventional cytology (CC) for detecting neoplastic cells in stabilized CSF samples from newly diagnosed aggressive B-cell non-Hodgkin's lymphoma (B-NHL) at high risk of CNS relapse, using a prospective, multicentric study design. Moreover, we compared the distribution of different subpopulations of CSF leukocytes and the clinico-biologic characteristics of CSF+ versus CSF-, patients, in an attempt to define new algorithms useful for predicting CNS disease. Overall, 27 (22%) of 123 patients showed infiltration by FCM, while CC was positive in only seven patients (6%), with three other cases being suspicious (2%). CC+/FCM+ samples typically had more than 20% neoplastic B cells and/or >or= one neoplastic B cell/microL, while FCM+/CC- samples showed lower levels (P < .0001) of infiltration. Interestingly, in Burkitt lymphoma, presence of CNS disease by FCM could be predicted with a high specificity when increased serum beta2-microglobulin and neurological symptoms coexisted, while peripheral blood involvement was the only independent parameter associated with CNS disease in diffuse large B-cell lymphoma, with low predictive value. FCM significantly improves the sensitivity of CC for the identification of leptomeningeal disease in aggressive B-NHL at higher risk of CNS disease, particularly in paucicellular samples.

Although Hodgkin lymphoma (HL) is not considered an AIDSdefining malignancy, population-based studies have demonstrated an increased incidence of this disease in the setting of HIV infection. In a prospective cohort study of 11,112 individuals who were positive for HIV, with 71,687 patient-years of follow-up, the incidence of HL was 14 times higher than in the general population. In contrast to other HIV-associated malignancies that occur more commonly with severe immunocompromise, HL is associated with moderate immunologic impairment and the incidence actually seems to decline at CD4 lymphocyte counts of less than 200/ L. Although incidence rates for the AIDS-defining malignancies (Kaposi’s sarcoma, aggressive B-cell non-Hodgkin lymphoma [NHL]) have fallen, the incidence of HL may actually be increasing since the advent of combination antiretroviral therapy (cART), perhaps as a consequence of improvement in the level of immune function. However, the increased relative risk of HL is substantially lower than that observed for aggressive B-cell lymphoma. As a result of the small number of cases, studies investigating approaches to management of HIV-associated HL have been largely retrospective in design. For the more common AIDS-defining lymphomas, diffuse large B-cell lymphoma and Burkitt lymphoma, outcomes have improved dramatically in the 16 years since the introduction of active antiretroviral therapies, which have transformed HIV disease into a survivable chronic illness. Prospective studies in the pre-cART era demonstrated 2-year overall survival (OS) in the 10% to 20% range with complete remission (CR) rates of 35% to 50%, far inferior to those observed in non-HIV–associated lymphomas. Prognosis at that time was largely dependent on the severity of immunosuppression rather than on features of the lymphoma. This experience changed with the advent of cART such that now treatment outcomes using standard regimens such as rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone or dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab approach those observed in the non-HIV–infected population, with CR rates of 65% to 77% and 2-year OS rates of more than 60%. The International Prognostic Index (IPI) score seems to be a significant prognostic factor in patients treated with chemotherapy and concurrent cART. On the basis of the age-adjusted IPI score, the survival of patients in one trial using rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone was similar to that achieved by patients with aggressive lymphomas who were not infected with HIV. HL in the HIV-seropositive population is more likely to have mixed cellularity or lymphocyte-depleted histology and is almost always Epstein-Barr virus–associated. The majority of patients present with advanced-stage disease. Before the introduction of cART, treatment outcomes for HIV-HL were poor. In an Italian retrospective study of 114 patients with HIV-associated HL who received various standard chemotherapeutic regimens, the median OS was 15 months. Sixty percent died, 35% of those from opportunistic infection, 33% from HL, and 12% from both. As has been the case for aggressive B-cell lymphomas in patients with HIV infection, small retrospective and prospective studies have suggested improvement in outcome with the advent of cART. A retrospective study of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) with cART in 62 patients with advanced-stage HIVassociated HL demonstrated a CR rate of 87% and 5-year OS of 76%. A prospective trial reported a CR rate of 81% and 2-year OS of 51% in 59 patients treated with the Stanford V regimen (doxorubicin, vinblastine, mechlorethamine, vincristine, bleomycin, etoposide, and prednisone) administered with antiretroviral therapy. The fact that only 10% of these patients received radiotherapy suggests that the regimen was either not delivered as designed or that the inclusion of patients with early-stage and low-bulk disease (factors associated with inferior outcome with this regimen) resulted in relatively disappointing outcomes. In the article that accompanies this editorial, the German HIV-Related Lymphoma Study Group presents data from the largest prospective trial ever conducted in patients with HIV-associated HL. In this study, 112 patients were allocated to treatment on the basis of stage and risk category. Those with early-stage favorable disease (IA/B or IIA/B) received two to four cycles of ABVD plus 30 Gy of involved-field radiotherapy. Patients with early-stage unfavorable disease received four cycles of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) at baseline or four cycles of ABVD followed by 30 Gy of involved-field radiotherapy if disease was 5 cm or residual disease was 2 cm. Those with advanced disease received eight cycles of BEACOPP with or without radiotherapy to sites 2.5 cm. Patients with advanced HIV disease, including Eastern Cooperative Oncology Group performance score 2, received ABVD. There were five toxic deaths: 4% with early favorable, 0% with early unfavorable, and 7% with advanced disease. CR rates were 96%, 100%, and 86% for these three groups, respectively, and 2-year PFS JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 30 NUMBER 33 NOVEMBER 2

VNCOP-B (Etoposide, Mitoxantrone, Cyclophosphamide, Vincristine, Prednisolone, Bleomycin) Plus Rituximab Therapy in Elderly Patients with Aggressive B-Cell Non-Hodgkin Lymphoma: A Phase II Study of Efficacy and Safety

A 7-Gene Microrna Signature Characteristic of Mantle Cell Lymphoma Reveals Focal Adhesion and Integrin Signalling, Proteasome-Mediated Degradation, and the PI3K Signalling Cascade As Important to MCL Pathogenesis

Pixantrone (Pixuvri®) is an aza-anthracenedione with a novel mode of action that is conditionally approved in the EU for use as monotherapy in adult patients with multiply relapsed or refractory aggressive B-cell non-Hodgkin's lymphoma (NHL). In the randomized, open-label, multinational, phase 3 PIX301 trial in patients with multiply relapsed or refractory aggressive NHL, the complete response (CR) plus unconfirmed CR (uCR) rate at the end of treatment (primary endpoint) was significantly higher with intravenous pixantrone monotherapy than with a single-agent comparator (vinorelbine, oxaliplatin, ifosfamide, etoposide, mitoxantrone or gemcitabine). Post hoc analysis also demonstrated a significantly higher CR/uCR rate in the subgroup of patients with centrally confirmed aggressive B-cell NHL who were receiving pixantrone versus a comparator agent as third- or fourth-line therapy. Pixantrone was generally well tolerated in PIX301, with a manageable adverse event profile. In conclusion, pixantrone is a useful option in patients with multiply relapsed or refractory aggressive B-cell NHL. Further results examining the use of pixantrone in combination with rituximab in patients previously treated with rituximab-containing regimens are awaited with interest.

Rituximab (MabThera, Rituxan) is an anti-CD20 monoclonal antibody that induces lysis and apoptosis of normal and malignant human B cells, and sensitises malignant B cells to the cytotoxic effect of chemotherapy. In phase III trials in patients with indolent or aggressive B-cell non-Hodgkin's lymphoma (NHL), intravenous rituximab in combination with chemotherapy was more effective as first- or second-line therapy than chemotherapy alone in providing tumour remission and patient survival. Likewise, in patients with chronic lymphocytic leukaemia (CLL), rituximab in combination with chemotherapy appeared more effective than chemotherapy alone as either first- or second-line treatment. In addition, rituximab maintenance therapy was shown to significantly prolong tumour remission and patient survival in patients with indolent B-cell NHL or CLL. The combination of rituximab with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) was cost effective as first-line therapy for advanced-stage diffuse large B-cell NHL compared with CHOP alone. Rituximab, either alone or in combination with chemotherapy, was generally well tolerated in patients with NHL or CLL. Overall, rituximab in combination with chemotherapy, is a valuable option for first- and second-line therapy in patients with advanced-stage indolent or aggressive B-cell NHL, and possibly those with B-cell CLL, and is included in current treatment guidelines for these indications. The drug is also potentially useful as maintenance therapy in patients with indolent B-cell NHL or CLL.

Background Human immunodeficiency virus is associated with the development of various aggressive non-Hodgkin B-cell lymphomas (NHL). Despite this, people living with HIV (PLWH) are often excluded from clinical trials. Here we analyze the change in clinical trial exclusion among PLWH resulting from multilateral advocacy efforts since 2017. Methods We identified all US-based clinical trials with the keyword “lymphoma” with start dates between January 01, 2014 and January 04, 2025 using the publicly available NIH Clinical Trial Database (https://www.clinicaltrials.gov/). All studies with aggressive B-cell NHL subtypes were included. Regression models were performed to analyze descriptive factors. Results 1,973 US-based clinical trials were captured, of which 945 met criteria for further analysis. PLWH were excluded from 59% pre-2018 versus 48% post-2018. After multivariate adjustment, NIH-funded trials (24% exclusion rate, p < 0.001), other funders (64% exclusion rate), and studies initiated post-2018 (48% exclusion rate, p < 0.001) were associated with inclusion, while CAR-T-related studies (62% exclusion rate, p < 0.05) were associated with exclusion. Conclusions Likely partly due to advocacy from ASCO, NCI, and NCCN, there was a significant decrease in exclusion among PLWH in US-based NHL clinical trials. Future research should analyze the safety and efficacy of immunotherapy in PLWH to foster inclusion and reduce stigma among physicians and researchers.

An open-label, Phase 2 study of dapolsertib (MEN1703, SEL24) as monotherapy and in combination with glofitamab in patients with relapsed or refractory aggressive B-cell non-Hodgkin lymphoma

A Phase I/II Trial of Combination Gemcitabine and Bortezomib (VELCADE®) for Relapsed/Refractory T-Cell Non-Hodgkin Lymphoma (NHL) and Aggressive B-Cell NHL