Comparison of R-CHOP-14 and R-mini-CHOP in older adults with diffuse large B-cell lymphoma-A retrospective multicenter cohort study.

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma entity, and its incidence increases with age. There is a paucity of data regarding use of biweekly R-CHOP (R-CHOP-14) in patients ≥80 years of age. We performed a retrospective cohort study of patients with DLBCL aged ≥80 years treated with R-CHOP-14 and R-miniCHOP in two academic tertiary centers in Germany between 01/01/2005 and 12/30/2019. Overall, 79 patients were included. Median age was 84 years (range 80-91). Despite higher CR rates with R-CHOP-14 (71.4% vs. 52.4%), no statistically significant difference could be found between patients treated with R-CHOP-14 and R-miniCHOP regarding overall survival (OS) (p = .88, HR 0.94, 95% CI = 0.47-1.90) and progression-free survival (PFS) (p = .26, HR 0.66, 95% CI = 0.32-1.36). At a median follow-up of 40 months, the 2-year OS rates were 56% with R-CHOP-14 and 53% with R-miniCHOP. Two-year PFS rates were 46% for R-CHOP-14 and 50% for R-mini-CHOP. Relative dose intensity of chemotherapy did not correlate with OS (p = .72). With the caveat of a retrospective cohort study, we conclude that lacking a difference in OS, R-miniCHOP should be preferred for most patients with untreated DLBCL aged ≥80 years.

DLBCL 1L-What to Expect beyond R-CHOP?

The R-CHOP immunochemotherapy protocol has been the first-line (1L) standard of care (SOC) for diffuse large B-cell lymphoma (DLBCL) patients for decades and is curative in approximately two-thirds of patients. Numerous randomized phase III trials, most of them in an "R-CHOP ± X" design, failed to further improve outcomes. This was mainly due to increased toxicity, the large proportion of patients not in need of more than R-CHOP, and the extensive molecular heterogeneity of the disease, raising the bar for "one-size-fits-all" concepts. Recently, an R-CHP regimen extended by the anti-CD79b antibody-drug conjugate (ADC) Polatuzumab Vedotin proved superior to R-CHOP in terms of progression-free survival (PFS) in the POLARIX phase III trial. Moreover, a number of targeted agents, especially the Bruton's tyrosine kinase (BTK) inhibitor Ibrutinib, seem to have activity in certain patient subsets in 1L and are currently being tested in front-line regimens. Chimeric antigen receptor (CAR) T-cells, achieving remarkable results in ≥3L scenarios, are being exploited in earlier lines of therapy, while T-cell-engaging bispecific antibodies emerge as conceptual competitors of CAR T-cells. Hence, we present here the findings and lessons learnt from phase III 1L trials and piloting phase II studies in relapsed/refractory (R/R) and 1L settings, and survey chemotherapy-free regimens with respect to their efficacy and future potential in 1L. Novel agents and their mode of action will be discussed in light of the molecular landscape of DLBCL and personalized 1L perspectives for the challenging patient population not cured by the SOC.

Ibrutinib- and bortezomib-extended R-CHOP induction in elderly higher-risk patients newly diagnosed with diffuse large B-cell lymphoma - first analysis of toxicity and efficacy signals.

Diffuse large-cell B-cell lymphoma (DLBCL) is the most common lymphoid malignancy. About 30-40% of the patients will not be cured by standard Rituximab (R)-CHOP-like immune-chemotherapy, and many of them experience relapse and eventually succumb to their disease. Enhancing first-line efficacy in patients at higher risk, among them many elderly, is key to improve long-term outcomes. Numerous attempts to combine R-CHOP with targeted agents failed in large randomized phase III trials. The addition of Ibrutinib enhanced survival in younger patients, but increased toxicity across all age groups, especially in the elderly. Older DLBCL patients impose particular challenges, since they often present with more advanced disease, and exhibit treatment-relevant comorbidities. ImbruVeRCHOP trial aims at identifying patients who need that benefit from rationally augmented first-line regimens without experiencing overt toxicity and detecting their molecular signatures of response. This first analysis presents encouraging feasibility, safety, and preliminary response data in elderly high-risk DLBCL patients.

Adaptive T-cell immunity controls senescence-prone MyD88- or CARD11-mutant B-cell lymphomas.

Aberrant B-cell receptor/NF-κB signaling is a hallmark feature of B-cell non-Hodgkin lymphomas, especially in diffuse large B-cell lymphoma (DLBCL). Recurrent mutations in this cascade, for example, in CD79B, CARD11, or NFKBIZ, and also in the Toll-like receptor pathway transducer MyD88, all deregulate NF-κB, but their differential impact on lymphoma development and biology remains to be determined. Here, we functionally investigate primary mouse lymphomas that formed in recipient mice of Eµ-myc transgenic hematopoietic stem cells stably transduced with naturally occurring NF-κB mutants. Although most mutants supported Myc-driven lymphoma formation through repressed apoptosis, CARD11- or MyD88-mutant lymphoma cells selectively presented with a macrophage-activating secretion profile, which, in turn, strongly enforced transforming growth factor ß (TGF-ß)-mediated senescence in the lymphoma cell compartment. However, MyD88- or CARD11-mutant Eµ-myc lymphomas exhibited high-level expression of the immune-checkpoint mediator programmed cell death ligand 1 (PD-L1), thus preventing their efficient clearance by adaptive host immunity. Conversely, these mutant-specific dependencies were therapeutically exploitable by anti-programmed cell death 1 checkpoint blockade, leading to direct T-cell-mediated lysis of predominantly but not exclusively senescent lymphoma cells. Importantly, mouse-based mutant MyD88- and CARD11-derived signatures marked DLBCL subgroups exhibiting mirroring phenotypes with respect to the triad of senescence induction, macrophage attraction, and evasion of cytotoxic T-cell immunity. Complementing genomic subclassification approaches, our functional, cross-species investigation unveils pathogenic principles and therapeutic vulnerabilities applicable to and testable in human DLBCL subsets that may inform future personalized treatment strategies.

A Phase I/II first-line study of R-CHOP plus B-cell receptor/NF-κB-double-targeting to molecularly assess therapy response.

The ImbruVeRCHOP trial is an investigator-initiated, multicenter, single-arm, open label Phase I/II study for patients 61-80 years of age with newly diagnosed CD20+ diffuse large B-cell lymphoma and a higher risk profile (International Prognostic Index ≥2). Patients receive standard chemotherapy (CHOP) plus immunotherapy (Rituximab), a biological agent (the proteasome inhibitor Bortezomib) and a signaling inhibitor (the Bruton's Tyrosine Kinase-targeting therapeutic Ibrutinib). Using an all-comers approach, but subjecting patients to another lymphoma biopsy acutely under first-cycle immune-chemo drug exposure, ImbruVeRCHOP seeks to identify an unbiased molecular responder signature that marks diffuse large B-cell lymphoma patients at risk and likely to benefit from this regimen as a double, proximal and distal B-cell receptor/NF-κB-co-targeting extension of the current R-CHOP standard of care. EudraCT-Number: 2015-003429-32; ClinicalTrials.gov identifier: NCT03129828.