We reveal how KLHL6 targets CD79B for degradation in normal and malignant germinal center B cells, thereby determining expression of the surface BCR complex. Our findings suggest precision medicine strategies to optimize Pola-V as a lymphoma therapeutic.

P1, N=50, Suspended, University of Washington | Recruiting --> Suspended

The phase III POLARIX study (NCT03274492) evaluated polatuzumab vedotin in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHP) as first-line treatment of diffuse large B-cell lymphoma (DLBCL). An increase of <50% in acMMAE/unconjugated MMAE exposure did not lead to a clinically meaningful increase in adverse events of special interest. ER data and the benefit-risk profile support the use of polatuzumab vedotin 1.8 mg/kg once every 3 weeks with R-CHP for six cycles in patients with previously untreated DLBCL.

P3, N=270, Active, not recruiting, Hoffmann-La Roche | Trial completion date: Dec 2025 --> Mar 2025

P2, N=99, Not yet recruiting, University College, London | Trial completion date: Jan 2028 --> Jul 2028 | Initiation date: Jan 2024 --> Apr 2024 | Trial primary completion date: Jan 2028 --> Jan 2027

P2, N=42, Recruiting, University of Washington | Trial completion date: Aug 2024 --> Dec 2025 | Trial primary completion date: Aug 2024 --> Dec 2025

P2, N=49, Recruiting, Barbara Ann Karmanos Cancer Institute | Trial completion date: Nov 2023 --> Nov 2026 | Trial primary completion date: Nov 2023 --> Nov 2025

P1/2, N=422, Active, not recruiting, Hoffmann-La Roche | Trial primary completion date: Oct 2024 --> Jan 2024

P1, N=50, Active, not recruiting, Hoffmann-La Roche | Trial primary completion date: Feb 2024 --> Jun 2024

P2, N=41, Active, not recruiting, City of Hope Medical Center | Trial completion date: Dec 2023 --> Mar 2024 | Trial primary completion date: Dec 2023 --> Mar 2024

P3, N=300, Recruiting, Nordic Lymphoma Group | N=200 --> 300 | Trial completion date: Feb 2026 --> Dec 2028 | Trial primary completion date: Feb 2023 --> Dec 2025

In treating diffuse large B-cell lymphoma (DLBCL), oncologists have traditionally relied on the chemotherapy backbone of R-CHOP as standard of care...With a replacement strategy, a breakthrough in treatment was identified with polatuzumab vedotin (anti-CD79B antibody/drug conjugate) plus R-CHP...Thus, we aim to highlight the challenges of DLBCL therapy as well as the need to address therapeutic regimens eventually no longer tethered to a chemotherapy backbone. In the intersection of artificial intelligence and multi-omics (genomics, epigenomics, transcriptomics, proteomics, metabolomics), we propose the need to analyze multidimensional biologic datato launch a decisive attack against DLBCL in a targeted and individualized fashion.

SN8 is the antibody component of polatuzumab vedotin, an anti-CD79b antibody drug conjugate, that has been widely used for therapy of diffuse large B-cell lymphoma (DLBCL)...Furthermore, simultaneous targeting of PD-1 strongly potentiates CD79a/CD79b-targeted therapy of B cell tumors. Flow cytometry analyses of CD79a/CD79b on malignant B cells of patients may provide a method for selection of the candidate patients for the CD79a/CD79b dual targeting therapy.

P2, N=20, Recruiting, Weill Medical College of Cornell University

P2, N=44, Recruiting, UNC Lineberger Comprehensive Cancer Center

P2, N=66, Recruiting, Christine Ryan | Initiation date: Oct 2023 --> Apr 2024

P1/2, N=132, Recruiting, Shanghai Hengrui Pharmaceutical Co., Ltd. | Not yet recruiting --> Recruiting

P1, N=30, Recruiting, National Cancer Institute (NCI) | Not yet recruiting --> Recruiting | Trial completion date: May 2025 --> Dec 2025 | Initiation date: Dec 2023 --> Sep 2024 | Trial primary completion date: May 2025 --> Dec 2025

P1/2, N=114, Completed, Hoffmann-La Roche | Phase classification: P1 --> P1/2

P1/2, N=188, Recruiting, Hoffmann-La Roche | Active, not recruiting --> Recruiting

P2, N=30, Recruiting, Yan Zhang, MD

These data demonstrate that mosunetuzumab plus polatuzumab vedotin has a favorable safety profile with highly durable responses suitable as second-line therapy in transplant-ineligible relapsed/refractory LBCL. ClinicalTrials.gov identifier: NCT03671018 .

P2, N=150, Not yet recruiting, Fondazione Italiana Linfomi - ETS | Trial completion date: Oct 2028 --> Jan 2029 | Initiation date: Oct 2023 --> Jan 2024 | Trial primary completion date: Oct 2028 --> Jan 2029

P1, N=170, Enrolling by invitation, Shanghai Hengrui Pharmaceutical Co., Ltd. | Recruiting --> Enrolling by invitation | Trial primary completion date: Dec 2023 --> Mar 2024

P1, N=50, Active, not recruiting, Hoffmann-La Roche | Recruiting --> Active, not recruiting

NEJM 2022)POLARIX trial has shown that first-line treatment with the Pola-R-CHP combination, showed a progression-free survival benefit over the R-CHOP regimen at 2 years and had a similar safety profile, other prospective therapeutic trials have shown benefit of polatuzumab based therapy in Relapsed/Refactory DLBCL. Polatuzumab vedotin has emerged as an innovative therapeutic option in the management of DBLCL. The experience in developing countries is limited and the outcomes, unexplored. In our study, Pola-R-CHP ORR was 66.

In 5 trials (N=204), 13 patients with Pola + atezolizumab (Ate) + obinutuzumab (Obi), 49 patients with Pola + Obi + venetoclax (Ven), 39 patients with Pola + Obi, 62 with Pola + Obi + lenalidomide (Len), and 20 patients with Pola + rituximab (Rit)...(N=41), Pola + Rit was compared with pinatuzumab vedotin (Pina) + Rit... Pola was well tolerated by most of the patients with FL alone or in combination with Obi, Rit, Len, Ven. Pola had relatively better response and survival rates as compared to Pina in combination with Rit. In early phase clinical trials, three drug regimens of Pola and Obi with Ven, and Len were effective in the treatment of heavily pretreated follicular lymphoma.

, 2020)Patients with DLBCL are typically treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone)...In the POLARIX phase 3 trial, polatuzumab vedotin (a monoclonal antibody to CD79b ubiquitously expressed on B cells) combined with R-CHP significantly improved 2 year progression-free survival compared to the routine R-CHOP therapy in previously untreated DLBCL patients...In conclusion, primary pulmonary DLBCL is a rare entity with only a few case reports in literature. It should be considered in patients presenting with large pulmonary masses, mimicking metastatic disease.

It is recently available in China and approved in combination with Bendamustine and Rituximab for r/r DLBCL. gov (NCT05940051) . We illustrated the flowchart of our study in Figure 2.

We observed a statistically significant difference by log-rank in OS2 in patients receiving platinum-based salvage chemotherapy followed by autologous stem cell transplant compared to other therapies in a contemporary cohort of pts with RR DLBCL. This difference is likely driven in part by transplant being a surrogate marker for efficacy of salvage chemotherapy. OS3 was also highest at 12, 24, and 60 months in patients receiving platinum-based salvage chemotherapy followed by transplant.

Therefore, the use of targeted drugs and the exploration of drug combination schemes are particularly important, among them, anti-CD79B antibody-drug conjugate (ADC) polatuzumab vedotin (Pola) combined with Bendamustine-Rituximab (BR) and Pola combined with R-CHOP are promising therapeutic options. The main adverse event was a pulmonary infection, of which 33% (4/12) were in the Polar-BR group and 25% (1/5) were in the Polar-R-CHOP group, and no severe pneumonia occurred in either group. Conclusion Compared with the traditional R-CHOP regimen, Polar+BR/RCHOP has better therapeutic effect and a better application prospects for R/R DLBCL patients.

P2, N=66, Recruiting, Matthew S. Davids, MD | Not yet recruiting --> Recruiting

P1/2, N=117, Completed, Hoffmann-La Roche | Active, not recruiting --> Completed

Patients received obinutuzumab 1000mg on Cycle (C) 1 Day (D) 1 to mitigate the risk of severe cytokine release syndrome (CRS). Glofit+Pola demonstrated high response rates and durable responses in heavily pre-treated patients, the majority of whom were refractory to their last prior therapy, across all histologies, including in patients with HGBCL and those with prior CAR T-cell therapy. The safety profile was manageable and consistent with the individual drugs. The rates of CRS events and AEs potentially consistent with ICANS were low.

Outcomes for R/R MCL pts with PD after the BTKi ibrutinib are very poor, demonstrated by a median overall survival of 2.9 months (Martin et al... Eligible pts had histologically confirmed R/R MCL and had received ≥2 prior regimens (including an anti-CD20 agent, BTKi, and anthracycline- or bendamustine-based therapy)...Ten pts (50%) experienced CRS events; 9 pts experienced Gr 1 events, and 1 pt experienced a Gr 2 event, which was managed with tocilizumab and low-flow oxygen... Fixed-duration Mosun SC in combination with Pola IV induced high CR rates in pts with R/R MCL who had previously received BTKi therapy, including those in high-risk subgroups and those who had received prior CAR T-cell therapy. CRs were observed early and persisted during the follow up period. M-Pola had a manageable safety profile, and all CRS events were low grade.

BT was classified as Polatuzumab (pola) based, intensive chemotherapy, lenalidomide/ Bruton tyrosine kinases inhibitors (len/BTKi), or others...Among all pts, 86 (47%) received Axicel, 49 (27%) Tisacel, 36 (20%) Lisocel and, 11 (6%) Brexucel... Our findings suggest that achieving a response to BT is associated with reduced tumor burden and inflammatory markers pre-LD, reflecting inherent disease biology and treatment-refractoriness. Further studies are required to evaluate which BT strategies may optimize the inflammatory cytokine environment for improved outcomes after CD19 CAR T cell therapy.

Loncastuximab teserine had a deleterious effect on several hematologic parameters, which was not observed with VIP924 or polatuzumab vedotin. The efficacy and tolerability observed in this study with VIP924 suggests further testing in human clinical trials is warranted.

R-miniCHOP, a reduced intensity regimen of R-CHOP, is currently the standard of care for this population, yet with limitation due to toxicities (Frédéric Peyrade et al., Lancet Oncol, 2011). Chemo-free regimens combining Bruton kinase inhibitors, rituximab and lenalidomide showed fewer toxicities, but compromised on efficacy in elderly DLBCL in multiple previous reports (Pengpeng Xu et al., Lancet Healthy Longev, 2022; Haiyan Yang et al., ASH 2022)... Based on these results in our study, ZPR regimen showed rapid and deep response in previously untreated frail and elderly DLBCL patients with manageable safety profiles. We registered and initiated a phase 2b trial (NCT05940064) to further evaluate the efficacy and safety of ZPR regimen as first-line treatment for this population. Ongoing treatment and follow up of these twelve patients will also be further updated.

Sys-CNS pts also received R-CHOP or DA-R-EPOCH while R-Sys-CNS pts received R-Polatuzumab or Polatuzumab-R-Bendamustine...Pts with simultaneous CNS and systemic relapse had worse OS. Prospective studies are needed to evaluate optimal treatment for SCNSL.