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Abstract Polatuzumab vedotin (Pola) is an approved therapy in combination with rituximab and bendamustine for relapsed or refractory diffuse large B‐cell lymphoma (RR‐DLBCL) based on positive results of the landmark phase II randomised G029365 trial. However, trial results for many approved novel therapies in RR‐DLBCL have not been replicated in routine care cohorts, as RR‐DLBCL patient populations are heterogeneous and trial eligibility is increasingly restrictive. We evaluated outcomes from pola ± bendamustine and rituximab in patients with RR‐DLBCL enrolled in a compassionate access program with no alternative treatment options identified via the Australasian Lymphoma and Related Diseases Registry according to their eligibility for the original phase II published study. Of 58 eligible patients, 74% met the criteria deeming them ineligible for the G029365 original study at the time of pola's commencement. Median progression‐free survival and overall survival in our cohort were 2.3 and 3.5 months, respectively. In contrast to the landmark trial cohort, more of our patients ceased therapy prior to completion, the majority due to progressive disease and only 8/58 received any subsequent treatment. Dismal outcomes in this Australian real‐world population demonstrate trial eligibility is challenging to meet, and newer treatments can be difficult to deliver in routine care. Clinically applicable results from therapeutic studies require trial cohorts to reflect representative clinical populations wherever possible, and more research is required to address the benefit of novel agents in the increasing majority who are ineligible for modern studies.

A novel antibody-drug conjugate (ADC), Polatuzumab vedotin has emerged as a promising player in the oncology field. This comprehensive review aims to elucidate the intricate details of Polatuzumab vedotin, encompassing its molecular structure, mechanisms of action, clinical applications, therapeutic efficacy, and ongoing research endeavors. With a focus on precision and targeted therapy, Polatuzumab vedotin stands as a beacon of hope in the battle against various malignancies. It has been regarded as a significant advancement in the field of targeted treatment of diffuse large B-cell lymphoma. As research continues to expand, our understanding of Polatuzumab vedotin, it is evident that its potential to improve patient outcomes and reduce the burden of cancer will remain a topic of great interest for the medical community.

BackgroundPolatuzumab vedotin, the first FDA-approved antibody-drug conjugate (ADC) targeting CD79b, is utilized in the treatment of previously untreated diffuse large B-cell lymphoma (DLBCL) or high-grade B-cell lymphoma (HGBL), as well as relapsed or refractory (R/R) DLBCL. Despite its approval, concerns persist regarding the long-term safety profile of polatuzumab vedotin. This study aims to evaluate the adverse events (AEs) associated with polatuzumab vedotin since its approval in 2019, utilizing data mining strategies applied to the FDA Adverse Event Reporting System (FAERS).MethodsSignal detection employed four methodologies, including reporting odds ratio (ROR), proportional reporting ratio (PRR), bayesian confidence propagation neural network (BCPNN), and multi-item gamma poisson shrinker (MGPS), to evaluate and quantify the signals of polatuzumab vedotin-associated AEs. Additionally, subgroup analyses based on patients age, gender, and fatal cases were conducted to investigate AEs occurrences in specific subpopulations.ResultsA total of 1,521 reports listing polatuzumab vedotin as a “principal suspect (PS)” drug were collected from the FAERS database. Through concurrent compliance with four algorithms, 19 significant Standardized MedDRA Query (SMQ) AEs and 92 significant Preferred Term (PT) AEs were detected. Subgroup analyses revealed a higher incidence of PTs in male patients compared to female patients, increased likelihood of polatuzumab vedotin-associated AEs in elder patients (>65 years), and AEs with a high risk of fatal cases include: blood lactate dehydrogenase increased, cytopenia, and hydronephrosis. The median time to AEs occurrence following polatuzumab vedotin initiation was 18.5 (5∼57.75) days, with 95% of AEs occurred within 162 days.ConclusionThis study identified various AEs associated with polatuzumab vedotin, offering critical insights for clinical monitoring and risk identification in patients receiving polatuzumab vedotin therapy.

Key Clinical Message This report highlights the risk of latent tuberculosis (TB) reactivation after treatment with Polatuzumab Vedotin (PV), Rituximab, and Bendamustine (PBR protocol) despite appropriate chemoprophylaxis. A 48‐year‐old male with refractory Burkitt's lymphoma (BKL) was treated with PBR protocol. At baseline, the patient had a negative QuantiFERON test result, which turned out to be positive prior to starting PBR. He received chemoprophylaxis for 9 months and was compliant with treatment. One year later, he was admitted with COVID‐19 pneumonia and was treated according to the protocol. His symptoms persisted for 1 month. Investigations yielded disseminated TB‐infiltrated bone marrow and pleura. Downstream B‐cell and T‐cell depletion secondary to CD20 and CD79b antagonism may potentially explain the increased risk of TB reactivation associated with the combination of PV and rituximab. Further research is necessary to monitor the risk of TB reactivation among patients receiving a combination of PV and rituximab, especially in endemic areas with high prevalence and incidence of TB.

Moosa Abdur Raqib,1 Abdul Haseeb,2 Muhammad Ashir Shafique,2 Tagwa Kalool Fadlalla Ahmed,3 Muhammad Saqlain Mustafa2 1Department of Medicine, Liaquat College of Medicine & Dentistry, Karachi, Sindh, Pakistan; 2Department of Medicine, Jinnah Sindh Medical University, Karachi, Sindh, Pakistan; 3Department of Medicine, Ahfad University for Women, Omdurman, SudanCorrespondence: Tagwa Kalool Fadlalla Ahmed, Department of Medicine, Ahfad University for Women, Omdurman, Sudan, Tel +249 969710718, Email tagwa.kalool@gmail.comAbstract: Polatuzumab vedotin (PV) is an antibody-drug conjugate that has shown promising results in the treatment of diffuse B-cell lymphoma (DLBCL) and high-grade B-cell lymphoma (HGBCL). This abstract summarizes the current understanding of PV’s use in these malignancies based on available clinical data. Multiple clinical trials have evaluated PV as a part of combination therapy regimens in relapsed/refractory DLBCL and HGBCL. The pivotal Phase II study, GO29365, demonstrated that PV in combination with bendamustine and rituximab (BR) significantly improved progression-free survival and overall survival compared to BR alone in patients with relapsed/refractory DLBCL who ineligible for stem cell transplantation were. Subsequently, the US Food and Drug Administration granted accelerated approval to PV in this setting. PV’s mechanism of action involves targeting CD79b, a cell surface receptor expressed in B-cell malignancies, and delivering the cytotoxic agent monomethyl auristatin E to CD79b-expressing cells. This approach enhances the selective killing of cancer cells while sparing normal cells. The safety profile of PV is generally manageable, with adverse events including infusion-related reactions, cytopenia, peripheral neuropathy, and infections. Overall, PV has emerged as a valuable treatment option for patients with relapsed/refractory DLBCL and HGBCL, offering improved outcomes when combined with appropriate chemotherapy regimens. Ongoing research and clinical trials are further exploring PV’s potential in various treatment settings, including frontline therapy and in combination with other novel agents.Keywords: polatuzumab vedotin, non-Hodgkin lymphoma

Preventing central nervous system (CNS) relapse is a major challenge in the treatment of diffuse large B-cell lymphoma (DLBCL). However, no previous studies have examined the efficacy of polatuzumab vedotin (PV)-containing regimens in preventing CNS relapse in patients with DLBCL. Here, we report two cases of CNS relapse after PV-containing chemotherapy for DLBCL. CNS relapse developed during combination therapy with PV, bendamustine, and rituximab (PV-BR) in one patient and six months after PV-BR in the other patient. PV-containing chemotherapy may be ineffective as a prophylaxis against CNS relapse; therefore, additional strategies for preventing CNS relapse in DLBCL patients are required.

Aim. To assess the pharmacoeconomic feasibility of using polatuzumab vedotin in combination with rituximab, cyclophosphamide, doxorubicin and prednisolone (R-CHP) in 1st line therapy of adult patients with diffuse large B-cell lymphoma in the Russian healthcare system, taking into account the currently used therapeutic practices in oncohematology.Materials and methods. The design of the study is a retrospective analysis of literature data. Clinical and economic analysis (incremental cost–effectiveness analysis, case-based approach) was performed using sensitivity assessment. The sources of data on the effectiveness of the analyzed drugs were publications on clinical trials, on the cost of drugs – the state register of maximum selling prices, data from the manufacturer.Results. An incremental cost–effectiveness analysis was performed using a case-based approach comparing the cost of progression-free life-year gained. Brentuximab vedotin, already included in the list of vital and essential drugs and provided at the expense of budgetary funds, was chosen as the reference drug. It has been established that the cost of progression-free life-year gained (ICER) with the use of polatuzumab vedotin in combination with rituximab, cyclophosphamide, doxorubicin and prednisolone (R-CHP) in 1st line therapy of adult patients with diffuse large B-cell lymphoma by 60.8 %, or 41.6 million rubles, lower than the cost of progression-free life-year gained when using brentuximab vedotin in combination with doxorubicin, vinblastine and dacarbazine in the 1st line therapy of patients with CD30-positive classical Hodgkin’s lymphoma. Sensitivity assessment showed the stability of the obtained results of clinical and economic analysis to changes in the cost of drugs in compared therapy regimens. The results were sensitive to changes in the efficacy of the compared regimens.Conclusion. The obtained results of the clinical and economic analysis demonstrated that the use of polatuzumab vedotin in combination with rituximab, cyclophosphamide, doxorubicin and prednisolone (R-CHP) in the 1st line therapy of adult patients with diffuse large B-cell lymphoma in the Russian healthcare system is economically appropriate.

Aim. To evaluate the pharmacoeconomic feasibility of using polatuzumab vedotin in combination with bendamustine and rituximab for the treatment of adult transplantation-ineligible patients with relapsed/refractory diffuse large B-cell lymphoma.Materials and methods. Study design - retrospective analysis of literature data. Pharmacoeconomic research methods - clinical and economic analysis (incremental cost-effectiveness analysis, case-based approach) using sensitivity assessment. The sources of the drug efficacy data were publications on conducted clinical trials; on the drugs cost -the State register of maximum selling prices, data from the manufacturer's company.Results. Polatuzumab vedotin is the unique drug from the class of monoclonal antibody-antimitotic agent conjugates registered in Russia for the treatment of adult transplantation-ineligible patients with relapsed/refractory diffuse large B-cell lymphoma. for this reason a case-based approach was applied as part of the cost-effectiveness analysis. As a result of clinical and economic analysis, it was found that the cost of progression free life-year added when using polatuzumab vedotin in combination with bendamustine and rituximab in patients with relapsed/refractory diffuse large b-cell lymphoma by 50.7 %, or by 11.4 million rubles, lower than the cost of progression free life-year added when using brentuximab vedotin in patients with relapsed/refractory Hodgkin's lymphoma. The sensitivity assessment showed the stability of the obtained results to changes in the input parameters of treatment cost and efficacy in a wide range of values.Conclusion. Use of polatuzumab vedotin in combination with bendamustine and rituximab for the treatment of adult transplantation-ineligible patients with diffuse large B-cell non-Hodgkin's lymphoma is pharmacoeconomically justified and appropriate.

Polatuzumab vedotin, marketed under the trade name POLIVY®, is a CD79b-targeted antibody-drug conjugate that preferentially delivers a potent anti-mitotic agent (monomethyl auristatin E) to B cells, resulting in anti-cancer activity against B-cell malignancies. In 2019, polatuzumab vedotin in combination with rituximab and bendamustine was approved by the United States Food and Drug Administration for the treatment of adult patients with diffuse large B-cell lymphoma who have received at least two prior therapies. Recent Health Authority guidance recommendations for submitting an Integrated Summary of Immunogenicity were followed including a comprehensive immunogenicity risk assessment, bioanalytical strategy, and immunogenicity data to support the registration of polatuzumab vedotin. Key components of the polatuzumab vedotin Integrated Summary of Immunogenicity and data are presented. Validated semi-homogeneous bridging enzyme-linked immunosorbent assays were used to detect anti-drug antibodies (ADA) to polatuzumab vedotin and characterize the immune response in patients with non-Hodgkin’s lymphoma. The overall incidence of ADA observed for polatuzumab vedotin was low across seven clinical trials. The low incidence of ADA is likely due to the mechanism of action of polatuzumab vedotin that involves targeting and killing of B cells, thereby limiting the development to plasma cells and ADA secretion. Furthermore, patients are co-medicated with rituximab, which also targets B cells and results in B-cell depletion. Therefore, the immunogenicity risk is considered low and not expected to impact the polatuzumab vedotin benefit/risk profile.

Up to 60% of patients with aggressive B-cell lymphoma who receive chimeric antigen receptor (CAR) T-cell therapy experience treatment failure and subsequently have a poor prognosis. Allogeneic hematopoietic stem cell transplantation (alloHSCT) remains a potentially curative approach for patients in this situation. Induction of a deep response prior to alloHSCT is crucial for long-term outcomes, but the optimal bridging strategy following relapse after CAR T-cell therapy has not yet been established. Polatuzumab vedotin, an antibody drug conjugate targeting CD79b, is a novel treatment option for use in combination with rituximab and bendamustine (Pola-BR) in relapsed or refractory disease. Patients: We report two heavily pretreated patients with primary refractory diffuse large B-cell lymphoma (DLBCL) and primary mediastinal B-cell lymphoma (PMBCL) respectively who relapsed after therapy with CAR T-cells with both nodal and extranodal manifestations of the disease. After application of three courses of Pola-BR both patients achieved a complete metabolic remission. Both patients underwent alloHSCT from a human leukocyte antigen (HLA)-mismatched donor following conditioning with busulfan and fludarabine and are disease free 362 days and 195 days after alloHSCT respectively. We conclude that Pola-BR can be an effective bridging therapy before alloHSCT of patients relapsing after CAR T-cell therapy. Further studies will be necessary to define the depth and durability of remission of this salvage regimen before alloHSCT.

Abstract Antibody-drug conjugates (ADC) represent a distinct family of chemoimmunotherapy agents. ADCs are composed of monoclonal antibodies conjugated to cytotoxic payloads via specialized chemical linkers. ADCs therefore combine the immune therapy with targeted chemotherapy. Due to the distinct biomarkers associated with lymphocytes and plasma cells, ADCs have emerged as a promising treatment option for lymphoid malignancies and multiple myeloma. Several ADCs have been approved for clinical applications: brentuximab vedotin, inotuzumab ozogamicin, moxetumomab pasudotox, and polatuzumab vedotin. More novel ADCs are under clinical development. In this article, we summarized the general principles for ADC design, and updated novel ADCs under various stages of clinical trials for lymphoid malignancies and multiple myeloma.

Diffuse large B-cell lymphoma (DLBCL) is a biologically and clinically heterogeneous disease. Despite good responses to standard of care frontline chemoimmunotherapy, the prognosis of relapsed/refractory (R/R) patients remains obscured by the possible inadequate responses to salvage therapy, eligibility for autologous transplantation, age and comorbidities. Polatuzumab vedotin is an antibody-drug conjugate formed by a CD79b antibody conjugated to the highly cytotoxic agent monomethyl auristatin E by means of a cleavable linker. Following significant clinical efficacy in R/R DLBCL, polatuzumab vedotin was granted accelerated Food and Drug Administration (FDA) approval in combination with bendamustine plus rituximab for patients who have failed at least two prior therapies. Other clinical studies involving polatuzumab vedotin in combination with other therapy regimens are also under evaluation for previously untreated DLBCL patients. In this article, we review the different phases from the preclinical development of polatuzumab vedotin to studies leading to its first approval, and highlight the potential future roles of this molecule in the treatment landscape of DLBCL.

Over the last few years, treatment principles have been changed towards more targeted therapy for many B-cell lymphoma subtypes and in chronic lymphocytic leukemia (CLL). Immunotherapeutic modalities, namely monoclonal antibodies (mAbs), bispecific antibodies (bsAbs), antibody-drug conjugates (ADCs), and chimeric antigen receptor T (CAR-T) cell therapy, commonly use B-cell-associated antigens (CD19, CD20, CD22, and CD79b) as one of their targets. T-cell engagers (TCEs), a subclass of bsAbs, work on a similar mechanism as CAR-T cell therapy without the need of previous T-cell manipulation. Currently, several anti-CD20xCD3 TCEs have demonstrated promising efficacy across different lymphoma subtypes with slightly better outcomes in the indolent subset. Anti-CD19xCD3 TCEs are being developed as well but only blinatumomab has been evaluated in clinical trials yet. The results are not so impressive as those with anti-CD19 CAR-T cell therapy. Antibody-drug conjugates targeting different B-cell antigens (CD30, CD79b, CD19) seem to be effective in combination with mAbs, standard chemoimmunotherapy, or immune checkpoint inhibitors. Further investigation will show whether immunotherapy alone or in combinatory regimens has potential to replace chemotherapeutic agents from the first line treatment.

2019 has been an excellent year in terms of peptides and oligonucleotides (TIDES) approved by the FDA. Despite the drop in the number of total drugs approved by the FDA in 2019 in comparison with 2018 (48 vs. 59), the total number of TIDES authorized increased (seven vs. three). Year after year, TIDES are increasingly present in therapy, as imaging agents, theragnostic and constituent moieties of other complex drugs, such as antibody drug conjugates. This means a consolidation of these kinds of drugs in the pharmaceutical arena, paving the way in the coming years for the approval of others for diverse medical indications. Here the TIDES approved in 2019 are analyzed in terms of chemical structure, medical target, mode of action, and adverse effects.