Introduction Of Rituximab Research Articles

Timing is essential: Humoral and cellular responses to SARS-CoV-2 vaccination in a cohort of patients with auto-immune diseases treated with rituximab

Rituximab (RTX), an anti CD20 monoclonal antibody, is now a gold standard treatment for several auto-immune and chronic inflammatory diseases. Receiving RTX exposes patients to more severe infections as vaccinations become virtually inefficient in terms of B cell responses. During the COVID-19 crisis, RTX–exposed patients exhibited more severe forms of the disease, and in some cases, the introduction of RTX was delayed or avoided to protect patients as much as possible against SARS-CoV-2 infections. We retrospectively collected cellular and humoral responses from thirteen patients with dermatological and rheumatological autoimmune diseases who had been vaccinated after receiving RTX. Memory T cells subsets from patients that exposed to RTX showed few differences when compared to a cohort of healthy donors. The IFNᵧ ELISpot assay using SARS-CoV-Prot_S1 showed that eight patients exhibited a positive response that was neither correlated to the time between RTX infusion and the sampling nor to the time between RTX and the vaccination. Conversely, analysis of the SARS-CoV-2 serology showed a clearly lower binding antibody units per mL in case of recent RTX infusion. The safe threshold forconsistently positive serology was to vaccinate at least 300 days after RTX infusion (p = 0.02). Our data illustrate the difficulty in obtaining a satisfactory response to vaccination after RTX treatment within almost a year after the latest infusion, and emphasize the need to better evaluate the risk of relapses in auto-immune diseases before administering RTX in order to maintain RTX only in patients whose medical situation requires it.

Novel Targets and Advanced Therapies in Diffuse Large B Cell Lymphomas.

Since the introduction of rituximab in the late 1990s, significant progress has been made in advancing targeted therapies for B cell lymphomas, improving patients' chance of being cured and clinicians' therapeutic armamentarium. A better understanding of disease biology and pathogenic pathways, coupled with refinements in immunophenotypic and molecular diagnostics, have been instrumental in these achievements. While traditional chemotherapy remains fundamental in most cases, concerns surrounding chemorefractoriness and cumulative toxicities, particularly the depletion of the hemopoietic reserve, underscore the imperative for personalized treatment approaches. Integrating targeted agents, notably monoclonal antibodies, alongside chemotherapy has yielded heightened response rates and prolonged survival. A notable paradigm shift is underway with innovative-targeted therapies replacing cytotoxic drugs, challenging conventional salvage strategies like stem cell transplantation. This review examines the landscape of emerging targets for lymphoma cells and explores innovative therapies for diffuse large B cell lymphoma (DLBCL). From Chimeric Antigen Receptor-T cells to more potent monoclonal antibodies, antibody-drug conjugates, bispecific antibodies, checkpoint inhibitors, and small molecules targeting intracellular pathways, each modality offers promising avenues for therapeutic advancement. This review aims to furnish insights into their potential implications for the future of DLBCL treatment strategies.

Outcomes of the transformation of follicular lymphoma to diffuse large B-cell lymphoma in the rituximab era: A population-based study.

Histological transformation (HT) to diffuse large B-cell lymphoma (DLBCL) is a common complication of follicular lymphoma (FL) and is usually associated with a dismal outcome. However, the survival rate of these patients has improved over the last 20 years with the introduction of rituximab. This study aimed to access the outcome of transformation to DLBCL (t-DLBCL) from FL in a retrospective series that began after the widespread use of rituximab use. In addition, we also compared survival between t-DLBCL and primary DLBCL (p-DLBCL) in the same timeframe. We utilized the Surveillance, Epidemiology, and End Results (SEER) database to identify patients with primary FL and patients with p-DLBCL between 2000 and 2020. Patients who had a subsequent diagnosis of DLBCL at least 2 months after FL diagnosis were identified as t-DLBCL. Finally, we identified 50,332 FL and 95,933 p-DLBCL. With a median follow-up of 119 months, 1631 patients developed t-DLBCL. The median time from FL diagnosis to t-DLBCL was approximately 4 years. The post-transformation survival (PTS) rate at 5 years was 49.6%, with a median PTS of 56 months. Older age, advanced stage, and early transformation were associated with worse PTS. Furthermore, t-DLBCL receiving chemotherapy or combined modality as initial therapy before HT was also associated with worse PTS, while the result was inverse when taking the impact of initial management strategy at HT into account. Taking t-DLBCL and p-DLBCL as a whole, comparable survival was observed between p-DLBCL and t-DLBCL receiving radiation or watch-and-wait as initial therapy prior to HT. The outcome of t-DLBCL in the rituximab era was better than historical series before the rituximab era. Due to the good prognosis, we did not recommend autologous stem cell transplantation for t-DLBCL receiving watch-and-wait or radiation as initial therapy before HT.

Asciminib Maintains Antibody-Dependent Cellular Cytotoxicity against Leukemic Blasts.

B cell acute lymphoblastic leukemia (B-ALL) is characterized by an accumulation of malignant precursor cells. Treatment consists of multiagent chemotherapy followed by allogeneic stem cell transplantation in high-risk patients. In addition, patients bearing the BCR-ABL1 fusion gene receive concomitant tyrosine kinase inhibitor (TKI) therapy. On the other hand, monoclonal antibody therapy is increasingly used in both clinical trials and real-world settings. The introduction of rituximab has improved the outcomes in CD20 positive cases. Other monoclonal antibodies, such as tafasitamab (anti-CD19), obinutuzumab (anti-CD20) and epratuzumab (anti-CD22) have been tested in trials (NCT05366218, NCT04920968, NCT00098839). The efficacy of monoclonal antibodies is based, at least in part, on their ability to induce antibody-dependent cellular cytotoxicity (ADCC). Combination treatments, e.g., chemotherapy and TKI, should therefore be screened for potential interference with ADCC. Here, we report on in vitro data using BCR-ABL1 positive and negative B-ALL cell lines treated with rituximab and TKI. NK cell activation, proliferation, degranulation, cytokine release and tumor cell lysis were analyzed. In contrast to ATP site inhibitors such as dasatinib and ponatinib, the novel first-in-class selective allosteric ABL myristoyl pocket (STAMP) inhibitor asciminib did not significantly impact ADCC in our settings. Our results suggest that asciminib should be considered in clinical trials.

Improved Survival with Rituximab-Based Chemoimmunotherapy in Patients with Primary Testicular Diffuse Large B-Cell Lymphoma

Background: Primary testicular lymphoma (PTL) accounts for 1% to 2% of non-Hodgkin's lymphomas. Diffuse large B-cell lymphoma (DLBCL) is the most common histological subtype of PTL, accounting for 80% to 98% of cases. The introduction of rituximab was a breakthrough in DLBCL treatment. However, the impact of rituximab on primary testicular DLBCL (PT-DLCBL) is controversial. A study by Gundrum et al (Gundrum JD, et al. J Clin Oncol 2009) found that PT-DLBCL survival did not improve in the rituximab era (i.e., after 2000). However, that study was based on a Surveillance, Epidemiology, and End Results (SEER) database cut-off of 2005. The follow-up period of PT-DLBCL patients in the rituximab era was relatively short, at only 4 years (from 2001 to 2005). Considering the wide use of rituximab in all kinds of DLCBL, we conducted a study based on the SEER database to evaluate the potential impact of the introduction of rituximab on PT-DLBCL. Methods: Data from the SEER 13 registries were analyzed in this study. Cases with PT-DLBCL diagnosed from 1992 to 2018 were included. Baseline characteristics, including age at diagnosis, laterality (left, right, bilateral), age, race, Ann Arbor stage, SEER cause-specific death classification, survival months, and vital status, were collected. Cancer-specific survival (CSS) was used as the study endpoint and defined as the time from diagnosis to death from DLBCL or last follow-up. The Kaplan-Meier method was used to build survival curves and the log-rank test used to compare groups. All p values were two-sided, and p-values < .05 considered statistically significant. All analyses were conducted using GraphPad PRISM 6. Results: A total of 961 patients were included in this analysis. Among them, 271 were diagnosed from 1992 through 2000 (pre-rituximab era) and 690 from 2001 through 2018 (rituximab era). In all, 435 patients showed unilateral left-side testicular involvement, 455 right-side, 63 bilateral, and 8 unknown. At last follow-up, 489 patients had died of PT-DLBCL. Patients diagnosed in the pre-rituximab era had more stage I disease than their counterparts in the rituximab era. No difference was found in age, race, or laterality across the two eras. For the entire cohort, there was a significant improvement in CSS in the rituximab era compared with the pre-rituximab era. The median CSS in the pre-rituximab era was 98 months compared to not reached in the rituximab era ( p = .001) (Figure 1A). We also compared the CSS of patients in different stages: early stage (I/II) or advanced stage (III/IV) in the pre-rituximab and rituximab eras. We found that CSS improved significantly in either early or advanced stage (early stage, p < .0017; advanced stage, p = .026; Figure 1B and 1C). We also explored the role of laterality in survival of PT-DLBCL. Compared with the pre-rituximab era, CSS of either left-side (Figure 1D) or right-side (Figure 1E) PT-DLBCL improved significantly (left-side, p < .001; right-side, p = .04) in the rituximab era. The introduction of rituximab decreased CSS by about 50% in patients with left-side PT-DLBCL but only about 30% in those with right-side disease, which indicated that patients with left-side (vs right-side) PT-DLBCL derived greater survival benefit from the introduction of rituximab. Conclusions: Survival of PT-DLBCL patients improved significantly in the rituximab era, with the survival curve reaching a plateau from the tenth year after treatment. Patients with left-side (vs right-side) PT-DLBCL derived greater survival benefit from the introduction of rituximab.

Survival Trends in Diffuse Large B-Cell Lymphoma (DLBCL) in the CAR-T Cell Therapy Era Vs Pre-CAR-T Cell Therapy Era in the United States: A Population-Based Study

Background Chimeric Antigen Receptors (CARs) are novel engineered proteins that alter T-cell antigen specificity. CAR-T cell therapy is a novel form of immunotherapy that uses T-cells engineered with CARs to target tumor-associated antigens. The Food and Drug Administration (FDA) granted approval to the first CAR-T therapeutic agents in 2017. Axicabtagene ciloleucel (axicel) is one such therapy currently in use that was developed to target CD19 - a pan-B cell marker for the treatment of Diffuse Large B-Cell Lymphoma (DLBCL). 1 Previous population-based studies have shown improvements in Overall Survival (OS) after the introduction of rituximab (anti-CD20 monoclonal antibody) for the treatment of patients with DLBCL. 2 However, there is limited data on survival after the introduction of CAR-T cell therapy at the population level. With this study, we hypothesized that improvements in survival have been made in recent years with the introduction of CAR-T cell therapy for the treatment of DLBC and aim to demonstrate these outcomes. Methods We used the Surveillance, Epidemiology and End-Results (SEER-17) research program data to conduct a retrospective study of patients diagnosed with DLBCL between 2013-2020. This period was divided into two cohorts: pre-CAR-T approval (2013-2016) and post-CAR-T approval eras (2017-2020). Statistical analysis was performed using SPSS version 25. Patient characteristics were expressed as number (N) and percentages (%). Categorical variables were compared using the Chi-Square Test. The Kaplan Meier method was used to compare OS of both eras. OS was defined as the time from diagnosis to death. Cox proportional hazard regression was used to compare both cohorts and expressed as hazard ratios. A p-value ≤0.05 was considered statistically significant. Results All results are highlighted in Table 1. A total of 41219 DLBCL patients were identified between 2013 and 2020. Splitting by cohorts, 20139 DLBCL patients were identified in the pre-CAR-T cohort and 21080 DLBCL patients were identified in the post-CAR-T approval cohort. Patients in the post-CAR-T era demonstrated a higher proportion of patients ≥65 years (56.6% vs 53.7%) and distant stage disease (53.4% vs 52.1%) at the end of the time period.. The pre-CAR-T era demonstrated a higher proportion of people dead attributable to DLBCL (33% vs 23.5%). Figure 1 depicts OS for each group, with the post-CAR-T era (2017-2020) demonstrating a statistically significant higher OS (0.031). The post-CAR-T era cohort was associated with an improvement in overall survival (HR = 0.951, 95% CI: 0.913-0.990, p-value ≤0.014). Other independent prognostic variables found in our study were, ≥age 65 (HR = 2.351 95% CI: 2.251-2.455, p-value ≤0.001), male sex (HR = 1.260, 95% CI: 1.212-1.311, p-value ≤0.001), distant stage disease (HR = 1.653, 95% CI: 1.573-1.737, p-value ≤0.001), which indicated worse prognosis. Chemotherapy (HR = 0.331, 95% CI: 0.314-0.349, p-value ≤0.001) was found to be an independent prognostic factor for improvement of OS in DLBCL. Conclusion: To the best of our knowledge, our study is the first US population-based study to evaluate survival outcomes in DLBCL patients after the introduction of CAR-T cell therapy. The survival in patients in the CAR-T era improved compared with the pre-CAR-T era. A limitation of our study is that the SEER database does not contain data on the type of chemotherapy given to patients. Also, due to the relatively recent introduction of CAR-T cell therapy as a treatment modality further studies over longer time periods are required to better characterize its association with improvements in survival.

Trends in non-Hodgkin lymphoma mortality rate in Japan and the United States: A population-based study.

Characterizing trends in mortality rates with consideration of trends in incidence rates at the population level could help identify unmet needs in public health and provide essential indicators of cancer control. In the late 20th century, the arrival of the first molecular targeted agent, rituximab, for non-Hodgkin lymphoma (NHL) led to a paradigm shift in NHL treatment. However, the public health impact of this arrival has not been fully clarified. Here, we evaluated trends in the mortality and incidence rates of NHL in Japan and the United States. Age-standardized rates of mortality reversed after the introduction of rituximab, around 2000, beginning to decline significantly with annual percent changes (95% confidence interval) of -2.6% (-3.6% to -1.6%) in Japan and - 3.9% (-4.2% to -3.5%) in the United States. Despite an increase in incidence, the mortality in all age groups weakened the upward trends or decreased in both countries. From a long-term perspective, the trends in mortality rates differed between the countries. In the United States, the mortality rate has declined continuously since the introduction of rituximab, with a declining incidence rate. In contrast, in Japan, the mortality rate stopped declining and the incidence rate increased remarkably. The introduction of rituximab has had a substantial impact at the population level across a wide range of individuals. To reduce the disease burden in terms of mortality, elucidating risk factors that lead to a decreasing incidence rate is warranted for NHL, as well as further development of novel treatments.

Transplanting highly sensitized patients

Immunological barrier posed by preformed antibodies against donor's human leukocyte antigen (HLA) antigens compounds the situation of global shortage of kidney donors. Pretransplantation sensitization carries a high risk of acute rejection and allograft loss. Therefore, there is a need for careful evaluation of potential recipients, based on HLA typing, HLA match, and comprehensive screening of antibodies (is conceptual). Sensitization events include previous transplantations, blood transfusions, or pregnancies. Despite advances in molecular techniques and solid-phase assays used to identify at-risk patients, kidney transplantation continues to be challenging in patients with calculated panel reactive antibodies greater than 85%. The development of desensitization protocols has been used to overcome acute rejection risk; however, the associated further increase in the risk of infection and malignancy is of significant concern owing to enhanced immunosuppression. The introduction of rituximab, bortezomib, plasmapheresis, and intravenous immunoglobulins has improved the success rate of desensitization protocols. On the contrary, paired (pooled) exchange kidney program has been instrumental in widening access to allografts to highly sensitized patients by offering lesser HLA mismatches. Moreover, desensitization protocols are rather expensive, leading to a high economic burden in the pretransplantation and posttransplantation period. This review aims to discuss the scientific basis and practical issues of managing highly sensitized patients.

Physical function, nutritional status, and quality of life before and after chemotherapy in patients with malignant lymphoma.

This study investigates the efficacy of and gender differences in exercise therapy in patients with malignant lymphoma undergoing chemotherapy. Twenty-six patients (13 men, 13 women) received physical therapy (based on the Borg Scale 13) during hospitalization. Physical function was measured using grip and knee extension strength, 6-minute walking distance, and body composition; nutritional status assessed via Mini Nutritional Assessment (MNA®); and serum albumin levels analyzed. Fatigue was evaluated using the Brief Fatigue Inventory, and health-related quality of life was assessed with the Medical Outcome Study 36-Item Short-Form Health Survey (SF-36v2). The analysis of all patients indicated that the right grip strength, skeletal muscle mass, skeletal muscle index, and leg muscle mass significantly decreased, whereas the serum albumin level, MNA® score, and scores of many items of the SF-36v2 significantly increased after chemotherapy. In a gender-specific analysis, only men showed significant declines in the skeletal muscle mass and skeletal muscle index, and improvement in the MNA® score after chemotherapy. In the SF-36v2, there were significant improvements in general health and physical component summary scores among men, and general health and mental component summary scores among women. Exercise therapy at a Borg Scale intensity of 13 may not prevent muscle mass decline in patients with malignant lymphoma, especially male patients. In addition, this study revealed that there is a gender difference in the effect of exercise therapy on quality of life. Thus, gender should be considered in exercise therapy for patients with malignant lymphoma.

Risk factors for antibody-mediated rejection in ABO blood-type incompatible and donor-specific antibody-positive liver transplantation.

Antibody-mediated rejection (AMR) is a refractory rejection after ABO blood-type incompatible (ABOi) or donor-specific antibody (DSA)-positive liver transplantation (LT). Pretransplant rituximab desensitization dramatically reduced posttransplant AMR development; however, risk factors for AMR in the rituximab era remain unclear in both ABOi living-donor LT (ABOi-LDLT) and preformed DSA-positive LT (pDSA-LT). Of our 596 adult LDLTs (≥18y) after rituximab introduction (2004-2019), 136 were ABOi-LDLT (22.8%). After excluding retransplants (9), acute liver failure (7), and protocol deviations (16), 104 ABOi-LDLTs were finally enrolled. Of these, 19 recipients developed AMR, 18 of which occurred within 2 weeks after transplantation (95%). ABOi-AMR significantly worsened graft and recipient survival than those without ( p =0.02 and 0.04, respectively). Model for End-stage Liver Disease (MELD) ≤13 (OR: 5.15 [1.63-16.3], p =0.005) and pre-rituximab anti-ABO IgM-titer ≥128 (OR: 3.25 [1.05-10.0], p =0.03) were identified as independent risk factors for ABOi-AMR development. Recipients fulfilling both factors showed significantly worse survival rates than those who did not ( p =0.003). Of 352 adult LTs, after introducing the LABScreen Single Ag method (2009-2019), pDSA with mean fluorescence intensity (MFI) ≥500 was detected in 50 cases (14.2%). After excluding 10 ABOi-LDLTs, 40 pDSA-LTs were finally analyzed, of which 5 developed AMR. The combination of high-titer (sum-MFI ≥10,000) and multi-loci pDSAs was a significant risk factor for pDSA-AMR development ( p <0.001); however, it did not affect the 5-year recipient survival compared with those without ( p =0.56). In conclusion, preoperative MELD ≤13 and pre-rituximab anti-ABO IgM-titer ≥128 for ABOi-LDLT, and the combination of sum-MFI ≥10,000 and multi-loci pDSAs for pDSA-LT, are risk factors for AMR in the era of rituximab desensitization. Characteristically, ABOi-AMR significantly deteriorated graft and recipient survival, whereas pDSA-AMR did not.

Survival of patients with mantle cell lymphoma in the rituximab era: Retrospective binational analysis between 2000 and 2020.

Mantle cell lymphoma (MCL) is a rare peripheral B-cell lymphoma characterised by eventual relapse and progression towards a more aggressive disease biology. With the introduction of rituximab- and cytarabine-based immunochemotherapy regimens, the prognosis of the disease has changed dramatically over the last two decades. To assess the real-world survival of patients with MCL, we used a population-based cohort of 564 patients with MCL who were diagnosed and treated between 2000 and 2020. Patient data were collected from seven Finnish treatment centres and one Spanish treatment centre. For the entire patient population, we report a 2-year overall survival (OS) rate of 77%, a 5-year OS of 58%, and a 10-year OS of 32%. The estimated median OS was 80 months after diagnosis. MCL is associated with increased mortality across the entire patient population. Additionally, we assessed the survival of patients after MCL relapse with the aim of establishing a cut-off point of prognostic significance. Based on our statistical analysis of survival after the first relapse, disease progression within 24 months of the initial diagnosis should be considered as a strong indicator of poor prognosis.

Infusion reactions to rituximab administration: algorithm of management

Background. Allergic reactions to rituximab, which have been used for the past 20 years, are common in 32–62 % of patients. The purpose of the study: to develop an algorithm for controlling adverse reactions that occur during the introduction of rituximab. Materials and methods. The personal experience of treatment of 46 patients with various kidney diseases who received rituximab according to the indications according to the established diagnosis was analyzed. Evaluation of infusion allergic reactions was performed according to P.М. Kasi et al. (2012) for 5 classes of side effects. Results. It was found that allergic reactions to rituximab occurred in 46 % of patients in the range from 1 to 4 classes. The probability of their occurrence according to the class was almost the same, but somewhat less documented for the 4th grade. Re-administration of diphenhydramine, methylprednisolone 125 mg or hydrocortisone 125 mg, if necessary salbutamol, oxygen allowed to eliminate most of the reaction, and then resumed the introduction of rituximab, starting from 25 mg/h, gradually increasing to 300 mg/h. This administration, performed 1–2 times, was effective in 1–3 classes of allergic reactions. For fourth grade, one patient required omalizumab. Generalized experience allowed to give a graphical and descriptive algorithm of actions in case of infusion side effects for rituximab. Conclusions. Based on special data and literature analysis, an algorithm for controlling infusion allergic reactions with intravenous rituximab was formulated.

SY08-3 Recent advances in targeted therapy for B-cell malignancies

The introduction of rituximab has represented a major milestone in the treatment of B-cell malignancies. However, a proportion of patients eventually will relapse or will be primary refractory. In this clinical setting, targeting new surface antigens either using monospecific antibodies or drug immunoconjugates are appealing treatment approaches. Additionally, exploiting cytotoxic T-cells using bispecific antibodies has been considered as a disruptive therapeutic strategy for lymphomas.

Mortality among patients with low-grade follicular lymphoma: A binational retrospective analysis.

BackgroundThe life expectancy of patients with follicular lymphoma (FL) has improved considerably since the introduction of rituximab. This study examined the proportion of deaths from progressive lymphoma and the impact of FL on survival compared with that in the general population.MethodsAltogether, 749 patients with grades 1 and 2 FL in 9 institutions between 1997 and 2016 were enrolled. Competing risk models were used to estimate the cumulative incidences of deaths from progressive lymphoma and from other reasons. Excess mortality was analyzed with respect to the corresponding background populations standardized for age and sex using the excess mortality model based on the penalized spline approach.ResultsThe median follow‐up duration was 69 months (range, 0‐226 months). The estimated 10‐year overall, disease‐specific, and net survival rates were 72.4%, 86.6%, and 86.4%, respectively. The cumulative incidence of deaths from progressive lymphoma was slightly smaller than that of other causes in the study population (estimated 10‐year cumulative incidences: 12.3% [95% CI, 9.6%‐15.3%] and 15.4% [95% CI, 12.2%‐18.8%], respectively). Excess mortality was observed for up to 10 years after diagnosis, and it slightly increased with time.ConclusionsDeaths from progressive lymphoma are nearly as common as deaths from other causes in FL patients during the rituximab era. Despite the improvements in survival, there was evidence of excess mortality resulting from FL for at least 10 years after diagnosis.

Time trends in primary therapy and relative survival of diffuse large B-cell lymphoma by stage: a nationwide, population-based study in the Netherlands, 1989\u20132018

It is unclear whether survival in diffuse large B-cell lymphoma (DLBCL) continues to increase in an era where rituximab-containing chemotherapy reigns for almost two decades. Therefore, we evaluated trends in primary therapy and relative survival (RS) among Dutch DLBCL patients diagnosed between 1989 and 2018. Analyses were performed separately according to the stage I (N = 6952) and stage II–IV disease (N = 20,676), stratified by calendar period and age (18–64, 65–74, and ≥75 years). The use of chemotherapy ± radiotherapy increased over time across all age and stage groups. As of the mid-2000s, >95% of chemotherapy-treated patients received chemoimmunotherapy, irrespective of age and stage. Overall, RS increased significantly over time across all age groups, especially after 2003 when rituximab-containing chemotherapy had become the standard of care. However, RS increased less pronounced between 2003–2010 and 2011–2018 than between 1989–2002 and 2003–2010. These findings were congruent across all studied stage groups. Five-year RS across the three age groups during 2011–2018 was 96%, 84%, and 67% for stage I DLBCL and 75%, 60%, and 46% for stage II–IV DLBCL. Collectively, survival in DLBCL increased modestly beyond the initial introduction of rituximab, with apparent survival differences across age and stage that warrant novel treatment approaches.

Current and emerging monoclonal antibodies, antibody-drug conjugates, and bispecific antibodies in treatment of lymphoma

The improvement in outcomes seen with the introduction of rituximab, a CD20 monoclonal antibody in combination with chemotherapy or as a single agent in the treatment of indolent non-Hodgkin lymphomas has paved the way for development of various forms of monoclonal antibodies that act in different ways against non-Hodgkin lymphoma tumor cells. These could directly target a single surface antigen resulting in various ways of tumor cells toxicity and killing. Other forms of monoclonal antibodies include antibody-drug conjugates and bispecific antibodies. The role of therapeutic monoclonal antibodies in the treatment of lymphoma will be reviewed, highlighting their mode of action, clinical efficacy, and side effects.

Current status and future prospects of diffuse large B-cell lymphoma treatment

R-CHOP therapy (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) has been used as the standard treatment regimen for patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL), since the introduction of rituximab in the early 2000s. Recently, polatuzumab vedotin and anti-CD19 chimeric antigen receptor T-cell (CAR-T) therapy have been introduced as potential treatment options for relapsed or refractory DLBCL. The effectiveness of polatuzumab vedotin, rituximab, cyclophosphamide, doxorubicin, and prednisone for newly diagnosed CD20-positive DLBCL, except for the low-risk group of the international prognostic index, was reported in 2022. Bispecific antibodies such as epcoritamab, mosunetuzumab, and glofitamab, anti-CD19 antibody drug tafasitamab combined with lenalidomide, CD19 antibody drug conjugate loncastuximab tesirine, oral selective inhibitor of nuclear export selinexor, and several new agents have been investigated for DLBCL. For non-germinal center B-cell type DLBCL, R-CHOP combined with acalabrutinib is being evaluated. This review summarizes the current standard of care for DLBCL and outlines the recently introduced therapeutic agents or those that are under development in Japan.

Therapeutic developments and advances in B-cell lymphoma

B-cell lymphoma accounts for approximately 70% of malignant lymphomas, and its treatment outcomes have drastically improved after the introduction of rituximab. Most patients with diffuse large B-cell lymphoma (DLBCL) are successfully treated with the current standard chemotherapeutic regimen of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). However, 30-40% of patients with DLBCL have unsatisfactory treatment outcomes. Molecular genetic research has greatly contributed to the identification of pathogenic mechanisms of lymphoma and factors leading to poor prognosis. Thus, novel agents for targeting factors in key signaling pathways, relevant targeted antigens, and epigenetic enzymes have been developed. Additionally, development of immunotherapies such as anti-CD19-chimeric antigen receptor (CAR) T cell and bispecific antibody therapy have led to a paradigm shift for relapsed or refractory DLBCL treatments. Herein, we discuss the results of clinically impactful studies on the treatment strategies of B-cell lymphoma, including DLBCL, follicular lymphoma, and lymphoplasmacytic lymphoma.

Living longer and better with haematological malignancies: a promise for older adults too?

For decades, we have known that most haematological malignancies have a worse prognosis in older patients. The case is particularly striking for acute myeloid leukaemia, for which the 5-year overall survival drops from 63% (95% CI 58–68) in young adults (15–39 years) to 16% (13–20) for patients aged between 65 and 74 years and 3% (2–5) for those aged 75 years and older. However, several indices indicate survival rates are improving. One of the earliest reported changes in survival trends was seen in patients with diffuse large B-cell lymphoma following the introduction of rituximab.

Primary therapy and relative survival in patients with lymphoplasmacytic lymphoma/Waldenström macroglobulinaemia: a population-based study in the Netherlands, 1989-2018.

SummaryIt is unclear how treatment advances impacted the population‐level survival of patients with lymphoplasmacytic lymphoma/Waldenström macroglobulinaemia (LPL/WM). Therefore, we assessed trends in first‐line therapy and relative survival (RS) among patients with LPL/WM diagnosed in the Netherlands between 1989 and 2018 (N = 6232; median age, 70 years; 61% males) using data from the nationwide Netherlands Cancer Registry. Patients were grouped into three age groups (<65, 66–75 and >75 years) and four calendar periods. Overall, treatment with anti‐neoplastic agents within 1 year post‐diagnosis gradually decreased over time, following a broader application of an initial watch‐and‐wait approach. Approximately 40% of patients received anti‐neoplastic therapy during 2011–2018. Furthermore, use of chemotherapy alone decreased over time, following an increased application of chemoimmunotherapy. Detailed data among 1596 patients diagnosed during 2014–2018 revealed that dexamethasone‐rituximab‐cyclophosphamide was the most frequently applied regimen; its use increased from 14% to 39% between 2014 and 2018. The 5‐year RS increased significantly over time, particularly since the introduction of rituximab in the early–mid 2000s. The 5‐year RS during 1989–1995 was 75%, 65%, and 46% across the age groups compared to 93%, 85%, and 79% during 2011–2018. However, the survival improvement was less pronounced after 2011. Collectively, the impressive survival improvement may be accounted for by broader application of rituximab‐containing therapy. The lack of survival improvement in the post‐rituximab era warrants studies across multiple lines of therapy to further improve survival in LPL/WM.