Acute kidney failure reveals primary renal non-Hodgkin lymphoma.

A male patient in his 60s was admitted to our hospital with symptoms of dyspnoea, asthenia, diaphoresis and acute kidney failure. No tumour or infection was detected in initial screening. However, laboratory examination suggested that the acute kidney failure was due to an intrarenal cause, exhibiting a tubular injury pattern and indications of tumour lysis syndrome. Initial hydration therapy, paired with intravenous rasburicase, rapidly improved the kidney function. Unfortunately, the kidney function deteriorated once again, prompting a kidney biopsy that revealed an aggressive diffuse large B-cell non-Hodgkin lymphoma of the kidney. The chemotherapy, comprised of R-CHOP scheme, led to a full recovery of the kidney function and complete remission of the lymphoma. Primary renal non-Hodgkin lymphoma without nodal manifestation is rare, and its pathophysiology is poorly understood. Therapy schemes can vary significantly between cases, relying primarily on non-renal-specific haemato-oncological guidelines. Therefore, further studies are needed to develop the best therapeutic approaches.

Initial Efficacy of the COVID-19 mRNA Vaccine Booster and Subsequent Breakthrough Omicron Variant Infection in Patients with B-Cell Non-Hodgkin's Lymphoma: A Single-Center Cohort Study.

It has been suggested that the effect of coronavirus disease 2019 (COVID-19) booster vaccination in patients with B-cell non-Hodgkin's lymphoma (B-NHL) is inferior to that in healthy individuals. However, differences according to histological subtype or treatment status are unclear. In addition, there has been less research on patients who subsequently develop breakthrough infections. We investigated the effects of the first COVID-19 booster vaccination for patients with B-NHL and the clinical features of breakthrough infections in the Omicron variant era. In this study, B-NHL was classified into two histological subtypes: aggressive lymphoma and indolent lymphoma. Next, patients were subdivided according to treatment with anticancer drugs at the start of the first vaccination. We also examined the clinical characteristics and outcomes of patients who had breakthrough infections after a booster vaccination. The booster effect of the COVID-19 mRNA vaccine in patients with B-NHL varied considerably depending on treatment status at the initial vaccination. In the patient group at more than 1 year after the last anticancer drug treatment, regardless of the histological subtype, the booster effect was comparable to that in the healthy control group. In contrast, the booster effect was significantly poorer in the other patient groups. However, of the 213 patients who received the booster vaccine, 22 patients (10.3%) were infected with COVID-19, and 18 patients (81.8%) had mild disease; these cases included the patients who remained seronegative. Thus, we believe that booster vaccinations may help in reducing the severity of Omicron variant COVID-19 infection in patients with B-NHL.

Single-cell transcriptome sequencing provides insight into multiple chemotherapy resistance in a patient with refractory DLBCL: a case report.

Relapsed and refractory diffuse large B-cell lymphoma (DLBCL) is associated with poor prognosis. As such, a comprehensive analysis of intratumoral components, intratumoral heterogeneity, and the immune microenvironment is essential to elucidate the mechanisms driving the progression of DLBCL and to develop new therapeutics. Here, we used single-cell transcriptome sequencing and conventional bulk next-generation sequencing (NGS) to understand the composite tumor landscape of a single patient who had experienced multiple tumor recurrences following several chemotherapy treatments. NGS revealed several key somatic mutations that are known to contribute to drug resistance. Based on gene expression profiles at the single-cell level, we identified four clusters of malignant B cells with distinct transcriptional signatures, showing high intra-tumoral heterogeneity. Among them, heterogeneity was reflected in activating several key pathways, human leukocyte antigen (HLA)-related molecules' expression, and key oncogenes, which may lead to multi-drug resistance. In addition, FOXP3+ regulatory CD4+ T cells and exhausted cytotoxic CD8+ T cells were identified, accounted for a significant proportion, and showed highly immunosuppressive properties. Finally, cell communication analysis indicated complex interactions between malignant B cells and T cells. In conclusion, this case report demonstrates the value of single-cell RNA sequencing for visualizing the tumor microenvironment and identifying potential therapeutic targets in a patient with treatment-refractory DLBCL. The combination of NGS and single-cell RNA sequencing may facilitate clinical decision-making and drug selection in challenging DLBCL cases.

Acute, long-term or non-vincristine-induced peripheral neuropathy among non-Hodgkin lymphoma survivors: Symptoms, daily activities, functional status, and quality of life.

PURPOSE: This study aimed to explore the incidence and severity of vincristine-induced peripheral neuropathy (VIPN) in non-Hodgkin lymphoma (NHL) survivors (primary aim) and its impact on daily life by comparing common cancer symptoms, functional status, and quality of life (QoL) among survivors with acute, long-term, and non-VIPN (secondary aim). METHODS: This cross-sectional study examined 144 NHL survivors. Standardized questionnaires were used to assess common cancer symptoms, functional status, and QoL with the European Organization for the Research and Treatment of Cancer - Quality of Life Questionnaire (EORTC-QLQ-C30). VIPN (Chemotherapy-Induced Peripheral Neuropathy) status was classified using EORTC-QLQ-CIPN20. A self-designed interference scale was developed to determine the impact of the VIPN on daily activities. The Kruskal-Wallis test and Spearman rank correlation were used in this study. RESULTS: Among the survivors of acute and long-term VIPN, the highest incidences and most severe symptoms were found for hand numbness and foot cramps. A significant moderate correlation was found between disturbances in daily activities and acute or long-term VIPN, including gait changes, going up or down the stairs, and imbalance-related falls. Acute and long-term VIPN survivors showed worse symptoms (fatigue, insomnia, and constipation) and lower QoL than non-VIPN survivors did. In acute VIPN, social function was significantly affected, whereas in long-term VIPN, emotional and cognitive functions were affected. CONCLUSION: Numbness and cramps should be addressed in survivors of acute and long-term VIPN. Preventing falls is recommended for NHL survivors with VIPN, and psychological support is suggested for long-term VIPN survivors.

Incidence and survival of second primary non-Hodgkin lymphoma: A Surveillance, Epidemiology, and End Results-based cohort study.

BACKGROUND: The aim of this study was to investigate patient survival and factors associated with survival in second primary non-Hodgkin lymphoma (NHL) compared with the first primary NHL. METHODS: The retrospective cohort study used data from the Surveillance, Epidemiology, and End Results (SEER) database between 2000 and 2014. Demographic characteristics, histological types, Ann Arbor stage, and treatment information were collected. Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for factors associated with overall survival (OS) and cancer-specific survival (CSS) in the first and second primary NHLs. RESULTS: Of 318,168 cases followed for 5 years, 299,248 patients developed the first primary NHL and 18,920 patients developed the second primary NHL. This study identified a rising incidence of first and second primary NHL from 2000 to 2014. For the second primary NHL, the OS risk was higher when compared to the first primary NHL (HR: 1.13, 95% CI: 1.11 to 1.15, P <0.001). Risk factors that negatively affected OS in the first primary NHL included being male, over 40 years of age, certain marital statuses, specific histological types, and advanced disease stages. In contrast, being of White race and having histological types such as Follicular Lymphoma (FL), Marginal Zone Lymphoma (MZL), and mantle B-cell NHL were associated with better OS outcomes. Treatments like surgery, radiation therapy, and chemotherapy were associated with a lower risk of OS and CSS in the first primary NHL. For the second primary NHL, the detrimental risk factors were similar but also included being over the age of 60. Certain histological types showed a lower OS risk relative to diffuse Large B-cell Lymphoma (DLBCL). While surgery and chemotherapy were beneficial for OS, radiation therapy did not improve survival in second primary NHL cases. Notably, undergoing chemotherapy for the first primary cancer increased the OS risk in the second primary NHL, whereas surgery and radiation seemed to offer a protective effect against OS risk in the second primary NHL (all P <0.05). CONCLUSION: Our findings emphasize the need for tailored strategies in managing the second primary NHL, given the distinct survival patterns and risk factor profiles compared to the first primary NHL. Future research should aim to further elucidate these differences to improve prognosis and treatment approaches for second primary NHL patients.

Outcome differences by sex in oncology clinical trials.

Identifying sex differences in outcomes and toxicity between males and females in oncology clinical trials is important and has also been mandated by National Institutes of Health policies. Here we analyze the Trialtrove database, finding that, strikingly, only 472/89,221 oncology clinical trials (0.5%) had curated post-treatment sex comparisons. Among 288 trials with comparisons of survival, outcome, or response, 16% report males having statistically significant better survival outcome or response, while 42% reported significantly better survival outcome or response for females. The strongest differences are in trials of EGFR inhibitors in lung cancer and rituximab in non-Hodgkin's lymphoma (both favoring females). Among 44 trials with side effect comparisons, more trials report significantly lesser side effects in males (N = 22) than in females (N = 13). Thus, while statistical comparisons between sexes in oncology trials are rarely reported, important differences in outcome and toxicity exist. These considerable outcome and toxicity differences highlight the need for reporting sex differences more thoroughly going forward.

Clinical pharmacology strategies to accelerate the development of polatuzumab vedotin and summary of key findings.

The favorable benefit-risk profile of polatuzumab vedotin, as demonstrated in a pivotal Phase Ib/II randomized study (GO29365; NCT02257567), coupled with the need for effective therapies in relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL), prompted the need to accelerate polatuzumab vedotin development. An integrated, fit-for-purpose clinical pharmacology package was designed to support regulatory approval. To address key clinical pharmacology questions without dedicated clinical pharmacology studies, we leveraged non-clinical and clinical data for polatuzumab vedotin, published clinical data for brentuximab vedotin, a similar antibody-drug conjugate, and physiologically based pharmacokinetic and population pharmacokinetic modeling approaches. We review strategies and model-informed outcomes that contributed to regulatory approval of polatuzumab vedotin plus bendamustine and rituximab in R/R DLBCL. These strategies made polatuzumab vedotin available to patients earlier than previously possible; depending on the strength of available data and the regulatory/competitive environment, they may also prove useful in accelerating the development of other agents.

Treatment outcomes and prognostic factors of patients with lymphoblastic lymphoma in East Asia.

Lymphoblastic lymphoma (LBL) is a rare, aggressive non-Hodgkin lymphoma (NHL) that has no established therapeutic approaches. The aim of this study was to investigate optimal treatments and prognostic risk models for patients with LBL in East Asia. We retrospectively examined the clinical data and treatment courses of adult patients diagnosed as LBL by WHO 2017 classification system. Median overall survival (OS) of the 78 patients with LBL was 38.3 months. There was no significant difference in OS between the patients who were treated with acute lymphoblastic leukemia (ALL)-like protocols and with NHL-like protocols (72.4 months vs 37.5 months, respectively, P = .546). The patients treated with ALL-like protocols had significantly shorter progression-free survival (PFS) (median 11.7 months for ALL-like protocols vs 27.0 months for NHL-like protocols, P = .030). A multivariable analysis found that central nervous system (CNS) prophylaxis, relapse of CNS lesions, leukemic transformation, and response to initial treatment were risk factors for OS of patients with LBL. Hematopoietic stem cell transplantation had no survival benefit, compared with chemotherapy-only treatment. Less intensive chemotherapy may be more optimal for patients in East Asia. Prophylaxis and management of CNS lesions should be emphasized throughout the treatment of LBL.

Gemcitabine-based conditioning compared to BEAM/BEAC conditioning prior to autologous stem cell transplantation for non-Hodgkin lymphoma: No difference in outcomes.

BACKGROUND: High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) remains an effective treatment for non-Hodgkin lymphoma (NHL). The limited availability of carmustine has prompted the exploration of novel alternative conditioning regimens. This study aimed to compare the efficacy and safety profile of GBM/GBC (gemcitabine, busulfan, and melphalan or cyclophosphamide) conditioning compared with the standard BEAM/BEAC regimens (carmustine, etoposide, cytarabine, and melphalan or cyclophosphamide) for ASCT in patients with NHL. METHODS: A retrospective analysis was conducted on 231 NHL patients, who underwent ASCT from October 2010 to October 2021 at the Institute of Hematology & Blood Disease Hospital, including both first-line and salvage settings. This resulted in the inclusion of 112 patients in the GBM/GBC arm and 92 in the BEAM/BEAC arm. Propensity score matching was employed to validate the results. RESULTS: Disease subtype distribution was similar between the GBM/GBC and BEAM/BEAC groups, with diffuse large B-cell lymphoma being the most common (58.9% vs. 58.7%), followed by PTCL (17.0% vs. 18.5%) and MCL (14.3% vs. 14.1%). At 3 months post-ASCT, complete response (CR) rates were comparable (GBM/GBC 93.5% vs. BEAM/BEAC 91.1%; p = 0.607). The 4-year progression-free survival (78.4% vs. 82.3%; p = 0.455) and 4-year overall survival (88.1% vs. 87.7%; p = 0.575) were also similar. Both groups exhibited low non-relapse mortality at 4 years (GBM/GBC 1.8% vs. BEAM/BEAC 3.5%; p = 0.790) with no transplant-related mortalities reported. The GBM/GBC cohort demonstrated a higher incidence of grade 3/4 oral mucositis and hepatic toxicity, whereas the BEAM/BEAC group had more frequent cases of bacteremia or sepsis (13 cases vs. 5 in GBM/GBC). CONCLUSIONS: The GBM/GBC regimen is effective and well-tolerated, offering outcomes that are highly comparable to those in NHL patients conditioned with BEAM/BEAC, as demonstrated in a prognostically matched cohort.

Treatment Outcomes with Standard of Care in Relapsed/Refractory Diffuse Large B-Cell Lymphoma: Real-World Data Analysis.

INTRODUCTION: Despite new therapies for relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL), treatments with chemotherapy, single-agent rituximab/obinutuzumab, single-agent lenalidomide, or combinations of these agents continue to be commonly used. METHODS: This retrospective study utilized longitudinal data from 4226 real-world electronic health records to characterize outcomes in patients with R/R DLBCL. Eligible patients were diagnosed with DLBCL between January 2010 and March 2022 and had R/R disease treated with ≥ 1 prior systemic line of therapy (LOT), including ≥ 1 anti-CD20-containing regimen. RESULTS: A total of 573 patients treated with ≥ 1 prior LOT were included (31.2% and 13.4% with ≥ 2 and ≥ 3 prior LOTs, respectively). Median duration of follow-up was 7.7 months. Most patients (57.1%) were male; mean standard deviation (SD) age was 63 (14.7) years. Overall and complete response rates (95% confidence interval (CI) were 52% (48-56) and 23% (19-27). Median duration of response and duration of complete response were 3.5 and 18.4 months. Median progression-free and overall survival (95% CI) was 3.0 (2.8-3.3) and 12.9 (10.1-16.9) months, respectively. Patients with a higher number of prior LOTs, primary refractoriness, refractoriness to last LOT, refractoriness to last anti-CD20-containing regimen, and prior CAR T exposure had worse outcomes (i.e., challenging-to-treat R/R DLBCL) compared with those without these characteristics. CONCLUSIONS: Outcomes in patients with R/R DLBCL treated with chemotherapy, single-agent rituximab/obinutuzumab, single-agent lenalidomide, or combinations of these agents remain poor, especially for those with challenging-to-treat R/R DLBCL. These findings underscore the unmet need for new, safe, and effective therapies, especially for challenging-to-treat R/R DLBCL populations.

Preclinical characterization and phase 1 results of ADG106 in patients with advanced solid tumors and non-Hodgkin's lymphoma.

ADG106, a ligand-blocking agonistic antibody targeting CD137 (4-1BB), exhibits promising results in preclinical studies, demonstrating tumor suppression in various animal models and showing a balanced profile between safety and efficacy. This phase 1 study enrolls 62 patients with advanced malignancies, revealing favorable tolerability up to the 5.0 mg/kg dose level. Dose-limiting toxicity occurs in only one patient (6.3%) at 10.0 mg/kg, resulting in grade 4 neutropenia. The most frequent treatment-related adverse events include leukopenia (22.6%), neutropenia (22.6%), elevated alanine aminotransferase (22.6%), rash (21.0%), itching (17.7%), and elevated aspartate aminotransferase (17.7%). The overall disease control rates are 47.1% for advanced solid tumors and 54.5% for non-Hodgkin's lymphoma. Circulating biomarkers suggest target engagement by ADG106 and immune modulation of circulating T, B, and natural killer cells and cytokines interferon γ and interleukin-6, which may affect the probability of clinical efficacy. ADG106 has a manageable safety profile and preliminary anti-tumor efficacy in patients with advanced cancers (this study was registered at ClinicalTrials.gov: NCT03802955).

Current Multidisciplinary Lymphoma and Myeloma Management for Surgeons.

Although there are more than 100 clinically distinct lymphoid neoplasms with varied prognoses and treatment approaches, they generally share high sensitivity to glucocorticoids, cytotoxic chemotherapy, and radiation. The disease control rates for lymphoid malignancies are higher than many solid tumors, and many are curable even when presenting with extensive involvement. Novel targeted therapies have improved disease control and cure rates for nearly all subtypes of lymphoid neoplasms. Surgical oncologists will primarily be involved in obtaining biopsies of sufficient quality to allow accurate diagnosis. However, there are scenarios in which surgical intervention may be necessary to address an oncologic emergency.

Safety of a 90-min duration of intravenous infusion of obinutuzumab in patients with B-cell non-Hodgkin's lymphoma in a tertiary hospital in China: a prospective, open-label, exploratory clinical trial.

This study aimed to analyze the safety and applicability of a 90-min duration of infusion (SDI) of obinutuzumab in patients with B-cell non-Hodgkin's lymphoma (NHL) in a tertiary hospital in China. This exploratory clinical trial was performed at Jiangsu Province Hospital. All patients were treated with the standard infusion regimen for the first infusion. If no grade ≥3 infusion-related reactions (IRRs) occurred, the subsequent infusions were given as SDI. The primary endpoint was the incidence of IRR during the standard infusion (3-4 h) and 90-min SDI regimens. This study enrolled 208 patients and all completed cycle 1. Forty-one patients (19.71%) had IRRs: five (2.40%) with grade 1, twenty-eight (13.46%) with grade 2, and eight (3.85%) with grade 3. The 41 patients had 71 IRRs, mainly fever (40.85%), chest pain/tightness (12.68%), and dyspnea (9.86%). The occurrence of IRRs in the first infusion was significantly lower in patients who received oral acetaminophen prophylaxis than those who did not (10.72% vs 30.21%, P<0.001). For the subsequent cycles with 90-min SDI, only two (0.25%) IRRs occurred among 814 infusions (one grade 1 hand numbness and one grade 2 chill/fever). The 90-min obinutuzumab SDI might be safe and feasible in patients with B-cell NHL in China.

A phase 1-2 trial of DA-EPOCH-R plus ixazomib for MYC-aberrant lymphoid malignancies: the DACIPHOR regimen.

ABSTRACT: MYC-aberrant non-Hodgkin lymphoma (NHL) is associated with poor outcomes with conventional chemotherapy. Ixazomib is an orally bioavailable proteasome inhibitor that targets drivers of MYC expression and has demonstrated preclinical activity in aggressive MYC-aberrant NHL. We conducted a phase 1/2 study evaluating the safety and efficacy of DA-EPOCH-R with adjunctive ixazomib in aggressive MYC-aberrant NHL. For induction, patients received 6 cycles of DA-EPOCH-R with ixazomib administered twice per 21-day cycle; responders continued weekly ixazomib maintenance for up to 1 year. Primary objectives were to determine the maximum tolerated dose in phase 1 and efficacy of DA-EPOCH-R with ixazomib as measured by 12-month progression-free survival (PFS) rate in phase 2. Thirty-six patients were evaluable for response. Median age was 63 years (range, 31-77) and 44% had double-hit lymphoma (DHL)/triple-hit lymphoma (THL). In phase 1, 3 mg of ixazomib was established as recommended phase 2 dose. Twenty-nine (76.3%) patients completed 6 cycles of DA-EPOCH-R and 25 (65.8%) underwent dose escalations. The ORR after induction was 97% (95% confidence interval, 81-100) with a CR rate of 69%. At median follow-up of 18.8 months, the 12-month PFS and overall survival (OS) rates were 78% and 86%, respectively. For DHL/THL vs dual expressor lymphomas (DEL), 12-month PFS rates were 53% vs 95% and 12-month OS rates were 65% vs 100%, respectively. Grade ≥3 toxicities were predominantly hematologic. Twenty-seven (75%) of patients experienced neuropathy, nearly all low-grade. DA-EPOCH-R induction with adjunctive ixazomib is feasible and appears effective in patients with DEL. This trial was registered at www.clinicaltrials.gov as #NCT02481310.

Multicenter phase II study of moderate low-dose radiotherapy in indolent non-Hodgkin lymphoma: CLCG-iNHL-01 protocol.

Background: Radiotherapy is an effective treatment for indolent non-Hodgkin lymphoma (iNHL); however, the optimal radiotherapy dose remains to be determined. We hypothesize that a suitable dose may exist between 4 and 24 Gy. Methods: This prospective multicenter phase II trial intends to recruit 73 sites of iNHL patients, who will receive involved-site radiotherapy of 12 Gy in four fractions. The primary objective is the 6-month clinical complete response rate. Tumor tissue, blood and conjunctival specimens will be collected to identify potential predictive biomarkers. Discussion: The CLCG-iNHL-01 trial will evaluate the efficacy and toxicity of 12 Gy in patients with iNHL and provide information on a novel hypofractionation regimen of low-dose radiotherapy. Clinical Trial Registration: NCT05543070 (ClinicalTrials.gov).

Laboratory and clinical features of tumor lysis syndrome in children with non-Hodgkin lymphoma and evaluation of long-term renal functions in survivors.

OBJECTIVE: The purpose of our study is to investigate the laboratory and clinical features of tumor lysis syndrome (TLS) and acute kidney injury (AKI) in childhood non-Hodgkin lymphomas (NHL) and to reveal their impact on long term kidney function in survivors. METHODS: Our single-center retrospective study included 107 patients (0-18 years old) with NHL who were admitted and treated at our hospital between 1998 and 2020. The relationship between TLS and age, gender, histopathological subgroup, tumor stage, lactate dehydrogenase (LDH) level at presentation, bone marrow and kidney involvement were assessed. The long-term renal functions of the patients were investigated. RESULTS: 80.3% of the patients were male with a median age of 9.8 years. The most common detected histopathological subgroup was Burkitt lymphoma. Hyperhydration with or without alkalinisation, and allopurinol were used in first-line treatment and prophylaxis of TLS. Laboratory TLS and clinical TLS was observed in 30.8% and 12.1% of patients, respectively. A significant correlation was found between young age, advanced stage, high LDH level at presentation, and TLS. AKI was observed in 12.1% of the patients. When the glomerular filtration rate values of the patients at the first and last admissions were compared after an average of 6.9 years, a mean decrease of 10 mL/min/1.73 m2 was found. It was not, however, found to be statistically significant. CONCLUSION: Lower age, advanced stage, and high LDH level at presentation were found to be risk factors for TLS in our study. Long-term renal function loss was not observed in the survivors who received early and careful prophylaxis/treatment for TLS. The survivors are still being followed up.

Polatuzumab vedotin plus rituximab and lenalidomide in patients with relapsed or refractory diffuse large B-cell lymphoma: a cohort of a multicentre, single-arm, phase 1b/2 study.

BACKGROUND: Diffuse large B-cell lymphoma comprises nearly 30% of non-Hodgkin lymphoma cases and patients with relapsed or refractory diffuse large B-cell lymphoma who are ineligible for stem-cell transplantation have few treatment options and poor prognoses. We aimed to determine whether the novel combination of polatuzumab vedotin in combination with rituximab and lenalidomide (Pola+R+Len) would provide a tolerable treatment option with enhanced antitumour response in patients with relapsed or refractory diffuse large B-cell lymphoma. METHODS: This completed phase 1b/2, open-label, multicentre, single-arm study (GO29834) evaluated the safety and efficacy of Pola+R+Len in patients with relapsed or refractory diffuse large B-cell lymphoma at 19 sites in three countries (USA, Spain, and UK). Patients (≥18 years old) were eligible for inclusion if they had histologically documented CD20-positive relapsed or refractory diffuse large B-cell lymphoma and Eastern Cooperative Oncology Group performance status of 2 or lower, had received at least one previous line of chemoimmunotherapy, including an anti-CD20 agent, and were ineligible for stem-cell transplantation. The dose-escalation phase (1b) used escalating doses of lenalidomide to find the recommended phase 2 dose. Patients received six 28-day cycles of induction treatment with intravenous rituximab 375 mg/m2 and intravenous polatuzumab vedotin 1·8 mg/kg (all cohorts) plus oral lenalidomide at the following doses: 10 mg (cohort A); 15 mg (cohort B); and 20 mg (cohort C). Rituximab and polatuzumab vedotin were administered on day 1 and lenalidomide on days 1-21 of each 28-day cycle. During the dose-expansion phase (2), patients received six 28-day cycles of Pola+R+Len at the recommended phase 2 dose established during dose escalation. In both phases, patients with a complete response or partial response at the end of induction were eligible for post-induction therapy with rituximab 375 mg/m2 on day 1 and lenalidomide 10 mg/day on days 1-21 of each 28-day cycle for a maximum of 6 cycles. The primary safety objective of the dose-escalation phase was identification of the maximum tolerated dose through incidence of dose-limiting toxic effects. The primary efficacy outcome of the dose-expansion phase was Independent Review Committee-assessed complete response rate at end of induction, based on PET-CT. Analyses were conducted in the safety population, which included all patients who received at least one dose of any study drug, and the efficacy population, which included all patients who received at least one dose of any study drug at the recommended phase 2 dose. This study is registered with ClinicalTrials.gov, number NCT02600897. FINDINGS: Between July 11, 2017 and Feb 3, 2020, 57 patients were enrolled (median age 71 years [IQR 60-75]; 38 [67%] were male and 19 (33%) were female; 47 [82%] were not Hispanic or Latino; and the median previous lines of therapy was 2 [IQR 1-3]). 18 participants were included in phase 1b and 39 were included in phase 2. Phase 1b confirmed a 20 mg recommended phase 2 dose for lenalidomide. After a median follow-up of 11·8 months (IQR 4·7-25·8), the complete response rate, as assessed by the Independent Review Committee, was 31% (90% CI 20-43). The most common grade 3-4 adverse events were neutropenia (35 [61%] of 57) and thrombocytopenia (eight [14%] of 57). Serious adverse events were reported in 23 (40%) of 57 patients and one patient died due to a treatment-related adverse event (neutropenic sepsis). INTERPRETATION: Although the combination of Pola+R+Len did not meet the prespecified activity threshold, some patients derived clinical benefit and the regimen had a tolerable safety profile in patients with relapsed or refractory diffuse large B-cell lymphoma. FUNDING: Genentech/F Hoffmann-La Roche.

Severe sperm DNA fragmentation may persist for up to 3 years after cytotoxic therapy in patients affected by Hodgkin lymphoma and non-Hodgkin lymphoma.

STUDY QUESTION: Does sperm DNA recover from damage in all men after 2 years from the end of cytotoxic treatments? SUMMARY ANSWER: The current indication of 2 years waiting time for seeking natural pregnancy after cytotoxic treatment may not be adequate for all men, since severe sperm DNA damage is present in a proportion of subjects even after this timeframe. WHAT IS KNOWN ALREADY: Data in the literature on sperm DNA fragmentation (SDF) in lymphoma patients after cytotoxic treatments are scarce. The largest longitudinal study evaluated paired pre- and post-therapy (up to 24 months) semen samples from 34 patients while one study performed a longer follow-up (36 months) in 10 patients. The median/mean SDF values >24 months after therapy did not show significant differences but the studies did not explore the proportion of patients with severe DNA damage and the analysis was done on frozen-thawed samples. STUDY DESIGN, SIZE, DURATION: In this study, 53 Hodgkin lymphoma (HL) and 25 non-Hodgkin lymphoma (NHL) post-pubertal patients were included over a recruitment period of 10 years (2012-2022). Among them, 18 subjects provided paired semen samples for SDF analysis at the three time points. SDF was evaluated in patients before (T0) and after 2 (T2) and 3 years (T3) from the end of, cytotoxic treatments (chemotherapy alone or in combination with radiotherapy). A cohort of 79 healthy, fertile, and normozoospermic men >18 years old served as controls (recruited between 2016 and 2019). PARTICIPANTS/MATERIALS, SETTING, METHODS: SDF was evaluated on fresh semen samples (i.e. spermatozoa potentially involved in natural conception) from patients and controls using TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling) assay coupled with flow cytometry. SDF median values were compared between groups: (i) HL and NHL patients versus controls at the three time points; (ii) HL versus NHL patients at baseline; and (iii) patients at T0 versus T2 and T3. Severe DNA damage (SDD) was defined for SDF levels above the 95th percentile of controls (50%) and the proportion of patients with SDD at all time points was established. MAIN RESULTS AND THE ROLE OF CHANCE: At T0, patients displayed higher median SDF than controls, reaching statistical significance in the NHL group: 40.5% [IQR: 31.3-52.6%] versus 28% [IQR: 22-38%], P < 0.05. Comparing SDF pre-treatment to that post-treatment, HL patients exhibited similar median values at the three time points, whereas NHL showed significantly lower values at T3 compared to T0: 29.2% [IQR: 22-38%] versus 40.5% [IQR: 31.3-52.6%], P < 0.05. The proportion with SDD in the entire cohort at T2 was 11.6% and 13.3% among HL and NHL patients, respectively. At T3, only one in 16 NHL patients presented SDD. LIMITATIONS, REASONS FOR CAUTION: TUNEL assay requires at least 5 million spermatozoa to be performed; hence, severe oligozoospermic men were not included in the study. Although our cohort represents the largest one in the literature, the relatively small number of patients does not allow us to establish precisely the frequency of SDD at T2 which in our study reached 11-13% of patients. WIDER IMPLICATIONS OF THE FINDINGS: Our data provide further insights into the long-term effects of cytotoxic treatments on the sperm genome. The persistent severe DNA damage after 2 years post-treatment observed in some patients suggests that there is an interindividual variation in restoring DNA integrity. We propose the use of SDF as a biomarker to monitor the treatment-induced genotoxic effects on sperm DNA in order to better personalize pre-conceptional counseling on whether to use fresh or cryopreserved spermatozoa. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by grants from the Istituto Toscano Tumori (ITT), Fondazione Ente Cassa di Risparmio di Firenze, the European Commission-Reproductive Biology Early Research Training (REPROTRAIN). C.K., G.F., V.R., and A.R.-E. belong to COST Action CA20119 (ANDRONET) which is supported by the European Cooperation in Science and Technology (www.cost.eu). The authors declare no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

Drug-Loaded Biomimetic Carriers for Non-Hodgkin's Lymphoma Therapy: Advances and Perspective.

Chemotherapy remains the mainstay of treatment for the lymphoma patient population, despite its relatively poor therapeutic results, high toxicity, and low specificity. With the advancement of biotechnology, the significance of drug-loading biomimetic materials in the medical field has become increasingly evident, attracting extensive attention from the scientific community and the pharmaceutical industry. Given that they can cater to the particular requirements of lymphoma patients, drug-loading biomimetic materials have recently become a potent and promising delivery approach for various applications. This review mainly reviews the recent advancements in the treatment of tumors with biological drug carrier-loaded drugs, outlines the mechanisms of lymphoma development and the diverse treatment modalities currently available, and discusses the merits and limitations of biological drug carriers. What is more, the practical application of biocarriers in tumors is explored by providing examples, and the possibility of loading such organisms with antilymphoma drugs for the treatment of lymphoma is conceived.