Elderly Diffuse Large B-cell Lymphoma Research Articles

Evaluating the cancer aging and research group model in predicting immunochemotherapy toxicity among elderly patients with diffuse large B-cell lymphoma

BackgroundThe management of diffuse large B-cell lymphoma (DLBCL) in elderly patients is complicated by an increased risk of treatment-related toxicity associated with aging. This study aimed to validate the effectiveness of the Cancer Aging and Research Group (CARG) model in elderly patients with DLBCL receiving rituximab-based chemotherapy. MethodsIn this prospective study, elderly DLBCL patients (aged 65 years or older) receiving rituximab-based chemotherapy were consecutively assessed between August 2016 and December 2021 at one medical center in Taiwan using the CARG model to predict treatment-related toxicity. Patients were categorized into low-, medium-, and high-risk groups based on their CARG scores. Comparisons were made regarding toxicities and survival rates among these groups. ResultsNinety-one patients, with a median age of 70 years (range 65–96), were included. A substantial 81 % (74 patients) experienced grade 3–5 toxicity. The overall 2-year survival rate was 63.8 % after a median follow-up of 28 months (range, 2–46). The risk of grade 3–5 toxicity was 83 %, 78 %, and 87 %, respectively, among the low-, medium-, and high-risk groups (p = 0.60). The receiver operating characteristic (ROC) curve for CARG was 0.521 (95 % CI, 0.376–0.666), which was significantly lower than that for the Eastern Cancer Oncology Group score (ROC = 0.701, 95 % CI, 0.571–0.831). Similarly, compared with those of low-risk patients, hazard ratios for overall survival were 9.22 (95 % CI, 1.23–69.1; p = 0.031) and 14.6 (95 % CI, 1.90–112; p = 0.010) for medium- and high-risk patients, respectively. ConclusionWhile CARG exhibited limitations in predicting treatment-related toxicity in elderly DLBCL patients, it demonstrated potential efficacy in predicting survival outcomes.

Clinical efficacy of prophylactic intravenous immunoglobulin for elderly DLBCL patients with hypogammaglobulinemia in the COVID-19 pandemic era.

Elderly patients diagnosed with diffuse large B-cell lymphoma (DLBCL) undergoing reduced intensity R-CHOP therapy are at a heightened risk of acquiring infections, notably coronavirus disease 2019 (COVID-19) infection. This study aimed to evaluate the efficacy of intravenous immunoglobulin (IVIG) as prophylaxis against COVID-19 in this vulnerable population. A total of 125 elderly patients with DLBCL undergoing reduced intensity R-CHOP therapy were analyzed in this prospective, multicenter study. Patients with hypogammaglobulinemia were categorized into IVIG and non-IVIG groups, while those with normal immunoglobulin levels constituted the observation group. The study evaluated COVID-19 infection rates, therapy response, and safety outcomes. Among the enrolled patients (median age: 77 years), 89 patients (71.2%) presented with hypogammaglobulinemia at diagnosis, and 56 patients enrolled in the IVIG administration group. IVIG administration remarkably reduced COVID-19 infection rates compared to non-IVIG recipients (8.9% vs. 24.6%; p =0.040). Notably, patients over 80 years old were more susceptible to COVID-19. Patients on IVIG exhibited good tolerance with manageable adverse events. Among patients with hypogammaglobulinemia who received IVIG, 40.5% of patients developed additional immunoglobulin deficiencies during chemotherapy. One or more new hypogammaglobulinemia occurred during chemotherapy in 72% of patients with hypogammaglobulinemia who did not receive IVIG, and in 61.3% of patients who did not have hypogammaglobulinemia at diagnosis. IVIG showed promise in reducing COVID-19 infections among elderly patients with DLBCL receiving reduced intensity R-CHOP therapy. This highlights IVIG's potential as a prophylactic measure, necessitating further investigation to optimize dosing, administration schedules, and potential interactions with vaccination strategies.

Polatuzumab Vedotin, Zanubrutinib and Rituximab Achieved Rapid and Deep Response in Previously Untreated Frail and Elderly Diffuse Large B-Cell Lymphoma Patients

Introduction: The incidence of diffuse large B-cell lymphoma (DLBCL) increases with age, while first-line treatment for frail and elderly DLBCL is a debating topic. 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). First-line treatment balancing efficacy with safety is urgently needed for frail and elderly DLBCL patients. Since polatuzumab vedotin was approved in China for first-line DLBCL this year and reportedly had synergistic effect with rituximab in cell line research (Natsumi Kawasaki et al., Br J Haematol, 2022), we conducted a study of polatuzumab vedotin plus zanubrutinib and rituximab (ZPR) in previously untreated frail and elderly DLBCL to assess the efficacy and safety. Here we present the characteristics of 12 enrolled patients and preliminary results. Methods: Previously untreated DLBCL patients aged over 70 years old, or aged between 60 to 69 with ECOG score 2 to 4 were enrolled in this study. All patients received a triplet regimen of ZPR. Twenty-one days was a cycle. Zanubrutinib was given 160mg twice a day orally from day 1 to day 21. Rituximab was given 375mg/m 2 intravenously on day 1. Polatuzumab vedotin was administered at a dosage of 1.8mg per kilogram intravenously on day 1. Patients would receive 6 cycles of ZPR regimen if assessed partial response (PR) or complete response (CR) after 3 cycles. If assessed CR after 6 cycles of ZPR, patients would receive zanubrutinib 160mg twice a day alone for another 6 cycles. Whole body 18F-FDG PET/CT scan or contrast-enhanced CT scan of cervical, thoracic, abdominal and pelvic parts was scheduled every 3 cycles. Treatment response was assessed by 2014 Lugano response criteria. Adverse events were graded by CTCAE 5.0. The primary endpoint is overall response rate (ORR) after 6 cycles of ZPR. The secondary endpoints are CR rate after 6 cycles of ZPR, and 2-year progression-free survival (PFS). Other endpoint is safety (Figure 1). Results: Twelve patients were enrolled in our study until Jul 24, 2023. Median age was 75 (range: 67-87). Six patients were female and six patients were male. Nine (75%) patients were classified non-GCB type according to cell of origin by Hans algorithm. Nine (75%) patients were assessed stage Ⅲ to Ⅳ by Ann Arbor staging system. Nine (75%) patients had an international prognostic index (IPI) score of 2 or more. One (11%) patient had double-hit risk factor in 9 patients with gene rearrangement results. Six (75%) patients had MYD88 L265P mutation in 8 patients with sequencing results. After a median follow up of 2.1 months, four patients had PET/CT assessment results after 3 cycles of ZPR, and four (100%) of them achieved CR. The ORR after 3 cycles of ZPR regimen was 100% (Figure 2).Grade 3 to 4 adverse events occurred in two patients, that one patient had grade 3 aspartate aminotransferase increase and alanine aminotransferase increase, and the other patient had grade 3 pneumonitis. Grade 1 to 2 adverse events included neutrophil count decrease (16%), dizziness (8%), and epistaxis (8%). All patients recovered from adverse events under best supportive care. There was no discontinuation of ZPR regimen due to severe adverse events. Conclusion: 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.

The ZR2-Minichop Study：Zanubrutinib, Lenalidomide, Rituximab, Cyclophosphamide, Vincristine, Epirubicin and Prednisone in Elderly Patients with Previously Untreated Diffuse Large B-Cell Lymphoma

Background: Diffuse large B cell lymphoma (DLBCL) is common in the elderly group. New schedules are required due to the toxicity in classic chemotherapy regimens. Previous studies reported that non-germinal center B cell (non-GCB) subtype aggregates in elderly patients with abnormality in the activated B cell receptor signal and nuclear factor kappa-B pathway. We conducted a prospective trial to investigate the efficacy and safety of the ZR2-miniCHOP schedule (zanubrutinib, lenalidomide, rituximab, cyclophosphamide, vincristine, epirubicin and prednisone) in elder patients newly diagnosed with non-GCB DLBCL. Methods: This multicenter, single-arm, phase II clinical study started in June 2021 at 6 centers in China. Eligible patients were newly diagnosed non-GCB DLBCL, aged 60 to 80 with Eastern Cooperation Oncology Group (ECOG) performance status over 2, or patients aged over 80 with ECOG status of 0-4. The purpose of this study is to discuss the response, safety and long-term survival with the primary endpoint of objective response rate (ORR) and the secondary endpoint of overall survival (OS) and progression free survival (PFS). Patients would receive 2 cycles induction period with zanubrutinib 160mg twice per day on d1-28, lenalidomide 25mg d1-10 and rituximab 375mg/m 2 d1, after then combine 4-6 cycles miniCHOP schedule as: cyclophosphamide 400mg/m 2 d2, vincristine 1.4mg/m 2 d2, epirubicin 35mg/m 2 d2 and prednisone 45mg/m 2 d2-6. Evaluation is conducted after 6 cycles of treatment including the ORR and CR rate by positron emission tomography-computed tomography (PET-CT) and 2-years OS and PFS. Results: At the data collection duration from June 2021 to June 2023, 45 patients were recruited in this trial. 34 patients were considered for result analysis as 2 withdrawals and 1 drop-out. 6 patients are still in the process of treatment. The median age of the 45 patients enrolled was 79 (range 65-90) years, with 34 (75.6%) patients over 75 years old. The ORR was 91.2% (31/34). Among the 34 assessable patients, 61.8% (21/34) of them reached CR after 6 cycles routine therapy. Besides, 29.4% (10/34) patients just achieved PR, and for these patients we then continued administered more 2 cycles with ZR2+miniCHOP. Later 5 of these 10 patients achieved CR. One patient stayed SD and 3 patients appeared disease progressing. The most common hematology-relevant adverse events (AEs) were neutropenia (13/34) and thrombocytopenia (10/34). Eleven patients appeared AEs over grade 3 occurred during therapy with neutropenia, thrombocytopenia, infectious pneumonia events. All these patients have been administrated the normal dose as the treatment resistance and the toxicity did not affect therapy. Two patients died of progressive disease. No treatment-associated death was observed. Generally analyzing, this trial achieved acceptable response and safety. Conclusion: The ZR2-miniCHOP schedule represented satisfactory efficacy and safety in elderly non-GCB DLBCL.

EBF1, MYO6 and CALR expression levels predict therapeutic response in diffuse large B-cell lymphomas.

Diffuse large B-cell lymphoma (DLBCL) is a hematological malignancy representing one-third of non-Hodgkin's lymphoma cases. Notwithstanding immunotherapy in combination with chemotherapy (R-CHOP) is an effective therapeutic approach for DLBCL, a subset of patients encounters treatment resistance, leading to low survival rates. Thus, there is an urgent need to identify predictive biomarkers for DLBCL including the elderly population, which represents the fastest-growing segment of the population in Western countries. Gene expression profiles of n=414 DLBCL biopsies were retrieved from the public dataset GSE10846. Differentially expressed genes (DEGs) (fold change >1.4, p-value <0.05, n=387) have been clustered in responder and non-responder patient cohorts. An enrichment analysis has been performed on the top 30 up-regulated genes of responder and non-responder patients to identify the signatures involved in gene ontology (MSigDB). The more significantly up-regulated DEGs have been validated in our independent collection of formalin-fixed paraffin-embedded (FFPE) biopsy samples of elderly DLBCL patients, treated with R-CHOP as first-line therapy. From the analysis of two independent cohorts of DLBCL patients emerged a gene signature able to predict the response to R-CHOP therapy. In detail, expression levels of EBF1, MYO6, CALR are associated with a significant worse overall survival. These results pave the way for a novel characterization of DLBCL biomarkers, aiding the stratification of responder versus non-responder patients.

Rituximab combined with Bruton tyrosine kinase inhibitor to treat elderly diffuse large B-cell lymphoma patients: Two case reports

Time series analysis is a valuable tool in epidemiology that complements the classical epidemiological models in two different ways: Prediction and forecast. Prediction is related to explaining past and current data based on various internal and external influences that may or may not have a causative role. Forecasting is an exploration of the possible future values based on the predictive ability of the model and hypothesized future values of the external and/or internal influences. The time series analysis approach has the advantage of being easier to use (in the cases of more straightforward and linear models such as Auto-Regressive Integrated Moving Average). Still, it is limited in forecasting time, unlike the classical models such as Susceptible-Exposed-Infectious-Removed. Its applicability in forecasting comes from its better accuracy for short-term prediction. In its basic form, it does not assume much theoretical knowledge of the mechanisms of spreading and mutating pathogens or the reaction of people and regulatory structures (governments, companies, etc. ). Instead, it estimates from the data directly. Its predictive ability allows testing hypotheses for different factors that positively or negatively contribute to the pandemic spread; be it school closures, emerging variants, etc. It can be used in mortality or hospital risk estimation from new cases, seroprevalence studies, assessing properties of emerging variants, and estimating excess mortality and its relationship with a pandemic.

A nomogram prognostic model for diffuse large B-cell lymphoma based on SUVmax and GNRI in elderly patients.

To establish a nomogram for elderly patients with diffuse large B-cell lymphoma (DLBCL) based on nutritional and imaging features. The data of 221 elderly pretreatment DLBCL patients were retrospectively analyzed. All cases were randomly separated into the training group and validation group. A nomogram was built based on the results of multivariate analysis. A nomogram was established based on maximum standardized uptake value (SUVmax), geriatric nutritional risk index (GNRI), and lactate dehydrogenase. The concordance index (C-index) of the nomogram was 0.772 for the training group and 0.729 for the validation group, and similar results were found in the area under the curve (AUC). The calibration curve showed favorable consistency between prediction and real survival. The decision curve analysis (DCA) also showed that the nomogram had favorable clinical effectiveness. The new risk-stratification model divided patients into three groups with obvious survival. The C-index and AUCs for the new model were greater than those of IPI and NCCN-IPI. The DCA curve suggested that the new model had better clinical effectiveness than the IPI and NCCN-IPI. The nomogram prognostic model based on SUVmax and GNRI performed superior to NCCN-IPI and equal to IPI for risk stratification of elderly DLBCL patients.

Phase II trial of split-dose R-CHOP for older patients with diffuse large B-cell lymphoma (DLBCL).

7554 Background: Management of elderly DLBCL is limited by age associated comorbid conditions and decreased tolerance of chemotherapy regimens. Many elderly or unfit/frail patients (pts) with DLBCL receive either non-anthracycline based treatment (tx) or attenuated regimens such as Rituximab (R)-miniCHOP which is ~50% dose reduction from standard R-CHOP-21. Split-dose (SD) R-CHOP is an alternative approach where pts receive CHOP at a 50% dose reduction on Days 1 and 15 of each 28-day cycle with full dose Rituximab on Day 1 for 6 cycles. The cumulative dose of SD R-CHOP delivered over each 28 day cycle is equivalent in dose intensity to one cycle of standard R-CHOP-21. Methods: This is a Phase II, prospective, open label study conducted through the Wisconsin Oncology Network and included two academic centers (NCT03943901). Older pts aged≥75 years or 70-74 years plus elevated cumulative illness rating scale for geriatrics score with untreated de-novo or transformed Stage IIX-IV DLBCL were eligible. Treatment consisted of two months (4 doses) of SD R-CHOP with growth factor support followed by interim response assessment with PET/CT and peripheral blood cell-free clonoSEQ minimal residual testing (MRD). Pts with interim PET/CT score of Deauville 1-3 and MRD negativity were offered abbreviated therapy with two additional months of SD-R-CHOP. All others completed 6 cycles. The primary endpoint was end of tx (EOT) complete response (CR) rate. We utilized a Simon 2-stage design with interim analysis requiring at least 8 EOT CR in the first 16 pts (Stage I) to proceed to stage II. Results: To date, 14 pts have completed tx. The median age was 81 years (73-88) and 57% (n = 8) were male. Most pts had stage 4 disease (n = 8, 57%). 8 of 14 pts were interim PET/CT negative and 8 of 12 MRD evaluable pts were interim MRD negative. 10/14 (71%) pts achieved EOT CR exceeding our minimal threshold to continue the study early. The remaining 4 pts had progressive disease (PD) either during tx or at EOT evaluation. 6 pts were both interim MRD and PET negative; 5 de-escalated to the abbreviated arm with all achieving CR with no relapses to date. 7 pts (50%) had Grade 3+ non-hematologic toxicities and 4 pts (29%) had Grade 3-4 neutropenia. There were 2 deaths, one from COVID-19 with concurrent PD and the other from PD. Median PFS or OS have not been reached with a median follow-up of 13 months for surviving pts. Conclusions: SD-R-CHOP offers older pts with DLBCL equivalent dose intensity as R-CHOP-21 through a fractionated dosing schedule improving tolerability. Prespecified interim efficacy endpoint was met early with 10/14 pts with EOT CR. Interim stratification by MRD and PET/CT allowed de-escalation of tx in early responding pts without compromising efficacy. Clinical trial information: NCT03943901 . [Table: see text]

Benefits of Dynamic Nomogram Models for Elderly Diffuse Large B-Cell Lymphoma Patients' Early Death Prediction and Clinical Application.

Diffuse large B-cell lymphoma (DLBCL) is an aggressive malignancy, and about 60% of the patients are diagnosed in their elderly age (≥65 years old). However, little is known about the early mortality and risk factors related to elderly patients with DLBCL. Methodology. From 2000 to 2019, elderly patients diagnosed with DLBCL in the Surveillance, Epidemiology, and End Result (SEER) database were involved in this research and served as test cohort. Moreover, elderly DLBCL patients from Peking University Third Hospital were used for external validation cohort. Risk factors were identified by univariate and multivariate logistic regression analyses. Nomogram models were constructed based on significance risk factors to predict the overall and cancer-specific early death. Besides that, the predictive value of the models was validated by receiver operating characteristic (ROC) analysis. Calibration plots were used to evaluate the calibrating ability. Clinical benefits of nomogram were evaluated by decision curve analysis (DCA). 15242 elderly DLBCL patients obtained from the SEER database and 152 patients from Peking University Third Hospital were enrolled in this research. In the SEER database, 36.6% (5584/15242) of the patients had early death and 30.7% (4680/15242) of them were cancer-specific early death. Marital status, Ann Arbor stage, surgical treatment, radiotherapy, and chemotherapy were significant risk factors for overall and cancer-specific early death of elderly DLBCL patients. Nomograms were constructed according to these risk factors. Then, ROC analysis showed that the AUC of OS was 0.764 (0.756~0.772), and CSS was 0.742 (0.733~0.751). In the validation group, the AUC of OS was 0.767 (0.689~0.846) and CSS was 0.742 (0.743~0.83). The calibration plots and DCA analysis revealed that the nomograms were good at early death prediction and clinical application. Predictive dynamic nomogram models for elderly DLBCL patients were established and validated, which might play an essential role in helping physicians enact better treatment strategies.

Lenalidomide maintenance fails to overcome the unfavourable prognosis of low NK-cell counts in rituximab-chemotherapy responsive elderly DLBCL patients: A LYSA group study.

Low baseline NK-cell counts (NKCCs) in patients with diffuse large B-cell lymphoma (DLBCL) are associated with a poor prognosis. The REMARC phase III trial (NCT01122472) showed that lenalidomide maintenance prolonged PFS in rituximab-chemotherapy responders. We conducted a REMARC ancillary study analysing the impact of lenalidomide maintenance on the prognostic value of low NKCCs. Blood samples from 335 elderly French patients enrolled in the REMARC trial were analysed by flow cytometry to obtain NKCCs at diagnosis (n = 220), at randomization (n = 186) and/or six months after randomization (n = 184). Baseline NKCCs < 100 cells/μl were associated with shorter PFS and OS (HRs=[2.2 (1.4, 3.3), p < 0.001] and [2.8 (1.7, 4.5), p < 0.001], respectively), independently of aaIPI. In a competing risk analysis, low NKCCs at baseline were associated with a higher risk of relapse/progression (p=0.0025), but not of death without progression (p=0.33). Lenalidomide did not affect the prognosis value of low baseline NKCCs (p =0.6349). Similar results were obtained for low NKCCs at randomization. Our results demonstrate that low NKCCs at baseline and post rituximab-chemotherapy are robust prognostic factors in DLBCL and reveal that lenalidomide has no impact on this parameter. Other therapeutic strategies aiming at improving NK-cell function could improve outcomes in DLBCL.

A chemotherapy-free regimen improves prognosis in elderly diffuse large B-cell lymphoma patients with a low-performance status score: A Chinese multi-center real-world study.

Because patients with diffuse large B-cell lymphoma (DLBCL) aged >80 years old typically experience dismal outcomes, it is essential to improve disease control and reduce side effects in such patients. This was a multi-center retrospective study. Patients aged ≥80 years with pathologically confirmed DLBCL were treated in four centers in the Guangdong province between January 2010 and November 2020. Clinical data from patients receiving different treatment modalities were extracted from electronic medical records. Finally, 50 patients aged ≥80 years were included; four (8.0%) refused treatment, 19 (38%) patients belonged to the chemotherapy-free group, and 27 (54%) patients were in the chemotherapy group. Patients receiving chemotherapy-free treatment had more often a non-germinal center B phenotype than those treated with chemotherapy (P = 0.006). The median progression-free survival (PFS) in the chemotherapy-free group was longer than that in the chemotherapy group (24.7 vs 6.3 months, P = 0.033). Good performance status (PS <2) was associated with higher PFS and overall survival (OS) (P = 0.03; P = 0.02, respectively). In patients with PS of ≥2, the median PFS and OS did not differ between the chemotherapy-free and chemotherapy groups (P = 0.391; P = 0.911, respectively). After stratifying patients with PS <2, the PFS and OS of the chemotherapy-free group were better than those of the chemotherapy group (58.1 vs 7.7 months, P = 0.006; 58.1 vs 26.5 months, P = 0.050). However, treatment-related toxicity did not differ between groups. PS was an independent prognostic factor of elderly DLBCL patients. Accordingly, patients aged ≥80 years with a PS of <2 could benefit from a chemotherapy-free regimen.

Zanubrutinib Plus Rituximab for the Treatment of Elderly Unfit Patients with Previously Untreated Diffuse Large-B Cell Lymphoma

Background: Diffuse Large B-cell lymphoma (DLBCL) is common in the elderly patients, Some elderly patients can not tolerate the standard dose of R-CHOP due to age, poor physical condition, and severe complications. The overall response rate of elderly unfit DLBCL patients who received a reduced dose R-CHOP regimen was only 60%. It is extremely important to explore new therapeutic options. Zanubrutinib is a Bruton tyrosine kinase (BTK) inhibitor which was still in an exploratory phase in patients with DLBCL. The efficacy of Zanubrutinib plus Rituximab in elderly unfit Patients with DLBCL is still unknown. Methods: In the present study, a prospective, single-arm, single-center study was conducted (CHiCTR-2000039342).patients who fulfil the inclusion and exclusion criteria were enrolled. Inclusion criteria: patients aged ≥65 years, and treatment-naive pathologically confirmed with DLBCL, and assessed unfit by Comprehensive Geriatric Assessment(IACA). Unfit patients were defined as follows: i.e. IADL score ≤7, or age >75 years, or CCI score ≥3, or serum albumin <3.4 g/ml. Exclusion criteria: history of malignancy with chemotherapy or radiotherapy before, or serious infectious disease, or bleeding tendency, or hemophilia. Patients enrolled were planned to treat with Zanubrutinib combined with rituximab (Zanubrutinib 160 mg orally twice daily and rituximab 375 mg/m2 day1 iv, every 28 days, ZR regimen), for a total of eight courses. After induction therapy, maintenance treatment with Zanubrutinib 160mg orally twice daily was given until disease progression or unacceptable toxicity. Efficacy was evaluated by PET/CT or enhanced Computed Tomography scan every two to four months, treatment-related adverse effects were evaluated every month. This study was approved by the Ethics Committee of Beijing Hospital, National Center of Gerontology, Beijing, China. Results: From July 2020 to June 2022, A total of ten elderly unfit DLBCL patients who fulfil the inclusion and exclusion criteria were enrolled(CHiCTR-2000039342).The median age was 86.5 years (80-93 years). The most common comorbidities were cardiovascular disease, hypertension, diabetes mellitus. The female to male ratio was 6:4. Two patients were classified as GCB pathological subtype, Seven patients were diagnosed with stage III-IV. At a median follow up of 9.5 months(2-24months). Eight patients could be evaluated for efficacy. Overall response rate(ORR) was 87.5% (7/8) , five patients (62.5%) achieved complete response(CR). In two patients with GCB pathological subtype, one patient achieved CR, the other one had partial response (PR). In six patients with non-GCB pathological subtype, four patients achieved CR, one had PR, one achieved progression disease(PD) . Median progression-free survival (PFS) was not achieved, one patient had progressing at 8 months, and died due to disease progression, with overall survival (OS) of 11 months. ZR regimen was well-tolerated, three patients had grade 2 urinary tract infections, one had grade 2 respiratory infections, one had grade 1 Petechial hemorrhages, two had grade 2 skin rash, two had acute kidney injury. No grade 3 or higher adverse events were observed. Ten patients had a dose reduction due to toxicity. Two patients had discontinued Zanubrutinib due to adverse events for one to three weeks. In addition, two patients who met exclusion criteria were also off-label use of ZR regimen therapy. They were classified as GCB pathological subtype, and diagnosed with stage III or IV. One patient was 72 years old with IADL score of 6, CCI score of 4, previously diagnosis of lung cancer and renal cancer, treated with radiotherapy and surgery. This patient achieved PR after 2 cycles and had disease progression after 4cycles, with PFS of 4 months. He had grade 2 Petechial hemorrhages or skin rash. The other patient was 81 years old, previously diagnosis of decompensated liver cirrhosis ，with bleeding tendency, IADL score of 2, CCI score of 4.She achieved SD after 2 cycles and had disease progression after 4 cycles, with a PFS of 4 months, and died due to disease progression, with OS of 5 months. Conclusion: Zanubrutinib in combination with Rituximab may be a well-tolerated and effective regimen in elderly unfit DLBCL patients. Dose reduction may be required for some patients to improve tolerability. A large sample size clinical trial is needed to further validate this conclusion in the future. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

The Incidence, Risk Factors and Predictive Nomograms for Early Death of Elderly Patients with Diffuse Large B-Cell Lymphoma

Background: Diffuse large B-cell lymphoma (DLBCL) is an aggressive malignancy that is diagnosed in approximately 60% of patients in older age. However, the early mortality and risk factors associated with elderly DLBCL are little known. Methods: Elderly patients diagnosed with DLBCL in the Surveillance, Epidemiology, and End Results (SEER) database from 2000 to 2019 were selected as a trial cohort. In addition, elderly DLBCL patients from Peking University Third Hospital were used as an external validation cohort. Univariate and multivariate logistic regression analysis were used to identify risk factors. Nomogram models were constructed according to significant risk factors to predict overalland cancer-specific early death. In addition, the predictive value of the model was verified by receiver operating characteristic (ROC) analysis. Calibration plotwas used to evaluate the calibration ability. The clinical value of nomogram was evaluated by decision curve analysis (DCA). Results: A total of 15242 elderly DLBCL patients from SEER database and 152 patients from Peking University third hospital were included in this study. In the SEER database, 36.6%(5584/15242) patients had early death, and 30.7%(4680/15242) patients had cancer-specific early death. Marital status, Ann Arbor stage, surgical treatment, radiotherapy and chemotherapy are significant risk factors for overall and cancer-specific early mortality in elderly patients with DLBCL. Nomograms were constructed according to these risk factors. ROC analysis showed that the AUC of OS was 0.764 (0.756-0.772) and that of CSS was 0.742(0.733-0.751). The AUC of the verification group was 0.767 (0.689-0.846) for OS and 0.742(0.743-0.83) for CSS. The calibration plots and DCA analysis showed that the model had good early death prediction and clinical application value. Conclusion: This study establishes and validates a predictive nomogram model for elderly diffuse large B-cell lymphoma, which plays an important role in making better treatment strategies for physicians. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Combination Anti-PD1 Antibody and Rituximab Followed By R-CHOP for Elderly Patients with Newly Diagnosed DLBCL: Analysis of the Phase II TREND Trial

Background: Patients with diffuse large B-cell lymphoma (DLBCL) in the elderly face challenges in treatment due to comorbidities and poor tolerance of chemotherapy. Age >60 years is an unfavorable risk factor in DLBCL in the International Prognostic Index (IPI) system. Besides, increased proportion of ABC/non-GCB subgroups, complex molecular features also lead to unfavorable prognosis with distinct biological or immune microenvironment features in elderly patients. Although clinical benefit of single-agent anti-PD-1 antibody in DLBCL was not obvious, pre-use anti-PD-1 antibody as first-line may be an opportune for elderly DLBCL. Toripalimab, a recombinant, humanized programmed death receptor-1 (PD-1) monoclonal antibody has been approved by the NMPA for the treatment of various cancers. Methods: Patients aged 60-85 years, ECOG 0-2 with untreated DLBCL or grade 3b follicular lymphoma and at least one measurable or evaluable lesion were enrolled. This study consisted of a phase 1b (Toripalimab dose escalation) followed by a Phase 2 expansion portion. In the phase Ib, a standard "3+3" design was utilized to identify the MTD, DLT and recommended phase 2 dosage (RP2D) of Toripalimab.In phase 2, patients received 2 cycles of Toripalimab (RP2D) plus Rituximab (375mg/m2) every 3 weeks. They allowed to accept two additional cycles of Toripalimab plus Rituximab (To-Ri) if they obtained complete response (CR) after the first 2 cycles. To-Ri followed by R-CHOP (21) up to 6 cycles without Toripalimab then Toripalimab (RP2D) maintenance 6 cycles (q 30 days) after CR or CMR post R-CHOP. All cases more than 75-year-old received R-miniCHOP. The primary endpoints were objective response rate (ORR) based on Lugano 2016 criteria and clinical benefit rate. Secondary endpoints were progression-free survival (PFS), overall survival (OS) and safety. Adverse events (AEs) were defined according to CTCAE 5.0. This trial was registered at ClinicalTrials.gov (NCT04058470). Results: From December 2020 to July 2022, 37 eligible patients were enrolled. Median age 67 years (range, 60-83), 16 (43.2%) male, 20 (54.1%) patients with stage III/IV, 27(73.3%) patients with extranodal disease, 8 (21.6%) patients with IPI score ≥ 3 points, and non-GCB(n=25), double expression (DEL, n=7), EBV+DLBCL(n=5), double/triple hit lymphoma (DHL/THL, n=2). In phase Ib, no MTD or DLT events were observed, RP2D of Toripalimab was 240mg. Of 34 response evaluable patients, 14 patients completed To-Ri×4, 26 (59.1%) achieved response including 15 (44.1%) patients with CR post To-Ri treatment. Key responded to To-Ri including non-GCB (81.8%, n=18), GCB (58.3%, n=7), EBV+DLBCL (50%, n=2), DEL (87.5%, n=7), DHL/THL (100%, n=2), primary gastrointestinal tract involved (75%, 6/8) and primary nasal involved (87.5%, 7/8). Five patients are still under treatment, ORR and CR post R-CHOP were 100% (32/32) and 87.5% (28/32). With a median follow-up of 8.2 months, estimated 1-year PFS and were 81.2% and 88.4%. Thirty-six (97.3%) patients reported treatment-related AEs (TRAEs). The most frequently observed (≥10%) TRAEs were abnormal liver function (43.2%), anemia (43.2%), lymphopenia (32.4%), neutropenia (27.0%), hypothyroidism (21.6%), nausea (18.5%). This clinical trial is still on going. Conclusion: Toripalimab plus Rituximab as a first-line treatment then followed by R-CHOP yielded high CR rate and manageable toxicities in elderly with newly diagnosed DLBCL, especially for patients with extranodal disease and high grade lymphoma. This therapeutic strategy deserves further clinical investigation. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Treatment Patterns and Survival Outcomes in Elderly Veterans Diagnosed with Diffuse Large B-Cell Lymphoma

Introduction: Diffuse large B-cell lymphoma(DLBCL) is the most common non-Hodgkin's lymphoma and its incidence steadily increases with age. The elderly population diagnosed with DLBCL are a heterogenous group with no standardized age cut-off in literature. There is also a paucity of data regarding the treatment of elderly DLBCL patients due to lack of participation and/or inclusion in clinical trials. The VHA (Veterans Health Administration) is one of the largest integrated provider of cancer care in the United States and its population, on average, is older than the general US population, giving us a unique advantage in exploring real-world outcomes in this elderly population. Methods: This is a retrospective chart review of 5199 randomly selected patients with an ICD code for lymphoma treated within the VHA between 1/1/2011 and 12/31/2019. Data abstractors collected baseline patient and disease characteristics and treatment responses. Survival time was determined via electronic health record query on 7/25/2022. Chi-square tests were used to analyze the relationship between age and variables of interest. Results: Of the 2697 patients that met the inclusion criteria, one-third of the patients were <65 years (n=916, 34%) and two-thirds of the patients were ≥65 years(n=1781, 66%) out of which 51.5%(n=1390) were within 65-79 years and 14.5% were above 80 years (n=391). Though ECOG status decreased with increasing age, more than 2/3rd of the patients within each of the above subgroups had a preserved ECOG score of 0-2. ABC phenotype was statistically more common in patients >80 years when compared to <65 years and 65-79 years as shown in Table 1. No difference was seen in the distribution of double or triple hit status between the three groups. The percentage of patients that did not receive any treatment increased with age (3.2% vs 6% vs 20.7% in <65, 65-79 and >80 year groups respectively, p<0.001), and the number of patients receiving 2 or more lines of treatment decreased with age (10.2% vs 7.5% vs 2.3%, p<0.001). Across all age groups, R-CHOP remained the common first-line regimen (73.3%, 67.9%, 39.1%) with more proportion of the >80 years group receiving R-mini-CHOP (0.3% vs 2.1% vs 15.1%) when compared to the other groups. In terms of completion of first-line treatment(R-CHOP or R-mini-CHOP), patients <65 years were more likely to complete 6 cycles when compared to patients >65-79 and 80 years (73.9% vs 67.8% vs 59.8%, p<0.001). The overall median OS decreased with increasing age, 63.7 months in <65 years, 48.3 months in 65-79 and 23.6 months in >80 years age group. Patients of all age groups, who received 6 or more cycles of first-line anthracycline-based regimen had almost double the duration of 1-, 2- year and overall survival when compared to patients who received ≤5 cycles as shown in Table 2. Conclusion: Veterans older than 65 years who are diagnosed with DLBCL present with a higher stage of disease, higher IPI score and ABC phenotype. Amongst them, the very elderly patients older than 80 years old had the shortest survival along with low treatment initiation and completion rates despite comparable functional status at diagnosis. When able to complete 6 or more cycles of first line R-CHOP/R-mini-CHOP they attained almost double the duration of median OS when compared to receiving <6 cycles of chemo-immunotherapy. Given that the incidence of DLBCL has been increasing over the age of 65 years, therapeutic approaches that optimize treatment efficacy while minimizing toxicity are needed. With the advent of genomic profiling and identification of molecular abnormalities in DLBCL, novel antibodies or small molecules with relatively low toxicity can increase tolerance in upfront setting leading more elderly patients towards completion of necessary lines of treatment and improved overall survival. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Reduced-Intensity Conditioning Prior Autologous Stem Cell Transplantion in Elderly DLBCL Patients

Introduction High-dose chemotherapy and autologous stem cell transplantation (HDCT/ASCT) is widely used in diffuse-large B-cell lymphoma (DLBCL) patients. Since HDCT/ASCT in elderly patients is associated with increased morbidity, the clinical impact is not well defined. In addition, only very few data for HDCT/ASCT with reduced intensity conditioning in elderly DLBCL patients exists. Methods We performed a single center retrospective analysis of 146 DLBCL patients aged 60 years and older who received HDCT/ASCT between 2005 and 2019. Statistical analyses were conducted with GraphPad Prism 5® and SAS V9.4. Results Patients were analyzed according conditioning regimens: 86 patients received standard intensity high-dose conditioning (SI-group) with BEAM (BCNU, etoposide, cytarabine, melphalan) or TEAM (Thiotepa, etoposide, cytarabine, melphalan) and 60 patients received reduced intensity high-dose conditioning (RI-group) with BM (BCNU, melphalan, 43.3%), TM (Thiotepa, melphalan, 16.7%), BCNU/or Busulfan-Thiotepa (38.4%) or Bendamustin-melphalan (1.7%). Comparing patients characteristics in the SI and RI-group, we found a difference for age (median age 65.5 vs. 71.8, p<0.001) and ECOG 0 vs ≥1 p=0.006, whereas we found no difference for other prognostic factors like disease stage, elevated LDH, extra-nodal disease or bulky disease. We found no statistical difference for remission status before ASCT (SI-group: PR/CR1 58.1%, PR/CR>1 25.6% and refractory disease (14%); RI-group: PR/CR1 41,7%, PR/CR>1 35% and refractory disease in 21.7% of patients), or lines of prior therapy (SI-group: 1 in 60.5% and ≥2 in 39.5% of patients, RI-group: 1 in 50% and ≥2 in 50% of patients). We observed no significant difference in frequency or severity of relevant toxicities like febrile neutropenia, enterocolitis, sepsis, lung infections, mucositis or atrial fibrillation. Median time of hospitalization did not differ between both groups (15 vs. 17 days). We found no difference for remission status after HDCT/ASCT between both groups. Cumulative incidence of relapse was higher in the RI-group: 30.8% (RI-group) and 23.4% (SI-group) at three years, p=0.034. We observed no difference in non-relapse mortality (NRM) 14.4% vs. 12.8% at three years. With a median follow-up of 62.4 month, we observed a 3-year overall survival (OS) of 67.1% and a 3-year PFS of 59.3%. Univariate analysis revealed several factors associated with inferior PFS and/or OS Table 1. Reduced intensity conditioning was associated with an inferior PFS, but not an inferior OS. Of note, in a multivariate Cox Regression analysis, we observed no difference in PFS (HR 0.74 (0.40 - 1.38) p=0.345), but a trend for better OS with reduced intensity conditioning (HR 0.45 (0.22 - 0.94) p=0.032) Table 2. Conclusion: Reduced-intensity conditioning with two alkylating agents and omission of etoposide and cytarabine is feasible in elderly patients. Our retrospective analysis indicates a comparable outcome of SI and RI conditioning, when corrected for multiple significant confounders. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

The efficacy and cardiac toxicity of different-dose pegylated liposomal doxorubicin in elderly patients with diffuse large B lymphoma.

In order to explore the impact of pegylated liposomal doxorubicin (PLD) dose intensity on survival outcomes of newly diagnosed elderly patients with diffuse large B-cell lymphoma (DLBCL), we performed a retrospective study to compare the efficacy and adverse effects of RCEOP (70 mg/m2 ), RCdOP (20-30 mg/m2 ) and RCDOP (30-45 mg/m2 ). The optimal PLD dose of patients with different clinical characteristics of subgroups was explored to provide a clue for the selection of clinical PLD dose. A total of 335 DLBCL patients (60-85 years old) who were newly diagnosed and completed at least four cycles of RCE(D)OP were selected. The patients were mainly divided into RCEOP (126 cases) (epirubicin 70 mg/m2 ), RCdOP (151 cases) (PLD 20-30 mg/m2 ) and RCdOP (58 cases) (PLD 30-45 mg/m2 ). The effects of different doses of PLD on clinical efficacy, cardiotoxicity and prognosis of patients were retrospectively analyzed. Subgroup analysis was performed to compare the clinical characteristics of different subgroups. Our study showed that PLD and epirubicin had similar efficacy (overall survival (OS) p=0.776; progression-free survival (PFS) p=0.959). RCDOP (30-45 mg/m2 PLD) group had a higher complete remission (CR) rate of 75.9% compared with RCdOP (20-30 mg/m2 PLD) group (P D vs. d=0.018). In the overall population, there was no significant difference in survival between RCDOP and RCdOP groups (OS P D vs. d=0.661; PFS P D vs. d=0.212). In patients with underlying cardiovascular diseases, the PFS of the RCDOP group was significantly better than the RCdOP group (p=0.043). Meanwhile, patients in the RCDOP group tended to have a better prognosis than those in the RCEOP group (OS: RCDOP vs. RCEOP p=0.054, PFS: RCDOP vs. RCEOP p=0.053). There was no significant difference in the incidence of cardiotoxicity and other adverse events among the three groups. For the low-risk (age-adjusted-International Prognostic Index=0/1) old patients without cardiovascular disease, RCdOP was considered a better strategy in OS (p=0.020). In the general population, the CR rate in the RCDOP group was significantly higher than that in the RCdOP group (p=0.018). For elderly DLBCL patients with cardiovascular disease, the effect benefit brought by the PLD dose was more obvious, and the PFS of the RCDOP group was significantly better than that of the RCdOP group (p=0.043). Full dose of PLD is an efficient alternative in the treatment of patients with preexisting cardiovascular diseases.

A Comparison of Clinical Prognostic Indices in Elderly Patients with Diffuse Large B-Cell Lymphoma Treated with a Pegylated Liposomal Doxorubicin Combination Regimen in China.

BackgroundThere is no consensus regarding the risk stratification scores for elderly patients with diffuse large B-cell lymphoma (DLBCL). We aimed to compare the prognostic predictive ability of the current clinical scoring indices in DLBCL elderly patients treated with the R-CODP regimen (rituximab, cyclophosphamide, pegylated liposomal doxorubicin, vincristine, and prednisone).MethodsWe retrospectively collected the data of elderly DLBCL patients who received the R-CODP regimen as the first-line treatment. The efficacy of the regimen was evaluated. The Akaike information criteria (AIC), concordance index (C-index), and integrated discrimination improvement (IDI) were used to assess the fitness and prognostic performance of the current clinical prognostic indices.ResultsIn the total of 158 patients enrolled, the median follow-up time was 6.7 years (95% CI: 6.3–7.9), and the 5-year OS was 52.8% (95% CI: 45.5%–61.2%). The International Prognostic Index (IPI), National Comprehensive Cancer Network-IPI (NCCN-IPI), and Elderly International Prognostic Index (E-IPI) were all significantly associated with OS (P < 0.001 for all). However, no significance was observed in 5-year OS in the low- vs low-intermediate-risk groups for IPI (P = 0.377), NCCN-IPI (P = 0.238), and E-IPI (P = 0.080). Compared with the IPI and NCCN-IPI, the E-IPI had the lowest AIC value of 747.5 and the highest C-index of 0.692. For predicting 5-year mortality, the E-IPI showed better performance (AUC: 0.715 for E-IPI vs 0.676 for IPI, P = 0.036), with the IDI of 6.29% (95% CI: 3.71%-8.88%, P < 0.001) and 4.80% (95% CI: 1.32%-8.28%, P = 0.007) compared to the IPI and NCCN-IPI, respectively.ConclusionThe E-IPI might be a better prognostic prediction model in Chinese DLBCL generics treated with R-CODP for predicting 5-year mortality. However, the IPI, NCCN-IPI, and E-IPI did not seem to be able to distinguish patients with a favorable prognosis well.

Gastric DLBCL clonal evolution as function of patient age.

Diffuse large B cell lymphoma (DLBCL) is the most common type of NHL, accounting for about 40% of NHL cases, and is one of the most aggressive lymphomas. DLBCL is widespread in individuals aged more than 50 years old, with a maximum incidence in the seventh decade, but it may also occur in younger patients. DLBCL may occur in any immune system tissue, including those around the gastrointestinal tract, and even in the stomach, though gastric DLBCL has yet to be sufficiently investigated. This study aimed to understand changes in gastric Diffuse Large B cell lymphoma (gastric DLBCL) development with age. Immunoglobulin (Ig) heavy chain variable region genes were amplified from sections of nine preserved biopsies, from patients whose age varied between 25 and 89 years, sequenced and analyzed. We show first that identification of the malignant clone based on the biopsies is much less certain than was previously assumed; and second that, contrary to expectations, the repertoire of gastric B cell clones is more diverse among the elderly DLBCL patients than among the young.

Pixantrone is a Safe and Effective Therapeutic Option for Elderly Patients with Relapsed Refractory Diffuse Large B-Cell Lymphoma in the Real-World Setting

Treatment of Relapsed/Refractory (R/R) Diffuse Large B-cell Lymphoma (DLBCL) remains an unmet need in every day clinical practice. Pixantrone is an approved by European Medicines Agency (EMA) for R/R DLBCL last generation anthracenedione developed to reduce the risk of cardiotoxicity. However real-world data regarding efficacy and safety of this agent are limited and controversial. In our study we analyzed 13 heavily pretreated elderly DLBCL patients who were treated with at least 1 cycle of pixantrone. The overall response rate was 46%; 3 patients achieved complete response and 3 patients had partial remission. All the responders were anthracycline sensitive as they had responded to anthracycline-based regimens upfront. Four responders had extranodal involvement (skin: 2, oropharynx: 1, oral cavity:1). Interestingly, 3 of the responders displayed long remission after first line therapy (87, 62 and 37 months, respectively). Regarding safety Pixantrone was well tolerated there was no treatment discontinuation due to Adverse Events. Our results indicate that Pixantrone is effective and safe in heavily pretreated DLBCL patients. Further studies are warranted to identify the subgroup of patients who may benefit from therapy with pixantrone and to identify the optimum positioning of the drug in the treatment of DLBCL.