First-line Systemic Therapy Research Articles

Progression-directed therapy in patients with oligoprogressive castration-resistant prostate cancer.

Oligoprogressive lesions are observed in a subset of patients who progress to castration-resistant prostate cancer (CRPC), while other lesions remain controlled by systemic therapy. This study evaluates the impact of progression-directed therapy (PDT) on these oligoprogressive lesions. This retrospective study included 40 patients diagnosed with oligoprogressive CRPC. PDT was performed for treating all progressive sites using radiotherapy. Fifteen patients received PDT using radiotherapy for all progressive sites (PDT group) while 25 had additional first-line systemic treatments (non-PDT group). In PDT group, 7 patients underwent PDT and unchanged systemic therapy (PDT-A group) and 8 patients underwent PDT with additional new line of systemic therapy on CRPC (PDT-B group). The Kaplan-Meier method was used to assess treatment outcomes. The prostate specific antigen (PSA) nadir was significantly lower in PDT group compare to non-PDT group (p=0.007). A 50% PSA decline and complete PSA decline were observed in 13 patients (86.7%) and 10 patients (66.7%) of PDT group and in 18 patients (72.0%) and 11 patients (44.0%) of non-PDT group, respectively. The PSA-progression free survival of PDT-B group was significantly longer than non-PDT group. The median time to failure of first-line systemic therapy on CRPC was 30.2 months in patients in PDT group and 14.9 months in non-PDT group (p=0.014). PDT-B group showed a significantly longer time to progression than non-PDT group (p=0.025). Minimal PDT-related adverse events were observed. PDT can delay progression of disease and enhance treatment efficacy with acceptable tolerability in oligoprogressive CRPC.

Analysis of Immune-Related Adverse Events of Atezolizumab and Bevacizumab in Patients with Hepatocellular Carcinoma: A Multicentre Cohort Study

Introduction: Despite the emergence of atezolizumab and bevacizumab (A + B) as standard first-line systemic therapy for unresectable hepatocellular carcinoma (HCC), a comprehensive understanding of the clinical significance of immune-related adverse events (irAEs) remains limited. We aimed to assess the impact of irAEs on patients with HCC undergoing A + B treatment. Methods: This multicentre retrospective study included consecutive patients with HCC who were treated with the A + B regimen from September 2020 to December 2022. Patients were categorized into three groups based on the severity of irAEs, ranging from those without any experience of irAEs to those with severe irAEs. Results: This study included 150 patients with HCC, with a mean age of 63.3 years. Among them, 93.3% of patients were classified as Barcelona Clinic Liver Cancer stage C, 52.0% had portal vein tumour thrombosis (PVTT), and 60.7% extrahepatic spread. Patients were classified as follows: group 1 (n = 84) had no irAEs, group 2 (n = 37) had mild irAEs (grade 1-2), and group 3 (n = 29) had severe irAEs (grade ≥3). The median overall survival (OS), progression-free survival (PFS), and time-to-treatment discontinuation (TTD) were 13.6, 5.7, and 3.6 months, respectively. Group 2 demonstrated significantly superior OS compared to group 1 (9.5 months) and group 3 (5.6 months), with a median OS of 23.0 months (p < 0.001). Furthermore, group 2 demonstrated significantly better outcomes in terms of PFS and TTD compared to both group 1 and group 3 (p < 0.001 for both). Multivariate analysis identified mild irAEs (hazard ratio [HR], 0.353; p = 0.010), ALBI grade 1 (HR, 0.389; p = 0.006), Child-Pugh class A (HR, 0.338; p = 0.002), and the absence of PVTT (HR, 0.556; p = 0.043) as independent predictors of better OS. Conclusion: Our study highlights the significant impact of irAE severity on the outcomes of patients with HCC receiving A + B. Notably, the occurrence of mild irAEs was independently associated with favourable survival, suggesting their potential role as surrogate indicators of HCC prognosis.

Excerpt from the 2023 American Association for the Study of Liver Diseases practice guideline: prevention, diagnosis, and treatment of hepatocellular carcinoma

The 2023 American Association for the Study of Liver Diseases practice guidelines (hereinafter referred to as the Guidelines) provide the latest approach for the prevention, diagnosis, and treatment of hepatocellular carcinoma. The prior American Association for the study of Liver Diseases (AASLD) HCC guidelines have been updated to reflect the clinically significant advances in multiple fields of HCC. Notable examples of these updates include recommendations for the use of ultrasound and alpha-fetoprotein for HCC monitoring, the expansion of surgical treatment indications, the addition of immunosuppressive therapy as first-line systemic therapy, and the implementation of clear multidisciplinary care and proactive care planning.

Standard-of-care systemic therapy with or without stereotactic body radiotherapy in patients with oligoprogressive breast cancer or non-small-cell lung cancer (Consolidative Use of Radiotherapy to Block [CURB] oligoprogression): an open-label, randomised, controlled, phase 2 study

Most patients with metastatic cancer eventually develop resistance to systemic therapy, with some having limited disease progression (ie, oligoprogression). We aimed to assess whether stereotactic body radiotherapy (SBRT) targeting oligoprogressive sites could improve patient outcomes. We did a phase 2, open-label, randomised controlled trial of SBRT in patients with oligoprogressive metastatic breast cancer or non-small-cell lung cancer (NSCLC) after having received at least first-line systemic therapy, with oligoprogression defined as five or less progressive lesions on PET-CT or CT. Patients aged 18 years or older were enrolled from a tertiary cancer centre in New York, NY, USA, and six affiliated regional centres in the states of New York and New Jersey, with a 1:1 randomisation between standard of care (standard-of-care group) and SBRT plus standard of care (SBRT group). Randomisation was done with a computer-based algorithm with stratification by number of progressive sites of metastasis, receptor or driver genetic alteration status, primary site, and type of systemic therapy previously received. Patients and investigators were not masked to treatment allocation. The primary endpoint was progression-free survival, measured up to 12 months. We did a prespecified subgroup analysis of the primary endpoint by disease site. All analyses were done in the intention-to-treat population. The study is registered with ClinicalTrials.gov, NCT03808662, and is complete. From Jan 1, 2019, to July 31, 2021, 106 patients were randomly assigned to standard of care (n=51; 23 patients with breast cancer and 28 patients with NSCLC) or SBRT plus standard of care (n=55; 24 patients with breast cancer and 31 patients with NSCLC). 16 (34%) of 47 patients with breast cancer had triple-negative disease, and 51 (86%) of 59 patients with NSCLC had no actionable driver mutation. The study was closed to accrual before reaching the targeted sample size, after the primary efficacy endpoint was met during a preplanned interim analysis. The median follow-up was 11·6 months for patients in the standard-of-care group and 12·1 months for patients in the SBRT group. The median progression-free survival was 3·2 months (95% CI 2·0-4·5) for patients in the standard-of-care group versus 7·2 months (4·5-10·0) for patients in the SBRT group (hazard ratio [HR] 0·53, 95% CI 0·35-0·81; p=0·0035). The median progression-free survival was higher for patients with NSCLC in the SBRT group than for those with NSCLC in the standard-of-care group (10·0 months [7·2-not reached] vs 2·2 months [95% CI 2·0-4·5]; HR 0·41, 95% CI 0·22-0·75; p=0·0039), but no difference was found for patients with breast cancer (4·4 months [2·5-8·7] vs 4·2 months [1·8-5·5]; 0·78, 0·43-1·43; p=0·43). Grade 2 or worse adverse events occurred in 21 (41%) patients in the standard-of-care group and 34 (62%) patients in the SBRT group. Nine (16%) patients in the SBRT group had grade 2 or worse toxicities related to SBRT, including gastrointestinal reflux disease, pain exacerbation, radiation pneumonitis, brachial plexopathy, and low blood counts. The trial showed that progression-free survival was increased in the SBRT plus standard-of-care group compared with standard of care only. Oligoprogression in patients with metastatic NSCLC could be effectively treated with SBRT plus standard of care, leading to more than a four-times increase in progression-free survival compared with standard of care only. By contrast, no benefit was observed in patients with oligoprogressive breast cancer. Further studies to validate these findings and understand the differential benefits are warranted. National Cancer Institute.

Pretreatment eosinophil count predicts response to atezolizumab plus bevacizumab therapy in patients with hepatocellular carcinoma.

Pretreatment peripheral blood markers have value in predicting the treatment outcome of various cancers. In particular, the eosinophil count has recently gained attention. However, no study has reported the influence of the pretreatment eosinophil count on the outcomes of atezolizumab plus bevacizumab (ATZ/BEV), which is the recommended first-line systemic therapy for unresectable hepatocellular carcinoma (u-HCC). We enrolled 114 patients with u-HCC treated with ATZ/BEV (n=48) or lenvatinib (n=66). The patients receiving ATZ/BEV or lenvatinib were divided into two groups by calculating the cutoff value of the pretreatment eosinophil count. The groups were compared regarding the clinicopathological characteristics, outcomes, and incidence of adverse events (AEs). Twenty-three of 48 patients (47.9%) who received ATZ/BEV therapy were categorized as the ATZ/BEV-eosinophil-high group, which had better responses than the ATZ/BEV-eosinophil-low group (P=0.0090). Kaplan-Meier curves revealed a trend toward significantly better progression-free survival (PFS) in the ATZ/BEV-eosinophil-high group than the ATZ/BEV-eosinophil-low group (the median PFS: 4.7months in the ATZ/BEV-eosinophil-low group vs 12.6months in the ATZ/BEV-eosinophil-high group; P=0.0064). Multivariate analysis showed that a low eosinophil count was an independent risk factor for worse PFS after ATZ/BEV therapy (P=0.0424, hazard ratio: 2.24, 95% confidence interval: 1.02-4.89). AEs (≥ grade 3) were significantly more likely to occur in the ATZ/BEV-eosinophil-high group (P=0.0285). The outcomes did not significantly differ between the LEN-eosinophil-high group and the LEN-eosinophil-low group. A high pretreatment eosinophil count predicted a better response to ATZ/BEV therapy for u-HCC and was associated with the incidence of AEs (≥ grade 3).

Differential Effect of Consolidative Thoracic Radiation Therapy in Extensive-Stage Small Cell Lung Cancer Based on Sex

BackgroundThe landmark CREST trial demonstrated that consolidative thoracic radiotherapy (cTRT) improved overall (OS) and progression-free survival (PFS) after initial chemotherapy (chemo) in extensive-stage small cell lung cancer (ES-SCLC), with potentially increased benefit in women compared to men. It is unknown whether similar findings would apply after chemoimmunotherapy (chemo-IO) became the standard first-line treatment. In this analysis, we report national practice patterns and survival outcomes of cTRT according to patient sex. MethodsWe included patients from a nationwide de-identified electronic health record-derived database diagnosed with stage IV SCLC (2014-2021) who completed 4-6 cycles of first-line systemic therapy (platinum-doublet chemo or chemo-IO). We evaluated OS and PFS using multivariable Cox proportional hazards regression with receipt of cTRT as an independent variable and stratified by sex. As a sensitivity analysis, we weighted the models by the inverse probability of receiving cTRT. ResultsA total of 1,227 patients were included (850 chemo, 377 chemo-IO). There were no statistically significant differences in baseline characteristics between patients who did and did not receive cTRT. Among women, cTRT was associated with superior OS (adjusted hazard ratio (HR) 0.67; 95% confidence interval [CI] 0.52-0.87) and PFS (HR 0.63; 95% CI 0.49-0.82) compared to those not receiving cTRT. Conversely, no OS or PFS benefit with cTRT was observed in men [(OS HR 1.03; 95% CI 0.80-1.31; PFS HR 1.12; 95% CI 0.85-1.47)]. Findings were similar in weighted analyses. ConclusionThe survival efficacy of cTRT may be moderated by sex, with female patients appearing more likely to benefit than male patients. These findings reflect sex-based survival trends with similar effect sizes to those observed in the CREST trial. While the underpinnings of this association need to be elucidated, stratification by sex should be considered for RCTs studying cTRT in ES-SCLC.

Efficacy of transarterial chemoembolization with drug-eluting beads combined with systemic chemotherapy and targeted therapy in colorectal cancer liver metastasis

BackgroundSystemic therapy is the standard treatment for unresectable colorectal cancer with liver metastasis (CRCLM). Transarterial chemoembolization with drug-eluting beads (DEB-TACE) is considered an effective treatment option for CRCLM. Few studies have investigated the combination of DEB-TACE, chemotherapy, and targeted therapy for CRCLM. In the present study, we evaluated the disease control rate (DCR), adverse events, and survival among patients with CRCLM who underwent the combination of DEB-TACE and chemotherapy/targeted therapy.MaterialsWe retrospectively reviewed 35 patients with CRCLM who were treated between January 2015 and January 2021. Standard systemic chemotherapy, targeted therapy, and 66 DEB-TACE procedures were administered. Data were collected on each DEB-TACE procedure, including chemotherapy agents, tumor burden of liver metastasis, number of DEB-TACE courses, and adverse events. Patients who received DEB-TACE after failure of first-line systemic therapy were categorized into the first-line failure group. Patients who received DEB-TACE after the failure of second-line, third-line, or fourth-line therapy were categorized into the other group. Subgroup analysis was performed to compare overall survival (OS) and progression-free survival (PFS) between the two groups.ResultsIn total, 35 patients with CRCLM (34 patients with adenocarcinoma and 1 patient with neuroendocrine carcinoma) were enrolled. In total, 13 patients (37.1%) had extrahepatic metastases at initial diagnosis. In this study, 66 DEB-TACE procedures were performed. The DCR was 54.3%. The median OS period was 47.4 months, and the estimated 3-year OS rate was 59.5%. The median PFS period was 6.3 months, and the estimated 1-year PFS rate was 20.6%. The PFS period was longer in the first-line failure group than in the other group (7.2 vs. 6.3 months). No significant difference was observed in OS between the two groups. Four episodes (6.1%) of grade 3 intra-abdominal infection were observed.ConclusionThe combination of chemotherapy, targeted therapy, and DEB-TACE can lead to a favorable DCR and survival outcomes in patients with CRCLM. Early intervention with DEB-TACE (i.e., after the failure of first-line therapy) has the potential to extend the PFS period in patients with CRCLM. Severe adverse events were rare and manageable. Further prospective, randomized controlled studies are warranted to obtain more conclusive findings.

Analysis of an Unselected Patient Cohort With Advanced Colorectal Carcinoma from a Maximum Care Center.

Systemic treatment for metastatic colorectal cancer (CRC) includes chemotherapy in combination with a targeted antibody. Novel targeted therapies and immunotherapies are introduced for specific molecular subgroups. Prognostic relevant determinants are still under investigation. Systemic therapies of an unselected patient cohort with metastatic CRC were retrospectively analyzed. Treatment outcome was evaluated according to time-to-next-treatment (TTNT) and frequency of conversion surgery and compared between subgroups stratified by primary tumor side, molecular profile, sex and age, and metastases sites. More than 50% of patients with locally advanced or metastatic CRC underwent secondary resection after first-line systemic therapy. Rectum carcinoma had the best prognosis under anti-EGFR-antibody treatment. Female patients had a worse prognosis than male patients in late disease stage. Young patients demonstrated poor response to systemic therapy, but a high rate of conversion surgeries. Conversely, elderly patients benefited from systemic therapy but underwent surgery less frequently. Liver and lung metastases had a worse prognosis than other metastases sites, whereas lung metastases were more likely to be resected than liver metastases in early disease stage. Patient age, sex, primary tumor localization, and metastatic sites are prognostic factors that could guide future treatment decisions for the therapy of metastatic CRC.

Impact of Maintenance Rituximab Following First-Line Systemic Therapy on Outcomes in Patients with Marginal Zone Lymphoma: Real-World Evidence from 10 US Centers

Introduction First-line treatment options for patients (pts) with marginal zone lymphoma (MZL) include rituximab monotherapy (R) and immunochemotherapy (IC), such as bendamustine with rituximab (BR) or RCHOP/RCVP. The efficacy of maintenance rituximab (M-R) has been studied in splenic (SMZL) and nodal (NMZL) MZL, showing a benefit in progression-free survival (PFS) when M-R is administered after BR (Rummel et al., ASCO 2018). However, the role of M-R in pts with extranodal MZL (EMZL) of the mucosa-associated lymphatic tissue (MALT), or those receiving R or RCHOP/RCVP, remains uncertain. In this study, we analyzed the outcomes of pts with MZL who received M-R after their first-line systemic therapy (R or IC) using data from a large multi-institutional retrospective cohort. Methods Adult pts with MZL (SMZL, NMZL, or EMZL) who were treated at 10 US medical centers from 2010 onwards were included. Pts who had received first-line treatment with either R or IC and achieved a partial (PR) or complete (CR) response to the initial therapy were divided into groups based on whether they subsequently received M-R or not. To avoid immortal-time bias, we required a minimum follow-up of 6 months from diagnosis. Outcomes included PFS, overall survival (OS) and cumulative incidence of histologic transformation (HT). Because of non-proportional hazards, Wilcoxon test was used to compare survival curves, and Cox models (augmented by multiple imputation to account for missing data) were bounded by 6 years of follow up. Multivariable models adjusted for prognostic factors including age, sex, performance status, stage, baseline hemoglobin, albumin, LDH, type of IC and CR/PR status at the end of therapy. Results The study included 427 pts with a median age of 63 years. Of these pts, 53% were women, and 49% had EMZL, 27% had NMZL, and 23% had SMZL. The first-line therapies received were R (54%), BR (36%), RCHOP (7%), or RCVP (3%). A CR was achieved by 70% (n=298) of pts after the initial therapy. Overall, 33% (n=140) received M-R with a median of 8 cycles. Among pts who initially had PR, 39% converted to a CR during M-R therapy. The median follow-up period was 5 years. Factors associated with a higher likelihood of receiving M-R included achieving a PR instead of a CR after the first-line therapy (41% vs 29% receiving M-R, respectively; p=0.02) and having the SMZL subtype (p=0.03, Fig 1A). Pts treated with RCHOP were less likely to receive M-R compared to those receiving other regimens (p=0.049). There was also evidence of hospital-level preference to either prescribe M-R or not. We analyzed survival outcomes separately for pts who received first-line IC or R monotherapy, stratified further by MZL subtype and the type of IC regimen. Among pts who received IC (n=197), M-R was associated with longer PFS (median of 9.0 vs. 6.8 years, p=0.008, Fig 1B). However, the statistical significance was lost in the multivariable model (adjusted HR=0.52, 95%CI=0.25-1.10). When evaluated by MZL subtype, pts with EMZL had a significantly longer PFS with M-R (p=0.01), while those with NMZL and SMZL did not (p=0.41 and 0.10, respectively). When examining the type of first-line IC, pts receiving RCHOP/RCVP had a prolonged PFS with M-R (p=0.03), whereas the difference was not statistically significant after BR (p=0.12). There was no difference in OS overall (p=0.09; adjusted HR=0.55, 95%CI=0.12-2.60) or in any subgroup. Among pts who received first-line R, there were no statistically significant differences in PFS (p=0.70; adjusted HR=0.99, 95%CI=0.59-1.66) or OS (p=0.17) based on the receipt of M-R, either in the entire cohort or any subset. A total of 14 transformation events occurred during the study, including 3 in the M-R group. The cumulative incidence of HT did not significantly differ between the two groups (sub-HR=0.76, 95%CI=0.21-2.82, p=0.68). Discussion In this large retrospective cohort study, the use of M-R in MZL was primarily influenced by local preferences, the quality of response after initial treatment, and the type of IC regimen. Receipt of M-R was associated with a longer PFS for pts receiving first-line IC, especially for those with EMZL and those receiving RCHOP/RCVP. These findings suggest a PFS advantage of M-R in EMZL, which is a novel observation. However, this advantage was not observed in terms of OS or the rate of HT. M-R after initial R did not show any significant differences in outcomes for MZL.

A Real-World Evidence Study of the Temporal Evolution in Treatment Patterns and Outcomes for Chronic Lymphocytic Leukemia

CONCLUSIONS Chronic lymphocytic leukemia (CLL) is the most common lymphoproliferative disorder in North America. Treatment of CLL is currently indicated only for patients with disease-related symptoms or organ compromise, such as cytopenias, with no evidence of survival benefit for the treatment of asymptomatic patients. Patients with CLL are not cured with conventional therapy and typically require repeated treatments over their lifetime. Median overall survival (OS) is difficult to estimate given recent advances in therapy options but is dependent upon disease features, patient characteristics, and treatment choice. Since the recent introduction of targeted therapy for CLL, there has been limited Canadian data on the evolution of management approaches in a real-world setting. Data are needed to improve the current understanding of the treatment landscape of CLL. This retrospective observational cohort study used real-world, population-level data to describe the baseline characteristics, treatment patterns, clinical outcomes, and healthcare resource use of individuals diagnosed with CLL in Alberta, Canada. The study cohort included all individuals in Alberta over 18 diagnosed with CLL between 2010-2020 and who subsequently initiated systemic therapy. Data were collected through electronic health records and administrative databases. OS was defined as the date of diagnosis to death from any cause or last known contact with the health care system. A total of 890 individuals diagnosed with CLL between 2010-2020 who initiated first-line (1L) systemic therapy were included in the analyses. The mean age at initiation of 1L therapy was 69 years, and 68% were male. Among individuals who initiated 1L therapy in 2020+, the primary form of 1L systemic therapy was ibrutinib monotherapy (IBR) (29%), followed by bendamustine plus rituximab (BR) (21%). A considerable number of individuals did not initiate subsequent lines of therapy, with a drop of approximately 40-45% between each successive line. The treatment landscape changed over time, particularly with respect to decreased use of 1L fludarabine, cyclophosphamide, and rituximab (FCR; 40% in 2010-2013 vs. 9% in 2020+) and increased use of 1L IBR (6% in 2014-2017 vs. 29% in 2020+). Individuals treated at an academic centre were more likely to receive 1L IBR than those treated at a community centre. The median duration of 1L therapy was considerably longer for patients treated with targeted therapy (IBR: 9.8 months) compared to chemoimmunotherapy (BR: 5.6 months, FCR: 5.6 months). The majority of individuals did not initiate therapy immediately after diagnosis, with a median time from diagnosis to initiation of 1L therapy of 24 months (recognizing that the population described includes only those who initiated 1L therapy such that time to first therapy would be much longer for the entire CLL population). The time to next line of therapy (from the start of each line to the start of the subsequent line) was 17 months from 1L to second-line (2L), 14 months from 2L to third-line (3L), and 12 months from 3L to fourth-line. Median OS from initiation of 1L was 104 months, 2L was 70 months, and 3L was 64 months. On average, individuals had 39 healthcare encounters within the first year of initiating 1L systemic therapy, with an average of one hospitalization, six ambulatory care encounters, 25 non-cancer practitioner encounters, and seven cancer physician visits. The mean number of healthcare encounters within the first year of front-line therapy tended to decrease over time, which may be attributable to the changing treatment landscape. These findings highlight the rapid changes in CLL therapy that have occurred over the last decade. Our results demonstrate the significantly smaller cohorts of real-world patients receiving 2L or later therapies compared to 1L and highlight declining survival with subsequent lines of therapy, and a decreasing trend of healthcare resource use over time.

Impact of Large Cells and Ki-67% on Outcomes in Patients with Newly Diagnosed Marginal Zone Lymphoma - Results from a Multicenter Cohort Study

Introduction Marginal zone lymphoma (MZL) is an indolent B-cell lymphoma primarily composed of small/medium cells with low proliferation. However, there are cases where large B-cells (LC) are increased on the biopsy or Ki-67 expression is higher. The significance of LC content and Ki-67 in MZL is uncertain compared to other lymphomas (e.g., follicular or mantle cell). Previous studies evaluating prognostic indices in MZL or the risk of histologic transformation (HT) to diffuse large B-cell lymphoma did not assess these factors. Clinicians and patients often have concerns about the meaning and implications of increased LC or Ki-67 expression. We analyzed a large dataset of US MZL patients to evaluate the impact of LC and Ki-67 on outcomes. Methods This retrospective, multicenter study involved adults with MZL treated at 10 US medical centers on or after 1/1/2010. We included patients with splenic (SMZL), nodal (NMZL), and extranodal MZL (EMZL) of the mucosa-associated lymphatic tissue (MALT). Cases with information on LC or Ki-67+ cell percentages determined by immunohistochemistry on the diagnostic biopsy were included. Patients with HT at or within 60 days after MZL diagnosis were excluded. The primary endpoint was progression-free survival (PFS) and secondary endpoints included overall survival (OS) and cumulative incidence of HT. We assessed PFS and OS from diagnosis and the start of first-line treatment for patients receiving systemic therapy. Cox models were adjusted for age, sex, performance status, MZL subtype, stage, hemoglobin, albumin, and lactate dehydrogenase (LDH), and used multiple imputation for missing data. Adjusted hazard ratios (aHR) with 95% confidence intervals (CI) are reported. Results The study included 783 MZL patients (median age: 63 years; 53% women; 60% EMZL, 20% NMZL, 20% SMZL). Of these, 91 (12%) had LC reported in the biopsy, and 44 (6%) had &amp;gt;10% LC content ( Fig. 1A). Ki-67 staining was performed on biopsies from 438 MZL patients. Of those, 235 (54%) had low Ki-67 expression (≤10%), and 98 (22%) had Ki-67 &amp;gt;20%, which we determined to be the best prognostic cutoff for high Ki-67 in MZL. Ki-67 &amp;gt;20% correlated with increased LDH (34% versus 20%, P=.017), but not with other clinical parameters or with the use of first-line RCHOP chemotherapy ( P=.07). The Ki-67 &amp;gt;20% group had significantly worse PFS (aHR=1.69, 95%CI=1.12-2.55, Fig. 1B) with a trend for worse OS from diagnosis (aHR=2.00; 95%CI = 0.97-4.15). These associations were statistically significant for survival outcomes measured from the start of first-line systemic therapy: both PFS (aHR = 1.84, 95%CI = 1.15-2.94) and OS (aHR = 2.71, 95%CI = 1.11-6.60). There were no significant differences in PFS or OS within the Ki-67 &amp;gt;20% group based on first-line therapy (R-CHOP vs. BR/RCVP). The cumulative incidence of HT was significantly higher in the high Ki-67 group (5-year risk, 9.8% versus 3.8%, p=0.013). LC presence was associated with higher Ki-67 but not other clinical characteristics. Patients with LC-containing MZL received R-CHOP as first-line chemotherapy (18%) more frequently than those without LC (5%; P=.004). Presence of LC was linked to shorter PFS from diagnosis (aHR = 1.56, 95%CI = 1.08-2.26), but not OS (aHR = 1.07; 95%CI = 0.53-2.18). Presence of LC did not affect PFS or OS from the start of first-line systemic therapy (n=523). Among patients with LC, there was no significant difference in PFS or OS according to the type of first-line therapy (R-CHOP vs. BR/RCVP). The cumulative incidence of HT (31 events, 5-year risk 3.7% [95%CI, 2.4-5.3%]), was higher in the group with LC (5-year risk 9.4% versus 2.9%, P=0.04). Comparing patients with &amp;gt;10% LC to others yielded similar associations without statistical significance for any endpoint (possibly due to few patients with &amp;gt;10% LC). Discussion In this large retrospective cohort of newly diagnosed MZL patients, Ki-67 staining &amp;gt;20% was an independent prognostic factor for worse PFS and OS. LC content in the tumor was not significantly associated with most outcomes. Anthracycline-based chemotherapy did not impact PFS or OS in the presence of high Ki-67 or LC. These findings, along with the increased risk of HT, suggest that MZL with Ki-67 &amp;gt;20% may represent a higher-risk subset to prioritize for experimental approaches. Patients with LC or high Ki-67 at diagnosis should undergo a repeat biopsy at relapse to assess for HT.

Effectiveness and Safety of Orelabrutinib Combined with Rituximab As First-Line Treatment in Marginal Zone Lymphoma

Background: Marginal zone lymphoma (MZL) collectively is the third most common type of B-cell non-Hodgkin's lymphoma (NHL) worldwide, with an increased trend in incidence during the last two decades (Rossi D E et al., N Engl J Med. 2022). The lack of predominant first-line systemic therapy and toxicities associated with current rituximab-based therapies have inspired the exploration of more optimal treatment strategies (Becnel MR et al., Br J Haematol, 2019). Given the crucial role of bruton tyrosine kinase (BTK) in the B-cell receptor signaling pathway, BTK inhibitor has been proven to yield robust outcomes with improved tolerability in the development of NHL (Dhillon S et al., Drugs, 2021; Xu W et al., Blood, 2019; Song Y et al., Blood, 2019). Orelabrutinib is a novel BTK inhibitor with high selectivity and has been approved in China for relapsed/refractory MZL recently (Dhillon S et al., Drugs, 2021). Meanwhile, several clinical studies reported that orelabrutinib in combination with rituximab in NHL could preserve natural killer cell-mediated antibody-dependent cellular cytotoxicity induced by rituximab and enhance the clinical efficacy (Yu H et al., Mol Ther Oncolytics, 2021; Qu C et al., Blood, 2023). However, orelabrutinib plus rituximab as the first-line treatment for MZL remains largely understudied, thus, we conducted a retrospective study to evaluate its effectiveness and safety. Methods: Between July 27, 2021 and March 18, 2023, 10 patients with MZL who received orelabrutinib (150 mg, qd, po) with rituximab (375 mg/m 2, iv, day 1 of each 28-day cycle) as first-line therapy were included in this retrospective study. After 6 cycles of treatment, patients underwent orelabrutinib monotherapy (150 mg, qd, po) as maintenance for a year. Dynamic dose adjustment was performed according to the patient's clinical status. Effectiveness was assessed by positron emission tomography/computed tomography-based 2014 Lugano criteria. The primary endpoint was the overall response rate (ORR); secondary endpoints were progression-free survival (PFS), overall survival (OS), and safety. Results: Ten patients (6 males; median age 63.5 years, range 45-76) were included in this study, 4 with extranodal MZL of mucosa-associated lymphoid tissue (40.0%), 2 with nodal MZL (20.0%), 1 with splenic MZL (10.0%), and 3 with unknown subtype (30%). Among a total of 10 patients, 3 (30%) achieved complete response (CR) and 6 (60%) attained partial response (PR) as their best response for an ORR of 90% ( Figure 1). After a median follow-up of 13.0 months (range 7.8-24.7), the median PFS was not reached and a 6-month PFS rate was 100% ( Table 1). OS could not be assessed due to there were no deaths occurred. As of the cut-off date (May 6, 2023), 8 patients received orelabrutinib maintenance treatment and the median duration of maintenance treatment was 9.6 months (range 3.0-17.8). The ORR was 75% (6/8) during maintenance treatment, while 1 patient had stable disease (SD) and 1 developed progressive disease (PD). In addition, abnormal hematology due to disease gradually recovered with the therapy within 4 months. No serious adverse events were observed. The off-target related AEs such as atrial fibrillation, diarrhea, and major hemorrhage were not reported. Conclusion: This retrospective data suggests that orelabrutinib with rituximab has an encouraging anti-tumor activity in MZL, with a favorable safety profile. These results provide a potential first-line treatment strategy in MZL. Further verification in prospective clinical trials of clinical outcomes of orelabrutinib in first-line MZL is warranted in the future.

The Role of Radiotherapy in Patients with Refractory Hodgkin Lymphoma after Brentuximab Vedotin and -/or Immune Checkpoint Inhibitors

Background: Brentuximab vedotin (BV) and immune checkpoint inhibitors (ICIs) had important roles in the treatment of relapse or refractory (R/R) Hodgkin lymphoma (HL). Treatment of refractory disease after BV and -/or ICIs remains a challenge. This study was conducted to evaluate the efficacy and safety of radiotherapy for R/R HL after failure to BV or ICIs. Patients and methods: We retrospectively analyzed patients in two institutions with R/R HL who had failed after first-line therapy, and were refractory to BV or ICIs, and received radiotherapy (RT) thereafter. The overall response rate (ORR), duration of response (DOR), progression-free survival (PFS) and overall survival (OS) were analyzed. Results: A total of 19 patients were enrolled. First-line systemic therapy consisted of ABVD (84.2%), AVD + ICIs (10.5%) and BEACOPP (5.3%), respectively. After first-line therapy, 15 patients (78.9%) were refractory, and 4 patients (21.1%) relapsed. After diagnosis of R/R HL, 8 patients (42.1%) received BV, and 17 patients (89.5%) received ICIs. RT was delivered in all 19 patients who failed after BV or ICIs. In 16 efficacy-evaluable patients, the ORR and CR rate were 100% and 100%. The median DOR was 17.2 months (range, 7.9 to 46.7 months). 3 patients progressed at outside of the radiation field. The in-field-response rate was 100%. The 12-month PFS and OS were 84.4% and 100%, respectively. No patients were reported with sever adverse events. Conclusion: This study concluded that radiotherapy was effective and safe for refractory HL after BV or ICIs. Further prospective studies were warranted. KEY WORDS: Radiotherapy; Hodgkin lymphoma; Brentuximab vedotin; Immune checkpoint inhibitors; Refractory; Relapse

Overall survival in advanced hepatocellular carcinoma treated with concomitant systemic therapy and stereotactic body radiation therapy or systemic therapy alone

IntroductionFirst-line systemic therapy (ST) options for advanced hepatocellular carcinoma (HCC) include tyrosine kinase inhibitors and immunotherapy (IO). Evolving data suggest prolonged overall survival (OS) when ST is combined with stereotactic body radiation therapy (SBRT), although evidence is significantly limited in HCC populations. We hypothesized that advanced HCC patients in the National Cancer Database (NCDB) would have improved OS when receiving ST+SBRT vs ST alone.MethodsStage III/IV HCC patients diagnosed from 2010-2020 and treated with first-line ST±SBRT were identified from the NCDB. The primary endpoint was OS from date of diagnosis stratified by the receipt of SBRT (ST+SBRT vs ST alone). Survival was estimated using Kaplan-Meier methodology and compared via log-rank. Multivariate analysis (MVA) was performed by Cox regression.ResultsOf 10,505 eligible patients with stage III disease, 115 (1.1%) received ST+SBRT and 10,390 (98.9%) received ST alone. Of 9,617 eligible patients with stage IV disease, 127 (1.3%) received ST+SBRT and 9,490 (98.7%) received ST alone. Median follow-up time was 6.8 months. Baseline characteristics were similar between cohorts. Patients with stage III disease receiving ST+SBRT had improved median OS (12.62 months vs 8.38 months) and higher rates of survival at 1-year (53.0% vs 38.7%) and 2-years (27.0% vs 20.7%) compared to those receiving ST alone (log-rank P=0.0054). Similarly, patients with stage IV disease receiving ST+SBRT had improved median OS (11.79 months vs 5.72 months) and higher rates of survival at 1-year (49.6% vs 26.2%) and 2-years (23.6% vs 12.0%) (log-rank P&amp;lt;0.0001). On MVA, receipt of SBRT predicted improved OS (HR=0.748, 95%CI 0.588-0.951; P=0.0178) and receipt of IO trended towards improved OS (HR=0.859, 95%CI 0.735-1.003; P=0.0538).ConclusionIn advanced HCC, patients receiving ST+SBRT had improved OS compared to those receiving ST alone. Prospective clinical trials are warranted to better identify HCC populations which may benefit from combined modality therapy.

Patient-Reported Outcomes, Tumor Markers, and Survival Outcomes in Advanced GI Cancer

Patient-reported outcomes (PROs), such as quality of life (QOL) and symptoms, are often associated with clinical outcomes in patients with cancer. In practice, oncologists use serum tumor markers (TMs) (ie, carcinoembryonic antigen [CEA] and carbohydrate antigen 19-9 [CA 19-9]) and imaging to monitor clinical outcomes in patients with gastrointestinal cancer. To examine associations of 1-month changes in PROs and TMs with treatment response and survival among patients with gastrointestinal cancer. This cohort study enrolled patients at Massachusetts General Hospital Cancer Center with at least 1 month follow-up from May 2019 to December 2020. Included patients were beginning first-line systemic therapy, aged 18 years or older, and had been diagnosed with metastatic pancreaticobiliary, colorectal, or gastroesophageal cancer. Data analyses took place from January 2021 to January 2022. PROs were collected, including QOL (Functional Assessment of Cancer Therapy General [FACT-G]), physical symptoms (Edmonton Symptom Assessment System [ESAS]), and psychological symptoms (Patient Health Questionnaire-4 [PHQ4] total, PHQ4-depression, and PHQ4-anxiety), as well as TMs (CEA and CA 19-9), at the time of chemotherapy initiation and 1 month later. Associations of 1-month changes in PROs and TMs with treatment response (clinical benefit vs disease progression) at first scan, progression-free survival (PFS), and overall survival (OS), adjusted for baseline values using regression models. This study included 159 patients, with 134 patients (84.3%) evaluable for analysis. Patients had a median (range) age of 64.0 (28.0-84.0) years and 86 (64.2%) were male. One-month PRO changes (FACT-G: OR, 1.07; 95% CI, 1.03-1.11; P = .001; ESAS-total: OR, 0.97; 95% CI, 0.94-1.00; P = .02; ESAS-physical: OR, 0.96; 95% CI, 0.92-1.00; P = .03; PHQ4-depression: OR, 0.67; 95% CI, 0.49-0.92; P = .01) were significantly associated with treatment response, but PHQ4-total or TMs were not. Changes in FACT-G (HR, 0.97; 95% CI, 0.95-0.99; P = .003), ESAS-total (HR, 1.03; 95% CI, 1.01-1.05; P = .004), ESAS-physical (HR, 1.03; 95% CI, 1.00-1.05; P = .02), PHQ4-depression (HR, 1.22; 95% CI, 1.01-1.48; P = .04), and CEA (HR, 1.00; 95% CI, 1.001-1.004; P = .001) were associated with PFS, but changes in PHQ4-total or TMs were not. Changes in ESAS-total (HR, 1.03, 95% CI, 1.01-1.06; P = .006) and ESAS-physical (HR, 1.04, 95% CI, 1.01-1.06; P = .015) were associated with OS, but changes in TMs were not associated with OS. These findings suggest that 1-month changes in PROs can be associated with treatment response and survival in patients with advanced gastrointestinal cancer. Notably, 1-month changes in TMs were not consistently associated with these outcomes. These findings highlight the potential for monitoring early changes in PROs to associate with clinical outcomes while underscoring the need to address the QOL and symptom concerns of patients with advanced cancer.

Targeted mutation-based therapy for intrahepatic cholangiocarcinoma

Intrahepatic cholangiocarcinoma (iCCA) is a highly aggressive primary liver cancer with limited treatment options and poor prognosis. Although gemcitabine combined with cisplatin (GEMCIS) or newly GEMCIS plus durvalumab is the first-line systemic therapy for iCCA, several promising treatment targets have been identified in the past decade in both first- and subsequent-line settings, including neurotrophic tropomyosin-receptor tyrosine kinase (NTRK) fusions, RET fusions, high microsatellite instability (MSI-H), high tumor mutation burden (TMB-H), as well as fibroblast growth factor receptor 2 (FGFR2) fusions, BRAF V600E mutation, isocitrate dehydrogenase (IDH)-1 and IDH-2 mutations, and human epidermal growth factor receptor 2 [HER2 (ERBB2)] amplifications. Corresponding small molecule inhibitors and monoclonal antibodies have demonstrated improved efficacy and survival benefits in phase 2 or phase 3 studies, gained regulatory approvals or recommendations in guidelines, and reshaped the therapeutic management for advanced cholangiocarcinoma. Numerous novel targeted drugs and combination therapies have been developed and are under evaluation. Despite the progress made in targeted therapy, it still faces challenges such as acquired drug resistance, precise patient selection, and serious adverse events. Therefore, large-scale randomized phase 3 trials of novel targeted agents and innovative regimens are warranted to benefit this population. Herein, we present a comprehensive review of the literature of clinical significance on targeted therapy for iCCA in recent years, focusing on the advances in mutation-based targeted therapy.

Circulating tumor cells as a predictor and prognostic tool for metastatic clear cell renal carcinoma: An immunocytochemistry and genomic analysis

BackgroundTreatment of metastatic clear cell renal carcinoma (mccRCC) has changed dramatically over the past 20 years, without improvement in the development of biomarkers. Recently, circulating tumor cells (CTCs) have been validated as a prognostic and predictive tool for many solid tumors. ObjectiveWe evaluated CTCs in blood samples obtained from patients diagnosed with mccRCC. Comparisons of CTC counts, protein expression profiling, and DNA mutants were made in relation to overall survival and progression-free survival. MethodsCTCs were isolated from 10 mL blood samples using the ISET® system (Isolation by SizE of Tumor Cells; Rarecells, France) and counted. Protein expression was evaluated in immunocytochemistry assays. DNA mutations were identified with next generation sequencing (NGS). ResultsBlood samples (10 mL) were collected from 12 patients with mccRCC before the start of first-line systemic therapy, and again 30 and 60 days after the start of treatment. All 12 patients had CTCs detected at baseline (median, 1.5 CTCs/mL; range: 0.25–7.75). Patients with CTC counts greater than the median had two or more metastatic sites and exhibited worse progression-free survival (19.7 months) compared to those with CTC counts less than the median (31.1 months). Disease progression was observed in 7/12 patients during the study. Five of these patients had baseline CTC counts greater than the median, one had higher CTC levels at the second blood collection, and one patient had CTCs present at 1 CTC/mL which positively stained for PD-L1, N-cadherin, VEGF, and SETD2. CTC DNA from six patients with worse outcomes was subjected to NGS. However, no conclusions could be made due to the low variant allele frequencies. ConclusionDetection of CTCs in patients with mccRCC receiving first-line treatment is a feasible tool with prognostic potential since increased numbers of CTCs were found to be associated with metastasis and disease progression.

The role of radiotherapy in patients with refractory Hodgkin's lymphoma after treatment with brentuximab vedotin and/or immune checkpoint inhibitors

BackgroundApproximately 10%–30% of patients with Hodgkin's lymphoma (HL) experience relapse or refractory (R/R) disease after first-line standard therapy. Brentuximab vedotin (BV) and immune checkpoint inhibitors (ICIs) have important roles in the salvage treatment of R/R HL. However, subsequent treatment for HL refractory to BV and/or ICI treatment is challenging. MethodsWe retrospectively analyzed patients in two institutions who had R/R HL, experienced BV or ICI treatment failure, and received radiotherapy (RT) thereafter. The overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS) were analyzed. ResultsOverall, 19 patients were enrolled. First-line systemic therapy comprised doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD, 84.2%); AVD plus ICIs (10.5%); and bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP, 5.3%). After first-line therapy, 15 (78.9%) and four patients (21.1%) had refractory disease and relapsed, respectively. After R/R HL diagnosis, six (31.6%), two (10.5%), and 11 (57.9%) patients received BV and ICIs concurrently, BV monotherapy, and ICI monotherapy, respectively. All patients received intensity-modulated RT (n = 12, 63.2%) or volumetric modulated arc therapy (VMAT; n = 7, 36.8%). The ORR as well as the complete response (CR) rate was 100%; the median DOR to RT was 17.2 months (range, 7.9–46.7 months). Two patients showed progression outside the radiation field; one patient had extensive in-field, out-of-field, nodal, and extranodal relapse. With a median follow-up time of 16.2 months (range, 9.2–23.2 months), the 1-year PFS and OS were 84.4% and 100%, respectively. PFS was associated with extranodal involvement (P = 0.019) and gross tumor volume (P = 0.044). All patients tolerated RT well without adverse events of grade ≥ 3. ConclusionRT is effective and safe for treating HL refractory to BV or ICIs and has the potential to be part of a comprehensive strategy for HL.

Phase 2 Study of Golidocitinib, a JAK1 Selective Inhibitor, As Maintenance Therapy in Patients with Peripheral T Cell Lymphomas after First-Line Systemic Therapy (JACKPOT26)

Introduction: Peripheral T cell lymphomas (PTCLs) are a group of rare non-Hodgkin's lymphomas. The first-line standard therapy is CHOP or CHOP-like regimens, and ~50-65% patients could achieve tumor response. However, approximately 40% of patients with complete response and 80% of patients with partial response had disease relapse within 2 years after initial tumor response, and the prognosis of relapsed patients was very poor. There is a lack of standard maintenance therapy for this group of patients. Golidocitinib is a JAK1 selective inhibitor which showed promising antitumor efficacy in patients with relapsed or refractory PTCLs. Here we report the antitumor efficacy and safety of golidocitinib as maintenance treatment after first-line therapy in a phase 2 clinical trial (JACKPOT26, CTR20213318). Methods: PTCL patients who achieved tumor response post first-line therapy were enrolled and received golidocitinib treatment at 150 mg once daily (QD). This study included two cohorts: cohort 1 (complete response post first-line therapy) and cohort 2 (partial response post first-line therapy). The objectives were to assess safety and antitumor efficacy of golidocitinib as maintenance therapy. The efficacy endpoints included the rate of patients who were 1-year and 2-year disease free survival (DFS) for cohort 1, and progression free survival (PFS), objective response rate (ORR), duration of response (DoR) for cohort 2, respectively. Tumor response was assessed by investigators based on CT images per Lugano 2014 criteria. Endpoints for safety assessments are treatment emergent adverse events (TEAEs) and serious adverse events (SAEs), etc. Results: A total of 48 patients with PTCL who had achieved tumor response post first-line treatment were enrolled, including 30 patients with complete response (cohort 1) and 18 patients with partial response (cohort 2). The median age was 58.5 years (range: 25 to 74), and 52.1% were male. Major pathological subtypes included: AITL (31.3%), NOS (27.1%) and NK/TCL (27.1%). All dosed patients were included in the efficacy and safety analysis. As of June 27, 2023, the median duration on treatment for all patients was 7.1 months. In cohort 1, with median follow-up time of 8.1 months, median DFS has not been reached, with 86.7% patients still responding. In nodal subtypes（AITL, NOS, ALK-ALCL）, with median follow-up time of 8.3 months, median DFS has not been reached, with 82.4% patients still responding. In cohort 2, with median follow-up time of 5.6 months, median PFS has not been reached, with 66.7% patients still responding. The ORR of cohort 2 was 38.9%, and complete response rate (CRR) was 33.3%. In 10 patients with measurable disease at the baseline, six patients (60%) achieved tumor response, with 5 patients achieved complete response. With medina follow-up time of 3.7 months, the median DoR has not been reached, with 85.7% of patients still responding. The estimated 6-month and 9-month DoR rates were 100% and 100%, respectively. The safety profile of golidocitinib was similar as what has been reported previously. A total of 32 patients (66.7%) reported ≥ grade 3 drug-related TEAEs. The most common ≥ grade 3 drug-related TEAEs were hematological adverse events in nature, including neutropenia (37.5%), leukopenia (31.3%), lymphopenia (10.4%) and thrombocytopenia (6.3%). The majority of these TEAEs were reversible and clinically manageable. Only one patient discontinued golidocitinib treatment due to drug-related TEAEs. No drug-related TEAEs leading to fatal outcome was reported. Conclusions: In conclusion, golodocitinib showed manageable safety profile and promising effect in maintaining and enhancing tumor response in patients with PTCL post first-line therapies. This result supports further clinical development of golidocitnib in the first-line setting. The updated data will be presented in the conference.

Development and External Validation of a Lymphoma-Specific Venous Thromboembolism Risk Assessment Model

Introduction: Venous thromboembolism (VTE) significantly affects cancer patients undergoing systemic therapy. Existing risk models developed in the pan-cancer population, such as the Khorana score, offer limited discrimination in cancer-specific setting. We aimed to develop and validate a risk assessment model (RAM) tailored for lymphoma patients, accounting for the clinical and sociodemographic heterogeneity across three distinct healthcare systems in the United States. Methods: Electronic health records (EHR) linked to cancer registry 2006-2021 from the Veterans Affairs national healthcare system (VA) with a total of 10,313 lymphoma patients were randomly divided into an 80% derivation cohort and a 20% internal validation cohort. Further external validation was carried out using data from two other healthcare systems - Harris Health System (HHS, N= 854, 2011-2020) and MD Anderson Cancer Center (MDACC, N=1,858, 2017-2020). Patients were included if they had newly diagnosed lymphoma requiring first-line systemic therapy within 1 year of diagnosis. Patients were excluded if they had recent diagnosis of acute VTE within the last 6 months or were prescribed anticoagulant within 1 month before index date. The index date was the time of systemic therapy, and all covariates were extracted on or before the index date. Incident VTE was defined using our published computable phenotype algorithm (PMID 36626707; 37067102). For RAM derivation (Figure 1), 32 candidate predictors were initially chosen based on clinical relevance and EHR data availability. Missing values were imputed via chain random forest. Parsimonious variable categories were selected by a combination of Least Absolute Shrinkage and Selection Operator (LASSO), Recursive Feature Elimination (RFE), and random forest to generate the final logistic regression model. For external validation, complete case analysis was performed using the derived beta coefficients without model refitting. Bootstrapped time-dependent c statistics and calibration curves for 6-month VTE were used to assess discrimination and fit. A pre-determined threshold of 8% VTE at 6-month from the predicted probability was used to stratify high vs. low-risk groups. Competing risk models were used to assess cumulative incidence. Results: At 6 months, the VTE incidence were 5.75% (n=469) in VA derivation and 6.12% (n=124), 8.24% (n=69), and 6.55% (n=112) in the VA, HHS, and MDACC validation cohorts, respectively. The three healthcare systems had different baseline characteristics in demographics, lymphoma types, systemic therapies, and comorbidities. Patients from VA were mostly older males with more comorbidities and remote history of VTE, patients from HHS were mostly uninsured minorities who were younger but with more aggressive histology, while those from MDACC were patients treated at a comprehensive cancer center. The variables in the final RAM included lymphoma type (4 groups ranging from very-low to very-high risk), body mass index, indwelling catheter, cytotoxic vs. targeted therapy, history of VTE, recent hospitalization, and paralysis/immobilization. Table 1 shows the variable prevalence in each cohort. As shown in Figure 1, the new RAM showed promising discrimination for VTE with a C-statistic of 0.69 in the derivation cohort and 0.67, 0.70, 0.72 in the internal and two external validation cohorts. By splitting patients using an 8% predicted risk threshold, the high- vs. low-risk group achieved a clear differentiation in risk stratification despite significant differences in baseline characteristics. This represented a noticeable improvement for lymphoma patients over the Khorana Score, which yielded C-statistics of 0.53-0.56. The overall calibration of the RAM appeared adequate. Conclusions: Using multiple cancer-EHR cohorts with heterogeneous patients and a wide range of lymphoma subtypes, we successfully derived and externally validated an improved RAM for VTE specifically in lymphoma patients requiring early initiation of systemic therapy. Along several well-known patient-specific risk factors, lymphoma type was an important predictor of VTE risk. The new RAM could improve VTE risk stratification and prevention efforts in lymphoma patients.