Long Term Follow up of the Resort Study (E4402): A Randomized Phase III Study Comparing Two Different Rituximab Dosing Strategies for Low Tumor Burden Follicular Lymphoma

BACKGROUND: E4402 was a randomized phase III study comparing two different rituximab dosing strategies for patients with previously untreated, low tumor burden follicular lymphoma (FL). The primary endpoint was time to treatment failure. The initial publication (Kahl, JCO 2014) demonstrated that a retreatment strategy utilized less drug and produced comparable time to treatment failure compared to a maintenance strategy. Here we provide long term follow up results, focusing on response duration, time to first cytotoxic therapy, overall survival, and risk of histologic transformation. METHODS: Eligible patients had untreated, low tumor burden (GELF criteria) FL. Patients received R 375 mg/m 2 weekly x 4 and responders were randomized to maintenance rituximab (MR) (single dose R q 3 months) or retreatment rituximab (RR) (R weekly x 4 doses at disease progression). Each strategy was continued until treatment failure. The primary endpoint, time to treatment failure, was defined as progression within 6 months of last R, no response to R retreatment, initiation of alternative therapy, or inability to complete protocol therapy. Secondary endpoints included time to first cytotoxic therapy, quality of life and safety. The ECOG Data Monitoring Committee recommended release of study results at a planned interim analysis in September 2011 and patients and providers were notified of results. Time to treatment failure data collection halted with release of the results but limited data collection on time to first cytotoxic therapy, response duration, and risk of histologic transformation continued. INITITIAL RESULTS: From 11/03 to 9/08, 384 patients with FL were enrolled. Complete or partial response was achieved in 289 patients (71%), who were then randomized to MR (n=146) or RR (n=143). Demographic features were similar in the two arms: median age 59 years; ECOG PS 0-1 in all patients, and FLIPI low-risk (14.9 vs. 16.4%), intermediate-risk (46.3 vs. 42.9%) and high-risk (38.8 vs. 40.7%) for MR vs. RR, respectively. At initial publication, with a median follow-up of 3.8 years, the time to treatment failure was 3.9 years for MR vs. 3.6 years for RR (p=NS). LONG TERM FOLLOW UP RESULTS: Immunoglobulin levels and risks for serious infections/late complications in MR patients will be updated at the annual meeting. For the endpoint of time to first cytotoxic therapy, the median follow up is 8.7 years. At 7 years, 83% of MR and 63% of RR remained free from first cytotoxic therapy (HR 2.37; 95% CI 1.50 - 3.76) [Figure 1]. For the endpoint of response duration, the median follow up is 12.1 years. At 10 years, 66% of the MR patients remained in their 1 st remission compared to 30% of the RR patients who remained in their 1 st remission [Figure 2]. The median response duration for RR patients receiving a single 4-week course of rituximab was 3.25 years. There was no difference in the overall survival at 10 years, 84% for MR vs. 83% for RR. There was a trend towards a lower risk of histologic transformation for patients receiving MR (n = 4) compared to RR (n = 11) (p = 0.11). CONCLUSIONS: With long term follow up, the RESORT data indicates that in previously untreated, low tumor burden, follicular lymphoma, MR was superior to RR for delaying time to first cytotoxic therapy and for response duration, with a trend towards reducing the risk of histologic transformation. MR did not improve the overall survival. The original publication concluded that the time to treatment failure is similar between the two dosing strategies. Due to study design, time to treatment failure could not be analyzed in this long term follow up analysis. Compared to the historical benchmark of 3 years median time to first cytotoxic therapy when watch and wait is utilized, single agent rituximab, administered by either dosing strategy, was highly effective at delaying the time to first cytotoxic therapy. Figure 1 Figure 1. Disclosures Kahl: AbbVie, Adaptive, ADCT, AstraZeneca, Bayer, BeiGene, Bristol-Myers Squibb, Celgene, Genentech, Incyte, Janssen, Karyopharm, Kite, MEI, Pharmacyclics, Roche, TG Therapeutics, and Teva: Consultancy; AbbVie, Acerta, ADCT, AstraZeneca, BeiGene, Genentech: Research Funding. Habermann: Incyte: Other: Scientific Advisory Board; Tess Therapeutics: Other: Data Monitoring Committee; Seagen: Other: Data Monitoring Committee; Morphosys: Other: Scientific Advisory Board; Loxo Oncology: Other: Scientific Advisory Board; Eli Lilly & Co.,: Other: Scientific Advisor. Schuster: Abbvie: Consultancy, Research Funding; Acerta Pharma: Consultancy; AstraZeneca: Consultancy; Adaptive Biotechnologies: Research Funding; BeiGene: Consultancy; Celgene: Consultancy, Honoraria, Research Funding; DTRM: Research Funding; Genetech: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Incyte: Research Funding; Juno Theraputics: Consultancy, Research Funding; Loxo Oncology: Consultancy; Merck: Research Funding; Nordic Nanovector: Consultancy; Novartis: Consultancy, Honoraria, Patents & Royalties, Research Funding; Pharmaclcyclics: Research Funding; Tessa Theraputics: Consultancy; TG Theraputics: Research Funding. Fenske: TG Therapeutics: Consultancy, Speakers Bureau; Servier Pharmaceuticals: Consultancy; Seattle Genetics: Speakers Bureau; Sanofi: Speakers Bureau; Pharmacyclics: Consultancy; MorphoSys: Consultancy; Kite (Gilead): Speakers Bureau; KaryoPharm: Consultancy; CSL Therapeutics: Consultancy; Bristol-Myers Squibb: Speakers Bureau; Biogen: Consultancy; Beigene: Consultancy; AstraZeneca: Speakers Bureau; ADC Therapeutics: Consultancy; Adaptive Biotechnologies: Consultancy; AbbVie: Consultancy.

Mapping Myeloma: A Roadmap of Daratumumab Use in Clinical Pathways

Background: While myeloma remains an incurable disease, novel therapies have significantly improved survival. Daratumumab is a human IgG1κ anti-CD-38 monoclonal antibody that is approved in several different combinations in the first line and relapsed refractory setting (Daratumumab. Package insert. Janssen Biotech, Inc.; 2021.). However, there is little guidance on treatment selection and sequencing. Clinical pathways have been implemented at different institutions as a decision support tool for the treatment of complex diseases. Dana-Farber Cancer Institute (DFCI) Clinical Pathways includes daratumumab based regimens in 11 of 15 nodes for myeloma treatment. Methods: This was a real-world, single-center, retrospective, observational study assessing daratumumab based navigations in multiple myeloma from August 2019 to August 2020. The primary objectives were to describe the usage and efficacy of daratumumab, and to evaluate the concordance between myeloma pathway navigation and actual clinical practice. We extracted all myeloma pathways navigations over a 13 month period, with specific focus on navigations for daratumumab-based regimens; for those patients, we performed chart review to determine efficacy endpoints (response rate, overall survival, time to response, duration of response, and time to treatment failure) and to compare the navigated pathway to the actual clinical setting and treatment. Differences between navigated clinical characteristics (e.g., line of therapy) or treatment selected compared to actual clinical context and/or treatment would be considered a discordant navigation. Results: There were 47 patients with a daratumumab based regimen, of which 45 patients received at least one dose of treatment. Daratumumab/pomalidomide/dexamethasone was used in 12 (45%) of patients, followed by daratumumab/bortezomib/dexamethasone 12 (26%), and daratumumab/dexamethasone in 6 (13%). Daratumumab/carfilzomib/lenalidomide/dexamethasone was used in 1 (2%) patient, and daratumumab/pomalidomide/bortezomib was used in 3 (6%) patients. Daratumumab based regimens were implemented as first line treatment in 1 (2%) patients, second line in 14 (30%) patients, third line in 21 (45%) patients, and fourth line or beyond in 11 (23%) patients. The overall response was 62% (95% CI: 47 - 76). Overall survival was not reached. The median time to first response and duration of response was 1 month and not reached, respectively (Table 1). The median time to treatment failure when daratumumab was used in the first line was not reached, 7.7 months in the second line, 3.7 months in the third line, and 2.5 months in the fourth line or beyond (Figure 1). Twenty-five (53%) patients moved on to subsequent therapy. This consisted of 12 (26%) patients adding a new medication to their current regimen, 3 (6%) patients continued daratumumab but changed combination agents to new treatments, and 10 (21%) patients receiving an entirely new regimen. There was no statistically significant difference in continuing daratumumab in the subsequent line (Figure 2). The median time on subsequent therapy was 3.4 months. Of the 47 navigations, 15 (32%) showed discordance between navigation and the actual clinical context. Reasons for discordance include discordance in the line of therapy (14.9%), drug selection in treatment plan (6.4%), both discordance in line of therapy and drug selection (4.3%), decision point discordance (4.3%) and no daratumumab received (2.1%). Conclusion: This hypothesis generating study suggests that daratumumab may improve clinical outcomes in earlier lines of treatment with diminished returns in later lines. Daratumumab used in the second line improved time to treatment failure by 4 and 5.2 months when compared to the 3rd and 4th lines, respectively. In subsequent lines, continuing daratumumab did not confer any additional benefit. While all patients received treatment as indicated by the medical chart, discordance between pathway navigation and clinical context occurred in 32% of patients. Reasons include differing definitions of line of therapy, select regimens only available in early lines of treatment, as well as the use of off-label combinations. The nuances of myeloma care present a challenge and opportunity for the development of clinical pathways and guidance in this field. Figure 1 Figure 1. Disclosures Mo: Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Epizyme: Consultancy; Eli Lilly: Consultancy; BMS: Membership on an entity's Board of Directors or advisory committees. Richardson: AstraZeneca: Consultancy; Karyopharm: Consultancy, Research Funding; Regeneron: Consultancy; Sanofi: Consultancy; Secura Bio: Consultancy; Janssen: Consultancy; Takeda: Consultancy, Research Funding; Protocol Intelligence: Consultancy; GlaxoSmithKline: Consultancy; AbbVie: Consultancy; Oncopeptides: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding. Nadeem: Takeda: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees.

The Systemic Immune Markers at Diagnosis Can Predict the Survival Benefit in Advanced Breast Cancer

Background/Aim: It has been difficult to establish prognostic markers for overall survival (OS) in patients with advanced breast cancer (ABC). Although systemic immune markers were reported as prognostic markers in several cancers, their utility in ABC remains unclear. Patients and Methods: We retrospectively analyzed 331 ABC patients, who received treatment at Fukuyama City Hospital between April 2009 and December 2020. Results: Patients with high absolute lymphocyte count (ALC), low neutrophil-to-lymphocyte ratio (NLR), and high lymphocyte-to-monocyte ratio (LMR) had significantly longer OS (p=0.025, p=0.010, and p<0.001, respectively). High ALC and high LMR were independently associated with longer OS (p=0.020 and p=0.015, respectively). High ALC was also independently associated with longer time to treatment failure (p=0.014). Conclusion: These systemic immune markers at diagnosis can predict not only a better OS but also a better TTF after first-line treatment.

Shorter duration of first-line chemotherapy reflects poorer outcomes in patients with HER2-negative advanced breast cancer: a multicenter retrospective study

Post-progression survival affects overall survival (OS) in patients with HER2-negative advanced breast cancer (HER2-ABC); thus, the optimal choice of first-line chemotherapy (1LCT) remains controversial. We investigated patients with HER2-ABC focusing on their sensitivity to 1LCT. We retrospectively analyzed patients with HER2-ABC who received 1LCT between January 2011 and December 2016 in three participating institutions. We identified 149 patients in the shorter and 152 patients in the longer time to treatment failure (TTF) groups. The median OS was significantly longer in the longer TTF group (hazard ratio [HR] 0.44, P < 0.001, log-rank). In the shorter TTF group, OS of patients who received paclitaxel plus bevacizumab (PB) therapy was significantly inferior to that of those who received chemotherapy other than PB (HR 2.57, P < 0.001, log-rank), and subsequent eribulin therapy significantly improved OS from 1LCT initiation (Wilcoxon P < 0.001); multivariate analyses showed that 1LCT PB therapy was an independent risk factor for poorer OS (HR 2.05, P = 0.003), while subsequent eribulin therapy was an independent prognostic factor for better OS (HR 0.56, P = 0.004). OS was significantly poorer in patients with HER2-ABC with a shorter duration of 1LCT, including PB therapy, while subsequent eribulin therapy improved OS.

236. Insight of Polymicrobial Prosthetic Joint Infections at a Referral Hospital

Background Approximately one-third of the prosthetic joint infections (PJIs) are polymicrobial. They are difficult to treat and there is an urgent need of clinical evidence that help to guide current protocols. We aimed to define the clinical characteristics and outcomes of patients with polymicrobial PJI. Methods We conducted a retrospective cohort study of patients with polymicrobial PJI treated at a referral hospital in Mexico City. Clinical data was retrieved and analyzed. Time to treatment failure, was evaluated for all cases. Results We identified 166 patients with a polymicrobial PJI from July 2011 to October 2020. The median follow-up period was 3.24 years (IQR, 1.45-6.42). Fistulae (77.7%) and pain (76.5%) were frequent. Patients required a median of 2 (IQR, 1-3) hospitalizations and 3 (IQR, 1-5) surgeries. Relapse, reinfection, and amputation ocurred in 21.1% (35), 10.2% (17), and 7.2% (12) of the cases, respectively. At 1-year follow-up 38.47% (63) patients failed to control the infection. At 2 and 5-year follow-up this rate increased to 50% (83) and 68% (112), respectively. The main infecting microorganisms were Staphylococcus epidermidis (51.8%), Enterococcus faecalis (47.6%), and Staphyloccocus aureus (34.9%). Anaerobes were identified in 38 (22.9%) cases. At 1 and 5-year follow-up, 39.31% (34) and 71.1% (61) of patients with S. epidermidis experienced treatment failure. On the other hand, those with S. aureus showed lower rates (log-rank p-value=0.03): 24.85% (14) and 50% (29), accordingly. Patients affected by anaerobes and E. faecalis exhibited similar trends, between them (log-rank p-value=0.73). Table1. Clinical findings of patients with polymicrobial PJI. Frequency distributions of sociodemographic factors, comorbidities, clinical presentation, outcomes, out-patient treatment, and etiology in patients with polymicrobial PJI. Data is presented as absolute frequency followed by relative frequency enclosed in parenthesis, otherwise specified. Abbreviations: SXT, Trimethoprim/Sulfamethoxazole. Figure 1. Kaplan‒Meier survivorship curve illustrating the time to treatment failure among patients with polymicrobial PJI. The shaded areas surrounding the gross line represent the 95% CI. Figure2. Kaplan‒Meier survivorship curves illustrating the time to treatment failure among patients with polymicrobial PJI, according to the infecting microorganisms.. Patients affected by S. epidermidis, E.faecalis, S. aureus, and anaerobes are represented with red, blue, green, and black lines, respectively. Conclusion Our study showed 61.53% of the patients with polymicrobial PJI controlled the infection at 1-year follow-up. This rate decreased over the years. These patients required a considerable number of hospitalizations and surgeries. Likewise, presenting with fistulae and pain ensured a high suspicion of PJI. S. epidermidis, E. faecalis, and S. aureus were the most frequent infecting microorganisms. The stratification of our cohort suggested the microbiology of polymicrobial PJI could have driven to differences in rates of treatment failure. Disclosures All Authors: No reported disclosures

Risks and benefits of reinduction ipilimumab/nivolumab in melanoma patients previously treated with ipilimumab/nivolumab

BackgroundIn melanoma patients who progress after prior ipilimumab/nivolumab (ipi/nivo) combination immunotherapy, there is no information regarding the risks and benefits of reinduction ipi/nivo.MethodsThis was a retrospective review of 26 melanoma patients treated at Memorial Sloan Kettering Cancer Center (MSKCC) since 2012 who received reinduction ipi/nivo at least 6 months following completion of an initial course of ipi/nivo. We collected data on demographics, genetics, immune-related adverse events (irAEs), best overall responses (BORs), time to treatment failure (TTF) and overall survival (OS).ResultsThe BOR rate (complete response+partial response) was 74% (95% CI 52% to 90%) after the first course of ipi/nivo but only 23% (95% CI 8% to 45%)) after reinduction. Response to reinduction did not correlate with response to the initial course. Among the 16 patients who had an objective response to the first course, only four (25%) responded to reinduction. Of five patients who did not respond to the first course, one responded to reinduction. For all patients, median TTF was 5.3 months after reinduction; TTF was shorter for reinduction than for the first course in 85% of patients. Median OS from reinduction was 8.4 months; estimated 2-year OS was 18%. Although reinduction was associated with fewer irAEs than the initial course of ipi/nivo (58% of patients vs 85% of patients in the initial course), eight (31%) patients experienced at least one new irAE after the second course.ConclusionsBOR rate and TTF were markedly less favorable after reinduction with ipi/nivo than after the initial course of ipi/nivo. Reinduction ipi/nivo was associated with frequent irAEs although less frequent than for the initial course.

A Novel Combination of Bevacizumab with Chemotherapy Improves Therapeutic Effects for Advanced Biliary Tract Cancer: A Retrospective, Observational Study

Background: Biliary tract cancer (BTC) is a heterogenous collection of biliary tract cancer at different primary sites, and the prognosis of advanced BTC is dismal. Systemic chemotherapy with gemcitabine and cisplatin (GC) has been the reference regimen since 2010. How to improve therapeutic effects of GC regimen is an urgent mission at present. Methods: Bevacizumab with a reduced dosage and modified schedule (10 mg/Kg/triweekly, 1 day before GS at the first 2 cycles) was combined with standard GC for patients with advanced BTC. Tumor response was assessed using Response Evaluation Criteria in Solid Tumors version 1.1 every 2 months. Kaplan–Meier curves were estimated for time-to-treatment failure (TTF), progression-free survival (PFS) and overall survival (OS). Result: A total of thirty cases of advanced BTC accepted this treatment, and the overall response rate (ORR) was 50.0%, and the disease control rate was 80.0% for all patients. The median TTF was 5.8 months, the median PFS was 8.4 months, and the median OS was 13.6 months. Most responses were noted at the first evaluation. Adverse effects (AEs) were mostly tolerable. Conclusions: After modifying the schedule, adding bevacizumab to a traditional GC regimen could increase the ORR with a shorter time-to-response, a better PFS and OS than GC alone but without the addition of AE. This regimen can be applied to patients with advanced BTC, especially those who are with a big tumor burden and who need a rapid response.

Partnering bevacizumab with irinotecan as first line-therapy of metastatic colorectal cancer improves progression free survival-A retrospective analysis

Colorectal cancer remains one of the most frequent malignancies (third place at both genders) worldwide in the last decade, owing to significant changes in modern dietary habits. Approximately half of the patients develop metastases during the course of their disease. The available therapeutic armamentarium is constantly evolving, raising questions regarding the best approach for improving survival. Bevacizumab remains one of the most widely used therapies for treating metastatic colorectal cancer and can be used after progression. This study aimed to identify the best chemotherapy partner for bevacizumab after progression. We performed a retrospective analysis of patients with metastatic colorectal cancer who were treated with bevacizumab as first- and second-line chemotherapy. Data were collected for 151 patients, 40 of whom were treated with double-dose bevacizumab after the first progression. The two standard chemotherapy regimens combined with bevacizumab were FOLFIRI/CAPIRI and FOLFOX4/CAPEOX. The initiation of first-line treatment with irinotecan-based chemotherapy improved progression-free survival and time to treatment failure but not overall survival. After the first progression, retreatment with the same regimen as that used in the induction phase was the best approach for improving overall survival (median overall survival: 46.5 vs. 27.0 months for the same vs. switched strategy, respectively). No correlations were observed between the dose intensity of irinotecan, oxaliplatin, 5-fluorouracil, or bevacizumab and the overall survival, progression-free survival in the first-/second-line treatment, and time to treatment failure. Interaction between an irinotecan-based regimen as a second-line treatment and double-dose bevacizumab after progression was associated with an improved overall survival (p = 0.06). Initiating systemic treatment with an irinotecan-based regimen in combination with bevacizumab improved the progression-free survival in the first-line treatment and time to treatment failure. In terms of overall survival, bevacizumab treatment after the first progression is better partnered with the same regimen as that used in the induction phase.