ALBERT

Description: Introduction: Recurrent/refractory diffuse large B cell lymphoma (DLBCL) remains an area of unmet clinical need. Although autologous stem cell transplant (ASCT), and more recently chimeric antigen receptor (CAR) T cell therapy, have made a significant impact, many patients are ineligible for these treatments due to advanced age, comorbidities, or financial or geographical limitations, or they have relapsed following these treatments. Survivin, a novel target in DLBCL, is overexpressed in approximately 60% of untreated DLBCL with higher rates in relapsed disease. DPX-Survivac, a T cell activating therapy, elicits a strong and prolonged immune response against tumors expressing survivin. DPX-Survivac is combined with pembrolizumab, an anti-PD-1 checkpoint inhibitor, and intermittent low dose cyclophosphamide (CPA), used for an immunomodulatory effect. Pre-clinical studies have demonstrated increased efficacy of this DPX-based drug combination in controlling of tumor growth in murine tumor models, resulting in improved survival (Weir et al. J Immunother Cancer 2016). Methods: "SPiReL" is a Phase 2 non-randomized, open label, efficacy and safety study. Subjects with recurrent/refractory DLBCL with confirmed survivin expression are eligible for participation. Participants must also be ineligible for curative therapy. Study treatment includes administering two doses of 0.5 mL of DPX-Survivac 3 weeks apart followed by up to six 0.1 mL doses every 8 weeks. Intermittent low dose cyclophosphamide is administered orally at 50 mg twice daily for 7 days followed by 7 days off. Pembrolizumab 200 mg is administered every 3 weeks. Study participants continue active therapy for up to one year or until disease progression, whichever occurs first. The primary objective is to document the response rate to this treatment combination using modified Cheson criteria. Secondary objectives include duration of response and safety. Exploratory endpoints include T cell response, tumor immune cell infiltration, and gene expression analysis. Enrollment is ongoing with a goal of up to 25 subjects in this national, multi-center study. Trial design is shown below the text. Results: At the time of data cut-off, 23 subjects have been screened and 12 have been enrolled. The demographics of enrolled subjects include: median age is 75.5 years (50-82), with 3 male subjects participating. The median number of prior therapies is 2.5 (1-6), with 4 subjects having previously undergone ASCT. The median time from diagnosis to screening is 31 months (8-151). Of the 12 enrolled subjects, 3 were not evaluable for clinical efficacy due to early disease progression. One subject has not yet reached the first time point for assessment. In the Per Protocol analysis of 8 evaluable subjects ("PP", N = 8); as compared to a Full Analysis Set ("FAS", N = 11); 7 of 8 subjects (PP = 87.5%) demonstrated clinical benefit, including 6 with tumor regressions (FAS = 63.6%); 2 subjects (PP = 25%) achieved a complete response, 1 of whom has completed the 1 year study period (FAS = 18.2%); 3 subjects (PP = 37.5%) had a partial response (FAS = 27.3%); and 3 (PP = 37.5%) had stable disease remaining on study for 4, 6 and 8 months (FAS = 27.3%). This treatment combination is well-tolerated with mostly grade 1 and 2 adverse events reported; a single grade 3 maculopapular rash and 1 case of grade 4 cytopenia has been observed. Of the 23 screened subjects, survivin expression analysis was performed on 18 subjects. All of the 18 samples analyzed were survivin positive, with a range of 60%-100% of lymphoma cells expressing survivin. Preliminary analysis of peripheral blood T cell responses to survivin by ELISPOT assay shows 2 of 4 subjects had strong survivin-specific T cell responses. Both of these subjects had clinical responses. Summary: DPX-Survivac, in combination with pembrolizumab and low dose cyclophosphamide, demonstrates clinical activity and a favorable safety profile in recurrent/refractory DLBCL with 87.5% of evaluable subjects deriving clinical benefit, including 2 complete responses (25%) and 3 partial responses (37.5%) to date. Enrollment is continuing to further explore the synergistic effect of this combination in this population. Figure Disclosures Berinstein: Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Stewart:Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Keytruda (pemroblizumab) is approved for use to treat Melanoma, Metastatic, Non-Small Cell Lung Cancer, Head and Neck Cancer, Hodgkin's Lymphoma, Urothelial Carcinoma, Gastric Cancer, Cervical Cancer, Hepatocellular Carcinoma, Merkel Cell Carcinoma, Renal Cell Carcinoma, and Small Cell Lung Cancer. In this trial, it is being used to treat Diffuse Large B-Cell Lymphoma.

Description: Background: In the era of chemo-immunotherapy, risk factors associated with survival in patients with diffuse large B-cell lymphoma (DLBCL) are largely limited to biologic characteristics of disease. Laboratory based studies have postulated that statins (through inhibition of the geranylgeranylation pathways) can induce apoptosis in DLBCL cells; pre-clinical data suggests an anti-cancer potential for metformin (through inhibition of cancer cell growth by activation of AMPK and inhibition of mTOR pathways) and cox-2 inhibitors (anti-proliferative effects through blockade of PI3K pathway, inhibition of angiogenesis and proliferation by blocking eicosanoid receptors). To date, these potential in-vitro benefits have not been demonstrated consistently in "real world" studies. Our objective was to assess the impact of medicines with a biologic potential on lymphoma outcome in the era of rituximab. Methods: We performed a retrospective population-based study of adults ≥66 years diagnosed with DLBCL or transformed lymphoma treated in Ontario, Canada. Administrative databases held at ICES were used to assess the impact of select medications on patient outcomes. All patients treated, with curative intent, with a rituximab containing regimen between January 2005 and December 2015 were included. A 1-year lookback of medication exposure prior to commencing rituximab was used. Cox regression analyses were performed to determine the relationship between medication exposure and lymphoma outcomes. Additional analyses were completed to control for known confounders of survival, including the number of comorbid conditions. Results: A total cohort of 4913 patients were treated with a rituximab containing regimen, most frequently R-CHOP, during the study timeframe. Median age was 75 years (IQR 70-80); 51% were male. The median number of cycles of chemotherapy was 6 (IQR 3-6). The median number of comorbidities was 11 (IQR 9-14). Sixty-nine percent had a high comorbidity score (≥10); 26.4% moderate (6-9); and 4.7% low (0-5). Where mortality data was available, 52.1% of the cohort died at a median of 1 year, of whom 67% died due to DLBCL. In the year prior to commencing lymphoma therapy 45.7% received statin therapy; 16.3% metformin; and 25.0% cox-2 inhibitor. In the univariate analysis, statin exposure (HR 0.88; 0.8 - 0.97) was associated with improved survival, but exposure to cox-2 inhibitor (HR 0.82; 0.65 - 1.04) and metformin (HR 1.11; 0.98 - 1.26) had a no impact, during this timeframe. Adjusting for time varying exposure and demographic variables including socio-economic factors and comorbidities, we demonstrated that additional exposure to statin and cox-2 inhibitors in the 365 days prior to commencing lymphoma therapy was associated with a survival advantage, when compared to those who were never exposed. Statin exposure for 30 days (HR 0.97 [0.96-0.98]), 180 days (HR 0.84 [0.80-0.89]) and 365 days (HR 0.71 [0.63-0.79]) and cox-2 inhibitor exposure for 30 days (HR 0.95 [0.95-0.98]), 180 days (HR 0.76 [0.66-0.86]) and 365 days (HR 0.57 [0.43-0.74]) were independently associated with improved survival. In contrast metformin exposure had no impact on survival in this cohort. Patients with moderate (HR 1.69; 1.25 - 2.29) and high comorbidity scores (HR 3.16; 2.36 - 4.21) had significantly higher risk of mortality (p

Description: Despite advances in treatment for diffuse large B cell lymphoma (DLBCL), approximately one third of patients will relapse, with known risk factors largely limited to the biology of the disease. Recently, patient selection bias has been highlighted as a concern in patients enrolled in DLBCL trials, as the need to categorize patients by cell-of-origin necessitates a prolonged screening period that might exclude patients with a need for urgent treatment and thus more aggressive biology (Maurer et al., JCO 2018). Whether an abbreviated diagnosis to treatment interval represents a surrogate for more aggressive disease and adverse prognosis is unclear in a "real-world" setting. We evaluated the time from diagnosis to treatment (and other pre-treatment time intervals) and additional socioeconomic and system-based variables and their impact on lymphoma outcomes. Methods : Using population-based health administrative databases held at the Institute of Clinical and Evaluative Sciences, Ontario, Canada, we identified adults ≥18 years with DLBCL or transformed lymphoma. We explored the impact of timelines prior to commencing treatment and socio-economic status, distance to treating hospital, inpatient/outpatient status, and type of treatment centre on overall survival (OS) and progression-free survival (PFS). Patients were followed from index (first rituximab treatment) until death, occurrence of a new primary cancer, or March 31, 2017. Cox regression analyses were completed to evaluate the impact of predictor variables on OS. Results: In the population evaluated (n=9446), the median age was 66 years and 54% were of male gender. Forty-four percent were from the top two income quintiles and 86% from urban settings. Educational attainment was evenly distributed. Median number of co-morbidities using the John Hopkins aggregated diagnostic groups (ADGs) was 11 (IQR 9-14) with 61% of patients having a high AGD score (≥10). Patients waited a median of 37 days from diagnosis to treatment (IQR 39), with 25% waiting 〉 60 days. From diagnosis, patients waited a median of 19 days to see a hematologist/oncologist (diagnosis to consult time; IQR 24), followed by a further 15 days before chemotherapy was initiated (consult to treatment time; IQR 22). The first cycle was delivered as an inpatient in 4%. Median number of cycles was 6 (IQR 2) with 61% of patients completing ≥ 6. Most patients lived within 20 km of the treating centre (64%); however, 13% travelled 〉 60 km. At the conclusion of study follow-up, 57% of the cohort were alive with median OS not yet reached (Figure 1). Of the 3499 patients with the cause of death available, 73% had DLBCL listed as primary cause with 9.3% of patients dying on active treatment. In Cox regression analysis, an extended time from diagnosis to treatment was associated with improvement in overall survival. Compared to patients who required treatment within 30 days of diagnosis, patients who were treated within 30 - 60 days of diagnosis (HR 0.72; CI 95% 0.67 - 0.78) and 〉 60 days from diagnosis (HR 0.78; CI 95% 0.71 - 0.85) experienced improved survival (Figure 2). Compared to patients who lived close to the initial treatment centre (〈 20 km), the survival of those patients who travelled more significant distances (〉 60 km was not meaningfully impacted (HR 0.91; CI 95% 0.82-1.01). Conclusion:An abbreviated diagnosis to treatment time in newly-diagnosed DLBCL predicts for inferior overall survival in a "real-world" setting, and is potentially reflective of more aggressive disease biology or clinical behaviour. Clinical trials that require extended screening periods may be inadvertently enriched with patients with lymphomas that exhibit less aggressive clinical behaviour (and improved prognosis). In daily practice, patients with less clinically aggressive presentations should be reassured that their outcome should not be adversely impacted by a reasonable wait time. Forthcoming multivariable analyses will be presented to evaluate the impact of additional socioeconomic and system based variables on survival. Disclosures Buckstein: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Description: Introduction The introduction of novel therapies has significantly improved outcomes in myeloma. However, the economic burden of enhanced healthcare utilization is significant and cannot be discounted. This study sought to identify baseline characteristics that may influence outcomes and subsequent healthcare utilization. Patients were also stratified by induction therapy to determine the impact newer combinations have on healthcare utilization. Methods This retrospective single-center study enrolled all newly diagnosed patients with myeloma between 2005 and 2020. Three outcome measures were used to determine healthcare utilization - total inpatient length of stay (LOS), number of admissions, and day ward attendances. Univariate and multivariable analyses were performed to identify significant covariates related to overall survival (OS) and healthcare utilization. Outcomes were subsequently adjusted for duration of follow-up and per patient year. Results There were 113 patients included; 60 (53.1%) female; median age at diagnosis was 67 years (IQR 62, 73 years) and 22.1% were high risk International Staging System (ISS). Further baseline demographics are presented in Table 1. Median duration of follow up was 3.2 years (IQR 1.50, 6.55). Sixty patients (53.1%) died, 91.7% attributable to myeloma or its treatment. Predictors of OS by multivariable analysis were advanced stage [ISS III (p