Vishnu, Prakash

Abstract Background: The treatment of NHL has witnessed a paradigm shift over time, with targeted immunotherapy, stem cell transplant (SCT) among others. Historically, XRT was used quite frequently for the management of NHL but with advent of better systemic therapy, its utilization has changed. Trends and patterns of care for XRT use have never been formally reported. Methods: We identified patients with NHL diagnosis in the National Cancer Database (NCDB) between years 2004 and 2015. Demographic, clinical, facility level, initial treatment and outcome data were collected. The utilization of XRT in diffuse large B-cell (DLBCL) and non-DLBCL NHL were analyzed separately by univariate and multivariate analyses. To analyze the trends in the rates of XRT, we applied segmented linear regression to calculate the average annual percent change (AAPC) and 95% confidence Interval (CI) with a 'p' value. AAPC and CIs were calculated using the segmented package in R studio v1.1.49. Rest of the analyses was conducted using StataCorp version 15.1. Results: A total of 133,182 DLBCL and 204,933 non-DLBCL patients were identified. Among patients with DLBCL, 27,895 (20.9%) patients received RT. The rate of XRT declined from 25% in 2004 to 18.4% in 2015 with estimated AAPC of -0.59% (95%CI: -0.70- -0.49), p= 0.03 (Figure 1). In a subgroup analysis, a similar decline in the rate of XRT was evident across all the age groups, combined stages I and II vs stages III and IV and nodal vs extra nodal DLBCL (Table 1). Among non DLBCL, 33,369 (16.3%) patients received XRT. There was a statistically significant decline in the rate of XRT from 18.03% in 2004 to 16.3% in 2014 with an AAPC of -0.26 (95%CI: -0.38- -0.14) p <0.001 (Figure 1). On the subgroup analysis, the utilization of XRT declined across all the studied subgroups except among patients aged 80 years and above (Table 1). On multivariate analysis, several demographic, clinical and facility level factors were found to be significantly associated with XRT utilization in NHL (Table 2). In particular, older age groups, racial/ethnic minorities, advanced stages, higher Charlson comorbidity scores and diagnosis in the more recent calendar years were associated with lesser chances of receiving RT. Extranodal DLBCL had lower utilization while extranodal non-DLBCL had increased XRT utilization. Conclusion: There has been a significant decline in the utilization of XRT among patients with NHL (DLBCL and non-DLBCL) in the US since 2004, likely due to introduction of practice changing systemic therapeutics. There is still significant heterogeneity noted in practice patterns regarding utilization of XRT across the US. Having more standardized guidelines will help streamline delivery of evidence-based patient care. Disclosures Ailawadhi: Celgene: Consultancy; Janssen: Consultancy; Amgen: Consultancy; Takeda: Consultancy; Pharmacyclics: Research Funding.

Abstract INTRODUCTION: Autologous hematopoietic stem cell transplantation can heavily impact the quality of life (QOL) of an individual. However, this procedure may be the only hope for a cure or a longer life for some individuals. When these patients develop severe neutropenia during transplantation, protective isolation is recommended to reduce the risk of infection. During protective isolation, patients may be confined to their hospital room which can decrease their physical activity. For autologous hematopoietic stem cell receipts (AHSCR), severe neutropenia may last several days to weeks. During this time, patients often experience social isolation, emotional encumbrances and also physical deconditioning.Data is inconsistent whether protective isolation does reduce the incidence of infections. In this study, we sought to investigate the impact of physical activity during hospitalization on Quality of Life in AHSCR with severe neutropenia using the Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) questionnaire. METHODS: We conducted a prospective observational study of 15 patients admitted to Mayo Clinic Florida during November 2017 to May 2018 for autologous hematopoietic stem cell transplantation, wherein we monitored the activity of each patient during hospitalization by recording the number of steps taken each day by using an activity tracker worn by the patient. Informed consent was obtained on admission before enrolling patients. Patients completed a Quality of Life (QOL) questionnaire (FACT-BMT version 4) on admission and prior to discharge from the hospital. RESULTS: Of the 15 patients that were enrolled, 5 walked ≤ 100 steps/day (group A, median, 71) and 10 walked > 100 steps/day (group B, median, 406). While there was no difference in the median time to engraftment and length of hospital stay, the mean QOL score decreased from 89.2 on admission to 81.4 on discharge in less active neutropenia patients compared to the ones who were more active. (Table 1; Figure 1) CONCLUSION: Lack of physical activity decreases QOL in AHSCR. During hospitalization, AHSCR should be encouraged to increase their activity to improve QOL. Having an activity tracker may make it easier for patients to monitor their activity, and thus lead to a better QOL. Figure. Figure. Disclosures Sher: Affimed: Research Funding. Ailawadhi:Pharmacyclics: Research Funding; Janssen: Consultancy; Takeda: Consultancy; Amgen: Consultancy; Celgene: Consultancy.

Abstract Background: CLL is the most common leukemia diagnosis in adults and its treatment has undergone significant change from chemotherapy, to immunotherapy and now targeted kinase inhibitors, leading to improved overall survival (OS). With improving survivorship, SPMs can occur but an in-depth analysis of risks and trends of SPMs in CLL survivors is lacking. We performed a population-based analysis to evaluate this. Methods: Patients in the Surveillance, Epidemiology and End Results (SEER) database diagnosed with CLL between 1973-2015 were included. Due to variation in management techniques over time, the cohort was divided in four time periods: 1973-1982, 1983-1992, 1993-2002 and 2003-2015. We evaluated differences in risk for SPMs among CLL survivors compared to risk of individual malignancies expected in the general population during these time periods and studied the effect of demographics and time since CLL diagnosis. Results: Over a nearly 270,000 person-year follow up, 6,467 new SPMs were diagnosed with a standardized incidence ratio (SIR) of 1.2 (95% CI 1.17-1.23), which resulted in a 39 excess cancers per 10,000 population. The CLL survivors had a 20% overall increased risk of developing SPMs (excluding non-squamous skin cancer) compared to the general population. The risks for both solid (SIR 1.15 CI 95% 1.12-1.18) and hematological malignancies (SIR 1.61 95% CI 1.5-1.73) was higher than the expected in the general population. However, the risk for individual cancers was heterogeneous. The tumors associated with the highest risk were Hodgkin lymphoma (almost 8 times higher), Kaposi Sarcoma (4 times), non-epithelial skin cancers (4 times), salivary gland cancer (3 times) and acute lymphocytic leukemia (3 times). In contrast, tumors in the hepatobiliary system, female breast and female genital system were associated with a lower risk than the general population. The highest SIR across the study periods was observed in the younger population (ages 15-49). Although the risk increased in all ethnicities, it was statistically significant only in Caucasians. There was no gender-wise difference in SIR during any of the four time periods. A statistically significant increase in SIR was observed for both men and women from 1973-1982 to 2003-2015. This was mostly due to an increase in risk of hematological malignancies from 1.08 early in the study to 2.56 in the most recent study period. The SIR in solid tumors did not change significantly over time; in absolute terms, however, lung carcinoma contributed the most to the excess risk, followed by non-epithelial skin cancers and non-Hodgkin's lymphoma. The risk of developing a SPM was higher for the CLL survivors during most of the latency periods, but it was statistically significant during the 2-5 months and 12-59 months after diagnosis. A multivariate analysis was conducted to evaluate the impact of period of diagnosis on the development of SPMs among these patients. After adjusting for gender, ethnicity, radiation therapy, chemotherapy, and age at diagnosis of CLL, patients diagnosed with CLL in the most recent time period were at 45% higher risk of developing SPMs as compared to the patient diagnosed during 1973-1982 (Hazard ratio(HR) =1.45 95%CI:1.34-1.6, p<0.001). Moreover increased HRs were also observed for 1983-1992 and 1993-2002 time periods (Fig. 1) Conclusions: With improving therapeutics for cancer treatment, survivorship is improving as well and the risk of SPMs needs to be better understood and addressed. This is truer for CLL, where majority of patients have a favorable survival. The risk of SPMs was 20% higher in CLL survivors than in the general population and was most prominent in the survivors aged 15-49 years at the time of CLL diagnosis. The risk of individual malignancies may be heterogenous but there has been an increase in risk of SPMs over time, mainly due to an increase of secondary hematological malignancies in recent years. Active survivorship plans and long-term surveillance for SPMs is crucial for improved outcomes of patients with a history of CLL. Disclosures Ailawadhi: Janssen: Consultancy; Celgene: Consultancy; Amgen: Consultancy; Takeda: Consultancy; Pharmacyclics: Research Funding.

Abstract Background Diffuse large B cell lymphoma (DLBCL) with high-risk features carries a poor prognosis despite treatment with immunochemotherapy regimen incorporating rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP). Hence, dose adjusted rituximab, etoposide, prednisone, vincristine, cyclophosphamide and doxorubicin (DA.R-EPOCH), a higher intensity regimen, is suggested as an upfront treatment of high-risk DLBCL. In our study, we analyzed the outcomes in a prospectively followed cohort of patients with de novo high-risk DLBCL who received DA.R-EPOCH, and compared them to the patients who received R-CHOP. Furthermore, we conducted a cost analysis to determine which of the two treatments produces a larger financial burden. Method Patients diagnosed with DLBCL who received chemo-immunotherapy at our center between January 2011 to December 2016 were included in the analysis. High-risk DLBCL was defined by the presence of any of the following features at diagnosis: NCCN- IPI score ≥4, tumor measuring ≥5 cm, MYC ± BCL2 or BCL6 rearrangement by FISH or MYC overexpression (>40% by immunohistochemistry [IHC]), Ki-67 index ≥80% and non-GCB immunophenotype by Hans algorithm. Responses were evaluated at middle and end of chemotherapy. Overall (OS) and progression free survival (PFS) were calculated. For the cost analysis, standardized costs were obtained from Mayo Clinic Florida cost data warehouse based upon patient encounters and treatments. Report cost-to-charge ratios were multiplied by the charges for all hospital billed services, and all resulting costs were adjusted to 2016 dollars with the Gross Domestic Product (GDP) Implicit Price Deflator. Patients who did not receive their complete planned treatment at our facility were excluded from the cost analysis. Results Of 80 patients with high-risk DLBCL, 52 (65%) patients were treated with R-CHOP and 28 (35%) with DA.R-EPOCH. The median follow-up was 11.2 months (range: 0.7- 151.3 months). The planned treatment completion rate and complete remission rate at the end of treatment were similar in both groups. There was no significant difference in OS and PFS among the patients treated with DA.R-EPOCH compared to R-CHOP. The hazard ratio (HR) for PFS was 0.79 (95% CI- 0.28-2.29, P=0.67) and OS was 0.86 (95% CI- 0.26-2.78, P=0.80) (Figure 1). In Cox-regression analysis, low baseline albumin, ECOG performance status ≥2, above-normal LDH, high NCCN- IPI and low cumulative chemotherapy doses were associated with poor OS and PFS. Overall incidence of grade ≥ 3 neutropenia, neuropathy, and unplanned hospitalizations were similar between the two treatment groups. Patients treated with DA.R-EPOCH required more red cell transfusions during the treatment (P=0.004). The total mean cost associated with DA.R-EPOCH and R-CHOP regimens was $106,940 ± $39,351 and $58,509 ± 24,588, respectively (P<0.001). The cost associated with hospital services, laboratory testing and evaluation and management were higher in DA.R-EPCOH group compared to R-CHOP group (P<0.001) (Table 2). Conclusion Our study showed that there was no significant difference in PFS and OS of patients with DLBCL with high-risk features when treated with R-CHOP compared to DA.R-EPOCH. DA.R-EPOCH was associated with higher red cell transfusion requirement and treatment related expenses. A prospective randomized comparison is warranted between these two regimens specifically for patients with high-risk DLBCL. Disclosures No relevant conflicts of interest to declare.

Abstract Background: Clinical trials are fundamental to advance therapeutics systematically and improve patient outcomes. Despite this, enrollment on clinical trials remains dismal in the United States (US) and is a constant focus of healthcare policy. We studied distribution of clinical trials for B-cell malignancies over time across the US and unique clinical trial opportunities i.e. individual clinical trials for the given diagnosis at a site that patients may have access to participate. Methods: We abstracted data from clinicaltrials.gov for all trials that had non-Hodgkin lymphoma (NHL) or multiple myeloma (MM) as an inclusion indication between 1999-2018. Clinical trial characteristics and distribution over US geographical divisions (West, Midwest, Northeast, and South) were studied, and differences were assessed by Chi-square test. Results: A total of 1930 trials were identified (NHL: 982, MM: 948), of which 483 were recruiting at the time of data abstraction (NHL: 250, MM: 233). Over the past 2 decades, 182691 patients were enrolled on the various trials (NHL: 81592, MM: 101099). Trials by phase of study included phase 1: 629, phase 1/2: 316, phase 2: 813, phase 2/3: 11 and phase 3: 161. Number of trials by phase separated by NHL and MM are shown in Figure 1. Of these, 197 trials were randomized (NHL: 67, MM: 130). Geographical distribution of trials by diagnosis type is shown in Figure 2. A total of 31806 unique trial opportunities were noted for MM and NHL, of which 9,513 were international and 22,293 were in the US, with a geographical distribution of 5080 in West, 8198 in Midwest, 3944 in Northeast, and 5071 in South. 4,883 of the unique trial opportunities were available at NCI/NCCN accredited sites and 17,410 were at non-NCI/NCCN sites in the US. Treatment characteristics of the trials included monoclonal antibodies in 1218, other targeted agents in 2641, stem cell transplant in 526, and other agents in 517 trials with several trials utilizing more than one of these therapeutic options. There was no statistically significant difference in the distribution of clinical trials by phase of study across various US geographical regions for MM (p=0.71), NHL (p=0.98) or combined MM+NHL (p=0.16). On the other hand, unique trial opportunities were significantly different by study phase and geographical distribution for MM, NHL or MM+NHL (all p<0.001) (Figure 3). Conclusions: Widespread access to clinical trials within a cancer diagnosis is imperative for generalizability of trial results. In a comprehensive, national analysis we noted that while it may appear that clinical trials are available across the US, sites where they are open are distributed unevenly, giving rise to a disparity in access to evidence-based therapeutic advancements for patients. Disclosures Ailawadhi: Janssen: Consultancy; Amgen: Consultancy; Pharmacyclics: Research Funding; Takeda: Consultancy; Celgene: Consultancy. Sher:Affimed: Research Funding.

Abstract Abstract 1184 Lenalidomide, a second generation immunomodulatory derivative of thalidomide, has demonstrated significant clinical benefit in myelodysplastic syndrome, multiple myeloma and B-cell malignancies. Its side effects include myelosuppression, particularly neutropenia, and impaired filgrastim induced stem cell mobilization in patients with myeloma. The precise mechanism of action of lenalidomide on hematopoietic and bone marrow microenvironment remains largely unknown. In this study, we investigated the effect of lenalidomide on survival, lineage commitment and differentiation of normal purified CD34+ hematopoietic stem cells. Mobilized peripheral blood progenitor cells (PBPCs) were obtained from a normal allogeneic stem cell donor with an informed consent, and were subjected to positive selection with the EasySep magnetic cell selection system to purify CD34+ cells (purity of 95%). Unsorted and CD34- accessory cells were used as controls. To assess the direct cytotoxic and proliferative effect of lenalidomide on purified CD34+ cells, lenalidomide (Celgene, NJ) was dissolved in DMSO and was diluted in culture medium to final concentration of 0.1, 1, 10, or 100 μM. Purified CD34+, CD34- and unsorted cells were plated in triplicates at a density of 2×104/mL in serum-free StemSpan® medium supplemented with growth factors and cytokines. 24 hours after plating the cells, lenalidomide or 0.1% DMSO as control was added. 72 hours following treatment, cells were counted with Beckman coulter counter and phenotypically analyzed using Accuri C6 flow-cytometer. The percentage of viable cells was determined using 7AAD staining. While no difference in viability was noted in the treated vs. untreated purified CD34+ cells, the viability of CD34- cells and unsorted cells was reduced to 30% and 40% respectively by lenalidomide. Contrary to our assumption, lenalidomide, in a dose dependant manner, induced proliferation of purified CD34+ cells. Maximal increase in proliferation was observed between 1mM and 10mM concentrations. The rate of growth plateaued beyond the 10mM concentration and 100mM concentration appeared to have no additional effect. At the peak of growth (10mM), the cell count nearly tripled. (Fig. 1) Lenalidomide appeared to be cytotoxic to CD34- and unsorted cells in a dose dependant manner. At 100mM concentration, the CD34- cell proliferation dropped by 4 fold and the unsorted cells by 7 fold. To examine the effect of lenalidomide on the clonogenic potential of purified CD34+ cells, 2,000 cells were seeded onto MethoCult® media (Stem cell technologies) supplemented with growth factors and cytokines. Cells were cultured in the presence of lenalidomide (0.1, 1, 10 and 100 μM) or 0.1 % DMSO as control. BFU-E, CFU-GM and CFU-mix were scored on day 14 with the use of an inverted microscope and standard morphological criteria. Significance of difference between groups was determined by student's t test for paired samples. Lenalidomide induced a significant increase in clonogenic activity of CD34+ cells (148 ± 27 colonies per 103 CD34+ cells, p = 0.01), most evident at the dose of 10 μM with enhanced formation of BFU-E (102 ± 23/ per 103 CD34+ cells, p = 0.01) but demonstrated no significant impact on CFU-GM (36 ± 14 per 103 CD34+ cells, p = 0.83) compared to control. (Fig. 2) This study demonstrates that lenalidomide has pronounced effects on both CD34+ and CD34- components of mobilized PBPCs. It enhances the proliferative and clonogenic potentials of CD34+ cells with lineage commitment towards erythroid differentiation. It also has cytotoxic activity towards CD34- cells. It is likely that neutropenia and impaired mobilization of stem cells in patients treated with lenalidomide is mediated via its impact on CD34- accessory cells in the bone marrow microenvironment. Further studies exploring the impact of lenalidomide on normal bone marrow stromal cells, T and NK cell mediated signaling are needed. Disclosures: No relevant conflicts of interest to declare.

AbstractThere is an association between Helicobacter pylori infection and immune thrombocytopenia (ITP), and few studies have suggested that eradicative treatment of H. pylori infection may improve platelet counts in patients with ITP. Conventional treatments for ITP include immunosuppressive agents, and more recently thrombopoietic agents. However, based on clinical reports of association between H. pylori and ITP, several medical societies increasingly suggest detection and eradication of H. pylori as a treatment for ITP. In this article, we reappraise recent medical literature to determine the effectiveness of platelet response after treatment of H. pylori infection in patients with ITP. We searched two online databases (MEDLINE and Google Scholar) for full articles published between January 2008 and May 2018, and found a total of 11 studies that presented data and outcomes of treatment of H. pylori infection in ITP patients. All the studies administered triple therapy (amoxicillin 500 mg, clarithromycin 250 mg and a proton-pump inhibitor each given twice daily for either 7- or 14-day course) for eradication of H. pylori. Median overall platelet response ranged from 27 to 69.2% with a complete response rate ranging from 0 to 65.4% and a partial response rate ranging from 0 to 29.4%. Although there is variability in the effectiveness between different populations, it appears to be of benefit to ITP patients with concomitant H. pylori infection when treated with triple therapy. However, further studies to understand the pathogenesis of H. pylori-associated ITP is necessary for the development of new therapeutic approaches for ITP.

Adverse drug reactions can be unpredictable. However, pharmacogenomic testing can help identify patients who may be more susceptible to the toxic effects of certain drugs. Genetic variations in the dihydropyrimidine dehydrogenase and thymidylate synthase genes have been shown to increase the risk of 5-fluorouracil toxicity. 5-Fluorouracil toxicity can be life threatening. Fortunately, there is treatment available for 5-fluorouracil toxicity, called uridine triacetate. Although, the indications for its use limit its administration to within 96 h of receiving 5-fluorouracil, we report a case of effective therapy in a patient started on uridine triacetate beyond the recommended 96 h, who was found to carry a thymidylate synthase gene variation but no dihydropyrimidine dehydrogenase mutations. This provides important implications for pharmacogenomic testing.