Treatment cost and life expectancy of diffuse large B-cell lymphoma (DLBCL): a discrete event simulation model on a UK population-based observational cohort.
ABSTRACT: Diffuse large B-cell lymphoma (DLBCL) is the commonest non-Hodgkin lymphoma. Previous studies examining the cost of treating DLBCL have generally focused on a specific first-line therapy alone; meaning that their findings can neither be extrapolated to the general patient population nor to other points along the treatment pathway. Based on empirical data from a representative population-based patient cohort, the objective of this study was to develop a simulation model that could predict costs and life expectancy of treating DLBCL.All patients newly diagnosed with DLBCL in the UK's population-based Haematological Malignancy Research Network ( www.hmrn.org ) in 2007 were followed until 2013 (n = 271). Mapped treatment pathways, alongside cost information derived from the National Tariff 2013/14, were incorporated into a patient-level simulation model in order to reflect the heterogeneities of patient characteristics and treatment options. The NHS and social services perspective was adopted, and all outcomes were discounted at 3.5 % per annum.Overall, the expected total medical costs were £22,122 for those treated with curative intent, and £2930 for those managed palliatively. For curative chemotherapy, the predicted medical costs were £14,966, £23,449 and £7376 for first-, second- and third-line treatments, respectively. The estimated annual cost for treating DLBCL across the UK was around £88-92 million.This is the first cost modelling study using empirical data to provide 'real world' evidence throughout the DLBCL treatment pathway. Future application of the model could include evaluation of new technologies/treatments to support healthcare decision makers, especially in the era of personalised medicine.
Project description:Limited data are available regarding treatment patterns, healthcare resource utilization (HCRU), treatment costs and clinical outcomes for patients with diffuse large B-cell lymphoma (DLBCL) in Japan. This retrospective database study analyzed the Medical Data Vision database for DLBCL patients who received treatment during the identification period from October 1 2008 to December 31 2017. Among 6,965 eligible DLBCL patients, 5,541 patients (79.6%) received first-line (1L) rituximab (R)-based therapy, and then were gradually switched to chemotherapy without R in subsequent lines of therapy. In each treatment regimen, 1L treatment cost was the highest among all lines of therapy. The major cost drivers i.e. total direct medical costs until death or censoring across all regimens and lines of therapy were from the 1L regimen and inpatient costs. During the follow-up period, DLBCL patients who received a 1L R-CHOP regimen achieved the highest survival rate and longest time-to-next-treatment, with a relatively low mean treatment cost due to lower inpatient healthcare resource utilization and fewer lines of therapy compared to other 1L regimens. Our retrospective analysis of clinical practices in Japanese DLBCL patients demonstrated that 1L treatment and inpatient costs were major cost contributors and that the use of 1L R-CHOP was associated with better clinical outcomes at a relatively low mean treatment cost.
Project description:Autologous peripheral stem cell transplantation (ASCT) with high-dose chemotherapy is a preferred treatment for relapsed non- Hodgkin lymphoma (NHL) patients. Estimated failure rates with current stem cell mobilization (SCM) regimens are 5% to 30%. Granulocyte colony-stimulating factor (G-CSF) with plerixafor (G P) is superior to G-CSF alone for SCM in heavily pretreated NHL patients.To conduct a cost-utility evaluation of G P versus G-CSF as a method for SCM in patients with diffuse large B-cell lymphoma (DLBCL), the most common subtype of NHL.A Markov model simulated the care process of DLBCL patients undergoing ASCT using data from the Washington University site of the plerixafor phase III study. Other data and utilities were taken from the literature. Costs were Medicare allowable. Using microsimulation we estimated the incremental cost-utility ratio (ICUR) over the patient's remaining lifetime.The expected lifetime cost of providing care for DLBCL patients using G P was $25,567 more than G-CSF, but they accumulated 1.74 more quality-adjusted life-years (QALYs) for an ICUR of $14,735 per QALY. In sensitivity analyses this result was robust to clinically relevant changes in assumptions.Using G P for SCM in ASCT of patients with DLBCL meets accepted standards of cost-effectiveness, primarily because of its effectiveness in SCM.
Project description:BACKGROUND: Current treatment of diffuse-large-B-cell lymphoma (DLBCL) includes rituximab, an expensive drug, combined with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy. Economic models have predicted rituximab plus CHOP (RCHOP) to be a cost-effective alternative to CHOP alone as first-line treatment of DLBCL, but it remains unclear what its real-world costs and cost-effectiveness are in routine clinical practice. METHODS: We performed a population-based retrospective cohort study from 1997 to 2007, using linked administrative databases in Ontario, Canada, to evaluate the costs and cost-effectiveness of RCHOP compared to CHOP alone. A historical control cohort (n = 1,099) with DLBCL who received CHOP before rituximab approval was hard-matched on age and treatment intensity and then propensity-score matched on sex, comorbidity, and histology to 1,099 RCHOP patients. All costs and outcomes were adjusted for censoring using the inverse probability weighting method. The main outcome measure was incremental cost per life-year gained (LYG). RESULTS: Rituximab was associated with a life expectancy increase of 3.2 months over 5 years at an additional cost of $16,298, corresponding to an incremental cost-effectiveness ratio of $61,984 (95% CI $34,087-$135,890) per LYG. The probability of being cost-effective was 90% if the willingness-to-pay threshold was $100,000/LYG. The cost-effectiveness ratio was most favourable for patients less than 60 years old ($31,800/LYG) but increased to $80,600/LYG for patients 60-79 years old and $110,100/LYG for patients ? 80 years old. We found that post-market survival benefits of rituximab are similar to or lower than those reported in clinical trials, while the costs, incremental costs and cost-effectiveness ratios are higher than in published economic models and differ by age. CONCLUSIONS: Our results showed that the addition of rituximab to standard CHOP chemotherapy was associated with improvement in survival but at a higher cost, and was potentially cost-effective by standard thresholds for patients <60 years old. However, cost-effectiveness decreased significantly with age, suggesting that rituximab may be not as economically attractive in the very elderly on average. This has important clinical implications regarding age-related use and funding decisions on this drug.
Project description:In this study we investigated whether the expression of cyclin D2 (CCND2) mRNA in activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL) was correlated with the efficacy of Rituximab combined with chemotherapy (R-CHOP) treatment and patient prognosis. Tissue microarray and RNAscope in situ hybridization were used to detect CCND2 mRNA expression in 117 ABC-DLBCL tumor tissues and associations between CCND2 expression and progression-free survival was analyzed. We also downloaded data from the Gene Expression Omnibus database to analyze CCND2 expression and the efficacy of R-CHOP treatment and prognosis of patients with newly diagnosed ABC-DLBCL. The positive expression rate of CCND2 mRNA in patients with ABC-DLBCL was 41%. Progression-free survival was significantly lower in patients with positive rather than those negative CCND2 expression (P = 0.005). Further, R-CHOP treatment was significantly more effective for patients with ABC-DLBCL with high CCND2 mRNA expression than those with low expression (P = 0.039). Multivariate regression analysis suggested that high CCND2 expression was an independent prognostic risk factor for progression-free survival for patients with ABC-DLBCL who achieved complete remission after R-CHOP treatment. CCND2 expression in ABC-DLBCL tumors, detected by RNA in situ hybridization, is closely related to the curative effect of R-CHOP and patient prognosis following R-CHOP treatment, and represents a potential biomarker for treatment efficacy and prognostic evaluation in patients with ABC-DLBCL.
Project description:Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of lymphoma, whose treatment still has a major challenge of achieving a satisfactory curative effect. The underlying mechanisms also have not been fully illustrated. N 6-Methyladenosine (m6A) has been identified as the most prevalent internal modification of mRNAs present in eukaryotes, which is involved in the pathogenesis of cancers. It remains unclear how m6A mRNA methylation is functionally linked to the pathogenesis of DLBCL. In this study, we sought to explore the roles of METTL3 on DLBCL development. The results showed that m6A level for RNA methylation and the expression level of METTL3 were upregulated in DLBCL tissues and cell lines. Functionally, downregulated METTL3 expression in DLBCL cells inhibited the cell proliferation ability. Further mechanism analysis indicated that METTL3 knockdown abates the m6A methylation and total mRNA level of pigment epithelium-derived factor (PEDF). However, Wnt/?-catenin signaling was not thus activated. Overexpressed PEDF abrogates the inhibition of cell proliferation in DLBCL cells that is caused by METTL3 silence. In summary, the above-mentioned results demonstrated that the METTL3 promotes DLBCL progression by regulating the m6A level of PEDF.
Project description:<h4>Background</h4>Chimeric antigen receptor (CAR) T-cell therapy, which is approved for the treatment of relapsed or refractory diffuse large B-cell lymphoma (DLBCL), can be associated with potentially severe and costly neurologic adverse events (AEs).<h4>Objectives</h4>To develop an evidence-based list of treatment-related neurologic AEs in patients with relapsed or refractory DLBCL, including AEs related to CAR T-cell therapies, and to estimate the healthcare costs associated with these neurologic AEs in a real-world setting.<h4>Methods</h4>We identified grade ?3 neurologic AEs that occurred in ?2% of patients by reviewing drug prescribing information and published clinical trials with therapies used for relapsed or refractory DLBCL. Data from 3 nationally representative claims databases were used to identify adults with relapsed or refractory DLBCL, who were eligible for the study if they received 1 of 4 types of therapy, including CAR T-cell therapy, high-intensity cytotoxic therapy, low-intensity cytotoxic therapy, or targeted therapies. The rates of neurologic AEs and total healthcare costs were calculated for patients with and without neurologic AEs within 30 days of treatment. The costs were inflated to 2019 first-quarter US dollars.<h4>Results</h4>A total of 16 types of neurologic AEs were identified, including 13 events related to CAR T-cell therapy and 5 related to conventional immunochemotherapy regimens, with 2 overlapping event types. Of these AEs, 11 were included in the claims analysis, based on available diagnosis codes. Of the 11,098 adults with relapsed or refractory DLBCL in the study, 118 patients received CAR T-cell therapy, 9483 received a high-intensity cytotoxic therapy, 1259 received a low-intensity cytotoxic therapy, and 238 received a targeted therapy. A total of 299 (2.7%) patients had ?1 neurologic AEs during the 30-day postindex period. Of these patients, 43 received CAR T-cell therapy (36.4% of the 118 CAR T-cell therapy users). The mean total healthcare cost was $71,982 higher for patients with neurologic AEs than for patients without neurologic AEs. The trend of higher costs in patients with neurologic AEs was consistent across the treatment groups and was most pronounced in CAR T-cell therapy users ($143,309; 95% confidence interval, $5838-$280,779).<h4>Conclusion</h4>Patients with relapsed or refractory DLBCL who had severe or life-threatening neurologic AEs incur substantially higher costs than their counterparts who do not have neurologic AEs, with the largest cost difference in patients who receive CAR T-cell therapy.
Project description:Diffuse large B-cell lymphoma (DLBCL) is the most common form of lymphoma in adults. The disease exhibits a striking heterogeneity in gene expression profiles and clinical outcomes, but its genetic causes remain to be fully defined. Through whole genome and exome sequencing, we characterized the genetic diversity of DLBCL. In all, we sequenced 73 DLBCL primary tumors (34 with matched normal DNA). Separately, we sequenced the exomes of 21 DLBCL cell lines. We identified 322 DLBCL cancer genes that were recurrently mutated in primary DLBCLs. We identified recurrent mutations implicating a number of known and not previously identified genes and pathways in DLBCL including those related to chromatin modification (ARID1A and MEF2B), NF-κB (CARD11 and TNFAIP3), PI3 kinase (PIK3CD, PIK3R1, and MTOR), B-cell lineage (IRF8, POU2F2, and GNA13), and WNT signaling (WIF1). We also experimentally validated a mutation in PIK3CD, a gene not previously implicated in lymphomas. The patterns of mutation demonstrated a classic long tail distribution with substantial variation of mutated genes from patient to patient and also between published studies. Thus, our study reveals the tremendous genetic heterogeneity that underlies lymphomas and highlights the need for personalized medicine approaches to treating these patients. 21 DLBCL cell lines and 70 DLBCL patient samples.
Project description:Some patients with B-cell non-Hodkin lymphoma Lymphoma (NHL) become refractory to rituximab (anti-CD20 antibody) therapy associated with chemotherapy. Here, the effect of the anti-CD37 antibody-radionuclide conjugate lutetium-177 (177Lu)-lilotomab (Betalutin®) was investigated in preclinical models of NHL. In SCID mice bearing DOHH2 (transformed follicular lymphoma, FL) cell xenografts, 177Lu-lilotomab significantly delayed tumor growth, even at low activity (100?MBq/kg). In athymic mice bearing OCI-Ly8 (diffuse large B-cell lymphoma, DLBCL) or Ramos (Burkitt's lymphoma) cell xenografts, 177Lu-lilotomab activity had to be increased to 500?MBq/kg to show a significant tumor growth delay. Clonogenic and proliferation assays showed that DOHH2 cells were highly sensitive to 177Lu-lilotomab, while Ramos cells were the least sensitive, and U2932 (DLBCL), OCI-Ly8, and Rec-1 (mantle cell lymphoma) cells displayed intermediate sensitivity. The strong 177Lu-lilotomab cytotoxicity observed in DOHH2 cells correlated with reduced G2/M cell cycle arrest, lower WEE-1- and MYT-1-mediated phosphorylation of cyclin-dependent kinase-1 (CDK1), and higher apoptosis. In agreement, 177Lu-lilotomab efficacy in vitro, in vivo, and in patient samples was increased when combined with G2/M cell cycle arrest inhibitors (MK-1775 and PD-166285). These results indicate that 177Lu-lilotomab is particularly efficient in treating tumors with reduced inhibitory CDK1 phosphorylation, such as transformed FL.
Project description:The activation of oncogenes can reprogram tumor cell metabolism. Here, in diffuse large B-cell lymphoma (DLBCL), serum metabolomic analysis revealed that oncogenic MYC could induce aberrant choline metabolism by transcriptionally activating the key enzyme phosphate cytidylyltransferase 1 choline-? (PCYT1A). In B-lymphoma cells, as a consequence of PCYT1A upregulation, MYC impeded lymphoma cells undergo a mitophagy-dependent necroptosis. In DLBCL patients, overexpression of PCYT1A was in parallel with an increase in tumor MYC, as well as a decrease in serum choline metabolite phosphatidylcholine levels and an International Prognostic Index, indicating intermediate-high or high risk. Both in vitro and in vivo, lipid-lowering alkaloid berberine (BBR) exhibited an anti-lymphoma activity through inhibiting MYC-driven downstream PCYT1A expression and inducing mitophagy-dependent necroptosis. Collectively, PCYT1A was upregulated by MYC, which resulted in the induction of aberrant choline metabolism and the inhibition of B-lymphoma cell necroptosis. Referred as a biomarker for DLBCL progression, PCYT1A can be targeted by BBR, providing a potential lipid-modifying strategy in treating MYC-High lymphoma.
Project description:Canine diffuse large B-cell lymphoma (DLBCL) is a common and aggressive hematologic malignancy. The lack of conventional therapies with sustainable efficacy warrants further investigation of novel therapeutics. The Janus kinase (JAK) and signal transducer and activator of transcription (STAT) pathways play important roles in the pathogenesis of hematologic malignancies in humans including DLBCLs. AZD1480 and CYT387 are novel JAK1/2 inhibitors that have been used in clinical trials for treating various hematologic cancers in humans. No studies have characterized the antitumor effects of JAK inhibitors on DLBCL in dogs.We hypothesize that JAK1/2 inhibitors AZD1480 and CYT387 can effectively inhibit growth of canine DLBCL in vitro. We aim to assess the antitumor activity of AZD1480 and CYT387 in canine DLBCL and to determine the underlying mechanisms of action.In vitro study of canine lymphoma cell growth, proliferation, and apoptosis by viability, proliferation and apoptosis assays.A significant decrease in viable canine lymphoma cells was observed after AZD1480 and CYT387 treatments. In addition, AZD1480 and CYT387 treatment resulted in decreased lymphoma cell proliferation and increased early apoptosis.AZD1480 and CYT387 inhibit canine lymphoma cell growth in a dose-dependent manner. Our findings justify further phase I/II clinical investigations of the safety and efficacy of JAK1/2 inhibitors in canine DLBCL and suggest new opportunities for novel anticancer therapies.