R-CHOP In Diffuse Large B-cell Lymphoma Research Articles

Real-world cost of disease progression (PD) after frontline (1L) R-CHOP in diffuse large B-cell lymphoma (DLBCL): An analysis of a large US claims database.

e19036 Background: Previous studies on the cost of PD in DLBCL do not reflect evolving standards of care and contain limited data on novel therapies in the relapsed/refractory setting. Here, we evaluated the cost of DLBCL PD after 1L therapy using recently available data from a US healthcare database of largely commercial health plan claims. Methods: Using previously published methods (Burke, et al. 2023), this retrospective cohort study analyzed data from IQVIA PharMetrics Plus. Patients (pts) with DLBCL receiving 1L therapy with R-CHOP between October 2016 and March 2021 were included. Index date was defined as a ≥60-day gap in treatment or initiation of new agents. Pts who received non-R-CHOP therapy after 1L were assigned to the ‘PD cohort’ and those not receiving second-line (2L) treatment for ≥2 years to the ‘no PD’ cohort. All pts had continuous enrollment in medical and pharmacy benefits from R-CHOP initiation to ≥2 years post index date, allowing time for post-1L relapse. Unadjusted all-cause healthcare costs per-patient-per-month (PPPM) and 3-year cumulative costs (2023 USD) were compared between cohorts. Generalized linear models were used to adjust for baseline characteristics including age, gender, US region, payer type, Charlson Comorbidity Index (CCI), index year, and healthcare costs 1 year before index date. Results: Overall, 824 pts were included (PD cohort, n=156; no PD cohort, n=668); mean follow-up was 41.6 months. In the overall cohort: 41% were female; and at index mean (SD) age was 58.6 (11.8) years and CCI (non-cancer comorbidity) was 2.5 (3.0). Baseline characteristics were generally similar between cohorts. In the PD cohort, 76 pts (48.7%) had multiple relapse events (3L+), 67 (42.9%) received stem-cell transplant, and 27 (17.3%) received chimeric antigen T-cell therapy (CAR-T). Adjusted mean PPPM cost was higher among the PD than no PD cohort ($11,432 vs $1,698, respectively; p<0.001). A major cost driver was inpatient cost (40.1% and 21.6% of total cost for PD and no PD cohort, respectively). Treatments with CAR-T in the PD cohort were associated with an 18-fold increase in PPPM cost vs the no PD cohort ($29,794 vs $1,689, respectively; p<0.001), and a 4-fold increase vs pts with PD who did not receive CAR-T ($7,829; p<0.001). Adjusted 3-year cumulative costs were higher in the PD ($456,045) vs no PD ($60,519) cohort. Conclusions: Compared with a previous analysis on cost of PD after 1L R-CHOP in DLBCL (2010–2018; Burke, et al. 2023), this updated analysis indicates the cost is considerable, especially among pts receiving CAR-T in later lines, and is increasing, likely due to increasing utilization of novel, more expensive therapies. 1L treatments that prevent or delay relapse could thus reduce the economic burden of PD. Our findings are of use in determining the economic value of emerging 1L options that can successfully reduce the risk of relapse.

Impact of the Mexican Healthcare Reform on Optimal Treatment Delivery, Survival, and Response Rates Among a Cohort of Patients with Diffuse Large B Cell Lymphoma in a Single National Reference Institution

Introduction: The creation of Seguro Popular (SP) in Mexico, back in 2003, was the first step towards creating a universal healthcare system. After it was implemented, there was a 4-times boost in health spend and the creation of the Protection Fund Against Catastrophic Expenses, a fund meant for covering the costs of illnesses with a high financial burden, such as most cancers. As of January 2020, the Health Institute for Wellbeing (INSABI, Spanish acronym) has taken its place with promises to provide free health coverage for everyone. This scheme has been accompanied by multiple shortages of cancer medications due to its lack of planning and budget allocation. As a consequence, a proportion of lymphoma patients haven't been able to receive full treatment regimens. Our study aims to identify differences in survival and response rates among patients with diffuse large B cell lymphoma (DLBCL) receiving R-CHOP as first line treatment under SP and INSABI, in the National Cancer Institute (INCan) in Mexico City. Methods: This is a retrospective study where two groups with histologically documented DLBCL were compared. Group A consisted of a cohort of adult patients treated at INCan from 2011 to 2018 under the SP scheme, receiving full funding for diagnostic approach and treatment with R-CHOP as first line therapy. Group B consisted of a cohort of adult patients treated at INCan from 2020 to 2021 under INSABI's gratuity policy, receiving R-CHOP as first line therapy. Variables collected included sex, age at diagnosis, comorbidities, B-symptoms, molecular subtype, stage, bulky disease, and IPI, among others. Optimal treatment was evaluated and defined as the proportion of patients who received full drugs' dosage according to the recommendation of the attending physician. Response was assessed with 18F-FDG PET-CT according to the Lugano classification, and was defined as the proportion of patients with complete remission (CR) for all patients evaluable for response. Event free survival (EFS) was defined as time to relapse or progression during treatment. Overall survival (OS) was defined as time to death in years from the date of primary diagnosis. The significance of variation in the distribution of outcomes with healthcare regime (SP, INSABI) was assessed with Pearson's Chi-square tests or Fisher's Exact test as appropriate. Survival distributions were done with Kaplan-Meier methodology. Cox regression analysis was used to evaluate factors influencing on relapse rate and survival. All statistical testing was two sided and differences between groups were regarded as significant for p values <0.05. Results: Group A consisted of 505 patients, 258 were female (51%), with a mean age of 55.5 ± 13.6 years. Group B consisted of 169 patients, 94 were female (55%), with a mean age of 55.9 ± 12.7 years. Other demographic and clinical prognostic factors were similar in both groups, as shown in table 1. While both groups received treatment in 100%, 14.2% patients in group A received diminished doses of chemotherapy due to attending physicians' criteria, no other causes of dose modifications were found. In group B, 11.2% of patients received diminished doses of chemotherapy due to medical reasons as indicated by attending physicians, while 33.7% of patients received diminished doses of chemotherapy due to drug shortages. Overall response rate (ORR) for group A was 82.7%, while for group B was 73% (p = 0.05). CR for group A was 75.2%, and for group B was 60.4% (p = 0.00). Progression rate for group A was 14.8%, while for group B was 13%; relapse rate for group A was 14.6%, while for group B was 12.4%, not statistically significant (p = 0.5). EFS for group A was 85.3% and for group B was 87.6%, while OS for group A was 75.8% and for group B was 78.1%. Conclusion: Our study shows important differences in optimal treatment delivery for first-line R-CHOP in DLBCL during the INSABI era, compared to the SP era. Under the SP regime, the only reason for diminishing chemotherapy doses were medical reasons, usually in relation to cardiac comorbidities or patient's performance status. During the INSABI era, drug shortages account for incomplete treatment delivery in 33.7% of the cases. After Cox regression analysis, the administration of an optimal treatment was a factor that tends to influence EFS (p = 0.34). However, a longer follow-up time and further research is needed to assess the long term effects of the incomplete chemotherapy administration in group B.

Mutation profiling of circulating tumor DNA identifies distinct mutation patterns in non-Hodgkin lymphoma.

Circulating tumor DNA (ctDNA) is emerging as a versatile biomarker for noninvasive genotyping and response monitoring in specific B-cell lymphomas; however, few studies have been conducted to explore ctDNA-based mutation profiling across non-Hodgkin lymphomas (NHLs) and genomic changes after initiation of chemotherapy. A targeted sequencing of 362genes was performed to detect the mutation profiles in paired blood and tissue samples from 42NHL patients. Genomic alterations were explored in 11 diffuse large B-cell lymphoma (DLBCL) patients using paired blood samples collected pre- and post-R-CHOP chemotherapy. The frequencies of PIM1, MYD88, MYC, ZNF292, JAK, and MAF mutations were higher in aggressive than in indolent B-cell lymphoma and NK/T subtypes. Tumor mutation burden in blood samples was higher in aggressive than in indolent B-cell lymphomas and higher in patients who progressed than in those who responded to treatments. Our data also revealed significant enhance of concordance index through integrating mutated genes that were significantly associated with prognosis into International Prognostic Index-based prognostic model. Moreover, acquisition of mutations such as PCLO_p.L1220Tfs*3 was associated with resistance to R-CHOP in DLBCL patients. Our findings illustrated distinct mutation patterns across various NHL subtypes and suggested the association of genomic alterations in ctDNA with treatment outcomes.

Safety and Efficacy of Induction and Maintenance Avelumab Plus R-CHOP in Patients with Diffuse Large B-Cell Lymphoma (DLBCL): Analysis of the Phase II Avr-CHOP Study

Safety and Efficacy of Induction and Maintenance Avelumab Plus R-CHOP in Patients with Diffuse Large B-Cell Lymphoma (DLBCL): Analysis of the Phase II Avr-CHOP Study

Activity of ibrutinib plus R-CHOP in diffuse large B-cell lymphoma: Response, pharmacodynamic, and biomarker analyses of a phase Ib study

IntroductionThis unplanned post-hoc analysis was based on data from the phase Ib DBL1002 study (NCT01569750) and evaluated the association between molecular biomarkers and clinical response to combined treatment with ibrutinib plus rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in diffuse large B-cell lymphoma (DLBCL) subtypes. MethodsDLBCL subtyping was conducted using immunohistochemistry. Next-generation sequencing using immunoglobulin H primers assessed minimal residual disease (MRD). A quantitative assay evaluated Bruton's tyrosine kinase (BTK) occupancy by ibrutinib in peripheral blood mononuclear cells. Targeted DNA sequencing examined genetic variants by DLBCL subtype. Secreted protein expression was evaluated with a SomaLogic analyte panel. ResultsAmong 21 patients with DLBCL (median age 53.5 years), 17 achieved a complete response (CR) and 4 a partial response (PR). Of the 11 subtyped patients, 9 had a CR (5/7 germinal center B-cell–like [GCB] and 4/4 non-GCB) and 2 had a PR (both GCB). Nine of 12 patients tested for MRD achieved early (cycle 2 day 1) MRD negativity; most had a CR. There was near-complete BTK occupancy at 4 h postdose. Mutation analysis (n = 19) revealed variants including CREBBP, KMT2D, LRP1B, BCL2, and TNFRSF14; only 1 CD79B and TP53 each; no CARD11 or MYD88. ConclusionsIn this study, first-line ibrutinib plus R-CHOP benefited patients with DLBCL, with good overall response rate and early MRD negativity. With a caveat of small sample size, our results showed that a favorable genetic profile and younger patient age may be important to beneficial clinical outcome with ibrutinib plus R-CHOP in DLBCL.

Potential Factors That Impact Lenalidomide/R-CHOP Efficacy in Previously Untreated Diffuse Large B-Cell Lymphoma in the ROBUST and ECOG-ACRIN 1412 Studies

Potential Factors That Impact Lenalidomide/R-CHOP Efficacy in Previously Untreated Diffuse Large B-Cell Lymphoma in the ROBUST and ECOG-ACRIN 1412 Studies

The lower peripheral blood lymphocyte/monocyte ratio assessed during routine follow-up after standard first-line chemotherapy is a risk factor for predicting relapse in patients with diffuse large B-cell lymphoma

A specific predictor during routine follow-up to ascertain risk for relapse after standard first-line chemotherapy in non-Hodgkin's lymphoma (NHL) has not been identified, although blood counts, lactate dehydrogenase (LDH) and imaging studies, such as computed tomography (CT) scans or positron emission tomography, have been recommended. Therefore, we studied the absolute lymphocyte count/absolute monocyte count ratio (ALC/AMC ratio) as a marker of poststandard first-line chemotherapy for predicting relapse in patients with diffuse large B-cell lymphoma (DLBCL). 220 consecutive DLBCL patients, originally diagnosed, treated with CHOP or R-CHOP and followed up at two institutions. ALC/AMC ratio was obtained at the time of confirmed relapse or last follow-up. Patients at the time of confirmed relapse (n = 163) had a lower ALC/AMC ratio compared with those at last follow-up (n = 57) (P < 0.001). ALC/AMC ratio at the time of confirmed relapse was a strong predictor for relapse with an area under the curve = 0.813 (P < 0.001). The sensitivity and specificity for ALC/AMC ratio at the time of confirmed relapse or at last follow-up were 68.1% and 87.7%, respectively, and the relative risk of relapse with an ALC/AMC ratio < 2.8 at the time of confirmed relapse or at last follow-up was 1.845 with an odds ratio of 15.247 (95% cumulative incidence: 6.473-35.916) after CHOP or R-CHOP in DLBCL. Patients with an ALC/AMC ratio (< 2.8) had a higher cumulative hazard rate of relapse compared with an ALC/AMC ratio (≥2.8) (P < 0.001). This study suggests that the lower ALC/AMC ratio can be used as a marker to assess risk of DLBCL relapse during routine follow-up after standard first-line chemotherapy.

Long term results of a phase 2 study of vincristine sulfate liposome injection (Marqibo®) substituted for non‐liposomal vincristine in cyclophosphamide, doxorubicin, vincristine, prednisone with or without rituximab for patients with untreated aggressive non‐Hodgkin lymphomas

Vincristine sulfate liposome injection (VSLI; Marqibo(®) ; M) is active in relapsed and refractory lymphomas, and approved in the United States for relapsed and refractory adult acute lymphocytic leukaemia. We evaluated VSLI (2·0 mg/m(2) without dose cap) substituted for non-liposomal vincristine (VCR) in a cyclophosphamide, doxorubicin, vincristine, prednisone ± ritiximab (CHOP±R) regimen, creating CHMP±R in 72 untreated, aggressive non-Hodgkin lymphoma patients, including 60 with diffuse large B-cell lymphoma (DLBCL). The overall response rate was 96% (69/72) including complete response (CR) in 65 (90%) and unconfirmed CR in 2 (3%). Median progression-free survival (PFS) and overall survival (OS) were not reached at median follow-up of 8 and 10·2 years, respectively. The 5- and 10-year PFS and OS were 75%, 63%, 87%, and 77%, respectively. Despite VSLI exposure of up to 35 mg, the safety profile of CHMP±R was comparable to that reported for CHOP±R. Grade 3 peripheral neuropathy was reported in 2 (3%) patients; there was no reported Grade 3/4 constipation. CHMP±R was highly active, generally well tolerated, and compared favourably to historical trials with R-CHOP in DLBCL. This enhanced activity probably reflects VCR dose intensification, pharmacokinetic optimization, and enhanced delivery afforded by VSLI. A Phase 3 trial of R-CHMP versus R-CHOP in elderly patients with untreated DLBCL is ongoing.

The Addition of Bevacizumab to Standard Therapy with R-CHOP in Patients with Previously Untreated Diffuse Large B-Cell Lymphoma Is Associated with an Increased Rate of Cardiac Adverse Events: Final Analysis of Safety and Efficacy Outcomes From the Placebo-Controlled Phase 3 MAIN Study

Abstract 58 Vascular endothelial growth factor (VEGF) is involved in lymphoma growth, suggesting a potential therapeutic role for anti-VEGF therapies. This randomized, placebo (PBO)-controlled, double-blind, multicenter, phase 3 trial (MAIN study) evaluated if adding the anti-VEGF antibody bevacizumab (Bev) to standard R-CHOP therapy improves outcomes for patients (pts) with previously untreated CD20+ diffuse large B-cell lymphoma (DLBCL). The study was designed to detect a 27% reduction in the risk of a progression-free survival (PFS) event (Hazard ratio [HR] = 0.73, R-CHOP + Bev vs R-CHOP). Pts with DLBCL (IPI score ≥2 or bulky disease, ≥7.5 cm irrespective of IPI) and normal cardiac function were randomized (1:1) to receive Bev or PBO + site pre-specified immunochemotherapy (8 cycles R-CHOP-21 or 6 cycles R-CHOP-14 followed by 2 cycles R). R-CHOP-21 & R-CHOP-14 cohorts received Bev at 15 mg/kg q21d & 10 mg/kg q14d, respectively. Response was assessed at the end of induction; pts achieving complete remission continued Bev monotherapy (15 mg/kg q21d, up to 1y from study start, Bev arm) or observation (PBO arm). To observe the required 326 events the planned sample size was 1060 pts followed for 60 mo. The protocol specified strict cardiac monitoring; left ventricular ejection fraction (LVEF) was measured at baseline (bl), after 4 & 8 cycles of therapy, and at 1y. LVEF adverse events (AEs) were defined as a ≥20% absolute decline from bl and/or a decline of ≥10% from bl to As part of ongoing serial safety monitoring, in May 2010 the independent Data and Safety Monitoring Board (DSMB) observed an increased number of LVEF AEs in the Bev arm. Given a low probability of the study meeting the primary efficacy endpoint, the DSMB concluded an unfavorable benefit–risk profile for pts treated with R-CHOP + Bev. Therefore, Bev treatment was immediately discontinued and further enrollment stopped. The study was revised and completed as a safety-oriented follow-up of the enrolled pts. The final analysis included 787 pts (enrolled 7/07 to 6/10) who were followed until 12 mo after the last pt had received the last dose of chemotherapy. Study arms were balanced for age, gender, planned chest irradiation, history of hypertension, cardiac risk factors, and bl LVEF. Efficacy of R-CHOP was not significantly affected by the addition of Bev; median PFS was 42.9 (PBO) vs 40.2 mo (Bev) (HR = 1.09, P =.49). While survival data are immature, no difference was evident (deaths 83/397 [20.9%] PBO vs 82/390 [21%] Bev). Pts in the Bev arm vs the PBO arm had higher rates of LVEF (18.0 vs 8.0%; OR 2.51, 95% CI [1.60;3.93], respectively) and CHF AEs (16.2 vs 6.5%; OR 2.79; 95% CI [1.72;4.54], respectively). Further analysis of CHF AEs by treatment and age group indicated that pts ≥65y had a higher rate than younger pts; both in the Bev arm (20.0 vs 14.0%) and PBO (9.3% vs 4.7%). Incidence of CHF AEs varied according to backbone regimen and in the Bev arm was 16.8% (R-CHOP-21) and 13.8% (R-CHOP-14), and in the PBO arm was 4.6% (R-CHOP-21) and 13.8% (R-CHOP-14). As this was an unplanned analysis on a non-randomized pt population an imbalance of relevant bl features was observed (e.g. age and race composition). CHF events began to increase (determined by Kaplan–Meier analysis) at a cumulative doxorubicin dose of 200 mg/m2 and above in both treatment arms, and increased further at a cumulative doxorubicin dose ≥300 mg/m2 in the Bev arm vs. the PBO arm. Pts in the PBO arm were more likely to resolve their CHF events without sequelae (by investigators reporting, 77.8% in PBO arm vs 63.2% in Bev arm), and also had fewer unresolved CHF events (14.8% vs 20.6%). Fatal CHF AEs were comparable in both arms (1/386 vs 2/395). In conclusion, this study demonstrates that the addition of Bev to R-CHOP is associated with an increased risk of LVEF/CHF events in pts with DLBCL. Following the DSMB recommendation, recruitment was stopped and Bev was discontinued. Data suggest that, regardless of randomization CHF risk is increased for pts ≥65 y of age, and the addition of Bev increases the cardiac toxicity rate of doxorubicin. The current data do not support further evaluation of Bev with R-CHOP in DLBCL. Disclosures: Seymour:Roche/Genetech: Honoraria. Off Label Use: The addition of bevacizumab to standard therapy with R-CHOP in patients with previously untreated diffuse large B-cell lymphoma. Pfreundshuh:Roche: Consultancy, Research Funding; Celgene: Consultancy; Pfizer: Consultancy; Mundi Pharma: Consultancy; Onyx: Consultancy; Amgen: Research Funding. Coiffier:Roche: Consultancy. Trneny:Roche: Consultancy, Honoraria, Research Funding. Sehn:Roche: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding. Csinady:Roche: Employment.