For Follicular Lymphoma Patients Research Articles

The Outcome of the First-Line Therapy of Patients with Follicular Lymphoma during COVID-19 Pandemic. a Real-World Data from the Polish Lymphoma Research Group (PLRG)

Introduction: Anti-CD20 antibody plus chemotherapy is one of the standard treatments for follicular lymphoma (FL) patients in need of therapy. Obinutuzumab-based regimens demonstrated improved progression- free survival (PFS) compared to rituximab plus chemotherapy (NCT01332968). Recently, the course of treatment of FL patients was disrupted by the COVID-19 pandemic due to immunosuppressive nature of therapy, in particular, of the maintenance treatment with the anti-CD20 antibody. Patients and Methods: We report on the results of obinutuzumab combined with different chemotherapy induction regimens in consecutive FL patients who started treatment at hemato-oncology centers in Poland between August 2018 and December 2022. The choice of chemotherapy (CVP, CHOP or bendamustine) was left to the discretion of the centre providing the treatment. Obinutuzumab maintenance was given to patients who achieved at least partial response (PR) after induction immunochemotherapy. Patients, who developed signs or symptoms suggesting acute COVID-19 infection were tested for the presence of SARS-COV 2. In other cases tests were performed according to local policy. The response was evaluated with computed tomography or positron emission tomography according to Lugano 2014 Criteria. Chi-square test was used to compare percentages. Survival analyses were based on the Kaplan-Meier method. Results: The study group included 257 treatment-naive FL patients. The median age (range) was 55 (27-89) years, 42.4% of patients were males. 65.0% (n=167) of patients had comorbidities. According to FLIPI 47.1% of patients were classified as high risk, 33.9% as intermediate and 19.1% as low risk, whereas 39.5%, 23.2% and 37.3% of patients were in PRIMA PI high, intermediate and low risk groups, respectively. Median number of GELF criteria was 3 (range 0-9). Induction chemotherapy included: CVP in 52.1% (n=134), CHOP in 33.1% (n=85) and bendamustine in 14.8% (n=38) of patients. Median number of cycles was 6 (range 1 - 8). After induction immunochemotherapy complete response (CR), PR, stable disease (SD) and progression disease (PD) rates were: 66.0%, 29.6%, 0.4% and 4.0%, respectively. Maintenance treatment was given to 217 patients (85.1%). Progression within 2 years of the start of treatment (POD24) occurred in 5.8% (n=15) of patients. With a median follow up of 23.7 months, 7.4% patients (n=19) relapsed, 13.2% of patients died (n=34). Death was caused by COVID-19 in 20, and by other infection in 2 cases. Three patients died from FL, 2 patients - due to other malignancy, and one each from myocardial infarction and treatment toxicity. Cause of death was unknown in five cases. The SARS-CoV-2 infection was detected in 125 patients with no apparent relation to the type of chemotherapy regimen (p=0.762). COVID-19 severity was unknown in 8.1% (n=9) and defined by investigators as asymptomatic in 23.4% (n=26), mild in 44.1% (n=49), severe 19.8% (n=22) and critical in 4.5% (n=5). The highest increase in the number of COVID-19 occurred in the first six months of 2022. 13.8% of patients (n=17) had SARS-COV-2 infection prior to immunochemotherapy, 28.5% (n=35) during induction immunochemotherapy, 53.7% (n=66) during maintenance, and 4.1% (n=5) after completion of the treatment. 3-year OS and PFS was 84% (95%CI: 78%-90%) and 74% (95%CI: 66% - 82%), respectively (Figure 1AB). 3-year OS of patients without COVID-19 was 92% (95%CI: 87% - 98%), while 3-year OS of patients with COVID-19 was 78% (95%CI: 69% - 88%) (p = 0.007), (Figure 1C). Conclusions: The survival of our real-world series of patients treated with obinutuzumab-based regimens was apparently worse than in the original study. These results may have been influenced by more prevalent high and intermediate risk factors, high tumor burden, as well as high frequency of SARS-COV 2 infection in our group of patients. OS was particularly lower among patients who had symptomatic COVID disease . These results seem to support a recommendation to initiate treatment in strictly symptomatic FL patients only, even if they formally meet GELF criteria. In the context of COVID-19 pandemic, CVP or CHOP might be preferred over more immunosuppressive bendamustine, and obinutuzumab maintenance treatment should be considered with caution as appropriate.

Prognostic value of interim 18F-FDG PET/CT in adult follicular lymphoma treated with R-CHOP.

The prognostic value of interim 18F-FDG PET/CT (I-PET) for follicular lymphoma (FL) is controversial, and may be related to the lack of strict standards in terms of age, chemotherapy regimen, and evaluation criteria in previous studies. This study aimed to investigate the prognostic value of I-PET in adult FL patients treated with R-CHOP. I-PET was performed in 30 adult FL patients after treatment with 3-5 cycles of R-CHOP. PET/CT images were assessed using the Deauville 5-point scale (D-5PS) criteria. Baseline PET/CT (B-PET) was performed in 24 of the patients with FL before treatment. The PET/CT image parameters, such as the SUVmax, TLG, and tMTV, were recorded. The prognostic values of sex, age, grade, Ann Arbor stage, LDH level, and I-PET were evaluated. Kaplan-Meier analysis and Cox regression showed that sex, age, grade, Ann Arbor stage, LDH, and I-PET using the D-5PS criteria could not predict the PFS of adult patients with FL treated with R-CHOP (P>0.05). ROC curve analysis evaluated the predictive values of SUVmax, TLG, and tMTV in B-PET and I-PET and showed that none of them was predictive of PFS in adult FL patients (P>0.05). However, the variation in SUVmax (∆SUVmax) was predictive of PFS in adult FL patients (AUC=0.83, P=0.040), and the cutoff threshold was 4.85. I-PET using the D-5PS criteria cannot predict the PFS of adult FL patients treated with R-CHOP. However, the ∆SUVmax between B-PET and I-PET is applicable for the prognosis of adult patients with FL.

Impact of Coronavirus (COVID-19) Pandemic on Maintenance Therapy for Follicular Lymphoma (FL) and Mantle Cell Lymphoma (MCL)

Introduction Rituximab maintenance after frontline treatment has significantly improved progression-free survival (PFS) in follicular lymphoma (FL) and PFS and overall survival (OS) in mantle cell lymphoma (MCL). Patients with hematologic malignancies are at higher risk of morbimortality from COVID-19, particularly those with B-cell NHL treated with immunochemotherapy (ICT) including anti-CD20 MoAbs which, in addition, deeply impair the seroconversion rate after vaccination. The aims of our study were to explore the incidence and severity of the COVID-19 pandemic in patients with FL and MCL receiving anti-CD20 maintenance infection and their seroconversion rate. Patients and Methods We retrospectively reviewed all patients diagnosed with FL and MCL from March 2020 to March 2022, treated upfront (1L) and eligible for maintenance therapy with rituximab or other anti-CD20 MoAb in 6 tertiary centers from March 2020 to March 2022. Patients starting maintenance therapy, either starting it during the study period or already on treatment by March 2020 were included in the "maintenance” group and compared with those not receiving maintenance. The severity of the COVID-19 infection was graded according to the need for either hospitalization or intensive unit care (ICU) care. Seroconversion rate was assessed according to the positivity of antibodies titer. Results Out of 253 patients included in the study (205 with FL and 48 with MCL), 230 (91%) received maintenance, whereas 23 (9%) did not. The reasons for not receiving maintenance were progressive disease in 3 cases (13%) and physician's decision based on advanced age, comorbidities or COVID-related conditions in the remaining 20 patients. Median age for the overall cohort was 60 years, but patients not receiving maintenance were older (69 vs. 59 years, p=0.036). One hundred and twenty-seven (49%) were female and 27 (11%) had limited stage disease. FLIPI was categorized as intermediate risk for most (67%) FL patients and MIPI as high-risk for most (58%) MCL. Risk categories in both diseases were well balanced between maintenance and non-maintenance. Induction treatment was CHOP-based in 213 patients (84%), bendamustine-based in 25 (10%) and other regimens in 15 patients (6%), all of them in combination with an anti-CD20 MoAb. After induction, 194 patients (77%) attained a complete response (CR), 55 (22%) a partial response (PR) and 4 patients (1%) progressive disease (PD). Twenty-four patients (9%) received consolidation with autologous stem cell transplantation (ASCT) after 1L. Temporary interruptions or dose delays during maintenance due to COVID-19 infection or vaccination were reported in 99 cases (39%) and definitive suspension in 50 (20%) patients. COVID-19 infection was diagnosed in 101 patients (40%), of which 49 (48.5%) were hospitalized due to severe COVID-19 infection and 10 patients (10%) of all those admitted requiring ICU care. No significant differences in either infection rate or severity were observed between maintenance and non-maintenance patients. Up to 227 patients (90%) were vaccinated against SARS-CoV2, most of them receiving ≥3 doses (72% of FL and 90% of MCL), being Spikevax™ (Moderna) being the most frequent brand used. The seroconversion rate was 23% in the overall cohort, with a trend to higher seroconversion rate in patients not receiving maintenance (39% vs. 22%). With a median follow-up of 16.3 months, 38 patients (15%) have relapsed (31 FL and 7 MCL) and 23 (9%) patients have died due to COVID-19 pneumonia (12 patients [5%], 9/230 in the maintenance group, and 3/23 in the non-maintenance group), causes related to lymphoma (4 patients) and other causes (7 patients). Conclusions Despite immunochemotherapy being associated with a higher risk of COVID-related complications, neither the rate nor severity of COVID-19 infection were higher in the group of maintenance with anti-CD20 MoAbs in comparison with the patients not receiving maintenance. Nevertheless, a trend to a lower seroconversion rate after vaccination was observed in the maintenance group. COVID-19 infection caused treatment delays in 40% and suspensions in 20% of patients receiving maintenance therapy. Modifications in maintenance due to COVID-19 infection could have long-term consequences on the course of these diaseases, especially in the case of MCL patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Lifetime Costs for Treated Follicular Lymphoma Patients in the US

The objective of this study was to estimate the lifetime costs of patients receiving treatment for follicular lymphoma (FL) in the United States. A Markov model was programmed in hēRo3 with a 6-month cycle length, 35-year time horizon (lifetime projection), and health states for line of treatment, response, receipt of maintenance therapy among responders, transformation to diffuse large B-cell lymphoma (DLBCL), development of second primary malignancy (SPM), and death. The model was used to estimate the expected lifetime costs of FL (in 2019 USD), including costs of drug acquisition and administration, transplant procedures, radiotherapy, adverse events, follow-up, DLBCL, SPM, end-of-life care, and indirect costs. Model inputs were based on published sources. In the US, patients with FL receiving treatment have a life expectancy of approximately 14.5 years from initiation of treatment and expected lifetime direct and indirect costs of US$515,884. Costs of drugs for induction therapy represent the largest expenditure (US$233,174), followed by maintenance therapy costs (US$88,971) and terminal care costs (US$57,065). Despite the relatively advanced age of these patients, indirect costs (due to patient morbidity and mortality and caregiver lost work time) represent a substantial share of total costs (US$40,280). Treated FL patients spend approximately 6.9 years in the health states associated with first-line therapy. Approximately 66 and 46% continue to second- and third-line therapies, respectively. The mean (95% credible interval) of expected lifetime costs based on the probabilistic sensitivity analyses was US$559,202 (421,997-762,553). In the US, the expected lifetime costs of care for FL patients who receive treatment is high. The results highlight the potential economic benefits that might be achieved by treatments for FL that prevent or delay disease progression.

Autologous Transplantation Improves Survival Rates for Follicular Lymphoma Patients Who Relapse within 2-Years of Chemoimmunotherapy: A Multi-Centre Retrospective Analysis of Consecutively Treated Patients in the Real World

Introduction: Although rituximab-based chemoimmunotherapy (RChemo) significantly improves overall survival (OS) for follicular lymphoma (FL), approximately 20% of patients experience initial time to progression (TTP1) of ≤2 years (early relapse) and relatively poor OS. We conducted a retrospective study to evaluate OS rates for patients with early relapse who were treated with or without high dose therapy and autologous stem cell transplantation (ASCT).Methods: A retrospective, multi-centre, study was conducted to identify all patients aged 18 to 70 years who were consecutively diagnosed in Alberta with grade 1 to 3a FL prior to 2011, and eventually received RChemo as their initial systemic therapy. Patient characteristics including Follicular Lymphoma International Prognostic Index (FLIPI) factors at RChemo, treatment details including Rituximab-maintenance (RMaintenance), TTP post-RChemo, frequency of transformation at relapse, and treatments after relapse were obtained. TTP and OS following RChemo and ASCT were evaluated in univariate and multivariate analyses.Results: Interrogation of the Alberta Cancer Registry identified 397 patients diagnosed with FL prior to 2011 who received RChemo. At a median follow-up of 92 months (3-179), 148 (37.3%) of the 397 patients relapsed from RChemo, including 82 (20.7%) with early relapse ≤2years and 66 (16.6%) with late relapse >2years.Table 1.0 lists characteristics of the 148 patients who relapsed after RChemo. Seventy-one (48.0%) patients underwent ASCT at relapse. Conditioning regimens included high dose melphalan (n=49, 69%, of whom 35 also received total body irradiation), BEAM (carmustine, etoposide, cytarabine, melphalan, n=21, 29.6%), and CBV (cyclophosphamide, BCNU, VP-16, n=1, 1.4%). In total, there were 29.1% (n=43) deaths following relapse, with majority of deaths due to FL (n=32, 74.4%).The projected 10-year OS following first RChemo was 93.8% in those with no relapse, 76.4% with late relapse, and 56.9% with early relapse (logrank p<0.001). Of the 71 patients who received ASCT, the 5-year TTP post-ASCT was 66.8% vs 70.6% for early (n=44) vs late (n=27) relapse patients, respectively (logrank p=0.85). Although the use of ASCT was not associated with OS for patients with late relapse (p=0.72), OS was superior for early relapse patients who received ASCT compared to those who did not receive ASCT (Figure 1.0) with 5-year OS rates of 86.0% vs 57.0%, respectively (HR 0.36, 95%CI 0.16-0.71, logrank p=0.005). Of note, relapse after RMaintenance vs no prior RMaintenance was not associated with OS (p=0.55). Table 2.0 lists the only factors that were associated with OS for patients with early relapse after RChemo in both univariate and multivariate analyses. The use of ASCT remained independently associated with improved OS for patients who relapsed <2 years of RChemo even when controlling for the other significant factors, which included baseline high risk FLIPI and transformation at relapse. Similar results were found when analyzed from time of first relapse following RChemo instead of from the time of first RChemo.Conclusions: Our study strongly suggests that the use of ASCT for FL patients who relapse within 2 years of RChemo is associated with improved OS. [Display omitted] DisclosuresPeters:Gilead: Honoraria; Janssen: Honoraria; Lundbeck: Honoraria; Roche: Honoraria; Abbvie: Honoraria. Stewart:Merck: Honoraria; Janssen: Honoraria; Abbvie: Honoraria; Gilead: Honoraria; Seattle Genetics: Honoraria; BMS: Honoraria; Roche: Honoraria; Amgen: Honoraria; Servier: Honoraria; Lundbeck: Honoraria.

Predicting Survival in Veterans with Follicular Lymphoma Using Structured Electronic Health Record Information and Machine Learning.

The most accurate prognostic approach for follicular lymphoma (FL), progression of disease at 24 months (POD24), requires two years’ observation after initiating first-line therapy (L1) to predict outcomes. We applied machine learning to structured electronic health record (EHR) data to predict individual survival at L1 initiation. We grouped 523 observations and 1933 variables from a nationwide cohort of FL patients diagnosed 2006–2014 in the Veterans Health Administration into traditionally used prognostic variables (“curated”), commonly measured labs (“labs”), and International Classification of Diseases diagnostic codes (“ICD”) sets. We compared performance of random survival forests (RSF) vs. traditional Cox model using four datasets: curated, curated + labs, curated + ICD, and curated + ICD + labs, also using Cox on curated + POD24. We evaluated variable importance and partial dependence plots with area under the receiver operating characteristic curve (AUC). RSF with curated + labs performed best, with mean AUC 0.73 (95% CI: 0.71–0.75). It approximated, but did not surpass, Cox with POD24 (mean AUC 0.74 [95% CI: 0.71–0.77]). RSF using EHR data achieved better performance than traditional prognostic variables, setting the foundation for the incorporation of our algorithm into the EHR. It also provides for possible future scenarios in which clinicians could be provided an EHR-based tool which approximates the predictive ability of the most accurate known indicator, using information available 24 months earlier.

Radiotherapy for early and advanced stages Follicular Lymphoma

OBJECTIVESTo evaluate the results of radiotherapy (RT) for follicular lymphoma (FL) under different management scenarios.METHODSWe retrospectively assessed consecutive patients with FL who had undergone irradiation between 2010 and 2018. All patients had biopsy-proven FL and were positron emission tomography-staged, although some (35.3%) were reassessed with computed tomography after treatment alone. Rituximab was only available to FL patients after 2016.RESULTSThirty-four patients were selected, with a mean age at diagnosis of 61.6 years (34-89 years). The median follow-up duration was 49.4 months. Most patients were female (58.8%) and showed good performance on the Eastern Cooperative Oncology Group (ECOG) scale (ECOG 0-55.9%). The mean overall survival (OS) and progression-free survival were 48.7 and 33.6 months, respectively, with four deaths reported. OS rates at 2 and 3 years were 94.1% and 91.2%, respectively. Four patients showed transformation into aggressive lymphomas and underwent rituximab-based systemic treatment. Transformation-free survival was 47.8 months, and all patients with transformed disease were alive at assessment. Five patients had in-field relapse, all of them also relapsed elsewhere, and the mean relapse-free survival time was 40.3 months. No median end points were reached on assessment.CONCLUSIONFL is an indolent disease. Our findings show good outcomes for patients treated with radiation, with a low transformation rate and excellent management of relapsed disease. RT is an important part of these results.

Mutational Profile and Copy Number Alterations of Follicular Lymphoma Patients with Different Clinical Behavior

Introduction Outcomes for follicular lymphoma (FL) patients are generally good. Clinical and biological variables have been studied to identify patients at higher risk of early relapse, which markedly impacts survival. However, the genetic landscape of FL according to its clinical behavior (need of treatment and timing of relapse) is not well characterized, which was the aim of the present study. Patients and Methods We included 67 samples from 55 grade 1-3A FL patients from a single institution [55 samples at diagnosis (D), and 12 at relapse (R)]. Five groups were defined according to their clinical behavior: never required treatment after &amp;gt;5 years (y) of follow-up [never treated (NT), n=7]; treated and did not relapse after &amp;gt;9 y of follow-up, [non-relapsed (NR), n=19]; treated and relapsed beyond 24 months of frontline therapy [late relapse (LR), n=14]; treated and relapsed within 24 months of frontline treatment [early relapse (ER), n=11]; and primary refractory (PR, n=4). Of the 48 treated patients, 96% received R-CHOP. Patients developing histologic transformation were not included. DNA was extracted from FFPE tissue biopsies. Copy number alterations (CNA) were assessed in 50 D and 11 R samples [OncoScan CNV Assay (Thermofisher)], and single nucleotide variants (SNV) and insertions/deletions (indels) in 51 D and 10 R samples using a B-cell malignancy NGS panel examining 121 genes (SureSelectXT, Agilent Technologies). Genes and genomic regions were considered altered if they harbored SNV/indels and/or CNA. For comparisons and plotting, only the 52 D samples with both NGS and CNA data were considered. Non-parametric statistical tests were used. Results Median age was 56 y (range, 26−79), and 30 patients (55%) were female. Forty-two patients (76%) had stage III-IV disease, without significant differences among groups. Thirteen patients (25%) had a high-risk FLIPI score, a percentage that was higher in the LR and PR groups (50 and 67%, respectively, P=0.02). With a median follow-up of 12.9 y, 10-y overall survival estimates were 71, 100, 74, 82, and 0% for NT, NR, LR, ER, and PR patients, respectively. We detected CNA in all samples, with a median number of 7 (range, 1−27) for D samples, and of 6 (2−19) for R samples. We also identified SNV/indels in all samples, with a median number of 10 (1−23) for D samples, and of 9 (3−18) for R samples. The most commonly altered genes at diagnosis were KMT2D (82%), CREBBP (73%), SPEN (38%), TNFRSF14 (38%), ARID1A (33%), and BCL2 (33%) (Figure). There were no significant differences in the number of altered genes/regions among the five groups. Genes or regions with significantly different alteration frequency among groups were: CARD11 (57, 12, 0, 9, and 0% for NT, NR, LR, ER, and PR, respectively, P=0.014), CD70 (12% for NR, 50% for PR, and 0 for the remaining groups P=0.026), HIST1H1B (29% for NT, and 0% for the remaining groups, P=0.020), HVCN1 (43, 6, 0, 18, and 0% for NT, NR, LR, ER, and PR, respectively, P=0.048), KLHL6 (12% for NR, 75% for PR, and 0 for the remaining groups, P=0.002), PRKCB (0, 6, 0, 18, 50%, P=0.037), and 13q14.2-q14.3 loss (DLEU1/DLEU2) (24% for NR, 50% for PR, and 0 for the remaining groups, P=0.015). Two genes had a significantly lower alteration rate comparing the cases with a favorable (NT, NR, LR) and more aggressive (ER, PR) clinical behavior: CIITA (22 vs. 53%, P=0.043), and PRKCB (3 vs. 27%, P=0.044). Of the 51 patients for which the m7-FLIPI was calculated, six (12%) had a high-risk score. Of note, none of the high-risk patients belonged to the NT or NR groups. No significant differences were found in the number of altered genes/regions between D and R, or in the alteration frequency of each gene/region. We identified the presence of an ancestral common precursor cell with a divergent evolution in all paired cases. The median percentage of shared alterations between D and R was 50% (range 28−63%). Conclusions In this comprehensive genetic analysis of 55 FL patients, categorized into five groups according to their clinical behavior, alterations in the chromatin modifying genes KMT2D and CREBBP were the most frequent, and CIITA and PRKCB were more frequently altered in cases with a shorter duration of response. These data warrant further study of the mechanisms underlying these mutations, mutual exclusivity/co-occurrence, and relationships with B-cell biology and the tumor microenvironment. Disclosures Nadeu: Janssen: Honoraria. Giné:Gilead: Research Funding; Janssen: Research Funding; Roche: Research Funding. Armando:Janssen: Research Funding; Roche: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Celgene: Consultancy, Research Funding.

Evaluation of the Different Stratification Models for POD24 Prediction in Patients with Follicular Lymphoma

Evaluation of the Different Stratification Models for POD24 Prediction in Patients with Follicular Lymphoma

Long‐term survival and prognostic analysis of advanced stage follicular lymphoma in the rituximab era: A China single‐center retrospective study

The prognosis and treatment options for follicular lymphoma (FL) remain heterogenous. This study aimed to analyze the prognostic impact of rituximab maintenance and evaluate the prognostic models in Chinese FL patients. We retrospectively evaluated patients with treatment-naïve advanced stage FL who were treated in Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College between January 2008 and December 2018. We compared the baseline characteristics, long-term survival outcomes, prognostic factors and the performance of four common prognostic models (i.e., FLIPI, FLIPI2, PRIMA-PI and LDH+β2M) between them. A total of 158 patients were included (rituximab maintenance group, 77 patients; observation group, 81 patients). The median follow-up time was 61.0 months. The rituximab maintenance group showed significantly higher 5-year progression-free survival (PFS; 83.3%vs 52.7%, P<0.001) and overall survival (OS; 97.8%vs 84.1%, P=0.032) than the observation group. FLIPI2 showed a more discriminating C index than the other three models. This study showed that rituximab maintenance after chemoimmunotherapy induction can prolong both PFS and OS in patients with advanced-stage FL, and FLIPI2 is a promising prognostic model.

Low initial trough concentration of rituximab is associated with unsatisfactory response of first-line R-CHOP treatment in patients with follicular lymphoma with grade 1/2.

For follicular lymphoma (FL) with grade 1/2, the complete response (CR) rate of the first-line R-CHOP treatment was significantly low. In this study, we assessed the rationality of the administration of rituximab for FL patients with grade 1/2 based on concentration-response relationship analyses. Thus, we conducted a prospective pharmacokinetic (PK) study in 68 FL patients with grades 1-3 treated with R-CHOP at 21-day intervals. Plasma rituximab concentrations were quantified using ELISA and the population PK modeling was established with Phoenix® NLMETM. The first cycle trough concentration (C1-trough) of rituximab was a significant independent risk factor for achieving CR in matched-pair logistic regression analysis, rather than the concentrations in later cycles; the recommendatory minimum optimal C1-trough was 13.60 μg/mL. Patients with grade 1/2 had significantly lower C1-trough compared with grade 3 (12.21 μg/mL vs. 23.45 μg/mL, P < 0.001), only 30% patients with grade 1/2 could reach 13.60 μg/mL, compared with 91.67% in patients with grade 3, which was in accord with its unsatisfactory CR rates (43.33% vs. 76.32%). The stage indicating the tumor burden (the target) was a crucial influence factor for C1-trough, accounting for 40.70% of its variability, 70% patients with grade 1/2 were stage IV in this study, since the systemic therapy only started at the disseminated disease stage. The initial dose of 1800 mg was recommended by Monte Carlo simulation for patients with grade 1/2. In summary, low C1-trough accounted for low-grade FL's unsatisfactory CR rate, designing the first dosage of rituximab should be a very important component of individualized therapy for FL.

Cost-effectiveness analysis of treatment regimens with obinutuzumab plus chemotherapy in Japan for untreated follicular lymphoma patients

Aims Obinutuzumab (GA101; G) is a new treatment for follicular lymphoma (FL) that is anticipated to have greater efficacy than the current treatment, rituximab (R). The aim of this study was to evaluate the cost-effectiveness of G plus chemotherapy (G + Chemo) against that of R plus chemotherapy (R + Chemo) for patients in Japan with previously untreated FL. Materials and methods We localized a previously reported cost-effectiveness model using the Japanese cost data. For estimating costs adapted in the model, FL patients treated with R were identified from Japanese hospital-based claims database and classified into three treatment regimen groups according to chemotherapies used with R: CHOP, CVP, and bendamustine (B). Based on services per patient and cost items, parameters determining the cost amounts were derived using a multivariate generalized linear mixed model to estimate the direct medical costs for each treatment regimen group for G and R. For the utility, same values in the previous model were used. Lifetime cost and quality-adjusted life year (QALY) were estimated under the payer’s perspective. Results The calculated incremental cost-effectiveness ratios (ICERs) in million JPY per QALY for G-CHOP vs. R-CHOP, G-CVP vs. R-CVP, and G-B vs. R-B were 5.4, 4.3, and 4.8, respectively. ICERs were lower than 7.5 million JPY per QALY, which is the cost-effectiveness threshold for cancer treatments, and showed that G + Chemo is a cost-effective treatment regimen for Japanese patients with previously untreated FL. Lifetime direct medical costs were lowest in the R-B group because hospitalization costs that accounted for most of the total cost were lowest in this group. Limitations and conclusions: The cost-effectiveness of G + Chemo is acceptable in Japan. Differences in the direct medical costs among treatment regimen groups were mostly due to hospitalization costs. This is probably because many Japanese hematologists choose inpatient treatments over outpatient treatments in CHOP-based induction therapy.

PCN234 TREATMENT PATTERNS OF FOLLICULAR LYMPHOMA PATIENTS: A CLAIMS ANALYSIS

Despite considerable improvements in available therapies for follicular lymphoma (FL), the most common indolent lymphoma, a consensus is lacking on optimal treatment sequencing. This study evaluated real-world treatment patterns among commercially insured FL patients in the United States. A retrospective cohort of newly diagnosed FL patients were identified from June-2008 to Sept-2016 using the IBM MarketScan® database. Patients were followed from FL diagnosis (defined by ICD-10 [c82.xx] and looking back for ICD-9 codes for FL or indolent Non-Hodgkin's Lymphoma) until loss of follow-up or end of the study. Outcome variables were the distribution of treatment regimens, line of therapy (LOT), and time to treatment. Of 4,232 eligible FL patients with a median follow-up of 3.6 years, 2712 (64%) had at least one treatment for FL. Treated patients had a median age of 61 years, and 53% were male. 2,111 patients had only one LOT, 476 patients had two LOTs, and 175 patients had three or more LOTs. The most common first-line treatment included Bendamustine + Rituximab (B-R, 39%), Rituximab + Cyclophosphamide + Doxorubicin + Vincristine (RCHOP, 20%), and Rituximab monotherapy (R-mono, 19%). The most common second LOT were R-mono (34%), B-R (27%), and Rituximab + Cyclophosphamide + Vincristine (RCVP, 9%). Lastly, R-mono was most common (57%) for third or greater LOTs. Median time from FL diagnosis to initiation of first, second, and third LOT were 50, 577, and 776 days, respectively. In a contemporary cohort of patients diagnosed with FL in the US, most patients had one or fewer lines of therapy during a median follow up of 3.6 years. Rituximab therapy predominated both in monotherapy and in combination. Consensus on optimal treatment sequencing is currently lacking, and patients receive a variety of active regimens during routine practice.

Patterns of change in treatment, response, and outcome in patients with follicular lymphoma over the last four decades: a single-center experience

Although the introduction of immunotherapy has improved outcomes for follicular lymphoma (FL) patients, histological transformation (HT) and early relapse still confer a poor prognosis. We sought to describe the patterns of change in treatment, response, and outcome of FL patients at our institution over the last four decades. Seven hundred and twenty-seven patients (389 F/338 M; median age, 57 years) consecutively diagnosed with grade 1-3a FL between 1980 and 2017, categorized into four decades according to the time of diagnosis, constituted the study population. Clinical characteristics, treatment, response, absolute and relative survival, HT, second malignancies (SM), and causes of death were assessed. Median OS for the entire cohort was 17.6 years. From decade 1 to 4, there was an increase in the complete response rate (48 to 70%), progression-free survival (40 to 56% at 5 years), OS (77 to 86% at 5 years), and relative survival ratio (0.83 to 0.94 at 5 years), with no significant differences in the risk of HT or SM. Lymphoma remained the most common cause of death in all four decades. These findings illustrate the overall improvement in outcome for FL patients, but support the need for further research into risk stratification and management.

Follicular lymphoma polygenic risk score is associated with increased disease risk but improved overall survival among women in a population based case-control in Los Angeles County California

IntroductionAlthough clinical prognostic indicators exist for follicular lymphoma(FL), patient outcomes remain heterogeneous. Material and methodsWe evaluated the association between survival and a polygenic risk score(PRS) composed of five previously identified FL susceptibility loci(rs12195582, rs13254990, rs17749561, rs4245081, rs4938573) among women who participated in a case-control study of non-Hodgkin lymphoma in Los Angeles County between 2004-2008. Risk associations were estimated through logistic regression, calculating the odds ratios(OR) and 95 % confidence intervals(95 % CI). Survival was estimated under a Cox proportional hazards model and hazard ratios(HR) and 95 % CI were calculated. ResultsAmong 437 non-Hispanic White controls and 100 non-Hispanic White FL patients, we confirmed a 2.6-fold increased risk of FL associated with the highest PRS tertile (95 % CI:1.35-4.86). After accounting for clinical indicators, the PRS was associated with improved overall survival in non-Hispanic women (HR:0.31; 95 % CI:0.10-0.96). ConclusionPRS was associated with increased risk of FL, but improved overall survival.

Real world data on follicular lymphoma patients treated by rituximab-containing immunochemotherapy and rituximab maintenance.

Background/AimsReal-world data about the treatment outcomes of patients receiving rituximab-containing immunochemotherapy followed by rituximab maintenance are required to understand better the treatment for follicular lymphoma (FL).MethodsA cross-sectional study analyzed FL patients who were treated with R-CVP (rituximab, cyclophosphamide, vincristine, and prednisone) or R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) and rituximab maintenance.ResultsOf 139 patients, 85 patients received R-CVP and 54 received R-CHOP. The characteristics did not differ significantly between the groups. Only grade 3 of FL was more common in R-CHOP. The complete response rate did not differ significantly between R-CHOP (50/54, 92.6%) and R-CVP (77/85, 90.6%). The number of disease relapses during rituximab maintenance did not differ significantly between the groups (p = 0.798). Therefore, the comparison of progression-free survival (PFS) showed no significant difference: the 3-year PFS rates for R-CVP and R-CHOP were 77% and 85%, respectively (p = 0.567). Although five of 56 hepatitis B virus (HBV) core antibody (anti-HBc)-positive patients experienced HBV reactivation, all cases of HBV reactivation were identified during regular monitoring for HBV DNA in blood, and were successfully managed with antiviral treatment.ConclusionsThe survival outcomes of FL patients on rituximab maintenance after responding to R-CVP or R-CHOP were similar. Rituximab-containing immunochemotherapy followed by rituximab maintenance can be safely used for anti-HBc-positive patients if HBV DNA titer in blood can be regularly monitored.

Combination lenalidomide-rituximab immunotherapy activates anti-tumour immunity and induces tumour cell death by complementary mechanisms of action in follicular lymphoma.

SummaryChemotherapy plus rituximab has been the mainstay of treatment for follicular lymphoma (FL) for two decades but is associated with immunosuppression and relapse. In phase 2 studies, lenalidomide combined with rituximab (R2) has shown clinical synergy in front‐line and relapsed/refractory FL. Here, we show that lenalidomide reactivated dysfunctional T and Natural Killer (NK) cells ex vivo from FL patients by enhancing proliferative capacity and T‐helper cell type 1 (Th1) cytokine release. In combination with rituximab, lenalidomide improved antibody‐dependent cellular cytotoxicity in sensitive and chemo‐resistant FL cells, via a cereblon‐dependent mechanism. While single‐agent lenalidomide and rituximab increased formation of lytic NK cell immunological synapses with primary FL tumour cells, the combination was superior and correlated with enhanced cytotoxicity. Immunophenotyping of FL patient samples from a phase 3 trial revealed that R2 treatment increased circulating T‐ and NK‐cell counts, while R‐chemotherapy was associated with reduced cell numbers. Finally, using an in vitro model of myeloid differentiation, we demonstrated that lenalidomide caused a reversible arrest in neutrophil maturation that was distinct from a cytotoxic chemotherapeutic agent, which may help explain the lower rates of neutropenia observed with R2 versus R‐chemotherapy. Taken together, we believe these data support a paradigm shift in the treatment of FL – moving from combination immunochemotherapy to chemotherapy‐free immunotherapy.

Prognostic Value of PRAME Activity in Tumor Cells of Follicular Lymphoma

Aim. To set survival parameters for follicular lymphoma (FL) patients with different PRAME expression levels in tumor cells. Materials &amp; Methods. The study was conducted on samples of lymph nodes, blood, and bone marrow of 34 patients with newly diagnosed FL. PRAME expression levels were measured in tumor cells (centrocytes and centroblasts) by quantitative real-time PCR. The impact of different PRAME expression levels on survival parameters was studied with median follow-up of 29 months. Clinical and laboratory characteristics used for FLIPI-1 and FLIPI-2 calculations in different patient groups were compared. Results. A high (&gt; 5 % against ABL control gene) PRAME expression level correlates with higher Ki-67 activity (p = 0.043) and larger tumor mass (p = 0.04). Survival parameters were worse with high PRAME expression level in FL cells. Combination of both high FLIPI-1/FLIPI-2 risk and high PRAME expression level determines extremely unfavorable prognosis and may result in death. Conclusion. In FL patients high PRAME expression level in tumor cells has negative prognostic value, but only in the presence of parameters determining high FLIPI-1 and FLIPI-2 risk. Juxtaposition of PRAME expression level and FLIPI-1/ FLIPI-2 values enables most reliable prediction of early mortality in FL patients.

90 Y-ibritumomab-tiuxetan as a therapeutic alternative for follicular lymphoma (FL): A single-center experience.

Follicular lymphoma (FL) is the most frequent indolent lymphoma subtype in adults. Maintenance therapy with rituximab is frequently applied to FL patients with complete or partial response following initial chemoimmunotherapy. However, radioimmunotherapy with 90 Y-ibritumomab-tiuxetan represents a therapeutic alternative. To compare the clinical and the prognostic impact of both therapies, a study collective of n=56 patients diagnosed with indolent B-cell lymphoma was retrospectively investigated. The study collective was subdivided into two groups: n=36 patients treated with rituximab maintenance therapy vs n=20 patients treated with 90 Y-ibritumomab-tiuxetan. No prognostic differences for performance status, FLIPI score, gender, or B-symptoms were found for 90 Y-ibritumomab-tiuxetan or rituximab maintenance therapy. Overall survival rates and progression-free survival did not differ between both maintenance therapies. Our retrospective single-center analysis of two patient groups without major differences in prognostic parameters revealed similar outcome with two different maintenance therapies. Hence, 90 Y-ibritumomab-tiuxetan therapy might offer a valuable alternative treatment option for FL patients with partial response. However, large prospective trials are needed to confirm the reported findings.

The Combination of Rituximab and Bendamustine as First-Line Treatment Is Highly Effective in the Eradicating Minimal Residual Disease in Follicular Lymphoma: An Italian Retrospective Study.

R-Bendamustine is an effective treatment for follicular lymphoma (FL). Previous large trials demonstrated the prognostic role of the molecular minimal residual disease (MRD) during the most frequently adopted chemotherapeutic regimens, but there are not yet conclusive data about the effect of combination of rituximab (R) and bendamustine in terms of MRD clearance. Thus, the aim of this retrospective study was to assess if and in what extent the combination of rituximab and bendamustine would exert a significant reduction of the molecular disease in 48 previously untreated FL patients. The molecular marker at baseline was found in the 62.5% of cases; no significant differences were observed between patients with or without the molecular marker in respect of the main clinical features. Moreover, the quantization of the baseline molecular tumor burden showed a great variability: the median value was 1.4 × 10−2 copies, ranging from 3 × 10−5 to 4 × 104. The initial molecular tumor burden did not correlate with clinical features and did not impact on the subsequent quality of response. After treatment, 93% of cases became MRD-negative; the median reduction of the BCL2/JH load was 4 logs. The 2-years PFS was 85%; it was significantly longer for patients in complete than for those in partial response (91 vs. 57%; p = 0.002), and for cases with lower FLIPI-2 score (88 vs. 60%; p = 0.004). On the contrary, PFS did not differ between patients with or without the molecular marker at baseline; a molecular tumor burden 15 times higher was observed in the relapsed subgroup in comparison to the relapse-free one, but this difference did not change the PFS length. The 2-years OS was 93.6%; the only variable that significantly impacted on it was the FLIPI-2 score; the presence of the molecular marker at baseline or its behavior after treatment did not impact on survival. This study, even if retrospective and conducted on a small series of patients, would represent a proof of concept that R-bendamustine is able to so efficaciously eradicate MRD that it could be able to by-pass the prognostic significance of MRD already demonstrated for other chemotherapeutic regimens in FL.