International Prognostic Index Risk Group Research Articles

Ibrutinib combined with immunochemotherapy with or without autologous stem-cell transplantation versus immunochemotherapy and autologous stem-cell transplantation in previously untreated patients with mantle cell lymphoma (TRIANGLE): a three-arm, randomised, open-label, phase 3 superiority trial of the European Mantle Cell Lymphoma Network

Adding ibrutinib to standard immunochemotherapy might improve outcomes and challenge autologous stem-cell transplantation (ASCT) in younger (aged 65 years or younger) mantle cell lymphoma patients. This trial aimed to investigate whether the addition of ibrutinib results in a superior clinical outcome compared with the pre-trial immunochemotherapy standard with ASCT or an ibrutinib-containing treatment without ASCT. We also investigated whether standard treatment with ASCT is superior to a treatment adding ibrutinib but without ASCT. The open-label, randomised, three-arm, parallel-group, superiority TRIANGLE trial was performed in 165 secondary or tertiary clinical centres in 13 European countries and Israel. Patients with previously untreated, stage II-IV mantle cell lymphoma, aged 18-65 years and suitable for ASCT were randomly assigned 1:1:1 to control group A or experimental groups A+I or I, stratified by study group and mantle cell lymphoma international prognostic index risk groups. Treatment in group A consisted of six alternating cycles of R-CHOP (intravenous rituximab 375 mg/m2 on day 0 or 1, intravenous cyclophosphamide 750 mg/m2 on day 1, intravenous doxorubicin 50 mg/m2 on day 1, intravenous vincristine 1·4 mg/m2 on day 1, and oral prednisone 100 mg on days 1-5) and R-DHAP (or R-DHAOx, intravenous rituximab 375 mg/m2 on day 0 or 1, intravenous or oral dexamethasone 40 mg on days 1-4, intravenous cytarabine 2 × 2 g/m2 for 3 h every 12 h on day 2, and intravenous cisplatin 100 mg/m2 over 24 h on day 1 or alternatively intravenous oxaliplatin 130 mg/m2 on day 1) followed by ASCT. In group A+I, ibrutinib (560 mg orally each day) was added on days 1-19 of R-CHOP cycles and as fixed-duration maintenance (560 mg orally each day for 2 years) after ASCT. In group I, ibrutinib was given the same way as in group A+I, but ASCT was omitted. Three pairwise one-sided log-rank tests for the primary outcome of failure-free survival were statistically monitored. The primary analysis was done by intention-to-treat. Adverse events were evaluated by treatment period among patients who started the respective treatment. This ongoing trial is registered with ClinicalTrials.gov, NCT02858258. Between July 29, 2016 and Dec 28, 2020, 870 patients (662 men, 208 women) were randomly assigned to group A (n=288), group A+I (n=292), and group I (n=290). After 31 months median follow-up, group A+I was superior to group A with 3-year failure-free survival of 88% (95% CI 84-92) versus 72% (67-79; hazard ratio 0·52 [one-sided 98·3% CI 0-0·86]; one-sided p=0·0008). Superiority of group A over group I was not shown with 3-year failure-free survival 72% (67-79) versus 86% (82-91; hazard ratio 1·77 [one-sided 98·3% CI 0-3·76]; one-sided p=0·9979). The comparison of group A+I versus group I is ongoing. There were no relevant differences in grade 3-5 adverse events during induction or ASCT between patients treated with R-CHOP/R-DHAP or ibrutinib combined with R-CHOP/R-DHAP. During maintenance or follow-up, substantially more grade 3-5 haematological adverse events and infections were reported after ASCT plus ibrutinib (group A+I; haematological: 114 [50%] of 231 patients; infections: 58 [25%] of 231; fatal infections: two [1%] of 231) compared with ibrutinib only (group I; haematological: 74 [28%] of 269; infections: 52 [19%] of 269; fatal infections: two [1%] of 269) or after ASCT (group A; haematological: 51 [21%] of 238; infections: 32 [13%] of 238; fatal infections: three [1%] of 238). Adding ibrutinib to first-line treatment resulted in superior efficacy in younger mantle cell lymphoma patients with increased toxicity when given after ASCT. Adding ibrutinib during induction and as maintenance should be part of first-line treatment of younger mantle cell lymphoma patients. Whether ASCT adds to an ibrutinib-containing regimen is not yet determined. Janssen and Leukemia & Lymphoma Society.

Circulating-tumor DNA Assessment in Diffuse Large B-cell Lymphoma to Determine Up-front Stem Cell Transplantation: A Pilot Study.

This study evaluated the possibility of clinical use of circulating-tumor DNA (ctDNA) as a biomarker to determine up-front autologous stem cell transplantation (auto-SCT) for patients with high-risk diffuse large B-cell lymphoma (DLBCL) in practice. To explore the dynamics of ctDNA in DLBCL, blood samples were collected sequentially before and after treatment from patients with newly diagnosed DLBCL who received rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) chemotherapy. To conduct ctDNA genotyping and ctDNA monitoring simultaneously, targeted sequencing by cancer personalized profiling using deep sequencing was used. Ten patients between the ages of 50 and 60 years were enrolled. Based on the international prognostic index (IPI), seven patients were classified as high-IPI-risk group, and three patients were classified as low-IPI-risk group. The IPI risk group correlated with total metabolic tumor volume. All patients completed six cycles of R-CHOP chemotherapy, and seven patients achieved complete response. Changes in ctDNA mutation numbers did not correlate with changes in PET scan images and treatment response. In most high-risk patients, new mutations appeared in ctDNA after completion of chemotherapy that conceivably marked resistant clones. Notably, disease relapse did not occur in high-risk patients with poor prognostic mutations who underwent autologous SCT. ctDNA monitoring was meaningful in high-risk patients. Moreover, ctDNA and well-known prognostic factors should be considered in the decision making for auto-SCT. If a new genetic mutation in ctDNA with a negative prognosis would emerge during treatment, high-risk patients should consider auto-SCT.

An Externally Controlled Trial to Indirectly Compare Tazemetostat Plus Lenalidomide and Rituximab Versus Lenalidomide and Rituximab after at Least One Prior Systemic Therapy in Patients with Refractory and Relapsed Follicular Lymphoma

BACKGROUND: Follicular lymphoma (FL) is an indolent, incurable lymphoma with a heterogeneous clinical course characterized by multiple relapses. Recent data indicate a potential synergism between tazemetostat and lenalidomide and an additive effect with rituximab, offering a clinical rationale for this as a combination strategy (Batlevi, Blood 2022). SYMPHONY-1 Phase 1b, Stage 1 (EZH-302; NCT04224493) is an open-label, single-arm, safety run-in trial to evaluate the safety and tolerability of tazemetostat combined with lenalidomide plus rituximab (R2). This study indirectly compares the efficacy results of the SYMPHONY-1 Phase 1b single arm trial with an external control arm (ECA) derived from the Flatiron Health Research Database (FHRD), consisting of real-world FL patients treated with R2 after receiving ≥1 prior systemic therapy. METHODS: This study utilized individual patient data from SYMPHONY-1 based on a data cutoff date of July 10, 2023, and the FHRD, a large database of electronic health records from oncology practices in the United States, including data through December 31, 2022. The treatment arm consisted of patients enrolled in the safety run-in portion of SYMPHONY-1 treated with a combination of tazemetostat plus R2, followed from enrollment to the data cutoff date. The ECA was constructed by applying eligibility criteria adapted from SYMPHONY-1 to real-world patients from the FHRD treated with R2 in second line (2L); patients were followed from the start date of the earliest eligible line of therapy (LOT) to the end of the patient's record. The primary endpoint was objective response rate (ORR), defined as the proportion of patients who achieved a complete or partial response. In SYMPHONY-1, ORR was assessed by an independent review committee according to the 2014 Lugano Classification. In the ECA, real-world ORR (rwORR) was determined by the treating clinician's interpretation of change in disease burden. The analysis set included patients from the treatment arm with ≥1 evaluable response assessment and patients from the ECA with ≥1 radiographic assessment documented in the FHRD. The statistical analysis used propensity score weighting (PSW) to adjust the distribution of seven prespecified baseline patient characteristics of the ECA to align with the treatment arm. These characteristics were age, Eastern Cooperative Oncology Group Performance Status, disease grade at diagnosis, progression of disease within 24 months (POD24) from diagnosis, lactate dehydrogenase (LDH) > upper limit of normal (ULN), size of the largest node, and Follicular Lymphoma International Prognostic Index (FLIPI) risk group. An impute-then-exclude multiple imputation strategy was used to handle missing data for variables required in the eligibility criteria and PSW. The primary endpoint was indirectly compared by estimating the difference between the ORR of the treatment arm and rwORR of the balanced ECA on each imputed dataset, and the associated standard errors were approximated using bootstrapping. Rubin's rules were applied to combine the results into a single estimate with a 95% confidence interval and corresponding two-sided p-value. RESULTS: The primary analysis compared 42 patients in the treatment arm from SYMPHONY-1 and a median of 36 patients (range: 34 to 38) in the ECA among 815 total patients in the FHRD across ten imputed datasets. The unweighted analysis found an ORR of 95.2% in the treatment arm and 75.7% in the ECA, resulting in a difference of 19.6% (95% confidence interval [CI]: 3.6-35.5) (Table 2). After PSW, the distribution of baseline characteristics for the ECA was comparable with the treatment arm (all standardized mean differences < 0.16), and the median effective sample size was reduced to 12.7 (range: 4.9 to 19.1) (Table 1). ORR was 95.2% in the treatment arm and 77.9% in the ECA, resulting in a difference of 17.3% (95% CI: -17.5-52.1; two-sided P = 0.16) (Table 2). CONCLUSIONS: This ECA study found that patients treated with tazemetostat combined with R2 were estimated to have a higher ORR than those treated with R2, though inference is limited due to small sample sizes. These findings help contextualize the SYMPHONY-1 Phase 1b single-arm trial results and combination potential of tazemetostat plus R2. There is a randomized Phase 3 confirmatory trial underway to confirm the clinical benefit of tazemetostat plus R2 (SYMPHONY-1 Stage 2, NCT04224493).

Lower Prognostic Performance of the International Metabolic Prognostic Index Compared to the Conventional IPI and NCCN-IPI in a Real-World Cohort of Diffuse Large B-Cell Lymphoma

Introduction: The international metabolic prognostic index (IMPI) is a recently proposed model that shows improved outcome prediction for patients with diffuse large B-cell lymphoma (DLBCL) compared to the International Prognostic Index (IPI) (Mikhaeel et al.). IMPI combines total metabolic tumor volume (TMTV) as continuous variables with clinical factors, allowing individualized prognosis estimation. However, the applicability of IMPI to routine clinical practice remains uncertain since the model construction was based on data from clinical trials. Furthermore, the comparison of the model performance between IMPI and the National Comprehensive Cancer Network IPI (NCCN-IPI) is not reported so far. Methods: We performed retrospective analysis of consecutive patients with newly diagnosed DLBCL who were initially treated with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) at Kameda Medical Center between 2006 and 2020. Patients who had no fluorodeoxyglucose-avid lesions were excluded. TMTV was defined as the volume of lymphoma-associated lesions with a standardized uptake value of ≥4 as the absolute threshold (Metavol, Hokkaido University, Japan). According to the original study (Mikhaeel et al.), IMPI was calculated using the following formula: 0.003077330 × (MTV lower than the median of 307.9ml) - 0.002761985 × (MTV higher than the median of 307.9ml) + 0.008092449 × Age -0.114645415 × Stage 2 + 0.281141117 × Stage 3 + 0.322247142 × Stage 4. The receiver operating curve (ROC) for predicting 5-year survival was compared among IMPI-, IPI-, and NCCN-IPI-based classifications. The predictive performance of these three systems was evaluated using the Akaike information criterion (AIC) and Harrell's concordance index (c-index). Results: A total of 314 patients were included in the study. The median age was 72 years old (interquartile range [IQR] 64-79), which was younger than the original data (median 62, IQR 51-70). Regarding the distributions of IPI risk groups, this cohort had a lower number of low-risk patients (27.0% vs. 32.4%) and a higher number of high-risk patients (23.9% vs. 19.5%). The median TMTV was 168 (IQR 47-530), which was approximately two times lower than that in the original study (median 307, IQR 77-838). After calculating and ranking the individual IMPI scores, nearly half of the patients (n=147, 46.8%) were reclassified into different risk groups from the original IPI categories (Figure 1); 76 (51.7%) were upstaged, and 71 (48.3%) were downstaged. Of note, the reclassification resulted in a significantly better OS prediction only for the IPI high-risk group (5-year OS rate, IMPI high-risk vs. IMPI not high-risk, 41.9% vs. 59%, P =0.042), while it did not for the IPI low-, low-intermediate-, and high-intermediate-risk groups. The area under the curve (AUC) from the ROC curve predicting 5-year survival was not significantly different between IMPI- (AUC 0.65) and either IPI- (AUC 0.67, P =0.42) or NCCN-IPI-categories (AUC 0.68, P=0.25). Finally, the predictive performance and model fitness were compared among these three indices. IMPI had the highest AIC (1117.68) and the lowest c-index (0.643) for OS prediction, whereas NCCNIPI yielded the best performance (AIC 1097.66 and c-index 0.677) (Table 1). Conclusions: We demonstrated that the IMPI model did not outperform the conventional IPI and NCCN-IPI systems in a real-world cohort of DLBCL patients. The difference in age and tumor burden, which are the major components of IMPI, may lead to poorer prognostic performance. Further large-scale studies are warranted to validate the prognostic value of IMPI outside of clinical trials.

Genetic and transcriptomic analyses of diffuse large B‐cell lymphoma patients with poor outcomes within two years of diagnosis

Background: R-CHOP immunochemotherapy is the first-line treatment for DLBCL, but approximately 30%–40% of patients still experience refractory or relapsed (R/R) disease. We aimed to characterize the molecular features of DLBCL derived from patients with early R/R disease and develop a prognosis model to identify those high-risk patients. Methods: We performed a comprehensive genomic and transcriptomic characterization on 161 R-CHOP-treated DLBCL samples. These patients were grouped by follow-up outcome status after R-CHOP treatment. The first group had R/R disease within two years of diagnosis (poor outcome; n = 50), and the second group remained in remission at two years following R-CHOP treatment (good outcome; n = 111). In an addition, external cohorts were included in the validation analysis (GSE117556, n = 374; GSE181063, n = 810). Results: Patients with poor outcomes more often had an advanced stage of the disease, a high international prognostic index (IPI) and a non-GCB subtype of the tumor. We identified a set of frequent somatically mutated targets (Figure 1A), including PIM1, TP53, MPEG1 and ROBO1, as well as a specific mutational signature (activation-induced cytidine deaminase related) in DLBCLs with poor outcomes. Transcriptomic analyses further showed a distinct gene expression pattern and a less inflamed tumor microenvironment in these patients (Figure 1B). Finally, we developed an 11-gene signature as an independent prognostic marker for DLBCL patients treated with R-CHOP (Figure 1C). The 11-gene signature could further stratify DLBCL patients based on their IPI scores (Figure 1D). Additionally, the use of 11-gene signature to identify high-risk patients was also validated in two independent cohorts, suggesting the robustness of the risk model. Furthermore, our model effectively identified high-risk patients, including those with double-hit and MCD genetic subtypes that are associated with poor survival outcomes. FIGURE 1 (A) The mutation pattern between poor outcome and good outcome DLBCLs. (B) Tumor-infiltrating immune cells in DLBCL patients with poor and good outcomes. (C-D) Kaplan–Meier survival analysis of PFS between high-risk and low-risk groups (C) and the association of 11-gene risk scores and IPI risk groups (D). Keywords: Aggressive B-cell non-Hodgkin lymphoma, Diagnostic and Prognostic Biomarkers, Genomics, Epigenomics, and Other -Omics No conflicts of interests pertinent to the abstract.

Evaluation of clinical and prognostic factors for primary gastric diffuse large B-cell lymphoma: Single-center experience.

Primary gastric lymphomas, which make up the vast majority of extranodal non-Hodgkin lymphoma, are rare and the most common subtype is primary gastric diffuse large B-cell lymphoma (PG-DLBCL). In our study, we investigated the clinical and prognostic factors of this lymphoma type as a single-center experience. Between January 2001 and February 2021, 91 patients aged ≥18 years, registered with the diagnosis of primary gastric DLBCL, diagnosed histopathologically, and whose evaluation parameters were reached, were retrospectively scanned. The median age of 91 patients with a diagnosis of PG-DLBCL was 58 (20-81, minimum-maximum) years. Of the patients, 64.8% were men and 35.2% were women. While the number of patients with an International Prognostic Index (IPI) score of 0-2 (low-low-intermediate risk) was 54 (59.4%), the number of patients with an IPI score of 3 (high intermediate) was 19 (20.9%), and the number of patients with an IPI score of 4-5 (high risk) was 18 (19.8%). While 52.7% of the patients had a complete response, 20.9% had a partial response, 3.3% had stable disease, and 23.1% had progressive disease. The 10-year event-free survival (EFS) and overall survival (OS) rates for all patients, respectively, were 52.1% and 53.2%. We found factors affecting survival in univariate analysis; age groups (≤60/>60), ECOG groups (0-1/≥2), Lugano stage (I-II/III-IV), LDH level (normal/high), IPI risk groups (low/low-intermediate/high-intermediate/high) and radiotherapy (yes/no). In multivariate analysis, only; age groups (≤60/>60) and IPI risk groups (low/low-intermediate/high-intermediate/high) were found to be independent factors affecting survival. In addition, in our study, we determined that the division of the IPI intermediate risk group into low intermediate and high intermediate is one of the factors predicting prognosis. Few studies of PG-DLBCL have investigated the long-term survival rates of patients and primarily examined small patient groups because of the low incidence of the disease. In our study, we think that detailed evaluation of age and especially IPI risk groups play a role in predicting survival.

Benefit of rituximab maintenance is associated with Follicular Lymphoma International Prognostic Index in patients with follicular lymphoma.

Rituximab maintenance (RM) prolongs the progression-free survival (PFS) of responding patients with follicular lymphoma (FL), but the maintenance efficacy in different Follicular Lymphoma International Prognostic Index (FLIPI) risk group is still confusing. We performed a retrospective analysis of the effect of RM treatments in patients with FL responding to induction therapy based on their FLIPI risk assessment carried out prior to treatment. We identified 93 patients between 2013 and 2019 who received RM every 3 months for ≥4 doses (RM group), and 60 patients who did not accept RM or received rituximab less than 4 doses (control group). After a median follow-up of 39 months, neither median overall survival (OS) nor PFS was reached for the entire population. The PFS was significantly prolonged in the RM group compared to the control group (median PFS NA vs 83.1 months, P = .00027). When the population was divided into the 3 FLIPI risk groups, the PFS differed significantly (4-year PFS rates, 97.5% vs 88.8% vs 72.3%, P = .01) according to group. There was no significant difference in PFS for FLIPI low-risk patients with RM compared to the control group (4-year PFS rates, 100% vs 93.8%, P = .23). However, the PFS of the RM group was significantly prolonged for FLIPI intermediate-risk (4-year PFS rates, 100% vs 70.3%, P = .00077) and high-risk patients (4-year PFS rates, 86.7% vs 57.1%, P = .023). These data suggest that standard RM significantly prolongs the PFS of patients assigned to intermediate- and high-risk FLIPI groups but not to low-risk FLIPI group, and pending larger-scale studies to validate.

Deep Learning–Based Nuclear Morphometry Reveals an Independent Prognostic Factor in Mantle Cell Lymphoma

Blastoid/pleomorphic morphology is associated with short survival in mantle cell lymphoma (MCL), but its prognostic value is overridden by Ki-67 in multivariate analysis. Herein, a nuclear segmentation model was developed using deep learning, and nuclei of tumor cells in 103 MCL cases were automatically delineated. Eight nuclear morphometric attributes were extracted from each nucleus. The mean, variance, skewness, and kurtosis of each attribute were calculated for each case, resulting in 32 morphometric parameters. Compared with those in classic MCL, 17 morphometric parameters were significantly different in blastoid/pleomorphic MCL. Using univariate analysis, 16 morphometric parameters (including 14 significantly different between classic and blastoid/pleomorphic MCL) emerged as significant prognostic factors. Using multivariate analysis, Biologic MCL International Prognostic Index (bMIPI) risk group (P=0.025), low skewness of nuclear irregularity (P=0.020), and high mean of nuclear irregularity (P=0.047) emerged as independent adverse prognostic factors. Additionally, a morphometric score calculated from the skewness and mean of nuclear irregularity (P=0.0038) was an independent prognostic factor in addition to bMIPI risk group (P=0.025), and a summed morphometric bMIPI score was useful for risk stratification of patients with MCL (P=0.000001). These results demonstrate, for the first time, that a nuclear morphometric score is an independent prognostic factor in MCL. It is more robust than blastoid/pleomorphic morphology and can be objectively measured.

MO30-3 Clinical characteristics of DLBCL patients experiencing early disease progression among lower IPI risk groups

We have previously reported early disease progression within 24 months (POD24) could be a surrogate marker for a substantially increased risk of death (2016 The Japanese Society of Hematology annual meeting). The aim of this study was to clarify clinical characteristics of DLBCL patients experiencing POD24 among lower International Prognostic Index (IPI) risk groups.

Machine Learning Models for the Diagnosis and Prognosis Prediction of High-Grade B-Cell Lymphoma.

High-grade B-cell lymphoma (HGBL) is a newly introduced category of rare and heterogeneous invasive B-cell lymphoma (BCL), which is diagnosed depending on fluorescence in situ hybridization (FISH), an expensive and laborious analysis. In order to identify HGBL with minimal workup and costs, a total of 187 newly diagnosed BCL patients were enrolled in a cohort study. As a result, the overall survival (OS) and progression-free survival (PFS) of the HGBL group were inferior to those of the non-HGBL group. HGBL (n = 35) was more likely to have a high-grade histomorphology appearance, extranodal involvement, bone marrow involvement, and whole-body maximum standardized uptake (SUVmax). The machine learning classification models indicated that histomorphology appearance, Ann Arbor stage, lactate dehydrogenase (LDH), and International Prognostic Index (IPI) risk group were independent risk factors for diagnosing HGBL. Patients in the high IPI risk group, who are CD10 positive, and who have extranodal involvement, high LDH, high white blood cell (WBC), bone marrow involvement, old age, advanced Ann Arbor stage, and high SUVmax had a higher risk of death within 1 year. In addition, these models prompt the clinical features with which the patients should be recommended to undergo a FISH test. Furthermore, this study supports that first-line treatment with R-CHOP has dismal efficacy in HGBL. A novel induction therapeutic regimen is still urgently needed to ameliorate the poor outcome of HGBL patients.

Population-Wide Introduction of Dose-Adjusted EPOCH-R Is Associated with Improved Outcome of High Grade B-Cell Lymphoma with MYC and BCL2 Rearrangements with Diffuse Large B-Cell Lymphoma Morphology

Population-Wide Introduction of Dose-Adjusted EPOCH-R Is Associated with Improved Outcome of High Grade B-Cell Lymphoma with MYC and BCL2 Rearrangements with Diffuse Large B-Cell Lymphoma Morphology

International Prognostic Index-Based Immune Prognostic Model for Diffuse Large B-Cell Lymphoma.

BackgroundThe International Prognostic Index (IPI) is widely used to discriminate the prognosis of patients with diffuse large B-cell lymphoma (DLBCL). However, there is a significant need to identify novel valuable biomarkers in the context of targeted therapy, such as immune checkpoint blockade (ICB).MethodsGene expression data and clinical DLBCL information were obtained from The Cancer Genome Atlas and Gene Expression Omnibus datasets. A total of 371 immune-related genes in DLBCL patients associated with different IPI risk groups were identified by weighted gene co-expression network analysis, and eight genes were selected to construct an IPI-based immune prognostic model (IPI-IPM). Subsequently, we analyzed the somatic mutation and transcription profiles of the IPI-IPM subgroups as well as the potential clinical response to immune checkpoint blockade (ICB) in IPI-IPM subgroups.ResultsThe IPI-IPM was constructed based on the expression of CMBL, TLCD3B, SYNDIG1, ESM1, EPHA3, HUNK, PTX3, and IL12A, where high-risk patients had worse overall survival than low-risk patients, consistent with the results in the independent validation cohorts. The comprehensive results showed that high IPI-IPM risk scores were correlated with immune-related signaling pathways, high KMT2D and CD79B mutation rates, and upregulation of inhibitory immune checkpoints, including PD-L1, BTLA, and SIGLEC7, indicating a greater potential response to ICB therapy.ConclusionThe IPI-IPM has independent prognostic significance for DLBCL patients, which provides an immunological perspective to elucidate the mechanisms of tumor progression and sheds light on the development of immunotherapy for DLBCL.

The Absolute Lymphocyte Count Is Associated with the Prognosis in Patients with Peripheral T-Cell Lymphoma, Not Otherwise Specified

IntroductionPeripheral T-cell lymphomas (PTCLs) are a heterogeneous group of tumors that belong to the category of aggressive lymphomas and are roughly subdivided into specified and not otherwise specified (NOS) types. Clinically, the International Prognostic Index (IPI) has been the effective prognostic model to discriminate the prognosis of patients with PTCL-NOS. Also, Prognostic Index for T-cell lymphoma (PIT) has been proposed, which further modified to the Bologna score (modified PIT, mPIT). However, no simple prognostic marker has been satisfactory in predicting treatment outcomes in patients with PTCL-NOS. In this study, we investigate the association between absolute lymphocyte count at diagnosis and the prognosis of patients with PTCL-NOS.MethodsAs a retrospective study, we searched the Lymphoma Registry of Asan Medical Center and Inje University Sanggye Paik Hospital. From April 2001 to Jun 2016, we identified 131 patients diagnosed with PTCL-NOS initially treated with CHOP or CHOP-like regimens. Patients diagnosed with PTCLs other than PTCL-NOS and primary cutaneous lymphoma were excluded. Event-free survival (EFS) was calculated from the date of diagnosis to the date of disease progression, treatment failure, relapse, or death from any cause. Overall survival (OS) was calculated from the date of diagnosis to the date of death from any cause. Lymphopenia was defined as absolute lymphocyte count < 1000 / μL. The association between clinical characteristics and response was analyzed by the Fisher's exact test. Survival curves were analyzed by the Kaplan-Meier method and compared with the log-rank test.ResultsAmong 131 patients, 42 (32.1%) patients showed lymphopenia, 58 (44.3%) patients showed B symptoms, and 46 (35.1%) patients showed bone marrow involvement. The median absolute lymphocyte count was 1392/μL (range, 61-10092/μL). According to the International Prognostic Index (IPI) scores, 33 (25.2%) patients belonged to the low risk group (L), 36 (27.5%) to the low-intermediate risk group (LI), 38 (29.0%) to the high-intermediate risk group (HI), and 24 (18.3%) to the high risk group (H).In univariate analysis, treatment outcomes including CR, EFS, and OS were associated with lymphopenia, B symptoms, performance status, lactate dehydrogenase, extranodal involvement, Ann Arbor stage, IPI risk group, and the Prognostic Index for T-cell lymphoma (PIT) risk groups. After multivariate analysis, lymphopenia was independently associated with CR (≥1000 vs. <1000, odd ratio [OR]: 2.899, 95% confidence interval [CI]: 1.229-6.841, P=0.015), EFS (≥1000 vs. <1000, hazard ratio [HR]: 0.523, 95% CI: 0.339-0.807, P=0.003), and OS (≥1000 vs. <1000, HR: 0.599, 95% CI: 0.375-0.955, P=0.031). IPI risk group was also associated with CR (L/LI vs. HI/H, P <0.001), EFS (P <0.001), and OS (P <0.001).ConclusionsAbsolute lymphocyte count is an independent prognostic factor for the patients with PTCL-NOS. Lymphopenia (<1000/μL) at diagnosis was associated with worse prognosis of patients with PTCL-NOS. Because the absolute lymphocyte count easily obtained from the initial complete blood count, it seems to be simple prognostic factors to estimate the prognosis of patients with PTCL-NOS. The larger scaled study is warranted to confirm our result. DisclosuresNo relevant conflicts of interest to declare.

Circulating Tumor DNA Is a Reliable Measure of Tumor Burden at Diagnosis of Diffuse Large B Cell Lymphoma: An International Reproducibility Study

▪Background: Pretreatment tumor burden is a known prognostic factor in diffuse large B cell lymphoma (DLBCL). Components of the International Prognostic Index (IPI), including lactate dehydrogenase (LDH) and clinical stage, attempt to capture tumor burden but lack specificity. Tumor volume is an alternative metric for disease burden, but requires specialized radiographic interpretation. We recently described circulating tumor DNA (ctDNA) levels as a novel quantitative biomarker for disease burden in DLBCL (Scherer F and Kurtz DM, Sci Transl Med 2016). To validate the performance of ctDNA across a diverse cohort of patients and medical centers, we assessed pretreatment ctDNA levels in patients with DLBCL from six centers around the world.Methods: We performed Cancer Personalized Profiling by Deep Sequencing (CAPP-Seq) on pretreatment cell-free and germline DNA from patients undergoing curative-intent anthracycline-based therapy. Somatic mutations were identified and variant allele fractions were determined. Levels of ctDNA were determined using the mean tumor allele fraction and the total concentration of cell-free DNA; absolute concentration of ctDNA was expressed as haploid genome equivalents per mL (hGE/mL). Finally, we correlated levels of ctDNA with clinical factors including stage, IPI, pretreatment metabolic tumor volume (MTV), and patient outcomes.Results: A total of 183 patients from six centers were enrolled (Stanford University, n=52; University of Eastern Piedmont, n=36; MD Anderson Cancer Center, n=21; Hospital Le Bocage, Dijon, n=25; the National Cancer Institute, n=33; and University Hospital Essen, n=16). Pretreatment cell-free DNA was sequenced deeply; ctDNA was detectable prior to therapy in 97% of patients. The performance of ctDNA detection was consistent across cohorts, with >90% of patients from each center having detectable ctDNA. Concentration of ctDNA was not significantly different across cohorts, with a median of 295 hGE of tumor DNA / mL (one-way ANOVA, P=0.62; Fig 1A). Using pretreatment plasma, all but 5 patients had mutations identifiable via non-invasive genotyping without knowledge of tumor genotype. In 88 patients with tumor samples available, a median of 81% (interquartile range: 34-92%) of variants identified via non-invasive genotyping were confirmed by tumor sequencing on a per-patient basis.We next sought to correlate levels of ctDNA with independent measures of tumor burden. We found a significant difference in ctDNA levels between patients in different IPI risk groups (one-way ANOVA, P<0.0001; Fig 1B). We also found that patients with higher-stage disease had higher ctDNA levels (P<0.0001); ctDNA levels also correlated with LDH (P<0.0001). We demonstrated a robust correlation between MTV and ctDNA level (P<0.0001; Fig 1C). This correlation was consistent across all three cohorts with MTV available (Essen: P=0.0005, r=0.80; Dijon: P<0.0001, r=0.73; Stanford: P=0.006, r=0.50). Finally, pretreatment ctDNA concentration was continuously associated with EFS and OS (P<0.0001 and P=0.0014). Using the median to divide patients into groups with high or low ctDNA, we found patients with high ctDNA levels had significantly inferior EFS compared to those with low ctDNA (P=0.005, HR 2.7, 95% CI 1.4-4.6; Fig 1D).Conclusions: Circulating tumor DNA is a robust biomarker of disease burden in DLBCL in patients from multiple medical centers across North America and Europe. Patients from different centers have similar levels of ctDNA despite pre-analytical variation. Concentrations of ctDNA correlate with stage, IPI, and tumor volume; furthermore, ctDNA level prior to therapy is prognostic of clinical outcome. This study validates previous findings and provides evidence that ctDNA is a reliable biomarker in aggressive lymphomas that could be used to refine clinical estimates of disease burden including stage.Figure 1: Reproducibility and clinical significance of pretreatment ctDNA. A) A stacked scatter plot compares ctDNA levels from patients across 6 cohorts. B) A stacked scatter plot shows ctDNA levels from patients with different IPI risk categories. C) A scatter plot compares metabolic tumor volume to ctDNA level. D) A Kaplan Meier estimate demonstrates event-free survival from the start of therapy for patients with pretreatment ctDNA level above and below the median value. (ND: Not detected). [Display omitted] DisclosuresHüttmann:Bristol-Myers Squibb, Takeda, Celgene, Roche: Honoraria; Gilead, Amgen: Other: Travel cost. Casasnovas:Roche: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria. Westin:Apotex: Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Membership on an entity's Board of Directors or advisory committees. Gaidano:Roche: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria. Diehn:Roche: Consultancy; Novartis: Consultancy; Quanticel Pharmaceuticals: Consultancy; Varian Medical Systems: Research Funding. Alizadeh:Gilead: Consultancy; CiberMed: Consultancy; Roche: Consultancy; Genentech: Consultancy; Celgene: Consultancy.

The Prognostic Implication of Inflammatory Factor-Based Scoring System in Diffuse Large B-Cell Lymphoma Patients in the Rituximab Era

▪BackgroundPrognostic scoring system has made a progress to better predict progression and survival of diffuse large B-cell lymphoma (DLBCL) patients. International prognostic index (IPI) is still valid even after the advent of rituximab for the treatment of DLBCL, however, there is still need for sophisticated prognostic scoring system with simply testable variables to individualize prognosis in patients treated with immunochemotherapy. In this context, various inflammatory factors detected by complete blood count and chemistry have been evaluated in several studies: the white blood cell count, the absolute lymphocyte count (ALC), the absolute monocyte count (AMC), the platelet-to-lymphocyte ratio, the neutrophil-to-lymphocyte ratio, the lymphocyte-to-monocyte ratio, lactate dehydrogenease (LDH), albumin, C-reactive protein (CRP), ferritin, and beta 2-microglobulin. This study aimed to make an inflammatory factor based scoring system for predicting survival and disease progression in DLBCL patients undergoing rituximab-based chemotherapy and estimate the possibility of elaboration of IPI with inflammatory factor based scoring system.MethodFive hundred and twenty-three patients with DLBCL treated with at least 2 or more cycles of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) as a first-line treatment were retrospectively analyzed. Each 6 factors for inflammatory scoring system were dichotomized by the reference of previously published papers and were given 1 point for each variables after the following criteria: the ALC < 1100/mm3, LDH > normal, albumin < 3.0 g/dL, CRP > 1.0 mg/dL, ferritin > 500 ng/mL, and beta 2-microglobulin ≥ 2.5 mg/L. Patients were further classified by inflammatory factor-based scoring system: score 0 (points 0-1), score 1 (points 2-3) and score 2 (points 4-6) and these scores substituted LDH in the IPI. The IPI scores plus scores by inflammatory factor-based scoring system was further classified into 4 risk groups: low (score 0-1), low-intermediate (score 2), high-intermediate (score 3), and high (score 4-6).ResultThe median follow-up duration was 37.61 months (range 0.60 - 139.03 months). All of the variables including the ALC < 1100/mm3, LDH > normal, albumin < 3.0 g/dL, CRP > 1.0 mg/dL, ferritin > 500 ng/mL, and beta 2-microglobulin ≥ 2.5 mg/L were statistically significant for progression free survival(PFS) and (OS) by univariate analysis. In multivariate analysis, LDH > normal and CRP > 1.0 mg/dL remained statistically significant for OS and CRP > 1.0 mg/dL was marginally significant for PFS (Table 1). By inflammatory factor-scoring system, score 0, 1, and 2 showed statistically significant OS (Figure 1, P= 0.000) and PFS (Figure 2, P= 0.000), and modified IPI risk groups showed significant differences in OS (Figure 3, P= 0.000) and PFS (Figure 4, P= 0.000).ConclusionThe risk groups stratified by inflammatory factor-based scoring system showed significant difference in both progression-free and overall survival in DLBCL patients in the Rituximab era. The inflammatory factor-based scoring system can further make delicate modification to IPI, substituting LDH. Validation of the finding in a larger cohort of patients is needed. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Identification of miRNA-34a and miRNA-155 as prognostic markers for mantle cell lymphoma.

ObjectiveMicroRNAs (miRNAs) with functional relevance have not been previously identified in mantle cell lymphoma (MCL). Here, we aimed to evaluate the relationships between miR-34a and miR-155-5p and MCL clinicopathology and prognosis.MethodsSeventy-five paraffin-embedded tissue samples from patients with MCL who completed at least four cycles of chemotherapy from January 2006 to October 2016, and 27 samples from control patients with reactive lymphoid hyperplasia (RLH), were collected. MiRNA expression levels were measured by qRT-PCR.ResultsThe miR-155-5p levels were significantly higher in patients with MCL than in the controls. The Eastern Cooperative Oncology Group (ECOG) ≥ 2 and Sex-Determining Region Y-Box transcription factor 11 (SOX11) < median value (M) groups presented lower miR-34a expression than the ECOG < 2 and SOX11 ≥ M groups, respectively. MiR-155-5p expression differed between low, intermediate, and high MCL International Prognostic Index risk groups. The AUCs of miR-34a and miR-155-5p were 0.5819 and 0.7784, respectively. The median survival times of the miR-34a ≤ 0.2150 and miR-155-5p > 2.11 groups were shorter than those of the miR-34a > 0.2150 and miR-155-5p ≤ 2.11 groups, respectively.ConclusionsLow miR-34a and elevated miR-155-5p levels may be correlated with poor prognosis in MCL.

Early Stage Diffuse Large B Cell Lymphoma in the Era of PET and Rituximab: Benefits from Radiotherapy in all NCCN International Prognostic Index Risk Groups

The use of radiotherapy (RT) remains controversial in the treatment of early stage diffuse large B-cell lymphoma (DLBCL) in the era of rituximab and PETCT, and it is unclear which subgroups of patients may benefit from RT. We sought to retrospectively review modern early stage I-II DLBCL patients treated with rituximab and staged by PETCT to better define which patients benefit from consolidative RT. An IRB approved retrospective review was performed of patients treated at our institution with early stage I-II DLBCL from 1998 to 2017 coinciding with our utilization of R-CHOP and PETCT. Inclusion criteria included AJCC 7th edition stage I-II DLBCL, treatment between the years of 1998-2017, chemotherapy as first line management, and age> = 18 years. Patients were excluded if they had prior RT or were diagnosed with multiple malignancies. Relevant clinical information including age, sex, ECOG performance status (PF), LDH values, tumor location (bulky, bony involvement, and extranodal), tumor size, and B symptoms was used to calculate NCCN IPI scores. Kaplan Meier survival analysis and Cox proportional hazards model were utilized for evaluation of prognostic factors of overall survival (OS). Between 1998 and 2017, 1040 adult patients were treated with lymphoma at our institution, with 144 patients with early stage DLBCL meeting inclusion criteria. Of these, 96 received chemotherapy alone while 48 received chemotherapy followed by RT. No prognostic factors examined were significantly correlated with receipt of RT. On univariate analysis, age(p<0.001), LDH (p = 0.005), ECOG PS (p<0.001), extranodal disease (p = 0.004), and NCCN IPI (p<0.001) were significantly correlated with OS. There was no correlation with either bony involvement (p = 0.67) or bulky disease (p = 0.58). Ten-year OS was 70.3% vs. 56.8% (p = 0.075) in favor of RT. When stratified by NCCN IPI risk group, RT trended towards benefit in all subgroups: 10-year OS for Low 100% vs. 80.1% (p = 0.14), Low-Int 73.6% vs. 62.0% (p = 0.095), and High-Int 35% vs. 16.5% (p = 0.096), with too few high-risk patients to analyze. Higher 10-year OS was noted among extranodal patients receiving RT 62.4% vs. 44.9% (p = 0.069) with no significant difference at 5-years following RT for patients with either bulky (79.1% vs. 54.8% (p = 0.37)) or bony (80% vs. 66.7% (p = 0.66)) involvement, respectively. On multivariate analysis, NCCN IPI (HR 2.56 (1.93-3.39), p<0.001) and RT (HR 0.44 (0.25-0.74), p = 0.002) were both significantly correlated with OS. The current analysis supports the use of consolidative RT in early stage DLBCL given an OS benefit noted on MVA that was maintained when controlling for NCCN IPI scores. There was no significant difference seen in bulky disease or bony involvement. Further prospective randomized data is needed to confirm these findings.

Multicenter Study of Risk-Adapted Therapy With Dose-Adjusted EPOCH-R in Adults With Untreated Burkitt Lymphoma.

Burkitt lymphoma is an aggressive B-cell lymphoma curable with dose-intensive chemotherapy derived from pediatric leukemia regimens. Treatment is acutely toxic with late sequelae. We hypothesized that dose-adjusted etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone, and rituximab (DA-EPOCH-R) may obviate the need for highly dose-intensive chemotherapy in adults with Burkitt lymphoma. We conducted a multicenter risk-adapted study of DA-EPOCH-R in untreated adult Burkitt lymphoma. Low-risk patients received three cycles without CNS prophylaxis, and high-risk patients received six cycles with intrathecal CNS prophylaxis or extended intrathecal treatment if leptomeninges were involved. The primary endpoint was event-free survival (EFS), and secondary endpoints were toxicity and predictors of EFS and overall survival (OS). Between 2010 and 2017, 113 patients were enrolled across 22 centers, and 98 (87%) were high risk. The median age was 49 (range, 18-86) years, and 62% were ≥ 40 years. Bone marrow and/or CSF was involved in 29 (26%) of patients, and 28 (25%) were HIV positive. At a median follow-up of 58.7 months, EFS and OS were 84.5% and 87.0%, respectively, and EFS was 100% and 82.1% in low- and high-risk patients. Therapy was equally effective across age groups, HIV status, and International Prognostic Index risk groups. Involvement of the CSF identified the group at greatest risk for early toxicity-related death or treatment failure. Five treatment-related deaths (4%) occurred during therapy. Febrile neutropenia occurred in 16% of cycles, and tumor lysis syndrome was rare. Risk-adapted DA-EPOCH-R therapy is effective in adult Burkitt lymphoma regardless of age or HIV status and was well tolerated. Improved therapeutic strategies for adults with CSF involvement are needed (funded by the National Cancer Institute; ClinicalTrials.gov identifier: NCT01092182).

Clinical characteristics and prognostic factors of 40 cases of primary systemic anaplastic large cell lymphoma

目的分析原发系统型间变性大细胞淋巴瘤（ALCL）的临床特征及预后因素。方法回顾性分析2013年1月至2018年12月期间在浙江大学医学院附属第一医院住院治疗的40例ALCL患者的临床资料，总结其临床特征并分析其预后相关因素。结果①40例患者中男29例，女11例，中位年龄41（14～67）岁，Ann Arbor分期Ⅲ～Ⅳ期36例（90.0％），IPI评分中高危、高危23例（57.5％）；25例（62.5％）有B症状，发热最为常见，其次为消瘦、盗汗；38例（95.0％）有结外侵犯；25例（62.5％）LDH升高；25例（62.5％）Ki-67≥80％；ALK阳性22例（55.0％），中位年龄29（14～67）岁，ALK阴性18例（45.0％），中位年龄51.5（19～67）岁，年龄差异有统计学意义（P＝0.003）。②40例患者均接受化疗，采用CHOP（环磷酰胺+多柔比星+长春地辛+泼尼松）方案18例，ECHOP（依托泊苷+CHOP）方案12例，其他方案10例；26例（65.0％）获得完全缓解（CR），ALK阴性（P＝0.029，OR＝13.458）和Ki-67≥80％（P＝0.04，OR＝14.453）是CR的独立影响因素，ECHOP方案的CR率高于CHOP方案［83.3％（10/12）对38.9％（7/18），P＝0.026］。③LDH水平、IPI评分、ALK表达情况以及化疗方案的选择对无进展生存（PFS）和总生存（OS）影响有统计学意义（P<0.05）。结论ALCL发病男性居多，青少年至中老年均有发病，ALK阳性中年轻患者居多，诊断时临床分期晚，多数患者有结外侵犯，半数以上患者有B症状、LDH升高、Ki-67高表达；ALK表达与否、Ki-67表达水平以及化疗方案的选择可影响疗效，LDH水平、IPI评分、ALK表达与否以及化疗方案的选择可影响PFS和OS；ECHOP是较优的化疗方案，可改善预后。

Academic Centers Compared With Nonacademic Centers for Patients With International Prognostic Index Risk-stratified Diffuse Large B-cell Lymphoma: A Survival Outcomes Analysis

IntroductionDiffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease associated with varying outcomes. The International Prognostic Index (IPI) has been the standard for the baseline prognostic assessment in these patients. The present study aimed to determine the effect of the treatment facility on the overall survival outcomes in patients with DLBCL stratified by IPI risk groups. Materials and MethodsThe National Cancer Database was used to identify patients with a diagnosis of DLBCL from 2004 to 2015. DLBCL was stratified by the IPI risk score from low- to high-risk disease, and the overall survival of those treated at academic centers was compared with that of those treated at nonacademic centers. ResultsTreatment at academic centers was associated with significantly improved overall survival for all patients with DLBCL (108.3 months) compared with those treated at nonacademic centers (74.5 months; P < .001). The median survival for patients with high-risk disease treated at academic centers (33.5 months) was more than twice that of high-risk patients treated at nonacademic centers (14.4 months; P < .001). The median survival for the other risk categories was similarly improved, although less pronounced in the lower IPI score groups. The long-term overall survival for all patients with DLBCL at academic centers was improved at 5 and 10 years (59% and 43% survival, respectively) compared with those treated at nonacademic centers (51% and 35% survival, respectively; P < .001). ConclusionPatients with DLBCL treated at academic centers demonstrated improved survival compared with those treated at nonacademic centers, especially those with high-risk disease. Further investigations into the factors contributing to such disparities are required to help standardize care and improve outcomes.