Enhancement of the Follicular Lymphoma International Prognostic Index (FLIPI) with lymphopenia (FLIPI-L): a predictor for overall survival and histologic transformation.
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ABSTRACT:
SUBMITTER: Yang G
PROVIDER: S-EPMC6938796 | biostudies-literature | 2020 Jan
REPOSITORIES: biostudies-literature
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Enhancement of the Follicular Lymphoma International Prognostic Index (FLIPI) with lymphopenia (FLIPI-L): a predictor for overall survival and histologic transformation.
Yang George G Mills Matthew M Kim Youngchul Y Figura Nicholas B NB Doyle Catherine C Oliver Daniel D Grass G Daniel GD Robinson Timothy T Chavez Julio J Kim Sungjune S
Blood cancer journal 20200102 12
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Project description:Although histologic analysis is the gold standard for diagnosing follicular lymphoma (FL) transformation, many patients are diagnosed with transformation by clinical factors as biopsy specimens often cannot be obtained. Despite the frequency of clinical diagnosis, no clinical assessment tool has yet been established for FL transformation in the rituximab era. We derived and validated a transformation scoring system (TSS) based on retrospective analyses of 126 patients with biopsy-proven FL and histologic transformation (HT) at two hospitals of the National Cancer Center of Japan. In the derivation set (76 patients), the detailed analyses of the clinical characteristics at disease progression showed that lactate dehydrogenase (LDH) elevation, focal lymph nodal (LN) enlargement, hemoglobin <12 g/dl, and poor performance status (PS) (2-4) were associated with HT. The weights of these variables were decided based on the regression coefficients. Next, we constructed a TSS encompassing the above four factors: LDH, (> upper limit of normal [ULN], ≤ULN ×2) (1 point), (≥ULN ×2) (2 points); focal LN enlargement, (≥3 cm, <7 cm) (1 point), (≥7 cm) (2 points); hemoglobin <12 g/dl (1 point); poor PS (2 points). We identified a high positive predictive value (PPV) (96.4%) and negative predictive value (NPV) (85.4%) for diagnosing HT when a cutoff score of 2 was selected for our TSS. In an external validation set (50 patients), the probability of HT was high with scores ≥2 (PPV, 93.3%; NPV, 82.9%). We developed a TSS that offers a simple, yet, valuable tool, for diagnosing HT, especially in patients who cannot undergo biopsy.
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Project description:Background/aimsThe Follicular Lymphoma International Prognostic Index (FLIPI) and FLIPI2 are well-known prognostic models for patients with follicular lymphoma (FL). However, their prognostic relevance has not been examined before in Korean patients with FL.MethodsWe reviewed clinical and laboratory information from our database of patients between 1995 and 2012. In total, 125 patients were stratified in three categories according to FLIPI or FLIPI2 scores: low-, intermediate-, and high-risk groups. We compared FLIPI and FLIPI2 in terms of progression-free survival (PFS) and overall survival (OS).ResultsAmong the 125 patients, the prognostic value of FLIPI and FLIPI2 was evaluated in 73 patients who fulfilled the criteria of both prognostic models. Risk stratification by FLIPI and FLIPI2 showed significant differences in unfavorable parameters among each risk group, particularly between low- and intermediate-risk groups. The high-risk group b was significantly associated with poor PFS on both FLIPI and FLIPI2 (p < 0.05). However, the OS was significantly different only in the risk groups determined by FLIPI2 (p = 0.042). In a subgroup analysis of patients who received rituximab-containing chemotherapy, the risk stratification of both prognostic models showed a significant impact on PFS, especially in the low-risk group.ConclusionsFLIPI and FLIPI2 are appropriate prognostic models in Korean FL patients, especially for discriminating low-risk patients from intermediate- and high-risk groups.
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Project description:Follicular lymphoma (FL) is an indolent disease, but 30%-40% of cases undergo histologic transformation to an aggressive malignancy, typically represented by diffuse large B cell lymphoma (DLBCL). The pathogenesis of this process remains largely unknown. Using whole-exome sequencing and copy-number analysis, we show here that the dominant clone of FL and transformed FL (tFL) arise by divergent evolution from a common mutated precursor through the acquisition of distinct genetic events. Mutations in epigenetic modifiers and antiapoptotic genes are introduced early in the common precursor, whereas tFL is specifically associated with alterations deregulating cell-cycle progression and DNA damage responses (CDKN2A/B, MYC, and TP53) as well as aberrant somatic hypermutation. The genomic profile of tFL shares similarities with that of germinal center B cell-type de novo DLBCL but also displays unique combinations of altered genes with diagnostic and therapeutic implications.
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Project description:Follicular lymphoma (FL) is a common B-cell lymphoma and typically affects the elderly population. It is urgently required to enhance our comprehension of disease-specific outcomes in elderly FL patients and identify a reliable predictive indicator to assess patient risk and guide treatment options for them. Therefore, we retrospectively analysed clinical data of 128 elderly patients (aged 60 years or older) with FL treated at Tianjin Medical University Cancer Institute & Hospital from 2002 to 2020. Univariate and multivariate analyses were performed to identify high risk prognostic factors, and we evaluated the predictive capacity of several prognostic scoring models by survival analysis and receiver operating characteristic (ROC) curves. Our analysis revealed that the age ≥70 was a significant independent predictor for both OS and PFS. FLIPI2 model can classify elderly FL patients into two risk groups with different prognoses, but the FLIPI and PRIMA-PI scoring systems may not be as applicable to this specific patient population. Based on the above results, we modified the FLIPI2 scoring system to set age ≥70 years as a risk factor and developed a novel prognostic index called the Age-adjusted FLIPI2 (A-FLIPI2), which effectively classified older FL patients into three distinct groups with significantly different outcomes. Among the four scoring systems evaluated, A-FLIPI2 showed the highest AUC for predicting risk of death (0.793) and disease progression (0.678). And the performance of A-FLIPI2 is validated in an external validation cohort. Thus, A-FLIPI2 is a better prognostic model for elderly FL patients. In conclusion, the newly developed prognostic index A-FLIPI2 in this study offers improved risk stratification for elderly FL patients.
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Project description:Follicular lymphoma (FL) is an indolent but largely incurable disease. Some patients suffer histological transformation to a more aggressive subtype with poorer prognosis. This study aimed to improve our understanding of the genetics underlying FL histological transformation, and to identify genetic drivers or promoters of the transformation by elucidating the differences between FL samples from patients who did and did not transform. We conducted targeted massive parallel sequencing of 22 pre-transformed FL/transformed diffuse large B-cell lymphoma pairs and 20 diagnostic samples from non-transformed FL patients. Additionally, 22 matched samples from 11 transformed FL patients (pre-transformed FL and diffuse large B-cell lymphoma) and 9 non-transformed FLs were studied for copy number variation using SNP arrays. We identified recurrently mutated genes that were enriched at transformation, most notably LRP1B, GNA13 and POU2AF1, which have roles in B-cell differentiation, GC architecture and migration. Mutations in POU2AF1 might be associated with lower levels of expression, were more frequent in transformed FLs, and seemed to be specific to transformed- compared with de novo-diffuse large B-cell lymphomas. Pre-transformed FLs carried more mutations per sample and had greater subclonal heterogeneity than non-transformed FLs. Finally, we identified four mutated genes in FL samples that differed between patients who did and did not transform: NOTCH2, DTX1, UBE2A and HIST1H1E. The presence of mutations in these genes was associated with shorter time to transformation when mutated in the FL biopsies. This information might be useful for identifying patients at higher risk of transformation.
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Project description:PurposeBurkitt lymphoma (BL) has unique biology and clinical course but lacks a standardized prognostic model. We developed and validated a novel prognostic index specific for BL to aid risk stratification, interpretation of clinical trials, and targeted development of novel treatment approaches.MethodsWe derived the BL International Prognostic Index (BL-IPI) from a real-world data set of adult patients with BL treated with immunochemotherapy in the United States between 2009 and 2018, identifying candidate variables that showed the strongest prognostic association with progression-free survival (PFS). The index was validated in an external data set of patients treated in Europe, Canada, and Australia between 2004 and 2019.ResultsIn the derivation cohort of 633 patients with BL, age ≥ 40 years, performance status ≥ 2, serum lactate dehydrogenase > 3× upper limit of normal, and CNS involvement were selected as equally weighted factors with an independent prognostic value. The resulting BL-IPI identified groups with low (zero risk factors, 18% of patients), intermediate (one factor, 36% of patients), and high risk (≥ 2 factors, 46% of patients) with 3-year PFS estimates of 92%, 72%, and 53%, respectively, and 3-year overall survival estimates of 96%, 76%, and 59%, respectively. The index discriminated outcomes regardless of HIV status, stage, or first-line chemotherapy regimen. Patient characteristics, relative size of the BL-IPI groupings, and outcome discrimination were consistent in the validation cohort of 457 patients, with 3-year PFS estimates of 96%, 82%, and 63% for low-, intermediate-, and high-risk BL-IPI, respectively.ConclusionThe BL-IPI provides robust discrimination of survival in adult BL, suitable for use as prognostication and stratification in trials. The high-risk group has suboptimal outcomes with standard therapy and should be considered for innovative treatment approaches.
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Project description:Follicular lymphoma (FL) is an indolent neoplasia comprising approximately 20% of lymphomas. FL is generally considered incurable, with a median survival exceeding 10 years. A subset of FL patients experiences histological transformation (HT) to a more aggressive lymphoma, resulting in markedly poorer clinical outcome, with a reduced median survival after transformation of 1-2 years. Early, reliable prediction of HT would be valuable in the clinical setting, allowing pre-emptive therapeutic intervention. We previously used proteomics to identify the glycolytic enzymes fructose-bisphosphate aldolase A (aldolase A) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) as candidate predictors of FL transformation. Now, we use immunohistochemistry to evaluate expression of these enzymes in paired primary FLs from patients with (n = 41) or without subsequent HT (n = 49), to test their value as predictive biomarkers. At initial FL diagnosis, patients with subsequent HT had significantly higher expression of aldolase A and GAPDH (p<0.001 and p<0.01) compared with patients without HT. Furthermore, high expression of aldolase A and GAPDH was associated with significantly shorter transformation free survival (p = 0.018, p = 0.001). These data suggest that high expression of aldolase A and GAPDH, may indicate increased metabolic turnover, and that these enzymes may be useful biomarkers in primary FL for predicting the risk of subsequent lymphoma transformation.
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