Electronic FRAIL score may predict treatment outcomes in older adults with myeloma

IntroductionFrailty is a known risk factor for older patients with myeloma. Here we present realworld data using a computer-generated frailty assessment score (FRAIL score), based on 5 clinically derived parameters, in predicting patient outcomes.MethodsOlder patients with newly diagnosed multiple myeloma who received frontline treatment with cyclophosphamide-bortezomib-dexamethasone had their FRAIL score retrospectively assessed. Treatment outcomes were assessed using standard IMWG criteria, and event free survival and overall survival determined.Results155 patients were analysed. Compared to those who were assessed as non-frail (FRAIL score 0–1) likely-frail patients (score ≥ 2) were less likely to complete the full course of treatment (24.3% vs 53.4%, p = 0.002), and more likely to terminate treatment due to toxicities (35.1% vs 22.0%, p = 0.109), as well as having a greater number of patients stop treatment early for reasons other than toxicity or progression (27.0% vs 10.2%, p = 0.010). After a median follow up of 42.5 months, likely-frail patients were found to have a trend for shorter event-free survival (median EFS, 8.7 vs 17.9 months, p = 0.064) and statistically inferior overall survival (median OS, 30.2 vs 49.8 months, p < 0.001). After adjusting for age, stage, and Charlson comorbidity index, FRAIL score was prognostic for OS (HR = 3.47, 95% CI 1.88–6.4), but not EFS (HR = 1.28, 95%CI 0.79–2.06).ConclusionThe FRAIL score is independently predictive of overall survival in older patients with myeloma receiving bortezomib-based induction chemotherapy and can help identify those patients more likely to experience treatment toxicity.     

Improving outcomes for patients with diffuse large B-cell lymphoma

Diffuse large B-cell lymphoma (DLBCL) is the most commonly occurring form of non-Hodgkin lymphoma in the western world. Until the mid 1990s the incidence of DLBCL increased in both sexes, across racial categories, and across all age groups except the very young, the etiology of most cases remains unknown. DLBCL is associated with an aggressive natural history, but it can be cured with combination chemotherapy regimens like cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), which has been the mainstay of therapy for several decades. Remarkable progress has been made in understanding the biological heterogeneity of DLBCL and in improving survival for DLBCL patients with novel combinations of chemotherapy and immunotherapy. Gene expression profiling (GEP) has uncovered DLBCL subtypes that have distinct clinical behaviors and prognoses, and the addition of the monoclonal antibody, rituximab, to CHOP has markedly improved outcomes. Future approaches to DLBCL management will use molecular signatures identified through GEP to provide prognostic information and to isolate therapeutic targets that are being evaluated for DLBCL patients who relapse or those with high risk disease.     

Evolution of R-CHOP therapy for older patients with diffuse large B-cell lymphoma

Non-Hodgkin's lymphoma is the fifth most common malignancy in adults in the USA. This disorder is especially relevant in the elderly patient population, as the median age of patients with this disorder is 65 years. Almost half of these disorders in older patients are of a diffuse large B-cell (DLBCL) subtype. The therapy of DLBCL has undergone a renaissance in the past decade, with the addition of rituximab to standard regimens, such as cyclophosphamide- doxorubicin-vincristine-prednisone (CHOP). Over this time, there have been several large Phase III treatment trials in which the CHOP and rituximab-CHOP (R-CHOP) regimens have been prospectively compared, including three trials confined to the elderly patient population. In these trials, it has been demonstrated repeatedly that the addition of rituximab results in an improved outcome, with higher response rates and prolongation in parameters including progression-free, event-free, disease-free and overall survival. In addition, this regimen has been well tolerated, even in older patients. Based upon these data, the R-CHOP regimen has now been established as the standard for initial therapy of DLBCL in older patients with DLBCL. However, issues still remain with regard to the ideal schedule of R-CHOP administration, specifically the optimal number of cycles of therapy (six vs eight), as well as cycle length (14 vs 21 days).     

Evolution of R-CHOP therapy for older patients with diffuse large B-cell lymphoma

Non-Hodgkin’s lymphoma is the fifth most common malignancy in adults in the USA. This disorder is especially relevant in the elderly patient population, as the median age of patients with this disorder is 65 years. Almost half of these disorders in older patients are of a diffuse large B-cell (DLBCL) subtype. The therapy of DLBCL has undergone a renaissance in the past decade, with the addition of rituximab to standard regimens, such as cyclophosphamide– doxorubicin–vincristine–prednisone (CHOP). Over this time, there have been several large Phase III treatment trials in which the CHOP and rituximab-CHOP (R-CHOP) regimens have been prospectively compared, including three trials confined to the elderly patient population. In these trials, it has been demonstrated repeatedly that the addition of rituximab results in an improved outcome, with higher response rates and prolongation in parameters including progression-free, event-free, disease-free and overall survival. In addition, this regimen has been well tolerated, even in older patients. Based upon these data, the R-CHOP regimen has now been established as the standard for initial therapy of DLBCL in older patients with DLBCL. However, issues still remain with regard to the ideal schedule of R-CHOP administration, specifically the optimal number of cycles of therapy (six vs eight), as well as cycle length (14 vs 21 days).     

Bcl-2 gene expression as a predictor of outcome in diffuse large B-cell lymphoma

Diffuse large B-cell lymphoma (DLBCL) is an aggressive lymphoma with a 5-year survival rate of 35%-60%. Various clinical factors included in the International Prognostic Index have failed to identify the patients with DLBCL who will not benefit from the standard R-CHOP (cyclophosphamide/doxorubicin/vincristine/prednisone plus rituximab) treatment regimen. Bcl-2 has been implicated in conferring resistance to chemotherapy in non-Hodgkin's lymphoma and is therefore a candidate prognostic marker in DLBCL. To identify the correlation between Bcl-2 expression and response to rituximab-containing treatment regimens, histologic materials were analyzed from 292 elderly patients with confirmed DLBCL. Of these, 155 patients had received R-CHOP (53%) and 137 had received CHOP (47%). One hundred ninety-three patients (66%) were found to express high levels of Bcl-2 protein in > 50% of the tumor cells. Of the 193 Bcl-2-positive patients, the patients who received R-CHOP had a better 5-year overall rate than patients treated with CHOP (56% vs. 42%; P = 0.01), whereas in the patients with Bcl-2-negative disease, there was no statistically significant difference in the 5-year overall survival rates between the R-CHOP and CHOP regimens (58% vs. 52%; P = 0.6). Therefore, the addition of rituximab to the standard chemotherapy regimen seems to have overcome the Bcl-2-associated resistance to chemotherapy.     

Gene expression-based risk score in diffuse large B-cell lymphoma

Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma and displays heterogeneous clinical and molecular characteristics. In this study, high throughput gene expression profiling of DLBCL tumor samples was used to design a 12-gene expression&ndash;based risk score (GERS) predictive for patient''s overall survival. GERS allowed identifying a high-risk group comprising 46,4% of the DLBCL patients in two independent cohorts (n=414 and n=69). GERS was shown to be an independent predictor of survival when compared to the previously published prognostic factors, including the International Prognostic Index (IPI). GERS displayed a prognostic value in germinal-center B-cell&ndash;like subgroup (GCB) and activated B cell&ndash;like (ABC) molecular subgroups of patients as well as in DLBCL patients treated with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) or Rituximab-CHOP (R-CHOP) regimens. Combination of GERS and IPI lead to a potent prognostic classification of DLBCL patients. Finally, a genomic instability gene signature was highlighted in gene expression profiles of patients belonging to the high-risk GERS-defined group.     

99例结外弥漫性大B细胞淋巴瘤的治疗结果

目的 探讨结外弥漫性大B细胞淋巴瘤的临床特征和治疗结果.方法 回顾性分析2000--2006年期间收治的99例结外弥漫性大B细胞淋巴瘤(DLBCL),所有病例经过病理和免疫组化确诊.胃肠道原发32例,原发中枢神经系统和睾丸共14例,其余部位53例.结果 结外DLBCL的临床特点主要表现为高龄、男性略多见、全身症状少见、Ⅰ～Ⅱ期多见、一般状态较好、国际预后指数评分多为中低分.全组5年总生存率为78.9%,原发胃肠道、原发中枢神经系统和睾丸、其他原发部位的5年总生存率分别为82.5%、37.0%、74.6%.全组病例单因素预后分析显示PS评分、结外受侵>1个及国际预后指数评分对5年总生存率有影响.结论 结外DLBCL为一组异质性疾病,预后良好,但原发于中枢神经系统和睾丸部位的病例预后可能较差.     

Improved survival with rituximab-based chemoimmunotherapy in older patients with extranodal diffuse large B-cell lymphoma

Using the Surveillance, Epidemiology, and End Results (SEER)–Medicare database, we investigated the relative benefits of adding rituximab to CHOP chemotherapy in diffuse large B-cell lymphoma (DLBCL) of extranodal origin, and found similar advantage for nodal and extranodal lymphomas. Hazard ratio for overall survival was 0.64 for nodal, and 0.70 for extranodal DLBCL. Hazard ratios for lymphoma-related death were 0.62 and 0.57, respectively. The advantage was largest for DLBCL of the spleen, liver and lung. Conversely, it was not evident for thyroid or testicular lymphomas. Compared with nodal DLBCL, spleen was the only site with significantly better prognosis after R-CHOP.     

Racial differences in treatment and survival in older patients with diffuse large B-cell lymphoma (DLBCL)

Background  

Diffuse large B-cell lymphoma (DLBCL) comprises 31% of lymphomas in the United States. Although it is an aggressive type of lymphoma, 40% to 50% of patients are cured with treatment. The study objectives were to identify patient factors associated with treatment and survival in DLBCL.     

Venous thromboembolism in patients with diffuse large B-cell lymphoma

We conducted a retrospective record review to determine the frequency of venous thromboembolism (VTE) in patients with diffuse large B-cell lymphoma (DLBCL). All records from 1990 to 2001 of patients with the diagnosis of DLBCL at a tertiary care hospital were reviewed. Those with transformation from low-grade lymphoma, central nervous system lymphoma, HIV-related lymphoma or with incomplete records were excluded. All episodes of symptomatic VTE confirmed by imaging studies that were either present at diagnosis or occurred during initial treatment were identified. VTE occurred in 27 of 211 patients (12.8%). Stage I disease was associated with a low risk, whereas a high international prognostic index score increased risk. Of patients with VTE, thrombosis was present at diagnosis in 37% and occurred during the first chemotherapy cycle in 22% and during the first three cycles in 82%. The median survival of patients with VTE was 1.04 years [95% confidence interval (CI) = 0.75 - 1.33] compared to 5.2 years (95% CI 1.8 - 8.6) for those without VTE (P = 0.038). We conclude that VTE is a frequent complication of DLBCL that occurs particularly at diagnosis and during initial therapy, and it is associated with a worse prognosis.     

Conditional survival of patients with diffuse large B-cell lymphoma

BACKGROUND: Prognosis of lymphoma patients is usually estimated at the time of diagnosis and the estimates are guided by the International Prognostic Index (IPI). However, conditional survival estimates are more informative clinically, as they consider those patients only who have already survived a period of time after treatment. Conditional survival data have not been reported for lymphoma patients. METHODS: Conditional survival was estimated for 1209 patients with diffuse large B-cell lymphoma (DLBCL) from the population-based LYFO registry of the Danish Lymphoma Group. The Kaplan-Meier method was used to estimate conditional survival at 0-5 years after diagnosis. RESULTS: The probability of surviving 5 years increases with each year survived for the first 3 years after diagnosis, after which the increase is minimal. The median survival increases from 38 months for all patients to between 108 and 120 months, conditioned on survival for at least 3-5 years. The prognostic capacity of the IPI and the age-adjusted IPI was high at diagnosis, but the significance gradually declined in the first years after diagnosis. Furthermore, the prognostic impact of the individual clinical variables of the IPI was also significant at diagnosis, but 2 years after diagnosis only age had prognostic impact. Multivariate analysis of patients who survived > or = 3 years identified only age as a prognostic factor. CONCLUSION: For patients with DLBCL who have survived more than 1 year after diagnosis, the conditional survival probability provides more accurate prognostic information than the conventional survival rate estimated from the time of diagnosis.     

Treatment of elderly patients with diffuse large B-cell lymphoma

With the implementation of rituximab, tremendous progress has been achieved in the treatment of diffuse large B-cell lymphoma (DLBCL). Nevertheless, the majority of patients with DLBCL are over the age of 65 years and the management of these patients is often suboptimal. Standard chemo-immunotherapy with curative approach should be appropriate for all elderly patients who can tolerate it. Therefore, a careful evaluation of each patient is mandatory prior to treatment allocation. R- CHOP regimen (rituximab, cyclophosphamide doxorubicin, vincristine, prednisolone) remains the standard of care, but special attention has to be paid to rigorous supportive care. Patients not fit enough for R-CHOP are candidates for dose-reduced therapy or other palliative strategies.     

弥漫性大B细胞淋巴瘤的治疗选择

弥漫性大B细胞淋巴瘤（diffuse large B-cell lymphpma,DLBCL）是非霍奇金淋巴瘤中最常见的类型,在分子遗传学、免疫表型等方面具有高度异质性,患者临床预后也截然不同。R-CHOP方案为DLBCL标准治疗方案,如何进一步提高DLBCL疗效是近年来的研究热点。2015年美国临床肿瘤学会（ASCO）提出基于细胞起源分型进行R-CHOP+X方案治疗的策略,但这些方案相继失败。基于更加精准的分层方法,筛选出不同DLBCL亚组并进行针对性治疗,是未来DLBCL治疗的方向。此外,抗体-药物偶联物、双特异性抗体和嵌合抗原受体T细胞（chimeric antigen receptor T-cell,CAR-T）等免疫治疗近年来取得突破性进展,为DLBCL患者带来新的希望。本文针对基于精准分层的DLBCL靶向治疗、免疫治疗的最新进展及遗传学检测方法予以综述。      

Current treatment approaches for diffuse large B-cell lymphoma

There have been two major developments over the last decade that has led to improvements in outcome and longer survival for patients with diffuse large B-cell lymphoma (DLBCL). These developments have been firstly to increase the dose of active cytotoxic drugs and shorten the time between cycles, resulting in dose-dense and/or dose-intense regimens and secondly the addition of the anti-CD20 monoclonal antibody rituximab to chemotherapy. Both strategies have been associated with higher response rates, lower relapse rates, longer event-free survival (EFS) and improved overall survival (OS), particularly in better prognostic groups. A combination of dose-dense and dose-intense chemotherapy regimens plus rituximab is currently being tested to confirm that the use of both approaches confers survival advantage. High-risk, poorer-prognosis DLBCL remains a challenge, and new treatment strategies are required for these patients. Improvements in outcome may potentially be achieved through a greater understanding of the genetic abnormalities specifically associated with poorer-prognosis disease, and factors that lead to unresponsiveness to chemotherapy. The role of radiotherapy is currently less clearly defined than at anytime in the management of DLBCL and the current evidence for using radiotherapy in this disease is therefore rigorously reviewed.     

Debulking surgery for patients with diffuse large B-cell non-Hodgkin's lymphoma

Chemotherapy and radiotherapy have been the principal modalities of treatment for diffuse large B-cell non-Hodgkin's lymphoma (B-NHL) for over 30 years. Various treatment regimens have been designed over the years to try to increase response and cure rates. The role of surgery has been generally restricted to defined and limited situations including diagnostic tissue biopsies and treating abdominal emergencies such as organ rupture or perforation. We present two cases of refractory B-NHL, where surgery was used as a part of stepwise and multi-modal treatment with curative intent. In both cases, the treatment approach included standard dose chemotherapy, eradication of residual mass by surgery, high dose chemotherapy (HDC) with stem cell support and posttransplantant immunotherapy. Currently, 2 years after completing the therapy, both patients are well with no evidence of active disease. Based on our experience with 2 patients we believe that in specific cases of residual chemo-resistant lymphomatous mass, surgery should be considered as a part of a multimodal approach.     

Clinical impact of controlling nutritional status score on the prognosis of patients with diffuse large B-cell lymphoma

The controlling nutritional status (CONUT) score is a nutritional index calculated from serum albumin and total cholesterol levels and lymphocyte counts. Its role in predicting clinical outcomes of diffuse large B-cell lymphoma (DLBCL) has not been evaluated. In this retrospective study, data from 476 patients with DLBCL were analyzed. The cutoff value of the CONUT score was set as 4. CONUT score significantly stratified the overall survival (OS) and the progression-free-survival (PFS) (5-year OS, 49.0% vs 83.2%, P < .001; 5-year PFS, 46.1% vs 73.1%, P < .001) of the patients. Among patients at high-intermediate or high risk, as per the National Comprehensive Cancer Network International Prognostic Index (NCCN-IPI), 5-year OS was lower in patients with high CONUT scores than in those with low CONUT scores (high-intermediate risk, 51.2% vs 75.5%, P < .001; high risk, 29.9% vs 63.3%, P = .007). Additionally, in patients with high CONUT scores, maintenance of relative dose intensity (RDI) of chemotherapy did not affect the 5-year OS (RDI > 80% vs RDI ≤ 80%: 59.8% vs 50.9%, P = .73). In the present study, we have demonstrated that the CONUT score is an independent prognostic factor in patients with DLBCL.