19 Nov 2018

Diffuse large B-cell lymphoma: 10 years’ real-world clinical experience with rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisolone

Treatment with rituximab plus a regimen of cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP) for patients with diffuse large B-cell lymphoma (DLBCL) has proven efficacy in clinical trials. The present study investigated its application in clinical practice. This single-center, retrospective database analysis included patients with DLBCL treated at the Slovenian Institute of Oncology Ljubljana between 2004 and 2013. Overall survival (OS) and progression-free survival (PFS) were assessed according to International Prognostic Index (IPI) and revised IPI (R-IPI) categories. Overall, 573 patients with DLBCL were included in the study (median follow-up, 45.3 months; range, 0.1–143.0). Patients were categorized as IPI ‘low’ (n=170; 30%), ‘low-intermediate’ (n=134; 23%), ‘high-intermediate’ (n=129; 23%) and ‘high’ (n=140; 24%) risk. R-IPI groups were indicated with ‘very good’ (n=59; 10%), ‘good’ (n=245; 43%) and ‘poor’ (n=269; 47%) prognosis. Ten-year OS and PFS rates were 51 and 72%, respectively; median OS was 124 months and median PFS was not reached. Ten-year OS rates were 80 and 87% in low-risk and ‘very good’ prognosis groups, respectively, and 30 and 37% in high-risk and poor prognosis patients, respectively. This analysis of patients with DLBCL indicated that many patients treated with R-CHOP and R-CHOP-like regimens in the real-world setting have excellent outcomes.

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphomas, constituting up to 40% of cases globally (). Global epidemiological data on DLBCL are limited, but the estimated incidence is 7 per 100,000 in the USA (). In Slovenia, the annual incidence of non-Hodgkin lymphomas was 374 in 2013 (); 36% of these cases are believed to be DLBCL () Although most commonly observed in older patients, DLBCL can affect any age group, including children ().

DLBCL is an aggressive condition and many patients have advanced disease at diagnosis (). The prognosis of a patient with DLBCL can be predicted using their International Prognostic Index (IPI) score. The IPI score is calculated based on age, serum lactate dehydrogenase level, Eastern Cooperative Oncology Group performance score, disease stage, and the number of extranodal disease sites ().

Treatment for patients with DLBCL generally consists of a combination of chemotherapy [cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP)] and rituximab (R-CHOP). Although many clinical trials have demonstrated the efficacy and tolerability of R-CHOP in patients with DLBCL, () less is known about the use of this regimen in the real-world setting.

Real-world studies can complement the results of clinical trials and provide additional information that can help guide physicians making treatment decisions. Clinical trial data may not be generalizable to the broad range of patients commonly encountered in the clinical setting, as they may be limited to younger patients with good baseline characteristics. Patients encountered in real-world clinical practice may be older and have comorbidities that would have excluded their participation in rigorously designed clinical trials. Consequently, real-world studies can provide a valuable insight into these less widely studied patients.

We previously described the real-world use of R-CHOP in patients with DLBCL in Slovenia (). We now present the results of extended follow-up in an expanded patient group.

Records were searched for all patients with DLBCL who were treated at the Institute of Oncology Ljubljana between 2004 and 2013 for inclusion in this analysis.

All procedures followed in this study were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and the Helsinki Declaration of 1975, as revised in 2000. Individual patient consent was not collected for this study as this was a retrospective database analysis and the institutional informed consent form for treatment included consent to use the patient’s data, materials and/or test results for research purposes. The study was approved as such by the institutional review board of the Institute of Oncology Ljubljana.

Patient characteristics, pathohistological diagnosis, disease stage, and response to treatment were taken from patient records. Survival data were retrieved from the Cancer Registry of the Republic of Slovenia [www.slora.si]. Treatment response was evaluated according to Cheson criteria, with the exception of criteria regarding positron-emission tomography (PET) evaluation, which was not routinely used in Slovenia before January 2016 (). Progression-free survival (PFS) and Overall survival (OS) were calculated using Kaplan-Meier survival curves. PFS, which was determined for patients receiving first-line treatment only, was defined as the time from the beginning of treatment to disease progression for patients achieving complete or partial remission; OS was defined as the time from the beginning of treatment to the time of death or the end of observation for all patients.

Patients were categorized according to IPI () and revised IPI (R-IPI) () scores. We also compared younger patients (aged <60 years) with good (IPI 0 or 1) vs. poor (IPI ≥2) prognosis and we compared older (aged ≥60 years) vs. younger (aged <60 years) patients. Statistically significant differences were calculated using log-rank and χ2 tests.

Between 2004 and 2013, 624 patients with DLBCL were treated at the Institute of Oncology Ljubljana, Slovenia. The diagnosis of DLBCL was established histologically in 523 patients (84%) and cytologically in 101 patients (16%). Patient characteristics are summarized in Table I.

Long-term follow-up data for patients with DLBCL are scarce, particularly among patients treated in the real-world setting. We have described the use of rituximab-based regimens in over 600 patients of varying ages and disease stages over a prolonged follow-up period. To the best of our knowledge, no other studies have assessed outcomes in patients with DLBCL in the real-world setting.

In our patient population, an overall 10-year PFS rate of 72% was observed, ranging from 64% in patients classed according to IPI as ‘high-intermediate’ risk (IPI 3) to 75% in patients with low risk (IPI 0 or 1) and from 66% in patients with R-IPI poor prognosis (R-IPI 3–5) to 84% in those with very good prognosis (R-IPI 0). Median PFS was not reached in any of the IPI risk categories. PFS rates were numerically but not statistically significantly higher in patients aged <60 years compared with those aged ≥60 years, with 79% of younger patients and 70% of older patients free from progression after 10 years. Coiffier et al reported a 10-year PFS rate of 37% in their group of patients aged 60–80 years in the LNH-98.5 trial () lower than the 10-year rates seen in our older patients. The median PFS was 4.8 years in the LNH-98.5 trial; median PFS has not yet been reached in our group of patients after a median follow-up of 45 months. However, differences between the two patient populations and study designs call for caution when comparing the results of the two studies.

With regard to OS, we observed a 10-year OS rate of 51% in the overall population and 41% in older patients, the latter being comparable with the 43.5% reported for patients aged ≥60 years in the LNH-98.5 study (). Purroy et al reported a 10-year OS rate of 64% in their group of patients with DLBCL, with little difference between older and younger patients (64% for those aged <60 years and 63% for those aged ≥60 years) in contrast to the present study (). They also reported a 10-year OS rate of 59% in patients with high-risk disease (IPI score ≥3), somewhat higher than the rates we observed in our patients. Once again, however, cross-study comparisons are complicated by many factors, including differences in the treatment settings and patient populations.

We observed a statistically significant difference in OS between younger patients with good vs. poor prognosis, with 10-year OS rates of 87 and 67%, respectively. This was in line with our observations at the 5-year timepoint (). Younger, high-risk patients clearly represent a population for whom better treatment options are needed. Intensive regimens such as R-CHOEP-14 (rituximab, cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisolone) and megaCHOEP (high-dose cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisolone) (,) and R-ACVBP (rituximab, doxorubicin, vindesine, cyclophosphamide, bleomycin, and prednisolone) () are frequently used () but have not been shown to be superior to R-CHOP in this patient population (). Consequently, European treatment guidelines currently recommend recruitment into clinical trials for young ‘high-risk’ and ‘high-intermediate’ risk patients (). In the activated B-cell subtype of DLBCL that is more commonly seen in older patients, the addition of bortezomib, lenalidomide, or ibrutinib to standard therapy has provided encouraging indications of activity in early (,). Results from ongoing studies such as ROBUST (NCT02285062) and PHOENIX (NCT01855750) will provide an indication as to whether this is a valid approach for this poor-prognosis group of patients.

A plateau was observed in our PFS curves according to IPI category, with few relapses after 6 years in patients with ‘low-intermediate’ and ‘high-risk’ disease. This mirrors observations in the LNH-98.5 study (). In contrast, an analysis of the SWOG S8736 and S0014 studies, which only included patients with limited-stage disease, revealed a pattern of late relapse in those patients (). Patients with limited-stage disease comprised 40% of our patient population; in our group of ‘low-risk’ patients, some evidence of late disease progression was evident at 5–7 years post therapy, highlighting the need for continued observation of these patients.

Five-year OS rates ranged from 86% in IPI ‘low-risk’ patients to 45% in IPI ‘high-risk’ patients. Our OS rates were higher than the 5-year OS rates reported for patients in a large validation study by Olszewski et al those authors reported 5-year OS of 74, 58, 49, and 33% for ‘low-risk’, ‘low-intermediate’, ‘high-intermediate’ and ‘high-risk’ patients, compared with 86, 67, 58, and 45%, respectively, in the present study (). Five-year OS rates in our study were higher in all three R-IPI categories compared with the validation study (‘very good’ prognosis: 96% vs. 87%; ‘good’ prognosis: 73% vs. 64%; ‘poor’ prognosis: 51% vs. 41%, respectively), differences that may have been due to the characteristics of the two patient populations.

Some limitations of the present study should be considered in addition to those inherent in retrospective observational studies. PET was not used for disease staging until 2016; consequently, some patients may have been understated at diagnosis. Since the introduction of diagnostic PET, we have observed discrete paraspinal lymphomatous masses in some patients that might have been overlooked with computed tomography. This has the potential to affect our survival data.

Although many studies have examined the efficacy of R-CHOP and similar regimens in patients with DLBCL, real-world data are scarce for these patients. We have shown that many patients treated with R-CHOP and R-CHOP-like regimens in the real-world setting can have excellent outcomes; however, accurate disease staging is essential to confidently assign prognostic scores and assess likely outcomes for patients.