INTRODUCTION
The number of older patients with diffuse large B-cell lymphoma (DLBCL) has increased because of population aging; 40% are aged >70 years.[ 1 ] R-CHOP remains the standard frontline treatment for DLBCL patients aged 60–80 years. In those aged 75–79 years, full-dose R-CHOP improves OS,[ 1 ] but it can be harmful to those elderly (>80 years). Compared to younger patients, treatment of elderly patients is challenging because physicians must consider age-related co-morbidities, poor physical status, insufficient organ function, and a lack of social support. Only 5% of drug trials for hematological malignancies focus on elderly patients; 69% of trials exclude such patients.[ 1 , 2 ] Those aged >80 years typically experience dismal outcomes, given the limited treatment options. The international prognostic index (IPI) considers age as an independent (negatively) prognostic factor of DLBCL. Accordingly, the complete response (CR) and overall survival (OS) rates decrease with age; the CR falls from 65% in those aged 60 years to 39% in those aged 74 years, and the 5-year OS drops from 52% to 14%.[ 3 , 4 ] For DLBCL patients >80 years old, a dose intensity of doxorubicin-based chemotherapy of ≥85% was associated with poorer 1-year OS than a dose intensity of <85% (59% vs 70%), indicating that high-dose treatment may not be feasible for elderly patients. However, the similar 2-year OS between these two groups (53% vs 48%) suggests that a lower dose was also inadequate as it may cause higher recurrence. However, nearly 40% of patients unwilling to receive treatment had a median OS of only 1.9 months.[ 5 ] Therefore, the R-miniCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) regimen, which features a 50% dose intensity reduction, is recommended as standard treatment for DLBCL patients aged ≥80 years.[ 6 ] However, most deaths among such cases were caused by disease progression, suggesting that low-dose chemotherapy is associated with poor prognosis. Despite the numerous novel agents in the market, as almost all clinical trials exclude very elderly patients, there are no safety and efficacy data available and the optimal treatment remains unclear. Thus, new mild but effective regimens that benefit elderly DLBCL patients are urgently needed. Here, we retrospectively analyzed 71 DLBCL patients aged ≥80 years in terms of clinical features, prognostic factors, and survival outcomes.
METHODS
Patients
Patients aged ≥80 years diagnosed with DLBCL between January 2010 and November 2020 with a last follow-up visit in January 2021 were retrospectively selected as candidates at four centers in the Guangdong province in China. The inclusion criteria were an age of ≥80 years and pathologically diagnosed DLBCL; the exclusion criteria were age <80 years and other cancer sub-types than DLBCL. Clinical data including baseline complications, age, sex, Ann Arbor clinical stage, cell of origin (COO), performance status (PS), presence of B symptoms, IPI, serum lactate dehydrogenase (LDH), bone marrow involvement, extranodal involvement, bulky disease, Cmyc/Bcl2-expression status, double- or triple-hit status, treatment regimen, response evaluation, survival status, and adverse events were collected for all patients. Patient clinical information was extracted from the electronic medical records at the four centers. Written informed consent was obtained from all the patients. The study adhered to the ethical principles of the Declaration of Helsinki and was approved by the Institutional Review Board of Guangdong Provincial Peoples’ Hospital.
Pathological diagnosis and DLBCL phenotype assessment
All patients were diagnosed using the 2016 criteria of the World Health Organization.[ 7 ] The COO was determined using the immunohistochemical method of Hans et al .[ 8 ] Cmyc/Bcl2 expression status was defined as Cmyc (in ≥40% of tumor cells) and Bcl2 (in ≥50% of tumor cells) co-expression.[ 9 ] Fluorescent in situ hybridization was used to examine Cmyc, Bcl2, and Bcl6 gene status; double-hit lymphoma was defined as Cmyc translocation accompanied by Bcl2 or Bcl6 translocation, and triple-hit lymphoma was defined as Cmyc, Bcl2, and Bcl6 translocation.[ 9 ]
Statistical analysis
The objective response rate (ORR) comprised the CR rate plus the partial response (PR) rate. Progression-free survival (PFS) was defined as the date from treatment to disease progression or death by any cause. OS was calculated from the date of treatment to the last follow-up date or death by any cause. Categorical variables were compared using the Pearson Chi-square test or the Fisher exact test. Univariate analysis was conducted using the Kaplan–Meier method, and differences among sub-groups were compared using the log-rank test. The Cox proportional hazards model was used to identify independent prognostic factors. Two-tailed P values of <0.05 were considered statistically significant. All statistical analyses were performed using SPSS ver. 22 software.
RESULTS
Patient characteristics
We identified 71 very elderly cases diagnosed with DLBCL. Twenty-one had no clinical information about lymphoma in the electronic medical records and were not included in the following analysis. Therefore, 50 patients with available clinical data were included [Figure 1 , Table 1 ]. The median age at diagnosis was 81 years (range, 80–93 years); 31 (62%) were male and 19 (38%) were female. Thirty-six (72%) had Ann Arbor disease stage III or IV, and 27 (54%) had a PS of ≥2. Thirty (60%) patients had a non-germinal center B cell (non-GCB) sub-type. Twenty-five (50%) were at high clinical risk (IPI ≥4). Thirty-six (72%) underwent bone marrow biopsy; three (8.3%) were positive. Nineteen (38%) patients exhibited ≥2 sites of extranodal involvement, but only five (10%) had bulky disease. Over half of the patients (63%) had underlying diseases [Supplemental Table 1 ].
Figure 1: Flow diagram of the study
Table 1: Clinical features of elderly DLBCL patients (n =50). Chemotherapy group (n =27) and chemotherapy-free group (n =19)
Supplementary Table 1: Basic diseases of elderly DLBCL patients (n =50). Chemotherapy group (n =27) and chemotherapyfree group (n =19)
Treatments and outcomes
Of the 50 patients, 46 (64.7%) received treatment, of whom 19 (41.3%) received chemotherapy-free regimens [R2: lenalidomide, rituximab (n = 10); monotherapy with lenalidomide (n = 4) or rituximab (n = 1); IR2: lenalidomide, rituximab, ibrutinib (n = 4)]. Twenty-seven (58.7%) patients received chemotherapy with either R-miniCHOP (n = 13) or other combination chemotherapy regimens (n = 14), including R-GDP (rituximab, gemcitabine, cisplatin, dexamethasone), R-CEPP (rituximab, cyclophosphamide, etoposide, prednisone procarbazine), and BR (bendamustine, rituximab). Patients who received chemotherapy-free treatment more often had a non-GCB phenotype than those treated with chemotherapy (84.2% vs 40.7%, P = 0.006). No differences in other clinical characteristics were observed between the chemotherapy-free and chemotherapy groups.
Of the 46 cases, eight (four per group) were not included in efficacy analyses because of insufficient data (n = 6) or death from severe infections prior to response evaluation (n = 2) [Figure 2 ]. In all treated patients, the ORR was 78.9% and the CR rate was 39.5%. As many elderly patients cannot tolerate standard treatments, we stratified the cohort based on treatment strategy: chemotherapy-free treatment (n = 15) was superior to chemotherapy (n = 23) but not significantly so (CR: 46.7% vs 34.8% and ORR: 93.3% vs 69.6%; P = 0.514, P = 0.114).
Figure 2: Response to treatment of all patients (n = 38), the chemotherapy group (n = 23), and the chemotherapy-free group (n = 15). Abbreviations: CR, complete response; PR, partial response; ORR, overall response rate; C-F, chemotherapy-free; C, chemotherapy
Three of the 46 cases were lost follow-up; thus, 43 patients were included in the survival analysis. The median follow-up time for the entire cohort was 9.9 months [95% confidence interval (CI) 6.14–13.59 months], and the overall median PFS and OS were 23.0 (95% CI 4.61–41.32) and 26.5 (95% CI 13.26–39.67) months, respectively. The median follow-up time in the chemotherapy-free and chemotherapy groups was 12.1 (95% CI 1.48–22.78) and 5.8 (95% CI 4.22–7.38) months, respectively. The former group exhibited a significantly longer PFS than the latter (24.7 vs. 6.3 months, P = 0.033). The median OS was 34.1 and 26.5 months (P = 0.274), respectively; despite
the considerable difference, statistical significance was not reached [Figure 3 ]. In the former group, the 3-year PFS and OS were 45% and 43%, whereas in the latter, they were only 15% and 21%, respectively. Notably, the median PFS and OS of patients on the R2 regimen were 24.7 and 34.1 months, respectively; accordingly, this regimen seems to be better than chemotherapy, even if not significantly so (P = 0.076; P = 0.269).
Figure 3: Survival analyses and performance status under the different treatments (a-f). (a and b) PFS and OS in the chemotherapy (n = 27) and chemotherapy-free (n = 16) groups. (c and d) PFS and OS by performance status [PS <2 (n = 21) vs. PS ≥2 (n = 22)]. (e and f) PFS and OS of patients with PS of <2 in the chemotherapy (n = 13) and chemotherapy-free groups (n = 8). C-F, chemotherapy-free; C, chemotherapy; PS, performance status
Next, we stratified all patients by (PS ≥2 or PS <2). Patients with a good PS (PS <2) had a longer PFS and OS (36.5 vs 7.2 months, P = 0.03; 36.5 vs 12.1 months, P = 0.02, respectively). Figure 3 shows hierarchical PS survival curves. A stratified analysis by PS score indicated that in patients with PS <2 (n = 21), there is a longer median PFS and OS in the chemotherapy-free group (n = 8) than in the chemotherapy group (n = 13) (58.1 vs 7.7, P = 0.006; 58.1 vs 26.5 months, P = 0.050, respectively). Moreover, the PFS of regimen R2 (n = 5) was significantly better than that of the R-CHOP (n = 7) (58.1 vs 36.5 months, P = 0.042) and other chemotherapy regimens (n = 6) (58.1 vs 6.3 months, P = 0.009). The median OS of patients receiving R2 and R-CHOP was 58.1 and 36.5 months (P = 0.157), respectively, and that of those on other chemotherapies was 7.7 months; the difference between the R2 regimen and other chemotherapy regimens was significant (P = 0.03). In patients with PS of ≥2, the median PFS and OS did not differ between the chemotherapy-free and chemotherapy groups (9.7 vs 5.8 months, P = 0.391; 12.13 vs 5.83 months, P = 0.911, respectively).
Uni-variate and multi-variate analyses
The results of uni-variate and multi-variate analyses are shown in Tables 2 and Table 3 , respectively. In uni-variate analyses, poor PS ≥2, bulky disease, and chemotherapy seemed to predict a shorter PFS (P = 0.036, P = 0.030, P = 0.040, respectively), whereas PS of ≥2 and bulky disease predicted a shorter OS (P = 0.029, P = 0.015, respectively). In multi-variate analyses including a PS of ≥2, bulky disease, and chemotherapy, the PFS was influenced by the PS [hazard ratio (HR) 2.89, 95% CI 1.18–7.10; P = 0.020] and chemotherapy (HR 3.04, 95% CI 1.16–7.97; P = 0.023). Based on those results, PS ≥2 and bulky disease were included in the multi-variate analysis of OS; patients with PS of ≥2 had shorter OS (HR 2.97, 95% CI1.12–7.85; P = 0.029).
Table 2: Uni-variate analyses of PFS and OS in elderly patients
Table 3: Multi-variate analyses of PFS and OS in elderly patients
Treatment-related toxicity
Treatment-related toxicity was evaluated in 35 patients [Table 4 ]. Anemia, thrombocytopenia, and neutropenia were the most frequent hematological toxicities, with 57.1%, 37.1%, and 25.7% of any grade and 20%, 25.7%, and 14.3% of grades 3 and 4 among all patients. The most common non-hematological toxicities were fatigue, infection, pneumonia, hypohepatia, and renal injury (74.3%, 62.9%, 48.6%, 31.4%, and 28.6%, respectively; any grade). Further, the treatment-related adverse events did not differ between the chemotherapy-free and chemotherapy groups.
Table 4: Treatment-related toxicity in 35 patients in total of the chemotherapy and chemotherapy-free groups
DISCUSSION
The tolerance of elderly patients with DLBCL to chemotherapy depends on their PS. Recently, a phase III randomized trial reported that R-miniCHOP combined with lenalidomide did not improve survival but increased grade 3–4 treatment-related adverse events for DLBCL patients aged ≥80 years compared to R-miniCHOP alone.[ 10 ] Therefore, combining drug X (oral drug, e.g., lenalidomide) with full- or reduced-dose R-CHOP might increase toxicity, particularly in elderly subjects. In our study, the proportion of patients of a poor PS of ≥2 was 52%, much higher than those in other studies.[ 6 ] Most Chinese patients aged >80 years are in poor physical condition and may not be suitable to receive traditional chemotherapy and intensive therapy.
In this study, we analyzed survival outcomes for elderly DLBCL patients receiving chemotherapy-free and chemotherapy regimens. Those who received chemotherapy-free treatments seemed to have a superior PFS to those on chemotherapy (P = 0.033). The response rate was also much higher in the chemotherapy-free group than in the chemotherapy group [Figure 2 ], although the difference was not significant (possibly attributable to the small sample size). Moreover, patients with good PS (PS <2) had significantly longer PFS and OS in the chemotherapy-free group than those in the chemotherapy group (P = 0.006; P = 0.050). Specifically, in patients with the PS <2 sub-type, the PFS of the R2 group was significantly longer than that of the R-CHOP group (P = 0.042) and the other chemotherapy groups (P = 0.009). Accordingly, patients with good physical conditions may benefit from chemotherapy-free regimens such as R2. In fact, a previous study had shown that patients aged ≥65 years were likely to benefit from lenalidomide, with a CR rate of 30% compared with 6.9% in patients aged <65 years.[ 11 ] This may reflect immunosenescence as the numbers of CD8+ stem cell memory T-cells and CD4+ and CD8+ naïve T-cells decrease with age.[ 12 ] For R2 regimen, lenalidomide is an immunoregulator that may kill lymphoma cells induced by rituximab via NK cell- and monocyte-mediated antibody-dependent cellular cytotoxicity.[ 13 ] The above results provide a potential mechanism for the advantages of the R2 regimen in elderly patients. In addition, in our study, no R2-treated patients with a PS of <2 died from infection and R2 did not increase treatment-related adverse events. A previous clinical trial[ 10 ] suggested that lenalidomide combined with R-miniCHOP failed to improve the outcomes while increasing side effects. Thus, compared with chemotherapy or intensive therapy, chemotherapy-free treatments such as R2 appear to be well tolerated in elderly patients with good PS; in particular, lenalidomide (10 mg daily) was not only effective but tolerable.
However, our data showed that chemotherapy-free regimens failed to improve prognosis in cases with PS of ≥2; thus, optimal treatment regimens remain need to be identified for this sub-population. A recent study suggests using PD-1 inhibitors as maintenance therapy as this could improve the 2-year relapse-free survival for DLBCL patients.[ 14 ] In case chemotherapy and targeted therapies are ineffective, immunotherapy may be beneficial.
Regarding adverse prognostic factors, the efficacy of IPI has declined in the era of rituximab treatment. Vlatka et al .[ 15 ] suggested that lower hemoglobin, albumin, lymphocyte, and platelet scores were associated with unfavorable prognosis in DLBCL, and Tyagi found that the non-GCB sub-type had more extranodal involvement and poor response to chemotherapy.[ 16 ] In our study, patients who received chemotherapy-free treatment had more often a non-GCB phenotype. In fact, only two patients in the GCB group received chemotherapy-free treatment; as such, not enough data were available to analyze the discrepancy in curative effects between phenotypes. In addition, the PS at diagnosis was the most significant predictor of treatment-related mortality.[ 5 , 6 , 17 ] Recently, a new prognostic index based on 1,353 DLBCL patients aged ≥ 65 years categorized patients aged ≥80 years as unfit or frail to chemotherapy.[ 18 ]
The limitations of this study are the small number of patients and the lack of head-to-head controlled study. Thus, biomarkers for predicting the responses to the chemotherapy-free regimen should be evaluated in studies with a larger population. Therefore, for patients aged ≥80 years with poor PS, a chemotherapy-free regimen may be more appropriate and could include a prophase treatment (e.g., prednisone or vincristine 1 mg intravenously 1 week before the first R2 dose) that improves PS prior to R2 delivery.
In summary, based on our results, PS appears to be an independent prognostic factor in elderly DLBCL patients and a chemotherapy-free regimen could be ideal for patients with good PS. Although an optimal treatment remains to be identified for patients with poor PS, a prophase treatment followed by a chemotherapy-free regimen (e.g., R2) may be appropriate.
Financial support and sponsorship
This work was supported by the Third Batch of Summit Project of Guangdong Provincial People’s Hospital (No. DFJH2020025), 2019 GDPH Supporting Fund for NSFC Program (8190010361), Guangdong Medical Research Foundation (B2021030) and the Investigator-Initiated Clinical Trial (No.GDREC2020099H).
Conflicts of interest
There are no conflicts of interest.
Acknowledgements
We particularly thank Prof. Zhigang Zhu, Prof. Ying Zhao, and Prof. Qingqing Cai for sharing data.
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