Retrospective analysis of diffuse large B-cell lymphoma treated with the R-CHOP regimen at a Malaysian tertiary hospital.

Background
Lymphoma ranks as the fourth most common malignancy in Malaysia, following breast, colorectal, and lung cancers. It accounts for 5.2% of all cancer cases, according to the latest Malaysian Cancer Registry report [1]. The number of lymphoma diagnoses is expected to rise in the coming years due to factors such as a growing population, increased life expectancy, and heightened public awareness, which encourages early medical consultation for suspected malignancies.
The World Health Organization has established a comprehensive classification system for lymphomas, with its most recent update released in 2022 [2]. Diffuse large B-cell lymphoma, not otherwise specified (DLBCL, NOS), is the most commonly diagnosed subtype worldwide. It is characterized by medium-sized lymphoid cells featuring round to ovoid nuclei, vesicular chromatin, and a mature B-cell immunophenotype, but lacking the defining traits of specific large B-cell lymphoma [2].
DLBCL represents a biologically diverse group of disorders with variable clinical presentations, underlying molecular profiles, and responses to treatment. A recent review paper summarized multiple studies on DLBCL in Malaysia, highlighting prevalence, histological subtypes, prognostic indicators, presenting clinical features, and available patient outcomes [3].
Severe prognostic factors influence survival in DLBCL patients. The most widely used model is the International Prognostic Index (IPI), a 5-point scoring system based on age, disease stage, performance status (PS), serum lactate dehydrogenase (LDH) levels, and the number of extranodal disease sites. Based on the IPI score, patients are categorized into risk groups: low (0–1 point), low-intermediate (2 points), high-intermediate (3 points), and high risk (4–5 points). In the original retrospective study that validated the IPI, 5-year survival rates ranged from 73% in the low-risk groups to 26% in the high-risk groups [4].
Several prognostic models have been developed to improve risk stratification beyond the IPI [5]. Some of these models incorporate hemoglobin and serum albumin levels using various cutoff points [6–9]. However, these models are often challenging to replicate due to the complex data analysis required and associated costs, which limit their broader validation [10].
It is well established that genetic subtypes of DLBCL are associated with differing prognoses. Studies have consistently shown that the germinal center B-cell (GCB) subtype is linked to more favorable outcomes compared to the non-GCB subtype [11]. A local review conducted at a university hospital reported a higher prevalence of the non-GCB subtype than GCB (49% vs. 37%, n = 79). Patients with the non-GCB subtype had significantly shorter median survival than those with the GCB subtype (11 months vs. 19 months; p = 0.013) [12].
Standard treatment for DLBCL generally includes combination chemotherapy, most commonly the R-CHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone). Clinical trials from the early 2000s confirmed the efficacy and tolerability of R-CHOP in DLBCL patients [13, 14]. Patients with localized bulky disease may receive consolidation radiotherapy following R-CHOP chemotherapy [15]. For those with relapsed or refractory disease after R-CHOP, salvage chemotherapy followed by autologous stem cell transplantation may be pursued if remission is achieved.
The patients in the high-risk group demonstrated poor outcomes in earlier retrospective studies conducted in the pre-rituximab era [4]. Even with the addition of rituximab to the CHOP regimen, outcomes remained suboptimal [16]. Various strategies have been explored to improve the R-CHOP backbone, including the development of alternative chemotherapy regimens. One such approach is dose-adjusted etoposide, prednisolone, vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH-R), which has been proposed as a potential alternative for high-risk DLBCL patients. However, a phase III trial comparing R-CHOP with DA-EPOCH-R found no significant differences in two-year overall survival (OS) and progression-free survival (PFS). Notably, DA-EPOCH-R was associated with a higher incidence of clinically significant adverse events [17]. Consequently, the R-CHOP regimen remains the globally accepted first-line treatment for DLBCL.
There is limited evidence regarding the effectiveness of R-CHOP in real-world clinical settings. Results from clinical trials may not fully reflect outcomes in the broader patient population, as such trials typically enroll individuals with favorable baseline characteristics. Real-world studies are, therefore, essential complements to clinical trials, offering deeper insights that support clinical decision-making. These studies provide valuable information on patient population often underrepresented in controlled trials [18].
This retrospective study aimed to describe the demographic and clinical characteristics of patients newly diagnosed with DLBCL who received the R-CHOP regimen at Sarawak General Hospital, Kuching, Sarawak. The primary objective was to assess OS and PFS, while the secondary objective was to analyze the impact of various prognostic factors on treatment outcomes.

Materials and methods
This retrospective cohort study was conducted at a single center and included all consecutive patients diagnosed with DLBCL at Sarawak General Hospital between January 2015 and December 2020. The hospital functions as the primary hematology referral center for southern Sarawak. Information regarding lymphoma diagnosis, patient demographics, and treatment details were extracted from medical records. Patients were monitored until death, loss to follow-up, or the end of the study period (December 31, 2023), whichever came first.
The inclusion criteria comprised patients aged 18 years and above with a histologically confirmed diagnosis of de novo DLBCL. All included patients had initiated R-CHOP chemotherapy at Sarawak General Hospital during the specified study period. The exclusion criteria included patients with transformed DLBCL arising from other hematological malignancies, those treated with intensive chemotherapy regimens other than R-CHOP, individuals diagnosed outside the study timeframe, patients presenting with relapsed or refractory DLBCL at initial evaluation, individuals who declined intensive treatment or opted for palliative care, and those with incomplete medical records.
Collected data encompassed sex, age, ethnicity, time from diagnosis to initiation of therapy, DLBCL subtype, and the presence of B symptoms (fever > 38 °C, unexplained weight loss > 10% over 6 months, or drenching night sweats). Baseline PS was assessed using the Eastern Cooperative Oncology Group (ECOG) scale. Laboratory parameters included hemoglobin level, white blood cell count, absolute neutrophil count, platelet count, renal function, and serum levels of albumin and LDH. Disease staging was assessed using the Ann Arbor classification based on either computed tomography (CT) or positron emission tomography–computed tomography (PET-CT), and the presence of extranodal involvement was documented. Additional variables included the number of chemotherapy cycles administered, treatment outcomes, and the dates of relapse and mortality.
The patients in our study received the R-CHOP regimen every 21 days. The regimen consisted of intravenous (IV) rituximab at 375 mg per square meter of body surface area (mg/m2), IV cyclophosphamide 750 mg/m2, IV doxorubicin 50 mg/m2, and IV vincristine 1.4 mg/m2 (capped at 2 mg) on the first day of each chemotherapy cycle, and oral prednisolone 60 mg/m2 for 5 consecutive days. Due to the high cost of rituximab, its dose was capped at 500 mg per cycle. Supportive care measures—including monitoring and treatment for tumor lysis syndrome, administration of granulocyte colony-stimulating factor, management of neutropenic sepsis, and prophylactic antiviral therapy for patients with a history of hepatitis B—were implemented to maintain chemotherapy dose intensity and minimize treatment delays. Treatment response was assessed by the treating physician. Interim evaluations were generally performed using CT scans after 4–5 cycles of chemotherapy, while final response assessments were conducted upon completion of six cycles using either CT or PET-CT. Clinical outcomes were determined based on the Cheson response criteria [19]. A complete response (CR) was defined as the disappearance of all signs of disease, whereas a partial response (PR) was defined as a reduction of more than 50% in the sum of the diameters of measurable lesions. Disease progression was defined as relapse or failure to achieve CR or PR. For patients without end-of-treatment imaging, response was determined based on interim scan findings. Patients with residual bulky, localized disease after chemotherapy received radiotherapy. Those with relapsed or refractory disease, or with only a PR, were considered for salvage chemotherapy followed, where feasible, by high-dosetherapy and autologous stem cell transplantation.
OS was defined as the duration from the date of lymphoma diagnosis to the date of death or last follow-up. PFS was measured from diagnosis to either disease progression or death from any cause. Patients lost to follow-up were censored at the date of their last recorded clinical evaluation. The objective response rate was defined as the proportion of patients who achieved either CR or PR.
Descriptive statistics were used to summarize demographic and clinical characteristics, including sex, age, ethnicity, PS, disease stage, and IPI score. Univariate analysis using the chi-square test was conducted to identify factors associated with OS and PFS at 3 years post-DLBCL diagnosis. Examined prognostic variables included sex, age, ethnicity, time to treatment initiation, presence of B symptoms, PS, disease stage, number of extranodal sites, and baseline hemoglobin, serum albumin, and LDH levels. Variables with p values < 0.10 in univariate analysis were entered into a multivariate analysis using the Cox proportional hazards regression model. Hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) were calculated. OS and PFS estimates were generated using the Kaplan–Meier method, and survival differences between IPI risk groups were compared using the log-rank test. A two-sided p value of < 0.05 was considered statistically significant. All statistical analyses and graphical outputs were performed using the Statistical Package for the Social Sciences, version 23 (IBM Corp., Armonk, New York).
This study was conducted in accordance with the ethical principles of the Declaration of Helsinki (1975), as revised in 2000. Ethical approval was granted by the Malaysian Medical Ethical Committee, Ministry of Health Malaysia [Research ID: RSCH ID-24–03195-XD2; NMRR ID:24–02003-JQW (IIR)]. Ethical standards were maintained throughout the study, and all data were used exclusively for research purposes. Informed consent was not required, as this was a retrospective review of existing medical records.

Results
A review of medical records identified 276 patients diagnosed with DLBCL between January 2015 and December 2020. Of these, 74 patients were excluded from the analysis for the following reasons: refusal of chemotherapy or opting for palliative care (n = 38), diagnosis of transformed DLBCL (n = 14), receipt of intensive chemotherapy regimens other than R-CHOP (n = 9), transfer to other hospitals for treatment (n = 7), age below 18 years (n = 4), and referral for relapsed disease (n = 2). The final cohort included 202 patients.

Patient characteristics
Baseline characteristics of the study population are summarized in Table 1. The cohort was predominantly male (n = 118, 58.4%) with a median age of 58 years [interquartile range (IQR), 20 years]. The cohort consisted of 89 patients (44.1%) from indigenous groups (50 Bidayuh, 32 Iban, and 7 from other ethnicities), 63 Malay patients (31.1%), and 50 Chinese patients (24.8%). DLBCL subtypes were unclassified in the majority of patients (n = 123, 60.9%), whereas 33 patients (16.3%) were classified as GCB subtype and 46 (22.8%) as non-GCB subtype. Most patients presented with advanced-stage disease (n = 119, 58.9%) and B symptoms (n = 118, 58.4%). The majority also had good functional status, with 67.8% having an ECOG performance score of 0–1. The median time from diagnosis to initiation of chemotherapy was 13 days (IQR, 21 days). According to the IPI, 62 patients (30.7%) were classified as low risk, 54 (26.7%) as low-intermediate risk, 60 (29.7%) as high-intermediate risk, and 26 (12.9%) as high risk.

Treatment characteristics and response assessment
Treatment responses are presented in Table 2. All patients received at least one cycle of the R-CHOP regimen. During first-line chemotherapy, 37 patients died due to disease progression. Post-treatment evaluation revealed that a majority of patients (72.3%) achieved an objective response, with 57.9% attaining a CR. Among those who initially achieved CR, 10 patients experienced disease relapse during follow-up. Of these, seven received salvage chemotherapy, and two subsequently achieved a second CR. Additionally, 36 patients received salvage chemotherapy following PR or progressive disease, of whom 17 attained CR after salvage treatment.
Fourteen patients (6.9%) underwent radiotherapy as consolidation therapy following chemotherapy. Seven patients proceeded to autologous stem cell transplantation after salvage chemotherapy for relapsed or refractory disease; five of them achieved CR post-transplantation.
With a median follow-up duration of 50.1 months (IQR, 64.6 months), the 3-year OS and PFS rates were 60.9% and 58.4%, respectively. Of the 79 recorded deaths, causes included disease progression (n = 65), neutropenic sepsis (n = 1), unrelated medical conditions (n = 10), and unknown causes (n = 3). Median OS and PFS were not reached among patients in the low and low-intermediate IPI risk groups. In contrast, patients in the high-intermediate and high-risk categories had median OS durations of 23.5 months and 20.3 months, respectively. Median PFS durations for the same groups were 13.3 months and 12.3 months, respectively.
In the univariate analysis, the presence of B symptoms, advanced-stage disease, involvement of more than one extranodal site, hemoglobin level < 100 g/L, serum albumin < 35 g/L, and elevated LDH were significantly associated with inferior OS and PFS. In multivariate analysis, age > 60 years, B symptoms, advanced-stage lymphoma, and elevated serum LDH emerged as independent predictors of poorer OS and PFS. Notably, hypoalbuminemia was significantly associated with worse OS (p = 0.0040), but not with PFS (p = 0.16). The detailed results are presented in Tables 3 and 4.
Patients classified into lower IPI risk categories showed significantly improved OS and PFS compared to those in higher-risk groups (p < 0.0001 for both outcomes). Survival curves are illustrated in Figs. 1 and 2.

Discussion
This retrospective study analyzed the 3-year survival outcomes of patients with DLBCL who received first-line chemotherapy across a 6-year timeframe. An OS rate of 60.9% at 3 years was recorded in our cohort, with survival ranging from 34.6% in the high-IPI-risk group to 88.7% in the low-risk group.
Data on survival outcomes for newly diagnosed DLBCL patients in the Asia Pacific region remain scarce. In Brunei Darussalam, a registry-based retrospective study involving lymphoma cases reported a three-year OS of 61.2% among patients with DLBCL (n = 129) [20], though specific chemotherapy protocols were not described. Conversely, a retrospective study conducted at a regional center in southern Taiwan observed a 3-year OS of 55.6% among DLBCL patients (n = 241) [21]. A registry-based observational study spanning Latin American countries reported a 5-year OS of 69.0% in patients with DLBCL (n = 1,457), with survival outcomes differing by country [22]. The OS observed in our cohort was generally consistent with outcomes reported from neighboring regions.
In the Latin American study, patients with low and low-intermediate IPI scores achieved notably better 5-year OS rates (87.3% and 75.2%, respectively) than those with high-intermediate and high IPI scores (57.6% and 45.6%, respectively) [22]. These findings support the survival trends associated with IPI scores observed in our cohort.
Additionally, our study found that patients older than 60 years and those presenting with advanced-stage disease (stage III or IV) experienced significantly poorer OS and PFS. Similar observations were made by Pei et al., who reported reduced OS and event-free survival in patients over 65 years and those diagnosed at advanced stages [21]. Similarly, a retrospective cohort analysis using the Swedish Lymphoma Registry revealed worse OS in DLBCL patients aged > 60 years than in the general population [23].
Large-scale retrospective studies have established low serum albumin as a significant prognostic marker for survival in DLBCL patients treated with the R-CHOP regimen. Hohloch et al. found that serum albumin levels below 35 g/L were strongly associated with poorer OS and PFS in elderly patients (aged 61–80 years) diagnosed with aggressive B-cell lymphoma [24]. A recent retrospective study from Japan identified serum albumin as the sole predictor of OS and PFS in DLBCL patients aged over 80 years who were treated with R-CHOP or equivalent chemotherapy regimens [25]. Comparable associations have also been observed in smaller retrospective studies involving younger populations. For instance, Dalia et al. reported that serum albumin levels under 37 g/L were linked to worse 4-year OS and PFS in patients receiving R-CHOP (median age at diagnosis: 58 years) [26]. Similarly, Kim et al. demonstrated that a low albumin-to-globulin ratio (< 1.22) in DLBCL patients treated with R-CHOP was associated with reduced CR rates and poorer OS and PFS [27].
Low serum albumin is also widely recognized as a prognostic indicator in various solid tumors, including gastrointestinal, hepatic, pulmonary, and breast malignancies [28–30]. Hypoalbuminemia in these settings often reflects a higher tumor burden and more advanced disease, alongside adverse patient-related factors, such as comorbidities, poor nutritional status, and diminished tolerance to aggressive chemotherapy [31].
Despite extensive investigation, the pathophysiological basis of hypoalbuminemia in malignancies, including lymphoma, remains incompletely understood. As a negative acute-phase reactant, albumin synthesis in the liver is downregulated by pro-inflammatory cytokines, such as interleukin-6 and tumor necrosis factor, contributing to reduced serum albumin levels [32]. Another proposed mechanism involves increased vascular permeability in cancer patients, which facilitates albumin leakage into the extracellular space [33].
Our study demonstrated that the IPI remains a reliable predictor of survival in patients with DLBCL. Although the IPI was originally developed in the pre-rituximab era, its prognostic relevance has persisted in subsequent decades, even after rituximab was incorporated into the CHOP regimen, establishing a new standard of care for newly diagnosed DLBCL [4]. A later large-scale study confirmed that the IPI continues to be the most important prognostic tool for patients treated during the rituximab era [34].
Although the R-CHOP regimen is widely accepted as first-line therapy for DLBCL, our cohort revealed several unmet needs in its application. Rituximab remains considerably more expensive than the other R-CHOP components. As a result, many patients are administered a fixed dose of 500 mg rituximab instead of the recommended weight-based dose of 375 mg/m2 as a cost-containment strategy. This deviation from standard dosing may compromise treatment efficacy. In a retrospective study comparing DLBCL patients treated with a flat 500 mg dose of rituximab to a historical cohort that did not receive rituximab, no significant difference was observed in treatment response or 3-year OS [35]. However, the study’s authors noted that the sample size may have been insufficient to detect meaningful differences.
DLBCL is characterized by significant molecular heterogeneity and can be subdivided into three distinct molecular cell-of-origin subtypes based on gene expression profiling (GEP): GCB; activated B-cell (ABC), which is thought to arise from post-germinal center B-cells; and primary mediastinal B-cell lymphoma (PMBL) [36]. Patients with PMBL were not included in our cohort. A retrospective study reported that patients with the GCB subtype had a significantly better 3-year OS than those with the ABC subtype when treated with the R-CHOP regimen (80% vs. 45%, p < 0.0001) [37].
However, performing GEP for every patient with DLBCL is expensive and impractical. In routine clinical settings, immunohistochemical algorithms have been adopted as surrogates for GEP, though their concordance varies. The most widely used immunohistochemical-based classification system is the Hans algorithm, which utilizes staining for CD10, BCL6, and MUM1 to determine DLBCL subtypes. A study by Hans et al. showed that the algorithm correlated well with the corresponding GEP results and that there were clear survival differences between the GCB and ABC subtypes [38]. However, due to financial constraints, these markers were not consistently available at our treatment center during the study period. Consequently, only 39.1% of patients in our cohort had a defined DLBCL subtype, limiting our ability to conduct a meaningful analysis of the impact of subtypes on survival outcomes.
This study has several limitations. First, it was a retrospective, single-center cohort study, which introduces the potential for selection bias. Among patients excluded from analysis, more than half (38/74 [51.4%]) either opted for palliative care or declined intensive chemotherapy. This relatively high attrition rate may have affected the completeness and robustness of data interpretation. It is also likely that these patients had substantial comorbidities, poor PS, or diminished quality of life, making them unsuitable for intensive chemotherapy due to a heightened risk of early treatment-related mortality.

Conclusion
Despite these limitations, this retrospective analysis provides insight into the demographic and clinical characteristics of patients with DLBCL in Malaysia. We identified several key prognostic factors—age, presence of B symptoms, disease stage, baseline serum albumin, and LDH levels—that may assist in predicting survival outcomes in newly diagnosed DLBCL patients. These findings could inform clinical decision-making, contribute to the development of a national cancer management framework, and support resource allocation strategies. However, due to the inherent limitations of retrospective studies, our results should be validated in well-designed prospective clinical trials.