|Year : 2017 | Volume
| Issue : 2 | Page : 430-435
Long-term outcome of diffuse large B-cell lymphoma: Impact of biosimilar rituximab and radiation
P Ganesan1, TG Sagar1, K Kannan1, V Radhakrishnan1, S Rajaraman2, A John3, S Sundersingh4, V Mahajan5, TS Ganesan1
1 Department of Medical Oncology, Cancer Institute (WIA), Adyar, Chennai, Tamil Nadu, India
2 Department of Cancer Registry Registry and Biostatistics, Cancer Institute (WIA), Adyar, Chennai, Tamil Nadu, India
3 Department of Radiation Oncology, Cancer Institute (WIA), Adyar, Chennai, Tamil Nadu, India
4 Department of Pathology, Cancer Institute (WIA), Adyar, Chennai, Tamil Nadu, India
5 Department of Radiology, Cancer Institute (WIA), Adyar, Chennai, Tamil Nadu, India
|Date of Web Publication||21-Feb-2018|
Dr. P Ganesan
Department of Medical Oncology, Cancer Institute (WIA), Adyar, Chennai, Tamil Nadu
Source of Support: None, Conflict of Interest: None
INTRODUCTION: Rituximab (R)-CHOP improves survival over CHOP in diffuse large B-cell lymphoma (DLBCL). The availability of biosimilar rituximab in India has increased access of this drug. We report on the impact of treatment on outcomes with special emphasis on the impact of biosimilar rituximab and radiation. METHODS: Outcomes of adults (age 15–60 years) treated with CHOP+/- Rituximab radiation were analyzed retrospectively to look at baseline features, treatment, and event-free and overall survival (EFS and OS). RESULTS: In the period 2000–2013, 444 patients (median age 47 years: 15–60; males: 288 [65%]; Stage III/IV: 224 [50%]; age-adjusted international prognostic index [aaIPI] Score 2 or 3 in 50%) received either CHOP (n = 325 [73%]) or RCHOP (n = 119 [27%]) therapy. Biosimilar rituximab and the original were used in 95 (80%) and 24 (20%) patients, respectively. Radiation was given in 134 (30%) patients (Stages I and II, 100/220 [45%] and Stages III and IV, 34/224 [15%]). After a median follow-up of 46 (0.2–126) months, the 5-year EFS and OS were 59% and 68%, respectively. The factors predicting inferior EFS and OS were age >40 years, performance status 2–4, Stage III/IV, hemoglobin <12 g/dL, the aaIPI Score 2 or 3, and nonuse of rituximab and radiation. Radiation used in early stage disease benefitted all subgroups regardless of bulky disease, use of rituximab, or the number of cycles of chemotherapy. Addition of rituximab improved survival across all categories of aaIPI. CONCLUSION: Availability of biosimilar rituximab has increased access and survival of patients with DLBCL in India. Radiotherapy improved outcomes in early stages.
Keywords: Biosimilar, chemotherapy, diffuse large B-cell lymphoma, radiation, rituximab
|How to cite this article:|
Ganesan P, Sagar T G, Kannan K, Radhakrishnan V, Rajaraman S, John A, Sundersingh S, Mahajan V, Ganesan T S. Long-term outcome of diffuse large B-cell lymphoma: Impact of biosimilar rituximab and radiation. Indian J Cancer 2017;54:430-5
|How to cite this URL:|
Ganesan P, Sagar T G, Kannan K, Radhakrishnan V, Rajaraman S, John A, Sundersingh S, Mahajan V, Ganesan T S. Long-term outcome of diffuse large B-cell lymphoma: Impact of biosimilar rituximab and radiation. Indian J Cancer [serial online] 2017 [cited 2019 Nov 15];54:430-5. Available from: http://www.indianjcancer.com/text.asp?2017/54/2/430/225797
| » Introduction|| |
Diffuse large B-cell lymphoma (DLBCL) is one of the common subtypes of lymphoma. Rituximab combined with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) given for 4–6 cycles in early stages and 6–8 cycles in advanced stages is the standard therapy., Although the original rituximab (Mabthera ®) has been available in India since 2002, its use was limited as it was expensive. Since 2007, a biosimilar version of rituximab (Reditux ®) has been available in India which is less expensive and increased its accessibility to patients. However, there is little published data available on the efficacy of biosimilar rituximab from India.
We report the outcomes of young patients with DLBCL diagnosed over 14 years at a tertiary cancer center catering largely to patients of lower socioeconomic status. For example, the demographic profile of patients with chronic myeloid leukemia treated at our center showed that ≥70% of patients have income <#10,000 (≤$150) per month. Only 26% of the patients in this report received rituximab (mostly Reditux). This is the first report from our center documenting the efficacy of addition of biosimilar rituximab to CHOP chemotherapy regimen. The role of addition of radiotherapy to the site of disease was another variable that was evaluated.
| » Methods|| |
Patients in the age group of 15–60 years with a histological diagnosis of diffuse DLBCL who received CHOP/RCHOP therapy at the cancer institute were included in the analysis. The lower cutoff of 15 years was chosen as patients up to this age were treated by pediatricians at our center. We included only patients if they had received at least one cycle of chemotherapy. Patients with primary central nervous system lymphoma, primary mediastinal B-cell lymphoma, and those who were HIV positive were excluded from the study. Pretreatment characteristics (age, sex, clinical stage, performance status [ECOG], and bulky disease status) were obtained from the medical records. Age-adjusted international prognostic index (aaIPI) for each patient was calculated. For the purpose of this analysis, bulky disease was defined as any site of disease ≥7 cm. Staging the extent of disease was performed using contrast-enhanced computed tomography (CECT) scans of the abdomen and pelvis and chest along with unilateral bone marrow biopsies. A proportion of patients diagnosed after 2007 were staged using whole body positron emission tomography-computed tomography (PET-CT) scans.
Treatment and response
All patients received standard doses of CHOP ± rituximab. Rituximab (Mabthera) was administered to any patient who could afford it (either through insurance or out of pocket) before availability of the biosimilar version. After 2007, the cost of rituximab reduced and the frequency of administration increased. Most patients received biosimilar rituximab (Reditux ®, Dr. Reddy's Laboratories) whereas few received the original product (MabThera ®, Roche). Patients with advanced stage disease (III, IV) received 6–8 cycles of chemotherapy whereas patients with early stage received either 3–4 cycles, followed by involved field radiation or 6 cycles chemotherapy alone according to preference of the physician. According to an earlier policy of administering two additional cycles afterachievement of complete remission (CR), some of the patients received 7–8 cycles of chemotherapy. Radiation was generally used in patients with early stage disease and those with bulky sites and/or extranodal disease. However, there was variability in the use of radiation depending on preference by the individual or the physician. Other variable factors were definition of “bulky” disease and the feasibility of delivering radiation safely. Since this was a retrospective analysis, the exact reasons for the choice of radiation in a given patient could not be reliably captured.
Response to treatment was assessed clinically after every cycle, clinical ± imaging after 3–4 cycles, and by CECT or PET-CT at the end of therapy. Evaluation of final response in this report was always at the end of planned therapy. Bone marrow biopsy was only repeated if initially it was positive for disease. Patients were followed 3 monthly for 2 years, every 6 months from 3 to 5 years, and yearly thereafter. Follow-up was both passive as well as active, with the hospital tumor registry making efforts to ascertain the status of patients who had not reported for their scheduled clinical visits. Relapses were confirmed by radiology as well as biopsy, wherever feasible. The treatment of relapse was variable and depended on individual physician. Most patients were offered only supportive treatment after relapse in this period. Very few patients underwent salvage and transplantation. The data on treatment of relapse was not part of the current assessment.
Descriptive statistical analysis was done for the baseline variables. We compared the patients who received RCHOP and CHOP with respect to their baseline variables. Overall survival (OS, from the date of start of therapy till death due to any cause) and event-free survival (EFS, from the date of start of therapy till death, disease progression, and/or relapse) were calculated using Kaplan–Meier method and the baseline variables were compared using log-rank test. Since the addition of rituximab to chemotherapy (RCHOP vs. CHOP) and use of radiation were the two important variables related to treatment, these were analyzed separately to understand the subgroups that benefit.
| » Results|| |
Between January 1, 2000, and December 31, 2013, we identified 469 patients of DLBCL (age 15–60 years) who received therapy at our center. Of these, 25 received only palliative intent treatment with oral medications, steroids, or cyclophosphamide, vincristine, and prednisolone. The other 444 patients who received CHOP/RCHOP chemotherapy are included in the current analysis. The median age at diagnosis was 47.1 years and 65% were men [Table 1]. Only four patients were below 18 years of age. The distribution of stages of disease was as follows: I, 86 (19%); II, 134 (30%); III, 104 (23%); and IV, 120 (27%). Sites of disease were bulky in 77/220 (35%) with early stage and 91/224 (40%) with advanced disease. Since the data on lactate dehydrogenase (LDH) were available in only 383 patients, aaIPI was calculated in these and the distribution was as follows: Score 0: 52 (14%), Score 1: 139 (36%), Score 2: 129 (34%), and Score 3: 63 (16%). At least half the patients (50%) at presentation had intermediate-to-high-risk aaIPI scores (Scores 2, 3).
|Table 1: Baseline characteristics of all patients and comparison between those who received CHOP and RCHOP|
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Response to treatment
CHOP was given to 325 (73%) patients while 119 (27%) received RCHOP. Majority of those receiving RCHOP were treated with the biosimilar product (Reditux) (n = 95, 80%) and only a few (n = 24, 20%) received the innovator rituximab (Mabthera). The proportion of patients receiving rituximab increased over the years with almost three-fourth receiving RCHOP in 2013 [Figure 1]. The median number of cycles of chemotherapy administered was 6.,,,,,,, More than 6 cycles of chemotherapy were used in 173 (39%) patients whereas 42 patients received ≤4 cycles of chemotherapy. Radiation was given at the end of therapy in 134 (30%) patients. Among patients with early Stage (I and II, n = 220), 100 (45%) received radiation while in those with advanced Stage (III and IV, n = 224), only 34 (15%) received radiation. Among patients with bulky disease (n = 168), only 52 (31%) received radiation.
|Figure 1: Clustered bar graph showing the increasing proportion of patients receiving RCHOP (grey bar) compared to CHOP (black bar) over the years. Years are represented serially from 2000 (0) to 2013 (13). Note the steady spike in numbers of patients treated with RCHOP since the year 2007 when the biosimilar rituximab became available|
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Response to treatment could be assessed in only 437 patients (four patients died due to treatment-related toxicity and three were lost to follow-up before assessment). Of these patients, at the end of therapy, 239 (78%) had achieved a CR, 16 (4%) had a partial remission, and 82 (19%) had progressed. The CR rate was better with RCHOP compared to CHOP (83.8% vs. 73.7%; P = 0.024). The CR rate was also better in those patients with low-risk aaIPI (Score 0, 1) compared to intermediate and high risk (Score 2, 3) (85.3% vs. 67.2%, P < 0.001).
After a median follow-up of 46 (0.2–126) months in all patients (n = 444), the median EFS and OS were not yet reached. Overall, the actuarial EFS and OS at 5 years were 59.3% Standard Error (SE: 0.025) and 68.1% (SE: 0.026), respectively. The 5-year EFS and OS for Stages I, II, III, and IV were 81%, 65%, 43%, and 50% and 89%, 74%, 49%, and 59%, respectively (P < 0.001 across all stages for both EFS and OS). The aaIPI predicted 5-year EFS and OS survival for patients with aaIPI 0, 1 versus 2, 3 were 75% versus 43% and 83% versus 61% (P < 0.001), respectively. The factors predicting inferior EFS and OS on univariate analysis were [Table 2] age >40 years, performance status at diagnosis 2–4, Stage III/IV at presentation, hemoglobin <12 g/dL, higher aaIPI score, nonuse of rituximab, and nonuse of radiation [Figure 2]. Bulky disease predicted for inferior EFS but not OS. On multivariate analysis, the factors predicting for inferior EFS and OS were age >40 years, aaIPI 2 or 3, nonuse of rituximab, and nonuse of radiation [Table 3]. Hemoglobin level was significant in predicting OS but not for EFS on multivariate analysis.
|Figure 2: Kaplan–Meier survival figures of patients of diffuse large B-cell lymphoma. Top Panel shows the differences in event-free survival – (a) between aaIPI low (black) versus high (gray, broken); (b) between RCHOP (black) versus CHOP (gray, broken) and (c) between those who received RT (black) versus those who did not receive RT (gray, broken). Bottom panel shows the differences in overall survival – (d) between aaIPI low (black) versus high (gray, broken); (e) between RCHOP (black) versus CHOP (gray, broken), and (f) between those who received RT (black) versus those who did not receive RT (grey, broken). aaIPI = Age-adjusted international prognostic index; RT = Radiation therapy|
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|Table 3: Multivariate analysis of event-free survival and overall survival for all patients|
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Impact of rituximab on overall survival
Among patients who received biosimilar rituximab alone (n = 95/119), the survival with RCHOP was superior to CHOP (n = 325) (5-year OS 81% vs. 64%, P = 0.040). There was no difference (P = 0.5) in the 5-year survival among those who received biosimilar (78%) versus innovator rituximab (86%) among patients treated with RCHOP (n = 119). Patients with low-risk aaIPI (Score 0, 1, n = 191), 45 (23%) who received rituximab had a better survival (5-year OS 95% vs. 81%, P < 0.001). Patients with higher risk aaIPI (Score 2, 3, n = 192), 62 (32%) who received rituximab also had a better survival (5-year OS 71% vs. 43%, P < 0.001). In early stage disease (n = 220), 43 patients who (19%) received rituximab had a better survival which was not statistically significant (RCHOP vs. CHOP 5-year OS 90% vs. 78%, P = 0.28). In advanced stage disease (n = 224), RCHOP significantly improved survival of patients. OP(5-year OS 76% vs. 46.5%, P < 0.001).
Impact of radiation therapy on overall survival
Patients with early stage (I and II) disease (n = 220), the 5-year-OS was significantly better (90%) when they received radiation as compared to those who did not (71%) (P < 0.001). Within this group, 34/77 (44%) with bulky disease received radiation therapy (RT) whereas 66/143 patients (46%) with nonbulky early-stage disease received RT. The magnitude of impact of RT on survival was better in those with bulky disease (n = 77, 5-year OS: RT vs. no RT: 92% vs. 57%, P < 0.001) compared to those with nonbulky disease (n = 143, 5-year OS: RT vs. no RT: 88% vs. 78%, P < 0.001). The impact of radiation on survival in early stage disease was independent of the number of cycles of chemotherapy used. Among those who received ≤4 cycles of chemotherapy, 5-year OS among those who received RT versus no RT was 94% versus 69%, P < 0.001. Among those who received more than four cycles of radiation, the 5-year OS of RT versus no RT was 89% versus 71%, P < 0.001. In patients with early stage disease treated with rituximab (n = 43), the benefit of adding radiation (n = 16) persisted (RT vs. no RT, 5 year-OS 100% vs. 84%, P < 0.001). Since only a small fraction (34/224, 15%) of patients with advanced stage disease received radiation, further analysis of this subgroup was not feasible.
| » Discussion|| |
This report documents the outcome of patients with DLBCL over 14 years in a single center. Although the analysis is based on retrospective collection of data, it provides important insights regarding the usefulness of biosimilar rituximab and the role of radiation in early stage disease. The evolution of management varied over time with better recognition of prognostic factors that impacted on treatment. Rituximab was undoubtedly the single most important advance in the management of DLBCL. Unfortunately, the innovator product was not accessible to the majority of patients previously at our center as it was expensive. In this report, most patients received biosimilar rituximab, and this was clearly superior to CHOP even after multivariate analysis adjusting for clinical variables. Although the decision to administer rituximab was based on economic situation of the patient, the patients receiving RCHOP and CHOP were comparable [Table 1].
Biosimilar products have greatly increased the accessibility to costlier antibodies in low- and middle-income countries like India. However, these drugs are often approved for use without large Phase III efficacy trials comparing them to the innovator molecules. The production of biosimilar rituximab in India was an important development. The drug was, however, licensed based on a single-arm study in patients with DLBCL. Hence, a retrospective analysis like this is often the only means to understand the efficacy of these drugs. The only other data in this regard published earlier from India showed equivalence between these two molecules. Although these results are not a substitute for randomized Phase III trials, these can increase confidence among physicians using the biosimilar molecule when it is not possible (due to economic considerations) to use the innovator product. At our center, >90% of patients of DLBCL treated in 2014–2015 received rituximab and this has been possible due to the availability of biosimilars. A randomized blinded trial comparing the innovator and biosimilar rituximab mentioned in this article has been now completed and the results are awaited.
The role of radiation as an adjunct to chemotherapy in DLBCL had been studied in multiple randomized trials in the pre-rituximab era, especially in early stage disease.,,, After the introduction of rituximab, the data supporting the use of radiation come from a few retrospective studies.,, There was a clear benefit of adding radiation among patients with early stage disease even after adjusting for factors such as bulky disease, use of rituximab, or the number of cycles of chemotherapy. This is concordant with the most recent data from SEER database of over 50,000 patients which showed that the 5-year survival with or without radiation was 82% versus75% among patients with Stage I and II disease despite the use of modern multiagent chemotherapy. Even among patients with advanced disease, retrospective data as well as subgroup analysis from large trials suggest additional benefit of radiation., In our series, only a small fraction of patients with advanced disease received radiation despite bulky disease being present in 41% (91/224) precluding any meaningful analysis.
The other factors predicting survival were as expected with factors comprising the international prognostic index score such as stage, age, performance status, and LDH levels being significant. In addition, we found that inferior survival correlated with lower hemoglobin at presentation. Baseline anemia is an important prognostic factor (using a cutoff of 10 g/dL) in DLBCL though not incorporated in usual predictive scores. We used a cutoff of 12 g/dL as this has been shown to be proven important in patients with follicular lymphoma. Anemia may represent bone marrow involvement or may be an independent factor representing biology or represent tolerance to therapy in lymphomas.
On comparing the outcomes with the results from the MabThera International Trial (MInT) which addressed as similar age group (age 18–60 years), we found that the 3-year OS was much higher (93%) in the latter. However, only 28% of patients in the MInT had advanced stage disease and <1% having aaIPI ≥2. In our study, half the patients had Stage III, IV disease as well aaIPI 2 or 3 at presentation. Our low-risk aaIPI patients had a survival of 93% which is similar to that reported in the MInT study. The other published study on biosimilar rituximab had stage distribution similar to our study and reported comparable survival (76% with biosimilar RCHOP).
DLBCL is a diverse disease with multiple molecular subtypes with varying outcomes. Molecular studies have identified various subtypes (germinal center, activated B–cell, and “double hit” DLBCL) which may impact treatment decisions. However, in resource-constrained settings, with limited access to expensive investigations, the focus has been to provide best possible therapy for the patients. Although these data are limited by its retrospective nature and the variability of treatment choices based on economic and individual physician preferences, it remains one of the largest reports of DLBCL from India and reflects the real-world treatment outcomes.
| » Conclusion|| |
In this analysis, we found that availability of biosimilar rituximab increased access to targeted therapy and improved survival of patients with DLBCL. Addition of radiotherapy to chemotherapy improves outcomes in early stage DLBCL.
Financial support and sponsorship
The study was financially supported by Cancer Institute (WIA) funds.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]
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