Abstract
Background
In international prognostic index (IPI) risk-tailored adult patients with diffuse large B-cell lymphoma (DLBCL), it is still unclear whether the addition of maintenance rituximab (MR) improves progression-free (PFS) and overall survival (OS), after RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) therapy.
Methods
In our study, 207 patients (age: 21–59 years) received six 14-day cycles of RCHOP and gained overall response. After RCHOP, 98 patients were enrolled in the observation (OBS) arm. 109 patients continued to receive MR therapy.
Results
In IPI risk <2 profile, PFS at 5 years reached 72.9% (MR arm) versus 56% (OBS arm) (P = 0.033). In IPI risk ≥2 profile, PFS estimation at 5 years was 44.9% (MR arm) versus 33.5% (OBS arm) (P = 0.006). It is noteworthy that patients with IPI ≥2 who received MR achieved PFS similar to that for patients in the OBS arm with the IPI <2, 44.9% versus 56% (P = 0.97). In patients with an IPI <2, OS at 5 years was 83.2% (MR arm) versus 81.2% (OBS arm) (P = 0.708). In patients with an IPI ≥2, 5-year OS estimation was 44.6% (MR arm) versus 40.5% (OBS arm) (P = 0.067). Subgroup analysis of patients with an IPI ≥3 risk profile shows a survival benefit for patients receiving MR. OS at 5 years was 62% (MR arm) versus 49% (OBS arm), (P = 0.033).
Conclusions
In conclusion, maintenance rituximab after RCHOP improves progression-free survival. In addition, overall survival is improved for patients with an IPI ≥3 risk profile receiving MR.
Keywords: Rituximab, Diffuse large B-cell lymphoma, RCHOP-14, International Prognostic Index, Adult patients
Introduction
Diffuse large B-cell lymphoma (DLBCL) accounts for approximately 40% of all new cases of non-Hodgkin’s lymphoma (NHL). DLBCL is very chemosensitive and highly curable, even in the setting of extranodal involvement. Since the mid-1970s, the standard treatment of DLBCL has consisted of combination chemotherapy with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) or CHOP-like regimens (Gottlieb et al. 1973). The Southwest Oncology Group (SWOG) analysis demonstrates sustained long-term outcomes for some patients (McKelvey et al. 1976). Despite this major advancement in the management of non-Hodgkin’s lymphoma (NHL), a substantial proportion of patients are still not cured (Mark and Cerny 2010).
Prior to the rituximab era, CHOP chemotherapy was widely used as first line chemotherapy. Six or eight courses of CHOP without radiation were associated with a 77% failure-free survival at 5 years (Miller et al. 1998). DLBCL routinely expresses the pan–B-cell antigen, CD20. Development of anti-CD20 antibody therapy heralded a new era in treatment approaches for NHL. Rituximab, a CD20-specific antibody, is used with chemotherapy as a treatment for DLBCL (Koivula et al. 2011). The addition of rituximab to CHOP (RCHOP) in patients has demonstrated superior survival. Currently, RCHOP is recommended for poor responders.
The use of maintenance rituximab after induction with chemoimmunotherapy that includes rituximab has been associated with prolongation of progression-free survival in follicular low-grade lymphomas (Salles et al. 2011). Further, the E1496 study provides the first phase III data in untreated indolent lymphoma that maintenance rituximab after chemotherapy significantly prolongs progression-free survival (PFS) (Hochster et al. 2009). However, this finding does not appear to apply equally to DLCL. Habermann et al. reported (Habermann et al. 2006) rituximab administered as induction or maintenance with CHOP chemotherapy significantly prolonged failure-free survival in older DLBCL patients. But after RCHOP, maintenance rituximab (MR) provided no additional benefit. Initial RCHOP chemotherapy for patients with DLBCL is often successful, but the relapse rate in high-risk patients remains problematic.
DLBCL patients with relapse or primary progressive disease have a poor prognosis with conventional salvage therapy. These patients are typically treated with high-dose chemotherapy followed by autologous stem cell transplantation (ASCT). Despite PFS and OS rates ranging from 40 to 60%, more effective treatments are needed to improve prognosis (Josting et al. 2000; Kewalramani et al. 2000; Moskowitz et al. 1999; Philip et al. 1995; Vose et al. 2001). MR after ASCT has been evaluated as a means of reducing minimal residual disease. In two independent studies, improvements in disease-free survival and OS were reported after the use of rituximab post-ASCT (Khouri et al. 2005; Horwitz et al. 2004). In post-RCHOP chemotherapy for risk-tailored adult patients with DLBCL, it is still unclear whether the addition of MR improves long-term survival. This study aims to address this question. We analyzed the PFS and OS of different IPI risk-adapted patients, comparing maintenance rituximab versus observation as post-RCHOP therapy.
Methods
Study population
All patients included in the study were treated between April 2005 and January 2011. Five Chinese academic medical centers participated as study sites. Pathology review was completed at each center and classified according to WHO criteria (The Non-Hodgkin’s Lymphoma Pathologic Classification Project: National Cancer Institute sponsored study of classifications of non-Hodgkin’s lymphomas: Summary and description of a working formulation for clinical usage 1982). All patients were stratified by IPI scores: Ann Arbor stage III–IV (Lister et al. 1989), elevated lactate dehydrogenase (LDH) levels, Eastern Cooperative Oncology Group performance status (PS) ≥2 (Shipp and Harrington 1993) and extranodal organ involvement ≥2.
Inclusion criteria
(1) Adult patients (15–60 years old) met the World Health Organization (WHO) diagnostic criteria for DLBCL (Harris et al. 1999). (2) Patients treated with a standardized RCHOP-14 therapy regimen (six cycles). (3) Patients with complete records of IPI scores.
Exclusion criteria
(1) Patients were less than 15 years or greater than 60 years of age. (2) Patients with transformed follicular lymphoma, central nervous system (CNS) involvement, history of HIV infection, inadequate organ function, or non-hematologic malignancy. (3) Patients with incomplete clinical records.
Treatment schedule
All patients underwent RCHOP-14 as initial treatment. Patients were stratified into two groups: IPI <2 (zero or one factor) or IPI ≥2 (two or more factors). Within each group, patients received either MR or OBS (Fig. 1) after 6 total cycles RCHOP-14.
Fig. 1.
Study design and patient disposition
RCHOP-14 regimen
RCHOP-14 was administered in the standard dosage (rituximab, 375 mg/m2, day 1; cyclophosphamide, 750 mg/m2, doxorubicin 50 mg/m2 and vincristine 1.4 mg/m2, given intravenously on day 2, and prednisone 60 mg/day given orally on day 2–5). The regimen was repeated every 14 days for a total of 6 courses.
MR regimen
Maintenance rituximab (375 mg/m2) was used once per month for 12 months, during the first study year. Subsequently, rituximab 375 mg/m2 was continued once every 3 months during the second study year.
Study endpoints
Study endpoints included overall response rate (ORR), complete remission (CR) and partial remission (PR). Criteria for CR: all lymph nodes ≤1.0 × 1.0 cm or, if larger, biopsy-negative nodes or no enlargement during 3 months without therapy, and no bone marrow involvement. PR criteria was ≥50% reduction in the sum of the products of the diameters of measurable lesions. Progressive disease was defined as a more than 25% increase in the sum of the products of pretreatment lesions or new disease. Stable disease met none of these criteria (Hochster et al. 2009). Best response required confirmation at 4 weeks.
Computed tomography (CT) scans were repeated every 4 weeks after the last day of RCHOP treatment in addition to every 2 cycles until best response. CT scans were assessed according to National Cancer Institute (NCI) sponsored international working group (2009) (Cheson et al. 1999). PET-scans were not routinely used.
Progression-free survival (PFS) was defined as time from diagnosis until progression or death from any cause. Overall survival was measured from diagnosis until death from any cause. Patients without a PFS or OS event at the date of last contact were censored. Response was assessed by the treating physician after the end of treatment according to the Cheson et al. criteria (Cheson et al. 1999).
Statistical analysis
Statistical analysis was performed with SPSS 13.0 statistical software. Age and median number of days between cycles were compared by T test. ORR, IPI risk factors, prognosis outcomes and adverse event response were evaluated by Pearson Chi-square test. PFS and OS were estimated by the Kaplan–Meier method. P value <0.05 was considered statistically significance.
Result
Response to RCHOP therapy
228 adult patients received RCHOP-14 regimen therapy. 84/99 patients (88.42%) with IPI <2 reached CR, compared to 58/129 patients (51.79%) with IPI ≥2 (P < 0.001, Table 1). 11.58% patients with IPI <2 achieved PR, and 48.21% patients with IPI ≥2 reached PR. Further, the ORR for patients with IPI risk-tailored <2 was 95.96% compared with 86.82% for patients with IPI ≥2 (P = 0.018, Table 1). Only 21 patients did not reach OR (9.21%), 8 of 228 patients (3.51%) had disease that was unchanged. 11 of 228 patients (4.82%) had disease progression, and 2 patients (0.88%) died during RCHOP therapy (Table 1).
Table 1.
Treatment responses after RCHOP (6 courses)
| IPI risk-tailored | IPI <2 | IPI ≥2 | P value | ||
|---|---|---|---|---|---|
| n | (%) | n | (%) | ||
| Patients | 99 | 129 | |||
| Overall response | 95 | (95.96) | 112 | (86.82) | 0.018 |
| CR | 84 | (88.42) | 58 | (51.79) | <0.001 |
| PR | 11 | (11.58) | 23 | (48.21) | |
| No remission | 4 | (4.04) | 17 | (13.18) | |
| Stable | 1 | (1.01) | 7 | (5.43) | |
| Progressive | 2 | (2.02) | 9 | (6.98) | |
| Death | 1 | (1.01) | 1 | (0.77) | |
Enrolled patient with post-RCHOP therapy characteristics
207 patients (age range: 21–59 years old) fit selection criteria (Fig. 1). Median number of days between cycles was 15 days (Table 2). 43 of 207 patients (20.77%) had extranodal involvement in ≥2 organs. 146/207 patients (70.53%) were Ann Arbor stage III–IV when they were diagnosed. 144/207 patients (69.56%) in both groups had elevated LDH, and fewer than 12% patients had performance status ≥2. After receiving 6 cycles of RCHOP-14 therapy, 98 patients continued in the OBS arm while 109 patients continued to receive MR therapy. Baseline patient characteristics between the two cohorts were balanced in age (P = 0.89) and IPI prognostic factors (P = 0.40) (Table 2).
Table 2.
Patient characteristics
| Characteristic | OBSa | MRb | P value | ||
|---|---|---|---|---|---|
| n | (%) | n | (%) | ||
| Eligible patients | 98 | (47.34) | 109 | (52.66) | |
| Age (median, range) | 40 | (21–59) | 40 | (23–59) | 0.89 |
| Sex | |||||
| Male | 58 | (59.18) | 55 | (50.46) | |
| Female | 40 | (40.82) | 54 | (49.54) | |
| Median of days until next cycle (median, range) | 15 | (14–19) | 15 | (14–19) | 0.74 |
| Extranodal involvement ≥2 | |||||
| Yes | 18 | (18.37) | 25 | (22.94) | |
| No | 80 | (81.63) | 84 | (77.06) | |
| Ann Arbor stage III–IV | |||||
| Yes | 65 | (66.33) | 81 | (74.31) | |
| No | 33 | (33.67) | 28 | (25.69) | |
| Elevated LDH | |||||
| Yes | 76 | (77.55) | 68 | (62.39) | |
| No | 22 | (22.45) | 41 | (37.61) | |
| Performance status ≥2 | |||||
| Yes | 11 | (11.22) | 13 | (11.93) | |
| No | 87 | (88.78) | 96 | (88.07) | |
| IPI | |||||
| <2 | 48 | (48.98) | 47 | (43.12) | 0.40 |
| ≥2 | 50 | (51.02) | 62 | (56.88) | |
a OBS patients who underwent observation only
b MR patients who received maintenance rituximab
Progression-free and overall survival
Patients were stratified by IPI (<2 and ≥2) risk profile. During 5-year follow-up, 147/207 patients (70.33%) remained in remission, while the other 60/209 patients (28.71%) had disease progressive or died (Table 3). Patients with IPI <2 were more likely to remain in remission than patients with IPI ≥2 (80% versus 63.39%, P < 0.001).
Table 3.
Outcome of patients at 5-year follow-up
| Outcome | IPI <2 | IPI ≥2 | P value | ||||||
|---|---|---|---|---|---|---|---|---|---|
| OBS | MR | OBS | MR | ||||||
| n | (%) | n | (%) | n | (%) | n | (%) | ||
| Patients | 48 | 47 | 50 | 62 | <0.001 | ||||
| Stable | 32 | (66.67) | 44 | (93.62) | 21 | (42) | 50 | (80.65) | |
| Progressive or death | 16 | (33.33) | 3 | (6.38) | 29 | (58) | 12 | (19.35) | |
Kaplan–Meier method analysis showed that 5-year PFS was 63.5% in IPI <2 arm, compared to 40.9% in patients with IPI ≥2 arm (P = 0.002, Fig. 2a). Similarly, 5-year OS in patients with IPI <2 was superior to that of patients with IPI ≥2 (81.6% versus 56.7%, P < 0.001, Fig. 2b). In patients with IPI risk <2, patients receiving MR gained more satisfactory PFS compared to the OBS group: PFS at 5 years reached 72.9 versus 56% (P = 0.033) (Fig. 3a). 5-year PFS in MR arm was also markedly higher compared to the OBS arm in patients with IPI risk ≥2 profile: 44.9% versus 33.5% (P = 0.006). Moreover, patients in the MR arm with IPI ≥2 attained 5-year PFS similar to that for patients of OBS arm with the IPI <2 profile: 56% versus 44.9% (P = 0.97) (Fig. 3a). There was no difference in OS between MR and OBS arms in patients with IPI <2 risk profile: 5-year OS was 83.2% versus 81.2% (P = 0.708) (Fig. 3b). Meanwhile, OS for patients in the MR arm was not superior to OBS arm in IPI ≥2 risk profile: 44.6 versus 40.5% (P = 0.067) (Fig. 3b).
Fig. 2.
a PFS of IPI risk arms (<2 and ≥2). b OS of IPI risk arms (<2 and ≥2)
Fig. 3.
a PFS of maintenance therapy arms with IPI risk profiles (<2 and ≥2). b OS of maintenance therapy arms with IPI risk profiles (<2 and ≥2)
In a subgroup analysis, we stratified patients by IPI risk profiles ≤2 and ≥3 risk profile. In patients with IPI risk ≤2, patients receiving MR had improved PFS compared to patients in the OBS arm. PFS at 5 years reached 69 versus 47% (P = 0.005) (Fig. 4a). Moreover, in patients with an IPI risk profile ≥3, PFS in the MR arm was also markedly higher compared to the OBS arm 65 versus 39% (P = 0.015). There was also no difference in OS between MR and OBS arms in IPI ≤2 profile (P = 0.50), however, in IPI ≥3 risk profile, OS at 5 years was 62% (MR arm) versus 49% (OBS arm) (P = 0.033, Fig. 4b).
Fig. 4.
a PFS of maintenance therapy arms with IPI risk (≤2 and ≥3). b OS of maintenance therapy arms with IPI risk profiles (≤2 and ≥3)
Adverse events for chemotherapy
The RCHOP-14 regimen was well tolerated (Table 4). Peripheral blood counts of 34 patients showed agranulocytosis, but only 7 patients incurred severe infection (WHO grade 3 or 4). 11.11% patients had obvious nausea-vomiting symptoms. Only a small number of patients had serious but controlled multisystem adverse events (WHO grade 3 or 4): allergy (4.35%), cardiovascular (2.42%), liver dysfunction (1.45%) and renal insufficiency (0.48%).
Table 4.
Main adverse events related to RCHOP-14 regimen
| WHO grade 3 or 4 | RCHOP-14 | |
|---|---|---|
| n | (%) | |
| Total patients | 207 | |
| Neutropenia | 34 | 16.43 |
| Infection | 7 | 3.38 |
| Nausea-vomiting | 23 | 11.11 |
| Allergy | 9 | 4.35 |
| Cardiovascular | 5 | 2.42 |
| Liver dysfunction | 3 | 1.45 |
| Renal insufficiency | 1 | 0.48 |
Patients in the OBS group did not receive any chemotherapy and reported no adverse events after RCHOP-14 (Table 5). In addition, there were no serious multisystem adverse events (allergy, cardiovascular, liver dysfunction and renal insufficiency) in the MR arm. Only 0.92,1.83 and 6.42% patients had serious agranulocytosis, infection and nausea-vomiting. However, there were no differences in the incidences of neutrophil and infection, between MR and OBS groups (P = 0.53 and P = 0.28).
Table 5.
Main adverse events in OBS versus MR arms
| WHO grade 3 or 4 | OBS arm | MR arm | P value | ||
|---|---|---|---|---|---|
| n | (%) | n | (%) | ||
| Total patients | 98 | 109 | |||
| Neutrophil | 0 | 0 | 1 | 0.92 | 0.53 |
| Infection | 0 | 0 | 2 | 1.83 | 0.28 |
| Nausea-vomiting | 0 | 0 | 7 | 6.42 | 0.01 |
| Allergy | 0 | 0 | 0 | 0 | |
| Cardiovascular | 0 | 0 | 0 | 0 | |
| Liver dysfunction | 0 | 0 | 0 | 0 | |
| Renal insufficiency | 0 | 0 | 0 | 0 | |
Discussion
Rituximab is an anti-CD20 monoclonal antibody that has demonstrated efficacy in patients with various lymphoid malignancies, including indolent and aggressive forms of B-cell non-Hodgkin’s lymphoma (NHL) and B-cell chronic lymphocytic leukemia (CLL). At present, rituximab in combination with CHOP chemotherapy has emerged as a new treatment standard for previously untreated DLBCL. Our results demonstrate that the potential advantage of rituximab maintenance chemotherapy in adult patients with DLBCL compared to observation. Although it is a retrospective nonrandomized study, there was no difference between the cohorts in age and IPI risk profiles. Undoubtedly, IPI risk profile is an important factor affecting response rates and long-term survival of DLBCL. Patients with IPI <2 have good overall response rate (95.96%), 5-year progression-free survival (63.5%) and overall survival (81.6%). On the contrary, RFS and OS at 5-year patients with IPI ≥2 were 40.9 and 57.6%, respectively.
A recent prospective study (Habermann et al. 2006) in elderly patients with DLBCL receiving RCHOP-21 (6 cycles) shows 3-year failure-free survival and OS were 52 and 67%, respectively. In that study, rituximab administered as induction or maintenance with CHOP chemotherapy significantly prolonged PFS in older patients (≥60 years old) with DLBCL. After RCHOP, no benefit was provided by MR. In our study 5-year PFS is 51.4%, and OS at 5 years was 63.3% for adult patients (<60 years old) with DLBCL receiving RCHOP-14 (6 cycles). Patients who received MR therapy had longer PFS compared to the observation group, regardless of IPI risk <2 or ≥2 score. Furthermore, patients with IPI ≥2 who received MR therapy attained the same PFS as patients with IPI <2 in the OBS arm. 5-year PFS was 56% versus 44.9%. Nevertheless, MR chemotherapy in patients with IPI ≥2 does not improve OS. Moreover, low IPI risk <2 is also not superior to OBS group in 5-year OS. In summary, rituximab administered as maintenance with post-RCHOP significantly prolonged PFS in adult DLBCL patients, but there was no difference in overall survival when patients were stratified by IPI risk <2 or ≥2. Analysis of high-risk patients, IPI ≥3, MR did improve overall survival and equaled the 5-year survival rate of observation patients with IPI ≤2 (P = 0.37).
Certainly, Habermann et al. (Habermann et al. 2006) showed a significant difference in the effect of maintenance rituximab therapy according to the type of induction therapy in patients with DLBCL. In our study, we cannot assess the difference of efficacy between CHOP and RCHOP regimen. Our enrolled patients all receive RCHOP-14 (6 cycles) chemotherapy. The two cohorts in our study are comparable with respect to age and IPI prognostic factors. Our data support that the advantage of MR is irrespective of the original induction chemotherapy protocol, age or IPI risk profile. All patients had good compliance to regular maintenance therapy.
Infusion-related reactions occur in the majority of patients treated with rituximab; these are usually mild to moderate flu-like symptoms that decrease in frequency with subsequent infusions (Plosker and Figgitt 2003). Some scholars have reported a significantly higher bacterial infection rate in rituximab-treated patients than in patients who did not receive rituximab (Benekli et al. 2003). Compared with conventional chemotherapy, rituximab is associated with markedly reduced hematological events such as severe neutropenia, as well as associated infections. In our cohort, treatment with maintenance rituximab was generally well tolerated, particularly in terms of adverse hematological effects (agranulocytosis, 0.92%) and serious opportunistic infections (only 1.83%). The clinical benefit of adding maintenance rituximab was not accompanied by an increase in side effects of treatment; the therapy toxicity was tolerable and comparable in MR groups.
Currently, the IPI risk score is the most widely accepted stratification of patients with DLBCL (Ziepert et al. 2010). This process takes into account 5 clinical variables: advanced age (our patients ≤60 years old), poor performance status (Eastern Cooperative Oncology Group ≥2), elevated serum LDH levels, advanced stage lymphoma (Ann Arbor criteria III–IV) and involvement of ≥2 extranodal sites (Shipp and Harrington 1993). These parameters differentiate patients into 4 risk groups—low (IPI = 0 or 1), low-intermediate (IPI = 2), high-intermediate (IPI = 3), and high (IPI 4–5)—each with a different prognosis. This prognostic index yields treatments that are calibrated more precisely to the individual patient. In the era of rituximab, the optimal treatment of adult patients with IPI risk DLBCL remains open for debate. Our data support that it is not only an additive effect for rituximab (Habermann et al. 2006). The findings demonstrate that MR improves RFS for different IPI risk patients. Rituximab as maintenance treatment of adult patients after RCHOP may provide a new strategy in future post-RCHOP treatment protocols.
Acknowledgments
We would like to thank all the patients and the clinicians from the participating sites. Jessica Yu supported the substantial English revision. This work was supported by grants from the Natural Science Foundation of Inner Mongolia (200711020952) and Natural Science Foundation of Guangdong Province Grant (10151600301). All authors discussed the results and commented on the manuscript.
Conflict of interest
I would like to declare on behalf of my co-authors that the work described was original research that has not been published previously, and not under consideration for publication elsewhere, in whole or in part. All the authors listed have approved the manuscript that is enclosed.
Footnotes
Bin-Tao Huang and Qing-Chun Zeng equally contributed to this work.
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