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- Patients and methods
This study was designed to assess the efficacy and safety of an infusional DA-EPOCH (dose-adjusted etoposide/vincristine/doxorubicin/bolus cyclophosphamide/prednisone) and rituximab (DA-EPOCH-R) regimen for patients with poor prognosis diffuse large B-cell lymphoma (DLBCL). Thirty-three patients, aged 21–76 years, with an age-adjusted International Prognostic Index (IPI) of 2 or 3, were enrolled, and 31/33 patients were evaluable for response. Consolidative radiation therapy was given to eight patients with bulky (≥10 cm) disease at presentation. Overall, 26 patients (83·8%) achieved a complete remission (CR), four patients (12·9%) achieved a partial remission, and one patient (3·2%) died during induction. Two patients relapsed (7·6%) within 15 months. Grade 3–4 neutropenia developed in 52% of cycles and neutropenic fever in 14% of cycles (51% of patients). The estimates for event-free survival (EFS) and overall survival at 2 years were 68% and 75% respectively. The only factor related to poor EFS was the presence of three age-adjusted IPI-risk factors. We conclude that DA-EPOCH-R has clinically significant activity with a favourable toxicity profile for poor-prognostic DLBCL patients. The administration of DA-EPOCH-R as an outpatient regimen by using a single portable infusion pump may be a feasible alternative to improve the compliance and to reduce the total cost of this very effective regimen.
Poor prognosis diffuse large B-cell lymphoma (DLBCL), including intermediate–high and high-risk disease according to the International Prognostic Index (IPI) (Shipp & Harrington, 1993), accounts for approximately 20% of new cases of lymphoma, with overall cure rates of 25–35% with conventional anthracycline-based chemotherapy (Tilly et al, 2003; Vose et al, 2003; Pfreundschuh et al, 2004a,b). In an effort to improve cure rates for these patients, induction therapy followed by upfront high-dose chemotherapy (HDT) with autologous stem-cell transplantation (ASCT) has been investigated over the last decade, with variable results in randomised trials (Haioun et al, 2000; Kluin-Nelemans et al, 2001; Gisselbrecht et al, 2002; Milpied et al, 2004). In addition, more than half of the patients are not eligible for the procedure because of advanced age. Thus, the treatment of poor-prognosis DLBCL is a difficult challenge and optimal treatment remains uncertain (Abramson & Shipp, 2005). Recently reported randomised trials in elderly patients focused on the addition of rituximab, a monoclonal anti-CD20 antibody, to the conventional CHOP21 regimen (cyclophosphamide + doxorubicin + vincristine + prednisolone every 21 d) (Coiffier et al, 2002; Feugier et al, 2005) or increased the dose density of conventional CHOP21 by shortening the interval between cycles from 3 to 2 weeks (Pfreundschuh et al, 2004b). These two strategies increased the likelihood of a complete response (CR) and long-term event-free survival (EFS) by 15–25% in elderly patients with poor-prognosis DLBCL. Most recently, a major attempt to improve the outcome of DLBCL has been to combine dose-dense CHOP chemotherapy with rituximab, given every 14 d (R-CHOP14). According to the published data from two small uncontrolled and prospective studies involving a total of 36 poor-prognosis patients, R-CHOP14 showed promising results, with 2-year EFS and overall survival (OS) rates of 50% and 39–49% respectively (Brusamolino et al, 2006; Rigacci et al, 2006). A more definitive phase III study of CHOP14 with or without rituximab for elderly patients is currently being conducted by the German High-Grade Non-Hodgkin Lymphoma Study Group. An efficacy interim analysis (so far published only in abstract form) confirmed that outcome was improved with R-CHOP14 for poor-prognosis patients, with a 2-year OS rate of 50% (Pfreundschuh et al, 2005). Although, all these studies were performed in DLBCL patients aged over 60 years, a similar degree of benefit of R-CHOP14 is expected but not yet reported for DLBCL patients under 60 years of age who have an intermediate–high or high IPI-risk disease. Despite this expected improvement in outcome, it is likely that 40–50% of these patients will experience primary treatment failure or relapse after an initial response. Thus, further improvements in initial therapy are required for poor prognosis DLBCL.
Recently, DA-EPOCH (dose-adjusted etoposide/prednisone/vincristine/cyclophosphamide/doxorubicin), an infusional regimen that incorporates a dynamic dose-adjustment strategy based on haematopoietic nadir to overcome inadequate drug concentrations (Ackland et al, 1989; Gutierrez et al, 2000), showed a CR rate of 86%, with a 5-year EFS rate of 58% in 22 previously untreated poor-prognosis DLBCL (Wilson et al, 2002a). Overexpression of BCL2, which is associated with activated B-cell origin, was the only factor associated with treatment failure. Other preliminary study suggested that DA-EPOCH with added rituximab may help overcome the adverse effects of BCL2 (Wilson et al, 2002b). In this study of 23 patients, 85% achieved CR and 85% were progression-free with a median follow-up of 12 months. However 40% of patients in the series had low IPI-risk disease and all the patients were considered as a single group, without separate evaluation of patients with an intermediate-high or high IPI-risk disease. Moreover, a longer confirmatory study for this strategy in poor prognosis DLBCL has not been reported. Therefore, we performed a prospective study with DA-EPOCH plus rituximab (DA-EPOCH-R) in newly diagnosed intermediate–high and high-risk DLBCL. Herein, we report the results of a single-centre prospective observational study designed to confirm the efficacy of this immuno-chemotherapy regimen as well as assess prognostic factors predicting long-term survival. In addition, we evaluated the feasibility and toxicity of this programme in patients aged ≤60 years when compared with patients aged >60 years. The rationale for various aspects of this programme include: (i) the age-adjusted IPI was used to identify poor prognosis patients for whom conventional regimens give relatively low chance of cure; (ii) we do not believe that a subdivision of patients into young or elderly patients is justified, because it has been shown that the disease biology is consistent with age (Knight et al, 2004) and the prognosis of patients aged >70 years was not significantly different if their frequent comorbidities did not compromise the adherence to the therapeutic regimen (Pfreundschuh et al, 2004b); Thus, we have used this programme as a standard of care for poor prognosis DLBCL irrespective of age; and (iii) doxorubicin, vincristine and etoposide were administered over 96 h because it was shown that optimising the administration of these agents was very active even in doxorubicin-resistant lymphomas (Gutierrez et al, 2000); in addition, etoposide, doxorubicin and cyclophosphamide, the cytotoxic drugs with the highest efficacy in DLBCL, were given at the maximum tolerated doses.
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- Patients and methods
Poor prognosis DLBCL accounts for approximately 50% of all DLBCL with overall cure rates ranging from 50% to 60% with modern immuno-chemotherapy regimens such as R-CHOP14. Therefore, the search for new therapies should continue. An infusional and dose-adjusted approach of EPOCH may be an alternative strategy in this group of patients, irrespective of age, and promising results have been reported in a previous phase II study, with estimated 5-year EFS and OS rates of 79% and 58% respectively (Wilson et al, 2002a). The addition of rituximab to DA-EPOCH-R seems to improve the outcome (Wilson et al, 2002b). Despite these excellent results, only modest experience has been acquired concerning this treatment modality primarily due to the inconvenience of a 4-day continuous infusion. We felt that this was absolutely justified given the otherwise poor prognosis of high-risk patients with DLBCL. Thus, we conducted a non-randomised phase II study to confirm the efficacy and safety of DA-EPOCH-R in a homogeneous population of 33 poor prognosis DLBCL patients.
To our knowledge, this is the largest clinical study ever published on patients with poor prognosis DLBCL treated with frontline DA-EPOCH-R. In agreement with previously reported results (Wilson et al, 2002b), our study confirms the high efficacy of DA-EPOCH-R regimen in a homogeneous cohort of patients with poor prognosis DLBCL. Overall, 83·8% of patients achieved CR/uCR at the end of entire treatment, and the estimated 2-year EFS and OS rates were 68% and 75% respectively. The high survivals observed were a result of the absence of disease progression during therapy and lower rates of relapse after reaching CR. Although comparison of the results of DA-EPOCH-R with other recent approaches is difficult, it should be mentioned that our results compare favourably with the previously published study of DA-EPOCH alone (Wilson et al, 2002a) and with more recent programmes, such as dose-dense CHOP with or without rituximab (Table IV). Of note, in our series half of the patients had a high-risk IPI score, while this figure ranged between 16% and 40% in recent trials with CHOP14 or R-CHOP14. In addition, 24% of our patients had bulky disease. These factors suggested that our cohort of patients represent a group with particularly unfavourable outcome. Nevertheless, a high response rate was achieved with DA-EPOCH-R for the entire group. The Memorial Sloan Kettering Cancer Center treated a cohort of 22 patients, comparable with our patients, with R-CHOP14 (Halaas et al, 2005). The 2-year EFS and OS rates were 70% and 78%; however, it was a retrospective study with a high-selection bias (included only patients refusing or not eligible for protocol-based therapy). Altogether, it thus appears that the results obtained with DA-EPOCH-R are superior to those obtained with CHOP14 or R-CHOP14.
Table IV. Major studies evaluating the best conventional chemotherapy regimens in poor prognosis DLBCL.
|Regimen/reference||Type of study||No. of patients|| Study population (%)||CR (%)||EFS (%)||OS (%)||TRM (%)||Relapse (%)|
|DA-EPOCH (Wilson et al, 2002a)||Uncontrolled, single institution||26||Aged 20–88 years, HR 19||92||58||65||0||26|
|DA-EPOCH-R (Wilson et al, 2002b)||Uncontrolled, single institution||14||Aged 21–81 years, HR 19||85||85||79||7||0|
|CHOP14 (Pfreundschuh et al, 2004b)||Randomised, multicentre||80||Elderly, HR 31||76||43||53||3||NOS|
|R-CHOP21 (Feugier et al, 2005)||Randomised, multicentre||121||Elderly, HR 28||<75||41||48||6||38|
|R-CHOP14 (Halaas et al, 2005)||Uncontrolled, single institution and retrospective||22||Elderly, HR 40||NOS||70||78||0||13|
|R-CHOP14 (Pfreundschuh et al, 2005)||Randomised, multicentre||312||Elderly, HR 16||NOS||NOS||64||NOS||NOS|
|R-CHOP14 (Brusamolino et al, 2006)||Uncontrolled, single institution||18||Aged 22–70 years, HR 36||NOS||51||49||3||8|
|R-CHOP14 (Rigacci et al, 2006)||Uncontrolled, single institution||18||Elderly, HR: NOS||72||NOS||39||3||25|
|DA-EPOCH-R (present study)||Uncontrolled, single institution||31||Aged 21–76 years, HR 51||83||68||75||6||7|
It has been suggested that more pronounced myelosuppression of aggressive chemotherapy regimens might interfere with the effector mechanisms of rituximab. However, our data suggest that rituximab given in conjunction with DA-EPOCH can improve the outcome of poor prognosis DLBCL. In fact, the relapse rate of 7·6% observed in the present study is different from that one reported with DA-EPOCH without rituximab, which found a 25% of rate of relapse in 22 poor prognosis DLBCL patients (Wilson et al, 2002a). These data are consistent with results from another preliminary study that suggested that the addition of rituximab to DA-EPOCH reduced the likelihood of relapse (Wilson et al, 2002b).
The benefit of applying adjuvant radiotherapy to sites of nodal bulky disease in patients with advanced poor prognosis DLBCL has been indicated by two randomised trials showing that radiotherapy improved EFS and OS in these patients (Wilder et al, 2001; Aviles et al, 2004). However, these studies were performed before the era of combined immuno-chemotherapy and the inclusion of 18FDG-PET into clinical practice. The results of a recent metaanalysis of 18FDG-PET in the restaging of patients with DLBCL indicate that 18FDG-PET is a valuable tool for the restaging of patients, with a median sensitivity of 90·3% and a median specificity of 91·1% (Isasi et al, 2005). In our series, seven (87·5%) of eight patients with bulky disease at diagnosis had a complete metabolic response after the immuno-chemotherapy programme, and none of these patients have relapsed. Obviously, it is not possible to determine whether adjuvant radiotherapy to prior bulky lymphoma contributed to improve the outcome in this high-risk group. However, our data provide an interesting and provocative question, taking into consideration whether local irradiation can be safely omitted from the treatment in patients with a negative 18FDG-PET, after being treated with the modern immuno-chemotherapy programmes. Specific trials should be performed to address this hot issue.
Another aim of this study was to determine the prognostic value of pre-existing clinical characteristics. In the present study, univariate and multivariate analysis showed that the presence of three risk factors according to the age-adjusted IPI was a highly significant prognostic factor for EFS. Patients with age-adjusted IPI = 2 seemed to be a favourable subgroup with a 2-year EFS of 91%, while patients with age-adjusted IPI = 3 represented a less favourable subgroup with only 45% 2-year EFS. The respective 2-year OS were 91% and 59%. In the favourable subgroup (age-adjusted IPI = 2) further improvement will be difficult to achieve, but the results in the less favourable subgroup warrant further improvement. We therefore have designed a trial to investigate the efficacy of six cycles of DA-EPOCH-R followed by HDT/ASCT supplemented with rituximab in patients younger than 65 years of age with three age-adjusted IPI factors.
Dose-adjusted etoposide/vincristine/doxorubicin/bolus cyclophosphamide/prednisone and rituximab was found to be feasible and relatively well tolerated, even in patients who had either an advanced age or co-morbidities. Three patients with previous cardiac disease and three patients with HCV antibody showed no severe cardiac or significant hepatic toxicity during chemotherapy. Readily reversible haematological toxicity and short-lived oral mucositis were the more common side effects. In our experience, delays due to severe neutropenia occurred only in 1% of cycles. In addition, 14% of cycles resulted in neutropenic fever; which was similar to the 20% reported in the study of DA-EPOCH without rituximab (Wilson et al, 2002a) and higher than the 4% reported in a dose-dense R-CHOP14 supported by filgrastrim (Halaas et al, 2005) or pegfilgrastrim (Brusamolino et al, 2006). Stratifying by age, neutropenic fever occurred in 21% of the cycles in patients older than 60 years of age compared with 10% of cycles in patients younger than 60 years of age. This justifies the close monitoring of older patients. In our series, no cases of P. jiroveci pneumonia were documented. The association of DLBCL with VTE is increasingly being reported, with incidence rates of 7–12% (Mohren et al, 2005; Komrokji et al, 2006). The present clinical study found a 9% incidence of symptomatic VTE. This observation suggests that DA-EPOCH-R is not associated with a higher rate of VTE when compared with other chemotherapy regimens. Age older than 70 years was the only risk factor for VTE. Interestingly, these three VTE patients exhibited a favourable response to their DLBCL treatment. Future studies could evaluate the effectiveness and feasibility of VTE prophylaxis in subgroups of patients at higher risk for developing VTE. Finally, we observed one patient who developed AML FAB M5b (normal karyotype) at 8 months from the end of DA-EPOCH-R. There is considerable debate over the actual incidence or risk of therapy-related myelodysplastic syndrome or AML (t-MDS/AML) in non-Hodgkin lymphoma patients treated with any particular modality. Although worrisome, the incidence of t-MDS/AML in our cohort (3%) was similar to that observed in modern trials (Armitage et al, 2003). The t-AML was more likely to exhibit topoisomerase II inhibitor-like t-AML (short onset and lack of prodromal phase). Because etoposide and G-CSF were given to all patients, it is possible that both agents can act as co-operative factors for leukaemogenesis in patients with genetic predisposition to drug-induced second cancers (Relling et al, 2003).
This study has several limitations. It was a single centre, uncontrolled study of a relatively small number of patients. The median follow-up was relatively short at only 23 months, although it was a reasonable period to evaluate EFS and OS for poor prognosis DLBCL. The improved outcome relative to recent approaches may be due to selection bias; however this issue was decreased through the use of the standardised age-adjusted IPI as an eligibility criterion.
We recognise the difficulty and toxicity of delivering DA-EPOCH-R in older patients, mainly in comparison with the preliminary results reported with R-CHOP14 as an outpatient regimen in 18 elderly patients with DLBCL and an intermediate–high or high-risk IPI (Rigacci et al, 2006). Although the number of elderly patients was small, our data suggest that the DA-EPOCH-R seem to be more active than R-CHOP14 in this age subgroup, with higher CR rate (83% vs. 72% in the R-CHOP14 study), lower relapse rate (9% vs. 30% in the R-CHOP14 study) and better 2-year OS rate (73% vs. 39% in the R-CHOP 14 study). However, whether DA-EPOCH improves outcome over either R-CHOP21 or R-CHOP14 in this patient group awaits the results of randomised trials, such as the currently ongoing randomised Cancer and Leukemia group B trial.
In conclusion, the results achieved with the combination of rituximab and DA-EPOCH are the best reported to date for poor prognosis DLBCL patients. This regimen has an acceptable toxicity profile, even in elderly poor prognosis patients. Although our data suggest that DA-EPOCH-R can be expected to result in a 15–20% improvement in EFS and OS over R-CHOP14, this must be confirmed in further randomised trials. The administration of DA-EPOCH-R as an outpatient regimen by using a single portable infusion pump may be a feasible alternative to improve the compliance and to reduce the total cost of this very effective regimen.