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Keywords:

  • poor-prognosis diffuse large B-cell lymphoma;
  • dose-adjusted EPOCH;
  • rituximab;
  • age-adjusted IPI;
  • toxicity

Summary

  1. Top of page
  2. Summary
  3. Patients and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

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.

Patients and methods

  1. Top of page
  2. Summary
  3. Patients and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

Patient eligibility

Thirty-three consecutive patients with newly diagnosed DLBCL were prospectively included in the protocol from November 2002 to May 2006. Patients eligible for the study had previously untreated DLBCL, according to the World Health Organization (WHO) classification (Jaffe et al, 2001), were aged between 18 and 80 years, and had at least two adverse prognostic factors as defined by the age-adjusted IPI for non-Hodgkin lymphoma (namely stage III or IV disease, elevated lactate dehydrogenase level and Eastern Cooperative Oncology Group performance status of 2–4) (Shipp & Harrington, 1993). Bulky disease was defined by a mediastinal mass exceeding one-third of the maximum intrathoracic diameter or by a nodal mass larger than 10 cm. Patients were also required to have adequate organ function as defined by a left ventricular ejection fraction (LVEF) ≥50%, serum creatinine <150 μmol/l, serum bilirubin <30 μmol/l, control of other medical conditions such as infection, white blood cell count ≥3·5 × 109/l and platelet count ≥100 × 109/l unless caused by lymphoma infiltration of marrow or spleen. Exclusion criteria included: pregnancy or lactation, a recent history of other malignant disease except for non-melanoma skin cancer or carcinoma in-situ of the cervix, prior radiotherapy or chemotherapy, history of indolent lymphoma, central nervous system (CNS) involvement at diagnosis and seropositivity for human immunodeficiency virus. Staging procedures included clinical examination, thoracic and abdominal computerised tomography, blood count, bone marrow biopsy and echocardiography, with evaluation of LVEF. All patients gave written informed consent.

Approximately 20 patients <80 years of age with newly diagnosed DLBCL are seen at the Príncipe de Asturias University Hospital each year. Of these, approximately 11 patients/year have at least two age-adjusted IPI risk factors and would meet eligibility criteria for this study. The study complied with all provisions of the Declaration of Helsinki and was conducted in accordance with Good Clinical Practice rules. The protocol was approved by the Institutional Ethical Committee.

Therapy

The immuno-chemotherapy programme (DA-EPOCH-R) consisted of rituximab (375 mg/m2) on day 1, followed immediately by DA-EPOCH. The DA-EPOCH starting dose level consisted of doxorubicin 10 mg/m2 as a continuous i.v. infusion on days 1–4, etoposide 50 mg/m2 as a continuous i.v. infusion on days 1–4, vincristine 0·4 mg/m2 as a continuous i.v. infusion on days 1–4, cyclophosphamide 750 mg/m2 i.v. on day 5 and prednisone 60 mg/m2 orally on days 1–5. All patients received granulocyte colony-stimulating factor (G-CSF; filgrastrim 5 μg/kg/d) beginning on day 6 and continued until the absolute neutrophil count (ANC) exceeded the nadir >0·5 × 109/l. Erythropoietin (darbepoetin alfa 2·25 μg/kg) was administered when haemoglobin concentration declined to a level ≤100 g/l. The cycles were repeated every 3 weeks, and patients received at least two cycles beyond CR for a minimum of six and a maximum of eight cycles. Details on treatment delivery and dose modifications have been published elsewhere (Wilson et al, 2002a,b; ). At the end of DA-EPOCH-R, adjuvant radiotherapy (30 Gy) was planned to sites of prior bulky disease at diagnosis (≥10 cm). Throughout their treatment, cotrimoxazole was given 480 mg b.i.d. thrice weekly to all patients for prophylaxis against Pneumocystis jiroveci pneumonia.

Response evaluation

The procedures for the response evaluation were the same as those used for staging at diagnosis. All patients were re-evaluated after four cycles of chemotherapy and underwent a complete restaging at the end of the programme and then every 3 months for the first 2 years of follow-up. Thoracic and abdominal computerized tomography were programmed every 6 months for the first 2 years and then at the treating physician's discretion. 18F-2-deoxy-2-fluoro-d-glucose positron emission tomography (18FDG-PET) was carried out in the presence of residual measurable disease at the end of immuno-chemotherapy, and at the end of therapy to prove a complete remission. In addition, all eight patients with bulky disease at diagnosis were evaluated through computerized tomography and 18FDG-PET at the end of the immuno-chemotherapy programme, and 6 weeks after the adjuvant radiotherapy was concluded. Tumour responses were classified as CR, unconfirmed CR (uCR) or partial response (PR) according to the International Workshop criteria (Cheson et al, 1999). CR response was defined as the disappearance of all lesions and of radiological or biological abnormalities observed at diagnosis and the absence of new lesions. Unconfirmed CR was defined as a CR with the persistence of some radiological abnormalities, which had to have regressed in size by at least 75%. PR was defined as the regression of all measurable lesions by more than 50%, the disappearance of non-measurable lesions, and the absence of new lesions.

Toxicity and feasibility evaluation

Toxicity of therapy was calculated over a total of 233 cycles, while feasibility was calculated over a total of 200 cycles, as the first cycles of therapy, which were not susceptible to delay or dose reduction because of toxicity, were not considered. A complete blood count was performed on days 1, 9, 12, 15 and 18 of each cycle of therapy. The limiting haematological values for recycling were as follows: ANC <1 × 109/l and/or platelet count <100 × 109/l. Relative dose intensity (RDI) for each drug of the EPOCH combination was calculated according to Hryniuk & Bush (1984). Haematological and extra-haematological toxicities were scored according to the WHO criteria (Miller et al, 1981). Severe adverse events were defined by the occurrence of a documented infection, and/or by organ or system toxicity requiring hospitalisation.

Statistical analysis

The primary endpoint of this prospective, single-arm, observational study were response to therapy and survival. Rates of CR and progression were defined as percentage of patients with CR/uCR or progression under treatment, respectively, among all eligible patients. EFS was measured from the start of treatment to the first adverse event (i.e. disease progression, relapse, diagnosis of a secondary malignancy, institution of a new and unplanned anticancer treatment, treatment-related death without progression or progression after PR) or to the last follow-up at which the patient was known to be alive. OS was measured from the start of treatment to the date of death or the last follow-up at which the patient was known to be alive. Secondary endpoints investigated were feasibility (defined as the proportion of patients who completed all planned therapy) and toxicity. Frequencies of adverse reactions were compared between patients with age ≤60 vs. >60 years) by the chi-squared test. EFS and OS were estimated according to the method of Kaplan and Meier and statistical differences among curves were evaluated by the log rank test. Several clinical variables (age ≤60 vs. >60 years, extranodal involvement, bulky disease, BCL-2 status, proliferation rate, dose-intensity and age-adjusted IPI score 2 vs. 3) were evaluated with univariate analysis for their ability to predict outcome. The significance of these variables also was evaluated in the multivariate analysis, using the stepwise Cox-regression model. All reported P-values are two-sided; P-values of 0·05 or less were considered statistically significant. All statistical analyses were performed using the Statistical Package for the Social Sciences (spss) software, version 10.0 (SPSS Inc., Chicago, IL, USA).

Results

  1. Top of page
  2. Summary
  3. Patients and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

Patient characteristics

All 33 enrolled patients with poor-prognosis DLBCL were included in the analysis of survival outcomes, feasibility and toxicity. Table I shows the patient characteristics. The median age of our patient population was 55 years (range: 21–76 years) and nearly one-third of patients were older than 60 years of age. The majority of the patients were in stage III and IV and one-quarter had bulky disease at presentation. Assessment using the age-adjusted IPI found high–intermediate-risk score in 48·5% of patients and high-risk score in 51·5% of the patients. Three patients were hepatitis C virus (HCV) positive before the initiation of DA-EPOCH-R; these three patients had mild or no signs or symptoms (grade 0 and 1) of HCV infection except for a positive serological test. The HCV RNA was not titrated and none of these three HCV-positive patients received a specific antiviral treatment during the immuno-chemotherapy programme. In addition, three patients had a pre-existing cardiac disease with a preserved contractility on echocardiography. These three patients received dexrazoxane 300 mg/m2 i.v. as cardioprotective agent before every cycle of DA-EPOCH-R. Of the 33 patients treated, 31 were evaluable for response; it was too early to evaluate the remaining two patients. Among 31 patients evaluable for response, 20 patients (64·5%) were treated with eight cycles of DA-EPOCH-R, 10 patients (32·2%) received six cycles and the other patient died after the fourth cycle.

Table I.   Characteristics of the 33 poor-prognosis patients treated with DA-EPOCH-R.
CharacteristicsNumber of patients (%)
  1. ECOG, Eastern Cooperative Oncology Group (increasing score indicates declining performance); DA-EPOCH-R, dose-adjusted etoposide/vincristine/doxorubicin/bolus cyclophosphamide/prednisone) and rituximab.

Total enrolled patients33
Age
 Median age – years (range)55 (21–76)
 ≤60 years20 (60·6)
 60–69 years6 (18·1)
 ≥70 years7 (21·2)
Male sex17 (51·5)
Ann arbor stage
 II5 (15·1)
 III/IV28 (84·8)
ECOG performance status
 <212 (36·3)
 ≥221 (63·6)
Lactate dehydrogenase
 Normal level6 (18·1)
 Above normal27 (81·8)
Extranodal sites
 <220 (60·6)
 ≥213 (39·3)
Bulky disease (≥10 cm)
 Present8 (24·2)
 Absent25 (75·7)
Age-adjusted International Prognostic Index score
 216 (48·5)
 317 (51·5)
Tumour proliferation rates
 <80%11 (33·3)
 ≥80%22 (66·6)
BCL2
 Negative10 (30·3)
 Positive17 (51·5)
 Unknown6 (18·1)

Response to treatment

On an intention-to-treat basis, 96·7% of patients (30/31) had an objective response; 80·6% (25/31) achieved a CR or uCR and 16·1% (5/31) had a PR at the end of DA-EPOCH-R. One patient (3·2%) died of toxicity. The overall complete remission rate was not different in the two age subgroups (77% in younger patients vs. 83·3% in elderly patients). Consolidation radiotherapy was administered to all eight patients with bulky disease, seven of whom were in CR (18FDG-PET scan negative) after DA-EPOCH-R and were irradiated at the site of prior bulky disease while one patient was given radiotherapy to PET-positive residual disease. This patient entered a CR after radiotherapy with normalisation of 18FDG-PET-uptake. Altogether, 26 of 31 patients (83·8%) achieved a CR or uCR at the end of the complete treatment (Table II).

Table II.   Response at the end of entire treatment*.
ResponseNumber of patients (%)
  1. *Tumour responses were classified according to the International Workshop criteria (Cheson et al, 1999).

Complete response24 (77·4)
Unconfirmed complete response2 (6·4)
Partial response4 (12·9)
Progressive disease0
Death without progression
 During treatment1 (3·2)
 After treatment0

Of the four PR patients, two eventually converted to CR status with HDT/ASCT, one patient died 14 months after the start of the study, of progressive disease despite salvage therapy and the other patient is alive with stable disease after salvage regimen. Twenty-four of 26 patients who achieved CR or uCR are in continued remission after a median observation time of 17 months from entry of remission. Notably, only two CR patients relapsed (7·6% of those who achieved remission); one patient relapsed into CNS at month 12 and died 16 months after the beginning of DA-EPOCH-R and another patient relapsed in the initial nodal sites at month 15 and died early of progressive lymphoma.

Survival

At the time of this analysis, the median follow-up for the entire group was 23 months (range: 3–47+). Eight events were registered: two cases of progressive disease after PR, two PR cases were transformed to CR by HDT/ASCT, two relapses and two deaths not related to tumour progression [one case during treatment and other case as a result of secondary acute myeloid leukaemia (sAML)]. The 2-year actuarial EFS was 68% (Fig 1A).

image

Figure 1.  Event-free survival (top panel) and overall survival (bottom panel) in patients with poor-prognosis DLBCL treated by DA-EPOCH-R.

Download figure to PowerPoint

Altogether, five patients have died so far; the causes of death were: relapse (two patients), disease progression after PR with disease-related complications (one patient), neutropenic sepsis after the fourth cycle of DA-EPOCH-R therapy (one patient) and sAML (one patient). The 2-year actuarial OS was 75% (Fig 1B).

In addition, a stratified analysis according to age-adjusted IPI score, showed significantly better 2-year EFS (91% vs. 45%; log rank, P = 0·0126) for patients with age-adjusted IPI 2 compared with those with an age-adjusted IPI of 3. However, the difference in 2-year OS was only of borderline significance (91% vs. 59%; log rank, P = 0·0587).

Prognostic factors

Multiple variables were evaluated by univariate analysis for their possible correlation with outcome. Only age-adjusted IPI score of 3 was shown to have independent adverse prognostic value for EFS (HR = 8·29, 95% CI = 1·03–67, P = 0·04); this variable maintained its independent adverse prognostic value for EFS after multivariate analysis (HR = 6·75, 95% CI = 1·02–56, P = 0·04).

Feasibility

Overall, 32 patients (96·9%) completed the planned DA-EPOCH therapy. Immuno-chemotherapy was interrupted in one patient because of toxic death. At the end of DA-EPOCH-R, consolidation radiotherapy with 30 Gy was delivered to all eight patients with previously bulky disease.

Of the 200 cycles considered, 181 (90·5%) were delivered on time, at the planned dose. Most patients required dose escalations to achieve an ANC nadir, with 33% of cycles having at least 144% of the entry-dose level and 1% having below the entry level. The average RDI was 133% for etoposide, doxorubicin and cyclophosphamide, and 99·7% for vincristine. The planned dose of rituximab was delivered in 100% of cycles. Therapy was delayed on 19 occasions (five in younger patients and 14 in elderly patients); 12 cycles (6%) were postponed because of infection, two (1%) because of limiting neutropenia, two (1%) because of diarrhoea (1%), one (0·5%) because of serious constipation and two (1%) because of cardiac arrhythmia. Younger patients (aged ≤60 years) required slightly higher dose rates than older patients (>60 years) to achieve the targeted ANC nadir (P = 0·09).

Toxicity

We assessed the toxicity of DA-EPOCH-R over 233 cycles: 140 cycles were administered to younger patients (≤60 years) and the remaining 93 cycles were administered to elderly patients. Overall, DA-EPOCH was well tolerated. There were two toxicity-related deaths (treatment-related mortality, 6%). One patient died from neutropenic sepsis on week 16 of immuno-chemotherapy. Another patient died subsequently after a secondary AML (FAB M5b) that occurred at 8 months after the end of DA-EPOCH-R. Grades 3 and 4 neutropenia, thrombocytopenia and anaemia were recorded in 52%, 22% and 6% of cycles and occurred in 100%, 27% and 33% of the patients, respectively; patients older than 60 years showed a significantly (P < 0·001) higher rate of grades 3 and 4 neutropenia (74% of cycles) compared with younger patients (38% of cycles) (Table III).The median duration of grade 4 neutropenia was 3 days (range: 2–5).The ANC nadir was invariably observed around day 10–12 of treatment. Most important, the clinical effect of the haematopoietic toxicity was limited, with no cases of haemorrhage and only 34 cycles (14% of total) were complicated by neutropenic fever occurring in 17 patients (51% of patients). Elderly patients had a significantly (P < 0·01) higher rate of neutropenic fever (21% of cycles) compared with younger patients (10% of cycles). Thirty patients (90·9%) required erythropoietin support during the study.

Table III.   WHO grades 3 and 4 toxicity profile of DA-EPOCH-R in 33 patients.
 All patients (n = 33)≤60 years (n = 20)>60 years (n = 13)P-value
No. of patients (%)No. of cycles (%)No. of patients (%)No. of cycles (%)No. of patients (%)No. of cycles (%)
  1. NS, not significant; VTE, venous thromboembolism; AML, acute myeloid leukaemia.

Neutropenia33 (100)123 (52)20 (100)54 (38)13 (100)69 (74)<0·001
Thrombocytopenia9 (27)52 (22)4 (20)18 (12)5 (38)34 (35)NS
Anaemia11 (33)14 (6)5 (25)3 (2)6 (46)11 (11)NS
Neutropenic fever17 (51)34 (14)9 (45)14 (10)8 (61)20 (21)<0·01
Nausea or vomiting3 (1)10 (4)2 (1)5 (3)5 (5)2 (2)NS
Oral mucositis5 (15)14 (6)3 (15)8 (5)2 (15)6 (6)NS
Diarrhoea3 (9)3 (1)1 (5)1 (0·7)2 (15)2 (2)NS
Neurological toxicity3 (9)3 (1)003 (23)3 (3)NS
Cardiac toxicity2 (6)2 (0·8)002 (15)2 (2)NS
VTE3 (9)3 (1)003 (23)3 (3)NS
Secondary AML1 (3)1 (0·4)001 (7)1 (1)NS
Acute toxic deaths1 (3)1 (0·7)1 (5)1 (0·7)00NS

Altogether, severe non-haematological toxicities were registered in 36 of the 233 cycles (15% of all cycles). These severe adverse events consisted of gastrointestinal toxicity in 11 patients (33% of patients), motor toxicity in three patients (9% of patients), cardiac arrhythmia in two patients (6% of patients) and non-fatal venous thromboembolism (VTE) in three patients (9% of patients). Focusing on the three patients with non-fatal VTE, in all cases the age of the patients was more than 70 years and thrombosis occurred during the first four immuno-chemotherapy cycles. Two of these patients were in PR, while the other case was in CR. A precise clinical cause for the occurrence of VTE (other than advanced age) could not be identified although our analysis could not include haemostatic factors that may be relevant to the pathogenesis of VTE in this setting. The liver toxicity of DA-EPOCH-R in the three patients with HCV infection was low, although two of the three patients experienced a mild and transient increase of liver enzymes levels (grade 1). Discontinuation of treatment was not required in these cases. There were no episodes of doxorubicin-related heart failure. Table III lists the incidence of the main toxicities per patient and per cycle according to age.

Discussion

  1. Top of page
  2. Summary
  3. Patients and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

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/referenceType of studyNo. of patients Study population (%)CR (%)EFS (%)OS (%)TRM (%)Relapse (%)
  1. CR, complete response; DLBCL, diffuse large B-cell lymphoma; EFS, event-free survival; HR, high-risk IPI score; NOS, not otherwise specified; OS, overall survival; TRM, Treatment-related mortality; DA-EPOCH-R, dose-adjusted etoposide/vincristine/doxorubicin/bolus cyclophosphamide/prednisone) and rituximab; R-CHOP, cyclophosphamide + doxorubicin + vincristine + prednisolone chemotherapy with rituximab.

DA-EPOCH (Wilson et al, 2002a)Uncontrolled, single institution26Aged 20–88 years, HR 19925865026
DA-EPOCH-R (Wilson et al, 2002b)Uncontrolled, single institution14Aged 21–81 years, HR 1985857970
CHOP14 (Pfreundschuh et al, 2004b)Randomised, multicentre80Elderly, HR 317643533NOS
R-CHOP21 (Feugier et al, 2005)Randomised, multicentre121Elderly, HR 28<754148638
R-CHOP14 (Halaas et al, 2005)Uncontrolled, single institution and retrospective22Elderly, HR 40NOS7078013
R-CHOP14 (Pfreundschuh et al, 2005)Randomised, multicentre312Elderly, HR 16NOSNOS64NOSNOS
R-CHOP14 (Brusamolino et al, 2006)Uncontrolled, single institution18Aged 22–70 years, HR 36NOS514938
R-CHOP14 (Rigacci et al, 2006)Uncontrolled, single institution18Elderly, HR: NOS72NOS39325
DA-EPOCH-R (present study)Uncontrolled, single institution31Aged 21–76 years, HR 5183687567

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.

Acknowledgements

  1. Top of page
  2. Summary
  3. Patients and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

We thank our colleagues of the Department of Haematology (Príncipe de Asturias University Hospital) for their expert collaboration.

References

  1. Top of page
  2. Summary
  3. Patients and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References
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