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Rituximab versus observation after high-dose consolidative first-line chemotherapy with autologous stem-cell transplantation in patients with poor-risk diffuse large B-cell lymphoma
original article
Annals of Oncology 20: 1985–1992, 2009 doi:10.1093/annonc/mdp237 Published online 30 June 2009
Rituximab versus observation after high-dose consolidative first-line chemotherapy with autologous stem-cell transplantation in patients with poor-risk diffuse large B-cell lymphoma 1 Service d’He´matologie Clinique, Centre Hospitalier Universitaire, Groupe Hospitalier Henri Mondor-Chenevier, Assistance Publique-Hoˆpitaux de Paris et Universite´ Paris XII, Cre´teil; 2Service d’Onco-He´matologie, Centre Hospitalier Universitaire Archet 1, Nice; 3Service de Pathologie, Hoˆpital Ambroise Pare´, Assistance Publique-Hoˆpitaux de Paris, Paris; 4Service d’He´matologie et de Me´decine Interne, Centre Hospitalier Universitaire Nancy-Brabois, Vandoeuvre les Nancy; 5Service d’He´matologie, Hoˆpital Lyon Sud, Hospices Civils de Lyon, Pierre Be´nite; 6De´partement d’He´matologie, Centre Henri Becquerel, Rouen; 7Service d’He´matologie, Centre Hospitalier Universitaire Purpan, Toulouse; 8Service d’He´matologie, Institut Gustave Roussy, Villejuif; 9Service d’He´matologie Clinique, Groupe Hospitalier Pitie´-Salpeˆtrie`re, Assistance Publique-Hoˆpitaux de Paris, Paris; 10De´partement d’He´matologie et d’Oncologie, Centre Hospitalier Universitaire de Strasbourg, Strasbourg; 11Service des Maladies du Sang, Centre Hospitalier Universitaire de Lille, Lille and 12Service d’He´mato-Oncologie Adulte, Hoˆpital Saint Louis, Assistance Publique-Hoˆpitaux de Paris, Paris, France
Received 18 March 2009; accepted 20 March 2009
with doxorubicin, cyclophosphamide, vincristine, bleomycin and prednisone (ACVBP) before high-dose therapy (HDT) followed by autologous stem-cell transplantation (ASCT) for patients with poor-risk diffuse large B-cell lymphoma (DLBCL). A second randomisation compared rituximab with observation post-ASCT. Materials and methods: Four hundred and seventy-six patients <60 years old with newly diagnosed CD20+ DLBCL were randomised to induction with ACE or ACVBP. Three hundred and thirty responders received HDT followed by ASCT. After ASCT, 269 patients were re-randomised to receive either maintenance rituximab or observation alone. Randomisation was stratified by the quality of response to ASCT. The primary end point of this study was event-free survival (EFS). Results: At a median of 4 years’ follow-up from the second randomisation, there was a trend (P = 0.1) towards increased EFS for patients who received rituximab compared with observation. Conclusion: The type of induction therapy (ACVBP or ACE) did not significantly affect overall survival at a median 51 months’ follow-up. Key words: autologous transplantation, diffuse large B-cell lymphoma, poor-risk lymphoma, rituximab
introduction Before the widespread integration of rituximab into induction therapy, high-dose therapy (HDT) followed by autologous stem-cell transplantation (ASCT) was a promising option for front-line therapy in patients with aggressive B-cell nonHodgkin’s lymphoma (NHL). Several randomised phase III studies have shown that such an approach is beneficial in terms of progression-free survival and is superior to consolidation chemotherapy (CT) in high-risk patients [age-adjusted International Prognostic Index [1] (aa-IPI) 2 or 3] <60 years. The role of HDT plus ASCT has been extensively studied in
*Correspondence to: Dr C. Haioun, Service d’He´matologie Clinique, Hoˆpital H. Mondor, 51, Avenue du Mare´chal de Lattre de Tassigny, 94010 Cre´teil, France. Tel: +33-1-4981-20-51; Fax: +33-1-49-81-20-67; E-mail: [email protected]
high-risk patients who experienced a good response to induction CT [2–10]. One objective of the LNH 98-3 study was to improve upon the response rate achievable with the intensive regimen of doxorubicin, cyclophosphamide, vindesine, bleomycin and prednisone (ACVBP) every 14 days, which has been extensively reported by the Groupe d’Etude des Lymphomes de l’Adulte (GELA) [11], by using a new induction regimen which introduces etoposide and a higher dose of cyclophosphamide [doxorubicin, cyclophosphamide and etoposide (ACE)]. A phase II study [12] in relapsing or refractory aggressive lymphoma had shown that durable responses could be achieved with rituximab alone and indicated that rituximab may have a role in relapsing aggressive B-cell lymphoma and could be worth testing to increase the response rate of initial induction therapy. When the LHN98-3 study was designed, it was not
ª The Author 2009. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected]
original article
Background: This study compared the induction regimens doxorubicin, cyclophosphamide and etoposide (ACE)
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C. Haioun1*, N. Mounier2, J. F. Emile3, D. Ranta4, B. Coiffier5, H. Tilly6, C. Re´cher7, C. Ferme´8, J. Gabarre9, R. Herbrecht10, F. Morchhauser11 & C. Gisselbrecht12
original article
materials and methods patients Eligible patients were 18–60 years old and had newly diagnosed CD20+ diffuse large B-cell lymphomas (DLBCLs) or other high-grade B-cell lymphoma (initially transformed B-cell, lymphocytic, marginal zone, follicular or nonclassified high-grade lymphomas), diagnosed according to the World Health Organisation (WHO) classification. Patients were also required to have an aa-IPI score of 2 or 3. Exclusion criteria included other lymphoma diagnoses (e.g. Burkitt’s lymphoma, transformed previously diagnosed low-grade lymphoma), contraindication to anthracyclines (i.e. cardiac insufficiency, left ventricular ejection fraction <50% or recent myocardial infarct) or corticosteroid treatment, serious psychosis, sepsis or uncontrolled diabetes, neutrophils <1.5 · 109/l or platelets <100 · 109/l not considered related to lymphoma, renal insufficiency (serum creatinine > 150 lM/l), hepatic disorders (total bilirubin > 30 mM/l or transaminases > 2.5 upper normal limit), positive serology for HIV or hepatitis B, previous organ transplant and pregnancy.
assessments The primary study outcome parameter was EFS. An event was defined as disease progression during or after treatment, a required change in treatment regimen or death without progression. Response to treatment was classified according to the International Workshop Criteria [14]. CR required the disappearance of all clinical signs and symptoms of disease and normalisation of biochemical values. CRu included patients with a residual lymph node mass >1.5 cm in greatest transverse diameter that had regressed by >75% in the sum of the product of greatest diameters. PR was defined as a 50% decrease in the sum of the product of greatest diameters of the largest dominant nodes or nodal masses with no increase in any other nodes, liver or spleen and no new lesions. Stable disease or progressive disease required withdrawal from treatment (Figure 1).
treatment This study employed two randomisation stages (Figure 2). In the first randomisation (R1), eligible patients were allocated to induction therapy
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with ACVBP or AC/ACE (regimens are described in Table 1) and stratified according to centres and aa-IPI score. Patients received four cycles of induction therapy, given at 2-weekly intervals, with leukapheresis after the third and/or fourth cycles (weeks 6 and/or 8). Patients’ disease was then reassessed and those who experienced a ‡50% response (i.e. CR, CRu or PR) received two courses of high-dose methotrexate (3 g/m2) followed by leucovorin rescue, with a 2-week interval. Patients then received HDT between days 80 and 90. HDT consisted of mitoxantrone (45 mg/m2, day 1), cyclophosphamide plus etoposide (1500 and 250 mg/m2, respectively, days 2–5) and carmustine (300 mg/m2, day 6) followed by ASCT rescue. Response was reassessed between days 45 and 65 (after ASCT) and patients were stratified according to their response (CR versus CRu + PR). Patients with at least a PR were eligible for second randomisation if they had a good haematological recovery (ANC ‡ 1 · 109/l and platelets ‡ 100 · 109/l) and adequate renal and hepatic functions. After the second randomisation (R2), patients received four doses of rituximab (375 mg/m2 i.v.) at weekly intervals starting no later than day 65 (after ASCT) or observation alone. Patients were assessed every 6 months during the year after the end of treatment, then annually for 5 years.
statistical methods The primary end point was EFS estimated 2 years after ASCT. EFS was measured from the date of randomisation (either first or second randomisation, depending on the comparison) to the date of the first event. Calculation of sample size was based on the primary end point. To detect a change of 15% (null hypothesis 60% and alternative hypothesis 75%), we calculated that 300 patients treated with ASCT should be randomised over 4 years and followed-up for at least 1 year, to provide the trial with 90% power at an overall 5% significance level (130 events). The trial began in October 1999. At a planned interim analysis in February 2003 (when 170 patients had been enrolled), by the data and safety monitoring committee, a total of 37 events had been observed with no significant difference in 2year EFS between groups (rituximab 82% versus observation 72%; P = 0.14). As this number of events was lower than that expected (37 and 60 for rituximab and observation, respectively), it was considered that the study would take much longer to complete than originally anticipated. Furthermore, at that time, there was growing evidence that combining rituximab with the induction regimen might dramatically improve the efficacy of CT. Consequently, the GELA scientific committee decided to stop the study in May 2003, when a total of 269 ASCT patients had been randomised and were being followed to assess EFS. At a median follow-up of 4 years, 65 events were observed and the revised power of the study was 0.60. Survival functions were estimated by the Kaplan–Meier method and compared by log-rank test. Differences between the results of comparative tests were considered significant if the two-sided P value was <0.05. All statistical analyses were carried out using SAS 9.13 (SAS Institute Inc., Carry, NC) software. The study was designed by the GELA scientific committee and monitored by the GELA coordinating centre that issued treatment randomisation by fax after confirmation of the patient eligibility [stratification on aa-IPI (2 versus 3) and tumour response (CR versus CRu/PR) to induction treatment (ACE versus ACVBP)]. Case report forms collected at participating centres were sent to the GELA centralised database and keyed in twice for verification. Outliers and erroneous values were checked routinely. Queries and on-site monitoring were used for final validation. The protocol was approved by local or national ethics committees and the national regulatory agency according to the French and Belgian regulatory laws. Patients had to give written, informed consent before being randomised onto the study. The study was entered on the National Institute of Health website (NCT00169169).
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known how best to incorporate rituximab in the first-line treatment of NHL, i.e. as a part of induction or later on as maintenance. Ideally, the GELA would have investigated rituximab plus ACVBP as a potentially improved induction regimen, but in the absence of availability of preliminary data for rituximab in combination with ACVBP, the ACE regimen was proposed as the investigational treatment based on promising preliminary results [13]. Doxorubicin was administered at the same dose (75 mg/m2) as in ACVBP, the cyclophosphamide dose was increased (2000 instead of 1200 mg/m2) and vindesine and bleomycin were omitted while etoposide was added (150 mg/m2 for three consecutive days). To exploit the potential benefits of rituximab in this study, patients who achieved a sustained response post-HDT and ASCT were randomised (second randomisation) to receive single-agent rituximab weekly for four consecutive weeks or observation. The main objective of this part of the study was to determine whether rituximab delivered after first-line CT followed by HDT and ASCT could improve event-free survival (EFS) in patients with poor-risk aggressive B-cell NHL. At the time of the second randomisation, patients were stratified by their response to HDT + ASCT [complete response (CR) versus partial response (PR) or unconfirmed complete response (CRu)], as the quality of this response might influence the outcome.
Annals of Oncology
original article
Annals of Oncology
476 patients randomised
ACVBP induction: 241 patients
AC/ACE induction: 235 patients
402 patients with PR or better response to induction
72 withdrawals before HDT
330 with PR or better response to HDT+ ASCT
61 dropouts after HDT 8 progression, 7 cytopaenia, 1 PTCL after review, 4 hepatitis, 1 VZV, 3 SAE, 5 deaths, 6 patient refusal, 26 protocol violations
476 patients randomised post ASCT
139 patients received maintenance rituximab
130 patients received observation
Figure 1. CONSORT diagram showing patients in the LNH98-3 study. ACVBP: doxorubicin, cyclophosphamide, vincristine, bleomycin and prednisone; AC/ACE: doxorubicin, cyclophosphamide and etoposide; PR: partial response; HDT: high-dose therapy; ASCT: autologous stem-cell transplantation; PTCL: peripheral T-cell lymphoma; VZV: varicella zoster virus; SAE: serious adverse event.
results patients From October 1999 to November 2004, 476 eligible patients were enrolled in the study at 40 recruiting centres. Patient demographics and baseline disease characteristics are shown in Table 2. At the first randomisation, the groups receiving each type of induction therapy were well balanced.
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response to induction CT and HDT Of the 476 patients who received induction therapy, 402 (84.5%) experienced a PR or CR and were therefore eligible for HDT (Table 3). CR (or CRu) rates to induction treatment were 63% with ACVBP and 65% with ACE. PRs were also similar in the two groups: 22% and 19%, respectively. Seventy-two patients (18%) who experienced PR or CR following induction therapy did not receive HDT, primarily as
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74 withdrawals (37 ACVBP, 37 AC/ACE) 17 leukapheresis failure, 5 refused therapy, 25 early failure, 18 SAE, 1 protocol violation, 6 on histological review, 2 hepatitis
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Annals of Oncology
Induction randomisation
AC then ACE x 3 Leukapheresis after cycles 3 and 4
ACVBP x 4 Leukapheresis after cycles 3 and 4
Responders re-randomised 45-60 days post ASCT
Observation only
Rituximab 4 cycles weeks 21-24
Figure 2. Trial schema for LNH 98-3. ACVBP: doxorubicin, cyclophosphamide, vincristine, bleomycin and prednisone; AC/ACE: doxorubicin, cyclophosphamide and etoposide; MTX, mitoxantrone; CBVM: cyclophosphamide, carmustine, etoposide and mitoxantrone; ASCT, autologous stem-cell transplantation Table 1. Induction therapy regimens ACVBP regimen Doxorubicin Cyclophosphamide Vindesine Bleomycin Prednisone Methotrexate (intrathecal) G-CSF (s.c.)
Dose
Days of cycle 2
75 mg/m 1200 mg/m2 2 mg/m2 10 mgb 60 mg/m2 15 mgb 5 lg/kg/day
1 1 1, 5 1, 5 1–5 2 6–13
AC/ACE regimen Doxorubicin Cyclophosphamide Etoposidea Prednisone Methotrexate (intrathecal) G-CSF (s.c.)
Dose
Days of cycle 2
75 mg/m 1000 mg/m2 150 mg/m2
60 mg/m2 15 mgb 5 lg/kg/day
1 1, 2 1–3 1–5 2 6–13
a
Cycles 2–4 only. Total dose per day. G-CSF, granulocyte colony-stimulating factor.
b
a result of early failure (n = 25), leukapheresis failure (n = 17) or following a serious adverse event (SAE; n = 18); six patients were excluded following histological review, five patients refused further treatment and there was one protocol violation (Figure 1). Overall, 402 patients completed induction, but 72 patients withdrew from the study before receiving HDT, which was administered to 330 patients. Of these, 61 were not randomised to the observation or
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rituximab groups following ASCT, mainly as a result of protocol violations (n = 26). Thirteen patients progressed or died (eight progressions and five deaths) during or shortly after HDT, seven patients remained with cytopenia, six patients refused treatment, four developed hepatitis and three experienced a SAE. One patient was diagnosed with peripheral T-cell lymphoma after review and one patient developed varicella zoster virus infection.
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If response >50%, MTX weeks 10 and 12 then CBVM then ASCT
original article
Annals of Oncology
Table 2. Patient demographics and baseline disease characteristics First randomisation (induction therapy) (n = 476) 48 (18–60) 287/189 371/408 (90)
47 (18–59) 181/88 226/239 (95)
111 (23) 189 (40) 176 (37)
69 (26) 115 (43) 85 (32)
21 455 448 127 196 311 176 131
8 261 253 56 102 170 101 63
(4) (96) (94) (33) (47) (65) (38) (28)
(3) (97) (94) (24) (43) (63) (38) (24)
Observation (n = 130)
47 (19–59) 89/50 115/119 (97)
47 (18–59) 92/38 111/120 (93)
35 (25) 64 (46) 40 (29)
34 (26) 51 (39) 45 (35)
4 135 132 27 53 84 55 33
(3) (97) (95) (23) (41) (60) (40) (24)
4 126 121 29 49 86 46 30
(3) (97) (93) (26) (44) (66) (36) (24)
11 (2) 326 (69) 138 (29)
3 (1) 202 (75) 64 (24)
1 (1) 108 (78) 30 (22)
2 (2) 94 (74) 34 (26)
241 (51) 235 (49)
138 (51) 131 (49)
72 (52) 67 (48)
66 (51) 64 (49)
a
Confirmation by pathological review in 408 patients (85%). DLBCL, diffuse large B-cell lymphoma; LDH, lactate dehydrogenase; 1N, normal level; b2-m, b2-microglobulin; aa-IPI, age-adjusted International Prognostic Index; ACVBP, doxorubicin, cyclophosphamide, vindesine, bleomycin and prednisone; ACE, doxorubicin, cyclophosphamide and etoposide.
Table 3. Responses to induction therapy (IWC 1999 criteria)
CR CRu PR SD/PD Deatha Not available
ACVBP group % (n = 241)
ACE group % (n = 235)
20 43 22 10 4 2
20 45 19 9 3 4
a
Mainly toxicity related. IWC, International Workshop Criteria; ACVBP, doxorubicin, cyclophosphamide, vindesine, bleomycin and prednisone; ACE, doxorubicin, cyclophosphamide and etoposide; CR, complete response; CRu, unconfirmed complete response; PR, partial response; SD, stable disease, PD, progressive disease;
Overall, 139 patients were randomised to receive rituximab (72 and 67 from the ABCVP and AC/ACE groups, respectively) and 130 to observation (66 and 64 from the ABCVP and AC/ ACE groups, respectively). At the second randomisation, 130 patients were considered in CR (without any residual disease) and 139 were in CRu or in PR.
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Long-term outcome At a median of 4 years’ follow-up from the second randomisation, there was a nonsignificant trend for increased EFS in the rituximab arm {EFS 80% [95% confidence interval (CI) 72% to 86%]} compared with the observation arm [EFS 71% (95% CI 62% to 78%); P = 0.099; Figure 3]. Similarly, when patients were stratified by aa-IPI score, no statistically significant difference in EFS was observed for rituximab compared with observation (aa-IPI 2: EFS 82% and 73% for rituximab and observation, respectively; P = 0.156; aa-IPI 3: EFS 70% and 65% for rituximab and observation, respectively; P = 0.598). The type of induction therapy received by patients had little effect on the outcome of therapy, with similar response rates from ACVBP and AC/ACE and no significant difference in overall survival (OS) at a median follow-up of 51 months (53% and 48%, respectively, P = 0.505; Figure 4). When patients were stratified by quality of response to HDT, a statistically significant difference in EFS was identified for patients receiving rituximab (n = 70) compared with observation alone (n = 60; Figure 5), in patients who achieved a CR following HDT. In these patients, EFS for those who received rituximab was 86% (95% CI 75% to 92%), compared with 68% (95% CI 53% to 79%) for those who received no consolidation (P = 0.023). However, for patients who
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Median age (range) Male/female DLBCLa, n (%) Performance status, n (%) 0 1 >1 Ann Arbor stage, n (%) I–II III–IV LDH > 1N, n (%) b2-m ‡ 3 mg/l, n (%) Albumin £ 35 g/l, n (%) >1 extranodal localisation, n (%) Bulky disease > 10 cm, n (%) Bone marrow involvement, n (%) aa-IPI score, n (%) 1 (low–intermediate) 2 (high–intermediate) 3 (high) Induction regimen, n (%) ACVBP ACE
Second randomisation (maintenance therapy) All (n = 269) Rituximab (n = 139)
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Annals of Oncology
A)
1.00
0.75
Survival distribution function
Survival distribution function
ACVBP ACE
0.50
0.25
1.00
CR
0.75
Rituximab
0.50
Observation
0.25
p=0.505 p=0.02 0
1
2
3
4
5
0.00
6
0
Time (years)
Survival distribution function
1.00
0.75
0.50
Rituximab
2
3
4
5
6
Time (years)
B)
Survival distribution function
Figure 3. Overall survival by induction therapy (median follow-up 51 months). No significant difference in overall survival was detected between the two induction therapy groups. ACVBP: doxorubicin, cyclophosphamide, vindesine, bleomycin and prednisone; AC/ACE: doxorubicin, cyclophosphamide and etoposide.
1
1.00
CRu or PR
0.75
0.50
Rituximab Observation
0.25
Observation p=0.91 0.00 0.25
0
1
2
3
4
5
6
Time (years) p=0.10 0.00 0
1
2
3
4
5
6
Time (years) Figure 4. Event-free survival (EFS) by maintenance therapy. A trend towards increased EFS was observed for patients who received maintenance therapy with rituximab following a complete response after stem-cell transplantation.
experienced a CRu or PR following HDT, no such difference was apparent; EFS was 74% (95% CI 62% to 83%) and 73% (95% CI 61% to 82%) for patients receiving rituximab (n = 69) and observation only (n = 70), respectively (P = 0.91).
safety and tolerability The incidence of grade 3 and 4 adverse events during induction therapy was largely similar for patients receiving ACVBP and AC/ACE for liver, cardiac, neurological, renal and lung events (all £3% of patients for any individual cycle). There was a slightly higher incidence of infection and mucositis events in patients who received AC/ACE compared with ACVBP during each cycle of induction. The incidence of grade 3 or 4 infection during cycles 1–4 was 5%, 3%, 5% and 3% for ACVBP and 8%,
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Figure 5. Event-free survival (EFS) by response to high-dose therapy (HDT) (A) patients in complete response (CR); (B) patients in unconfirmed complete response (CRu) or partial response (PR). In this planned subgroup analysis, there was a significant improvement in EFS for patients who experienced a CR following autologous stem-cell transplantation and received maintenance rituximab compared with those who received observation only.
9%, 8% and 9% for AC/ACE, respectively. Similarly, the incidence of grade 3 or 4 mucositis during cycles 1–4 was 3%, 7%, 5% and 4% for ACVBP and 3%, 9%, 10% and 12% for AC/ACE, respectively. Rituximab therapy was well tolerated. The 139 patients randomised to receive rituximab received 545 infusions in total. Among this group, there were eight cases of neutropenia (6%; four grade 3 and four grade 4), three of thrombocytopenia (2%; all grade 3) and two of Herpes zoster infection (1%). Prophylactic treatment of infections was not reported, and infections were only recorded if reported as SAEs.
discussion The main objective of the study was to determine whether rituximab delivered after first-line CT followed by HDT and
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responses (with more true CRs) at induction is of paramount importance and more effective induction regimens are needed to improve prognoses for patients. To this end, the addition of rituximab to dose-intensified CT such as ACVBP followed by ASCT appears to increase progression-free survival and OS in young patients with poor-risk lymphoma [23]. Others have recently published encouraging results using the same approach [24–27]. Moreover, we and others [28–30] have also demonstrated the value of a good response as assessed by positron emission tomography (PET) imaging to guide therapy decisions and identify patients early for whom HDT and ASCT is the best potential option early on. This approach is also under evaluation by GELA in the ongoing protocol for poorprognosis DLBCL. This study reported a nonsignificant trend towards better 4-year EFS in patients who received rituximab for 4 weeks after induction CT followed by HDT and ASCT. A significant benefit of the addition of rituximab was reported in patients who achieved a true CR after HDT and ASCT compared with those who experienced a lesser response, showing the importance of the quality of response after induction treatment to long-term prognosis. In the time since the inception of this study, the treatment of DLBCL has changed, with rituximab CT considered to be the standard induction regimen, the evaluation of response by PET scan [31] as a guide to subsequent therapy decisions and the identification of patients with poor prognosis via genetic, tumour and peripheral blood phenotype (as with some of the patients in the present study [32]). These data emphasise the importance of achieving a true CR to the long-term prognosis of the patient, and the challenge to increase the proportion of such responses to induction therapy remains. However, the maintenance of a true CR is also a pressing issue, and these data indicate that rituximab may have a role in this respect for some patients. Maintenance therapy with rituximab has been investigated in follicular lymphoma (the primary maintenance study) and is under investigation in mantle cell lymphoma; further investigation of this strategy, using modern induction regimens, is now warranted in DLBCL.
funding Programme Hospitalier de Recherche Clinique (PHRC-AOM 98-117); Ministry of Health; Rituximab supplied by Roche; The study was also supported by grants from Roche and Amgen.
acknowledgements The following clinicians actively participated in the LNH 98-3trial: N. Albin, D. Assouline, B. Audhuy, M. Azagury, K. Belhadj, M. Kuentz, M. Blanc, S. Bologna, D. Bordessoulle, R. Bouabdallah, F. Boue´, S. Cailleres, P. Carde, O. Casasnovas, J.P. Cassuto, S. Castaigne, B. Chauffert, L. Chauvenet, B. Christian, J. Collignon, T. Cosnard, H. Cure, D. Decaudin, R. Delarue, A. Delmer, V. Delwail, H. Demuynck, B. De Prijck, T. De Revel, H. Dombret, F. Dreyfus, J.C. Eisenmann, M. Fabbro, G. Fillet, O. Fitoussi, M. Flesch, N. Frenkiel, C. Fruchart, H. Gonzalez, M.C. Gouttebel, F. Guilmin, O. Hermine, A. Huyn, E. Jourdan, P. Lederlin, I. Leduc, F. Lejeune, G. Lepeu, X. Levaltier, M. Macro, M. Maerevoet, L. Marechal, G. Marit,
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ASCT could improve EFS in patients with poor-risk aggressive B-cell NHL, and the study was powered to detect a 15% difference at 2 years (75% versus 60%). Other end points included response rate to induction treatment, response rate at the end of treatment, survival and safety. At a median follow-up of 4 years after the second randomisation, rituximab given weekly for four consecutive weeks after HDT and ASCT did not significantly increase EFS but there was a trend towards improvement with rituximab (EFS 80% and 71% with and without rituximab, respectively; P = 0.10). A planned subgroup analysis of EFS according to post-HDT response showed that rituximab significantly prolonged EFS for patients who achieved a CR, but not for patients who had CRu or PR. Although the findings of subgroup analyses are generally less robust than those of the main analysis, this result is of clinical importance and is reinforced by the fact that patients were intentionally stratified by response to HDT at the time of the second randomisation. The intensified ACE induction regimen, with the addition of an even higher dose of etoposide (450 mg/m2) than the German high-grade lymphoma study group’s cyclophosphamide, doxorubicin, vincristine, etoposide and prednisone regimen (300 mg/m2) [14, 15], did not provide a significant improvement in response rate over ACVBP (63% and 65%, respectively), with a trend towards higher toxicity with ACE. Furthermore, the type of induction regimen had no effect on EFS, and overall the two induction regimens appear to be equivalent. Data on rituximab maintenance in DLBCL during first-line treatment are very limited. In the Eastern Cooperative Oncology Group 4494 phase III trial [16], which compared induction with combination chemotherapy with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) or R-CHOP (with rituximab administered twice before cycles 1 and 2 and 2–3 days before cycles 3 and 5) with a second randomisation to rituximab maintenance (4-weekly infusion every 6 months for a total of 2 years) versus observation, rituximab maintenance showed a statistically significant benefit in EFS over observation. This effect was limited to those patients who received CHOP as induction regimen. Moreover, in the light of superior results achieved in the R-CHOP GELA study [17] with eight infusions of rituximab in elderly patients, the induction schedule used in the EGOG study may not have been adequate. CT plus rituximab is also effective in younger patients (<60 years with low-risk DLBCL), as recently demonstrated in the MabThera International Trial [18]. Despite dramatic advances in treating DLBCL, patients with poor prognoses still exist; progression-free survival after 7 years in the GELA R-CHOP study was <50% for high-risk patients. The use of the aa-IPI score in patients who received R-CHOP does not appear to be sufficiently accurate to discriminate among groups of patients with poor prognoses [19]. The identification of patients with the highest risk disease may therefore require the assessment of new disease markers including an increased use of phenotyping and genotyping to better characterise DLBCL [20–22]. There is a need for further increasing the response rate and the quality of response, as the EFS at 4 years for patients with poor-prognosis aggressive highgrade NHL is still quite low; increasing the rate and quality of
original article
references 1. A predictive model for aggressive non-Hodgkin’s lymphoma. The International Non-Hodgkin’s Lymphoma Prognostic Factors Project. N Engl J Med 1993;http:// content.nejm.org/cgi/content/full/329/14/987. 329: 987–994. 2. Arranz R, Conde E, Grande C et al. Dose-escalated CHOP and tailored intensification with IFE according to early response and followed by BEAM/ autologous stem-cell transplantation in poor-risk aggressive B-cell lymphoma: a prospective study from the GEL-TAMO Study Group. Eur J Haematol 2008; 80: 227–235. 3. Gianni AM, Bregni M, Siena S et al. High-dose chemotherapy and autologous bone marrow transplantation compared with MACOP-B in aggressive B-cell lymphoma. N Engl J Med 1997; 336: 1290–1297. 4. Glass B, Kloess M, Bentz M et al. Dose-escalated CHOP plus etoposide (MegaCHOEP) followed by repeated stem cell transplantation for primary treatment of aggressive high-risk non-Hodgkin lymphoma. Blood 2006; 107: 3058–3064. 5. Greb A, Bohlius J, Trelle S et al. High-dose chemotherapy with autologous stem cell support in first-line treatment of aggressive non-Hodgkin lymphoma—results of a comprehensive meta-analysis. Cancer Treat Rev 2007; 33: 338–346. 6. Haioun C, Lepage E, Gisselbrecht C et al. Benefit of autologous bone marrow transplantation over sequential chemotherapy in poor-risk aggressive nonHodgkin’s lymphoma: updated results of the prospective study LNH87-2. Groupe d’Etude des Lymphomes de l’Adulte. J Clin Oncol 1997; 15: 1131–1137. 7. Haioun C, Lepage E, Gisselbrecht C et al. Survival benefit of high-dose therapy in poor-risk aggressive non-Hodgkin’s lymphoma: final analysis of the prospective LNH87-2 protocol—a Groupe d’Etude des lymphomes de l’Adulte study. J Clin Oncol 2000; 18: 3025–3030. 8. Milpied N, Deconinck E, Gaillard F et al. Initial treatment of aggressive lymphoma with high-dose chemotherapy and autologous stem-cell support. N Engl J Med 2004; 350: 1287–1295. 9. Mounier N, Simon D, Haioun C et al. Impact of high-dose chemotherapy on peripheral T-cell lymphomas. J Clin Oncol 2002; 20: 1426–1427. 10. Stewart DA, Bahlis N, Valentine K et al. Upfront double high-dose chemotherapy with DICEP followed by BEAM and autologous stem cell transplantation for poorprognosis aggressive non-Hodgkin lymphoma. Blood 2006; 107: 4623–4627. 11. Coiffier B. Current strategies for the treatment of diffuse large B cell lymphoma. Curr Opin Hematol 2005; 12: 259–265. 12. Coiffier B, Haioun C, Ketterer N et al. Rituximab (anti-CD20 monoclonal antibody) for the treatment of patients with relapsing or refractory aggressive lymphoma: a multicenter phase II study. Blood 1998; 92: 1927–1932. 13. Dumontet C, Thieblemont C, Espinouse D et al. A prospective study of intensive induction therapy with high-dose consolidation in patients with aggressive nonHodgkin’s lymphoma and two or three adverse prognostic factors. Leukemia 2000; 14: 2159–2165.
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14. Cheson BD, Horning SJ, Coiffier B et al. Report of an international workshop to standardize response criteria for non-Hodgkin’s lymphomas. NCI Sponsored International Working Group. J Clin Oncol 1999; 17: 1244. 15. Pfreundschuh M, Trumper L, Kloess M et al. Two-weekly or 3-weekly CHOP chemotherapy with or without etoposide for the treatment of elderly patients with aggressive lymphomas: results of the NHL-B2 trial of the DSHNHL. Blood 2004; 104: 634–641. 16. Habermann TM, Weller EA, Morrison VA et al. Rituximab-CHOP versus CHOP alone or with maintenance rituximab in older patients with diffuse large B-cell lymphoma. J Clin Oncol 2006; 24: 3121–3127. 17. Coiffier B, Lepage E, Briere J et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 2002; 346: 235–242. 18. Pfreundschuh M, Trumper L, Osterborg A et al. CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with goodprognosis diffuse large-B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) Group. Lancet Oncol 2006; 7: 379–391. 19. Sehn LH, Berry B, Chhanabhai M et al. The revised International Prognostic Index (R-IPI) is a better predictor of outcome than the standard IPI for patients with diffuse large B-cell lymphoma treated with R-CHOP. Blood 2007; 109: 1857–1861. 20. Wilson WH, Dunleavy K, Pittaluga S et al. Phase II study of dose-adjusted EPOCH and rituximab in untreated diffuse large B-cell lymphoma with analysis of germinal center and post-germinal center biomarkers. J Clin Oncol 2008; 26: 2717–2724. 21. Malumbres R, Chen J, Tibshirani R et al. Paraffin-based 6-gene model predicts outcome in diffuse large B-cell lymphoma patients treated with R-CHOP. Blood 2008; 111: 5509–5514. 22. Natkunam Y, Farinha P, Hsi ED et al. LMO2 protein expression predicts survival in patients with diffuse large B-cell lymphoma treated with anthracycline-based chemotherapy with and without rituximab. J Clin Oncol 2008; 26: 447–454. 23. Belhadj K, Jais JP, Feugier P et al. Rituximab combined to ACVBP (R-ACVBP) supported by pegfilgrastim as a new inductive treatment followed by high-dose consolidative autotransplantation (HDC) for poor risk diffuse large B-cell lymphoma (DLBCL) in first-Line. Results of LNH 03-39B. A GELA Study. Blood 2007; 110: 1007A (Abstr 3437). 24. Coso D, Sebban C, Boulat O et al. A phase II trial of rituximab as adjuvant to intensive sequential chemotherapy in patients under 60 years with untreated poor-prognosis diffuse large B-cell lymphoma. Bone Marrow Transplant 2006; 38: 217–222. 25. Tarella C, Zanni M, Di NM et al. Prolonged survival in poor-risk diffuse large B-cell lymphoma following front-line treatment with rituximab-supplemented, early-intensified chemotherapy with multiple autologous hematopoietic stem cell support: a multicenter study by GITIL (Gruppo Italiano Terapie Innovative nei Linfomi). Leukemia 2007; 21: 1802–1811. 26. Milpied NJ, Lamy T, Casassus P et al. Front-line high-dose chemotherapy (HDT) combined with rituximab for adults with aggressive large B-cell lymphoma (DLBCL): Goelams 074 Trial. ASH Annual Meeting Abstracts 2004; 104: (Abstr 902). 27. Zanni M, Di Nicola M, Patti C et al. Rituximab-supplemented high-dose sequential (HDS) chemotherapy with autograft is highly effective in high-risk (aaIPI 2-3) diffuse large B-cell lymphoma: results of a prospective multicenter study on 91 consecutive patients treated at diagnosis. ASH Annual Meeting Abstracts 2004; 104: (Abstr 891). 28. Meignan M, Haioun C, Itti E et al. Value of [18F]fluorodeoxyglucose-positron emission tomography in managing patients with aggressive non-Hodgkin’s lymphoma. Clin Lymphoma Myeloma 2006; 6: 306–313. 29. Haioun C, Itti E, Rahmouni A et al. [18F]fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) in aggressive lymphoma: an early prognostic tool for predicting patient outcome. Blood 2005; 106: 1376–1381. 30. Kasamon YL, Wahl RL. FDG PET and risk-adapted therapy in Hodgkin’s and nonHodgkin’s lymphoma. Curr Opin Oncol 2008; 20: 206–219. 31. Cheson BD, Pfistner B, Juweid ME et al. Revised response criteria for malignant lymphoma. J Clin Oncol 2007; 25: 579–586. 32. Plonquet A, Haioun C, Jais JP et al. Peripheral blood natural killer cell count is associated with clinical outcome in patients with aaIPI 2-3 diffuse large B-cell lymphoma. Ann Oncol 2007; 18: 1209–1215.
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C. Martin, P. Morel, J.N. Munck, H. Naman, G. Nedellec, S. Nunhuck, F. Offner, H. Orfeuvre, J.M. Pavlovitch, P.Y. Pe´aud, A.M. Peny, P. Pierre, I. Plantier, C. Platini, M. Puntous, B. Quesnel, C. Rose, B. Salles, G. Salles, G. Sebahoun, C. Sebban, M. Simon, C. Sohn, C. Soussain, A. Thyss, C. Traulle, B. Valenza, X. Vallantin, E. Vandenneste, A. VanHoof, A. Vermeulen, M. Wetterwald and M. Zini. We also gratefully thank Antoine Allain, Jean Baptiste Golfier and Nicolas Nio for their determinant help in data management and Marion Fournier for statistical analyses. We also thank all the pathologists involved in the study for pathological review, especially Josette Brie`re, Thierry Molina and Philippe Gaulard. The authors also wish to thank Christine Wilkinson-Blanc and Martin Quinn of Prism Ideas, Ltd who provided editorial assistance. We would like to dedicate special thanks to Felix Reyes, deceased in August 2006, for his help in launching this study.
Annals of Oncology
Annals of Oncology 20: 1985–1992, 2009 doi:10.1093/annonc/mdp237 Published online 30 June 2009
Rituximab versus observation after high-dose consolidative first-line chemotherapy with autologous stem-cell transplantation in patients with poor-risk diffuse large B-cell lymphoma 1 Service d’He´matologie Clinique, Centre Hospitalier Universitaire, Groupe Hospitalier Henri Mondor-Chenevier, Assistance Publique-Hoˆpitaux de Paris et Universite´ Paris XII, Cre´teil; 2Service d’Onco-He´matologie, Centre Hospitalier Universitaire Archet 1, Nice; 3Service de Pathologie, Hoˆpital Ambroise Pare´, Assistance Publique-Hoˆpitaux de Paris, Paris; 4Service d’He´matologie et de Me´decine Interne, Centre Hospitalier Universitaire Nancy-Brabois, Vandoeuvre les Nancy; 5Service d’He´matologie, Hoˆpital Lyon Sud, Hospices Civils de Lyon, Pierre Be´nite; 6De´partement d’He´matologie, Centre Henri Becquerel, Rouen; 7Service d’He´matologie, Centre Hospitalier Universitaire Purpan, Toulouse; 8Service d’He´matologie, Institut Gustave Roussy, Villejuif; 9Service d’He´matologie Clinique, Groupe Hospitalier Pitie´-Salpeˆtrie`re, Assistance Publique-Hoˆpitaux de Paris, Paris; 10De´partement d’He´matologie et d’Oncologie, Centre Hospitalier Universitaire de Strasbourg, Strasbourg; 11Service des Maladies du Sang, Centre Hospitalier Universitaire de Lille, Lille and 12Service d’He´mato-Oncologie Adulte, Hoˆpital Saint Louis, Assistance Publique-Hoˆpitaux de Paris, Paris, France
Received 18 March 2009; accepted 20 March 2009
with doxorubicin, cyclophosphamide, vincristine, bleomycin and prednisone (ACVBP) before high-dose therapy (HDT) followed by autologous stem-cell transplantation (ASCT) for patients with poor-risk diffuse large B-cell lymphoma (DLBCL). A second randomisation compared rituximab with observation post-ASCT. Materials and methods: Four hundred and seventy-six patients <60 years old with newly diagnosed CD20+ DLBCL were randomised to induction with ACE or ACVBP. Three hundred and thirty responders received HDT followed by ASCT. After ASCT, 269 patients were re-randomised to receive either maintenance rituximab or observation alone. Randomisation was stratified by the quality of response to ASCT. The primary end point of this study was event-free survival (EFS). Results: At a median of 4 years’ follow-up from the second randomisation, there was a trend (P = 0.1) towards increased EFS for patients who received rituximab compared with observation. Conclusion: The type of induction therapy (ACVBP or ACE) did not significantly affect overall survival at a median 51 months’ follow-up. Key words: autologous transplantation, diffuse large B-cell lymphoma, poor-risk lymphoma, rituximab
introduction Before the widespread integration of rituximab into induction therapy, high-dose therapy (HDT) followed by autologous stem-cell transplantation (ASCT) was a promising option for front-line therapy in patients with aggressive B-cell nonHodgkin’s lymphoma (NHL). Several randomised phase III studies have shown that such an approach is beneficial in terms of progression-free survival and is superior to consolidation chemotherapy (CT) in high-risk patients [age-adjusted International Prognostic Index [1] (aa-IPI) 2 or 3] <60 years. The role of HDT plus ASCT has been extensively studied in
*Correspondence to: Dr C. Haioun, Service d’He´matologie Clinique, Hoˆpital H. Mondor, 51, Avenue du Mare´chal de Lattre de Tassigny, 94010 Cre´teil, France. Tel: +33-1-4981-20-51; Fax: +33-1-49-81-20-67; E-mail: [email protected]
high-risk patients who experienced a good response to induction CT [2–10]. One objective of the LNH 98-3 study was to improve upon the response rate achievable with the intensive regimen of doxorubicin, cyclophosphamide, vindesine, bleomycin and prednisone (ACVBP) every 14 days, which has been extensively reported by the Groupe d’Etude des Lymphomes de l’Adulte (GELA) [11], by using a new induction regimen which introduces etoposide and a higher dose of cyclophosphamide [doxorubicin, cyclophosphamide and etoposide (ACE)]. A phase II study [12] in relapsing or refractory aggressive lymphoma had shown that durable responses could be achieved with rituximab alone and indicated that rituximab may have a role in relapsing aggressive B-cell lymphoma and could be worth testing to increase the response rate of initial induction therapy. When the LHN98-3 study was designed, it was not
ª The Author 2009. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected]
original article
Background: This study compared the induction regimens doxorubicin, cyclophosphamide and etoposide (ACE)
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C. Haioun1*, N. Mounier2, J. F. Emile3, D. Ranta4, B. Coiffier5, H. Tilly6, C. Re´cher7, C. Ferme´8, J. Gabarre9, R. Herbrecht10, F. Morchhauser11 & C. Gisselbrecht12
original article
materials and methods patients Eligible patients were 18–60 years old and had newly diagnosed CD20+ diffuse large B-cell lymphomas (DLBCLs) or other high-grade B-cell lymphoma (initially transformed B-cell, lymphocytic, marginal zone, follicular or nonclassified high-grade lymphomas), diagnosed according to the World Health Organisation (WHO) classification. Patients were also required to have an aa-IPI score of 2 or 3. Exclusion criteria included other lymphoma diagnoses (e.g. Burkitt’s lymphoma, transformed previously diagnosed low-grade lymphoma), contraindication to anthracyclines (i.e. cardiac insufficiency, left ventricular ejection fraction <50% or recent myocardial infarct) or corticosteroid treatment, serious psychosis, sepsis or uncontrolled diabetes, neutrophils <1.5 · 109/l or platelets <100 · 109/l not considered related to lymphoma, renal insufficiency (serum creatinine > 150 lM/l), hepatic disorders (total bilirubin > 30 mM/l or transaminases > 2.5 upper normal limit), positive serology for HIV or hepatitis B, previous organ transplant and pregnancy.
assessments The primary study outcome parameter was EFS. An event was defined as disease progression during or after treatment, a required change in treatment regimen or death without progression. Response to treatment was classified according to the International Workshop Criteria [14]. CR required the disappearance of all clinical signs and symptoms of disease and normalisation of biochemical values. CRu included patients with a residual lymph node mass >1.5 cm in greatest transverse diameter that had regressed by >75% in the sum of the product of greatest diameters. PR was defined as a 50% decrease in the sum of the product of greatest diameters of the largest dominant nodes or nodal masses with no increase in any other nodes, liver or spleen and no new lesions. Stable disease or progressive disease required withdrawal from treatment (Figure 1).
treatment This study employed two randomisation stages (Figure 2). In the first randomisation (R1), eligible patients were allocated to induction therapy
1986 | Haioun et al.
with ACVBP or AC/ACE (regimens are described in Table 1) and stratified according to centres and aa-IPI score. Patients received four cycles of induction therapy, given at 2-weekly intervals, with leukapheresis after the third and/or fourth cycles (weeks 6 and/or 8). Patients’ disease was then reassessed and those who experienced a ‡50% response (i.e. CR, CRu or PR) received two courses of high-dose methotrexate (3 g/m2) followed by leucovorin rescue, with a 2-week interval. Patients then received HDT between days 80 and 90. HDT consisted of mitoxantrone (45 mg/m2, day 1), cyclophosphamide plus etoposide (1500 and 250 mg/m2, respectively, days 2–5) and carmustine (300 mg/m2, day 6) followed by ASCT rescue. Response was reassessed between days 45 and 65 (after ASCT) and patients were stratified according to their response (CR versus CRu + PR). Patients with at least a PR were eligible for second randomisation if they had a good haematological recovery (ANC ‡ 1 · 109/l and platelets ‡ 100 · 109/l) and adequate renal and hepatic functions. After the second randomisation (R2), patients received four doses of rituximab (375 mg/m2 i.v.) at weekly intervals starting no later than day 65 (after ASCT) or observation alone. Patients were assessed every 6 months during the year after the end of treatment, then annually for 5 years.
statistical methods The primary end point was EFS estimated 2 years after ASCT. EFS was measured from the date of randomisation (either first or second randomisation, depending on the comparison) to the date of the first event. Calculation of sample size was based on the primary end point. To detect a change of 15% (null hypothesis 60% and alternative hypothesis 75%), we calculated that 300 patients treated with ASCT should be randomised over 4 years and followed-up for at least 1 year, to provide the trial with 90% power at an overall 5% significance level (130 events). The trial began in October 1999. At a planned interim analysis in February 2003 (when 170 patients had been enrolled), by the data and safety monitoring committee, a total of 37 events had been observed with no significant difference in 2year EFS between groups (rituximab 82% versus observation 72%; P = 0.14). As this number of events was lower than that expected (37 and 60 for rituximab and observation, respectively), it was considered that the study would take much longer to complete than originally anticipated. Furthermore, at that time, there was growing evidence that combining rituximab with the induction regimen might dramatically improve the efficacy of CT. Consequently, the GELA scientific committee decided to stop the study in May 2003, when a total of 269 ASCT patients had been randomised and were being followed to assess EFS. At a median follow-up of 4 years, 65 events were observed and the revised power of the study was 0.60. Survival functions were estimated by the Kaplan–Meier method and compared by log-rank test. Differences between the results of comparative tests were considered significant if the two-sided P value was <0.05. All statistical analyses were carried out using SAS 9.13 (SAS Institute Inc., Carry, NC) software. The study was designed by the GELA scientific committee and monitored by the GELA coordinating centre that issued treatment randomisation by fax after confirmation of the patient eligibility [stratification on aa-IPI (2 versus 3) and tumour response (CR versus CRu/PR) to induction treatment (ACE versus ACVBP)]. Case report forms collected at participating centres were sent to the GELA centralised database and keyed in twice for verification. Outliers and erroneous values were checked routinely. Queries and on-site monitoring were used for final validation. The protocol was approved by local or national ethics committees and the national regulatory agency according to the French and Belgian regulatory laws. Patients had to give written, informed consent before being randomised onto the study. The study was entered on the National Institute of Health website (NCT00169169).
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known how best to incorporate rituximab in the first-line treatment of NHL, i.e. as a part of induction or later on as maintenance. Ideally, the GELA would have investigated rituximab plus ACVBP as a potentially improved induction regimen, but in the absence of availability of preliminary data for rituximab in combination with ACVBP, the ACE regimen was proposed as the investigational treatment based on promising preliminary results [13]. Doxorubicin was administered at the same dose (75 mg/m2) as in ACVBP, the cyclophosphamide dose was increased (2000 instead of 1200 mg/m2) and vindesine and bleomycin were omitted while etoposide was added (150 mg/m2 for three consecutive days). To exploit the potential benefits of rituximab in this study, patients who achieved a sustained response post-HDT and ASCT were randomised (second randomisation) to receive single-agent rituximab weekly for four consecutive weeks or observation. The main objective of this part of the study was to determine whether rituximab delivered after first-line CT followed by HDT and ASCT could improve event-free survival (EFS) in patients with poor-risk aggressive B-cell NHL. At the time of the second randomisation, patients were stratified by their response to HDT + ASCT [complete response (CR) versus partial response (PR) or unconfirmed complete response (CRu)], as the quality of this response might influence the outcome.
Annals of Oncology
original article
Annals of Oncology
476 patients randomised
ACVBP induction: 241 patients
AC/ACE induction: 235 patients
402 patients with PR or better response to induction
72 withdrawals before HDT
330 with PR or better response to HDT+ ASCT
61 dropouts after HDT 8 progression, 7 cytopaenia, 1 PTCL after review, 4 hepatitis, 1 VZV, 3 SAE, 5 deaths, 6 patient refusal, 26 protocol violations
476 patients randomised post ASCT
139 patients received maintenance rituximab
130 patients received observation
Figure 1. CONSORT diagram showing patients in the LNH98-3 study. ACVBP: doxorubicin, cyclophosphamide, vincristine, bleomycin and prednisone; AC/ACE: doxorubicin, cyclophosphamide and etoposide; PR: partial response; HDT: high-dose therapy; ASCT: autologous stem-cell transplantation; PTCL: peripheral T-cell lymphoma; VZV: varicella zoster virus; SAE: serious adverse event.
results patients From October 1999 to November 2004, 476 eligible patients were enrolled in the study at 40 recruiting centres. Patient demographics and baseline disease characteristics are shown in Table 2. At the first randomisation, the groups receiving each type of induction therapy were well balanced.
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response to induction CT and HDT Of the 476 patients who received induction therapy, 402 (84.5%) experienced a PR or CR and were therefore eligible for HDT (Table 3). CR (or CRu) rates to induction treatment were 63% with ACVBP and 65% with ACE. PRs were also similar in the two groups: 22% and 19%, respectively. Seventy-two patients (18%) who experienced PR or CR following induction therapy did not receive HDT, primarily as
doi:10.1093/annonc/mdp237 | 1987
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74 withdrawals (37 ACVBP, 37 AC/ACE) 17 leukapheresis failure, 5 refused therapy, 25 early failure, 18 SAE, 1 protocol violation, 6 on histological review, 2 hepatitis
original article
Annals of Oncology
Induction randomisation
AC then ACE x 3 Leukapheresis after cycles 3 and 4
ACVBP x 4 Leukapheresis after cycles 3 and 4
Responders re-randomised 45-60 days post ASCT
Observation only
Rituximab 4 cycles weeks 21-24
Figure 2. Trial schema for LNH 98-3. ACVBP: doxorubicin, cyclophosphamide, vincristine, bleomycin and prednisone; AC/ACE: doxorubicin, cyclophosphamide and etoposide; MTX, mitoxantrone; CBVM: cyclophosphamide, carmustine, etoposide and mitoxantrone; ASCT, autologous stem-cell transplantation Table 1. Induction therapy regimens ACVBP regimen Doxorubicin Cyclophosphamide Vindesine Bleomycin Prednisone Methotrexate (intrathecal) G-CSF (s.c.)
Dose
Days of cycle 2
75 mg/m 1200 mg/m2 2 mg/m2 10 mgb 60 mg/m2 15 mgb 5 lg/kg/day
1 1 1, 5 1, 5 1–5 2 6–13
AC/ACE regimen Doxorubicin Cyclophosphamide Etoposidea Prednisone Methotrexate (intrathecal) G-CSF (s.c.)
Dose
Days of cycle 2
75 mg/m 1000 mg/m2 150 mg/m2
60 mg/m2 15 mgb 5 lg/kg/day
1 1, 2 1–3 1–5 2 6–13
a
Cycles 2–4 only. Total dose per day. G-CSF, granulocyte colony-stimulating factor.
b
a result of early failure (n = 25), leukapheresis failure (n = 17) or following a serious adverse event (SAE; n = 18); six patients were excluded following histological review, five patients refused further treatment and there was one protocol violation (Figure 1). Overall, 402 patients completed induction, but 72 patients withdrew from the study before receiving HDT, which was administered to 330 patients. Of these, 61 were not randomised to the observation or
1988 | Haioun et al.
rituximab groups following ASCT, mainly as a result of protocol violations (n = 26). Thirteen patients progressed or died (eight progressions and five deaths) during or shortly after HDT, seven patients remained with cytopenia, six patients refused treatment, four developed hepatitis and three experienced a SAE. One patient was diagnosed with peripheral T-cell lymphoma after review and one patient developed varicella zoster virus infection.
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If response >50%, MTX weeks 10 and 12 then CBVM then ASCT
original article
Annals of Oncology
Table 2. Patient demographics and baseline disease characteristics First randomisation (induction therapy) (n = 476) 48 (18–60) 287/189 371/408 (90)
47 (18–59) 181/88 226/239 (95)
111 (23) 189 (40) 176 (37)
69 (26) 115 (43) 85 (32)
21 455 448 127 196 311 176 131
8 261 253 56 102 170 101 63
(4) (96) (94) (33) (47) (65) (38) (28)
(3) (97) (94) (24) (43) (63) (38) (24)
Observation (n = 130)
47 (19–59) 89/50 115/119 (97)
47 (18–59) 92/38 111/120 (93)
35 (25) 64 (46) 40 (29)
34 (26) 51 (39) 45 (35)
4 135 132 27 53 84 55 33
(3) (97) (95) (23) (41) (60) (40) (24)
4 126 121 29 49 86 46 30
(3) (97) (93) (26) (44) (66) (36) (24)
11 (2) 326 (69) 138 (29)
3 (1) 202 (75) 64 (24)
1 (1) 108 (78) 30 (22)
2 (2) 94 (74) 34 (26)
241 (51) 235 (49)
138 (51) 131 (49)
72 (52) 67 (48)
66 (51) 64 (49)
a
Confirmation by pathological review in 408 patients (85%). DLBCL, diffuse large B-cell lymphoma; LDH, lactate dehydrogenase; 1N, normal level; b2-m, b2-microglobulin; aa-IPI, age-adjusted International Prognostic Index; ACVBP, doxorubicin, cyclophosphamide, vindesine, bleomycin and prednisone; ACE, doxorubicin, cyclophosphamide and etoposide.
Table 3. Responses to induction therapy (IWC 1999 criteria)
CR CRu PR SD/PD Deatha Not available
ACVBP group % (n = 241)
ACE group % (n = 235)
20 43 22 10 4 2
20 45 19 9 3 4
a
Mainly toxicity related. IWC, International Workshop Criteria; ACVBP, doxorubicin, cyclophosphamide, vindesine, bleomycin and prednisone; ACE, doxorubicin, cyclophosphamide and etoposide; CR, complete response; CRu, unconfirmed complete response; PR, partial response; SD, stable disease, PD, progressive disease;
Overall, 139 patients were randomised to receive rituximab (72 and 67 from the ABCVP and AC/ACE groups, respectively) and 130 to observation (66 and 64 from the ABCVP and AC/ ACE groups, respectively). At the second randomisation, 130 patients were considered in CR (without any residual disease) and 139 were in CRu or in PR.
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Long-term outcome At a median of 4 years’ follow-up from the second randomisation, there was a nonsignificant trend for increased EFS in the rituximab arm {EFS 80% [95% confidence interval (CI) 72% to 86%]} compared with the observation arm [EFS 71% (95% CI 62% to 78%); P = 0.099; Figure 3]. Similarly, when patients were stratified by aa-IPI score, no statistically significant difference in EFS was observed for rituximab compared with observation (aa-IPI 2: EFS 82% and 73% for rituximab and observation, respectively; P = 0.156; aa-IPI 3: EFS 70% and 65% for rituximab and observation, respectively; P = 0.598). The type of induction therapy received by patients had little effect on the outcome of therapy, with similar response rates from ACVBP and AC/ACE and no significant difference in overall survival (OS) at a median follow-up of 51 months (53% and 48%, respectively, P = 0.505; Figure 4). When patients were stratified by quality of response to HDT, a statistically significant difference in EFS was identified for patients receiving rituximab (n = 70) compared with observation alone (n = 60; Figure 5), in patients who achieved a CR following HDT. In these patients, EFS for those who received rituximab was 86% (95% CI 75% to 92%), compared with 68% (95% CI 53% to 79%) for those who received no consolidation (P = 0.023). However, for patients who
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Median age (range) Male/female DLBCLa, n (%) Performance status, n (%) 0 1 >1 Ann Arbor stage, n (%) I–II III–IV LDH > 1N, n (%) b2-m ‡ 3 mg/l, n (%) Albumin £ 35 g/l, n (%) >1 extranodal localisation, n (%) Bulky disease > 10 cm, n (%) Bone marrow involvement, n (%) aa-IPI score, n (%) 1 (low–intermediate) 2 (high–intermediate) 3 (high) Induction regimen, n (%) ACVBP ACE
Second randomisation (maintenance therapy) All (n = 269) Rituximab (n = 139)
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Annals of Oncology
A)
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Figure 3. Overall survival by induction therapy (median follow-up 51 months). No significant difference in overall survival was detected between the two induction therapy groups. ACVBP: doxorubicin, cyclophosphamide, vindesine, bleomycin and prednisone; AC/ACE: doxorubicin, cyclophosphamide and etoposide.
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Time (years) Figure 4. Event-free survival (EFS) by maintenance therapy. A trend towards increased EFS was observed for patients who received maintenance therapy with rituximab following a complete response after stem-cell transplantation.
experienced a CRu or PR following HDT, no such difference was apparent; EFS was 74% (95% CI 62% to 83%) and 73% (95% CI 61% to 82%) for patients receiving rituximab (n = 69) and observation only (n = 70), respectively (P = 0.91).
safety and tolerability The incidence of grade 3 and 4 adverse events during induction therapy was largely similar for patients receiving ACVBP and AC/ACE for liver, cardiac, neurological, renal and lung events (all £3% of patients for any individual cycle). There was a slightly higher incidence of infection and mucositis events in patients who received AC/ACE compared with ACVBP during each cycle of induction. The incidence of grade 3 or 4 infection during cycles 1–4 was 5%, 3%, 5% and 3% for ACVBP and 8%,
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Figure 5. Event-free survival (EFS) by response to high-dose therapy (HDT) (A) patients in complete response (CR); (B) patients in unconfirmed complete response (CRu) or partial response (PR). In this planned subgroup analysis, there was a significant improvement in EFS for patients who experienced a CR following autologous stem-cell transplantation and received maintenance rituximab compared with those who received observation only.
9%, 8% and 9% for AC/ACE, respectively. Similarly, the incidence of grade 3 or 4 mucositis during cycles 1–4 was 3%, 7%, 5% and 4% for ACVBP and 3%, 9%, 10% and 12% for AC/ACE, respectively. Rituximab therapy was well tolerated. The 139 patients randomised to receive rituximab received 545 infusions in total. Among this group, there were eight cases of neutropenia (6%; four grade 3 and four grade 4), three of thrombocytopenia (2%; all grade 3) and two of Herpes zoster infection (1%). Prophylactic treatment of infections was not reported, and infections were only recorded if reported as SAEs.
discussion The main objective of the study was to determine whether rituximab delivered after first-line CT followed by HDT and
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responses (with more true CRs) at induction is of paramount importance and more effective induction regimens are needed to improve prognoses for patients. To this end, the addition of rituximab to dose-intensified CT such as ACVBP followed by ASCT appears to increase progression-free survival and OS in young patients with poor-risk lymphoma [23]. Others have recently published encouraging results using the same approach [24–27]. Moreover, we and others [28–30] have also demonstrated the value of a good response as assessed by positron emission tomography (PET) imaging to guide therapy decisions and identify patients early for whom HDT and ASCT is the best potential option early on. This approach is also under evaluation by GELA in the ongoing protocol for poorprognosis DLBCL. This study reported a nonsignificant trend towards better 4-year EFS in patients who received rituximab for 4 weeks after induction CT followed by HDT and ASCT. A significant benefit of the addition of rituximab was reported in patients who achieved a true CR after HDT and ASCT compared with those who experienced a lesser response, showing the importance of the quality of response after induction treatment to long-term prognosis. In the time since the inception of this study, the treatment of DLBCL has changed, with rituximab CT considered to be the standard induction regimen, the evaluation of response by PET scan [31] as a guide to subsequent therapy decisions and the identification of patients with poor prognosis via genetic, tumour and peripheral blood phenotype (as with some of the patients in the present study [32]). These data emphasise the importance of achieving a true CR to the long-term prognosis of the patient, and the challenge to increase the proportion of such responses to induction therapy remains. However, the maintenance of a true CR is also a pressing issue, and these data indicate that rituximab may have a role in this respect for some patients. Maintenance therapy with rituximab has been investigated in follicular lymphoma (the primary maintenance study) and is under investigation in mantle cell lymphoma; further investigation of this strategy, using modern induction regimens, is now warranted in DLBCL.
funding Programme Hospitalier de Recherche Clinique (PHRC-AOM 98-117); Ministry of Health; Rituximab supplied by Roche; The study was also supported by grants from Roche and Amgen.
acknowledgements The following clinicians actively participated in the LNH 98-3trial: N. Albin, D. Assouline, B. Audhuy, M. Azagury, K. Belhadj, M. Kuentz, M. Blanc, S. Bologna, D. Bordessoulle, R. Bouabdallah, F. Boue´, S. Cailleres, P. Carde, O. Casasnovas, J.P. Cassuto, S. Castaigne, B. Chauffert, L. Chauvenet, B. Christian, J. Collignon, T. Cosnard, H. Cure, D. Decaudin, R. Delarue, A. Delmer, V. Delwail, H. Demuynck, B. De Prijck, T. De Revel, H. Dombret, F. Dreyfus, J.C. Eisenmann, M. Fabbro, G. Fillet, O. Fitoussi, M. Flesch, N. Frenkiel, C. Fruchart, H. Gonzalez, M.C. Gouttebel, F. Guilmin, O. Hermine, A. Huyn, E. Jourdan, P. Lederlin, I. Leduc, F. Lejeune, G. Lepeu, X. Levaltier, M. Macro, M. Maerevoet, L. Marechal, G. Marit,
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ASCT could improve EFS in patients with poor-risk aggressive B-cell NHL, and the study was powered to detect a 15% difference at 2 years (75% versus 60%). Other end points included response rate to induction treatment, response rate at the end of treatment, survival and safety. At a median follow-up of 4 years after the second randomisation, rituximab given weekly for four consecutive weeks after HDT and ASCT did not significantly increase EFS but there was a trend towards improvement with rituximab (EFS 80% and 71% with and without rituximab, respectively; P = 0.10). A planned subgroup analysis of EFS according to post-HDT response showed that rituximab significantly prolonged EFS for patients who achieved a CR, but not for patients who had CRu or PR. Although the findings of subgroup analyses are generally less robust than those of the main analysis, this result is of clinical importance and is reinforced by the fact that patients were intentionally stratified by response to HDT at the time of the second randomisation. The intensified ACE induction regimen, with the addition of an even higher dose of etoposide (450 mg/m2) than the German high-grade lymphoma study group’s cyclophosphamide, doxorubicin, vincristine, etoposide and prednisone regimen (300 mg/m2) [14, 15], did not provide a significant improvement in response rate over ACVBP (63% and 65%, respectively), with a trend towards higher toxicity with ACE. Furthermore, the type of induction regimen had no effect on EFS, and overall the two induction regimens appear to be equivalent. Data on rituximab maintenance in DLBCL during first-line treatment are very limited. In the Eastern Cooperative Oncology Group 4494 phase III trial [16], which compared induction with combination chemotherapy with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) or R-CHOP (with rituximab administered twice before cycles 1 and 2 and 2–3 days before cycles 3 and 5) with a second randomisation to rituximab maintenance (4-weekly infusion every 6 months for a total of 2 years) versus observation, rituximab maintenance showed a statistically significant benefit in EFS over observation. This effect was limited to those patients who received CHOP as induction regimen. Moreover, in the light of superior results achieved in the R-CHOP GELA study [17] with eight infusions of rituximab in elderly patients, the induction schedule used in the EGOG study may not have been adequate. CT plus rituximab is also effective in younger patients (<60 years with low-risk DLBCL), as recently demonstrated in the MabThera International Trial [18]. Despite dramatic advances in treating DLBCL, patients with poor prognoses still exist; progression-free survival after 7 years in the GELA R-CHOP study was <50% for high-risk patients. The use of the aa-IPI score in patients who received R-CHOP does not appear to be sufficiently accurate to discriminate among groups of patients with poor prognoses [19]. The identification of patients with the highest risk disease may therefore require the assessment of new disease markers including an increased use of phenotyping and genotyping to better characterise DLBCL [20–22]. There is a need for further increasing the response rate and the quality of response, as the EFS at 4 years for patients with poor-prognosis aggressive highgrade NHL is still quite low; increasing the rate and quality of
original article
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C. Martin, P. Morel, J.N. Munck, H. Naman, G. Nedellec, S. Nunhuck, F. Offner, H. Orfeuvre, J.M. Pavlovitch, P.Y. Pe´aud, A.M. Peny, P. Pierre, I. Plantier, C. Platini, M. Puntous, B. Quesnel, C. Rose, B. Salles, G. Salles, G. Sebahoun, C. Sebban, M. Simon, C. Sohn, C. Soussain, A. Thyss, C. Traulle, B. Valenza, X. Vallantin, E. Vandenneste, A. VanHoof, A. Vermeulen, M. Wetterwald and M. Zini. We also gratefully thank Antoine Allain, Jean Baptiste Golfier and Nicolas Nio for their determinant help in data management and Marion Fournier for statistical analyses. We also thank all the pathologists involved in the study for pathological review, especially Josette Brie`re, Thierry Molina and Philippe Gaulard. The authors also wish to thank Christine Wilkinson-Blanc and Martin Quinn of Prism Ideas, Ltd who provided editorial assistance. We would like to dedicate special thanks to Felix Reyes, deceased in August 2006, for his help in launching this study.
Annals of Oncology