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Originally published as JCO Early Release 10.1200/JCO.2003.10.023 on September 29 2003 © 2003 American Society for Clinical Oncology High-Dose Therapy Improves Progression-Free Survival and Survival in Relapsed Follicular Non-Hodgkin’s Lymphoma: Results From the Randomized European CUP Trial
From the University Hospital Maastricht, Maastricht, and the Erasmus Medical Center, Rotterdam, the Netherlands; Medical Research Council Clinical Trials Unit, London, United Kingdom; Norwegian Radium Hospital, Oslo, Norway; Ospedale P.F. Calvi, Noale, Italy; University Hospital of Uppsala, Sweden; Herlev University Hospital, Copenhagen, Denmark. Address reprint requests to Harry C. Schouten, MD, PhD, University Hospital Maastricht, Department of Internal Medicine, Section of Hematology-Oncology, PO Box 5800, 6202 AZ Maastricht, the Netherlands; e-mail: hsch{at}sint.azm.nl.
Purpose: To determine, in a randomized clinical trial, whether high-dose therapy (HDT) followed by autologous stem-cell transplantation is more effective than standard treatment with regard to progression-free survival (PFS) and overall survival (OS) in patients with relapsed follicular non-Hodgkin’s lymphoma; and to assess the additional value of B-cell purging of the stem-cell graft with regards to PFS and OS. Patients and Methods: Patients received three cycles of chemotherapy. Responding patients with limited bone marrow infiltration were eligible for random assignment to three further cycles of chemotherapy (C), unpurged HDT (U), or purged HDT (P). Results: Between August 1993 and April 1997, 140 patients were registered from 36 centers internationally, and 89 were randomly assigned. Reasons for not randomizing included patient refusal, early progression, or death on induction therapy. With a 69-month median follow-up, the log-rank P value for PFS and OS were .0037 and .079, respectively. For PFS, the hazard ratios (95% CIs) for U versus C, P versus C, and P versus U were 0.33 (0.16 to 0.70), 0.38 (0.19 to 0.79), and 1.02 (0.51 to 2.05), respectively. The hazard ratio (95% CI) for C versus U + P was 0.30 (0.15 to 0.61). Hazard ratios (95% CIs) for OS were 0.43 (0.18 to 1.06), 0.43 (0.18 to 1.02), and 0.72 (0.32 to 1.63). For C versus U + P, the hazard ratio (95% CI) was 0.40 (0.18 to 0.89). Kaplan-Meier estimates (95% CIs) of 2-year PFS for C, U, and P were 26% (8% to 44%), 58% (37% to 79%), and 55% (34% to 75%), respectively. OS at 4 years for C, U, and P are 46% (25% to 67%), 71% (52% to 91%), and 77% (60% to 95%) respectively. Conclusion: HDT significantly improves PFS and OS. There is no clear evidence of benefit through purging.
PATIENTS WITH a follicular lymphoma have a relatively good prognosis. Johnson et al1 have reported their experience with patients with follicular non-Hodgkin’s lymphoma (NHL) in a single center. These data may be extrapolated to all patients with a follicular lymphoma. They concluded that in extensive disease, responses with chemotherapy could be obtained in 75% to 80% of the patients. This translated into a median overall survival (OS) of 9 years. The majority of patients, however, relapse, and in relapsed disease, cure is very unlikely, resulting in a median survival duration of 4.5 years after recurrence. Deaths from causes other than lymphoma are rare. The introduction of new agents like interferon alfa, fludarabine, 2-chloro-deoxyadenosine (2-CDA), and anti-CD20 may have influence on morbidity, but is not very likely to change the survival pattern significantly.2,3 High-dose therapy (HDT) followed by autologous stem-cell transplantation in relapsed large-cell NHL is effective and can result in longstanding remissions.4 Depending on disease status at the time of transplantation, response to previous chemotherapy and duration of follow-up, long-term disease-free survival may be possible in over 50% of patients. Several series of patients with relapsed follicular NHL treated with HDT and stem-cell transplantation have been published.5–18 They all report long remissions, but follow-up is too short for researchers to come to meaningful conclusions about its effects on OS, and none had a randomly assigned control group. Follicular NHL is frequently accompanied by marrow infiltration. Autologous transplantation may, therefore, be complicated by a significant risk of reinfusing tumor cells after ablative therapy. Purging the graft may be an effective way of reducing relapses after transplantation. Several reports suggest that this approach is efficacious10,19; however, data from randomized studies are lacking. In addition, registry studies do not support the efficacy of purging.20 Neoplastic cells may be heterogeneous with respect to antigen density. The simultaneous use of several antibodies for a variety of differentiation antigens (antibody cocktail) may be the most efficacious approach. In previous studies, the efficacy of immunomagnetic purging using monoclonal mouse antibodies against five different B-cell antigens (CD19, CD20, CD22, CD23, CD37) was established.21,22 Based on these considerations and clinical questions, we designed a randomized trial in the early 1990s to answer two questions as to whether HDT followed by autologous stem-cell transplantation is more effective than standard treatment with regard to progression-free survival (PFS) and OS in patients with relapsed follicular NHL, and whether the addition of immunomagnetic ex vivo purging of the stem-cell graft could have an impact with regard to PFS and OS. Here, we present the results with a median follow-up of 69 months.
Patients Adult patients with relapsed or progressive follicular NHL were invited, after appropriate informed consent, to participate in this randomized controlled phase III trial. They had to be aged between 15 and 65 years, with a WHO performance status of 0, 1, or 2. Patients were excluded if they had had previous radiotherapy (precluding total-body irradiation) or bone marrow harvest; CNS localization; cumulative doxorubicin dose of more than 300 mg/m2; prior malignancies with the exception of those originating in the skin (nonmelanoma) or cervical carcinoma stage I; cardiopulmonary, neurological, liver (liver enzymes more than 3x the upper limit of normal) or renal (creatinine > 150 µmol/L) dysfunction; evidence of histologically proven transformation; or HIV positivity.
Investigations at Trial Entry
Trial Design
Induction therapy. Following registration, all patients were treated with three cycles of chemotherapy. CHOP chemotherapy (3-week cycle; cyclophosphamide 750 mg/m2 intravenous [IV], doxorubicin 50 mg/m2 IV, and vincristine 1.4 mg/m2 IV on day 1; prednisone 100 mg orally on days 1 to 5) was the recommended regimen, but any other suitable regimen was acceptable. Response was then assessed. Response criteria. Complete remission (CR) was defined as disappearance of all disease-related symptoms and measurable disease, normalization of chest x-ray, computed tomography scan of the chest and abdomen, and no evidence of bone marrow infiltration in histology. Partial response (PR) was defined as a decrease of at least 50% in the product of 2 diameters in all measurable lesions, and residual bone marrow infiltration of less than 20% lymphoid cells in bone marrow histology (paratrabecular infiltration). Progressive disease (PD) was defined as involvement of new sites, recurrence in originally involved sites, or increase of more than 25% in original tumor masses. No response (NR) was defined as assessable but not qualified for response or progression. Random assignment procedure. Patients who achieved a CR or PR to induction therapy, had a WHO performance status of 0 to 2, had limited bone marrow infiltration (defined as < 20% B cells in marrow aspirate using a cocktail consisting of anti-CD19, CD20, CD22, CD23, and CD37), and gave informed consent were eligible for random assignment. Patients who were not eligible for random assignment were taken off trial therapy and treated at the discretion of the responsible physician. They remained on trial for follow-up and were included in analyses of response and survival. Random assignment, using the method of minimization, was performed at the Medical Research Council Clinical Trials Unit (MRC CTU) in London, United Kingdom (formerly MRC Cancer Trials Office, Cambridge, United Kingdom), by telephone or fax. Patients were stratified according to marrow infiltration (> 10% or < 10% B cells) and transplantation center. Initially patients were randomly assigned with a 1:1:1 ratio between chemotherapy (C), unpurged HDT (U), and purged HDT (P), respectively. However, there were some centers that felt uncomfortable treating relapsed patients without HDT and transplantation. To enable such centers to take part in this trial, the protocol was amended in March 1996 to enable these centers to randomly assign patients with a 1:1 ratio between HDT with or without purging (UP option) only. C patients. These patients had three additional cycles of chemotherapy. Patients randomly assigned to arm C would be treated according to the same schedule as before random assignment. The treatment should commence as soon as possible following random assignment. U and P patients. Stem-cell harvesting had to take place as soon as possible after full recovery from the third cycle of chemotherapy. Bone marrow was aspirated from the bilateral iliac bones by multiple punctures. A total of at least 2 x 108 nucleated bone marrow cells per kilogram of body weight had to be collected. If the patients were randomly assigned to the no-purging group, buffy-coat cells were prepared, cryopreserved, and stored until use.
Before starting the protocol each participating center underwent a training course for immunomagnetic purging of bone marrow and peripheral blood progenitor cells. The first purging procedure done in individual centers was also performed under the supervision of an experienced technician. The method used has been described previously,21,23 and an outline of the purging procedure together with a summary of buffers and media is presented in Figure 2
Within 4 weeks after harvesting, the patients had to be treated with cyclophosphamide 60 mg/kg on 2 days, in combination with fractionated or unfractionated total body irradiation. Cryopreserved stem cells were thawed and infused by the IV route within 20 to 40 minutes. All patients: additional treatment issues. Supportive care was given according to local guidelines. No posttransplantation treatment with a cytostatic agent was performed. With regard to postchemotherapy treatment with radiotherapy, areas of prior bulky disease (> 5 cm) as assessed at time of entry in the trial, and/or areas that still showed residual masses 2 months after transplantation or after the completion of the chemotherapy could be irradiated, if this was considered feasible. Follow-up was performed at 3 months after random assignment and then every 4 months during the first 2 years, and twice yearly thereafter, with careful monitoring for new symptoms, progression, and initiation of therapy. If initiated, the therapy used and the response to therapy were reported. Restaging was performed at 3 months, and then every 4 months for 2 years or when clinically indicated.
Statistical Considerations
Trial Administration The trial started accruing patients in August 1993. In 1997, Baxter withdrew from the trial, and the MRC CTU took over both data collection and data management. The trial was closed to accrual in April 1997. Some baseline and treatment data missing at this stage could not be retrieved; all missing data items are identified in the Tables.
Protocol Revisions
Between August 1993 and April 1997, a total of 140 patients from 36 centers in 11 countries in Europe and Australia were registered on this trial. Of these, 89 patients were randomly assigned. Recruitment to the trial was discontinued at the point at which the sample size required for the C and P comparison had been achieved. The accrual rate was considerably lower than that required to address the other comparisons adequately. The median age at inclusion was 48 years (range, 29 to 64 years), with the expected male predominance (60%). The majority of patients had experienced one prior relapse only. The main (International Working Formulation) histology types24 were follicular small (29%) and follicular mixed (67%). Of all randomly assigned patients, 27 had central pathology review and diagnosis was confirmed.
Forty-two percent of patients had negative bone marrow trephine. The median percent of positive B-cell in bone marrow aspirate was 14 (range, 0 to 91) as assessed by flow cytometry. According to the age-adjusted International Prognostic Index (IPI) risk groups,25 13 (11%) of patients had low-risk disease, 69 patients (61%) had low-/intermediate-risk disease, 26 patients (23%) had high-/intermediate-risk disease, and 6 patients (5%) had high-risk disease. It was not possible to allocate 26 patients to the IPI risk group, as some data were not available. The presenting features of all registered patients are summarized in Table 1
Induction Treatment and Assessment Sixty-seven percent of patients received 3 cycles of CHOP in their induction treatment, and another 33% patients had other regimens (eg, mesna + ifosfamide + mitoxantrone + etoposide). Response to induction therapy was reported for 114 patients. Details are given in Table 2  , with the assessments of WHO performance status and percentage of bone marrow B-lymphocytes after induction therapy.
Treatment Allocation Eighty-nine patients were randomly assigned. The reasons for not being randomly assigned were NR or PD in 28, patient refusal in 6, persistent marrow infiltration (> 20% B-lymphocytes) in 4, patient death in 4, CNS involvement in 2, histologic pathology in 2, and unknown reasons in 5 patients. One patient with a WHO performance status of 4 was randomly assigned. Based on the intention-to-treat principle, all 89 randomly assigned patients were included for the analyses of treatment comparisons. Of the 89 randomly assigned patients, 70 were assigned among three treatment arms (C, U, and P), and 19 between the U and P arms only. Thus, 46 were included in the CU comparison; 48, in the CP comparison; and 65, in the UP comparison.
The characteristics were balanced across randomly assigned arms on both randomization choices. Patients were similar between the two randomization options (CUP and UP). They are presented in Tables 3
Treatment Received There were 21 (88%) of 24 patients in C, 28 (85%) of 33 patients in U, and 21 (67%) of 32 patients in P patients who received protocol treatments (excluding the missing data). Of the purged patients, nine received peripheral blood stem cells. The other treatments received are shown in Table 5 . Twenty-six U patients (79%) received total-body irradiation with a median dose of 9 Gy, while 18 P patients (56%) received total body irradiation with a median dose of 12 Gy.
PFS PFS data for patients randomly assigned between three arms are shown in Figure 4 . The total number of progressions or deaths (whichever occurred first) was 40 (20 in C, nine in U, and 11 in P) for patients randomly assigned to the CUP option, and 12 (seven in U and five in P) in the UP option. Fourteen patients died (13 from progressive disease or relapse) in C, 13 patients died (nine from progressive/relapse disease, three from procedure-related toxic death) in U, and 10 patients (six from progressive/relapse disease, two from procedure-related toxic death) in P. The P value of the log-rank test for progression-free survival, according to three randomized arms, was .0037. The hazard ratio (HR) is presented in Table 6. This Table includes only the patients in the three-arm randomization (CUP), except for the comparison between UP patients. Also, a comparison was made between C patients and UP patients combined; however, it was limited to the patients randomly assigned to CUP, showing a significant reduction in HRs for progression-free survival in favor of the U and P arms.
OS The OS from the date of registration for all registered patients is shown in Figure 3 . With a median follow-up of 69 months for surviving patients the 5-year survival is 50%. Overall survival for patients randomized between three arms is shown in Figure 5. Fourteen patients have died (13 progressive disease or relapse) in C, 13 patients have died (nine progressive/relapse disease, three procedure related toxic death) in U, and 10 patients (six progressive/relapse disease, two procedure related toxic death) in P. The P value of log-rank test for OS, according to three randomized arms, is .079. The HRs are shown in Table 6 . This Table includes only the patients in the three-arm randomization (CUP) except for the comparison between UP patients. Also, a comparison was made between C patients and UP patients combined, however limited to the CUP randomized patients showing a significant reduction in hazard rates for survival when the two transplantation arms were combined.
From this randomized trial, we conclude that HDT followed by autologous stem-cell transplantation (in patients with relapsed follicular NHL) translates into improved PFS (for the three-arm comparison) and overall survival (comparing the chemotherapy patients with the UP patients combined). The data do not provide evidence to suggest that purging of the stem-cell graft improves outcome. Despite the relatively low numbers of patients randomized, the data are important since the patient groups were well-balanced according to patient (including IPI) and treatment characteristics. Several points merit discussion. This is the only trial in relapsed follicular NHL addressing the questions of HDT and purging. For the chemotherapy versus purged transplantation question, the planned sample size was achieved, and this did contribute a significant benefit to HDT with respect to progression-free survival but not for overall survival (P = .54). For the question of any HDT versus chemotherapy, we also found a significant difference for PFS in favor of HDT, but also OS. We cannot fully address the purging question with this data, because the trial had to be closed early due to the slow accrual of patients. This slow recruitment is not due to a poorly designed trial; instead, it reflects the change of clinical practice in the field of autologous transplantation. At the design of the trial, the general feeling was that HDT for this relatively indolent disease might be too toxic. This made several groups hesitant to enter patients. After the introduction of peripheral blood stem cells and its inherent decreased toxicity, enthusiasm for HDT increased. However, this did not increase the accrual for this trial significantly, probably due to the published results of a series of phase II studies with very encouraging results5–15,17,18,26,27) in relation to an acceptable morbidity and mortality, which shifted the field to standard transplantation. However, despite the relatively small number of patients randomized, we feel the trial data presented herein are all the more important, because there will almost certainly be no further trials in this field; the patient groups were well balanced according to patient (including IPI) and treatment characteristics. The results obtained in the transplant arms and the chemotherapy arms do not significantly differ from previously reported phase II studies in transplantation14 or chemotherapy.28 The purging regimen used in this trial was chosen because of its high efficacy.21–23 That we were not able to find a response difference in favor of purging may be due to several factors. Firstly, purging may work; however, the number of patients was too low to come to a meaningful conclusion. The second reason, which may be of equal importance, is that purging was done in many centers, with few purging procedures performed in each center. It may be very likely that despite the presence of a clear protocol, the experience in each center was too small to obtain the same excellent results as obtained in single-center studies. This, if true, may have important implications as to whether purging should be restricted to larger centers performing significant numbers of purging procedures. Another explanation that cannot be excluded is that the reduction of tumor cells in the graft relative to the numbers of remaining tumor cells in the patient is too insignificant to alter the outcome for the patients. This observation is not necessarily in contrast with the data published by Gribben et al,29 who was able to show that purging the graft to PCR negativity results in better outcome. Our preliminary quantitative PCR data has shown that it may be easier to purge the graft to negativity in patients with a smaller tumor load and that this also result in a higher molecular remission in the bone marrow after high-dose therapy (Kvalheim et al, unpublished data). These data may be interpreted in the way that it may be easier to purge the graft to negativity in patients with a smaller tumor load. Patients in our trial were transplanted after three cycles of standard reinduction chemotherapy, and not at the time of maximal response, which potentially could have led to better results and a potential advantage for purging. Comparing the outcome with patients treated with an allograft suggests the results to be comparable (49% relapse-free survival for the allotransplanted patients with comparable follow-up30) compared with approximately 50% to 55% in our trial. Taking into account the possibility of a graft-versus-lymphoma effect in follicular lymphoma, which should lead to a decreased relapse rate in allotransplanted patients, one would not expect purging to lead to a lower relapse rate in autologous transplants. In addition, because of the comparable relapse rate attention must be directed to the remission status at the time of transplant. Pretransplant in vivo purging using monoclonal antibodies like anti-CD20 may be helpful to achieve this goal. However, this has to be proven by randomized trials, which are currently ongoing. Although the follow-up, compared with the natural survival of patients with relapsed follicular NHL may be relatively short, even if with longer follow-up relapses may continue to occur, the survival difference and the prolongation of progression-free survival may be very worthwhile for the individual patient. The data do not support a specific timing of this treatment modality in the course of the disease. The majority of patients were entering in this trial at their first relapse. The number of patients transplanted later than their first relapse is too small to come to meaningful conclusions. However, the low treatment-related mortality does not make it necessary to postpone the treatment to later phases of the disease, which may be related to more frequently resistant disease leading to higher morbidity and mortality in extensively pretreated patients. In a recent nonrandomized single-center study, Freedman et al27 observed a 3-year PFS of 63%, which is marginally superior to that observed by this trial. Of course, a randomized trial also should determine the merit of HDT in first remission. Such trials are currently underway in Germany31 and France.32 The relative early application of this treatment modality may be the explanation for the absence (with current follow-up) of myelodysplasia in the transplanted patients, which seems to be in contrast with other reports.33,34 The results may, in our view, be applicable to the overall patients with relapsed follicular lymphoma. The composition of patients entered generally reflects the patients presenting with follicular lymphoma based on IPI risk groups.35 The important question that arises, therefore, is what the standard treatment for a patient with relapsed follicular lymphoma should be. Based on our demonstration that the results with chemotherapy are inferior to HDT, either with or without purging, our recommendation would be to offer patients an autologous transplantation without purging the graft if the patient has minimal marrow infiltration, as defined in our trial (< 20% B lymphocytes). For patients with an HLA identical sibling one has to trade-off between allografting and an autologous transplantation or an allograft after relapse from autologous transplantation. Up to now, the data do not suggest a major difference for allografting and one has to take into account the significant morbidity and mortality subsequent to graft-versus-host disease. Whether the introduction of nonmyeloablative transplants, wider application of Fludarabine and a better exploitation of the immunological antitumor effect will change this is open for future studies.
The authors indicated no potential conflicts of interest.
CUP Participating Centers. Country: Center (clinician: patients randomized) Australia: Adelaide (Dart G.W., To L.B.: 2); Denmark: Copenhagen (Geisler. C: 6) Herlev (Johnsen H.: 6); Finland: Tampere (Lehtinen M.: 3) Turku (Salminen E.: 5); France: Paris Cedex 10 (Gisselbrecht C.: 1); Germany: Augsburg (Hempel D.: 2) Berlin (Schmidt D.: 1) Erlangen (Rosler W.: 2) Homburg (Kranzhofer N.: 1) Mainz (Huber C.: 1); Italy: Bari (Pavone V.: 2) Bologna (Gherlinzoni F., Tura S.: 2) Bolzano (Mitterer M.: 3) Cremona (Porcellini A., Manna A.: 12) Genova (Spriano N.: 4) Perugia (Tabilio A.: 1) Pescara (Angrilli F., Iacone A.: 5) Roma (Mandelli F.: 5) Sardinia (Olmeo N.: 2) Torrette di Ancona (Olivieri A.: 3) Venezia (Chisesi T.: 2); Netherlands: Brunssum (Wals J.: 2) Groningen (Daenen S.: 2) Heerlen (Fickers M.: 2) Maastricht (Schouten H.C.: 6) Rotterdam (Bos G., Cornelissen J.J., De Greef I.G.R., Hagenbeek A., Sonneveld P., Voogt P.: 11) Sittard (Bron H., Erdkamp F.: 5) the Hague (Wyermans P.: 1); Norway: Oslo (Holte H., Kvaloy S.: 22) Tromso (Kolstad A.: 2); Spain: Madrid (Bornstein R.: 2); Sweden: Gothenburg (Hagberg H.: 3) Lund (Johnson U., Nilson-Ehle, Stahl E.: 4) Umea (Erlanson M., Lindh J.: 3) Uppsala (Enblad G.: 2); United Kingdom: Cambridge (Marcus R.: 1) London (Carr R.: 1).
We thank Drs Goldstone, Marcus, Dörken, and Machin, who contributed essentially to the design of this study.
This trial was partially supported by a grant from Baxter GmBH (Unterschleissheim, Germany).
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 test. OS time relating to the whole population was defined as the time from the registration to death; it was defined as the time from random assignment to death from any cause for only those analyses involving patients who went on to be randomly assigned; patients still alive at the time of analysis were censored at the time of last follow-up. PFS was defined as the time from random assignment to first appearance of progression/relapse, or death from any cause; patients alive without progression/relapse by the time of analysis were censored at the time of their last follow-up. Frequencies of site of progression or relapse by treatment were displayed; differences were compared by the 
