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Originally published as JCO Early Release 10.1200/JCO.2006.09.8327 on May 21 2007 © 2007 American Society of Clinical Oncology. Myeloablative Therapy With Autologous Bone Marrow Transplantation for Follicular Lymphoma at the Time of Second or Subsequent Remission: Long-Term Follow-Up
From the Cancer Research UK Medical Oncology Unit, St Bartholomew's Hospital, London, United Kingdom; and the Department of Hematologic Malignancies, Dana-Farber Cancer Institute, Boston, MA Address reprint requests to Ama Z.S. Rohatiner, MD, FRCP, Cancer Research UK Medical Oncology Unit, St Bartholomew's Hospital, 45 Little Britain, London EC1A 7BE; e-mail: ama.rohatiner{at}cancer.org.uk
Purpose: The aim of this retrospective analysis was to determine the outcome of patients with follicular lymphoma who received myeloablative therapy supported by autologous bone marrow transplantation as consolidation of second or subsequent remission, with a minimum follow-up of 12 years. Patients and Methods: One hundred twenty-one adults received cyclophosphamide (CY) and total-body irradiation (TBI) supported by autologous bone marrow transplantation, with the marrow mononuclear cell fraction having been treated with monoclonal antibodies and complement. Data from St Bartholomew's Hospital and Dana-Farber Cancer Institute were combined for the purpose of this analysis because the patients were treated in an identical manner. Results: Fifty-seven patients are alive, 41 without progression between 9 and 19 years; 64 patients have died, 20 without progression. With a median follow-up of 13.5 years, 60 patients have developed recurrent lymphoma. There is an apparent plateau on the remission duration curve at 48% at 12 years. Survival of patients treated in second remission was significantly longer than the survival of patients treated later in the course of the illness. Both remission duration and overall survival were also significantly longer for patients treated in second remission compared with an age-matched, remission-matched group of patients treated at St Bartholomew's Hospital before the introduction of this treatment. However, use of CY+TBI was associated with a significant risk of secondary myelodysplasia and secondary acute myeloblastic leukemia, resulting in 15 patient deaths. Conclusion: These mature data confirm that prolonged freedom from recurrence may be achieved with myeloablative therapy and that a plateau on the curve seems to emerge with long follow-up.
It had become clear by the early 1980s that the natural history of follicular lymphoma could be modified by irradiation and chemotherapy, such that the median survival time was approximately 10 years, with the average patient having been treated three times at approximately 3-year intervals and then ultimately succumbing to the disease or to complications of its treatment.1-3 There was little evidence of cure, except perhaps for a proportion of patients with localized disease who were treated with radiotherapy.4-6 Relatively modest attempts to improve the prognosis by intensifying the initial therapy yielded improvements in response rate, with more complete remissions and longer duration of remission than with alkylating agents alone, but had no impact on overall survival because of the recurring/remitting nature of the disease.7-11 Despite this and encouraged by the experience in treating the more aggressive lymphomas,12-14 the concept of intensifying therapy beyond the dose-limiting toxicity of myeloablation began to be explored, with the hope that prolonged remission might be converted into cure. Several phase II studies of high-dose therapy were undertaken in follicular lymphoma.15-19 In some patients, an attempt to circumvent the potential risk of reinfusion of lymphoma was made by treating the bone marrow in vitro with monoclonal antibodies and complement.20 When differences in patient selection are taken into account, the results are broadly similar; namely, the majority of patients survived the treatment in the short term, and the duration of remission was longer than might have been expected with conventional therapy.16,17,21 The best results were achieved when the treatment was administered earlier rather than later in the course of the illness, and results were uniformly better in patients in whom the treatment was administered in the setting of remission rather than relapse.18,19 However, demonstrating a potential survival advantage, even using historical controls for comparison, was difficult because of the significant mortality from secondary myelodysplastic syndrome (MDS) and acute myeloblastic leukemia (AML), which was predominantly seen in patients who had been heavily pretreated and in whom the myeloablative regimen was cyclophosphamide (CY) and total-body irradiation (TBI).22-27 Therefore, in the absence of compelling phase III data, myeloablative therapy, although transiently popular for approximately 10 years, has been relatively unenthusiastically received in the hematologic oncology community as a whole. The exciting demonstration that a relatively nontoxic new therapy, rituximab, when combined with chemotherapy, lengthens progression-free survival and overall survival, both at the time of initial therapy and at recurrence, has lessened enthusiasm still further, although the follow-up time for the studies with rituximab is quite short.28-30 To put the undoubted early 21st century advances into context, an analysis of the combined experience gained from the use of CY+TBI as treatment for follicular lymphoma at two institutions pursuing the same strategy has been undertaken 12 years since treatment of the last patient and the time at which the combined data were last reported.31
Patients Between February 1985 and August 1992, 121 adults in second or subsequent, complete or partial remission of follicular lymphoma (Table 1) were treated with CY+TBI supported by autologous bone marrow, which had been treated in vitro with monoclonal antibodies and complement as previously described.20 Pretreatment evaluation included clinical examination, computed tomography scans, and unilateral bone marrow aspirate and biopsy in all patients. Post-treatment surveillance consisted of computed tomography scans and unilateral bone marrow biopsy 3 months after therapy and annually thereafter.
Historical Control Group For the purposes of comparison with patients who received high-dose therapy in second remission, a historical control population was used. This population comprised 34 patients with follicular lymphoma (without evidence of transformation at any point in the course of the illness) treated at St Bartholomew's Hospital before the introduction of myeloablative therapy in 1985. All controls were aged less than 60 years and had received either chlorambucil or CY, vincristine, and prednisone as initial therapy and at the time of first recurrence.17
Definitions and Statistical Methods
Freedom From Progression Forty-one patients are alive without progression between 9 and 19 years, with recurrence documented in 60 patients (Fig 1). Fifty-five percent of patients were free of disease at 5 years (95% CI, 45% to 63%), and 48% were free of disease at 10 years (95% CI, 39% to 57%). There was no correlation between duration of freedom from progression and the quality of remission in which the therapy was administered (complete remission or partial remission), the numerical remission in which the therapy was administered, bone marrow status at the time of therapy, the number of previous treatments, or the time from diagnosis to initial therapy.
Survival With a minimum follow-up time of 9 years, 57 patients are still alive (Fig 2A); 64 patients have died, 20 without progression. Thirty-seven patients died as a result of recurrent lymphoma, and 27 patients died as a result of other causes, as shown in Table 2.
Seventy-one percent of patients were alive at 5 years (95% CI, 62% to 78%), and 54% of patients were alive at 10 years (95% CI, 45% to 62%). The survival time of patients treated in second remission was longer than the survival time of patients treated later in the course of the illness (P = .004; Fig 2B).
Comparison With Historical Controls
These mature data illustrate the survival pattern of patients with follicular lymphoma treated in a second or subsequent remission with myeloablative therapy supported by autologous bone marrow. Encouraging comparisons with historical controls aside, the results strongly suggest that prolonged freedom from recurrence may be achieved with this treatment and that there may be a plateau on the curve, albeit not becoming evident for 12 years. It is important to note that, although freedom from progression is statistically the same regardless of whether patients were treated in second or subsequent remission, the survival curves for these two groups are different. This reflects increased mortality in patients treated later in the disease, particularly in relation to second (if not secondary) malignancy (Fig 4), which is probably ascribable in part to the therapy. The longer survival of patients treated in second remission compared with patients treated later in the illness could also be because patients receiving myeloablative therapy in third or subsequent remission had already survived longer from the time of diagnosis.
Comparison of these results with the results of other series, usually with shorter follow-up, lends support to the suggestion that, if myeloablative therapy is to find continuing use in the management of follicular lymphoma, it should be administered in responding patients and no later than the second remission. A small randomized trial indicates that there is an overall survival advantage to using CY+TBI in second remission compared with conventional therapy,33 although the limited patient accrual failed to provide evidence that in vitro purging held any advantage over an unpurged graft. Similar data for myeloablative therapy in first remission are lacking.34-36 However, the maximum follow-up time in some of the recent phase III trials testing myeloablative therapy in first remission34-36 is not long, which may be significant because the plateau on the remission duration curve in this study did not become apparent until 12 years. It should also be noted that the patients described in this study received autologous marrow rather than peripheral-blood progenitor cells, which were not routinely being used to support myeloablative therapy at that time. Justifiable concern has been expressed about the life-threatening complication of myelodysplasia.21-27 The results of this analysis and those of the Groupe d'Etude des Lymphomes de l'Adulte36 and German Low-Grade Lymphoma Study Group25 randomized trials in patients in first remission show that the risk (with CY+TBI as the myeloablative regimen) is lower when CY is used early in the disease, presumably because of an overall lesser exposure to chemotherapy. Again, this supports consideration of myeloablative therapy earlier rather than later in the illness. However, the risk of treatment-related MDS or AML may be related not just to the amount of prior chemotherapy, but also to the specific regimens used.25 Other factors, including older age at the time of myeloablative therapy, the quantity of reinfused cells, and previous exposure to fludarabine and external-beam radiotherapy, have also been implicated in treatment-related MDS/AML risk.24,26,37 In most centers, CY+TBI has been replaced by carmustine, etoposide, cytarabine, and melphalan (BEAM); registry data indicate that the efficacy is the same, but the incidence of secondary MDS/AML is lower38 with the drug-only regimen. This is obviously important if the concept of myeloablative treatment is to be pursued. However, once again, it must be emphasized that the treatment failed for half of the patients and that the plateau, if it exists, did not appear for 12 years. There clearly remains much room for improving the myeloablative regimen, both to increase efficacy and to reduce toxicity. But is the treatment relevant or necessary now? Will rituximab render it redundant? The answers to both of these questions are not yet known. It is exciting and gratifying that randomized trials have shown an overall survival as well as progression-free survival advantage for the combination of chemotherapy and rituximab compared with chemotherapy alone as initial therapy for follicular lymphoma.28-30 Moreover, continuation of rituximab after chemotherapy or chemoimmunotherapy after the first recurrence is also extremely promising.39,40 It remains to be seen, with longer follow-up, how great the advantages will be. However, it is unlikely that the ultimate goal of treatment for follicular lymphoma is going to be realized yet. There are already patients for whom chemoimmunotherapy, as it is now perceived, has failed. The potential of different treatment modalities administered in sequence should be considered. The European Organisation for Research and Treatment of Cancer trial (recently closed to accrual) evaluating the use of BEAM preceded by and/or followed by rituximab in patients in second or subsequent remission should provide useful, additional information. A proposed trial, which would test chemoimmunotherapy followed by continuation of rituximab versus the same therapy complemented by BEAM, will further elucidate the role of myeloablative therapy for follicular lymphoma. An open mind is essential.
The authors indicated no potential conflicts of interest.
Conception and design: Ama Z.S. Rohatiner, Lee Nadler, Peter M. Mauch, T. Andrew Lister, Arnold S. Freedman Provision of study materials or patients: Ama Z.S. Rohatiner, John Apostolidis, John G. Gribben, Peter M. Mauch, T. Andrew Lister, Arnold S. Freedman Collection and assembly of data: Ama Z.S. Rohatiner, Andrew J. Davies, John Apostolidis, Donna Neuberg, Lee Nadler, John G. Gribben, Arnold S. Freedman Data analysis and interpretation: Ama Z.S. Rohatiner, Lee Nadler, Andrew J. Davies, John Apostolidis, Donna Neuberg, Janet Matthews, Arnold S. Freedman Manuscript writing: Ama Z.S. Rohatiner, Andrew J. Davies, John Apostolidis, T. Andrew Lister, Arnold S. Freedman Final approval of manuscript: Ama Z.S. Rohatiner, Lee Nadler, Andrew J. Davies, John Apostolidis, Donna Neuberg, Janet Matthews, John G. Gribben, Peter M. Mauch, T. Andrew Lister, Arnold S. Freedman
We acknowledge the contributions of the medical and nursing staff of St Bartholomew's Hospital (London, United Kingdom) and of the Dana-Farber Cancer Institute (Boston, MA).
published online ahead of print at www.jco.org on May 21, 2007. Supported by Cancer Research UK. Presented in part at the 9th International Conference on Malignant Lymphoma, June 8-11, 2005, Lugano, Switzerland. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Forstpointner R, Dreyling M, Repp R, et al: The addition of rituximab to a combination of fludarabine, cyclophosphamide, mitoxantrone (FCM) significantly increases the response rate and prolongs survival as compared with FCM alone in patients with relapsed and refractory follicular and mantle cell lymphomas: Results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood 104:3064-3071, 2004 31. Rohatiner AZ, Freedman A, Nadler L, et al: Myeloablative therapy with autologous bone marrow transplantation as consolidation therapy for follicular lymphoma. Ann Oncol 5:143-146, 1994 (suppl 2)[Medline] 32. Kaplan E, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1958[CrossRef] 33. Schouten HC, Qian W, Kvaloy S, et al: High-dose therapy improves progression-free survival and survival in relapsed follicular non-Hodgkin's lymphoma: Results from the randomized European CUP trial. J Clin Oncol 21:3918-3927, 2003 34. Deconinck E, Foussard C, Milpied N, et al: High-dose therapy followed by autologous purged stem-cell transplantation and doxorubicin-based chemotherapy in patients with advanced follicular lymphoma: A randomized multicenter study by GOELAMS. Blood 105:3817-3823, 2005 35. Lenz G, Dreyling M, Schiegnitz E, et al: Myeloablative radiochemotherapy followed by autologous stem cell transplantation in first remission prolongs progression-free survival in follicular lymphoma: Results of a prospective, randomized trial of the German Low-Grade Lymphoma Study Group. Blood 104:2667-2674, 2004 36. Sebban C, Mounier N, Brousse N, et al: Standard chemotherapy with interferon compared to CHOP followed by high-dose therapy with autologous stem cell transplantation in untreated patients with advanced follicular lymphoma: The GELF-94 randomized study from the GELA. Blood 108:2540-2544, 2006 37. 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Forstpointner R, Unterhalt M, Dreyling M, et al: Maintenance therapy with rituximab leads to a significant prolongation of response duration after salvage therapy with a combination of rituximab, fludarabine, cyclophosphamide, and mitoxantrone (R-FCM) in patients with recurring and refractory follicular and mantle cell lymphomas: Results of a prospective randomized study of the German Low Grade Lymphoma Study Group (GLSG). Blood 108:4003-4008, 2006 Submitted November 9, 2006; accepted April 4, 2007. This article has been cited by other articles:
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
