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Originally published as JCO Early Release 10.1200/JCO.2003.07.981 on September 29 2003 © 2003 American Society for Clinical Oncology
High-Dose Therapy for Follicular Lymphoma Revisited: Not If, but When?St Bartholomew’s Hospital, London, UK THE JUDICIOUS use of relatively innocuous chemotherapy resulting in the familiar, tantalising clinical course of follicular lymphoma, recognizable by a remitting recurring course over several years, has made the illness an obvious target for testing the ‘more is better’ hypothesis. Half a century ago, it was shown that chlorambucil given continuously in low doses resulted in remissions in the majority of cases, benefit being observed within six weeks.1,2 A quarter of a century ago, the first comparative trials were undertaken. In essence it was shown that combination chemotherapy and prolongation of therapy yielded higher response rates and longer first remissions than short-term alkylating agents alone, but with no improvement in overall survival,3–10 because no plateau appeared on the freedom from recurrence curves and the illness was repeatedly responsive to therapy. Much more recent studies of more intensive, but nonmyeloablative chemotherapy report the attainment of molecular as well as clinical remission.11 There is, however, still no evidence for cure. With the indication that myeloablative chemotherapy or chemoradiotherapy supported by autologous bone marrow rescue might be curative for patients with chemosensitive recurrent aggressive lymphoma,12 phase II trials of cyclophosphamide and total-body irradiation began in selected patients with follicular lymphoma who had had at least one recurrence.13–17 In some patients, the bone marrow harvest was treated in vitro with monoclonal antibodies and complement to deplete it of potential contamination with lymphoma. Molecular remissions were reported to occur and appeared to confer an advantage in freedom from progression.14,17 Early results were promising, and as the procedure became safer with the introduction of peripheral-blood progenitor cell rescue to reduce the length of aplasia,18,19 the popularity of the procedure transiently soared. The procedure was also tested in first remission20–23 and the results have been variously and prematurely interpreted. Even by comparison with historic controls, despite markedly improved freedom from progression and hints of durable response for patients in continuing molecular remission, no survival advantage has been shown, possibly as a function of a disturbing incidence of myelodysplasia.24–29 Hence, for those who have championed the therapy, important results of a randomized trial are presented in this issue of the Journal of Clinical Oncology.30 One hundred forty patients were recruited from 36 centers over a 5 year period. First-line therapy for follicular lymphoma had failed in them all, and they were re-treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). Those entering complete or partial remission were randomly assigned to proceed either to three more cycles of CHOP, or cyclophosphamide and total-body irradiation with hematopoietic stem cell rescue, with or without in vivo purging. The limited accrual precluded any analysis of the benefit of purging, but a significant advantage in terms of both progression-free and overall survival was demonstrated for those receiving high-dose therapy as opposed to CHOP. It is clearly possible to criticize the major conclusion on the basis of the patient selection, reflected in the small number of patients accrued and the even smaller number randomized; however, these issues are addressed in the article. When read within the context of the long follow-up of the open phase II studies14 and the data from the Groupe Etude Lymphome d’Adultes trial31 in patients in first remission, the positive results should be heeded carefully, and the negative ones should be treated with caution. Even if the therapy does not translate into cure, which it does not, at least for a considerable proportion of patients, it appears to have altered the clinical course of the disease from the time of first treatment failure. Such observations do not occur frequently. The issue of the efficacy of in vitro purging may have become irrelevant with the increasing evidence that at least short-term in vivo purging may be achieved with monoclonal antibodies. A large European Bone Marrow Transplant trial is addressing the role of rituximab before stem cell harvest preceding BCNU, etoposide, cytarabine and melphalan, and also afterwards. Additionally, the significance of molecular remission is likely to become clearer as more data are generated using standardized techniques of quantitation of the polymerase chain reaction product. Will these results reverse the recent trend away from the use of myeloablative treatment for follicular lymphoma? This will depend on how much they fulfill the prejudices of physicians and also how a treatment, which found much favor up until 5 years ago but with declining recent popularity, fits into the myriad of newer treatments which have appeared in the meantime. Interferon alfa passed the test of conferring a survival advantage when given with moderately intensive chemotherapy in a randomized study,32 with subsequent confirmation in the report of a large meta-analysis,33 but it has not become accepted as a component of "best standard of care." Although much has to be learned about antibody therapy,34–36 antibody with chemotherapy37 has almost become routine initial therapy for follicular lymphoma in the United States. In addition, targeted irradiation is yielding provocative results,38–40 large trials of vaccine therapy are in hand, and there is guarded excitement about the graft-versus-lymphoma effect of reduced intensity allogeneic transplantation.41,42 At the beginning of the 21st century, we are fortunate to have so many alternative ways to treat follicular lymphoma. It is without a doubt that in some circumstances it is possible to induce molecular as well as clinical remission, and this is likely a good thing to do. All treatments are clearly not appropriate for all patients, but we are gradually getting better at creating prognostic indices,43 which will help us to select treatment. The challenge is to see if, with all the treatments we currently have, it is now possible to cure the disease, and if not, what the best algorithm of care is. Today it would seem that the question about high-dose therapy is not "if," but "when," and for whom. AUTHOR’S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author indicated no potential conflicts of interest. REFERENCES
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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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