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Journal of Clinical Oncology, Vol 23, No 25 (September 1), 2005: pp. 6264-6266 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.01.6360
In Reply:Department of Internal Medicine III, Ludwig-Maximilians University, Munich Grosshadern, Germany We would like to thank Dr Nabhan for his comments regarding our report on the incidence of secondary hematologic neoplasias following myeloablative radiochemotherapy and autologous stem-cell transplantation in indolent lymphoma.1 These data have to be interpreted in the context of currently available data as well as the course of the disease and the patients perspectives. Regarding the currently available data, the authors strongly disagree with the statement that the value of myeloablative radiochemotherapy with subsequent stem-cell transplantation (ASCT) for first-line therapy of indolent lymphomas is "still nebulous." The results of three large randomized trials are available. The trials compare ASCT with conventional therapy,2-4 and all three trials show a significant prolongation of the duration of remission. While in the study of the German Low Grade Lymphoma Study Group (GLSG) the follow-up is still too short to definitively assess the impact of ASCT on overall survival,2 a significant prolongation of survival was reported by the Groupe d'Etude des Lymphomes de l'Adulte (GELA) study.3 In the trial by Groupe Ouest Est des Leucemies et des Autres Maladies du Sang (GOELAMS),4 the overall survival was not different, due to a rather high rate of secondary myelodysplastic syndromes (MDS) and acute myeloid leukemias (AML) being as high as 7%. These data show that the concern about late MDS and AML is certainly justified. When looking at the three trials in more detail, however, remarkable differences become evident: in the GELA study, no MDS/AML occurred; in the GOELAMS study, the incidence was 7%; and in the GLSG trial, it was 3.8%. In all three trials, similar conditioning regimens were used including total-body irradiation. Hence, it seems that the observed differences may be due to different forms of pretransplantation chemotherapy rather than to the procedure itself. This conclusion is supported by a more detailed analysis of the GLSG trial indicating that secondary MDS/AML occurred in 5.1% of patients receiving initial therapy by a combination of mitoxantrone, chlorambucil, and prednisone (MCP) as compared with only 1.0% after induction therapy with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone). Thus, applying one of the most commonly used first-line regimens, the risk of 1% of secondary MDS/AML seems to be well balanced with respect to the 30% gain of 5-year progression-free survival. In addition, one must be careful in relating secondary MDS/AML predominantly or even exclusively to ASCT, neglecting the preceding therapies. In this context, it seems inappropriate to consider such risk "neglible" after radioimmunotherapy since no controlled data are yet available. Furthermore, comparing the results of three large multicenter trials with a promising phase II study seems inappropriate. Although the authors strongly agree that the report by Kaminski et al demonstrated very promising results,5 we would like to cite the following from the accompanying editorial: "the report... describes the outcome for a highly selected group of younger-than-average patients with a low-to-moderate tumor burden and a slowly progressive disease..."; and further, "Sufficient to claim that patients are being cured? No ... Sufficient to justify adoption ... as primary treatment for follicular lymphoma? No. Sufficient to justify additional clinical trials? Yes."6
According to GLSG criteria, most patients entering the radioimmunotherapy trial would probably not have been treated. In this context, we regret that the description of our entry criteria may have been not clear enough. We therefore like to point to the respective parts of the article indicating that patients had to have advanced-stage disease and had to require therapy as defined by the presence of "B" symptoms and/or hematopoietic insufficiency (granulocytopenia < 1,500/µL, anemia < 10 g/dL, thrombocytopenia < 100,000/µL) and/or rapidly progressive disease as defined by 50% progression in the past 6 months and/or bulky disease (largest diameter > 5 cm). In addition, patients with seriously impaired cardiac, pulmonary, hepatic (ALT/AST No detailed data are currently available for patients receiving ASCT after relapse on the interferon alfa maintenance arm. However, the recently published CUP trial reported an improved PFS and overall survival after ASCT as compared with conventional therapy in relapsed follicular lymphoma demonstrating the efficacy of ASCT in relapsed disease as well.7 The authors agree with Dr Nabhan that combining chemotherapy with the anti-CD20 antibody Rituximab reveals very promising results.8,9 To our knowledge, no data have been reported to date about secondary MDS/AML. Preliminary data by the GLSG, however, suggest that ASCT following a combined immunotherapy may add to the long-term outcome.9 In conclusion, we consider myeloablative radiochemotherapy followed by ASCT as an effective treatment option for young patients (< 65 years) with advanced-stage indolent lymphoma since it significantly improves progression-free survival and, potentially, overall survival. Especially after a CHOP-like induction therapy, the increase of secondary hematologic neoplasias is moderate and acceptable. As new approaches such as the combination of chemotherapy with monoclonal antibodies such as rituximab are implemented in multimodal approaches, the role of ASCT may have to be redefined. It may become unnecessary; however, it may also remain an essential tool in the still limited armentarium of therapeutic options for advanced-stage indolent lymphomas. The potential risk of secondary hematologic malignancies should not be overestimated and should not preclude the application of this effective treatment measure to young high-risk patients with follicular lymphomas today. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest. REFERENCES
1. Lenz G, Dreyling M, Schiegnitz E, et al: Moderate increase of secondary hematologic malignancies after myeloablative radiochemotherapy and autologous stem-cell transplantation in patients with indolent lymphoma: Results of a prospective randomized trial of the German Low Grade Lymphoma Study Group. J Clin Oncol 22:4926-4933, 2004
2. 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 3. Sebban C, Coiffier B, Belanger C, et al: A randomized trial in Follicular lymphoma comparing a standard chemotherapy regimen with 4 courses of CHOP followed by autologous stem cell transplantation with TBI: The GELF94 trial from GELA. Hematol J 4:150, 2003 (abstr)
4. 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 the GOELAMS. Blood 105:3817-3823, 2005
5. Kaminski MS, Tuck M, Estes J, et al: 131I-tositumomab therapy as initial treatment for follicular lymphoma. N Engl J Med 352:441-449, 2005
6. Connors JM: Radioimmunotherapy: Hot new treatment for lymphoma. N Engl J Med 352:496-498, 2005
7. 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
8. Marcus R, Imrie K, Belch A, et al: CVP chemotherapy plus rituximab compared with CVP as first-line treatment for advanced follicular lymphoma. Blood 105:1417-1423, 2005 9. Hiddemann W, Dreyling MH, Forstpointner R, et al: Combined immuno-chemotherapy (R-CHOP) significantly improves time to treatment failure in first-line therapy of Follicular lymphoma: Results of a prospective randomized Trial of the German Low-Grade Lymphoma Study Group (GLSG). Blood 102:352, 2003 (abstr) Related Correspondence
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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3x upper limits and/or bilirubin 
