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Journal of Clinical Oncology, Vol 26, No 24 (August 20), 2008: pp. 4046-4047 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2008.17.9846
In ReplyClinical Hematology Division, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
Department of Paediatrics Oncology/Bone Marrow Transplantation, Bristol Royal Hospital for Children, Bristol, United Kingdom
Clinical Hematology Division, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
Department of Haematology, Asklepios Klinic St Georg, Hamburg, Germany We thank Koen W. Van Besien for his interest in our comparative analysis between reduced intensity conditioning (RIC) and myeloablative conditioning regimen in relapsed or refractory Hodgkin's lymphoma,1 and his careful review of the article. We completely agree that this study, like other retrospective multicenter analyses, may have important shortcomings: missing values are always one of the major limitations of retrospective registry studies and, although every effort is to be made to go back to the centers and obtain this missing information, sometimes these efforts are unsuccessful. This is of special importance in the present article, where we are dealing with a heavily pretreated population of patients who have a long prior medical history before undergoing the allogeneic procedure. To deal with missing data, we followed one of the approaches recommended in the literature, coding "missing" as a separate category for risk factors with a high frequency (> 10%) of missing values.2 This procedure has allowed us to keep as much data as possible for the multivariate analysis and to compare the results of the population of patients with a given missing data with the results of those with no missing information, ensuring that a selection bias is not being introduced.
The patient's age is known in all cases. In Table 1, age is not divided into three different categories but we are showing the number of patients In this analysis, carmustine, etoposide, cytarabine, and melphalan (BEAM) has been considered an RIC regimen because there have been some reports of autologous hematopoietic recovery in patients being treated with this conditioning regimen3 and due to the good results in terms of low transplantation-related mortality that the United Kingdom Co-operative Group has recently published in patients with lymphoproliferative disorders undergoing an allogeneic stem-cell transplantation.4 The definition of what is considered an RIC protocol is still a matter of debate at present, and the situation can be even more complicated if we consider the inclusion of the comorbidity index4 in the definition itself. What seems to be clear is that the intensity of immunosuppression and myelosuppression widely varies from one protocol to the other. In this sense, the Seattle protocol combining 2 Gy total-body irradiation (TBI) with or without fludarabine is mostly immunosuppressive, whereas the combinations of fludarabine plus different alkylating agents are basically myelosuppressive. The number of patients treated with the BEAM protocol in our series is low (eight patients, representing 4.7% of the whole series). We did perform the same analysis considering the BEAM patients in the myeloablative group. Results were not significantly different from those that have been published. Performance status and detailed information regarding the different types of conditioning regimen were not included in the original manuscript. With respect to the performance status at the time of transplantation, it was not statistically different between the two groups of patients: Eastern Cooperative Oncology Group performance status less than 2 in 75% of the patients treated with a myeloablative conditioning regimen and 80% of the patients in the RIC group. In the myeloablative group (n = 79), 39 patients (49%) received the combination of cyclophosphamide plus TBI, 18 patients (23%) received busulfan plus cyclophosphamide, and 22 patients (28%) received other chemotherapy-containing protocols. In the RIC group (n = 89), the vast majority of the patients received allograft with fludarabine-containing regimens: fludarabine plus melphalan, 30 patients (33%); fludarabine plus cyclophosphamide, 23 patients (26%); fludarabine plus busulfan, 12 patients (13%); and other combinations, nine patients (10%). Only seven patients (8%) received low-dose TBI in the conditioning regimen. Although the number of patients treated with low-dose TBI was low, all of them experienced relapse after transplantation and died as a result of disease progression. Intensity of conditioning regimen seems to be important, taking into account the heavily pretreated and sometimes refractory population of patients who are included in allogeneic protocols, as has been indicated by others.5 AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. REFERENCES
1. Sureda A, Robinson S, Canals C, et al: Reduced-intensity conditioning compared with conventional allogeneic stem-cell transplantation in relapsed or refractory Hodgkin's lymphoma: An analysis from the Lymphoma Working Party of the European Group for Blood and Marrow Transplantation. J Clin Oncol 26:455-462, 2008 2. Klein JP, Rizzo JD, Zhang MJ, et al: Statistical methods for the analysis and presentation of the results of bone marrow transplants. Part 2: Regression modelling. Bone Marrow Transplant 28:1001-1011, 2001[CrossRef][Medline] 3. Sorror M, Storer B, Sandmaier BM, et al: Hematopoietic cell transplantation-comorbidity index and Karnofsky performance status are independent predictors of mortality and morbidity after allogeneic nonmyeloablative hematopoietic cell transplantation. Cancer 112:1992-2001, 2008[CrossRef][Medline] 4. Laporte JP, Fouillard L, Douay L, et al: GM-CSF instead of autologous bone-marrow transplantation after the BEAM regimen. Lancet 338:601-602, 1991[CrossRef][Medline] 5. Anderlini P, Saliba R, Acholonu S, et al: Fludarabine-melphalan as a preparative regimen for reduced-intensity conditioning allogeneic stem cell transplantation in relapsed and refractory Hodgkin's lymphoma: The updated M. D. Anderson Cancer Center experience. Haematologica 93:257-264, 2008
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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16 years, 
45 years). Cytomegalovirus risk group as stated in Table 1 is only missing in 30 patients of 168 patients included in the analysis (17.9% of the series) and this percentage does not differ between the conventionally treated and the RIC group. It is true that disease stage at diagnosis and bulky disease at diagnosis are missing in 48% and 58% of the patients included, respectively. Disease stage at diagnosis had no impact on progression-free survival (PFS); patients with missing information for this factor did not significantly differ in terms of PFS from those with complete data. With respect to the presence of bulky disease at diagnosis, once again, there were no differences between those patients with complete data and those with missing information. In the multivariate analyses, bulky disease was identified as an adverse risk factor for PFS when compared with patients without bulky disease at diagnosis. Belonging to the "unknown" category did not have any impact on the outcome outlined before. Obviously, this finding is of no interest for the clinicians, but including "this missing category" is a strategy particularly useful in registry studies to avoid losing patients for the multivariate analysis models. 
