Defining Conditioning Regimens for BMT—Recognition of “Regimens of Intermediate Intensity”

Abstract

In their recent paper, Giralt et al. (2009) [1Giralt S. Ballen K. Rizzo D. et al.Reduced intensity conditioning regimen workshop: defining the dose spectrum. Report of a workshop convened by the Centre for International Blood and Marrow Transplant Research.Biol Blood Marrow Transplant. 2009; 15: 367-469Abstract Full Text Full Text PDF PubMed Scopus (558) Google Scholar] addressed the issue of defining the criteria for classifying a reduced-intensity conditioning (RIC) regimen. One of the reasons for addressing this question was to enable the transplant community to “perform adequate retrospective and prospective analyses of different regimens,” and for the comparison of the outcome following RIC compared to non-RIC regimens. Criteria for the definition of an RIC regimen included in this paper were “any regimen that does not require stem cell support for hemopoietic recovery and that results in low nonhematologic toxicity and mixed donor-recipient chimerism in a substantial population of patients in the early posttransplantation period.” As part of this work the authors categorized a number of regimens as RIC, but excluded the BEAM regimen. This classification is in agreement with the definitions of the European Blood and Marrow Transplant (EBMT) Lymphoma Working Party (LWP) who have also classified BEAM as a non-RIC regimen. We became interested in using BEAM conditioning for allogeneic bone marrow transplantation (BMT) because it was a regimen with a well-recognized efficacy as a conditioning regimen in autologous transplantation for lymphoma with a low toxicity profile (<5% nonrelapse mortality [NRM]). We have previously published our initial experience with BEAM-alemtuzumab regimen as a conditioning regimen prior to allogeneic stem cell transplantation (ASCT) for lymphoproliferative diseases [2Faulkner R. Craddock C. Byrne J.L. et al.BEAM-Alemtuzumab reduced intensity allogeneic stem cell transplantation for lymphoproliferative diseases: GVHD toxicity and survival in 65 patients.Blood. 2004; 103: 428-434Crossref PubMed Scopus (166) Google Scholar]. Similar to other RIC regimens, the NRM was <10% at 1 year, and effective long-term disease control was achieved. This was recognized in a recent paper from the EBMT LWP, who, in a retrospective analysis of RIC versus myeloablative transplants for Hodgkin lymphoma (HL), included BEAM in the RIC group because of the reported low NRM and good clinical outcome [3Sureda 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 Europen Group for Blood and Marrow Transplantation.J Clin Oncol. 2008; 26: 455-462Crossref PubMed Scopus (258) Google Scholar]. BEAM-alemtuzumab conditioning is now being used in 2 National Cancer Research Network (NCRN) Lymphoma trials in the UK (for mantle cell lymphoma and refractory Hodgkin disease). Although we have no problem with the nonclassification of BEAM-alemtuzumab as an RIC regimen by Giralt et al. [1Giralt S. Ballen K. Rizzo D. et al.Reduced intensity conditioning regimen workshop: defining the dose spectrum. Report of a workshop convened by the Centre for International Blood and Marrow Transplant Research.Biol Blood Marrow Transplant. 2009; 15: 367-469Abstract Full Text Full Text PDF PubMed Scopus (558) Google Scholar], and we agree that although it does not qualify under the “Champlin criteria,” the problem is that by default it becomes classified as a myeloblative regimen and grouped with regimens that have a high NRM, particularly in lymphoma. This same point was eloquently made in a recent paper by Marks et al. (2008) [4Marks R. Potthof K. Hahn J. et al.Reduced toxicity conditioning with Fludarabine BCNU and Melphalan in allogeneic haemopoietic cell transplantation: particular activity against advanced haematologic malignancies.Blood. 2008; 112: 415-424Crossref PubMed Scopus (76) Google Scholar], who have used a regimen comprising fludarabine (Flu), melphalan (Mel) (140 mg/m2), and BCNU (400 mg/m2) plus antithymocyte globulin (ATG) as a conditioning regimen for a variety of hematologic malignancies. These doses of BCNU and Mel are comparable to that used in BEAM. In their article, Marks et al. [4Marks R. Potthof K. Hahn J. et al.Reduced toxicity conditioning with Fludarabine BCNU and Melphalan in allogeneic haemopoietic cell transplantation: particular activity against advanced haematologic malignancies.Blood. 2008; 112: 415-424Crossref PubMed Scopus (76) Google Scholar] also reported a low NRM of 3.7% at 1 year in patients with early disease. Furthermore, this regimen had significant antileukemic efficacy in patients with advanced leukemia at transplant with event-free survival (EFS) of 40% at 5 years. These authors concluded that disease control by (Flu/Mel) was similar to myeloablative conditioning (MAC), but with regimen-related toxicities and NRM comparable to that seen with RIC regimens. We suggest that regimens such as BEAM-alemtuzumab and Fly-Mel/ATG, which combine low toxicity and NRM with significant antitumor efficacy should be classified as neither RIC nor myeloablative regimens, but “regimens of intermediate intensity” or “toxicity-reduced conditioning” regimens. This is particularly important in avoiding the categorization of such regimens as “myeloablative” in registry comparisons of outcome of RIC versus myeloblative-conditioned transplants.