Bone Marrow Transplantation (2002) 29, 191–195 2002 Nature Publishing Group All rights reserved 0268–3369/02 $25.00 www.nature.com/bmt Special report Second EBMT Workshop on reduced intensity allogeneic hemopoietic stem cell transplants (RI-HSCT) A Bacigalupo Divisione Ematologia II Ospedale San Martino, Genova, Italy Summary: from AMGEN Europe, held a Workshop in Zurich on allo- geneic transplantation following non-myeloablative con- A second meeting on reduced intensity allogeneic stem ditioning. Tentative conclusions drawn from the 1999 cell transplants (RI-HSCT) was convened in Zurich in EBMT/AMGEN Workshop were published (1) and were February 2001 and focused on transplant-related mor- as follows: tality (TRM) and graft-versus-host disease (GVHD). Retrospective and prospective studies from the EBMT, • The term ‘minitransplant’ is probably misleading and national groups and single institutions included over reduced intensity allogeneic hematopoietic stem cell 900 patients: the incidence of acute GVHD grade III– transplantation (RI-HSCT) is preferred. IV was 12% (1–17%), extensive chronic GVHD 42% • RI-HSCT is an experimental procedure. (25–51%) and TRM 20% (14–38%). Conditioning regi- • RI-HSCT involves the use of normal donors and ethical mens could be classified into four major groups based issues apply as with any allogeneic transplant. on (1) total body irradiation (TBI) 200 cGy, (2) busulfan • Donors should be carefully evaluated because their 8 mg/kg, (3) thiotepa 10 mg/kg, and (4) melphalan 140 (probable) older age exposes them to an increased risk mg/m2: most of these regimens are given in association of complications. with fludarabine in different doses and use mobilized • At present, RI-HSCT should be offered to patients who peripheral blood as a source of stem cells. The incidence are otherwise not eligible for conventional allogeneic of TRM is similar if not identical for all four regimens, HSCT. whereas the risk of acute GVHD and chronic GVHD • Acute leukemia and myelodysplastic patients are prob- may vary with different protocols. Reduced intensity ably not good candidates for RI-HSCT. transplant programs are being explored in patients • RI-HSCT may be appropriate in chronic disorders such above the age of 60 and in patients with solid tumors: as chronic lymphoproliferative diseases. Chronic encouraging results are being recorded in individual myeloid leukemia (CML) should be studied. patients. Overall these data confirm that allogeneic • Multiple myeloma (MM) patients may pose particular HSCT can be performed in elderly patients, although a problems. TRM of approximately 15% must be expected and is • It remains to be determined whether RI-HSCT is ben- age dependent. A high rate of extensive chronic GVHD eficial in patients with solid tumors. is seen and should be followed carefully. The term mini- • Immune reconstitution should be investigated further. or micro-transplant is probably misleading and one should refer to this procedure as an allogeneic HSCT With these conclusions in mind a second Workshop was and further classify the intensity of the conditioning organized 2 years later by EBMT together with AMGEN. regimen. We now report the outcome of the second Workshop. Bone Marrow Transplantation (2002) 29, 191–195 DOI: 10.1038/sj/bmt/1703355 Keywords: reduced intensity conditioning regimen; Retrospective studies hemopoietic stem cell transplants; graft-versus-host disease The Acute and Chronic Leukemia Working Party of the EBMT analyzed 154 acute leukemia and 270 chronic leuke- mia patients receiving reduced intensity transplants. France- In February 1999, the European Group for Blood and Mar- sco Frassoni and Jane Apperley presented the data. Median row Transplantation (EBMT), with an educational grant age was 50 years: TRM was 20% for the acute leukemias and 22% for the chronic leukemias, the incidence of severe Correspondence: Dr A Bacigalupo, Divisione Ematologia 2 (PAD 5/II), grade III–IV acute GVHD was 10% and 14%, respectively, Ospedale San Martino, Largo Rosanna Benzi 10, 16132 Genova, Italy and extensive chronic GVHD was 40% in both groups. The Received 18 June 2001; accepted 23 August 2001 outcome of 58 chronic myeloid leukemia (CML) patients Second EBMT Workshop on RI-HSCT A Bacigalupo 192 was comparable. The French and Italian Groups for Mar- cyclophosphamide (CY) 60 mg/kg as proposed by the row Transplantation (SFGM and GITMO) presented 92 and French SFGM group, TBI 400 cGy + FLU 90 mg/m2 + CY 44 patients, respectively, with a median age of 50 and 52 60 mg as proposed by the Munchen group, TBI 100 cGy years, and a TRM of 38% and 14%. Overall, these presen- + thiotepa (THIO) 10 mg/kg + CY 100 mg/kg as proposed tations comprised 969 patients with an average age of 47.7, by the Genoa group, and finally melphalan (MEL) 200 an average follow-up of 300 days, with medians ranging mg/m2 for a first autograft followed by TBI 200 cGy + from 244 to 814 days: the majority of them achieved full FLU 90 mg/m2 proposed for myeloma patients as will be donor chimerism (79%). Severe acute GVHD developed in discussed later. 12% and extensive chronic GVHD in 42% of patients. The average transplant-related mortality was 20%, which may Busulfan 8 mg/kg + FLU 125 mg/m2 + antithymocyte be considered low for a cohort of patients with advanced globulin (ATG) age and advanced disease. This was first described by Slavin and coworkers in 1998.4 The original publication included 26 patients receiving Immunosuppressive conditioning regimens HLA-identical sibling peripheral blood cells following the BU + FLU + ATG regimen. With a median follow-up of Immunosuppressive regimens involve the use of agents 240 days and a median age of 33 the TRM was 15%, and with no significant long-term toxic effect on stem cells, severe acute and chronic GVHD was 15% and 34%. Vari- such as cyclophosphamide, fludarabine and antibodies ations on this protocol presented in Zurich included BU 4 against T cells. CY alone has been used in over 5000 mg/kg + FLU 150 mg/m2 + ATG proposed by the French patients with non-malignant disorders, who were not dis- SFGM and BU 8 mg/kg + FLU 150 mg/m2 + CY 120 cussed at the Workshop. The combination FLU-CY first mg/kg. Shimon Slavin reported on the Workshop held earl- described by Khouri and coworkers,2 was discussed for ier this year and suggested that the original BU 8 + FLU Hodgkin’s disease and for solid tumors, without specific 125 + ATG protocol will be compared with BU 8 + FLU update. Because this regimen relies entirely on the immuno- 125 + CAMPATH 1H, to test whether a reduction in acute logic effect of the graft, most programs in Europe at present and chronic GVHD could be obtained. include one or more agents with some depleting effect on stem cells and therefore also on the tumor. Thiotepa 10 mg/kg + cyclophosphamide 100 mg/kg Thiotepa has been extensively used by M Martelli and Reduced intensity conditioning regimens coworkers in Perugia for mismatched grafts in conjunction with TBI and cyclophosphamide.5 More recently this group Reduced intensity regimens involve the use of agents toxic was the first to introduce fludarabine in the conditioning for stem cells and tumor cells, such as busulfan or total regimen.6 The program without TBI (THIO-CY) was body radiation, but in reduced doses as compared to a con- described in 1996 with THIO 15 mg/kg + CY 150 mg/kg7 ventional transplant. The regimens presented at the Work- followed by HLA-identical PB grafts. The reduced intensity shop could be divided into four major groups, most of them version THIO10 + CY100 was recently published in combined with fludarabine. extenso.8 Forty-four patients were grafted in Genova, Fir- enze, Torino, Milano and presented at EBMT 2001.9 The Total body irradiation (TBI) 200 cGy median age was 52 years and median follow-up 814 days. Acute GVHD was low (2%), possibly because post-graft This program was originally described by Storb and CsA + methotrexate (MTX) was not discontinued early, as coworkers,3 and is also being explored in Leipzig, Germany reported in other studies. The rate of extensive chronic as well as other transplant centers in the USA and in Eur- GVHD was also low (25%) possibly for the same reason. ope. A summary was given by Dietger Niederwieser on 109 The overall TRM was 14%: it was 9% in patients receiving patients receiving TBI 200 cGy and fludarabine followed bone marrow grafts (BM) and 18% in patients receiving by unmanipulated peripheral blood (PB) cell transplants PB grafts. A variation of this regimen included THIO 10 from HLA-identical siblings, and GVHD prophylaxis with mg/kg + CY 60 mg/kg + FLU 60 mg/m2 developed by cyclosporin (CsA) and mycofenolate mofetyl (MMF). The Paolo Corradini in Milano10 and used for lymphoma median age was 50 (18–71), the median follow-up 241 patients, with very low TRM (6%). The latter protocol is (100–934) days. There was no need for hospitalization in now being used in Italy (GITMO) for low-grade lym- many patients, although some patients required admission phomas. Another variation is THIO 10 mg/kg + FLU 120 to hospital for prolonged periods of time. Consistent with mg/m2 used in patients with myelodysplasia. this is the fact that cGVHD developed in the extensive form in 50% of the patients. This may be due to several causes, Melphalan (MEL) 140 mg/m2, fludarabine 150 mg/m2 and among which are the use of unmanipulated PB transplants CAMPATH 1H in all patients, old age, and early reduction or discontinu- ation of CsA. Overall TRM was low (15%) and pro- This was originally described11 by S McKinnon: 44 patients gression-free survival at 2 years 43%.