Special Report Second EBMT Workshop on Reduced Intensity Allogeneic Hemopoietic Stem Cell Transplants (RI-HSCT)

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 allogeneic 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 leukemia 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 discontinuation 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%. Variations of the with lymphoma were grafted with this regimen in the UK, original TBI 200 cGy regimen include the addition of flud- their median age was 41 (18–56) and median follow-up 365 arabine (FLU) 90 mg/m2 as described, TBI 500 cGy + days (60–870). In this regimen grade III–IV acute GVHD

Bone Marrow Transplantation Second EBMT Workshop on RI-HSCT A Bacigalupo 193 and extensive chronic GVHD were virtually absent, poss- cGy, is unknown at present. However, we do have consist- ibly as a consequence of using CAMPATH 1H in the con- ent data on conventional transplant in myeloma, and very ditioning regimen. TRM was 16% and progression-free sur- little data on reduced intensity transplants, which should vival at 2 years 66%. An update on 74 patients was still be considered investigational in young patients. discussed with similar results. The study is being extended to other UK centers. Lymphoma If we now compare results obtained with these four regimens in over 200 patients, one can appreciate some simi- Norbert Schmitz reported 147 patients allo-grafted in 34 larities and some diversities. The latter were median patient transplant centers, 80 of whom had received a prior auto- age (older in the TBI2 and THIO-CY programs) and graft. A high relapse rate (60% at 2 years) suggested that median follow-up (longer in the THIO-CY). Also different reduced intensity conditioning in advanced and/or high was the incidence of acute GVHD grade III–IV and exten- grade lymphomas is unlikely to be successful. Progression- sive chronic GVHD, lower in programs using either con- free survival (PFS) at 2 years was superior in patients with ventional 6–12 months in vivo immunosuppression or chemosensitive disease, as compared to patients with chem- CAMPATH 1H. However, transplant-related mortality was oresistant disease (30% vs 10%; P Ͻ 0.0001). A state of comparable if not identical, ranging between 14% and 15%. remission or minimal residual disease prior to RI-HSCT This suggests that we can allograft older patients with might be desirable in patients with lymphoma. Some cen- advanced disease, with a 15% mortality. Although some ters in Europe will be using a melphalan + FLU or FLU + data on other outcome measures such as survival and CY regimen for poor risk Hodgkin’s disease (patients with relapse were presented, it is probably better to restrict the early relapse or patients not entering complete remission). present discussion mainly to GVHD and TRM, also In Italy a GITMO trial in patients with low grade non- because of the patient heterogeneity. Hodgkin’s lymphomas is being coordinated by Paolo Cor- radini: the primary end point is molecular remission. Cen- ters in the UK are going to explore the association of MEL Specific disease-related programs + FLU + CAMPATH under the coordination of University College London. Finally, the French group is exploring a Solid tumors (ST) regimen based either on BU 8 or TBI 500 in patients with lymphoma. The solid tumor experience was summarized by Giovanni Rosti and showed an increased interest in allogeneic HSCT for this indication: 20 patients grafted in 1998, 47 in 1999 Chronic lymphocytic leukemia (CLL) and 97 in 2000. Within the ST Working Party, Dieter Nied- Mauricette Michallet presented data on 14 CLL patients erwieser is responsible for the allogeneic program and Olle prepared for an allograft with fludarabine and an alkylating Ringden, in particular, for renal cell carcinoma. Nine renal agent (either BU or MEL): at a median follow-up of 7 cell carcinoma patients were grafted using the TBI 200 cGy months TRM was 7% and GVHD was seen in 47% of regimen and two are alive and well. Felipe Prosper patients. CLL patients are being entered in programs presented protocols for breast cancer, colon cancer, mela- designed for low grade lymphomas. noma, ovarian cancer, and biliary tree neoplasms. It is probably too early to give a clear message on the role of allogeneic RI-HSCT in patients with solid tumors. Some High risk leukemia and myelodysplasia (MDS) responses are being recorded in breast cancer and renal cell It may be difficult to maintain remission in patients with carcinoma. Results in melanoma seem to be less encour- fast pace disease, such as acute leukemia in relapse or trans- aging. It would seem wise to assess the role of allograft formed MDS. Indeed there are little data available for these from HLA-identical sibling transplantation before indications, and disappointing results were also presented expanding the program to unrelated donors. at ASH.12 Some of these patients were included in the TBI 200 cGy regimens, in the BU 8 mg/kg or the THIO 10 Myeloma mg/kg regimens. There was no specific program described for patients with acute lymphoblastic leukemia. Ghosta Gahrton presented the outcome of allogeneic HSCT in myeloma: results have improved considerably with time, such that mortality has now been halved to less than 25%. Specific transplant procedures and GVHD An EBMT study was presented in which patients are first autografted with melphalan 200 mg/m2, and then, in the Allogeneic transplants after RI conditioning are designed presence of an HLA-identical sibling, they are offered an to reduce toxicity and exploit the immune effect of the allograft using the TBI 200 cGy + FLU regimen. This pro- graft: for this reason many programs call for discontinu- gram derives from the Seattle program for patients with ation of in vivo immunosuppression as early as day +60 myeloma. It was not entirely clear which patients would be after HSCT, and/or infusion of donor lymphocytes (DLI) eligible for this trial: the protocol reads 18–65 years of age. to maximize this effect. The difficulty of bringing this into Whether a 35-year-old patient with myeloma should practice is shown by the TBI 200 cGy regimen which was undergo a conventional allogeneic HSCT or an autograft designed to give DLI to all patients, but which ended up with melphalan 200 followed by an allograft with TBI 200 by infusing lymphocytes in only approximately 10% of

Bone Marrow Transplantation Second EBMT Workshop on RI-HSCT A Bacigalupo 194 the patient population. This is mainly due to the fact that or melphalan 140 mg/m2, most of them in combi- older age and early discontinuation of CsA cause severe nation with fludarabine. Variations of these four regi- acute GVHD in 15–20% of all cases and makes DLI mens are described. impossible. The factors in PB allografts also induce exten- (6) Extensive chronic GVHD is seen in a considerable sive chronic GVHD in approximately half of patients, proportion of patients and should be carefully moni- which is good for disease control, but less so for quality tored: guidelines for long-term effects have been of life. In a study of the French group SFGM, early dis- developed by EBMT and should be followed. continuation of CsA had a significant negative impact (7) Reduced intensity programs are being optimized and on survival. tested in selected indications including unrelated Programs involving CAMPATH 1H in conditioning were donor transplants. followed by little or no acute or chronic GVHD: whether (8) The comparison with conventional programs will this is desirable remains to be determined. However, pre- probably be tested. vention seems the most effective way to manage GVHD, (9) As in 1999, it was agreed that the term ‘minitran- since treatment is currently unsatisfactory. splant’ is misleading for patients and physicians: we may want to refer to this procedure as an allogeneic hematopoietic stem cell transplant (HSCT) and the Unrelated donor transplants conditioning regimen may be further classified. (10) Donor complications were not described, although The largest series reported is from Seattle/ Leipzig with 41 older age calls for particular care. patients receiving TBI 200 cGy + FLU 90 mg/m2. Median (11) The next Workshop in 2003 will bring further results age was 48 (6–65), 34 were PB and seven BM transplants. and indications on best strategies. Engraftment was achieved in 37 patients. Acute GVHD grade II–IV was seen in 62% and TRM in 7/41 patients Finally, reducing the intensity of the conditioning regi- (17%) at a median follow-up of 185 days (5–471). The men is one way of minimizing toxicity. Other ways are median duration of CsA treatment was 6 months. Recently, being explored, among which is graft engineering with the BU 8 + FLU 125 + ATG regimen of Shimon Slavin expanded cell sub-populations (such as mesenchymal stem has also been explored in 16 young patients (median age cells) which may then be infused in conjunction with hemo- 17) grafted from unrelated donors:13 three patients poietic stem cells, following conventional or intensified conditioning regimens. We will also be awaiting results of developed grade III–IV acute GVHD, and three died of 14 transplant-related complications. Although these are rela- these studies, some of which seem promising. tively early results, they indicate that alternative transplants can be performed in some patients with reduced intensity conditioning. This may be particularly appealing in patients Acknowledgements with non-malignant diseases. An ongoing program of the EBMT Severe Aplastic Anemia Working Party calls for This Workshop was organized with an unrestricted educational FLU 120 mg/m2 + CY 1200 mg/m2 + ATG followed by grant from AMGEN Europe. I am grateful to my co-chairpersons + Shimon Slavin and Francesco Frassoni for their contribution, as unmanipulated marrow and CsA MTX post transplant: it well as to all discussants: Jane Apperley, Paolo Corradini, Ghosta has enrolled 12 patients and eight are alive and well, with Gahrton, Anthony Goldstone, Mauricette Michallet, Dietger Nied- full donor chimerism, and little or no GVHD. erwieser, Felipe Prosper, Olle Ringden, Giovanni Rosti, Norbert Schmitz, Shimon Slavin, Alvaro Urbano Ispizua.

Lessons from the 2001 Workshop References Some tentative conclusions from the 2001 Workshop are as follows: 1 Bacigalupo A. Hematopoietic stem cell transplants after reduced intensity conditioning regimen (RI-HSCT): report of a workshop of the European Group for Blood and Marrow (1) Reduced intensity allogeneic HSCT can now be per- Transplantation (EBMT). Bone Marrow Transplant 2000; 25: formed with relatively low toxicity in patients over 803–805. the age of 50. 2 Khouri IF, Keating M, Korbling M et al. Transplant lite: (2) There is, however, an ‘age effect’ in almost all pro- induction of graft versus malignancy using ﬂudarabine based grams, when reported, and patients above 50 do worse non ablative chemotherapy and allogeneic blood progenitor than patients below 50 years. cell transplantation as treatment for lymphoid malignances. J (3) The preferred stem cell source is peripheral blood: a Clin Oncol 1998; 16: 2817–2824. prospective randomized trial is under way to compare 3 Storb R, Yu C, Sanmeier BM et al. Mixed hemopoietic chim- blood and marrow in this setting. erism after marrow allografts. Transplantation in the ambulat- ory care setting. Ann NY Acad Sci 1999; 872: 372–375. (4) The preferred GVHD prophylaxis is CsA + MTX or + 4 Slavin S, Nagler A, Naparstek E et al. Nonmyeloablative stem CsA MMF. ATG or CAMPATH antibodies are used cell transplantation and cell therapy as an alternative to con- in some programs, and reduce the risk of GVHD. ventional bone marrow transplantation with lethal cytoreduc- (5) There are four major conditioning regimens based on tion for the treatment of malignant and nonmalignant hemato- TBI 200 cGy, busulfan 8 mg/kg, thiotepa 10 mg/kg logic diseases. Blood 1998; 91: 756–763.

Bone Marrow Transplantation Second EBMT Workshop on RI-HSCT A Bacigalupo 195 5 Aversa F, Tabilio A, Terenzi A et al. Successful engraftment allografted from HLA-identical siblings. Bone Marrow Trans- of T-cell-depleted haploidentical ‘three-loci’ incompatible plant 2001; 27: S282. transplants in leukemia patients by addition of recombinant 10 Corradini P, Bregni M, Tarella C et al. Allografting for high- human granulocyte colony-stimulating factor-mobilized per- risk hematological and solid tumors: reduced intensity chemo- ipheral blood progenitor cells to bone marrow inoculum. therapy followed by the reinfusion of lymphocytes engineered Blood 1994; 84: 3948–3955. with thymidine kinase (TK) gene. Bone Marrow Transplant 6 Aversa F, Tabilio A, Velardi A et al. Treatment of high-risk 2000; 25: S134. acute leukemia with T-cell-depleted stem cells from related 11 Kottaridis PD, Chakraverty R, Milligan DW et al. A non-mye- donors with one fully mismatched HLA haplotype. New Engl loablative regimen for allogeneic stem cell transplantation JMed1998; 339: 1186–1193. with a low incidence of GVHD. Bone Marrow Transplant 7 Bacigalupo A, van Lint MT, Valbonesi M et al. Thiotepa 2000; 25: S26. cyclophosphamide followed by granulocyte colony-stimulat- 12 Uberti J, Ayash L, Reynolds C et al. Lower intensity of pre- ing factor mobilized allogeneic peripheral blood cells in adults parative regimen for allogeneic stem cell transplantation from with advanced leukemia. Blood 1996; 88: 353–357. related donor in patients with advanced hematologic malig- 8 Raiola AM, van Lint MT, Lamparelli T et al. Reduced inten- nancy is associated with poor outcome. Blood 2000; 96: sity thiotepa–cyclophosphamide conditioning for allogeneic 201a (Abstr.). hemopoietic stem cell transplants (HSCT) in patients up to 60 13 Nagler A, Aker M, Or R et al. Low-intensity conditioning years of age. Br J Haematol 2000; 109: 716–721. is sufﬁcient to ensure engraftment in matched unrelated bone 9 Busca A, Bosi A, van Lint MT et al. Transplant-related mor- marrow transplantation. Exp Hematol 2001; 29: 362–370. tality (TRM) in patients receiving reduced versus conventional 14 Lazarus H, Curtin P, Devine S et al. Role of mesenchymal intensity thiotepa–cyclophosphamide (THIO-CY) condition- stem cells (MSC) in allogeneic transplantation: early phase I ing: the impact of stem cell source in 176 consecutive patients clinical results. Blood 2000; 96: 392a (Abstr.).

Bone Marrow Transplantation