A second meeting on reduced intensity allogeneic stem cell transplants (RI-HSCT) was convened in Zurich in February 2001 and focused on transplant-related mortality (TRM) and graft-versus-host disease (GVHD). Retrospective and prospective studies from the EBMT, national groups and single institutions included over 900 patients: the incidence of acute GVHD grade III–IV was 12% (1–17%), extensive chronic GVHD 42% (25–51%) and TRM 20% (14–38%). Conditioning regimens could be classified into four major groups based on (1) total body irradiation (TBI) 200 cGy, (2) busulfan 8 mg/kg, (3) thiotepa 10 mg/kg, and (4) melphalan 140 mg/m2: most of these regimens are given in association with fludarabine in different doses and use mobilized peripheral blood as a source of stem cells. The incidence of TRM is similar if not identical for all four regimens, whereas the risk of acute GVHD and chronic GVHD may vary with different protocols. Reduced intensity transplant programs are being explored in patients above the age of 60 and in patients with solid tumors: encouraging results are being recorded in individual patients. Overall these data confirm that allogeneic HSCT can be performed in elderly patients, although a TRM of approximately 15% must be expected and is age dependent. A high rate of extensive chronic GVHD is seen and should be followed carefully. The term mini- or micro-transplant is probably misleading and one should refer to this procedure as an allogeneic HSCT and further classify the intensity of the conditioning regimen.
Bone Marrow Transplantation (2002) 29, 191–195 doi:10.1038/sj.bmt.1703355
In February 1999, the European Group for Blood and Marrow Transplantation (EBMT), with an educational grant from AMGEN Europe, held a Workshop in Zurich on allogeneic transplantation following non-myeloablative conditioning. Tentative conclusions drawn from the 1999 EBMT/AMGEN Workshop were published (1) and were as follows:
The term ‘minitransplant’ is probably misleading and reduced intensity allogeneic hematopoietic stem cell transplantation (RI-HSCT) is preferred.
RI-HSCT is an experimental procedure.
RI-HSCT involves the use of normal donors and ethical issues apply as with any allogeneic transplant.
Donors should be carefully evaluated because their (probable) older age exposes them to an increased risk of complications.
At present, RI-HSCT should be offered to patients who are otherwise not eligible for conventional allogeneic HSCT.
Acute leukemia and myelodysplastic patients are probably not good candidates for RI-HSCT.
RI-HSCT may be appropriate in chronic disorders such as chronic lymphoproliferative diseases. Chronic myeloid leukemia (CML) should be studied.
Multiple myeloma (MM) patients may pose particular problems.
It remains to be determined whether RI-HSCT is beneficial in patients with solid tumors.
Immune reconstitution should be investigated further.
With these conclusions in mind a second Workshop was organized 2 years later by EBMT together with AMGEN. We now report the outcome of the second Workshop.
The Acute and Chronic Leukemia Working Party of the EBMT analyzed 154 acute leukemia and 270 chronic leukemia patients receiving reduced intensity transplants. Francesco Frassoni and Jane Apperley presented the data. Median age was 50 years: TRM was 20% for the acute leukemias and 22% for the chronic leukemias, the incidence of severe grade III–IV acute GVHD was 10% and 14%, respectively, and extensive chronic GVHD was 40% in both groups. The outcome of 58 chronic myeloid leukemia (CML) patients was comparable. The French and Italian Groups for Marrow Transplantation (SFGM and GITMO) presented 92 and 44 patients, respectively, with a median age of 50 and 52 years, and a TRM of 38% and 14%. Overall, these presentations comprised 969 patients with an average age of 47.7, an average follow-up of 300 days, with medians ranging from 244 to 814 days: the majority of them achieved full donor chimerism (79%). Severe acute GVHD developed in 12% and extensive chronic GVHD in 42% of patients. The average transplant-related mortality was 20%, which may be considered low for a cohort of patients with advanced age and advanced disease.
Immunosuppressive conditioning regimens
Immunosuppressive regimens involve the use of agents with no significant long-term toxic effect on stem cells, such as cyclophosphamide, fludarabine and antibodies against T cells. CY alone has been used in over 5000 patients with non-malignant disorders, who were not discussed at the Workshop. The combination FLU-CY first described by Khouri and coworkers,2 was discussed for Hodgkin's disease and for solid tumors, without specific update. Because this regimen relies entirely on the immunologic effect of the graft, most programs in Europe at present include one or more agents with some depleting effect on stem cells and therefore also on the tumor.
Reduced intensity conditioning regimens
Reduced intensity regimens involve the use of agents toxic for stem cells and tumor cells, such as busulfan or total body radiation, but in reduced doses as compared to a conventional transplant. The regimens presented at the Workshop could be divided into four major groups, most of them combined with fludarabine.
Total body irradiation (TBI) 200 cGy
This program was originally described by Storb and coworkers,3 and is also being explored in Leipzig, Germany as well as other transplant centers in the USA and in Europe. A summary was given by Dietger Niederwieser on 109 patients receiving TBI 200 cGy and fludarabine followed by unmanipulated peripheral blood (PB) cell transplants from HLA-identical siblings, and GVHD prophylaxis with cyclosporin (CsA) and mycofenolate mofetyl (MMF). The median age was 50 (18–71), the median follow-up 241 (100–934) days. There was no need for hospitalization in many patients, although some patients required admission to hospital for prolonged periods of time. Consistent with this is the fact that cGVHD developed in the extensive form in 50% of the patients. This may be due to several causes, among which are the use of unmanipulated PB transplants in all patients, old age, and early reduction or discontinuation of CsA. Overall TRM was low (15%) and progression-free survival at 2 years 43%. Variations of the original TBI 200 cGy regimen include the addition of fludarabine (FLU) 90 mg/m2 as described, TBI 500 cGy + cyclophosphamide (CY) 60 mg/kg as proposed by the French SFGM group, TBI 400 cGy + FLU 90 mg/m2 + CY 60 mg as proposed by the Munchen group, TBI 100 cGy + thiotepa (THIO) 10 mg/kg + CY 100 mg/kg as proposed by the Genoa group, and finally melphalan (MEL) 200 mg/m2 for a first autograft followed by TBI 200 cGy + FLU 90 mg/m2 proposed for myeloma patients as will be discussed later.
Busulfan 8 mg/kg + FLU 125 mg/m2 + antithymocyte globulin (ATG)
This was first described by Slavin and coworkers in 1998.4 The original publication included 26 patients receiving HLA-identical sibling peripheral blood cells following the BU + FLU + ATG regimen. With a median follow-up of 240 days and a median age of 33 the TRM was 15%, and severe acute and chronic GVHD was 15% and 34%. Variations on this protocol presented in Zurich included BU 4 mg/kg + FLU 150 mg/m2 + ATG proposed by the French SFGM and BU 8 mg/kg + FLU 150 mg/m2 + CY 120 mg/kg. Shimon Slavin reported on the Workshop held earlier this year and suggested that the original BU 8 + FLU 125 + ATG protocol will be compared with BU 8 + FLU 125 + CAMPATH 1H, to test whether a reduction in acute and chronic GVHD could be obtained.
Thiotepa 10 mg/kg + cyclophosphamide 100 mg/kg
Thiotepa has been extensively used by M Martelli and coworkers in Perugia for mismatched grafts in conjunction with TBI and cyclophosphamide.5 More recently this group was the first to introduce fludarabine in the conditioning regimen.6 The program without TBI (THIO-CY) was described in 1996 with THIO 15 mg/kg + CY 150 mg/kg7 followed by HLA-identical PB grafts. The reduced intensity version THIO10 + CY100 was recently published in extenso.8 Forty-four patients were grafted in Genova, Firenze, Torino, Milano and presented at EBMT 2001.9 The median age was 52 years and median follow-up 814 days. Acute GVHD was low (2%), possibly because post-graft CsA + methotrexate (MTX) was not discontinued early, as reported in other studies. The rate of extensive chronic GVHD was also low (25%) possibly for the same reason. The overall TRM was 14%: it was 9% in patients receiving bone marrow grafts (BM) and 18% in patients receiving PB grafts. A variation of this regimen included THIO 10 mg/kg + CY 60 mg/kg + FLU 60 mg/m2 developed by Paolo Corradini in Milano10 and used for lymphoma patients, with very low TRM (6%). The latter protocol is now being used in Italy (GITMO) for low-grade lymphomas. Another variation is THIO 10 mg/kg + FLU 120 mg/m2 used in patients with myelodysplasia.
Melphalan (MEL) 140 mg/m2, fludarabine 150 mg/m2 and CAMPATH 1H
This was originally described11 by S McKinnon: 44 patients with lymphoma were grafted with this regimen in the UK, their median age was 41 (18–56) and median follow-up 365 days (60–870). In this regimen grade III–IV acute GVHD and extensive chronic GVHD were virtually absent, possibly as a consequence of using CAMPATH 1H in the conditioning regimen. TRM was 16% and progression-free survival at 2 years 66%. An update on 74 patients was discussed with similar results. The study is being extended to other UK centers.
If we now compare results obtained with these four regimens in over 200 patients, one can appreciate some similarities and some diversities. The latter were median patient age (older in the TBI2 and THIO-CY programs) and median follow-up (longer in the THIO-CY). Also different was the incidence of acute GVHD grade III–IV and extensive chronic GVHD, lower in programs using either conventional 6–12 months in vivo immunosuppression or CAMPATH 1H. However, transplant-related mortality was comparable if not identical, ranging between 14% and 15%. This suggests that we can allograft older patients with advanced disease, with a 15% mortality. Although some data on other outcome measures such as survival and relapse were presented, it is probably better to restrict the present discussion mainly to GVHD and TRM, also because of the patient heterogeneity.
Specific disease-related programs
Solid tumors (ST)
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 and 97 in 2000. Within the ST Working Party, Dieter Niederwieser is responsible for the allogeneic program and Olle Ringden, in particular, for renal cell carcinoma. Nine renal cell carcinoma patients were grafted using the TBI 200 cGy regimen and two are alive and well. Felipe Prosper presented protocols for breast cancer, colon cancer, melanoma, 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 responses are being recorded in breast cancer and renal cell carcinoma. Results in melanoma seem to be less encouraging. It would seem wise to assess the role of allograft from HLA-identical sibling transplantation before expanding the program to unrelated donors.
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%. An EBMT study was presented in which patients are first autografted with melphalan 200 mg/m2, and then, in the presence of an HLA-identical sibling, they are offered an allograft using the TBI 200 cGy + FLU regimen. This program derives from the Seattle program for patients with myeloma. It was not entirely clear which patients would be eligible for this trial: the protocol reads 18–65 years of age. Whether a 35-year-old patient with myeloma should undergo a conventional allogeneic HSCT or an autograft with melphalan 200 followed by an allograft with TBI 200 cGy, is unknown at present. However, we do have consistent data on conventional transplant in myeloma, and very little data on reduced intensity transplants, which should still be considered investigational in young patients.
Norbert Schmitz reported 147 patients allo-grafted in 34 transplant centers, 80 of whom had received a prior autograft. A high relapse rate (60% at 2 years) suggested that reduced intensity conditioning in advanced and/or high grade lymphomas is unlikely to be successful. Progression-free survival (PFS) at 2 years was superior in patients with chemosensitive disease, as compared to patients with chemoresistant disease (30% vs 10%; P < 0.0001). A state of remission or minimal residual disease prior to RI-HSCT might be desirable in patients with lymphoma. Some centers in Europe will be using a melphalan + FLU or FLU + CY regimen for poor risk Hodgkin's disease (patients with early relapse or patients not entering complete remission). In Italy a GITMO trial in patients with low grade non-Hodgkin's lymphomas is being coordinated by Paolo Corradini: the primary end point is molecular remission. Centers in the UK are going to explore the association of MEL + FLU + CAMPATH under the coordination of University College London. Finally, the French group is exploring a regimen based either on BU 8 or TBI 500 in patients with lymphoma.
Chronic lymphocytic leukemia (CLL)
Mauricette Michallet presented data on 14 CLL patients prepared for an allograft with fludarabine and an alkylating agent (either BU or MEL): at a median follow-up of 7 months TRM was 7% and GVHD was seen in 47% of patients. CLL patients are being entered in programs designed for low grade lymphomas.
High risk leukemia and myelodysplasia (MDS)
It may be difficult to maintain remission in patients with fast pace disease, such as acute leukemia in relapse or transformed MDS. Indeed there are little data available for these indications, and disappointing results were also presented 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 mg/kg regimens. There was no specific program described for patients with acute lymphoblastic leukemia.
Specific transplant procedures and GVHD
Allogeneic transplants after RI conditioning are designed to reduce toxicity and exploit the immune effect of the graft: for this reason many programs call for discontinuation of in vivo immunosuppression as early as day +60 after HSCT, and/or infusion of donor lymphocytes (DLI) to maximize this effect. The difficulty of bringing this into practice is shown by the TBI 200 cGy regimen which was designed to give DLI to all patients, but which ended up by infusing lymphocytes in only approximately 10% of the patient population. This is mainly due to the fact that older age and early discontinuation of CsA cause severe acute GVHD in 15–20% of all cases and makes DLI impossible. The factors in PB allografts also induce extensive chronic GVHD in approximately half of patients, which is good for disease control, but less so for quality of life. In a study of the French group SFGM, early discontinuation of CsA had a significant negative impact on survival.
Programs involving CAMPATH 1H in conditioning were followed by little or no acute or chronic GVHD: whether this is desirable remains to be determined. However, prevention seems the most effective way to manage GVHD, since treatment is currently unsatisfactory.
Unrelated donor transplants
The largest series reported is from Seattle/ Leipzig with 41 patients receiving TBI 200 cGy + FLU 90 mg/m2. Median age was 48 (6–65), 34 were PB and seven BM transplants. Engraftment was achieved in 37 patients. Acute GVHD grade II–IV was seen in 62% and TRM in 7/41 patients (17%) at a median follow-up of 185 days (5–471). The median duration of CsA treatment was 6 months. Recently, the BU 8 + FLU 125 + ATG regimen of Shimon Slavin has also been explored in 16 young patients (median age 17) grafted from unrelated donors:13 three patients developed grade III–IV acute GVHD, and three died of transplant-related complications. Although these are relatively early results, they indicate that alternative transplants can be performed in some patients with reduced intensity conditioning. This may be particularly appealing in patients with non-malignant diseases. An ongoing program of the EBMT Severe Aplastic Anemia Working Party calls for FLU 120 mg/m2 + CY 1200 mg/m2 + ATG followed by unmanipulated marrow and CsA + MTX post transplant: it has enrolled 12 patients and eight are alive and well, with full donor chimerism, and little or no GVHD.
Lessons from the 2001 Workshop
Some tentative conclusions from the 2001 Workshop are as follows:
Reduced intensity allogeneic HSCT can now be performed with relatively low toxicity in patients over the age of 50.
There is, however, an ‘age effect’ in almost all programs, when reported, and patients above 50 do worse than patients below 50 years.
The preferred stem cell source is peripheral blood: a prospective randomized trial is under way to compare blood and marrow in this setting.
The preferred GVHD prophylaxis is CsA + MTX or CsA + MMF. ATG or CAMPATH antibodies are used in some programs, and reduce the risk of GVHD.
There are four major conditioning regimens based on TBI 200 cGy, busulfan 8 mg/kg, thiotepa 10 mg/kg or melphalan 140 mg/m2, most of them in combination with fludarabine. Variations of these four regimens are described.
Extensive chronic GVHD is seen in a considerable proportion of patients and should be carefully monitored: guidelines for long-term effects have been developed by EBMT and should be followed.
Reduced intensity programs are being optimized and tested in selected indications including unrelated donor transplants.
The comparison with conventional programs will probably be tested.
As in 1999, it was agreed that the term ‘minitransplant’ is misleading for patients and physicians: we may want to refer to this procedure as an allogeneic hematopoietic stem cell transplant (HSCT) and the conditioning regimen may be further classified.
Donor complications were not described, although older age calls for particular care.
The next Workshop in 2003 will bring further results and indications on best strategies.
Finally, reducing the intensity of the conditioning regimen is one way of minimizing toxicity. Other ways are being explored, among which is graft engineering with expanded cell sub-populations (such as mesenchymal stem cells) which may then be infused in conjunction with hemopoietic stem cells, following conventional or intensified conditioning regimens. We will also be awaiting results of these studies, some of which seem promising.14
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