Haematologica, Vol 92, Issue 3, 418-420 doi:10.3324/haematol.10521
Copyright © 2007 by Ferrata Storti Foundation
Stem Cell Transplantation |
Reduced intensity stem cell transplantation for advanced soft tissue sarcomas in adults: a retrospective analysis of the European Group for Blood and Marrow Transplantation
Simona Secondino,
Matteo G. Carrabba,
Paolo Pedrazzoli,
Luca Castagna,
Francesco Spina,
Federica Grosso,
Alexia Bertuzzi,
Jacques-Olivier Bay,
Salvatore Siena,
Paolo Corradini,
Dietger Niederwieser,
Taner Demirer on behalf of the European Group for Blood and Marrow Transplantation (EBMT) Solid Tumors Working Party (STWP)
From the Divisione Oncologica Falck, Ospedale Niguarda Ca’ Granda, Milan, Italy (SSec, PP, SSie); Dept of Hematology, Istituto Nazionale per lo Studio e la Cura dei Tumori and University of Milan, Milan, Italy (MGC, FS, PC) Istituto Clinico Humanitas, Milan, Italy (LC, AB); Dept. of Medical Oncology, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy (FG); Centre Jean Perrin-CHU, Clermont Ferrand, France (J-OB); University Hospital Leipzig, Leipzig, Germany (DN); Ankara University Medical School, Ankara, Turkey (TD).
Correspondence:, Simona Secondino, Medical Oncologist, Divisione Oncologica, Falck, Ospedale Niguarda, Ca’ Granda, Piazza Dell’ Ospedale, Maggiore, 3, 20162 Milan, Italy., E-mail: simona.secondino{at}ospedaleniguarda.it
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ABSTRACT
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We conducted a retrospective analysis on adult patients with advanced soft tissue sarcoma (STS) other than rhabdomyosarcoma who received allogeneic stem cell transplantation and were registered at the EBMT database. The aim of of the study was to assess whether an immune-mediated graft-versus-tumor (GVT) effect could be generated in this disease. Among 26 patients included in the registry, 14 were eligible for this analysis as they had received reduced intensity stem cell transplantation for chemorefractory disease. Two patients died of transplant-related complications and eight of progressive disease; four are alive and experienced long-lasting disease stabilisation following transplant. Our study may suggest that an immune-mediated effect cannot be excluded in some STS.
Key words: non-myeloablative, allogeneic SCT, soft tissue sarcoma, graft-versus-tumor.
The investigational application of reduced intensity stem cell transplantation (RST) in patients with refractory non-hematologic cancers proved that a meaningful graft-versus-tumor effect can be generated in patients with renal cell cancer and possibly in those with other solid tumors.1,2 RST has been proposed as a therapeutic option in patients with advanched soft tissue sarcoma (STS) for two main reasons: i) the poor prognosis of this disease, with a median survival of about 1 year with conventional treatments,3 ii) the evidence of an immune-mediated effect against sarcoma in experimental animal models of allogeneic transplantation.4,5. However, only single case reports and small series of patients with STS treated with RST from HLA-matched siblings have been reported. Although some authors have reported some evidence of a graft-versus-sarcoma effect in humans,6–8. the largest study that has been published so far included nine patients with various histotypes9 and did not show any evidence of cancer regression after RST. We have retrospectively reviewed, on behalf of the European Group for Blood and Marrow Transplantation (EBMT) solid tumor working party (STWP), the EBMT database providing results from the largest so far published series of patients with STS who had been treated with RST. This series of patients, while including different STS histotypes, is relatively homogeneous as for concerns type of conditioning regimen and tumor status at transplantation. Patients with rhabdomyosarcoma were excluded as this is most frequently a pediatric disease with an extremely different natural history.
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Design and Methods
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Twenty-six adult patients with STS who underwent allogeneic stem cell transplantation and were registered in the EBMT database were considered. Because of the lack, from a preliminary analysis, of important clinical data, including type of conditioning regimen in several cases, all centers were re-contacted for missing data. Patients with chemosensitive disease at transplantation (n=9) and patients who received myeloablative chemotherapy (n=3), were eventually excluded. This was done in order to limit confounding elements as much as possible (e.g. disease response to drugs included in the conditioning regimen) which could affect the possibility of investigating the existence of a graft-versus-sarcoma effect. Fourteen patients with a complete data set, transplanted in seven European institutions from 2000 to 2005, were analyzed. All patients had metastatic or locally advanced disease, which was bulky (conventionally considered as a tumor mass with a maximum diameter 
10 cm) in five. The median age was 43 years (range: 22–51). The ECOG performance status (PS) was 0–1 in 12 patients, and was not reported for the other two patients. All patients received a fludarabine-based reduced intensity conditioning regimen followed by allogeneic stem cell transplantation from an HLA identical or one antigen-mismatched sibling donor. The patients’ relevant characteristics are reported in Table 1. The median time from diagnosis to transplantation was 31.6 months (range: 5.6 to 197 months). Engraftment was achieved in all patients. Not lineage-specific peripheral blood full donor chimerism, was documented in 11 patients and mixed chimerism in 3 patients. Tumor response was reported according to RECIST criteria.
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Results and Discussion
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After a median follow-up of 201 days from transplant two patients had died of acute graft-versus-host disease (GVHD) for an overall treatment related mortality of 14%. Given the early occurrence of these deaths (at 50 and 59 days post-treatment), these patients were not evaluable for disease response. Overall, acute GVHD was reported in nine out of the 14 patients (64%) and was grade 3–4 in four cases (28%) and grade 2 in 5 cases (36%). Chronic GVHD occurred in 4 out of 9 evaluable patients (44%) and was extensive in two. In this series of heavily pre-treated patients, albeit limited, morbidity and mortality appear to be similar to those reported for patients with hematologic malignancies treated with RST.10
After a median follow-up of 326 days, 8 out of 12 patients, evaluable for a disease response, had died of progressive disease (PD, 66%), while four patients remained progression-free at 196, 206, 446 and 868 days after transplant (Table 1). The Kaplan-Meier estimates of progression-free and overall survival (PFS and OS) are illustrated in Figure 1A and 1B, respectively. The median OS was 326 days (range 50–1078 days), whereas the median PFS was 103 days (range 50–565). The mean time from transplantation to assessment of response was 57 days (range 13–260 days)
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Figure 1. Kaplan-Meier estimates of progression-free survival (A) and overall survival (B) for STS patients treated with RST; red marks represent patients who are progression-free (A) and patients who are still alive (B).
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No objective responses have been reported suggesting that the postulated graft-versus-sarcoma effect might not occur following RST. However, it is important to note that: i) patients with these characteristics have an extremely poor prognosis and do not have further therapeutic options that have proven to be safe and effective; ii) the presence of chemo-refractory and progressing disease at the time of transplantation is associated with poor outcome even in patients with hematologic malignancies known to be susceptible to a graft-versus-tumor effect; iii) three patients, none of whom had bulky disease at the time of transplantation, obtained a relatively long-lasting disease stabilization after RST. For these reasons we believe that the results presented in this study do not completely rule out the possibility that an immune-mediated effect might have contributed to tumor control in some patients.
A well designed phase II study, enrolling patients with limited tumor burden and slow growing tumors, is required to define the possible role of RST in patients with STS in whom conventional treatments have failed.
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Footnotes
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SSec and MGC contributed equally to the study.
Authors’ Contributions
SSec and MC contributed equally to re-contacting each center and analyzing the data. The other authors provided data that were missing from the EBMT database.
Conflict of Interest
The authors reported no potential conflicts of interest.
Funding: supported by Grant Regionale AIRC to PP and PC. SSec is recipient of a research contract supported in part by OCGO (Oncologia Ca’ Granda ONLUS)
Received for publication December 5, 2006.
Accepted for publication January 29, 2007.
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References
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- Renga M, Pedrazzoli P, Siena S. Present results and perspectives of allogeneic reduced intensity hematopoietic stem cell transplantation for treatment of human solid tumors. Ann Oncol 2003;14:1177-84.[Abstract/Free Full Text]
- Carella AM, Beltrami G, Corsetti MT, Nati S, Musto P, Scalzulli P, et al. Reduced intensity conditioning for allograft after cytoreductive autograft in metastatic breast cancer. Lancet 2005;36:318-20.
- Clark MA, Fisher C, Judson I, Thomas JM. Soft tissue sarcomas in adults. N Engl J Med 2005;353:701-11.[Free Full Text]
- Deichman GI, Kashkina LM, Kluchareva TE, Vendrov EL, Matveeva VA. Inhibition of experimental and spontaneous lung metastases of highly metastatic Syrian hamster sarcoma cells by non-activated bone marrow and peritoneal exudate cells. Int J Cancer 1983;3:609-15.
- Moscovitch, Slavin S. Anti-tumor effects of allogeneic bone marrow transplantation in (NZB X NZW) F1 hybrids with spontaneous lymphosarcoma. J Immunol 1984;132:997-1000.[Abstract]
- Makimoto A, Kami S, Mineishi S, Tanosaki R, Kanda Y, Kim S-W, et al. Reduced-intensity allogeneic stem cell transplantation (RIST) for patients including children with refractory sarcoma. Proc ASCO 2003;3355a[abstract].
- Misawa A, Hosoi H, Tsuchiya K, Iehara T, Sawada T, Sugimoto T. Regression of refractory rhabdomyosarcoma after allogeneic stemcell transplantation. Pediatr Hematol Oncol 2003;20:151-5.[CrossRef][ISI][Medline]
- Pedrazzoli P, Da Prada GA, Giorgiani G, Schiavo R, Zambelli A, Giraldi E, et al. Allogeneic blood stem cell transplantation after a reduced-intensity, preparative regimen: a pilot study in patients with refractory malignancies. Cancer 2002;94:2409-15.[CrossRef][ISI][Medline]
- Castagna L, Sarina B, Todisco E, Mazza R, Santoro A. Lack of activity of allogeneic stem cell transplantation with reduced-intensity conditioning regimens in advanced sarcomas. Bone Marrow Transplant 2005;35:421-2.[CrossRef][ISI][Medline]
- Corradini P, Tarella C, Olivieri A, Gianni AM, Voena C, Zallio F, et al. Reduced-intensity conditioning followed by allografting of hematopoietic cells can produce clinical and molecular remissions in patients with poor-risk hematologic malignancies. Blood 2002;99:75-82.[Abstract/Free Full Text]
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ABSTRACT
Design and Methods
