Evolving trends in hematopoietic cell transplantation for solid tumors: tempering enthusiasm with clinical reality

R. W. Childs

NHLB/NIH, Bethesda, MD, USA

In this edition of the Annals of Oncology, Gratwohl and colleagues [1] from the European Group for Blood and Marrow Transplantation (EBMT) and The Working Party Solid Tumours (STWP) present a detailed analysis on the current practice of hematopoietic cell transplantation (HCT) for solid tumors in Europe over the past 12 years. The vast majority of transplants conducted over this time interval used dose-intensive conditioning followed by autologous stem cell rescue in patients with metastatic tumors deemed incurable or at high risk for relapse with conventional chemo/radiotherapy. The disease-specific transplant trends from this study can be categorized into three groups: (i) diseases where a continuous and steady increase in procedures have been performed (i.e. Ewing’s sarcoma, neuroblastoma); (ii) diseases where transplant numbers have remained stable (germ cell tumors, gliomas, soft tissue sarcomas); and (iii) diseases where transplants initially increased then abruptly declined (i.e. breast, ovarian, lung cancer). Although outcome data are not presented, one is able to infer treatment efficacy from these trends, with increases or decreases being temporally related to the publication of favorable or negative data from sentinel transplant trials in specific tumors. This is best seen in breast cancer, the disease accounting for the vast majority of autologous transplants in the mid-1990s; an initial rapid increase in autologous procedures up to 1997 was followed by an abrupt and significant decline in transplants temporally related to the publication of negative data from large clinical trials [2]. Indeed, the dramatically smaller number of transplants performed for all categories of solid tumors in 2002 (1913) compared with 1997 (4154) is predominantly the consequence of fewer transplants being performed for metastatic breast carcinoma, given the perception that the procedure offers little to no advantage over conventional chemotherapy [3]. A similar downward spiral in the number of autologous transplants for metastatic breast carcinoma was recorded by The International Bone Marrow Transplant Registry (IBMTR), from a peak of 3178 transplants in 1996–1997 to just 97 transplants in 2000–2001 (D. Rizzo and P. Stiff, personal communication).

The transplant trends presented here and elsewhere also provide direct insight into the level of enthusiasm of physicians and patients alike for HCT in specific diseases. In contrast to hematological malignancies where disease-free and overall survival can be prolonged (i.e. relapsed lymphoma, multiple myeloma) [46], data supporting a beneficial role for autologous transplantation in most solid tumors are lacking. The plateau and decline in autologous transplants, in contrast to a recent increase in reduced intensity allogeneic transplants, reflect the painful reality that only a minority of patients with advanced solid tumors seem to benefit from ‘dose intensification’. Even in tumors where evidence of a dose–response relationship exists (i.e. neuroblastoma, Ewing’s sarcoma, germ cell tumors), randomized studies showing a survival advantage of autologous transplantation compared with conventional chemotherapy are lacking [7].

In contrast to autologous HCT, the number of allogeneic transplants performed for metastatic solid tumors appears to be on the rise, from just 15 in 1997 to 159 in 2002. Allogeneic transplantation is now known to induce curative donor immune-mediated graft-versus-tumor (GVT) effects in patients with a variety of hematological malignancies. Remission induction of relapsed leukemias following treatment with donor lymphocyte infusions and the isolation of donor T lymphocytes with anti-tumor activity are just a few of many lines of evidence supporting the critical role of the GVT effect in curing malignancies following allogeneic HCT [8]. A heightened appreciation of the GVT effect has recently resulted in a paradigm shift in our perception of factors that cure of patients with hematological malignancies, de-emphasizing the benefits of dose intensification while highlighting the powerful nature of the GVT effect.

Two important sequelae have emanated from this paradigm shift. The first is that an increasing number of allogeneic transplants are now being performed using dose-reduced conditioning regimens (e.g. non-myeloablative or ‘mini transplantation’), based on the observation that GVT effects without myeloablative chemotherapy may be sufficient to cure some hematological malignancies [9]. The second is that an increasing number of investigational allogeneic transplants in non-hematological malignancies are now being performed, testing the hypothesis that a graft-versus-solid tumor effect, analogous to the graft-versus-leukemia effect in hematological malignancies, might be induced against chemotherapy-resistant metastatic tumors [10]. Recent case reports and small case series describing GVT effects in renal cell carcinoma, breast carcinoma, ovarian and colon carcinoma provide preliminary evidence of the ‘plasticity’ of alloreactive T cells in terms of their anti-malignant potential [11, 12].

Similar trends showing an increase in allogeneic transplants in solid tumors have also been observed in North America. Therefore, the European data presented by Gratwohl et al. [1] should be taken in a global context, as they reflect worldwide enthusiasm for HCT that has evolved from knowledge gleaned from both large randomized clinical trials and pilot studies highlighting potential benefits of allogeneic immunotherapy.

Despite promising reports of solid tumors regressing as the consequence of a GVT effect, it is critical that investigators do not repeat the mistake that occurred with autologous transplants for metastatic breast carcinoma, namely a premature rush to conduct large numbers of transplants based on an overly optimistic assumption of efficacy fueled by limited clinical data. Rather, it will be far more important that enthusiasm levels be tempered until the advantages and pitfalls of such a treatment strategy become clear. Regimen-related mortality rates of 10% or more and low overall response rates are limiting factors that will likely keep the number of allogeneic transplants for metastatic solid tumors at relatively low numbers for the time being. Although allogeneic HCT alone is unlikely to cure most patients with metastatic tumors, these pilot studies have been invaluable as they have provided important ‘proof of concept’ of the therapeutic potential of the GVT effect. Based on these observations, second-generation regimens that incorporate strategies to cyto-reduce tumors before transplantation (i.e. auto-transplantation followed by non-myeloablative allotransplantation, surgical or chemotherapeutic ‘debulking’, targeted small molecules etc.) [13] as well as methods to target the donor immune system specifically against the tumor (e.g. tumor vaccination strategies) will likely be forthcoming.

R. W. Childs

NHLB/NIH, 9000 Rockville Pike, Bethesda, MD-20892-1652, USA (E-mail: childsr@nih.gov)

REFERENCES

1. Gratwohl A, Baldomero H, Demirer T et al. Hematopoetic stem cell transplantation for solid tumors in Europe. Ann Oncol 2004; 15: 653–660.[Abstract/Free Full Text]

2. Stadtmauer EA, O’Neill A, Goldstein LJ et al. Conventional-dose chemotherapy compared with high-dose chemotherapy plus autologous hematopoietic stem-cell transplantation for metastatic breast cancer. Philadelphia Bone Marrow Transplant Group. N Engl J Med 2000; 342: 1069–1076.[Abstract/Free Full Text]

3. Berry DA, Broadwater G, Klein JP et al. High-dose versus standard chemotherapy in metastatic breast cancer: comparison of Cancer and Leukemia Group B trials with data from the Autologous Blood and Marrow Transplant Registry. J Clin Oncol 2002; 20: 743–750.[Abstract/Free Full Text]

4. Philip T, Guglielmi C, Hagenbeek A et al. Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin’s lymphoma. N Engl J Med 1995; 333: 1540–1545.[Abstract/Free Full Text]

5. Child JA, Morgan GJ, Davies FE et al. High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma. N Engl J Med 2003; 348: 1875–1883.[Abstract/Free Full Text]

6. Attal M, Harousseau JL, Stoppa AM et al. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Francais du Myelome. N Engl J Med 1996; 335: 91–97.[Abstract/Free Full Text]

7. Rosti G, Pico J-L, Wandt H et al. High-dose chemotherapy (HDC) in the salvage treatment of patients failing first-line platinum chemotherapy for advanced germ cell tumors (GCT); first results of a prospective randomised trial of the European Group for Blood and Marrow Transplantation (EBMT): IT-94 study. Proc Am Soc Clin Oncol 2002; 21: (Abstr 716).

8. Kolb HJ, Mittermuller J, Clemm C et al. Donor leukocyte transfusions for treatment of recurrent chronic myelogenous leukemia in marrow transplant patients. Blood 1990; 76: 2462–2465.[Abstract]

9. Anagnostopoulos A, Giralt S. Critical review on non-myeloablative stem cell transplantation (NST). Crit Rev Oncol Hematol 2002; 44: 175–190.[ISI][Medline]

10. Storb RF, Lucarelli G, McSweeney PA, Childs RW. Hematopoietic cell transplantation for benign hematological disorders and solid tumors. Hematology (Am Soc Hematol Educ Program) 2003; 372–397.

11. Childs R, Chernoff A, Contentin N et al. Regression of metastatic renal-cell carcinoma after nonmyeloablative allogeneic peripheral-blood stem-cell transplantation. N Engl J Med 2000; 343: 750–758.[Abstract/Free Full Text]

12. Chakrabarti S, Childs R. Allogeneic immune replacement as cancer immunotherapy. Expert Opin Biol Ther 2003; 3: 1051–1060.[CrossRef][ISI][Medline]

13. Carella AM, Beltrami G, Lerma E, Cavaliere M, Corsetti MT. Combined use of autografting and non-myeloablative allografting for the treatment of hematologic malignancies and metastatic breast cancer. Cancer Treat Res 2002; 110: 101–112.[Medline]





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