High-Dose Therapy With Stem-Cell Transplantation in the Malignant Lymphomas
High-Dose Therapy With Stem-Cell Transplantation in the Malignant Lymphomas
The number of new cases of Hodgkins disease and non-Hodgkins lymphoma diagnosed and treated each year are increasing. Although human immunodeficiency virus (HIV) infection and toxins in the environment and workplace may be responsible for the development of these diseases in some patients, explanations for this increase remain elusive. Lymphoid malignancies continue to be among the most responsive to chemotherapy and radiation therapy, however, and a sizeable percentage of affected patients are cured after primary therapy.
For Hodgkins disease, newer, more dose-intensive regimens, such as Stanford V and the recently described BEACOPP (bleomycin, etoposide, Adriamycin, cyclophosphamide, Oncovin, and prednisone), appear to be highly effective as initial therapy. For the non-Hodgkins lymphomas, newer initial therapies, such as hyper-CVAD (cyclophosphamide, vincristine, Adriamycin, and dexamethasone), shown to be potent in mantle cell lymphoma, may be superior to the standard approach using CHOP (cyclophosphamide, doxorubicin HCl, Oncovin, and prednisone).
Monoclonal antibodies, alone or in combination with chemotherapy, appear to show great utility in treating B-cell non-Hodgkins lymphomas.[5,6] The choice of monoclonal antibodies is increasing, and includes preparations with several different radiolabels and new products effective against T-cell lymphoid malignancies, as well as B-cell lymphomas.
For patients who relapse after induction treatment, or for those who do not achieve an initial remission (primary refractory disease), the outlook using conventional therapeutic approaches continues to be bleak. The use of high-dose chemoradiation and hematopoietic progenitor-cell transplantation appears to be an effective salvage modality for these groups of patients.
Transplantation in Lymphoid Malignancies
Dr. Winter reviews the data on the use of autologous and allogeneic transplantation in Hodgkins disease and non-Hodgkins lymphoma. She eloquently summarizes the current efficacy and toxicity data for a wide variety of lymphoproliferative disorders.
Hematopoietic stem-cell transplantation, a term that encompasses autologous or allogeneic transplantation of stem cells from bone marrow, peripheral blood, or umbilical cord blood, is an effective modality for the treatment of variety of malignant and nonmalignant conditions. It is estimated that 30,000 to 40,000 transplants are performed yearly worldwide, and the number continues to increase by 10% to 20% per year. More than 20,000 people now have survived 5 or more years after a hematopoietic stem-cell transplant.
In addition to the questions to be answered by the two phase III trials outlined by Dr. Winter, a number of challenges remain regarding the use of this modality in the treatment of lymphoid malignancies. Will patients who relapse after the newer, more dose-intensive conventional regimens be able to tolerate the high-dose chemotherapy preparative regimens, and will such patients derive less benefit from transplantation due to the induction of tumor resistance? What is the role, if any, for involved-field radiation therapy? What is the best strategy for mobilization of stem cells? How should long-term complications be addressed? How should the choice between allogeneic vs autologous transplant be made?
Role of Involved-Field RadiationThe rationale for the use of involved-field radiation therapy is supported by the recently completed Eastern Cooperative Oncology Group (ECOG) and Southwest Oncology Group (SWOG) trials.[9,10] Several studies of transplantation in lymphoid malignancy suggest a benefit for this intervention, but contemporary use of radiation therapy in combination with high-dose therapy largely reflects institutional practices.[11-14] The issue of efficacy likely can be resolved only after randomized trials are conducted and analyzed.
Moreover, the timing of this maneuver appears to differ. In Europe, radiation treatment generally is given after transplantation, while the reverse may be the case in North America.
When Stem-Cell Mobilization is UnsuccessfulThe switch from bone marrow-derived to blood-derived hematopoietic progenitors appears to have greatly reduced the morbidity and, possibly, mortality of transplantation. How should one approach patients who do not undergo successful mobilizationa dilemma affecting perhaps as many as 20% of autologous transplant candidates?
Although some groups believe that such patients may fare well with supplementation of bone marrow to blood stem cells, the experiences of other groups have not been as favorable. Data from the latter groups support the use of newer agents for stem-cell mobilization. These include various cytokines, including flt3 ligand (FL), myelopoietin, stem-cell factor, and leridistem (interleukin-3 [IL-3]/granulocyte colony-stimulating factor [G-CSF] receptor agonist).
Posttransplant ComplicationsResidual visceral organ dysfunction (lung, cardiac, and marrow/stroma injury) and secondary malignancy continue to remain the legacy of successful transplantation.[7,15] Although patients with lymphoid malignancy appear to be at increased risk for myelodysplasia, acute leukemia, and solid tumors, such risk may be amplified by transplantation. A number of factors need to be considered, including induction therapy and the use of certain chemotherapeutic agents, such as etoposide, in the mobilization regimen.
The Future of Autologous Transplantation
The future of autologous transplantation in lymphoid malignancies appears to be promising. Given the enhanced safety of this approach and the greater efficacy of the agents now being used, patients are being referred earlier than previously. Risk-adaptive strategies, in which transplantation, including the use of novel regimens, is performed earlier in high-risk patients, ie, the sequential high-dose approach,[17-19] will need to be tested in phase III trials to demonstrate an improved benefit.
What is the optimal preparative or conditioning regimen to employ? To date, data have not demonstrated the superiority of any one myeloablative transplant regimen. It is unlikely that regimen intensity can be increased significantly; the trade-off for enhanced potency may be greater toxicity, although some studies have demonstrated that this strategy can be employed successfully. It is more likely that future strategies will focus on the use of more selective autologous transplantation regimens, such as those that use radiolabeled monoclonal antibodies.
It is also likely that further improvements in transplantation for lymphoid malignancies will be based on advances in the timing of transplantation, improved stem-cell collection techniques, and posttransplant approaches, including the use of immune therapies, such as interleukin-2 (Proleukin), monoclonal antibodies, antitumor vaccine strategies, and, possibly, angiogenesis inhibitors.
A novel, autologous transplant approach may be the use of agents to induce the graft-vs-host (and graft-vs-tumor) effect in lymphoma. This strategy was used in breast cancer but proved to be disappointing.[23,24]
Choosing Patients for Allogeneic vs Autologous Transplantation
Can criteria be established to determine which patients should be considered for allogeneic rather than autologous transplantation? Early data derived using mini allogeneic transplantation appear to demonstrate that the significant morbidity of an allogeneic transplant can be avoided while providing for the graft-vs-lymphoma effect. Sykes and colleagues recently showed that human lymphocyte antigen (HLA)mismatched bone marrow can be used to accomplish the same goal.
Hematopoietic stem-cell transplantation appears to be an effective and essential component of the treatment armamentarium for patients with lymphoid malignancies. Dr. Winter poses many of the important and interesting clinical and translational study questions. The future appears to be encouraging for patients and challenging for investigators.
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