Commentary (Lazarus): High-Dose Therapy With Stem-Cell Transplantation in the Malignant Lymphomas

The number of new cases of Hodgkin’s disease and non-Hodgkin’s 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 Hodgkin’s disease, newer, more dose-intensive regimens, such as Stanford V[1] and the recently described BEACOPP (bleomycin, etoposide, Adriamycin, cyclophosphamide, Oncovin, and prednisone),[2] appear to be highly effective as initial therapy. For the non-Hodgkin’s lymphomas, newer initial therapies, such as “hyper-CVAD” (cyclophosphamide, vincristine, Adriamycin, and dexamethasone),[3] shown to be potent in mantle cell lymphoma, may be superior to the “standard” approach using CHOP (cyclophosphamide, doxorubicin HCl, Oncovin, and prednisone).[4]

Monoclonal antibodies, alone or in combination with chemotherapy, appear to show great utility in treating B-cell non-Hodgkin’s 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 Hodgkin’s disease and non-Hodgkin’s 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.[7] 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.[8] More than 20,000 people now have survived 5 or more years after a hematopoietic stem-cell transplant.[8]

Current Challenges

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 Radiation-The 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 Unsuccessful-The 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 mobilization-a 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 Complications-Residual 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.[16] 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.[20] 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.[21]

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),[22] 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.[25] Sykes and colleagues[26] recently showed that human lymphocyte antigen (HLA)–mismatched bone marrow can be used to accomplish the same goal.

Summary

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.

References:

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2. Diehl V, Franklin J, Hasenclever D, et al: BEACOPP: A new dose-escalated and accelerated regimen, is at least as effective as COPP/ABVD in patients with advanced-stage Hodgkin’s lymphoma, interim report from a trial of the German Hodgkin’s Lymphoma Study Group. J Clin Oncol 16: 3810-3821, 1998.

3. Khouri IF, Romaguera J, Kantarjian H, et al: Hyper-CVAD and high-dose methotrexate/cytarabine followed by stem-cell transplantation: An active regimen for aggressive mantle-cell lymphoma. J Clin Oncol 16:3803-3809, 1998.

4. Fisher RI, Gaynor ER, Dahlberg S, et al: Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin’s lymphoma. N Engl J Med 328:1002-1006, 1993.

5. Coiffier B, Haioun C, Ketterer N, et al: Rituximab (anti-CD20 monoclonal antibody) for the treatment of patients with relapsing or refractory aggressive lymphoma: A multicenter phase II study. Blood 92:1927-1932, 1998.

6. Czuczman MS, Grillo-López AJ, White CA, et al: Treatment of patients with low-grade B-cell lymphoma with the combination of chimeric anti-CD20 monoclonal antibody and CHOP chemotherapy. J Clin Oncol 17:268-276, 1999.

7. Leiper AD: What is in store after stem-cell transplantation? Lancet 353: 1544-1545, 1999.

8. Horowitz M: Uses and growth of hematopoietic cell transplantation, in Thomas ED, Blume KG, Forman SJ (eds): Haematopoietic Cell Transplantation, 2nd ed, pp 12-18. Oxford, England, Blackwell, 1998.

9. Glick JH, Kim K, Earle J, et al: An ECOG randomized phase III trial of CHOP vs CHOP + radiotherapy (XRT) for intermediate grade early stage non-Hodgkin’s lymphoma (NHL) (abstract). Proc Am Soc Clin Oncol 14: 391, 1995.

10. Miller TP, Dahlberg S, Cassady JR, et al: Chemotherapy alone compared with chemotherapy plus radiotherapy for localized intermediate- and high-grade non-Hodgkin’s lymphoma. N Engl J Med 339:21-26, 1998.

11. Phillips GL, Wolff SN, Herzig RH, et al: The treatment of progressive Hodgkin’s disease with intensive chemoradiotherapy and autologous marrow transplantation. Blood 73:2086-2092, 1989.

12. Phillips GL, Fay JW, Herzig RH: The treatment of progressive non-Hodgkin’s lymphoma with intensive chemoradiotherapy and autologous bone marrow transplantation. Blood 75:831-838, 1990.

13. Mundt AJ: High-dose chemotherapy and stem cell rescue for aggressive non-Hodgkin’s lymphoma: Pattern of failure and implications for involved-field radiotherapy. Int J Radiat Oncol Biol Phys 39:617-625, 1997.

14. Poen JC, Hoppe RT, Horning SJ: High-dose therapy and autologous bone marrow transplantation for relapsed/refractory Hodgkin’s disease: The impact of involved field radiotherapy on patterns of failure and survival. Int J Radiat Oncol Biol Phys 36:3-12, 1996.

15. del Canizo C, Lopez N, Caballero D, et al: Haematopoietic damage persists 1 year after autologous peripheral blood stem cell transplantation. Bone Marrow Transplant 23:901-905, 1999.

16. Andre M, Henry-Amar M, Blaise D, et al: Treatment-related deaths and second cancer risk after autologous stem-cell transplantation for Hodgkin’s disease. Blood 92:1933-1940, 1998.

17. Stahel RA, Jost LM, Kroner T, et al: A prospective study of risk-adapted therapy for large cell non-Hodgkin’s lymphoma with VACOP-B followed by high-dose CBV and autologous progenitor cell transplantation for high-risk patients in remission. Br J Haematol 104:763-769, 1999.

18. Carde P: Should poor risk patients with Hodgkin’s disease be sorted out for intensive treatments? Leuk Lymphoma 15 (suppl 1):31-40, 1995.

19. Gianni AM, Bregni M, Siena S, et al: High-dose chemotherapy and autologous bone marrow transplantation compared with MACOP-B in aggressive B-cell lymphoma. N Engl J Med 336:1290-1297, 1997.

20. Reece DE, Nevill TJ, Sayegh A, et al: Regimen-related toxicity and non-relapse mortality with high-dose cyclophosphamide, carmustine (BCNU) and etoposide (VP16-213) (CBV), and CBV plus cisplatin (CBVP) followed by autologous stem cell transplantation in patients with Hodgkin’s disease. Bone Marrow Transplant 23:1131-1138, 1999.

21. Liu SY, Eary JF, Petersdorf SH, et al: Follow-up of relapsed B-cell lymphoma patients treated with iodine-131-labeled anti-CD20 antibody and autologous stem-cell rescue. J Clin Oncol 16:3270-3278, 1998.

22. Margolin KA, Van Besien K, Wright C, et al: Interleukin-2-activated autologous bone marrow and peripheral blood stem cells in the treatment of acute leukemia and lymphoma. Biol Blood Marrow Transplant 5:36-45, 1999.

23. Nakamura H, Nakao T, Ujiie H, et al: Induction of autologous graft-vs-host disease after autologous peripheral blood stem cell transplantation. J Allergy Clin Immunol 103:S457-S461, 1999.

24. Kennedy MJ, Hess AD, Passos Coelho J-L, et al: Autologous graft vs host disease (AGVHD) as immune therapy after high dose chemotherapy (HDC) for metastatic breast cancer (MBC): Medium-term follow-up and comparison with historical controls (abstract). Proc Am Soc Clin Oncol 15:335, 1996.

25. Khouri IF, Keating M, Körbling M, et al: Transplant-lite: Induction of graft-versus-malignancy using fludarabine-based nonablative chemotherapy and allogeneic blood progenitor-cell transplantation as treatment for lymphoid malignancies. J Clin Oncol 16:2817-2824, 1998.

26. Sykes M, Preffer F, McAfee S, et al: Mixed lymphohaemopoietic chimerism and graft-vs-lymphoma effects after non-myeloablative therapy and HLA-mismatched bone-marrow transplantation. Lancet 353:1755-1759, 1999.