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

Autologous hematopoietic stem- cell transplantation has become an accepted therapy for some patients with Hodgkin’s disease and non-Hodgkin’s lymphoma. Convincing evidence for a graft-vs-lymphoma effect has led to increasing use of allogeneic transplantation in these patients. Dr. Winter has written an excellent overview of transplantation in the lymphomas. She has focused on several areas of controversy and described results of randomized trials.

Physicians who perform transplants are continually faced with decisions about the suitability of patients for autologous hematopoietic stem-cell transplantation, as well as the timing of the procedure. These decisions cannot be made without standardized definitions that allow us to interpret the literature.

Dr. Winter discusses the difficulties in defining “primary refractory” disease. This issue was also addressed at the International Consensus Conference on Hematopoietic Stem-Cell Transplantation in Aggressive Non-Hodgkin’s Lymphomas.[1]

Philip et al noted no long-term disease-free survivors after autologous hematopoietic stem-cell transplantation in patients with primary refractory disease.[2] These patients had failed to attain a complete remission and had

disease progression while receiving salvage chemotherapy. However, the terms “primary refractory” and “induction failure” have also been used to describe patients who attain a partial remission or a “very good partial remission” with primary therapy. These patients are not refractory and may have an excellent prognosis following autologous hematopoietic stem-cell transplantation.[3,4]

Early Transplantation in Poor-Prognosis Patients

Dr. Winter also discusses the role of early transplantation as part of primary therapy for poor-prognosis non-Hodgkin’s lymphoma patients. One example of a poor prognosis is a slow response to initial chemotherapy.[5] Two prospective randomized trials have addressed the use of autologous hematopoietic stem-cell transplantation to improve results in these slow responders. The first trial randomized patients in partial remission after three cycles of CHOP (cyclophosphamide, Adriamycin, Oncovin, and prednisone) to receive either autologous hematopoietic stem-cell transplantation after one more cycle of CHOP or five more cycles of CHOP.[6] The second trial randomized patients who were in partial remission two-thirds of the way through primary therapy to recieve treatment with either autologous hematopoietic stem-cell transplantationor six cycles of DHAP (dexamethasone, cytarabine, and Platinol) salvage therapy.[7]

Neither trial showed a survival benefit of autologous hematopoietic stem-cell transplantation, although the results of these trials should not necessarily be interpreted to mean that slow responders do not have a poor prognosis or that autologous hematopoietic stem-cell transplantation cannot improve outcome for these patients. These trials seem to suggest that a single course of high-dose therapy followed by autologous hematopoietic stem-cell transplantation can substitute for a certain number of cycles of CHOP or similar conventional chemotherapy. It may be unreasonable to expect a single course of high-dose therapy to benefit patients who have a significant residual tumor burden after receiving a partial course of their initial conventional chemotherapy regimen.

Although these trials did not show a benefit of autologous hematopoietic stem-cell transplantation when used at the time of slow response, it is possible that autologous hematopoietic stem-cell transplantation might be beneficial at a later time. This hypothesis could be tested by a clinical trial that randomizes slowing responding patients to receive either additional conventional chemotherapy alone or additional chemotherapy followed by high-dose therapy and autologous hematopoietic stem-cell transplantation.

Incorporating Transplantation Into Primary Therapy

Dr. Winter also discusses the conflicting results of trials that have incorporated autologous hematopoietic stem-cell transplantation into primary therapy, including the Groupe d’Etude des Lymphomes de l’ Adulte (GELA) LNH93-3 trial.[8] Poor-prognosis patients in this trial were initially treated with a brief induction chemotherapy regimen and then were randomized to either additional conventional chemotherapy or high-dose therapy followed by autologous hematopoietic stem-cell transplantation.

Again, the failure of autologous hematopoietic stem-cell transplantation to improve outcome in this trial may be attributed to the fact that transplantation was utilized too early in the course of disease, before significant cytoreduction was obtained. Interestingly, the international consensus committee also recognized that the only trials that showed a benefit of early autologous hematopoietic stem-cell transplantation in poor-prognosis non-Hodgkin’s lymphoma patients were those that employed a full course of standard induction therapy prior to autologous stem-cell transplantation or those that incorporated high-dose therapy into the initial induction regimen.[1]

The randomized trials of early autologous hematopoietic stem-cell transplantation for poor-prognosis non-Hodgkin’s lymphoma seem to indicate that there is a narrow window of applicability if patients are to benefit from this approach. Transplantation cannot be used too early (before sufficient cytoreduction is obtained with conventional therapy), and it appears that autologous hematopoietic stem-cell transplantation is only likely to benefit patients with adverse prognostic characteristics. The role of early autologous hematopoietic stem-cell transplantation can be refined if we enroll patients in trials like the intergroup study described by Dr. Winter.

Pretransplant Cytoreduction for Relapsed Non-Hodgkin’s Lymphoma

Another area discussed by Dr.Winter involves the role of pretransplant cytoreduction in patients with relapsed non-Hodgkin’s lymphoma. It is common practice to administer a brief course of conventional chemotherapy to reduce tumor burden and test chemosensitivity prior to autologous hematopoietic stem-cell transplantation. The use of pretransplant cytoreduction chemotherapy has only been tested in one randomized trial,[9] which led to the consensus opinion that patients with relapsed non-Hodgkin’s lymphoma should receive additional salvage therapy prior to their high-dose therapy regimen.[1]

It is not clear, however, that all patients should be treated in this manner. For example, patients with acute myelogenous leukemia have similar outcomes whether allogeneic transplantation is performed in untreated first relapse or in second remission.[10] In addition, retrospective analyses have shown that some non-Hodgkin’s lymphoma patients who are transplanted in “untested” relapse may have excellent outcomes.[3] Furthermore, in a retrospective analysis, we demonstrated that Hodgkin’s disease patients who are transplanted in untested relapse had significantly better overall survival than patients who received conventional salvage chemotherapy prior to autologous hematopoietic stem-cell transplantation.[11] An analysis from the European Group for Blood and Marrow Transplantation also failed to show that Hodgkin’s disease patients who underwent transplantation in untested relapse had inferior outcomes.[12]

Phillips et al have reviewed the use of conventional salvage chemotherapy prior to autologous hematopoietic stem-cell transplantation, and they present the potential disadvantages of this approach.[13] While pretransplant cytoreduction is likely to be beneficial for many, if not most, patients, it is not clear whether this approach is appropriate for all patients, such as those with a minimal tumor burden at relapse.

Conclusions

Over the last 15 years, autologous hematopoietic stem-cell transplantation has become an accepted therapy for certain patients with relapsed or refractory lymphoma. However, only recently have prospective trials conclusively demonstrated survival benefits in certain situations. Continued patient participation in randomized trials is necessary to define the role of autologous hematopoietic stem-cell transplantation in lymphoma.

References:

1. Shipp M, Abeloff M, Antman K, et al: International consensus conference on high-dose therapy with hematopoietic stem cell transplantation in aggressive non-Hodgkin’s lymphomas: Report of the jury. J Clin Oncol 17:423-429, 1999.

2. Philip T, Armitage J, Spitzer G, et al: High-dose therapy and autologous bone marrow transplantation after failure of conventional chemotherapy in adults with intermediate-grade or high-grade non-Hodgkin’s lymphoma. N Engl J Med 316:1493-1498, 1987.

3. Mills W, Chopra R, McMillan A, et al: BEAM chemotherapy and autologous bone marrow transplantation for patients with relapsed or refractory non-Hodgkin’s lymphoma. J Clin Oncol 13:588-595, 1995.

4. Vose J, Rowlings P, Lazarus H, et al: Multivariate analysis of autotransplants for patients with aggressive non-Hodgkin lymphoma failing primary induction therapy (abstract). Blood 90(suppl 1):594a, 1997.

5. Haq R, Sawka C, Franssen E, et al: Significance of a partial or slow response to front-line chemotherapy in the management of intermediate-grade or high-grade non-Hodgkin’s lymphoma: A literature review. J Clin Oncol 12:1074-1084, 1994.

6. Verdonck L, van Putten W, Hagenbeek A, et al: Comparison of CHOP chemotherapy with autologous bone marrow transplantation for slowly responding patients with aggressive non-Hodgkin’s lymphoma. N Engl J Med 332:1045-1051, 1995.

7. Martelli M, Vignetti M, Zinzani P, et al: High-dose chemotherapy followed by autologous bone marrow transplantation versus dexamethasone, cisplatin, and cytarabine in aggressive non-Hodgkin’s lymphoma with partial response to front-line chemotherapy: A prospective randomized Italian multicenter study. J Clin Oncol 14:534-542, 1996.

8. Reyes F, Lepage E, Morel P, et al: Failure of first-line inductive high-dose chemotherapy (HDC) in poor-risk patients (PTS) with aggressive lymphoma: Updated results of the randomized LNH93-3 study (abstract). Blood 90(suppl 1):594a, 1997.

9. Bosly A, Sonet A, Salles G, et al: Superiority of late over early intensification in relapsing/refractory aggressive non-Hodgkin’s lymphoma: A randomized study from the GELA: LNH RP 93 (abstract). Blood 90(suppl 1):594a, 1997.

10. Clift R, Buckner C, Thomas E, et al: The treatment of acute non-lymphoblastic leukemia by allogeneic marrow transplantation. Bone Marrow Transplant 2:243-258, 1987.

11. Bierman P, Anderson J, Freeman M, et al: High-dose chemotherapy followed by autologous hematopoietic rescue for Hodgkin’s disease patients following first relapse after chemotherapy. Ann Oncol 7:151-156, 1996.

12. Sweetenham J, Taghipour G, Milligan D, et al: High-dose therapy and autologous stem cell rescue for patients with Hodgkin’s disease in first relapse after chemotherapy: Results from the EBMT. Bone Marrow Transplant 20:745-752, 1997.

13. Phillips G, Reece D, Wolff S, et al: The use of conventional salvage chemotherapy before dose-intensive cytotoxic therapy and autologous transplantation for aggressive-histology lymphoma: A case for re-evaluation. Leuk Lymphoma 26:507-513, 1997.