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Hematopoietic Cell Transplantation for Non-Hodgkin's Lymphoma: Yesterday, Today, and Tomorrow

Fred Hutchinson Cancer Research Center and University of Washington, Seattle, WA

YESTERDAY

Twenty-five years ago (it seems like yesterday), we published a brief review of the use of hematopoietic cell transplantation (HCT) for the treatment of non-Hodgkin's lymphoma (NHL) summarizing early results using autologous, syngeneic, and allogeneic sources of marrow.¹ The first series of patients treated for recurrent NHL using high-dose chemotherapy with cryopreserved autologous marrow support was published in 1978 in a study showing that cryopreserved marrow did, indeed, hasten hematopoietic recovery and that this approach could cure otherwise incurable patients, at least in the setting of recurrent Burkitt's lymphoma.² Several years later, we reported the result of syngeneic HCT for NHL, demonstrating cure of patients with recurrent NHL of more common histologic subtypes using high-dose chemoradiotherapy with syngeneic marrow support.³ Our initial study of allogeneic HCT for recurrent NHL likewise reported long-term survival in a minority of patients, suggesting that allogeneic transplantation is an option for patients with known marrow involvement and further raising the question of a graft-versus-lymphoma effect, analogous to that reported for leukemia.⁴

TODAY

Twenty-five years after that initial review, HCT for NHL has become a widely used therapy. In 2005, more than 4,000 patients with NHL were treated with HCT in the United States, approximately 80% of whom received autologous transplants.⁵ Most of the studies defining current indications of HCT in the treatment of NHL were performed in the pre-rituximab era and thus bear repeating. But given our current knowledge, autologous HCT is the standard of care for patients with diffuse large-cell lymphoma who have suffered their first relapse, on the basis of well-controlled prospective randomized trials.⁶ Whether autologous HCT has a role in the initial treatment of patients with diffuse large-cell lymphoma remains a matter of debate. A recent meta-analysis of randomized trials addressing this question found no conclusive evidence of an overall benefit with HCT in first remission, although patients with poor-risk disease, defined as having more than one International Prognostic Index factor, seemed to have improved survival if they underwent transplantation.⁷ The possible benefit of consolidation with HCT after chemotherapy with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone for patients with intermediate- and high-risk International Prognostic Index scores is the subject of the current intergroup trial (S9704) led by the Southwest Oncology Group. In general, the role of allogeneic HCT for patients with diffuse large-cell lymphoma has been limited. Comparisons of outcomes of myeloablative allogeneic HCT with those after autologous HCT found decreased relapse rates with allogeneic HCT but increased treatment-related fatalities.⁸ The use of reduced-intensity conditioning (RIC) has resulted in a substantial reduction of transplant-related fatalities. Baron et al⁹ recently published a report demonstrating 31% 3-year survival with allogeneic HCT using RIC in patients with aggressive lymphomas who had previously experienced treatment failure with autologous HCT. Given the poor prognosis of such patients, this outcome raises the possibility of a broader role of RIC followed by allogeneic transplantation for aggressive lymphomas.

On the basis of retrospective studies and at least one prospective randomized trial, autologous transplantation for patients with relapsed follicular lymphoma seems to extend disease-free and overall survival.^10,11 Whether patients with recurrent follicular lymphoma can be cured using autologous HCT is unsettled, with at least one study showing a late plateau in the survival curve of patients undergoing transplantation for relapsed disease.¹² The role of autologous HCT for follicular lymphoma in first remission has been the subject of at least three randomized trials. All three showed improved disease-free survival with transplantation, but none showed improved overall survival at the time of publication.^13-15 Results after further follow-up will be of great interest, but given the large number of emerging therapies for follicular lymphoma, including alternative antibodies, vaccines, and radio-immunoconjugates, it seems unlikely that autologous HCT will assume a large role in initial therapy, at least in the United States. Because of a high incidence of transplant-related toxicities, allogeneic transplantation using high-dose preparative regimens has generally been limited to patients with advanced disease. More recently, encouraging results have been reported with the use of RIC followed by allogeneic transplantation in patients with recurrent follicular lymphoma. The Seattle group, for example, recently presented data on 46 patients with follicular lymphoma, median age of 54 years, who had received an average of six prior regimens. The 3-year estimated overall and progression-free survival rates were 52% and 43%, respectively.¹⁶ Khouri et al¹⁷ have reported even more impressive results, albeit in a group of patients treated earlier in their disease course, with an 85% 3-year disease-free survival rate and an 88% overall survival rate among 47 patients.

The role of HCT in less common lymphomas, such as mantle-cell lymphoma (MCL) and T-cell lymphoma, is less clear, largely because of difficulties performing broad phase II and randomized phase III studies in these rarer histologic subtypes. Autologous HCT using a novel preparative regimen that includes high-dose I-131 tositumomab has shown promise in recurrent MCL.¹⁸ A single randomized trial of autologous HCT as part of initial therapy of MCL has been conducted and showed that HCT led to a significant prolongation of disease-free survival, with a less apparent impact on overall survival, in part because autologous HCT was used as salvage therapy for some of the control group.¹⁹ MCL seems to be quite sensitive to a graft-versus-tumor effect, and early results of reduced-intensity transplants for recurrent disease show considerable promise.²⁰ Although data are limited, encouraging results have also been reported with allogeneic HCT using RIC in peripheral T-cell lymphomas.²¹

Despite the studies defining indications for HCT in NHL, in the majority of cases, these indications are not followed. As noted above, prospective trials have demonstrated a survival advantage with autologous HCT for recurrent large-cell and follicular cell lymphoma. It is estimated that more than 60,000 new cases of NHL were diagnosed in the United States in 2007, and more than 18,500 patients died of the disease, yet only 4,000 transplantations were performed. The reasons for this apparent underutilization are likely complex but deserve study.

It is also disappointing that there hasn’t been more progress in improving the general techniques of HCT. Today's most commonly used ablative preparative regimens before autologous transplantation, cyclophosphamide/total-body irradiation and carmustine, etoposide, cytarabine, and melphalan (BEAM), are essentially the same as those used 25 years ago. There has been a switch in the source of autologous stem cells from bone marrow to peripheral blood, and although this has greatly reduced the toxicity and improved the safety of the approach, whether it has impacted survival is uncertain. We still have not developed ways to assure that the autologous stem-cell source is tumor-free, nor has any post-transplantation manipulation been proven to prevent disease recurrence. A major change in allogeneic transplantation has been its greatly widened availability with the use of unrelated donors and cord blood as stem-cell sources. A further change has been the application of RIC regimens for patients unable to tolerate more intensive treatment. But, as in the case of autologous transplantation, no preparative regimen with greater antitumor capacity has been broadly applied, and no technique to segregate the potentially powerful graft-versus-lymphoma effect from the toxicities of graft-versus-host disease has yet been developed.

TOMORROW

If, 25 years ago, we had been asked about the role of HCT for NHL in 2008, we might have optimistically predicted that with improvements in more standard approaches, the era of transplantation would have come and gone. In fact, more transplantations for NHL are performed today than ever before. Because it does not seem that HCT is going away any time soon, continued effort to improve patient outcomes would seem to be a worthwhile investment.

It is inevitable that the indications for HCT will change over the next few years. The use of genomic and proteomic profiling, other molecular diagnostics, and positron emission tomography hopefully will lead to a better understanding of those patients who will most benefit from early HCT and those who can be cured with more conventional approaches.

As supportive care has improved, the major and almost sole reason for failure of autologous transplantation is disease recurrence, emphasizing the need for the development of improved preparative regimens, a need that was recognized 25 years ago. Studies led by Press et al²² and others²³ suggest that the use of high-dose radioimmunotherapy may offer our current best hope to improve on standard transplantation conditioning regimens. A current prospective randomized trial is being conducted by the Bone Marrow Transplant Clinical Trials Network comparing standard BEAM conditioning with BEAM plus I-131 tositumomab. Although this is a reasonable and uncomplicated study, it should also be recognized that the dose of radioimmunotherapy being tested is far less than is used in some of the most promising pilot studies.

Just as the success of autologous HCT emphasizes the importance of dose in the cure of NHL, so the results of allogeneic HCT using RIC emphasize the role of T-cell immunity in eradicating disease. The early post-transplantation period is an attractive setting for immunotherapy both because of a reduced tumor burden and because the ablated immune system should allow rapid expansion of specifically targeted T cells. A general strategy has been to isolate T cells with high avidity for tumor-associated antigens, expand such cells in vitro, and reinfuse them early post-transplantation. Work in this area has revealed many of the scientific and practical obstacles to this approach, but at the same time occasional dramatic clinical responses have been achieved in specific settings.²⁴ Although it is possible to identify tumor-specific antigens for specific individuals, such as immunoglobulin idiotype, such an approach will be difficult to apply broadly and so a goal has been to use antigens expressed specifically or preferentially by tumors from broad populations of patients, such as CD19 or CD20. One way to target such antigens is to introduce into T cells chimeric antigen receptors specific for these surface molecules.^25,26 Clinical trials using such cells are currently underway.

Although we can lament that we have not made more progress over the last 25 years in the application of HCT for the treatment of NHL, we have also learned a great deal and now have more knowledge of the biology of NHL, as well as more ways to enhance the dose-response and immunologic effects of HCT, than ever before. Capitalizing on this knowledge requires the hard work of clinical investigation, and every patient treated off of a clinical trial is a lost opportunity.

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest.

REFERENCES

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This Article Full Text (PDF) From JCO 1983 Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Google Scholar Articles by Appelbaum, F. R. PubMed PubMed Citation Articles by Appelbaum, F. R.