Originally published as JCO Early Release 10.1200/JCO.2003.05.984 on September 8 2003

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The Graft-Versus-Lymphoma Effect: Fact, Fiction, or Opportunity?

Experimental Transplantation and Immunology Branch, National Cancer Institute, Bethesda, MD

A CLINICALLY relevant, immune-mediated antitumor effect against malignant lymphomas after allogeneic hematopoietic stem-cell transplantation, referred to as the graft-versus-lymphoma effect, was suggested slightly less than 15 years ago,¹ and similarly had been observed against acute and chronic leukemias, especially chronic myelogenous leukemia (CML).^2,3 The potency of the graft-versus-leukemia effect has subsequently been demonstrated in multiple reports by the high response rate of CML to donor lymphocyte infusions.⁴ In marked contrast, there have been relatively few reports to support the existence of a clinically relevant graft-versus-lymphoma effect against non-Hodgkin’s lymphoma (NHL). Ratanatharathorn et al⁵ conducted a prospective trial comparing allogeneic to autologous bone marrow transplantation after myeloablative conditioning in 66 consecutive patients with recurrent NHL. The progression-free survival was not statistically different between the two groups; however, the probability of disease progression was significantly higher in the autologous group (P = .001), suggesting a graft-versus-lymphoma effect. In a multivariate analysis of these results, chemotherapy-sensitive disease and the use of an allograft were found to have a significant favorable influence on progression. Unfortunately, there have been no randomized trials that have determined if a clinically relevant graft-versus-lymphoma effect exists.

To address this question, the databases of the International Bone Marrow Transplant Registry, the European Group for Blood and Marrow Transplantation, and the Autologous Blood and Marrow Transplant Registry were combined and analyzed. In this issue of the Journal of Clinical Oncology, Bierman et al⁶ present the results of this analysis, which compared the relapse rates of NHL patients who underwent either syngeneic, autologous (purged v unpurged), or allogeneic (T-cell replete v T-cell depleted) hematopoietic stem-cell transplants. The data from this analysis are compelling and raise the question of whether a graft-versus-lymphoma effect is either completely absent or of so little potency that it is clinically irrelevant. On the basis of their interpretation of these data, the authors state that a clinically relevant graft-versus-lymphoma effect was not detectable in NHL patients who received an allogeneic stem-cell transplant, and suggest that greater emphasis should be placed on autologous stem-cell graft contamination, relative to its contribution to relapse.

However, the data should be reviewed and interpreted cautiously. The design of this analysis is based, in part, on a previous analysis by the International Bone Marrow Transplant Registry that demonstrated a graft-versus-leukemia reaction in association with graft-versus-host disease (GVHD) after allogeneic bone marrow transplantation.³ This previous analysis included a relatively homogeneous patient population; it only included patients with acute leukemia in first complete remission or CML in chronic phase. In marked contrast, the analysis presented here is extremely heterogeneous relative to histology and multiple other characteristics of NHL. The heterogeneity of the data set is highlighted if one examines the major factors that influence the consideration of NHL patients for hematopoietic stem-cell transplantation. These factors include histology, availability of stem-cell source (allogeneic donor availability and bone marrow involvement), disease status (induction failure v remission v relapse), and disease sensitivity to chemotherapy. The overwhelming majority of NHL patients referred for autologous stem-cell transplantation have chemotherapy-sensitive disease, regardless of histology. This assertion is supported in this data set by the fact that more than 70% of patients who underwent autologous stem-cell transplantation had chemotherapy-sensitive disease, as opposed to less than 40% of patients who underwent allogeneic stem-cell transplantation. An additional concern is that chemotherapy sensitivity was either unknown or untested in more than 50% of the patients who underwent allogeneic stem-cell transplantation, as compared with 15% and 29% of autologous and syngeneic patients, respectively. Adjustments were made to compensate for the lack of data for chemotherapy sensitivity, but the numbers of comparable patients then become increasingly smaller, especially when additional variables, such as histology, are included.

After the serious limitations of this analysis are taken into careful consideration, the question remains: If a graft-versus-lymphoma effect does exist, why was evidence of it not observed in this analysis? It must first be pointed out that the relapse rates associated with syngeneic transplants in this analysis, especially in low-grade histologies, were so low that it made the demonstration of a possible graft-versus-lymphoma effect statistically difficult. There are several potential explanations for the low relapse rate associated with syngeneic stem-cell transplantation. The first, and the one most readily supported by the data set analysis, is the absence of tumor within the syngeneic graft. The contribution to relapse by an autograft contaminated with tumor cells has been suggested previously by several investigators. Gribben et al⁷ demonstrated that the inability to purge residual lymphoma cells from the autograft was an important prognostic indicator in predicting relapse after autologous bone marrow transplantation. The results of the combined registries’ analysis support the contention that the infusion of malignant cells within autografts may contribute to relapse and suggest there is clinical utility for ex vivo purging of autografts in patients with lymphoma.

A second possible explanation for the excellent results with syngeneic transplantation is selection bias. There seems little to support this contention because the choice of a syngeneic graft seems consistent across histologies; however, chemotherapy sensitivity may still have been a factor. Another explanation is the theoretical possibility that the syngeneic graft provides a positive immunologic effect. A significant difference between autografts and syngeneic grafts is that immunologic repertoire of the autografts is limited by prior therapy, whereas the syngeneic graft contains lymphocytes from a healthy, immune-competent individual.⁸

There are several anecdotal reports of GVHD after syngeneic stem-cell transplantation.^9,10 Even if a possible graft-versus-lymphoma effect was associated with syngeneic stem-cell transplantation, it would be assumed to be more pronounced with an allogeneic stem-cell transplant. More importantly, it would be expected that the relapse rates would have been higher with T-cell depletion or lack of chronic GVHD, but they were not.

The strongest argument that a clinically relevant graft-versus-lymphoma effect exists is the demonstration of NHL regression after withdrawal of immune suppression or the infusion of donor lymphocytes posttransplantation in other series.^11–13 It is possible a graft-versus-lymphoma effect was present among the patients that were analyzed in this analysis, but the effect could not be detected to provide a clinically beneficial effect relative to other disease characteristics, such as histology and chemotherapy sensitivity. With regard to histology, the efficacy of donor lymphocyte infusion in NHL has primarily been limited to follicular or low-grade histologies, with only anecdotal cases in patients with diffuse large-cell or more aggressive histologies. This may reflect the biologic characteristics, such as growth rate or antigen expression, of the respective histologies.

What may be the most important factor in syngeneic, autologous, and allogeneic stem-cell transplantation for NHL is chemotherapy sensitivity. For patients with chemotherapy-sensitive disease, a graft-versus-lymphoma effect, if it exists, may contribute little or nothing because patients may already be cured by myeloablative conditioning. In extremely chemotherapy-refractory patients, it may be insufficiently potent to be detectable because the tumor growth rate exceeds the ability of the immune effect to eliminate disease. In all multivariate analyses run on the combined registry data, chemotherapy sensitivity was a significant variable across all histologies. If one goes back to the analogy of acute leukemias and CML, it would have been difficult to identify a graft-versus-leukemia effect if it had been performed in relapsed acute leukemias and advanced-phase CML.

This analysis is especially relevant in light of the current interest in the use of nonmyeloablative and reduced-intensity allogeneic hematopoietic stem-cell transplantation in NHL. Any possible graft-versus-lymphoma effect may be more clinically evident in the nonmyeloablative and reduced-intensity settings where the beneficial—if not curative—effects of high-dose therapy are significantly reduced. However, chemotherapy sensitivity remains an important prognostic factor in reduced-intensity allogeneic stem-cell transplantation for NHL, as well. In a retrospective analysis from the European Group for Blood and Marrow Transplantation on the use of reduced-intensity allogeneic stem-cell transplantation in malignant lymphomas, the 1-year progression-free survival for patients with chemotherapy-sensitive and chemotherapy-resistant disease was 71% and 23%, respectively (P = .001).¹³ Interestingly, there were no relapses among patients receiving transplants from unrelated donors, suggesting that greater histocompatibility differences may accentuate a beneficial graft-versus-lymphoma effect. Another important observation from this report was that the use of donor lymphocyte infusions in 14 patients with recurrent or persistent disease resulted in responses in ten patients, including six complete responses.

The current combined analysis by these three registries has still not documented whether a clinically relevant graft-versus-lymphoma effect exists, and has raised more questions with regard to graft contamination, immune competence of the graft, and the need to further understand and accentuate alloreactivity toward NHL. These questions are all extremely relevant to hematopoietic stem-cell transplantation for NHL and will, it is hoped, be addressed in future clinical trials.

AUTHOR’S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author indicated no potential conflicts of interest.

REFERENCES

1. Jones RJ, Ambinder RF, Piantadosi S, et al: Evidence of a graft-versus-lymphoma effect associated with allogeneic bone marrow transplantation. Blood 77:649–653, 1991[Abstract/Free Full Text]

2. Weiden PL, Flournoy N, Thomas ED, et al: Antileukemic effect of graft-versus-host disease in human recipients of allogeneic-marrow grafts. N Engl J Med 300:1068–1073, 1979[Abstract]

3. Horowitz MM, Gale RP, Sondel PM, et al: Graft-versus-leukemia reactions after bone marrow transplantation. Blood 75:555–562, 1990[Abstract/Free Full Text]

4. Porter DL, Antin JH: The graft-versus-leukemia effects of allogeneic cell therapy. Annu Rev Med 50:369–386, 1999[CrossRef][Medline]

5. Ratanatharathorn V, Uberti J, Karanes C, et al: Prospective comparative trial of autologous versus allogeneic bone marrow transplantation in patients with non-Hodgkin’s lymphoma. Blood 84:1050–1055, 1994[Abstract/Free Full Text]

6. Bierman PJ, Sweetenham JW, Loberiza FR, et al: Syngeneic hematopoietic stem-cell transplantation for non-Hodgkin’s lymphoma: A comparison with allogeneic and autologous transplantation. J Clin Oncol 21:3744–3753, 2003[Abstract/Free Full Text]

7. Gribben JG, Freedman AS, Neuberg D, et al: Immunologic purging of marrow assessed by PCR before autologous bone marrow transplantation for B-cell lymphoma. N Engl J Med 325:1525–1533, 1991[Abstract]

8. Mackall CL, Gress RE: Pathways of T-cell regeneration in mice and humans: Implications for bone marrow transplantation and immunotherapy. Immunol Rev 157:61–72, 1997[CrossRef][Medline]

9. Hood AF, Vogelsang GB, Black LP, et al: Acute graft-vs-host disease: Development following autologous and syngeneic bone marrow transplantation. Arch Dermatol 123:745–750, 1987[Abstract/Free Full Text]

10. Reiter E, Greinix HT, Mitterbauer G, et al: Graft-versus-host disease following second syngeneic stem cell transplantation for relapsed chronic myeloid leukemia. Ann Hematol 77:283–286, 1998[CrossRef][Medline]

11. van Besien KW, de Lima M, Giralt SA, et al: Management of lymphoma recurrence after allogeneic transplantation: The relevance of graft-versus-lymphoma effect. Bone Marrow Transplant 19:977–982, 1997[CrossRef][Medline]

12. Mandigers CM, Meijerink JP, Raemaekers JM, et al: Graft-versus-lymphoma effect of donor leucocyte infusion shown by real-time quantitative PCR analysis of t(14;18). Lancet 352:1522–1523, 1998[CrossRef][Medline]

13. Robinson SP, Goldstone AH, Mackinnon S, et al: Chemotherapy-resistant or aggressive lymphoma predicts for a poor outcome following reduced-intensity allogeneic progenitor cell transplantation: An analysis from the Lymphoma Working Party of the European Group for Blood and Bone Marrow Transplantation. Blood 100:4310–4316, 2002[Abstract/Free Full Text]

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