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© 2002 American Society for Clinical Oncology
Critical Factors in Optimizing Graft-Versus-Leukemia Effect for Relapsed LeukemiasBristol Royal Hospital for Sick Children, Bristol, United Kingdom To the Editor:Graft-versus-host disease has been shown to reduce the risk of relapse for acute leukemias,1 both lymphoid and myeloid, after an allogeneic transplantation, but donor lymphocyte infusion (DLI) is rarely effective in curing relapsed acute leukemias. One explanation for this phenomenon is the rapid progression of acute leukemias and accelerated chronic myeloid leukemia (CML). Chemotherapy alone is not effective in achieving a long-term cure in patients with these diseases. The approach used by Levine et al2 is probably the most rational one in that it uses cytoreduction before DLI. However, this approach failed to improve the disease-free or overall survival significantly. Graft-versus-host disease was associated with worse outcome and did not translate to a graft-versus-leukemia (GVL) effect.1 Given these findings, it would be tempting to hypothesise that the GVL effect does not cure relapsed leukemias. However, there are a few issues that need to be addressed in order to optimize the GVL effect. The concept of using mobilized DLI after chemotherapy is the same as a nonmyeloablative transplant. In that context, the timing of the DLI is probably critical. Bacigalupo et al3 reported that the impact of low-dose cyclosporine in reducing the relapse risk was in the first 10 days after transplantation. This is probably the period of maximal cytopenia and is the right milieu for the proliferation of donor effector cells with minimal or no competitive effect of host lymphocytes. Levine et al2 used DLI 10 to 14 days after the chemotherapy, which is not within this critical time period. On the basis of this observation, DLI should probably be scheduled within the first 3 days after chemotherapy, in accordance with the same principle as in a transplant procedure. One study suggested that patients with a greater burden of host lymphocytes respond less well to DLI.4 This concept is bolstered by the observation that after immunosuppression-based reduced-intensity conditioning, remission is achieved faster in CML patients than it is usually after DLI alone,5 and conversion to full donor chimerism in the T-cell lineage precedes a GVL response.6 Levine et al2 did not clarify how many patients received purine analog–based regimens and whether that influenced the outcome. There is probably a rationale for using purine analogs or other immunosuppressive drugs in the pre-DLI chemotherapy regimens to eliminate host lymphocytes that might impair the alloreactivity of donor lymphocytes by inducing tolerance. This brings in the question of T-cell chimerism and efficacy of DLI. Our limited experience with lineage-specific chimerism following both conventional and reduced-intensity transplantation suggests that donor T -cell engraftment lags behind granulocyte chimerism, which is often not picked up on chimerism analysis of whole blood or marrow. It would have been interesting to study the lineage-specific chimerism in relation to remission in the report by Levine et al.2 The final point we would like to highlight is that granulocyte colony-stimulating factor (CSF)–mobilized apheresis products might be important in preventing post-DLI aplasia, but the present body of literature suggests that granulocyte CSF might have a negative effect on alloreactivity.7 The use of granulocyte-macrophage CSF in mobilization, both before and after DLI, needs to be explored in an attempt to improve antigen presentation to the effector cells and improve the GVL effect. REFERENCES 1. Ringden O, Labopin M, Gorin NC, et al: Is there a graft-versus-leukaemia effect in the absence of graft-versus-host disease in patients undergoing bone marrow transplantation for acute leukaemia? Br J Haematol 111: 1130-1137, 2000[CrossRef][Medline]
2.
Levine JE, Braun T, Penza SL: Prospective trial of chemotherapy and donor leukocyte infusions for relapse of advanced myeloid malignancies after allogeneic stem-cell transplantation. J Clin Oncol 20: 405-412, 2002
3.
Bacigalupo A, Lamparelli T, Gualandi F, et al: Increased risk of leukemia relapse with high dose cyclosporine after allogeneic marrow transplantation for acute leukemia: 10 year follow-up of a randomized study. Blood 98: 3174-3175, 2001 4. Verdonck LF, Petersen EJ, Lokhorst HM, et al: Donor leukocyte infusions for recurrent hematologic malignancies after allogeneic bone marrow transplantation: Impact of infused and residual donor T cells. Bone Marrow Transplant 22: 1057-1063, 1998[CrossRef][Medline]
5.
Slavin S, Nagler A, Naparstek E, et al: Nonmyeloablative stem cell transplantation and cell therapy as an alternative to conventional bone marrow transplantation with lethal cytoreduction for the treatment of malignant and nonmalignant hematologic diseases. Blood 91: 756-763, 1998
6.
Childs R, Clave E, Contentin N, et al: Engraftment kinetics after nonmyeloablative allogeneic peripheral blood stem cell transplantation: Full donor T-cell chimerism precedes alloimmune responses. Blood 94: 3234-3241, 1999
7.
Korbling M, Anderlini P: Peripheral blood stem cell versus bone marrow allotransplantation: Does the source of hematopoietic stem cells matter? Blood 98: 2900-2908, 2001
Response
University of Michigan, Ann Arbor, MI In Reply:Dr Chakrabarti notes that acute leukemia relapse rates in adults were lower when less immunosuppression was given in the first 10 days after myeloablative transplantation. Recipients of lower-dose immunosuppression who were younger than 30 years had superior survival, but this benefit did not hold true for patients older than 30 years.1 On the basis of this observation, Chakrabarti speculates that the optimal time to achieve the graft-versus-leukemia (GVL) effect is to administer donor lymphocyte infusion (DLI) earlier than the 10 to 14 days following chemotherapy, as was performed in our study.2 However, earlier administration of DLI may increase the risk of graft-versus-host disease (GVHD) unless postinfusion immunosuppression is provided. In a myeloablative murine model, Xun et al3 showed that delaying T-cell infusion from day 0 to day 4 after total-body irradiation (TBI) led to a substantial reduction in GVHD -related mortality. Conditioning-related tissue damage and subsequent inflammatory cytokine release might be important mechanisms for the risk of lethal GVHD after T-cell infusion.4 Although Chakrabarti puts forth an interesting hypothesis, further study will be needed to determine whether an earlier DLI will result in a greater GVL effect, worse GVHD, both, or neither. Chakrabarti interprets the failure to observe a survival benefit of GVHD after DLI in our study to mean that a GVL effect was not operative. This is not necessarily true. Horowitz et al5 showed that the GVL effect need not occur in the context of clinically evident GVHD. However, in the absence of a randomized comparison, we make no claim of superiority of our approach over any other. For example, Pawson et al6 recently reported overall survival of 60% and disease-free survival of 28% at 58 months after a second nonmyeloablative transplant for acute leukemia relapse following a failed first allogeneic transplant. We believe that further investigation into inducing meaningful GVL effects while minimizing regimen-related and GVHD-related mortality is warranted for patients with advanced myeloid leukemia relapse after allogeneic stem-cell transplantation. REFERENCES
1.
Bacigalupo A, Lamparelli T, Gualandi F, et al: Increased risk of leukemia relapse with high dose cyclosporine after allogeneic marrow transplantation for acute leukemia: 10 year follow-up of a randomized study. Blood 98: 3174-3175, 2001
2.
Levine JE, Braun T, Penza SL, et al: Prospective trial of chemotherapy and donor leukocyte infusions for relapse of advanced myeloid malignancies after allogeneic stem-cell transplantation. J Clin Oncol 20: 405-412, 2002 3. Xun CQ, Tsuchida M, Thompson JS: Delaying transplantation after total body irradiation is a simple and effective way to reduce acute graft-versus-host disease mortality after major H2 incompatible transplantation. Transplantation 64: 297-302, 1997[CrossRef][Medline]
4.
Hill GR, Crawford JM, Cooke KR, et al: Total body irradiation and acute graft-versus-host disease: The role of gastrointestinal damage and inflammatory cytokines. Blood 90: 3204-3213, 1997
5.
Horowitz MM, Gale RP, Sondel PM, et al: Graft-versus-leukemia reactions after bone marrow transplantation. Blood 75: 555-562, 1990 6. Pawson R, Potter MN, Theocharous P, et al: Treatment of relapse after allogeneic bone marrow transplantation with reduced intensity conditioning (FLAG +/- Ida) and second allogeneic stem cell transplant. Br J Haematol 115: 622-629, 2001[Medline]
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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