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© 1999 American Society for Clinical Oncology
Purine Analog Regimens for Allogeneic Transplant?Washington University School of Medicine, St Louis, MO To the Editor: For patients with leukemia undergoing allogeneic transplantation, the primary goals of the conditioning regimen include elimination of malignant cells for disease control and recipient lymphoid cells to permit durable donor hematopoietic stem-cell engraftment. To meet these objectives, conditioning regimens for allogeneic transplantation are characteristically myeloablative and lymphoablative. Such regimens are associated with substantial risk of morbidity and mortality. Older patients (age > 50 years) and those with confounding medical conditions are frequently not eligible for allogeneic transplantation because of the excess risks associated with these regimens.
Attempts to improve the outcomes of allogeneic transplantation by altering the conditioning regimen have been explored. Clift et al1 observed that intensification of the conditioning regimen by increasing the total dose of irradiation significantly decreased the risk of leukemic relapse; however, treatment-related mortality (TRM) was increased, resulting in no improvement in survival. Recently, several groups evaluated less intense conditioning regimens in an attempt to reduce treatment-related toxicity. Such low-intensity conditioning regimens could improve disease-free survival if the reduction in TRM was not offset by increased relapse risk. These regimens would be safer to administer to high-risk patients who may not have historically been considered candidates for this procedure because of advanced age or concurrent medical illnesses. Khouri et al2 and Giralt et al3 presented outcomes of patients who underwent allogeneic transplantation with purine analog–based conditioning regimens which are immunosuppressive but not myeloablative. Khouri et al2 treated 15 patients with chronic lymphocytic leukemia or lymphoma and observed that this regimen was well tolerated, with one TRM (6.7%) and rare
Giralt et al3 treated 15 patients with advanced leukemia or myelodysplasia with purine analog–based nonmyeloablative conditioning regimens for allogeneic transplantation. The regimen was well tolerated, with only two patients developing The data presented by Khouri et al2 and Giralt et al3 support the conclusion that purine analog–based regimens for allogeneic transplantation are well tolerated. However, these regimens are not myeloablative and seem to be lymphoablative in only a minority of patients, based on the low likelihood of complete donor chimerism after transplantation. In the few who achieved 100% donor chimerism, the durability of engraftment was unclear. Although these patients had relapsed or refractory disease before transplantation, the relatively high probability of failure to achieve CR early after transplantation and the rapid recurrence in many who did achieve CR suggests that the antileukemic activity of this strategy is modest to poor. Perhaps chronic myelogenous leukemia (CML), a disease frequently responsive to the graft-versus-leukemia immunologic effect, would be a better choice to further explore this strategy. However, a preliminary report by Giralt et al5 presented data suggesting that this may not be appropriate. Among four patients with chronic-phase CML treated with a purine analog–based conditioning regimen and allogeneic transplantation, only transient hematologic and cytogenetic remissions were observed. The curative potential of allogeneic transplantation is due to the combined effect of the conditioning regimen and the graft-versus-leukemia effect of durably engrafted donor lymphoid cells. The studies by Khouri et al2 and Giralt et al3 demonstrated that decreasing the intensity of the conditioning regimen reduced the nonhematologic toxicity. However, the low likelihood of complete donor chimerism and the high risk of leukemic relapse after transplantation, even in favorable patients with chronic-phase CML, suggest that the strategy of purine analog–based nonmyeloablative conditioning regimens for allogeneic transplantation should be pursued cautiously. This is especially true for good-risk patients with CML in chronic phase and acute leukemia in first remission who have a reasonably good prognosis with conventional regimens used for allogeneic transplantation. Although it could be speculated that good-risk patients who failed a nonmyeloablative allogeneic transplant regimen could subsequently be "rescued" with a conventional intense conditioning regimen for allogeneic transplantation, prior exposure to the donor cells during the first transplant procedure may sensitize the recipient to donor antigens and increase the likelihood for graft rejection after the second transplant. REFERENCES
1958.
Clift RA, Buckner CD, Appelbaum FR, et al: Long-term follow-up of a randomized trial of two irradiation regimens for patients receiving allogeneic marrow transplant during first remission of acute myeloid leukemia. Blood 92:1455-1456 1998 1958. Khouri IA, 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[Abstract]
1958.
Giralt S, Estey E, Albitar M, et al: Engraftment of allogeneic hematopoietic progenitor cells with purine analog-containing chemotherapy: Harnessing graft-versus-leukemia without myeloablative therapy. Blood 89:4531-4536 1997 1958. van Besien KW, Khouri IF, Giralt SA, et al: Allogeneic bone marrow transplantation for refractory and recurrent low-grade lymphoma: The case for aggressive management. J Clin Oncol 13:1096-1102 1995[Abstract] 1958. Giralt S, Gajewski J, Khouri I, et al: Induction of graft-vs-leukemia (GVL) as primary treatment of chronic myelogenous leukemia (CML). Blood 90:418a, 1997 (abstr 1857)
ResponseM.D. Anderson Cancer Center, Houston, TX In Reply: Bone marrow transplantation was initially developed as a means to deliver supralethal doses of chemotherapy and radiation for treatment of malignancies. The transplant per se was considered a supportive-care modality to restore hematopoiesis. Over the last decade, however, it has become clear that the high-dose therapy does not eradicate the malignancy in many patients and that the therapeutic benefit of allogeneic marrow transplantation is largely related to an associated immune-mediated graft-versus-malignancy effect. This concept is supported by intensive clinical and experimental data. These include a reduced risk of relapse in transplant recipients with leukemia and chronic graft-versus-host disease1-3 and a higher relapse risk after syngeneic bone marrow transplantation.4-6 T-cell–depleted allotransplants are also associated with an increased risk of relapse, particularly in patients with chronic myelogenous leukemia.2 Minimal residual disease can be detected in most patients after high-dose chemotherapy, using polymerase chain reaction–based techniques for bcr-abl rearrangement.7,8 The malignant cells are eliminated in most patients who receive unmodified marrow transplants during the first 6 months after transplantation. The most direct evidence of this graft-versus-malignancy effect, however, is the finding that many patients who relapse after allogeneic transplantation can be reinduced into remission by simply infusing additional donor lymphocytes after transplantation, presumably because of the graft-versus-leukemia (GVL) effect.9,10 These observations are suggesting an alternative strategy, using a low-dose, nonmyeloablative, preparative regimen designed not to eradicate the malignancy but to provide sufficient immunosuppression to achieve engraftment of an allogeneic blood stem cell and development of a graft-versus-malignancy effect. We performed severe pilot studies in patients who were considered ineligible for high-dose myeloablative preparative regimens because of advanced age or comorbidities. Indolent lymphoid malignancies were of particular interest because these disorders typically affect older and often debilitated patients. Hence we designed a phase I trial that used a combination of fludarabine and cyclophosphamide, which we reported in the Journal of Clinical Oncology.11 The trial was designed to allow engraftment with the least possible toxicity. With the lowest dose level of fludarabine/cyclophosphamide, two of five patients engrafted myeloid donor cells; with the highest dose level, five of five patients engrafted. The percentage of donor cells in the marrow was 50% to 100% at 1 month after transplantation. One patient had 75% donor cells in his marrow at 6 weeks after transplantation and converted to 100% donor cells after a donor lymphocyte infusion. There were no adverse effects. We initially reported one treatment-related mortality caused by liver failure in a patient who had hepatitis C infection at the time of transplantation. A recent autopsy report has instead shown progressive large-cell lymphoma in the liver. This trial was designed to address the feasibility of the procedure. In order to assess overall response, one has to consider only the 11 patients who achieved engraftment. As such, eight patients (72.7%) achieved a complete response. This is a rate comparable to the 80% that the authors were referring to in a group of patients who were younger and without any comorbid medical illness, who were previously treated at our institution with high-dose chemotherapy. The optimal intensity of the preparative regimen depends on several factors, including its susceptibility to graft-versus-malignancy effects, the aggressiveness of the underlying malignancy, immunocompetence of the host, and genetic disparity between donor and recipient. Immunocompromised patients, such as those with advanced chronic lymphocytic leukemia, require less intensive immunosuppression therapy to achieve engraftment than a fully immunocompetent recipient. Also, such indolent malignancies may not require major cytoreduction and may respond dramatically from GVL effects. More cytoreduction, however, is necessary to achieve at least a short-term remission in patients with highly proliferative malignancies, such as acute leukemias and aggressive lymphomas, to allow time for development of an effective GVL response. This explains the short survival in the 15 patients with advanced leukemia or myelodysplasia reported in Blood.12 The regimen used was mild, consisting of a combination of fludarabine/idarubicin and cytarabine at conventional doses. The same regimen, however, has been recently shown to be successful for consolidation of remission in patients at high risk of relapse. Nine of 10 patients who received transplants in such condition are in remission for more than 1 year (Giralt et al, unpublished data). Although the preliminary results are encouraging, the ultimate role for the nonmyeloablative preparative regimen and induction of graft-versus-malignancy effects is uncertain. This strategy allows treatment of older and medically infirm patients who cannot tolerate conventional high-dose preparative regimens. Whether the benefit of reduced toxicity will offset the reduced cytoreduction compared with full-dose preparative regimens must still be determined for each diagnosis and category of patient. Controlled trials are necessary to compare this approach with standard, ablative transplantation regimens. REFERENCES 1. Weiden PL, Sullivan KM, Fluornoy N, et al: Antileukemic effect of chronic graft-versus-host disease: Contribution to improved survival after allogeneic marrow transplantation. N Engl J Med 304:1529-1532 1981[Medline]
2.
Horowitz MM, Gale RP, Sondel PM, et al: Graft-versus-leukemia reactions after bone marrow transplantation. Blood 75:555-562 1990 3. Sullivan KM, Storb R, Buckner CD, et al: Graft-versus-host disease as adoptive immunotherapy in patients with advanced hematologic neoplasms. N Engl J Med 320:828-834 1989[Abstract] 4. Gale RP, Champlin RE: How does bone marrow transplantation cure leukemia? Lancet 2:28-30 1981 5. Fefer A, Cheever MA, Greeberg P: Identical-twin (syngenic) marrow transplantation for hematologic cancers. J Natl Cancer Inst 76:1269-1271 1986
6.
Gale RP, Horowitz MM, Ash RC, et al: Identical-twin bone marrow transplants for leukemia. Ann Intern Med 120:646-652 1994
7.
Hughes TP, Morgan GJ, Martiat P, et al: Detection of residual leukemia after bone marrow transplant for chronic myeloid leukemia: Role of polymerase chain reaction in predicting relapse. Blood 77:874-878 1991
8.
Radich JP, Gehly G, Gooley T, et al: Polymerase chain reaction detection of the BCR-ABL fusion transcript after allogeneic marrow transplantation for chronic myeloid leukemia: Results and implications in 346 patients. Blood 85:2632-2638 1995
9.
Drobyski WR, Keever CA, Roth MS, et al: Salvage immunotherapy using donor leukocyte infusions as treatment for relapsed chronic myelogenous leukemia after allogeneic bone marrow transplantation: Efficacy and toxicity of a defined T-cell dose. Blood 82:2310-2318 1993
10.
Kolb HJ, Schattenberg A, Goldman JM, et al: Graft-vs-leukemia effect of donor lymphocyte transfusions in marrow grafted patients. Blood 86:2041-2050 1995 11. Khouri I, Keating M, Korbling M, et al: Transplant lite: Induction of graft-versus-leukemia using fludarabine-based nonablative chemotherapy and allogeneic blood progenitor cell transplantation as treatment for lymphoid malignancies. J Clin Oncol 16:2817-2824 1998 12. Giralt S, Estey E, Albitar M, et al: Engraftment of allogeneic hematopoietic progenitor cells with purine analog-containing chemotherapy: Harnessing graft-versus-leukemia without myeloablative therapy. Blood 89:4531-4536 1997
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Copyright © 1999 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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grade 3 nonhematologic toxicity. Eleven patients had engraftment of donor cells, but only five of these patients had complete (100%) donor chimerism early after transplantation. Four patients did not engraft donor cells but recovered with autologous hematopoiesis. Because only two of the 15 patients had assessment of chimerism beyond 6 months after transplantation, it is unclear whether durable donor engraftment can be achieved with this regimen. In this report, control of disease was also of concern. Although eight patients (53%) achieved complete response (CR) after transplantation, an earlier report from the same institution using an intense conditioning regimen reported that 80% of similar patients achieved CR.
