Purine Analog Regimens for Allogeneic Transplant?
Authors: D. Adkins, R. Brown, L. Goodnough, H. Khoury, J. DiPersio, Issa Khouri, Richard Champlin
Journal: Journal of Clinical Oncology (1999)

Article Tools Correspondence Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.1999.17.6.1958 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 10561238 Purine Analog Regimens for Allogeneic Transplant? D. AdkinsxD. AdkinsSearch for articles by this author , R. BrownxR. BrownSearch for articles by this author , L. GoodnoughxL. GoodnoughSearch for articles by this author , H. KhouryxH. KhourySearch for articles by this author , J. DiPersioxJ. DiPersioSearch for articles by this author Issa KhourixIssa KhouriSearch for articles by this author , Richard ChamplinxRichard ChamplinSearch for articles by this author Show More Washington University School of Medicine, St Louis, MOM.D. Anderson Cancer Center, Houston, TX https://doi.org/10.1200/JCO.1999.17.6.1958 First Page Full Text PDF Figures and Tables © 1999 by American Society of Clinical OncologyjcoJ Clin OncolJournal of Clinical OncologyJCO0732-183X1527-7755American Society of Clinical OncologyResponse01061999In 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.9,10These 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.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::1529,1981-1532 Crossref, Medline, Google Scholar2. Horowitz MM, Gale RP, Sondel PM, et al: Graft-versus-leukemia reactions after bone marrow transplantation. Blood 75::555,1990-562 Crossref, Medline, Google Scholar3. 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::828,1989-834 Crossref, Medline, Google Scholar4. Gale RP, Champlin RE: How does bone marrow transplantation cure leukemia? Lancet 2::28,1981-30 Google Scholar5. Fefer A, Cheever MA, Greeberg P: Identical-twin (syngenic) marrow transplantation for hematologic cancers. J Natl Cancer Inst 76::1269,1986-1271 Medline, Google Scholar6. Gale RP, Horowitz MM, Ash RC, et al: Identical-twin bone marrow transplants for leukemia. Ann Intern Med 120::646,1994-652 Crossref, Medline, Google Scholar7. 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::874,1991-878 Crossref, Medline, Google Scholar8. Radich JP, Gehly G, Gooley T, et al: Polymerase chain reaction detection of the fusion transcript after allogeneic marrow transplantation for chronic myeloid leukemia: Results and implications in 346 patients. Blood 85::2632,1995-2638 BCR-ABL Crossref, Medline, Google Scholar9. 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::2310,1993-2318 Crossref, Medline, Google Scholar10. Kolb HJ, Schattenberg A, Goldman JM, et al: Graft-vs-leukemia effect of donor lymphocyte transfusions in marrow grafted patients. Blood 86::2041,1995-2050 Crossref, Medline, Google Scholar11. 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::2817,1998-2824 Link, Google Scholar12. 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::4531,1997-4536 Crossref, Medline, Google Scholar