Background The ability of allogeneic bone marrow transplantationto cure chronic myeloid leukemia (CML) is due to both the conditioningregimen and the antileukemic effects of the lymphocytes in thegrafted marrow. We studied the ability of interferon alfa-2band infusions of mononuclear cells from the marrow donor toinduce a graft-versus-leukemia reaction in patients with CMLin relapse after bone marrow transplantation.
Methods Eleven patients with relapsed CML after allogeneic bonemarrow transplantation were treated with interferon alfa-2band infusions of mononuclear cells. The patients were monitoredfor toxic effects, for hematologic and cytogenetic responses,and, with use of the polymerase chain reaction, for eliminationof cells containing the bcr/abl messenger RNA transcript characteristicof the leukemic cells.
Results Six of the eight patients with stable CML after relapsehad complete remissions according to molecular genetic criteria,since no cells with bcr/abl messenger RNA transcripts were detected(the method can identify 1 leukemic cell among 1 million normalcells). The three patients with accelerated CML after relapsedid not enter remission. Myelosuppression was prominent in eightpatients. Grade I acute graft-versus-host disease (GVHD) occurredin six patients, and grade III acute GVHD occurred in three.Limited chronic GVHD developed in five patients.
Conclusions The induction of a graft-versus-leukemia reactionwith interferon alfa-2b and infusions of donor mononuclear cellsin patients with CML in relapse after bone marrow transplantationis an effective antileukemic therapy that may offer an alternativeto a second marrow transplantation.
Source Information
From the Division of Hematology-Oncology, Brigham and Women's Hospital and Harvard Medical School, Boston (D.L.P., C.M., J.L.M.F., J.H.A.), and the Division of Hematology-Oncology, University of Michigan Medical Center, Ann Arbor (M.S.R.).
Address reprint requests to Dr. Antin at the Division of Hematology-Oncology, Brigham and Women's Hospital, 75 Francis St., Boston, MA 02115.
Stumpf, A. N., van der Meijden, E. D., van Bergen, C. A. M., Willemze, R., Falkenburg, J. H. F., Griffioen, M.
(2009). Identification of 4 new HLA-DR-restricted minor histocompatibility antigens as hematopoietic targets in antitumor immunity. Blood
114: 3684-3692
[Abstract][Full Text]
Dey, B. R., Spitzer, T. R., Hasserjian, R. P.
(2009). Case 28-2009 -- A 68-Year-Old Man with Fatigue, Cough, and Peripheral-Blood Monocytosis. NEJM
361: 1099-1106
[Full Text]
van der Veken, L. T., Coccoris, M., Swart, E., Falkenburg, J. H. F., Schumacher, T. N., Heemskerk, M. H. M.
(2009). {alpha}{beta} T Cell Receptor Transfer to {gamma}{delta} T Cells Generates Functional Effector Cells without Mixed TCR Dimers In Vivo. J. Immunol.
182: 164-170
[Abstract][Full Text]
Kolb, H.-J.
(2008). Graft-versus-leukemia effects of transplantation and donor lymphocytes. Blood
112: 4371-4383
[Abstract][Full Text]
Bishop, M. R., Dean, R. M., Steinberg, S. M., Odom, J., Pavletic, S. Z., Chow, C., Pittaluga, S., Sportes, C., Hardy, N. M., Gea-Banacloche, J., Kolstad, A., Gress, R. E., Fowler, D. H.
(2008). Clinical evidence of a graft-versus-lymphoma effect against relapsed diffuse large B-cell lymphoma after allogeneic hematopoietic stem-cell transplantation. Ann Oncol
19: 1935-1940
[Abstract][Full Text]
Chen, D.-P., Tseng, C.-P., Tsai, S.-H., Wu, T.-L., Chang, P.-Y., Sun, C.-F.
(2008). Systematic Analysis of Stutters to Enhance the Accuracy of Chimerism Testing. Annals of Clinical & Laboratory Science
38: 264-272
[Abstract][Full Text]
Miller, J. S., Weisdorf, D. J., Burns, L. J., Slungaard, A., Wagner, J. E., Verneris, M. R., Cooley, S., Wangen, R., Fautsch, S. K., Nicklow, R., DeFor, T., Blazar, B. R.
(2007). Lymphodepletion followed by donor lymphocyte infusion (DLI) causes significantly more acute graft-versus-host disease than DLI alone. Blood
110: 2761-2763
[Abstract][Full Text]
Antin, J. H.
(2007). Reduced-Intensity Stem Cell Transplantation: "...whereof a little More than a little is by much too much." King Henry IV, part 1, I, 2. ASH Education Book
2007: 47-54
[Abstract][Full Text]
Porter, D. L., Levine, B. L., Bunin, N., Stadtmauer, E. A., Luger, S. M., Goldstein, S., Loren, A., Phillips, J., Nasta, S., Perl, A., Schuster, S., Tsai, D., Sohal, A., Veloso, E., Emerson, S., June, C. H.
(2006). A phase 1 trial of donor lymphocyte infusions expanded and activated ex vivo via CD3/CD28 costimulation. Blood
107: 1325-1331
[Abstract][Full Text]
Roman, E., Cooney, E., Harrison, L., Militano, O., Wolownik, K., Hawks, R., Foley, S., Satwani, P., Unal, E., Bhatia, M., Bradley, B., Del Toro, G., George, D., Garvin, J., van de Ven, C., Cairo, M. S.
(2005). Preliminary Results of the Safety of Immunotherapy with Gemtuzumab Ozogamicin following Reduced Intensity Allogeneic Stem Cell Transplant in Children with CD33+ Acute Myeloid Leukemia. Clin. Cancer Res.
11: 7164s-7170s
[Abstract][Full Text]
Imai, C., Iwamoto, S., Campana, D.
(2005). Genetic modification of primary natural killer cells overcomes inhibitory signals and induces specific killing of leukemic cells. Blood
106: 376-383
[Abstract][Full Text]
Schrier, R. W., Parikh, C. R.
(2005). Comparison of renal injury in myeloablative autologous, myeloablative allogeneic and non-myeloablative allogeneic haematopoietic cell transplantation. Nephrol Dial Transplant
20: 678-683
[Full Text]
Miklos, D. B., Kim, H. T., Miller, K. H., Guo, L., Zorn, E., Lee, S. J., Hochberg, E. P., Wu, C. J., Alyea, E. P., Cutler, C., Ho, V., Soiffer, R. J., Antin, J. H., Ritz, J.
(2005). Antibody responses to H-Y minor histocompatibility antigens correlate with chronic graft-versus-host disease and disease remission. Blood
105: 2973-2978
[Abstract][Full Text]
DeAngelo, D. J., Hochberg, E. P., Alyea, E. P., Longtine, J., Lee, S., Galinsky, I., Parekkedon, B., Ritz, J., Antin, J. H., Stone, R. M., Soiffer, R. J.
(2004). Extended Follow-up of Patients Treated with Imatinib Mesylate (Gleevec) for Chronic Myelogenous Leukemia Relapse after Allogeneic Transplantation: Durable Cytogenetic Remission and Conversion to Complete Donor Chimerism without Graft-versus-Host Disease. Clin. Cancer Res.
10: 5065-5071
[Abstract][Full Text]
Antin, J. H.
(2003). A 41-Year-Old Woman With Chronic Myelogenous Leukemia. JAMA
290: 1083-1090
[Full Text]
Billiau, A. D., Fevery, S., Rutgeerts, O., Landuyt, W., Waer, M.
(2003). Transient expansion of Mac1+Ly6-G+Ly6-C+ early myeloid cells with suppressor activity in spleens of murine radiation marrow chimeras: possible implications for the graft-versus-host and graft-versus-leukemia reactivity of donor lymphocyte infusions. Blood
102: 740-748
[Abstract][Full Text]
Marks, D. I., Lush, R., Cavenagh, J., Milligan, D. W., Schey, S., Parker, A., Clark, F. J., Hunt, L., Yin, J., Fuller, S., Vandenberghe, E., Marsh, J., Littlewood, T., Smith, G. M., Culligan, D., Hunter, A., Chopra, R., Davies, A., Towlson, K., Williams, C. D.
(2002). The toxicity and efficacy of donor lymphocyte infusions given after reduced-intensity conditioning allogeneic stem cell transplantation. Blood
100: 3108-3114
[Abstract][Full Text]
Perez-Simon, J. A., Kottaridis, P. D., Martino, R., Craddock, C., Caballero, D., Chopra, R., Garcia-Conde, J., Milligan, D. W., Schey, S., Urbano-Ispizua, A., Parker, A., Leon, A., Yong, K., Sureda, A., Hunter, A., Sierra, J., Goldstone, A. H., Linch, D. C., Miguel, J. F. S., Mackinnon, S.
(2002). Nonmyeloablative transplantation with or without alemtuzumab: comparison between 2 prospective studies in patients with lymphoproliferative disorders. Blood
100: 3121-3127
[Abstract][Full Text]
Billiau, A. D., Fevery, S., Rutgeerts, O., Landuyt, W., Waer, M.
(2002). Crucial role of timing of donor lymphocyte infusion in generating dissociated graft-versus-host and graft-versus-leukemia responses in mice receiving allogeneic bone marrow transplants. Blood
100: 1894-1902
[Abstract][Full Text]
Hayashi, S., Peranteau, W. H., Shaaban, A. F., Flake, A. W.
(2002). Complete allogeneic hematopoietic chimerism achieved by a combined strategy of in utero hematopoietic stem cell transplantation and postnatal donor lymphocyte infusion. Blood
100: 804-812
[Abstract][Full Text]
Guglielmi, C., Arcese, W., Dazzi, F., Brand, R., Bunjes, D., Verdonck, L. F., Schattenberg, A., Kolb, H.-J., Ljungman, P., Devergie, A., Bacigalupo, A., Gomez, M., Michallet, M., Elmaagacli, A., Gratwohl, A., Apperley, J., Niederwieser, D.
(2002). Donor lymphocyte infusion for relapsed chronic myelogenous leukemia: prognostic relevance of the initial cell dose. Blood
100: 397-405
[Abstract][Full Text]
Ballen, K. K., Becker, P. S., Emmons, R. V. B., Fitzgerald, T. J., Hsieh, C. C., Liu, Q., Heyes, C., Clark, Y., Levy, W., Lambert, J. F., Chiafari, F., Szymanski, I., Rososhansky, S., Popovsky, M. A., Stewart, F. M., Quesenberry, P. J.
(2002). Low-dose total body irradiation followed by allogeneic lymphocyte infusion may induce remission in patients with refractory hematologic malignancy. Blood
100: 442-450
[Abstract][Full Text]
Levine, J. E., Braun, T., Penza, S. L., Beatty, P., Cornetta, K., Martino, R., Drobyski, W. R., Barrett, A. J., Porter, D. L., Giralt, S., Leis, J., Holmes, H. E., Johnson, M., Horowitz, M., Collins, R. H. Jr
(2002). Prospective Trial of Chemotherapy and Donor Leukocyte Infusions for Relapse of Advanced Myeloid Malignancies After Allogeneic Stem-Cell Transplantation. JCO
20: 405-412
[Abstract][Full Text]
Kang, E. M., de Witte, M., Malech, H., Morgan, R. A., Phang, S., Carter, C., Leitman, S. F., Childs, R., Barrett, A. J., Little, R., Tisdale, J. F.
(2002). Nonmyeloablative conditioning followed by transplantation of genetically modified HLA-matched peripheral blood progenitor cells for hematologic malignancies in patients with acquired immunodeficiency syndrome. Blood
99: 698-701
[Abstract][Full Text]
Maloney, D. G., Sandmaier, B. M., Mackinnon, S., Shizuru, J. A.
(2002). Non-Myeloablative Transplantation. ASH Education Book
2002: 392-421
[Abstract][Full Text]
Yang, X.-F., Wu, C. J., McLaughlin, S., Chillemi, A., Wang, K. S., Canning, C., Alyea, E. P., Kantoff, P., Soiffer, R. J., Dranoff, G., Ritz, J.
(2001). CML66, a broadly immunogenic tumor antigen, elicits a humoral immune response associated with remission of chronic myelogenous leukemia. Proc. Natl. Acad. Sci. USA
98: 7492-7497
[Abstract][Full Text]
McSweeney, P. A., Niederwieser, D., Shizuru, J. A., Sandmaier, B. M., Molina, A. J., Maloney, D. G., Chauncey, T. R., Gooley, T. A., Hegenbart, U., Nash, R. A., Radich, J., Wagner, J. L., Minor, S., Appelbaum, F. R., Bensinger, W. I., Bryant, E., Flowers, M. E. D., Georges, G. E., Grumet, F. C., Kiem, H.-P., Torok-Storb, B., Yu, C., Blume, K. G., Storb, R. F.
(2001). Hematopoietic cell transplantation in older patients with hematologic malignancies: replacing high-dose cytotoxic therapy with graft-versus-tumor effects. Blood
97: 3390-3400
[Abstract][Full Text]
Storb, R. F., Champlin, R., Riddell, S. R., Murata, M., Bryant, S., Warren, E. H.
(2001). Non-Myeloablative Transplants for Malignant Disease. ASH Education Book
2001: 375-391
[Abstract][Full Text]
Blazar, B. R., Lees, C. J., Martin, P. J., Noelle, R. J., Kwon, B., Murphy, W., Taylor, P. A.
(2000). Host T Cells Resist Graft-Versus-Host Disease Mediated by Donor Leukocyte Infusions. J. Immunol.
165: 4901-4909
[Abstract][Full Text]
Lokhorst, H. M., Schattenberg, A., Cornelissen, J. J., van Oers, M. H. J., Fibbe, W., Russell, I., Donk, N. W. C. J. v. d., Verdonck, L. F.
(2000). Donor Lymphocyte Infusions for Relapsed Multiple Myeloma After Allogeneic Stem-Cell Transplantation: Predictive Factors for Response and Long-Term Outcome. JCO
18: 3031-3037
[Abstract][Full Text]
Craddock, C., Szydlo, R. M., Klein, J. P., Dazzi, F., Olavarria, E., van Rhee, F., Pocock, C., Cwynarski, K., Apperley, J. F., Goldman, J. M.
(2000). Estimating leukemia-free survival after allografting for chronic myeloid leukemia: a new method that takes into account patients who relapse and are restored to complete remission. Blood
96: 86-90
[Abstract][Full Text]
Bishop, M. R., Tarantolo, S. R., Pavletic, Z. S., Lynch, J. C., Morris, M. E., Zacharias, D., Armitage, J. O., Kessinger, A.
(2000). Filgrastim as an Alternative to Donor Leukocyte Infusion for Relapse After Allogeneic Stem-Cell Transplantation. JCO
18: 2269-2272
[Abstract][Full Text]
Guglielmi, C., Arcese, W., Hermans, J., Bacigalupo, A., Bandini, G., Bunjes, D., Carreras, E., Devergie, A., Frassoni, F., Goldman, J., Gratwohl, A., Kolb, H.-J., Iori, A. P., Niederwieser, D., Prentice, H. G., de Witte, T., Apperley, J.
(2000). Risk assessment in patients with Ph+ chronic myelogenous leukemia at first relapse after allogeneic stem cell transplant: an EBMT retrospective analysis. Blood
95: 3328-3334
[Abstract][Full Text]
Georges, G. E., Storb, R., Thompson, J. D., Yu, C., Gooley, T., Bruno, B., Nash, R. A.
(2000). Adoptive immunotherapy in canine mixed chimeras after nonmyeloablative hematopoietic cell transplantation. Blood
95: 3262-3269
[Abstract][Full Text]
Porter, D. L., Collins, R. H. Jr, Hardy, C., Kernan, N. A., Drobyski, W. R., Giralt, S., Flowers, M. E.D., Casper, J., Leahey, A., Parker, P., Mick, R., Bate-Boyle, B., King, R., Antin, J. H.
(2000). Treatment of relapsed leukemia after unrelated donor marrow transplantation with unrelated donor leukocyte infusions. Blood
95: 1214-1221
[Abstract][Full Text]
Dazzi, F., Szydlo, R. M., Craddock, C., Cross, N. C. P., Kaeda, J., Chase, A., Olavarria, E., van Rhee, F., Kanfer, E., Apperley, J. F., Goldman, J. M.
(2000). Comparison of single-dose and escalating-dose regimens of donor lymphocyte infusion for relapse after allografting for chronic myeloid leukemia. Blood
95: 67-71
[Abstract][Full Text]
Gao, L., Yang, T.-H., Tourdot, S., Sadovnikova, E., Hasserjian, R., Stauss, H. J.
(1999). Allo-Major Histocompatibility Complex-Restricted Cytotoxic T Lymphocytes Engraft in Bone Marrow Transplant Recipients Without Causing Graft-Versus-Host Disease. Blood
94: 2999-3006
[Abstract][Full Text]
Engels, F. H. C., Koski, G. K., Bedrosian, I., Xu, S., Luger, S., Nowell, P. C., Cohen, P. A., Czerniecki, B. J.
(1999). Calcium signaling induces acquisition of dendritic cell characteristics in chronic myelogenous leukemia myeloid progenitor cells. Proc. Natl. Acad. Sci. USA
96: 10332-10337
[Abstract][Full Text]
Falkenburg, J.H. F., Wafelman, A. R., Joosten, P., Smit, W. M., van Bergen, C. A.M., Bongaerts, R., Lurvink, E., van der Hoorn, M., Kluck, P., Landegent, J. E., Kluin-Nelemans, H. C., Fibbe, W. E., Willemze, R.
(1999). Complete Remission of Accelerated Phase Chronic Myeloid Leukemia by Treatment With Leukemia-Reactive Cytotoxic T Lymphocytes. Blood
94: 1201-1208
[Abstract][Full Text]
Drobyski, W. R., Hessner, M. J., Klein, J. P., Kabler-Babbitt, C., Vesole, D. H., Keever-Taylor, C. A.
(1999). T-Cell Depletion Plus Salvage Immunotherapy With Donor Leukocyte Infusions as a Strategy to Treat Chronic-Phase Chronic Myelogenous Leukemia Patients Undergoing HLA-Identical Sibling Marrow Transplantation. Blood
94: 434-441
[Abstract][Full Text]
Sawyers, C. L.
(1999). Chronic Myeloid Leukemia. NEJM
340: 1330-1340
[Full Text]
Porter, D. L., Connors, J. M., Van Deerlin, V. M.D., Duffy, K. M., McGarigle, C., Saidman, S. L., Leonard, D. G.B., Antin, J. H.
(1999). Graft-Versus-Tumor Induction With Donor Leukocyte Infusions as Primary Therapy for Patients With Malignancies. JCO
17: 1234-1234
[Abstract][Full Text]
Fernandez-Herrera, J., Valks, R., Feal, C., Fraga, J., Tomas, J. F., Garcia-Diez, A.
(1999). Induction of Hyperacute Graft-vs-Host Disease After Donor Leukocyte Infusions. Arch Dermatol
135: 304-308
[Abstract][Full Text]
Smit, W. M., Rijnbeek, M., van Bergen, C. A. M., Fibbe, W. E., Willemze, R., Falkenburg, J. H. F.
(1998). T cells recognizing leukemic CD34+ progenitor cells mediate the antileukemic effect of donor lymphocyte infusions for relapsed chronic myeloid leukemia after allogeneic stem cell transplantation. Proc. Natl. Acad. Sci. USA
95: 10152-10157
[Abstract][Full Text]
Chen, W., Chatta, G. S., Rubin, W. D., Clark, J. G., Hackman, R. C., Madtes, D. K., Ligitt, D. H., Kusunoki, Y., Martin, P. J., Cheever, M. A.
(1998). T Cells Specific for a Polymorphic Segment of CD45 Induce Graft-Versus-Host Disease with Predominant Pulmonary Vasculitis. J. Immunol.
161: 909-918
[Abstract][Full Text]
Mori, T., Nishimura, T., Ikeda, Y., Hotta, T., Yagita, H., Ando, K.
(1998). Involvement of Fas-Mediated Apoptosis in the Hematopoietic Progenitor Cells of Graft-Versus-Host Reaction-Associated Myelosuppression. Blood
92: 101-107
[Abstract][Full Text]
Alyea, E. P., Soiffer, R. J., Canning, C., Neuberg, D., Schlossman, R., Pickett, C., Collins, H., Wang, Y., Anderson, K. C., Ritz, J.
(1998). Toxicity and Efficacy of Defined Doses of CD4+ Donor Lymphocytes for Treatment of Relapse After Allogeneic Bone Marrow Transplant. Blood
91: 3671-3680
[Abstract][Full Text]
Warren, E. H., Greenberg, P. D., Riddell, S. R.
(1998). Cytotoxic T-Lymphocyte-Defined Human Minor Histocompatibility Antigens With a Restricted Tissue Distribution. Blood
91: 2197-2207
[Abstract][Full Text]
Papadopoulos, E. B., Carabasi, M. H., Castro-Malaspina, H., Childs, B. H., Mackinnon, S., Boulad, F., Gillio, A. P., Kernan, N. A., Small, T. N., Szabolcs, P., Taylor, J., Yahalom, J., Collins, N. H., Bleau, S. A., Black, P. M., Heller, G., Reilly, R. J. O', Young, J. W.
(1998). T-Cell-Depleted Allogeneic Bone Marrow Transplantation as Postremission Therapy for Acute Myelogenous Leukemia: Freedom From Relapse in the Absence of Graft-Versus-Host Disease. Blood
91: 1083-1090
[Abstract][Full Text]
Lokhorst, H.M., Schattenberg, A., Cornelissen, J.J., Thomas, L.L.M., Verdonck, L.F.
(1997). Donor Leukocyte Infusions Are Effective in Relapsed Multiple Myeloma After Allogeneic Bone Marrow Transplantation. Blood
90: 4206-4211
[Abstract][Full Text]
Higano, C. S., Chielens, D., Raskind, W., Bryant, E., Flowers, M. E.D., Radich, J., Clift, R., Appelbaum, F.
(1997). Use of alpha -2a-Interferon to Treat Cytogenetic Relapse of Chronic Myeloid Leukemia After Marrow Transplantation. Blood
90: 2549-2554
[Abstract][Full Text]
Bonini, C., Ferrari, G., Verzeletti, S., Servida, P., Zappone, E., Ruggieri, L., Ponzoni, M., Rossini, S., Mavilio, F., Traversari, C., Bordignon, C.
(1997). HSV-TK Gene Transfer into Donor Lymphocytes for Control of Allogeneic Graft-Versus-Leukemia. Science
276: 1719-1724
[Abstract][Full Text]
Keil, F., Haas, O. A., Fritsch, G., Kalhs, P., Lechner, K., Mannhalter, C., Reiter, E., Niederwieser, D., Hoecker, P., Greinix, H. T.
(1997). Donor Leukocyte Infusion for Leukemic Relapse After Allogeneic Marrow Transplantation: Lack of Residual Donor Hematopoiesis Predicts Aplasia. Blood
89: 3113-3117
[Abstract][Full Text]
Lee, S. J., Wegner, S. A., McGarigle, C. J., Bierer, B. E., Antin, J. H.
(1997). Treatment of Chronic Graft-Versus-Host Disease With Clofazimine. Blood
89: 2298-2302
[Abstract][Full Text]
Munshi, N.C., Govindarajan, R., Drake, R., Ding, L.M., Iyer, R., Saylors, R., Kornbluth, J., Marcus, S., Chiang, Y., Ennist, D., Kwak, L., Reynolds, C., Tricot, G., Barlogie, B.
(1997). Thymidine Kinase (TK) Gene-Transduced Human Lymphocytes Can Be Highly Purified, Remain Fully Functional, and Are Killed Efficiently With Ganciclovir. Blood
89: 1334-1340
[Abstract][Full Text]
Woo, S.-B., Lee, S. J., Schubert, M. M.
(1997). Graft-vs.-Host Disease. CROBM
8: 201-216
[Abstract][Full Text]
Walter, E. A., Greenberg, P. D., Gilbert, M. J., Finch, R. J., Watanabe, K. S., Thomas, E. D., Riddell, S. R.
(1995). Reconstitution of Cellular Immunity against Cytomegalovirus in Recipients of Allogeneic Bone Marrow by Transfer of T-Cell Clones from the Donor. NEJM
333: 1038-1044
[Abstract][Full Text]
Parker, R. I., Nguyen, P. L.
(1994). Case 37-1994- A Newborn Boy with Petechiae, Hepatosplenomegaly, Leukocytosis, and Thrombocytopenia. NEJM
331: 1005-1012
[Full Text]