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Journal of Clinical Oncology, Vol 16, 2817-2824, Copyright © 1998 by American Society of Clinical Oncology

ARTICLES

Transplant-lite: induction of graft-versus-malignancy using fludarabine- based nonablative chemotherapy and allogeneic blood progenitor-cell transplantation as treatment for lymphoid malignancies

IF Khouri, M Keating, M Korbling, D Przepiorka, P Anderlini, S O'Brien, S Giralt, C Ippoliti, B von Wolff, J Gajewski, M Donato, D Claxton, N Ueno, B Andersson, A Gee and R Champlin
Department of Hematology, University of Texas M.D. Anderson Cancer Center, Houston 77030, USA. ikhouri@notes.mdacc.tmc.edu

PURPOSE: To investigate the use of a nonmyeloablative fludarabine-based preparative regimen to produce sufficient immunosuppression to allow engraftment of allogeneic stem cells and induction of graft-versus- leukemia/lymphoma (GVL) as the primary treatment modality for patients with chronic lymphocytic leukemia (CLL) and lymphoma. PATIENTS AND METHODS: Fifteen patients were studied. Six patients were in advanced refractory relapse, and induction therapy had failed in two patients. Patients with CLL or low-grade lymphoma received fludarabine 90 to 150 mg/m2 and cyclophosphamide 900 to 2,000 mg/m2. Patients with intermediate-grade lymphoma or in Richter's transformation received cisplatin 25 mg/m2 daily for 4 days; fludarabine 30 mg/m2; and cytarabine 500 mg/m2 daily for 2 days. Chemotherapy was followed by allogeneic stem-cell infusion from HLA-identical siblings. Patients with residual malignant cells or mixed chimerism could receive a donor lymphocyte infusion of 0.5 to 2 x 10(8) mononuclear cells/kg 2 to 3 months posttransplantation if graft-versus-host disease (GVHD) was not present. RESULTS: Eleven patients had engraftment of donor cells, and the remaining four patients promptly recovered autologous hematopoiesis. Eight of 11 patients achieved a complete response (CR). Five of six patients (83.3%) with chemosensitive disease continue to be alive compared with two of nine patients (22.2%) who had refractory or untested disease at the time of study entry (P = .04). CONCLUSION: These findings indicate the feasibility of allogeneic hematopoietic transplantation with a nonablative preparative regimen to produce engraftment and GVL against lymphoid malignancies. The ability to induce remissions with donor lymphocyte infusion in patients with CLL, Richter's, and low-grade and intermediate-grade lymphoma is direct evidence of GVL activity against these diseases. This approach appears to be most promising in patients with chemotherapy-responsive disease and low tumor burden.
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C. Hosing, R. M. Saliba, P. McLaughlin, B. Andersson, M. A. Rodriguez, L. Fayad, F. Cabanillas, R. E. Champlin, and I. F. Khouri
Long-term results favor allogeneic over autologous hematopoietic stem cell transplantation in patients with refractory or recurrent indolent non-Hodgkin's lymphoma
Ann. Onc., May 1, 2003; 14(5): 737 - 744.
[Abstract] [Full Text] [PDF]

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M. Ritgen, A. Lange, S. Stilgenbauer, H. Dohner, C. Bretscher, H. Bosse, A. Stuhr, M. Kneba, and P. Dreger
Unmutated immunoglobulin variable heavy-chain gene status remains an adverse prognostic factor after autologous stem cell transplantation for chronic lymphocytic leukemia
Blood, March 1, 2003; 101(5): 2049 - 2053.
[Abstract] [Full Text] [PDF]

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S. Marktel, Z. Magnani, F. Ciceri, S. Cazzaniga, S. R. Riddell, C. Traversari, C. Bordignon, and C. Bonini
Immunologic potential of donor lymphocytes expressing a suicide gene for early immune reconstitution after hematopoietic T-cell-depleted stem cell transplantation
Blood, February 15, 2003; 101(4): 1290 - 1298.
[Abstract] [Full Text] [PDF]

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 BloodHome page
D. Niederwieser, M. Maris, J. A. Shizuru, E. Petersdorf, U. Hegenbart, B. M. Sandmaier, D. G. Maloney, B. Storer, T. Lange, T. Chauncey, et al.
Low-dose total body irradiation (TBI) and fludarabine followed by hematopoietic cell transplantation (HCT) from HLA-matched or mismatched unrelated donors and postgrafting immunosuppression with cyclosporine and mycophenolate mofetil (MMF) can induce durable complete chimerism and sustained remissions in patients with hematological diseases
Blood, February 15, 2003; 101(4): 1620 - 1629.
[Abstract] [Full Text] [PDF]

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 BloodHome page
R. Or, M. Y. Shapira, I. Resnick, A. Amar, A. Ackerstein, S. Samuel, M. Aker, E. Naparstek, A. Nagler, and S. Slavin
Nonmyeloablative allogeneic stem cell transplantation for the treatment of chronic myeloid leukemia in first chronic phase
Blood, January 15, 2003; 101(2): 441 - 445.
[Abstract] [Full Text] [PDF]

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 BloodHome page
M. Uzunel, J. Mattsson, M. Brune, J.-E. Johansson, J. Aschan, and O. Ringden
Kinetics of minimal residual disease and chimerism in patients with chronic myeloid leukemia after nonmyeloablative conditioning and allogeneic stem cell transplantation
Blood, January 15, 2003; 101(2): 469 - 472.
[Abstract] [Full Text] [PDF]

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 Stem CellsHome page
J. D. Down and M. E. White-Scharf
Reprogramming Immune Responses: Enabling Cellular Therapies and Regenerative Medicine
Stem Cells, January 1, 2003; 21(1): 21 - 32.
[Abstract] [Full Text] [PDF]

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 ASH Education BookHome page
G. Mufti, A. F. List, S. D. Gore, and A. Y.L. Ho
Myelodysplastic Syndrome
Hematology, January 1, 2003; 2003(1): 176 - 199.
[Abstract] [Full Text] [PDF]

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 ASH Education BookHome page
R. F. Storb, G. Lucarelli, P. A. McSweeney, and R. W. Childs
Hematopoietic Cell Transplantation for Benign Hematological Disorders and Solid Tumors
Hematology, January 1, 2003; 2003(1): 372 - 397.
[Abstract] [Full Text] [PDF]

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 BloodHome page
S. P. Robinson, A. H. Goldstone, S. Mackinnon, A. Carella, N. Russell, C. R. de Elvira, G. Taghipour, and N. Schmitz
Chemoresistant 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, December 15, 2002; 100(13): 4310 - 4316.
[Abstract] [Full Text] [PDF]

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 BloodHome page
J. A. Perez-Simon, P. D. Kottaridis, R. Martino, C. Craddock, D. Caballero, R. Chopra, J. Garcia-Conde, D. W. Milligan, S. Schey, A. Urbano-Ispizua, et al.
Nonmyeloablative transplantation with or without alemtuzumab: comparison between 2 prospective studies in patients with lymphoproliferative disorders
Blood, October 16, 2002; 100(9): 3121 - 3127.
[Abstract] [Full Text] [PDF]

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A. M. Krackhardt, M. Witzens, S. Harig, F. S. Hodi, A. J. Zauls, M. Chessia, P. Barrett, and J. G. Gribben
Identification of tumor-associated antigens in chronic lymphocytic leukemia by SEREX
Blood, August 28, 2002; 100(6): 2123 - 2131.
[Abstract] [Full Text] [PDF]

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 BloodHome page
A. D. Billiau, S. Fevery, O. Rutgeerts, W. Landuyt, and M. Waer
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, August 13, 2002; 100(5): 1894 - 1902.
[Abstract] [Full Text] [PDF]

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 BloodHome page
M. Y. Mapara, Y.-M. Kim, S.-P. Wang, R. Bronson, D. H. Sachs, and M. Sykes
Donor lymphocyte infusions mediate superior graft-versus-leukemia effects in mixed compared to fully allogeneic chimeras: a critical role for host antigen-presenting cells
Blood, August 13, 2002; 100(5): 1903 - 1909.
[Abstract] [Full Text] [PDF]

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 BloodHome page
M. Hunault-Berger, N. Ifrah, and P. Solal-Celigny
Intensive therapies in follicular non-Hodgkin lymphomas
Blood, July 30, 2002; 100(4): 1141 - 1152.
[Full Text] [PDF]

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 Arch Intern MedHome page
I. A. Tabbara, K. Zimmerman, C. Morgan, and Z. Nahleh
Allogeneic Hematopoietic Stem Cell Transplantation: Complications and Results
Arch Intern Med, July 22, 2002; 162(14): 1558 - 1566.
[Abstract] [Full Text] [PDF]

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K. K. Ballen, P. S. Becker, R. V. B. Emmons, T. J. Fitzgerald, C. C. Hsieh, Q. Liu, C. Heyes, Y. Clark, W. Levy, J. F. Lambert, et al.
Low-dose total body irradiation followed by allogeneic lymphocyte infusion may induce remission in patients with refractory hematologic malignancy
Blood, June 28, 2002; 100(2): 442 - 450.
[Abstract] [Full Text] [PDF]

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 BloodHome page
A. M. Krackhardt, S. Harig, M. Witzens, R. Broderick, P. Barrett, and J. G. Gribben
T-cell responses against chronic lymphocytic leukemia cells: implications for immunotherapy
Blood, June 17, 2002; 100(1): 167 - 173.
[Abstract] [Full Text] [PDF]

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 The OncologistHome page
P. McLaughlin
Progress and Promise in the Treatment of Indolent Lymphomas
Oncologist, June 1, 2002; 7(3): 217 - 225.
[Abstract] [Full Text] [PDF]

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 Ann OncolHome page
P. McLaughlin
Profiling: "Editorial on 'Survival after progression in patients with follicular lymphoma: analysis of prognostic factors' ", by S. Montoto et al. (Ann Oncol 2002; 13: 523-530)
Ann. Onc., April 1, 2002; 13(4): 499 - 500.
[Full Text] [PDF]

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 Clin. Cancer Res.Home page
T. Saito, Y. Kanda, M. Kami, K. Kato, N. Shoji, S. Kanai, T. Ohnishi, Y. Kawano, K. Nakai, T. Ogasawara, et al.
Therapeutic Potential of a Reduced-Intensity Preparative Regimen for Allogeneic Transplantation with Cladribine, Busulfan, and Antithymocyte Globulin against Advanced/Refractory Acute Leukemia/Lymphoma
Clin. Cancer Res., April 1, 2002; 8(4): 1014 - 1020.
[Abstract] [Full Text] [PDF]

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R. Chakraverty, K. Peggs, R. Chopra, D. W. Milligan, P. D. Kottaridis, S. Verfuerth, J. Geary, D. Thuraisundaram, K. Branson, S. Chakrabarti, et al.
Limiting transplantation-related mortality following unrelated donor stem cell transplantation by using a nonmyeloablative conditioning regimen
Blood, February 1, 2002; 99(3): 1071 - 1078.
[Abstract] [Full Text] [PDF]

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 JCOHome page
A. Josting, J. Franklin, M. May, P. Koch, M. K. Beykirch, J. Heinz, C. Rudolph, V. Diehl, and A. Engert
New Prognostic Score Based on Treatment Outcome of Patients With Relapsed Hodgkin's Lymphoma Registered in the Database of the German Hodgkin's Lymphoma Study Group
J. Clin. Oncol., January 1, 2002; 20(1): 221 - 230.
[Abstract] [Full Text] [PDF]

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 ASH Education BookHome page
N. E. Kay, T. J. Hamblin, D. F. Jelinek, G. W. Dewald, J. C. Byrd, S. Farag, M. Lucas, and T. Lin
Chronic Lymphocytic Leukemia
Hematology, January 1, 2002; 2002(1): 193 - 213.
[Abstract] [Full Text]

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 ASH Education BookHome page
D. G. Maloney, B. M. Sandmaier, S. Mackinnon, and J. A. Shizuru
Non-Myeloablative Transplantation
Hematology, January 1, 2002; 2002(1): 392 - 421.
[Abstract] [Full Text]

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P. Corradini, C. Tarella, A. Olivieri, A. M. Gianni, C. Voena, F. Zallio, M. Ladetto, M. Falda, M. Lucesole, A. Dodero, et al.
Reduced-intensity conditioning followed by allografting of hematopoietic cells can produce clinical and molecular remissions in patients with poor-risk hematologic malignancies
Blood, January 1, 2002; 99(1): 75 - 82.
[Abstract] [Full Text] [PDF]

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F. Weissinger, B. M. Sandmaier, D. G. Maloney, W. I. Bensinger, T. Gooley, and R. Storb
Decreased transfusion requirements for patients receiving nonmyeloablative compared with conventional peripheral blood stem cell transplants from HLA-identical siblings
Blood, December 15, 2001; 98(13): 3584 - 3588.
[Abstract] [Full Text] [PDF]

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I. F. Khouri, R. M. Saliba, S. A. Giralt, M.-S. Lee, G.-J. Okoroji, F. B. Hagemeister, M. Korbling, A. Younes, C. Ippoliti, J. L. Gajewski, et al.
Nonablative allogeneic hematopoietic transplantation as adoptive immunotherapy for indolent lymphoma: low incidence of toxicity, acute graft-versus-host disease, and treatment-related mortality
Blood, December 15, 2001; 98(13): 3595 - 3599.
[Abstract] [Full Text] [PDF]

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L. Luznik, S. Jalla, L. W. Engstrom, R. Iannone, and E. J. Fuchs
Durable engraftment of major histocompatibility complex-incompatible cells after nonmyeloablative conditioning with fludarabine, low-dose total body irradiation, and posttransplantation cyclophosphamide
Blood, December 1, 2001; 98(12): 3456 - 3464.
[Abstract] [Full Text] [PDF]

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D. A. Rizzieri, G. D. Long, J. J. Vredenburgh, C. Gasparetto, A. Morris, T. T. Stenzel, P. Davis, and N. J. Chao
Successful allogeneic engraftment of mismatched unrelated cord blood following a nonmyeloablative preparative regimen
Blood, December 1, 2001; 98(12): 3486 - 3488.
[Abstract] [Full Text] [PDF]

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 BloodHome page
C. D. Bolan, S. F. Leitman, L. M. Griffith, R. A. Wesley, J. L. Procter, D. F. Stroncek, A. J. Barrett, and R. W. Childs
Delayed donor red cell chimerism and pure red cell aplasia following major ABO-incompatible nonmyeloablative hematopoietic stem cell transplantation
Blood, September 15, 2001; 98(6): 1687 - 1694.
[Abstract] [Full Text] [PDF]

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 J. Immunol.Home page
F. Lan, D. Zeng, M. Higuchi, P. Huie, J. P. Higgins, and S. Strober
Predominance of NK1.1+TCR{alpha}{beta}+ or DX5+TCR{alpha}{beta}+ T Cells in Mice Conditioned with Fractionated Lymphoid Irradiation Protects Against Graft-Versus-Host Disease: "Natural Suppressor" Cells
J. Immunol., August 15, 2001; 167(4): 2087 - 2096.
[Abstract] [Full Text] [PDF]

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 Clin. Cancer Res.Home page
M. Bornhauser, C. Thiede, U. Platzbecker, A. Jenke, A. Helwig, R. Plettig, J. Freiberg-Richter, C. Rollig, G. Geissler, K. Lutterbeck, et al.
Dose-reduced Conditioning and Allogeneic Hematopoietic Stem Cell Transplantation from Unrelated Donors in 42 Patients
Clin. Cancer Res., August 1, 2001; 7(8): 2254 - 2262.
[Abstract] [Full Text] [PDF]

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 JCOHome page
M. Michallet, K. Bilger, F. Garban, M. Attal, A. Huyn, D. Blaise, N. Milpied, P. Moreau, P. Bordigoni, M. Kuentz, et al.
Allogeneic Hematopoietic Stem-Cell Transplantation After Nonmyeloablative Preparative Regimens: Impact of Pretransplantation and Posttransplantation Factors on Outcome
J. Clin. Oncol., July 15, 2001; 19(14): 3340 - 3349.
[Abstract] [Full Text] [PDF]

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 The OncologistHome page
S. A. Mink and J. O. Armitage
High-Dose Therapy in Lymphomas: A Review of the Current Status of Allogeneic and Autologous Stem Cell Transplantation in Hodgkin's Disease and Non-Hodgkin's Lymphoma
Oncologist, June 1, 2001; 6(3): 247 - 256.
[Abstract] [Full Text] [PDF]

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 BloodHome page
P. A. McSweeney, D. Niederwieser, J. A. Shizuru, B. M. Sandmaier, A. J. Molina, D. G. Maloney, T. R. Chauncey, T. A. Gooley, U. Hegenbart, R. A. Nash, et al.
Hematopoietic cell transplantation in older patients with hematologic malignancies: replacing high-dose cytotoxic therapy with graft-versus-tumor effects
Blood, June 1, 2001; 97(11): 3390 - 3400.
[Abstract] [Full Text] [PDF]

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 BloodHome page
F. Lan, D. Zeng, P. Huie, J. P. Higgins, and S. Strober
Allogeneic bone marrow cells that facilitate complete chimerism and eliminate tumor cells express both CD8 and T-cell antigen receptor-{alpha}{beta}
Blood, June 1, 2001; 97(11): 3458 - 3465.
[Abstract] [Full Text] [PDF]

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 JCOHome page
R. P. Witherspoon, H. J. Deeg, B. Storer, C. Anasetti, R. Storb, and F. R. Appelbaum
Hematopoietic Stem-Cell Transplantation for Treatment-Related Leukemia or Myelodysplasia
J. Clin. Oncol., April 15, 2001; 19(8): 2134 - 2141.
[Abstract] [Full Text] [PDF]

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 NEJMHome page
M. E. Horwitz, A. J. Barrett, M. R. Brown, C. S. Carter, R. Childs, J. I. Gallin, S. M. Holland, G. F. Linton, J. A. Miller, S. F. Leitman, et al.
Treatment of Chronic Granulomatous Disease with Nonmyeloablative Conditioning and a T-Cell-Depleted Hematopoietic Allograft
N. Engl. J. Med., March 22, 2001; 344(12): 881 - 888.
[Abstract] [Full Text] [PDF]

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 Stem CellsHome page
C. Cutler and J. H. Antin
Peripheral Blood Stem Cells for Allogeneic Transplantation: A Review
Stem Cells, February 1, 2001; 19(2): 108 - 117.
[Abstract] [Full Text]

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 ASH Education BookHome page
K. R. Rai, H. Dohner, M. J. Keating, and E. Montserrat
Chronic Lymphocytic Leukemia: Case-Based Session
Hematology, January 1, 2001; 2001(1): 140 - 156.
[Abstract] [Full Text] [PDF]

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 ASH Education BookHome page
R. F. Storb, R. Champlin, S. R. Riddell, M. Murata, S. Bryant, and E. H. Warren
Non-Myeloablative Transplants for Malignant Disease
Hematology, January 1, 2001; 2001(1): 375 - 391.
[Abstract] [Full Text] [PDF]

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 JCOHome page
A. M. Carella, M. Cavaliere, E. Lerma, R. Ferrara, L. Tedeschi, A. Romanelli, M. Vinci, G. Pinotti, P. Lambelet, C. Loni, et al.
Autografting Followed by Nonmyeloablative Immunosuppressive Chemotherapy and Allogeneic Peripheral-Blood Hematopoietic Stem-Cell Transplantation as Treatment of Resistant Hodgkin's Disease and Non-Hodgkin's Lymphoma
J. Clin. Oncol., December 1, 2000; 18(23): 3918 - 3924.
[Abstract] [Full Text] [PDF]


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