New, less intense conditioning regimens are being used today that retain the desirable effects of standard high-dose conditioning regimens, but with significantly lower transplant-related mortality (TRM).
Non-myeloablative and reduced-intensity conditioning regimens have also expanded the number of patients eligible to receive hematopoietic cell transplants.
Non-myeloablative or reduced-intensity regimens
Non-myeloablative (or reduced-intensity) regimens use significantly lower doses of pre-transplant chemotherapy drugs and/or radiation than the traditional high-dose, myeloablative regimens that have been in use for more than 35 years. Both terms are used to describe regimens that do not nesessarily completely eliminate malignant cells prior to transplant, but instead rely upon a graft-versus-malignancy effect mediated by donor-origin lymphoid cells, mostly T cells. [1]
These regimens typically use combinations of chemotherapy drugs such as fludarabine, busulfan, ATG and melphalan, with or without low-dose radiation. Due to their lowered toxicity, non-myeloablative or reduced-intensity transplants have expanded the number of patients eligible for hematopoietic cell transplantation, including:
Patients older than 55 years, which is a common upper limit for standard myeloablative transplantation
Patients with one or more co-morbidities that would ordinarily exclude them from undergoing myeloablative transplantation
Lower TRM and reduced rates of acute and chronic GVHD have been achieved in older patients and in patients with co-morbidities receiving non-myeloablative transplants, with rates comparable to those achieved by younger transplant patients. [2,3] In addition, a 2005 study of 150 non-myeloablative transplant recipients revealed no significant difference in non-relapse mortality and overall survival between patients older than 55 years and those younger than 55. [4]
A 2007 study of 110 non-myeloablative cord blood transplants in adults also showed promising results for this technique. In this study, two cord blood units were used in 85% of the transplants to achieve a minimum cell dose of 3.0 x 107 nucleated cells/kg. [5]
Clinical studies of non-myeloablative transplantation have shown that the graft-versus-malignancy effect is particularly pronounced in:
Chronic myelogenous leukemia
Chronic lymphocytic leukemia
Low-grade, indolent lymphomas [1]
Some transplant centers are also performing autologous transplants followed by non-myeloablative allogeneic transplantation. This treatment strategy combines the tumor cytoreduction of a high-dose autologous transplant with the lowered TRM of a non-myeloablative allogeneic conditioning regimen. This technique has been particularly promising in treating patients with multiple myeloma. [6,7]
Initial reports have shown that reduced-intensity regimens have acceptable remission rates and lower overall rates of toxicity compared to standard high-dose myeloablative therapy. [1,8,9] Rates of acute and chronic GVHD after reduced-intensity regimens are comparable to those observed in standard high-dose transplants, but the onset of GVHD is often delayed by weeks to months. [10]
Myeloablative regimens
Despite the encouraging early reports of transplantation using reduced-intensity conditioning regimens, fully myeloablative regimens are still used for the majority of patients undergoing hematopoietic cell transplantation. High-dose regimens are particularly useful in conditioning patients with aggressive malignancies, where there is a need for a strong anti-leukemia or anti-tumor effect.
Cyclophosphamide plus total body irradiation (TBI) and busulfan and cyclophosphamide are typical approaches for fully myeloablative regimens, but combining busulfan with fludarabine is increasing in use. [11,12,13]
Couriel DR, Saliba RM, Giralt S, et al. Acute and chronic graft-versus-host disease after ablative and nonmyeloablative conditioning for allogeneic hematopoietic transplantation. Biol Blood Marrow Transplant. 2004; 10(3):178-185. http://www.bbmt.org/article/PIIS1083879103004191/abstract
Hegenbart U, Niederwieser D, Sandmaier BM, et al. Treatment for acute myelogenous leukemia by low-dose, total-body, irradiation-based conditioning and hematopoietic cell transplantation from related and unrelated donors. J Clin Oncol. 2005; 24(3):444-453. http://jco.ascopubs.org/cgi/content/abstract/24/3/444
Corradini P, Zallio F, Mariotti J, et al. Effect of age and previous autologous transplantation on nonrelapse mortality and survival in patients treated with reduced-intensity conditioning and allografting for advanced hematologic malignancies. J Clin Oncol. 2005; 23(27): 6690-6698. http://www.jco.org/cgi/content/abstract/23/27/6690
Brunstein CG, Barker JN, Weisdorf DJ et al. Umbilical cord blood transplantation after nonmyeloablative conditioning: impact on transplantation outcomes in 110 adults with hematologic disease. Blood. 2007; 110(8):3064-3070. http://bloodjournal.hematologylibrary.org/cgi/content/abstract/110/8/3064
Maloney DG, Molina AJ, Sahebi F, et al. Allografting with nonmyeloablative conditioning following cytoreductive autografts for the treatment of patients with multiple myeloma. Blood. 2003; 102(9):3447-3454. http://www.bloodjournal.org/cgi/content/full/102/9/3447
Alyea EP, Kim HT, Ho VT, et al. Comparative outcome of nonmyeloablative and myeloablative allogeneic hematopoietic cell transplantation for patients older than fifty years of age. Blood. 2005;105(4):1810-1814. http://www.bloodjournal.org/cgi/content/full/105/4/1810
Giralt S, Logan B, Rizzo D, et al. Reduced-intensity conditioning for unrelated donor progenitor cell transplantation: long-term follow-up of the first 285 reported to the National Marrow Donor Program. Biol Blood Marrow Transplant. 2007; 13(7):844-852. http://www.bbmt.org/article/PIIS1083879107002170/abstract
Niederwieser D, Maris M, Shizuru JA, 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. 2003; 101(4):1620-1629. http://www.bloodjournal.org/cgi/content/full/101/4/1620
Kroger N, Zabelina T, Kruger W, et al. Comparison of total body irradiation vs busulfan in combination with cyclophosphamide as conditioning for unrelated stem cell transplantation in CML patients. Bone Marrow Transplant. 2001; 27(4):349-354. http://www.nature.com/bmt/journal/v27/n4/abs/1702802a.html
De Lima M, Couriel D, Thall PF, et al. Once-daily intravenous busulfan and fludarabine: clinical and pharmacokinetic results of a myeloablative, reduced-toxicity conditioning regimen for allogeneic stem cell transplantation in AML and MDS. Blood. 2004; 104(3):857-864. http://www.bloodjournal.org/cgi/content/full/104/3/857
Chae YS, Sohn SK, Kim JG, et al. New myeloablative conditioning regimen with fludarabine and busulfan for allogeneic stem cell transplantation: comparison with BuCy2. Bone Marrow Transplant. 2007; 40(6):541-547. http://www.nature.com/bmt/journal/v40/n6/abs/1705770a.html
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