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Myeloablative Conditioning Regimens
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High-intensity MAC regimens are reserved for young and otherwise-fit patients who can tolerate the associated regimen morbidity. Such regimens lead to a low risk of relapse at the expense of a high TRM compared with reduced-intensity conditioning (RIC) regimens.
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One of the largest registry studies comparing single-unit CB (n = 165) to PB (n = 888) or BM (n = 472) transplants in adults with acute leukemia using MAC regimens from 2002 through 2006 showed promising outcomes with CBT. Total body irradiation (TBI) constituted part of the preparative regimen in about half of patients in the CB group and about two-thirds in the comparative groups. Despite a significantly higher number of patients with fully HLA-matched PB or BM grafts (70%) compared to CB grafts (6%), the rates of disease-free survival (DFS) and relapse were similar among the groups, while the risks of acute or chronic GVHD were significantly lower with CBT. Also, TRM was similar with CBT compared with mismatched PB or BM grafts, but higher in contrast to fully matched PB (HR 1.62; 95% CI, 1.18-2.23; P = .003) or BM transplants (HR 1.69; 95% CI, 1.19-2.39; P = .003). This was offset by a significantly lower incidence of chronic GVHD compared with fully matched PB (HR 0.38; 95% CI, 0.27-0.53; P = .001) or BM transplants (HR 0.63; 95% CI, 0.44-0.90; P = .01) (4). Therefore, in the absence of matched PB or BM donors, CBT potentially offers better outcomes compared with mismatched alternative donor transplants.
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Similar encouraging results were noted in a study that compared 4-6/6 matched dCBT exclusively (using the MAC regimen including fludarabine 75 mg/m2, cyclophosphamide 120 mg/kg, and TBI 1,200 to 1,320 cGy [Flu/Cy/TBI]) to 8/8 MRD or MUD, or 1 allele–MMUD donors (7). This study also noted lower risk of relapse, higher TRM, lower GVHD, and comparable DFS after CBT compared to other groups. The risk of relapse was significantly lower after dCBT (15%, 95% CI, 9%-22%), compared with MRD (43%, 95% CI, 35%-52%) or MUD (37%, 95% CI, 29%-46%) transplants. Higher NRM was noted after dCBT (34%, 95% CI, 25%-42%) compared to MRD (24%, 95% CI, 17%-39%) or MUD (14%, 95% CI, 9%-20%) transplants, which resulted in comparable 5-year DFS between CB (51%, 95% CI, 41%-59%), MRD 33% (95% CI, 26%-41%), and MUD (48%, 95% CI, 40%-56%) transplants. The cumulative incidence of grades II to IV GVHD at day 100 after DCBT, MRD, and MUD was 60% (95% CI, 50%-70%), 65% (95% CI, 57%-73%), and 80% (95% CI, 70%-90%), respectively. The rate of chronic GVHD at 2 years was 26% (95% CI, 15%-35%), 47% (95% CI, 39%-55%), and 43% (95% CI, 34%-52%) respectively (7).
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In adults with high-risk acute lymphoblastic leukemia (ALL), CBT leads to similar overall survival (OS), TRM, and relapse risk, with significantly lower risk of acute or chronic GVHD, compared with PB or BM transplants. This was demonstrated in a recent registry study that compared outcomes after single or double 4-6/6 matched CB (n = 116) and 7-8/8 matched PB (n = 546) or BM (n =140) transplants after MAC regimens (22). More than half of the patients in the CBT group received Flu/Cy/TBI as the conditioning regimen, while about 75% of the patients in the PB or BM groups received TBI/Cy-based regimens. There were no differences in the 3-year OS rates (44%, 44%, and 43%, respectively); relapse risk (22%, 25%, and 28%, respectively); or TRM (42%, 31%, and 39%, respectively) among the groups. However, the risk of acute grades II to IV GVHD (27%, 47%, and 41%, respectively) or grades III and IV acute GVHD (9%, 16%, 24%, respectively) was appreciably lower after CBT compared with 8/8-matched and 7/8-matched PB or BM transplants, respectively (22).
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Reduced-Intensity Conditioning Regimens
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The advent of RIC regimens extended the utility of CBT to older patients and those with comorbid conditions that otherwise restrict the use of the MAC regimens. It is noteworthy that a majority of trials in MRD or MUD transplants used an arbitrary age definition of greater than 55 to 60 years (to define “older patients”) as a threshold of using an RIC regimen. However, age greater than 40 to 45 years is generally chosen as a threshold for RIC in the CBT setting.
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Barker et al reported that the RIC with fludarabine 200 mg/m2, cyclophosphamide 50 mg/kg, and 2-Gy TBI (Flu/Cy/2Gy TBI) was well tolerated, with rapid neutrophil recovery, a sustained donor engraftment rate of 94%, and a low incidence of TRM (23). This regimen was associated with significantly better DFS compared with other RIC regimens (51% vs 28%, P = .0002, HR 0.53) (24). Multiple studies supporting the use of RIC CBT in patients who would not be able to tolerate more intensive preparative regimens have subsequently been reported (6,18,19,25,26,27).
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A retrospective single-center study compared the outcomes in patients older than 55 years who underwent CB and MRD SCT with RIC (primarily of Flu/Cy/2Gy TBI). There were no differences in TRM at 180 days (28%, 95% CI, 14%-41% vs 23%, 95% CI, 11%-36%); 3-year DFS (34%, 95% CI, 19%-48% vs 30%, 95% CI, 16%-44%); or 3-year OS (34%, 95% CI, 17%-50% vs 43%, 95% CI, 29%-58%) between the groups (6). These findings were confirmed by a registry analysis of patients with acute leukemia comparing the outcomes after CB (n = 161), 8/8-matched (313) and 7/8-matched PB (111) transplants with RIC regimens. Patients with CBT following a Flu/Cy/2 Gy TBI regimen had comparable results with 8/8 HLA-matched PB donors. However, higher TRM and lower OS and LFS were observed in recipients of CBT if they were treated with alternative RIC regimens, including busulfan plus melphalan, or cyclophosphamide with fludarabine and in vivo T-cell depletion with antithymocyte globulin (ATG) (27). Similar findings were reported by Eurocord and the European Group for Blood and Marrow Transplantation (EBMT) in patients with lymphoid malignancies. When patients with CB units (n = 104) were compared with 8/8-matched PB MUD (n = 541) transplants, no difference was noted in NRM (29% vs 28%), PFS (28% vs 35%), or OS (56% vs 49%) at 3 years (Fig. 14-1). Further, the risk of chronic GVHD was significantly lower in the CBT group (26% vs 52% at 3 years; P = .0005) (26). These studies supported the use of CBT with RIC as a suitable alternative for patients who may benefit from RIC SCT and who do not have a suitable related or unrelated volunteer donor in the time period transplantation is needed.
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