Sequential Intensified Conditioning and Tapering of Prophylactic Immunosuppressants for Graft-versus-Host Disease in Allogeneic Hematopoietic Stem Cell Transplantation for Refractory Leukemia

Abstract

For patients with advanced leukemia undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT), a major obstacle to success, especially in those with a high leukemia cell burden, is relapse of the underlying disease. To improve the outcome of allo-HSCT for refractory leukemia, we investigated the strategy of sequential intensified conditioning and early rapid tapering of prophylactic immunosuppressants therapy for graft-versus-host disease (GVHD) during the early stage after transplantation. A total of 51 patients with refractory leukemia (median age, 30.0 years; unfavorable karyotypes, 49%) received fludarabine (Flu) 30 mg/m(2)/day and cytarabine 2 g/m(2)/day (on days -10 to -6), 4.5 Gy total body irradiation (TBI)/day (on days -5 and -4), and cyclophosphamide (Cy) 60 mg/kg/day and etoposide 600 mg/day (on days -3 and -2) for conditioning. Cyclosporine A (CsA) was withdrawn rapidly in a stepwise fashion to avoid overwhelming GVHD reactions if acute GVHD (aGVHD) did not develop at day +30. All 51 patients developed regimen-related toxicities (13 with grade III-IV); 93.9% of them achieved complete remission by day +30. Median follow-up was 41 months (range, 6.6 to 92.2 months); 5-year overall survival (OS) and disease-free survival (DFS) were 44.6% +/- 8.1% and 38.2% +/- 7.7%, respectively. Thirteen patients relapsed; the 3-year cumulative incidence of leukemia relapse was 33.3%. On multivariate analysis, cytogenetic status was the only significant pretransplantation factor. Survival was better in patients with grade I or II aGVHD than in those without aGVHD. Our data indicate that the sequential strategy of cytoreductive chemotherapy followed immediately by intensified myeloablative (MA) conditioning for allo-HSCT and rapid tapering of prophylactic immunosuppressants for GVHD in the early stage after transplantation has an acceptable toxicity profile and may be a better approach to treating refractory leukemia.

Sequential intensified conditioning followed by prophylactic DLI could reduce relapse of refractory acute leukemia after allo-HSCT

“…To maintain consistency of primary disease category and minimum follow-up (12 months) between the study and historical groups, we removed 6 patients with chronic myelogenous leukemia with blast crisis (CML-BC) from historical data, and re-analyzed historical data on December 31, 2009 [15]. A total of 48 refractory acute leukemia undergoing allo-HSCT but not receiving DLI from May 2001 to December 2008 were enrolled in the historical group (patient's characteristics as shown in Table 1).…”

“…We previously introduced a strategy of sequential intensified conditioning, consisting of fludarabine (Flu)/cytarabine (Ara-C) salvage chemotherapy followed by TBI/CY/etoposide (VP-16) myeloablative conditioning, and early rapid tapering of immunosuppressant for inducing GVL in refractory advanced leukemia undergoing allo-HSCT [15]. The results indicated that this strategy had an acceptable toxicity profile and improved outcome for refractory leukemia, with 5-year overall survival (OS) and disease-free survival (DFS) of 44.6% and 38.2% [15]. Despite these encouraging results, relapse in our cohort was still considerable, with 3-year relapse rate of 33.3% [15].…”

“…The results indicated that this strategy had an acceptable toxicity profile and improved outcome for refractory leukemia, with 5-year overall survival (OS) and disease-free survival (DFS) of 44.6% and 38.2% [15]. Despite these encouraging results, relapse in our cohort was still considerable, with 3-year relapse rate of 33.3% [15]. Based on these, in this study, we modified our historical strategy mainly by interventions with prophylactic donor lymphocyte infusion (DLI) for inducing GVL.…”

Soluble Human Leukocyte Antigen G Molecule Expression in Allogeneic Hematopoietic Stem Cell Transplantation: Good Predictor of Acute Graft-versus-Host Disease

“…The conditioning regimens included: (1) total body irradiation (4.5 Gy/day, on days -5 and -4) + cyclophosphamide (60 mg/kg/day, on days -3 and -2) in 38 recipients; (2) busulfan (3.2 mg/kg/day, on days -7 to -4) + cyclophosphamide (60 mg/kg/day, on days -3 and -2) in 39 recipients; (3) busulfan (3.2 mg/kg/day, on days -6 to -3) + fludarabine (30 mg/m 2 , on days -6 to -2) in 21 recipients, and (4) fludarabine (30 mg/m 2 , on days -10 to -6) + moderate-dose cytarabine (2 mg/m 2 , on days -10 to -6) + total body irradiation (4.5 Gy/day, on days -5 and -4) + cyclophosphamide (60 mg/kg/day, on days -3 and -2) + etoposide (600 mg/day, on days -3 and -2) in 8 recipients [23]. …”

Sequential chemotherapy and myeloablative allogeneic hematopoietic stem cell transplantation for refractory acute lymphoblastic leukemia

“…Few studies have investigated survival in refractory acute leukemia after sequential treatment with chemotherapy and a myeloablative or non-myeloablative conditioning regimen for allo-HSCT [8][9][10]; however, high frequencies of relapse and treatment-related toxicities present major obstacles to survival. To overcome these drawbacks, we decided to administer DNR/VCR/PSL in anticipation of debulking of leukemia, followed by allo-HSCT using a conditioning regimen with VP/CY/TBI.…”