A Chemotherapy-Only Regimen of Busulfan, Melphalan, and Fludarabine, and Rabbit Antithymocyte Globulin Followed by Allogeneic T-Cell Depleted Hematopoietic Stem Cell Transplantations for the Treatment of Myeloid Malignancies

Abstract

We sought to develop a myeloablative chemotherapeutic regimen to secure consistent engraftment of T-cell depleted (TCD) hematopoietic stem cell transplants (HSCT) without the need for total body irradiation, thereby reducing toxicity, while maintaining low rates of GvHD and without increasing relapse. We investigated the myeloablative combination of busulfan and melphalan, with the immunosuppressive agents fludarabine and rabbit anti-thymocyte gloubin (r-ATG) as cytoreduction prior to a T-cell depleted HSCT. No post-transplant immunosuppression was administered. Between April 2001 and May 2008, 102 patients (median age 55 years) with a diagnosis of primary or secondary myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) underwent cytoreduction with Bu/Mel/Flu, followed by TCD grafts. T-cell depletion was accomplished by CD34+-selection followed by E-rosette depletion for peripheral blood stem cell grafts, and soybean agglutination followed by E-rosette depletion for bone marrow grafts. Donors included matched and mismatched, related and unrelated donors. Risk stratification was by ASBMT risk categorization for patients with primary disease. For patients with secondary/treatment-related MDS/AML, patients in complete remission (CR) 1 or refractory anemia (RA) were classified as intermediate-risk, and all other patients high-risk. Neutrophil engraftment occurred at a median of 11 days in 100/101 evaluable patients. The cumulative incidences of grade II–IV acute and chronic GvHD at 1 year were 8.8% and 5.9%, respectively. Overall- and disease-free survivals (DFS) at 5 years were 50.0% and 46.1% respectively, and the cumulative incidence of relapse and treatment related mortality were 23.5% and 28.4% respectively. Stratification by risk group demonstrated superior DFS for low-risk patients (61.5% at 5 years) compared to intermediate or high-risk (34.2, 40.0% respectively, p=0.021). For patients with AML, those in CR1 had superior 5-year DFS compared to those in ≥CR2 (60%, 30.6% respectively, p=0.01), without a significant difference in incidence of relapse (17.1%, 30.6% respectively, p=0.209). There were no differences in DFS for other patient, donor, or disease characteristics. In summary, cytoreduction with Bu/Mel/Flu and r-ATG secured consistent engraftment of TCD transplants. The incidences of acute/chronic GvHD and disease relapse were low, with favorable outcomes in this patient population with high-risk myeloid malignancies.

Busulfan Fludarabine and Melphalan is effective conditioning for pediatric and young adult patients with myeloid malignancies underdoing matched sibling or alternative donor transplantation

“…In a single institution study, pediatric (n = 17) and adult patients with AML/MDS received BU-MEL-FLU and ATG followed by a T-depleted PBSC graft. The dose of BU and MEL was lower, 8-9.6 mg/kg and 140 mg/m 2 when compared to our regimen of 12.8 mg/kg and 180 mg/m 2 respectively for MSD and URD transplants 27 . The PFS was only 47.2% for pediatric patients.…”

Standard Antithymocyte Globulin Dosing Results in Poorer Outcomes in Overexposed Patients after Ex Vivo CD34+ Selected Allogeneic Hematopoietic Cell Transplantation

“…Our data show that whereas the addition of ATG to myeloablative conditioning before ex vivo CD34-selected allo-HCT mitigates the risk of primary graft rejection, the use of weightbased ATG results in overdosing in heavier patients, ultimately leading to higher NRM and lower DFS and OS [19,25]. Patients receiving a total ATG dose >450 mg also appear to have a higher incidence of relapse, though this did not meet statistical significance.…”

“…In ex vivo CD34-selected allo-HCT, T cell depletion markedly reduces acute and chronic GVHD rates while maintaining highly favorable anticancer efficacy. In this setting, ATG is incorporated into the conditioning regimen specifically to promote engraftment and reduce the risk of graft rejection [16][17][18][19][20][21][22]. It is administered to patients who have received the majority of their myeloablative conditioning and are lymphopenic.…”

Antithymocyte globulin exposure in CD34+ T-cell–depleted allogeneic hematopoietic cell transplantation

“…Numerous studies have demonstrated favorable outcomes, using various ex vivo T cell depleted (TCD) techniques, including CD34-selection including low rates of GVHD after HCT (for malignant and non-malignant hematologic diseases). [12][13][14][15][16] However, a main limitation when compared to T replete allo-HCT is delayed CD4+IR. 17 In patients undergoing ex vivo CD34 selection, rATG is primarily used in conditioning regimen, and has proven to be effective, to prevent graft rejection.…”