Phase II Trial of a Chemotherapy-Only Regimen of Busulfan, Melphalan, Fludarabine and R-ATG Followed by Allogeneic T-Cell Depleted (TCD) Hematopoietic Stem Cell Transplants (HSCT) for the Treatment of Myeloid Malignancies.

In this trial, we wished to test whether a chemotherapeutic regimen combining myeloablation with busulfan (Bu) and melphalan (Mel) with fludarabine (Flu) and ATG could be used to secure consistent engraftment of T-cell depleted transplants thereby reducing GvHD and regimen-related toxicity without increasing risk of relapse in patients with advanced myeloid malignancies. Between 08/01 and 06/07, sixty two patients with a diagnosis of myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML) were enrolled on this trial, including 33 males and 29 females of a median age of 54.5 years (range 0.6–71.3 years). Eleven patients had primary AML in CR1 (N=4) or ≥ CR2 (N=7). Thirty two pts had primary (1°) MDS and 19 pts treatment related (2°) MDS/AML. Forty five of the 51 pts with 1° or 2° MDS had ≥ RAEB status at diagnosis and required chemotherapy prior to transplant. The status of MDS pts at the time of SCT included: CR1 (N=14), CR2 (N=3), primary RA (N=6), second RA (N=21), > RA (N=7). Thirteen pts received allografts from HLA-matched related donors, 4 pts from HLA-mismatched related donors, 22 pts from HLA-matched unrelated donors, and 23 pts from HLA-mismatched unrelated donors. Cytoreduction consisted of BU (0.8–1 mg/Kg/dose × 10 doses), MEL (70 mg/Kg/day × 2) and FLU (25 mg/m2/day × 5). Graft rejection prophylaxis included pre-transplant rabbit ATG (Thymoglobulin) (2.5 mg/Kg/day × 2) and no post transplant immunosuppression was administered. Fifty nine pts received G-CSF mobilized peripheral blood stem cell transplants (PBSCT) that were T-cell depleted by positive CD34 selection and sheep-RBC rosetting while three pts received soybean agglutinin E-rosette depleted marrow grafts. For the PBSCT grafts, the median CD34+ cell dose/Kg was 5.0 × 106 (range: 1.3–28.8 × 106) and the median CD3+ cell dose/Kg was 1.1 × 103 (range 0–12 × 103). Median follow-up was 16 months (range 0.7–68.7 mo). Engraftment occurred in 59 of 61 evaluable pts, but two recipients of unrelated donor grafts suffered a graft failure. Acute grade 2–4 GvHD occurred in 7 pts, and chronic GvHD in three of 40 evaluable pts. Twenty two pts died of infection (n=7), organ toxicity (n=6), GvHD (n=3), graft failure (n=1) or relapse (n=5). The two-year probabilities of overall survival (OS) and disease-free survival (DFS) for the entire patient cohort were 62% and 54% respectively with a two-year probability of relapse of 16.2%.The two-year DFS for recipients of HLA-matched related and unrelated grafts was 54% and 57% for recipients of HLA-disparate unrelated grafts. Two-year DFS was 58% for pts with primary AML, 57% for pts with primary MDS and 51% for pts with secondary MDS/AML. Two-year DFS was 60.6% for pts ≤ 50 years and 49.7% for pts > 50 years. In summary, cytoreduction with Bu Mel and Flu and rabbit ATG has secured consistent engraftment of T-cell depleted transplants for both HLA-matched or disparate, related and unrelated donors. The incidence of acute or chronic GvHD and disease relapse were low, with favorable outcomes in this cohort of older patients with high risk myeloid malignancies.