Donor CD34+ Cell Chimerism at Day 28 and Chronic Graft-Versus-Host Disease (GvHD) but Not High-Risk Cytogenetics Influence Outcome of Allogeneic Hematopoetic Cell Transplantation (HCT) Following Reduced Intensity Conditioning (RIC) in Patients with AML and MDS.

HCT after RIC is used increasingly to treat older or infirm patients with AML or MDS. In the current analysis we looked for risk factors influencing outcome including cytogenetics, kinetics of donor CD34+ and T-cell chimerism (CC).

Patients and methods: From July 1998 - December 2005, 119 consecutive patients [66 m/53 f; median age 60 (range 21–74) years] with AML (n=99; 83%) and high-risk MDS (n=20; 17%) were treated within the OSHO AML studies before HCT. Seventy (59%) of the patients had intermediate-risk cytogenetics and 44 (37%) high-risk cytogenetics. Patients were either in CR1 (n= 66; 55%), CR2 (n=18; 15%), >CR2 (n=28; 24%), or were untreated (n=7; 6%) at transplant. HCT was performed from matched related (n= 33; 28%) and matched unrelated (n= 86; 72%) donors after RIC (200cGy TBI + fludarabine 30 mg/m²/day on 3 consecutive days) and followed by immunosuppression with cyclosporine and mycophenolate mofetil. Marrow donor chimerism was determined in T-, and CD34+−cells at days (d) 28, 56, 84, and thereafter at 3 month intervals using either XY chromosome FISH in gender mismatched, or PCR based analysis of polymorphic micro satellite regions in gender matched HCT.

Results: Engraftment was documented in 112 (94%) of the 119 patients. Survival (OS), disease free survival (DFS), relapse incidence (RI), and non-relapse mortality (NRM) of engrafted patients was 40%, 38%, 46%, and 30% at 3 years respectively. In multivariate analysis, only >90% donor CD34⁺ CC at d 28, chronic GvHD, and CR1, but not cytogenetic risk factors were associated with an improved OS and DFS. Patients with >90% donor CD34⁺ CC at d 28 (group I) had an OS of 50% compared to 9% in patients with donor CD34⁺ CC <90% (group II) (p=0.002). Accordingly, RI in group I was 35% compared to 85% in group II (p<0.0001). Again, donor CD34⁺ CC at d 28 but neither donor T-cell chimerism nor high-risk cytogenetics correlated with relapse. Relapse occurred in 41/109 (38%) patients at a median of 121 d. All patients (n=19) with haematological relapse within 100 days post transplant died despite reduction/withdrawal of immunosuppression. Of the 22 patients with later relapse, six went into permanent complete remission by reduction/withdrawal of immunosuppression. A decrease of CD34+ chimerism was detected in a further six patients and all responded to a decrease in immunosuppression. The incidence of acute (grades ≥ I) and chronic (limited and extensive) GvHD was 50%, and 55% respectively. OS was 10%, 46%, and 62% for patients with no GvHD (A), acute GvHD only (B), and chronic GvHD (C) (p=0.0001). DFS for A, B, C was 20%, 38%, and 55% respectively ((p=0.0001). RI was highest for A (72%) compared to B (49%) and C (25%) (p<0.0001).

Conclusions: HCT after RIC offers long-term OS and DFS in AML/MDS even in patients with high-risk cytogenetics. CR1, donor CD34⁺ CC >90% at d 28 and chronic GvHD correlate with an improved outcome and decreased relapse incidence. Careful monitoring of donor CD34⁺ CC can identify patients at risk for relapse, thereby allowing early immunmodulation.