Use of Pre-Emptive Donor Lymphocyte Infusions To Achieve Durable Remission Following Alemtuzumab Based Reduced Intensity Conditioning (RIC) Transplantation for AML or MDS.
Authors: Lim ZiYi , Pearce Laurence , Ingram Wendy , Duarte Rafael , Devereux Stephen , Pagliuca Antonio , Ho Aloysius , Mufti Ghulam 
Published: April 2020

Use of alemtuzumab in RIC HSCT reduces the incidence of graft rejection and graft vs host disease(GvHD). However, there can be a delay in full T-cell donor engraftment. As a dominant donor T-cell chimerism may be important to achieve a strong graft vs leukaemia effect(GvL), we examined the impact of pre-emptive DLI (pDLI) on patients with falling donor chimerism. 76 patients with AML or MDS were treated with RIC HSCT (fludarabine 150mg/m2, busulphan 8mg/kg, alemtuzumab 100mg). Complete sublineage chimerism data up to day +100 was available on all patients. The underlying diagnoses were AML n=27, MDS n=49. 33 patients had early disease vs 44 advanced disease (advanced disease as defined by AML &gt;CR1, MDS RAEB or AML with multilineage dysplasia). The median recipient age was 51.6 years (range:19–72), with median follow-up of 526 days (range:137–1256). There were 30 sibling and 50 VUD allografts. Stem cell source was 61 PBSC vs 15 BM. 62 patients were fully HLA matched and 14 patients were HLA mismatched.

CD15 engraftment occurred rapidly with 95% of patients achieving full donor chimerism(FDC) at day 30 and 96% at day 100. In contrast, CD3 engraftment was significantly delayed, with only 50% of patients FDC at day 30, 47% at day 100. Incremental doses of pDLI were considered for patients with falling donor chimerism (&lt;50% donor) after day 100. Patients had immunosuppresion withdrawn, and had to have no GvHD. 20 patients received a total of 55 doses of pDLI. 10/20 had advanced disease, and 6/20 had unfavourable cytogenetics. Median donor CD3 chimerism at time of pDLI was 31.5%(range:7–59). The median CD3 dose of pDLI was 8.4x106/kg, with the first dose given at a median of day +176 (range:104–494). The median interval between pDLI was 8 weeks(range:4–22). 15 patients had FDC restored at median of 130 days following first doses of pDLI (range:36–523). 8/20 developed acute Gd II-IV GvHD following pDLI, with 2 patients dying of GvHD related complications. 2 patients relapsed with AML following treatment: with 1 death, and 1 patient currently undergoing treatment. 2 patients had not reached FDC at follow-up. A further 9 patients received DLI for cytogenetic or morphological relapse. Time to first dose of DLI was 257 days (range:76–837). The median CD3 dose was 1.67 x 107/kg. 3 patients were FDC and 6 patients MDC at time of relapse. All 3 patients with FDC failed to respond to DLI. Complete remission was seen in 3/6 patients with MDC. 4/9 patients developed acute Gd II-IV GvHD. 5/9 patients have died(all of underlying AML).

The outcome of patients receiving pDLI was compared with patients with FDC(n=28), and stable mixed chimerism(defined as donor CD3 chimerism &gt;70%) who did not receive DLI(n=18). There was no significant difference in recipient age, disease, disease stage, HLA type, cell source or cell dose between groups. However, there were more sibling donors in the group receiving pDLI(p=0.02). The 2 year DFS, OS and relapse rate was comparable between patients with FDC, stable chimerism and those receiving pDLI (59% vs 83% vs 67% p=0.22), (62% vs 88% vs 75% p=0.13), (12% vs 17% vs 15% p=0.74) respectively. In summary, pre-emptive DLI is effective in reversing falling donor chimerism, and can induce prolonged remission, even in a sub-group of patients with high risk disease. A dominant donor CD3 chimerism(&gt;70%) may be sufficient to acheive an allo-immune effect in majority of patients.