Reduced Intensity Conditioned Allogeneic Stem Cell Transplantation Is as Effective in Poor Risk as Standard Risk Acute Myeloid Leukaemia (AML).
Authors: Ingram Wendy , Lim Ziyi , Pagliuca Antonio , Devereux Stephen , Ho Aloysius , Mufti Ghulam 
Published: April 2020

Abstract
Poor risk cytogenetics and multi-lineage dysplasia are commonly found in older patients with acute myeloid leukaemia (AML) and despite intensive chemotherapy prognosis remains grim. We compared the outcome of standard risk to poor risk AML (both according to cytogenetic risk group and presence of underlying dysplasia) following reduced intensity conditioned (RIC) allogeneic haematopoietic stem cell transplantation (allo-HSCT) in 65 patients (32 males, 33 females) with a median age of 53years (range 22–65years). Conditioning regimen incorporated fludarabine(150mg), Alemtuzumab(100mg) and busulphan(8mg–16mg). 35/65 had a background of multi-lineage dysplasia (MLD-AML), 30/65 de-novo AML. According to cytogenetics, 48 were standard risk, 15 poor risk and 2 good risk (both good risk cases were in second remission). Median number of chemotherapy regimens administered prior to RIC HSCT was 3 (range 1–8), with 33/65 receiving FLAG chemotherapy and 2/65 a previous autologous HSCT. 57/65 were in complete remission (CR) at time of HSCT, 6/65 partial remission (PR) and 2/65 refractory disease. 51/65 were in first remission, 14/65 second remission. Sibling donor was used in 25/65, volunteer unrelated donor (VUD) in 40/65 (1 antigen mismatch 13/40, 2 antigen mismatch 3/40). Bone marrow (BM) was administered to 17/65 and peripheral blood stem cell (PBSC) to 48/65.
Median follow-up was 389days (range 36–1731) for all patients and for those alive 633days (range 71–1731). Failure to engraft occurred in 1 patient and late graft rejection in 3 patients. The day+100 transplant related mortality for all patients was 11%. The overall survival (OS) at 1year for siblings versus VUD was 77% v 58% (p=0.46) and the disease free survival (DFS) 50% versus 53% (p=0.98). The OS for de-novo AML versus TLD-AML at 1year 73% versus 59% (p=0.34) and DFS 59% versus 46% (p=0.06). Comparison of the OS at 1year for the standard versus poor risk cytogenetic groups was 63% versus 72% (p=0.33), and DFS 50% versus 57% (p=0.68) respectively. 15/65 developed acute GvHD grade II–III. The cumulative incidence of chronic GvHD was 19% in those surviving after day+100. 46% of patients achieved full donor engraftment on lineage specific chimerism at day+100. Incremental donor leukocyte infusions (DLI) were administered to 25 patients. 16/25 received DLI for mixed chimerism, 9/16 reverted to 100% donor, 4/16 continued with stable mixed chimerism and 3/16 developed relapsed disease. 9/25 received DLI for disease relapse resulting in complete remission in 3/9 cases. 10/23 patients administered DLI developed GvHD grade II–III. In summary, RIC allo-HSCT incorporating Alemtuzumab was equally well tolerated in both sibling and VUD allografts, with a low incidence of acute and chronic GvHD. The results show favourable outcome in a poor risk cohort of patients with AML, with comparable OS compared to standard risk/de-novo AML. DFS was not affected by cytogenetic risk however comparison of de-novo AML to MLD-AML did show a trend (p=0.06) in favour of de-novo AML.