Second Reduced Intensity Transplants Are Effective and Well Tolerated in Older Patients with Relapsed Myeloid Malignancies. A Single Centre Report.
Authors: Chen Frederick E. , Ahmad Humayun N. , Junagade Pritesh , Lim Zi , Devereux Stephen , Pagliuca Antonio , Ho Aloysius , Mufti Ghulam J. 
Published: April 2020

Abstract
Previous reports of second allografts for relapsed leukaemia involved either children or young adults. However, the majority of myeloid leukaemias present in patients over 50 years of age. Lower TRM from Reduced Intensity Conditioning (RIC) HSCT has permitted older, previously not eligible patients to undergo sibling and unrelated donor allografts. However, therapeutic options are extremely limited when patients relapse. We report the outcome of second non-myeloablative transplant for these patients. A retrospective analysis of non-myeloablative allografts performed at Kings College identified 18 patients who received double RIC allografts for myeloid malignancies (de novo AML (3), MDS (10), CML (3) and Myelofibrosis (2)), of which 16 relapsed and 2 developed graft failure following the first transplant. The median age at second transplant was 55 years (R: 18–69). For the first allograft, 14 were conditioned with Fludarabine (150mg/m2)/Busulphan(8mg/Kg)/Campath (100mg) (FBC), 2 with Campath(80mg)/TBI(200cGy), and one with Busulphan (12.8mg/Kg)/Cyclophosphamide (200mg/Kg) and one with Etoposide (60mg/Kg)/TBI (1440cGy). For the second allograft, 6 received FBC, 4 FB, one Cyclophosphamide(120mg/Kg)/ALG(45mg/Kg), one Campath (100mg), 2 Mylotarg (18mg/m2), one Campath/TBI, one Fludarabine(150mg/m2)/Melphalan(140mg/m2) and 2 Fludarabine (150mg/m2)/Cytarabine(10g/m2)/GCSF( 1800ug/m2) (FLAG). 11 patients received stem cells from the same donor as the first transplant (9 Sib, 2 VUD) and 7 from different donors (2 Sib, 5 VUD). The median cell dose was 4.7 x 106 CD34 /Kg (R: 0.57 12.48). Sixteen patients underwent a second allograft for relapse and two for graft failure. Seven received HLA-matched VUD and 11 HLA-matched sibling donor cells. Day 100 DFS was 50% and TRM 33% with no significant difference between sibling and VUD allografts. Median neutrophil and platelets engraftment took 13 and 14 days respectively. Five patients died of relapse and 8 of of transplant-related complications (4 GvHD, 2 infection, 1 encephalopathy, 1 VOD). With a median follow up of 233 days (R: 4–1690 days), the Kaplan-Meier DFS reached a plateau of 26% (5 patients) at one year. Further analysis showed improved outcome for those who received a second transplant following remission induction (dysplastic and hypoplastic CR) compared to those transplanted in frank relapse. Four out of eight patients (50%) transplanted in CR remain disease-free, whereas only one out of eight (12.5%) transplanted with relapsed disease remains alive. Two patients transplanted for graft failure died. Of 13 deaths, 5 died of relapsed disease (38.5%), 4 of severe GVHD (30.8%) and infection, 2 (15.4%) of infection, one of encephalopathy (7.69%) and one of VOD (7.69%). Relapsed disease was the major cause of mortality despite a second allograft, followed by GvHD and infection. Despite the high TRM, the results suggest that second donor allograft performed for patients with myeloid malignancies who achieve CR confers a DFS of 50% at 1 year. The risks of a second non-myeloablative transplant for selected patients who achieve remission prior to procedure are acceptable in comparison to conventional treatment for relapsed disease post transplant, even in patients over 50 years of age.