Clonal Gammopathies Following Reduced Intensity Conditioning Transplantation with Fludarabine, Busulphan and Alemtuzumab for Myeloid Malignancies Predict Improved Overall Survival.
Authors: Lim ZiYi , Pagliuca Antonio , Ingram Wendy , Milojkovic Dragana , Akthari Mojtaba , Ho Aloysius , Devereux Stephen , Duarte Rafael , Mufti Ghulam J. 
Published: April 2020

Abstract
Clonal gammopathies and autoimmune disease following standard conditioning haematopoietic stem cell transplantation (HSCT) are thought to reflect immune dysregulation post HSCT. Serial serum protein electrophoresis was performed on 124 patients with myeloid malignancies undergoing Alemtuzumab based reduced intensity conditioning (RIC) HSCT. The median age of patients was 53 years (range 22–72), with a median follow-up of 521 days (range 82–2096). The median follow-up for survivors was 720 days (range 82–2096). The majority of patients were treated for myeloid malignancies: MDS 84, AML 28, CML 10, others 2. There were 45 sibling and 79 VUD allografts. All patients received the same RIC protocol with FBC (30mg/m2 fludarabine iv day −9 to −5, 4 mg/kg busulphan oral from day −3 to −2; and 20 mg alemtuzumab iv from day −8 to −4) conditioning with cycloporine A for GvHD prophylaxis. Patients with autoimmune disorders or clonal gammopathies prior to transplant were excluded from the study. We observed the presence of clonal gammopathies in 49 patients (40%). On analysis of immunoglobulin sub-classes, the M component was identified as monoclonal in 21 (43%), biclonal in 16 (33%) and oligoclonal in 12 (24%). The predominant Ig isotype was IgG (84%), and gammopathies were present for a median time of 138.5 days (range: 27–462). The kappa:lambda ratio between samples was 1.6:1. The median level of gammopathies was 2.6 g/l (range 1.0–16.5). There was no evidence of plasma cell dyscrasia on bone marrow assessment in any of the patients. We compared the characteristics of patients with and without gammopathies. There were no significant differences in donor or recipient age, sex, disease type, stem cell source, stem cell dose. The incidence of viral infections, acute GvHD, donor lymphocyte infusion (DLI) was similar between the groups. However, patients with gammopathies were more likely to have chronic graft versus host disease (GvHD) (p=0.006). Bone marrow chimerism was available for analysis on 45 patients. At time of detection of gammopathy, 34 patients (76%) had achieved full donor chimerism, and 11 patients (24%) were mixed donor chimerism. Of the entire group of 124 patients, 11 patients (9%) developed autoimmune disorders. There was however no association between the presence of autoimmune disorders and clonal gammopathies (p=0.50). When patients with gammopathies were compared with those without, there was a significant difference in both disease free survival (54% vs 24%, p=0.012), and overall survival (69% vs 45%, p=0.007). On univariate analysis, early disease stage and presence of gammopathy were significant predictive variables for improved disease free survival and overall survival. On multivariate analysis, disease stage was the only independent variable for disease free survival (p&lt;0.01, HR 2.345, 95% CI 1.282–4.288), and both disease stage (p=0.05, HR 1.901, 95% CI 1.000–3.615) and presence of gammopathy (p=0.01, HR 0.421, 95% CI 0.217–0.815) were independent predictors of overall survival. The role of humoral responses following transplantation is still undefined, and it is possible that the gammopathies seen in our cohort are a surrogate response to a heterogenous group of stimuli. Clonal gammopathies are a frequent and benign occurrence following RIC HSCT, and its appearance may define a subgroup of patients with a favourable overall outcome.