34-Year Single Center Observational Review of Ex-Vivo T-Cell Depleted Allogeneic Hematopoietic Stem Cell Transplants for Chronic Myeloid Leukemia
Authors: Woolley Philippa , Slade David , Syzdlo Richard , Nesr George Nasry , Claudiani Simone , Caballes Irene , Fernando Fiona , Pavlu Jiri , Palani Renuka , Kanfer Edward , Olavarria Eduardo , Milojkovic Dragana , Apperley Jane 
Published: October 2019

Abstract
Introduction:
Ex-Vivo T-Cell Depletion (EX-TCD) has been shown, in multiple cohorts, to markedly decrease the incidence of graft-versus-host-disease (GvHD). This conditioning regime however, has been associated with high incidence of disease relapse. This single center, observational 34 year study, demonstrates outcomes of patients who underwent EX-TCD Allogeneic Hematopoietic Stem Cell Transplant (AHSCT) for Chronic Myeloid Leukemia (CML).
The total cohort consisted of 62 patients; all underwent EX-TCD AHSCT between 1984 and 1988. 58% (n=36) of the total cohort relapsed and 53% of relapsed patients (n=19) went on to have a second AHSCT (non-T-cell depleted) or donor lymphocyte infusion (DLI) with the remaining 47% (n=17) receiving conservative management. Given these differences in management, we used a competing risk model to adjust for the second AHCST or DLI on survival outcomes (using a second AHSCT or DLI as a competing risk).
The aim of this study was to determine from this cohort, which factors were associated with overall survival and survival following disease relapse.
Methods:
Within the relapsed cohort, univariate and multivariate standard Cox proportional hazard regression models were used to analyse various factors, which were hypothesized to be associated with survival. These included; age at relapse, gender and relapse grade. Competing risk model was used to analyse the contribution of a second AHSCT or DLI to survival.
Results:
The cohort underwent EX-TCD AHSCT for CML between 1984 and 1988. Age range of recipients was 15 to 53 years and all were sibling donors. At the 34 year follow-up mark, there was no difference in overall survival between those who relapsed (and received a second AHSCT or DLI) and those patients who did not relapse (p-value 0.86). Of the 26 % (n=16) of patients who remain alive, 50% (n=8) relapsed and received a second AHSCT or DLI. Most recent BCR-ABL polymerase chain reaction (PCR) confirm all patients remain in molecular remission (MR4 or below).
For the whole cohort, relapse was not affected by; donor gender, recipient age, CMV status, GvHD grade, duration of disease prior to AHSCT, Sokal score at diagnosis or duration to relapse following AHSCT. No parameter had a statistically significant association with survival or relapse, suggesting heterogeneity of disease could be an important consideration. 22 % (n=2) of the non-relapsed group and 17% (n=6) of the relapsed group developed acute GvHD. 37% (n= 23) of patients from the whole cohort developed chronic GvHD. Known causes of death included; relapse (36%, n=22), infection (16%, n=10), chronic GvHD (11%, n=7), other (8%, n=5). 26% (n=16) of patients remain alive today and 3% (n=2) were lost to follow-up.
Relapse was graded into 5 categories, mirroring monitoring methods at the time of relapse (prior to the development of BCR-ABL PCR). 6% (n=2) of patients developed a molecular relapse (grade 1), 58% (n=21) developed cytogenetic relapse (grade 2), 25% (n=9) developed hematological relapse (grade 3), 3% (n=1) relapsed as accelerated phase CML (grade 4) and 8% (n=3) relapsed with blast phase CML (grade 5). We divided patients into two groups; relapse grade <2 (cytogenetic or molecular relapse only) and grade >3 (hematological relapse or above). In a multivariate Cox proportional model, relapse grades were significantly associated with subsequent survival (log rank p-value 0.0057). Relapse grade >3 had an 11% increased hazard of death compared to relapse grade <2 (Hazard ratio (HR) 1.11; p-value 0.0068). 46% (6/13) of patients with relapse grade >3 underwent a second AHSCT or received DLI, compared with 56% (13/23) of patients with grade <2. In the competing risk analysis, those patients with relapsed grade <2 had a significantly improved survival with a second AHSCT or DLI (HR 1.34; 95% CI 1.06-13.70; p-value 0.03) whereas patients with a relapse grade >3 had no improvement in survival. (HR 0.96; 95% CI 0.93 to 6.8; p-value 0.07, Figure 1).
Conclusion:
In this cohort, EX-TCD was associated with high rates of relapse. However, patients remain alive from both the non-relapsed and relapsed cohorts. In the relapsed cohort, patients who received a second AHSCT or DLI had improved survival outcomes compared to conservative management. A competing risk analysis demonstrated that patients with lower relapse grades had a statistically significant improvement in survival after a second AHSCT or DLI.

Disclosures
Milojkovic: Incyte: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau. Apperley:Novartis: Honoraria, Research Funding, Speakers Bureau; Incyte: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau.