Increasing Genetic Complexity Predicts for Inferior Outcomes Following Reduced-Intensity Conditioning Allogeneic Transplant for Chronic Lymphocytic Leukemia
Authors: Jaglowski Samantha M. , Heerema Nyla A. , Elder Patrick , Byrd John C. , Devine Steven , Andritsos Leslie A 
Published: October 2019

Abstract
Abstract 3090
Several biologic markers have been identified which predict an unfavorable course in CLL. Reduced-intensity conditioning (RIC) allogeneic transplant may be able to overcome some of these. This retrospective analysis evaluates the effect of cytogenetics, including metaphase cytogenetics, on outcomes with RIC-allogeneic SCT.
From 2005–2011, 51 RIC-allogeneic SCTs were performed at The Ohio State University for CLL. There were 38 males (74.5%) and 13 females (25.5%) with a median age of 58 (range 37–73). The median interval between diagnosis and SCT was 48 months (range 9–270). Before SCT, a median 4 lines of chemotherapy were given (range 1–11). One patient was in CR at the time of SCT, 39 were in PR, and 11 had stable or progressive disease; the median CMI was 3 (range 0–7). Fifty-nine percent of patients had del17; 53% had 3 or more abnormalities on metaphase cytogenetics, and 37% had 5 or more abnormalities. The source was PBSC in 48 (94%), BM in 1 (2%) and CB in 2 (4%). Of the PB or BM SCTs, 19 donors (39.6%) were related and 29 (60.4%) were volunteer; 45 (92%) were matched and 4 (8%) had a 1 allele mismatch. There were 21 (41%) pairs with an ABO mismatch and 16 (31.4%) pairs with a gender mismatch. Conditioning was Flu/Bu +/− ATG in 42 patients (82.2%), FluCamTBI in 6 (11.8%), FluCy in 1 (2%), and FluCyTBI-based in 2 receiving CB (4%). Following transplant, 34 (66.6%) developed AGVHD (gr 1–2: 28, gr 3–4: 6) and 27 of 48 evaluable patients (56.3%) developed CGVHD (limited: 7, extensive: 20). With a median follow-up of 17.3 months (range 1–60), the estimated 3-year OS and PFS following transplant were 56.5% and 42.9% respectively. Table 1 lists variables which had a p-value of ≤0.1 on univariate analysis. The presence of del13 and ≥5 karyotype abnormalities remained significant on multivariate analysis for OS while ≥5 karyotype abnormalities and conditioning with an alemtuzumab-containing regimen were significant for PFS (Table 2). The estimated 3 year OS for patients with del13 was 32.2% and 23% for patients with ≥5 karyotype abnormalities, compared with 72.7% and 73.5% for those without, respectively. The estimated 3-year PFS was 21.5% for patients with ≥5 karyotype abnormalities and 0% for patients with an alemtuzumab-containing regimen and 53.9% and 49.3% for those without, respectively.Table.Variables included in multivariate analysis model.Variablelogrank p-valuePFSOSAge ≥550.0072*…Del13 ≥4.7%0.0039*Del17p ≥5.7%0.0019*0.0878Karyotype abnormalities ≥50.0002*0.0138*Karyotype abnormalities ≥30.0186*0.0623Largest node ≥4 cm0.0277*…Marrow involvement ≥50%0.0752…Alemtuzumab conditioning…0.0001*GVHD prophylaxis0.0001*0.0374*HLA mismatch<0.0001*…*statistically significant at p<0.05Table 2.Multivariate analysis of OS, PFS.OSVariableHR95% CIp-valueDel13q<4.7%1≥4.7%3.581.36 to 9.420.01Karyotype<41≥55.161.97 to 13.560.001PFSVariableHR95% CIp-valueConditioningno alemtuzumab1alemtuzumab9.83.28 to 29.290Karyotype<41≥54.351.67 to 11.280.002
Due to small numbers, the alemtuzumab data should be interpreted with caution, but are consistent with previous reports. Increasing genomic complexity is known to predict for diminished chemosensitivity. Accordingly, the presence of 5 or more abnormalities on metaphase cytogenetics was demonstrated to be a poor prognostic indicator for both PFS and OS following SCT. There was substantial, but not universal, overlap among patients with del17, del13, and highly complex karyotype; this interplay merits further consideration. Better understanding of the evolution of genetic complexity will better define how to time transplant to allow for maximum benefit to those patients likely to evolve.Figure 1.OS and PFS by KaryotypeFigure 1. OS and PFS by Karyotype

Disclosures:
No relevant conflicts of interest to declare.