Gene Deletions of 17p or 11q Are Independent Predictors of Decreased Progression-Free Survival and Overall Survival Following Allogeneic Hematopoietic Cell Transplantation for Chronic Lymphocytic Leukemia

Identification of genetic and molecular markers of high risk disease for chronic lymphocytic leukemia (CLL) have improved risk-stratification of these patients and allow for adapted treatment. Allogeneic hematopoietic cell transplantation (HCT) offers a chance for prolonged disease free survival and there is increasing use of this strategy for CLL. The risk which these factors incur on HCT outcomes remains uncertain.

We performed a retrospective analysis of all CLL patients who underwent aHCT at the Moffitt Cancer Center between 2003 and 2011. Our IRB approved study was designed to examine the effect of 13 variables upon overall survival (OS) via univariate and multivariate analysis. Secondary outcomes included progression free survival (PFS), non-relapse mortality (NRM), and relapse rate. Variables were: age (years) at HCT of <50 vs. 50–59 vs. >=60; HLA matched related donor (MRD)/matched unrelated donor (MUD) vs. mismatched unrelated donor (MMUD); Chemoresponsive to last therapy (CR/PR) vs. stable disease (SD) vs. progressive disease (PD); fludarabine vs. pentostatin-based conditioning regimen; Karnofsky performance status (KPS) <90%; presence of any acute GVHD; presence of deletion 17p; presence of deletion 11q; >=3 treatment regimens prior to HCT; >=3 enlarged lymph nodes (LN) areas at HCT; presence of >=5 cm LN (bulky disease) at HCT; >=30% CLL bone marrow involvement; HCT specific comorbidity index (HCT-CI) score >= 1.

43 patients, 37% female, were identified. At diagnosis of CLL 19% had B symptoms; 58% had a Rai stage of II-IV; and 35% had bulky disease. Genetic abnormalities present at any time before HCT were: 35% del 17p and 35% del 11p. Two patients had Richter's transformation. Prior to HCT conditioning, 88% had received fludarabine and 63% had received >= 3 regimens. Median age at HCT was 55 (34–65) years, 19% had bulky disease, and 63% had a Karnofsky performance status (KPS) of at least 90%. Disease status at HCT: CR (23%), PR (33%), SD (21%), PD (23%) and the number of LN areas at HCT >=3 in 65% patients. The HCT-CI was >= 1 in 56%; donors were 42% MRD, 35% MUD, and 23% MMUD (including 3 umbilical cord blood); conditioning regimens were 33% fludarabine+busulfan, 37% pentostatin+busulfan, 19% fludarabine+TBI and 11% other.

At a median follow-up of 2.6 (range:) years for survivors, median OS and PFS were 46.5 mo and 31.4 mo by Kaplan Meier estimate. By univariate analysis, 5 factors were found predictive of worse OS: age at HCT >=60 (HR=6.1,95%CI:1.5–24.9) vs reference < 50; MMUD (HR=3.3;95%CI:1.3–8.1); PD(HR=4.9,95%CI:1.9–12.4) vs reference CR/PR; presence of del 17p (HR=2.7,95%CI:1.1–6.2); and presence of del 11q (HR=5.2,95%CI:2.1–13.0). The same five factors were predictive for PFS compared to reference group: age at HCT >=60 (HR=5.5,95%CI:1.3–22.4) vs reference <50; MMUD (HR=3.6;95%CI:1.5–9.0); PD(HR=5.7,95%CI:2.2–14.4) vs reference CR/PR; presence of del 17p (HR=2.3,95%CI:1.0–5.3); and presence of del 11q (HR=4.2,95%CI:1.7–10.4).

The presence of del 11q (n=15) and del 17p (n=15) did not correlate (p=1.0). Median OS was significantly worse for del 17p patients (7 mo vs 46 mo, p=0.0193) or those with del 11q (7 mo vs. 55 mo, p=0.0001). The cumulative incidence of relapse was not different among del 11q (HR=0.82; 95%CI: 0.22 – 3.11) or del 17p patients (HR=0.86; 95%CI: 0.22 – 3.43) while NRM was worse for del 11q patients(HR=5.14; 95%CI: 1.82–14.6).

Published data is inconclusive on the influence of genetic risk factors upon outcomes after HCT for CLL. Therefore, we conducted a multivariable analysis recognizing the number of variables in the final model would be relatively large considering the limited number of events. In our model the following three variables were associated with worse OS: MMUD (HR=3.7; 95% CI:1.1–12.6; p=0.035); del 17p (HR=5.1; 95%CI:1.6–16.6; p=0.006); and del 11q (HR=10.9; 95%CI:3.1–38.4; p<0.001). These same 3 variables correlated with worse PFS: MMUD (HR=14.4; 95% CI:3.1–66.7; p=0.001); del 17p (HR=4.4; 95%CI:1.4–14.5; p=0.014); and del 11q (HR=16.0; 95%CI:3.8–68.5; p<0.001).

For patients undergoing HCT for CLL, the presence of del 17p OR del 11q predicted for worse OS and PFS; however, the risk of relapse did not appear different. Additional prospective studies should examine the independent effects of these variables in larger cohorts of CLL patients undergoing HCT.

No relevant conflicts of interest to declare.