S149: OTHER MALIGNANCIES IN THE HISTORY OF CLL: THE FINAL ANALYSIS OF THE INTERNATIONAL MULTICENTER STUDY CONDUCTED BY ERIC, IN HARMONY.

Background: Patients with chronic lymphocytic leukemia (CLL) have a higher risk of developing other malignancies (OMs) compared to the general population. However, the impact of CLL-related risk factors and CLL-directed treatment is still unclear.

Aims: We aimed to (i) determine the incidence of OMs in a population of patients with CLL, (ii) assess the overall survival (OS) of patients with CLL and OM, and (iii) find risk factors for the occurrence of OM in patients with CLL.

Methods: This is a retrospective international multicenter study conducted by the European Research Initiative on CLL, in the context of HARMONY. Investigators at each participating site provided data on consecutive sets of patients diagnosed with CLL/small lymphocytic lymphoma (SLL) or high-count CLL-like monoclonal B-cell lymphocytosis (MBL) between 2000-2016. The study was approved by the local institutional ethics committees.

Results: Data on 19,705 patients from 85 different centers in 33 countries was collected. The median age at CLL diagnosis was 65 years [interquartile range (IQR) 57-73], and the median follow-up from CLL diagnosis was 6.2 years (IQR 3.72-9.6). The majority of patients had CLL (18,386, 93.3%), while 528 (2.7%) and 791 (4%) were diagnosed with SLL and MBL, respectively. At last follow-up, 10,146 (53%) patients had received at least one line of treatment (median 1, IQR 1-2).

Diagnosis of OM was reported in 4,134/19,705 (21%) patients with CLL [633 (3.2%) had Richter transformation (RT) or B cell prolymphocytic leukemia]. In 2,910/4,134 (70.4%) patients, the OM postdated the diagnosis of CLL; in 854/4,134 (20.6%), the OM either antedated or was diagnosed concurrently with CLL; finally, in 322/4,134 (7.8%), an OM was diagnosed both before and after CLL diagnosis. Overall, 3,513 OMs were diagnosed in 130,166.9 years of follow-up after CLL diagnosis (26.9 OMs/1,000 person-years).

The most common hematological OMs were myelodysplastic syndrome (MDS) (87/19,705, 0.44%), followed by acute myeloid leukemia (AML) (42/19,705, 0.21%) and multiple myeloma (37/19,705, 0.19%). Treatment with fludarabine and cyclophosphamide with/without rituximab (FC+/-R) was the only statistically significant risk factor for MDS/AML in the multivariate analysis, while only 13q deletions were associated with hematological OMs (excluding MDS/AML and RT).

Non-melanoma skin cancers (NMSC) (986/19,705, 5%) and prostate cancers (PCs) (530/19,705, 2.7%) were the most frequent solid tumors (ST), followed by colon (382/19,705, 1.9%) and breast cancers (343/19,705, 1.7%). Male patients and those with unmutated immunoglobulin heavy variable (IGHV) gene status had a higher risk of developing an ST (excluding NMSC).

The most frequent STs (>100 cases) were analyzed separately and statistically significant (p<0.05) associations were found between (i) NMSC development and male gender, older age at diagnosis, and FC+/-R treatment; (ii) male gender and colorectal and bladder cancers; (iii) unmutated IGHV gene status and melanoma, lung and breast cancers.

The effect of CLL-directed treatment varied between different STs. Treated patients were more likely to develop NMSC and PC (OR=1.8;95%CI=1.36-2.41; p<0.001/OR=2.11;95%CI=1.12-3.97; p=0.021), while breast cancers were more frequent in untreated patients (OR=0.17;95%CI=0.08-0.33; p<0.001).

Patients with CLL and an OM had inferior OS than those without. MDS/AML conferred the worst OS (Figure).

Summary/Conclusion: OMs in CLL impact on OS. FC+/-R is associated with increased risk of MDS/AML. Accurate assessment of the risk of OMs in patients treated with chemo-free regimens requires further investigation.

Keywords: B cell chronic lymphocytic leukemia