Second primary malignancies in chronic lymphocytic leukaemia: Skin, solid organ, haematological and Richter's syndrome

Abstract Chronic lymphocytic leukaemia (CLL) is invariably accompanied by some degree of immune failure, and CLL patients have a high rate of second primary malignancy (SPM) compared to the general population. We comprehensively documented the incidence of all forms of SPM including skin cancer (SC), solid organ malignancy (SOM), second haematological malignancy (SHM) and separately Richter's syndrome (RS) across all therapy eras. Among the 517 CLL/small lymphocytic lymphoma (SLL) patients, the overall incidence of SPMs with competing risks was SC 31.07%, SOM 25.99%, SHM 5.19% and RS 7.55%. Of the 216 treated patients, 106 (49.1%) had at least one form of SPM, and 63 of 106 (29.2% of treated patients) developed an SPM 1.5 years (median) after treatment for their CLL. Melanoma accounted for 30.3% of SC. Squamous cell carcinoma (SCC), including eight metastatic SCCs, was 1.8 times more than basal cell carcinoma (BCC), a reversal of the typical BCC:SCC ratio. The most common SOMs were prostate (6.4%) and breast (4.5%). SHM included seven acute myeloid leukaemia (AML) and five myelodysplasia (MDS) of which eight (four AML, four MDS) were therapy‐related. Any SPM occurred in 32.1% of 53 Monoclonal B‐lymphocytosis (MBL) patients. Age‐adjusted standardised rates of SPM (per 100,000) for CLL, MBL and the general Australian population were 2648, 1855 and 486.9, respectively. SPMs are a major health burden with 44.9% of CLL patients with having at least one SPM, and apart from SC, associated with significantly reduced overall survival. Dramatic improvements in CLL treatment and survival have occurred with immunochemotherapy and targeted therapies, but mitigating SPM burden will be important to sustain further progress.


INTRODUCTION
Immune failure associated with chronic lymphocytic leukaemia (CLL) and small lymphocytic lymphoma (SLL) is one of the major and ongoing challenges of the disease. CLL immune failure results in an increased infection risk [1][2][3][4] but also a significant rise in the incidence of second primary malignancies (SPMs). The advent of immunochemotherapy (ICT) and targeted therapies have significantly improved CLLrelated survival, but this enables the emergence of SPMs including skin cancer (SC) and solid organ malignancies (SOM), second haematological malignancies (SHM) such as myelodysplasia (MDS) and acute myeloid leukaemia (AML) and high-grade lymphoid malignancies, that is, Richter's syndrome (RS).
The higher risk of SPM associated with CLL has been recognized for many years, well prior to the modern therapy era [5][6][7][8][9][10]. Manosow and Weinerman [5] in 1975 demonstrated a three-fold increase of SPM and an eight-fold increase of SC in CLL. Data from M.D. Anderson Cancer Centre (MDACC) in 2009, after the introduction of ICT but prior to the targeted therapy era, showed a 2.2-fold higher risk of SPMs in CLL/SLL compared to the general population [7]. In more recent reports, Ishdorj et al. [8] in 2019 demonstrated a four-fold increase in SC with decadelong follow-up of the Manitoba CLL population, while Bond et al. [11] in 2020 showed a 2.2-fold higher rate of SPM among CLL patients treated with BTK inhibitors.
As noted by others, SPM risk in CLL has not been systematically addressed [12]. In this detailed and comprehensive analysis from a single institution over 40 years, we evaluated all four major forms of SPMs assessed as separate entities viz; SC, SOM, SHM, and RS, that occur in CLL (including CLL, SLL and separately monoclonal B-lymphocytosis [MBL]). Furthermore, we compared the incidence rates of SPM with the CLL literature and with Australian Cancer registry and Australian Institute of Health and Welfare (AIHW) which provides Australian population data for malignancy.

Patient cohort
Data included in this study were obtained from patients managed

Statistical analysis
Statistical analysis and cumulative incidence (and 95% confidence lim- AIHW, an independent statutory Australian Government agency that provides health-related information and statistics (aihw.gov.au) [17].
Standardised incidence ratio (SIR) was calculated as the ASR for our cohort/ASR from the AIHW dataset. CLs were calculated using the methods described by Rothman et al. [18].

Other lymphoproliferative and plasma cell disorders
There were six patients (two FL, three MCL and one HCL) diagnosed with a second lymphoproliferative disorder (   Table 4). The one ALL patient was not on lenalidomide (See Table S2). RS was diagnosed at a median 6 years after the CLL and 1.5 years (median) after the last CLL treatment.
The median survival (from onset of RS) after RS diagnosis was 24 months.

OS and competing risk analysis
The OS of CLL patients with and without any SPM was illustrated by The occurrence of death before SPM can bias analyses of incidence.
Therefore, calculation of overall incidence of SPMs in the CLL cohort was adjusted using death as a competing risk (  Figure S5). Both the RS and AML/MDS numbers were small, and these effects need to be examined on larger numbers of patients.

Age standard incidence of SPM for CLL compared to the Australian population
The age standard incidence (ASR) for the CLL and MBL cohort was calculated as described in Methods. The RNSH North Sydney Area closely matches the general Australian population ( Figure S6). The ASR of SPMs for CLL and MBL (Table 6) were all substantially higher than the Australian population. AML and MDS had relatively small numbers resulting in wide confidence intervals.

DISCUSSION
The development of an SPM has a strong association with CLL. This association long pre-dates the advent of ICT and targeted therapy but appears to be a more significant clinical issue in the current era as patients survive much longer with their CLL. Following the introduction of ibrutinib in Australia in 2012 with the RESONATE trial [19], our centre observed, for the first time, higher mortality due to SC instead of CLL [20].
In the context of SC, melanoma is mandated as a cancer registry  with an ASR of 51.8 [26] but substantially higher in our CLL cohort (ASR 278.7, SIR 5.38, CL 4.0, 7.2, Table 6). Australian melanoma incidence rises with age with ASR from 80.2 for age 50-59 years to 229.1 over 80 years [27]. Similarly in CLL, both melanoma and NMSC rates rise with age with both substantially higher than general population highlighting both age [21] and CLL-related immune failure as contributing factors for SC in CLL. In younger patients, we observed a higher relative incidence of SPM again consistent with immune failure ( Figure S4). In our cohort, three of seven AML occurred with no prior CLL therapy.
The Danish CLL registry of 4286 patients recorded 40 (0.93%) acute leukaemia, and 34 (85%) had no prior therapy [10]. They found a fludarabine risk for MDS but not acute leukaemia (only two of six treated received fludarabine) [10]. Our data suggest an 'any CLL therapy' effect but not a specific fludarabine effect ( Figure S5) [36], while the German CLL8 trial showed the risk was higher in the FC (6.3%) than the FCR arm (3.2%) [32]. Analysis using death as competing risk, the HR of RS in treated CLL versus untreated was 2.18 (CL 0.95, 5.01, Figure S5). There is insufficient evidence, due to small sample sizes and wide confidence intervals to determine whether RS is associated with fludarabine. Future investigation with larger sample sizes is warranted.
The comprehensive analysis of all forms of SPMs over a very long follow-up is strength of this study. It accurately reflects the natural history of CLL in a large, mainly community-based, single institution cohort with relatively uniform management. Very long follow-up has potential ascertainment bias by selecting patients with more indolent CLL, and hence longer survival, perhaps enabling more of these patients to develop SPMs. CLL prognostic markers such as chromosomal mutations and IGHV status were available in a small proportion having become available late during this 40-year long timeframe; in any event, staging and karyotype are dynamic factors that change with time. CLL patients when diagnosed with an SOM were usually referred to an oncologist occasionally limiting our ability to precisely identify the cause of death, but most subsequent mortality appeared due to the SOM rather than CLL.
The high incidence of SPMs (ASR 2648 in CLL vs. 486.9 in population) has a substantial impact and health burden upon CLL patients, their management and survival. Routine monitoring of the skin and education to avoid sun exposure are essential for CLL patients, as data suggest these measures lower NMSC risk. Education and surveillance for SOM are also vital as these significantly shorten survival, and early detection has at least the potential to improve outcomes. Hence adherence to breast and prostate cancer surveillance guidelines, cessation of smoking, evaluation of iron deficiency for potential gastro-intestinal tract malignancy and investigation of suspicious symptomatology in other organ systems are important. As SPMs occur in over half of all CLL patients, the frequent exclusion of such patients in clinical trials limits our understanding of 'real-world' outcomes. CLL has seen dramatic improvements in treatment and survival since the introduction of ICT and targeted therapies, and the high incidence and health burden of SPMs may be a key limitation to further progress in this disease.