Second primary malignancies in treated and untreated patients with chronic lymphocytic leukemia
Authors: Moritz Fürstenau, Adam Giza, Thomas Stumpf, Sandra Robrecht, Christian Maurer, Hartmut Linde, Lutz Jacobasch, Steffen Dörfel, Ali Aldaoud, Julia von Tresckow, Michael Koenigsmann, Tobias Gaska, Ulrich Kaiser, Hanns‐Detlev Harich, Kirsten Fischer, Barbara Eichhorst, Michael Hallek, Anna‐Maria Fink
Journal: American Journal of Hematology (2021)

With the introduction of targeted agents into the treatment paradigm of chronic lymphocytic leukemia (CLL), outcomes for patients have markedly improved. With prolonged overall survival in the predominantly elderly population of CLL patients, second primary malignancies (SPM) become more relevant as competing causes of death. Prior analyses have consistently shown increased rates of SPM in patients with CLL in different treatment contexts when compared to the general population.1-4 With scarce data comparing treated and untreated patients with CLL, it remains unclear whether this increase in SPM can be attributed to CLL-inherent immunodeficiency, shared environmental or genetic risk factors of CLL and SPM or cancerogenic effects of antineoplastic treatments. To specifically assess the effect of CLL-directed treatment on SPM incidence, we analyzed a comprehensive data set of treated and untreated patients included in the registry of the German CLL Study Group (GCLLSG). The GCLLSG registry is a noninterventional prospective study and all patients with CLL and related malignancies are eligible for participation. Detailed patient, disease, and treatment characteristics are collected in a clinical database by annual visits, SPM are reported on separate forms. All enrolled patients with CLL and an observation time ≥ 24 months from CLL diagnosis were included in this analysis. All malignancies occurring after CLL diagnosis were considered as SPM except for aggressive B-cell lymphomas that were separately reported as Richter's transformations. Time to SPM was calculated from CLL diagnosis and first-line therapy and evaluated by competing risk analyses considering death as a competing event. Standardized incidence ratios (SIR) from time point of CLL diagnosis were used to compare the SPM incidence in our cohort with that in the German general population with SIR being defined as the ratio of observed SPM and the number of expected SPM based on sex-, age-, and calendar year-matched data from the population-based German cancer registry. We included 1303 patients with documented CLL diagnosis between 2013 and 2018 in this analysis. At the data cut (June 25, 2020) 480 (36.8%) of these patients had received at least one line of treatment and were categorized as treated while 823 (63.2%) patients were treatment-naïve at last follow-up and allocated to the untreated group. The median observation time from CLL diagnosis was 49.5 months (range, 24.1–88.4) for the full cohort, 55.3 months (24.1–88.1) for the treated cohort and 46.6 months (24.1–88.4) for untreated patients. In the treated group, most patients (78.5%) had only received one line of treatment, 14.8% had two prior lines and 6.7% had three or more CLL-directed therapies. First-line regimens were mostly bendamustine- and fludarabine-based (45.6% and 17.3%), 15.4% had BTK inhibitor-based first-line treatments and 11.7% of all regimens contained chlorambucil (Table S1). The median age was 68 years (range, 31–90) and 61.1% of the patients were male (Table S2). While pre-existing comorbidities and ECOG performance status were similar between treated and untreated patients, there was a higher proportion of patients with del(17p), unmutated IGHV, and advanced Binet stage in the treated cohort. Among the 1303 included patients, we observed 105 SPM in 95 patients. In the untreated cohort, 70.4% of all observed SPM were solid malignancies while only 9.3% were hematological malignancies and 20.4% were nonmelanoma skin cancers (NMSC). The distribution in treated patients was 60.8% solid malignancies, 17.6% hematological SPM, and 21.6% NMSC. The most common solid SPM in untreated patients were prostate colorectal and upper gastrointestinal cancer. In the treated cohort, prostate cancer, melanoma, and colorectal cancer occurred most frequently (Table S3). For competing risk analyses from CLL diagnosis, we considered all 1303 patients untreated until they were censored at the start of first-line treatment. In this cohort, estimated 2-year and 4-year incidences of any SPM were 2.3% and 5.8% (Figure 1A). Treated patients were analyzed separately from the start of first-line treatment and showed 2-year and 4-year incidence rates of any SPM of 5.4% and 9.7% (Figure 1B). To investigate possible associations of specific treatment regimens with the occurrence of SPM, we compared cumulative incidences of different therapies in time-to-SPM analyses. None of the regimens (bendamustine−/fludarabine-/BTK inhibitor−/chlorambucil-based) showed a significantly higher incidence of SPM when compared against all other regimens (Table S4). We calculated SIR to compare the observed incidence of SPM in our cohort with the incidence in the German general population. The overall risk of SPM in our GCLLSG cohort was not significantly higher than in the matched general population (SIR 1.16, 95% confidence interval [95% CI]: 0.94–1.42) (Table S5); however, a higher-than-expected incidence of hematological SPM was observed in our cohort (SIR 2.18, 95% CI: 1.19–3.65; p = .0053). The incidence of solid SPM and all subcategories of solid malignancies in our GCLLSG cohort showed no difference compared to the general population. While in the untreated cohort, no evaluated malignancy showed a significant increase compared to the general population, the incidence rates of all SPM (SIR 1.42, 95% CI: 1.04–1.90) and in particular hematological SPM (SIR 3.64, 95% CI: 1.66–6.90) were higher than expected in the treated group (Figure 1C). The few retrospective studies that compared SPM incidences in treated and untreated patients with CLL showed ambiguous results.1, 5 While earlier SEER data did not indicate significant differences in these two groups, the latest analysis showed a 38% elevated SPM risk for CLL patients who had received prior chemotherapy compared to a 16% increased risk in those untreated or without available treatment information.1 Notably, this risk increase was mostly driven by higher numbers of hematological SPM in the treated cohort, similar to our study. The SEER analysis showed a 61% higher risk for hematological malignancies compared to the general population, lower than we had observed in our study (SIR 3.64, 95% CI: 1.66–6.90). However, the SEER analysis assessed a very long time period and describes a significantly higher incidence of hematological SPM in the last studied period (2003–2015) with a SIR of 2.58 (95% CI: 2.32–2.86).1 The increase of hematological malignancies over time in the SEER data as well as in our data set can likely be attributed to better diagnostic tools but it is also conceivable that the introduction of more intensive treatment options for CLL (e.g. FCR) has contributed to an increase in hematological SPM.1, 4 A single-center study from the MDACC identified 797 long-term survivors of CLL, of which 227 were untreated.5 The authors compared incidence rates of SPM between the treated and untreated groups and could not detect a significant difference. However, the comparability of our data and the SEER as well as the MDACC data set is impaired by the prospective versus retrospective methodology, different observation periods, and differences in the availability of treatment information. In line with other studies, we observed a trend toward a higher incidence of melanoma in our treated cohort (SIR 3.53, 95% CI: 0.95–9.04). Increased incidences of melanoma were consistently found in most studies of SPM in CLL and the use of fludarabine-based treatments has been associated with a particularly high risk.1, 3 Our study has various important limitations: By restricting our cohort to patients with exclusively prospective data, the number of patients receiving different treatment regimens is limited, impeding comparisons between these treatment regimens. Furthermore, the above-mentioned differences in the baseline characteristics (genetic risk profile, disease stage) possibly influenced the risk to develop SPM beyond the impact of CLL-directed therapy. It has been hypothesized that CLL-related immunosuppression is the main driver behind the increased risk for second cancers.2, 3, 6 In their study on SPM in BTKi-treated patients, Bond and colleagues demonstrate that higher baseline CD8 counts are associated with a lower risk of developing SPM.3 While we did not obtain data on our patients' cellular and humoral immune status, individuals who developed SPM had a higher incidence of severe infections than those without SPM (p = .032) and more patients in our treated cohort had an advanced disease stage. Both factors suggest a more severe immune dysfunction in the treated cohort that possibly contributed to the higher incidence of SPM. It has also been discussed that the increase of SPM in patients with CLL is a correlate of more diagnoses of earlier stage cancer due to stringent observation and higher adherence to screening procedures.1 SPM that are subject to screening programs or tend to be detected by more frequent blood testing or imaging (cancer of prostate, breast, colon, lung) were not increased in our cohort compared to the general population (Figure 1C), thus our study does not support this hypothesis. In this analysis, we show that the incidence of SPM in treated patients with CLL was 42% higher than in the general population mostly due to a higher-than-expected incidence of hematological SPM while untreated patients with CLL had no increased risk of SPM compared to the general population. No significant differences in SPM incidence could be detected when comparing different first-line regimens. While the underlying mechanisms leading to increased cancer rates in patients with CLL are not yet fully explored, our study suggests that prior CLL-directed treatment has a role in the development of hematological SPM while it does not seem to affect the incidence of most solid malignancies. MF, AG, TS, SR, HL, LJ, SD, AA, MK, TG, UK, H-DH have no disclosures. CM has received travel grants by Amgen, Abbvie and Servier Deutschland GmbH and honoraria by Abbvie. JvT has received grants from Janssen-Cilag and Roche, consulting fees from Abbvie, Janssen and Roche, honoraria from Abbvie, AstraZeneca, Janssen and Roche and support for attending meetings/travel from Abbvie, AstraZeneca, Celgene, Janssen and Roche. KF has received travel grants and honoraria by Roche and honoraria by Abbvie. BE reports grants and personal fees from Janssen-Cilag, Roche, Abbvie, Gilead, personal fees from Novartis, Celgene, ArQule, AstraZeneca, Oxford Biomedica (UK) and grants from Beigene, outside the submitted work. MH reports personal fees and other from Abbvie, Celgene, Gilead Sciences, Janssen, Mundipharma, Pharmacyclics, Roche, outside the submitted work. A-MF reports research grants by Celgene, advisory boards by Abbvie and travel grants by Abbvie and F. Hoffmann-LaRoche. Data available on request from the authors Table S1. List of documented first-line treatments Table S2. Baseline characteristics at the timepoint of CLL diagnosis Table S3. Distribution of solid SPM Table S4. Cumulative incidence of SPM according to first-line treatment Table S5. Standardized incidence ratios Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. 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