AUTHORS
Léa Mazot, Rudy Ligtvoet2, Sandra Robrecht, MD, PhD3, Nisha De Silva, MD4, Othman Al-Sawaf, MD, PhD5, Paula Cramer, MD6, Julia Von Tresckow7, Arnon Philip Kater, MD, PhD8, Carsten Utoft Niemann, MD, PhD9, Kirsten Fischer, MD10, Eugen Tausch, MD, PhD11, Stephan Stilgenbauer, MD12, Michael Hallek Jr, MD13, Barbara Eichhorst, MD14, Moritz Fürstenau, MD15
AFFILIATIONS
1 Faculty of Medicine and University Hospital Cologne, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany
2 Faculty of Medicine and University Hospital Cologne, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany
3 Faculty of Medicine and University Hospital Cologne, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany
4 Department of Hematology, St. George´s University Hospitals NHS Foundation Trust, London, United Kingdom
5 Faculty of Medicine and University Hospital Cologne, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany
6 Faculty of Medicine and University Hospital Cologne, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany
7 Department for Hematology, Oncology and Palliative Care, Catholic Clinic Bochum, Ruhr University Bochum, Bochum, Germany
8 Department of Hematology, Cancer Center Amsterdam, University Medical Centers Amsterdam, Amsterdam, Netherlands
9 Department of Hematology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Copenhagen, Denmark
10 Faculty of Medicine and University Hospital Cologne, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany
11 Department III of Internal Medicine, University Hospital Ulm, Ulm, Germany
12 Department III of Internal Medicine, University Hospital Ulm, Ulm, Germany
13 Faculty of Medicine and University Hospital Cologne, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany
14 Faculty of Medicine and University Hospital Cologne, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany
15 Faculty of Medicine and University Hospital Cologne, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany
ABSTRACT
Background: Chronic lymphocytic leukemia (CLL) mainly affects older patients (pts) with a median age of 71 years (yrs) at diagnosis, only 8.8% of pts are younger than 55 yrs (SEER database). Data on outcomes in this subgroup are scarce and largely derived from real-world cohorts. Here, we analyzed pooled data from 6 prospective trials evaluating time-limited targeted therapies (TT) regarding outcomes of younger pts with CLL.
Methods: Data from pts receiving first-line treatment within phase II/III trials conducted by the German CLL Study Group (GCLLSG) (CLL2BAG, CLL2BIO, CLL2BIG, CLL2GIVe, CLL14 and CLL13 trials, evaluating chemoimmunotherapy (CIT) and TT) were pooled. A cut-off of 55 yrs defined a younger and an older subgroup. PFS and overall survival (OS) were analyzed using Kaplan-Meier method and Cox proportional hazards regression models. Survival data for the general population were obtained from the German Federal Statistical Office and matched for age and sex. Exposure-adjusted incidence rates of severe (CTCAE grade 3 - 5) infections were calculated based on the pre-defined reporting period between study entry and end of treatment (EoT), follow-up adjusted incidence rates of SPM based on the time period between study entry and end of study participation.
Results: Of 1487 included pts, 344 pts (23.1%) were 55 yrs or younger, 1143 (76.9%) were older. Median age of the younger subgroup was 51 yrs (range 27 – 55). Median observation time was 66.3 months (mo) (range 56.6 – 76.7). TP53 mutations and/or deletions were detected in 15 (4.5%) younger and 88 (7.9%) older pts, while IGHV was unmutated in 208 (61.9%) and 643 (58.8%) pts, respectively. A complex karyotype (≥ 3 aberrations) was observed in 65 (19.5%) younger and 198 (18.3%) older pts. Overall, 430 pts received CIT (85 younger 345 older), 1057 pts TT (259 and 798). Among younger pts treated with TT the rate of premature EoT was lower compared to older pts (6.2% and 17%), whereas 14.1% younger and 8.1% older pts prematurely discontinued CIT. For pts treated with TT, no difference was observed in rates of undetectable measurable residual disease (uMRD) at EoT (69.1% and 72.3%). Median PFS was 73.6 mo in younger and 77.3 mo in older pts (HR 1.17, 95% CI 0.94 – 1.47). 5-year OS rates were 97.9% and 89.8%, respectively, with longer OS in the younger cohort (HR 0.16, 95% Cl 0.07 - 0.4). Estimated 5-year OS rates in the corresponding age- and sex-matched general populations were 98.1% and 88.8%. For younger pts receiving TT, the incidence rate of severe infections was 6.32 (95% CI 4.91-8.01) cases per 1000 pts-mo as compared to 8.73 (95% CI 7.74-9.81) in the older cohort. The incidence rate of SPM was 2.66 (95% CI 1.92-3.58) and 4.75 (95% CI 4.15-4.5), respectively.
Given that all pts ≤ 65 yrs in the CIT arm of CLL13 trial were given fludarabine–cyclophosphamide–rituximab (FCR), the majority of younger pts treated with CIT in this pooled analysis received FCR (88.2%), while 11.8% were treated with chlorambucil-obinutuzumab (GClb). In the older cohort, the majority received GClb (59.1%), followed by bendamustine-rituximab and FCR with 22.9% and 18%, influencing efficacy comparisons within the CIT-treated cohort. uMRD rates at EoT were higher in the younger subgroup (62.4%) compared to the older pts (49%). Median PFS was 61.5 mo in younger and 42.1 mo in older pts (HR 0.64, 95% Cl 0.46 – 0.9), 5-year OS rates were 94.9% and 81.4%, in line with prolonged OS in the younger cohort (HR 0.21, 95% Cl 0.08 – 0.57). The incidence rate of severe infections did not differ between age groups when treated with CIT (9.49 [95% CI 6.26-13.81] and 9.45 [95% CI 7.83-11.3] cases per 1000 pts-mo), whereas there was a difference in the incidence rate of SPM (1.55 [95% CI 0.67-3.06] and 6.18 [95% CI 5.17-7.33]).
In a multivariable analysis of all younger pts (i.e. treated either with CIT or TT), unmutated IGHV status (HR 2.72, 95% Cl 1.82 – 4.07) and complex karyotype (HR 1.64, 95% Cl 1.09 – 2.45) were suggested as adverse independent prognostic factors for PFS.
Conclusion: Younger pts with CLL receiving frontline TT reached a 5-year OS rate of 97.9%, almost identical to that of a corresponding age- and sex-matched population. The incidence rate of SPM was lower in younger pts treated with TT. Therefore, TT should be considered a preferred first-line option for younger pts with CLL. Long-term results, also on sequencing of therapies, in this group of pts are urgently warranted.
DISCLOSURES
Léa Mazot: No relevant conflicts of interest to declare.