Although chronic lymphocytic leukemia (CLL) is a disease of elderly patients, subjects older than 65 years are heavily underrepresented in clinical trials. The German CLL study group (GCLLSG) initiated a multicenter phase III trial for CLL patients older than 65 years comparing first-line therapy with fludarabine with chlorambucil. A total of 193 patients with a median age of 70 years were randomized to receive fludarabine (25 mg/m² for 5 days intravenously, every 28 days, for 6 courses) or chlorambucil (0.4 mg/kg body weight [BW] with an increase to 0.8 mg/kg, every 15 days, for 12 months). Fludarabine resulted in a significantly higher overall and complete remission rate (72% vs 51%, P = .003; 7% vs 0%, P = .011). Time to treatment failure was significantly shorter in the chlorambucil arm (11 vs 18 months; P = .004), but no difference in progression-free survival time was observed (19 months with fludarabine, 18 months with chlorambucil; P = .7). Moreover, fludarabine did not increase the overall survival time (46 months in the fludarabine vs 64 months in the chlorambucil arm; P = .15). Taken together, the results suggest that in elderly CLL patients the first-line therapy with fludarabine alone does not result in a major clinical benefit compared with chlorambucil. This trial is registered with www.isrctn.org under identifier ISRCTN 36294212.

Chronic lymphocytic leukemia (CLL) is dramatically increased in patients above the age of 65 years up to an incidence rate of 22–30/100 000. Although elderly patients represent the largest group of CLL patients they are clearly underrepresented in clinical trials. One important prognostic factor in the elderly is the burden of comorbidity. Survival is significantly impaired in CLL patients with multiple comorbidities (≥2) or with severe comorbidity (Charlson score ≥2). Therefore, not only age but also the incidence and burden of comorbidity should influence the choice of treatment strategy for every patient individually. A reliable tool for measuring comorbidity is the Cumulative Illness Rating Scale. The German CLL Study Group (GCLLSG) has used this tool within their clinical trials to distinguish between physically fit and non-fit patients. Although chlorambucil is still the standard treatment of choice in non-fit patients, dose-reduced purine analogue-based combination therapies with or without immunotherapy are currently investigated within clinical trials. Because full-dosed combination treatment might cause increased toxicity rates in relapse situation, dose-reduced combination therapies should be considered in this situation. An adequate supportive treatment is necessary for the prevention of toxicities as well as for the improvement of health-related quality of life. In summary, the treatment decision in elderly CLL patients is carefully to be made in each patient individually considering not only the stage and risk factors of the disease but also the patients' physical condition and social environment.

In patients with chronic lymphocytic leukemia, Richter transformation (RT) reflects the development of an aggressive lymphoma that is associated with poor response to chemotherapy and short survival. We initiated an international, investigator-initiated, prospective, open-label phase 2 study in which patients with RT received a combination of the PD-1 inhibitor tislelizumab plus the BTK inhibitor zanubrutinib for 12 cycles. Patients responding to treatment underwent maintenance treatment with both agents. The primary end point was overall response rate after six cycles. Of 59 enrolled patients, 48 patients received at least two cycles of treatment and comprised the analysis population according to the study protocol. The median observation time was 13.9 months, the median age was 67 (range 45–82) years. Ten patients (20.8%) had received previous RT-directed therapy. In total, 28 out of 48 patients responded to induction therapy with an overall response rate of 58.3% (95% confidence interval (CI) 43.2–72.4), including 9 (18.8%) complete reponse and 19 (39.6%) partial response, meeting the study’s primary end point by rejecting the predefined null hypothesis of 40% (P = 0.008). Secondary end points included duration of response, progression-free survival and overall survival. The median duration of response was not reached, the median progression-free survival was 10.0 months (95% CI 3.8–16.3). Median overall survival was not reached with a 12-month overall survival rate of 74.7% (95% CI 58.4–91.0). The most common adverse events were infections (18.0%), gastrointestinal disorders (13.0%) and hematological toxicities (11.4%). These data suggest that combined checkpoint and BTK inhibition by tislelizumab plus zanubrutinib is an effective and well-tolerated treatment strategy for patients with RT. ClinicalTrials.gov Identifier: NCT04271956.

The prognosis of chronic lymphocytic leukemia (CLL) is very heterogeneous. Therefore, a plethora of prognostic factors has been identified to allow a better prediction of the individual prognosis of a given patient. The clinical staging systems by Rai and Binet have been the backbone of clinical management for several decades. The advent of genetic and biochemical markers, as well as next-generation sequencing has provided several markers that can predict the prognosis of patients with CLL. Using this knowledge, several scores have been created to improve predicting overall survival and/or treatment-free survival. These prognostic scores were developed in the era of chemotherpay/chemoimmunotherapy. Therefore, they now need to be tested with novel agents. However, despite tremendously improved therapeutic options, CLL patients with TP53 dysfunction or a complex karyotype remain at very high risk and seem to have a shorter (treatment-free) survival. The recently published international prognostic index (CLL IPI) incorporates most of these factors and provides a tool to analyze outcome in the modern era of targeted therapies.