Combined Treatment of Chronic Lymphocytic Leukemia in Frail Patients – Results from Real-World Clinical Practice

Treatment Options for CLL

CLL is typically diagnosed in older patients (median age of 72 years), who are often in poor physical condition. Combined chemoimmunotherapy (alkylating cytostatic chlorambucil in combination with the CD20 antibody obinutuzumab) has been shown in clinical trials to extend progression-free survival (PFS) in the first line of treatment compared to conventional chemotherapy, with a median PFS of up to 31.5 months.

However, CLL treatment in real-world clinical practice can result in different outcomes and adverse effects. Patient adherence to treatment is lower than in clinical trial settings, and treating physicians also more frequently resort to individualized dose reduction of the medication. Furthermore, the population of frail older patients with multiple comorbidities and obvious renal dysfunction is not adequately represented in clinical trials. Thus, the authors of the study focused on evaluating the efficacy of obinutuzumab in monotherapy or in combination with chlorambucil in the first line of CLL treatment in typical clinical practice settings.

Study Methodology

The retrospective multicenter study was conducted in collaboration with the European Research Initiative for CLL (ERIC) and the Israeli CLL Study Group (ICLLSG), including 437 patients (median age of 75.9 years) from 51 treatment centers, who were treated between 2014 and 2019 in Europe, Israel, Canada, and Argentina.

Data were retrieved from medical records, and patients with 17p13.1 deletion or p53 gene mutations were excluded from the analysis as they are currently typically treated with targeted therapies instead of chemotherapy. The clinical response to treatment was assessed 2–3 months after the completion of therapy, and PFS, time to next treatment (TTNT), and overall survival (OS) were also evaluated.

Results

408 patients were treated with the obinutuzumab/chlorambucil combination, while the remaining 29 received obinutuzumab monotherapy. The overall clinical response rate was 80.3% (41.6% of patients achieved a partial response, and 38.7% achieved a complete response). PFS was estimated at 27.6 months (95% confidence interval [CI] of 24.2−31.0 months). The median OS has not yet been reached, and the estimated 2-year overall survival was 88%.

Multivariate analysis confirmed that additional factors – high-risk disease (del(11q22.3) and/or unmutated IGHV), lymph nodes > 5 cm in diameter, obinutuzumab monotherapy, or reduced cumulative doses of the drug – were all independently associated with shorter PFS.

The most common severe adverse events (grade ≥ 3) were hematological toxicity manifestations, particularly neutropenia (14.4% of patients), and infections (7.8%).

Conclusion

In real-world clinical practice conditions, the combined treatment of chlorambucil and obinutuzumab provides PFS comparable to results achieved in clinical trials.

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Source: Herishanu Y., Shaulov A., Fineman R. et al. Frontline treatment with the combination obinutuzumab ± chlorambucil for chronic lymphocytic leukemia outside clinical trials: results of a multinational, multicenter study by ERIC and the Israeli CLL study group. Am J Hematol 2020 Feb 25, doi: 10.1002/ajh.25766 [Epub ahead of print].