This article written by Barbara Eichhorst and co-authors from the German CLL Study Group (GCLLSG), Department of Internal Medicine, Center of Integrated Oncology Cologne–Bonn, University Hospital, Germany, published in the Journal of Geriatric Oncology in Aug 2016 highlights the developing therapeutic options, provides details on treatment recommendations from different phase (I, II, III) clinical trials, discusses opportunities and challenges resulting from new treatment approaches that are now made available for older patients with CLL.
The key points of the article are as follows:
- Several new drugs have either received or are about to receive approval for treatment of CLL specifically in older patients being ineligible for standard dose fludarabine-based chemoimmunotherapy
- A recent phase III study demonstrated chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab (full dose FCR) as a current standard of care for untreated CLL in patients with good fitness and without increased comorbidity; dose attenuated FCR has also been evaluated in non-randomized phase II trials and observational studies showed that treatment of CLL with dose attenuated FCR was feasible in older patients without and with comorbidity. Another phase III study demonstrated that chemoimmunotherapy with bendamustine and rituximab (standard dose BR) was reported to be less efficacious but also less toxic than full dose FCR. Currently, dose attenuated BR schedules (e.g., bendamustine dosed with 70 mg/m2 instead of 90 mg/m2) are frequently applied to treat older patients with CLL, but no trials supporting such dose attenuation exist.
- Studies comparing obinutuzumab with rituximab, head-to-head demonstrated progression-free survival and time-to-next treatment (medians: 51 vs. 38 months) and showed clinically improved results with obinutuzumab. Another study called COMPLEMENT 1, showed a prolongation of the progression-free survival with ofatumumab plus chlorambucil (O-CLB) in comparison to chlorambucil alone (medians: 22 vs. 13 months)
- Kinase inhibitors ibrutinib and idelalisib, belonging to the group of ‘small molecules’ are now used for the treatment of CLL as they inhibit B-cell receptor signaling.
- A pivotal phase III study RESONATE-2 recently showed the advantage of ibrutinib chlorambucil with regard to progression-free survival (medians: not reached vs.19 months) and overall survival. Most common adverse events with ibrutinib were diarrhea and fatigue. Myelotoxicity was found to be minimal (rate of grades 3–5 neutropenia: 10%), and infection rates were reported to be in aggregate format.
- Lenalidomide is an immunomodulating drug that is approved for therapy of multiple myeloma but not yet for CLL. A study explored frontline treatment of CLL with lenalidomide in older patients; although the treatment was active and feasible in this study, the same treatment showed high mortality in the lenalidomide arm and was stopped prematurely.
- Venetoclax has been recently approved for treatment in CLL; and when combined with obinutuzumab showed to be feasible and highly active in older patients with increased comorbidity burden.
Single agent treatment with some of the novel compounds have demonstrated to be useful in controlling CLL but has limited capacity to eliminate minimal residual disease (MRD). It is essential to develop smart combination treatments capable to induced deeper molecular remissions in older patients with CLL for future clinical trials. Currently trials are ongoing in the older patient population to investigate combinations of various agents such as ibrutinib, idelalisib, venetoclax, and other small molecules with novel engineered CD20 antibodies such as obinutuzumab or ublituzumab. Results of these trials will hopefully demonstrate the advantages of new treatment approaches in elderly CLL patients.
The article can be found here
New treatment approaches in CLL: Challenges and opportunities in the elderly
The majority of patients with chronic lymphocytic leukemia (CLL) are over 70 years old. These patients vary in their vulnerability toward treatment efforts. Heterogeneity in fitness of older patients with CLL is mainly determined by individual differences in physiological aging and pathological conditions such as comorbidities and geriatric syndromes. Various options exist to treat older patients with CLL outside and inside clinical trials. Among these are newtreatment approaches, including chemoimmunotherapy with engineered CD20 antibodies(e.g., obinutuzumab), single agent therapy with kinase inhibitors (e.g., ibrutinib, idelalisib), other targeted drug therapy (e.g., venetoclax, lenalidomide), and combinations of these novel compounds. Treatment recommendations for older patients take patient-related as well as disease-related risk factors into consideration. Emerging new treatment approaches in older patients offer novel opportunities, but also novel challenges which are discussed in this review.