Combination treatments using drugs that target different CLL mechanisms have shown promising results for patients in clinical trials. And the great news is that some treatments that combine BTK and BCL2 inhibitors are now being approved as first line treatment options in Canada. For example, the combination of Ibrutinib and Venetoclax (I+V) is now approved and publicly funded in several Canadian provinces, and Acalabrutinib+Venetoclax (A+V) is expected to follow. .
We asked CLL Canada’s Medical Advisor, Dr. Graeme Fraser, what combination treatments mean for patients. Dr Fraser is a hematologist with the Juravinski Cancer Centre and an Associate Professor with the Department of Oncology at McMaster University.
Please note that the following comments do not constitute medical advice. Patients are advised to consult their doctor or health care team regarding their specific situation.
Do you see combination treatments as a major breakthrough or continuous improvement?
I see the combination treatments as continuous improvement, given the drugs are currently available and are recognized as good treatments on their own. The approval of these drugs to be used in combination gives doctors a new option in our toolkit to assess and choose based on patient disease characteristics, comorbidities and needs.
What is the significance of these combination treatments for patients?
The combination treatments are time-limited, meaning a patient is on treatment for a fixed period of time, usually a year, after which the treatment is stopped. This is compared to current BTKi treatments such as Ibrutinib, where patients are on continuous therapy for an indefinite period of time until the CLL progresses or side effects are too severe. This is an important advance since time-limited treatment may reduce: 1) exposure to side effects, 2) the risk of CLL developing resistance to treatment over time, 3) the length of time side effects must be endured and 4) cost to the health system. Time-limited therapy gives patients time off treatment and, importantly, combination treatments are showing durable remissions and deeper remissions than a BTKi alone.
In what circumstances might a combination treatment be favoured?
It’s important to consider factors such as the patient’s disease biology, patient priorities and situation to determine choice of first-line treatment. Since the combination treatment is given in pill form and no infusions are required, this means fewer hospital visits which can be very beneficial for patients with mobility challenges, those who must travel a great distance to a hospital, and those who work or who have family responsibilities. The side effects are generally the same as for the single agents themselves, so it’s really about factoring in the patient-specific scenario to see if a time-limited combination treatment is preferred. It’s very nice to have this option as a choice that can be considered.
What are the current treatment options if CLL returns in a patient treated with a combination therapy?
Several options are currently available when a patient relapses after first line time-limited therapy. The options will depend on what time-limited treatment was previously used, how long the remission lasted, and other patient specific factors. Options could include re-treatment with the original regimen, an alternative time-limited Venetoclax (a BCL2i) regimen (e.g. Venetoclax+Obinutuzumab or Venetoclax+Rituximab), or indefinite BTKi therapy. If relapse occurs soon after completing a time-limited approach this may indicate the development of drug resistance, thus the optimal choice of next treatment is very patient- specific. If a patient is currently on indefinite BTKi therapy when time-limited Acalabrutinib + Venetoclax or Ibrutinib + Venetoclax are approved, it remains to be determined if a patient could switch to a time-limited approach by adding in Venetoclax (this will likely be province-specific).
All things considered, is a combination treatment something patients should ask for?
I see combination treatments as one of many excellent options to consider, with the choice being dictated by a number of factors such as disease biology, side effects, comorbidities, and patient circumstance and priorities. At the end of the day, this is another solid option that patients should be aware of and discuss with their doctor based on their own personal situation.
For more information
Here are some links to videos and articles on the GLOW trial; the AMPLIFY trial, and the
GAIA trial (Venetoclax+Obinutuzimab)
Video: Drs. Susan O’Brien and Catherine Coombs review GAIA/CLL13 and AMPLIFY trials (12:13 min)
Article in Lymphoma Hub: Final analysis of the GAIA/CLL13 trial: Venetoclax combinations vs chemoimmunotherapy in CLL
AMPLIFY Trial (Acalabrutinib+Venetoclax)
Video Dr. Jennifer Brown speaks with Brian Koffman about the Amplify Trial
(10:22 min)
Article in Blood Cancer Today: AMPLIFY Study: Upfront Acalabrutinib-Based Combo Effective in High-Risk CLL
GLOW Trial (Ibrutinib+Venetoclax)
Video: Carsten Utoft Niemann, MD, PhD, Copenhagen University Hospital, discusses results from the GLOW clinical trial in CLL. (4:55 min)
You can also get more general information regarding treatment options and access on the CLL Canada website.