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Continuing Therapy in Relapsed/Refractory CLL

Insights From: Michael Choi, MD, UC San Diego Medical Center; Matthew S. Davids, MD, Dana-Farber Cancer Institute; William Wierda, MD, PhD, MD Anderson Cancer Center
Published: Friday, May 25, 2018



Transcript: 

Michael Choi, MD: A maintenance therapy following second-line treatment has also been studied. The CONTINUUM study, which was published last year in Lancet Hematology, showed the efficacy of using lenalidomide (Revlimid) in this setting. In this trial, patients who had at least a partial remission after second or later line of therapy were started on lenalidomide and continued until progression. There was a significant increase in the progression-free survival from about 9 months without maintenance therapy to more than 30 months with lenalidomide.

There was, however, no change in the overall survival. The authors and I speculate that it’s probably due to the availability of other treatment options, and that does not automatically lead me to adopt this as a treatment option. Perhaps the right patient with a more aggressive disease—or the patient whose response to first-line therapy was inadequate or whose first-line or second-line therapy was a bridge for other reasons—would then be a good candidate for lenalidomide. It’s also a reasonable option to monitor those patients closely and start drugs like ibrutinib (Imbruvica) or idelalisib (Zydelig) should that patient relapse.

Similarly, anti-CD20 antibodies have been studied as maintenance therapies after second-line therapy. Ofatumumab (Arzerra) was studied in this manner and is approved by the FDA to be used as maintenance therapy. With that regimen, patients would receive ofatumumab for up to 2 years. The PROLONG study, which is what led to the approval of ofatumumab for maintenance, did show a prolongation in PFS [progression-free survival], as well. In my practice, I have not been adopting this for most patients. Perhaps the thing that leads me to this decision is the knowledge that in other head-to-head studies, the kinase inhibitors have shown superiority to the single-agent monoclonal antibodies. Following second-line treatment of a patient who has already had ibrutinib or will not have easy access to the oral inhibitors, maintenance therapy with ofatumumab is an option.

The duration of maintenance therapy should be guided by the trials that studied it. For ofatumumab, the duration would be 2 years. For lenalidomide, the duration could potentially be several years or for as long as the patient does not progress. There are considerations of wanting to balance the risks of these agents with controlling the disease, especially if the patient has other treatment options available to them. These agents do have risk of immune compromise, viral reactivation, and other complications that are not dose limiting but not trivial, either. Patients should be monitored for infections or those complications. With maintenance therapy, I usually do not expect eradication of minimal residual disease; therefore, I do not necessarily monitor these patients by flow cytometry or by marrow biopsy. If there is a decision to be made about whether to continue or not, those tests can help guide patients one way or another.
              
In the third-line and beyond, fortunately, there are also options for our patients. The treatment options will be driven by what treatments they’ve had before. Patients who have already had chemoimmunotherapy and ibrutinib will likely be deciding between idelalisib, should a patient have had intolerance to ibrutinib but not progressed on it, or venetoclax (Vencexta), for patients who have progressed on ibrutinib or have deletion 17p. For patients who have not yet had ibrutinib, I would consider that the standard third-line option.

With the current treatment options, there are patients who can be treated in an entirely chemotherapy-sparing manner using regimens like ibrutinib, venetoclax, idelalisib, or monoclonal antibodies. Our group at the University of California, San Diego, often uses high doses of methylprednisolone (Medrol). For patients who are driven to avoid the potential toxicities of alkylating agents and purine analogues, there are, fortunately, a number of options. I do not think patients who have not had chemotherapy in the first-line setting and are now requiring treatment should feel compelled to receive chemoimmunotherapy. That decision should be made based on their fitness and based on their treatment priorities at that time.

Transcript Edited for Clarity 
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Transcript: 

Michael Choi, MD: A maintenance therapy following second-line treatment has also been studied. The CONTINUUM study, which was published last year in Lancet Hematology, showed the efficacy of using lenalidomide (Revlimid) in this setting. In this trial, patients who had at least a partial remission after second or later line of therapy were started on lenalidomide and continued until progression. There was a significant increase in the progression-free survival from about 9 months without maintenance therapy to more than 30 months with lenalidomide.

There was, however, no change in the overall survival. The authors and I speculate that it’s probably due to the availability of other treatment options, and that does not automatically lead me to adopt this as a treatment option. Perhaps the right patient with a more aggressive disease—or the patient whose response to first-line therapy was inadequate or whose first-line or second-line therapy was a bridge for other reasons—would then be a good candidate for lenalidomide. It’s also a reasonable option to monitor those patients closely and start drugs like ibrutinib (Imbruvica) or idelalisib (Zydelig) should that patient relapse.

Similarly, anti-CD20 antibodies have been studied as maintenance therapies after second-line therapy. Ofatumumab (Arzerra) was studied in this manner and is approved by the FDA to be used as maintenance therapy. With that regimen, patients would receive ofatumumab for up to 2 years. The PROLONG study, which is what led to the approval of ofatumumab for maintenance, did show a prolongation in PFS [progression-free survival], as well. In my practice, I have not been adopting this for most patients. Perhaps the thing that leads me to this decision is the knowledge that in other head-to-head studies, the kinase inhibitors have shown superiority to the single-agent monoclonal antibodies. Following second-line treatment of a patient who has already had ibrutinib or will not have easy access to the oral inhibitors, maintenance therapy with ofatumumab is an option.

The duration of maintenance therapy should be guided by the trials that studied it. For ofatumumab, the duration would be 2 years. For lenalidomide, the duration could potentially be several years or for as long as the patient does not progress. There are considerations of wanting to balance the risks of these agents with controlling the disease, especially if the patient has other treatment options available to them. These agents do have risk of immune compromise, viral reactivation, and other complications that are not dose limiting but not trivial, either. Patients should be monitored for infections or those complications. With maintenance therapy, I usually do not expect eradication of minimal residual disease; therefore, I do not necessarily monitor these patients by flow cytometry or by marrow biopsy. If there is a decision to be made about whether to continue or not, those tests can help guide patients one way or another.
              
In the third-line and beyond, fortunately, there are also options for our patients. The treatment options will be driven by what treatments they’ve had before. Patients who have already had chemoimmunotherapy and ibrutinib will likely be deciding between idelalisib, should a patient have had intolerance to ibrutinib but not progressed on it, or venetoclax (Vencexta), for patients who have progressed on ibrutinib or have deletion 17p. For patients who have not yet had ibrutinib, I would consider that the standard third-line option.

With the current treatment options, there are patients who can be treated in an entirely chemotherapy-sparing manner using regimens like ibrutinib, venetoclax, idelalisib, or monoclonal antibodies. Our group at the University of California, San Diego, often uses high doses of methylprednisolone (Medrol). For patients who are driven to avoid the potential toxicities of alkylating agents and purine analogues, there are, fortunately, a number of options. I do not think patients who have not had chemotherapy in the first-line setting and are now requiring treatment should feel compelled to receive chemoimmunotherapy. That decision should be made based on their fitness and based on their treatment priorities at that time.

Transcript Edited for Clarity 
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