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Recent Breakthroughs in the Treatment of Refractory CLL

Insights From: Naval G. Daver, MD, MD Anderson Cancer Center; Anthony Mato, MD, MSCE, Memorial Sloan Kettering Center
Published: Monday, Jun 24, 2019



Transcript:

Anthony Mato, MD, MSCE:
At the ASCO [American Society of Clinical Oncology] Annual Meeting 2019, we learned a lot about CLL [chronic lymphocytic leukemia]—in particular, how to manage challenging patients. Issues that were dealt with included intolerance to novel agents, how to treat patients with high-risk disease, managing patients with a chemotherapy-free approach in the frontline and relapsed refractory settings. Really moving the ball forward in terms of addressing questions that are important to patients with CLL.

Before the advent of the novel agents, or the targeted therapies, treatment for CLL was largely 1 size fits all for patients. Patients received chemoimmunotherapy or chemotherapy combinations with not really a lot of choice with the exception of how intensive therapies work. Now that we have several agents available in the relapsed-refractory setting, we are truly entering an era where medicine can be personalized for patients. Factors that we think about include patient age, their performance status, their medical comorbidities, and also their molecular and genetic profiles. All that taken together can help us to select an agent that is quite efficacious but also minimizes toxicity for patients.

Some of the more difficult patient populations to treat with CLL include those who are intolerant to kinase inhibitor therapy. There was an abstract presented here at the ASCO meeting looking at the use of acalabrutinib in patients who were intolerant to ibrutinib. The drug seemed to be active and well tolerated. We’re expecting longer term follow-up data to really help flesh out the toxicities in that particular patient population, but it is a potential option for patients who discontinue 1 drug to switch to another within the same class.

Other areas that we face with difficulty include, for example, treating patients who are older with CLL, particularly in the frontline setting. There was an abstract presented at this meeting looking at the combination of obinutuzumab with venetoclax as a first therapy. This is a CLL-14 trial, which randomized patients to obinutuzumab-venetoclax versus obinutuzumab plus chlorambucil. The trial results were overwhelmingly positive for the experimental arm in terms of response rate, depth of response, duration of response, and progression-free survival. But also more importantly, this represents a step forward in terms of targeted therapies because it’s the first therapy that will be approved for CLL with a fixed duration in the frontline setting that’s chemotherapy-free.

The study design was unique in that it took the combination of venetoclax plus obinutuzumab. Some aspects of it, which I wanted to highlight, were that first of all, the obinutuzumab was given before the venetoclax, which should theoretically debulk patients so that they are mostly managed in the outpatient setting. One of the challenges with venetoclax is that patients who are high risk for TLS, or tumor lysis syndrome, need to be hospitalized for at least the first 2 dose ramp-ups.

The study showed us that by giving obinutuzumab first, there could be a marked reduction in the lymphocytosis associated with CLL. Unfortunately, 1 of the limitations was that we didn’t have CT [computed tomography] scans performed immediately prior to venetoclax. So we can’t say with certainty how the risk status changed for patients, but the results are encouraging based on the obinutuzumab phase alone to suggest that most patients will be treated in the outpatient setting rather than required hospitalization in the setting of high-risk disease.

Another interesting aspect of the study design again is the fixed duration of the combination. So the drugs are given together for a total of 12 months of therapy. Obinutuzumab lead-in followed by venetoclax in combination, where all patients are stopping at that particular point in time.

The comparator is obinutuzumab plus chlorambucil, which is known as a CLL-11 regimen. One of the, I think, really smart things done in the design here was that the chemotherapy component of CLL-11 was extended from 6 months, which is the way that it was originally designed, to 12 months to give us a more fair comparison—12 months of oral venetoclax, 12 months of chlorambucil, 6 months of obinutuzumab, 6 months of obinutuzumab. It helps us to really understand when we’re giving therapy for the exact same length of time what the differences are between those combinations. I think it was really, really important that they did that.


Transcript Edited for Clarity
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Transcript:

Anthony Mato, MD, MSCE:
At the ASCO [American Society of Clinical Oncology] Annual Meeting 2019, we learned a lot about CLL [chronic lymphocytic leukemia]—in particular, how to manage challenging patients. Issues that were dealt with included intolerance to novel agents, how to treat patients with high-risk disease, managing patients with a chemotherapy-free approach in the frontline and relapsed refractory settings. Really moving the ball forward in terms of addressing questions that are important to patients with CLL.

Before the advent of the novel agents, or the targeted therapies, treatment for CLL was largely 1 size fits all for patients. Patients received chemoimmunotherapy or chemotherapy combinations with not really a lot of choice with the exception of how intensive therapies work. Now that we have several agents available in the relapsed-refractory setting, we are truly entering an era where medicine can be personalized for patients. Factors that we think about include patient age, their performance status, their medical comorbidities, and also their molecular and genetic profiles. All that taken together can help us to select an agent that is quite efficacious but also minimizes toxicity for patients.

Some of the more difficult patient populations to treat with CLL include those who are intolerant to kinase inhibitor therapy. There was an abstract presented here at the ASCO meeting looking at the use of acalabrutinib in patients who were intolerant to ibrutinib. The drug seemed to be active and well tolerated. We’re expecting longer term follow-up data to really help flesh out the toxicities in that particular patient population, but it is a potential option for patients who discontinue 1 drug to switch to another within the same class.

Other areas that we face with difficulty include, for example, treating patients who are older with CLL, particularly in the frontline setting. There was an abstract presented at this meeting looking at the combination of obinutuzumab with venetoclax as a first therapy. This is a CLL-14 trial, which randomized patients to obinutuzumab-venetoclax versus obinutuzumab plus chlorambucil. The trial results were overwhelmingly positive for the experimental arm in terms of response rate, depth of response, duration of response, and progression-free survival. But also more importantly, this represents a step forward in terms of targeted therapies because it’s the first therapy that will be approved for CLL with a fixed duration in the frontline setting that’s chemotherapy-free.

The study design was unique in that it took the combination of venetoclax plus obinutuzumab. Some aspects of it, which I wanted to highlight, were that first of all, the obinutuzumab was given before the venetoclax, which should theoretically debulk patients so that they are mostly managed in the outpatient setting. One of the challenges with venetoclax is that patients who are high risk for TLS, or tumor lysis syndrome, need to be hospitalized for at least the first 2 dose ramp-ups.

The study showed us that by giving obinutuzumab first, there could be a marked reduction in the lymphocytosis associated with CLL. Unfortunately, 1 of the limitations was that we didn’t have CT [computed tomography] scans performed immediately prior to venetoclax. So we can’t say with certainty how the risk status changed for patients, but the results are encouraging based on the obinutuzumab phase alone to suggest that most patients will be treated in the outpatient setting rather than required hospitalization in the setting of high-risk disease.

Another interesting aspect of the study design again is the fixed duration of the combination. So the drugs are given together for a total of 12 months of therapy. Obinutuzumab lead-in followed by venetoclax in combination, where all patients are stopping at that particular point in time.

The comparator is obinutuzumab plus chlorambucil, which is known as a CLL-11 regimen. One of the, I think, really smart things done in the design here was that the chemotherapy component of CLL-11 was extended from 6 months, which is the way that it was originally designed, to 12 months to give us a more fair comparison—12 months of oral venetoclax, 12 months of chlorambucil, 6 months of obinutuzumab, 6 months of obinutuzumab. It helps us to really understand when we’re giving therapy for the exact same length of time what the differences are between those combinations. I think it was really, really important that they did that.


Transcript Edited for Clarity
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