ONCAlert | Upfront Therapy for mRCC

CLL: Logistical Considerations for Venetoclax Administration

Targeted Oncology
Published Online:12:00 PM, Thu August 8, 2019

Harry Erba, MD, PhD: Let’s get back to specifically what you do for monitoring and dose reduction. How do you monitor blood counts and chemistries? What are some specific things you do?

Javier Pinilla-Ibarz, MD, PhD: Sure. We follow the rules of the prescription information in the ramp-up dose we do early. The first day of the new dose, it’s 20 and 50 mg. After that, obviously the 100, 200, and 400 mg are easier. After that, as far as the patients who don’t have neutropenia, we can really extend the period of time for which we see the patient. Neutropenia—you are right that this is 1 of the common reasons why we should sometimes stop the drug, use growth factor, or even really lower the dose, from 400 to 300 or 200 mg. Very interestingly, it happened to me a few times, this happened during the period in which you’re really coinciding with the monoclonal antibody. For people who are not familiar, the monoclonal antibody, obinutuzumab, is given for 6 months. So there’s another extra 6 months when the patient takes only venetoclax. You see a better tolerance in terms of neutropenia as soon as the monoclonal is out of the picture, and it’s something that obviously you need to be following closely.

Harry Erba, MD, PhD: You brought it up, so I need you to explain something that I’m still not understanding.

Javier Pinilla-Ibarz, MD, PhD: Sure.

Harry Erba, MD, PhD: Especially with rituximab, there’s this idiopathic or neutropenia that you can sometimes see. Why?

Javier Pinilla-Ibarz, MD, PhD: Absolutely. It is something that is fascinating for many, many years. Why can a monoclonal antibody really produce neutropenia? I have to tell you, I went through the literature more and more. The best thing I can really see is that when you really deplete B cells, it’s a very subtle relation between B cells and neutrophils that not many people understand. I personally do not understand.

Harry Erba, MD, PhD: OK, I’m not alone then. I’m glad to hear that.

Javier Pinilla-Ibarz, MD, PhD: Right. But you really hit the point, and we go to any of the drugs we are using as targeted drugs. They’re targeted drugs that are not really hitting the bone marrow. They are targeting the peripheral blood. As soon as we deplete the B-cell compartment, neutropenia happens and, as you know, it happens classically with Rituxan. It’s technically peripheral neutropenia because we know that these neutrophils are in the bone marrow. But with obinutuzumab, it happens even more. I think it’s fascinating that it happens with the BTK inhibitors, happens with venetoclax. I think it’s very interesting, and there is some scientific publication in which they’re trying to understand this relation between neutrophils and how B cells can collaborate to keep these neutrophils around.

Harry Erba, MD, PhD: Well, it tends to be a late phenomenon with the rituximab. It’s not in the first dose or 2, so this hypothesis that it’s related to the population of B cells seems to make some sense.

Javier Pinilla-Ibarz, MD, PhD: Absolutely, yes.

Harry Erba, MD, PhD: Well, that’s interesting. So you’ve already alluded to the ramp-up with it. When you use rituximab, do you delay it, or do you, like obinutuzumab, start it now early?

Javier Pinilla-Ibarz, MD, PhD: When I use Rituxan, I try to use the same regimen. I don’t really follow the recommendation of the MURANO trial, for which they were used at the same time. I really recommend to my colleagues in the community to use the monoclonal antibody of their choice because some people may be more familiar with Rituxan. As we know, obinutuzumab is a superior antibody, but it’s slightly more complicated to really manage infusion reaction. Regardless of whatever antibody they want to use, unfortunately in the second line, it’s Rituxan. In the frontline, obinutuzumab. After that, start the ramp-up dose after 2, 3 doses of this monoclonal antibody.

Harry Erba, MD, PhD: You already alluded to the problem with drug-drug interactions and CYP3A4 inhibitors. I assume it’s the same, avoiding grapefruits, and Seville oranges, and star fruit—if you can even find them in your grocer.

Javier Pinilla-Ibarz, MD, PhD: Yes, that’s exactly correct.

Harry Erba, MD, PhD: Any other instructions that you give your patient about dosing with food or without food?

Javier Pinilla-Ibarz, MD, PhD: I do not have any recommendation. Most of the time I ask them to really take it at the same time of the day. But I think it’s very, very important to go deeply about the list of medications patients are taking because, again, you will be surprised. And sometimes you may have 1 moderate and 1 mild inhibitor for which you may really be more cautious about how you do a ramp-up dose. Going through the list—classical azoles, posaconazole, voriconazole, fluconazole, verapamil, even ciprofloxacin. We are used to seeing patients on these agents. For example, when the patient has an infection, which antibiotic should we use at a certain point? I think it’s important to keep in mind, and obviously we work with our pharmacist to make sure our patients are safe.

Transcript edited for clarity.

Harry Erba, MD, PhD: Let’s get back to specifically what you do for monitoring and dose reduction. How do you monitor blood counts and chemistries? What are some specific things you do?

Javier Pinilla-Ibarz, MD, PhD: Sure. We follow the rules of the prescription information in the ramp-up dose we do early. The first day of the new dose, it’s 20 and 50 mg. After that, obviously the 100, 200, and 400 mg are easier. After that, as far as the patients who don’t have neutropenia, we can really extend the period of time for which we see the patient. Neutropenia—you are right that this is 1 of the common reasons why we should sometimes stop the drug, use growth factor, or even really lower the dose, from 400 to 300 or 200 mg. Very interestingly, it happened to me a few times, this happened during the period in which you’re really coinciding with the monoclonal antibody. For people who are not familiar, the monoclonal antibody, obinutuzumab, is given for 6 months. So there’s another extra 6 months when the patient takes only venetoclax. You see a better tolerance in terms of neutropenia as soon as the monoclonal is out of the picture, and it’s something that obviously you need to be following closely.

Harry Erba, MD, PhD: You brought it up, so I need you to explain something that I’m still not understanding.

Javier Pinilla-Ibarz, MD, PhD: Sure.

Harry Erba, MD, PhD: Especially with rituximab, there’s this idiopathic or neutropenia that you can sometimes see. Why?

Javier Pinilla-Ibarz, MD, PhD: Absolutely. It is something that is fascinating for many, many years. Why can a monoclonal antibody really produce neutropenia? I have to tell you, I went through the literature more and more. The best thing I can really see is that when you really deplete B cells, it’s a very subtle relation between B cells and neutrophils that not many people understand. I personally do not understand.

Harry Erba, MD, PhD: OK, I’m not alone then. I’m glad to hear that.

Javier Pinilla-Ibarz, MD, PhD: Right. But you really hit the point, and we go to any of the drugs we are using as targeted drugs. They’re targeted drugs that are not really hitting the bone marrow. They are targeting the peripheral blood. As soon as we deplete the B-cell compartment, neutropenia happens and, as you know, it happens classically with Rituxan. It’s technically peripheral neutropenia because we know that these neutrophils are in the bone marrow. But with obinutuzumab, it happens even more. I think it’s fascinating that it happens with the BTK inhibitors, happens with venetoclax. I think it’s very interesting, and there is some scientific publication in which they’re trying to understand this relation between neutrophils and how B cells can collaborate to keep these neutrophils around.

Harry Erba, MD, PhD: Well, it tends to be a late phenomenon with the rituximab. It’s not in the first dose or 2, so this hypothesis that it’s related to the population of B cells seems to make some sense.

Javier Pinilla-Ibarz, MD, PhD: Absolutely, yes.

Harry Erba, MD, PhD: Well, that’s interesting. So you’ve already alluded to the ramp-up with it. When you use rituximab, do you delay it, or do you, like obinutuzumab, start it now early?

Javier Pinilla-Ibarz, MD, PhD: When I use Rituxan, I try to use the same regimen. I don’t really follow the recommendation of the MURANO trial, for which they were used at the same time. I really recommend to my colleagues in the community to use the monoclonal antibody of their choice because some people may be more familiar with Rituxan. As we know, obinutuzumab is a superior antibody, but it’s slightly more complicated to really manage infusion reaction. Regardless of whatever antibody they want to use, unfortunately in the second line, it’s Rituxan. In the frontline, obinutuzumab. After that, start the ramp-up dose after 2, 3 doses of this monoclonal antibody.

Harry Erba, MD, PhD: You already alluded to the problem with drug-drug interactions and CYP3A4 inhibitors. I assume it’s the same, avoiding grapefruits, and Seville oranges, and star fruit—if you can even find them in your grocer.

Javier Pinilla-Ibarz, MD, PhD: Yes, that’s exactly correct.

Harry Erba, MD, PhD: Any other instructions that you give your patient about dosing with food or without food?

Javier Pinilla-Ibarz, MD, PhD: I do not have any recommendation. Most of the time I ask them to really take it at the same time of the day. But I think it’s very, very important to go deeply about the list of medications patients are taking because, again, you will be surprised. And sometimes you may have 1 moderate and 1 mild inhibitor for which you may really be more cautious about how you do a ramp-up dose. Going through the list—classical azoles, posaconazole, voriconazole, fluconazole, verapamil, even ciprofloxacin. We are used to seeing patients on these agents. For example, when the patient has an infection, which antibiotic should we use at a certain point? I think it’s important to keep in mind, and obviously we work with our pharmacist to make sure our patients are safe.

Transcript edited for clarity.
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