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Waldenstrom Macroglobulinemia: Ibrutinib + Rituximab

Insights From: Meletios A. Dimopoulos, MD, the National and Kapodistrian University of Athens School of Medicine; Steven P. Treon, MD, PhD, Dana-Farber Cancer Institute
Published: Friday, Apr 05, 2019



Transcript: 

Steven P. Treon, MD, PhD:
In deciding which Rituxan chemotherapy option to utilize, I think it’s important to take into account what it is that you’re treating. If it’s a patient who’s presenting with bulky adenopathy, a bendamustine-based approach would be appropriate. If you’re thinking about a patient who may have amyloid, something that’s fairly uncommon, you might what to think about a proteasome inhibitor. And if you’re thinking about somebody who’s presenting with peripheral neuropathy, one can either use a neuropathy-sparing proteasome inhibitor like carfilzomib, or an alkylator agent, or Rituxan as monotherapy when initiating treatment.

Ibrutinib represents a very exciting new option that can also be considered with rituximab. We now know, because of the iNNOVATE study, that we see higher response rates and durability of response over rituximab alone, and this would be an option that I would consider. I’d want to know that the patient has at least the MYD88 mutation. That’s present in about 95% of all patients. So this is an option that can be used across the board.

Meletios A. Dimopoulos, MD: The problem with BTK [Bruton tyrosine kinase] inhibitors is that treatment has to be administered indefinitely. In hopes that by combining an anti-CD20 with a BTK inhibitor, one may envision that they may administer therapy for a fixed duration of time. On the other hand, it appears that the combination of an anti-CD20 and a BTK inhibitor may have a greater effect in patients with poor prognosis genotypes, meaning patients who have wild-type MYD88 status and CXCR4 mutations.

Steven P. Treon, MD, PhD: In the iNNOVATE study, patients were randomized to receive ibrutinib plus Rituxan versus rituximab. This was a study that was meant to try to understand what the add-on would be to using ibrutinib along with Rituxan over rituximab alone. If you look at the SEER data as well as the data emerging from Europe from Dr Christian Buske’s study published in the Lancet Hematology, what we see is that rituximab is the community standard. Despite the fact that there has been a relative paucity of phase 3 studies, we see that rituximab is what’s used.

And so this was a study that was meant to see what the 2 drugs together—ibrutinib and Rituxan—would offer over the community standard. In this regard, this was a very exciting study. There were 45 centers that participated in 9 countries, so there was really a lot of experience there. Both treatment naïve as well as previously treated patients were included. And what we saw was that the overall response rate, which includes all responses—minor responses, major responses—was higher for the ibrutinib-plus-Rituxan arm over rituximab alone, as it was for progression-free survival. We saw a very big improvement both in treatment-naïve as well previously treated patients. And I think what was also exciting for me personally was to see that at least with the follow-up that we now have, which is about 26 months, the patients [who] had the CXCR4 mutation did as well as those who had no CXCR4 mutation—this among MYD88-mutated patients. Perhaps with due time we might see a separation, but I think that really is exciting to see, even at this juncture of time.

Meletios A. Dimopoulos, MD: We have performed a prospective randomized trial that included both untreated and pretreated patients with Waldenström macroglobulinemia. The patients were randomized to receive either single-agent rituximab, which was considered at that time to be the standard of care, or a combination of rituximab with ibrutinib. So what we saw was that there was a very remarkable improvement of progression-free survival in favor of the combination of ibrutinib with rituximab, with a median follow-up of 30 months. The hazard ratio was 0.2, so there is a very significant effect of the combination on patients with Waldenström macroglobulinemia.

The approval of this combination across all lines of therapy gives patients and physicians the option to be treated with this regimen if it appears to be indicated. This is a very powerful regimen that is associated with a very long progression-free survival. As I mentioned, the problem is that you need to administer ibrutinib continuously. So it is an advance in the treatment of this disease, and we’re expecting further evolutions in hopes to have regimens that could be given for a fixed duration of time.

Steven P. Treon, MD, PhD: I think for community oncologists it’s important to recognize that BTK inhibitors represent a new standard of therapy for patients with Waldenström. And it’s one that’s actually rationally appropriate based on the genomics as well as the signaling studies that have very nicely established that BTK is part of the signaling cascade for mutated MYD88—this being the mutation that we see in about 95% of patients. And I think what community oncologists should also get excited about is the fact that regardless of the number of lines of prior therapy, as well as prior refractory status, ibrutinib is very active in these patients.

The idea that ibrutinib and rituximab can be given safely together is very exciting. The fact that when the combination is given we see a decrease in the infusion reaction rates, and the IgM flare potential is also very exciting. And the idea that the combination of ibrutinib plus rituximab is producing high overall response rates and major response rates regardless of the underlying CXCR4-mutation status in MYD88-mutated patients is also worth getting excited over.

We’re going to need long-term follow-up to understand particularly the advantage of adding Rituxan to ibrutinib. But I think the message to our colleagues in the community is that BTK inhibitor therapy is very effective and represents an important new mainstay of therapy for patients with Waldenström macroglobulinemia.

Meletios A. Dimopoulos, MD: This regimen is very well tolerated. Patients should be advised of the possibility of atrial fibrillation. If they develop an arrhythmia or tachycardia, they should report this to their physician. And also, they should be advised that if they need a surgical procedure, they need also to advise their physician regarding holding ibrutinib for several days. Otherwise, it’s a very safe treatment.


Transcript Edited for Clarity 
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Transcript: 

Steven P. Treon, MD, PhD:
In deciding which Rituxan chemotherapy option to utilize, I think it’s important to take into account what it is that you’re treating. If it’s a patient who’s presenting with bulky adenopathy, a bendamustine-based approach would be appropriate. If you’re thinking about a patient who may have amyloid, something that’s fairly uncommon, you might what to think about a proteasome inhibitor. And if you’re thinking about somebody who’s presenting with peripheral neuropathy, one can either use a neuropathy-sparing proteasome inhibitor like carfilzomib, or an alkylator agent, or Rituxan as monotherapy when initiating treatment.

Ibrutinib represents a very exciting new option that can also be considered with rituximab. We now know, because of the iNNOVATE study, that we see higher response rates and durability of response over rituximab alone, and this would be an option that I would consider. I’d want to know that the patient has at least the MYD88 mutation. That’s present in about 95% of all patients. So this is an option that can be used across the board.

Meletios A. Dimopoulos, MD: The problem with BTK [Bruton tyrosine kinase] inhibitors is that treatment has to be administered indefinitely. In hopes that by combining an anti-CD20 with a BTK inhibitor, one may envision that they may administer therapy for a fixed duration of time. On the other hand, it appears that the combination of an anti-CD20 and a BTK inhibitor may have a greater effect in patients with poor prognosis genotypes, meaning patients who have wild-type MYD88 status and CXCR4 mutations.

Steven P. Treon, MD, PhD: In the iNNOVATE study, patients were randomized to receive ibrutinib plus Rituxan versus rituximab. This was a study that was meant to try to understand what the add-on would be to using ibrutinib along with Rituxan over rituximab alone. If you look at the SEER data as well as the data emerging from Europe from Dr Christian Buske’s study published in the Lancet Hematology, what we see is that rituximab is the community standard. Despite the fact that there has been a relative paucity of phase 3 studies, we see that rituximab is what’s used.

And so this was a study that was meant to see what the 2 drugs together—ibrutinib and Rituxan—would offer over the community standard. In this regard, this was a very exciting study. There were 45 centers that participated in 9 countries, so there was really a lot of experience there. Both treatment naïve as well as previously treated patients were included. And what we saw was that the overall response rate, which includes all responses—minor responses, major responses—was higher for the ibrutinib-plus-Rituxan arm over rituximab alone, as it was for progression-free survival. We saw a very big improvement both in treatment-naïve as well previously treated patients. And I think what was also exciting for me personally was to see that at least with the follow-up that we now have, which is about 26 months, the patients [who] had the CXCR4 mutation did as well as those who had no CXCR4 mutation—this among MYD88-mutated patients. Perhaps with due time we might see a separation, but I think that really is exciting to see, even at this juncture of time.

Meletios A. Dimopoulos, MD: We have performed a prospective randomized trial that included both untreated and pretreated patients with Waldenström macroglobulinemia. The patients were randomized to receive either single-agent rituximab, which was considered at that time to be the standard of care, or a combination of rituximab with ibrutinib. So what we saw was that there was a very remarkable improvement of progression-free survival in favor of the combination of ibrutinib with rituximab, with a median follow-up of 30 months. The hazard ratio was 0.2, so there is a very significant effect of the combination on patients with Waldenström macroglobulinemia.

The approval of this combination across all lines of therapy gives patients and physicians the option to be treated with this regimen if it appears to be indicated. This is a very powerful regimen that is associated with a very long progression-free survival. As I mentioned, the problem is that you need to administer ibrutinib continuously. So it is an advance in the treatment of this disease, and we’re expecting further evolutions in hopes to have regimens that could be given for a fixed duration of time.

Steven P. Treon, MD, PhD: I think for community oncologists it’s important to recognize that BTK inhibitors represent a new standard of therapy for patients with Waldenström. And it’s one that’s actually rationally appropriate based on the genomics as well as the signaling studies that have very nicely established that BTK is part of the signaling cascade for mutated MYD88—this being the mutation that we see in about 95% of patients. And I think what community oncologists should also get excited about is the fact that regardless of the number of lines of prior therapy, as well as prior refractory status, ibrutinib is very active in these patients.

The idea that ibrutinib and rituximab can be given safely together is very exciting. The fact that when the combination is given we see a decrease in the infusion reaction rates, and the IgM flare potential is also very exciting. And the idea that the combination of ibrutinib plus rituximab is producing high overall response rates and major response rates regardless of the underlying CXCR4-mutation status in MYD88-mutated patients is also worth getting excited over.

We’re going to need long-term follow-up to understand particularly the advantage of adding Rituxan to ibrutinib. But I think the message to our colleagues in the community is that BTK inhibitor therapy is very effective and represents an important new mainstay of therapy for patients with Waldenström macroglobulinemia.

Meletios A. Dimopoulos, MD: This regimen is very well tolerated. Patients should be advised of the possibility of atrial fibrillation. If they develop an arrhythmia or tachycardia, they should report this to their physician. And also, they should be advised that if they need a surgical procedure, they need also to advise their physician regarding holding ibrutinib for several days. Otherwise, it’s a very safe treatment.


Transcript Edited for Clarity 
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