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Waldenstrom: BTK Resistance and Emerging Therapies

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: Tuesday, Apr 09, 2019



Transcript: 

Meletios A. Dimopoulos, MD:
We believe that patients who are MYD88 wild type or those who express CXCR4 mutations have less of a chance to respond. They have fewer deep responses to BTK [Bruton tyrosine kinase] inhibitors. In these particular patients, there are some preliminary data that suggest that by combining with other agents, you may improve the outcome. For example, proteasome inhibitors with ibrutinib are being evaluated in that context in order to see whether you can reduce resistance to BTK inhibitors.

If the patient hasn’t responded well to a certain regimen, and if he or she has relapsed off therapy for several months or years, it may be very reasonable to repeat the same treatment to this particular patient. If the patient progresses on a specific therapy, then one would like to switch the class of agents and give drugs that the patient has not been exposed to. So it depends on the disease characteristics, the prior therapies, whether the patient is progressing on treatment or not, the age of the patient, and the comorbidities of the patient.

Steven P. Treon, MD, PhD: My personal experience with the use of ibrutinib in previously treated patients is that it’s an active drug regardless of the prior number of therapies, as we know from our own trial. But also, if the patient was refractory to their prior regimen, in our trial the average number of therapies was 2. In the iNNOVATE study, published by Dr Dimopoulos and his colleagues in Lancet Oncology, the median number of therapies is actually 4. So if you keep in mind that these are relatively heavily pretreated patients, yet we’re seeing overall rates in about 90% of patients in both of these study sets, I think is really important.

And in iNNOVATE, those patients were all Rituxan refractory. This represents a very brittle group of patients. Despite that, our response rates were the same as the response rates observed by Dr Dimopoulos and his colleagues in iNNOVATE. So I think this really speaks to the targeted nature of the therapy. If you can really understand the Achilles’ heel of a tumor and target it, this is what BTK inhibitors like ibrutinib offer us. They’re getting at the Achilles’ heel that helps support the growth and survival of Waldenström macroglobulinemia.

So among emerging therapies for Waldenström, we’re certainly very excited about other BTK inhibitors. We know that from the data that were just presented at ASCO [the American Society of Clinical Oncology Annual Meeting] and the European Hematologist Association that acalabrutinib as well as zanubrutinib are active in patients with Waldenström. We also know that the BCL2 inhibitor, venetoclax, is also very active in patients with Waldenström. Dr Jorge Castillo from our group presented the phase II data at the European Hematology Association. And I think looking ahead there are other very important drugs that are currently being investigated in this disease, including ulocuplumab. This is a CXCR4 antagonist that’s being utilized with ibrutinib in CXCR4-mutated patients. And also, daratumumab. This is a monoclonal antibody targeting CD38. This is an antigen that’s found in many patients with Waldenström. I think the ongoing clinical trial that’s being run by my colleague Dr Castillo will be a very important one in terms of giving us insight into the use of this drug as well.

Meletios A. Dimopoulos, MD: Venetoclax is an interesting agent that shows remarkable activity in patients with chronic lymphocytic leukemia [CLL] and in patients with myeloma. It is considered to act through BCL2 inhibition. A preliminary analysis in patients with Waldenström macroglobulinemia, in pretreated patients indicates activity of this agent. So in the future, we believe that a reasonable treatment would be to combine 2 oral agents, venetoclax and ibrutinib, for a fixed duration of treatment, let’s say for 1 or 2 years, to induce rapid responses and be able to give the patient a long treatment-free interval.

Steven P. Treon, MD, PhD: One of the combinations that we’re very excited about is combining venetoclax along with ibrutinib. This is based on very strong preclinical science that was generated by our group as well as others showing that BCL2 can block the activity of many drugs, including BTK inhibitors. The work that we’ve done shows that, at the preclinical level, we can actually induce cells. Many of the apoptotic triggers go up once you can combine a drug like the BCL2 inhibitor, venetoclax, along with ibrutinib, and we’re going to be testing out, in patients with Waldenström, combining the 2 drugs together to look at the impact of dual ibrutinib and venetoclax therapy in patients with treatment-naïve Waldenström macroglobulinemia.

We certainly are inspired by the data that we’ve seen from our CLL colleagues, and this represents a new and exciting approach to therapy that needs to be examined in patients with Waldenström.


Transcript Edited for Clarity
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Transcript: 

Meletios A. Dimopoulos, MD:
We believe that patients who are MYD88 wild type or those who express CXCR4 mutations have less of a chance to respond. They have fewer deep responses to BTK [Bruton tyrosine kinase] inhibitors. In these particular patients, there are some preliminary data that suggest that by combining with other agents, you may improve the outcome. For example, proteasome inhibitors with ibrutinib are being evaluated in that context in order to see whether you can reduce resistance to BTK inhibitors.

If the patient hasn’t responded well to a certain regimen, and if he or she has relapsed off therapy for several months or years, it may be very reasonable to repeat the same treatment to this particular patient. If the patient progresses on a specific therapy, then one would like to switch the class of agents and give drugs that the patient has not been exposed to. So it depends on the disease characteristics, the prior therapies, whether the patient is progressing on treatment or not, the age of the patient, and the comorbidities of the patient.

Steven P. Treon, MD, PhD: My personal experience with the use of ibrutinib in previously treated patients is that it’s an active drug regardless of the prior number of therapies, as we know from our own trial. But also, if the patient was refractory to their prior regimen, in our trial the average number of therapies was 2. In the iNNOVATE study, published by Dr Dimopoulos and his colleagues in Lancet Oncology, the median number of therapies is actually 4. So if you keep in mind that these are relatively heavily pretreated patients, yet we’re seeing overall rates in about 90% of patients in both of these study sets, I think is really important.

And in iNNOVATE, those patients were all Rituxan refractory. This represents a very brittle group of patients. Despite that, our response rates were the same as the response rates observed by Dr Dimopoulos and his colleagues in iNNOVATE. So I think this really speaks to the targeted nature of the therapy. If you can really understand the Achilles’ heel of a tumor and target it, this is what BTK inhibitors like ibrutinib offer us. They’re getting at the Achilles’ heel that helps support the growth and survival of Waldenström macroglobulinemia.

So among emerging therapies for Waldenström, we’re certainly very excited about other BTK inhibitors. We know that from the data that were just presented at ASCO [the American Society of Clinical Oncology Annual Meeting] and the European Hematologist Association that acalabrutinib as well as zanubrutinib are active in patients with Waldenström. We also know that the BCL2 inhibitor, venetoclax, is also very active in patients with Waldenström. Dr Jorge Castillo from our group presented the phase II data at the European Hematology Association. And I think looking ahead there are other very important drugs that are currently being investigated in this disease, including ulocuplumab. This is a CXCR4 antagonist that’s being utilized with ibrutinib in CXCR4-mutated patients. And also, daratumumab. This is a monoclonal antibody targeting CD38. This is an antigen that’s found in many patients with Waldenström. I think the ongoing clinical trial that’s being run by my colleague Dr Castillo will be a very important one in terms of giving us insight into the use of this drug as well.

Meletios A. Dimopoulos, MD: Venetoclax is an interesting agent that shows remarkable activity in patients with chronic lymphocytic leukemia [CLL] and in patients with myeloma. It is considered to act through BCL2 inhibition. A preliminary analysis in patients with Waldenström macroglobulinemia, in pretreated patients indicates activity of this agent. So in the future, we believe that a reasonable treatment would be to combine 2 oral agents, venetoclax and ibrutinib, for a fixed duration of treatment, let’s say for 1 or 2 years, to induce rapid responses and be able to give the patient a long treatment-free interval.

Steven P. Treon, MD, PhD: One of the combinations that we’re very excited about is combining venetoclax along with ibrutinib. This is based on very strong preclinical science that was generated by our group as well as others showing that BCL2 can block the activity of many drugs, including BTK inhibitors. The work that we’ve done shows that, at the preclinical level, we can actually induce cells. Many of the apoptotic triggers go up once you can combine a drug like the BCL2 inhibitor, venetoclax, along with ibrutinib, and we’re going to be testing out, in patients with Waldenström, combining the 2 drugs together to look at the impact of dual ibrutinib and venetoclax therapy in patients with treatment-naïve Waldenström macroglobulinemia.

We certainly are inspired by the data that we’ve seen from our CLL colleagues, and this represents a new and exciting approach to therapy that needs to be examined in patients with Waldenström.


Transcript Edited for Clarity
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