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Aimee Martin (Host):  Welcome to the Oncology Sound Byte, a podcast produced by the Seattle Cancer Care Alliance, designed to offer byte sized audible oncology education from one of the top cancer treatment centers in the nation. Medical professionals can tune in to learn from our nationally renowned team of experts representing Fred Hutchinson Cancer Research Center, UW Medicine and Seattle Children’s. We hope you’ll listen and learn while we share disease-specific advancements with the collective goal of improving cancer care and patient outcomes both regionally and beyond.

I’m your host, Aimee Martina Senior Physician Liaison at the Seattle Cancer Care Alliance. During this episode, we will focus on chronic lymphocytic leukemia or CLL and the treatment options available for standard risk and high risk patients. With that in mind, I’d like to introduce our subject matter expert joining us today, Dr. Mazyar Shadman. He’s an Assistant Professor at Fred Hutchinson Cancer Research Center and the University of Washington, an Attending Physician at the Seattle Cancer Care Alliance and a member of the NCCN Guideline Committee for CLL. Welcome to the show Dr. Shadman.

Mazyar Shadman, MD, MPH (Guest):  Thanks for having me Aimee.

Host:  We’re so glad to have you and wanted to start out by just asking you to explain your role here within the organization and professional background a bit more.

Dr. Shadman:  Yeah sure so, I’m a lymphoma and CLL physician. I take care of patients with chronic lymphocytic leukemia diagnosis and the focus of my research is also on CLL. I use novel therapeutic agents for treatment of CLL. I also have a focus on high risk CLL, and I use cellular therapies including CAR-T cell therapy and also stem cell transplant for selected patients who require more aggressive or more intensive therapy for CLL.

Host:  Fantastic. And just to dive right into our first question for today’s podcast; what is considered high risk CLL these days?

Dr. Shadman:  I think that’s a very important question. And before I give you a specific answer, we have to kind of go back a little bit and define the high risk in the setting of the treatment options that we had let’s say five, six, seven years ago and compare it to what we have these days. So, for example, if we go back to the era of what we call chemotherapy or chemoimmunotherapy when we used chemotherapeutic agents and we would combine them with what we call a monoclonal antibody like rituximab for example being the most commonly used one; in that era, we had some molecular markers in the CLL cells that would guide us and would help us maybe predict which patients will have a better response to chemotherapy compared to others. And for example, we know that the mutational status of the Igh3 [00:03:10] gene was very important in patients who for example had the mutation, their response to chemoimmunotherapy was much better compared to the ones who were considered to be unmutated.

So, that’s just one example of having a biomarker that would mean something in the setting of chemoimmunotherapy. Now that we have moved to the novel agent era, we have learned looking at different targeted therapies that maybe that marker is not as important as we used it in the chemotherapy era. And that’s just one example and we’re seeing more and more of these and some of the molecular markers looking at the fish and cytogenetics. For example, if a patient in the era of chemotherapy was receiving treatment and had an abnormality in the 11Q area of their chromosome, again their response to chemotherapy may have been shorter and they had a shorter time in remission. We’re not seeing that with most of our novel agents.

So, I think the point I’m trying to make is that the high risk disease is really defined in the setting of what’s in the CLL cell at the genomic level, but it also depends on what we are offering and what we are using for treatment. If I want to summarize, in the current era, which we call a nonchemotherapy or novel agent era, I think most of us agree that nonchemotherapy options for all CLL patients these days, again, we can discuss whether or not chemotherapy is still a viable option for selected CLL patients or patients with CLL but I think there are nonchemotherapy options for every CLL patient these days. So, in that setting, there are still a few markers that remain high risk. And namely I can talk about the P53 gene abnormalities. I mean these could be in the form of [00:05:11] at the site of that gene or a mutation. Basically if you have a dysfunctional or aberrated P53 gene, we still see that responses to novel agents if you compare that to the response that those patients achieved from chemotherapy, but compared to patients who don’t have these abnormalities, even novel agents don’t seem to be as effective as what we see in patients without P53 abnormalities.

So, deletion or mutation in P53 is a high risk feature. The other and I think again it kind of talking about the current era is that we are learning that there are another group of patients who are considered high risk based on their response to the novel agents. So, if I have a patient for example who let’s say received a treatment with ibrutinib which is one of the commonly used drugs and after years of responding we not that there is evidence of disease progression. That patient by definition, is considered high risk because now we are looking at a specific cohort of patients who despite their initial response to one of our best classes of drugs for CLL, they are now showing that their disease is becoming resistant or progressive on the therapy and we treat those patients differently than what we treat for a patient who is for example having disease progression after chemoimmunotherapy.

So, to summarize, I think there are disease specific factors and I would probably paint the P53 gene abnormalities and then there are basically findings that we have after starting treatment and that would be lack of response or progression on one of our novel agents namely one of the Bruton tyrosine kinase inhibitors like ibrutinib or HLA ibrutinib or venetoclax, if a patient has evidence of disease progression on venetoclax, that patient is considered high risk and we would treat that patient differently.

Host:  That’s great to know. Thank you so much for that really thorough explanation. What would you say is the treatment for standard risk CLL?

Dr. Shadman:  Yeah, we have been really fortunate to have access to so many really great drugs for CLL starting from Bruton tyrosine kinase inhibitors, we now have both ibrutinib and HLA ibrutinib approved for CLL in all kinds of all stages of disease in the frontline, in the refractory setting and for patients with P53 abnormalities as I said. We may have more coming. I mean a very promising drug is zanubrutinib is already approved for mantle cell lymphoma, it’s another BTK inhibitor and we are waiting too for studies that may lead to get approval of zanubrutinib for CLL. We do have venetoclax a BCL2 inhibitor and a very respected agent for CLL with a unique basically quality of maybe making us able to provide chemotherapy free and a time limited therapy treatment for patients. As we know for drugs like ibrutinib or HLA ibrutinib, we have to continue the treatment until it doesn’t work or until it causes toxicity. Or venetoclax, we know that there is a possibility of having a fixed duration treatment for one or two years depending on the setting that we are using that drug and the combination with monoclonal antibodies and we also have another group of drugs PLA (3) kinase inhibitors idelalisib or dubelasib [00:08:58] to be specific.

So, I would say these treatments are all very effective. We have to look at patient specific factors for example, if I have somebody with standard risk CLL meaning that they don’t have P53 deletion or mutation and I’m starting treatment, I think BTK inhibitors or venetoclax based therapy in combination with obinutuzumab are both very reasonable. They are very different though. So, with ibrutinib or HLA ibrutinib, you’re talking about the definite treatment until progression, so patients need to be aware that this treatment goes for – there’s no stopping plan for this treatment versus venetoclax based therapies are time limited. There are side effects for each drug that should be considered so I would say it’s hard to come up with a single answer for that setting but I can tell you my approach and most of my colleagues is to try to start patients on a chemotherapy free and also time limited treatment meaning that patients can finish treatment in a year and hopefully enjoy a remission without taking a medication. So, that’s the goal. We do have clinical trials now that we’re combining some of these novel agents together to again provide treatment for a fixed duration treatment and then having patients off treatment and without disease.

So, the short answer for standard risk patients we have many options in the frontline setting. We have BTK inhibitors and venetoclax. In the relapse setting, we still have BTK inhibitors, we have venetoclax based therapy in combination with rituximab and then there we get PIT kinase inhibitors also added to our list. The discussion has to happen between the physician and the patient looking at the specific side effects of each of these drugs and the patient’s medical comorbidities. Also patients desire to have a time limit of the therapy going on treatment for one year or there may be patients who really don’t mind being on an ongoing treatment as long as there is no side effects. So, for standard risk the goal is to minimize the time on treatment, the goal is to minimize the side effects. So, we use next generation kinase inhibitors. We use drugs like HLA brutinib because we know it has fewer side effects when we compare it to ibrutinib for example. Or we try a time limited therapy like venetoclax. So many options, really the goal is to have shorter time on treatment and fewer side effects.

Host:  Definitely. And that was an incredible explanation behind the different options available for those standard risk patients. And what would you say is the treatment options for those high risk CLL patients?

Dr. Shadman:  Yeah, I think for high risk CLL patients, things are a little bit different. So, they are in a situation where you have to be a little bit more careful in picking your first line treatment. You have to look very closely at the evidence and if you want to kind of walk through that journey from time of diagnosis for example, if I have a patient with division 17P or a mutated P53 gene and they meet the criteria for treatment, I think the best evidence is still with a Bruton tyrosine kinase inhibitor like ibrutinib or HLA ibrutinib. Again, to put it in contrast with our standard risk patients there, as I mentioned, you have both BTK inhibitors and venetoclax and the focus is really discussion with the patient on side effects and time on treatment.

Here, if you look at the published data and realizing that there’s no head to head comparison between these drugs; I think there’s a stronger data in terms of the long term efficacy of a drug like ibrutinib or HLA ibrutinib for the first line treatment. So, that would be usually the first line option and then patients who have [00:13:29] or issues on those drugs can then move to a venetoclax based therapy. Something that’s very important to remind ourselves here is that clinical trials play the major role for high risk CLL patients. So, we have made a lot of progress in treatment of CLL in treating CLL patients. One area that we have a lot of work to do is still the high risk operation as I defined it earlier either patients with 17P or P223 abnormalities or patients who have progression on one of the novel agents. So, I would highly encourage our colleagues or patients to think about clinical trials. And same approach for standard risk patients, there again, the focus is on less toxicity and shorter treatment. Here, we also – we’re not optimize our efficacy yet so here for high risk patients, that’s another need that we have to think about.

So, for high risk patients, we also have another treatment modality and that’s the benefit of having cellular therapy basically so for patients with high risk CLL, historically, allogenous stem cell transplant, that’s a type of [00:14:55] that’s a type of treatment with a very long track record for treating CLL and more recently, through clinical trials, we have access to CAR-T cell therapy for CLL. Again, we know that CAR-T is not currently approved for CLL. In some institutions, there is access to CAR-T through clinical trials and for example, for our patients here at SCCA, we – in our high risk CLL program, we start discussing this treatment modality with our patients who have high risk CLL and through clinical trials, we have provided that treatment to many patients.

That treatment of course has to be explained to the patient in terms of the toxicities and expected efficacy but again, it has to be part of the conversation with the patient with high risk CLL especially after their disease becomes resistant to one of the novel agents, really there is a need for a serious conversation about a treatment like CAR-T or even alginate transplant. A point that I wanted to make is that the time for referral to CAR-T therapy is not when a patient shows progression on both let’s say ibrutinib and venetoclax. That may be too late for such a referral because it becomes very difficult to control patient’s disease before – while we are preparing CAR-T therapy and also, they have to remember that there’s a chance that CAR-T doesn’t work of course and you want to have a reliable treatment option to offer to patients.

So, really, in my practice, and this is very consistent with some of the guidelines, is that when high risk CLL patients shows evidence of progression on either ibrutinib or HLA ibrutinib or venetoclax, and even if they are still responding to the next treatment, that’s the time to start thinking about a more definitive treatment, in this case being cellular therapy like CAR-T. Again, CAR-T there’s an access issue. It has to be on a clinical trial so if the clinical trial is not available, then the discussion would be alginate transplant and of course it’s beyond this conversation here, but the risk benefit ratio within the CAR-T alginate transplant are very different.

One last point that I wanted to make for high risk CLL is that in CLL we don’t treat patients until they need it. Meaning that as we know, there is standard criteria that we follow and if patients meet that criteria, we offer treatment. The reason we don’t offer treatment at the time of diagnosis is of course, because of the fact that we have used chemotherapy in the past in early diagnosis and we haven’t seen the benefit from earlier intervention. The question is what about the new drugs? What if you start somebody on for example ibrutinib at the time of diagnosis if you believe they have high risk disease? Or venetoclax for example? So, the study that used ibrutinib earlier in the course of the diagnosis has not yet shown overall survival benefit for patients and that study is – the initial report is out and was presented and at this point, we don’t believe that using ibrutinib in patients with high risk CLL before they meet the indication for treatment is beneficial. So, we don’t do that.

For venetoclax, the question is still unanswered and it’s important to not that there will be a national study by Southwest Oncology Group that will try to answer that question and a simple version of it is that patients who have high risk disease which includes patients with 17P deletion or P53 mutation, they can potentially start treatment with venetoclax and obinutuzumab and then we will need to follow these patients and learn more and more about their outcomes. Again, to summarize, for high risk patients, clinical trials, clinical trials, clinical trials. Patients have to be very smart about the way they pick their treatment. It is important to pay special attention to the treatment sequence and think about getting second opinion from centers that have access to cellular therapies like CAR-T therapy and alginate transplant early in the course of disease. It doesn’t hurt to get the information and have that initial conversation because when we are in the situation where treatments are all failing, it may not be the right time for having those long and complicated conversations with the patient.

Host:  Thank you so much for joining us today Dr. Shadman and thanks to our listeners for tuning in to the Oncology Sound Byte. For more information about today’s topic and other relevant healthcare provider news from SCCA, please visit our provider blog page www.seattlecca.org/provider-blog and subscribe to our e-newsletter for access to future episodes and clinical updates. You can also find the Oncology Sound Byte in your favorite podcast app plus if you like what you’re hearing, be sure to leave us a review. Until next time, thanks for listening and take good care.