Tag Archive for: TP53

What AML Mutations Are Associated With Adverse Outcomes?

What AML Mutations Are Associated With Adverse Outcomes? from Patient Empowerment Network on Vimeo.

Which acute myeloid leukemia (AML) mutations are linked to adverse outcomes? Dr. Naval Daver from the University of Texas MD Anderson Cancer Center shares insight..Learn about different mutations, treatment options, and the importance of testing.

[ACT]IVATION TIP from Dr. Daver:Check for mutations to the frontline setting…absolutely, these include FLT3, IDH1, IDH2, TP53, and NPM1 MLL this list will likely continue to grow as we get more targeted therapies in immunotherapies and find benefit in particular subsets, but also in the relapse setting to not depend on the baseline molecular profile because the lipids actually can change. We do see AML as a multiclonal disease, and there can be emergence and escape of different clones, so to check again in the relapse for those same mutations and both in the frontline, the relapse setting.

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Transcript: 

Art:

Dr. Daver, what mutations are associated with adverse outcomes in AML? What are the best time points to check for these mutations, and what therapeutic options do you consider for patients or harboring these mutations?

Dr. Naval Daver:

This is very, very important, a mutational targeted therapy is probably the biggest overarching change that has occurred in acute myeloid leukemia in the last decade, and of course to implement those therapies. One has to know the mutational profile, the five big mutations that whenever I speak to my patients in clinic today that I talk about wanting to know before I embark on any therapy are FLT3 or FLD3, IDH1, IDH2, TP53, and now, more and more recently, NPM1 or MLL, actually six different mutations, cytogenetic operations, and the reason is that we do have targeted therapies for these mutations, some of these targeted therapies are already approved in the frontline setting like the FLT3 inhibitors, some of these are being evaluated in ongoing Phase III  studies like the CD47 magrolimab for TP53.

As well as the menin inhibitors now in frontline setting in combinations of intensive chemo or HMA venetoclax (Venclexta), or MLL NPM1 but I think identifying these targets and getting the patients on the right clinical trial personalized to that target for them has historically shown significant improvements, 20 to 30 percent survival improvements in FLT3, IDH and potentially for the TP53 MLL NPM-1 so definitely on newly diagnosed, I would recommend getting that information and then going on to either standard of care the drugs already approved or clinical trial that incororates that targeted therapy or immunotherapy for a target in the relapse setting the two most important mutations today, or the three most important are FLT3, then IDH as well as MLL NPM1. 

Three inhibitors like gilteritinib (Xospata) are already approved. Similarly, IDH inhibitors and combinations of gilteritinib or IDH with venetoclax  are really showing very good outcomes, even in relapse three, which about 20 years ago was a very, very, very poor outcome. T

oday, we can get up to 80 percent of these patients to remission, half of them into transplant, and a good number may have long-term survival post-transplant, so it’s very important to not mislead to an IDH1, IDH2 to a relapse setting.

And then now with the menin inhibitors we’re also looking in all our patients for MLL rearrangement, NPM1 in relapse, because this could open the door for menin inhibitor-based therapy, which again can give up to 50 percent remission and a path to transplant. Now many patients at MD Anderson who have gone through too many inhibitors, transplant and are alive and ongoing at two and three years.

So the bottom line is, it’s important you check at my activation tip for this question is it’s important to check for mutations to the frontline setting…absolutely, these include FLT3, IDH1, IDH2, TP53, and NPM1 MLL this list will likely continue to grow as we get more targeted therapies in immunotherapies and find benefit in particular subsets, but also in the relapse setting to not depend on the baseline molecular profile because the lipids actually can change.

We do see AML as a multiclonal disease, and there can be emergence and escape of different clones, so to check again in the relapse for those same mutations and both in the frontline, the relapse setting.

To try to get on to a therapy, whether it’s approved or clinical trial that incorporates those targeted therapies, which has historically shown a significant improvement in both response and long-term survival. 

Challenges in Treating TP53-Mutated AML, Hope on the Horizon

Challenges in Treating TP53-Mutated AML, Hope on the Horizon from Patient Empowerment Network on Vimeo.

TP53-mutated acute myeloid leukemia (AML) treatment has some challenges. Dr. Naval Daver from the University of Texas MD Anderson Cancer Center shares his perspective. Learn about promising treatments on the horizon for this AML subgroup

[ACT]IVATION TIP from Dr. Daver: “The TP53 mutation remains the most difficult subset of acute myeloid leukemia, there is hope on the horizon with new treatments such as CD47 antibodies and targeted therapies like APR that are being looked at, and also a strong consideration for allogeneic transplant in TP53, because this seems to be the only modality associated with a good chance of cure after achieving remission with one of the frontline therapies.”

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Transcript: 

Art:

Dr. Daver, what have we learned about TP53-mutated AML? And what is the takeaway for these patients?

Dr. Naval Daver:

TP53-mutated AML remains the most difficult molecular subset of all acute myeloid leukemia. Patients who have this mutation, unfortunately, do not respond well to any of the established standard care therapies, including intensive chemotherapy, the HMA alone, such as azacitidine (Onureg or Vidaza), decitabine (Dacogen) alone, or even HMA venetoclax (Venclexta) with all of these, we do see responses, especially with HMA venetoclax or intensive chemotherapy, we can see 15 to 55 percent remission rate, but the remission, very short lived, early relapses and the median overall survival across all of these currently available standards of cares are between six to 10 months.

So there has been an intense effort in the last six, seven years to develop TP53-directed therapies or therapies that will work regardless of TP53 mutation, and there are two drugs this time that are very promising and being evaluated as ongoing Phase II and Phase III studies.

One of them is an immunotherapy drug called magrolimab which seems to have very similar activity and probability with good response rates in TP53-mutated AML. This has been completed in a single arm phase 1B study in front line TP53-mutated AML where we saw close to 50 percent CR, CRI complete permission rates. And median survival was above 11 months in older unfit TP53, which is better than any survival we have seen in the past in this population.

The other study was with the oral care targeted therapy towards TP53, called APR, and this therapy was specifically designed to target the TP53 mutation, and this is being evaluated in the frontline setting in combination with a society in venetoclax. We hope that these regimens are these novel therapies, one or both of them will be able to at least incrementally improve their current outcomes in TP53.

The other area where we have really been doing a lot of research, and I think the data is suggesting, is that allogeneic transplant may work for separate, and we are routinely considering transplant in these patients in the frontline setting, once they are able to achieve remission.

My activation tip is the TP53 mutation remains the most difficult subset of acute myeloid leukemia, there is hope on the horizon with new treatments such as CD47 antibodies and targeted therapies like APR that are being looked at, and also a strong consideration for allogeneic transplant in TP53, because this seems to be the only modality associated with a good chance of cure after achieving remission with one of the frontline therapies. 

A Look at Ongoing Acute Myeloid Leukemia Phase III Trials

A Look at Ongoing Acute Myeloid Leukemia Phase III Trials from Patient Empowerment Network on Vimeo.

What are the acute myeloid leukemia (AML) Phase III clinical trials that are ongoing? Dr. Naval Daver from the University of Texas MD Anderson Cancer Center shares his perspective about encouraging trials. Learn about the MORPHO Study and others. 

[ACT]IVATION TIP from Dr. Daver: “The maintenance with gilteritinib and the MORPHO Study, as well as the relapsed refractory study as well as the use of a e-selectin inhibitor called uproleselan, and hopefully this will lead to approval of the next batch of three or four drugs, which will further improve outcomes for frontline as well as relapsed AML.”

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Transcript: 

Art:

Dr. Daver, can you speak to some of the ongoing Phase III trials in AML, what are you most excited about?

Dr. Naval Daver:

This time there are numerous ongoing phase three in acute myeloid leukemia, some in the frontline, some in the relapse setting. In the frontline setting, the ones that I’m most excited about are trials incorporating a novel immunotherapeutic pathway called the CD47 antibody that works to activation of macrophages, these are looking at a very high-risk molecular group of acute myeloid leukemia, the TP53 in adverse cytogenetics, and there are two randomized phase threes with this agent, one focused on TP53 mutated AML looking at the azacitidine and magrolimab versus the current standard of care FDA-approved azacitidine-venetoclax (Onureg or Vidaza-Venclexta) in TP53 mutated. 

The other is actually looking at all older unfit AML so trying to improve on azacitidine venetoclax doublet with a triplet, so this is looking at azacitidine venetoclax magrolimab versus azacitidine-venetoclax placebo so if both of these trials are positive, then this will lead to incorporation of immunotherapy in the frontline setting in AML, which is exciting and something we’ve been working towards for the last 10, 15 years.

The other Phase III trials in the frontline setting or in the maintenance setting really that I’m excited about is called the MORPHO Study…this is using a FLT3 inhibitor gilteritinib (Xospata) as a maintenance post-transplant, so we know FLT3-mutated patients respond well, when they receive intensive induction FLT3 inhibitor, we still need to take them to transplant because even though the initial response is good, many can relapse. 

So we actually try to give to the cycles of intensive induction for the move to transplant, and then if we start there, we still see at about 40 percent of these patients can relapse in the next three years, so this has led to efforts to add a maintenance FLT3 inhibitor gilteritinib single agent post-transplant as a maintenance for one to two years versus placebo observation, which has historically been a standard of care, and so this is being looked at a large multi-center called the MORPHO Study that we hope to get data from in the near future.

Another study in the similar design that’s being done by the UK cooperative group is looking at maintenance with the oral azacitidine, post-transplant for non-FLT3, so similarly, can we overall improved outcomes not just for FLT3, but the general patient population is going to transplant by using the maintenance oral azacitidine post-transplant versus placebo.

And in the relapse setting, there is a very novel unique oral therapy drug called uproleselan, which is an e-selectin inhibitor, and this agent is now being combined with traditional salvaged chemotherapy such as FLAG-Ida mec versus the placebo mec plus FLAG-Ida or mec in the relapse setting.

And that’s what he’s actually been completed to enrollment, and we’re hoping to hear data from that in the near future. So these are the major randomized studies focusing on TP53, FLT3, and relapsed refractory AML  that we’re looking for in the near future and hopefully could lead to two or three more new approvals in the AML space.

My activation tip for this question is that there are ongoing numerous frontline Phase III as well as relapsed refractory Phase III, targeted immunotherapy approaches, specifically among these we’re excited about the CD47 antibodies. The maintenance with gilteritinib and the MORPHO Study, as well as the relapsed refractory study as well as the use of a e-selectin inhibitor called uproleselan, and hopefully this will lead to approval of the next batch of three or four drugs, which will further improve outcomes for frontline as well as relapsed AML. 

What Does Triplet Therapy in AML Mean for the Future?

What Does Triplet Therapy in AML Mean for the Future? from Patient Empowerment Network on Vimeo.

What do acute myeloid leukemia (AML) patients need to know about triplet therapy? Dr. Naval Daver from the University of Texas MD Anderson Cancer Center shares his perspective. Learn about the meaning, progress, and outlook for triplet therapy. 

[ACT]IVATION TIP from Dr. Daver:Some of the early data with the FLT3 inhibitor as well as the CD47 antibody triplets are showing very, very promising activity and are now moving into larger multi-center and randomized studies.”

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Transcript: 

Art:

Dr. Daver, what does triplet therapy in AML mean for the future?

Dr. Naval Daver:

So when we say triplet therapy, what we’re really thinking about is building on the existing FDA-approved combination of HMA venetoclax (Venclexta), so as a background venetoclax, showed a CR, CRI which is a complete remission rate of about 70 to 75 percent with the median survival in 15 months.

This was in older patients, about 75 years in age, those who were not considered fit for intensive chemotherapy, although this was a major step forward in comparison to what we have seen with traditional low intensities with azacitidine (Onureg or Vidaza), decitabine (Dacogen) alone, we do see the three-year survival is about 25 to 30 percent. 

So this is progress compared to 10 percent long-term survival, we used to get a decade ago, but, of course, we want to improve on that. Also, a molecular analysis of data has shown that there are certain molecular subsets that don’t respond as well to azacitidine, venetoclax or if they respond they relapse quickly these include FLT3 mutated and the TP53 mutated as well as potentially MLL rearranged.

And so here we have started incorporating the targeted therapies like inhibitors like the menin inhibitors like CD47 antibodies to target those specific high-risk or bad molecular cytogenetic groups, and we are seeing that with the combinations of these three drugs, especially for those particular molecular subsets.

So azacitidine and venetoclax for FLT3 inhibitor for FLT3 mutator, azacitidine, and venetoclax, magrolimab for TP53 mutated, the response rates that we’re getting, as well as the depth of response and the early trends towards survival are looking very, very promising compared to what we have seen with azacitidine venetoclax alone.

So we believe, and I personally believe that these three drug combinations, the so-called triplets will actually be eventually the way to go forward now, that means that one has to realize that when you add a third drug, there is a cumulative myelosuppression, azacitidine-venetoclax is already a myelosuppressive regimen. 

Yes, it’s manageable, but it is myelosuppressive. And the third drug, this can become more cumulative, so we have been working for the last three, four years and continue to work on those optimization because since we are seeing true synergy but pre-clinically and what we think in the clinic, we are not needing to give full doses and we’re doing reduced durations of venetoclax and those with FLT3 inhibitor, and now we feel that some of those triplets are actually giving very, very, very good efficacy.

There’s a lot of discussion in the community of whether we need to combine all two drugs up front or can be sequence these drugs or can we introduce a targeted therapy based on a molecular escape, and I think a lot of these will have to be evaluated and many of these are being looked at in various trials, but I do think the bottom line is that bringing in your targeted therapy or immunotherapies early on in the frontline setting and some way or the other is probably where you’re going to get the most bang for the buck and the most benefit in curing patients long-term rather than trying to reserve them for the salvage, because in salvage AML historically, nothing has really been able to improve the long-term cure rate significantly.

So the activation tip for this question is that now with the identification of certain molecular subsets that have poorer outcomes with the HMA venetoclax, we have started incorporating targeted and immunotherapies in the earlier settings, either up front in the three drug combination or an early sequential approach.

And we believe that with such combinations, we may be able to achieve deeper remission and longer responses. Some of the early data with the FLT3 inhibitor as well as the CD47 antibody triplets are showing very, very promising activity and are now moving into larger multi-center and randomized studies. 

A Look at Treatment Strategies for High-Risk AML Patients

A Look at Treatment Strategies for High-Risk AML Patients from Patient Empowerment Network on Vimeo.

What acute myeloid leukemia (AML) treatments are available for high-risk patients? Dr. Naval Daver from the University of Texas MD Anderson Cancer Center discusses various mutations, potential for cure, and clinical trials. Learn about the outlook for high-risk AML treatments.

[ACT]IVATION TIP from Dr. Daver:The best way to get up to these agents is to go on clinical trials and incorporate these therapies, both in the frontline setting as well as in the relapsed refractory setting.” 

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Transcript: 

Art:

Dr. Daver, what treatment strategies are available for high-risk AML patients?

Dr. Naval Daver:

High-risk AML patients includes a group of a number of different mutations, and cytogenetic abnormalities, this includes TP53 mutation, as well as adverse cytogenetics, which includes chromosome 17, deletion 5, deletion 7, as well as complex carrier type. This entire group historically had a poor outcome and has had limited responses to traditional intensive chemo, even if we achieve responses there, usually short-lived.

We do have some patients where we are able to achieve remission with intensive chemo or with azacitidine-venetoclax (Vidaza-Venclexta) and transition and transmission them transplant with about 25 to 30 percent potentially achieving a long-term remission and possible cure. 

But aside from that, there is very little potential to cure these patients with just traditional intensive chemo, venetoclax in this area, there has been developments with the emergence new class of immunotherapy drugs, called CD47 antibodies, the one that’s most advanced in this field is a drug called magrolimab, and we are evaluating the drugs such as magrolimab in combination with azacitidine as well as in combination with azacitidine-venetoclax and are seeing high remission rates, both in TP53 mutated and TP53 wild type.

So this pathway that works by activating a macrophages or the immune system to attack the tumor cells, seems to be in some way mutation agnostic with response rates being maintained even in the traditional high-risk subsets, especially such as TP53 and complex cytogenetics for some of the other high-risk groups such as MLL, we’re using targeted therapies like menin inhibitors, and these seem to work well in those patients who have these adverse cytogenetic molecular abnormalities, so there is progress, and we think that the CD47 antibody field and hopefully the main inhibitor feed will be able to improve outcomes in these traditionally molecular cytogenetic subsets.

My activation point related to this question is for high-risk mutations and cytogenetic commonalities such as TP53 complex carrier chromosome 17 MLL,  best hope at this time is in clinical trials evaluating novel therapies such as CD47 antibodies and menin inhibitors. These are not yet FDA-approved, but based on emerging data from the ongoing Phase I, II studies, we think that there is a good chance they will be approved in the future.

However, this time, the best way to get up to these agents is to go on clinical trials and incorporate these therapies, both in the frontline setting as well as in the relapsed refractory setting. 

What Different AML Subtypes Are More Prevalent in Certain Demographics?

What Different AML Subtypes Are More Prevalent in Certain Demographics? from Patient Empowerment Network on Vimeo.

Are some acute myeloid leukemia (AML) subtypes more common in some demographic groups? Dr. Naval Daver from the University of Texas MD Anderson Cancer Center discusses different forms of AML. Learn about the extent of knowledge about AML subtype demographics.

[ACT]IVATION TIP from Dr. Daver: “Patients, when they transformed what we call secondary AML or MDS, seemed to have a higher predilection for certain high-risk communications such as TP53, and these are best treated with ongoing frontline clinical trials at large academic centers.

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Transcript: 

Art:

Dr. Daver, what are the different subtypes of AML, are various subtypes more prevalent in certain demographics?

Dr. Naval Daver:

The main way we have classified AML has actually been changing, so when we talk about subtypes  there are actually two different classification systems like WHO and the ICC or ELM classification system. Traditionally, we have been using the ELM for prognostic classification of AML, this divides patients into three major buckets, what we call a favorable intermediate and adverse, and these are based on the underlying chromosome cytogenetics abnormalities and molecular or next-generation sequencing profile of the patients.

In general, in AML there has actually been limited data and publications regarding the demographic distribution, whether it’s regional or racial or cultural, one of the things that we do know, for example, in acute lymphoblastic leukemia is that in the Hispanic population, there seems to be higher frequency of things like FLT3-positive ALL. 

But in the AML population, there actually does not seem to be, at least based on published data, huge differences in the molecular or cytogenetic presentation. We have seen some data from different countries that there may be a difference in the prevalence of communications across different regions. For example, in Japan, we do see that the incidence of FLT3 and NPM1 appears to be lower than what has been reported in the United States.

Also, we see in Europe and United States, the incidence of these mutations with FLT3, NPM1 is similar, and then we are seeing in some of the larger academic centers in the U.S., there is an enrichment of referral of patients with TP53, which is very adverse and most difficult to treat mutation, and a lot of that we think is because patients with solid tumors and with other hematological malignancies are surviving longer with the CAR-T therapies, immunotherapies, and because it is over time, they have a risk of developing second AML, which is enriched for TP53 mutation, so we do see over the last two decades that from TP53, which used to be about 5 percent to 10 percent, is now up to 20 percent to 25 percent of AML and growing in proportion because it’s better survival and solid tumors and lymphomas.  

The activation tip related to this question is that in general, they don’t review discrepancies based on geography and race, and region in the molecular cytogenetics. However, we do see differences in patients who have received prior chemotherapy, radiation therapy, AML therapy for other solid tumors and lymphoma.

These patients, when they transformed what we call secondary AML or MDS, seemed to have a higher predilection for certain high-risk communications such as TP53, and these are best treated with ongoing frontline clinical trials at large academic centers. 

How Does the Presence of Molecular Markers Affect AML Care?

How Does the Presence of Molecular Markers Affect AML Care? from Patient Empowerment Network on Vimeo.

Dr. Farhad Ravandi-Kashani reviews how the presence of gene mutations can influence acute myeloid leukemia (AML) treatment choices and discusses new molecular markers being researched for future AML care.

Dr. Farhad Ravandi-Kashani is professor of medicine and Chief of the Section of Developmental Therapeutics in the Department of Leukemia at The University of Texas MD Anderson Cancer Center in Houston, TX. Learn more about Dr. Ravandi-Kashani.

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Transcript:

Laura Beth:

How do test results impact AML care and treatment decisions?  

Dr. Ravandi:

So, in the first place, the presence or absence of certain mutations can be predictable outcome. Some subsets of leukemias are, for the lack of a better term, more favorable.  

I personally don’t think there is anything favorable about any leukemia, but some are easier to treat, and some are easier to cure than others. There is one specific subtype called acute promyelocytic leukemia that we actually completely treat differently. We don’t use even chemotherapy in that subset of leukemia.  

It has almost 100 percent success rate. And the treatment of other subsets can also be tailored, depending on these molecular and chromosomal changes. So, the initial therapy can be actually changed. There are now, for example, targeted agents that can be added to the chemotherapy, during initial chemotherapy.  

And also, once the patient is in remission, depending on favorable or unfavorable their leukemia is, they may be offered allogeneic stem cell transplant. So, yes, this information is highly important. In fact, I would say crucial for our decision-making in leukemia therapy these days.  

Laura Beth:

So, what is new in AML research related to molecular markers?  

Dr. Ravandi:

Well, it depends on your definition of new, but FLT3 mutations are very important because they’re now several FLT3 inhibitors, and as I mentioned, the initial therapies are different, to some extent. The IDH mutations are very important, again, because they are specific targeted agents.  

TP53 mutations are important because, unfortunately, they are particularly unfavorable.  

This is completely hot off the press, but there are subsets of AML called MLL rearranged leukemias that can respond to these drugs called Menin inhibitors.  

There are other mutations that have been discovered, many other ones, that there are no specific treatments for at the moment, but there’s a lot of research on.  

How Do Genetic Mutations Impact a CLL Patient’s Prognosis?

How Do Genetic Mutations Impact a CLL Patient’s Prognosis? from Patient Empowerment Network on Vimeo.

What is the best approach for chronic lymphocytic leukemia (CLL) patients with genetic mutations? CLL expert Dr. Seema Bhat shares how mutations impact prognosis and treatment.

Seema Bhat, MD is a hematologist at The Ohio State University Comprehensive Cancer Center – The James. Learn more about Dr. Bhat.

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Transcript:

Katherine:

Okay, that’s great. Here’s one from Phil, “How do mutations affect longevity when surviving CLL? What new treatments help with P53 mutation?”  

Dr. Bhat:

So, there are certain prognostic markers for CLL, meaning certain tests that can tell us how a particular patient is expected to do. Some of these tests detect presence or absence of mutations in certain genes. For example, the IGHV gene can be mutated or unmutated. 

In patients with mutated IGHV, they do well, and patients with unmutated IGHV tend to have a more aggressive disease and may require treatment sooner. Similarly, TP53 mutations also tend to require treatment sooner, and more of these mutations do not respond well to conventional chemotherapy. However, targeted therapy has changed the outlook for these mutations, and it works very well for both these mutations. 

Managing CLL Symptoms and Treatment Side Effects

Managing CLL Symptoms and Treatment Side Effects from Patient Empowerment Network on Vimeo.

Chronic lymphocytic leukemia (CLL) expert Dr. Seema Bhat reviews common CLL symptoms and treatment side effects and approaches for managing them. Dr. Bhat stresses the importance of sharing any issues they may be having with their healthcare teams.

Seema Bhat, MD is a hematologist at The Ohio State University Comprehensive Cancer Center – The James. Learn more about Dr. Bhat.

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Transcript:

Katherine:

Can you please talk about common side effects of CLL – which, of course, we’ve covered already, but both the ones from the disease itself and then ones related to treatment, and what can be done about these? 

Dr. Bhat:

So, disease-related side effects, or we call them disease-related symptoms, include fatigue as a common symptom. Unintentional weight loss can happen. Fevers, chills, or drenching night sweats can happen. We call them, “B symptoms.” Spleen can enlarge, and the enlargement can cause belly pain or feeling of fullness quickly after a meal since spleen is close to our stomach, and as it enlarges, it limits the space stomach can take up in the belly. Lymph nodes can enlarge and can get uncomfortable. So, if any of these symptoms happen, then we have to treat the CLL, and once we start treating the CLL these symptoms should go away. 

As far as treatment-related side effects are concerned, for example, BTK inhibitors are associated with a certain set of side effects. For example, patients can have muscle cramping, muscle pain, joint pain. Patients can have diarrhea. Some of the side effects that we worry about is change in heart rhythm, for example, atrial fibrillation. We talked about that, or increased risk of bleeding.  

Those are some of the side effects we worry about, and if those were to develop, then, of course – for example, a patient has atrial fibrillation, and if it’s symptomatic, we hold the medication. We take care of the atrial fibrillation, usually in collaboration with cardiologists, and once that’s under control, then we have to decide what to do with the treatment. If the atrial fibrillation is under control, we can re-initiate the treatment, or we can go to one of the next-generation BTK inhibitors – the acalabrutinib (Calquence), the pirtobrutinib (LOXO-305), which have less of those side effects. 

Bleeding tends to be a concern, but anything that reduces the risk of bleeding like other medications, aspirin, clopidogrel (Plavix), other blood thinners, we can avoid them, monitor these patients very closely for any of these side effects, so that’s critical. With venetoclax, it’s usually very well-controlled. It’s the initial part of treatment that tends to be a little bit intensive because of the specific side effect called, “tumor lysis syndrome,” which means that the drug works very quickly, and cells die off quickly, they can release stuff in the blood, and things can collect in the blood. 

Uric acid can go up, electrolytes can be up, any number can go up. So, we are aware of this side effect, and we actually pre-emptively have things in place that can prevent this from happening, or if it happens, we manage it right away. For example, venetoclax has a specific dose initiation. For example, it’s called, “dose ramp-up.” We start it at a lower dose, 20 milligrams, for one week. Escalate it to 50 the next week, 100 the third week, 200 fourth week, and 400 the last week, which is the standard dose. They continue on 400 from there onward. 

And even with the slow dose escalation, in the early couple of weeks, we monitor them very closely. Once we initiate a dose, we bring them back to the clinic to recheck their blood work to see if there are any changes. If any changes have happened, we hydrate them, initiate medication for their tumor lysis syndrome. 

If the risk of tumor lysis is very high, then we monitor then admit them to the hospital. Otherwise, long-term side effects of venetoclax, what we have noticed mostly is gastritis, most side effects – mostly diarrhea. But that’s usually well-controlled. We can manage it well with supportive care. 

Emerging CLL Treatment Approaches

Emerging CLL Treatment Approaches from Patient Empowerment Network on Vimeo.

Are there emerging CLL treatments that are showing promise? Dr. Seema Bhat provides an overview of ongoing research and discusses when CLL patients should consider clinical trials. 

Dr. Seema Bhat is a hematologist at The Ohio State University Comprehensive Cancer Center – The James. Learn more about Dr. Bhat here.

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Understanding CLL Treatment Classes

Understanding CLL Treatment Classes

How Are Targeted CLL Treatments Administered

Educational Resources for CLL Patients

Educational Resources for CLL Patients

Transcript:

Katherine:  

Dr. Bhat, where do clinical trials fit into treatment? 

Dr. Bhat:  

So, clinical trials play a very important role to advance treatments. Clinical trials for CLL are done to test new treatments, new combinations of treatments, compare different treatments to each other. The goal of these clinical trials is to continue to do better than what we currently have available. This is how treatments improve. Despite all the advancements that we have had in CLL, in the recent years, it continues to be an incurable disease, even today. Our goal as researchers is never to stop until we get to that cure, and clinical trial is that pathway to that cure.

Katherine:

Are there emerging therapies that are showing promise? 

Dr. Bhat:

Yes, of course. There are a number of emerging therapies that are showing promise. So, we all know about ibrutinib and other BTK inhibitors. These work very well, but sometimes the disease can get resistant to these medications, meaning that it stops responding to these treatments. We are excited about this new kind of BTK inhibitor called, “pirtobrutinib,” which has shown great promise in these resistance cases, and we are hopeful that it’ll be approved soon. 

Katherine:

Are there other options that patients have? 

Dr. Bhat:

So, we all hear about what is called, “chimeric antigen receptor T-cell therapy,” or CAR-T therapy. This is studied under clinical investigation for CLL and looks very promising. The therapy uses the person’s own immune cell called, “T cell” to identify and attack cancer cells. 

T cells are taken from the patient’s blood and sent to a specific lab. There, the cells are modified so that they can better find and attack cancer cells. These modified T cells are then re-injected back into the patient to find and fight that cancer, to eradicate the disease. So, this looks very promising.  

How Are Targeted CLL Treatments Administered?

How Are Targeted CLL Treatments Administered? from Patient Empowerment Network on Vimeo.

Chronic lymphocytic leukemia (CLL) expert Dr. Seema Bhat explains how self-administered oral treatments work for CLL patients and what potential side effects doctors are watching out for. 

Dr. Seema Bhat is a hematologist at The Ohio State University Comprehensive Cancer Center – The James. Learn more about Dr. Bhat here.

See More from Thrive CLL

Related Resources:

Educational Resources for CLL Patients

Educational Resources for CLL Patients

How Does CLL Affect the Immune System

How Does CLL Affect the Immune System?

Managing CLL Symptoms and Treatment Side Effects

Transcript:

Katherine:

How are targeted therapies administered? 

Dr. Bhat:

So, most of the targeted therapies that we have, we are happy to say that these are oral agents. The BTK inhibitors, the three that we have available, are oral agents. Ibrutinib is taken once a day, zanubrutinib and acalabrutinib are twice a day. Venetoclax, similarly, is an oral agent and is taken once a day. Monoclonal antibodies are also considered targeted agents. These are given as infusions in the clinic or in the clinician’s office.  

Katherine:

The oral medications, patients take that at home? They don’t have to go into the hospital?  

Dr. Bhat:

They do not have to go into the hospital. However, venetoclax is associated with a specific side effect called, “tumor lysis syndrome,” where this medication works so well that initially the cells with die off quickly and then things can collect in the blood.  

For example, uric acid can go up, electrolytes can be up, any number can go up. So, we monitor what those initial weeks of starting venetoclax, we monitor patients very closely. We have them come back and forth to the clinic for monitoring, bloodwork, maybe hydration. And sometimes, if we think they’re at a very high risk for this tumor lysis syndrome, we admit them to the hospital.  

After we cross that, those are administered at home. They can take these at home. 

Understanding CLL Treatment Classes

Understanding CLL Treatment Classes from Patient Empowerment Network on Vimeo.

Chronic lymphocytic leukemia (CLL) expert Dr. Seema Bhat explains the different treatment classes available for CLL patients and how the standard of care has evolved.

Dr. Seema Bhat is a hematologist at The Ohio State University Comprehensive Cancer Center – The James. Learn more about Dr. Bhat here.

See More from Thrive CLL

Related Resources:

Educational Resources for CLL Patients

Educational Resources for CLL Patients

Emerging CLL Treatment Approaches

Emerging CLL Treatment Approaches

Managing CLL Symptoms and Treatment Side Effects

Transcript:

Katherine Banwell:

Dr. Bhat, when it’s time to start therapy, what types of treatments are available for CLL patients? 

Dr. Bhat:

So, when we think about treatment for cancer, we think about chemotherapy – the conventional chemotherapy that’s associated with side effects like hair loss, nausea, or vomiting. I’m very happy to say that conventional chemotherapy is no longer the standard of care for patients with CLL. Patients who need treatment for CLL are nowadays treated with what are called, “targeted agents.” 

And we have, in general, two different classes of targeted agents that have been approved for treatment for CLL. We have the BTK inhibitors, Bruton’s tyrosine kinase inhibitors, of which we have three. We have ibrutinib, we have acalabrutinib, and we have zanubrutinib. Then we have BCL-2 inhibitors, of which we currently have one approved, of which is called venetoclax. These treatments can be combined with monoclonal antibodies, which are directed towards the antigen called CD20. For example, rituximab or obinutuzumab. 

Typically, venetoclax is combined with monoclonal antibody as a time-limited therapy. BTK inhibitors usually are not combined with monoclonal antibody. 

Katherine:

What about stem cell transplant, does that fit in there? 

Dr. Bhat:

So, stem cell transplant still has a role for treatment of patients with CLL, but it has moved down the line with such highly effective and well-tolerated oral agents available. 

But, for refractory patients – what we call dual-refractory patients, we definitely are, especially in high – patients who have higher risk features, we do refer them to stem cell transplant. 

Katherine:

And what is a dual-refractory patient, exactly? 

Dr. Bhat:

Dual-refractory patients mean patients who have had a BTK inhibitor, be it ibrutinib, acalabrutinib, or zanubrutinib, and the disease has progressed on that. And then we give them venetoclax, which is a BCL-2 inhibitor. So, these are the two classes of targeted agents that we have available. If they have received ibrutinib, acalabrutinib, or zanubrutinib, and after that, a venetoclax, or venetoclax followed by a BTK inhibitor, and the disease has progressed on both. These patients are called dual-refractory, and currently they tend to be very resistant to whatever treatments we have available. And we looked at other modalities of treatment, be it clinical trials or stem cell transplants for that.  

Thriving With CLL | Tips and Support for Navigating Care

Thriving With CLL | Tips and Support for Navigating Care from Patient Empowerment Network on Vimeo.

What are the key elements that help patients thrive with chronic lymphocytic leukemia (CLL)? In this webinar, Dr. Seema Bhat discusses CLL treatment and research, explains how the side effects and symptoms of CLL are managed, and shares tools for managing daily life with CLL.

Seema Bhat, MD is a hematologist at The Ohio State University Comprehensive Cancer Center – The James. Learn more about Dr. Bhat.

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Expert Advice for CLL Self-Advocacy

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CLL Treatment Approaches: What Are the Types?

Setting CLL Treatment Goals WITH Your Team

Transcript:

Katherine:

Hello, and welcome. I’m Katherine Banwell, your host for today’s program. Today’s webinar is part of our Thrive series, and we’re going to discuss tools for navigating life with CLL. Before we get into the discussion, please remember that this program is not a substitute for seeking medical advice. Please refer to your healthcare team about what might be best for you.  

Let’s meet our guest today. Joining us is Dr. Seema Bhat. Dr. Bhat, welcome. Would you please introduce yourself? 

Dr. Bhat:

Hi, Katherine. Thank you for having me here on the program. My name is Seema Bhat, and I am an associate professor at Ohio State University with expertise in treating CLL.  

Katherine:

Excellent, thank you so much for taking time out of your schedule to join us. 

Dr. Bhat:

You’re welcome. 

Katherine:

Like all of the webinars in our Thrive series, we start with this question. In your experience, what does it mean to thrive with CLL? 

Dr. Bhat:

So, thriving with CLL to me means that we envision our patients with CLL leading normal, functional, and productive lives. You know, when patients hear the word “cancer,” or “leukemia,” it comes as a big shock to them. Cancer is also associated with drastic changing – life-changing experiences. Patients think about their shortened life span, and the difficulties they’ll have to endure in this shortened life span due to the treatments they will be needing for their cancer. But I want to tell my patients that even though they have a leukemia, they have a cancer, they can still focus on their life in general. 

They have – this has been made possible by very effective yet gentle treatments approved for CLL. Patients can have an enjoyable, fulfilling life focusing on their life in general, and thrive. 

Katherine:

Thank you for that, Dr. Bhat. That’s important for patients to know. Let’s move on to treatment and walk through CLL treatment classes and types. Some of our audience members may already know this information, but it’s a good baseline for newly diagnosed patients. First, CLL patients are often put in “watch and wait” when they’re first diagnosed. What does that mean? 

Dr. Bhat:

So, “watch and wait” means observation. CLL is a slow-growing cancer, generally, and one of the few cancers that’s managed by observation if it’s not causing any problems to the patient. These problems could include symptoms in the form of fatigue, unintentional weight loss, symptomatic enlargement of their lymph nodes or spleen, or we could see changes in their blood work in the form of decreased hemoglobin or decreased platelets. 

If this is not happening, observation is still the standard of care. And data from this comes from a number of clinical trials where patients were treated based on just having the disease without having any of the symptoms or signs I just mentioned. 

All these studies had negative results, meaning that starting treatment at diagnosis did not affect the overall survival of these patients. These patients – these studies were, however, done in chemoimmunotherapy era. Now, we have targeted agents. And also, now we are able to define CLL better, which means that we are able to predict who has higher risk disease. 

So, there’s renewed interest in these – what these are called, early intervention studies. But until we have those results are matured and available, “watch and wait” is still the standard approach. And during “watch and wait,” we see patients at regular intervals, we assess them for symptoms, we look at their bloodwork, and one of the main reasons for seeing these patients at regular intervals is to reinforce what symptoms we want them to pay attention to. So, educating patients at each visit is a very important part of these visits. 

“Watch and wait” may be all that 1/3 of our patients may need through their lifetime. They may never need any CLL-directed treatment. 

Katherine:

Dr. Bhat, when it’s time to start therapy, what types of treatments are available for CLL patients? 

Dr. Bhat:

So, when we think about treatment for cancer, we think about chemotherapy – the conventional chemotherapy that’s associated with side effects like hair loss, nausea, or vomiting. I’m very happy to say that conventional chemotherapy is no longer the standard of care for patients with CLL. Patients who need treatment for CLL are nowadays treated with what are called, “targeted agents.” 

And we have, in general, two different classes of targeted agents that have been approved for treatment for CLL. We have the BTK inhibitors, Bruton’s tyrosine kinase inhibitors, of which we have three. We have ibrutinib (Imbruvica), we have acalabrutinib (Calquence), and we have zanubrutinib (BGB-3111). Then we have BCL-2 inhibitors, of which we currently have one approved, of which is called venetoclax (Venclexta). These treatments can be combined with monoclonal antibodies, which are directed towards the antigen called CD20. For example, rituximab (Rituxan) or obinutuzumab (Gazyva). 

Typically, venetoclax is combined with monoclonal antibody as a time-limited therapy. BTK inhibitors usually are not combined with monoclonal antibody. 

Katherine:

What about stem cell transplant, does that fit in there? 

Dr. Bhat:

So, stem cell transplant still has a role for treatment of patients with CLL, but it has moved down the line with such highly effective and well-tolerated oral agents available. 

But, for refractory patients – what we call dual-refractory patients, we definitely are, especially in high – patients who have higher risk features, we do refer them to stem cell transplant. 

Katherine:

And what is a dual-refractory patient, exactly? 

Dr. Bhat:

Dual-refractory patients mean patients who have had a BTK inhibitor, be it ibrutinib, acalabrutinib, or zanubrutinib, and the disease has progressed on that. And then we give them venetoclax, which is a BCL-2 inhibitor. So, these are the two classes of targeted agents that we have available. If they have received ibrutinib, acalabrutinib, or zanubrutinib, and after that, a venetoclax, or venetoclax followed by a BTK inhibitor, and the disease has progressed on both. These patients are called dual-refractory, and currently they tend to be very resistant to whatever treatments we have available. And we looked at other modalities of treatment, be it clinical trials or stem cell transplants for that. 

Katherine:

How are targeted therapies administered? 

Dr. Bhat:

So, most of the targeted therapies that we have, we are happy to say that these are oral agents. The BTK inhibitors, the three that we have available, are oral agents. Ibrutinib is taken once a day, zanubrutinib and acalabrutinib are twice a day. Venetoclax, similarly, is an oral agent and is taken once a day. Monoclonal antibodies are also considered targeted agents. These are given as infusions in the clinic or in the clinician’s office.  

Katherine:

The oral medications, patients take that at home? They don’t have to go into the hospital? 

Dr. Bhat:

They do not have to go into the hospital. However, venetoclax is associated with a specific side effect called, “tumor lysis syndrome,” where this medication works so well that initially the cells with die off quickly and then things can collect in the blood.  

For example, uric acid can go up, electrolytes can be up, any number can go up. So, we monitor what those initial weeks of starting venetoclax, we monitor patients very closely. We have them come back and forth to the clinic for monitoring, bloodwork, maybe hydration. And sometimes, if we think they’re at a very high risk for this tumor lysis syndrome, we admit them to the hospital.  

Dr. Bhat:

After we cross that, those are administered at home. They can take these at home. 

Katherine:

Dr. Bhat, where do clinical trials fit into treatment? 

Dr. Bhat:

So, clinical trials play a very important role to advance treatments. Clinical trials for CLL are done to test new treatments, new combinations of treatments, compare different treatments to each other. The goal of these clinical trials is to continue to do better than what we currently have available. This is how treatments improve. Despite all the advancements that we have had in CLL, in the recent years, it continues to be an incurable disease, even today. Our goal as researchers is never to stop until we get to that cure, and clinical trial is that pathway to that cure.  

Katherine:

Are there emerging therapies that are showing promise?  

Dr. Bhat:

Yes, of course. There are a number of emerging therapies that are showing promise. So, we all know about ibrutinib and other BTK inhibitors. These work very well, but sometimes the disease can get resistant to these medications, meaning that it stops responding to these treatments. We are excited about this new kind of BTK inhibitor called pirtobrutinib which has shown great promise in these resistance cases, and we are hopeful that it’ll be approved soon. 

Katherine:

Are there other options that patients have? 

Dr. Bhat:

So, we all hear about what is called, “chimeric antigen receptor T-cell therapy,” or CAR-T therapy. This is studied under clinical investigation for CLL and looks very promising. The therapy uses the person’s own immune cell called, “T cell” to identify and attack cancer cells. 

T cells are taken from the patient’s blood and sent to a specific lab. There, the cells are modified so that they can better find and attack cancer cells. These modified T cells are then re-injected back into the patient to find and fight that cancer, to eradicate the disease. So, this looks very promising. 

Katherine:

Many CLL community members are interested in learning more about their disease. So, for newly diagnosed patients, what are a few educational resources you recommend to help them learn more about their condition? 

Dr. Bhat:

There are a number of well-established support groups or educational resources for our patients. These include the CLL Society, The Leukemia & Lymphoma Society, Lymphoma Research Foundation, and then we have Patient Empowerment Network, and we have Patient Power. All these resources provide support groups, organize webinars, and have educational material for our patients. 

Katherine:

What about patients who have been living with CLL for many years, or are quite knowledgeable about their disease? Are there more advanced resources for patients to stay up to date on the latest research and treatment? 

Dr. Bhat:

So, for patients who want to search for additional resources, especially looking for clinical trials, going on this website called clinicaltrials.gov, they can first search for CLL-related clinical trials. Also, NCCN, or “National Comprehensive Cancer Network,” has patient resources for each disease, and then they can find information on CLL there, also. I would also like to say that Google is a good resource, as long as you know where it is taking you. 

Katherine:

Exactly. You may not be able to rely on everything you find. 

Dr. Bhat:

Right.  

Katherine:

Yeah. Many people with CLL will experience fear and anxiety, whether it’s the stress of being in “watch and wait” or worrying about regression. Why do you feel it’s important for patients to share how they’re feeling with their healthcare team? 

Dr. Bhat:

So, one of the important things to know about CLL is that CLL, at this point of time, it’s not a curable disease. It is a lifelong disease. Patients will have to deal with CLL for the rest of their life in some form or other, either on watchful waiting, or on active treatment, or if they’ll complete a treatment, they’ll have this lurking fear of relapse at any time. A large part of what I do is to help my patients understand what it means to live with CLL. And, of course, anxiety is a big part of that living with CLL. 

Although at this time, we’re unable to cure our patients with CLL, I want my patients to understand that it’s very treatable, treatments are very well-tolerated with low toxicity, and patients live a long life. They can have good, productive, and active life. They should ask their care team about resources for social, emotional, and physical support. 

They should let them know about their concerns, talk about their feelings. 

Katherine:

That’s my next question, actually. How can a social worker provide support and are there other healthcare team members who might be able to help? 

Dr. Bhat:

So, yes, patients are on a rollercoaster – emotional rollercoaster with this diagnosis. With this diagnosis come lots of unknowns. Worries about possible shortened life span, anxiety over treatment, and effects of treatment. So, there’s lots to deal with, and lot of uncertainty, which causes a feeling of hopelessness for these patients. So, psychological support is very important. That’s where the role of social worker comes in. 

We get them involved to help patients deal with the diagnosis, and social workers – they can provide patients with tools to cope with this life-changing event. They use life tools like encouraging positive thinking, mindfulness, being aware of what the patient can control involving faith and family, and also involving self-care. 

That’s where we see the role of the whole team as such. If patients are having more difficulties, we can have other members of a team, like a mental health provider, connect with our patients. Social workers and other members of the team can help our patients get connected to support groups, or even to other patients who have had similar experiences. 

Katherine:

What about worry and anxiety related to COVID and compromised immunity? What would you like patients to know? 

Dr. Bhat:

So, COVID has become another source of anxiety, unfortunately, for many of our patients, and rightly so. Our patients with CLL are considered immunocompromised, meaning that their immune systems do not work that well, which makes these patients very susceptible to different kinds of infections, COVID being one of them. And this was actually shown by some of the early COVID-related studies that showed a very high mortality in patients with CLL. 

This has improved now, mostly because now we are better equipped to handle COVID. We have COVID-directed medications available, but the major impact has been made by the vaccines. So, we highly encourage our patients to get vaccinated against COVID and keep up to date with the latest CDC guidelines. Also, we have Evusheld available, which is under emergency use authorization, and our patients with CLL, due to their weaker immune system, are eligible to get this, which adds an extra layer of protection for our patients. 

Also, it’s important to know that our test – if our patients test do test positive for COVID, they should let their team of doctors know immediately, since now we have monoclonal antibodies and pills that can be used to treat symptomatic COVID. 

Katherine:

That’s great information, thank you. Financial concerns can be another source of stress for people with CLL. Obviously, everyone’s situation is different, of course, but what resources are available for patients who need financial support?  

Dr. Bhat:

So, financial barriers can be a real concern for our patients. Targeted therapies are very expensive, and although insurances do cover them, the approved FDA drugs, copays can be very high, and this adds on because our patients with – our treatments with CLL, some of them tend to be indefinite. That means patients have to take those medications on an ongoing basis, and when they face such situations, high copays, we look into financial assistance. We look for funding for copay assistance, and funding can be provided by pharmaceutical companies. We can also apply for grants through The Leukemia & Lymphoma Society and other resources to help out our patients with these financial concerns. 

Katherine:

So, does the patient work with the healthcare team to find financial support? 

Dr. Bhat:

Absolutely. We at our institution have what is called, “MAP,” or Medication Assistance Program. 

And when we see that – we run the medications through the insurance, then we see the copay is high, we refer our patients to the MAP program, and then they take over. They find them grants, they find them assistance through be it pharmaceuticals, copay assistance programs. So, invariably, almost all patients who come and see us are helped through that program.  

Katherine:

What about a nurse navigator or patient navigator? What do they do? How can they help? 

Dr. Bhat:

Well, so yes. Nurse navigators and patient navigators are also very important for caring for our patients. So, patients can have, besides our care for our patients which includes caring for their disease, caring for their symptoms, caring for their reduced hemoglobin and reduced platelets, our symptom management, they have psychological needs, they have functional needs, they have needs like family support.  

So, these are all the things that patient navigators can help patients set that up based on their – we have patients who travel from out of state, are from two or three hours away. So, these patient navigators look into what resources they should have available locally. Sometimes, patient navigators help us – some patients cannot do frequent travels back and forth, so we get them connected to local oncologists, also. So, patient navigators look into those appointments, look into those offices, so they provide a lot of help to us manage our patients. So, they provide more of a holistic management, rather than just treatment of CLL. 

Katherine:

Let’s answer a few audience questions that we received in advance of the webinar. This one is from William. Can you please talk about common side effects of CLL – which, of course, we’ve covered already, but both the ones from the disease itself and then ones related to treatment, and what can be done about these? 

Dr. Bhat:

So, disease-related side effects, or we call them disease-related symptoms, include fatigue as a common symptom. Unintentional weight loss can happen. Fevers, chills, or drenching night sweats can happen. We call them, “B symptoms.” Spleen can enlarge, and the enlargement can cause belly pain or feeling of fullness quickly after a meal since spleen is close to our stomach, and as it enlarges, it limits the space stomach can take up in the belly. Lymph nodes can enlarge and can get uncomfortable. So, if any of these symptoms happen, then we have to treat the CLL, and once we start treating the CLL these symptoms should go away. 

As far as treatment-related side effects are concerned, for example, BTK inhibitors are associated with a certain set of side effects. For example, patients can have muscle cramping, muscle pain, joint pain. Patients can have diarrhea. Some of the side effects that we worry about is change in heart rhythm, for example, atrial fibrillation. We talked about that, or increased risk of bleeding.  

Those are some of the side effects we worry about, and if those were to develop, then, of course – for example, a patient has atrial fibrillation, and if it’s symptomatic, we hold the medication. We take care of the atrial fibrillation, usually in collaboration with cardiologists, and once that’s under control, then we have to decide what to do with the treatment. If the atrial fibrillation is under control, we can re-initiate the treatment, or we can go to one of the next-generation BTK inhibitors – the acalabrutinib, the pirtobrutinib, which have less of those side effects. 

Bleeding tends to be a concern, but anything that reduces the risk of bleeding like other medications, aspirin, clopidogrel (Plavix), other blood thinners, we can avoid them, monitor these patients very closely for any of these side effects, so that’s critical. With venetoclax, it’s usually very well-controlled. It’s the initial part of treatment that tends to be a little bit intensive because of the specific side effect called, “tumor lysis syndrome,” which means that the drug works very quickly, and cells die off quickly, they can release stuff in the blood, and things can collect in the blood. 

Uric acid can go up, electrolytes can be up, any number can go up. So, we are aware of this side effect, and we actually pre-emptively have things in place that can prevent this from happening, or if it happens, we manage it right away. For example, venetoclax has a specific dose initiation. For example, it’s called, “dose ramp-up.” We start it at a lower dose, 20 milligrams, for one week. Escalate it to 50 the next week, 100 the third week, 200 fourth week, and 400 the last week, which is the standard dose. They continue on 400 from there onward. 

And even with the slow dose escalation, in the early couple of weeks, we monitor them very closely. Once we initiate a dose, we bring them back to the clinic to recheck their blood work to see if there are any changes. If any changes have happened, we hydrate them, initiate medication for their tumor lysis syndrome. 

If the risk of tumor lysis is very high, then we monitor then admit them to the hospital. Otherwise, long-term side effects of venetoclax, what we have noticed mostly is gastritis, most side effects – mostly diarrhea. But that’s usually well-controlled. We can manage it well with supportive care. 

Katherine:

Here’s another question from Anna. She asks, “What is MRD, and does that mean that the disease is cured?” 

Dr. Bhat:

So, MRD is minimal residual disease, and in CLL is defined as the number of leukemic cells that can be detected in the blood or bone marrow following treatment, meaning how many cancer cells are remaining after treatment? This can be checked by a couple of tests. Most commonly, we use flow cytometry. Undetectable MRD is currently defined as the presence of less than one cell – one CLL cell in 10,000 white cells. 

It’s emerging as an endpoint in a number of clinical trials, and presence of no MRD, also called, “MRD-negative status,” although not considered a cure, predicts better outcomes with longer remission. This is being done in combination treatment, and although it’s part of clinical trials currently, with more data available, we may start using this in clinical practice in the next coming years. 

Katherine:

Sophia wants to know, “Are there any clinical trials regarding Richter’s, or DLBCL, transformation?” 

Dr. Bhat:

So, Richter’s transformation means when CLL, which is a low-grade disease, changes into high-grade lymphoma, and most commonly it’s “diffuse large B-cell lymphoma,” or DLBCL. Currently available treatments for Richter’s transformation are, unfortunately, sub-optimal. So, clinical trials to find better treatments are critical for this division, and there are a number of these currently going on. For example, some trials add targeted agents to the backbone of standard chemotherapy called, “R-CHOP.” 

So, we have one trial where acalabrutinib is being added. There’s another clinical trail where venetoclax is being combined with R-CHOP. One of the problems with Richter’s Transformation is that it tends to be refractory to treatment, and it tends to come back or relapse. So, there are studies ongoing for relapse treatment as well, with combination of targeted agents. And CAR-T therapy, we just talked about that, is also being studied in Richter’s Transformation. So, there’s a lot going on to improve the outcome for this. 

Katherine:

Okay, that’s great. Here’s one from Phil, “How do mutations affect longevity when surviving CLL? What new treatments help with P53 mutation?” 

Dr. Bhat:

So, there are certain prognostic markers for CLL, meaning certain tests that can tell us how a particular patient is expected to do. Some of these tests detect presence or absence of mutations in certain genes. For example, the IGHV gene can be mutated or unmutated. 

In patients with mutated IGHV, they do well, and patients with unmutated IGHV tend to have a more aggressive disease and may require treatment sooner. Similarly, TP53 mutations also tend to require treatment sooner, and more of these mutations do not respond well to conventional chemotherapy. However, targeted therapy has changed the outlook for these mutations, and it works very well for both these mutations. 

Katherine:

Finally, our last question. One audience member would like to know more about how CLL affects the immune system, including wound healing, and how does CLL impact this? 

Dr. Bhat:

So, patients with CLL usually have a weaker immune system. The lymphocyte, which is the white cell, which is affected in CLL, is an important part for an immune system, and due to the presence of disease, these lymphocytes – although there are lots of them in patients with CLL, they tend to be non-functional. 

“Functionally incompetent,” that’s what they’re called. And it leaves the patient’s immune deficient and susceptible to a variety of infections. Also, the lymphocyte is component – the B lymphocyte is one component of immune system. There are other components like T lymphocyte, antibody, MK cell. There’s cross-dock between the B cells and what we call, the “microenvironment,” which is made of the T cells. This cross-dock is deficient in patients with CLL, again making them immune-deficient and susceptible to infection. So, that’s one impact on their immune system. 

Sometimes, there’s something else happening in the immune system where the immune system can go crazy, or wacky, and start attacking the patient’s own blood cells leading to, for example, decrease of hemoglobin or platelets, because these are immune complications. And also, due to a weak immune system, patients with CLL can have delayed wound healing, which also predisposes them to infection. 

So, being aware of these complications is important and using appropriate precautions can be very helpful. Again, because they have a weakened immune system, vaccines are very important. Using all measures to avoid infection, hand washing, staying away from patients, from people who are obviously sick, is very important. Sometimes, patients where we see they’re’ getting frequent infections, we can use what’s called, “IVIG,” intravenous immunoglobulin. These are pre-farmed antibodies which are injected into or infused into the patient at regular intervals before the sixth week, which reduce the chance of these infections. 

Katherine:

Thank you, Dr. Bhat, for all the information. And please continue to send in your questions to question@powerfulpatients.org, and we’ll work to get them answered on future programs. Dr. Bhat, as we close out our conversation, I’d like to get your thoughts on where we stand with CLL progress. Can patients truly thrive with CLL? 

Dr. Bhat:

So, we have made strides in CLL treatment in the past 10 years that really changed the lives of our patients. These treatments work extremely well, and the side effects are gentler than what we used to see with conventional chemotherapy. And it’ll continue to get better with ongoing research, so I will tell our patients to focus on their lives. We know that they have this disease, but we know how to control it well. So, live your life. Enjoy. Be assured that we have all the tools available for you so that you can thrive. 

Katherine:

Yeah. It seems like there’s a lot of hope in the field. Thank you so much for joining us today, Dr. Bhat. It’s been a pleasure. 

Dr. Bhat:

Thank you so much for having me. 

Katherine:

And thank you to all of our partners. To learn more about CLL and to access tools to help you become a proactive patient, visit powerfulpatients.org. I’m Katherine Banwell. Thanks for joining us today. 

What Do You Need to Know About CLL Treatment Side Effects?

What Do You Need to Know About CLL Treatment Side Effects? from Patient Empowerment Network on Vimeo.

CLL Expert Dr. Jean Koff discusses common side effects of CLL treatment and explains how they can be managed.

Dr. Jean Koff is an Assistant Professor in the Department of Hematology and Oncology at Winship Cancer Institute of Emory University. Learn more about Dr. Koff, here.

See More from Thrive CLL

Related Resources:

How Are CLL Symptoms Treated?

CLL Treatment Approaches: What Are the Types?

What is YOUR Role in Choosing a CLL Treatment Approach?

Transcript:

Katherine Banwell:

What are the common side effects of treatments, and how are they managed? 

Dr. Jean Koff:

So, each of the different classes of agents has a different profile of side effects. The BTK inhibitors, the first class that I mentioned with ibrutinib (Imbruvica) and acalabrutinib (Calquence), are usually very well tolerated. The most common side effects that we tend to see are things that the patients can feel or see, but also things that we can see on the labs when we’re monitoring patients. So, sometimes you can see a lower platelet counts or lower blood cell counts with ibrutinib. That’s something that you may not notice, but your doctor’s going to notice on the – the blood counts when you come to the office. Sometimes ibrutinib can cause a rash or GI upset, this is usually easily managed with supportive care from your physician.  

And then some more – some more common effects of the BTK inhibitors include joint pain and headache. And again, many physicians, because we’ve been using BTK inhibitors for a long time, have a good regimen for treating these side effects. More uncommon side effects of BTK inhibitors, particularly ibrutinib that we look out for would be abnormal heart rhythms and some tendency for bleeding. But these are relatively uncommon and with newer BTK inhibitors, we’re seeing lower rates of these side effects.  

Dr. Jean Koff:

So, in terms of venetoclax side effects we have a little bit of a different profile. This agent is much more likely to cause lower cell counts, especially in a white blood cell count known as neutrophil count, and so your doctor will be monitoring you for that. In terms of patient side effects that you can feel, it can cause a rash, it can cause some GI upset. These are usually relatively easily managed but we want you as the patient if you’re on venetoclax to talk to your doctor about these side effects so that they can help you feel better and help you manage those. In terms of the anti-CV20 monoclonal antibodies, which we use a couple in CLL more frequently, they have very similar side effect profiles.  

So, one is rituximab, and one is obinutuzumab. Obinutuzumab is usually used in combination with venetoclax in front-line CLL.  

Like I mentioned before, this is an infusion and most of the side effects that we think about and most commonly see in these anti-CV20s are side effects that patients have during the infusion. And these are referred to as infusion reaction. And these are relatively common, around 30 percent in these anti-CV20 monoclonal antibodies. So, what is an infusion center react – er sorry, what does an infusion reaction look like? This looks sort of like an allergic reaction. 

Katherine Banwell:

Hm. 

Dr. Jean Koff:

So, your nurses in the infusion center are going to be monitoring you very carefully once you start the infusion, and they’re going to start it at a low dose, very slowly. But the side effects they’re monitoring for, they’re looking for changes in your heart rate or blood pressure. You may start to feel hot or cold or sweaty, you may have chills. Sometimes patients can have swelling in their throat or their tongue. And what will happen is because these are fairly common, is we’re still able to give the anti-CV20, but what we do is the nurse will stop the infusion, they may give you some medications that calm down that infusion reaction. So, medications like antihistamines –  

Katherine Banwell:

Mm-hmm.  

Dr. Jean Koff:

Or steroids that help tamp down that immune response, and then they start the anti-CV20 infusion at a lower rate. The vast majority of patients will be able to receive an anti-CV20 antibody even if they have an infusion reaction. They may just need a little bit more of those immune tamping-down medications like antihistamines and steroids. And then the last thing to consider, which I think we’ve mentioned, especially in the venetoclax-containing regimens, is the tumor lysis syndrome. And so, that is a side effect like we mentioned is kind of like the venetoclax working really, really, really well, of the tumor breaking down too quickly.  

And so, patients who have tumor lysis, if they’re at high-risk, hopefully they’re already being monitored very closely with frequent lab draws, and they may receive medications that – that diminish the risk of adverse events happening because your electrolytes are out balance, for instance, your potassium is too high, or your calcium is too low. Because your doctors are monitoring you closely, they can give you medications that can help balance  out those – those electrolytes and help protect the kidneys. The tumor lysis is typically not a risk after the initial doses of venetoclax.  

So, the first couple weeks is when we typically monitor that, and then once the CLL has been broken down, or as I like to say, once it’s been cooled off a little bit, then you no longer have this risk of tumor lysis and it – it doesn’t require further monitoring. 

Katherine Banwell:

That’s great information, thank you.  

What Are the Current CLL Treatment Options?

What Are the Current CLL Treatment Options? from Patient Empowerment Network on Vimeo.

When is it time to treat CLL, and what are the current options? Dr. Jean Koff, from the Winship Cancer Institute of Emory University, reviews available CLL treatment approaches and discusses patient-specific factors that she considers when choosing therapy.

Dr. Jean Koff is an Assistant Professor in the Department of Hematology and Oncology at Winship Cancer Institute of Emory University. Learn more about Dr. Koff, here.

See More from Thrive CLL

Related Resources:

What Do You Need to Know About CLL Treatment Side Effects?

What Do You Need to Know About CLL Treatment Side Effects?

What is YOUR Role in Choosing a CLL Treatment Approach?

CLL Treatment Approaches: What Are the Types?

Transcript:

Katherine Banwell:

Many patients are overwhelmed by the different types and classes of treatment. When is it time to treat CLL, and what are the options? 

Dr. Jean Koff:

So, I boil down the criteria to when you need to treat your CLL to two main categories. One category is that the disease is progressing quickly, and the other category is the disease is causing problems of some kind, or getting ready to cause problems of some kind. Those are some of the broad categories that we think about when it’s time to start treatment for CLL. Now, this – the groups that research CLL have put out various criteria that help guide physicians about when it’s time to start treatment, and some of those more specific criteria include items like symptoms. So, symptoms are a very important part of that decision-making process.   

And the same symptoms that we mentioned, the B symptoms, fevers, chills, night sweats, weight loss that’s unintentional, or lymph nodes that you can feel, those would potentially be reasons that your doctor would want to start you on CLL therapy. But the CLL can cause issues even in a patient who’s not necessarily having symptoms. So, one of the most common ways that CLL can cause issues is the CLL cells can cause your other blood cells, the normal blood cells, to be low in number. There are several ways the CLL cells can do this. One of the most common ways is that the CLL cells, which are often circulating through your bloodstream, can also collect or overrun your bone marrow.  

And if you think about it, the bone marrow is the factory that makes all of your blood cells. So, when there are too many CLL cells in the bone marrow, they can crowd out the normal blood cells, like red blood cells or platelets. So, when red blood cells or platelets get low beneath certain thresholds, that’s a reason to start CLL therapy. 

Katherine Banwell:

Mm-hmm.   

Dr. Jean Koff:

So, there are a couple other criteria that we think about. CLL cells can collect in other areas, including the spleen. So – and if you remember, the spleen is a lymphoid organ that sits on the left side of your body that is right below the stomach. And so, if CLL cells collect in the spleen, they can cause it to be too big, it can press on the stomach, it can make it so you feel full, even if you haven’t eaten a full meal, that’s something we call early satiety. It can be uncomfortable, causing some abdominal pain. And if the spleen gets really, really big, it can cause it to not be able to do its normal job, which is to filter out the normal blood cells like it does every day. And so, that would be a reason to start therapy as well. And then the last – the last category I would think about is in CLL we have lots of – of CLL cells that are circulating in the blood that we can check with a routine blood count. And the absolute number of CLL cells is not as important as how fast that number is growing. So, your physician will track how fast that number of CLL cells is doubling.  

And if you meet criteria for what we call rapid doubling time, which is usually thought of as less than 12 months but certainly less than six months. So, if your count goes from 30,000 to 60,000 in under six months, then it may be time for you to start thinking about therapy. 

Katherine Banwell:

Right. So, Dr. Koff, would you briefly review the treatment classes? 

Dr. Jean Koff:

So, for first-line treatment, we have two main treatment classes that we think about at this time. The first is – is called BTK inhibitors, which is Bruton tyrosine kinase inhibitors. And these are oral medications, so medications that you take by mouth, and the most well-studied of these is called ibrutinib (Imbruvica), we typically prescribe ibrutinib by itself. There are other BTK inhibitors we are also now using in this space, one of them is called acalabrutinib  (Calquence), and that is often given with an IV monoclonal antibody called obinutuzumab (Gazyva).   

The other main class of drugs that we consider for first-line treatment of CLL is the BCL-2 inhibitors. Right now there’s only one BCL-2 inhibitor that’s approved for CLL and front-line and it’s called venetoclax (Venclexta). Usually, this drug is also given in the front-line with an anti-CD20 monoclonal antibody. So, the venetoclax itself is a pill you take. And the monoclonal antibody is an – either an IV or a subcutaneous injection.  

Katherine Banwell:

Where do clinical trials fit into CLL treatment? 

Dr. Jean Koff:

So, clinical trials are part of the reason, a big part of the reason that we’ve been able to make so much progress in how we treat CLL over the past few years. Clinical trials are how we figure out what treatments work for CLL, how patients feel on them, what sort of adverse events or side effects they have on individual treatments, and which treatments do better for keeping CLL symptoms under control, keeping the disease under control, and allowing patients to live longer and have a higher quality of life with their disease.   

Katherine Banwell:

Are there any other options available for CLL patients?  

Dr. Jean Koff:

So, there are other options. A clinical trial, if that is available to you as a patient is nearly always a good thing to consider if you have CLL. Because the vast majority of patients will not be cured by CL – by their treatment for CLL. Meaning that the – even though the treatments we have usually work for a very long time in most patients, ultimately the CLL will at some point, perhaps years down the road, progress and need another therapy. For that reason, we know we can do better. And we are hoping that the next  clinical trial is going to lead to the discovery of a new agent or a new combination – new  combinations of agents that will allow patients to live longer with a better quality of life with CLL.  

Katherine Banwell:

Mm-hmm. 

Dr. Jean Koff:

So, that’s always a good option to consider.