So, this is a 70-year-old female with a known diagnosis of CLL who had progression by elevated white blood cell count and also some anemia, and was also, importantly, symptomatic by her progressive splenomegaly, and therefore, was presenting for a discussion of treatment. Her important prognostic markers that were tested included a FISH showing a deletion of 17p, an

The diagnostic workup for CLL, particularly for patients who require treatment, includes prognostic markers that no longer only allow us to define how long the patient would respond to treatment or how long till they need treatment, but we&rsquo;re using these prognostic markers to determine the best course of action for CLL treatment. In this case, some of the markers that are critically important include the FISH test. FISH will test for deletion of 17p. I also, for patients starting treatment, check

mutations and deletion of 17p require a non-chemotherapy approach to the first-line treatment.

The risk status for this patient would be considered high to very high because she was found to have a deletion of 17p prior to any therapy.

This patient does require therapy by iwCLL treatment indications for a few reasons. First, she&rsquo;s symptomatic by her splenomegaly. That is, she&rsquo;s having left upper quadrant pains and has an enlarged spleen. The second reason that she would require treatment is that her anemia was reported as progressive. And now, 10 g/dl is less than the threshold where we consider requiring treatment.

There are many factors that I consider for each patient that requires treatment of their disease. Some of them are the patient&rsquo;s age and other organ functions. Especially with chemotherapy, the creatinine and their kidney function is critically important. The other factors that you consider is just how the patient&rsquo;s overall health status is. The average age, or the median age, of CLL diagnosis is around 72. So, many of these patients are older and do have other medical conditions that have to be taken into account.

Even with those factors considered, there are other key factors about the CLL that we take into account, and that&rsquo;s why it&rsquo;s important that these markers are checked ahead of time. The very key ones are the presence of the

dysregulation or dysfunction, and that can occur either through deletion of 17p or mutation of the

gene, and that is why it&rsquo;s critical to test those 2 factors.

Patients who have those really should be considered for nonstandard chemoimmunotherapy approaches. And that is because there&rsquo;s a lot of evidence that deletion of 17p or

mutation, those patients not only will not have a great response to chemotherapy, they also don&rsquo;t have a long duration of response. And finally, there&rsquo;s evidence that those patients are more prone to clonal evolution or change of their disease when the chemotherapy is given.

Diagnostic Workup and Risk Status for CLL

17p deletions in patients who have not been treated are not very common. About less than 10% of patients at the time of their diagnosis or at the time of their first treatment will have a 17p deletion detected. However, we know from multiple studies that this incidence increases by line of therapy. That is, for patients who have had treatment before and especially for patients who are refractory to chemotherapy, especially fludarabine. And the incidence of finding 17p deletion or

mutations goes up substantially to almost 40% or 50% of patients. Again, that&rsquo;s why it&rsquo;s important not only to be thinking about testing for FISH at first diagnosis, but also for patients who have relapsed disease. If they didn&rsquo;t have the deletion at the start of first treatment, check for it when they relapsed because it might change your focus in how recommend management for the patient.

Deletion of 17p, historically, has been the strongest prognostic marker because patients had a shorter time to treatment, a shorter time to first treatment, a shorter duration of response to therapy, and, historically, also a shortened overall survival. The reason I mention &ldquo;historically&rdquo; is a lot of the studies that looked at progression-free survival and overall survival were in the era of chemoimmunotherapy. Now, in the era of some of the novel targeted drugs such as ibrutinib or venetoclax, we&rsquo;re seeing a substantial improvement to patient&rsquo;s duration of response to their first treatment, as well as their survival.

mutation status is a very important prognostic marker for patients with CLL. In the frontline setting, or prior to patients receiving first-line treatment, which is considered the higher risk situation, about half the patients have a mutated

predicts that patients are much more likely to require treatments, have a shorter time to that first treatment, and have a shorter response to therapy no matter the response they achieve to that frontline chemotherapy. That is even for patients who achieve a complete response at the end of their chemotherapy. If they have an unmutated

, they have a shorter duration of response to that treatment.

Though I mentioned that about half the patients at diagnosis or before first treatment have unmutated

and half have mutated, this actually varies by the FISH status. That is, for patients with the higher-risk deletion, or the high-risk deletion 17p, many of those patients, the overwhelming majority, are expected to have an unmutated

. These prognostic markers tend to group together.

mutations, we don&rsquo;t recommend chemotherapy-based regimens. And, again, the reason for that is we expect attenuated response and a shortened response to that type of drug. And there&rsquo;s also concern that exposure to chemotherapy for patients with

dysfunction could lead to clonal evolution. Therefore, our frontline treatment options for patients with deletion of 17p really focus on the non-chemotherapy approaches. That involves currently now-approved ibrutinib frontline or other approaches such as high-dosed steroids and rituximab. So, combining the immunotherapy but avoiding chemotherapy.

This patient was enrolled on a clinical trial and treated with ibrutinib 420 mg daily, which is the standard starting dose for a CLL patient. The rationale for using ibrutinib is that it works by mechanisms independent of having an intact

function. That is, for patients with deletion 17p or

mutations, we&rsquo;re concerned that standard chemotherapy when achieved the responses we want or the duration of response. Therefore, the rationale for choosing ibrutinib is that, especially for older patients, we know that in the first-line treatment, frontline treatment, it&rsquo;s generally well tolerated, and it achieves particularly good responses in areas of bulky disease, such as the lymph nodes or spleen, which was her primary area where she was having symptoms.

CLL Prognosis and Treatment Options

So, this patient who was started on frontline ibrutinib as part of a clinical trial initially did very well. She had response in her symptoms. The left upper quadrant pain went away, her palpable spleen went away, and by about 18 months on therapy she achieved complete response by exam and was feeling well.

However, she had developed atrial fibrillation as a complication associated with the ibrutinib, and despite multiple interventions and working with the cardiologist, she was unable to continue on the ibrutinib. And then by the spring of 2017, she had to stop the treatment. Though she did OK for a couple months, pretty quickly and expectedly she progressed again both in her possible splenomegaly and symptoms, as well as her cytopenias. And at that point, she returned to discuss next lines of treatment.

At that time in discussing her treatment options and, importantly, considering that she had the deletion of 17p, we repeated her organ function and with a normal creatinine elected to start the patient on venetoclax-based therapy.

When patients with CLL who are treated with frontline therapy and then relapse, in general, I recommend repeating the FISH panel. And the reason for this is for patients who don&rsquo;t have 17p at the time of diagnosis, often we can see that change when they present with relapsed disease. I also recommend checking a full panel of chromosomes or karyotype, as we&rsquo;re increasingly recognizing the patients who have complex karyotype overall and have a lower duration of response to some of the targeted therapies. However, we know this patient had a deletion of 17p on their FISH panel. I would still recommend repeating and checking for a complex karyotype. At this time, we don&rsquo;t have a full understanding of the other prognostic markers that may be important in understanding the duration of response to venetoclax.

Considering Additional Molecular Testing for CLL

When considering second-line therapy for patients, I take into account multiple factors: the patient&rsquo;s age and their functional status, their end organ function, what their goals of therapy are, and what their profile of prognostic markers looks like. Again, for patients who haven&rsquo;t had

dysfunction found in either deletion 17p or

mutation, testing for this is critically important as that will take you down a different route of considering options.

However, in general, in the second-line setting, patients who had chemotherapy as a first treatment are likely to have a much shorter duration of response if chemotherapy is used in the second-line setting. And this is increasingly why we&rsquo;re using the novel targeted agents in the second-line setting over repeating chemotherapy, unless patients have a specific reason for the chemotherapy again or if they had a longer duration of response to chemoimmunotherapy as a first treatment.

For this patient who has a known deletion 17pbecause she&rsquo;s overall functional, wants a goal of treatment to keep her in a good quality of life for as long as possible, and she has sufficient organ function&mdash;I consider treatments that I think are going to get her the best response and the best duration of response. For her, ibrutinib was not tolerated and she progressed very quickly. Because she had a high burden of disease in the bone marrow as well, I considered venetoclax, as this is approved for patients with relapsed refractory CLL with the deletion of 17p in order to achieve a deep response, such as a complete response that hopefully will last her for many years.

BCL-2 has long been recognized as an important antiapoptotic protein. That is, it pushes cells away from the normal process of programmed cell death. When you target BCL-2, you take away that antiapoptosis and restore the normal process of cell death. Therefore, when venetoclax targets this protein, which is especially important in keeping the CLL cells in the antiapoptotic side, you push them more to the state of cell death.

Venetoclax has been studied in several phase I, II clinical trials for patients with previously treated or relapsed refractory CLL. In one of those studies, venetoclax was additionally combined with rituximab, and for those 49 patients, over half the patients achieved a deep complete response to their therapy, which was especially impressive given many of them had had several lines of prior treatment.

Choosing Treatment for Relapsed CLL

The key toxicities when considering venetoclax therapy are primarily focused on TLS, or tumor lysis syndrome, management. That is, when you target BCL-2 and take away that antiapoptosis, there can be a lot of cell turnover and death, particularly if patients have bulkier disease. Bulkier disease is defined not only in the size of the lymph node, but also in the presence of high white blood cell count for CLL patients. Therefore, when you consider this as the most important toxicity to consider when you&rsquo;re treating patients with venetoclax, it helps to understand why the dosing strategies through the clinical trials have been established.

All patients who initiate venetoclax are recommended to start in the dose ramp-up phase over the period of 5 weeks to achieve the targeted daily dose, which for CLL is 400 mg. Therefore, all patients will start at 20 mg and each week progress through the recommended ramp-up phase.

Whether patients are starting their venetoclax in the outpatient or clinic setting, versus whether they start in a monitoring inpatient hospital setting, really depends on their burden of disease. For patients with moderate or high burden of disease, these are the patients with increasing size of their lymph nodes or white blood cell count that is approaching over 25. It&rsquo;s recommended that these patients be admitted for tumor lysis monitoring. That is, patients start on allopurinol or another medication to lower their uric acids. They&rsquo;re given IV fluids and cardiac monitoring prior and subsequent to their first dose. Patients who do well during their initial phases can then move to the outpatient setting where labs are checked prior to the dose ramp up, 6 to 8 hours after the dose ramp up, and the following morning. Again, you&rsquo;re checking the tumor lysis labs to ensure that patients are not having any change in their electrolytes, their renal function, or any other markers of tumor lysis that would require active intervention and be prone to intervention.

The dosing guidelines and labeling for venetoclax outline what is considered a low, an intermediate or moderate, or a high tumor burden. And these are great guidelines to use when assessing a patient to consider whether they can start their treatment inpatient or outpatient. They&rsquo;re also very helpful in understanding, even if the first dose escalations are required inpatient, patients who do well who can then move their third, fourth, or fifth week escalation to the outpatient setting.

The portion of this that I would point out is just that these are rough guidelines to consider. And any patient who has additional factors, such as lower renal function or are coming directly from another targeted inhibitor where the risk of switching directly from one therapy to the next is high, you may consider this patient for an inpatient evaluation and monitoring while they&rsquo;re treated, even if they currently fall at a lower tumor burden.

The second factor to consider in terms of toxicity management for venetoclax is, even for patients without tumor lysis, some patients can develop cytopenias, and this does appear in multiple studies to be a true treatment of fact. The most common of this is neutropenia. And while patients can be managed through this period, it&rsquo;s important to recognize that this may develop and to manage patients accordingly.

Managing Venetoclax for CLL

For patients who may have considered to start on venetoclax therapy for treatment of their relapsed refractory CLL with deletion of 17p, I do consider adding rituximab to that regimen once they have reached the targeted dose. That is, rituximab is added after they reach the 400 mg of venetoclax. And it&rsquo;s generally given monthly by the CLL rituximab dosing for up to 6 months. The only exception to this, of course, would be if patients have a specific contraindication to receiving rituximab therapy. This recommendation is based on a phase IIb study where patients with venetoclax were started on rituximab, and it was felt that this was at least additive to their responses and, hopefully, their duration of response as well.

Out of that phase I, IIb study, there was a metaanalysis of several different venetoclax trials that looked at with and without rituximab, and rituximab was felt to provide a benefit without significantly added toxicity. Again, however, I&rsquo;ll highlight that the rituximab is only added in after patients reach the full dose of the venetoclax.

The consideration to add rituximab to venetoclax, which is listed in the NCCN guidelines as well, was largely based on phase I or phase II studies of adding this regimen. The MURANO study, which will be presented this year at ASH, is the first phase III study of using venetoclax in previously treated patients with CLL. In the MURANO study, patients were randomized between venetoclax and rituximab versus bendamustine and rituximab when they require treatment for their CLL. They were stratified by deletion 17p status and response to prior therapy as well as geographic region. Patients could have had prior bendamustine to be entered into the study. However, the duration of response to the bendamustine was required to be greater than 24 months. And the primary endpoint was to look at investigator-assessed PFS, or progression-free survival, after the treatments that the patient was randomized to.

Almost 400 patients were treated on the MURANO studyso about 200 patients in each arm&mdash;and they were fairly well balanced between the groups in terms of age, prior treatment, and response to prior treatment, as well as deletion 17p status, about one-quarter in each arm. At a median follow up of 24 months, there was a significant difference in the investigator-assessed progression-free survival of venetoclax/rituximab versus bendamustine/rituximab. It was a median not reached of response for the venetoclax/rituximab, compared to about 17 months&rsquo; progression-free survival for the bendamustine/rituximab arm.

The safety profile of both regimens was, as we expected, there was a higher incidence of grade 3-4 neutropenia in the venetoclax rituximab arm. However, importantly, this was not associated with an increase in febrile neutropenia or other adverse events.

In this first primary analysis of MURANO, there was a significant improvement in the progression-free survival of the venetoclax/rituximab arm. Importantly, there are also seen improvements in some of the secondary endpoints looking at the depth of response, such as complete response, and on peripheral blood minimal residual disease, or MRD status, which is increasingly being recognized as an important potential target in CLL treatment.

CLL: Clinical Data for Rituximab/Venetoclax

In addition to participation in the clinical trial of venetoclax and rituximab, since venetoclax has been approved, I&rsquo;ve not used the regimen of venetoclax plus rituximab in several previously treated high-risk patients with deletion 17p. My reason for selection of the venetoclax, again, is based on what the patients had prior, and under the current approval, these are the very high-risk patients who have deletion of 17p.

The reason I add rituximab for these patients is that, again, based on some of the earlier studies and then an analysis of venetoclax/rituximab versus venetoclax alone, there at least seems to be an additive benefit in the response and duration of response to therapy when you&rsquo;re adding in the rituximab. This is particularly true in my experience for patients who have had a long interval since they&rsquo;ve had rituximab, or if patients, such as the patient in this case, actually have never had exposure to an anti-CD20 antibody. Anti-CD20 antibodies such as rituximab have historically been very key to the treatment of CLL and, therefore, I think it can benefit patients, again, if they have not had it for a period of time or if they&rsquo;ve, in this case, never had the treatment.

As I highlighted before, the way that the rituximab is given with venetoclax needs to be after the patient reaches the full dose of venetoclax. Again, this is primarily out of a concern for safety in that you want to make sure patients are tolerating the venetoclax alone, both from a tumor lysis standpoint and a cytopenia standpoint, before you are adding in the rituximab.

Overall, however, once patients added this in, they generally do well. We&rsquo;re looking for the results of some of the larger studies to know if this does seem to increase some of the other toxicities, such as neutropenia. However, I would highlight in studies thus far, the neutropenia being of higher incidence does not necessarily translate into higher risk of febrile neutropenia or higher risks of other adverse outcomes from their cytopenias. Most patients can be managed through this time period with no expectations of this to happen and can receive growth factor, other standard of care approaches.

The one last thing that I also always counsel patients about, as well as discuss with the other oncologists that I may be collaborating with in care for the patient, is that it&rsquo;s always best to err or the side of safety. Again, the dosing guidelines are a nice guideline to help us assess whether a patient is low-, moderate-, or high-risk based on their tumor burden for either the start of therapy or the addition of any rituximab later. However, you know the patient best sitting in front of you, and if they&rsquo;re a higher risk because of perhaps borderline kidney function or they&rsquo;re coming directly from another prior therapy with a more rapidly progressing disease, then it&rsquo;s better to be conservative and manage the patient more aggressively for tumor lysis so that the patient can both be safely treated as well as long-term benefit from the response of the treatment.