Can you reflect on the implications of rapid development in the chronic lymphocytic leukemia (CLL) treatment landscape?

The treatment landscape for patients with CLL has changed dramatically with the advent of targeted therapies. Drugs such as ibrutinib, which targets the enzyme Bruton tyrosine kinase (BTK), or venetoclax, which targets the survival protein BCL2, have demonstrated therapeutic activity in patients who had failed treatment with chemotherapy. Over the last few years, we have seen head-to-head clinical trials that challenge the notion that traditional therapy, such as chemotherapy, or chemotherapy with an anti-CD20 antibody (chemoimmunotherapy), is superior to targeted therapies, showing instead that targeted therapies may be better tolerated and more effective. Indeed, targeted therapies have ushered in a paradigm shift in how we treat our patients.

The benefit of targeted therapies is most evident in those patients who have prognostic features indicating they may fare poorly with chemoimmunotherapy. We have learned that patients who have CLL cells with del(17p) or mutations in the gene TP53, which encodes P53, typically are resistant to chemotherapy, which can cause highly problematic suppression of marrow function, particularly in such patients. Also, patients with leukemia cells that express unmutated immunoglobulin variable region genes (IGHV genes) typically do not enjoy a particularly long progression-free survival [PFS] after chemoimmunotherapy, even if they had an apparently successful clinical response at the end of treatment. On the other hand, some patients with CLL cells that use mutated IGHV can experience long-term remissions following chemoimmunotherapy lasting more than a decade. These findings encouraged development of treatment algorithms that initially recommended targeted therapies only for patients with leukemia cells that use unmutated IGHV and/or that have del(17p) or mutations in TP53.

However, recent head-to-head clinical trials of chemoimmunotherapy versus targeted therapies are challenging this view, even for patients who have CLL cells with good-risk features. For example, patients randomized to receive treatment with drugs such as ibrutinib experienced longer PFS and/or fewer adverse events than patients randomized to receive chemotherapy or chemoimmunotherapy regimens, such as chlorambucil or bendamustine and rituximab. Furthermore, patients with relapsed disease who were randomized to receive treatment with venetoclax and rituximab, fared better than patients randomized to receive treatment with bendamustine and rituximab. Also, recent phase III studies involving patients over age 65 who have medical comorbidities showed that initial therapy with venetoclax and obinutuzumab provided more effective treatment than chlorambucil and obinutuzumab. Finally, an Eastern cooperative group study for younger patients in need of therapy demonstrated a superior outcome for patients treated with ibrutinib and obinutuzumab than those treated with fludarabine, cyclophosphamide, and obinutuzumab. This improved out-come also appeared evident for patients with leukemia cells that use mutated IGHV and/or do not have del(17p) or TP53 mutations. The results of these studies have challenged the notion that targeted therapy should be considered only for a subset of patients with adverse prognostic features.

What are some of the more significant challenges with the growth of the treatment armamentarium, particularly when it comes to the use of targeted monotherapies and combination regimens?

Success with targeted therapies unfortunately has [led to] new challenges. One challenge is the need for continuous therapy with some of these targeted therapies. Long-term therapy with ibrutinib can be well tolerated but is not able to cure the disease or even induce a complete response [CR] in most patients. Even after a year of therapy, only about 5% of patients will achieve a CR. Such a low CR would be considered unsatisfactory for chemoimmunotherapy regimens, which generally are of a fixed duration. However, fixed-duration therapy with targeted drugs, such as ibrutinib, generally is not recommended, as the discontinuation of therapy can result in a disease flare associated with marked increases in lymphadenopathy and/or recurrence of disease-related cytopenias, particularly if the therapy is discontinued within the first year of therapy. However, continuous therapy raises issues regarding the cost of treatment, possible complications of long-term therapy, and patient preferences. Moreover, chronic therapy with drugs such as ibrutinib can increase the risk for hypertension or atrial fibrillation. Although the risk for atrial fibrillation fortunately is very low, it is nevertheless a complication that we have to be aware of and manage appropriately. The problems associated with chronic therapy have resulted in a push to develop treatments with combinations of targeted drugs that result in higher CR rates and that possibly allow for fixed-durations of treatment.

Venetoclax has factored in development of fixed-duration therapy. Venetoclax inhibits BCL2, which protects the cell from undergoing cell death. It is quite effective, so much so, that patients may develop severe, and potentially lifethreatening tumor lysis syndrome [TLS] when they initiate therapy. This is apparent for patients who have large tumor burdens; the lysis of many tumor cells all at once can result in a marked increase in the plasma potassium level, which, if too high, can cause cardiac arrest. This complication of therapy needs to be avoided at all costs.

One strategy that has been successful in mitigating the complications of TLS is to identify patients prior to therapy who are at risk for developing severe TLS. The relative risk of TLS relates to the amount of tumor the patients have prior to treatment. Patients with bulky (large) lymph nodes and/or high leukemia-cell counts are at highest risk for TLS. Also, patients with impaired renal function may be more susceptible to the hazards of TLS even when their tumor burden is relatively modest. On the other hand, patients with leukemia cell counts less than 25,000 and lymph nodes less 5 cm in diameter may be considered at low risk for severe TLS; such patients may be initiated on therapy as an outpatient provided there is close monitoring of the patient&rsquo;s renal status and electrolytes before during and after initiation of therapy. Patients at intermediate and high risk may require hospitalization with close monitoring. Regardless of a patient&rsquo;s risk for TLS, the current strategy is to ramp up therapy in stages, starting at a low dose of 20 mg per day of venetoclax, and then increasing the dose each week over a 5-week period to the final dose of 400 mg per day, monitoring the renal status and electrolytes with each weekly ramp up.

Strategies are in development to reduce the amount of tumor burden prior to the initiation of venetoclax. In particular, monoclonal antibodies, such as rituximab or obinutuzumab, have been tested in combination with venetoclax. Such studies have shown that such anti-CD20 antibodies can improve the CR rate to venetoclax. If the antibodies are given prior to the institution of venetoclax, the patient&rsquo;s risk for TLS actually can be lowered, providing for easier initiation of venetoclax therapy.

This strategy was used in a large international phase III study that compared the response to treatment with obinutuzumab and venetoclax versus obinutuzumab and chlorambucil in patients over age 65 and who had medical comorbidities that precluded them from being candidates for more aggressive forms of chemoimmunotherapy. The duration of therapy for patients in this trial was 1 year. Patients in either arm received obinutuzumab for 6 months and then received either chlorambucil or venetoclax for 12 months. Therapy with obinutuzumab plus venetoclax was very well tolerated and produced very high rates of clinical response (both complete and partial) that were significantly higher than the rates observed for patients treated with obinutuzumab and chlorambucil. Moreover, patients treated with obinutuzumab and venetoclax also experienced high rates of clearance of detectable minimal residual disease (MRD), which prior studies noted was associated with a particularly long PFS after therapy. Based on these data, the FDA has allowed for treatment of patients with this combination as a frontline regimen.

Can you address combination regimens based on ibrutinib?

Ibrutinib has been used in combination with anti-CD20 antibodies, such as rituximab, with the goal of improving the response to therapy. Although patients treated with such combinations may have less lymphocytosis after initiation of ibrutinib therapy, such combinations have not been found to allow most patients to come off therapy.

A very notable study by the ALLIANCE group was presented at ASH 2018 and published in the

. In this study, [investigators] compared treatment outcomes of patients over age 65 who were randomly assigned therapy with either bendamustine and rituximab, ibrutinib and rituximab, or ibrutinib alone. It was apparent from this study that patients treated with ibrutinib, or ibru- tinib and rituximab, fared very well compared with patients treated with bendamustine and rituximab. However, the PFS of patients treated with ibrutinib and rituximab was identical to that of patients treated with rituximab alone. This finding has challenged the assumption that more is invariably better; in my opinion, the data do not yet show a benefit to using anti-CD20 antibodies in combination with ibrutinib.

What do you anticipate for the future of combination regimens in the treatment of CLL? What concerns do you have about the current treatment approaches and directions in research?

Quite frankly, I&rsquo;m alarmed by some of the combinations that I see being tested. Oncologists have a way of combining agents with one another based solely on whether or not the drugs used in a combination regimen have different toxicities. The idea behind this approach is that we can combine such drugs together and eke out a higher therapeutic index with the drug combination.

A better approach, in my opinion, is to develop combinations that target distinctive tumor-survival or tumor-growth-promoting pathways. Such combinations may have a higher chance of having synergistic clinical activity. In the case of developing combination therapy with drugs such as ibrutinib, we need to ask the question of why patients are not achieving CRs in response to single-agent ibrutinib. In other words, what keeps the leukemia cells alive in the setting of ibrutinib therapy?

This also applies for drugs such as venetoclax. We now know that not all patients will clear MRD with venetoclax therapy, even when used in combination with anti-CD20 antibodies and/or drugs such as ibrutinib. We need to think about combinations with venetoclax [that may] lead to eradication of the leukemia even in patients who fail to clear MRD. This does not appear likely through the addition of standard chemotherapy to therapy with venetoclax, as venetoclax in one sense mimics the mechanism used by chemoimmunotherapy to kill the tumor cell. Indeed, the capacity of most chemotherapy drugs to kill leukemia cells revolves around their ability to induce expression of P53, which in turn induces pro-apoptotic molecules of the BCL2 family, such as PUMA or NOXA, which in turn active like venetoclax to inhibit BCL2. Because the mechanisms for killing cells of venetoclax or chemotherapy revolves around the inhibition of BCL2, it seems less likely that chemotherapy in combination with venetoclax will be synergistic. The possibility for achieving synergy is increased if we know we&rsquo;re targeting distinctive pathways.

There is a combination of ibrutinib with venetoclax that is also worth discussing. This combination does seem to be better tolerated than I thought it would be, given the fact that both ibrutinib and venetoclax are metabolized via the same pathway. Moreover, we know that using both drugs together increases the plasma concentrations of each. This may account for the higher rates of neutropenia observed in patients treated with this combination. However, I am not sure whether we are achieving a much better response to therapy than with treatment with venetoclax and antiCD20 antibodies, as the same percentages of patients who fail to clear MRD appear similar for either combination. I am hopeful we can devise combinations that truly take into consideration the biology of the leukemia and how this biology is distinctive from that of normal cells. Such combi- nations may be more effective and potentially curative for a large proportion of patients.

What is your advice to clinicians who have the ability to incorporate various combination approaches?

A major message is borrowed from history, namely &ldquo;doctor, do no harm.&rdquo; It is important to recognize that there is perhaps no therapy that lacks potential for causing adverse effects. We need to be aware that there are patients with CLL who have indolent disease that is asymptomatic and does not appear to shorten their life expectancy, particularly for patients of advanced age and/or who have other major medical comorbidities. Subjecting such patients to therapy would not have a low risk-benefit ratio, no matter how safe the therapy. We also do not know whether patients with indolent disease that ultimately will require therapy will benefit from early intervention prior to when they develop disease-related complications, symptoms, or clear evidence for more-rapid disease progression. This also applies for patients who have disease features associated with a high-risk for early disease progression, such as leukemia-cells that use unmutated IGHV. Certainly, studies are in progress to determine whether we can improve the long-term outcome of such patients through early intervention. Until we know the outcome of such studies, it prudent to withhold even targeted therapies from patients who lack disease-related complications or symptomatic disease, as per the guidelines of the international workshop on CLL [iwCLL].

For patients requiring therapy as per iwCLL guidelines, the first things to consider are the associated risks and costs of therapy and how therapy may complicate other medical comorbidities. Of course, we should not attempt to eradicate CLL at the cost of the patient&rsquo;s life. Furthermore, when using any drug, it&rsquo;s important to know what to look for in terms of potential toxicities or complications so that you can take steps to mitigate the risk of complications and/or identify therapy-related adverse events as they occur. For example, drugs such ibrutinib cause impairment in platelet function, enhancing the risk for bleeding, especially when the platelet counts are subnormal. Patients should be cautioned to hold therapy with ibrutinib prior to elective surgery for a few days, as they would be advised to stop drugs such as aspirin. However, therapy should not be held for periods longer than 1 to 2 weeks, as this risks having the patient experience a flair in disease progression. For patients who require systemic anti-coagulation, then extra caution should be exercised when deciding whether to initiate therapy with drugs such as ibrutinib.

As you reflect on the CLL treatment spectrum and the explosion of targeted therapies, what are some of most prevalent questions that need to be answered? What do you think should be emphasized on the research front?

What&rsquo;s very important to understand is not just the issues that have given us success, but also to study the challenges that define our current treatment failures. Why do patients fail to obtain a CR with ibrutinib therapy even after protracted therapy duration? Why do patients fail to clear the disease with venetoclax even in combination with ibrutinib or rituximab or obinutuzumab? Until we figure these things out, we will be left with situations in which we won&rsquo;t have therapies that will be successful in all patients. [Moreover], we will have patients who may do well for a time, but then come back with recurrent relapsed disease that might prove refractory even to the targeted therapies of today.

We should continue research aimed at discovering the answers to these questions and continue our development of therapies that can complement today&rsquo;s targeted therapies. Indeed, patients are living longer with these improved treatments. As the prevalence of patients with CLL increases so will the challenges increase for defining improvements in therapy. Such improvements will come through continued research on the biology this disease, addressing what accounts for the resistance to today&rsquo;s targeted therapies.

Articles

Clinical Articles

Thomas Kipps, MD, PhD, discusses the&nbsp;chronic lymphocytic leukemia treatment spectrum and the explosion of targeted therapies in the field.&nbsp;

Navigating the CLL Treatment Field With Caution Q&A With Thomas Kipps, MD, PhD

Given the rapid developments in the chronic lymphocytic leukemia (CLL) treatment landscape, can you reflect on what you feel were the most important and significant therapeutic trends from the past year?

There have been 2 major inflection points in the field over the last year, and one of them is the data that came out initially at the ASH [American Society of Hematology] annual meeting last yearand were subsequently published in the New England Journal of Medicine

examining ibrutinib compared to current standards of care in younger and older patients. The whole field pivoted after ASH and subsequent publication of data toward more use of ibrutinib. The NCCN [National Comprehensive Cancer Network] guidelines were updated accordingly, and for a period of time, ibrutinib was the only novel agent-based approach recommended for all types of patients, all risk factors, etc.

That period was relatively short lived, as the second major inflection point in the past year was the FDA approval of venetoclax plus obinutuzumab. The combination was approved in May,

and at the ASCO [American Society of Clinical Oncology] meeting in June, we saw the data for the first time publicly. I moderated that session at ASCO and gave a discussion on the abstract to try to put it in context. In my opinion, this new regimen, venetoclax/obinutuzumab, is, in some ways, the best of both worlds: Like ibrutinib, it&rsquo;s a novel agent-based approach, so you don&rsquo;t have to deal with the adverse effects of chemoimmunotherapy. But like chemoimmunotherapy, venetoclax/obinutuzumab is designed as a time-limited treatment.

The data look strong for venetoclax/obinutuzumab so far: It was designed as a 1-year-long therapy, and about 1 year after patients completed therapy, 88% were still in remission. Although these data suggest that this is likely to be a durable benefit, I do caution that the follow-up was short, and it will be important to follow up on what happens in the next year. If a lot of patients begin to progress, the feasibility of a time-limited regimen becomes harder to justify. But what we&rsquo;re seeing so far looks good, and the adverse effect profile is also manageable.

Compared with ibrutinib, venetoclax/obinutuzumab is certainly a more challenging regimen to start from a logistics perspective. First, you have to deal with the infusion component of obinutuzumab and the risk of infusion reactions. Then, the venetoclax dose ramp-up begins and takes 5 weeks, with laboratory monitoring for tumor lysis syndrome [TLS] required a couple of days each week. Therefore, you need to invest some time and energy up front to get patients started on this regimen. In comparison, ibrutinib is pretty easy to start; the monitoring is much less, but on the flip side, there is the need for long-term continuous therapy. I think there are some potential real advantages for a time-limited regimen. Since its approval, venetoclax/obinutuzumab has made its way into the NCCN guidelines, and it is certainly a good thing for patients to have different options to choose from.

What are the benefits of the combination approach of venetoclax/obinutuzumab?

One of the elements about the CLL144 study that led to the approval venetoclax/obinutuzumab, [was] that [the] patient population was restricted [to only] those with significant medical comorbidities (CIRS [Cumulative Illness Rating Scale] score greater than 6), so the patients on in the study were generally older patients, along with some younger patients with significant medical issues. One question that arises is how applicable the data from CLL14 are outside of this comorbid population. In my practice, I get a lot of questions from younger patients who are fit regarding their candidacy for venetoclax/obinutuzumab. They like the idea of the time-limited therapy, and they think that&rsquo;s really appealing, rather than the idea of being on long-term ibrutinib. Personally, I have been comfortable applying the data from the CLL14 study for my younger patients, and I have started some on venetoclax/obinutuzumab. But if you&rsquo;re a true data purest, then you would say there should be some more data for that young, fit population before using the regimen more widely in such patients. This is similar to where we were with ibrutinib a couple of years ago, when we only had phase III data with chlorambucil as a comparator. In that situation, oncologists were also fairly comfortable using ibrutinib in younger patients.

Can you discuss the factors you consider when you are talking with a patient and potentially suggesting a combination regimen like venetoclax/obinutuzumab?

Specific to the venetoclax/obinutuzumab combina- tion, one thing I think about is that starting obinutuzumab in a patient with a high disease burden can sometimes be challenging, because it&rsquo;s common for patients to get infusion reactions. We see [that] about 20% to 30% of patients have some kind of infusion reaction, so it is important to prepare patients for that possibility. Then, having some expertise on the nursing end, to be able to know when to stop the infusion and how to adjust the rate, and so forth.

One of the interesting things is that in the CLL14 study, there were 3 cases of tumor lysis syndrome, all of which occurred after the obinutuzumab, so before the patients even received venetoclax, and that was kind of something that wasn&rsquo;t on our radar as much with that drug. Fortunately, these were laboratory changes only; they weren&rsquo;t actually cases of clinical TLS. But I think it is important for oncologists to be aware that patients with a large disease burden [who are] starting obinutuzumab are at risk.

Interestingly, because the obinutuzumab was so effective in cytoreducing the patients in the CLL14 study, the tumor bulk was a lot lower when patients started the venetoclax. Thus, their risk was generally lower for TLS than we saw in previous studies, where venetoclax was given as monotherapy. But patients do still need to be monitored closely. There&rsquo;s always the option with venetoclax to admit patients to the hospital, so in some practices, that&rsquo;s a necessary step to be able to do the necessary tumor-lysis monitoring. Even if you&rsquo;re doing the monitoring in the outpatient setting, it does require some back and forth on the part of the patient to ensure they can safely start the drug.

With ibrutinib, starting is much simpler. Patients can begin taking the drug at home, and then we may bring them back a week or two later to check their labs and see how they are tolerating it. If things are going well, we see them a month or so later, and then every 3 months after that, so it&rsquo;s a fairly convenient schedule. When I&rsquo;m meeting with a patient and going through the pros and cons of both regimens, I spend a lot more time on ibrutinib talking about all of the different adverse effects and a lot less time talking about the logistics; whereas with venetoclax/obinutuzumab, I spend more time talking about logistics and not as much time talking about adverse effects, because there are not as many to describe.

With added interest in combinations like venetoclax/obinutuzumab, what is the value of a monotherapy in the treatment of CLL, particularly with ibrutinib?

I think that monotherapy for novel agents will continue to play an important role in CLL going forward, because it can be a convenient and effective option for many patientsfor example, if I have an older patient who finds it hard to get back and forth to the center, or has trouble tolerating IV [intravenous] fluids. There are a number of scenarios like this in which putting someone on a single novel agent is simple and straightforward, and they can do well for many years, especially if they&rsquo;re tolerating it well. Patients can do very well long term on ibrutinib, and some of the recently published long-term ibrutinib data reinforce that.

When it comes to weighing risks and benefits, what factors do you consider? To what extent does the duration of investigation matter?

One of the most important aspects to consider is efficacy, and particularly durability of response. What happens for a patient who has received 1 year of venetoclax/obinutuzumab, goes off therapy for a period of time, and then relapses? What happens when we then treat them again with venetoclax? Do they go back into remission or not? Increasingly, a variable we&rsquo;re going to be looking at is actually time to next class of drug. For example, someone might get venetoclax/obinutuzumab for a year, go into remission for 2 years, get venetoclax/obinutuzumab again for a year, go into remission for a year, and get venetoclax/obinutuzumab again, and [go into] remission for 6 months. That patient may eventually move on to ibrutinib, but they benefitted for 4 or 5 years from the venetoclax/obinutuzumab regimen used intermittently. If, on the other hand, patients receiving venetoclax/obinutuzumab relapse, and they don&rsquo;t respond well to the same regimen a year or two later, that&rsquo;s a little more troublesome, and that is going to limit the benefits [of] time-limited therapies.

Sometimes patients are hesitant to stop a therapy, knowing that their CLL probably is not cured. But one of the things we&rsquo;ve noticed emerging with novel agent mono- therapy is resistance. From a scientific perspective, there&rsquo;s a hope that by giving time-limited combination approaches, rather than continuous novel agent monotherapy, we might be able to reduce the development of resistance. Finally, even if you&rsquo;re giving a couple of drugswhich could be more expensive in the short term&mdash;if you&rsquo;re doing it over a shorter period of time, it might actually be less expensive for the healthcare system compared [with] many years of continuous novel agent therapy.

Could you talk about the ibrutinib plus venetoclax combination that is under investigation? Specifically, what might a combination like this offer patients, and how could it impact the overall treatment spectrum?

In the laboratory setting, we and others found this combination had great potential to be synergistic, and now we&rsquo;re seeing this play out in CLL clinical trials. Based on findings from the CLARITY trial and the MD Anderson [Cancer Center] study recently published in the Journal of Clinical Oncology and New England Journal of Medicine,

respectively, we are seeing unprecedented survival curves, with almost no progression so far, with a couple years of follow-up. We will see over time how things play out with longer follow-up, but certainly the initial results look very promising.

It&rsquo;s obviously expensive to put these 2 drugs together, so having a minimal residual disease (MRD)guided, time-limited approach is going to be important. We now have several effective regimens in CLL, so one question is going to be where this one fits in with the others. I think that for the highest-risk patientsthose with TP53 aberrancy, like 17p deletion, for example&mdash;that is a group where using the 2 drugs at the same time might make the most sense, because we know that such patients less commonly have a durable response to ibrutinib or venetoclax when given as monotherapy.

Could you offer your thoughts on how acalabrutinib, which was recently granted fast-track designation by the FDA, might fit into the treatment market?

If we are giving continuous therapies, we need to be mindful of toxicities, because patients will be on these drugs for many years. The early trial data for acalabrutinib, along with my own anecdotal clinical experience with some patients I have treated outside of a clinical trial setting with acalabrutinib, show that this drug is generally well tolerated. We&rsquo;ve seen somewhat lower rates of significant adverse effects compared with ibrutinib when we look across studies, particularly rates of more serious atrial fibrillation, other cardiac arrhythmias, or major bleeding events, and also less in the way of rash and hypertension.

I anticipate that acalabrutinib will get a label in CLL fairly soon. At the 2019 ASH meeting, we will see data from the ELEVATE-[TN] treatment-naïve study, which has demonstrated a PFS benefit with acalabrutinib with or without obinutuzumab over chlorambucil with obinutuzumab. We are also excited to eventually see the results of [the] ELEVATE-RR study, which is directly comparing ibrutinib with acalabrutinib head to head, so that should be an informative study. It&rsquo;s designed as a noninferiority study around a PFS primary end point. It is likely that acalabrutinib is noninferior to ibrutinib from a PFS perspective, but we are also interested in the safety comparison between the 2 arms. If it looks like, in a randomized setting, that acalabrutinib is better tolerated and comparably efficacious to ibrutinib, that would strongly support using acalabrutinib going for- ward as the preferred BTK [Bruton tyrosine kinase] inhibitor in CLL, not just with monotherapy, but also for patients who are receiving combination approaches.

Shanafelt TD, Wang XV, Kay NE, et al. Ibrutinib-rituximab or chemoimmuno- therapy for chronic lymphocytic leukemia.

. 2019;381(5):432-443. doi: 10.1056/NEJMoa1817073.

Woyach JA, Ruppert AS, Heerema NA, et al. Ibrutinib regimens versus chemoimmunotherapy in older patients with untreated CLL.

. 2018;379(26):2517-2528. doi: 10.1056/NEJMoa1812836.

FDA approves chemotherapy-free regimen, venetoclax plus obinutuzumab, as first-line treatment for CLL/SLL. The ASCO Post website. ascopost.com/issues/ may-25-2019/fda-approves-chemotherapy-free-regimen-venetoclax-plus-obinutu- zumab-as-first-line-treatment-for-cllsll/. Published May 25, 2019. Accessed October 21, 2019.

Fischer K, Al-Sawaf O, Bahlo J, et al. Venetoclax and Obinutuzumab in Patients with CLL and Coexisting Conditions.

;380(23):2225-2236. doi: 10.1056/NEJMoa1815281.

Hillmen P, Rawstron AC, Brock K, et al. Ibrutinib plus venetoclax in relapsed/ refractory chronic lymphocytic leukemia: the CLARITY study.

. 2019;37(30):2722-2729. doi: 10.1200/JCO.19.00894.

Jain N, Keating M, Thompson P, et al. Ibrutinib and Venetoclax for First-Line Treatment of CLL.

. 2019;380(22):2095-2103. doi: 10.1056/NEJ- Moa1900574.

Matthew S. Davids, MD, MMSc, discusses the rapid developments in the chronic lymphocytic leukemia treatment landscape.

Weighing Fixed Duration Versus Continuous Therapy for CLL Q&A With Matthew S. Davids, MD, MMSc

and treatment guidelines have adapted. Developments in targeted therapies, monoclonal antibodies, and combination regimens have benefited those with high-risk disease, improving outcomes even for patients with del(17p) or TP53 mutations.

Treatments that have already been approved as monotherapies have been, and continue to be, combined in experiments to potentially benefit wider rang- es of patients and generate better outcomes. Over the past year in particular, new data have prompted the approvals of different targeted drugs and combina- tion therapies, most recently in November with the approval of acalabrutinib as initial or subsequent therapy for adults with CLL or small lymphocytic lym- phoma (SLL). With so many developments in the CLL treatment spectrum over a short amount of time, the National Comprehensive Cancer Network (NCCN) has issued multiple updates to its treatment guidelines in 2019.

As the therapeutic landscape continues to evolve, identifying treatment regimens that optimally align with individual patient profiles is essential. This article reviews significant developments in the CLL treatment landscape over the past year, including data presented and/or published that are related to ibrutinib, acalabrutinib, and venetoclax combination regimens.

Recent and Current Developments in CLL Treatment

Key findings from several phase III studies examining ibrutinib in different populations were presented at the 2018 American Society for Hematology Annual Meeting and helped shape new directions in treatment of CLL. The data had immediate impact, particularly for patients with untreated CLL, as the NCCN overhauled its guidelines to elevate ibrutinib to first-line treatment status.

Findings from the iLLUMINATE trial demonstrated that, when compared with standard chemoimmunotherapy, ibrutinib combined with a monoclonal antibody was effective in patients with previously untreated CLL. This led to the FDA approval of ibrutinib plus obinutuzumab in January 2019. Participants were 65 years and older (median, 75 years) and had untreated CLL or small lymphocytic leukemia, were separated into 2 groups: those with significant comorbidities or high-risk cytogenetics, and those without.

Treatments were assigned randomly 1:1, with patients either given ibrutinib plus obinutuzumab (n = 113) or chlorambucil plus obinutuzumab (n = 116).

The trial met its primary endpoint and improved progression-free survival (PFS), with a median follow-up of 31.3 months. At 30 months, the PFS rate was 79% in the ibrutinib/obinutuzumab group and 31% in the chlorambucil/obinutuzumab group.

Results also showed a 77% reduction in risk of progression or death in the ibrutinib/obinutuzumab arm compared with the chlorambucil/obinutuzumab arm (HR, 0.23; 95% CI, 0.15-0.37), which ultimately led to the combination&rsquo;s approval.

The patients with high-risk disease, representing 65% of the ibrutinib armthose with del(17p)/TP53 mutation, del(11q), or unmutated IGHV&mdash; experienced an 85% reduction in risk of progression or death.

Additionally, patients in the ibrutinib/obinutuzumab group had an overall response rate (ORR) of 88%, compared with 73% in the chlorambucil/obinutuzumab cohort.

Grade 3 and 4 adverse events (AEs) were similar in both groups; the most common were pneumonia and febrile neutropenia.

Results of the phase III ALLIANCE trial backed the choice of ibrutinib as a standard-of-care treatment in older patients with CLL.

The study analyzed the efficacy of ibrutinib alone (n = 182) and in combination with the monoclonal antibody rituximab (n = 182) against bendamustine plus rituximab (n = 183), which had been the standard-of-care chemotherapy for older patients with CLL.

Patients were 65 years and older with previously untreated CLL, as defined by International Workshop on CLL criteria.

At 2 years, PFS was 87% with ibrutinib alone, compared with 88% with ibrutinib/rituximab and 74% for bendamustine/rituximab.

Both ibrutinib monotherapy and the ibrutinib/rituximab combination showed favorable safety profiles compared with bendamustine plus rituximab. Grade 3, 4, and 5 hematologic AEs occurred at a higher rate in the bendamustine/rituximab group compared with the ibrutinib monotherapy and ibrutinib/rituximab groups (61% vs 41% and 39%, respectively).

Based on these findings, the investigators concluded that in this setting, no significant difference exists between ibrutinib-plus-rituximab and ibrutinib monotherapy treatments.

The randomized, open-label, phase III E1912 trial also evaluated the combination of ibrutinib plus rituximab; in this case, researchers compared it with the standard chemoimmunotherapeutic regimen of fludarabine, cyclosphosphamide, and rituximab (FCR) in patients 70 years or younger with previously untreated CLL.

Between March 2014 and June 2016, patients were assigned 2:1 to ibrutinib/rituximab (n = 354) or to FCR (n = 175).

Patients with del(17p) were excluded from the study. The primary and secondary endpoints were PFS and overall survival (OS), respectively.

With a median follow-up of 33.6 months, patients in the ibrutinib-plus-rituximab arm experienced better PFS compared with those in the chemoimmunotherapy group (89.4% vs 72.9% at 3 years; HR for progression or death, 0.35; 95% CI, 0.22-0.56;

AEs of grade 3 or higher were comparable between the groups (80.1% vs 79.7%).

While continuous ibrutinib/rituximab therapy resulted in superior PFS and OS compared with 6 months of chemoimmunotherapy, investigators questioned the practicality of indefinite use of ibrutinib therapy, as it has been associated with significant expense and potential long-term toxic effects, including risk of drug resis- tance.

Based on these results, a supplemental new drug application (sNDA) for ibrutinib plus rituximab for first-line treatment of CLL or small lymphocytic leukemia in those aged 70 years or younger was submitted.

In May 2019, the combination of venetoclax plus obinutuzumab was granted approval by the FDA for patients with previously untreated CLL. Venetoclax was initially approved by the FDA in 2016 for previously treated patients with CLL with 17p deletion genetic mutation, based on data from a single-arm clinical trial that showed 80% of patients achieved complete or partial remission.

The combination of venetoclax plus rituximab was then approved in 2018 for patients with or without 17p deletion, with at least 1 prior therapy.

The recent approval of the combination regimen was based on efficacy outcomes from the open-label, multicenter, randomized, phase III CLL14 study, presented at the 2019 American Society of Clinical Oncology Annual Meeting. Results showed significant improvements in PFS in patients who were administered venetoclax plus obinutuzumab compared with patients who received chlorambucil plus obinutuzumab (HR, 0.33, 95% CI, 0.22-0.51;

<.0001). The venetoclax/obinutuzumab arm also showed a greater ORR of 85%, compared with 71% in the chlorambucil/obinutuzumab cohort.

As a result of these findings, the NCCN guidelines have been updated, making venetoclax plus obinutuzumab a preferred first-line regimen for patients with previously untreated CLL.

Further combinations with venetoclax are also under investigation, including venetoclax plus ibrutinib. Findings from the phase II CLARITY study were published this year, showing that the venetoclax-plus-ibrutinib combination is effective and safe in patients with relapsed/refractory CLL. The primary endpoint of the study was the eradication of minimal residual disease (MRD) in the bone marrow and peripheral blood, such that there was fewer than 1 CLL cell in 10,000 leukocytes following 12 months of the combination treatment. Of the 53 patients included in the study, 28 patients reached MRD negativity in peripheral blood and 19 patients showed MRD negativity in the bone marrow. Results also demonstrated that after 12 months, 47 participants had responded to treatment and 27 patients had achieved complete remission. This regimen will be explored further in phase III studies.

Other potential combinations with venetoclax have been explored in preclinical studies, some of which potentially may improve efficacy without significantly increasing tox- icity. Combinations of venetoclax with anti-CD20 immuno- therapy and B-cell signaling inhibitors, are being tested, with an eye to minimize patient exposure to cytotoxic che- motherapy.17 Other trials are actively testing whether could be efficacious in patients with CLL.

Acalabrutinib, a BTK inhibitor that has been FDA approved since 2017 for previously treated adult patients with mantle cell lymphoma, was recently approved as initial or subsequent therapy in adults with CLL or SLL.

The approval followed significant findings from the ELEVATE-TN and ASCEND trials that, earlier this year, led the FDA grant breakthrough designation to acalabrutinib for the treatment of CLL in adult patients.

ASCEND is a randomized, global, multicenter, open-label phase III trial evaluating the efficacy and safety of acalabrutinib compared with the investigator&rsquo;s choice of either rituximab plus idelalisib or rituximab plus bendamustine in patients with relapsed/refractory CLL.

Findings were presented at the 24th European Hematology Association Congress. The primary endpoint of the study was PFS, and the secondary endpoints were OS, independent review committee (IRC)-assessed ORR, and safety. Eligible patients (N = 310) were randomized to 100 mg of acalabrutinib twice daily until disease progression, 150 mg of idelalisib twice daily plus 8 intravenous infusions of rituximab (375 or 500 mg/m2), or 70 mg/m2 of intravenous bendamustine on days 1 and 2 of each cycle plus intravenous rituximab (375 or 500 mg/m2) on day 1 of each 28-day cycle for up to 6 cycles.

The IRC-assessed ORRs did not significantly differ between the acalabrutinib arm and the 2 other cohorts (81% vs 75%). However, at a median follow-up of 16.1 months, acalabrutinib showed significant prolonged PFS compared with rituximab/idelalisib and rituximab/bendamustine, representing a 69% reduction in risk of progression or death (median, not reached vs 16.5 months; HR, 0.31; 95% CI, 0.20-0.49;

ELEVATE-TN is a randomized, multicenter, open-label phase III study evaluating the safety and efficacy of acalabrutinib as a monotherapy or in combination with obinutuzumab compared with chlorambucil plus obinutuzumab in previously untreated CLL patients.

The patient population consists of 535 patients, randomized 1:1:1 to 3 cohorts. The primary endpoint, PFS, was reached by the acalabrutinib-plus-obinutuzumab group, showing meaningful improvements compared with the chlorambucil-plus-obinutuzumab group.

Acalabrutinib has also shown promise in patients intolerant to ibrutinib. Investigators presented findings at the 15th International Conference on Malignant Lymphoma from a phase II trial in which patients (median age, 70 years) had relapsed/refractory CLL and had received at least 1 prior therapy. Investigator-assessed ORR was 72%, and median follow-up was 23 months, with 63% of patients remaining on acalabrutinib and 80% remaining on the study. Reasons for discontinuation of acalabrutinib included progressive disease, AEs, patient withdrawal, and investigator decision.

Because of these combined findings, acalabrutinib monotherapy for patients with relapsed/refractory CLL has been added as a first-line, category 1 therapy in the most recent NCCN guidelines.

Given the many important developments emerging from new trial results and from approvals for numerous agents in the past year, the CLL treatment spectrum will likely continue to evolve at an accelerated rate. As new evidence continues to demonstrate the clinical benefits of targeted therapies, it is incumbent upon physicians to keep up with the data and integrate these agents into real-world settings.

Seymour C. Breakthrough therapies enrich evolving CLL paradigm. OncLive website. onclive.com/web-exclusives/breakthrough-therapies-enrich-evolving-cll-paradigm. Published September 19, 2019. Accessed October 21, 2019.

Sharma S, Rai KR. Chronic lymphocytic leukemia (CLL) treatment: so many choices, such great options.

. 2019;125(9):1432-1440. doi: 10.1002/cncr.31931.

Jain N, O&rsquo;Brien S. Initial treatment of CLL: integrating biology and functional status.

. 2015;126(4):463-470. doi: 10.1182/blood-2015-04-585067.

NCCN Clinical Practice Guidelines in Oncology. Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, version 4.2019. National Comprehensive Cancer Network website. nccn.org/professionals/physician_gls/pdf/cll.pdf. Updated March 15, 2019. Accessed May 10, 2019.

NCCN Clinical Practice Guidelines in Oncology. Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, version 2.2020. National Comprehensive Cancer Network website. nccn.org/professionals/physician_gls/pdf/cll.pdf. Updated October 8, 2019. Accessed October 30, 2019.

Loguidice CT. Experts dissect 3 practice-changing studies for newly diagnosed CLL. OncLive website. onclive.com/publications/Oncology-live/2019/vol-20-no-7/experts-dissect-3-practicechanging-studies-for-newly-diagnosed-cll. Published April 1, 2019. Accessed October 28, 2019.

Moreno C, Greil R, Demirkan F, et al. Ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab in first-line treatment of chronic lymphocytic leukaemia (iLLUMINATE): a multicentre, randomised, open-label, phase 3 trial.

. 2019;20(1):43-56. doi: 10.1016/S1470-2045(18)30788-5.

Columbus G. FDA approves ibrutinib plus obinutuzumab in frontline CLL/SLL. OncLive website. onclive.com/web-exclusives/fda-approves-ibrutinib-plus-obinutu-zumab-in-frontline-cllsll. Published January 28, 2019. Accessed October 28, 2019.

Helwick C. Ibrutinib vs standard of care in front-line treatment of older patients with chronic lymphocytic leukemia. The ASCO Post website. ascopost.com/issues/december-10-2018/ibrutinib-vs-standard-of-care-in-older-patients-with-cll. Published December 10, 2018. Accessed May 7, 2019.

Shanafelt TD, Wang XV, Kay NE, et al. Ibrutinib-rituximab or chemoimmuno-therapy for chronic lymphocytic leukemia.

Tucker N. Ibrutinib/rituximab seeking approval as frontline treatment for CLL. Targeted Oncology website. https://www.targetedonc.com/news/ibrutinibritux-imab-seeking-approval-as-frontline-treatment-for-cll. Published November 12, 2019. Accessed November 15, 2019.

FDA approves new drug for chronic lymphocytic leukemia in patients with a specific chromosomal abnormality [news release]. Silver Spring, MD: FDA; April 11, 2016. fda.gov/news-events/press-announcements/fda-approves-new-drug-chronic-lymphocytic-leukemia-patients-specific-chromosomal-abnormality. Accessed October 21, 2019.

Lawrence L. Venetoclax/rituximab combo approved for CLL/SLL. Cancer Network website. cancernetwork.com/news/venetoclaxrituximab-combo-approved-cllsll#targetText=The%20United%20States%20Food%20and,at%20least%20one%20prior%20therapy. Published June 18, 2018. Accessed October 21, 2019

FDA approves chemotherapy-free regimen, venetoclax plus obinutuzumab, as first-line treatment for CLL/SLL. The ASCO Post website. ascopost.com/issues/ may-25-2019/fda-approves-chemotherapy-free-regimen-venetoclax-plus-obinutu-zumab-as-first-line-treatment-for-cllsll/. Published May 25, 2019. Accessed October 21, 2019.

Hillmen P, Rawstron AC, Brock K, et al. Ibrutinib plus venetoclax in relapsed/refractory chronic lymphocytic leukemia: the CLARITY study.

Schieber M, Ma S. The expanding role of venetoclax in chronic lymphocytic leukemia and small lymphocytic lymphoma.

. 2019;9:9-17. doi: 10.2147/BLCTT.S177009.

Ibrutinib and Obinutuzumab With or Without Venetoclax in Treating Patients With Chronic Lymphocytic Leukemia. clinicaltrials.gov/ct2/show/NCT03701282?term=NCT03701282&draw=2&rank=1. Updated November 8, 2019. Accessed November 15, 2019.

Testing the Addition of a New Anti-cancer Drug, Venetoclax, to the Usual Treatment (ibrutinib and obinutuzumab) in Untreated, Older Patients With Chronic Lymphocytic Leukemia. clinicaltrials.gov/ct2/show/NCT03737981?term=NCT0373798 1&draw=2&rank=1. Updated November 7, 2019. Accessed November 15, 2019.

FDA takes second action under international collaboration, approves new treatment option for patients with chronic lymphocytic leukemia. FDA website. Posted November 21, 2019. https://bit.ly/2s7EiSz. Accessed November 27, 2019.

Ghia P, Pluta A, Wach M, et al. ASCEND phase 3 study of acalabrutinib vs investigator&rsquo;s choice of rituximab plus idelalisib (IDR) or bendamustine (BR) in patients with relapse/refractory (R/R) chronic lymphocytic leukemia (CLL) [abstract LB2606]. Presented at: 24th European Hematology Association Congress; June 13-16, 2019; Amsterdam, the Netherlands.

EHA 2019: ASCEND trial compares acalabrutinib vs investigator&rsquo;s choice in relapsed or refractory CLL. The ASCO Post website. ascopost.com/News/60168. Updated June 19, 2019. Accessed October 21, 2019.

Calquence phase III ELEVATE-TN trial met primary endpoint at interim analysis in previously-untreated chronic lymphocytic leukaemia [news release]. Cambridge, UK: AstraZeneca; June 6, 2019. astrazeneca.com/media-centre/press-releases/2019/calquence-phase-iii-elevate-tn-trial-met-primary-endpoint-at-interim-analysis-in- previously-untreated-chronic-lymphocytic-leukaemia06062019.html. Accessed October 21, 2019.

Powers V. Acalabrutinib shows high response, prolonged survival in ibrutinib-intolerant R/R CLL. Targeted OncologyTM website. targetedonc.com/publications/ targeted-therapy-news/2019/September-2019/acalabrutinib-shows-high-response-prolonged-survival-in-ibrutinibintolerant-rr-cll. Published September 24, 2019. Accessed October 29, 2019.

The treatment spectrum for chronic lymphocytic leukemia has expanded significantly with the development and approval of several new agents.

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