Jennifer Woyach, MD:
At this time, we have numerous frontline therapy options for patients with CLL. Established options include the BTK inhibitors ibrutinib and acalabrutinib (with or without an anti-CD20 monoclonal antibody), the BCL-2 inhibitor venetoclax plus obinutuzumab, and chemoimmunotherapy.¹

Jennifer Woyach, MD:
Before we look at targeted therapies, an important question to discuss is whether there are current and future roles for chemoimmunotherapy in patients with CLL. For the most part, we are done with using chemoimmunotherapy. However, there is a subset of patients who are young (65 years of age or younger) and fit with IGHV-mutated disease and no high‑risk genetic abnormalities who can potentially be cured with chemoimmunotherapy.^2-3,8 We could consider chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab (FCR) for a patient with these characteristics. That said, most other patients would be better served with targeted therapy.

Anthony Perissinotti, PharmD, BCOP:
In my practice, I can say that this option is often a hard sell for patients when we present it, because you can tell them that they may be cured but also that many acute and long-term toxicities are associated with this regimen. Of importance, there is potential for secondary malignancies with this regimen, so you are essentially telling the patient, “We may be able to control your CLL, but in doing so, you may develop a more aggressive cancer like AML or MDS.” So, FCR is not something that our patients are eager to start anymore, even though the data are available. More frequently, we end up having a discussion about a choice between a BTK inhibitor and venetoclax-based regimens.

Jennifer Woyach, MD:
The first class of targeted therapy that we will discuss is BTK inhibitors.

Jennifer Woyach, MD:
We currently have the longest follow-up data with the first-generation BTK inhibitor ibrutinib. In 2016, ibrutinib was approved by the FDA for patients with CLL/SLL.⁴ This approval was based on the phase III RESONATE‑2 trial, which randomized 269 patients aged 65 years or older with previously untreated CLL to receive ibrutinib or chlorambucil.⁵ At 7 years, 59% of patients who received ibrutinib remained progression free and alive vs 9% of patients who received chlorambucil.⁶ This is a phenomenal example of how targeted therapy has changed how we treat patients with CLL.

The RESONATE‑2 trial has been criticized because its control arm received chlorambucil, which is not a standard treatment option for our patients with CLL.⁷ Since then, multiple studies have compared ibrutinib‑based regimens to more standard chemoimmunotherapy, as we will now discuss.

Jennifer Woyach, MD:
The first of these studies was the phase III E1912 trial, which compared ibrutinib plus rituximab vs FCR in patients aged 70 years or younger with previously untreated CLL.⁸ Both progression-free survival (PFS) and overall survival results favored ibrutinib plus rituximab. The 3-year PFS rate was 89.4% for patients who received ibrutinib vs 72.9% for patients who received FCR (P <.001), and the 3-year overall survival rate was 98.8% vs 91.5%, respectively (P <.001).

Most of the benefit observed with ibrutinib plus rituximab was in patients with higher‑risk, IGHV-unmutated disease.⁹ In the updated analysis presented at the 2019 American Society of Hematology (ASH) annual meeting, the curves are fairly close between ibrutinib plus rituximab vs FCR for patients with low‑risk, IGHV-mutated disease—the population who can potentially be cured by FCR. We await longer follow-up to see if there is an advantage for ibrutinib‑based regimens in that particular population.

Jennifer Woyach, MD:
Turning to older patients, the phase III A041202 trial randomized patients aged 65 years or older with previously untreated CLL to receive ibrutinib with or without rituximab vs bendamustine plus rituximab.¹⁰ My colleagues and I¹¹ presented the most recent analysis at ASH 2021 and reported that, at a median follow-up of 55 months, the ibrutinib‑containing regimens maintained improvement over bendamustine plus rituximab. At 48 months, 76% of patients who received ibrutinib or ibrutinib plus rituximab remained progression free vs 47% of patients who received bendamustine plus rituximab.

Again, there does not appear to be much difference between either of the ibrutinib-based regimens vs bendamustine plus rituximab in the low‑risk, IGHV-mutated subgroup, although we will continue to monitor this in extended follow-up.

Jennifer Woyach, MD:
The second-generation, covalent BTK inhibitors acalabrutinib and zanubrutinib were designed to be more specific for BTK than ibrutinib.¹⁴ This increased selectivity was hypothesized to improve tolerability, and this has been observed in the clinical trials we will now discuss.

Nichole Fisher, RN, BSN:
With the second-generation BTK inhibitors, there are generally fewer off‑target effects, particularly on kinases such as TEC, EGFR, and ITK. When these are inhibited, particular AEs can occur. For example, with higher inhibition of TEC, the risk of bleeding and cardiotoxicity appears to increase.

Jennifer Woyach, MD:
Turning to emerging therapies, there has been interest in combining BTK inhibition with BCL-2 inhibition with or without obinutuzumab. CAPTIVATE and GLOW are 2 larger studies with data that have been presented recently.

Jennifer Woyach, MD:
Results from the phase III ELEVATE‑TN trial led to FDA approval of acalabrutinib for CLL.¹⁵ In this trial, patients with previously untreated CLL who were aged 65 years or older or younger than 65 years with comorbidities were randomized to receive acalabrutinib with or without obinutuzumab vs chlorambucil plus obinutuzumab.¹⁶ There was a significant PFS advantage for both acalabrutinib‑containing arms vs chlorambucil plus obinutuzumab (P <.0001 for both comparisons). At a median follow-up of 28.3 months, the median PFS was not reached for both acalabrutinib-containing arms vs 22.6 months with chlorambucil plus obinutuzumab.

Jennifer Woyach, MD:
AEs with acalabrutinib are generally manageable, and we do not see many new AEs occurring at later points in time.^16-17 In patients on clinical trials, there were fairly low rates of grade ≥3 atrial fibrillation (0.6%) and grade ≥3 bleeding (1.7%).

Nichole Fisher, RN, BSN:
For acalabrutinib, the most common nonhematologic AE is typically diarrhea.^17-18 Diarrhea often occurs early in treatment and is managed with supportive care and antimotility agents. Headaches are the most unique AE of acalabrutinib. They often occur early in treatment and do not typically recur once they subside. Headaches often are addressed with hydration and caffeine. Another common side effect of acalabrutinib is fatigue. Arthralgias are also common with BTK inhibitors, and are seen more often with ibrutinib.

Jennifer Woyach, MD:
For a head-to-head comparison of BTK inhibitors, we must turn to the phase III ELEVATE‑RR trial, which compared acalabrutinib vs ibrutinib in the setting of previously treated CLL and demonstrated that acalabrutinib was noninferior to ibrutinib in terms of efficacy.¹⁸ At a median follow-up of 40.9 months, the median PFS was 38.4 months in each arm.

In terms of tolerability, many of the AEs common with ibrutinib were less common with acalabrutinib. This included arthralgia, diarrhea, bruising, hypertension, and atrial fibrillation.

Jennifer Woyach, MD:
To summarize, these clinical trials demonstrated that BTK inhibitors with or without anti-CD20 antibodies are more effective than chemoimmunotherapy in frontline CLL. Anti‑CD20 antibodies might offer greater efficacy when combined with acalabrutinib.

Regarding differences between BTK inhibitors, acalabrutinib is as efficacious as ibrutinib and is better tolerated in terms of certain AEs. However, acalabrutinib must be taken twice daily, whereas ibrutinib is taken once daily.^4,19 The current formulation of acalabrutinib cannot be taken with a proton pump inhibitor, although this may change in the near future with a new tablet formulation of acalabrutinib.²⁰ There also are a little less follow-up data with acalabrutinib, but I do not consider that a major disadvantage.

We did not discuss zanubrutinib in detail, but this agent does show a safety profile similar to acalabrutinib with perhaps a little less atrial fibrillation.¹⁴ Zanubrutinib is currently under investigation for CLL, with data available from the phase III ALPINE (NCT03734016) and SEQUOIA (NCT03336333) trials.

Jennifer Woyach, MD:
We will next discuss venetoclax, a BCL-2 inhibitor.

Jennifer Woyach, MD:
In 2019, the FDA approved venetoclax plus obinutuzumab for CLL/SLL.²¹ This approval was based on the phase III CLL14 trial, which compared venetoclax plus obinutuzumab vs chlorambucil plus obinutuzumab in patients with previously untreated CLL and comorbidities.²² At a median follow-up of 4 years—which encompasses 1 year of treatment followed by 3 years of follow-up—the 4-year PFS rate was 74.0% for patients receiving venetoclax plus obinutuzumab vs 35.4% for patients receiving chlorambucil plus obinutuzumab.²³ Among those receiving venetoclax plus obinutuzumab, patients with IGHV‑mutated disease had the longest median PFS, which was not yet reached, whereas the median PFS was 57.3 months among patients with IGHV-unmutated disease.

Jennifer Woyach, MD:
Many of the AEs associated with venetoclax plus obinutuzumab are fairly similar to those of chlorambucil plus obinutuzumab, including the hematologic toxicities.²²

Nichole Fisher, RN, BSN:
Some of the most common AEs we have seen with venetoclax are hematologic, with neutropenia being the most common. Another common AE is thrombocytopenia, which can increase the risk for bleeding. Tumor lysis syndrome is another AE that can occur with venetoclax-based therapy. This is caused by the rapid breakdown of cancer cells with this therapy and can be mitigated by appropriate early dosing strategies, premedication with antihyperuricemic agents, and hydration.

Jennifer Woyach, MD:
When we do a cross-trial comparison, we see that the 4-year PFS rate for venetoclax plus obinutuzumab (74.0%) is similar to that reported for ibrutinib (76%).^11,23 However, venetoclax-based regimens may be associated with a shorter median PFS in patients with TP53 abnormalities and potentially those with IGHV-unmutated disease. Long‑term results will be critical to comparing the efficacies of these regimens, especially in high‑risk patient subgroups.

Jennifer Woyach, MD:
With several potential options for frontline treatment of CLL, how do we choose? The first consideration would be efficacy. We have data out to approximately 4 years with ibrutinib, acalabrutinib, and venetoclax plus obinutuzumab. All appear relatively equivalent, with the potential exception that patients with high-risk disease (ie, TP53 abnormalities and IGHV unmutated) may have a slightly shorter median PFS with venetoclax plus obinutuzumab.

We will have actual comparative data in the future for these regimens. The phase III CLL17 trial (NCT04608318) is comparing venetoclax plus obinutuzumab vs ibrutinib with or without venetoclax, but it will be a long time before we see those data.

Anthony Perissinotti, PharmD, BCOP:
As mentioned, one factor that may suggest the consideration of a BTK inhibitor over other forms of therapy is mutated TP53. There are now impressive pooled data from 4 trials of frontline ibrutinib that included patients with TP53-mutated and/or del(17p) CLL.²⁴ In general, historical data suggest that patients with these aberrations who receive chemotherapy will live only for approximately 2-3 years. Data from the pooled analysis showed that at 4 years, 79% of patients with CLL with a TP53 mutation who received ibrutinib were progression free, which is very impressive.

An updated analysis of ELEVATE-TN was also recently presented, and this showed a 4-year PFS of approximately 75% with acalabrutinib with or without obinutuzumab in patients with CLL with del(17p) and/or mutated TP53.¹⁷ With these data, I think many would lean toward the BTK inhibitor class for patients with CLL with mutated TP53.

That said, it is not an absolute that these patients must receive a BTK inhibitor, so if we have patients with factors that would make a BTK inhibitor less desirable (eg, uncontrolled atrial fibrillation, a mechanical heart valve, and receiving warfarin), even if they have TP53-mutated CLL, we might consider venetoclax plus obinutuzumab, which also has great activity compared with chemoimmunotherapy for patients with CLL with del(17p) and/or mutated TP53. 

Anthony Perissinotti, PharmD, BCOP:
To illustrate some of these points, let’s look at a case. A 75-year-old female patient presented with a white blood cell (WBC) count of 13,000/µL, an absolute lymphocyte count (ALC) of 9 x 10⁹/L, hemoglobin (Hgb) of 13 g/dL, and a platelet count of 160,000/µL. Flow cytometry indicated a typical CLL pattern. She was observed for 5 years, but she began to experience progressive weight loss, splenomegaly, and bulky lymphadenopathy with WBC 310,000/µL and Hgb 9 g/dL. She had IGHV-unmutated, TP53-mutated, del(17p) CLL.

With a patient like this, my role would be to educate the team on any new literature that could inform treatment. Numerous major positive clinical trials have occurred over the past 5 years or so, and it can be challenging to keep up to date regarding what literature applies to individual patients. 

In this case, the patient is 75 years of age. Assuming she is less fit, I likely would apply the data from RESONATE-2 and iLLUMINATE (ibrutinib), ELEVATE-TN (acalabrutinib), and CLL14 (venetoclax plus obinutuzumab) to this patient. Each of those therapies would be an appropriate option for this patient, who is symptomatic and requires treatment.

Because the patient has TP53-mutated, del(17p) CLL, I might consider a BTK inhibitor, although I wouldn’t say that a venetoclax-based regimen is inappropriate. If the patient did not have TP53-mutated, del(17p) CLL, this would not change my thoughts on optimal treatment, as this is an older patient with IGHV-unmutated CLL for whom I would not recommend FCR or bendamustine plus rituximab based on the 2 phase III E1912 and A041202 studies discussed previously. Both novel targeted therapies can be considered in this scenario.

Jennifer Woyach, MD:
If we cannot use efficacy to differentiate between regimens, can we consider safety factors? There are predictable toxicities with BTK inhibitors. With ibrutinib, we see any-grade atrial fibrillation in 4% to 17% of patients on clinical trials, most frequently among older patients.^4,5,8,10 We also see hypertension, with grade ≥3 events in up to one third of patients and lower‑grade hypertension in even more. We see low-grade bruising at very high rates, but grade ≥3 bleeding or major hemorrhage is relatively uncommon. Ventricular arrhythmias are uncommon with ibrutinib but do occur and have significant morbidity and mortality.

With acalabrutinib, many of these toxicities occur at lower rates. Grade ≥3 bleeding occurs at a similar rate with acalabrutinib and ibrutinib, although other toxicities are generally less frequent with acalabrutinib.

Venetoclax is not associated with those toxicities characteristic of the BTK inhibitor class but does have higher rates of neutropenia. Febrile neutropenia does occur, albeit at low rates. High-grade gastrointestinal toxicity also can occur.

Anthony Perissinotti, PharmD, BCOP:
Of note, if we have started a patient on ibrutinib, and the patient cannot tolerate this agent despite dose adjustments and medical management of the AEs, we often will move to a second-generation BTK inhibitor. There are data demonstrating that if a patient does not tolerate ibrutinib, they may tolerate acalabrutinib and/or zanubrutinib.^25-26 Acalabrutinib and zanubrutinib were both designed to have more specificity for inhibiting BTK as opposed to other kinases, resulting in fewer off-target effects. 

Nichole Fisher, RN, BSN:
As mentioned, key safety considerations can impact treatment decisions for individual patients. We look at potential AEs with each medication and the comorbidities of the patient, and we perform a full review of their medications when considering potential therapy options.

Certain medications can impact treatment decisions. We often work with our pharmacist to determine whether there are any potential medication interactions. For example, with the current formulation of acalabrutinib, an exclusionary medication is any sort of proton pump inhibitor. With the nursing aspect, we speak a lot about food interactions (eg, BTK inhibitors and grapefruit and Seville oranges) and drug interactions (eg, supplements, herbals, St. John’s wart, etc), making sure we let patients know what the potential interactions are and why it is important to discuss any new medications prior to starting.

Jennifer Woyach, MD:
For many patients, the decision between therapies is driven by other factors. One factor is treatment duration with venetoclax plus obinutuzumab being the fixed-duration option (in the CLL14 trial, dosing for venetoclax plus obinutuzumab was limited to twelve 28-day cycles of venetoclax and six 28-day cycles of obinutuzumab) vs indefinite therapy with a BTK inhibitor. However, the trade-off is that BTK inhibitors can be started very easily and quickly and do not require a lot of clinic visits, whereas venetoclax plus obinutuzumab has a more intensive run‑in. This consideration has been especially relevant during the COVID-19 pandemic.

Another factor is that ibrutinib is taken once daily, whereas acalabrutinib is taken twice daily, which makes a difference for some patients. Cost also comes into play, although the actual cost of these regimens is still a little unclear once you factor in the potential hospitalizations and increased monitoring required with venetoclax-based regimens.

Ultimately, the choice of a BTK inhibitor vs venetoclax plus obinutuzumab is patient specific and involves discussion of these data and consideration of the pros and cons with each treatment option.

Nichole Fisher, RN, BSN:
Patient lifestyle considerations are important when deciding on treatment. Some questions to consider include: Would the patient be okay with coming into clinic more frequently for anti-CD20 antibody IV treatments? Or would they prefer to just take pills at home? Would they prefer a fixed-duration therapy or indefinite treatment? With BTK inhibitors, patients will be receiving treatment indefinitely, but with venetoclax, some patients may need to receive treatment only for a finite amount of time. Practical considerations also can play a role in therapy choice. If a patient is living several hours from clinic, is it an option for them to come in 3 times during each of the first 2 weeks of the venetoclax ramp-up or for a more intensive IV treatment? Cost also impacts treatment options pending the patient’s ability to afford the medication copayments. Often, we depend on our pharmacists to seek out copayment assistance options for the patient.

Anthony Perissinotti, PharmD, BCOP:
If safety and efficacy are relatively equal for an individual patient, we should consider cost to our patients, as well. The venetoclax plus obinutuzumab regimen has a finite treatment duration (1 year based on the CLL14 study).²² We now have follow-up data that most patients can remain off therapy beyond 3 years after completing venetoclax plus obinutuzumab; at 4 years post randomization, the PFS rate was 74%.²³ This is in contrast to BTK inhibitors, where patients take daily oral medication indefinitely, albeit with excellent long-term efficacy, as we discussed earlier. However, when we assess cost, in general, there will be less cost with a finite-duration therapy.

As alluded to above, another factor in contemporary decision-making is COVID-19. With BTK inhibitors, you can easily just take a pill at home. When possible, we have been doing virtual visits where patients present on their computer at home, resulting in less exposure to our healthcare system. This is in contrast to venetoclax-based treatment, particularly for patients with a higher risk of tumor lysis syndrome, who must be admitted, and low-risk and intermediate-risk patients, who still have to come into our healthcare facilities for frequent laboratory monitoring. During the COVID-19 pandemic, treatment that allowed fewer visits to healthcare facilities was desirable. It also should be noted that we typically recommend venetoclax with a monoclonal antibody directed against CD20—obinutuzumab. This treatment depletes B-cells substantially, and that has implications with our COVID-19 vaccines. Patients with CLL generally have very low responses to vaccinations at baseline; with the addition of obinutuzumab, responses may be very low. However, now that COVID-19 is starting to be more controlled with multiple boosters and antibodies to help some of our patients with CLL or hematologic disorders, we are starting to consider venetoclax-based regimens more frequently again.

Jennifer Woyach, MD:
The phase II CAPTIVATE trial enrolled patients aged 70 years or younger with previously untreated CLL/SLL.²⁷ This trial has 2 cohorts: Patients in the first receive fixed-duration ibrutinib plus venetoclax for 1 year and are then observed; patients in the second cohort receive ibrutinib plus venetoclax before being stratified by minimal residual disease status and randomized to receive additional treatment. After a median time on study of 27.9 months in the fixed-duration cohort, the 24-month PFS rate was 95% in all treated patients, with a 96% rate in those with high‑risk disease harboring del(17p).²⁸

The phase III GLOW trial is comparing ibrutinib plus venetoclax vs chlorambucil plus obinutuzumab in patients aged 65 years or older or younger than 65 years with comorbidities who have previously untreated CLL.²⁹ Again, the follow-up is very short at a median of 27.7 months. Nonetheless, the median PFS is significantly improved with ibrutinib plus venetoclax vs chlorambucil plus obinutuzumab (not reached vs 21.0 months, respectively; HR: 0.212; P <.0001).

Anthony Perissinotti, PharmD, BCOP:
Unfortunately, with the GLOW study and others, chlorambucil plus obinutuzumab is no longer a standard of care regimen for most patients; this makes it difficult to compare the efficacy of this newer regimen with current standards.

Anthony Perissinotti, PharmD, BCOP:
Additional combination studies of interest include the phase II AVO trial of acalabrutinib with venetoclax and obinutuzumab; this combination is now being assessed in a phase III trial (NCT03836261).³⁰ We also have seen data with the phase II BOVen regimen of zanubrutinib, venetoclax, and obinutuzumab.³¹ Ideally, these combinations will have a finite duration of therapy, so instead of continuing treatment indefinitely, the aim would be very deep remissions with the combination. 

Anthony Perissinotti, PharmD, BCOP:
Let’s return to our case. Recall that this was a 75-year-old female patient who presented with WBC 13,000/µL, ALC 9 x 10⁹/L, Hgb 13 g/dL, and platelets 160,000/µL. Flow cytometry indicated a typical CLL pattern. She was observed for 5 years, but she began to experience progressive weight loss, splenomegaly, and bulky lymphadenopathy with WBC 310,000/µL, Hgb 9 g/dL, and platelets 15,000/µL. She had IGHV-unmutated, TP53-mutated, del(17p) CLL.

We had discussed some of the efficacy considerations in selecting therapy for this patient; let’s now look at some additional considerations. With this patient having a WBC count of 310,000/µL, I would likely educate the care team that if we were to start a BTK inhibitor, we should anticipate that the patient’s WBC count is going to rise, as BTK inhibitors are associated with lymphocytosis based on their mechanism of action. Essentially, BTK inhibitors inhibit various adhesion molecules in the lymph node microenvironment, resulting in CLL cells leaving the lymph nodes and entering the peripheral blood. I would educate the team that the WBC count could rise substantially and not to worry about that rise, because it is not generally associated with tumor lysis or complications from hyperleukocytosis.

It also is notable that the patient’s Hgb and platelet levels are quite low, so we would be thinking about the bleed risk for the patient if she was starting a BTK inhibitor. I also would want to know what other medications the patient is on and what other comorbidities she has before deciding on therapy.

Regarding treatment with venetoclax, it is notable that this patient has bulky lymphadenopathy. For part of our stratification of risk for tumor lysis syndrome, we use the ALC and the bulk of the tumor. I would guess that this patient would be stratified as having a high risk of tumor lysis syndrome, so she would need to be admitted to a hospital for venetoclax dose escalation, which would mitigate the risk of this syndrome. I do find that a lot of healthcare professionals who do not use venetoclax often are quite fearful of tumor lysis; with the patient having a WBC count of 310,000/µL, many might be reluctant to recommend venetoclax. I would say that if we follow the package insert recommendations for high-risk patients and we’re monitoring them, I am very confident that tumor lysis will not cause substantial issues for patients. If patients are adequately hydrated and receiving the appropriate prophylaxis and monitoring, most will tolerate venetoclax very well.

Another thing that can happen when starting venetoclax is neutropenia. I manage neutropenia differently depending on when it occurs. For early neutropenia, I usually recommend treating through it because I know that treatment is ridding their bone marrow of CLL cells. This will open the marrow for normal hematopoiesis, and over time, their absolute neutrophil count will rise. If the patient experiences neutropenia a few months into therapy on the target dose and started with a normal WBC count, I would consider holding the venetoclax to wait for their counts to recover. I would then restart venetoclax.

Jennifer Woyach, MD:
These data show that, first, the combination of BTK inhibition plus BCL-2 inhibition is associated with outstanding short‑term PFS rates. The long‑term outcomes are unknown but will emerge over the next few years.

Jennifer Woyach, MD:
The most important takeaway is that the future of frontline CLL therapy is bright. We have many effective regimens, with more on the horizon. For most patients, targeted therapies are preferred to chemoimmunotherapy, and the choice of which targeted therapy is determined by patient preference and sometimes safety considerations. Ongoing and future studies will be crucial to continue to move the field forward, so please consider enrolling your patients on clinical trials to help contribute toward improvement in care for our patients with CLL.

Now, let’s return to the question from earlier in the activity.