Nicole Lamanna, MD:
Treatment paradigms for patients with CLL have undergone rapid evolution in recent years, largely due to the approval of novel targeted therapeutics, including the BTK inhibitors ibrutinib and acalabrutinib and the BCL-2 inhibitor venetoclax, which now form the standard of care for most patients. In this activity, we will discuss changes in treatment paradigms for patients with CLL and how these have affected clinical practice, with an emphasis on treatment selection and key considerations with novel therapies.

Nichole Fisher, RN, BSN:
Advances in treating CLL have provided patients with treatment options that no longer include chemoimmunotherapy, with novel targeted therapies associated with improved efficacy and fewer adverse events for most patients. As a registered nurse, changes in treatment paradigms often mean changes in how we assess our patients for potential adverse events and how we educate our patients.

As new treatment options become standards of care, our patient education evolves, with new education on adverse event profiles and management and overall differences between treatment options. We educate on concomitant medication interactions with novel agents, often working with our pharmacist. We also work with our pharmacy team on cost assistance to search for copay assistance programs or grants. Providing information on support groups and other educational forums is also essential, and I often help connect new patients with other patients who are on the same medication so that they can hear their point of view.

As mentioned, chemoimmunotherapy now plays a diminished role in treating patients with CLL. It has been important to educate on how adverse events can vary from chemoimmunotherapy to targeted therapy and to communicate to patients that chemoimmunotherapy regimens such as fludarabine, cyclophosphamide, and rituximab or bendamustine plus rituximab are often harsher and attack healthy cells, leading to increased adverse events compared with targeted therapy.

For many patients, there are multiple viable targeted options for frontline therapy, including BTK inhibitor–based and venetoclax-based treatment regimens. Particularly in the community cancer center environment, it is important for patients to advocate for themselves and to ask for molecular testing to be done, as patients’ molecular profile can affect how they are treated, as we will discuss in a moment. From a nursing perspective, it is important to be an advocate for patients and make sure they are advocating for themselves. 

Anthony Perissinotti, PharmD, BCOP:
I have been in practice for approximately 10 years, so I have seen the evolution in CLL treatment from chemoimmunotherapy to targeted therapies, which began with the approval of ibrutinib in 2014. When chemoimmunotherapy was the only treatment option for patients with CLL, the logistics actually were a little bit easier, because when you decided on treatment, you just asked your patients to go to the infusion center and they received their therapy. At that time, nonadherence wasn’t as big of a problem as it is now, as there was an objective way to document nonadherence (either the patient showed up at the infusion center for treatment or they didn’t). With the targeted oral medications, including the BTK inhibitors and venetoclax, it can be more difficult to specifically assess adherence. Studies have shown that when patients with B‑cell malignancies are nonadherent to their BTK inhibitors, their progression‑free and overall survival is worse.^1,2 As outlined in these studies, even adherence of less than 80% can result in worse outcomes. As such, we now spend a tremendous amount of time and resources to emphasize the importance of adherence with patients. With BTK inhibitor therapy, patients are likely to receive treatment for several years, so it’s important to educate them that even though they feel well now with their disease, it doesn’t necessarily mean their disease is gone. Adherence with our finite-duration therapeutic regimens can potentially be improved, because there’s an endpoint (eg, 12 months with venetoclax plus obinutuzumab), but it’s still very important for patients to adhere to the recommended dosing, because we want to get the deepest remission possible so that they can stay off therapy for longer.

Part of nonadherence with the transition from chemoimmunotherapy to oral targeted therapies is related to the learning curve with managing unique adverse events. With chemotherapy, we all knew what to expect and how to manage the adverse events, as these had been managed by the medical community for 50‑plus years. With the novel targeted agents, we might not recognize a low‑grade toxicity, which over time can become higher grade and lead to nonadherence. With venetoclax, there has been a learning curve surrounding the management of tumor lysis syndrome risk. 

For these reasons, we spend a lot more time now educating patients and the entire clinical team on recognizing and managing the toxicities associated with novel agents. We want to catch these as early as possible so that they don’t become higher grade and necessitate a hold in therapy, which can affect survival.

Logistical barriers have also arisen with new treatment options. It is often not as simple as writing a prescription for these oral therapies, after which patients can walk into our pharmacy and pick up their drug. Unfortunately, there can be delays due to insurance authorizations and the need for copay assistance. Some insurers require specific pharmacies and mail orders to dispense these agents, which can cause roadblocks. I have seen patients wait weeks to even a month to receive their targeted oral drugs. These are things we should keep in mind with these therapies in order to help our patients start and maintain treatment. Programs have been built to help manage all the logistics with these therapies, and this includes financial coordinators, pharmacists, and nurses to help get patients their drugs and assist with patient adherence to therapy.

Nicole Lamanna, MD:
CCO has gathered data from an online treatment decision support tool, for which 5 CLL experts provided treatment recommendations for numerous case scenarios in CLL yearly from 2017 to 2022. Healthcare professionals (HCPs) can enter case-specific characteristics into the tool, along with their planned treatment, and receive expert recommendations. For parts of this discussion, we will compare the intended treatment plans for cases entered into the tool by HCPs with expert recommendations. The current version of this tool can be found at clinicaloptions.com/CLLtool.³

Nicole Lamanna, MD:
Let’s look at some case examples and how treatment has evolved for these patients. To begin, let’s examine treatment for patients with CLL with del(17p) or a TP53 mutation. Based on data from CCO’s tool, in 2017, each of the 5 CLL experts surveyed recommended ibrutinib‑based therapy for patients with this profile. Ibrutinib was first approved for patients with del(17p) CLL in 2014. In 2018, CLL experts were still recommending ibrutinib for their patients with CLL with a del(17p) or TP53 mutation.

Venetoclax and obinutuzumab received FDA approval for first-line treatment of CLL in 2019, as did acalabrutinib.^4-6 These approvals began to be reflected in the expert recommendations for patients with CLL with a del(17p) or TP53 mutation; in 2019, many experts moved from ibrutinib (25%) to acalabrutinib-based therapy (35%) or venetoclax-based therapy. This movement has continued through 2022, with most experts now recommending acalabrutinib-based therapy (67%), with general BTK inhibitor–based therapy and venetoclax-based therapy recommended for specific patients.

Anthony Perissinotti, PharmD, BCOP:
There are now impressive pooled data from 4 trials of frontline ibrutinib that included patients with TP53-mutated and/or del(17p) CLL.⁷ 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 TP53.⁸ 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. 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 TP53.⁹

Nicole Lamanna, MD:
HCPs who used the tool more slowly adopted BTK inhibitors for these patients. In 2017, when 100% of experts recommended ibrutinib for patients with CLL with a del(17p) or TP53 mutation, fewer than 40% of HCPs selected this therapy as the optimal choice for these patients, and 36% were still choosing chemoimmunotherapy. In 2018, a larger share of HCPs had shifted to recommending ibrutinib‑based therapy (58%), and just 24% were using chemoimmunotherapy. In 2021, only 4% of HCPs would still recommend chemoimmunotherapy for a patient with CLL with del(17p) or a TP53 mutation.

Overall, these data show that for patients with CLL with del(17p) or a TP53 mutation, the experts recommend novel therapy over chemoimmunotherapy, and encouragingly, there has been an accompanying drop in the recommendation of chemoimmunotherapy by HCPs in this population.

In addition to key molecular alterations, an expert’s choice of treatment can also be influenced by a patient’s comorbidities. Within the subset of patients with a del(17p) or TP53 mutation, experts were more likely to recommend venetoclax-based therapy for patients who had a history of cardiac arrhythmias, anticoagulation therapy, or difficult-to-control hypertension (from 2020, when the tool began including these factors, to the present), although experts also considered acalabrutinib for these patients, with treatment selection frequently depending on the severity of the cardiac issues.

For patients with diminished creatinine clearance or renal function or with bulky disease, we see a strong preference for BTK inhibitor‑based therapy, possibly with an anti-CD20 antibody, rather than venetoclax‑based therapy. The experts likely expected that patients with poor renal function, bulky disease, or a high lymphocyte count would have a harder time tolerating frontline venetoclax plus obinutuzumab.

The expert recommendations for patients with del(17p) or a TP53 mutation but with none of these comorbidities were essentially the same as for those with bulky disease or poor renal function. All the experts agreed on BTK inhibitor–based therapy with or without an anti-CD20 antibody. Within that BTK inhibitor preference, we see a large shift toward the use of acalabrutinib in the last 2 years (80% in 2022). Of note, there was no recommendation for chemoimmunotherapy use in this setting.

Nicole Lamanna, MD:
A very different pattern of frontline treatment recommendations emerged for patients who are young and fit and who do not have del(17p) or TP53-mutated CLL but do have a favorable IGHV mutation. Again, recommendations have changed considerably in the past 5 years. In 2017, chemoimmunotherapy was used in this patient group much more than it is now, although we do still see it recommended for use in a small percentage of these low‑risk patients (experts recommended it for 59% of the tool case patients in 2017 vs 10% in 2022). Even so, with the advent of novel treatments, experts have largely moved away from chemoimmunotherapy toward treatment with either a BTK inhibitor or venetoclax-based therapy in this patient population as well. HCPs have also reported less use of chemoimmunotherapy, especially by 2021 (27%), and a concomitant increase in the usage of BTK inhibitor and venetoclax‑based therapies, although the adoption of the newer therapies appears slower than among CLL experts.

Nicole Lamanna, MD:
Finally, let’s look at first‑line treatment of patients with unmutated CLL—those with no del(17p) or TP53 or IGHV mutation. In 2017, the CLL experts were mostly recommending ibrutinib‑based therapy for these patient cases in the tool (80%; 20% recommended chemoimmunotherapy), whereas HCPs were largely recommending chemoimmunotherapy (77%). During the past several years, there has been a shift away from chemoimmunotherapy among experts and HCPs. Since 2019, we’ve seen the introduction of venetoclax plus obinutuzumab and then acalabrutinib. As in the other patient populations, we see more widespread adoption of these new therapies among the CLL experts. By 2022, experts were recommending either BTK inhibitor–based therapy (43%) or venetoclax plus obinutuzumab (57%) for this patient population, with no chemoimmunotherapy being recommended. The treatments favored by HCPs using the tool in 2020 and 2021 were more varied but did show some evolution over time, with only 15% still recommending chemoimmunotherapy in 2021.

Nicole Lamanna, MD:
Next, we discuss some patient cases to walk through how an HCP might evaluate treatment options based on the patient’s comorbidities and CLL‑specific findings.

Our first case is a 63‑year‑old man with newly diagnosed CLL. He presents to his primary care provider with lymph node swelling and increasing fatigue. He has a past history of some hypertension, which is medically controlled, as well as atrial fibrillation. Upon examination, he is found to have axillary lymphadenopathy, and his spleen is not palpable. Laboratory results show progressive lymphocytosis, mild anemia with a hemoglobin level of 10.3 g/dL, and a platelet count of 107,000/mm³. Analysis by FISH reveals that the patient has a del(11q), and molecular analysis shows he has unmutated IGHV.

With this individual’s hypertension well controlled, treatment with a BTK inhibitor could be an option, although I would likely choose a second-generation BTK inhibitor for the more favorable toxicity profile. It’s also likely that you would need to adjust his other medications. If he’s on coumadin or another anticoagulant, or if you’re concerned about his history of atrial fibrillation and hypertension, venetoclax plus obinutuzumab would also be an option for this patient.

Nicole Lamanna, MD:
Let’s now consider a younger treatment-naive patient. A 57‑year‑old man presents with progressive lymphadenopathy requiring treatment and is found to have del(17p) and unmutated IGHV. As discussed earlier, we would not use chemoimmunotherapy for a patient with CLL with del(17p), a TP53 mutation, or a complex karyotype with 3 or more chromosomal abnormalities.

Anthony Perissinotti, PharmD, BCOP:
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.

Because the patient has del(17p) CLL, I might consider a BTK inhibitor, although I wouldn’t say that a venetoclax-based regimen is inappropriate.

Nicole Lamanna, MD:
For this patient, I would recommend a BTK inhibitor with or without an anti-CD20 monoclonal antibody. Venetoclax plus obinutuzumab could also be an option. Results to date from the phase III CLL14 study of venetoclax plus obinutuzumab in previously untreated patients suggest that progression‑free survival in individuals with del(17p) may not be as long with this regimen.^7-10 Of course, there has been longer-term follow-up with ibrutinib because it has been on the market longer. We’re awaiting longer‑term data on patients with del(17p) treated with venetoclax plus obinutuzumab, which will help provide a better comparison between these regimens. With current evidence, many HCPs still favor chronic continuous BTK inhibitor therapy, but that may change over time. Many ongoing clinical trials in CLL will undoubtedly play a role in the evolution of CLL expert treatment recommendations.

Nicole Lamanna, MD:
Our last case revisits the 80‑year‑old male with untreated CLL with unmutated IGHV and normal FISH assay results. He presented with worsening symptomatic anemia with a hemoglobin level of 8.9 g/dL. He had no evidence of hemolysis, his platelets were mildly reduced at 90,000/mm³, and his white blood cell count was elevated, at 325,000/mL.

The patient had bulky disease, with 7 x 7 cm bilateral axillary lymph nodes and 12 x 12 cm retroperitoneal and para aortic lymph nodes, along with significant chest lymphadenopathy. He also had a long-standing history of hypertension and diabetes, along with chronic renal insufficiency with a creatinine level of 2 mg/dL.

Let’s return to our question from earlier in the activity.

Nicole Lamanna, MD:
For older patients with unmutated IGHV, I generally prefer to avoid chemoimmunotherapy. This patient’s case is also complicated by the fact that he has bulky disease and a history of hypertension, diabetes, and chronic renal insufficiency. Treating him with venetoclax plus obinutuzumab would make me very nervous. He would have to be admitted to the hospital for very close monitoring of his kidney function. And given his bulky disease and white count of 325,000/mL, he has an exceedingly high risk of tumor lysis syndrome with venetoclax or obinutuzumab, even if you started the obinutuzumab first.

Instead, I would consider using a BTK inhibitor–based therapy for this patient, possibly without an anti-CD20 antibody. Given the favorable outcomes seen with second-generation BTK inhibitors in head‑to‑head trials with ibrutinib, I tend to recommend that new patients start with a second-generation BTK inhibitor when these agents are optimal for the patient.^11,12 Acalabrutinib would be a fair option for this individual, and it could potentially have a more favorable adverse event profile than ibrutinib, which is especially important for a patient with hypertension. However, it would be important to work with other members of this patient’s care team, such as an internist or cardiologist, so they would be aware that he might need adjustment in his hypertension medications even with a second-generation BTK inhibitor.

Nichole Fisher, RN, BSN:
Although many aspects of nursing care have changed with updates to the treatment landscape for CLL, the core nursing skills required to care for this patient population have not changed. We’re still providing education and assessing our patients; we are just tailoring it more to the needs of the treatment that they are receiving. 

Anthony Perissinotti, PharmD, BCOP:
Many things have changed in the pharmacist’s world as treatment for CLL has evolved. There is now considerably more work for us, but it’s very rewarding work. A recent study demonstrated the considerable personnel cost that it takes to manage the toxicities associated with novel agents, including acalabrutinib, ibrutinib, and venetoclax.¹³ It can be challenging in a busy clinic to manage patients who are technically not on our schedule but are calling because they have questions about their new therapy, or they’re messaging us because they have adverse events. This is different from when chemoimmunotherapy was the standard of care, because with chemotherapy, many times the adverse events were so severe that the patients would go right to our emergency room where they would be managed by a different team. Many patients experiencing adverse events now come directly to our clinics, because these events are not severe enough that they need to be admitted but may be troublesome enough that they require clinical assistance to help them.

With the rapid evolution of CLL treatment paradigms, it can be challenging to keep up with all the new data. At our institution, we have been a part of 10 or more clinical trials that have been pivotal in this transition, with many ongoing trials. I think that my role, as a pharmacist, is to know the data inside and out; I often educate our HCP team and our patients on novel therapies. It is important to remember that not all patients have access to a CLL expert or even to a more general leukemia or lymphoma expert. In those settings, it is essential to have a team‑based approach where you have pharmacists and nurses who can assist patients.