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Practical Guidance on Optimizing CLL Care in the Era of Molecular Therapies

Emily Bucholtz Headshot
Emily Bucholtz, RPh
Nichole Fisher Headshot
Nichole Fisher, RN, BSN
Jeff P. Sharman, MD
Released: July 17, 2019
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Practical Guidelines on Optimizing CLL Care in the Era of Molecular Therapies

In this module, Jeff P. Sharman, MD, together with Nichole Fisher, RN, BSN, and Emily Bucholtz, RPh, review patient cases and emerging clinical data to provide expert guidance on optimizing care for patients with chronic lymphocytic leukemia (CLL).

The key points discussed in this module are illustrated with thumbnails from the accompanying downloadable PowerPoint slideset that can be found here or downloaded by clicking any of the slide thumbnails in the module alongside the expert commentary.

Clinical Care Options plans to measure the educational impact of this activity. A few questions will be asked twice: once before the discussion that informs the best choice, and then again after that specific discussion. Your responses will be aggregated for analysis, and your specific responses will not be shared.

Patient Case 1: A Young Patient With Normal Risk

Jeff P. Sharman, MD:
The first patient case involves a 58-year-old man who presented with asymptomatic lymphocytosis. Molecular characteristics demonstrated mutated IGHV and del(13q), and blood tests showed elevated β2-microglobulin and normal lactate dehydrogenase levels. During 3 years of observation, the patient developed more rapid accumulation of lymphocytes and several lingering upper respiratory infections. His hemoglobin level and platelet count fell to 10 g/dL and 90,000/mL, respectively.

There are various first-line therapeutic options available for physically fit, young patients with CLL and a normal risk of progression, but it is fair to say that the era of chemoimmunotherapy is giving way to targeted agents. Currently, it remains controversial whether chemoimmunotherapy is appropriate for any patient with CLL in the frontline setting. As I discuss later, the CLL10 study demonstrated superiority of frontline FCR over BR in fit patients with CLL without del(17p), particularly in those with mutated IGHV.[1,2]

Ibrutinib with or without rituximab was superior to chemoimmunotherapy as frontline therapy for CLL in phase III trials although there was no added benefit from rituximab.[3,4] Ibrutinib plus obinutuzumab is another regimen that has demonstrated benefits in frontline CLL and was approved by the FDA in early 2019. However, whether obinutuzumab offered additional benefit remains uncertain at this point.

In summary, this patient could be suitable for an intensive chemoimmunotherapy-based approach using fixed-duration FCR or sustained targeted therapy with ibrutinib with or without obinutuzumab.

Patient Case 2: An Older Patient With Normal Risk

Jeff P. Sharman, MD:
In the second patient case, we have an 84-year-old woman who presented with 5-year history of progressive lymphocytosis, and molecular characteristics showed no del(17p) or TP53 mutation. During the last 3 months, she has had 4-fold increase in lymphocyte count without any obvious infection. Her hemoglobin level and platelet count are still normal, but she complains of increasing fatigue.

Intensive chemoimmunotherapy such as FCR would be contraindicated for this older patient due to toxicity and BR is also quite difficult to tolerate for a patient in this age group. Ibrutinib has demonstrated superiority over BR as frontline treatment in older patients with CLL and adding rituximab did not yield additional benefit.[4] In the iLLUMINATE study, first-line ibrutinib plus obinutuzumab was superior to chlorambucil plus obinutuzumab in older or unfit patients with CLL.[5] Therefore, ibrutinib with or without obinutuzumab would be a good option for this patient. Currently, acalabrutinib is not approved in CLL, although it could be an option for patients who are intolerant to ibrutinib.

Venetoclax plus obinutuzumab is another new frontline regimen for CLL that was recently approved by the FDA based on results from the CLL14 study.[6] This regimen offers a fixed-duration therapy that showed improved outcomes compared with chlorambucil plus obinutuzumab, making it another good option for this patient. If the patient had del(17p) and/or TP53 mutation, I would recommend ibrutinib with or without obinutuzumab or venetoclax plus obinutuzumab because both regimens have shown robust activity in high-risk patients. Now let’s take a look at the data behind my recommendations.

Phase III CLL10 Trial of FCR vs BR in Previously Untreated CLL

Jeff P. Sharman, MD:
The phase III CLL10 study conducted by the German CLL Study Group compared first-line FCR with BR in 561 patients with CLL who were physically fit and lacking high-risk cytogenetics such as del(17p).[1] The primary endpoint was noninferiority of BR vs FCR with an HR < 1.388.

CLL10: PFS and OS

Jeff P. Sharman, MD:
In CLL10, median PFS was 41.7 months for BR vs 55.2 months for FCR with an HR of 1.643, demonstrating that BR is inferior to FCR.[1] OS, however, was quite similar with a 3-year OS rate of 91% for FCR and 92% for BR. Compared with BR, more toxicities from FCR were observed especially in those patients aged 65 years or older.

Based on these data, intensive chemoimmunotherapy such as FCR may be considered for patients younger than 65 years of age with favorable molecular characteristics including mutated IGHV, although its popularity is diminishing among experts. 

Phase II FCR300 Trial of FCR as Initial Therapy for CLL

Jeff P. Sharman, MD:
One of the rationales for considering intensive chemoimmunotherapy instead of targeted agents that may be associated with less toxicity is the durable benefit that some patients get from chemoimmunotherapy. In the original FCR dataset from a 300-patient phase II trial conducted at MD Anderson Cancer Center in frontline CLL, there is a plateau in PFS curve among patients with mutated IGHV, with more than 50% of patients remaining progression free at approximately Year 10 and beyond.[2] However, this benefit is most restricted to those patients with mutated IGHV. In patients with unmutated IGHV, fewer than 10% achieved long-term progression-free status. 

Phase III E1912 Trial of Ibrutinib Plus Rituximab vs FCR in Previously Untreated CLL

Jeff P. Sharman, MD:
The phase III E1912 trial directly compared ibrutinib plus rituximab with FCR in fit patients aged 70 years or younger with previously untreated CLL excluding those with del(17p).[3] In total, 529 patients were randomized 2:1 to receive either ibrutinib plus rituximab or FCR. The primary endpoint was PFS and secondary endpoints included OS and safety. 

E1912: PFS

Jeff P. Sharman, MD:
Although median PFS had not been reached at the time of analysis, ibrutinib plus rituximab significantly improved PFS compared with FCR in the intention-to-treat (ITT) population (HR: 0.35; 95% CI: 0.22-0.50; P < .00001). Similar results were seen in eligible patients as well with an HR of 0.32.[3]

E1912: PFS by IGHV Status

Jeff P. Sharman, MD:
When looking at PFS curves by IGHV mutation status, ibrutinib plus rituximab was profoundly better than FCR with considerably more dramatic separation of the curves in patients with unmutated IGHV (HR: 0.26; 95% CI: 0.14-0.50; P < .00001). In patients with mutated IGHV, however, there was considerable overlap of the curves (HR: 0.44; 95% CI: 0.14-1.36; P = .07).[3]

Again, these data could support the argument to use FCR in young and fit patients with CLL with mutated IGHV, although this is becoming increasingly less popular.

E1912: OS

Jeff P. Sharman, MD:
Besides PFS, ibrutinib plus rituximab also significantly prolonged OS compared with FCR in both the ITT population (HR: 0.17; 95% CI: 0.05-0.54; P < .0003) and eligible patients (HR: 0.13; 95% CI: 0.03-0.46; P < .0001).[3]

E1912: Causes of Death

Jeff P. Sharman, MD:
There were considerably more deaths from CLL in the FCR arm (6 out of 175) compared with the ibrutinib plus rituximab arm (1 out of 354).[3] Other causes of death were relatively sporadic—2 patients died from respiratory failure in the ibrutinib plus rituximab arm and 1 patient each died from metastatic colon cancer or drug overdose in the FCR arm.

E1912: Grade 3-5 Treatment-Related Adverse Events

Jeff P. Sharman, MD:
Despite longer duration of ibrutinib treatment, considerably lower rates of grade 3-5 hematologic toxicities and infection were seen for patients who received ibrutinib plus rituximab vs FCR. Grade 3-5 atrial fibrillation and hypertension occurred more frequently in the ibrutinib plus rituximab arm (2.9% vs 0% and 7.4% vs 1.9%, respectively), and bleeding was relatively uncommon (1.1% vs 0%).[3]

Nichole Fisher, RN, BSN:
In our experience, bleeding can be mitigated with temporary hold of ibrutinib. Also, we typically hold ibrutinib for 3-7 days around any medical procedures to help decrease the risk for bleeding. We have also seen diarrhea during ibrutinib therapy, but it is typically self‑limiting. Occasionally, we use antimotility agents to control diarrhea, but we rarely have to reduce dose for ibrutinib due to diarrhea.

Ibrutinib: Patient Counseling and Education

Emily Bucholtz, RPh:
There are several other factors on which we can educate patients. Ibrutinib is available both as capsules and tablets. We have found that switching from tablets to capsules has been successful for a few patients having gastrointestinal distress without having to stop treatment. Capsules also allow for gradual escalation of doses in situations where a patient’s ability to tolerate the full dose is unclear.

Ibrutinib can be taken with or without food, but we always remind patients that it is important to take this medication at the same time each day. Ibrutinib does have interactions with some food, such as grapefruit, so we educate patients about this in advance. We strongly emphasize ibrutinib compliance because there are data showing a greater risk of recurrence if it is discontinued for longer than just a few days.[7] We monitor these patients closely and really try to educate them regarding the importance of timely refills.

Regarding financial aspects of ibrutinib, most commercial insurance plans provide good coverage, and there is a copay card that decreases patient out-of-pocket cost to < $20 per month. Finding a specialty pharmacy that actually dispenses the drug can be a little tricky, but there are several of them throughout the country. Ibrutinib is a tier 5 specialty category medication under Medicare, so the patient copay is pretty high. Usually the first monthly copay in a calendar year is approximately $2,700 and then it falls to approximately $600 per month. Typically, there are grant programs for patients with CLL to assist them with copays, but unfortunately, the patient assistance program offered by the manufacturer of ibrutinib has very restrictive financial parameters. 

Phase III A041202 Trial of First-line Ibrutinib With or Without Rituximab vs BR in CLL

Jeff P. Sharman, MD:
Now let’s look at the data for older or unfit patients with CLL. The phase III A041202 study compared ibrutinib vs ibrutinib plus rituximab vs BR in previously untreated CLL or small lymphocytic lymphoma (SLL).[4] In total, 547 patients aged 65 years or older with adequate marrow reserve and creatinine clearance were enrolled. Patients who were receiving warfarin anticoagulant were excluded from participation. The primary endpoint was PFS and crossover from BR to ibrutinib arms was allowed.

A041202: PFS

Jeff P. Sharman, MD:
The primary endpoint of PFS was significantly improved with ibrutinib or ibrutinib plus rituximab vs BR (P < .001), and there was no significant difference between ibrutinib and ibrutinib plus rituximab arms (P = .49).[4] Median PFS was not reached for the ibrutinib-containing arms vs 43 months for the BR arm; 2-year PFS rates were 87% for ibrutinib, 88% for ibrutinib plus rituximab, and 74% for BR. As shown by these data, there was no clear benefit of adding rituximab to ibrutinib.

A041202: PFS by Cytogenetics

Jeff P. Sharman, MD:
When we look at those patients with high‑risk factors such as del(17p) or del(11q) determined by FISH testing, the magnitude of PFS benefit with ibrutinib was very pronounced, particularly in those with del(17p).[4] The commonly held belief among experts is that chemoimmunotherapy is contraindicated in patients with high-risk cytogenetics. For those patients with no del(17p) or del(11q), the PFS curves were considerably closer, although there was still some separation between ibrutinib arms and BR arm.

A041202: PFS by IGHV Status

Jeff P. Sharman, MD:
When it comes to PFS by IGHV mutation status, once again we see more pronounced benefit with ibrutinib among patients with unmutated IGHV.[4] For those patients with mutated IGHV, the separation of the PFS curves was considerably more narrow, as we saw in the E1912 trial discussed earlier. So if a patient strongly desires a fixed-duration therapy instead of long-term oral medication, you would reserve chemoimmunotherapy primarily for those with mutated IGHV.

A041202: Safety

Jeff P. Sharman, MD:
In terms of safety, the rates of hematologic toxicities, particularly neutropenia, were significantly higher in the BR arm compared with the ibrutinib arms. However, given that BR is not quite as difficult to tolerate as FCR, these differences were not as large as we saw in E1912. There were also significantly more incidences of febrile neutropenia in patients who received BR. The rates of atrial fibrillation, hypertension, and bleeding were higher in the ibrutinib arms.[4] Overall, grade ≥ 3 toxicities occurred at similar rates in patients receiving ibrutinib plus rituximab or ibrutinib alone.

Phase III RESONATE-2 Trial of Ibrutinib vs Chlorambucil in Older Patients With Untreated CLL

Jeff P. Sharman, MD:
One of the earlier trials that directly compared ibrutinib with chlorambucil is the randomized phase III RESONATE‑2 study, which included 269 patients aged 65 years or older with previously untreated CLL/SLL with no del(17p).[8] The primary endpoint was PFS, and secondary endpoints included OS, ORR, and safety.

RESONATE-2: Results

Jeff P. Sharman, MD:
Ibrutinib solidly outperformed chlorambucil monotherapy in both PFS (HR: 0.16; 95% CI: 0.09-0.28; P < .001) and OS (HR: 0.16; 95% CI: 0.05-0.56; P = .001).[8] ORR was also significantly higher with ibrutinib compared with chlorambucil (86% vs 35%, respectively; P < .001). So chlorambucil monotherapy really is only an option in low-resource situations or where ibrutinib is not available. 

Phase III iLLUMINATE Trial of First-line Ibrutinib Plus Obinutuzumab vs Chlorambucil Plus Obinutuzumab in CLL

Jeff P. Sharman, MD:
The standard of care in untreated older patients with CLL/SLL had evolved from chlorambucil monotherapy to chlorambucil plus obinutuzumab after the CLL11 study demonstrated superiority of the combination regimen.[9] The phase III iLLUMINATE study was launched to compare ibrutinib plus obinutuzumab with chlorambucil plus obinutuzumab in 229 patients with untreated CLL patients aged 65 years or older or with comorbidities.[5] The primary endpoint was PFS by independent review committee (IRC) in the ITT population. Secondary endpoints included PFS in high-risk patients, ORR, OS, and safety. 


Jeff P. Sharman, MD:
Once again, we see a substantial separation of PFS curves in favor of the ibrutinib‑containing regimen, with an HR of 0.23 and a highly statistically significant P value (P < .0001). Median PFS for ibrutinib plus obinutuzumab was not reached, and it was 19 months for chlorambucil plus obinutuzumab.[5]

iLLUMINATE: PFS by Subgroup

Jeff P. Sharman, MD:
The PFS benefit with ibrutinib was observed across all patient subgroups, and it was more pronounced in high-risk population including del(17p), del(11q), and mutated TP53.[5] Patients with unmutated IGHV derived more PFS benefit from ibrutinib vs those with mutated IGHV. Based on these results and other studies, an ibrutinib-based regimen would be a suitable therapeutic option in high-risk patients.

iLLUMINATE: Serious Adverse Events

Jeff P. Sharman, MD:
Serious adverse events related to ibrutinib included pneumonia (5%), atrial fibrillation (5%), and febrile neutropenia (4%). The death rate due to adverse events was higher in the ibrutinib arm (9% vs 3%, respectively) but median duration of treatment was much longer with ibrutinib (2.5 years vs 5.0 months, respectively).[5] Based on the results from iLLUMINATE, the FDA approved ibrutinib plus obinutuzumab as frontline treatment for CLL in January 2019.

Phase III CLL14 Trial of First-line Venetoclax Plus Obinutuzumab vs Chlorambucil Plus Obinutuzumab in CLL With Coexisting Medical Conditions

Jeff P. Sharman, MD:
The combination of venetoclax and obinutuzumab is another chemotherapy-free regimen approved by the FDA recently in frontline CLL. The approval was based on data from the phase III CLL14 trial, which enrolled  432 patients with previously untreated CLL who were randomized 1:1 to receive either fixed-duration venetoclax plus obinutuzumab or chlorambucil plus obinutuzumab. Venetoclax and chlorambucil were given for 1 year and obinutuzumab was given for 6 months.[6,10] The CLL14 study population was generally older with a median age of 72 years and had coexisting medical conditions (Cumulative Illness Rating Scale Score > 6 and/or calculated creatinine clearance < 70 mL/min). The primary endpoint was investigator‑assessed PFS, and secondary endpoints included IRC-assessed PFS, MRD negativity, ORR, and OS, and safety.


Jeff P. Sharman, MD:
At a median follow-up of 28 months, superior PFS was demonstrated for the venetoclax‑containing regimen with an HR of 0.35 (95% CI: 0.23-0.53; P < .001). The 2-year PFS rate also was higher in the venetoclax plus obinutuzumab arm compared with chlorambucil plus obinutuzumab arm (88% vs 64%).[6,10]

CLL14: PFS by IGHV and TP53 Status

Jeff P. Sharman, MD:
Overall, 14% of enrolled patients had TP53 deletion and/or mutation and 60% had unmutated IGHV. A PFS benefit with venetoclax was observed regardless of TP53 deletion/mutation status. By contrast, the PFS benefit with venetoclax was more pronounced in patients with unmutated IGHV vs those with mutated IGHV.[6,10]

CLL14: OS and Response

Jeff P. Sharman, MD:
No significant difference in OS was observed between the 2 groups and median OS was not reached in either arm (HR: 1.24; 95% CI: 0.64-2.40; P = .52).[6,10] Response rates also favored venetoclax-containing arm. ORR was 85% (CR rate of 50%) in the venetoclax plus obinutuzumab arm vs 71% (CR rate of 23%) in the chlorambucil plus obinutuzumab arm (P < .001).

CLL14: MRD Negativity

Jeff P. Sharman, MD:
When assessed by PCR, 76% of patients in the venetoclax plus obinutuzumab arm achieved MRD negativity (< 10-4) in peripheral blood vs 35% of patients in the chlorambucil plus obinutuzumab arm (P < .001). In bone marrow, MRD negativity rates were 57% and 17%, respectively (P < .001).[6,10] Overall, MRD negativity with venetoclax occurred early and was durable. There was an additional effort in this study to evaluate MRD status using next-generation sequencing–based technology, which was able to detect deeper levels of MRD negativity at < 10‑6. Using this method, MRD negativity rate (< 10-6) was also higher in the venetoclax arm.

CLL14: Safety

Jeff P. Sharman, MD:
Grade 3/4 adverse events including hematologic toxicities, infusion-related reaction, and infections generally occurred at similar rates between the 2 arms. The rate of metabolic complications was higher in the venetoclax plus obinutuzumab arm compared with the chlorambucil plus obinutuzumab arm (12% vs 6%, respectively; P = .02). Grade 5 events occurred in 8% and 4% of patients, respectively. Tumor lysis syndrome (TLS) was reported in 3 patients in the venetoclax plus obinutuzumab arm, but all cases occurred during treatment with obinutuzumab and before treatment with venetoclax.[6,10]

In my experience, venetoclax is a well-tolerated medication. For patients who are able to get through the dose ramp up, they are often satisfied with the medication and adverse events are generally infrequent.

Nichole Fisher, RN, BSN:
One of the main adverse events that we see for venetoclax is TLS. To help mitigate the risk, patients are typically started on allopurinol and hydration (typically 2-3 L/day), prior to venetoclax administration. For those patients at higher risk for TLS, some are given IV rasburicase, and some are hospitalized to initiate administration of venetoclax.

We have also seen grade 3/4 neutropenia and thrombocytopenia during venetoclax therapy, for which we typically do drug hold instead of dose reduction and initiate granulocyte-colony stimulating factor support. If they continue to occur with drug hold, we then dose reduce.

For those patients reporting gastrointestinal problems such as nausea, we recommend taking venetoclax at bedtime to help decrease the risk.

Jeff P. Sharman, MD:
We risk-stratify patients for TLS and those with intermediate risk or high risk or patients who have diminished creatinine clearance are typically hospitalized for the first 20-mg and 50-mg doses. The risk for TLS is substantially reduced once the patient has been at the 50-mg dose level for 1 week, and further dose escalations can be performed in an outpatient setting with close monitoring of lab results. For patients at lower risk for TLS, initial dose escalations can also be performed in an outpatient setting.

Venetoclax: Patient Counseling and Education

Emily Bucholtz, RPh:
Because dose schedule of venetoclax is very important regarding risk mitigation for TLS, we provide patient education at dispensing to make sure that they get allopurinol, know when to start it, and understand the schedule for venetoclax administration, We highlight the fact that venetoclax is taken with food at the same time each day. In addition, it is important that tablets are taken whole and not crushed or broken, so we remind patients to use the correct dose of tablets. Although nausea and vomiting have not been an issue with venetoclax, we do discuss these adverse events with patients and ensure that they have an antiemetic on hand. The same is true for managing fatigue and diarrhea.

Regarding out-of-pocket costs for patients, the manufacturer offers an easy-to-obtain copay card for those with commercial insurance and has a nice assistance program for Medicare patients as well.

Phase I/II ACE-CL-001 Trial of Acalabrutinib in CLL

Jeff P. Sharman, MD:
Acalabrutinib is another BTK inhibitor that is commercially available besides ibrutinib. Currently, it is not approved by the FDA for patients with CLL but is recommended by major guidelines as a treatment option for those patients who are intolerant to ibrutinib. Furthermore, FDA approval for acalabrutinib in CLL is expected soon based on new data that I will discuss later.

The phase I/II ACE-CL-001 trial was a multicohort study in CLL including a treatment-naive cohort that initially examined 2 different oral dosages of acalabrutinib: 100 mg twice daily and 200 mg once daily. After a protocol amendment, all patients received 100 mg twice daily until progression or toxicity. The primary endpoint was safety and secondary endpoints included investigator-assessed ORR, duration of response, and PFS.[11]

ACE-CL-001: Adverse Events of Clinical Interest

Jeff P. Sharman, MD:
In terms of adverse events of clinical interest, atrial fibrillation was seen in 6% of patients. Infections were relatively common at 83%, although most were not severe, such as urinary tract infections and sinusitis.[11] It is important, however, to monitor for atypical infections such as fungal infections when administering any of the BTK inhibitors, particularly if patients are on concurrent steroid therapy. It is hard to tell from the data whether acalabrutinib differentiates itself from ibrutinib regarding bleeding events. However, in my experience, there are fewer occurrences of ecchymosis and contusions, but this is just anecdotal. There was also some hypertension seen with acalabrutinib therapy, but again, we do not have enough data to know how hypertension rates compare among the available BTK inhibitors.

Nichole Fisher, RN, BSN:
Some of the most common adverse events with acalabrutinib that I have seen are bleeding events. Same as with ibrutinib, acalabrutinib should be held for approximately 3‑7 days around a medical procedure to mitigate bleeding risk. History of antiplatelet or any anticoagulation medications is important, as those also can increase the risk of bleeding. Diarrhea is the most common nonhematologic adverse event. We usually treat that with loperamide hydrochloride or diphenoxylate plus atropine to ensure that the patient is hydrated. If diarrhea continues or worsens to grade ≥ 3, then we would typically hold acalabrutinib until it resolves. Infections are also common, and one of the most common grade 3/4 events is pneumonia.

Jeff P. Sharman, MD:
Headaches are probably the most unique adverse events with acalabrutinib. They tend to occur very early, within the first month, and do not recur once they subside. Predisposition to headaches does not seem to matter regarding incidence. Headaches tend to be addressed easily with hydration, and sometimes caffeine can help. If necessary, either ibuprofen or acetaminophen can be used. It is uncommon for headaches to be very severe, and most patients are able to get through them without too much difficulty.

ACE-CL-001: Efficacy

Jeff P. Sharman, MD:
The 3-year PFS rate was 97% and median PFS was not reached. Investigator-assessed ORR was 97% with a CR rate of 5%. Median duration of response was not reached, and the 3-year duration of response rate was 98%. In high-risk patients including those with unmutated IGHV, del(17p), TP53 mutation, or complex karyotype, ORR was 100%.[11]

Acalabrutinib: Patient Counseling and Education

Emily Bucholtz, RPh:
Acalabrutinib can be taken with or without food every 12 hours, which can pose a potential compliance problem. We encourage patients to use pill boxes or phone reminders to help them remember to take both doses per day. It is also important that this medication is not taken with grapefruit juice. The potential for bruising is less with acalabrutinib compared with ibrutinib, which is a nice benefit that many patients notice. Headaches do occur in some patients but usually they are fairly minor and resolve easily with acetaminophen or ibuprofen.

Acalabrutinib also has a copay card available for patients with private insurance. For Medicare patients, the manufacturer has a helpful assistance program. We have been very successful in getting financial assistance for our Medicare patients when coverage is denied due to the lack of indication in CLL. 

Phase III ELEVATE-TN Trial of Acalabrutinib With or Without Obinutuzumab vs Obinutuzumab Plus Chlorambucil in Previously Untreated CLL

Jeff P. Sharman, MD:
It is worth noting that acalabrutinib is being investigated as frontline therapy for CLL in the phase III ELEVATE-TN trial. This is a 3-arm study that compares acalabrutinib with or without obinutuzumab with obinutuzumab plus chlorambucil in 535 untreated CLL patients aged 65 years or older or those with significant comorbidities.[12] The primary endpoint was PFS (acalabrutinib plus obinutuzumab vs chlorambucil plus obinutuzumab). Unfortunately, this study is not statistically powered to definitively answer the question of whether obinutuzumab adds benefit to acalabrutinib, but it may provide some clues.

In June 2019, it was announced that ELEVATE-TN met its primary endpoint at interim analysis and full results are eagerly awaited from this trial, which are expected to be presented later in 2019.

Patient Case 3: An Elderly Patient With Relapsed Disease

Jeff P. Sharman, MD:
We are now moving to the relapse/refractory setting. This third patient case is a 72-year-old man who presented with CLL 6 years ago and was treated with BR after 2 years of observation. The previous healthcare provider did not test for IGHV mutation or perform FISH testing. The patient had disease progression 4 years later with symptomatic bulky adenopathy and modest lymphocytosis in the absence of anemia or thrombocytopenia. Molecular characteristics showed unmutated IGHV as well as del(11q) and del(13q). Ibrutinib was initiated but the patient developed symptomatic atrial fibrillation after 3 months and was also bothered by hand cramps and arthralgias.

In the relapse setting, chemoimmunotherapy has a minimal role due to the lack of supporting data. Acalabrutinib is recommended as a treatment option for patients who are intolerant of ibrutinib by major guidelines. Therefore, acalabrutinib is a good option for this patient. Idelalisib plus rituximab and duvelisib monotherapy could be potentially considered but PI3K inhibitors are shifting more to the later lines. Based on the phase III MURANO data,[13] which we will discuss later in this module, venetoclax plus rituximab is also a reasonable option for this patient.

Phase III RESONATE Trial of Ibrutinib vs Ofatumumab in Previously Treated CLL/SLL

Jeff P. Sharman, MD:
The phase III RESONATE trial looked at ibrutinib vs ofatumumab in patients with previously treated CLL/SLL.[14] In total, 391 patients were randomized 1:1 to receive either ibrutinib or ofatumumab, and those receiving ofatumumab were eligible for crossover upon disease progression. The primary endpoint was PFS.


Jeff P. Sharman, MD:
Both PFS and OS favored ibrutinib despite the crossover trial design. There was a 78% reduction in risk of progression or death with ibrutinib (HR: 0.22; 95% CI: 0.15-0.32; P < .001). There was also a significant OS benefit with ibrutinib (HR: 0.43; 95% CI: 0.24-0.79; P = .005).[14]

RESONATE: Summary of Adverse Events

Jeff P. Sharman, MD:
Rates of grade 3/4 toxicities from ibrutinib were relatively low with some hematologic toxicities in the form of neutropenia, thrombocytopenia, and anemia. All-grade infection was the most common adverse event at 70%, with 8% of grade ≥ 3 pneumonia. Although bleeding/bruising was common, grade ≥ 3 events were rare with no grade 5 events. Atrial fibrillation was observed in 5% of patients, including 3% with grade ≥ 3 events.

Phase III MURANO Trial of Venetoclax Plus Rituximab vs BR in Previously Treated CLL/SLL

Jeff P. Sharman, MD:
The phase III MURANO trial randomly assigned 389 patients with relapsed/refractory CLL/SLL to receive  venetoclax for up to 2 years plus rituximab for 6 cycles or BR.[13] The primary endpoint was investigator-assessed PFS and secondary endpoints included IRC-assessed PFS, ORR, OS, MRD negativity, and safety. 


Jeff P. Sharman, MD:
We again see a substantial PFS benefit in favor of the targeted therapy approach, with the median not reached for those patients who received venetoclax plus rituximab and 17 months for those receiving BR (HR: 0.17; 95% CI: 0.11-0.25; P < .001).[13] There was also an OS benefit associated with venetoclax plus rituximab (HR: 0.48; 95% CI: 0.25-0.90). 

MURANO: Safety

Jeff P. Sharman, MD:
In terms of grade 3/4 adverse events, we see a higher rate of neutropenia with venetoclax plus rituximab vs BR (58% vs 39%). However, as mentioned previously, occasional use of filgrastim or a temporary dose hold generally alleviates neutropenia. Febrile neutropenia occurred less frequently with venetoclax plus rituximab vs BR (4% vs 10%, respectively).[13] TLS remains a concern, so careful monitoring is essential for patients receiving venetoclax.

Phase III Trial of Idelalisib Plus Rituximab vs Placebo Plus Rituximab Followed by Idelalisib in Relapsed CLL

Jeff P. Sharman, MD:
Looking at the role of PI3K inhibitors, final results from the pivotal phase III trial that led to the approval of idelalisib in CLL were published recently.[15] The trial examined idelalisib plus rituximab vs placebo plus rituximab in 220 patients with heavily pretreated CLL. The primary study was followed by an extension study using single-agent idelalisib. The primary endpoint was PFS, and secondary endpoints included ORR, OS, and safety.

Phase III Trial of Idelalisib Plus Rituximab in Relapsed CLL: PFS and OS

Jeff P. Sharman, MD:
The primary endpoint of PFS was prolonged with the addition of idelalisib to rituximab (median: 19.4 vs 6.5 months) and so was median OS (40.6 vs 34.6 months). At the time this study was conducted, patients with previous BTK inhibitor exposure were not included because these drugs were being developed side by side. So we do not really have data from prospective trials to know the efficacy of PI3K inhibitors following previous ibrutinib. 

Phase III DUO Trial of Duvelisib vs Ofatumumab in Relapsed/Refractory CLL/SLL

Jeff P. Sharman, MD:
The other PI3K inhibitor that has phase III data in CLL is duvelisib, a dual inhibitor of PI3K-δ and PI3K-γ. The phase III DUO trial directly compared duvelisib with ofatumumab in patients with relapsed/refractory CLL/SLL and no previous treatment with BTK or PI3K inhibitors.[16] The primary endpoint was PFS.

DUO: PFS (Primary Endpoint)

Jeff P. Sharman, MD:
Duvelisib demonstrated superiority over ofatumumab regarding PFS (median: 13.3 vs 9.9 months, respectively; HR: 0.52; P < .0001).[16] Based on data from the DUO trial, the FDA approved duvelisib for treating patients with relapsed/refractory CLL/SLL who have received ≥ 2 previous therapies in September 2018.

Phase III Trials of PI3K Inhibitors in Relapsed/Refractory CLL: Safety

Jeff P. Sharman, MD:
The most common grade ≥ 3 adverse event associated with PI3K inhibitors is neutropenia, which can be managed using standard approaches.[15,16] A noticeable adverse event with PI3K inhibitors included diarrhea that tends to be inflammatory rather than just a motility issue. Therefore, interruption of therapy until diarrhea subsides and initiation of corticosteroids are recommended for these patients. Rates of grade ≥ 3 diarrhea can be quite high, and it can be very symptomatic for patients. In the setting of any fever or uncertain infection, cytomegalovirus reactivation should be considered. Pneumocystis pneumonia prophylaxis is also recommended for patients receiving PI3K inhibitors, as it occurs almost exclusively in patients who did not receive proper prophylaxis.

Nichole Fisher, RN, BSN:
As Dr. Sharman just mentioned, some of the clinically significant adverse events with PI3K inhibitors that I have seen are diarrhea and colitis. They are typically managed with drug holds and delays and initiation of budesonide to help decrease the time to diarrhea resolution. Usually, diarrhea resolves in approximately 1 week to 1 month after drug hold. Increases in liver function test levels can also be seen in some patients receiving PI3K inhibitors. For those patients, a drug hold is recommended, followed by dose reduction if necessary. Pneumonitis is also a common adverse event, so evaluation should be performed if the patient is experiencing cough, shortness of breath, or hypoxia. Again, drug hold is recommended until resolution of symptoms.

PI3K Inhibitors: Patient Counseling and Education

Emily Bucholtz, RPh:
Idelalisib is taken twice daily so it is important to educate patients on correct timing and drug compliance. It can be taken with or without food, and it does not have any particular food interactions to be aware of. It is important for patients to take the tablets as a whole, so if a dose reduction is needed based on adverse events, it is best to get a prescription for a reduced dose rather than splitting tablets. The manufacturer has a good financial assistance program for Medicare patients, as well as a copay card for patients with private insurance.

Duvelisib has a Risk Evaluation and Mitigation Strategy (REMS) program associated with it. Although there is no particular physician or patient agreement required as part of the REMS strategy, it is important that a patient safety wallet card is provided to patients, along with education regarding the importance of presentation of the card to any emergency department or urgent care physician they come in contact with. Duvelisib is also taken twice daily, with or without food and should be taken whole. As with idelalisib, there are no particular food interactions. 

Phase III ASCEND Trial of Acalabrutinib vs Idelalisib Plus Rituximab or BR in Previously Treated CLL

Jeff P. Sharman, MD:
The phase III ASCEND trial compared acalabrutinib with investigator’s choice of idelalisib plus rituximab or BR in previously treated CLL. Patients with previous exposure to venetoclax or BTK inhibitors were excluded. A press release in May 2019 announced that the trial has met its primary endpoint of PFS and will stop early. Data from the ASCEND study were recently presented at European Hematology Association 2019 annual meeting.[17] 


Jeff P. Sharman, MD:
PFS was significantly improved with acalabrutinib vs idelalisib plus rituximab or BR (HR: 0.31; 95% CI: 0.20-0.49; P < .0001). Median PFS was not reached with acalabrutinib and it was 16.5 months in patients receiving idelalisib plus rituximab or BR. The 12-month PFS rate was 88% and 68%, respectively.[17] Similar PFS benefit was observed in patients with high-risk cytogenetics. However, there was no difference in OS (HR: 0.84; 95% CI: 0.42-1.66; P = .6) and median OS was not reached in either arm.

ASCEND: Safety

Jeff P. Sharman, MD:
Headache occurred more frequently in the acalabrutinib arm, although grade ≥ 3 events were rare (1%). Rates of neutropenia and diarrhea were lower in patients receiving acalabrutinib. Among adverse events of clinical interest for acalabrutinib, bleeding occurred in 26% of patients, with 2% being grade ≥ 3. Rates of atrial fibrillation and hypertension were 5% and 3%, respectively.[17]

Phase III ELEVATE-RR Trial of Ibrutinib vs Acalabrutinib in Patients With High-Risk Relapsed/Refractory CLL

Jeff P. Sharman, MD:
In terms of awaited data, one of the highly anticipated ongoing studies is the phase III ELEVATE-RR trial with a head-to-head comparison of ibrutinib vs acalabrutinib in patients with high‑risk relapsed/refractory CLL.[18] This is a noninferiority trial enrolling 533 patients, and the primary endpoint is PFS. Key secondary endpoints include OS and safety. The trial is fully accrued and it is uncertain when data from this study will be available. Results from ELEVATE-RR should provide insights into the differences between these 2 BTK inhibitors.

Phase I/II ACE-CL-001 Trial of Acalabrutinib in Ibrutinib-Intolerant Cohort

Jeff P. Sharman, MD:
Finally, we have data from the previously presented phase I/II ACE-CL-001 study that looked specifically at acalabrutinib in patients who were intolerant of ibrutinib.[19] Of 33 patients, 23 remained on acalabrutinib, and there were no dose reductions. Of 61 ibrutinib-related adverse events, 72% did not recur and 13% recurred at a lower grade with acalabrutinib. The ORR was 76% and 1-year PFS rate was 83.4%. Therefore, in patients who are intolerant to ibrutinib, acalabrutinib is a reasonable alternative.

Nichole Fisher, RN, BSN:
I have a patient who experienced pneumonitis while on ibrutinib therapy. After several doses of steroids, ibrutinib was discontinued due to intolerance. The patient then received acalabrutinib, pneumonitis has subsided, and the patient is doing quite well.

Emily Bucholtz, RPh:
We have had 2 patients in the clinic who had some interesting adverse events from ibrutinib. One patient had pretty pronounced mucositis and the other one had a lot of changes in fingernails. Both patients were switched to acalabrutinib due to ibrutinib intolerance, and they have been maintained successfully on acalabrutinib.


Jeff P. Sharman, MD:
In summary, frontline therapies for CLL have expanded rapidly with several reasonable options including ibrutinib-based and venetoclax-based regimens. Treatment choices in patients with previously untreated CLL depend on age/fitness and molecular characteristics. In relapsed/refractory CLL, available treatment options include BTK, BCL-2, and PI3K inhibitors. Previous therapies and individual patient characteristics can determine the optimal treatment choice in the relapsed/refractory setting.

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