Key Takeaways

• When selecting treatment for chronic lymphocytic leukemia, consider IGHV mutation status, del(17p), mutated TP53, age, comorbidities, and patient preferences.
• First-line therapy recommendations are acalabrutinib ± obinutuzumab, ibrutinib, venetoclax + obinutuzumab, and—if del(17p)/TP53 mutation present—zanubrutinib.
• Treatment selection for relapsed/refractory chronic lymphocytic leukemia depends on the first-line therapy, with PI3K inhibitors an option for high-risk patients ineligible for venetoclax and who failed or are ineligible for a BTK inhibitor.
  

The treatment paradigm for patients with chronic lymphocytic leukemia (CLL) has undergone rapid evolution in recent years. In this commentary, William G. Wierda, MD, PhD, discusses select recent results in CLL treatment and their potential influence on the current standard of care.

When to Treat
A patient’s journey with CLL often begins with an incidental diagnosis of elevated absolute lymphocyte count by their primary care provider, followed by a referral to a hematologist/oncologist. Patients typically initially are asymptomatic and unaware that they have CLL, although on rare occasion they may have enlarged lymph nodes due to CLL involvement. Most patients are monitored until they develop an indication to start treatment. This can be progressive B symptoms such as fatigue, night sweats, or weight loss; progressive lymphadenopathy; extranodal involvement; or perhaps bone marrow infiltration with correspondingly low hemoglobin level and platelet count. Of importance, even with high-risk features, patients do not need treatment in the absence of an aforementioned treatment indication.

Today, targeted agents produce substantially better outcomes than the previous standard of care, chemoimmunotherapy. However, patients with del(17p) are still high risk for shorter progression-free survival (PFS) and treatment-refractory disease, as well as a shorter time to treatment in the watch-and-wait phase. Patients with del(11q) typically have shorter time to treatment, but these patients do very well on current targeted treatment. Although mutated IGHV is associated with shorter time to treatment, responses to newer agents are similar with mutated or unmutated IGHV.

Current Targeted Therapies
BTK Inhibitors
Two BTK inhibitors are currently approved by the FDA for CLL: ibrutinib and the second-generation inhibitor acalabrutinib, which is highly selective for BTK. Another second-generation BTK inhibitor, zanubrutinib, is approved for other B-cell malignancies and is expected to be approved for CLL. All have comparable efficacy, with response rates >90% as a single agent or in combination regimens with an anti-CD20 monoclonal antibody. For example, in RESONATE-2, PFS at 7 years was 59% with ibrutinib, and in ELEVATE-TN, PFS at 5 years was 72% with acalabrutinib alone and 84% with the addition of obinutuzumab.

BTK Inhibitors: Safety and AE Management
Selectivity and the adverse event (AE) profile differ between first- and second-generation BTK inhibitors. The more selective the inhibitor for BTK, the fewer expected AEs. BTK inhibitors can cause AEs such as atrial fibrillation, bleeding disorders, bruises, infectious complications, and arthralgias potentially related to off-target kinase inhibition. The most important AEs associated with BTK inhibitors include grade 3/4 cytopenias such as neutropenia, which is most common with ibrutinib (13%-29%). Thrombocytopenia is less common with acalabrutinib and zanubrutinib (5%-10%) than ibrutinib (up to 17%). Grade 3-5 infections are seen in up to 29% of patients receiving ibrutinib and approximately 20% of patients receiving acalabrutinib and zanubrutinib. Of note, lymphocytosis on treatment initiation is seen in more than three quarters of patients receiving ibrutinib but only 26% and 41% of patients receiving acalabrutinib and zanubrutinib, respectively.

Atrial fibrillation is of particular concern, as approximately 6% of patients with CLL will develop this toxicity, and it is a known risk with BTK inhibitors. For example, in the ELEVATE-RR study, atrial fibrillation was seen in 16% of patients receiving ibrutinib vs 9% of patients receiving acalabrutinib, and in the RESONATE study, atrial fibrillation was seen in 3% of patients receiving ibrutinib vs 0% of patients receiving ofatumumab. This risk increases as patients remain on treatment for an extended time; in a retrospective review, treatment-emergent atrial fibrillation in CLL was seen in 9% of patients at 6 months, 12% at 1 year, and 16% at 2 years.

Other toxicities seen with BTK inhibitors include bleeding and bruising, diarrhea, nausea, musculoskeletal events, pain, arthralgias, headache, and fatigue. Most of these are less common and more tolerable with the second-generation inhibitors, which improves adherence. The treatment-related discontinuation rate with ibrutinib is approximately 20%. By contrast, in the ELEVATE-RR study it was 15% with acalabrutinib, and in the ALPINE study, only 8% of patients discontinued treatment with zanubrutinib due to AEs.

Toxicity management with BTK inhibitors is important to help patients remain on maintenance treatment; dose reductions or interruptions can potentially diminish outcomes. Neutropenia should be managed with growth factors, and infections should be managed aggressively (eg, with intravenous immunoglobulin). Lymphocytosis may occur with treatment initiation but is not a reason to stop treatment and resolves as patients continue treatment. Caffeine can treat acalabrutinib-related headache, an AE that can occur in the first weeks to month of treatment and that typically resolves. Ibrutinib can be dose reduced to manage cardiac toxicity.

BCL-2 Inhibitors
Venetoclax is the sole approved BCL-2 inhibitor for CLL and is given with obinutuzumab. This combination was approved based on the phase III CLL14 trial, which showed a 63% PFS rate at 5 years with venetoclax and obinutuzumab vs 27% with chlorambucil and obinutuzumab. Investigational BCL-2 inhibitors include lisaftoclax, which in early clinical trials appears to have efficacy and appears safe. Alternative second-generation BCL-2 inhibitors will need cautious investigation and clinical development to assess for improved toxicity profiles.

BCL-2 Inhibitors: Safety and AE Management
The most common toxicity reported from CLL14 is grade ≥3 neutropenia, which was seen during treatment in 51.9% of patients receiving venetoclax/obinutuzumab vs 47.2% of patients receiving chlorambucil/obinutuzumab. This can usually be managed with 1-2 days of filgrastim with no dosing modification; serial recurrence or febrile neutropenia may warrant holding treatment, then restarting at a lower dose. Tumor lysis syndrome can be mitigated by using ramp-up dosing for venetoclax, including for patients at high risk due to bulky disease or a high lymphocyte count.

PI3K Inhibitors
Two PI3K inhibitors have been approved by the FDA to treat relapsed/refractory CLL: idelalisib combined with rituximab and duvelisib after ≥2 prior therapies. Idelalisib was approved based on a clinical trial of 220 patients with relapsed CLL showing a median PFS of 10.7 months with idelalisib plus rituximab vs 5.5 months with placebo plus rituximab. Duvelisib was approved based on the phase III DUO study (N = 196) in which the median PFS was 16.4 months with duvelisib vs 9.1 months with ofatumumab (HR: 0.40), with response rates of 78% and 39%, respectively.

Copanlisib, zandelisib, and parsaclisib are all PI3K inhibitors in clinical trials for CLL. Umbralisib was approved for marginal zone lymphoma and follicular lymphoma. However, following results from the UNITY-CLL trial showing a higher risk of death with ublituximab/umbralisib vs obinutuzumab/chlorambucil, in June 2022 the sponsor withdrew the application for approval of this combination in CLL/small lymphocytic lymphoma (SLL).

PI3K Inhibitors: Safety and AE Management
The 3 biggest concerns with PI3K inhibitors are hepatotoxicity, colitis and associated diarrhea, and pneumonitis. Hepatotoxicity of any grade can occur in up to 70% of patients (grade ≥3: 3%-40%) but is limited to elevations in aspartate aminotransferase and alanine aminotransferase, with no increase in bilirubin or alkaline phosphatase. Because this can be severe and fatal, patients should be monitored every 2 weeks for the first 3 months, then monthly, with treatment interruption for any grade 3/4 events. Diarrhea/colitis is seen in up to 77% of patients, with grade ≥3 in up to 42%. All cases should be urgently evaluated, with late-onset grade 2 diarrhea treated as higher-grade toxicity. To manage this, hold the PI3K inhibitor for higher-grade events and consider steroids or alternative treatments for severe events. Pneumonitis (noninfectious) is seen in 1% to 17% of patients and is associated with treatment-related, off-target immune dysfunction. Of note, a broad differential should be considered for respiratory complaints. This can be best managed proactively with infection prophylaxis (eg, Pneumocystis jirovecii pneumonia). If pneumonitis is truly suspected, hold the PI3K inhibitor and consider steroids.

CD20-Targeted Monoclonal Antibodies
The 2 most commonly used CD20 monoclonal antibodies in CLL are rituximab and obinutuzumab. As a class, an important consideration is that hepatitis B can be reactivated. There is also an increased rate of viral infections. In addition, infusion reactions are common but manageable. More hypertension is seen with obinutuzumab, as are some cytopenias, which are not associated with rituximab. This manifests as more leukopenia, neutropenia, and thrombocytopenia with venetoclax plus obinutuzumab or even with obinutuzumab alone (eg, in older patients). Rituximab has been extensively used in CLL, and the issues of joint pain, backache, and dizziness are well known and not deterrents.

CLL Treatment Selection: Key Factors
The short list of patient characteristics to consider when selecting treatment include IGHV mutation status, del(17p), and mutated TP53. In patients with prior BTK inhibitor treatment, assessing for BTK and PLCG2 mutations can be helpful if there is the question of poor treatment compliance. Age and comorbidities are factors in many settings and tumor types, including CLL, as patients with these issues tend to have more toxicities regardless of treatment.

First-line therapy recommendations (category 1, per the National Comprehensive Cancer Network) for patients without del(17p)/TP53 mutation are acalabrutinib with or without obinutuzumab, ibrutinib monotherapy, and venetoclax plus obinutuzumab. First-line recommendations for patients with del(17p)/TP53 mutation are the same plus zanubrutinib. Chemoimmunotherapy is not recommended due to low response rates in this subgroup.

But how are physicians to choose between BTK and BCL-2 inhibitors? No compelling survival data direct to either inhibitor, with patient preference and the risks of off-target effects often being the deciding factors. The BTK inhibitors are easier to initiate, require less initial monitoring, and are given continuously until progression. There is no need to monitor for tumor lysis syndrome (unless combined with a CD20 monoclonal antibody). However, there is notable risk of cardiac toxicity with BTK inhibition. Nevertheless, these agents provide very favorable outcomes for patients with high-risk features such as del(17p)/TP53 mutation. Either approved BTK inhibitor will produce good responses in patients with CLL. Of importance, BTK inhibitors should not be taken with strong CYP3A-inducing drugs or foods, such as grapefruit, Seville oranges, and St John’s wort (an herb). Also, BTK inhibitors should be avoided in patients who are receiving immunosuppressive therapy or live vaccines.

The BCL-2 inhibitor venetoclax induces deep remissions, including undetectable measurable residual disease (MRD) in blood and marrow, in the majority of patients. It is effective in patients with del(17p)/TP53 mutation, but some physicians may prefer first-line therapy with a BTK inhibitor (with or without obinutuzumab) as continuous maintenance treatment. Venetoclax + obinutuzumab is commonly used to treat patients without del(17p)/TP53 mutation but has notable activity treating patients with del(17p)/TP53 mutation.

Treatment selection for relapsed/refractory CLL depends strongly on the first-line therapy. For example, a patient refractory to a BTK inhibitor would logically receive a BCL-2 inhibitor next, and vice versa. PI3K inhibitors were developed before many current options for CLL were available, and their current use is quite limited. That said, PI3K inhibitors remain options for high-risk patients who failed a BTK inhibitor or who cannot access that therapy and are not candidates for venetoclax.

Other Clinical Challenges in CLL
COVID-19
COVID-19 infection is a notable risk for patients with CLL, for whom vaccine responsiveness in general can be very modest, so some physicians have been recommending pre-exposure prophylaxis with tixagevimab plus cilgavimab. This is regardless of patients’ vaccination status or antibody levels.

Antibiotic Prophylaxis
Patients with CLL should receive antibiotic prophylaxis following treatment. For obinutuzumab or rituximab, the subsequent antibiotic is typically acyclovir. Other antibiotics used in CLL include sulfamethoxazole/trimethoprim and pentamidine. The antibiotics can be stopped either with a 3-month timed approach or by assessing CD4+ cell counts after stopping therapy. However, if a patient is receiving a BTK inhibitor, some physicians may continue acyclovir indefinitely.

Additional Monitoring
Patients also should be monitored for CLL-associated complications: autoimmune phenomena, Richter transformation, and second malignancies. Second cancers are typically skin cancer, so patients are recommended to be regularly screened by a dermatologist.

Future Directions in CLL
CAPTIVATE
At the 2022 American Society of Clinical Oncology Annual Meeting, my colleagues and I presented 3-year follow-up results from the fixed-duration (FD) cohort of the randomized phase II CAPTIVATE study of frontline ibrutinib followed by ibrutinib plus venetoclax in CLL/SLL. In the FD cohort primary analysis, the trial met its primary endpoint with a complete response (CR)/CR with incomplete blood count recovery (CRi) rate of 57%. Patients with del(17p)/TP53 mutation (n = 27) and unmutated IGHV (n = 89) had an overall response rate (ORR) of 97%, including CRs in more than one half of patients. The 3-month posttreatment rate of MRD <10^-4 (undetectable MRD) was 57%, which dropped to 43% at 12 months post treatment, indicating durability in responses. At 3 years, median PFS had not been reached for any population. Of note, there were more progression events than expected with del(17p). Clinical benefit of FD venetoclax plus ibrutinib over venetoclax plus obinutuzumab is yet to be determined. The CLL17 trial of the German CLL Study Group will provide insights in this regard.

GLOW
Results from the phase III GLOW trial were reported at the 2021 European Hematology Association Annual Congress and more recently published in the New England Journal of Medicine. GLOW was a first-line study of FD ibrutinib plus venetoclax vs chlorambucil plus obinutuzumab in previously untreated CLL (N = 211). Ibrutinib plus venetoclax demonstrated superior PFS (HR: 0.216; P <.0001) and had a CR rate of 38.7%, considerably higher than the CR/CRi rate of 11.4% for chlorambucil plus obinutuzumab. Undetectable MRD rates also were higher with ibrutinib plus venetoclax in both the bone marrow and peripheral blood. The CR/CRi and undetectable MRD rates were slightly lower with ibrutinib plus venetoclax in GLOW compared with those observed in CAPTIVATE. This may be due to the older age and presence of comorbidities for patients in GLOW, who may not have been able to tolerate as much treatment as those in CAPTIVATE. Regarding safety in GLOW, there was a slightly higher rate of neutropenia among patients who received chlorambucil plus obinutuzumab; more in-class toxicities associated with BTK inhibitors, such as hypertension and atrial fibrillation, were observed in the ibrutinib plus venetoclax arm.

Pirtobrutinib
Patients who fail acalabrutinib, ibrutinib, and/or zanubrutinib should be considered for clinical trials of the noncovalent BTK inhibitors pirtobrutinib or nemtabrutinib, particularly those who also have failed venetoclax-based treatment. The phase I/II BRUIN study of pirtobrutinib enrolled more than 250 patients with CLL who had previously received a covalent BTK inhibitor. Responses were seen in nearly 70% of patients, and among patients who had received various prior therapies (BTK inhibitors, BCL-2 inhibitors, PI3K inhibitors, or chemotherapy), all responded similarly. Moreover, median PFS has not yet been reached, and only 1% of patients discontinued due to AEs. ORR was similar among patients with CLL with and without the BTK C481 mutation, confirming that pirtobrutinib overcomes this resistance mechanism. The importance of pirtobrutinib for patients with previous BTK inhibitor exposure cannot be understated.

TRANSCEND CLL 004
The open-label phase I/II TRANSCEND CLL 004 trial examined the CD19-directed CAR T-cell therapy lisocabtagene maraleucel (liso-cel) in relapsed/refractory CLL. In the monotherapy cohort, ORR—both in total population or when examined by either dose level—was in the 80% range, with the CR rate up to 56% depending on dose. The blood and bone marrow undetectable MRD rates were up to 75%. Many responses were quite durable, even among patients who had failed multiple lines of conventional or targeted therapies. Among patients receiving combined ibrutinib and liso-cel, ORR was 95% in the overall population (n = 19), with 63% of patients achieving a CR/CRi and 89%/79% achieving peripheral blood/bone marrow unconfirmed MRD.

Expert Guidance on Treatment Selection: Interactive Decision Support Tool
CLL can be a challenging disease to manage. To get the perspectives of multiple experts, take a look at our updated Interactive Decision Support Tool for CLL, which offers treatment recommendations customized to common patient scenarios from 2 panels of 5 experts.