Clinical outcomes for patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL; hereafter referred to as CLL) have improved substantially in recent years, due in part to the availability of multiple new therapies, especially small-molecule covalent Bruton’s tyrosine kinase inhibitors (cBTKis).¹ Resistance or intolerance to cBTKis remains a major challenge, however, and data on effective therapies in the post-cBTKi setting are limited. Moreover, published data on the optimal selection, combination, and sequencing of agents for patients with refractory or resistant disease are lacking. The advent of alternative agents with distinct mechanisms of action, such as noncovalent BTKi (ncBTKi) like pirtobrutinib or B-cell lymphoma 2 inhibitors (BCL2i) like venetoclax, provides additional treatment options for patients with relapsed/refractory CLL following cBTKi therapy.

Treatment of cBTKi Resistance and Intolerance

cBTKis have demonstrated good efficacy and tolerability in CLL, yet most patients eventually discontinue treatment, mainly due to resistance or intolerance.¹ For patients bearing common BTKi resistance mutations (eg, at the C481 position), re-treatment using an alternative cBTKi is not recommended since all cBTKis interact with the same BTK binding site.^1,2 In contrast, binding of a ncBTKi like pirtobrutinib is independent of C481 and can thus overcome cBTKi resistance.³ Apart from resistance, some patients discontinue cBTKi due to treatment-related adverse events, which may account for approximately half of all discontinuations.^4,5 In one study, 41% of patients had discontinued first-line ibrutinib (63.1% due to adverse events and 15.8% to disease progression).⁶ Another found that 39% of patients with CLL will discontinue ibrutinib within 5 years, with nearly 22% due to toxicity or complications.⁷

Selection of Post-cBTKi Therapy

The BCL2i venetoclax and the ncBTKi pirtobrutinib have been shown to be effective in the treatment of relapsed/refractory CLL and are now considered standard-of-care therapy for patients who previously received a cBTKi.^8-12 Preferred treatment options in this setting include BCL2i-containing regimens, a ncBTKi for patients with resistance or intolerance to cBTKi, or an alternative cBTKi in the setting of intolerance to the initial cBTKi used.¹² Choice of agent depends on various factors such as prior treatment, comorbidities, comedications, and patient preference.¹³ Patients who were treated with first-line venetoclax plus rituximab may receive a cBTKi. Treatment for those who previously received a cBTKi depends on the reason they discontinued first-line therapy. Patients who discontinued due to intolerance to a given cBTKi could receive an alternative cBTKi, ncBTKi, or venetoclax/rituximab (if venetoclax-naive) (Figure 1).^5,14,15 Those who discontinued due to resistance and disease progression should be switched to an agent with a different mechanism of action such as a ncBTKi (eg, pirtobrutinib) or else a venetoclax-based regimen.¹⁵

Venetoclax Plus Rituximab

Venetoclax, alone or in combination with rituximab, is an established treatment option for venetoclax-naive, cBTKi-refractory patients.⁵ The MURANO phase III open-label trial evaluated the combination of venetoclax and rituximab vs bendamustine and rituximab in 389 patients with CLL who had received at least one prior line of therapy. Venetoclax was administered once daily for up to 2 years; intravenous (IV) rituximab was administered monthly for 6 months. Bendamustine/rituximab was also given via IV for 6 months. The treatment arms were well balanced. The median number of prior lines of therapy was one, and most patients had received prior chemotherapy with or without anti-CD20 antibody therapy. A minority of patients (2%) had received prior cBTKi therapy. A 17p deletion was detected in 27% of patients, TP53 mutations in 26%, and 68% had unmutated IgHV. The primary endpoint was independent review committee–assessed progression-free survival (PFS). Results demonstrated that the combination of venetoclax/rituximab was superior to bendamustine/rituximab in patients with relapsed/refractory CLL (median follow-up for PFS 23.4 months; hazard ratio [HR] = 0.19; 95% confidence interval [CI] = 0.13–0.28; P < .0001).^16,17 Grade ≥ 3 adverse events were 82.0% vs 70.2%, while treatment discontinuations due to one or more adverse event were 12.9% and 9.0%, respectively.¹⁶ These results led to U.S. Food and Drug Administration (FDA) approval of venetoclax for the treatment of adult patients with relapsed/refractory CLL.¹⁷ In the 7-year follow-up analysis, median PFS was 54.7 months and 17.0 months, respectively.¹⁸

In trials of venetoclax as monotherapy or in combination with rituximab or obinutuzumab for CLL, the most common (≥ 20%) adverse events were neutropenia, thrombocytopenia, anemia, diarrhea, nausea, upper respiratory tract infection, cough, musculoskeletal pain, fatigue, and edema.¹⁷ In the MURANO trial, the most common adverse events (any grade) with venetoclax/rituximab were neutropenia (60.8%), diarrhea (39.7%), upper respiratory tract infection (22.2%), and nausea (21.1%).¹⁶ Venetoclax prescribing information indicates that use of this agent is associated with risk of tumor lysis syndrome (TLS), neutropenia (including grade ≥ 3), and fatal and serious infections.¹⁷ While a venetoclax/rituximab regimen offers the option of fixed-duration therapy, the potential benefits of this approach must be weighed against the risk of toxicities such as TLS. According to Andrew Lipsky, MD, of Columbia University Irving Medical Center, “Some patients prefer a fixed-duration approach, while others find IV treatments and frequent monitoring inconvenient. I always assess patients for impaired renal function and very bulky disease, as both increase the risk for TLS.”

Some patients prefer a fixed-duration approach [to venetoclax/rituximab treatment], while others find IV treatments and frequent monitoring inconvenient. I always assess patients for impaired renal function and very bulky disease, as both increase the risk for TLS. Andrew Lipsky, MD

Pirtobrutinib 

Pirtobrutinib was previously approved by the FDA for the treatment of patients with CLL who have received at least two prior lines of therapy, including a BTKi and a BCL2i, based on results of the phase I/II BRUIN trial.¹⁹ BRUIN CLL-321 was the first prospective phase III randomized clinical trial, conducted exclusively in patients with CLL/SLL following cBTKi therapy, and demonstrated a statistically significant and clinically meaningful benefit of pirtobrutinib. The trial compared pirtobrutinib vs investigator’s choice of idelalisib/rituximab or bendamustine/rituximab in patients previously treated with a cBTKi (primary endpoint: independent review committee–assessed PFS). Patients had received a median of 3 prior lines of therapy; 44% had 17p deletion and/or TP53 mutation, and 69% had unmutated IGHV. A statistically significant improvement in PFS with pirtobrutinib was seen in the primary analysis. With a median duration of follow-up of 6.6 months, the PFS HR was 0.58 (95% CI = 0.38–0.89; P = .0105); median PFS was 11.2 months vs 8.7 months (42% relative reduction in risk of relapse, disease progression, or death).²⁰ PFS benefit was seen across patient subgroups.²¹ Subsequently, at a median follow-up of 17.2 months, pirtobrutinib demonstrated a median PFS of 14.0 months vs 8.7 months for idelalisib/rituximab or bendamustine/rituximab (HR = 0.54; 95% CI = 0.39–0.75).²² The median time to next treatment was 24 months with pirtobrutinib and 10.9 months with the comparator arm (HR = 0.37; 95% CI = 0.25–0.52).²²

In a safety population across pooled trials, the most common (≥ 30%) adverse reactions were decreased neutrophil count, decreased hemoglobin, decreased leukocytes, fatigue, decreased platelets, decreased lymphocyte count, and calcium decreased.²⁰ In the BRUIN CLL-321 trial, the most common (≥ 20%) treatment-emergent adverse events were infections (63.8%), neutropenia (26.7%), pneumonia (22.4%), bleeding (21.6%), and anemia (20.7%).²² Dose reductions due to an adverse event occurred in 11.2% of pirtobrutinib-treated patients and 36.7% of those on the comparator arm, while discontinuations due to an adverse event occurred in 17.2% and 34.9% of patients, respectively (5.2% vs 21.1% due to a treatment-related adverse event).²² Pirtobrutinib prescribing information indicates that serious and fatal infections and hemorrhage have occurred, as well as cytopenias (some grade ≥ 3) and hepatotoxicity (including drug-induced liver injury). Cardiac arrhythmias including atrial fibrillation or flutter occurred in 3.4% of patients and second primary malignancies in 9% in the full safety population of patients with B-cell malignancies treated with pirtobrutinib.²⁰ Results of the BRUIN CLL-321 trial led to expansion of pirtobrutinib labeling to include treatment of adult patients with relapsed/refractory CLL/SLL who previously received a cBTKi.^20,22 Nitin Jain, MD, of The University of Texas MD Anderson Cancer Center, cautioned that cross-trial comparisons between CLL-321 and other relapsed/refractory CLL studies such as MURANO are difficult because the patient populations, prior treatments, and era in which patients were enrolled were quite different.

Optimizing Outcomes With Second-Line Therapy for Relapsed/Refractory CLL

In the real-world setting, barriers can exist in the selection and appropriate use of relapsed/refractory CLL therapy that may affect treatment outcomes. These include nonadherence to treatment guidelines and suboptimal shared decision-making between patients and providers. Adherence to CLL guidelines can be less than ideal in clinical practice. A recent survey found that up to half of U.S. community and academic practitioners reported no or limited knowledge of CLL treatment guidelines.²³ This may be due to provider knowledge gaps, which could limit therapeutic options offered to patients and result in the use or sequencing of treatments that are not guideline-concordant.

Dr. Jain suggested that a lack of familiarity and experience with ncBTKis could contribute to such practice gaps. “It’s possible that some oncologists consider pirtobrutinib to be in the same class and therefore to work in the same way as covalent BTK inhibitors, so they may not consider pirtobrutinib as a valid treatment option,” he said. “Or perhaps they think that once their patient is resistant to or intolerant of a BTK inhibitor, they should move to venetoclax without considering pirtobrutinib. In the post–covalent BTK inhibitor space, I think that a noncovalent BTK inhibitor can be an appropriate strategy that is supported by data.”

In the post–covalent BTK inhibitor space, I think that a noncovalent BTK inhibitor can be an appropriate strategy that is supported by data. Nitin Jain, MD

Shared decision-making is key in informing CLL treatment selection, so clinicians must consider patient preference as well as disease assessment when considering relapsed/refractory CLL therapy. Shared decision-making has become increasingly important in light of the increasing number and variety of available treatment options. Yet over 40% of patients do not discuss new CLL therapies with their provider.²⁴ Patient preference regarding drug selection can be influenced by route, duration of treatment, toxicity profile, and potential quality-of-life impact. In a survey of patients with CLL, the most important driver of treatment preference was prolonging PFS; additionally, patients generally preferred taking a daily pill over monthly IV therapy.²⁵ Dr. Jain confirmed the importance of considering patient preference in decision-making. “Some patients might choose a time-limited venetoclax-based regimen since they do not mind coming to the hospital for infusions and regular TLS lab monitoring in an effort to complete treatment faster,” he noted. “Those who live far away from the medical center or have transportation or caregiver issues might prefer the convenience of a daily pill such as a noncovalent BTK inhibitor.”