Targeted Therapies in Chronic Lymphocytic Leukemia

Alexey V. Danilov, MD, PhD

Among patients with chronic lymphocytic leukemia (CLL) needing treatment, IGHV mutation and TP53 absence are associated with good response rates and deep remissions with chemoimmunotherapy.¹ However, many patients have complicating factors, including comorbidities and older age, that make them poor candidates for chemoimmunotherapy. Treatment selection can be further confounded by the heterogeneous biology of CLL, which manifests in variable clinical presentations and encompasses mutational and chromosomal alteration differences between patients.²

Hence, many patients do not fall within the first-described category. However, particularly for individuals with high-risk CLL, targeted agents are changing the treatment landscape.¹ Current efforts to address the needs of patients with high-risk CLL are focused on the investigation and use of Bruton tyrosine kinase (BTK) inhibitors and B-cell lymphoma 2 (BCL-2) inhibitors.²

“Today in CLL we are mostly moving away from chemotherapy-based regimens. The 2 main mechanisms that are employed in the therapy of CLL [are] targeting B-cell receptor signaling with BTK [inhibitors] such as ibrutinib [Imbruvica] and acalabrutinib [Calquence] and targeting BCL-2 with venetoclax [Venetoclax]. And there are some other drugs in development that also target BCL- 2,” said Alexey V. Danilov, MD, PhD, professor in the Department of Hematology and Hematopoietic Cell Transplantation and associate director of the Toni Stephenson Lymphoma Center at City of Hope Comprehensive Cancer Center in Duarte, California, in an interview ahead of the Society of Hematologic Oncology (SOHO) 2021 Annual Meeting with Targeted Therapies in Oncology™.

The patient’s particular disease biology also should be considered when selecting chemotherapy for patients with CLL. “I think it is important to know as much about [the patient’s] CLL at the time [of] that patient’s first treatment. It is important to know their genetic disease composition. For example, if patients have del(17p), they should not receive chemotherapy, they should only receive novel agents,” said Danilov during the Society of Hematologic Oncology 2021 Annual Meeting.

B-cell receptor (BCR) signaling involves kinases and phosphatases involved in B-cell activation. Normally, random segmental rearrangements of IGH and IGL result in a B cell’s distinctive antigen-binding site, which is rarely shared with other B cells. The rarity of shared BCRs, however, does not occur in approximately 30% of patients with CLL, in whom BCR expression is similar if not identical across B cells. Also, patients with shared BCR features share clinical features. Furthermore, patients with less than 2% of IGHV mutation have been shown to have increased BCR polyreactivity and disease aggression, poor biomarkers, and reduced survival times. BCR signaling is blocked by BTK inhibitors. Except for T cells and plasma cells, BTK is expressed in all hematopoietic cell lines and is involved in the amplification and transmission of cell surface molecule signals. Inhibition of BTK, therefore, affects cell migration, proliferation, and survival mechanisms.²

BTK Inhibitors

Ibrutinib, the first BTK inhibitor to be approved by the FDA for use in CLL, is a covalent BTK inhibitor that earned approval in 2014 for use in previously treated CLL after it was associated with an objective response rate (ORR) of 71% in a phase 1b/2 clinical trial.^1,3,4 In subsequent clinical trials, ibrutinib continued to demonstrate superior overall survival (OS) and progression-free survival (PFS) over those of anti-CD20 monoclonal antibody ofatumumab (Arzerra) in high-risk, relapsed or refractory (R/R) patients.1,5 In the first-line setting, ibrutinib treatment improved OS and PFS compared with chlorambucil (Leukeran), a trend that persisted at a 60-month follow-up.^6,7 However, ibrutinib toxicities and disease progression on the therapy present a challenge to its continuation in patients with CLL. This pattern was observed, for example, in a real-world study that reported a rate of ibrutinib monotherapy discontinuance of 41%.^1,8

The second-generation BTK inhibitor acalabrutinib was approved by the FDA for use in CLL in 2019, and retrospective data suggest that it may be tolerated better than its first-generation predecessor.^9-11 This characteristic is attributed to the agent’s reduced off-target binding (eg, with EGFR and ITK) relative to that of ibrutinib.¹² Two phase 3 trials demonstrated acalabrutinib efficacy in terms of PFS in both the first-line and R/R settings.^13,14 Although a head-to-head trial comparison of acalabrutinib with ibrutinib has yet to be completed, an ongoing phase 3 trial (NCT02477696) is investigating acalabrutinib vs ibrutinib in high-risk patients with PFS as the primary end point and adverse events (AEs) as secondary end points.¹⁵

“We now have emerging good data that second-generation [BTK inhibitors] such as acalabrutinib and zanubrutinib [Brukinsa], even though they seem to have similar efficacy to ibrutinib, they have fewer [adverse] effects, particularly atrial fibrillation,” Danilov said.

Venetoclax-Based Regimens

Another signaling target is BCL-2, which sequesters proapoptotic proteins Bak and Bax and in CLL cells has been found to be overexpressed. BCL-2 also has been associated with therapy resistance.² Venetoclax is a BCL-2 inhibitor approved for use in patients with CLL and del(17p). It also was approved in combination with obinutuzumab (Gazyva) in the first-line setting.16 The combination of venetoclax with obinutuzumab was studied in a phase 3 trial (NCT02242942) in which the combination demonstrated improved PFS over chlorambucil combined with obinutuzumab in the first-line setting.¹⁷ Another phase 3 trial (NCT02005471) examined the combination of venetoclax and rituximab (Rituxan) compared with bendamustine and rituximab in patients with R/R CLL and found improved PFS in the venetoclax-rituximab trial arm.¹⁸

“If patients progress on [BTK inhibitors], they typically will have 3 options, and the best option so far, in terms of approved therapies, would be a venetoclax-based regimen. This approach is associated with highest response rate in this setting. The newer options are drugs like noncovalent BTK inhibitors, which also seem to have response rates. So that would be an alternative option in the near future. However, it is important to enroll these patients in clinical trials,” Danilov said.

The fixed duration of venetoclax administration in the phase 3 trials also suggested the possibility of a set time period without chemotherapy, which appeals to high-risk patients with restricted treatment options.¹

However, Danilov pointed out, progression on these agents remains a challenge for patients with CLL. “Resistance to these agents is still inevitable, particularly in patients with high-risk CLL, such as those who have complex karyotype or del(17p), who are more likely to develop resistance and have shorter PFS on both BTK inhibitors and venetoclax combinations. There are ongoing efforts to address this problem where patients progress on [BTK inhibitors] or venetoclax,” Danilov said.

A disadvantage of covalent BTK inhibitors’ irreversible binding is the contribution to patient resistance. The irreversible inhibitors are not able to efficiently bind BTK in treated patients when BTK variation occurs. However, noncovalent BTK inhibitors such as fenebrutinib have demonstrated sustained activity toward variations of BTK.¹²

compounds that have advanced the farthest in clinical trials are noncovalent BTK inhibitors. In CLL, resistance to ibrutinib and acalabrutinib is mediated by a mutation in the ATP binding domain of the BTK so that those drugs can no longer fit and inhibit its kinase function. The noncovalent BTK inhibitors bind different BTK and therefore they can overcome this resistance mechanism,” Danilov said.

In the 2021 BRUIN phase 1/2 study (NCT03740529), 323 patients with R/R B-cell malignancies were treated with 7 dose levels of the noncovalent BTK inhibitor pirtobrutinib (LOXO-305).19,20 The study’s primary end points were the maximum tolerated dose (phase 1) and ORR (phase 2). For patients with CLL or small lymphocytic lymphoma who had previously been treated with a covalent BTK inhibitor, the ORR was 62% with pirtobrutinib (95% CI, 53%-71%). The ORR in patients with CLL and with covalent BTK-inhibitor resistance was 67%, and the 117 patients who showed response have remained progression free.²⁰

Additional Novel Approaches

Other agents that target myeloid cell leukemia-1 (MCL-1) or BCLX are in early clinical trial phases. The MCL-1-targeting agent AZD5991 is being investigated in a phase 1/2 trial (NCT03218683) as a monotherapy or combined with venetoclax in patients with R/R hematologic malignancies.²¹ A phase 1b dose-escalation study will involve several arms, with 1 including AZD5991 with azacitidine in patients with hypermethylated and biomarker-negative acute myeloid. In a phase 1b/2 trial (NCT03013998), patients will be enrolled into hypermethylated and biomarker-negative cohorts.²² Also, AZD4320, an agent targeting both BCL-2 and BCLX, was in a first-time-in-human phase 1 trial (NCT04214093) that has been completed (results not yet reported) in patients with advanced solid tumors, hematologic malignancies, lymphoma, and multiple myeloma.²³

“The most difficult population is patients who progressed on both a BTK inhibitor, such as ibrutinib and acalabrutinib, and venetoclax. For these patients, we have some therapies, such as MCL-1 inhibitors and CDK9 inhibitors, in development, but also an interesting field [that] shows great promise is cellular and immune therapies. In particular, CAR [chimeric antigen receptor] T cells have shown efficacy in this patient population,” Danilov said.

CAR T-cell Therapy

CAR T-cell therapy has also been an ongoing facet of investigation in R/R CLL.^24,25 Modifications to the CAR T cells have defined each generation of the therapy, thereby improving efficacy. With the fourth generation, CAR T cells have modifications, including transgenes that encode for cytokine secretion. There are numerous ongoing trials of CAR T-cell therapy in CLL that target the CLL surface antigens CD19, CD20, or CD23 (eg, NCT04732845, NCT04007029).^26,27 “Among patients treated with CAR T cells, responses are [approximately] 80% to 90%, including in patients who are refractory to both ibrutinib and venetoclax. In some patients, these responses are durable. So, this is one potential approach for patients with CLL who have progressed on both venetoclax and BTK inhibitors,” Danilov said. “Another novel approach is bispecific antibodies. Bispecific antibodies have very high efficacy in diffuse large cell lymphoma and in follicular lymphoma, and mosunetuzumab (BTCT4465A), glofitamab, epcoritamab, and other drugs are currently in clinical trials.”

Most bispecific antibodies (bsAbs) have been developed to support the engagement of T cells and to activate antitumor cell antibody-dependent cellular toxicity (ADCC) and to activate or inhibit cell surface receptors. BsAbs have versions of heavy and light chain domains and may or may not retain the fragment crystallizable (Fc) region, the portion of the structure that is bound by cell surface receptors. Most of the bsAbs that have advanced in clinical trials possess the Fc region and therefore also retain the advantages of IgG antibody pharmacokinetics and lower immunogenicity. The latter characteristic results in better tolerability with these agents.²⁸

Mosunetuzumab is a bsAb that has been studied in other types of lymphomas such as follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL).²⁸ In patients with relapsed FL, mosunetuzumab was associated with a 68% ORR and with 50% of the patients achieving complete remission (CR). With a median study time of 14.5 months, 62% of the responders remained in remission at the data cutoff, with a median duration of response of 24 months.²⁹ Mosunetuzumab is also being investigated in the first-line setting in DLBCL as monotherapy and combined with chemotherapy in a phase 1/2 trial (NCT02500407). The trial’s early results showed that the ORR in patients treated with mosunetuzumab was 58% and the CR rate was 42%.³⁰ There is now a phase 1/2 dose escalation study NCT02500407) under way of mosunetuzumab with or without atezolizumab (Tecentriq) in patients with R/R non-Hodgkin lymphoma and CLL.³¹

“Because of the special mechanism of cellular and antibody-based therapies, bispecific antibodies are still effective in patients who have high-risk disease such as del(17p) and complex karyotype. There is a lot of excitement there in terms of drug development,” Danilov said.

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